UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
111012,267 12/16/2004
13897 7590 10/24/2016
Abel Law Group, LLP
8911 N. Capital of Texas Hwy
Bldg 4, Suite 4200
Austin, TX 78759
FIRST NAMED INVENTOR
Viswanathan Srinivasan
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
3205-P25383 2125
EXAMINER
CHANNA V AJJALA, LAKSHMI SARADA
ART UNIT PAPER NUMBER
1611
NOTIFICATION DATE DELIVERY MODE
10/24/2016 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
mail@Abel-IP.com
hmuensterer@abel-ip.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADE11ARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
1-, -\rl-S\L' 'N' \'I-'H \-N SRIN-l\' 11.s· AN- J-Lr \NC \R1 OS "Kf,_NcN·1-)c'7 _:,.x parte , .. _ 1v' l-'- _ · 1 _ _ _f _ : k. _ _ _ '1-\..~ 1-1... , ,, i _ -1 _.J- . _L, k. lv1 _,,.1 _L~ _ • _ L~l-~~
VENKA TESH BALASUBRAl\1ANIAN,
SOIV1PHET PETER SUPHASA \VUD, RALPH BRCY\iv'N,
and DA YID BRO\VN 1
Appeal 2016-006545
Application 11/012,267
Technology Center 1600
B >f' > rTI R-IK-F' -\JiJ JI::NKS P·('l"!TJT:r JN:T:i 'I-' HA -R-l ()W e ore \_) ./ _ _ :: V\I • _!:', L ' " /-\._ /"-.!_ l !:', _, _ _ _c _ • __ f-\_ __ , )
and TUv10THY G. 1\tfAJORS, Administrative Patent Judges.
Yv1AJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving clairns to dosage
forms of diphenhydramine, which have been rejected as indefinite, obvious,
and provisionally r~jected for obviousness-type double patenting. vve have
jurisdiction under 35 U.S.C. § 6(b).
1 Appellants identify the Real Party in Interest as Sovereign
Pharmaceuticals, LLC. (App. Br. 3.)
Appeal 2016-006545
Application 11/012)67
\Ve reverse the rejection that the claims are indefinite and obvious,
and enter a new ground of rejection. We affinn the double-patenting
rejections.
STATEl\tiENT OF THE CASE
According to the Specification, "[d]iphenhydramine is a histamine
antagonist that possesses antihistaminic, anthussive, sedative, antimotion-
sickness, antiemetic, and anticholinergic effects." (Spec. ~-!- 2.) As further
background, the Specification discloses:
Allergic reactions, in particular, which can be treated or
ameliorated with diphenhydramine are often accompanied by
conditions which cannot satisfactorily be ameliorated or treated
with diphenhydramine, but may be treated with other dn1gs, e.g.,
expectorants, mucus thinning drugs, decongestants, (morphine
derived) antitussives, and/or analgesics.
A single dose of diphenhydramine can provide a therapeutically
effective plasma concentration for about 4 to 6 hours, whereas a
single dose of other drugs will often provide a therapeutically
effective plasrna concentration for a considerably shorter or
longer period. For example, a single dose of an expectorant such
as guaifenesin will usually provide relief for only about one hour.
***
It -vvoukl be desirable if patients suffering fror:n, e.g., respiratory
congestion, inflammation of the respiratory mucosa and sinus
cavities, weeping eyes, rhinorrhea, eustachian tube congestion,
cough, nausea, aching joints, headache and fever and related
symptoms, for which diphenhydrarnine is indicated, would also
obtain relief, over a similar time period, from one or rnore
conditions for which drugs different from diphenhydramine are
indicated, by the administration of a single dose of a dosage fonn
such as, e.g., a tablet, liquid, syrup, suspension, capsule or gel
2
Appeal 2016-006545
Application 11/012)67
and the like which provides both diphenhydramine and one or
rnore other drugs.
(Id. at ~i,l 2----3.)
Claims 112-114, 117, 118, 122-129, 137-159, and 162-195 are on
appeal. Claim 112 is illustrative:
112. A phannaceutical dosage form which comprises (a) a first
dn1g which is at least one of diphenhydramine and a
pharmaceutically acceptable salt thereof and (b) at least one
second drug, wherein the dosage form provides a plasrna
concentration within a therapeutic range of the at least one
second drug over a period which is coextensive with at least 70 r%
of a period over which the dosage fr)rm provides a plasma
concentration within a therapeutic range of the first drug.
(App. Br. 29 (Claims App'x).)
Claim 171, rather than requiring diphenhydramine and at least one
other drug, requires one form or layer of diphenhydramine, and a second
(different) form or layer of diphenhydramine, wherein the two fonns/layers
are released over a different period and rate. (Id. at 38.)
The claims stand rejected as follows:
L Claims 146----149 under 35 U.S.C. § 112, second paragraph (pre-
AIA) for being indefinite.
IL Claims 112-114, 117, 118, 122-129, 137-159, and 162-195
under 35 U.S.C. § 103(a) over Blume2 and Lech. 3
2 Blume et al., US 6,372,252B1, issued Apr. 16, 2002 ("Blume").
3 Lech et aL, US 5,681,577, issued Oct 28, 1997 ("Lech").
3
Appeal 2016-006545
Application 11/012)67
IIL Claims 112----114, 117, 118, 122----129, 137----159, and 162----195
are provisionally rejected for nonstatutory obviousness-type
double patenting over claims in Application Nos. 11/102)26
(claims 89-132), 10/939,351(claims129-133, 140-142, 146,
149-164, 174-205, and 214-256),·1 and 111115,321 (claims
157-166, 168, 173, 176-179, 184-189, 194-196,203-205,
214----271, 280, and 301----311).
RELATED f\/fA TTERS
We note the updated disposition of the following related appeals and
applications:
L A .. pplication No. 10/939,351. See Ex Parte Srint-vasan, No. 2013-
009326 (PTAB decided June 23, 2016) (atlirming rejections of claims
129----256 under§ 103(a); reversing as to claims 222, 227, and 244);
2. Application No. 111115,32 l. See Ex Parte Srinivasan, No. 2013-
011051, (PTAB decided Oct 20, 2016) (affirming rejections of claims
157-311 under§ 103(a));
3. Application No. 101736,902 (Notice of Appeal filed Sept 22, 2016);
4. i\pplication No. 11/102,726 (appeal withdrawn following Request for
Continued Examination ('"RCE")); and
5. Application No. 101798,884 (appeal withdrawn following RCE).
(See also App. Br. 3-4.)
4 Following appeal, a Notice of AIIowance was entered on Sept. 6, 2016 for
Application No. 10/939,351.
4
Appeal 2016-006545
Application 11/012)67
1---- INDEFINITENESS
The Examiner rejected claims 146----149 under 35 U.S.C. § 112, second
paragraph. (Ans. 2.) According to the Examiner, these claims "recite the
phrases 'from about' and 'to about' that are vague and indefinite" because
these phrases "do[] not define a specific limit and allow[] for variation" with
respect to the clahned drug concentrations. (Id.)
Appellants argue the Examiner has not sufficiently explained why use
of the word "about" in this context would be unclear to the person of
ordinary skill in the aii. (App. Br. 8.) According to Appellants, use of
"about" in connection with the recited dn1g concentrations "merely indicates
that the lower and upper values of the numerical ranges ... are not exact
values but that small deviations from these values are permissible." (Id.)
I\1oreover, Appellants argue further clarity is provided because claims 146-
149 depend from claim 137, which expressly requires the drugs' periods of
therapeutic effectiveness overlap by a certain percentage. (Id. at 9.)
On the record before us, Appellants have the better position. The
Examiner's position demands absolute certainty, and is not reasonable here.
l\llodine A1anufacturing Co. v. U.S. ITC, 75F.3d1545, 1554 (Fed. Cir. 1996)
("Such broadening usages as 'about' must be given reasonable scope; they
must be viewed by the decisionmaker as they would be understood by
persons experienced in the field of the invention. Although it is rarely
feasible to attach a precise limit to 'about,' the usage can usually be
understood in light of the technology embodied in the invention.") We are
not persuaded the skilled artisan would be unable to understand the phrases
5
Appeal 2016-006545
Application 11/012)67
"from about" and "to abouC' when used in connection with the drug
concentrations recited in claims 146----149. Accordingly, we reverse.
II-OBVIOUSNESS
issue
Has the Examiner established by a preponderance of the evidence that
claims 112----114, 117, 118, 122-----129, 137----159, and 162----195 would have
been obvious over Blume and Lech?
Findings of Fact (Ff)
FF l. The Examiner's statement of Rejection II is provided at pages
5-----15 of the Final Action dated J\1ay 20, 2015. (See also Ans. 5-----17.)
FF 2. Blume teaches "strategies and designs in formulation of
modified release guaifenesin dosage fonns .... [including] a novel sustained
release formulation comprising guaifenesin.'' (Blume coL 3, lL 20-25.)
Blume further teaches "a modified release guaifonesin which comprises two
discrete portions (a bi-layer tablet), a rapid release portion and a sustained
release portion." (Id. at coL 3, lL 44---47.)
FF 3. Blume teaches formulations, including a "tablet [that] is
capable of releasing therapeutically effective amounts of guaifenesin over an
extended period, i.e. twelve or rnore hours." (Id. at col. 3, 11. 41-44.) 1\!fore
specifically, Blume discloses
the bi-layer tablet also provides sustained release of guaifonesin
over at least a twelve hour period from one dose. The bi-layer
tablet ... further maintains semrn concentration levels ... at a
therapeutically effective level for at least a twelve hour period
without an increase in the dn1g strength of the dosage form.
6
Appeal 2016-006545
Application 11/012)67
(Id. at coL 3, L 64 through coL 4, L 3.)
FF 4. Blume teaches the addition of other active agents:
[T]he sustained release formulation may comprise a combination
of guaifonesin and at least one other drug including, but not
limited to; an antitussive, ... a decongestant, ... an antihistmnine
such as . .. diphenhydramine hydrochloride, ... or a combination
thereof
(id. at col. 5, 11. 49----64 (emphasis added).)
FF 5. Lech teaches cold/sinus medications comprising a "mixture of a
decongestant such as pseudoephedrine and an antihistamine such as
diphenhydramine." (Lech Abstract) Lech teaches
[t]he combination of two active cold medications provides the
present invention with dual action relief . . . [by] including
antihistamines which provide relief to nmning, watery eyes and
congested sinuses by blocking the effects of histamines ... [and
by including] a decongestant which provides systemic relief by
dilating and opening clogged or swelled nasal passages for easier
breathing . ..._,
(Id. at col. 2; L 59 through coL 3, L 3.) Lech further teaches additional
active agents "such as the antitussive dextromethorphan hydrobrmnide and
the analgesics meclofenamic acid, aspirin, ibuprofen and the like may also
be incorporated in the tablet" (Id. at col. 2, lL 53----55.)
Anazvsis
Claim 112
The Examiner finds that Blume and Lech teach phannaceutical
dosage fr)rms combining multiple dn1gs. For example, the Examiner finds
"Blume teaches sustained release tablet fonnulations for guaifonesin. an ._, ;
expectorant ... [that J maintain[] serum level of guaifenesin at a
7
Appeal 2016-006545
Application 11/012)67
therapeutically effective level for at least twelve hours." (Ans. 5----6.) The
Examiner further finds that "Blume teaches that the sustained release portion
is mixed with other types of dn1gs such as a decongestant (pseudoephedrine)
or antihistamine (diphenhydramine hydrochloride) or combinations thereoC'
(Id. at 6.) The Examiner finds Lech teaches "multiple acting cold/sinus
preparations in the form of tablets wherein a decongestant and an
antihistarnine is combined," and specifica11y "suggests diphenhydramine
with pseudoephedrine decongestant~' (Id.) The Examiner further finds "a
skilled artisan would have been able to control the release of the drugs \vhen
used in combination Le., decongestant and diphenhydramine ... in the
bilayer tablet of Blume, by appropriately incorporating a suitable control
release polymer in appropriate amounts.~' (Id. at 8.)
The Exarniner concludes
it would have been obvious ... to employ diphenhydrarnine
cl1lc>ride of I11trtne ill tl1e secc>nd layer c>f tl1e lJilayer tal;let a_s a
second dn1g together with the first dn1g guaifenesin because
Lech suggests the combination of other drugs with an
antihistamine provides simultaneous relief for cold, sinus and
aHergies.
(Id. at 7.) With respect to the amounts of the drugs, the Examiner concludes
"a skilled artisan would be able to determine the amount of dn1g depending
on factors such as age; body weight etc.; which is conventional in the
phannaceutical dosage forms.~' (Id.) And, with respect to the claimed
therapeutic ranges being coextensive, the Examiner reasons "the dn1gs
guaifonesin and diphenhydramine meet the claimed combination of drugs
and fmiher possess the therapeutic efficacy claimed because the drugs taught
8
Appeal 2016-006545
Application 11/012)67
by the cited prior mi and instant claims are the sarne." (Id.) The Examiner
further concludes
it would have been obvious for one of an ordinarv skill in the art .,
administering a combination of drugs that the dn1gs require an
overlap in the bioavai1ab11ity of the drugs so as to provide the
desired therapeutic effoct because it is not uncommon to see that
the symptoms of cold, cough and allergy occur simultaneously
or at least overlap significantly. Hence, one skilled in the mi
would be motivated to treat conditions that overlap by
administering drugs that are released and also provide
therapeutic effect that is coextensive for a significant period of
release.
(Id. at 15.)
i\.ppellants argue Blume is a long document ''spanning 24 columns~'
and that there is only one passage in Blume where it discloses combining
guaifenesin with other dn1gs. (App. Br. 13----14.) Appellants argue that
Blume and Lech teach different dosage forms (e.g., sustained release
formulations including guaifenesin versus a chewable cold/sinus preparation
that does not menticm guaifenesin). (Id. at 14-15.)
Appellants further point out that claim 112, for example, requires "a
plasrna concentration within the therapeutic range of the at least one second
drug which is coextensive with (overlaps) at least 70 %) of the period over
which the plasma concentration of diphenhydramine ... is within the
therapeutic range." (Id. at 15-16.) Appellants argue that whether this period
of overlap is met depends on rnany parameters, and "the Examiner has not
provided any explanation, let alone support" for the position that the prior art
teaches or suggests this claim limitation. (id. at 17 .) Appellants similarly
contend "neither BLUJ\l1E nor LECH contains any reference to the duration
9
Appeal 2016-006545
Application 11/012)67
of therapeutic effectiveness of one dn1g (e.g., guai fenesin) in relation to the
duration of therapeutic effectiveness of another drug." (Id. at 18.) As to the
Examiner's conclusion that "'it would have been obvious for one of ordinary
skill in the art administering a combination of dn1gs that the d1ugs require an
overlap in bioavailability ... to treat conditions that overlap [cold, cough,
and allergy] by administering drugs that are released and also provide a
therapeutic effect that is coextensive for a significant period of release'''
(Reply Br. 6 (quoting Answer)), A .. ppellants argue "none of [these]
allegations amounts to more than a statement of the Examiner's opinion[]
[and] [n]one of the Examiner's allegations is supported by any written (or
other) evidence whatsoever" (id.).
As to Examiner's conclusion of obviousness, Appellants' argument is
persuasive. Although the Examiner's reasoning is rooted in common sense
--------that it would have been obvious to treat multiple cold and allergy
symptoms with fon11ulations of combined cold and allergy dn1gs having
substantially overlapping periods of therapeutic activity--------the present
record lacks sufficient evidentiary support For this reason alone, we reverse
the rejection as to claim 112 and the claims depending from claim 112.
Because independent claims 137 and 162 include similar limitations
concerning the extent of overlap between the drugs' periods of therapeutic
activity, we reverse the rejection as to claims 137 and 162 (and the
respective dependent claims) as well.
10
Appeal 2016-006545
Application 11/012)67
Claim 171
As noted above, claim 171 requires a fonnulation with two forms or
layers of diphenhydramine wherein the respective forms/layers release
diphenhydramine over a ditlerent rate and period.
The Examiner finds "a skilled artisan would have been able to include
diphenhydramine of Blurne in one or both layers of the bilayer tablet of
Blume~ in addition to guaifenesin.~' (Final Act. 11.) And, according to the
Examiner, the "rejection of record provides the requisite rnoti vation to
include the claimed drugs such as ... diphenhydramine (of Blume) in either
layers of the bilayer tablet of Blume depending on the desired combination
of medications." (Id. at 11-12; see also Ans. 14.)
Appellants argue "BLlJrvfE is devoid of any teaching or suggestion
that an immediate release formulation disclosed therein may contain any
additional drug (in addition to guaifonesin), let alone diphenhydramine
hydrochloride.'' (App. Br. 21.) Appellants also contend "LECH[] fails to
disclose any dosage form which may comprise two or more ditlerent release
formulations." (Id. at 22.) Thus, Appellants argue5 the art of record "fails to
nromQt one of ordinary skill in the art to provide a diphenhydramine-
containing dosage form which comprises at least two different
diphenhydramine-containing release fmmulations.'~ (Id.)
On the present record, we agree with Appellants. The cited art lacks a
sufficient teaching or suggestion to include diphenhydramine in two forms
or lavers with different release kinetics. The Examiner reasons a skilled .,
artisan "would have been able to include diphenhydramine" in both layers.
(Final Act 11.) But the Examiner has not adequately explained why the
11
Appeal 2016-006545
Application 11/012)67
skilled artisan would have done so. "[R]ejections on obviousness grounds
cannot be sustained by mere conclusory statements; instead, there must be
some articulated reasoning with some rational underpinning to support the
legal conclusion of obviousness.~' K5'R Jnt'l Co. v. Teleflex Inc., 550 U.S.
398, 418 (2007) (quoting In re Kahn, 441 F .3d 977 5 988 (Fed. Cir. 2006).
For these reasons, we reverse the Examiner's rejection of clairn 171
over Blume and Lech. Claims 172----195 depend (directly or indirectly) from
claim 171 and so we reverse as to those claims as well.
III - DOUBLE PATENTING
The Examiner provisionally rejected all of the pending claims for
obviousness-type double patenting over claims in Application Nos.
111102,726, 10/939,351, or 11/115,321. (Final Act 2----5.)
Appellants state "[t ]hese provisional rejections are not presented for
review.'' (App. Br. 9-10.) \Ne thus summarily affirm.
12
Appeal 2016-006545
Application 11/012)67
NE\V GROUND OF REJECTION
vVe enter a ne\v ground of rejection pursuant to 37 C.F.R. § 41.50(b)
of claims 112, 137) 162, and 171 as obvious under 35 U.S.C. § 103(a) over
Fanara,5 Davis '508,6 Davis '318, 7 Paradissis,8 Vadino,9 Blume, and Lech.
\Ve adopt the Exarniner's findings regarding the scope and content of
Blume and Lech, and Findings of Fact 2-5 discussed above.
Findings of Fact (FJ1)
FF 6. Fanara teaches phannaceutical compositions "allowing for the
controlled release of at least one active substance." (Fanara Abstract.)
Fanara teaches "multi-layered pharmaceutical compositions, including at
least one layer of the inventive composition." (Id.) Fanara also teaches the
"release of active substances during oral administration can be controlled by
means of matrix-type pharmaceutical compositions." (Id. at col. 1, 11. 14----
16). For instance, Fanara teaches
phannaceutical compositions which can be administered oraHy,
compnsm_g
A. at least one layer comprising an active substance and
excipients which allow immediate release of the said
active substance after administration, and
5 Fanara et al., 1.JS 6,699,502B1, issued I\1ar. 2, 2004 ("Fanara"), submitted
in the information disclosure statement ("IDS") of Oct 27, 2006.
6 Davis et aL, US 2003/0215508 Al) pubL Nov. 20, 2003 ("Davis '508"),
submitted in the IDS concun-ent with this decision.
7 Davis et al., US 2003/0049318 Al, publ. \/far. 13, 2003 ("Davis '318"),
submitted in the IDS concurrent with this decision.
8 Paradissis et al., US 5,445,829, issued Aug. 29, 1995 ("Paradissis''),
submitted in the IDS of l\llay 4, 2005.
9 Vadino, US 4, 777 ,050, issued Oct 11, 1988 ("Vadino"), submitted in the
IDS concurrent with this decision.
13
Appeal 2016-006545
Application 11/012)67
B. at least a second layer which a11ows the contro11ed release
of the same or of a second active substance, comprising
the said same or second active substance, at least one
matrix-type excipient and at least one alkalinizing agent
(Id. at col. 5, lL 48-58; see also id. at claim 7.)
FF 7. Fanara teaches it is desirable "to control the release of
pharmaceutically active substances so that they can be administered in a few
daily doses, ideally in a single dose." (Id. at col. 1, 11. l l----13.) Fanara
teaches that its compositions "allow[] the controlled release of
pharmaceutically active substances such that a satisfactory therapeutic effect
is observed over fairly long periods, for example in only one or two daily
doses . . . and a11ow regular and continuous release of active substances
over periods of at least 12 hours.~' (Id. at col. 3, 11. 24----32.) Fanara also
teaches
it is increasingly therapeutically advantageous to be able to
simultaneously administer bv the oral route an active substance .. .,
released immediately after administration, and the same or a
second active substance released gradually and regularly after
administration. In the case where the same active substance is
simultaneously administered for immediate release and for
prolonged release, this makes it possible to rapidly release a
sufficient dose of active substance to trigger the desired effect
and to maintain this effect by a gradual and prolonged release of
the same active substance. in the case where an acti11e substance
is released immediately and another active substance is released
gradually, this makes it possible to obtain combined therapeutic
effects by means (?l tivo active substances having ve1y d~{ferent
pharmacokinetic projUes.
(id. at col. 2, 11. 36----50 (emphasis added).)
14
Appeal 2016-006545
Application 11/012)67
FF 8. Fanara teaches the active substances may include
"vasoconstrictors, antihistamines, analgesics, antitussives and the like.'' (Id.
at coL 4, lL 57----58.) J\1ore specifically, Fanara discloses
[n]onlimiting examples of such active substances are
pseudoephedrine, ephedrine, phenylephrine,
phenyipropanolarnine, trapidil, hydrocodone, cetirizine,
efletirizine, hydroxyzine, rnedizine, buclizine, pentoxyverine,
codeine, morphine, their optical isomers or their
pharmaceutically acceptable salts.
As regards the dose of active substance used, it depends
on the effective dose and may therefore vary within very wide
limits depending on the said active substance.
(Id. at col. 4, 1. 62 through col. 5, 1. 3.) Fanara discloses working examples
with cmnbinations of active substances, such as pseudoephedrine/cetirizine
and immediate-release hydrocodone/pro1onged-release hydrocodone. (Id. at
col. 6, 11. 20-29; id. at col. 9-10, Example 4; id. at col. 12-13, Example 7.)
FF 9. Davis ; 508 teaches "strategies and designs in fonnulations of
modified release guaifonesin and guaifenesin combination dosage forms."
(Davis '508 il 15.) Davis further teaches "a modified release composition
which comprises two portions (e.g. a bi-layer tablet, or capsule\ an
imrnediate release formulation (IR) and a sustained release formulation
(SR)." (Id. at ii 16; see also id. at i! 17.)
FF 10. Davis '508 teaches "[t]he tablet is capable of releasing
therapeutically effective amounts of guaifenesin over an extended period,
e.g. twelve or more hours and at least one additional dn1g immediately, over
an extended period, or both." (Id. at iJ 15.) Similarly, Davis '508 teaches
[t]he bi-fayer tablet also provides sustained release of guaifenesin
over about a twelve hour period frmn one dose ... [and] [i]n one
embodiment the bi-laver tablet rnaintains serum concentration
' .. ·
15
Appeal 2016-006545
Application 11/012)67
levels of at least one additional drug at a therapeutical~y ej]ective
level for about a t1,velve hour period i.vithout an increase in
dosage strength
(id. at ~T 18 (emphasis added).)
FF 11. Davis '508 teaches
the sustained release formulation may comprise a combination of
guaifenesin and at least one additional dn1g . . . [that] may be
selected from, but is not limited to, an antitussive . . . a
decongestant ... an antihistamine such as ... diphenhydramine
hydrochloride, . . . an analgesic . . . or combinations thereof
Preferably, the dn1g is dextromethorphan hydrobromide,
pseudoephedrine hydrochloride, or a combination thereof.
(Id. at~ 93 (emphasis added); see also id. at ii~ 220-223 (disclosing
imrnediate-re1ease and sustained-release lavers comprising g·uaifonesin and .; ,_,
dextromethorphan), 232-234 (disclosing immediate-release and sustained-
reiease layers comprising guaifonesin and pseudoephedrine ); see also id. at
claims l---2, 91----92.)
FF 12. The relevant teachings in Davis '318 are similar to those in
<....·
Davis '508. (See Davis '318 iii! 5-7, 16-20, 45, 122, 130; see also id at
~1 . 1 7 20 1 'I , d 81 ·, c mms , , , ':!, _ . ..:.,, an .J
FF 13. Paradissis teaches "extended release pharmaceutical
formulation[s] which [are] capable of approaching zero order release of drug
over a 12 to at least a 24 hour period." (Paradissis col. 3, 11. 21----24.)
Paradissis teaches formulations comprised of immediate- and extended-
release particles. (Id. at col. 3, 11. 25----32.) Paradissis further teaches the
drugs "may be selected from a wide variety of pharmaceutical formulations
with particular pharmaceutical compounds being analgesics, anti-
16
Appeal 2016-006545
Application 11/012)67
inflammatories, antihistamines, antitussives, expectorants, decongestants ...
and mixtures thereof" Ud. at col. 3, 11. 34---41; see also id. at col. 4, 11. 31----
64.) Paradissis further teaches "antihistamines, such as ...
diphenhydrmnine hydrochloride" are suitable active agents in the extended-
release formulations. (Id. at coL 4, 11. 31-43 (emphasis added).) Paradissis
teaches "the appropriate amounts of immediate and extended release
particles are mixed to achieve the desired activity and release pattern.
When administered in proper dosage forms, the formulations are able to
deliver the drugs in zero order release rates to achieve from about 12 to 24
hours dn1g delivery." (Id. at col. 9, 11. 18----39.) Paradissis discloses working
examples, including a formulation with extended release particles of the
decongestant pseudoephedrine and the antihistamine chlorpheniramine,
blended with immediate release particles. (Id. at col. l O; 1. 64 through col.
11, 1. 49; see also id. at col. 11, L 50 through col. 12, L 29 (Example 3,
disclosing immediate and extended release combination of
pheny lpropanolamine hydrochloride and chlorpheniramine maleate).)
FF 14. Vadino teaches "a controlled release dosage form comprising
three actives: acetaminophen, pseudoephedrine and dexbrompheniramine."
(Vadino Abstract) Vadino teaches these three well-known drugs
comprising an analgesic, decongestant, and antihistamine are combined ''in a
single long-acting tablet'' (id. at col. 1, 11. 55----62; see also id. at col. 1, 11.
15---27.i Vadino teaches a "combination of three actives in a single
,• t,_,
homogeneous matrix, from \vhich matrix each active component is released
at an appropriate rate to provide the desired activity over a period of 2-14,
preferably 8-12 hours. The components of the matrix are preferably chosen
17
Appeal 2016-006545
Application 11/012)67
so that a dosage ... releases the actives over a period of 12 hours." (Id. at
col. 1, l. 67 through col. 2, l. 7.) Vadino further teaches this composition
presents an advantage over cold and allergy sufferers by
providing a single sustained-release medicament with
antihistaminic, decongestant and analgesic properties. Thus;
repeated administration of several single-component dosage
forms throughout the day may be avoided.
(id. at col. 2, 11. 26----33.)
Analysis
Claim 112
Fanara teaches phannaceutical dosage fonns, for example, tablets
comprising multiple layers. (FF 6.) Fanara teaches that one layer may be an
immediate-release layer, and at least one layer may be a controlled-release
layer. (FF 6.) Fanara further teaches that the immediate- and sustained-
release layers may include the same or different active agents, and these
active agents may comprise well-known cold and allergy medications such
as decongestants, antihistamines; analgesics, antitussives, and expectorants.
(FF 6, 8.)
Fanara provides working examples of immediate- and sustained-
release formulations. (FF 8.) In one example (Example 4\ Fanara combines
5 mg of immediate-release cetirizine (antihistamine) and 120 rng of
prolonged-release pseudoephedrine (decongestant) in a bi-layer tablet, and
describes the percentage release of the two drugs over a period of 24 hours.
(FF 8 (see Fanara Table 10).) In another working example (Example 7);
Fanara provides a double-layer tablet with imrnediate- and controlled-
release hydrocodone (e.g., an antitussive), and describes the percentage
18
Appeal 2016-006545
Application 11/012)67
release of hydrocodone from this formulation over 12 hours. (FF 8 (see
Fanara Table l 7).)
Fanara teaches the advantage of controlling the release of active
substances with matrix compositions to provide for regular and continuous
release of active substances over extended periods- such as over 12 hours.
(FF 7 .) Fanara teaches ideally the "controlled release of pharmaceuticaHy
active substances [is] such that a satisfactory therapeutic effect is observed
over fairly long periods, for example in only one or two daily doses.~' (FF
7.) Fanara teaches "[i]n the case where an active substance is released
immediately and another active substance is released gradually, [Fanara's
matrix material] makes it possible to obtain combined therapeutic effects by
means of two active substances having very different phannacokinetic
profiles." (FF 7 .)
·with respect to pending claim 112, Fanara does not expressly identify
diphenhydramine among its list of antihistamines. (FF 8.) Also, Fanara
does not expressly disclose the percentage overlap of the periods during
which the plasma concentration of the drugs is maintained at a
therapeutically effective level.
Davis '508 teaches formulations that cmnprise immediate- and
sustained-release layers of the expectorant guaifenesin. (FF 9.) Davis '508
further teaches its fonnulations rnay include at least one additional drug,
which may be in the immediate-release layer, the extended-release layer, or
both. (FF 9----1 L) Davis '508 teaches the additional drug may be the
antihistarnine diphenhydramine hydrochloride. (FF l L) Davis '508 teaches
a bilaver tablet that maintains sennn concentration of guaifenesin at a
J ~
19
Appeal 2016-006545
Application 11/012)67
therapeutically effective level for about twelve hours from a single dose and
also "maintains the serum concentration levels of at least one additional drug
at a therapeutically effective level for about a twelve hour period without an
increase in dosage strength.'' (FF 10; see also FF 12.)
It would have been obvious to the skilled artisan at the tirne of the
invention to design a fonnulation comprising a first dn1g that is
diphenhydramine and a second drug, such as pseudoephedrine or
guai fenesin. Although Fanara does not identify diphenhydramine, H was a
\vell-known alten1ative antihistamine for use in combined cold and allergy
formulations as reflected by numerous prior mi references of record. Davis
'508, Paradissis, and other prior art suggest combinations of
diphenhydramine with other drugs, such as expectorants, decongestants, and
analgesics. (See, e.g., FF 4-5, 11-13.)
In addition, it would have been obvious to the skilled artisan to design
a formulation including diphenhydramine and a second dn1g where both the
first and second drugs maintain therapeutically effective plasma
concentrations for similar periods of time. Davis '508 teaches formulations
with guaifenesin and a second d1ug (listing diphenhydramine\ and expressly
teaches that both guaifonesin and the second drug are formulated to maintain
therapeutic effect for up to twelve hours. (FF l 0.) The skilled artisan would
have reason to design such a fonnulation to irnprove patient compliance by
extending therapeutic activity and limiting administration of multi-d1ug
fon11ulations to one or two daily doses. (FF 7.) The skilled artisan would
have further desired the therapeutic effects of the dn1gs to substantially (if
not entirely) overlap- as taught in at least Davis '508- so that the subject
20
Appeal 2016-006545
Application 11/012)67
taking the medication obtains the therapeutic benefit over approximately the
same periods of time. Othenvise, the subject might lose the benefit of a
shorter acting drug (e.g., an expectorant like guaifonesin or a decongestant
like pseudoephedrine ), while a longer-acting drug like diphenhydramine
remains therapeutically active for many hours. 10 And, based on the cited
teachings of the art of record, the skilled artisan would have had a
reasonable expectation of success in designing such a multi-dn1g
fo1mulation.
Other applied art suggests the advantages of administering multiple
cold and allergy medications in a single dose with substantially overlapping
therapeutic activity. Vadino, for example, teaches extended-release
formulations that include an antihistamine, decongestant, and analgesic to
"provide the desired activity [i.e., therapeutic activity]" for "preferably 8-12
hours." (FF 14.) In this way, "repeated administration of several single-
component dosage forms throughout the day may be avoided." (FF 14.)
The skilled miisan would have predictably applied such teachings to a
pharmaceutical formulation that comprises a well-known antihistamine
(diphenhydramine) and other dmgs commonly used to treat the symptoms of
a cold or allergy.
10 Davis '508 teaches that the plasma half-life of guaifenesin and
pseudoephedrine are about 1 hour and 4-6 hours respectively. (Davis '508
ii~ 11-12.) The half-life of diphenhydrarnine is longer. (See Simons et al.,
Diphenhydramine: Pharmacokinetics and Pharmacodynamics in Elderly
Adults, Young Adults, and Children, 30 J. CLIN. PHA.Rl\!li\COL. 665-671
(1990) ("Simons'') (reporting half-life of diphenhydramine of 9.2 ± 2.5
hours in adults), submitted in the IDS concurrent with this decision.
21
Appeal 2016-006545
Application 11/012)67
Indeed, this is consistent with Fanara's working exarnples and other
teachings. Example 4 of Fanara shows the combination of a controlled-
release decongestant (pseudoephedrine) and immediate-release antihistamine
(cetirizine- a known long-acting antihistamine). (FF 8.) By using
controlled- rather than immediate-release pseudoephedrine, its therapeutic
activity is prolonged within the longer therapeutic window of cetirizine.
(See Fanara Fig. l (comparing plasma concentration curves of contro11ed-
vs. immediate-release pseudoephedrine).) So, the fonnulation in Example 4
\vith controlled-release pseudoephedrine increases the extent of overlap of
the drugs' therapeutic activity over a twelve-hour period. Absent persuasive
evidence to the contrary, it is reasonable to conclude that Example 4 of
Fanara would exhibit the degree of overlap that is claimed (at least 70 %).
In re Best, 562 F.2d 1252, 1255 (CCPA 1977). 11 A .. nd, to the extent smne
differences in the percentage of overlap may exist, the skilled artisan would
have modified those percentages through predictable optimization based on
the desire to create multi-dn1g formulations with substantial overlap in
therapeutic effect as discussed above. (FF 7, 10, 12, 14.) See Jn re Aller,
220 F.2d 454, 456 (CCPA 1955) ("[\V]here the general conditions of a claim
are disclosed in the prior art, it is not inventive to discover the optimum or
workable ranges by routine experimentation.").
11 Paradissis also provides working examples that combine decongestants
and antihistamines in extended-release formulations, and describes the
release over 8, 12, and 24 hour periods. (FF 13.) Although neither
Paradissis nor Fanara express] v use diphenhvdramine in their working .,, ,.,t ...._,
examples, the skilled artisan would have recognized that drug is merely an
alternative antihistamine. (FF 4-5, 11, 13.)
22
Appeal 2016-006545
Application 11/012)67
For the above reasons, we conclude that claim 112 would have been
obvious over Fanara, Davis '508, Davis '318, Paradissis, Vadino, Blume,
and Lech.
(-'l . l "' 7 j aim j !
Claim 137 is sirnilar to claim 112, but specifies (1) a bi-layer tablet,
(ii) that the second drug is selected from decongestants, antitussives,
expectorants, mucus thinning drugs and analgesics, and (iii) that the overlap
in the period of therapeutic activity is "at least 80 %.'' (App. Br. 3 l.)
At least Fanara and Davis '508 disclose sustained-release
formulations in the form of bi-layer tablets. (FF 6, 9.) Davis '508,
Paradissis, and other art disclose diphenhydrarnine combined with
decongestants, expectorants, etc. (FF 4-5, 10-11, 13). Davis '508 is
reasonably interpreted as teaching that the overlap in periods of therapeutic
activity over a 12-hour period is up to 100 %1. (FF 10.) For these reasons,
and those discussed above, claim 137 would have been obvious.
Claim 162
Claim 162 is shnilar to claim 112, but specifies that the second drug is
selected from decongestants, antitussives, expectorants, mucus thinning
drugs and analgesics, and further recites that the second drug "has a second
plasma half-life which differs from the first plasrna half-life [of
diphenhydramine] by at least about 2 hours." (App. Br. 36.) The half-lives
of the relevant dn1gs here would have been knmvn to the person of ordinary
skill in the art. As noted previously, Davis '508 teaches that the plasma
half-life of guaifenesin and pseudoephedrine are about 1 hour and 4-6 hours
respectively. (Davis '508 ,-ri111-12.) The plasma half-life of
23
Appeal 2016-006545
Application 11/012)67
diphenhydramine is noted to be about 9 hours. (Seen. 10 supra.) The
combinations of diphenhydramine and other drugs taught and suggested in
the prior art thus satisfy the limitation of claim 162 concen1ing a difference
in the dn1gs' respective half-lives.
For these reasons, and those discussed above concerning claim 112,
claim 162 would have been obvious.
Claim 171
Fanara discloses formulations having immediate- and sustained-
release forms or layers of the same dn1g. (FF 6.) In a working example,
Fanara discloses a double-layer tablet with immediate-release hydrocodone
(an antitussive) in one layer and controlled-release hydrocodone in another
layer. (FF 8.) Fanara teaches its formulations may be used with
antihistamines (FF 8), and the skilled artisan would have known that
diphenhydramine would provide a suitable, alternative antihistarnine. (FF
4----5, 11----13.) The skilled artisan would have been motivated to use
diphenhydramine in a formulation of Fanara to provide the benefit of
imrnediate and extended therapeutic benefit of the drug- for exarnple, to
provide short and long-term antitussive effect and amelioration of allergic
reactions for which diphenhydramine is known to be indicated.
Davis '508 and Paradissis further disclose formulations that provide
imrnediate-release and extended-release forms or layers including rnuHiple
dn1gs. (FF 11. 13.i Both Davis '508 and Paradissis identifv
"-' ' / ,• .;
diphenhydramine as one of several suitable antihistamines. (Id.) It would
have been obvious based on the express teachings of Davis '508 to design a
formulation (e.g. bi-layer tablet) with guaifenesin and diphenhydramine in
24
Appeal 2016-006545
Application 11/012)67
both an immediate-release and sustained-release layer. Similarly, it would
have been obvious to use diphenhydramine rather than chlorpheniramine as
the antihistamine in, for instance, Example 2 of Paradissis. (FF 13 (Example
2 includes imrnediate- and extended-release chlorpheniramine combined
with pseudoephedrine).) Because claim 171 does not exclude the presence
of drugs other than diphenhydramine in the respective fonns/fayers, these
modified fonnulaticms fhnn Davis '508 and Paradissis are encompassed by
the clairn. These modified fonnulations would also provide the different
fon11s or layers of diphenhydramine, having different release rates and
periods as in claim 171.
\Ve conclude claim 1 71 would have been obvious over Fanara, Davis
'508, Davis '318, Paradissis, Vadhm, Blume, and Lech.
No inference should be drawn from the failure to make a new ground
of rejection of other claims. Should there be further prosecution before the
Examiner, \Ve leave to the Examiner to determine whether to make a new
ground of rejection of any other claims. See 37 C.F.R. § 4L50(b); see also
l\rlanual of Patent Examining Procedure (l\t1PEP) § 1213.02. Under 37
C.F.R. § 4 L50(b), the Board may, in its decision, make a new rejection of
one or rnore of any of the claims pending in the case. Because the exercise
of authority under 37 C.F.R. § 41.SO(b) is discretionary, no inference should
be drawn from the decision to exercise that discretion with respect to some
but not all of the claims on appeal.
25
Appeal 2016-006545
Application 11/012)67
SUlVrfv1ARY
vVe reverse the rejection of claims 146----149 under 35 U.S.C. § 112,
second paragraph.
\Ve reverse the rejection of claims 112-114, 117, 118, 122-129, 137-
159, and 162-195 under 35 U.S.C. § 103(a) over Blume and Lech.
We affinn the provisional obviousness-type double patenting
rejections of claim 112----114, 117, 118, 122----129, 137----159, and 162----195
over clairns in Application Nos. 11/102,726, 10/939,351, or 11/115,321.
vVe enter a ne\v ground of rejection of claims 112, 137, 162, and 171
under 35 U.S.C. § 103(a) over Fanara, Davis '508, Davis '318, Paradissis,
Vadino, Blume, and Lech.
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 41.50(b). 37 C.F.R. § 41.50(b) provides "[a] new ground of
rejection pursuant to this paragraph sha11 not be considered final for judicial
review."
37 C.F.R. § 41.50(b) also provides that Appellant, vVITHIN TvVO
MONTHS FROl\I[ THE DATE OF THE DECISION, must exercise one of
the following two options with respect to the new grounds of rejection to
avoid tennination of the appeaJ as to the rejected claims:
(1) Reopen prosecution. Subrnit an appropriate amendment of the
cJaims so rejected or new evidence reJating to the claims so rejected,
or both, and have the matter reconsidered by the Examiner, in which
event the proceeding will be remanded to the Examiner. ...
(2) Request rehearing. Request that the proceeding be reheard under
§ 41.52 by the Board upon the same record ....
Should the Appellant elect to prosecute further before the Examiner
pursuant to 37 C.F.R. § 4L50(b)(l), in order to preserve the right to seek
26
Appeal 2016-006545
Application 11/012)67
review under 35 U.S.C. §§ 141or145 with respect to the affinned rejection,
the effective date of the affirmance is defon-ed until conclusion of the
prosecution before the Examiner unless, as a mere incident to the limited
prosecution, the affirmed rejection is overcmne.
If the Appellant elects prosecution before the Examiner and this does
not res uh in allowance of the application, abandonment or a second appeali
this case should be retun1ed to the Patent Trial and .Appeal Board for final
action on the affinned rejection, including any tirneiy request for rehearing
thereof
AFFIRJ\t1ED~ 37 C.F.R. § 41.SO(b}
27
Notice of References Cited
*
Documeni Number Date
Country Code-Nun1ber-Kind Code MM-YYYY
A US- 4777050 10-1998
B US- 2003/0049318 03-2003
c US- 2003/0215508 11-2003
D US-
E US-
F US-
G US·
H US-
US-
J US-
K US-
L US-
M US-
*
Document Number Date
Country Code-Number-Kind Code MM-YYYY
N
0
p
Q
R
s
T
Application/Control No.
l li012,267
Examiner
U.S. PATENT DOCUMENTS
Name
Vadino
Davis et aL
Davis et al.
FOREIGN PATENT DOCUMENTS
Couniry
NON-PATENT DOCUMENTS
Name
Appiicant(s)IPatent Under Patent
Appeal No.
2016-006545
Art Unit
[ l 61 l I Page 1 of1
Classifica1ion
Classifica1ion
* Include as applicable: Au1hor, Tille Date. Publisher. Edition or Volume, Pe1iinen1 Pages)
u Diphenhydramine: Pharmacokinetics and Phannacodynamics in Elderly Adults, Young Adults, and Children
Simons et al. 1990
v
w
x
*!\copy of this t"eference :snot be1n9 furnished wnn tn:s Off;ce act:on (See MPEP § 707.05(a).)
Dates in MM-YVYY forrna.t are publication dates. Classifications n1ay be US or foreign.
U.S. Pa.tent and Trademaok Oftice
PT0-892 (Rev 01-2001) Noiice of References Cited Part of Paper No.
Diphenhydramine: Pharmacokinetics and
Pha:rmacodynamics in Elderly Adults,
Young dults, and Children
Keith J, Simons, PhD, Wmie T. A. Watson, MD, FRCP(C), Tara J. Martin, BSc Pharm,
Xue Yu Chen, MSc, and F, Estelle FL Simons, MD, FRCP(C)
---------------.-~~ ............ ------------
The pharrnm:::okine!ici> and pharmacodyrwmics of the .H1-receptor antagonist diphenhy-
dromine were s!udied in 21 fasting subjects dii~frted into three ag.e groups= e!ded;-j'~ ("mean
age 69A ± 4.3 years), young adults, (mean age 31.5 ± WA ~rears), and children, [mel'.!n
age K9 ± 1.7 years/. All subjects ingested a single dose of diphenhydramine syrup I.25
mg/kg, in mean doses of 86.D :.t 7.3 mg, 87,9 ::t 12A mg, and J!U5 ± B.J' Health &l~m1;e11 Clinical R~rd'l Cerotra, Facultiei> (If Pluff·
m11q, MllK!icin~, <11ml Sdence (Or, Keith J. Simons), rocutty ol Medi·
;::in12<, (Ors" Watwn and L E!>!i!!ll!J, 840 S!ier!:lrook Sttieet, Winro~peg, Misnit11bi3,
Cani!>dill R3A i.S l.
hour:s. 12 There are no comprnhemive pharmacody-
namic studies of the antihistaminic effect of diphen-
hydramine in adults, and neither pharmacokinetic
nor pharmacodynamic studies have bean reported
in children.
We hypothesized that the serum elimination half.
life value and duration of action of diphenhydra-
mine would be longer in the elderly than in young
adults, and longer in young adults than in children,
as demonstrated previously for other Hi-receptor an-
tagonists such as chlorpheniramine, hydroxyzine,
and terfenad i ne. n-~~ Further information about di-
ph enhydr-amine pharmacokineHcs and pharmaco-
dynamics is rnquirnd to facilitate devj;;lop:ment of
optimal, ~;afer diphenhydrn.mine dosage regimens for
patients of various ages:.
METHODS
The protocol for this study was approved by the fac-
ulty Committee on the Use of Human Subjects in
SIMONS ET AL
Research of the University of Manitoba, and each
par-t!dpant gave wrilten informed consent before
5:tudy entry. Adult participants were normal volun·
teers. The children who participated had mild aller¥
gic rhiniti~« Partidpants were eligible for the study if
they were in good health, as determined by history
and physical examination, within 10% of norm.al
weigh! for height, not requiring any medication reg¥
ularly, and had normal hepatic and renal function,
as evidenced by normal total and direct serum bili·
n.1.bin.. serum protein. an.d albumin, alanine amino-
transfornse, a:spartase aminotr-au.sferase, lactate de¥
hydrogenase, gamma-g!utamyl transferase, urimi
analysis, serum crnatinine, and blood urea nitmgen.
Participants were excluded from the study if they
had any acute or chronic illness, except for allergic
rhinitis, if they had ever taken an H1 ~receptor an tag~
onist regularly, if they had ever smoked, or if they
ingested alcoholic or xanthine-contain.ing beverages
excessively.
The participants visited the Health Sciences Clin-
ical Research Centrn at B:OD ,<\M hours. after an B-
hour fast An in.dwelling venous catheter with "hep-
arin lock'' was inserted and blood samples of 5 mL
for measuremen! of serum diphenhydrnmine con~
centre.Hon were collected beforn, and 1, 2. 3, 4, 5, fi.
6, HJ, 12. and Z4 hours afler administration of di-
phenhyd:rnmine 1.25 mg/kg, as Benad.ryl® elixir
(Parke-Davis, Scarborough, Ontario. Canada), with
250 mL water.
The first 1.0 mL of each blood sample was dis-
carded and after each sample was obtained, the hep¥
ar!n lock was rinsed with 1.0 mL 0.9% saline, fol~
lowed by IJ.5 mL of a solution containing 10 U hep!!·
rin per 1 mL 0.9% salineo In all of the adults, blood
samples were also collected by venipunctme at :rn
and 48 hours after diphenhydramine administra~
tion. In the elderly adults, additional samples were
collected at 60 and n hours.
A standardized snack was served 2 hours after the
dose, and standardized meals were served 4 and 8
hours postdose. Caffeine and other methylxanthine
containing beverages and foods wern not permitted.
for the first 6 hours of the study, No other medica-
tion was permitted by mouth before or du.ring the
study. Reclining chairs were available for partici¥
pants who wished to sleep.
Blood samples were centrifuged at 3700 r-/min
(1370 X g}. Serum was transferred to glass tubes and
stored, securely capped, at ~20'0 C. Diphen.hydra~
mine concentrations wern determined by high per-
formance liquid chromatography (HPLC). Fifty mi-
cw!Hers of lhe internal standard, qproheptadine
(50 ng/HJO µL) were !!dded to t,0 mL standard or
study sample, Samples wern alkalinized with 200 µ:L
rn<;tr, KOH and extracted with 5 mL freshly di5:tilled
ether by mixing 011 a vortex mixer for 30 seconds
and centrifoging to separate the phases. The lower
aqueous phase was frozen. in an acetone-dry ice
bath and the ether was transferred to a dean test
tube cont<1ining 100 µL of 0.5% phmphoric acid.
After extraction and freezing, the ether- layer was
discarded and remaining traces of ether were evapo-
rated by a stream of dry. nitwgen.
The total acid phase plus two 50-µ1, add washes of
test tube were injected directly into the HPLC, com~
prised of a Ll6K injector, a 6000A pump, a 480 U~V
absorbance detector and a 730 data module and in¥
tegrator (Waters Associates, Milfor-d, MA), A Cmµ.¥
Bond.apak 0.4 x ao cm stainless steel column
(\.>Vaters} Wa5: used.
The mobile phase was 32% acetonitrile in a 63%
ammonium phosphate buffer, OJJ75 M, pH 2.7. Ah¥
sorh;mce was measured at 229 nm. At a flow rate of
2,2 ml/min and operating prnssurns of 1500-2000
psi, diphenhydramine and the internal standard had
re!en.tion times of 5.8 and 10.4 minutes, respectively,
The diphenhydramine assay was specific, No inter-
fering peaks were observed. in the predose samples.
The assay had a limit of sensitivity of 3 ng/m.L with
a mean coefficient of variation of 8.9 ± 2.3% over a
months. It was possible to detect concentrations as
low as 0,5 ng/mL. Calibration curves, constructed
by plotting the peak height ratios (diphenhydra-
mine/internal :standard) versus diphenhydrnmine
concentration, were linear over the concentration
range 0-100 ng/mL.
A skin test with histamine phosphate was per~
formed ei:ich time a blood sample was obtained.
Adults had intra.dermal injections with histamine
phosphate, 0.01 mL of a !11 mg/mL solution; chi!~
dren had epicutaneous tests with histamine phos-
phate, 1 mg/mL. A different site on the volar surface
of the for-earm was U5:ed for each lest and the se-
quence of sites chosen was identical in all partici-
pants, Wheal and flare circumferences were traced
at 10 mim1.tes with a fo!t tip pen and trnnsfotred to
transparent paper. Injections and tracings of the
wheal and flare circumference were made by the
same investigator. Wheal and flare areas were m.ea~
sured using an IBM PC digitizer tabhit, and stereo~
metric software.25 During the study, the coefficient
of variation with one observer tracing wheal and
flare areas was 7 .3% for areas of 0.1 cm2 , representa~
tive of the smallest wheal arnas traced, and 1.B'?f., for
areas of approxi ma tel y 1. O cm i, represen ta H ve of the
average flarn area,
Each Hme a blood test and skin test were per-
formed, participants were awakened if neces~aty,
questioned about adverse effects such as sleepiness,
PHAHMACOKfNE'T!CS AND PHARMACODYNAMfCS Or DIPHENHYDRA.MlNE
TABLE
Age" (yrn)
Weight (kg)
Dose (mg)
Gp,.,..._ (ng/ml)
t,,.,.. (h}
ti12 (h)
C! {ml/min/kg}
Vd,. {l/kg)
Vd (lkg)
Aue (ng/ml/h)
MRT (h}
69.4 ± 4.3
71.0 ± 11.4
86.0 ± 73
lBB.4 ± 54.5
1,7 i {l.8
13.5 ± 4.2
11.7 ± 3..1
10.2 ± 3.0
13.6± 6.3
1902 ± 572
14.S ± 2.8
light-headedness, feelings of disorientation or dizzi-
ness, dry mouth, visual changes, or difficulty uri-
nating.
Pharmacokinetlc parameters were calculated
using the same equations as :reported ptcviously 1 ~·26
and the PKCALC interactive computer p:rogramu on
an IBM PC The histamine-induced wheal and flare
areas were analyzed as absolute values and as per-
rnmt reduction of premedicatkm control values.. The
two~way ANOVA using subject and sample time or
subject and age as the criteria of classification, and
the Tu key /Bonfern:mi multiple range tests were
used for all comparisons.ia Differences were consid-
ered to be significant at P < .01 and .P < J)5.
RE.SULTS
Twenty-one nonobese, nonsmoking Caucasians par-
ticipated in the study. No patients required any
medication by mouth in the month preceding the
study, or during the study. None of the patients had
ever taken H1 -receptor antagonists regularly. All
had normal hepatic and renal function, Thelr mean
age, weight, and diphenhydramine dose are summa-
rized in the Table,
· The mean peak serum diphenhydramirw concen·
trations were 1BB.4 :t 54.5 ng/mL, 133.2 ± 37.6
ng/mL, a.nd at.a ± 30.2 ng/mL in elderly adults,
young adults, and children respectively, occurring
at a mean time of 1.7 ± OJ:! honrs, 1,7 ± 1.0 hours,
and 1.3 ± 0.5 hours, respectively (Figure 1}. The
pharmacokinetk data are summarized in the Table.
Mean semm elimination half-life values for diphen·
hydramine were 13.5 ± 4.2 hours, 9.2 ± 25 hours,
and 5.4 ± 1.8 hours, in the elderly adults, young
adults, and children respectively.
ANTI-INFLAMMATORY /IMMUNOSUPPRESS!VE/ANTIHlSTAM!NE
31.5 ± 10.4
70.3 ± ~t9
87.9 ± 12.4
133.2 ± 37.6
L7 ± LO
9.2 ±. 2.5
23.3 ± 9A
1•t6 ± 4.0
17"'4 ± 4.8
1031 ± 437
1L3 ± 3.1
~19 ± L7
3U5± 6,8
39.5 ± B.4
8L8 :!: 30.2
1.3 ± 0.5
5.4 :t L8
49.2 ± 22.8
17.9 .t: 5.9
2L7 ± 6J)
415 :t 137
6.4 :i: L6
A plot of diphenhydrnmine elimination half-life
versus age yielded a slope of 0.11, an intercept of
5.28 hours and a linear correlation coefficient of
0.675, A plot of total body clearance versus age
yielded a slope of -0.51, an intercept of 46.80 mL/
min/kg and a linear correlation coefficient of OJWO.
A plot of apparent volume of distribution versus age
yielded a slope of-0.106, an intercept of 18.15 L/kg
and a linear correlation coefficient of 0527 o
Six of seven eldiarlv adults, six of seven young
adults, but none of tl1e children experienced seda.
t ~.M.A.
'" ~ 13.5~&2 S'l;,Agil: tWA t&.3 V·
ro
Figure L Serum diphen'1.vdromh1e com;en!rution vei"Siu:s lime pfo!s
after l'l si11gfo dow of diphenhyriromine, !.25 mg/kg lri elderly
cidults, yo1.rng adults m~d children.
SIMONS ET AL
tion from 1 to 6 hours after a single dose of diphen-
hydrnmine. Dry mouth was reported by six of seven
elderly adults, five of seven ym.rn.g adults, and no
children. Blurred vision was: reported by one of
seven. young adults and by no elderly adult or child.
Diphenhydra.mine significantly suppressed the
histamine-induced wheal and flare from 3-10 hours
and 1-12 hours, respectively, in the elderly (P < .01),
with a maximum wheal :smpprmision of 39.6 ± 22.5%,
and a maximum flam suppression of 46.5 ± 32.1 % at
5 and 6 hours, respectively. Diphenhydramine sig·
nificantly suppressed the histamine-induced wheal
and flare from 1-10 hours and 2, 4, and 6 hours,
respectively. in young adults (P < ,01), with a maxi-
mum wheal :suppression of 45.5 ± 25.0%, and a
maximum flare suppression of 53.4 ± 16.9% at 6 and
4 hours, respectively. Diphenhydramine signifi-
cantly suppressed the histamine-induced wheal and
flare from 1-8 hours and 1-12 hours respectively in
children, with a maximum wheal suppression of
68.4 ± 10.2% and a maximum flare suppression of
87 .2 ± 4.2% at 2 hours {Figure 2).
DISCUSSION
In this parallel group study we reported the pharma~
cokinetics and pharmacodynamics of diphenhydra-
mine in elderly adults with a mean age of 69.4 ± 43
years, young adults with a mean. age of 31.5 ± 10.4
years, and children with a mean age of 8.9 ± 1.7
years, The dose of diphen.hydrnrnine glven to the
subjects was 1.25 mg/kg. There was no significant
difference {P > ,05) in the mean dose given to the
elderly adults, BIHi ± 'i.3 mg, and the mean dose
given to the young adults, 87.9 ± 12.4 mg, as !he
mean weights of these groups. 71.0 ± 11.4 kg and
70.3 ± !HI kg, did not differ significantly (P > .05),
The mean dose given to children, 39.5 ± 8.4 mg, was
significantly lower {P < .05} than the mean dose
given to adults because of the significantly smaller
size of the children., (P < .05).
The mean maximum serum diphenhydramine
concsntra tion found in the elderly, 188.4 ± 54.5
ng/mL was significantly higher {P < .05) than that
found in the young adul!s, 133.2 ± 37.6 ng/mL, an.d
the values in the elderly and young adults were sig·
nificantly higher than the mean maximum serum
diph~mhydrnmine concentrations found in the chil-
dren, !H.8 ± 30.2 ng/mL, probably as a result of the
decreasing apparent volume of distribution with ad·
vandng age. There was no significant difference (P
> .05j in the mean times at which the maximum
serum diphenhydrnmine concentrations occurred in
c.
Figi;re l. WherJl om:! jlarn orros (mean :±: SEM) after fntraderrnal
inieclion of O.f.ll ml Msiam!ne phosphole (fJ.1 mg/ml,J before and
from 1-48 ho .05). This wa10 attributed to lhe small
number of subjects studied and to the wide variation
!n values within each age group, as evidenced by the
large standard deviations.
Diphenhyd:ramine is metabolized by the hepatic
cytochrome P-450 enzyme system, therefore, the in-
creased serum~elimination half-life values, slower
clearance .rates, and a trend towards decreased vol~
umes of distribulion with Increasing age might be
expected, as age 0 related dec:reases in hepatic func 0
ticm, including decreased liver blood flow, smaller
liver size f.lnd diminished numbi:>r and metaboUztng
capacity of hepatocyles have been well documented
in geriatric populations.i"'~~~ Diphenhydramine eHm~
ination half¥Hfe values, clearance ratm;, and vol¥
umes of distribution plotted versus subject ages
yielded correlation coefficients similar to those _re.
ANii 0 !NFLAMMATORY/! MM UNOSUPPRESS!VE/ ANTI HIST AMINE
parted pnwiously for h.ydrm:y?-ine.21 Other H1-re 0
ceptor antagonists metabolized by the cytochrome
P450 :;ystem, chlorphenirnmine, lJ~i~,w and terfena~
dine,11-w also have significantly longer serum elimi~
nation half-life values, lower clearance rates and
decreased volumes of distribution with adwmc-
ing age<
The wheal and flam response to histamine is an
objective, standardized biologic assay, valid in pa¥
tients of all ages.J~ In elderly and young adults, di-
phenhydramine inhibited the histamin.e~induced
wheal and flare areas significantly f:rom approxi-
mately ! to 12 hourn, comparnd lo prndose value!S,
while in children the significant suppression lasted
onl v from 1 to B hours,
\Vhen the data were analyzed as pe.rcen.t suppres-
sion of wheal and flare a:mirn, maximum wheal sup-
pression in the elderly, 39.6 ± 22.5% at 5 hours, was
not significantly different (P > .05) from that found
in young adults, 45.5 ± 25.0% al 6 hou.rs. The maxi-
mum wheal 10uppression in children, 68,4 ± 10,2% at
Z hours, was significantly greate.r (P < .05) than the
maximum suppression found in the elderly or in
young adults. Similar results were found for percent
reduction of flare, with maximum suppression in
the elderly of 46.5 ± 32.1% at 6 hours not being
significantly different {P > .05) f.rom the maximum
suppression of 53.4 ± 16,9% found a! 4 hours in the
young adults" In both the elderly and young adults,
maximum flare suppression was significantly less {P
< .05 J than the maxim nm suppression of 87 .2 ± 4. 2 %
found al 2 hours in the children. De!>pite having
lower serum concentrations, the children appea.red
ta have a mo.re rapid onset of action and a more
intense res_pon:rn to diphenhydramine than the
adults did,
Semilogarhhmic _plots of mean percent supprns-
$ion of wheal or flare area!> ve.rsus time yielded
curves simila.r to the serum diphenhydramine con°
centration versus time curveio (Figure 1). Half-life
values calculated from the terminal linea:r portions
of the _plots fo:r wheals warn 47 .2 hours in the el 0
derly, 54.9 hours in young adults, and 9.B hours in
children, while half~l!fe values for flares were 41.B,
a2. 7, and 3. 9 hours in. el de rt y, young adults, and
children., respectively, Half-!ifo values of response
were much. longer in the elderly and young adults
when compared to serum elimination half-life
values, whili:> the values in children we:re more simi-
lar to the serum elimination half-life values. How-
ever, the histamine-induced wheal and flare sup-
pression in elderly and young adults wa:; not signifi·
cant (P > .01) afte.r 12 hours when compared to
predo10e values.
SIMONS ET AL
Mean percent suppression of histamine-induced
wheals by diphenh.ydramine was plotted 'l1mn1s
mean diphenhydramine concentrations from. 4 to 24
hou:rs when absorplim1 was complete, and values for
E,,,~~ and ECr.ir were calculated.:1~ The values for E,,,~~
were 35,3. 45,7. and. 99.8% l:n the elderly, young
adults, and children, respectively, while EC50 values
were 7,8, 8.0, and 38.7 ng/mL, respectively, There
was considerable scatter in the data, resulting in rel-
atively large residual sum of squares values. The
results found in elderly and young adults were simi·
lar. The results in children. indicated th.at they had a
better response to diphenh.yd:rnmine than the el-
derly or young adults did.
Both the semilogarithmic and Em<». methods of
pharmacodynamic analysis assume a dose relation.-
ship between the serum diphenhydramine con.cen~
trntion and the pharmacologic response to diphen-
hvd.ramin.e, When. these method10 of analysis were
applied to the data there appeared to be a lag in the
onset of the response and a lag in the return to base~
line. There was insufficient evidence to determine if
these lag times were due to a delay in distribution nf
diphenhydramine to the site of action in the skin, a
delay in eHmination of diphenhydrnmine from the
skin relatl'le to a decline in serum diphenhydrnmine
concentrations, or a delay in H 1-antagonist receptor
response and recovery, Further investigation of this
phenomenon ls required..
Sedation following diph.enhydramine ingestion,
although absent in the children. was noted in almost
all the adults, and correlated with peak serum di-
phenhydrnmine concentrntion.s, Thi:;: correlation of
central nervous system adverse effects with peak
serum diphenhydrami:ne concentrations has been
demonstrated in some,'·11 but not aH,~·12 studieg bv
other author!>. ·
Newer, non-sedating 10econd generation H1-recep-
tor antagonists are supplanting the relatively sedat-
ing first generation H1 ~:.receptor antagonists in the
treatment of disorders such as allergic rhinitis. Di-
phenhydrnmi:rrn, however, wm likely remain in
therapeutic usage for some time, as, being one of the
few H1 -rnceptor antagoni:>ts available for intrave-
nous administration, it is widely pre!>cribed. fo.r
symptomatic treatment of acute urticaria! and ana~
phylactic reactions. The results of this study will
facilitate optimal usage of diphenhydramine i[l pa-
tients of different age;; and will en.able physicians to
have a morn realistic understanding of the limita-
tions of this venerable medication..
Th0 Bui.hors admn•>'ledge the support of !.he Hee.lBh Sdences
Centro R;;search Founda!ion and nf P1.1rke-Davis C:a.mida Inc. Lim-
[!ed. Tarn Martin wa.~ th'3 recipien!. of 11 Medk..l!l Rese11rch Cmmdl
of Cem:ai:b Summer Shidentsbip. Dr. Wad" W is!son was the recipi-
ent of 11 Samfo:!' Clini>-el Re!sddphia. W.E. Saunders
Compal'ly, 1987.
3. Hatris.::m's Principles of ln!ernar Medicine foleveriih etlitii:m).
BrnurowGld !::, lsselbachet KL Peteroodorf RG, Wilson JD, Martiro jB,
Fomci AS {0;0ds): New York, McGrnw-HHl. 1':IB7.
11.. Aloor! KS, Hll:Hmark MR. Sakrrrnr E. Weidler D!, '.\'e.gm~r fG:
Phe.rmBcoldnetic.s of diph"mhydrsmine in men. J Phorm SiO'-
prmrm tf<75:3:l59-- l7fl.
:;, E!il:e.M W, Gunder!-Remy U, Visher E: RelB!iO'nship b'3tween
e.riHhb!:unisik adlvity e.m:I plssms l011el of ciiphenhydramine.
Eur I Clin Plmrmacol W74;7:31~'1-'.:!95.
a Gla:tko Aj. Dill WA, Yoilng RM. Smi!b TC, Ogilvi., RI: Meta~
boHc diroposlHoro of diphenhydramine. Clin Pharmcrcol Ther
1974; 15: 1065-1076.
1. Ce.rruthers SC, Shoerno:m OW, Hignite CE. Aziurooff DL: Corr!l·
lation heiweero pia~ma diphenhydrnmi.ne !Olve! e.nd sedative 0>nd
antihistamine effects. Clin Plmmmcol Ther 197fl;23:375-362.
~, Spi>dOr R, Choudhury AK, Chisng C-K, Goldberg MJ. Ghoneirn
MM: Diphenhyclrnmimi in Ori~mtal~ and C1rncm>iBn~. Clil'l Phar-
rnacol Ther 1930;2B:l:l9-l34,
!:t Li;ns BG. Srnvone jM, GmenblaH DL Hefrnaia: IS. Shad!>t R!:
Dipherohydrnm~ne pherm!lcoidne!ico in women rr·
formance, Clin Ph<1rmnrnl T!wr 196fl:45:1S-21.
lZ. Ber!ingH WG, Goldberg ML Spedur R. Chifing C·K. Ghonioirn
MM: Di.ph~mhyd,.:aimiM: Kimiiic~ etod psyd1ornotor effect,; in el-
derly women. Clin Phurmaco! Ther 19BZ:32:387-31:H.
U. Thompson ,A, B!oedow DC. Leffert F'H: Pharmarnkisietics of
intrnveno•.is chlorphenirnmine In ·~hildnm. J Pharm Sci
l fjij 1;70:1284-l 2e6.
l'J, Simons FER, L11ch~k GH, Simons Ki: Phiirmacoklnetics 11rod
efficacy of chlorpheniramina in children.! A!!<'rgy Clin lmm>;nol
t 9B:l:69:37t;.....:ia 1.
1$, Yao::obi A. StoH RG, Chau GC. Carter IE. Be.eskB IJM, et fi!:
EvahrnB i(Hl of sts~teined ·ilClion d1lorph0roire mi B1e·pse •.ido0phe·
drine dosage forms in h!.!mans. / Plwrm Sr.i H!B!l:fi.9:1077-HJBL
w. H!.!11>ng S·M, Atheniksr NK SrhHiar K. Huang Y ·C. Chiou WL:
Pil:airnrnco~ineiics of d1lorpherolrnmine after intrave10ou~ and
orel administraHon in norms! ad~hsc f.i;r j Clin Pharmornl
1002;ZZ:35\':l-3B5.
17, Simons FER, W:ai!Mm WTA. Simons KJ: The pharmai::okinetics
end pharmacooynamics Qf t<:lrfon;:k ofsubsensitivity
PHAHMACOKINETfCS AND PHARMACODY?:y<:im-. m d1Hdrm1
with ~topic derrni!Hlis. I Pooiatr l9!l4:W,UZ3-ll7.
2%. Simons FER, Sirnrm~ K). Frith EM: The plur.rns;swkimi!irn aBJd
Gntihist01minic o:iffect~ of the H,·recep!or antilgoriist hydroxy:drie.
J Allergy Clin Immmwl 'jgf.1'1:73:.69-75.
ZJ, Gen0,>o FM, Debr>" ..mzo I. Yton:hsk A. Ll:lve S, Miller !K: Ttrn
re!aHvs osntihislarninlc and p~ychnmn!or effects of hydrmq.:»irse
1md ceHrh:ine. Clin Pharnmwl Ther 1987;42:Z65-Z72.
24. S~rnon:B K~~ ~V~t:ton lAlTA. Cht:n XY, Si~nons FER: Pharrrt(?~X~~
kinehr. s.nd. phermacod.ynamic s!utlies of the H, ·wceptor ;ma.:igo-
flis! hydroxy:zino:i in the ddocrly. Chn Phorm Ther rna9;45:9-1'1.
~5. G~mdrnsu-R.eid L, Simons Kl. Simons FER: Compi!ris•Jn of the
s!.!pprewive effect of astemizok terfrmil<:Hnoc, and hydro-,:;y:i:ine on
histarnirm-indm::e1orn j: Drug prescribing for t!ci> elderly. Arch
lntem Med i 98f.i< l 46:2393-:&396.
:n. Lei C-M, Ve~tsl RE: Drug mel<1bobrn in !he eld;,dy. Phurmu·
rn! Ther 1981J;36:131-H9.
Jl. Goldberg PB. Roberts J: Pharmacoioij.ic bfl~ie for cl1o>Vping
retiof!al drug regimens for elderly patierl!s. Med Clin North Am
1 %3:137 :315-3 31.
Jl, Shephenl i\MM: Ph ysl•::ilogicel dia nges wi!h agi r>g. Releviln>.:e
to drng sl!.!dy de.:;ign, In C!l!!er NR. Ni;rnng PK (edroj: Drug Studies
ill ihe Eldedy----Metliodoiogicol Com:erns. New York, Plenum
P!.!blish ing. 1936:49-67,
34. Montamat SC, Cusack Bj, Vestal RE: Manegernen! of drug
ihernpy in the elderly. N Engl! Med HMJ9;3Zl:30J-309.
.15. Sl.:assB-Srod;ik W. Marod;,m:heid J.C. Michel r·R Bousquet!:
Ski.n !est mi!cHvi!y to hisiarnlroa fo::im infaf!cy to old age. I Allergy
Clin lmmtmol 1907;6[1:71 t-7113.
<16. Ho!ford NHG. Sheirwr LB: Und!lrslanding the doiie·effed re-
la!!onship: din!c<1l application of phi.1rmecokhmUc-pharrnacooy·
n<1rnlc mot:leb. C!in Phurmomkinee 1981:6:421:}.-453.
United States Patent P9J
Vadino
[54] corrrnOU.ED-RELEASE DOSAGE FORM
COMPRISING ACETM:iINOPH.EN,
f'SEUDOEPHEDRINE AND
DEXBROMPHENIRAMlNE
F:i] fovenwr: Wim;ton A, Vadfrm, Whiteh(mse
Sml:ion, N .. r
[73] A:;sign~e; Scherlag Olrpondion, Kenilworth,
N.J.
[21] Appl. No.: 29,032
[22.J Filed; M!!I'. 13, l9S7
[5!] Int. Ct4 .. .., ........ ., .... rn. A6lK 31/74; A6lK 9/10;
A6lK 9/21
[52] U,S, Ct rn ... ,. ••. "o"'"'"""'"'"'"" 424/468; 424/436;
424/480; 424/488; 424/493; 424/4')9; 514/731
[531 Fidd uf S.,!!I'fb """ ........ 424/468, 436, 4SO, 488,
424/493, 499: 514/781
[1 q Patent Number~
f451 Date of Patent:
4,777,050
Oct, 11, 1988
[56] Refor<;:;1m::s Cit;id
U.S PATEl'<'T DOCUhrnNTS
4,389,393 6/19iB &hor et ;;t ,. ........................ 424/l'!
4,i.ifJ!,894 7/19&6 ifanna et al. ................... ,. .... 4?A/El
'l,657,75i 4/l 987 Harma e:t al. ................. ., ..... 424/4HH
4,695,591 9/19!1""1 f-bmJJr, t'.t ~l ........ ", ... ,, ......... 514/781
Primary E~1.1miner-Michael R. Lustgmin
Auom;;y, Agrnt, c'r Firm---An.i!;i W. MagM!i; Stephen I.
MElieo: James R. Nelson
[S7] ABSTRACT
The [nver1tion refotes to a controlled rele»~ dosage.
fomt comprising three Ective~: acetaminopher., p:;eudo-
ephedrioie and dexbromplieniram1ne.
4,777,050
1
CONTROLLED·RELEASE DOSAGE FORM
COMPRIS!NG ACETAMINOPHEN,
PSEUDOEPHE.DlUNE AND
DEXBROMPHENlRAMlNE
SUMMARY OF THE INVENTION
The present i.uventiori relate<> to ;w ornl controlled·
rele;,se moitrh dosage form which combin~ three phar~
rnaceuticals, acetaminophen, pse!ldoephedrfile or 11
pharmaceutically ac.1-)Cptf.ble salt thereof and dexbrom-
pheBJhmnlne or ll pharmaceti~kally ~ceptabk salt
thereof, one- or more polymers, and excipie.ms,
BACKGROUND OF THE INVENTION
2
three actives in a smgk homogeneou~ matril, from
which matri11 each active component is rdea,;ed at an
appropriate r;ste to provide the d<:sired aci:iviminophen, pseucloephcrlrine ;md
pyretic which red11ces tl:Je discomfort m:id fever due to de.xbromphenimmine may be present m an apprmi:iamte
cold$ imd other viral infoctirn1~t weight ratio of 200:2G'.l, for example, ;m.d !he desired
Pswdoephedrine and pharm&c:euticaliy ar.;:ceptable sirntained rcle3Se rates for each are still obtained. It is
salts thereof, <:~g. the sulfate and the hydrochforide, are W also une:ii:pecte throughout the day m1'y be avoidoo. Moreover, it
4,389,39'.t However, •Wntro1kd-release dosage forrna is app&r<:nt that, ill addition to the wel!-knov.·n pharma-
whic!i combine t<.vo bctives an~ noi. common, Mad but J5 rological advMl.ages of a contmlkd-rdea."" f>::>rumla-
f U o;:i p N 4 601 "94 d u s p ""' ~ t: -7 7"7 tion i.n geueral (e,g, more coru>tant blood levels of the or ·'-'· at o. , "' an . . . at. ,.,;o, .. ,,,:i , , -" ,
wherein hydro;s;yprnpyl metbylcellulose must be pr~ drugsJ, tht do.sage form of thr; pre$ent invention i~ eas-
eut as a bis:idei:'. no contrnUed-rele~ do!>age forms com- ier &&Jd more r;conomk:fil to memufac::>ne or more polymers
bining mill ti pie actives, e~h \!o"i.th differo;nt chemical ~ m1Jst always be present fil the dosage form of the inven-
and pbysicill cbru:acteristies, different :release rn~es, dif- tion, tbe concentration~ Qf t!ie active~ and polymer may
ferera balf-livee; and different dosage si:U:$, vary. For the filler imd other excipients, the mstt1rio a~
The mechaui.sm by w!iic!i controiloo-releiise dos.age well as each concei:'ltnt~ion of the component may also
forms act to dispen~e the ;sctive i_ngredientl over a per- 45 vll.ty.
iod ·;)f time hli.ve been de~criboo at iengt~ in the Jiternh Acetaminophen may be pr~nt at from 400 to 750
ture; ree for emmple Manford Robinson, Chaplet !4, mg/U>blei, prefornbly 500 mg/table!. P$eudoep!iedrine
"Si.!$12.ined Action 0o;lage Fo=", The Theo;y arid sulfote may be present at from 15 to 75 mg/t,1b1et, prl:'f-
Prnctke of lt1.dustriaf Phal"m(H:y, 2nd, ed., ed. L. l~ch- ernbly 60 mg/tablet. Dexbrnmp:h~niramine maleate
man, H. Uebernmn and J, Kmrig (Philadelphia; Lea & 50 m;sy be presenl in tile range of l to 5 mg/tllblet, with 3
Febiger, I97Q). mg/tablet being preferred.
. ,c • . ,.., While a nwnber of polymers might be used as binder
DE iA!LED DF;SCRIPTlON OF THE fur the rnatri:.;, lhis invention particuloo:ly contemplates
IN\i ENT10N Ille = of cellulosic polymer.> ,'le!ected from methylcc!-
The con~mlled-reh::are do~age form which is the sub- 55 htlo:ie, hydroxypropykd1ulose, hydrm:yrne~hylccl·
jec~ of thi.~ invention presents ai novel m:lvancernent of folose, !iydroxye!hyk.dlulose, c1arboxymethylcelhtlose,
the Jlrt ~ince ~t c-;:m1bmes three actiw;: lligred!eriti;, acet- carboKye~hykdh.J~me, £0dimn crucboxyme!hyke!lulose
aminorhen, pseudoephedrme or a pharmaiceuticaily and wdiumcruc1:m&:yethyl cellulose or combinations of
fACCCptable salt thereof, prefer-,i.My g:i~eudo::'.pherlrine si.iid cellulosk polymers rmd e!hykellu1ose or other
imlfate, and dexbrompheniraml.ue or a ph.1:rroaceutic1ally ® cellulose ethern, A single cel!ulosic polymer m::iy be
acceptable salt thereof, preferably de;;;brompheniraminc used, or a mixtun: of celfol0$ic po!ymere; of di!Ierent
male3te, in a single lor1g·acting tablet \Vhil.e antihisti.i· molecular weight and strnC:tJJre m variety of gradea, panic!e sizes antl/or
and combirled in conti.nuou,Hwtion capsules, the ptescrit v~~ooitie11. Preferred c~lfolooic polymers are !iydro:>.:y-
lnvei"i!icin reletes to a s\lrprningly simple combi1mtim1 of propylcellulos.e imd hydro:ii:yethyk:elhslose.
4,777,050
Of the total polymer weight, 10fi-55% m3y be a cd-
!ufo~!c polymer or" mix nm:: of ce!lulosic polymers l'l.nd
0-45% may be a cellulo:s.e ether, preferably e!hykel1n-
k»e. For dm:d polymer systems, i;;,g. wherein 99-5'.Vi'h of
the total polymer weigh! may bell cellulmic polymer or
a mixture of celhtlo:;;[c polymers and 1-45% m::iy be a
cdliiln""' dher, vrdcned raage.s nfpnlymer weight ~re
61i5-55% ce!lulosi<. polymer and 33"'.i-45% c:ell1Jki5e
ether. When only a ce.llu!osic polymer or a mixture of
cdlulmic polymer,; ls m;i::d, the total polymi::r c:onten!. W
reyre:>ent~ 1-3% by wtig:M ofihe dosage form (i.e., the
uaicoated cote do~age foran),. and for a dual syste.m the
total polymer content represent.>; 8--15% by weight of
the dosage form. A i:m::frrred rn11ge for the. totr.J amount
of polymer pre.rent for the single polymer system is 15
6~65% by weight of the do~age form, mid for the dual
polymer ~ys!em the preforrdl nmge is 1 L5-125'Jf., In a
prefei:red embodim.eEJt, on!y one cdhtlosk polymer is
u:;w, i.e. \C-01% cellulosk polymer, preferably hydroxy~
propyl cellulose or hydroxyethyl celln.lose. AEJoth<:r 20
preferred eiribodirmmt. is a dl.lll.! polyrner system having
a tot~ polymer weight of l J.5 .. 12.5% .:;if t!ie dosage
form and •:::ompriaing about 55-60<.'7" cellulosic polymex
a11d about 40-45% celh.1fo15e e~her.
Alw p~nt in the matrili: are one or more fillers such
(;$ diba-;ic calcium pho~ph~te dihyd.rnte or Jacwse, with
dibasic ca!cimn phospkite dihydrnte being preforred.
The faller is pre..'lent in a amouEJt to 10~ \3% of the totul
doa.age form ·,veight, with abo11t 12% being preforred.
Whefl the weight of the polymer co:ruponeEJt is var· JI)
icd, corrrnponcling variations in the filler weight are
made in order io maiEJtain constant tablet weight and
contrnilel'.ic acid and 0.25 to 0.78%
magnesi12m stearnte. 40
O!her excipient~, such as disintegrnting agents, color~
ing agents and fbv·oriEJgs, m;,y be added lit ~he dlscre·
tion of thom:: sknli::d in the art
The 11.bove componems nro; combined to form the
matrix and fanned into tablets by conventionoo means '15
(see Exmnpk J.). The iablets may be used a~ such, bllt
are prdernbfy .;;oated by technique:; well known fo the
art An example of s11ch a tablet coating fa 5h0\vri in
Example 1.
The following Examples describe typk:al baidi ;md SD
single ~aMet formuh5 of \he con1rolled-teleru;<; dos::ige
forms of this invention<
lngredielll.l
Aknhol 3A SD (f:Y8por::.:.t~:;}
Appro~im:,.t,, Usi~'.·nit~g ,,...,.~~~~h~i·si-. 1,:~y h~ ~~r~d~ • .. d1h cnm~'io~:>,~j()I~ ;.idj~:-:.!·
me:~l4: i~ (~~ ...::.;,:.;~ w..::~lf:1~. ~h~ .1m1.:n;N llf ~~k~ l}l' bc11.~-
-1--..,"'E~-~~.fr·,.~~e-r!t tn ;J:):~ ;i'!,.8 .~~rnm-ir!•:·p~~~
Me.!hod of Mmmfaciure
B!end I, II, dicakimn phosphate dihydrn.te and hy-
drollypropyl.e<::lla.lose for 5 .. JQ m1nutes in a suirnbk
mixer. Dissolve HI in 2te NF
Prnpyl p-hy,frm:yb~~~m\!" NF
Furifirate'!)
Cfllmi"g Ag~n1
A :ppro.r.im;,.;.'=;
g/!Jatch
3(!()
14.4
Ul.S
(I)
(2)
mJlit:ibkt
)2
i),12
Q.M
0) 3t:fftde~I~ -0.f:l(•iiJ~!~ {1f'PRr!fc~d W-)r~;;- P.rr~ JJ54:.j ~ ~-t~l~;~~ct 'r. ~t':-C: ~;;.i,1j!lg. '{'!"~?.-:.::..
ft) A!"t ~~~rcf'ri:u~ ~i..m: uf 0i t:o:o:ri.'lg ~'l!"ia i:~.r:,. )~ok•r ,-fa~~br~ v:.Eru> rfi.:.I.'./ b'-"
.)ck:r:a.
Method of Manufacture
Prepare polymer solution usi1Jg s!Mdard methods.
Combine polymer solution 'Nith coloring agent {in dfa-
persion) and sufficient wawr. Coat W.bl.e's with colored
polymer wlutinn a!ld polish the coated tablets using
st~nd ard p;-ocedutes.
EXAMPLE2
'lablet Cores
At.:e=~mirre Moles!e USP
B.ydrypr•:ipylcellolo>n
lf.<,08(}
37.5
EXAMI'LE l
Tablet Cares
SS sw.~rl;: Add Nf
Magne>i~m 5t.:3rn!e NF
J.140
120
/uocwmio:ophc~ USP '!Q% 0)
f'.Si;:uU~phttiritJ~ 5,.i.!fati:;
USF(H)
~:-::hrnmphenjramEr~e Mi1fr~ai;e
USP i,lH)
li yrl rn>.c~ pmpy kdlu loe><
Dfoo:;i.; c~kh>m Ph~pbe.t~
Dihyd:<>l1: IJSP
S~eilric l\cj,j NF
Mcgnf"Sium s~ci11';'!€c Nf;
Pu rf fo~d W . We•~M {g}
App,m;i:na:e O;;e Yidd (·~m~>)
90,{'.IG9
lW1::itm
60 'U~ [O" 5'!< ;01;01o>"<>";ia,; OV<~;!Jo,~~ fl!>.)'!» "ode•i wi'~ "~°'~'""'i"~ oejo>C·
m~~t:. i:'"' lhi:'.' -t:U~!'. wdgh~ m O:Sf!'l.Vt.m: ivf fi~kf <:r b·:i1h
Me1hod of Manufaclure
M Blend L dl·:::Blcium phosphate dlhydrnte, 11 and hy 0
drnxyprnpykdJulase in a :mitable mixer for 5-30 min-
utes. Di~«olve lH and ethylcdlu!.:;ise in 3A alcohol and
use it to gran1;la1e the powder blend, Dry ;md mill the
5
4~777~050
gnmufation using a ;;uitable size ;;creen. Add re.mRfoing
ing>cdien!s and blend for J.·-15 minutes. Compress into
sui1abie size lllble!!i.
6
3. A dosage form of dailm Z compri;;ir1g 500 mg of
ruxtaminophen, 60 mg of r~eudoephedrine ;;ulfo.k and 3
mg of dexbrnrnpheniramim~ malente.
4. A dos.:i.g:e form of claim 1 ;:omprising 100-.'.i5%.' The tablet cores may be coate(l in n m;mner similar to
ahat described in EL1mple J,
EXAMPLE 3
Tablet Co.::ires
5 cdlulosic polymers and 0-45% cellufose ether, one or
mcire h1bricants sel<:eted from ;;tearic ad.cl, rrrngnesium
st<:arate, c;ikium stearate, waKeS, polye!hylene glycol
and magnesium lauryl sulfate, and one or more fillers
&dected from dibasic calcium phm;ph!cium Ptlusf!haw. !fAOO 95
i)ihydmre USP
5tearic aml NF 1,100 w
Magm S;rao-~te NF -lt[) 4
Purififfi Water USP (evapiei)
Aknhol :iA 50 (evapomle:<}
Appm:tim~t~ ffa!eh Weigh.t {g) 93,000 773
Appr<.»ion>tiUp H:- .)% m::w.~t0:r.:~1.r•10J~ CPir.:rc.~rY,:~ ffi,.)y ~ ~-i::3ed w!(l:5 l:(H•i.~j~-S..'1~~1~g 1:1.lJjt~t-
~n~~ :~ ~~~ •:r.:r{.: '~'d"gh(, I~~ ;:i~o~~;r;.$. n~ c1U~r. or tb::.rh.
15
21}
13
lmic polymer, wherein the. total polymer weight n::pre-
sents 1-8% of !he total dosage fm:ro weight, the totii!J
filler weight n::preseEJts 10-!3% of ~he toaa{ do3<1ge-
form weight, and the total lubricam weight represenl'i
1-3% of the total do~age form. weight.
6. A do:;11ge form of c!.:rim 5 wherein the polymer is
!00% hydrm:yprnpykdluloM:.
7. A d~age form of claim 5 wherein the polymer is
100% hydro:F.:yethyk:d!nio:se.
K A dosage form of d11im 5 wherein the filler is rliba-
~i.c cald.um ptiosphate. dihydrn.re.
9. A dosi.ge fmm of daim. 5 wherein the hibricimts
am stearic add aEJd mngae;-;ium stearate.
to. A dos!lge form of claim 5 cumpri~ing i-8% cdlu-
la.sic polymer, HJ-13% dibasic caJdmn pho~phale dihy-
drnte and ~-3% of a cumbirui.Hon of stearic acid and
magm~sium s•earate.
Method of Manufacture U. A drnmge form of da!m .rn comprising l-8%
.JO hydmxyprnpykeliulose.
Prepare tnblets< as d~cribed in Ell:ge form comprising
an analgesic.effective amount of acetmninophen, aD 35
mnou.nt of psc!lcloephcdrine c-r a pharmaceuticaUy ac-
{."eptii.ble :;alt thereof effective in redud.ug n~al conges~
tion, and an imtihlst.amicic-£ffective ru:nooot of de:-;-
bromphenirnmine or a phan.n'aceutica!Jy ;,cceptable $;l.1i. ::, hydro!lymethykellulo~, hy·
dm;o;yethylceUulose, carbo:bmmphenirrunine ma\e.1te. W
t\5
11. A d<.:?.!Jige form as claimed in claim lG comprisi11g
1-8% hydro&yethyk:ellmose.
13< A dosage form of claim 11 comprising 400 w 75(}
mg acetaminophen. 15 to 75 mg pae~idoephe!.irine sul-
fate and l to .5 mg dexbwrnphenirn.mine maieate.
14. A dosage forni of claim l2 comprising 400 to 750
mg acetaminophen, 15 to 75 mg pseudoephedrim: sul-
fate- and 1 to 5 mg dexbromphcnirn.mir!e makate.
15. A dosage form of daim 4 wherein the polymer
comprises 99-.'.i5% cellulosic polym.er am:! 1.--45% ethyl·
ceHulose, !he total polymer weight represen!.£ 10-15%
of the total dosage form wdght, the lolal filler wdght
n:presents 10-13% of the tow do8age foms weigh!, and
lhe total lubricari~ weight repre!ient,; 1 --3% of !he tot11J
dosage form weight.
16. A dosage form of claim 15 wherein !he polymer i:;
66.5-55% cdlulosic polymer and 3.JS-45% e!hykdlu-
lo~e.
11. A d~:>Sage form of daim :rn wherei11 the fiUer fa
dibrmic cr.!.du.m phosphate dihydrat<:\
13. A doo-age form of claim Ul wherein the iubdcan!s
are ~-tetio11 of ;;~earic acid llnd magnesi~m ste1m1re.
10. A. dosage fom.i of claim 19 comprising 400-750
mg acetaminophen, 15 to 75 mg psr;udoephcdrine sul-
fate and 1 to S mg de;>bmmphcnirnmine malea.te.
* * » * $
II 1111111111 111111111111111 11111 11111 111111111111111111
US 20fJ:\0049:1lKAl
(J9) United. States
02) Patent Application Publication
Havis ct at
(10) Puh. Noo! lJS 2003/0049318 Al
(-i.1) Pu.b, Date: ·rviar. 13~ 2003
(54) SUS]:'\INED RELEASE. FORMULATIONS OF
GllAWENES!N A.NU AUDlTIONAL !)Rl){_;
INGREDIENT'.j
(21)
( 2:?.)
(51)
!nvenlnr:;· R1il1er1 IJ, Davis, Arlinghlfl, TX (US);
Ul!l!ph W. Bh.11nc, Fon Worth, TX
(US); Ur.im1!d Jcllh~J K~~·s>.'L
Srnllhlake, TX (US)
Cortlospondu10~ Addrc<;..;;:
BROBECK, PHLEGKR & HARH.ISON, LLF
ATTN: lNTELLECTtIAL PfmPERTY
DEPARTMENT
D:B H STREET, N,W. SlJITE !WO
WASmNtaUN, oc .W·OUS WS}
Appl. No.: I0/!2!,70(;
Fik:d: Api~ 15, ZUUZ
ConlinuJ.tiun-in-p;W of appli<:,Hio11 No. O'i·55<1,542,
filed oil Apr. 28, :won. Dow P;i1. Nu. (J,372,152.
int. CL' .......................... A6.lK i;!!.20; Ml K 9.<22
('i'l)
The inv;;n!im1 n:hk:; <·.) ;i novd ph;irmaceiiriul :o;JJs1_ained
n:lni~ formuhitio11 ·A girnifoncsin and ai kasl tin" addiiiwnl
dmg ingrcdicnL Th<.: fornmhtion may compri_:;;.; a hydw-
pbi1i·.: pn!ymn, rr~ kr;;hly ;; hydroxyprnpyl rndhykd]1_<.> rd;,1''"
to a moJilh;J n:l<:0aeU'>laim:d tl;kii~':' fornrn-
fation nf gim.ifcni:;;in, wb·~r<.:in on~. or ho\h ponioils lws a!
kast om: ;iddiiiona! drng ingnxl[011t. Th" rnodiJkd rd<:a:><:
prmlui:t ha.', a maximum guaii't:ri..csin ;,emm cur1<.:cnlra!im1
tquivakrll lo llu! of ;,_n imm,,d[;,,I~ rd~~'.'e guaif,,ntsin 1.abk1,
and [,,. cJ.p;ibk ol prnviduig !hcrapui!ical!y ctli.:<:riv~ bw-
avaihhili1y of g,uaili.•n<:sin for at k1is! twdvc h.01ir<; ""'
100~----------~----i
80 I - - ~y'
60 ' :'J!'~'w ~~ ' ~~ ~ ~
40 --l ,.....e::: -·- •n,,,....e::.....~ ,_,_ ' " 97 i
20---~~~~~~~~~----~~~~~~
0 =-y =- i - b -l'!llllll ~ ~
1 2 4 6
TIME (HH)
FIG. 8
8 10 12
--+-- FORMULATION l
--... FORMULATiON !I
--6-- FORMULATION H!
-*:- FORMULATION IV
...,
ti;; -<'e = ....
>
"e
'O -rr ,..,.
.s·
:::::l
~
i:::::
%: ;::;·
:::i,, .... ;:s·
:::::;
~
t;:,
:i -_,l'...M
l::.J e e
(.#
IF,
:::::r
~
~ ,,,.
O(;
¢ .... -i;x:
.....
'-
':J)
t"" .:;:
8 --·: e
.a;;.,
~
~ ....
::i;::,
> -
Patent Application Publication Mar. 13~ 2003 Sheet 9 of 18 US 200'3!0049318 Al
+ +
co
r
-0::::
6
c:>
~m
(/')
0
=Cl CJ
0::: '
UJ -
t;: LL
=
c:i = 0 ,,,,.,.,. =
(1w;nu) NO!l\ffilN38NC()
Patent Application Publication Mar. 13~ 2003 Sheet HI of 18 US 2003/0049318 Al
+.+
·=
~
£_
~o
8~
"'° 0
0
ffi C)
r- ~-~
~ ll.,
t..U
:E
j::::
~ ~
I . /
~"
x
=
0 = = = = = = ,,,..... = = =
{lw15u} NOll VCLLN3'.JNO'.J
2000
1800
moo
HOO
-· ____ J E
~ 1200
~ -+-- 600 mg FASTED
~ 1000
t;:
-u~ 1200 mg FASTED
-..... 1200 mg FED
w
800 (_) z
0
(_)
600 -
400
200
0
0 2 4
"';I
;.;, -(\) ~ ->
'Cl
'E..
,:;·
t.:> -oo ..,..
Figure 12
Daxtromethorphan HBr Dissolution Release Rates for Muclnex DM
1200 mg Gualfanesln f 60 mg Dextromethorphan HBr {Mean, Standard Error)
100 l
Figure 13
Gualfenesin Plasma Concatrations Following the Admlnistrat!on of 1200 mg Guaifenes!n and
60 mg Dextromethorphan Hydrobromide to Norma! Volt..mteers in Three Formulations
(Mean$ Standard Error}
Time After Dosing (hr)
4
2
Figure 14
Dextromethorphan Phmma Concentrations Following the Administration of 1200 mg
Gualfonesin and 60 mg Dextromethorphan Hydrobromlde to Normal Volunteers in Three
Formu~aUons (Mean, Standard Error)
·-•••0••••«0-·•"""~'""'"""'"""'",."1
4 8
! I
12
l
r..........,. Reference I
.,,,..... Formulation B I
__..__Formulation U
16
Time After Dosing (hr)
I
t
20 24
Figure 15
Dextrorphan Plasma Concentrations following the Administration of 1200 mg Guaifenesin
and 60 mg Oextromethorphan Hydrobromide to Normal Volunteers in Three Formulations
(Mean, Standard Error)
-+-Reference
.......... Formulation B
~Formulation C
50
0
0 4 8 12 16 20
Time After Dosing (h:r)
24
Figure 16
Pseudoephedrine HC! Dissolution Release Rates for Mudrwx 0
1200 mg Guaffenesinl 120 mg P§~Udoaphedrine HCl
i..,....._......_,..... __ _,.._ ___ ~-- '
I' ......- PSOHJl65 (Cl.lnlcal Batch} \ ------- ~PB01-M68 \
1--,&i."- P80i ·M71 j -.............-._._._._,.,. ............ ---.-........-~-----...... ----...... ~I'"-~ ........... - ............ .:
flgurn 17
Plasma Guaifonesin ConcentrnUon Following Administration of 1200 mg Gualfenesln Along
wftl1120 mg Pseudoephedrine HCI to Normal Volunteers (Mean, Standard Error}
0 4 8
.,.,.,,.._Reference
........,. Formulation B
........, Fommlatlon C
12 16
Time After Do.ishag (hr)
20 24
0
Figurl? 18
Plasma Pseudoephedrine Concentration FoBowing Administration of 120 mg
Pseudoephedrine HCf akmg with 1200 mg Guaifones!n to Normaf Volunteers
(Mean~ Standard Error)
-+--Reference
-a- Formulation B
~Formulation C
~
i
!
4 8 12 16 20 24
Time After Dosing {lir)
US 2003/0049318 Al
SUST-\l'f•Wn Hl<~l.F.AS~: FOntVllH.J\.:HONS OF
GUAWENESIN AND ADl.HTlONAL mmc
~NGHlm§.ENTS
CROSS-RLH."lff.NCL TU Rll.AfLD
APPUCAT!ONS
[OOtH j Thi;; .1ppli":i!inn i~ a rnrilimt <1 su>.la iJJcd
rdc;tS1,: furnwbl ion for ornl ;1drniuis1r:,1ion compr::>ing
gua[J";;,n,:;,jn dnd ill kM.l one drtl\; ingr<:tfa~fll and mdhod!i or
nrnnufa.elur~ lhen:nl !ii 1rnr!icular, lbc iuvcnllm1 i:~ ui[c<.:t~·u
J<·, a susl;ii1icd rd.;asc frmrn1fation whid1 nrnintains <1 1.hera-
pcutica!Jy dkcti'v'e blood <:l\ll£.'Ullt~!io11 of guaircncf'in ;rnd
ill k:;:;J one drng ingr<::di-;;nt for 2! duratmn ur a! leas! lwelvt
hours. T!it: prc:.c\:nl inv<:Dlirni [11nh<:r rdak,.; lu a mudilil'd
n:k:i«;o;: hi-by1::r J;ihkl nrnlaining gu;,1f<:fle-~i11 . io rnudi
fow<:r cbily doses 1han !btir imm<.:di3i<.: rdea:.;s; :..:ounkr~::iarts
Mid g<:n1:rnlly adii~v<: improved I ht:.rnp;:;;lli<: t:·ffe<:! and dh-
cien..:v in th;: ti::wu !.failv .;Jo:-.<::s.
[l'.!(106] h•r namp!t, iu a "l.imtl a.rn.1 <.k<:rea.S<:s
provide 3 r:11 icnl \V.itll 3 ;;lion window of appropriate Hood
<:OtK<~lllialinn oi' !he rr1l'dicam;:fll for oplirnurn !h;:rnpyc A
l?J~J mg s1islaiued rek;i:;e tbsa-,;e fnrm, ;m lht other h;rnd,
m~y only ll,n"<.' to b" adininistcr('d to a p;,!kn! Oilce <.:h,ry 12
hn11ri; 10 adJi(:vc ihi:rnpc.i11 ic d1u:-i .. Su>aaincd n;k;1y,; do"-'1ge
forms gener,;Jl.y CDntmJ I hr, rak ur ;,dive dnig :;hc-.:>rp!inn, !iP
a.~ ~o avo~J t:X•..:c.~~i~l~ drug ab~}rptiun wh1k nrninlaining
dfrdivt h1uc.rJ Ci'm:efllr:ll lUfl '-l f 1. he d flJ _<,: lP pmvidt a fl3. ti<::nl
wilh ;1 <.X>n,o;isk:nt !herapeut1c dfcc1 owr Ml <,:;.;temkd di1rH'>lai1ied
r<:k.a&.: dos1gt: form~ g~·n<:rnl!y hdp h'llmx ,.,j(k dfocts
c1~u:~d hy a drug, Br..;:.·i:HJ'o\~ su:-.;la~ned r~le:..~-..;e tk\.o.;:ag~ fonTi~
d<:liv<:r lh<.~ drn~ in s!ovi, in•:rcmenla! amuun1s v1.,J-sus th<:
cydk' hig,l1 and low <.'l'•ilCrnlrntio11s of irnmcdiah; ffk~s"
fonmilations, ii i:> •;;i.siu for :o pnl irnl ';; body "-' dig;:;sl lh<~.
drug, Jherehy ;ivoiding Jlll(ksirabk ~i-:k-dTe·.:I!;. I'm patient:>
wh;; ~A:ff-atlrnini.~tl'r -thenpies, SllSl~im;d rde3;..c UO~age
1
J'vfa L J3, 2003
form,; g<:rioerally result in grtJ(er n'mpli:im:t d•_te t•:i lhio luwtr
.frequency of dosing, lower qu; for 1he ;,;.;;qu-.;rni»l or
1.imt:d idea:-"_; ur meu[1.:;m1t:n!:-. Mt'. wdl Kfl(W,"[] ifl th•.: arL
G::ner;i lly, s1Kh f;;rmul;ilinns nml~ in drng parrides mi);ed
with m co'""red by ~polymer materi?1l, <'r bknd ol 111akriab,
wllid1 is r;:;i;i;;lant lo d<.:grnd,11.iun or disi.nt;:;gr;1l t
llydroxypropyl mdliykd.l11Jo~, llydroxyprupvl cd lulow, ,ir
Pullubri l.o formul:m: !ms1.aincd rnkaS<:: l.ahle1s or <:H tbncby sfo,-v!y diffuf'ing lb<.~ a;;iiv<;
rncdic3rn;.;n! whkh i.>. 1..--.:mtain<:d wiltiin lb~ polymer ftlillrix.
Wil<.:ll the ~d <:nt..;rs 11 hid1cr pH rnvim11mcnt ~-lJ1.~ll af'. that
found in It;;: ink:c.tinc,.,, 1;;-,._,,<:v:.:1, il dis.-~ilv<:" tt,.,ulting in ;1
ks_" nmtrolk.d drng rekJt.;.;:. ·n, prnvid<:: bdter su.~l;iin~d
rekaso: properties in higher pH cnviwnmcrns. :>om" phar-
rnz.<:c1Hi;;:a) m11m•fodurcrs use pnlymns which di.ssolve only
al high;:r pl b, ~•-Kh as anyli<: re,;ir;:,;, acrylic li1lex Ji~pnÂ
silm:;, cellubM; an:l;ite ph!IJ;ibk, la!e, -~ilh<:r a!one tH in ('.\lrnhin1timi ;,1ciH1
tiydrophili<: polyflKrs.
[OOWJ (i(;n;.crally, !bes-.' fornrnlR1ion>. fir'-' prr:pM1.·d by com-
lii.ning \ht: m<.:di..::1rnrn\ v1ith a tlndy divided puwdn of I 11~
hydmphi!i;.: [mlyma, Of th<:: hydrnpbilic and Wiil<::f·ll1!mluhk
pulym<::rs. The.'<' ingredients ;m: mil(('.d and grnmi bled w!lli
v1akr or ari urgm·•ic ~oJ·,Tnl .:&9..:d into ubkis.
[OOH] i\_l!llou,;h these tYP'-"" uf fommlztions haw been
SH•X<:t>:ifu!ly JJS<::d In marni fa,_;l.me dn:-;;ig~ formt.; wbic!i tkm-
OflS!rak :;uslaiu~·d rd ease Jlfiljll:Eli~-.~. ! h<.:s<: fmmulalions
grncrnlly do not hav<.·. th·;; desired reka:><.: pmhk: or 'il'rnrn
(.'()Ji<:rnlrnl tOll of mcdicmr1rnl O'JU :m n:lcmicd period ot
lim-;. Tli·-;&!; S\l&li:i1wd rdl'.J'il'. rornmlmions g<.aKrn!ly r.;;~.llll
in a ddav in th<:'. app<:anmn: ut drng in !h-c bbuJ s!1<::am,
1h,:rehy 'kby.ing lh<0r:.pt:ulic <::tl'c>.:l. .Addi!rr.m:iHy, wh<::n lb;:
drug tkies appu:L iu; rm1x1mum Scrum con<:en!rt:!iun !C"'""}
b [ow~r ihan lhc maximum -::01K'~n!ra1ion t•~quir<.:d for 111<.:
rnnsl cffo:uiv,~. 1h;.;rnp<:utic rcsu!L Funhnmorc, me,<;! fomm-
lations wh1c!i claim l\<."dve hrnn pulern:y rek;o!x: almu:>t all
nf llKir drug withifl six I_() ~'lghl l·mur:~, making lh<:: fumll.l-
J;i1ion lc>.s lht:l3fh:ll i i·~:d.iy dkcl !<."!,'.. tO\VMd;, ltll: rnd ur I ti!.'.
twdvc bc·JJf p<:dt>d. Tu prcvoni blood f'<:n1m concrntrnlions
of 3.cllv<: drug rmm falling bdt•W a lhtl3ptu!icaJly effedlV<'
kvd ~.! <0>;krnkd l.imt p~rio,l!;, m;rny m in a -.;s_>iKornirn.n1 inc;1.,~se in
s1dc-dfcetc'.
(Oli12] To improve, ib .. ; r;;k<1'il: protik of -,;-,;rt;tin su:>l"in•xl
n:: ic;i_;..c dosi!g<:: (urms, some pha11T1a·-·~·u1i;.;al man u faclll r<:'rs
hav-;: mmk whl1;1_~ ;md "'']J!;1Jk;; whi.:h ,_;-;»mprit-i'~ ;, cnmhi-
na!i0n of an imrncdi1iK f<..'lc~.9-: rornrnlat10n and a su:>l~incd
t'<.'ka&; f;_c.ffmiln [mpwv"s !hr
C ---·and knglh of lum; bdure 1ht: drng app~rn, '-'>''°'Y mt:d1.G1m.:nl has di IT1;;reril solu-
bility prop<.:nics and pH d<.:poadcnd< .. :" whid1 affect i1s dis-
,:,:1hHio11 rnte, ,rnd lKllC(; tl'> bio:ov3H::i)ili!y. Binav;,[labi.lilv
,;;m a\,:,:, !>"' ~ff":di~d hy ~ rnJmher uf L1-::1m:~ sud1 a.'. th~
?,ffmtmb. 'trtd typ~s nr adjuv;m!;; u~ci, lh(; :.i_r;imJl3limi pm-
cc:>:,, c•.Jmprc:>.si,:in fore<:~. (in tabkl mltd .:hicv<: appropriM<.· bin«vaibb.ility for optimum
Hicraprnl!i~; dfoc1 ..
[OOHJ Gtiaifrncsia is kmwi!l dicm~;:ally ,~;; '.'i-(2-im:i.hux-
yphrnoxy)- L2 -prnpam:dioL l! j,; an o:pectnnnr. ~. drug
'>'<"hidi iflcrt:~s.::.;s io:::;piratury lrad lfoid s.i.;cre!irn1s :md hd]l!< 1.u
!u-:1M::1 phlegm :rnd hmndiial ~u~liuns .. lly rt:d1Jcillg the
vii;c,1si.ly of s<:cn.:1ions, gu3_ifo..,nt:::.in i11...:re3sc,.';~ the..' cfficitt]-.:y
ol a <:(1ugb fl.:llc.:x a11d ol' dli:.ry ;;e1ion Ill removing ac-::11-
mt1foted ~n~tiom; from lrn.cht::t ;iml hrnm:hi. (Ju;1ifer11::;in i:.;
;c;idily absmlx:d frum :.be: in1eslir1al lrau Mid is rapidly
md:ihilli:·'.•.:d aml excr;;kd in urine. ()u;;iftont:::crd.ion of gt11iffc:a<.o;,in, typk;;{
,mmedi;,k: 1ekaS<: du:~agt l«bkts or gu;iiF~fl<:O.~in pmvidt
r.mly a ';t;, >rl v.·indnw or ther;;peulic eJle..:iiv;::m:s:.; l[;r p;;I ielll s
r-.;s;1liiog lrl th..: varic>w; r•.Xt>gniz<.:d prubkms cksn·ib..:d
;ibov;;,
[lWH5] Nm1t uf lb•:'. prtur ar! !rn:; de.<:uiht:J a SLlHarn,·u
rdea<.e dos:J;:>,t: f,lrm C, non..: nr I h.;; prim ;ir! ha~ d1::-,n ihed ;i. susiain.:tl
rd<:aM: Joo;1g<: fo:m llr :su~l!i:.;n1::-,i11 wbid-1 !J1s a C,n,,x eqmva-
km !o !h3.t <.>!"au immedi2;1e rdo:.;ui<.'. fomwh11ion, :oppr.:;;rs in
1!J.;; bJ..xid stream as qui-::k!y ""an imm<.:dii•k rdc:a~.1: fonm1-
[;;I ion, ye! snsl.J.ins th1.:rq:x.:\1ti.c dfri..:! for al ka;,< lwdve
bnuo;-;
SlJh!MAHY Of THE !NVENTWN
[ Mll 6] Tht: pr<;;St:nl .inv<.:n!infl iwercumt:s thi: prnhkm;, ;rntl
disadvantages ilS.'illnakJ w·i1ti •:1muil :c.l1~t-.;gi.:s ;rnd de>.igns
m forrn11 l~1ion:; of modified rc!c;i;;.~ ,;u<1ikn•:';in doMge
form:-;.
[0017] This i11v<:11!it>n rdates lo a novd sust11ined fdu:sc:
pb;irnucc._11 ir.::d f0Hm1 la! ron .:nrupfisrng guaif<.:rJ<.:si n y Ix. in a mug~ of 3.bnul urK·lo-on~ (l: l) 10 abou1
niric-ln-nne (9: l ), rr1on~ pn~ftrnh!y In a 1;rngt' nl ;'I.bout
lh(CCAlHWt< (.'L:} \li about Sti::·ll<"('nt'. (6: l)., iHKl mt;:;! prt'.f·
o:rnbly in a r;in£<: uf ~l;uul l\vn-lo-mH~ (2: J) to ahotH lPUi-
\(l--(llle 0: .l}. V>/ticn a li,bk! comprisin;; the ;;ust:oind release.:
formulation ;, r:xposr:cl 1.0 an aqi..:tous mnfa1m of !ow· pH.
;;m;b as !bat four1J iu !h.c s!mnadi, !be F{llvrncr <:mnhinaliori
gels c~Uc'iing guail<:rn::;in ;iml the drng .ingrcJit:nl (p di!fo:c.e
frc·m the: gd. \!/tirn the ubk! p .. 1.'iscs lo the intc;;tiw:c- whac.:
an ;)qU·~O\J'i mtdii1rn of highn· pH is present, !he ;;d !x,:;;ins
lo :in: !cm.tr:.; ,md ;j(
kas! one additio[rnl drug ingrcdtcrll u11mnl[atcly, «va an
cxt;;ndcd p·~riod, or both
[iHH§j This invrnl i(in :1lso ent<)lllp;1sS<.~s a modifo~.d
rdt3f'C CDmpo<;iticn;k f-OJ1.iOnS
(e.g.. " !ii-laye; l;ibk1., OJ c;ip:-;uk), ;in immedi:;k [ek<1~1:
formiilatioll arnJ ;, "u:-,tai.m:d n:;k;,?;.;: fnrrmilatinn. Em;b l<1r-
rm1!Mion (0l1lpfiS<.:<; a sps:<.'ilk q·tiamity uf g,uaifi:nrsi11 ll i«. fonnu!a1nl 10 ifa;<;olvc Ul
2iquel1us a•.·iJj,_; m1;;.;Jium, sm:h a.« that found in lh.: :;lnm;ich,
lo w:.i,1in<.:cl rdtiiii'; pr•fiis_in l1l3.)i cc>mprisi:
a ;;mnbirrnrn: ( l: l J 1.u alxm!
nin.:-lu·om: (9: 1 ), more preft:tA'ht a range of ;;brnil thn:t:·
t(,+11sJ {3:2) !n abrnil_ six-1<."'H,lll<: {6:1), and mos1 pr-.;frrnb!y
fmrn ahnit two-10-mJ<.: (2: l} to abotll four-lo-on~. (J.: 1}.
[O!H9 j The: pi<.""-'lll iavcnlf()!) ~!'io rc!3_k:s to sii:-;1ain<:d
rd~a:;.:: prqn1rnl i,ms or lht: ;yp~ dc'>cxibul n. /.!JS13 tnt:d fdt: .. ;iJl bt: dt:-,nibnJ
in de!::il in ; he cnnlo;t nr 1.he hi-fayen;;J t;ihki emhrnJimenl.
[0020] Tb<:0 hi-Li_vcr labkl of lbe pr.:~ril iw>c;ntion tkrn-
nn;;1rnk:; a maxinrnm :ll (C
01
.,J ;rnd lim<.:
of ;wa[!itbili1.y in Ibo: blood sl re;Jtn 1h;11 arc <.:quivaicn! lo &n
imrncdiak n:kB"'-' tabkl .. Ibc: bi-layn t3hk1 3J'" pwvkks
susliltn,;d rd~a .. v.: ol gu;,ileno::c.irJ u-.:er ~l kasl a twdvc !i..,m·
reri(;d from one dPc~ Th-.: hi-lay f'i!rnm co11..::cnlralion kvds l&in<.'d rdcas•; fornrnla1inn, irnm·;;dLk l"dt&"'-'
tormul:!linn, nr both, Jn one ·~mbodirni;nl .. lh<.: hi-!;11-"~r wbkl
ni' lhe pr<;;.'ient ·iflv..:minn mJifll;,ins :-;;;:mm nm:cnlraliun
kveb of al kast ;me alklil1f
m;wufoduring <><1>t1innl rdc:~~.c: fonrwliilions aml bi-!ayn·
uibkls or tb<: pres-::.:nl mvcntiur1 .. An tx;impk of a maim fa~'"
tming mdhnd for a :~Lrrm1lalion w fom1
a bi.Jay.er ra!ikl. !foe: tabkl may then hc uplirnia!ly cnat..;u
'Wilh Cl rmJ.t:di··i<'. co;J!ing which f:OjlidJy di-;solve;; Pf di.~Â
pl:ff-;(.::-1: ~n ga:-ttfi1: j~J icts.
[{ll!l2J] Olhn oli_jt:cb, advan!agt:s cuiu t:mbuuimrnls nf r!1~
invrnl ion :lfl.'. o.;;1 f(•r!h in p;1n in lhc dc.;S<::riptimi wllidi
follows. and in pan, will b<.'. t>bviou:> from 1his dcs.<:npii<)!l,
rn may I:•.: karn~;d Imm the pra.:tic<;', or lht: invcnlioll.
BR!EF l}lSClUPmJN 01 Tlil DRA\V!N{;S
[OllJ24] FIC. t [c;" !low dugtam d<::pi<:!illg skps [n a \n·t
granulafrm mt:1hrnl for m;mul'actiiring th,; susLliried rt:k3se
fornmlalion of the pn;$l:nt invention.
[0025] FIC. 2 i:c. ,, How diagram tkpic1i11g :;1<.:p;; in:<. dry
grn@l3.lion mdhod tor manufa;..Turing lhc sus1airnxl rckRse
forrn\J lat ion of lb~ prcs<.:nt inv<.:nl ion.
[Oil.26] FIG, 3 is u Jfow drngrnm dcpk!ing _,;tqJs in a
m<.'.lholl for mam1fo(HJring the bi-l;,y-.:t· li•hk1 uf the pn;:s;;n1
in'lcfH~un.
l 01:!27] FIG. ~ is ~ gH1ph dcmm1sirn!ing 1hc .Jissoltnion
pmfiks or llbkos nm1pr [sing l'w\) di ffert:ll( sm;llin~d re lease
formt1l~1.inns nr ihe pn:s~fll inv hi-byef'.'d modill~d r<.~.k:t'it: tm
f gu;;ifc:n1.,·.;in t kmiwn in I ht: :;rt :iml :i hi·byned mrnJiikd rt:k;i!;.~ lahlel
lot of t!w prn;;.:m invention,
[OO~U] FH~. Hl is 20 graph dtmori:;1.ra1.ing 1Jic pb.~ma
i.:om:rn1r:11 ion of guaifrn·~sin nv<.:r tim~ {the bH 1.w<::.iv~, hour
inkrval of !!w 11 1wdv1.: hour inlcrv;~!s dc~.cribcd ;,bovo} in
b~ahby bum;m -_,•tJ!unkcJ~, from an immuJiak rd<:asc !llhld
bl lrnown tr1 !ti<~ <1l1 ;m;J a bi-by<~[ CJ modiikd reka,'i<' la!Jlct
l\\l or 1hc pn;:;,;nl iovcn!ion.
l:lHlJ41 FIC, Ji Is a gri!Jlh demnn:c.tratirig the avt'.rag<.'d
pla;;m3. ;..:O[K'.'n!rnlion uf gu,1if...,nmin ov<.~r a 16 hour pc:rio;:I tn
'27 !M,lflly lrnm;rn ''oliintccr'i from (j(l() mg b!-bycr·~d modi -
tied rckas1.: iablu;; of lhc pre.sent invention admi:1isitn:d to
fas1ing volrni!t:ei~, ! ?.00 1n:~ bi-l;;yernl mc.JilieJ rdt:a.-v..;
1;ibkl'i or !ht: pn~scnl im,~;nlimi administt:n:d l.O fa>Jin~
vo!unkus, and 1200 mg br-by who had
hem t'cd ;J. IHgh rm mc:1L
[!J035] FIG, H is a grnph dcmon«trnting the di~$<:>lu!ion
pmflk or <.kxlmmeihorph;in !!Hr :i:c. me~:;1m:d by thn~c
dill"t:ren1 haldws nr a L?C~l Cllg giiaiferi~sin .(iO mg de K·
1_mmelhorphlln labl« llVci a 12 huur pcrio;J '"" mca>,mt:J by
th(: \vcig.ht p<:fl.'.cn18gc ol' ;fo:.' ;JjJfrn::nl i'ormubiiPflS.
DI:T/>+.lLED DESCHJl'rnJN OF THE
lNVENTiON
l:lHl42 I Th~ pr<.'~Dl invenl ion cm:om pas.se~ « nuvd ;;u:s-
1.,iDg gu~ifi.:rn:;;in ;u1d ._d
US 2003/0049318 Al
b1sl onilioo \vhidi mpri~:< 3. SfX'•.:iJh; quan!i!y or g1tiuf-;;m:sin itnd mav <:-ilnt: (]: ! ) tu ;ihrnll flHlt:·llH;n<' (9: l ), more rrtit'.f:JhJy
ii raug1.; u!' a!i.:JW. !fm.:t·llHWu (J:'.:;) l_U ahoul MkllHHJC (6: l J,
and most prckrably iu :i rnn)~~ or aboul tv.-0-10-on<.0 (2:I) lu
,~[mu! four-10-ow: ('J. l).
[rnl4J] Th<.0 pn::;;;~nl uivc1Hion abo rd;ll<.0:'. lo sustai11<.0d
fcl"""'' prcpuations ,-,f tlx·. typ<0 tk&:rih-.:d abov<.'. in the torn1
ur bi- by<0rf.'.d l.abk1s or capsuks ha'v'J(lg ;1 .;-ombinalillll or
he:ub or gr;1rniks nf imm,;diat-c r-ck<.1s<' frmnuLHiou and
h<'3do, nr grrnuks of ,;.uslaint:J rtkaM: fi.>rmuhlimi. Alwrna·
1iv~ly, the su~t"im;d .rdczsc 1::)rrrHJi~!ion may <:ornpriw a
cor<: ihat [c; CMhxl by a bya of irnrnnfo1K r<.0kasc fonmJ-
!atmn In form it singk lahld. Fm Jllffj10:.;;" nf ilh1:;lr2Hmn only,
lht: in\'t:n!inn wdl h--~ dt:"'.:rihcd in ddail ifl tbi~ <:unk,.\! uf tb(
bi-fayned t;;blt:I <::mhntlimrnr. Wh<'fl th<:: emhmhm-cn! i:.; il
hi-!ay-.:Kd labkL 1h .. , labk'l is made of twY• portis.,ns: on<:
portion ·~~:)mpd.-.;iu1 ; ;1 e;ustoiincd r1:k;i.:>e fonmiblion aml a
S'-'c<.md. plJrtinn comprising ,w i.mmediak r<'ba:>•., fmmub-
!toll. ln a prderinl <:mhoJirm:ril, the al kasl ;m1.; additional
dmg ing,r;.·.cknt <.:.nc w~lc;"in.~ol•.Jhk polyrnn. in ;i forlh<'i ernhudirn;.;n!,
;h" ~usl:lirnod rek:t:x: i'ormublion m:w ,;nmpnS'-' a n1mbina-
1ioJJ uf guaifrn<.0sin and m kasl on.-: additional drug ingn:-
di·~nl, whcr·~i.n the ~ddi1io1.13.I dnig ingr~dicnl indndc<;, bu1
1 he rcol'. Frd-
;.: rabl v, the dmg mgn:dienl is lkx!mmdhnrph:tn hydrc·hm-
midc, jlS'-'Utioqibt:Jrine bydrnchlnridi;, or ;i curnht[•alinn
lh·~r~or.
[ Oil46] Uydmphifo: poh1mns suiL1bk fnr u.'i<'. in the sux"
iain.-:d rdcaS<: fornw!Mion indutk: on<.' or rnor<.' ll3.iurn! or
pMli;,H~' oo lsAil!y symhc:ic hydrophjfo; gum!-> well hS ar,1-
ci;i, grnn ;rng:1c3nlh, lm.:usl b~sn gtim, gudillt.d <.0ellii!mi1.: xuhs!irnn:s sm:h ;1:; mc11Jvkdl1i-
!ii2«:., hydrmwrndhykdlulo;;;;, bydn•xyiunpyJ mdhyb::!lu"
J'vfa L J3, 2003
].;'"""' hydrnxyrrnpy1 cdlufo:;e, hydmxye:.hyk:dluln~e, .:<1r-
bpxym<.01bykdluln;;.;; pml<:inai:1:ous .subs1am:•.'" sud1 ,1s
;igar, r·>~lin, car.ragccn, and a!ginai<::s: and olhcr tiydrnph.itic
puly1rn.;;,., ;c,w:.h "'"' <:arl)DX'.fjldymdbylt:w:, gdatin, rn~in,
:ct.in, h<::nl.nnik, m;igrn::;ium aiumimim .~rliGH<', JlOly,;an:h;i-
t·idcs, msxliliv:I surch '--kriv;,tiv<:s, gd <>lves in nrnlmlbJ q•.Jan!ili<~:' in !lie high<::i pl!
m·~ditim. wkri; 1!1~ g'.lsikn..-sin arnl the drng ingri;d11:tll iain'--'d rd1.,11s<.' of guaifrn<.0stn
and <>l ka~! one drng ingn:dicul ltmm;;;huul lhe JigtMivt:
!rat:l. Frri'l;'m~d hydrnphil.i<: rc·lvmi;rs ilH' lhr hydroxvpmpyl
rnclhykcllulo.-;;~;; ,;;uch :ts !tll\.'.<: rtrnnifo<:Wrul by The Dow
Chcrnka! c·,_,mpm1y Mld kno;vn a~. METHOCEL dlKriJSlain<.0d rdca;;;; forrmil3liou
tile hydrnrhiJi,: polym"r i:; a M L.TllOCEL dh-cr known ,hi<:h
!:'.rncrnlly d(• rwl di.'i"'ll\'( in soliJlion'i of 3 pll lidow 5, ~lld
dio:so!v" nwr,, -;k:wly in bask solmfon,~ !11M1 !he hydrophilk
pulymf.'.r. {kc11t1.'<.: the polym<.0r i:~ insolnhk in low pl-{
t>Wiirmmitfll'i such ;1,; lhn:;..:; found in g;isl.ri'° lluid, i! a.ids i:·~·;mM:
th·~ polymer d.issolvcs more ~-lowly in "'.ilul.ions ol' high~-' pl1
th;w hydrophilic polymers, it ,:ids in n:tnnling drng rd1:as;;
thmuglioul tli<:: m!esrines. Thi:; DV<'r:ill iklay,;d reka~
n::suHs ~n ~ Hh}f'>..' ~.ffcif(;n-n ~crun~ eo1x:tntr:itj-::~n (~f guaii~r1~
<::sirr.
[0049] The W'1l1:r"imililuhk polym<'rs ,;uitahle t'nr w;r;. m
lhis invrn!im1 iriduJ<::: polyauy!i<.0 ;Kid:~, affyhc re~ins,
:icryli·~ lnrn: disp~rsi.uns, cd lulu.~ 3cct:tlc phth3.l:,1c, poly-
vrnyl :.ccldrkh.
[fi!)5!}j ;\ MlS!ain<:J rcka.c<: fmrnuJalion of !fl-;:' [Jff.'<:fll
invcn1ioll lllil)' forihn cornpri~ phllfm1Ko:t11i<.0<1l ~ddi!ivo:<;
indnding, bul m11 lttmt('.d !n: Jut>ri1.:Mlls ;;ud1 a;; rrugn~siurn
<;!(~;,rnk, 1.'aki1•rn :>tcarn1c, zi11-.: skan.11.;, pov,;dcr.;;d sWMk
acid, hydmgnrnkd vegdabk ciih, wlc, pulyethykm: glycol,
:;ml mic:iernl nil; u11onnch ii~- su1.~rcis•:, la1.'Ju.S<.'.,
gdatin, sl.llrd1 pask, '<·~n;;:i.z., tr~g;t>::Mllh, povidon" polyl-'th-
yk<>rbitan, polo!Jabiliza-;:
cxcipicnb. s11d1 a~ 111.:!m;;;, rirnrmi!ol, glucc.:'il'.. l'rndUSl:',
.><.yln.~e. gdl:iclo!'<:, sii<:m:;o:, m:ollu;;-.:, xvli1d., :;..:;rhito!, <:hlo·
ri(k, sultale and pho.·;phdK s;1ll'> of po!a"siurn, ~;:;.dnim, mid
m;1_i;m,:e;iurn: ..:s
kn•,lWn lo lhns;:; or skiH in lhc ;irt, Colnr:rnt;; ind1id·~, bul M<.'.
nul limtted tn, Emn,!ld (lreen Lili<:, FD&C Rt:d #'10, FD&C
Yellow 116, l'D&C Ydlovi iflO, ._;; i•D&C Blue- #L hi '.iflt:
US 2003/0049318 Al
prdtrrcd ;:mbndim.;,rJ\, ;i ;;u:.;13.irn,d n:kil!i<: t'nrnml.3.ti·;;n for-
liler oxripriS<.''' riugne,iurn ·.;lt~r3.lc: aJJd Ema3.kl Circ:u1
Lal;('. .. Jn nno1her prdcrrcd cmlx>dirn"nl, ~ ni,;13 in·~d rckils('.
formufalion furlhn nm1pri:,iurn :<1.eantk ;,m]
rn&C Blue NI i\limiinum L;kc l}y;:.
[ 005 r! /\ sti:;J3imxJ rdc;i.se formuL;i irni nl !he present
irivem1m1 e;m compri:.;~· al ka:;J twu Jrng tr1E;rtdwm:<, al k3:t one w:ilt:r-im;nliihk roly-
mc:L l l>1J<.: plurmao:1.1fic;i] addiiiv<.· in :uiy <>fllr. 1.b.1! 1e:;uli.:< in a thn;>pcW.tul.lly c!f;;x:!iv~: scrnm
cc·m:<::n!ratinn prc·IHe for ;i foll twelve hours. ifl a pr;.:foni:d
<:emb<.)utmenl, a .'.U»lained rdeast fuffr1i.ilal!ur1 cnrnpris;.::;
from 3huul 7y::; tu 3boul 95'/i gu,1iknc.::>.in by w~ight, f.r,m1
:tbcrn! F.t l0 al'".J11t 15'.{. by vioighl uf ,~ w:ldilion~l drng
irigH"dirnl, i'mrn ahuu! l 'l l'.l ab,.rn! JO'X· hydmxypmpyl
mdhykdlu.ln:.;,:, (mm ut 0.-Yf to ahouJ l .5"X rm1gne~iDrn s!(;J.mK,
.wd from ;ilxw1 fHH 'X· !o ~.bout 1 '/~·. eolornnt h:,· weight. fo "
fll<)f( pfdnrcd embt1dimn11. 3 su>.fained rd:;;is;; t>.irmu bl [on
Clll i<: furmu la-
11011 :.:umrnls rekci:;;c ·:Jf guaifent·s[n ciml ~! lea.'.ltm1;,di l'<:er>.uc. int~si.trial ln1d) drnrig<:es. hi ;, rnou:.
lutinn ral<'. of gu;,i.t'<::m:sin I hrnughrnH th<:'.
Jig<:estive Ind lS ltm:; of prirnaiy llTl[Jllr!3.flCt UI udt:fflllfllllg
conr<.:lll1«11ions of guaik n<.,sin aH. :1 drng frnm1fa1ioll is di1!,(;skd.
[ fill53] Tu m3inlain . ol lhe :~~:f wbidi C',llilifcm."iJl can diffu>;.:. \'.'llc:n
!he gdkd pulyr:Rr n>mhirrn!iun [:.; <:'.xpuseJ tu medi1 llf a
high<::r pl!, lh,; gel h;:gins 1.0 :;lowly dis."'.llv;;: lh;;:rnhy rde.<'<'<·
rng guaikn,;>m al ,1 <.".lnlff·lkd ate.
[l!ll54] /\ddrti·:>mlly, when ;:J k:i:;l one ;;ddiliun;il drng
iDgrnlirnl is ;m;>,efil in :.he ~:ombirrntim1 of bydmphilic ;,nJ
waler· insnlullk pt•lymerf' of th(; si1sl~ined rtk,es !'mm !he gel 'Nh<::n ibe cumbinalioll gds whefl
o:pu);vo:J by the h)('d ard Llrng AJmini~lration (fl):\), !lie
5
J'vfa L J3, 2003
;;u,;t;1i.fl.cd rdc~S<: formula.fr;n m;,y h<:: frnTrnJ!Jied to mimic
th..: blood sawn pro!lk of lh>-' ,~ddi!ional drug as dcsnilwd
[n rlK dini·::ill documrnls ii led wi1ti ihe FDA Gr ;is required
hy th·~ FD/> .. In olher wmds, 1he :~u:<1'1iDed reka:~ formufa-
tilm rdeases illl11''r<:i~Hy av;;i!abk formi1btion, thcrd'Y prnvidirig ;1
l!icrnprn!i...:a!ly dfrc1[ve attllillJll or the nddiii(>nJ.l drng.
[0055) in" prd~rn;d emhndiment of Hi<:: pres;:nl inverJlion,
a :;)til
nnc-!ln-m1(. !, 9: l ), mur~' preforn!Jly
the rnngi: i;; abnt1l three·f(•-two ('.L?) \(; ;;boul ;;i>>l!Hme
{6: l ), ;mJ muH pn:forai.i!y I.he r;,rrg;;: or byJmphilic pdymtt
lu \Vilt Cf· insnlllbk pulym·~r A;; ;,boul l'
abuul fouc-to-on~. {4:1). In anmhn c:mbtidimcm, lh'.'. sus-
tained rd\Case l'urmulalic·n :.:-:imp1tses nol 1m:·r·e rtrnn alxrnl
1 ff;'.,'·· h:v·drophifo: polym"r, pr;;:l'er nm mor;; t!uri 2.5'X· or lil<.: hydm-
philic pnlymcr by w~ighL !n :tno1h;;r pr~krrd emhodimrnl,
the hydmphill.;; polymc;r [;; hydmx.ypmpyl mdhykdl1ik;"1;:
and th•:' v.:akr-iri.e ~ll op1inul
ther;;peuJic nmn:ntralinn for at lu:;t twdvi: h·.JU:S.
[005~,i I A :.;i>siain<.'d rdca';<.: fornmla1ion ,if th .. ; prt';<.'.fit
invrntion may b;; m3nufoc111r,~d a;;conling to my 3ppwpri ·
;\le me1.hnd ~nnwfl Ju I ho:;.: nl· skill i'1 !he ;;rt nt p:i:irmptiilk polymer m3y Ii<.: mixed in 3 mi:<·~r 'Ntth Ml
aliquol nf w~1u 10 form :1 w<:l grnnulal[on. Thr: gont1b.1ion
may he dried !o nbl«ifl hydmphiJi,;; pn!ymer em:;ipsuL;led
;;rnmi!es uf gu~ifer1e.sin. The rc:" iUm rni>l.ed wil.h a prnttcliv-;; cn;il.irJg whi"h
rapidly d i.o;_~ulves m dispel:it:S iu g;;slric ju icts.
[O\i37j A prd<::rt'd embodirneni t>f <1 m<.:tliod of pr<.:paring
a ,.,u;;l;iinef GUJ\lfl;.NES!N
:incl <>l»oul 2 kg of l\1ETHOCEL EWM into .;V<::n minutes dl il mixiflg .>p.c.cd of ;ihmJl
J SO !<'.PM ;rnll lll iJv,~ minul'~";
whik 3.bout 49 kl', of "'mKr ;,rr ndckd t(i !Ii;,' rni)(U .. ;onknl'.
The mixer ma-,· b,,, nm fo1 !we· adJt!i•:>nal mi1mlt.~ ln t:nrn-
pltk gr3.f\IJ!atinn. Jn 3 rlJrih;;:r prd~:rrtr.1 (;mhrnJimr.nl, th;;;
sh<>l o[f for lh<: mixer load is si..'r lO 21 kilowatt:>.
l:llOSlq The; w;;l ,-,:r;mul3linn may he'. t:mptied inln nlil tlJ,, grnrwhirion is clrinl l(> a moi<;lure cont~n! of no
rnor<,, than G.5'/~ ~ lri ~1.nulhcr prd'ew;d ernblYJirnrnt. ih1; o.>11tld
lcmp\.'.rnlirrc 1s :>O lo :1 etH·olt ot 18~ C. Jn ytt amJlhtr
prdurnd emhrnJiment, an «gi!;ilor in ihr; fluid bed bnwl m 1llrrn1gb 3 HM mesh :;c:eeu 3.nd nol more:
ih~n abom 10".{. of tll0 rcwhing gr.rnu!al.ion is rnaiac:d on .'l
I{) mesh s-;:reen. !n mic: rrererred ,;mhndimen\, the dri;;d
granufalion may he passed i!mmgh a mill tirkd with a 0.
I 09" -;i"t ."<:n:rn at ;J mill sp•.:ed of ;1h<;111 )00 1.o ;ihoii\ l SOO
RPM 3.nd a serc'"ilh ,\bout
Mlothc:r OJ> kg ut METHOCEJ .. EJ{Jr,,·1, :1ht•1H 0.3 kg ilf a
color:1lll such ""' Emu;!ld Grt:cll L3.kc o; fD&C BLlJE lil,
armu! 0.7 kg '.lf magm::sium >-'tantk, ;md ahuw. j .] kg or
Ci\RBOPO! 974P. The .;;nmhim:linn m;1y he hkrnkd J('r
aboul !hr.ct: minute;;_
[1W59] !n ;rnuthcr prd'crn:d (mL>odirn1~111 nl' a mdlmu of
prt:paring ;i. susl;1inr;d rdease formul:1lirn1 oC I ht:. pro;::sent
inv.;nl.ion m~y -.:t•mpri».:: !oJdin,; abot11 Wl kg !t> .!
C/\HBOPOL@ ':l7•1P, and ;tho1J! cH) g io ahout 2-10 g or
colornn1 into a higti "ilc:3f mixu. ff be.:
3.dd<:d, then abou! 1 kg 10 Jbt>lll L5 kg of rnagn·:;:c;i11rn
:~1.<:arn1.e is aJded "'" welL Th,, ingt,,Jicme< may be rni.\ed fm
'tbnul 1.eo In c\!J,;ul ] 2 miou!es ,!J ~ m1xirJgsp,:;:d of :.ihu1Jl liU
RPM .:Jul :moJJ lil't•!. Th<: mixiug
3ml ·:hopping speed;; m3y 1hc:n 1: .. ~ inn;;3scd to :obu1H 200
RPM wd .~(Kill RPf\·1, n:''l'''oivdy, J:<:ir abu111 !h'<.: ir1im1t<.:s
whik op1iun3Uy ahm1t 29 J.:g urw:tl<::r an: :iddt:d I(; lht: mix<::r
,x,nknls. lf mi wain i.s ;;dJt,J, lhl:ri lmm 3houl l h:g tu ahuul
l .5 kg of mngw~»ium slc:anik ;;;m IK• 3dd;;d dl ibis rime The.:
mixu may Ix~ rnn fot· t<.~n addtlium1l rnimJlfs tu compk!•:
1;rnnul:o1ion Jn a tlintin prd'c:rrcd c,;mbodim;;nt, tb·~ :;fan off
for lh<: mixn [.::;,(] is !i<:I In .? l Kil"· nr 9(00 (TM arnl 'tn inlet kmp1;ra1urn t•f ;;hou\ 3H" C.
lu .lun: <.:umenl of mi
mon.: !h~n 05'X. in f •18° C [n yc:I anntkr
prd-1.:rrcd 1.•mbo;:lim-.;n!, 11n ngil.akll' in lh<.~ fivid hn! hov;cj may
bt: rnn inrcm:iiH<:nlly dur.ing dryinf .. Th" dri<:d granu liil ion
mil)' h<.: pa<;."<:d thmu~h l mna: t hart al:{ml 3W~i. uf lht rc::~u !ting
,;ranul:o1ion coini.:;,; 1hw11gh a ll~i rn;;s!J S<:r;;;;n :rnd not rnor~
1!J~n ahm.11 rn~1, t>f th<: rcs\Jlllllg grnmJ!ation i;,; r.:iain<:d un ,1
10 mt;sh ;}i:ft('.ll. !n rnw rrcreff<::d ,;mbndimwl, the dri-;;d
grnnuhlion nrny bi~ pa.c,,c,cd lhnmgh ~ mill Jinell wi1.h ~ ,.,it:(
;;neen uf 3hnu t 0. ] (}'J" lo 3hnut 0.1 2'i" ;; l ;; mill .~peed d
;~lmu! 5U{i 10 abom 15i}O RPM and a .S<:rcw f<.:<.:d ml<: of aborn
.15 l may Ix: auy ~pproprial!..'. weigh!.
;;iho, 3fl•:J shape tkpemllng lm \b<:: d"sin:tl dmage srrenglh d
!alJleL ln (>ne ,;mlmdim"nl, the~ !abkts may Jtu1hn be
6
J'vfa L J3, 2003
].;;3,ded imo :J ,;o;;ling p;rn and mm nMted with Opa.drv
Y-S-~~-714 (supplied by Colon:·on, Inc.} ancl 3if dciccl in !!Jc:
parL
[0062] i\nuthcr nnlx>dirnrnt ot I h<: rw:lht>d t>f prqMring a
susl.fttll<.•d r-.;k3sc. formuhili'..ill of 111-.; pr<.:~<.:nl inv<0nlion nuy
curnpri;;( bkndirig the drn~ wg;;;::Ji•.onh, byumpht!i<.: pn[y-
mer, ·,i,ata in'i>'.lluhl,; pulym<::r, and an>' pbrm~<.·<;;ulica[ ;,ddi-
tivcs. Tb<; t'<.'Slll!in; b!cnd nrny lilrn h<.~ cumpr<0s9..:d inlo
lat> kl~ irnd, .if d~sircd, lil.m <.:OiOled 'Ntlh it prott:·~l ivl• cnalin1;
wbkll rapidly Ji.o;.-;o[v.;~. •H di-,.~">~f~<.~:> in gMMic juices. In a
rreforred t'mb;xJimt'.DI of ;;u ... :h a m;:'lhud, ;1hrnJ( J 2.h kg ;if
()SJAffLNLS!N DC (abnu! 9Y/. pllrily), almul 2.() kg uf
METHOCEL EWM. ablllll t .3 kgd ('/dUlOPOL 974P ~ud
abutn 0.333 kg of <1 c·okirnnt sudi as EmcralJ Green L11::1; ur
l'D&C BLUE #l m<>y be loaded inlll a JO cubic fool \i
Hlembr The ingn~dient:; m;iy he hl;:nded for ;1ho111 20
rninult:s al which tirn;: a!>uul 0.6 k,; or ma,;n<::sium :;tt:;ff."uling !o rowi 1ahkK The tahkb
may bc: any 3pproprial~ w~i1)il, ';ize, M1d shap•: dqx.:11d.in21,
on 1!11.: 1ks1r<.:d dosage f'l.n:ng,11l qf till: rnbicr. Th<:f'<: !abkt>
m3y fonti·~f bt: loadt:d into ;l <..~)ating pGri 3.nd rilm !.'.Uilled
with Opadrv Y-S·J-71 .. ~ (supplld by Cl1lrnwn, !nc.) aml ait
drred in thc: p;;n.
[{lti63j hb[r:cts t:llmJ!li.'.ing a Sll<.laint:d tdt:;>M:: formu[alilln
nf 1.fk: pr,;:;<:11l inv<:!ll inn w<:r~ pr,;p;n,;d ;rnd ksb:J t<>r holh lfl
Vtlm nnd in vivo rd.:a~.c dJMRClc:nsti<.~s as dc'iZ'ribi.:d tn
Exampks !., 2, 1md 3 ['.do,1-·. !u 1ti~ 1n vitro ks1ing, lh<:
dis.;(;fo1im1 r:Jles or 1hr;:;e 1.ahkis were <.:ump:tr<'.d <'.gilin-;l
mndifid rde3se t:ihlt:t:'. llirmuialt:tl wilhuur ;tnyfo: rt:~ifl
(LXAMFLL l), n :md the o!b1:r
I wo l11:in;;: Jll(;;.lilkd h:kb<: KirnmJ;uions 1';,bkN ,xin1pfisi ng
lh(. '.~!JeV"r a !w<:lvc hour pt:riod 1bnn any of tbc mbc:r !abkVi
(s1.:c EX/\},.WLE 1 flml 1, and FIGS, 4 ~11d S)c
[0064] ln ib;; in 'v'ivo tcs!ing, strum <:;>c guatficn,,.',ill !abkt;;
fom:rnl~kd \Vitllnlll ai.:rylic rt:siu I_~;; [~:X!~MPLE 3 ;ind
flG, 6). Tallk1s comprisrng the s;Jsl~ined r~k;i.St: forimJla·
I.inn c·f rb,; prn:.;iml invefll i<:m ~ml l.h<.'. m:·:ximum
serum cnm;..;nlralinn {C, .. ,J ni' girni!Cnt:;;in in \he:;~ subjed
was le:.;;.;; than half of 1ba1 of th<.' si1bj;;ds thking th.; imm<:-
dbic rduS<: t1ibkt:>.
[il06S] '.':. Modilkd !kkns•: ProdtJcl
l:ilOMJ! 'ih impr-:we the C'"'"· ;rnd speed of apJJedi·
US 2003/00493 i 8 A I
rm:m, c f,irmulalt(in, the imnv.~dlatc
n:k;i.v.; termub1ion. or h(>ih (k:p~.nding iipon !he d·~'>in;d
df.;;d. \:Vhrn Bsing drug i.ngrt:dienl!; r"
muhl.ion, imm;;d[;\le r~.Jcz«C f..JmwJ:niun, c•f bo1h may h<.:
formuhtcd !•_i mimic lh1: hloud senim prohk cf tbv :iddi-
1io113[ dmg :os des~:rilx'.J i1l lbc dinical do<:•;rn;;ni;; tikd wilh
lhe FD/<. ;ir as n:quird hy tlit: ri)A. lri Ulbti words. 1_ht:
stist;.; prndud nuy r1.,kM":: 1Jw "( kch( om: ,iddi-
1i0Jl3l dnig :n :1 simi13r rnk In lh<.: crnmncrcia!ly i•Vfiilabk
i'.:;rmublJO!J, th1;;r,:hy prnvidi.<.: product cmi Ix in llv.c form c·f
hi-lay,,n;u labkls, Clj!SUlt>, !rnving ti::.rninc:d rc:k:11sl:
formul:tlion compris<.:s a ·~•.)f·~ ilrnl is cusr"d by 3 Lty<:r nf l_h(;
immdiai<.: rr:ln1"' l'c·rm\llad0n. F<.1r p11rposv or 1 llllslrn1 ion
univ, lbe tffv'cn!im1 will k; J>;;:;•,:i-ihi;d in de!ail in the nmk>:I.
uf lht: hi-by<::n'.d lahld cmhudimenL
l OOM!:] Tb~: im me11rfoc,; acriv<: ~gcn lf'.
pn.:&'rvatiws, :>l<1hiliz..rs, il'> cbcd[l;;d «hf ~kiH in th<.:
ar!. In one ernlx:.Jirn,;nt, !he immediate rek;o~e byer ,;,im-
priw.s ,it ka;.,1 om: drng ingrt:dit:nL hi anulbn ernhudirrK'n!.
llle imm(;di;;t<.: rd;;;>;>; !aycr ;;ompriscs 31 kz.sl. 1wo drug
ing;1.,dkn1s. ill :ypwpyl rndh-
ylcd!ulus~ .. s.:1dium :;t;;rd1 glycc·lar~, :rnd m;;,gn1;;!;rnm skar-
a1x. lri yet <1no1_hcr jitdl:rn;d <::mhudimenl, an immeJia.lt
rck:u;r; formubii(lfl nwy comprisc al}:)til 47'7:' !o ~l:"ml 5W{
gu3ik1K~.in, about 3Yt io nbou1 42'X. micrncry»1<1!lin~ ;;d-
hdo>::<:, ;;bum .v;;. to dhou1 K'!i sodium surd1 glyrolal<.:. 3_nJ
af>:::-JH 0 .1% t.;; ;,hnut 05;( rirngn<'iillm SkMal-,; by Wt:iglJ! ln
yd am>tlier pn:t'i.:rred ernh1d[m1:fll., 2m imm-c<.foile rdease
t'ormulR.tioa mRy '.:ompri:i<; ahoui 4 7% IX• about Sc:··;; g11aifru-
;;sin. a['.{Wt Yk I(< a!m\.lt y;; or al k;;>;I ()11<.: ~ddi1iotml dni:;
ingrcdi1.,n!, .\11 42··;; micrn1.,r:1srn!lim: ;:dlu--
[use, ;,(luul 2r;;. lD abuul '.i'/- hydrnxypmpyl rnethykd!ulnse,
alJ.;;ut 3% in ;,h:;JJli H'l ~;..;idiiim starch gly<.:ulak, and ;il_1rnJl
0.'.'.1//i lQ aiXHJi 0.501 rn;;g/1<.:;;iurn Sl!.'.ilf3!!.'. by w;;igb(.
[l'M169] Tb.: hi-fay1;;r l:~hkl m;;y h;; m tho>;.; of skill m Hw arl. Ttw
n:;;u It i llQ, I ablci m O llJat llJ'.'. fac:e of <.:J.ch jl(>rtiOU if'
•.oxpt>!K:d ;1-; -Ctlb-cr !ht: l'.ljl or hut•'.lfll uf lh;; \ahk\, Of lht:
f<;;!mltin is •.;xpos1::d. ln a prcf<:rr,'.d
emhodirnem, "b'l-hylh;;r :>11
!hal thv faL« ol' 1;:.1d1 pc·r!im1 i:-; n:.pused.
[0070] Jn a prden"J mdhoJ of rnamiLtclming !hr; hi-l~yn
labkb uf ifl<: prt:-;enl invi:fllirnl a 'i~.Sl_alfleJ rdt;'L'it'. f(>Wlll-
7
MaL 13, 2003
h!ion is prqrnred an:urding lo 1~iH1.:r a wet grnmilalirni t>r
dry grnrn1la1ion method~-" d<:&:ribd abov1.'. Th<.' imrn<."Jia!'.:
rcl,;as,;: fornrnlMio11 m:iy [,_;; pt'l.'PM(od hy simply blending tbc
i:;u:iifon<.'.'itn w[!b m1y ph;urn;irni1in1! addil.ivcs. lf '11 kast
orit ;:ddilinnal drng ingredi;;nt is pre.' the in"'rnfo:nls afld hknd·.:d for
d-:•oul kn mort minui~s ~c- mak~ JJl imm-:.dia:.e rek~~
fornrn!iltio[L l'orlinll'> of the susl.ainni ;dr.; madiinc cfipabk nf fi.:.nr1in;;; hi-b1yn
lahk:ts. lri -:Jn~ emhndimenl, theS<: tah!t:tii mi1y further he
uJa!t:d wilh ;t pmleciiw !ilm whi,;h rapidly lfointegr,11ed nr
di:.;:;olves iri gastric jllin:s.
[0071 j Th,: lahkl.s may h;; m&'cl abcw1:, !lw
.: drug and rml !o t:H:•.o•.od lh<
rna.':immri -1\'/o (3::2) to ;1i:K>t1f mm:-10-onc: (fJ:l) hy w<:igtit~ aml
rnor<.: pr,;frrnbly, the r:itio uf guaifru,.:sin lt> al k;os! om;
addittOEJa! dri.1:; u1gn:di(;nt i::; nboin lhrce-lo-on;; CL 1) lo
ahuul '.::0:1 hy Vitigbt. \Vhw pn~s.t:nl m tb.;; immetli:ik
rdt:<\~. i;J.}'ne additiona[ Urug ingre-
di<::.!Jl, if pre.<.<:m, i:~ abolJ! fnur .. llMme (4: l) tu abnw (me·1n·
ou~ (I:J.), prefrrnbly, Hi<.' rntio is abou1 11im:-Jo-onc (9:1) !u
abulll ibrn: -lu-lwt> (\:2), mid morc prdcrnbly, lb<.: r:H io uf
g1Jaifom;~[n f(;. ;:J least om: additiofl;;I dmg ingn:die irnmnli;:k r<:kase forrnul:n[on whit:h
re,ulls iJrnling til
<>nt:-1.tHlW'. ( 1; l) lo about 49: l by wt:igh!, prekr;;hiy I h~ rntin
i>< :1bou1 1hr;;e-lo-1w,1 (.3::2) lo a!'!llJ! l '>: l, and rnon; prdu-
~bly, !!J,;. rnlio uf gt1aifom:sin dic;t;tin<.:d
rd•~av~ rc.rnmb1irn1 :ind lb~ immetli:m: reka.'i<: formulation i!;
;:houl li·,·~:-lrH~ (:'i: [)lo aboul ni.-w-f1i-(>ne (9: l) by W;:'tgh!,
r""l-'"-'divdy. For <:>:2mpk, in '.! l::'OO mg hi--laycr mod.!lied
r'.;k&'il.' i:;uaifr11;.:sin tabk1 of lh<: prvsrnl i11venlio11, lb'.'.ft' may
hv abnnt :wo mg uf gtli11fow.:sin in th;; imrrn:diak r1.'k<1&.:
J:iya :iml alx:-m H!J.)() mg nf giMil.crJct1srnirnxl n.:k.U>.!a[m;J n:ka.<.<:
fi>rmt1latin11 ;;nd th<:: immt:di;ite rd<'lairn;d rek:.:;c tormt1Ll-
1io11 and immc(fo:K n:ka~,c formub!ioll •.vh<.oicin ilw r~tio of
addt!i.,mal drng ingn:di<.!fll i:o ab.:,ul UlKH'.Hlll<.! ( l: l} to ahtiul
19: I hy weight, rrn.l<:r:ihly th,; ratio is of ,'tdditiom:l drug ing,r<.:di<.:n! di~lributul wi1hin l_h;;
>.U.'.laim:d rde,l.:-.<: rm rmifa1irnl .HIU lb.: irr1medi,lle n;:k;t<,e
formt1blin11 j~ ;i.hrn1t lhr<.:t'.·l(Hl[]e (1: 1) lo abUIJI frrnr·IO-rnle
(4: !) by weight, r~:~p<.:divdy_
[0074] !11 ori,o pn:frm:d o:mb(;dim,:n1 ot' marrnL>cl.uring :i
12lK~ ms hi-layer ;,u;.;1aim:d rdeJ"" gu,~ifoni:;.;in tahk1, ;,boul
1:05 kg of GUAU:ENESlN DC, 01hou1 1.5 kg of fvfETHO-
CU_ L l OM, abuw ! .2'.'i kg nl CARBOfl_lL 9'!,1P, ;ind abuul
o __ ::n1 k-,: of !.'.mer;; Id ()rt'.t:n l ;ike ur FD&C Bl .UE !fl in a l 0
<:ubi<.: foul PX. hknd!O[ for almul tv-1.:rJlY rni11uk'<. Ahml! 0.6
ki; nf m:ign<.:si1mi sk::trm~ may 1h1.:11 h·~ added ~nd bknding
conlinuvd for cobou1 l:llolh1.:r kn m1nt:les to prqMr<.· th<:
>.u>.lained [dtaei>.:' furnrnla1irn1. Apprm:inrnldy 2 l ki.; <"r
GlJA[FLNES!N DC .l[JJlf('Xim~kly 1 L7:5 Jig of micmcrys-
l:illin1.: cd!uh>.~, and 3ppwxirmitdy ,'; h:g or sodium :'.larch
glycolaic may b<.' bkndcd in a :1 cu bi<.: foot P.K bkndn for
:1!HJH! 1.wu11.y rnirwlcs. Appr<_>Xtffrntdy (U kg uf nlilgne'>11Hll
~1ear;i1_e mwy thtT• be :Jd(kd aod h!ending ,;ontimr,od for .ihoul
another l_<::n rr1irmk>. 10 prqrnrt the immtdia1_<:: rdt:;i:;•~ fc.r.
1m1l;;I i•.m, Th;; t'>vo fonmJ!atiorh m'1)' th<'n be >.:omprt:sscd lo
nrnkc bi-layer rnbkts wh<:rein tH 15··;; pf ''"''h o.h1c1 mny
ht: :.;11.'ilaimxl :el-;;~:.;;c J\irmufalinn and bom OH4 kg of FD&C BLUE #1
;n.: bknd.:d in a Hl .:uhi.: foul Day rnix<:r for ,ibnul lwdv<:
mimJk>i. Thern<'i'ln, ;,bout 29 kg or Wil!<::r l'i ;:tkkd arnJ iht:
mixrnr<.' is hkmkd for an addi1i0nal W 111i1rn!<:1>, follov,i<.:d by
drying. Aboul. -1 kg of m3gn-~';ium sti.:<1 h'-'
:iddtxl JrnJ hkml.ing umlirllJed for ahnul :molher k:n mimll.e>
In jlrt'.JJ3rt: lht: s~t.~t;tined rdca~ fomrn!at100. About 4:'.f· kg
uf GU/\.!H.'.NLSIN, al_lUlll '.\.6 kg ur lll ka,<.t Ufle adJitiumil
drug ingredient sJJcil as d(;:f
~rnJium slardi i.;lyu1J"ie are bkndeJ in a ] <.:ubi;.; foot Day
mixn fur 3hnu1_ 1.?. mirnJ\(~S. Thaeatkr" <1hou! 36 kg ot' w;tkr
is m
n;.;uat1.: m;;y lhrn t:"~ 1tddcd 1md blending com inued for about
;1nothcr kn m inllles lusiJinnl reka·-;;; formui3_ti0n and about 2:5?i if i:adi
lah!ct m3y be imm·~·;liat·~ rt:J.;;~.'-C formub1!on. The 13blus
may be ;,ny (b:~agc slr.:ngr!1, .~ize, m :..b~pe, In ;, prdcned
t:rnhodimeol, I .'WO mg lahkts afe mt1rnJ arnJ ah;iut '" im:h m
di3_111cl<.a', llhou! {) 31 inch -0 34 iw;h tn lhi<.:ktK&>, w<.:igll
:lb(>\JI [$_:'\ grnms :ind have a b3tdncK<, t~rl\~;,; of about 15-·35
SCU. In another proforrcd <.:rnbodi111<.:!ll, GHO mg rnh!c!s nn:
mund and alwlll './> ind! in Jiamder, d>nlll 0.22 iuc:b "0.26
inch io thkkn<,.:<~, weigh ':.· pH, ,;udi
a:~ thM found in lh<.: sh:::.macb, !O q1.1id:!y rd;;;_Ji'\.' th<.: r;;naifr:n-
1:sin •:m1laiw.'d wi!hrn lh<:: pnrlirni. This result,., in niptd
hi.u,iva il;:bilily -:;r f ,;uail'erir.!;in. /b
Jrn1on.~trnkd w EXAM!'l .L 6 and F!GS. 9 and Hi bduw,
ttw ii11nwtlia1'.; r<.:kas<.: purtis_)Jl ;_>f Ill<.: lii-hy;;r ublc1 r>.;;;uh'i in
a ttlHXlllllJm i;uum ..:ono-.:nfrnli<)(I (C",J Bud limo; of maxi-
mum sernm n;nc:i::nlration {Tmocxl t:qu iv;i knl ln !he C,.,,,_x
ubl,lirn-d wben tb.: Jir.~I qf llm:t: do'<<'< uf a "'"lldMd im1m:-
di:t1;; rdea.<;<.: fonmil3tion h:iving one !bi.rd tbe amm1u1 or
gu;tift:m:;.;in i:> dosed <.:very four ho-iH-s ov<.:r a 11 hour p<.:riod.
['0077 j Th~: .;u;;.rnincd rck3_"'' por!io11 gels \vbcn •.:xpo"-'ccl tu
rndia of lw.v pH 3.Jfo,,ving th<: ;;usrnin-.xl r<.:k11;;c. µor!ioll uf
th(. ub!u lo he pa~'«.:d illlo !he in!<.:stinal 1rn;.;i. l u !!Jc
inlc.~lin-;;s, the gdkd -;ustained rd<::ase r·nrttlm i~ cxpn:.;;cd li\
rnt:dia of a highn pH, c:at1sin-,; lb'-' gd !o sllfwly di;<.dincd rcka;;;,.' bi-!ay<;r
l«hkt is in..:r1.:a.<;<.:d lo mor1.: tb;in .~ hollt.', ;,nd 1b1.: tnbkl has Ml
,\!)Ci"i p.h;; ari::;i 1rnda" pl;i:.;nn com:i::ntratinn v~r.:i>l! ill thal a GOO mg li>bkr h;1d a T""'" nJt:ivaki1l
to thal uf" J 200 mi,: ~nd ~ ( ,"''' and ,r\SJC;,,r appmxirnatdy
hal.f of a ! 200 mg lahkL ·rbus, wi1h1_•1Jl ;;djusliflg or ;:h<1r1g-
ing !he <:OHl}l(c<:iiJiGll of !h!; Sl!Sli!ined n:lncS\.: fomrn]alioll Ot
hi-by;;r labkl, :l J<>Vi<;f dc~;a1~~ slrenglh girnifcfl•~o;in t;lbkl Of
th<: pr<.:srn! invemion ;;xhib[t:> pfasm;o con..::cn!rntion prolik
that is ;:ppm:om;ikly directly pmpmlional Jo th;J( ur a higher
df.Ntge :-,(rer1g\t1 guaifrnt:>.in tabkl abo uf llJe j!tC,.Cill im·efl·
1 ion. As flirt her drnwns1rated in EXA_Ml'LE 7 and flt;, H,
the hi-Liyn iabkl'i uf the prv;.;111 i1wc111ion hHJ ;1no!h"r
"lirptising rt.':ulr in !ha1_ thc C'""' aud AUC,.,1 uf <> 120.:l mg
Lihkl adminisltr~d to vnlllfll.et'.1':.; who had hte<:n t:is1ing :onin -M) mg
dex!mmcihorphan HBr formulation (•f Exampk ti w<.:n:
diR',.-AV•.;d !ur ixrind. The releo<.~cJ amc-uril
US 2003/0049318 Al
or -:kxtmmdtwrph;rn HHr wa.:" dckrmiried ;JS a Wt:i~hl
}l<.'.t"<.'r.·ni of dio;,solv<.:J d<.·xiromcH1orpllm1 in contrast K, th<::
loial wci.gll1 of dcl ahnul 86% to W.i'.li hy w;;1ghl l•f th<-: di.:nrnrncl h(1rphm1
Imel disS<:>lvcd. T!rns. ihe fonnula!ions of the inv•.;n1io11
h'[mJJl!i:ib!y rde sinul;,r lo !.he rd<.:ren<..·<-
fornwlatioo. Th<.: r<,,frrcnc1.o fprmtJ!"1ion for FIG" B 'Nios
f.xmu talion l V '.Jf Exam pk 'i. I'm rrrnlaltuu !l compri"'-'d
77-S'f, gB~a(e~es~:i hy ~ri_~]ghE~ 5.8~/b hy Y.·'~ighl d~x~rom~~ho~
rph;in, 9.1 rz. by wdgh1 niicrncrys1<1ll1w: cc!lu !OS\:, .l .'F.~ by
\v<:i~!n MET!!!JCE.L ElOM, and tl.'H CA.H.DOPOUD 974P.
F<)fmul3tinn C o::orr1prif;,;d 76 Yli by w~igti! gn31kni.:>, nf the invt:nlion diu not
inkrf-;;re wilh lhe rd<::a:>e nf gui;;fi:.u<::sin. hi r;micul;;r, ~rkr
12 hnurs Fr.1rn111!J1io11 C rcka""'d s1: of guiaf<;H-
csiu !h~n !he rdi.'.rem.:~ fomnil3fi·;in.
romm] FormulHions B illld c or l'IG. l.J W·~ft: cornparcd
Jgain:>1 a n:kr..:onco: consisting of an ''Xlo:ndcd rdc;1sc fnnrw-
!all<.m or .;Jextmmdhmph;m cummerd~lly av;;rbbk under
!h.: name Dd:>yrn ~old hy Cdlt.<:d1 Mcdirn. Tb.: rnrnirnr1S<:rH invrnlil•lJS had no durin1rnla! c:t!'cd upon the
r·.;ka·;,;.' profik uf dnnromdlmrp!rnn.
liMJ81] Ann!llcr mdhod h> moni1or d<.:xlrc•m.;thorplwn
plil!>lllirnibr dcxlWf·
phan con,ccntr,l!ions, \Vith Formu!a {." ''xhibititlQ. tile lligh;;s1
dcxlrorphan \:urKen!ra!imi af!er l 2 hum:-;. F~C. i5 lk-rnrn1-
strak:; th31_ the fomnifalinn:< ;)r the present inv,omiun nm-
iainrng gu;ukn1:sin do nc>l mhibil thr.o rd1:;is;..: ot dc:x-
1ronKllkirph<111, ~s d-.;lcrmincd by mi.:asuring the pr,;s<-:mx c)f
ibc rnci,1b(1]it;; d;;x!rorptun_
[iMJ811 Thrco: b3ldic~ or tb<.: LWO mg gu3 ifem.:c:.in · l20 mg
p'>':udo"µhdriw: HC! formub.tic>n t)f Ex;rn1pk !{l w<.:l'r.'
Jissulvcd lu dcb:rniin1: lb.: armmm of !l·""''udocphcdrirn: I l( '[
rckit&:d nv•.:r time. c;,:m:rali.y, th<:: !nrmul:Hi-:;ns h:1d I :COO mg
of gu:tikm:s[n HXi l'.!O ms pscudocphcdrln•: HCl 3.lld wi:rc
f'tucli\.~,: ov•;;r ;, 12 hou: period. Thl'. rd.;a;;..;;d :1111011n1 of
Jl-Y~udm:phdrini.: l lCl ''';1!> dct1:rrnind as;; wo;;igh; pcr;;;;nt d
dissolved p~.;eudm:phetlririe OCl ifl umtrast !n !he tula[
wi~ighl or [.'Stu(h>;:pfo:drinc I !Cl prim t<> dis>.ulult'lrL Al!cr l
9
J'vfa L J3, 2003
hour ~html 4.V.;~:, lo 45Si .. ;,!'the ps.t:wk,-.:phttlrinc HCI h:id
di~.';olv<-:d. Aft.~r 2 hours !he :ibrnH :>W.li to r,(v;;. di:;c;olv~d,
« by wcighl of !hi: ps .. ;udoq:ihc:drint !JC!
h;id .;Jis.:)rnpri . ,.~d 7Yi hy ·wcighr gu:dlrnesin DC
7.7'-X. by 1H:ig!1t ~Y><::l.ldtK'.phnlriu1:, 9'.f hy \v;;igh1. rmcrocrys-
t;d.linc -~~j.lu.!n.';c. J_.w;; by weight METHOCEL EJ.Olvl, ;md
O.'fq., by w<:igbt CARBOPOU!J) 97'1-P hmnu!a1imis Band C
cxhihikd ~imilar bd1avinr w :ii0 pan1dy ;;dmini:;ler,;.;J ror-
nrnfo!ions. !ll\ls derno11s1ra1.ing tha1 formul3.tions of iii<:
prcsnil illv~11lhm did WJf inkrkrc wi!il tbc pwlilc rdcM;c ot
[Jti>.01Jdot: ph-;;drinr ..
[00~4] Thc pln!>ma conc<-:111rmhm hir ps-~uducphcdrinc
IICl '>vns sllldir.·d 10 dckrmwc whdhtr th<.: furrm1fa1ion.> uf
tht: presenl inv<::ntion inrerfered ·with !ht: rdease prnillc uf
[JS<.:llJt1q1b<::drirn:. Hie ll"'-'uJoqib<:dririt pb~rn;i cum:n1Ua-
tion.~ frn 1h<-: forrmilation~ nt FIG. fl \;,1;;n: pi(11fcd lW<:r ;t 21
lw11r µcric>d. As ill1isHat<:d in FIG. 18, Formi1blions B 1n1d
C •Jf flG, J7 <-:xhibiJd higher p.5.<.:11do1:phcdrini.: cnnccntrn·
1inn:-; lh:m the r;;;frr<::m:t: lr.>rmul:tlion. Thus, lhe ,;omh.iri,;d
forrrml<>tiur;c; u( !he prL>;1:nl i:ivcrilirni rekaS\.: p.Yeml•.Jcphe-
drim.' in comp~rahk or bdkr r•:k.1.s.:.: prt>liks th~n formu!a-
t[nn:> C<.>nt:iiriing F''Cllducphcdrinc ;;Jori<:.
LXAtv1fl .LS
[tl\:1'85] T!Jr.' imi'-'ll!ioll is lunllu ddino;;d hy rcfrn:n apr;m:fll tu lhnse skilled ifl lhe
M1 that m:rny modi!ka!ions. bo11J to mMcrials mid rndht>d<;;,
rnay bo: prncticcd wi1hout (kp:~ning from rhc purpoc;c ~lld
inler,o,;t ur lhi:; iflvenlirm
Exarr.pk
i:mml'i_I 1\ balt:h nl' ~;1J.'rn lahl·~I:;,
LDllrlLH-'.\l i C, wilb ih<: following com[~D;.,iiiun wa.~ p1<:-
puctl:
C:l.SJ"' or·
c..lErHOCl·l EIUM
E!rn.:;~1frJ (i~~":".:..~~ L~1k~:
~:ti~) mg
3~) mg
4 mg
US 2003/0049318 Al
-r:0n1[nur:d
~ki.g~1::::s:11ffi S.tf~1~~~~I('.
Op:ldf\· Y-:>-.'·- :141 ~<
{..,;~ fflt::'.
!.'..Ill m:c
[OORT! /\nnlh"r hiw;J;iirn:d rd;:;i~ gtMil.t:ne.,in
!«hie!,.! .tMt7! Jl. 0 32FC wilh th<: rn1lnwir.g Ulmjli.t'itinn w;;-;
jH<:jJiUl'.J'
tol't\U-,.2,~t:S!~; DC
~AHHOCl·]. l·om from lo! 7LB
frc-111 lot 7LB-3'.!l:\ · w<.:t"C' tc::.tcd tot" in vitro gu,1i[cm::.;in
n:ka.~ u"wg Ml A.:idilh"'-' di.'lulion {:~li;;h!Jy 1rn1dtlk;J
U S. Pl 7LB-31 w,1:; illrn dropp<.~d
inlo c;1ch vessel
l Ol.l89] Al 1.h'-' Oil•;. llo\lf <:fld t'NG hour in1c:rvr:l1< of !1.:siing,
5 ml ;;ampk'; of d.i<;5.o!i11 ion :;ohilion \ve.r~ ,_1-·irhdri1\vr1 from
'-'Bdl vcs.<.cl :i!lidr~wr1, 22:i ml uf 0.2M >.n pl-l
w ahoul. G.R The di«solulion was nin for t<.:n mor<.~ tr:.it1rs, 2.fl
ml s~mpl<.:s being wilhdf3wn from cadi v-~;;._"<'.] at !he ·1 llr ..
?I hr, 10 hr., ;i.ml L? hr, inkrv:th;. Th<: lilkrnl t-;:imrks :~mm
each sampling illh:rval were tlicn nrn uu an !!PLC w
dct<:rmin·~ reri,,\:!l( ::;u;ij kncsin reka~cd frorn cad1 ;;,bkl ill
·~;ldi nf the ;;arnplrng inl:::tva!s.
[!)(l90J Tile sam<.~ dissolmion Ksting Pff"-~eduf<.' w.<~- p<:r-
fonm;d br 101 7lB-.12 Fe. Till' luh !~,av•~ di&<.oluti•.m prol\ks
shown below aml ckpic1nl [n FiG, 4.
v~-:::,st:"; ;! I IE< ' ;m 4 !JR ~ rm 1<) !lR 1·' rm
1.<'l 7l.B-.•I
;_t, . <.~~ :i~· 77 ~>1 :-<,"\
=
'7 _)~,I 54 75 ~: ~ ("(:-
37 s;i .·.-.. 7~ (i;;:
::) :n -ll f)'~ n .i{~
s .~{J s.:: }~: -:--'.1 0 ,, 2-~ .. \." ·19 ·: '~ ,·--:] ~
A•,1__'1}~g{:' =~-:' 3~'--~ :tl.~ i.<.ll 19.7 ~
.,
10
J'vfa L J3, 2003
-;,,:o 111. i fl 111:d
le-I 7Uk12f'C
.~5 ~"(• r _q s~.1 \~,<)
:•.1 .:.;~, ~r: :"7 ~.I Nr
.-:'.:c 3X ·Vi ~~(./ ~~5 =-~~)
-l c.-1- 3.~ -<:· .q ,:~u (-.::;
-' ,.\ . ~~} u -~-1 _i') ,,.~
6 ~3 Ji .. ~) sn ,5:. 5{.t
;\ ~-.;:- •(~ ~/~ .x~ J~,7 4~.n .'4.> 5:f.t; ~~~' '\
[{l(Wl] llotb fmmuhl!inn;., J<:mm1Mrat-d .'i'1im:d rd<:;;;,.;
ni' gu«ifr flesi ll m'l~ r :t I 2 lii>u r fA::rintl. I (;t 7! .H-'.\.?! '(' tk m·
on::.trn1d idcmkal rnk""' propnli<.~s to lot 7LD-'.HfC tn
0.J.N HC'l. Ill butknxl soh1i.i..in. h <'(lmrxi-;ir1g M ElHOCEL LlOM and nu
CARBOPOL 1,vu, mcfc ;,;ontwlkd rd<:3&c \vi1h long<.:r d111:;_ ad;on
in vivo----n !i:vorahk dii1f3<.:tcristic for ph:inn~<:ctil.ical pmd-
ud:> 1.:0fllaifliflg <'< J-i.igJ-i G)f]<_"<:fllritliml uf Ml at:tivc ingrcdi<::nl
with a shm! trnll·lir'-'.
Lxamph~ :~
[0092] A di.,milulirn1 .'<1.udy wa:~ [ 1m lu C'.ll'fl}Mft di:"-0,du!iun
rmllb; ni' k;b 7l.ll-1::>FC and 71.l!-11FC wilh .;;1irr<:n1iy
availabk guaifom.:sin r.ki,,;;;,;c form". On.: imm>:dia><: n:·ka:>-<:
lahk!. OlH.;ANJrnN Nlt nnd 1wn su~u,incd rde3.-'tib_i<.~cl<:tl t•..> ihc
.';am<: di,,solllliun study as d-csnibcd tor lots 7! .lk> l i:i: · ;rnd
'!LB-32.H. ·in Lxampk 1 abuv1:. Th<: fo!!nwin!.\ is a :~ dq)kt;:;d in FIG. 5.
OHGA.:-.:~D:'N :«:r.. lll'.\1U31D LA. DUlJ'ilTSS
.,, g ~i;~ ~ f.r ;-i.£: :-:: ~J1 .,, t~ ii;~~ f.f' H~!. ~ '1 .,. t;Jl~ifr~i~!j._:.1
r{:r::F,::d n:r::F,::.J n·l.::?.~t:d
J llr j ~ J< i ,3(,. :'.-'I
? It' ;~]_). "d 3~1
4 HR ;:J4 ,_ 47
:-: m: :'l.'\ 'r1 !.~
1;; fl!~ !!L< lf(°} 10...:{)
JC IE<. :n:; jl)) t;;_:
(OtWJJ Th1.: im1wxli@c rdcas•.; ORGA..N!D!N r·.;k~s1.:d
H~YX (lf GUBifrncsin conKnl wi1hit1 lhc fast l!Ollf or 1fo;.-;.u-
lultml. Th<'. !wn ;;1israin<::d rdease du:;;;ge forms which H<::
cun<:w.ly availabk b-:Jlb ckmom;lrnh;d ;{ slower rdt.~s·.c of
;;u3ifon~sin, J kiw;;vcr, l:-orti 1.h<: HUMmm LA and DURA-
TUSS rcka-;;<.:d gu<:ifon<.:;<.in more r,1pid!y tbJ.n dthu· Lc•I
7U3-.1 l.FC or 7U3-:12FC. Hnth HUllAl BlO L/\ ~rnl DURA-
i"U':>S wuuld, tbt:rd"rnc, cdiibil a fa:<1.er r;ik ut' rcka>~ ;rnd
thus a shmler liv<::d lhcrareutic d1~;:l in vivo.
Example-\
[0094] Tbt. in v1vu bdrnvior ·:Jf Sllslaincd rdtao-<: !ablds uf
I Pl 7LH---' 1 re ;md I .ot 71 H-:1?l:C from Exam pk l \Wrn
i:ompar<:d \(> lbt in vivu hch;wiot" of nn tmm<:d[at<.~ rckasi:
fornrnltition (ORli/\NlDIN NR}. Th<: opcn-l~.bd ~!Udy
invo[v1:d ') h1,:allhy voltm\;;<.:fS a\!Crng;ng }!fa;_! [,(}I )'<.:3!':'; uf
ag~ with;{ rang;; nl' ?..~ ye<1rs lo 5S y;;ar~ nC :tg<:. Th,; t.;1ih_i;;;;J:.;
weighed !7'.i.'i6.:t2'1.22 lh". witb a r;rngi: uf l 1D ln 210 lb:-,.
US 2003/0049318 Al
Om: suhji;;<·l w;1s t'<::mak «fld Hi<:: rtmmmkr wer-;~ m;1k. Ltch
subj1:c1 r<.:cciv1x: <.oitb<.'r one i:::nu mg dos;; of on<.: uf tb" lw0
ah_iv.~ (ks.::-rihcd q1,;Utin:.:d rcka.'"° Utbkw ur ,Wfi mg cvny
fow tmufo rm· J do:.;,~;.; o( 1.h;; immcdial<; [d\~a~ forn1ula1irn1.
[01395] Bkwl s;1mpkf' (7 ml wi1b sodium bqmrin as anti-
n,agulrnl) ·,>;~:re !akcn prior 1.0 Jrn;ini;; amJ a! "P"cllk: tflk:i-
ving. _,\11 hlnrnl s;,mpks '"1cre
d1illcd ,ind ccn:rifog<:cl \Vtlbu1 :30 rnim1h:s of bl'ing tlrnw11.
Tti~. plasma w3.,; :><.'j_larakd, lrrnsfrm;d 1u '1 polypropylcn~
lube fmzco at -1\1& C. or hdow ;Ulll siortd frnZl'tl 11n!il
hl:ing shirped t».>r g1iaifonesin ::naly:;is.
[OIH6] Th<- j!hs.rna :;19 ! Three di!forem mndi!bJ rnkase t:ohkt !ul:; \'itr<::
prcpMnl with tbc fr>lk-wing <.'omposiiic·ns:
[IHO!}j
'fob kl
fi', c_ 'C j~_i.;
(;[-AWl·>;;!';-;1-.: DC
\lt:nlOfl'.L Ew~,j
CAf\BOPOL '-'7'1P
E~n-o;;i lfJ \ c ~c.:.:ri f ;i b·~
\·fri ~l}e-t- ! u r.-:. Ste r~~·~te
j.:'.N} rn~
,:~) mg
-~~ ~ mg
1 mg
(),0 mg
t;~ ~r: i { i2~ F~'1o·m~·ki i:'r: 1',,.,,., (~r. ! c"''"' (i.f,;.:,,'~nl
, {I'~ r""p~~: 1n ! ', T, .. (~>' •. I (~r".ug/mli
7U~-3-l F\' =-•lll N::: ]J;~2 48! ]_~t; 4.!l4
7U3-3JW l."IJ ~yu.s -H/6 .. ~·-~ ~. 7l
-' iUl-.>I vr 1.51! f:>:i2.44 ~IEI~ _,_._;.j
iLB-3::ff n.7S 6.?SA~ .2Fi' l.i)fl 2n~~.rn! :t~l~.H: :;;1)1]
il 71 ll-J2FC :'.iii! J .:t/_:j"; l'Y:'.+ __ ;:;_ ~ ,53
o:mA:-.:tr.J::-.· ~.:.:. II.Sil ~J~O.. ..,,,,.+_:{ ,1.,., 11' P.!11! ~-.~Y,·<'.~·. [)_ ).·~
:_) O!-Ui/-..~U)lX '.\b'. ll.Sll ::;:-;,:c. J -~!() '13t>?).!·) li.c:'
~b.o 7LB-3lfT c. 1)7 kt? :..-::.7 4:;<: ;,74 _1,9_1
:'vfo;~i1 n ILCFC c_:_::; ; n ! ~)- ~~1 :tedn __ ~-i :t, ~· ~
,\k;:i1 O[(Co\:-.:mi:-: :-;)<. l. 7;<:i ,::_:1~-~/• I '~}.'~~.~~s U,;.:n
f'Jt~o "iUL>J H"JR 'i~i .2-~ -~(:,_~r) ~(i,t.r) +i,~ . ..:.·i
l{,it!u ?I .IL>~F! -. IR I L.{J. -"4.9~ 7_:!:_.{7 fl;.!_
[01197] Suhj.-:cl:; giv<~n lh<' ; 20fl mg l'urmuLilirn 7LB-
:r~r<.' rtachcJ niaxrnmm p!a~ma guaittm:sin ,_,._lnu::El\r;;',[ons
of !Gli-' pg;/mL in 1.25 bnurs and had mi AUCi,,r of 7(16.3
hr' f·'giml. The ,;uby:ch givtn fornml
jH~akcd l c;i1cJ ~\l';l;l incd rdt3.-'
\V<:rc !nngr:r, 5.77 !Kl'!H'S frir lb<.~ 7LB<'\2fC iolld ~'i.5(> !lours k·r
1b,: 1LB<1l !·C um1pa11.:J h' 0.8 bc•Ur.'• for the irnm;;:d[;-;k:
rde:isi;: form1Jlaiit:-i-1, OH\!J\NID!N NR.
[ l!ll98] Bntb formub1 itins 7i .H· :nFc (v.ilh both MFn !(}.
CLL L!OM ,wd CARBOFOL 'll4P) and 7LB-31H _ _' (wi1b
METHOCEL UOM on!y) crnnml 1bt rclci1>.c ol' g11,iiftn>~i;in
from the; tabk1 iXHnpan:d to til<.: 1mrn1:dut<: fl'k;;:;,1:
ORG!\!,HD!N NR. l·urrnulafrm 7{Jl.:)2! C, ;he lt>rnml;;linri
cont!J.~\aim:d n.:k;is;; [onrrnh11inn bas ;DI'
i-~'he;oc! y;,-t~:.lE:H: Cdl~~J·:O;..;'..- ( A'...-'{CEL1
:~:;.;.:;Jiuv: ~l;~!d1 {1it;t..:L· .. ~~w..: {!:XPLOT•\B~
:\'1fr~~1}C'i-rnm S~.i::.r~_;,·)tf;
SR f'nn~"'!.U l<1tif.1-fi
i_il'i\lltSE-;i~. or·
'.lUHC·Cl'I l'ill'.l
CAfWOi>Ol \l'/.ff
fmf1"c~kJ G~e-t~1 L~ke
:\1~ •~gni<:~, i um Sa.-:~:·:! t.e
r:' fllj:.!
.;ri !11.~
~-·(! m2
- mg
~-;~ ff1_~
'7 - rng
J.~.:i- mg
-' mg
..;._~t mg
fU102] Su>;3;ii11d ilck~-"><.: Forrr1ul3\io11 !IL hi-lay;;r•~·d, 600
rng lR mid (in(J mg SR
GL-\1 FE:"E:>!:'\ DC
::\~iL•·:1•...:r;,.~l;-!: :·,~1-t:- C!.'"l luic:~;".; ( /-..ViCl:r )
t·JO.~~ mg
J.:-:.1 mg
US 2003/0049318 Al
S~,d~~~111 ~i:r~!·'.,h (;l3·i::~-~11~;'=' (f.XPl.OTAB1
Mt(;;;)::_..:] r.1r:~ Sj::;w11c
SK. !:--1 .. 1·•nLthni·:1r1
ii( A.IH >.VSl:'I. DC
~llLDJOI El UG:>l
r i'3UOl.'OJ_ 0741'
!:~rw•-ild (C~{"0::-'1 ! ~1~t~
~1:1g:ctf l11~~~ :3a.:;11"<"~~t:
'~~ ~. j mr,
_::. m~
f,_;;{r.x m~;
-Â¥) mf
,?0 I~~{.
i m~
(}.~ I!!~
l {l103] The in vivo bd1:wior of "";;h of th<.'. tb1~<.: su'<.t;iifl<.'.d
rdea:'.<: lahkL~ amJ ;rn tm1rn:diab.: Pck:a:'.<: fmmublion
(O!Hl/~.NID!N NR) 'Nn<:: cnmp3.r;;d. The op1;;11-1abd :>ludy
invulv~.J l S hc;;l!hy volunleen-; avern.ging J l .67 + J l .N9
year;; of :tg1.' ;viti:J ~ rnflg<.: d 20 ye?rs lo 51 ~-·.;£•Vi r.f age. Th'"
subj;;ct;; weighed i 61 U{J +25.05 lb>.. with a r,;ng<.: ut t '.:.1 to
.?. L? lh;;. At! l.'i subiec!~. v.·ere ;tdmirnsln<::d "100 mg nC the
irr1m<.:dit!h: rek;;~ !iJrniulalion (\'(:iY 4 Imm":'. for ;j I Ula] ur l :1
hou"' in on on~: d;iy. On ;molh<.:r day, S ;;uhjccis wer('.
Mlministcn:d Susrninccl Formuli1!ion I, .tain\'.d Fonnu lil1 ion U, ~ind )'\'.1 ar101hn
5 :-;Lmr1pks (7 ml wi11:J 'inlin LS. Tile rc;-;l1li& 0f itw plrnrnrn-
•.:nklm:lic p:!rarnekrs :rnalys1s arc hdowc
TT.I'•< (\,\:0'' i\~:c~i l.' rl r\~:c,111
u1~.:: (p~)·~11]) {ht"'p~/ml ~ f:,1·~~-.J (h("pg'mj)
\lear, OR(: 2.~~5 ~) ! 1';. ; _ ~ P·
[f!W6] Stt:>t~in<:d Fnrm11l.atinris i! ludy was ruu 10 ,;;nmpar" dtsM.ilutiou
pmnks nf Formu lal1mpostlion:
(;l_:Alff'.':b!'.': [)('
\·~it.:~·,,,,_:r~·::;L~;; ~~1t.· (',_·] lwc;:~c ( /.,_\·'l{ ··=:~ .)
:·>J.111m Slt~~~.:·:111:
.::11 mg
dN mg
,?.t) mg
!'l'ti:'.'
;n:':i m~
;\ m~
!25 rn~
-' ··' mg
5.. 7 n1~~
[0108] The fol!l•willg \S :< <;urt1m3ry ot !he.: n.:'"ll!>< \<.·-tiid1
MC· r:lso dcpici<.'.d ill FIG, S.
I
-·
~ ,,
:~
l:J
J'•
"' "' '" "' !ir
Ii;
h.
Flm"'!"'!ul;.:;liH~ I
''r E.:k:~~s.ld
.1·~
4_=-i
5(J
j~
(:~
(if~
r-\-.. r~u1!,;,iti',Jf~ n
rclc-1:,i::J
-4'::,
~1!
~L.;;:
!')
n
7:!.
tJ
Fl~rf!~ulatiur1 iH F"~1md:~~~l~!1 !V
1
"( H.h:;,~c.J •·;- fi.:!c;i:-.cci
.'.~; '.':9
4~', x;
5~~ ~"
~~ : s.~
('}~~ (10
'ii.) i.•\~
7.::,, 7.1
[0109] hirmu!alilln 1" !be nt)(I IJt-by<::ttd 1.~hk!, dcmrn1-
slrakd lbc :;lnwt0 :;t n:bl!i<'.· nf guaift:n,;:.;in. 1-'ormulali<.m n ;md
Fornrnfoiion m h!!d ti:J,: fa_c;1.est rate'<. ,,f rdeaS<.~ and ~voukl,
ih·~r<.:t"or·~, exhiblt 3 bskr rn!·~ of ri.;kasc rnd l.hns 3 shoner
lived ther;1pl~lllk dfocl iri vi\'P. i'ormubi.ion P/ h.l:i a rnlr. or
idt:a:.;;_: which was L;skr limn l'mrrm!allo11 !, cc·mpri:;ing no
irmne.di;,le rd<.:aM: hknd, but .'duwcr tban hmnula!iPn !l arJd
Formulmion m, boib cmr1pri:;ing more.: imrndiale rd<.::is;;
hknd 1.h.w Fonrn1Lnioil lVC
Lxampk 6
[OHO] Tlle in vivo behifvi.or of Fnrnrn !ii Ji.on !V hi-byned
ta!>k:ls, [Hep;;red ;,:-, desuih;;;J ;;Ix'""'· i11 EXAMPU.=. 'i, wa>.
nimpar1;;d wan immedi;;f;;: n:le~se furmubli(m (ORCAl'·li-
D!N NR}. Tb'; op~cn-hbd. nw!tipk d'..l-'i<.'., rn.ndornin;d,
:2·-wny cro~co;ova ~nxly inw•h't:d :?.fi b~alihy Yt>lun1Cl:Vi ;iwr-
cigrng }j .. ) I "'9.1' I y;;;ir;; nr ,;ge wilh ;[ r.ampks {5 ml with S>:Xl[um ll<.:pHill a~- Rnli-
CGaguLm!) weK !~k.::n ~xir.r to dt>si11g. ou day;, l, +, 5, and (1.
On Day L ;iddil ional blnnd ;;;1mpl<.:s {5 m I Vil th ·'·odium
h~p;;rin as ;mliuJ3g!Jlarr1) wer<:: abn oblained :ti n.s, 0.75, 1,
L), 2, '.{, ~,-L'i, 'L''i, ), 55, 6, 7, ?', K\ ~U\ 'l, IJ,5, W_ l 1,
US 2003/0049318 Al
:rnd l~ hnurs ~lkr lhe trJitia1 du.~. OrJ Day 6, additimi;,I
hlood :"ample.;; (5 ml 'Ni1h soxlium heparin as aJllicoagi.i!ani)
we.re al,;,:1 obtaincd at 0.5. !US, I. l.:\ 2, ?A, ~5. 4.7:'l. 5,
S 5, 6,. 7, 8, f< 5, 8.75, 9, 95, lO, 11, [:'., H, [6, <>.nd :04 hum.<.
aner !h~ initial dust:. Pfasm:: 1,\•itS s~raf;Jl~d arnl !he plasma
froz.;;i uniil analyzed fot· (";\13.ifoncs:n conl•.;n1 Tb1.o r1.·suhiug
pfasm11 eoneentrntion d:i!a wns subji;c1ed 10 phumacoki:1d ic
,~ml ,;.rn!istical analysis in :xdcr to tkk:rrninc: if illc sti:>rnim~d
rdeaM: 1abk1.s r:..:rfm1rn.:d "" cc·ntrnlkJ rdcaskb ;-ll
~i~ad:./ sL~le.
[IJH2] TIK' n::~L,ling ;_irt. Jq1ic1eJ in HG. W_
[0115] The 200:JOOH mg hl·fa.yn<:d tabkt exhil>itr:J a
C ;,nJ :t .'\UCi.,f ,:quivakol !u I hat ni'll«: imm<'lli3H: rekn in J sbo:t p<:riod of I l1rn.'., V<-'1
nrnintw.ns un df·::c:1i,,,:: ·::onc:·~nlrnlion of gu:i.ikn<.:sill in the
hlood sln:a.m lt>f 3 full \\vdvc hoJJrs.
Lxw1pb 7
[0116] A ~tudy W'1S p<:ori\.>rn1,;d to cxamint: lilt: rl'.lmivc
bioaY;n~ 600 mg and («TJe L?.ll'O mg,
wi~;-,; prqxHt'd acnHding ((> !ht' folluwlflg ;:ornposi!iuri.
( il 'MH ·SE'il".'. DC : Ul:' kji
~Afr,1~x~; \'S~1~ifo~t t ·.:~: h.:k~.:;;: (j\}i~CEL PB IO~: i ! L 75 kg
-1.,0JJl.ifllO<.:d
:,rixbm :31c,,d; Olyc.,:~:e (E~.; DC
r :~·darxvp~f..1-r:-y! Mi::~hyl C dhdn',;(!"
('Ml''l'MOCi·1_ i'J:JM>
C)it·c·mer (CARBOPOL \•"/:H'~
FD&C Bfo::~ #J ;\jvmi1~~!rn L:1k< D_1:·.::;
\·-Sag~I::-.iu rn Sh:ar:~l·..:
Id ·1',lf.l:~;I SE:'. DC
~·li·.:r•.:·,·oy,,1,·clli11t Ctllock'"' (AV[Cfa l'lJ.!'!:'.1
Wdi~~!n ~tr:.!·d' . .;-(J';·.~al~1~~ (i:XPLOJ: .. \D)
~vSag·1.i::~;um Sh.:ar;,l,__.
SR fr.)!f!'!UkH~O~I
{ ol 'Al!-'L";Le>[;>; DC
[fvdfHX_l:"j1~fl'['Y: "<·:f~~j~yl c~~:.:~;i(l.s..::Â
t\ll :nm•: 'l'l 1·1r1:,1,
C(•;bcrn·~I' (CA.HBOrOL 9?-'~PI
f'D&C tllll< ilJ Abni1;,,m Like l•Y<:
\1-1~;:csiu r!! Sw,11 .:- d:;)..;.~gc fornn;, b;:~Cng: lh~~i ~ l~i:: L~c,n rn{. l(•bk:t ~x1~;1~ii~t"~iJ
:~b;.:1._.J :.'1\·i~x· ;~:--. m~!'-~~ r:.f .::;!d•. ir.~r·x!Icri: ~·::-:. ~h{ ~:1(>l; m:; rnhk I
[01I7] Tbt: ifl \'JVP hdrnvirns of a 6(10 mg tabln "umrn-
isicrcd h> V(•)uulccrs in the r.i~1 iug Sldose m1r[l al>uut :t lx .. m-c, ;;Cier d.:isir1g), ar1J !lie
l 2UO mg t;.,bkl aJrnini:~kn:d lo Ylllurikcr:; a!kr ;; litgh fa!
rncnl {com,um<:d wtibin :m n1inuks of dosrng) w;;n: cnrn-
punl. The open fabcl study involved 2 7 h\.':J.!tby ;.·.:ilu111eu:'
b~PN\:Ctl lb·~· :ig·~S or 18 aml 55. Tb~ n1bj~I..'[$ weighed 'Nil bin
[:'/{. of tbl.':if lde;il Body \V;;ighl a>< defined by Ille 1983
:\.k!topd[L;iri l jfo drnn. ·nic 27 vo!urileefa '.>.'ert: dt·,:idt:d inlu
:\ 11calrno:ri! grc-llps, 9 receiving lh~: 600 mg labld, 9 rec<:[v,
ir1g lb..: l 20fl mg lahkr '>'.'bik fasling, MJJ 9 rectivillg_ a 1200
rng rnbkl ,.tkr rofls•_imins a high fol meal for P<:riod l of ihi:
tri>ll A1kr <:ompk1iot1 of P1.:t·iod J_, Hie vcJlunl.cvf:> wu<.:
uu.<.'.<.I ttiat !he 9 volurik<:rs wbu
bad beef! f<:(:e.iving 1b~ fl()(! mg lahkl in Periud J rec<:iv<::d tile
l 2UO mg t;-tbki ·.1c·hik b,'lllnll'.l'.f \V~~; :rnipks {7 rnl \Vt!h 9.:>dium ilqnrin ,1<. m11i-
coagi.i!,mO were cikcll ~i_xnil. on~ llullr prior 10 do~ing and :ti
:;pe"ifk ifllerv;;l-; up !o lh ho:irs ;;l'it:r dnsing ii1l. 0.25, O.'.'i,
0.75, J, 1."i, 2, }, '1, 6, !<., ! 0, ! 2. l 4, and l 6 lirn1r-;). All blond
s~rnpk>, w<:re dii!bJ rnd ccrilrifogcd w•ilhin :m minute.-; uf
bdni; drawn. Tile p!asm;1 W:l'> ,;,~p:inled, 1ransforn;d lo ;·i
pc•lypropyknc luhc, frozrn ;H --20'' C or bd.:>w mid s1or0d
US 2003/0049318 Al
rrozvfl Hfllil bi;frig -;hippt:d l'·;>r "HJifrne-;!ri ~.fl:tlysis. Th,.
vollmk·~rs \V('.f(' then <;i"'•~ll Rl kas1 n scvu1 day wwdiout
pcdud (wb·~f('. no gu;iikncsin \\.W; adm!nislcr·~d to lhnn
lHJcl..;r the study} prior ro bcit1g ;.:m<;;.;ed-ov•.;r lo th1.: next
lre~lmerH grmip.
[0119] Th1.'. plasma f'rlmpks w1.:r,; <•JJRlyznl by R folly
validaicd !-!PLC m.;:il::wd. The rcs1;l1s M<.' ckpii:icd in FIG.
Ji. Thi:-; r,;;;1i1!ing pbsm;i. com:entnlio11 v. lim,: ifaU w;;-;
suhj<:cied lo Jlhoirmilcnl,;ineti1.· am1!ysi'i u-;ing no11-c·nmp:irl-
1n~fl('1! analysis wiiJ1 '>Virmonlin l 5. Tbe tesuhs or tb~
phRrm:tcokln1.:1i,; p3r:tm<.'.!vrs 11nzJysis M<'. bdo\V
T'""" cill.,,,~ Al:t"'-': T,., A~-C~oi
~·1:·r•rnibli~'1fi Ou.) (o·~(ml ~ (rir"'5;~;ml; ('irco .. J (hr"'/~~ m~,~
\1c;i:~ 1>'!11 m~ ko:--~cJ li.:-:1 JI!?.\·~" ::<,~-~_n::. ~ O;\ ?i[-.7!.
lli<.e l '..'f~~ mg, !3.hk1. Tb<.:(""'" of ttJ,: 6UO mg L~bkl ''°'af' ahutll
:;;;r;;. tll3l nf1hc I100 mg tnh!u. Tbc AUCn.,~ ol' tile 6m) mg
w.blc! wac. :tbotn 48';? 1 ~mt of ! b1; I :::ix~ mi; !ah le! and the;
AUC,,,, lli' Ille fiOO mg tab kl w,;,,, al.iow -1.fr'X·. that. oi" lhe l 200
mg. irnpmved =rnm niwxnlra!ion llf gll3iforn:sin and ;;n
incica,;cd ovenH ·~··:mn:lllrn!ion wilti lime, llicir ba]f.[ife was
cnmprorni'i>:d.
[ {112 rj The l 2.01) mg laold dcnwristrnitd th al I ht: hi.fayer
!ah[ds llf lfll:., inv<:flli('ll g,r<:ally n:duo~ lb<: fuod dTcd in
hic)a,·ailaf'..ility ,,nd .';uum concrnlr:tl [on of guaiforn;.~in. The
C,,,"~ of the L'.(Kl rng t, ahou! t02'il-. of !h~o ('"'"'' of ob<: J2(!{l mg
l;,bh:I ;idminif;lernl ting (ta!; led l:iokl). The AUC1, . ._,
Of t!J<.: 1100 lllg_ f!:d lab!ct \Va!> ;'\OOlll <)f.:·'/1. illf I ho: foslvd labkL
[0122 J T\v<.> bawbo.:;;, of g,t1 nif1.,ne~.in/d1:x1mmd !mrpb11 HDf
hi·layn lableis, m1e 600 mg and UllC 1200 mg, wtte pte·
p;ircd ncconling !o lb<: folhiwing compo.~ilion. !n th..: _)0 mg
dt:Jilf<>mclhorpb
O,\.:C YPLLO\"V :;~n
s\lumim1m L3b~ (J-~--~t~~·.;.i
'.\i ;1 ~ ·1~:~ i u 1~ ~ Si~: t mh.:
lUl.l;ll
~ .. ill
15!!
5 1)1)
14
-<.:o 111. in ll <.:d
(i11aiCci"Jo·-:.:~io:o. t'SP
Oex\rom
\.fo.·;-.._1-..·ry~ t~dj ::H: Cd li1;~-;.!:o.;
(AV!CEL l'!ilf):2)
'.\'!l·TH(X"H. l'Hl\1. i·sp
\·~;~gt~.;..'::1.i.trn~ ==tk:;~!~le~ ~F
(tlll3]
Gl~~tlf~;~e-,ii:
fk . .;_11um-Lli1·:1ff1f·i:vl-:-J~.1hi
>1he ~~!Cf\''> I :d : : ~{ c{" 11u:1:•:>.(
(,",,V[CEL rrnu.0 :
\lETWX:EL Uli\1. t'Sf'
\·~:~g_l'1C'1!LJI~~ S~<.'.':l'•"o![.L_ ,,F
J'vfa L J3, 2003
.J.5.~~\J
Jh.l
+.u::
ll.ll.IYJ
4,:i()
.'.11:1
Lil
45 .~}~j
-;_ ~-i( 1
[011..f] Th<.'. foibwin;,; is a summary uf lhi.: U>.'.X!mmethm-
pb:rn HBr Di:>.·;nlufom lbl<..' of th<.: l200 mp, gu:oi.foncs(n .. (;O
mg d0xtn1rn,;iborph,rn rnbkl f,'.su!ts which u•.; 3Jsu dq•ki<.:d
ill FIG. 12.
l-l~!"!11ula\ iur~ ! F,·1;m:_:b~~·-'".!'i1 [! F1: .. rr~·~u ; .. ~ioa II[
.. ".r fl.:k;):o;{·,J '',: n :r:~\~i{·,J r; H·lo::-i :>1iJdicd by mt'.,tsuririg th<'. plasm~
ccmccni(3Jion of gt1;1ifon0~.in, d1:x1rom~'.Lhorplliln HBr, mid
the rnctabolit<.'. <.kxtrorptun FltiS. 13-l.5 illu>lf~i0 !h"
pbsma wm:~·nlnlil>n for c;id1 drug Gf m1;1ahllil1; in lwp
f'ormul;;lions, Fnrnmlalinn ll and Furnrnla!inn C., durin.~ a ::'.iJ
hum jKtitiJ. hnm~dt3.!dy ;,,fkt ;dmimslr~!ion tbt: pl~srna
US 2003/0049318 Al
nlrn:<::'ltfatiPfl nf guaifrm,t;in f'<'.i1k'i iri ahOll1 ari hnllf, ln]-
k>ViCd hy a g,rndual pfasma i:oriccntrntion dccr,:aS<.'. twcr 24
llot1rs. I rnmcdi 3tdy a lkr ad m inisl r:o i ion, g11a i fcm:sin p J;n ncvcr <.b:r-.:a.<,\;d ((1 k:.'V; !b;in 200 ng/m! t•vcr
t:; boll!s. TIKn.'..'lfa'.f, gi1aifrn<.'.sin pfasm3 conc<.:ntr.ci1ion
grnJuaHy Jectl:ac.<:U uvi:r the nc.;.t 12 limn.~. i1b.sr11~ conccrt-
lrnl1<.m of ·:kx;romciliorpl:ian Ullr p;:;,h .
[Oi 26] A :;HJdy Y.'ii:i p<::rf[;m1<::d lo ornm1m: !tit: n:bliv<::
biocwailabili:.y of a snst<:in"d n:ka>,(; guaifon<.:sill with dcx-
lrorw::thurplmn fornm!&tion ot' tb" prc~nl invo:nti.on wil h
nonmi!, bl:J.!l.by nrnk and:or fomnk vt>luni<.:uc;. A b.H<:h of
gu;iikn(·.<;iri ~nd tlcKW.m1dbo11>han bi-foyc:r u.bk'.1, 1100 mg.,
·w;i:~ prqrnrcJ ac<:orJir1g ln the crnnpu'ii!ltm Jcscrih,;J alwve
l(;r Ex;imrk R
[0.1271 Tht: in vivo bdi~viors of lh·~ 120\J mg t>1bk1
Mimimstucd K1 voh1n!<.'<.'r;; in lb<.'. fasiing slal.<.'. (a.bout 10
ilnllrs prt·do.>;i: m1til abmH 4 boub alkr uu.'iwg} w.tudy invl1lvc:d 29 healthy vohwte.:r'i
ht:tw.:<::n !he ;;gcs uf 18 3rnl 55. Th<:: ,;1ihjc•.:I:; weighed wilhin
!'i%. d tbi::.ir lJt~l llody Weigh! a>. Jdlried by the 198:'
Mclflp(1Ji;;rn Ldc chilfl. Tbc :;9 vnltirik•~r>, >vtro: dividvl [nlu
Jw(i trrntmcm gwups ba.!f n:1),,,iving tiw l 200 mg table!
\Vllik fos1ini; 1)3 Pniod ! or th<.: lri31. bdi v\JltHJk~r '"-'a&
:tdmint&k:icd one cios<.: uf th<.'. appropriaw tabk1 Jml !b<.:n
mnm!on:d over a ·1 6 tmm rcriod.
[012111 B!d sartipkf; (7 ml wttb s<:>d1um heparin,,:; ;mli-
cc-aguhnl) w1:r0 rnken 11bmn Otit: hour pdor ((« d..:<;ing and f1l
~ll-~c.itic in!<.:rvals up lu 1 {) bnurs a!'k:r dusin!!, (ai !i.25, O 5,
0.7), l, 1.5, 2, 1, 4, 6, :-1, .l 0. 1.1., 14, r gu:tifen<.,siii and .;k xtrnm<.:1 bo-
rplHw annlysis.
[lH29] The plasma .~ampks wer-;:· arn;Jy:c<:'.d hy a llllly
v~1li<.bted !!PLC mdhffJ hy !lPD !kvekpm1;n! nno Lkm-
i11g Wny Suik: J'JO, ;\-!idd!uon, \Viscom,in 53562). The
fc~.;ul!ing pl11sma ct>!lC(;nJJ't1-cl•mpar!mcurn I am1Jy,;i;;
wi1h \Virnmoliri J • .'i. The rnomlb of lh<:: rharm;,cnki'1~ti"
pmarrH::krs amlvsic; f,x gmafrn.:sin indlld.: a T,., .. " c.r J .4?\
hr. C,,,,,, (pg: ml) nf ?. I 9n . .1\UC,,. ,._. (hrxpg!ml} u( 1'702, T, .. ,
uf 1 .. 1.'. hrs., ::nd , :m3[y;;is for dc:<-
l{(ll}1!.'.!horpllnn [ududc il T""" (1f 5.0 hf';, C"'"· (ug/ml) d
S .157. AUC0 _,: (hr~,ug/rni) of 7'1209, T~ .. '. nf 7.93 bts., :ind :;n
AUC,"r (hr'pg:irn!} of 7'i0l 6.
[0130] JY.··o [n!dH::~ ni' guaif<:n<::~rn-pseuu'.'ej!h<:Jrine !!Cl
bi-lay<::r t;,bkl~, l'!le 6{)0 mg ;rnd o!le [ 200 mg, wete pre-
par<:J :teix1rding: !o tbe frilbwir!g 01r1ipu:-,ili<'ll.
15
lFT!JOCEL EI '1\1:
CARBor·oL i!'/:~p :.;r·
HJ-'< C' Ydbw >;'·'· ''
Alu1<~i<~i1m l;1J. .. c": (i5-!~-~.~)
M?.g_n°::s.iL1m 'SH.<'.~3l{
( ;u,1lfrac·;ii~ DC (95,..-·~ )
)~·fo.'.•Dl.."! y~t~~:J; :1'!:~ '.~ ~ 1 lii:c·~\:
(/1o.\tH -~'.L Pl·nn::;
S...:.•iJiu1;; S~<'"K"~I { ! ; ;,;.i_:ddr..'.
\·fo~l~.C-Si.l1m S(o;'t:.rnl·C. si.-:-
fOLH]
G~=t·!fon 1~>ii1~ DC (9Y";.1~
F:-.o:._LlJccphcJrtai: Hl'I
Ef:,·fJrn: .. yrmp•;i :&JI !OCEL El u>,J i
ru .~ C R{:d '.'n -ti1 ;\!lw;.:.,ur.-·:
lzi.ke (.!-~--.:J/;.)
:'.''t•9.1.g;)cs.~u m ~learn:;~
{ ''·"!C:'en°::s.i1o !)( · ('-l"S~';,f
\ji.Gtcu·y~ti.~!!irii::: C.;!!1Jb~~
~xfa~rn St~~~ .;.~t. Glyc.:-i)a:e
~·l:i.£.;H;:':.~ll I!! S~..:~lt<~;i.;, ;\:'f
J'vfa L J3, 2003
I'· ?.91!
1:·.:.~ i
43)
j~_\10
~.!..~'··
~). 10tl
[tl132j Tilt: following if> a s•_inmury o[ lb<.: psc1icki(;pbc-
dm1e ! lisM>l111im1 Rale or rh':: [ 21.ftl 10 mg gu1ifr;ne~in"60 mg
[N::udoqiti,·Jrin<: !;'!ble1 resuh~ whtd1 are abn Jqitdi:d m
FIG. 16.
t\;r;nul;alrn; ! F•:·~·1Yi~!.'ilior1 [! F"r 1;;u i;,~ ;,_~~1 ll[
·~- cd;;:~M:d '> l'f:-]~:~1:-::.;:d 1)- ~ {: 1 ~~~},·fd
I lie ~" ''-1 .g •. Ii: f_lO \(' ~N . '
t· i,, tf'j ~fi .:c
1: 1 ... f)7 9~ ')()
US 2003/0049318 Al
[0!33 J The iri viv(J hehavi.ur nf the 1'.0i) mg g1i3itern::c.in
and 120 mg psi;11do<.;phccclrim; rnbkl was srndicd by measur-
ing !be plasm;, ·~':)mxnrrniion ol gu~ifonc~in. ~nd ps,;u-
doqihcdrine i!Cl. HGS. 17-Hi illusl_rnk t!H~ pbisrrni cm1cer1-
tratiun l'.:Jr uch drug {Fmmulatimi B 1i! inl
llour. fo!iowul by ~ grnd11 al plasnrn con<.~<.~nlrnlioo dccru:sc
u-v·cr 24 hour:.;_ !mrn>:'.·:liatdy afltr a.drnimsl!~linn, guaifcw:.sin
pbsma n-1rK<'.nlrillim1 n<'.ver dccrt:M,c;d ht:lnw :'OH n"'iml PY<'f
l :2 h.-,ms. Thu\:Jtlcr. guaifrrn.:sin pfasmr1 ('CHJ-..\.:ntrn1ion
o;rJdunl!y dcetl::i:.;..;d r•ver lilt: m.'Kl 11 hcn.1r;;. Pli>sma cunccll-
1rn1im1 n( pS1:uJoq1b prepared :iccording 10 the cnmposiliou dt:s>:ri[: .. ;d above
for L\arnpk W.
l 0135] The in vivo behaviors ,;fa 120{1 mo; nbkt 3_d min-
i:-,kreJ lo vdunkn:-. in the (:isling .s!ak (;d.iuul l 0 liu<.Jr:-,
pre-dn-;e un1d :ih:>u( 4 h-:;uP.; ,tfl.
,~dmin[,:.tcrcd •Jnc dos<.'. of lb<.'. appropri;11t tabk1 aml 1b,~11
rmmi!ored uvn a 16 hc·llr ptl·iod.
l 0136] Blood snmpkf' {7 ml Wtlb sodwm heparill as anti-
cT<1gu Lrnr) v.'ere l ;ikui J.hou t Prnc hour prim lo llosin;,: and ;;\
:>[J<;'.Cilic inktvals up lu ]{) huws al'kr i!"rn,·sin anJ pM::ud-:>cphe·
drinc Mlalysis ..
[ {! U 7] The Jl lasm3 :;<1rnrk~ wcr;; ari:1 ly .i:t-:d by ;i folly
valicfotnl HPLC mdhod by PPD [kvdopm'-.'.ni_ 02."\0 Dern-
i11g W:1y Suit<.0 UJn, Middk1on. Wi~. 5?\%2). The rcsul1iug
pfasma .;;om:<:ril.ralion v. lime 'fa.ta wa-; suh1<'<:h:d t•:> ph<1rrrnl-
·-··:Jkindi;.; analysis u~iug non·;.;umpanmenl;;J Mlaly~is witb
\Vinminli.ril' I .. .5. The resulh of !he pharm-Gudneph.;xlfim:
iridude a T,,,_,x of 6 hr~, C"'"" (pgiml) of JOO, AUt 'v-•~
(hr~pgiml) of 'l20!, T,.·;: of s::m brs., :rnd :in ./\UC,.,r(llr'/<'g/
ml) ol 47(V-J
[OB8J Olh<.'.f cmbod1m<.~111s and w;.;s of !h<: invention \vill
b;; appar;:;nt 10 1tirn;.~ ot sktll in U1<.0 Ml from cunsin :iml prndicc ur lht: inv;;n!ion disdo"<:tl
h<~rcill. '!'he :-.ptciJl.:;;!im1 :wd e1;:;1rnpks slmulll be C' ..)flsidcr;;ll
16
J'vfa L J3, 2003
<'.XCmjlfaf)' nnJy witb the lme sn-,pc ,rn<.\ :ijlirit Pt' tbe ill'i<'.TI-
(iOD indi1.~:At<.'.d by the fo!low[og dc~ims. As \Vil! Ix: cr1sily
urnkrstoud by 1hnsc •.J{ ski)! [n ibc 3t1, vari~tiow; ~rnl
modilici.!i•:lrn·, d c:-tch uf lhe ciisdlw~d trnhtiJirnt:rJl.s CMJ IK
t:<:sily rnmk wilfiin the ~'.(;jlC oi' !his inv<:nfinn iL'i Jeiim:d hy
t!w fo!lowing dairns
Wbn! is daim<.:d is:
l ..-<.. mrnlifo,d rde:>:;..~ tlru~ producl cnmpfr;i.rig l'ND por-
tirni:;, a riE~l pmliun rnrn11Eisi1Jf,; ~ fost quamity c-l guaifrll-
""in in ;ill im1m~diak rde~."-' forrnuhlion whcr<:in !h<0
!:~uaikncsw [l(.(<)m;;s bioavailabk in lb<.0 s11bjc<:1 "s slom~di:
and n <;nli!y of
guaikm:sin, a (w;! yu:rn!il_y ur al !c:-tsl uric adJilwirnl Jrng
ingredient, and " rnka.'ie-tkbying maifon;:;sin h:u; ~ C, .. -., .. x in :< h11m3tl -~11bjccl
':quivn!cni to lhc C,,".x c·hlilincd wllrn 1_hc Jirsi of lhrcc
dns<.'S of 3 sU1nd;ird imm<.0diak rd.e3.sc formublk-n
h~c rfl ;J !rnrrun
suhj(><.:t a,,;eord[ng w :v..:mm analysis ..
2. Th<' modillr.d rd.ease rJrng pmd1ic1 :H:o.>rdtng 1.0 cohlirn
1, wberern !h~ byJmpbilic pnlymct is a<.0acia, ~.um wi.ga·
cz.wil, loe1is! he;rn r;um. 2;\1ar gt1m, birny1i gum, modi!kd
~·dlulosic, mcH1ylcdh1k·:-<:... hydrnxyrnctbyk<.~llulu.o;.;,
hydmxypmpyl mcthyk<'.!luh<.<::, hydmxy]Jmpyl ,;;;][uln.'<;:,
hydru.\y1;;11Jykd!uJos.::_,, c:Mho:-.ymdbykdlulu.'.c, ;igar, p!0e-
1in, Gtfnge~ri. 3Jgm2ilc, t:arboxypolym<'.ihyknf., gd;iliri __
i:as1:i11, zcin, brnlllniix, magn<.:si-iim alumwiJm stlic;,l<.'.,
poly,;:u:·::hari(k, moddicd :>l:; drug prmhtd ;'.vh~rdn !li<.> 2dddioniil dni1; iug.rulirnl ic. rn anl [llJs.sivi.:. "
1'.lt:.1.:c•n::;t;s1anl~ l~fl iH1:jh~sL,rnjnr,, di1 ;~n:..-dgl;;;~i.'-.'.. or i.:cimhin;:i~
tilm:; tbert',d.
7 Tbe rnoJifo~d tdea:-ie drug pmJl.!d according ((' dairn
6, wil~rcill lb~ add1!innal dwg i11grdi~lll is d<.0K!f0ff1<.'.thur-
pha_n hydrobmmkk, .... <:>G<:inc, hydi-c,,~otk,nc, ph,:nykphri!W
hydmd1lmidi.:, pbt:Bylprnpar1o!amiu,· hydmd1lmtJe, p_<.<::u·
dnr-ph~drin<' hyJrn,:hlnri.d•.\ cph;:drimo, >:hlnrph:ninmine
nuk2Jc, hmmphniirnrninc rnnkat<.~, phcnillthrnint: lilrtrntc,
pyrifarni11~> rnak,'ll<:., -:kni:ylarnrn<; ~.\l•.xiiMk, plK11yl1olo:rnrn-
.in~. ciH:H<.0, diph·~-nhydr:m1in<.0 hydrochhiridv, prom<.0thalin;:;,
ckmasrine himnak, aspifin,_ ibiipmf;;n, at:t:t;imim,ph.cri,
llapmsin, llr '-.'.umbin;-tli' .. )ilS lbtn:;A.
US 2003/0049318 Al
R The modib:d n.~b;,:;,.: drug pmdt1cl daim
I , Iii fi h•.:r crnnpri:;ing hi ml-ors, t:ulornrib, en: ip ie fll.~, g l idaflls,
h1bri<::rnt;;, preS<:rv~liv;.>s, st.1billznf., s\iffa.A.
Hi Th('. rnodilkd rcbi&~ dmg pr·:xlm:I ac·X>rtlin2; w daim
·:}, wherei.ri lilt: luhricrnl is magm;-;iurn !ilr..;i.r:tl.<;;, .;;;1ki1irn
:;l.1;;arnlt:, 1:irn: sle:trnk, pDwtkrrd slt::tri•.: ~cid, hydmg-or.akd
vq;mbirn.iinn ih~.o<.:oL
12. Tile modifi .. ;.J n::kas..» drng pf(Ki11d a <:t>l loidal silklln dioxid<.:, I ale .. or :t
• .. :ombimliun lht'.feoL
B. The mudi!1d 1d"a~.<: drng product according lo daim
9, 'Nhaein th1;; -;urfoc1;; adivc: ~o;;enl i:> :;odillm lauryl sulL1l1;,
dio<.~iyl c;(~diurn 1>11lfost1ci:i11:1..!<: .. iricllrn110bmt1K, pulyoxy1:d1-
ykn·~ 'Y:xhitan, pnloxalkoL qtliilcrn3ry mm11,mium Si11l.s, or a
combination lll;;rwf.
14. Til<.' 11wditk.J rnk:aS<.: drng pwd11d ;HX'ording in dairn
9, wht:n:in Ille <:xcip·i~n! is rnarm·i1ol, gltK·ose, fnKlo:'"" ..
xylw,,;;, g,ibclU!it:, m;,J(l·g,,;, xyl.itol, !iorbitol, imt:1!~'.i1im chlo-
iid<.:., pt>rn&<>itm1 sulfmc, p.:.rn~ium pbusplrn11: .. ~>dium dilo-
.rid<.:, S<'•:liurn sulfat·~ .. 'Y:)dium pho:;phat·~ .. magn<.:si11rn chlo-
ridr.. lll3.f.:,fl,;:;mm !>ll.1f~l.e, m;J_IJ,flE!iicom pfin:ijlhdlf..,
mi•::mcrys!:tllim: ;:dluluS<.:. sodium st:trd1 ;;:lyn;l;ilc. m .<: drng product according lo d:iim
I, whet·cin the lirsi pmliun furlher u;mp1 i'•"" rninrn:ty:~l~lÂ
litl(· <:~·llukisc_ Vldiilm ,o;tard1 glyc.\Jiok'., aud rnagn<:f'tllrtl
;;t .. ;arnte"
.17. Tile moditkd n:ka;;;z: dn1g prod\1ct nc:cording 10 d3im
I, wher,;iri th1;; lu!al q1i;rntil.y of guait'i:n~-;iri if; fr;>m .ihoul
600 mg lo abm:! 1200 1T1g.
rn Tilt: mudii[,:;;j n::ka:-;.;: drng pHxJm:I_ accordirig lo dairn
l. who::rcill I lw rntio t1<1l quanlily ol !;uaikncsin tu the
addiii .. ~1rnl drng i~~ from .. 1bout 1: 1 10 8bou1 4: 1 by w1.,igh1..
}'il_ Th('. modilkd rd:..:;1,,,; drug prod11ct a~·rding 10 dairn
I, whert:in the r::l in nl" ! he tnUI qu:rnlilv ol' g1J;Jif1;;rit:sin 1.u iht:
addl!i· .. Jmil drug i-; from about 3:2 lu Jboul 9: l hy wtoighl.
20. Th1;; mndifi;;d rnka>;<;; dmg prrnhod ;i"cordirJg In d;iim
1orl7, wbcr1.oin lh<: rntio n( lh<: Jirsl qu;rn!ily of ;!;tJaifrncsill
w !he :<;<;; dmg rrrnlm:t ;i<:cc·rdin:~ 10 d;iim
I m i 7, wbcKiri lh.: ratio oi" Jbc Jli:..;! q1J:rnti1y -:if guaifenesiri
IP lht 'i<"-:t>nd q1i;rnti1y uf gu:1il"t;n1;;:;i11 l .. ~ i'rnm ~.hDIJl :'. .. ) IU
,11Ju\ll i: Fi.
22. The moditi .. ;.J rd<.»l\S<.'. drng ~:r<.'~'ording, 10 dairn
P, wbcri..:in gu:i1kncsiu witbin Hi~: iabkl !J3s :t C""" d Jl
l;;;i~l .!hrn11 19(){) ; 1,·hidi lurm a htiaycr
(;1hkL
17. The rnodilicd r<;kns1.' drug produc! aixording !o claim
1, whcffin th<.' <;<»~·oml portion i;; coat<.»d hy ~ fayer of !h<.' iirst
pt>rtion.
28. The modified rek;i:;t; drug pr;xlud acumllng ln daim
17, -.d1l:1eiD !be >-.<:cPnd prn1i()fl n"mpri_c;e~ !'mm -,in.
2!). t\ motlifhod relt:;::;..o dmg prrnJud ·~:nmjl[i:;irig two
pt>rtions, a firsl pLlrlimi cornprisiag a firs! quanti1y uf
!;•nitcncsw n1 ~u wm1<:d1ak rdc;1v~ l'nnmibl ion wh;;rdn !Ii<.:
gu:1if0n<:1>i11 h;comc~. bioavaiL,bk. ill tb<..' subject-~. stom<1d1:
anll a .'it'.•.:nnd poll ion com pr if>i[lg ll :-.:cmid quarili!y uf
gu.~.ifom;,;ir. ilr.d ;iJ lea~l nrie add!tinnill drug ingrt:dieril in a
sustain<.:d rdcfo>.c form
,,,.-hert:in lbt: guaifrn"'siri bas a C'""" in ~ hum.ni >.Hbj<:ct
cquivakn! lo l!ic C.,,,,x nhiaiud when th,; fa~! o[ 1lir~~
dusc" of '' <>i;1ml<1rci immc:diak rdca~.: tornmlaiil>ll
llavin;; on~i lhird 1h~ an~omi! of g113if<.:n~sin !s (foi;~.d
ev-or}' him hrnir~ ffi<'f 3 I .? limn p1;; ri.ml 3.mj ..,,, hen: in l he
pmdticl prc·vid[s a 1.hcrapei.ilica!ly •:ffeciiv•: hin~vai!,
ahk ,;u3.ifoncsin dt>s1.i kH al kasi iwdvc hours afl<.»r <1
~ingk dl•c'i!.'. 1f1 i1 human si;hjccl according lo c'<.011llll
amlv:;is aml a l.haapuiti;:;illy effet:tive hi·:>availahk
lio.~t c.r lb~ ,1,!Jirim1al drng ingn:dien!.
30. The mndi.lk;;d quanti1y of gi1,1il'cm:sin is frurn ,~lx:nil
(J(IO Hll', 10 abou1 l 20() mgc
J l. Th~ rnodilicd rd..:ns..: drug produel accnrdu;g to cla ill\
29, wher<:in th1;; addi!infl;;l drug ingfedienl [-; aD anlillrnsive,
a lkcunge,,lafll, all Mllihislamifl•:., Ml mulgc.',ic, ur nirnbina-
1 i .. m,., H1<.: rcoL
32. Tbc moditkd rdoa;;o drng producl according iu daim
3J., whcrdu the :tddi1ion3I drug ingrc;Jic:nr i.s dc> d~irn
:29, w.krcirJ the ra1io ot lh<: !cud qu:mtily uf gu3ifcm::>in to
!Ii<: nddilit>nlll drue, i:> from about t· 1 10aboi11.4:1 hy 'Nc:igbL
35. The rnudifi~J n:ka~ drn;::; prrn.lL<<.:I a.:i:ording h> dairn
2'), whendri the P.liD or lh;; lnl.al qu;rntily uf g11aiferit:sin IU
!ht'. ;iddil it>n;il drB~ [:; fmm ahtml '.'.:2 lo ahlllll ':I;] by WeigbL
36. Th·:; nK,diJkd r·.;k<1sc drng prnduo.:t of cbim 19,
wti•~rcin the rnli(> of lhc tir;..( qu;rn!ily Of gu&ifc;n1.::>in (O !he
><.;<.:Pnd q1H.ntny uf .su;.irc:n;.:sin i>i ahoul 1: l ''-' nhuu~. l :'19.
37. The: mmlillnl rek~s.::.: Jrn;::; JHrnJud In dciirn 29,
\Vhaein tht· nliu or Ihle lire~:. qu;rntily of guailem:sin lo ltn;
><.;<.:(>ild quan!i1y uf gu;,irc;m:sin tS ahmn 2:3 tsJ aholll l:l').
38. The im>ditied rd,: a&: drng pfodu~'l aci.nrding 10 daim
3(1, 'Nh<.T.;in gu~iknesin hJs ,, C,.,,, .. from abnut !(;«JO to 2500
pg/ml anJ irn AU( ·,"r (lf a!K111! 'i(iOO to K7'i0 hr~,<f <:I. least 1900 ng/ml
and H1 AlJC,
0
r of al. k3.>il. 70VO hr*pg/mL
4if The m0ditkd rck~·"' drng produ:.::t ;,,;,:o;ding 10 daim
3(1, wh<.,rein !he C:lH1tfcn,;:'>in bil'> il C' . .,"~ of i1bou1 tiOO hi J.:250
pg/ml ;mJ ~n Ali( ·,,.r ('f almut 2?100 l.o 4.'175 hr~pg/m1.
41 Tile mudi(i.;;d rdea>..: drni,; product di.tkd n.::k""" drug µ;odud a1.,~'0iding 10 daim
10. wlJ,;rcin 1hc '•!,u;ii kncsin h:os 3. h:iff Hf;; of a1 ka~t rllre(
ho~;.~ a,.. dch:nn{;·,,xl by s<::rnrn rn,ily.sis.
43. The mudili<:d idea>..: drni,; prod1KI Hmlially pln11u lay<.,rs wbii:h form 11 bihyn
l:ibkl
+! Th('. rnodilkd rck3'>-~ dmg prodi1d <1<:<..'<)ttling tn dairn
29, wherein !h<: ~nmd purtinri i:c. ;.:u,," llrsl
IJOf!l(iil enmpri:«: fornrnla!tc·n \vher<::in gu;,ifenc-;in
h .. xo>1m::s bioavfii!abk: !n lhe subje<:t ';.. siomad1; ~ml 3 second
por1ion <.::ompri;..ing :1 c'C<::ond qi1nnilty of :;;uaif.;;ne::.[n &~d ~Â
fir.;I quaDI ity oC ;JI ka,;t m1e addi!ilm;;l Jm:<'- ingreJie:nl ill a
;..m:laincd rcka.'i<: lorrnu!~tion
wh.:;ein the ratiu of !Ix: ffr,,1 qL<':'> of 3 i;l;mdard imml:diMe rcknsc furmu talion
bvirig um; lhird lhe amnunl uf gu;iifonesin is uu'4:d
every 1~'tlr h::t m:cnnliu1; to .';i.:rnm ;malysJs and a
lhernprnli<.:0.
'·v·her•:irt 1he ;id(i.i: ion~I dru~; i11gr·~dicn! is d(;X!rnrnuhorph;iri
hv1Jrobr<.,rnid1:, <.'od': inc, hytlro<.'U( J:2 lo ;1[xn1f 9:1 hy 'Neigb!.
55. TIJ<.: drug rck~s'' produd i•<::t:. product m;cordins t0 d3.im 48,
wlicr~in the .;u:;ifenesin is ;i.bout 80U lll l :'.SO pg: ml and
;h~ AUC,,f i:s frum ahml 2?li)(l lo -Bi'> ilr",11g..1m1.
59. The dru" reka:;;; pmdm:! m:conliDg tn daim ~'.
whcn:-in ihe gu~·[l'cm:sin C,,,"" [s al least wnn pglml Mld the
AUC,.,r is ~t kasl 3:100 hr'.fl!!/rnl.
M}. The time. n:kas<.: product "'~~'<.wJing to daim .:18.,
wlindn the gt1,:lfon1.,sin !13.:'- 3. b:dJ llfo of at leas! 1hrcc !lours
;;,.. deitTrnined hy : .ncenlrnlton pwlik t,f FlC. Hl
US 2003/0049318 Al
ii!\. A md.hml -:;r 1rn;i1ing nr prnvwling nmghirig J.rnJ
;;ymplums or dis,;11~i; ili;&H:'i3kd wilh ·::m1ghiug whid1 ·::om-
pr.iscs 3.dmillisl.cri11g In il ';Jil_~icd in need nf ';uch 1rcr.1mn1I or
prtv<:n!ion 3 thcrnpnnic;:!ly or pwphyladical!y dkc1ivc
3ffWlifl\ nC ;J drug n:k.'Y:>1.'.i~:1ed wilh nH1ghing in lh<: ;;uhjt:cL
67 Th·~ mcihnd :iccurding lu d.aim 66, wherein 1h~ drug
rdca_'iJ.: prodti.~1 is admin.iswrd ornlJy_
Ml The mo.:lbod :t .. :cordillg lu o.:bim (:,(), w!Jc:rcin IJK
hydropllilic pol-;..-m<.:t· i;; a1.~a_ci.<, gi1m 1f~_1;.1·.:r.n!k k•ct1;;1 :x;;.iJ
gum, _l]:ll2tf gum, kar:yr·mpyl methyl~
,;d !ulnw., liydroxypmpy 1 ccl111ln.~e, hydmxyc lhykdlu low.,
carboxymci.tiyl<.-\'.llulosc, :og3r, po.:u.in, carra1>,ccn, ali;imtK,
c;;rhoxyix>lyrncihylcu!.'.., i~~btin. ·::3sdu, zcin, h<,:nJt>uiK,
1rn1gmcsiurn ,1!tnninum ~-ilk,1tc, pulysardiarid~., msxlifkd
~t;;n.:li tkrivalives, nr a comhinalim1 tli.;;rrni'.
69. The mc\li;xl 3crnrding tn daim 66, wher.;;rn the
w;il_er~in:-;oliihk polym.;;r is fl''ly:;crylic ~tcid. :!•._TyJt,· ri::;m,
:icry!ic blcx disp!'.ic;ion, ;;c1!ii1o;;..: 3.c~t:ile phtha1ak, polyvi-
nyl i1Cclak ptithalill<,:, tiydruxypropyl m~1hyl·~':;H•.Jlosc ph1ha-
!at<:, or 3. ·::ombinal ion 1hcrcof.
10. The mc!hod .t•.:<:0rdit1g to r!i.im 61.i, wlicr(:tn l_h<:
hydropliilic polym<.'.t' is hydrt'Kypropy! mdhy!cd!ulus<.c mid
lhe \4/otlt'.f·inSC•liJhJc f,nlymt'.f IS i!fl iH.:ryJi(: rt:sin.
7J. Tht: mt'.lhrnJ ;.,:nlfding l.u d.1im 66, whlCrcio lhc f\r.>1
pnninn (unht:r compris;;:;; :ll. k;i:;I one hil qualltt!y of gu.t:contl ymmtily ·:Jf
,;uaifon•:sin is abutil l J 10 about J :49 by \V;;\~;ht.
/IL The rn,:thlod ;11xot·ding to daim <)(1, 'Nhi:rdn gu~ircnÂ
,,~-;in within llw tah[d ha'> J. c .. ".~ of ai h;aSl abuut 1 ()(_10 .Hsiml
and an /\UC,"r or al kll'i\ ·moo lu-~pg/rnl.
7\l. The meihnd m;.;:unlirig lo t:l;;[m 66, wht:rein lhe scc:uml
pPninn comprise-; ahH1! 'h'.'{. w J.ln>u! 9'.i'X bv wn~bl <•f
19
J'vfa L J3, 2003
gu.3.iferiesin, l'rnm J.bnut l '.'Ir l.o <-lll W'X. o!' th<.: hydt·o-
plli Ii·~ polymc.r, illld nbuul 0.5?;. tn ;1bou1 2.5'!( wat·s-in-
solubk pt>lymcr by w0ighL
§it A 1nl'.lhod mpri:«irig two
plltl t(>Jls. 3 fii.,_,1 por1 t(HJ ..:om pr i".iug '' hrs\ q:.ia nti1y of
gu,1ifon'-"iin in ing a second qu~nliiy of
guaifew:::~in, a l°ir'il ljUalllil_)' uf ;:! !;,;3:-;( Ufl'c iiddiltrnl'.l] drn~
irigr<:dicol, ;rnd "- rt:k~:;o;-tld<1..yirig ma1ri.x,
wticr<.:in ihc ;d0;1s0-dcbying rn3trix compfis<.:s <1 hydro·
philic poJymcr and a wmcr--ins<)[ubk polymer in a
wdghl rat in oi' hvdmjlhilic pnlvmer l.O Wii.lef·lfl.~U]ubk
pulyrw::r fr um al},JUI_ l: l !o about ;): l,
\Vhcn:ill !ht gt•aif>:n<.:'>ill has ii C"'"-' ill ~- [l\l!ll,~ll s-iib_i<.'.d
o.:quivabl! lo lh<: c"""· oh1ained wl;.;n the Jif'i! uf lhr;;,:
duses of a S(MKbrd im medi;;t;o rekaM: formula!illn
having om·. third the ;;m;;ufll nf pii!ilenesin i:; dnsi::d
ev.:1y fom huur~ ov~a- a l 2 hrnn period, aml rde11eettlically el1;.;,·1ivc hiu:w:1ibhlt: gu;i\kn~sin (].;;~
for <:s 3se.,,x:ia1cd ·wi1h o:iugiling \vhkh rorn-
pfi,'.{:s Bdmirnslcr1ng ro a e>•.Jbj!.'.cl in need n{ f'.t!<:h trcatmrnl ur
prtv.;;n!inn ;i !hcr;iptulically m prc·phyLictic;lly dl't'.!.'.tive
amc-un! of ;'! drng rck<1:-;t: pmtllld having [WU pt•r!illfb,
wh-crtin a lk'l pm!tc·n O.:C·mpti""'"';: fo:-;l quamily <·f guaifcn-
;;sin in an imm<.:diat<.: rd.ca;;,; k·rni which bccc•rm:s fully
himivailablc in lh<: sul:-jcd 's st;;rri:i..:h mxl . or ii f't:rndanl
irmnediiHgk do:;c in a Imm Ml :~uhjci:I actunli11g tc· '>'-~rum iltli:lysi-;;.
82. Thr.: mdhod ritwrdin:;, w daim l.fcr..:d tdin,1 10 cbirn 81, 'Nh<:ro.:in !lie
bydrqptiili:.: p<:, hydmxym0lhykdltolosc, hydmxypmpyl mC!hy!-
i:dlulosc, llydruxypmpy! cc!!ulu;;,;, hydm:i.:yvthyk;,:llulusc,
C3tboxyrnd hykdh.dnsc ag3r, pn'li!I, G3mtg:.:cn, nlgitiat<.:,
carl.>n.1:ypulym~·\bykr1t:, gshtin, G1seir1, t:ein, berJ!miite,
rlli!!;rlt:Simri alumirrnrn s[fa:a!c, rmly>.acdJ~rtd<:, mndilkd
slardi dt:ri'. ;ilivts, '·'r a :.:umbin;i1im1 tbcrcoL
US 2003/0049318 Al
R4. The mcl.h-:;d :i<:,:nrding ln d<'.im Fi!, whernni th"-
wa1cr-inwh1bl1.c pulynv,cr [:~ polyncryli<.' ;i_r,'id, a1.~rylic n.:>ifl,
a·::ryl.!-: hwx dispnsiou. cdlubsc '1·::d<1t~ pllllliibl.c, P''IY'·'i-
r1yl aL·u;ik phlhnL:k, hvdmxypmpyl r1ic1bykdlulm;,: phlba-
!at;;, Pr a .;.;.;>mbirrnl ion Jht:rec·I'.
85. Thl: mcfr1ud a1.·cordini:; k1 d~im 81, wb1.:rcin th<;
hydmphihc polymer i,; hydwxypwpyl mdhylcdlulu"-'.: ;md
ill,: \Vntcr-insolvhk polymer i:> Ml ,,,;rylic resin.
20
J'vfa L J3, 2003
1i!f0c Tht: m<::1hod ;H:nmJirig 1<' daim in, wh·,,n:in lht rnliu
of tbc lirst qumlliiy iA r;,uailrncsin tc. 1h1.· S<.:...:oml qu;~mi1y of
g1i:oi.kncsiu [;; ;ibolJl J: t to nbnul t :49 by 'Ncight.
g7. The mdhoJ ;w.:rnding lo daim 8l, v,.fo:r<::iri guaifon-
i.:;;in wilhin th<:: tablet ha:> ;1 C'""" or al least 20hou1 J 9f1Dpf;_iml
,ind Ml /\UC,.,.- of Jl ki.M 7{lf;{) hr*pg/m l.
II 1111111111 11111 1111111111111111111111111 111111111111111111
US 200:1021'.'i:'iOKAl
(J9) United. States
02) Patent Application Publication
Havis ct at
(10) Puh. Noo! lJS 2003/0215508 Al
(-i.1) Pu.b, Date: Nov~ 20~ 2003
(54) SUS]:'\INED RELEASE m•" GllAffl<:NESIN
COMHINATION UHlJGS
(21)
(22)
(5.i)
!nvwl.or.s: n.~ilwrt 0. Davis, /\rlingl<;n, TX (US);
R>ilph \.\', Bh.1m~, h•rl Won.b, TX
(US); Uumdd ,i{'.ffn:'J Kt·y~r.
s~imh!akc, TX (VS)
Correspnmlen<.:e ./\,tklre.>0;:
HUNTON & W~LLIAMS
INTELLECTUAL PROPEftTY BEPARTMENT
1000 K STREET, N.W,
SLllTE LHHl
\'\'~'\SHfNCTON, DC 2fHi06-Bil9 {US)
Appl. No.:
!ibJ: Apr. 15, 1003
Ci,ntinu:tiion-in-pan ,_,r ~ppliulion No. i0,'1.?J,70·:\
tiklJ on Apr. 15, 2002, wllkh is" 1X•lliim1a1ion-in-pm-t
or 3ppHc,,1ion No. (fi.l.'.))i.K .~l UTi
(:'i'l) j\BSTR/1.CT
The inven1ion rd,11i:s lo a novd plliomw1x,u1[;::nl t110diJkmpri:;e a hydmrhili.in, in a rati<• rnngr
ot ,1boui l1m:-10-om; {l: t) to abr.-u1 nin<:-10-t>l!l'. {'J: 1}, rnor<:
prcf<-'flbiy il r,Hlg<.0 of abolll l!Jf(;(;-10-l\'i(o (?>:2) [O abou!
!>t:«lC•"C.llt: (6: l), and mm .. ! pn.:forably in a rang\'. '.lf alxrn!
l.W(J-ln-om; (.'.:I) lo ;iholll fou.r-1n-D!le ( 4. l) hy weig!:iL "Ibis
foErm1lation <.'Spabk of pruvklin;;; 1h.:;rnp.::utier1lly df;;;;tiv<:
bio,1v:i.iLthill1y d g,uz.ikncsin for M ka;;t twdvl'. hours aficr
dt>sin~~ in a tlilnmn subjl:cl The invn11ion aL'itl ro:l11ic.:s io ;1
mndilkd reka~ pmdud '••1hich has lwi> pilrli(;ns: a Jlr:;I
pur!ion baviflg 3."fl irmnt:Jidli: n;ka:Â¥: rur muJatirni or guaifrn-
i;;;in and '' :;..;.:;oml portion h3smg 3 ;;ti;;win~d rdc<~;;<.: forrm1 -
fo1ion c-·f gu~if<::n<.:sin. wher<.,in om' or bo1b portions for!hcr
u1mprist:s cicxtrumdhurpbmi. Th,, moJillnl ;cka.'.<.: prmlw:!
lrns d ma.xirnurn guaikn~sin ;..<.:rum <.:onccnl.r;,l.iun c4uivakn!
li> lh;;I of an immedi~\e rdea~e g1i3iii::m:.';in labld, ;;rid i:;
cfivaiLI fwdvl hour.-. alicr do.«ing i11 :J
hum.!
i ~{\ ~
~
20-
1) -
·~-~---~--~ ~"--"' ¥ • '""jt
·-~-~-"~~-~--~·~-r··-.:-~- .
a 10 i2
TIME {t,ffi}
Patent. AppJkaOon Publication Nov, 20~ 2003 Sheet 5 of 45
0
LU
Figure S
~ 00-i--~~~~~-~-~~--·~-.....-a
0::
"#..
Q ....+-~---r.....,._.-"""""""lr------··'·---r·:
4 g_
Wl4E (HR)
·-' --~-
US 2003/0215508 Al
~ ORGAN[}!.N NR
---- HUMlSID lA
_...., DURAfUSS
Patent Application PuMkation NO"'<', 20, 2003 Sheet 6 of 45 lJS 2003/0215508 Al
Patent. AppJkathm Publication Nov, 20~ 2003 Sheet 7 of 45
Tl.If AflE!l. DOS£ {HR)
US 2003/0215508 Al
:::ii.~i:'P.~E ~
1 -~- MO\.llfl:ORElfJ\Sfl _.,,,.... 1ID'JrU Ffi£~t U ,
-it- M-01)1.f!ffi RB:tN>E.'li I
Patent Application PuMkation NO"'<', 20, 2003 Sheet 8 of 45 lJS 2003/0215508 Al
:Figure 8
-4- f ORMULAHON !
-*--- fORMUtAT!ON H
-1.- fORMULAt!ON !!I
~ FORMiJlATION !Â¥
· G ~-._---r-~·--,.,1,........,_~~1"'"· ~-~--1""""""~-1
1 2 4 6 10
1IME {HR)
Patent AppJication Publkat.ion Nov. 20~ 2003 Sheet 9 of 45 US 2003/0215508 Al
ioooo _l ___ ,_., _________ ._ .----~-----------------~~------------------·--
--·--~~
~ !MMHill\1E nELEASE
-~ IAOOfflHJ !lil.Eft.SE
j(l 1i
Patent. Application Publication Nov, 20~ 2003 Sheet 10 of 45 lJS 2003/0215508 Al
j
I
rn -;------..-------~~----------.---·-----~~-........,------r-- -~~--l
~ ~ fj g ~~ 12
11MOHrn oo:,WlG (~!Ri
~-~ IM!.tfOLATE Rl:lfASC
-->Ill- MOO!flED flHfA.'ff
Patent Application Putdication NO"v< 20~ 2003 Sheet ll of 45
Figure i 1
US 2003/0215508 Al
~-€0l~FASrtO
~88~ noomgfASJEO ,
~ mOl1l{lffO )
<........-~~..;;... ___ ___,
Patent Appfo:::atfon Publication No-v. 20, 20-03 Sheet l2 of 45 US 2003/0215508 Al
Figure ·12
O@io:trorn'!lt!mrph~n HIJ~ Ofal!!Qlutlo~ R~leaE';e f:l':<~i&i!I for Miue::h1ol! DM
1 ::!CG mg G1;;AllYJl'!em Mydrobm~11!de to Normal V<'.lh.111h:~ern In Thre0
f(Um!l!~tlorii> {Me:inell8 o
two mg Girnii'.i•Hi~!r;J U(l m.lJ Pr;~udn.iphedf!n& HC!
80--·--·----
40 --~~-------~ .. _,, ________________ _
US 2003/0215508A1
Patent Application Publication Nov. 20~ 2003 Sheet l7 of 45 US 2003/0215508 Al
Figure 17
:Phu;ma G1.ui.~fuiesln Com::arntratlon FoUowing AclminlstraJii;1n of 1200 mg Gua~ftmesln Along
with 120 mg P!!leudcephadrl11a HCI to ~Qrm<1! Voh..;nt!ll~ts (MQO!ln. Standard Error)
!600 >
~ W!O
~ 120(} ,,__.
~
,g \000
GS
!::
~ soo ....
i::::
0
u 600
ll 16 24
llrnt1 AHr:r Drisfog (hi"~
Patent Application Publication No"" 20. 2003 Sheet 18 oi' 45 US 2003/0215508 Al
50
l:<'ig:ure 18
P~g;$ma Pseudoephedrine Con(;.1!m\rat!on Following Admk1islr1S1Hon of tW mg
Ps!lludooph<&drirw HCI lllong with 1.200 mg Guaiffin91dn 10 Normal Volunteers
(McM, Standard Error}
~ RdereilCC
.....__ Pmnml.iteon B
-111r- Pomwhlinri C
l6
Patent Application Publication Nov. 20~ 2003 Sheet l ~t of 45 US 2003/0215508 Al
Iiigure 19
P'i;.1$.mM Gl.!fl'w~fr.$ tl'lt ~1~1'tr.-.lj(m of 1:100 MO G1.rail:f~ri~fri in
Thrill'(I! tliff~nirri: farr'ftU'l"'ii!Jm i-s;i l'1!tmr"1!f 'th;ihm!~f'l!
!~~. :St~nlj~rd Erun}
Patent Application Publication Nm.1, 20. 2003 Sheet 20 of 45 lJS 2003/0215508 Al
~Figure 20
P11:~h~1•~ P~~~Jli' C~iJ.MrdiUe'.Si'.<1ip.~dri11>ll! H}'dro.thkirl.~ lo N<•ms.;::i Valb!rrh:l.i:~ ,i.M Ttire;.t' O!ff&'!=i: fmt~~1~
f l'&~n, ~a~r..e:ird Err~r)
Patent Application Publication NoY. 20, 201)3 Sheet 21 of 45 US 2003/0215508 Al
Figure 21
Plasm11 Guaifsm~sin Com:::{lntrnilonis F1>1lowing tha Adm!nhitratlon of Gualfi::J.rU~$ln In tiiffer~nt
F.::irrmdll!tlons and Oiffarsnt Doses '10 Normal Vl'lh.!nt&af'§
T
Q111'1ean, Stamfard l?:n"ml
,-~ TM3U1'Hli11! A l
~ Trna!.m~M B I
--w-Trnatm!'Jnt C
S-OO t i
• L·----.--~--...,.........-=~==~===~===::~&~:s:==~""~-=*"'<~,;;=;:JJ.
I)
Patent Application Publication Nov. :w~ 2003 She.et 22 of 45 US 2003/0215508 Al
Figure 22
Plasma Pseudosphadrin-<1 Com:ent.rRtlo"$ FoUow!ng the Adminl5trat!on of Two DiHl.lferd. Dose
strnng!hi! of Psm.1di::mphml'rlne Hvdroch!oridD ::i~ well a1> Different Fotmula.Uons to Notmf&!
:wo ,........-~---- ·-------~o!u"td!!2r_f! ________ , _ ~------~----·
(Mc~n. Standard Error)
~50
--Tm;.Umesnt A
,.,.,.._ Tree:lmem S
.......,s.--Tl>Wl!m<1!'\IC
~
700
~
"'
1~ 1
~
1
::: e.
" .., >::'.
a.
w
rn~.
1l 16
1!trm Mer Dsisff!G {t\13~ri;.)
-1
Patent Application Publication No-v. :w. 2003 Sheet. 23 of 45 VS 2003/0215508 Al
Figure 23
Pfll&mi~e$!n
.Along with i:lO mg P$ieSJ&Joeph~driMe Hydrm;Moride !11 Two Oiffsmuit f1;H-mulaUon1&
Following the Com;uim.ptfon. r::rf ~ Hlgh·Fat Ma~!
· {M$an, St1;1!ld1u-d Error} .
0 . n 1i.!
T!m"' .Mir$1!1(! {!isr)
Patent Application Publication No-v. :w. 2003 Sheet. 24 of 45 VS 2003/0215508 Al
:Figun.': 24
FIMm& P .. a ... !.ioo-13foiidrlr1 .. Cl.ln&:'i!ntnstll'llt°"'ing a1 O!!:iw l:)f ~~O ,;ng P$&~"~~1IM ~§.i'i!el-d!'k
Mml,..Jli>t•ws.~ l"I """~ Dltl.::N C:"1:>mi11.u'!'!ptl<:1n .:>f II! Hlijh--r.!!.t M1111!.'!I
{Pr}
Patent AppJkat.fon Publication Nov. 20, 2003 Sheet 25 of 45 US 2003/0215508 Al
Figure 25
!l'iallld~~ f'!rusrn111 G111t!(-£/n COOO!llll~@mll f(l!l~lng Shill' Mml111$~rn!:km M '11 O~illl!! (If 1-am mg Gualfo~@I~
llls:<;igwi!h 1:J!Q m~ P~&ud~p!'il!dflfllil< Hyil!'Ucil!orld@ in .t Dlff&~M l"orm1.1li!IU~r;i to Nf.!mizl V~!iml.ffrn
IM&M. Sl.iiM$ro Ers-Joni.rath:ms Followfog the Adminl>sinllan cf 1200 mg G~iform~!n
with or wlthi:nit the C:>O!(hnhtl~trntk~n of 120 mg Pcaeudoaphm:fri§'HI! iiyd-rus::h!orido in Nom&!
\l'Qh.sriteer.it
'~ -
2tiW r·--~~-~--~ !M.~itD. S~m_q~rd Etf2!i_. -~---
:;
(
moo J
-§,, 1too
.~
" ~ 1~
h-
"' "
-~ fjCQ 1
t'
12
llm* Jl~'i!'r ~l11g !Mw~)
Patent AppJicatfon Publication Nov. 20~ 2003 She.et 28 of 45 US 2003/0215508 Al
Figure 28
Plasma f>is0udoepfwdlimi Conef!ntrat!cm!! Fal!owlng the AdmlrimtrntJor11of1l!l mg
P!<0udi>i:iphedrk1e Hydmetilor!de to Norm!il Voh.mteern with or wUhou:t tho Coadmlrdstr!!ltlon
of 12:01) mg G~alforie$lo
{Mean, Sil.'indmd Error}
tl
'f!m~ AH!ll C~111>l11Q (hr}
Patent Application Publication Nov. :w~ 2003 She.et 29 of 45 US 2003/0215508 Al
Figure 29
Pm~ma Gt.mifaneiin Canc{lntraih;ms foUi:swlng ~h& Mm!ol$trn.tion of 1:200 mg G1.1alh:me1i>ln ind 120
mi;i Pll
MPO
::i
~ a. j:l'{,lf,,l
.$.
c
..2 1008)
~
c
"' MIO " "' " v
ooa
l
j
i
I
•WO
WO
0 ~~~"'.'~'£_.,,~, .. ~~"''1-........-JaJ
ll
Patent Application Publication No-v. :w. 2003 Sheet. 30 of 45 VS 2003/0215508 Al
Figure 30
Pla:sfma Pse~dQ-cpn~dr!ne Com::i~ntra!!.ons Foi!OW !ng !fl~ Admlni$tratlon of "!W mg of
P1S.eudo@pl'l:$drlno HydrocMoride l!li"id 1260 mg a1.mifo:i!'l!'::'llin lo an E:ic:~sim~~tai FormM!~tlO!
to Nl:~rmal Vc!unimm~ Lind.er Foo and fa&tad CO'nditkins
{M!!B-fl, S:bitt.dard Error}
Patent AppHcation PuMication N~p,i, 20. 2003 Sheet 31 of 45 US 2003/0215508 Al
/ f"~,~~·"_"_"_""'~ .. -·:J I 1 ~.., .._._.-- i.~- 1 u«.rnw.-.
1 -- 0 '~~' toJf'OOl~5
20 I 1· ~ ·- "'V' ~ ,., ~ i>wJ1!46~
j - ·-'O - ' t." l>'!lo111.>!6W
I ~~ -Iii ~ l6! f'Wl~~
I - --o- ·- t.-~, ~k:o11
~ ..................... -..... .,,...... ... ,..
0 · -----6---~--~--,.r---..__,,---~ """""MO-J
!Vfodnexrn D ffJtiHl ru:ci.ifr:ncsin di~solulirin pr0filt~S for varinus dlnicQI bM.chcs used in the
bfr'a v >)i lo.ibi 1 lt y s n1die$ w llh as:itxiatc~~1.~~~
~-"'n~m~
l<>P7~ 1\.tti~\,l\l
l<>IN!O\~
tul r>ooa.is;.~
~~B>t'c'rlt':ls~M
!.,,,..,~---~---------
0 --'------~:l---....--~ ............... -----------~?··~--~....----.........--------·~--.,.-
4 B 1G 12
Time {h)
Mucincxâ„¢ D meon p::;cudoepl!txhine HCL tfo::olu1ion p.rnfik;; for >'SOd!ltr:d di1;$oltHion c:;pt"dfkarions..,
Patent Application Publication NoY. 20~ 2603 Sheet 33 of 45 US 2003/0215508 Al
li'igure 33
Gualfoiw$i!"I Pl::i11 Following the Admlriigtrat!on cf -12m:i mg Gualf@n0sln
wltl'l or without the Co·Adminlnstration of 60 mg Oerjn:un~Uti0rpf'!afl Hydml:lro-mida to
Norm.al V'olamteer$
ieoo 1
(Me.!)n, St;amdard Error}
'°"I \
[. ·--------~ -..-f'orm~2:atiD11 A -llll-- M l>Cii'l ll:>1
·--~-····-~~~~-
:;;::::; :, ;:: :::::: :: *
n 16 20 2~
7!rll.i>:trom~!hc;rptl:;m H;tdtobromldi;i hi D!ffeN-nt Forml.l§J:JU!'ms, Oo~eis ~nd Doslng Rtiglm~m·~
Patent Application Publication Nm.1. 20. 20{)3 Sheet 35 oi' 45 US 2003/0215508 Al
.Figure 35
Peasnrn G1.m!fonosln Coneemr~tlons F()Howlns ll'!e Administration of 12.00 mg G1.m!f1:1:n1mfn Afong
wsth W Ooxtro!'M'ih1'rph~m Hydrobmml&'.1. in Thl"OO Dlffgroont Formuittllons to Nomml Volu!OOr~
(M&a~, Standard Et'ror'}
400.
0 4 9 12
I --+-Fcrrrm!atiof! A {Rll!!~li:ln~~ l ·~Formu!::Hkm 9 (flc,lmooc~) !
f - - * .. .feorrtm111.tloo C f1"oot) J
'fl.m~ MotHlng tho Admlnlmrattoo ct 1200 mg Guaife-ne$h;~ &incl
6ll m!J Da:w:trt:nnM'horp!'l.an !n af'! &§M!rlmental fomn:i!OO:km to Normal Vn ~~f!:lm!dll.' •.rn .
Mueln~" D~ \
. ~"*"" M tt'll O<.!~ 1.m1i!ltllr.imll;,ri ~ D0fu>'l'!'' (
L ! ~- -~~----------... ---------~
.11a
Til'l'I~ O>:i~!~ (l'!t)
Patent .AppJication Publication Nov, 20~ 2603 Sheet 43 of 45
60 ¢J It ?KV.:f.i!;,~1
fia;Jt blend iii !.he
ll,i'i!Jt~
~:r·-·~-~··-·
~·¥~~¢-ci ~~
gti:;~utat~m
'Jl)l.J tit~i\n ud f'A)~!,~ ln1; ti
US 2003/0215508 Al
Sampling poiri! reor
ti1Jli>. rdt!.it~IW\!j:j)!...<""°'
(\'o'h&'i~
C~ "'"Sl"""'<'~ =i ~"'" - -~-----
~-100C
~'<\)
~t!t'~~W}
Ciil~~_NF
\'\""-'*PM'A')
~i i'l81~"&" ~11) W<,,,,,
(l'~~J
""'"'.,..""•" !.>~ ~<>1 i2':1«'l
~~K..'l~ L-'e-~~d.'W1
~-~-''"""''"""·l.I~ ~~~ ~ro~~ (' «.:aJ.~
~~@vflj~~>
m~;;!Noorn ·~ M '""'° ~
L,..__-~-----~---'
Patent Appfo:::atfon Publication No-v. 20, 20-03 Sheet 4.5 of 45 US 2003/0215508 Al
Figure 45
P!ocmis; Fil!:IW D!'3i.srsms fiN Gu~!~&.!NP'8eud~§'lfl~ril'lhkol$}
lmrrnolfll>W R.!.~Mj (lffl Us)'!J ~
(Wt>\l>o)
G>..-.....i..oc
{'>5'f>}
~.,.~•'l<"n~
c~~as~- '.lll>j
~--prv~~
\ !)""'-<\Om:.,
---~~-
.l~OJJ,.,3,
f'r{ V-P'J>OOffl'
m<1>10H~f lQ>'!'li~
;).H.~To:~MJ'vm
1: oJll'!!! i0d Rl!!l8'&~-s !MR) L'lJIOC
(0f"'"8"'l
~
~~
al><«E r"' 1 o om
US 2003/0215508 Al
S!JST">INEn J.rnu;'.A~i;: OF ClJA!FENESIN
COl\·~mNATmN DRUGS
CRUSS-ULFlRlNCL TO RLLAllU
/~PP! .WAl'lONS
[tillOJ.] Thi;,. applic;ilion is:. on11tmialion-in--pul nt Unil<.:d
SLili'.!i r:ilrnl appli<.c:i!inlh l'f Vihi<:h m"<.c il <;Ofl!JtllHltitHJ-Hl-pHt Of U .'). p-11<.:iJl
:tppli<:3Jion S<.:r. No. w·c L 7{l(l V.'hii:h ·was filed(<[] Apr. 15,
2{)02 (p<:.:nding} wbid-, is a ~:\lllltrnHlimi-tri-patl of U.S. l'aL
Nu. 6,172,2"12 Y-'hid1 w;rn Jlled on Apr . .?.:i, 200(} as 31'jlli-
<.~Biion ';c;r. No. {)(.1/559542 and is:>ucd un Apr. l0, 2002 all
of which Jr·~ hud1y incoq:(JfiHed in 1ll·~ir enlirdy by rcf~rÂ
<:rJce.
llACK{;!ZOUND 01· TUl !NVLNTHJN
[firnU] Thc ir.vnilimpri,.,ing crnnhina-
1ion'i nl guail.f:n"'sinli n1nc.:r1-
lraliu11 nf guaiCuiesin am] npl k;rrnHy th<.: \1rs. Tll-.; invrnli<.ll1 funhu
rd1ues to <:ombi1m1inns which dcmc11islnlc n maxinrnrn
:;i..'.nim concrnlrnlion 1:qni',·~k;n1. to ~n irnmcdiat>: n:kfo;;c
lahld, l'-'hile rnainlainirig lhn3p::uti;;;;tiy ,;fft-ct_tve l:ib dfoidans and !heir pali<.:nJs. Sustained
fdc;;1.~ cb-;ags f•xms pn:ivitk for frwu daily dose ad min-
is!1 a! i-.Jric; than ~h.:ir irmrn:-diait' reka.<.<: ·~·-.Junlcrp;,;rls. h'r
cxt:fltS or three sernm
•:orn.:;;;n!rn!ion prnllk;; in th\'. p;1i[1:nl sli-:Jwing ~ t;ipi;J im:r\'.~.s•:
uf dni 2; followed by ;; i;imil3r rnpid dccr<.:llS<.:. As 3 result,
f'iltlt!11S MC proviclfd 'Nith •)l1[y ;_l slJon windu'N of t!Jt
~pproprfatc hl.ocd ccmccmr;nion of tbc medi-.:;:irn·~nr for '"Jlit-
mum th<0rnpy. /\. 120\l mg slls!aim:d rdu1'iC dlis~gt form, mi
lh<.: ulher h;;nd, may requir;;. admini:;tratinrJ once cvtory
1wdvi: hlli_:rs to a<:htc;v;; illerJpcu1i1.· din:t. Sus13.ined rek;,~."
dn:i<1g" rorrns gcn..,nlly conl rol ihc rnlt ol drug :ih;;orpl1lm,
1u ;ivuid o:ce~;\v;;; drng ;1l~uq1tinn -.;,hik mairJtairJing elfr,;-
!tv•,: hJc.ud ctmu.:ulralirni ofltie drug lo pmvidc <> palit:Ell with
it n>nsit;lent therilpnili>.: dT1~·;;i over an '-'Xkm],;d dur:ll.ion or
limo.:.
[Afl!M] iksidc.'. rtducing lhe frequrncv or Josin;; and
providing :< more C('lls1st<.:n1 !h<.'r:op<.:ulk ·~.Jkci, ;;ustnui<:d
ro.:ka;'1: dosa_g,,,, forms g<.:nvrnl!y hdp fd11i:-,: svk cBi<:ls
L·;msnl by a drug. lkeau~ su;,.l (>[" imrmxlial<.~ rdc;io:';c;
fonm1lal.ion-;;, it is "~-;;i.-:f for 3 p~tient ·,,body to dig<.:st th"
drug, lh<.:rcby :ivoidin!~ irn,ksirnbk t;i;k-dh:cls. Fm pa!Jvtlts
whu :it:JC.admirnsler lhuapies., suslained reka;;<: d;Js:i~t'
f-.Jrms ;;rn..:rally n-sul! in grealer oirnpli~nc.: duck> lhe lu""er
1
Nov, 20, 2003
fr;;qmcrn;y or do~ifl_i,;;, fowt:f (jllJ.fllily ur dusag,; unils ;n h,-,
comurm:d, ;rnd r<.:dtii:1.:d 11mksifd skk-dk<.~ts.
[tlO'lJ5j G<.:ncrnl!y, e>D:'ilaind rdc;;,;;,; formulations uii1Uoin
dmg p3r1ides mixd •.vith or cov<.~r<:d by~ po!ymu rn3t<.:fi;i.0,!anr lP degr adaltt>ll <.ir
dtsifl1e,i,;;r;Hiirn ill lht: Stilmil•~·h 3mli(;r lfl !he inles!ine rnr a
sekctnl jllymu m hypromdlosr :tnd is used in1cr-
ch2n~;cnh!y 11Jrougllow 1!J.:; 3.pph-.:;;11 ion). hydwxypropyJ c~l -
lulu:>t, or P11l1uhm lo l'nrmuhH'. SU'iLtincd rde3_,-;;;; l<->.hfot'< or
capsules. Tht.Sl:' pohme1:s fir>:po;;t:d tu
;rn <1qu<.:UlJ:> <.~nvir•_i1rn1,:u1 of k•w pH lh<:n:by s!Gwl:: dil:fo:;itig
tlK itcliw m<.'di<:ilrncnl 1ha! i;,. -:..'<)t1t;;1t1t:d wirhin 1hc polymer
rnsJrix. WJJ,~n lh•.; ~.;:;1 ent<.~rs 3_ bigh,~r pH rnvironmcnl sud1
''" !h;tl lourJd ifl !ht ini1cstine>,, bowever, il di'i-.-;olvc:s r<0su lliDg
in ;, le.'ic~ cun!rnlled drn_i.;; rde,1.~t:. ·n-, rrnvitk bet.kr su.c.l;iil;;le, ·~ilher a!ont ut in (:ornhin1timi wiHi
hydropbili.;: polynKrs.
ffli}U/ J (iqM·a!Jy, lhcs-.' fornrnlR1ions fir'-' prr:pM1.·d by wm-
lii.ning ih~ m;;dicnrnrni v1ith a tlndy divided puwdn of I h!.'.
hydmphili;.: rn!yma, or th"' hydrnrtiilic and w:ifully JJ:><::d !n m3.mJL!dm'-' do!;;,gc furm,; I hit I dtmo!l-
StHIC .~uslaincJ rdcasc pmpn!ics, lheM: [orrnubtions gni-
<:L ck:>in;d rd•.;il&..: pfo!ik 01· si..:rnrn
C(lli'..'.rnlr:n ion of medicmr1rnl ()';(;( :lrl n:ltmicd period ot
tim•.;. Tli·.;s,, >H&li:incd rdeJ"'-'. [ornmlmions g<.aK:rn!ly r.;;~.iilt
in a ddav in lb<: app<0an1nu:: ut drug in ih..: bbud ;,.!1cam,
111,~rchy deby.ing !h'-'fapt:ulit: dl'cd .. Addit[r_m:;Hy, wh"'n ih;;;
dru~ tkies appu:L it::; maximum svrum concenlr:t!iun g_~"""J
is tffwcr 1han lhe maximum ·::01K'~lllrs1ion r·~quir!.'.d for 1!1<.:
rnnsl dfruiv·~· lb<:rnp<:utic rcsu!l. Funhi:rmorc, mc .. <;l fomm-
latiofls lhal d;iim lwdv;;; hnur 1m1~rn:y rek;::;c; almcd "-'rt1i11 i:onccntntit>ns of clrug
from falling bdmv a lhtr:.i.pwtil·;;lly em'eli->'e !t:"Tl (C,.,,.) al
'-'XkrJded tim;; pr.duds,, m3ny m;rnufodun;rc~ irJcrn;i:-;;:. it!"'
dmg stfenglh ul' !he th~;ige form. Tht inneasc in drn:-J
<;!f<.'nglh, howc;v,,r, rcsullf> in a -..;,_,n<.:ornirn.nl ifKf<-'ll"'-' in
~1dc-dfoc!f'.
[OO'lJ9] O!hH phi:rnmx:uli .. :\1! rnalltlfa<.:lUrcrs have rnad<.:
ta!ikb anJ cap;;uks conlaini[]g a cornhwallmi c-r an imme-
di.ui:h ;fa Ilic .~momi!>. and lyp·~:~ ('r
adjuvafl(S u;;..:d, the grarmlati,m rmo.:s,<;, •.Xlmjm~.;;..<;inn l-
l11!ion :rnd cnviwnrtl•Allal factor::~ siJd1 M' ag;ta1wn in lb(
:;.toimod1 and rh" Pf'-'"Cllcc (~f ahs.:;ncc ;:if food. DiN lo t bc>.c
flUITICrtlLl.\ faclors, ~{hc~·)J]\; fmumfaltOU'; play all impor!i-l>lid dos:tge
forms. pani<::u!ar!y in tile prq>;·1ratio11 (•f c,ulid dns:. ~ d·~i:ong<~slrnl a.:1.i,:n rni
lh<' nasal mm:o:.;;, P_wudnt:phedrim: produce:> p·.~riphtn>.l
dkCls ,,lrnilar to tbusc of cpllcdrint and ;snlrnl <.~fftcls
s.imi lM lo, !ml k:~'; illlenR<'. th3n, <1mphelamin·~';. JI tw; th1.:
pnlec:iti.~.l fur <.:xcihtmy ~ ffrn>.. /\I Hie r>::comm~rn.kd mill
dnse, ii h;os lrHle or rnJ pr<;;s.sor dfoc\ in nnrmul\:risive ad1Jlts.
P2«~ll, he<.:fi >J1Pwn lo b;:r1·~ a m.:;m dirnir1;i-
tio11 ha!l'-lifc of 4-6 hP!Hf'.
f.0013] Dcx1rumdborphJn 3.ds <.'rn!rnlly tc> ckv,11e the
1llresh•.ild for ·~ou,;hing_ lt has no i1m1l,;es1c or Midiuiv1.:
prnp"r1i<:s. Tb1.: riujor <.'irctilating md<:boliK is dc:>arc·rplrn11.
[{l(lH·J The nc<.~d .. ;xis1;;. Cora su-;;tmo,~d ffki•"" dos.as-;; form
ol guaiknesin <1loni; ;rnd in 1.:oml:·im1tww;, which arc cap;; bk
uf susu:inin.g lli<.:r;q:;.;utic dl:Cdive for n:kmkd [X'rtods d
lime l'mtber lhe m'.f'.d ~xisls for susl:lin<;;Ll rdca"" dG'i.cdiat<.c fdc;a.<:-e fonm1-
l;itiun, appears )fl !be hluud Hrearn ':!'; qllicklv as an irnme·
dial<.: rdc;,:-;,: furnrnJalirnl, and .'.igrn; in
frirnmiMions of rnoditkd release gt1aifrncsin ~lld gu~i[cnÂ
c::>.iu cumhinz.tiou dthin rnd at kast <•ne i!iklillcma 1 drn~. Tht: suslain\:tl
rd..:a.<.c fonnuta1iufl (SR) may rnrnprise a s:ombimlinn ui' ;it
kM't one hydwptlilic polymer ;;nd al k•..-;1l<:r"inM1lubk pl1lymer may he in a rang.: '.lf a.bout
om;-10-um: ( l · l) ln ahnut c:iin<;;-Jp .. ;;m: {9: I"), mnr<;; prekrnbly
in a rnng1.: of ahom tbrc1:-tc·-lwo (3.2) to ~hout six-tc·-0n1.:
(11· J.), 3.nd most pr·.;ftrnbly [n a range; of ~bout !wo-(o-on>.:
(2:I) hl :dxHll fo11r·UHm1.: ("i: l). Wtirn a ubkt compri;;ing
lh\: :;1islained n:kzsc fornrniatinD is expn.'«::d I<; an aquemi:>
m<.:dimn (1[' kw,· pl!, :~udi ;is !ba! four1d in lh.: stornadi, the
2
Nov, 20, 2003
pnlyma cumhin. lo dissnl<:. Tht: t:;blr.t is
<.:.llS {~.g. ;i
ht-bytt· l"bk!, OJ c1.psuk), a:1 immnli"lt: rdc;,.<,c formub-
tion (IR) ;ind n SlJsrnincd rck;u;i; fornllllatimi (SR). E:idi
formulation cnmpri~_,,, a "P"'"'ilk qu;m1iiv of guaifcn.;-sin .c J1J<,,dium, such ;,;; tb;;; found in the sitim~Kb,
to qukk!y r·.;ka.<;<; ;;u3.ifon<:sin conH,irn.:d within tlit ponioo,
;wd <>pti.m1;1lly quickly rcka.<.<;: til1.: a! k;;sl one ~dditiotul
drug. The :;w;laiu;;d rdt2t:>\·; purti<.m m:;y ·~\lmpri~: a ;:nmhi-
rrn!inn uf hydwphihc polymer ;ind a walct-inwlubk pnlv-
rncr in 3 rsiin rnng·~ of 3.bout un·>tn-0111.: (1: ! ·i !o 2bm1l
uinc-10-omc {~1:1), nwrc prcfrrably ;1 rnnsc of al'0t11 11Jrc1:-
((Hwu {'.'<:'.>) !o ~huBf six·k:-.tmc \f:.:l ), and mn-;l prdt:iah!y
frmn about !wn-l,Hme (2:]) lo a!io1H fuuH.thHK ('i:l).
l .ik<.:v.·ist:, !h<; :iJJSlained rel~·b<: rurlinri may~ l:«l •."Olll;liri I ht:
add it [rnnl drn g(:> ).
[llOrij llK· invrnl ion nlso r<:fat~s !G sus1a in·.:d rde,·1.se
prcpMatton-;; of tbt 1yµc ck~•~ribcd abc.vc in lbt form of
c:tpsuks baving b-~;ods or grnrnilcs of bol ti immcdia!e rekaR<'.
formiil.alino <.:rek
beads e3~'ll haviog, only ono,c of !ht SR or IR f<)fil'EJ[;,!ions .c formulaiic·n 10 forn1 a singk :abkt. Fur
purixiS<.'. .;,if illl•sHaJion only, tb<.: inv-.;n!i•.)n 'Nill he di::scrikd
iri ddail in lbt: <.:omc.1:1 ur tile ;,i.faytred l_abkt .:mbollim..:m.
It ';hmild be u11<.krnlond lhal fc,r \:ilh<'r lh<.: rn1mtdiak rtkasc
and-'or !h<.: ~-usrnin0d rdcasc }K•flit>n th~ ;;uaif·;;ntsin ~11d
optionally lhe add.itionnl dru1; may 1-,.,; m[:.;:cd '>Nilhin !h~: ,;mw;
m3.lrix ponion or n>mpri'1) &>.~parnk rdc,1::.c portions wbid1
aK lbcn either nlmprc>,.<.cd or mixed for 1.:aps;iks {.:.g.
n;mpri.~~ .'<:paral<' b"iuh or gr.mu ks) de.
[O!H.SJ /\ hi·laytr labkl dernou:;lrlfl:nrn th<1t MC cqiHvaknt to an irmrn.:di;l(~ rek,tR<'. tilhkL
Th<.~ hi-layef ub!d also provkk:s su;;rnin1.:d rdcasc of
guaifone:~lll UVC! a[:{llll ;; twd<;-;:: hom IX:HC.iJ frc·m •.me du.<:<.:.
Th<: bi-favn !;ihlcl hir1her m:oinlilim; -;crnm nmrnntr:ilinc:i
kvds ur 1;;u;;ifrnesin at 3 1hcr3f'l'.lll [cally clk:divc kvd for
ahulJl 3. twdv-.; hour p<.'.ric·d wi1bolll an illerc,1se in dosage
'ilr1:ngl11. A~ tile t•i·l;1y1.:r tabl1:t may ~L,;o 1.:ontain at kas! <)'1!.'.
,1ikliam13[ drng, lh~ additinu:;I drn(j can he formuhled
·wilhin !be :-ill';l;iiri~.d Edta.se funmJh1lion, imm~diah" r<.:'kasc
tonm1!alion, nr both. Jn •.Jn~ •:rnb1xlirn<:nl, 1hc bi-bycr l;ihkl
maint:ins .'1:nim ;.x>n>.'<.al1rnlion kvv!s nf 3J lca~.1 ti!lC ;-iddi-
tioml drug :;I ;i lherar:;;;1i1i._:;,l!y dTei:!iv-o kvt:l for ;ilmul a
lwdvt: bt>ur p<;;riuJ wi1.boul an ir1n.:M.<; in dus;>gt et:nlinn pw-.·1de a Cm;,, whidi is ;i.bovc the. fl•oC<::'i.'~aiy
US 2003/0215508 Al
1ha«r<0u.ti1.:~ Hy dk>.:tiv<' lc.:
[Oil2n Tb;.: lilYC!Jtion ,'\lst> ro,Jatcs ll• rn<:tbuds or mam1fa;:-
!urini; :.,ustairn:d n:k~.-;;;: t'llrmulaltc·n>. ~nd hi-lay;:r lahbt:;. An
examrle uf:: manufactming. mdtmd i'ur .<:>. rni.\ing a hvdwphi!ic l!"ll'rn<:; ~nd
aclh'·~ ingrcdicnts in il mb:-~r. 3.dding 'NM~r to the mix1ur~
MJcl rnminiJtng w mi)( ,iud diup, drying th<.'. mixnirr: Jr> c·brnin
fiyump!JiJ[._; p'.J!yrw:r efJU!jlSU!at<::J l\[3flUks, milling auu
:~crcu1irig !be re:~ulliri~ granuhlii'fl, aml bknJing i1_ \';ilti
v;iriouc:. pb;mnac•~iJlkill Jddilives, ~ddi!iotul bydwpbillc
polym·~r. ~nd \Vii\1.or [11<;0lublc pu!yrncr. Th;; formulation m~y
1b..:n b<.0 tahkkd and m~y funbu lx: Hlm :<>mpk of J llll<: Jn_ig v.··itb vaEirnis <~xcipienb, cob-
rmlls, amJ.'or· oth<:.r pharnl:K<.:utkal additiw:<.. lo f;>rm :in
irnm.xliah, ri;ok(1si,,: fornrn!Jtion, sq•y !h<:n upli;ina!ly b;: cn:.ikd wi1b
a prolcdivc c·:J3ting \Vbid1 rnpidly dissoh-'<.OS or disperses in
gRslf ic j uk1.o:<.
[0023] 01her ohie<:b, adv;mlag<::s ;rnd <.0mhrnJimrnb or lhW and ,,.m he t•bvi;)tJ~ l'rnn; lhi'>
dr:s,;ription and prndi<.'.'. of !b<.: inv~'niion.
muu IH'SCRJPT!ON OI· Tllt l}R;\\V!Nfn m~!ht:·d t<>r m;im1l3.c11iring lh.;; suslained n:ka" a grnpb d~mon.~lnliug lb;; d[s&olutiou
prom,;,, ,,r lahkL~ nimprising IW(J di Ill: r<::nt :.;w<\a iued r<:: h;;;:;t0
f.xmu lcirion:.,_
Nov. 20, 2003
[001~) l'I(;, 5 JS ;J grnpl:J lkmuns1rnli.ng I.he d[s.-;;:,lulinn
prnli!c~. of~ com111<.~n:i<1l!y ,ivnilabk imm<.0JfoK r<.:kRS<.' dm-
;i:;-,~ form :ind iwo ~U'>13in·~d rd<.:ase (h~;ogc forms of gu3 ikn-
1:sin.
[(!029] FIG, {i is a ~JJpb dcm,.,ns!Ltling llK~ pLlsmJ ''On-
c<:mratirni uf gllail'enesin uv.:r lim<: tr1 h(~ in !JUd!hy tllJftl;lrl V(li -
Ull!L'.t:ni fwm a uimmerc:ia!ly ld of the iuv<:n!mu,
;rntl IW(> hi-l:Jyt:rcd rnrnJiJled rd<:::i:~ l<; fornml~Jis_in inid lb" oHwr
rnie ~"->rnpri>.wg -1UO mg llf immelliak rekci"'-' formub!illn
:rnd 80H mg uf :>JJslained rdea<;<: i'nrmublimi).
[OOJl] FIC. S 1" ;J grnpb llemuuslra!rng lb~ .:Ji:-iM'•lBlimi
rmflk;; ui' fom s1rnl.a.imx1 rdea<;<: tablets: tme L1bld iii
non-layered, compri;.;ing 1200 mg of ;;us!aincd rdi:aso.:. fo1·-
nrn !Mion; .) lfl
be;Jlthy hum3n vuluflkers rmm :fv,1h; 'k""-;rib;;.J <1bovc') in
budihy twm1m ·,·oluntecrs l'rnm 3f1 m1rned13k rdC»$<..: l;ibki
;rnd a hi-layer;;.;] mudiiied rdeacS<:: lahk1 •:if the invrnl iun.
[tlOJ..tj flG, H 1s u grapli dvmonslrnling lll<: cwr:nig<.od
ptbrn3 umc.:ri!ralic·n uf gu;iift'..11<:>.iri ov.:r a l r:. hour pniDd in
?.7 hea!ihy [mman volunle<::rs lfnm 600 mg hi-!3ytred rnndi-
fad rl·k;1~.<.:' labkh of th..:. invcnHon adrniniskn:d io fa;;.ting
vohHHl'.l'.f", 1200 mg bi-by(of<.'.d modir1 .. ;d ro:ka5'; l3bkl'> of
lhc invrn1ion ;Jdminislerd lo Lislillg 'Johmk<:r~, "lld !2(~~
mg hi.-layaecd modilb.l rek;i:;.;; t:;hlt:ts (Ji' lhl' invrnlirni
administ,;n:d lu ._,dunker" wh·.> bad bt!'.U ftd ;i high fol meal.
[(!OJ5] f'iC, U is a graph (knwBslrn!ing !he: dts.."'!u!irni
pwlii.e or dt:x!rnmeth~'f]Jhafl HBr <1,S mt:asured by Ihm<::
dt!frrrnl h;ilcht:i or a 1.?00 mg gu:nknesiri-----60 mg dt:x,
ln:•mdborplwn rnbk! "'"'''r ~- 12 hour P'-'riod M' 111;;,r,sui-;; a graph d·;:mon:0r.udm;p!ie-
drino HC! lo 'o'oh1nh:<.:rs in !bE·cc diJino11t formuLHions
[lXl~2 J Flf;, t 9 is a graph tl;;rnon~irn!ing th;; ]Jhsma
l-
:tg<::5 in grGup~. A, B, and C s>f cxampk 12.
lOil-43] flC. 20 i!; m:;J.mpk l 2.
[Oi.l*41 F§C, 21 is ~ gr;ip!i tkrn;inslrMing th-c pla,,m3
corn::r:nlrn!ion of ibrcv diffcrc:nl Q(Kl mg g1nifon<.:SH1 dos-
ages for tr~ii!rw:nl$ A" ll and C of c:nmpk U.
[OllH5 J FIC. 20 i-;; a graph dcrnon«.irn1rng lhc phsrna
c:nnt:nllr;,\ion of lhr·~<:: ditkrenl J 20 mg i:io>cudo<.:pb·~;lr.in~
dnvJ_\;<'.>i rnr lte<1im;,,;ngc s1rrngtlL
l Oi.!47] FIG. 22 (]..;pkts pR;u.J,,_;cphnlrin<.' pla;;ma cuncrn-
1r;11[,ms folhrwing admi11is1rntion d iwo ddkr•;nt dose
strcng1h-;; uf p:>1;11dc...;phcdrinc, 3:< '8dl as, diJfor<.:lll formuhl-
!tc·lfi.
[tiilM!] FIG, 23 dqJict'' guail'cnrnin nmcct1lrntrons fo]!(w1-
ing 3dmillis\r;;tion nf J :mo mg nC gu;;i!.;;nesiD wil.!i PO mg
iw;.;L tollowing ndmini;;1raii011 or ll do&;s ot i:w
mg pscudoeph<.:drirn: w.ith ! ::no llll,\ or gtuifoncsi.u in 1\'.·'0
diJfore1rn1iun or illl c:!Ld t:Ot1dil ion;;,
[0055] §c'IC, ~) dqiids ps-~udocpb~'drim: pl;,>;ma <:OllC<:n-
1.ra1ion-;; following adminimrnlron of :rn 1.:xp,:t·im<.:nh1l 12UO
mg ;;unifi.::nesiu-t20 mg ps<:cuduq1b~·d1im: rormu!arimi lo
vnluni.c:er;.; 1mda frd ,rnd Casr::d cnmli!ie,lrn1 ion d do:lromdh,1 -
rph<1n bydf<.:bwmid<: in ditl'o.;[(;!Jt fornrnlniions, do;;os r:nd
dosing rt:ginH_-:ns.
[iJOMij flG. 35 dc;pic1-;; plasm,'l guaifrrn.:sin co11ccntrn1ions
follo·»:ing llic adn1inislritliun or l 200 mg g_L.ifl along
wrlh 60 .;Jn:lrnmt:llmrph;m hydrnhmmidt: ill !hr-c<: di!for.;;nl
fonm1la!i•)ns.
l:lHJ6 l I FIC, 36 ik picl.:< de:>:I mmd!iorph3.!1 pla~m;i Grnc<.:n-
tratio1Y.i foJl0'Ning 1lJ<.: adminisfrnlinll Of (l(f mg dtXl!OmdhO-
q;IJ;,n hydmhromidt 31 1.hK1.'. ditl'<.'.,·,,nl wk;;.
l:ll062 I FIC, 37 depicts pl;isrnkJ.dy-slille pfat;ma c;,:;n;, ~nlr;,1 ion.s
nf guaifrn~';;iri following th~ nmllipk dusc admi1m.!ra!im1 of
L?(~:J mg gu;i.ikncsill in di(kn:n! f,irmufoi!ons.
i:mMS I FIC, -Ml deprds m1;;3n slt:ady-!>1<\lt; g1iJifrnesin.
pb,;nu con·.:enHaii•JiHi1111.~ protik-;;.
[0061\j l'~(;. 41 dtptdS slt:ady·:..: admin[s-
lrnt!on of (>(i rng lkxtmmclhGrptnn llydrol:-romi(k in ditfor-
u11 formulntfons andior di[,:n::.ni do»c~::;<: rntv,:,.
[0067] HG, 41 dq1ic1sdcxtromdborph:tn plac>ma •.:01K<.'.il-
lra1ion;; following lhc admini~tratiou nf 60 mf~ d1:xlrnm~tlloÂ
rphafl hydmhrnmidte i11 diffe~fll rurmul:Jlinns ;rnd du:;ag<;;
ml!'..
US 2003/0215508 Al
[006~] FIC. 43 1.kpic1, a pn,,_;,;;,;, Jluw di;igr;im for th,.
m<.).
[0069] F!C. M depid:< a prm:t:"-'- !low di:1gram Cnr :i
g1.laifon1:sinipS>..:1Jdnq1h;:;drin~ prudud ( J.10{),. ! :w mgj uib-
k:I_<;;_
ffilml] FIG. 45 dcpkls "- procc"" flow (fo~;rnm !i)r
gu;iifoncsin ps;,;uduq1bcdiinc pn:>dll<.'i (DOO:(i{J mg) tabk:1s.
DETl\ll tD DESCRlPTlON OF Tl!E
!NVEN-mlN
[MJ71] Tb>: invn1lim1 rdaks to ;;u;-;taim:d n.:ka;..: lormu-
!atiow; d' guaifu1cs1t1. in 2 prdcrr<.:d i::mtiodimu11, 1h~ hr-
nmhitiolls aiso ,,,->inpfi<;,: al ka:-;1 on" 1ddi1i-:>1Mi drng in
irrnrn.:di:ik: n.:li.::-:>Y;c: form, su:~!aintd rd<:asc form, ur holh.
Etch furm1i1a!im1 <:nmpriOi<:s ;i speciiic qumility or guai!'<:rJ-
esin nnd ilrny c•flic•nally cc-nlain '11 lc;h( one addi1i.:>ml drug.
Tb<.: im11K:dif!l1.: ;c:k,'ls-..: fornwfation 1-> formufalt:d to dissolve
in ;1qlH.:•Jti,; :.ddic medium, su;,;h ;i.'} tha1 fouml in !h1: .~iomÂ
ohibk
pnlyrm-;r in ~ rn\t.:J tang:~: o!' a1xml Oflt·llHme ( J: l} lC· a.boul
riin<:-lu-une (9: !), mPrc pn:frrnltl y a rang;j of abmi l l hn~i~Â
\l,-twn (.1:'.!) 1i> abi>ut ,;ix·ln«>m: (6: 1 ), am] mo:;I prekrahiv in
a rnngc of aboui. !wo-lc•--(HJ<.: (2: l} to ,,bom fo11r-to-i>nc ( 4: 1)
[{l(J72] !n :; p:efom;d rn1l1udim<:nl i!k hydmphilic ptily-
mq-> ,u._, sc!<:O\.:d from a<.~<1cia, g,um 1rngcK&nlh, !oms! :)em1
1;um, gti:or gi1rn, or l-;3rnya gum, mc1hykclll1kw,,;:, hydrnx-
orn,;1hykeH1J1u0i<:, hydmxyrmry! mt:ihyln:H1i1o"1::, bydrnx-
ypmry! ce!lu!n.<:<::, hydrnxye!hyk-;;llilh;,it!, carhu}:ymethyl-
C<.~Hulnk:c, agM, pr..:tin, crm·ag<.:cn, 3Jgin<•!<.os,
c:irboxypolyrnl·lbykrK., gda!i1L ;,;a.<,<.:in, l'.t:in, lxn1omk,
m;1g,n<::lysardrnrkk->, and modi-
lk:u _,;!ard1 derivafr,'c'>. ln a mnn: prcfrn,,u icmt-{1uirncnl the
hydmphi1ic pnlymr.rs are >irk,·wd from cell1J!u:;c ether.<,. [n
;i 111Dsl µrdcm:d i:mhodimcm tbc byclwphilic polym1.~rs m-<.:
~.<.:k<:i"d from hydwxypropyl melbykdluloscs such ros
Mclbon;] {L!OM). Prdcm:u lol.lyrncr ;idtbl ~1rnr;;kly
in form 1h<.: rdci;'i>~--ddiying matrix i,; pr~knhly fmm abo1.l!
0 5'11 ta 4.or:.;. and mr';" pg:f;;rnb!y fo_im ;,bciu1 J. ,;y;.; .. \o :: .l:Y-'i.
11 «bould b;:; r<:cogni:cd that fhl-'5': ;m1ounh may bf.'. propor-
!ionally pr-;;;;,ml in rmuhl-
!tc·ll ,,!n.:ng\ti_
[0073 J !n 3. prefcm:d embodim<:nt the ·,;,a!a·inv:-h1hle
pnlymn:< are seb.:led fmm rx'lyacryllc acid:<, acrylic re:, ,-dJulw;,.; acd3.lt'. ph1.h:tl<>.t<'., pnly-
viny! 3_1:..,l:ll<.: pl1tlrn.!it1e, bydroxyprupy! m·~ihykdhil·:)s<.:
phllml.3.k. ln <1 more prckrrcd e111bodi1W.'.n1 til<.: w:ikr- in-
soluhk polyrnr:r~. ;,n;: sckc1cd from ;, .. ;rylic r''"ins. fo a mus!
preferred t:mb;xJimrnl lhe wakr"im;nluhk pi>l/mn:< :ire
:.;ekch·:.d frnrn (~;~rbomer acryl ~c r~:i;i n~ ~u'~~h a;;; C;arhumf. r
(_rqp, !-'rt:fnr~d <1m0Hlli.:< of' ifo; w;tlef-lfl?>Olt1bk pdymG
indmk mor<.: th2n ;;lxrnr 0 y_;; 2nd k~,; frmn 3.hm.:t 2.5'!:' by
weigh!. tiJr a J.10(i mg !ahkL More pr~fornb!y hydrophilic
pokmer a.mom1ls indudc~. rnur<: !hmi abnul O.T-i1.:;. and ks.s
thaCT <:lxml I .. "'/i;'., amJ mosl prdnahly nmre !h2m about 0 9':.I·
;im] ks.« lhJCT L:'.5<:L ll shm1ld b,; n-..~ngrJized !h:;l thesio
amount;; m11y be prupl1r1 t('llaHy prc:!'iCnt :n :. 6HO mg labld or
;my ,i.;_~if~d IC.irnniia!irni .qreng1!1.
l:il0741 The: tflV(:nliorJ :ilsn rnh>.tc;, in ,;u:;1;,iri•.od rdea:.e
pr~pnrit!i.ono> of tbe 1ypc ik5'.:rib"d ;ibove in iii<: t'.)mbi11atiun of b·.;1,Js
or granuks of immediate rdo.~: fnrmulation and b·.;;ids ur
-~r;mules uf su:;l;iiCTtd releaS<: i'ormublion. r\l!ermtivdy., the
sust;;[CTt:d n'k;i:;;; k·rnJIILHton may compri:'.<: ;: c;;iE: Iha! is
niakd by;, byer of immedi:il~ rd,;;,;;,;: t'ormul;,1_i,>n lo l"orm
:)S<.: uf illu,;trn!ion •.m!y, 1t1f.'. inv·rn!ion
wil! Ix: cb;,;rihed .in dd3il in 1ti~ nm1n1. ot !b" bi--laycr~d
tr.hk1 cmlxidimcn1. V./brn !Ii<.: <.:mbo;lims:ni [;; a bi-fayn<.:d
lablet, th-;; l3h]d i:; made: t;i' lwo pnrrinrJs: nm; pnrliun
cnmpri:;ing ;i su:!<.:m·-
;il8, NF for :i 1u1a! >iUSt~rntd rd<:a.<;:; we.igbl. of 12'.'.8.0 mg. !n
;i prekrr<:d embndimc:m lh<' immt:di:ik rek:;t;e iay<:r h:is the
l'oUm,,·ing pmpmlirnis: '.::! O.'i mg Guaifenesin I)(' (li'i'k}
['.:'.(J{U) mg of guait'rncsin, USP a-larch
glycnlak, Nl< [lXPLO !All]; and l .O mg nrngnt:;;ium >.lear-
c!le, NF !(,r ,\ lulal immediate rd<:'·C -weight uf y;;eo
i'"'~~ \'=~)'
SH L;,n:;
i.o.mikf"(\.:'~in DC ( 115~.·1-'
H:·.Jrn:-.:.;;propy! me(h;,:kdk;k,s.;:: e~~~:HlOt~f"I :~)
P::.1:L1.'.k;.c:ph-t:dr:;1{: h\ d~f~'.]1k:~id~:
::-/ ·~Jil
Jt;~,q
US 2003/0215508 Al
~ i·,,:r~:-t.:7 \'r-.~.~i!!ii;l: c-L"i i ulo:~-L
Sc··..l~:..: .. ss ~-;,~;-~~ .. -~1 gl,·-.:.:.~htt~
("'riilJom.::' '):::.1i.)
~i.-:bgfi_t::-,;•)!11 j,,t.f,1~1~tt.
fU-.~C' Rr.J #-ln Alumi1~11m l,::1h·
(1-J .. le'', J
')..-~Ht~- :)ll1~:~t.d
tB.:!M~d ,:-:;ri [i.;~leh r..~/~; (cf lJ:i:O (l[)D ld-::Cd.~;
A1nou~1~
(mµ_.l;,·.«'
I ;n:'·='·'''
Nov, 20, 2003
-.(~~•i;~·c~1~:..;.i11 d~~t:t:~ ...:omp~··..::;::.s1\Ja us.:ci ;';~ d1i: m:rnu.~'a·..:lu1~'1g l}HK:t:s:~ 1..:1:1;;:,i;::.h ul'9_"i~~ (1u.;1!!i:~c:~{~1.
l'~P. ,;;i";r. :·v1·droxp~i.1:.ry: mi'.'.::~hyk~i'.':lh~!rHc. t·sr (>-1~-:th:..:i..:-d l'M EJt;\.-~; t':-:.rn.ij:1!~·d v;:n, T'•.~,ifl,;,;-d
?•-li::r. l -':W l·~~1.;.c K~).
-'W'akT i~, ,.~mc~·xd L:11r)nt rnx:c~~,in~ ,~f ('n;~•f{ "i1::i,l1~ i '.-IC" 1)~t'~
[0077] !ii iHK>lh<:r prckrrcd 1:rnhod1111cnt <1 6(1{1 mg
G•J~ik11csin:'f;O mg P>-;u<.k><;phl'.drinr Tabkl lrn> tb1.' folkrn ...
ing ingn.:dkntt; ~ml proportion~:
-c011timi<:d
Rc:::.:·1.:'-~·~ 'J~;"ttl~s::
ik\t(h {k~l!
R("" prf:-:->i::i~t~~i :·~·{;
b;-ild~ (S:1'? '~ l
~;H. L;~~·t.·;
C·:..:~ikn1;·s.lt~ rx· (95.->·~·
3-~i.-drr:.X~Tl Gf!Y~
:ntEP:kt!!ul~);:.-t:
P·h.:~l:f.H . :ei 1 ~ ~
Px.c.;~.J~K r~~;'_;.u [i~1t_
hyJ:-01.;:t:!nt·!d.:~, l:'.').P
\~ i \~rrn -,.-;·~-~'~ j j i r; c
\..~~1hi!o•:1.!
~.(;.,;fr~~!H :-:J,'11+,!1 ~ly..: >l:~l.o;
(':~•t1•m1::r ~_i_qE>
~i.-:bgfi_c:-.;•.'i11 !-o;ot-c,1~1~tt.
ti:i:; .. 55
: ~i J:
/\!D(':klf!~
(v~g/tt:J,lt:~; IR I"'."'
R;,:: p.l {~:-)'!.: ~ l~~ I; ... ·~·
'""""- (k~I'
lR L~y.;:~·
r..~::~~ i ,i;::SG: ~f~i ~ ;·.., C
!~..;!~d· (k~ )J
SR Lwu
U.;,_~.:-C- '-r{-=llav,c !N:
/"1..im1 liN.!lll l ~k~
I j~-j N:'',:. ~
'-\'~~~.;:1\ ;m111i,:J
'.'<,'/\
:-'.~U.l})
:\ '·"
':\.//\
j ~1.b_ -~~~
.~·_i,'XI
"..',\
l.3J
·.;~/ .. '~(,
:'I.IHI 1.111(,.,1.i•,
l;~;~·-_cci rn1 b::td1 :~~~·-_..-: (J J __ -l'\\ltl.UOn ~'1~,k~:.,.
11;~.r: -i:;~:~~~f~!lt~·Ui d!!"·~d c,_-..,_,~!!pf1~t·~~l[lj~ i.;:-;ed [ij \[j•! •!!::lfl\~~-)1~Wl'~1~p_ [1lC~'·~s;.._.. .::-Gf~S.it·t~
fJf '.:51> .::_~i1.:1lt-~:!'1.\:':'1.~1~. l ':SP. y--,·" hy ... h ... ~x:;:op'.1'! rn~:-~hyh.:d lulG.'>t~, l.SP' (:1ki j~f>-
-:-i;,/_.\
'.' .. A
' _-i, .'ii~)
'}J~l :-·H
D.;.:_..n·j~·t!on
/\\ ~:r.'i.~·~ "foh!d ;;,,:{ •gh~
~t~:-.:,~: ·c·:,ld..-:.n·~::-..,,
i;~~'·,-:i'.::: nta;;fof::-1.--:.
!:i~::-:hllty
~ n:-.~, 0:1 !"k?lr.~
~mo~s.lun:~
/l,)i~--~I Y-t;~!f;_ ~~~I !'.:--;.i SJ
\~~~';:~:~./ ";; i ~;~~;~~:;:~-l~r~~\·:;;--~!~~}~~~:1~~~~j~2;1 1f~;:-~ ~~-~::~:1~1~: ~} ~t~ ~~~-
[0078] hi ;muther exampk, a L~OO rn;,; (;uaikfl·~-~in/120
rn.g Psi.:ud·:x:phcdr.iu•: Tablet may !llso llnvo: t!Jc following
prup1.:rti;.s
'i .. <:: I '-f!.1-!1'
:-.=;..f(': l.,~-:r~
''.:\ff :·.r:'>·
>.::\fl' J,! "i'-~ r:~~."~;>;i~dc.s..:::
l.:--':.(U~:-.l.'.t1fr~~ rng·~.:1bk~
('J;i,1)-J:);i,;J'i-;
.. \:·~'><-1y-P~,cuiJoq;~1·..::Ui!i1..-: J ;:(,.{, w !~i'\_4 mg..'lt:.hk,_
l-!yJ; ~1.;..+ ;,:.·6dc {')3J~--1 ~JI J),..})
.:"-Hnif,::11;·:sCn T~'~ 1d::11~~n.:) i:·:Hf~ ·~Jf ;_h~~ ~11k nti~alt~i:::d r~.-An ;_h:"~ /~:-,:-::r:~
~J;;.~H~!fo«~~I ~Gr. .~\ p11.~p-1: '.ltirrn m:1kh.;:-.:;_ t!11~i of th~ S~<1wkwJ pr,i;~p;~ r::.11 lD1<.
(j~i~~jfo.1C!H!I ["kk~Hith:::~1t~·=·i~ Bi A ,jee::1-.,:h_{"(ry reJ :8' p~~l'po=~i::: 1.._.:1:0! i•.- pr,JJ'..~c~d.
P..;Lo:_.il~K'j1~-L'"Jr:~:c b•,'dr~~·t:fd'!..H·icio:._ n~t_ fC~(.!l~ioa li:m: ·>l' litt :""'-L'"t1~. 0M,1i1~c.;J fmrn d~t_ ,1\r~s~\
l~kw.: ~~·:ttlim• 1\ pr:;p;•.-::11 ;i m m:n ... -h{·~, I ~<~l of I ~c ;)i:rn ... t--lnJ pnT;•.•.1! !~Jr:_
P'.!>r.:.:do,;;-p]K1J1·~·~~~~ hy1...hoc;1!uw:l::: Tt!t: Ht ';:!t"\.."lrnm rn,1~ch~~s. trkll ·:.::•f tili; ~~;ifi_d:Hd i1~ ~he 2:\JfJ c::n 1 ~o
~.J.-.::J1t!!ic~~I ~or. n ::~}) : !1~gc ... -rn 1
~k1 r-.•~ t.~riiCnr:nit\· ~-,.. R~D °':-i...n· \1 [)•~;. e:-.:. R~D :-..:MT-; ~i-; :·~-1r ! :~~:.~I n1
/di !r:divi{l;_;~l ·.,.-;1lu.;:~ h.-:S\.'-'Ccr: i5.U-l L'>}f·-~
(F1.~i- ~ .;'.;'>''...-1 !L (;r1!.· \~~uo:._ b. ~m:;';!,'r.::ci ~)u\;jJc tt5-.0--j J5.1V~, !-.u~
l~O~J{: '.Y~:l:-..i{k 75.l~- l.~S-~ i'';-1
US 2003/0215508 Al
D~ =:,~,.__.Iii r ;~· ~ :1:
( ~~· h<~·,·1.: lh(; i'oJl(v,vrng pwp-
.;r!i\;s:
jk~ .. c1irLim•
A;·i,:_1.4mg--ri:::: LN rn~)
:.l_:'.41~ ~-i.2(,.~"'
1'.'-'-: SCI'
:--;;sr n.:Y'-
S\'1'T ~'. .~y·:-.
'.'\Vfr ~ ~; x~ o:o•r~,.,~~it dn~,..;~
S :10.[~--{130.U fnf._'{,ri:'.'>)e~('-'5.l r--.:.U5.u'-;·· ~
.'-(~--= ~._1 :(1 ! .X ;;_;~:Ct1hkl
(<.t_i_(;c.11)7.cl"i·I
Nov, 20, 2003
7
j.Jcr:~: :~l:;Hini~ /.,._
(;...._:~,,frner-rn
!~k~;1 ::;.,--atlD~\ R
111t :u.c:~H:o11 ~i!Ht o:· th1;: p-e:1~k o1.1-f~!f:~'J ft'l~m th.:~ A:-:::,~•y
r''-T'm~~i.:~•; rrn~~d-,;~s_ l~,H c.f th;:: :'-.I ;rn~!tuJ j1n:p:~r:Hii10l
A de~1H.:lwrcy ~.eJ tc !.:n .. 1 rpr1~;e ... ~1}1ci~ l·.- pmd~i..:rxi.
l'~r::!d.;:1r2ph.::fJnfl:: ~y~!rc·ch 1::-:iri:k "Cl!:; -:-;:[(·i1'1 ••:•fl S••n:: o~· I h:: cx·~k ohl,.~;r;r:{] !'n)m I h:: /~s~o:~t l.-~1ik•rnJi!'• f•;. RSD ~MT .f).n··;, e:~ RSD ~;.,_n~ 7.w·; f-:-)~· L<.-i.··.:-l Bi
ACC ~:uli\·iJ:_;?..; \;ilw:~ ti<.:h"-'t'Cf! 8~.n-! l:'i-.(l'~·
(For Le"~·d H~ c1l~~ v:1il1.: i•. al[cr,_-.,.-:~d mihi:J~ ."'1:5J~--ll~Jl 1 '!-. h~=~ !~O!V.:Â
D~~i~ld~ 7.;;:.n----1.:s.D'>f
~ fi'.-.:--:clo..~:.i.~'•;)' ! Hom: "'\:.\.iT .~,··V.i-
(:i'.,_:;Hf~fLf::Hl~ 2 U:::::-~ti': -·f J ·-t:J .~.'.
•:: fl.;:.;,~r: "7 ?.- 1 )J··:.~
I~'. !-k••H~ ~ 1 ·3- 'l.'(J'",:
Pi.-..~':'l~i~i_n;\: ~ u.~.~,1·. >·'.>,1T '.)ti;"l'.·
r~.c;_;sJm·r:~::{lri!l.:.: (-:-\·drc,1~'1l.:-1rl.J;: ! ~3rnff: 5t.i--/t1'!
~Hom: :"-.:l r B(l'f-
t:~ Hom: "SLT kt5·>
l!WJSO] In om: rnibodimcm, the 1:200·60 mg gu3ifon,;;sini
dextromdhorphion wdg!ll spcci1l.n11iou is l 5.'1-0.4 m2; ;;:.'i,O'l,
corn::;Jmfldrng lil a rnng" d i41'l4.5" l '5Hi,"l mg, Fnr the
(Jlll}/_~,(1 mg 1ahk1, Int weigh! spt:di.:;i1iun is 705 .. 7, mg
t1 Wii,, t:nrrespmiding tu 21 r;mge nf 7 42 .. ?" 7:",1L? mg. This
~p·~citic~l,i•Jrl r;cn,;c of :>;_,-,_{)";\°, nf tht lhc(il WCtghl is
s,imilar tr• lh<.: g1rnifcu·~';in alon<.: J.200 mg ;rnd ()(~0 mg l3bk1s,
r<.:spn:livt: ly,
l Oil8 ~] The propoN:d ilud1J<.'f'-'' MKl 1hid;_o,,ss sp<.'cilkatioas
fot· 1bc 12(f0/{J0 mg guaifn1•;;sinidcx1romtthorpllan tJhk:1 ar.;
15-i_i'.i SCU ;rnd 0.310"-0.34!'!", rcsp<:r.Jivdy. l'bbkts prc'''''d
M 517 lpm .->• [-'Jr:w1ckr ( !2LBR6B) ran;;-~d :'rom
0 33 ! ""(U3S" and l '<:'.·1 SCU. 'l110: friabilily rnnguJ [rum
0 20-03\Y.:{. Di:;8u!u!illn k~ling \.<."G..'; pcrfnm1eJ for ~oach k~l
uindi1,ton (527 lpm ;wd '?.i7 1.pr:1) wiltiin one h(mr <•r
compn:ssioa. No sigaiiicani dtff<:rc:ncc \VH:'\ ~."1:n in ih1:
rdt~&- prntik b(;l'cV(;(;[] Hw h:-s! s;ompkc; and lb<.: pi!o!
h:i!d1cs.
i:mua 1 ! mlher l?,hlers pr<::;;X'.d :;:,; thin and ;is hard ;;:; th<:
press \voukl :il!o\v ;;t speeds of 527 !pm ( 12lB8CiC) ;rnd 737
tpm (J 2LBE6D} pru·,i.cbl ii thid.:nc--;,._ range ot 0.3(1.'\" -
{L~>i-7" w·i1h ;i <:mTe!ip'-mding inili<'.l h<'-60
S{ ·u r'nr !ht: !abkls pn:s>.<:d al 'i27 lpm. The kirdne.ss r;m;~e
on lhc liflh d~y atkr <:ornprt:'>''iotJ \Vile< 4)<,.)(l SCU frH H1!.'.
tnblus pn:w~d at 737 !pm. Again, lht db.solu![nn prnl'ik for
1,he !<:"!sample.<, <:Dffe,.,pon
fot· the {JOn.r;o m;-; g11aikt1-.;si11.·'ckxtwmd!wrp!un Ubkl
wi~re l 5-6'i S{ ·u arJd tL'.L':'O"'-iL"261l'" n~~.pecfr.'i<:d dt thio minimum hHdm;s~ pa.r61" aml 8-11 SCU. The friahility r;;:igcod
from iU 3-0.16',:{ .. Di,c,,.,,hninn 1.esling W>l.~ ;Krf:;ir1rn:d for
·~.;id1 11.:sl cnndiiiun {527 lpm and 840 lpml '''if bin nn~ !\(•iir
uf <.'.flmpression Nu signd"k:ant difl:«..;renc<; w;is ""-'"'n in t!1v
rdea:'.<: pmfile ('i,;!'.:s.
[!Wl841 Tahkb wne !hen pn:~<....:d :;,<; 1hi1J and ;is hard :h the
pn~:i.0, wuuld ,i!low. A rnr1ge uf O .. L'>T'-0.2,1-J '' "'''is ubi.awetl al
•.ximpn;;;,sin:i wi1h ;; u1rn:spnndi:ig hard:ie~" r:on~in~ !'rnm
15-30 SCU evnil h (i3y ;ilkr
compre:<:;imi ra.nged from 28-34 SCU. A r:w~e of 0.2~>0"-
0.24 l" wc.s ulnai[K"d al cornjffe"·'irni with a •:orn.:sj!muling
hardness rnnging from 23--30 SCUM .":40 lpm (J2U385D).
Th" fri3bility rnng;;d from 0.00-{UJCJ. Th" h;irdn~s.-. on thv
:"<:vca!h day after <:ompressisJn rnng<.:d from 1.8-33 S( 'U
Ai;ain, the dis.'i<>lW.llHl pmiik 1'.ir lb<~ ksl >.;m1pks (sev.:fl
day-; ;ifl,in,..60 mg do:-
lmmdhorph;m c d
0.1.'.lff' -(r.~ftll", ;m avaage tablet hHdnt:;,s uf .?.0-~'1) SCU (ill
imi;:i~;.;~), ;mu an 'lvi~rag<~ lah[d hmdnes.~ Pi" 10-'il SCU (;>l
lim(; ol" r1.:kiis~ through n:pirMion date).
[!Wl87] The sp,xificili;,Jn ur NMTlLN"i·! ~d for !he friahility
of both t;ii3ikn~sin/(kx!rrnnetll<)fj~!un t"blc1 streng\!1;; is
hastd on ltil' hrnit <:';i;ihli:>h(;d ·,vtth 1 IK g11aifrn;;sin a low~
l;ihkl;.;. The ;,pet:iJkatiufl l'.:Jr l ns.s on Drying is cnmp;ff;ihh:
ln gi.rnifon('.sin a!m1~., i.e. Ntv1T 2JV;.;-.. The m<-.islure lir:1i! i>,
2.0% nf l.ht: !olal th<:nn::i .. :;il 13.htel \':<::ighl, rnn>r(kd in
mg/uni! du&.;,
[lP!lll8] The rangt for th1: specifa:al1c•ll fr-.r guaifrnesiri is
h~s1;d (>!l lfa: li1hdnl a1twuHL L?OU mg •.)f (i00 mg :t4.W:r F·.>r
ill;:; l'.::00:60 mg gu;tikllcsu1\kxtrornula•rJ;b3n tnbk1, th1:
nnge is l l."i'.'..O-l 2clli.O mg per !::hh~1 ! "nr the M!O.:_~O mg
guai1:~ne,sinide.x1mmdhmph;rn tabkl, !b;,; r;mge is 'i71d)-
62~.n mg per ~ahld. Tile rnn1~~ tor ill·~ sp1.:::ifo:ati.on fo.r
dcxlr(:mdhorplHuJ HBr t$. haS,
8
Nov, 20, 2003
thJn 4l, mor<:: pn:for::bly kss Hun :~8, more prdernhly less
fh3.n 37, and mor" pn:fvrnbly hd'Nt<.'.fl 32 3.nd 35. SCU 1,;
;llso prcfornbly gr(;3tcr til;m 1 ! , more prcfornhly 1~.r·~;iln 1tun
1·l, mm~' p1eforab!y gteah:t t!rnn 28, and mot;; pr.:forahly
".ft2Her rh;rn _'IJ.
[0\}911] Tbe weigh! ul W bi-by<~r girniCet1('.sin.·pti<:l.!tloepht-
drrno: 1.abkis ( 1200 mg!l 20 mg) is prei"<,rahl.y le~; th:m Uvl
g, me-re rHeforabJy !fo.''-'< !ha[] j 6.:b g, Hl-'.'ft' prdernbJy k'i.';
tila.n JA29 g, rnnr<.: prdi.:rably k"'"' ili::n l6.2:'.: g, morv
prckrably k"' lh<:n 16,J 6 g, nmf>.' p1dcrnhly kss than 1C1. lO
g. morn pmfrr;ihly ks;, th3ri In 04 g., :;:id mnr<:: pr.;;frrahly
hdwern t'i.71 g and lf'.J)_) g. Thi; w~,\gh! of JO bi-!ayer
rnbk1s i;; afao prdtrnhly grcaln th:m 15.'15 g, mor" pr<:l'o.:r-
ab!y ;;;realer !lrnn 15.4\l g, more pr<.:fonobly grv~!(:f th,1J1 !SA(i
g. mor1.: prderahly iif\'.iller 1h2m l 5.53 ~;, nC>.Jf('. p.rdnably
gr1:;31er than J 5.S9 ~, mnr;; pn:frr;ihly ~realer lhan .I S.6'i g.
[O!Wl] Oth1;r •.;mbodimrnrs mid diar«cl<.Tisti,:~, of !!1<.:
invenli(lfl are deS<:rib('.d in runhn tldail hduw.
[!J092j S%lain<.'d fkk11s~, Fornlllfo1ion
[0093] Ju :>l1ihlt fK"lvmer. !n J forlht'.f i.:mbndimeril, lht: :ms,
tr,[ncJ n.:k11S<; lt>rmufa.lion m;,y i:ompri><.: ;, <.:omhinatit•n of
i;u::iknesin nnd al k:a~t on1.: addi11on:i l drng, wllcr•~.in the
;iddi1innal drng m3y he M':k,·l<:d from, hul i,; no1 limi!t~d In.,
all anlilm.~i>·~, ,,ud1 as d-cxl;r-mdlmr pban hydrnbrnmid.:,
cor_kin1.:, hydrocodon•:, :i dccong~stanl such as plwnykpll-
l'i ne bydrochloi id<-~, pbrnylprop:: nuh: mine liyd t ud1lorid;;,
p&n1dsx~plx~df im; hydrodilorick or cphcdr in<.:, ;rn ~lltihisrn -
mi1K' s~d1 as d1!lirpher1[r;,mine mak~t.:, brumpheniramir1<::
rnak;11e, pheni[]damirit. !;irlra!e, pyriL;mine maleak, dnxy,
famim.: SlHXini!l'.'., phcnyholox::mif!>.' ciW1lc, diplwnhy-
drnmin1.: ilydrod1hiride, prorndtu~inc. ~.ml ckmanine furn-
<::r:11.<::, .rn a:ialgt:!iii: sm:h 3.s aspirin, ihupmf-:11, n:ipm-;in, ;md
a•xlamimipbtn, m cnmhina>irnis ther-cnf. !'rdnably, !he
dmg i~ dex!mmdhorjlban bydrobrornidc, j!S-~udoq1btdrine
hydmch!ori(k, or ;t <:t>mbinatiml thn;:;nf.
[tHl9'4] The suslained rdca"" niatri~ ulili:t.~s pulymtr,; 'l"<
dcs-:::rib1.:d bdnw to ;id1i•:vc the r·~quir~d dday r•:k~sc pmlik
in vivo. Tu obiain 1.lle reka:.;,: p;otik prop,~r mixing f:lld
Jorrnu[;;til•n is r-;:;quired. l·w in:;lann', !o-:' much hyJmphilic
pu!ymt:t· will r.:»1d! in lm> qi.;ick nt' ;i rcka:<<:: and nn! aJky,,,.-
l'or 11 hmn rdid' whi k: HJo much hydrophobic pnlymt:r will
t·esul1 hi irnickqi1 ate C""'~ for rdk f of :.>at:h nl.ht:r pm'1i1.k ;;
ma!t·ix wh1d1 is lb.en forrm1lak·d ao:.:ordrng lo >lK' bd:w..-
mdhud;; l.n provid<.: th<: ,ippropr[ak o(;k:i!l'£ pro!lk:.
1:0095 I !!ydrnphilic pn!y:ikr.~ suit;ihk for u:~.: in I ho;; st1~Â
ui1n<::d rck<::, hydrnxypwpyl. mclhyk:dlu-
]o&e, hydmxypropyl cd!tJkise, hydrnxycthykdlulo~.(;, car-
hoxym<.:1bykdlulos.::: prolcina<:<:ous subs!.Hlc<-'" ~.u;;li ,1;;
;·igar, pv.:lin, c:arngecn, <.: fnrmuiation, <:ff polym<.0r:>. whid1
;;~tuaalty do nol di:>.'i-i)\11;; in ."l>h1ti•.H1>< ;;J ;1 pl I bduvv 5, aml
di;;sohT mor1.' slowly [n b,1sic solutions !h;in t!K' llydropbili<:
]lnlymn. lkcaU'i'.'. tbt pulyrna t.\ insdi.;hk in bw pl i
<:rivimnrn,;ms such ;i.~ 1hw;.; i'nurn.1 in g:islrk Huid, il :iid:c. in
f<-'Luding drn;;; rd"&;;.; in those; r1.,gions. Ltk<:wisv, b<:1:;n1;;"
lil<.: polymer di.ssolve:; r.rior•~ ';lowly in SO[\JI lrt; un1fu~ni ."1cfUH~ t..·ont:1-=--nlr&liDn of gu~~f .. ;n~
c:>ill.
l 01:!91'\] Thr: w;1tn-iJJ."l>h1bk poiyrnus ;;11i1<1hk tc·r i1;><; in
1his invention im:l11d" for c:in Cubupol 97·tP i'Hp-
pfaJ liy Bl' (iomlricli.
[!)()99] A !msuin<'d nokaoi<' fnrmul;;1ion nt' inv<:nl.inn m;iy
fur !bs:r .:nm pri:~· pharnrn~:eu tic:3 ! addi1i \.">.'.s indudi ng, hu l nol
!imil<.:d to: lubricmlls sndi ,'ts 1rn1g1i-.;sium sKnrnt·;;, cak[um
slcarnt.;;. ?:in;; ;;furnK., po'-'>"(kr~d ;;to;aric 3cid, hydmg<.:natcd
vcg<:1.nbk r.iils. l,'lk, polydhyknc glycol, .'lml rnin~crn! nil;
nilurams; bindei" sud1 "'' sucm.'.<:, LKkw.t, gda!in, ,,tardi
jM!ile, 3.cm:i;;, lr;ogi.:, m;wniloL glucose, i'rnc\mL. xyltnl-', g3lrbt!lll, dilorid..:. sulfaK Mid
plwsphale "ali.s of pOla;.,..ium, MKimm, and rnagm::sillm;
itm.1_.-'or ilflJ' ulh<:r ph;irm<'<.'<:lll.ic·,;J 3.ddi!iV<'.S kllPWfl l.O !ho&'. or
skill in \ht: ;:rt. Cnloranls Jfldutk, bul are n<;l limikd hL,
Emcrnkl Gn.o;,:n L1k1;, fD&C Red No. 40. FD&C Ydlov: No
lain1.'d r1.:kns>.:
fornwia JiiJ£>, '.'We nf wbictJ j,,
9
Nov, 20, 2003
gu.a.ifent:sin, <-OltJblc polymer. ,ind cH ka;;\ •)JJC plrnrrna<:n1ti>.'al
;iddiJivc which permits di;;solution nr drng;; in a tllcnp<:\l-
1.ically eff1 modified n::k;!'<-' for-
rnlllalion compris<.cs from a!".llll 7'i<;1. !o about 9Y~ guaifrn,
<:siri by weight, from ;ihulJI l '}i, lo ;ibrnH l y:4 by y,•,;ighl oi'
,w 3dd!!in11al dn1g, frnrn ;ibmi! fi.Yi tr• c{bnul lfr;>. hydmx-
:1propyl rntthykdlulosc, frurn al_h.'llll ti.5')i. to ,'tboi11 2.5'/[
iKrylic rt:<:+. lu about (:.<,;;-,
byJrw.:yprnpyl mdhykelllllo,..:, from alinul l 'H- lo ahm!
j 5~:f. ~~.;:~~·]l,~: re.~:in~ from ;~hoBl O.?t;;. iu ~diou! jl~,;:-. mi:~rB:=-;ium
S11.:aral<.:. and frnm ,'lboul 0.(tV:r,, io ~bou! 0.13'/~, cGlornlll by
weigh! ..
[iHtH] Tti~ nht:m1•:d rdr::1sc forrmil11lion con1rols !ilc
rdca:>r: of g:niifcncsin and opriona!ly al Jc,1s1 onv addiilon:i.l
dmg in\o lfir; dig-;;:.;liVlO \r;;c\ UYCf 3[! o:lt:nded perJc•d of limt:
n.::'iulling in an improved pmlik when com[.''ff"d 1.0 imrn.o-
di::k rdea;;e \:ombiri:nic·ns. _p1aifont:siri :v:Jlubiliry is dfock·:l
h~' tlK'. pH of lhv uiviwHmk,ll! in whid1 il is pr<.~S\.·nt {i ... ;.
st•Jrn:t·~h wrsus int·~slrniil lritcl). Jn a mot·~ itddic uwiron -
merit., sud1 a-; the -;!nmM.'h, g1Jaifem,.~in i:; k~; N.>luhk whik
in a highn p! l ,,nvirnnrnrnl, :;ud1 ;;.~lb~· i11!<0"lin<:s, guailcn-
c;.;in is KoltJblc. The pH d1;;ns-:;s throi1:o}lwut die
d1g<.:'iliv1.: I r;id clJi<:! !hc dis~olmiof1 r;,tc ol' guaift:u<.:sin mid
M1.' pMltally d<.~KrminalC of llk conr<.'.JJW•lions ot gu.tifon<::>.in
an~ined in !h<~ bl:.x-1J and lt.'.~Ut:~ ..
[!JHl2] Tb maim~ in i1 llkx:'d cou·~'~nlr:Hion of guaifl.n<.:s1n
which pr•:ivide.s good l.haapr.H!ic ,;lTe•.:I, 1.hr; rd~;-,;c.~, nr
J[;;,sc·llltiuri, of guai!'tfl':'-:~in frllm a ((,rnm!atJOIJ fll;J[HX lS
prcfcrnbly f<-~l.udv:I and/or cuulfolkd lhrough tih: illl>.·stim:s.
Tile hydrophilic aud wat<.:r-1thoh1bk pc1lym1.:rs (>{ th<.: s;is-
rn incd rd1.ca:-;i; forrnu h:1i0n gd ·,v]J •. ; n ''"-1JO><.'d lo rn.:-d i,'l uf Jov,
pi L Ti-ii.~ i,;d m;;(rt.\ aJllrN>. ;_ht '>ll.~taiucd rdm.w drngs, 1.:.g.
gu:tifcont'.'lll «lom~ <.ff in ix;mtJiflMion wilh ;; ,'i<'nmd drng lo
tlt!fosv J.l a >.'Ofllrolkd rJ.!<: wh1:n cxpoS<.:d lt> a. bigh<:r pH
cnv irurnr1t nl.
[OHB] V-/tin1 u:~ing Jrug" ''[-'pmvd by tti~. h1od Jnd Drn!<'.
Adminis1rnli(ined rdcnsc k>m1ul3!ion
rnJ.y h<: fornwfal·.;d 10 mimk' lb<.: b[o(,J si.m;m prntik of
i,;ll1ikn<0"e as
1.ks,:riht:d ifl lh,; diflintl du•.:1Jments ilkd wil.h ih<' fl)/\ nr :i.-<
rcqnHd by th>.c FDA. in •-1lhl:'t' Wl>rds, lhi.'. susta.mr:d rd1:asi:
fomrnlation r,,k;1sc:' 3.1. kas1 mw addilinnal drug al suslaincd n:'ka:<-<:
l'nrmuL;I inn 0·1rnpriS<::s ,, hydrnph.ilic polymer and d wm~ {l: 1) tG
aht>tll 11inc-iu-l'•ll1.' (9: l), lll-unt (2: ! ) k1 ahuw. four-l<.H>ne {-1: l }.
US 2003/0215508 Al
!rJ ;mulha cmhodim<:;.n!, lhe sus!::iritd n:k;i:;<:; funnul:ilion
;.xirnpdS<.~·; nol rnor<.~ limn ~.buul I w;i. bydmpbilk polymu.
pn:fcrnbly, nm more 1hK> corn-
pri-.es rml mi>rt'. lha[l ?..<;"f. ;Jr ihe w;;ln"iu.,.nlilhk polym<;r hy
wdg!H. In anoih<.'f prnfrt·rnd l.'.111btkltm,~m. lh<: wr,11.,r- hydro-
philic p<.>lym~r ii; hydwxypmpyl rw~.lhyk:dluh>."'.'. :md lti(.
\'-'fllC1·-ia"o!ubk polym<.'r jc; acryli<: r''"in. Th<.' rallo1< result in
a S<.:rnrn •:om:\'..nlrali-:in prollk uf guaiteu~";in lhal provides ;;n
or1im;i.l 1.ht'.rn[Jt'.1.0ti<.· com:erilnlirni ft:-r ;,hom 1wd·ie hrnirs.
[OW5] A sustained rdcasc k·rmuhlit•n may ho m;muLu:·
lurell an:rnding lo ar1y appmfffiak mdbuJ J...[](w,"n lu 1Jm:<<:'
ol c'kill in tile HI (•f pharmacrnl i(ll) 11rn11ufadurc. !n ow~.
.:mhoclrm<.:nt, guJifone;&ia and a hydwphilic pnlyrnn m;,y bv
mi.~ed in <> mixn ;vi!f1 all 1liquol '.lf w~k:1 lo fmm a ,,,.d
gramil:Jfr,n. The grilm1b1 inn may h;; dri"d !n cfoain hydm-
phillc pulyrner <:l'IG•P"'llbl<:J grnnuk~ ol guaifoncsin. Tih·
;c~,;ul!ing g,rnmiLuioa may lx' rnilltd, ~.;r.'r•.;1;1J<.'.d, mid Hx~a
bknclcd with Yf:s w gastri<.' ji1ic~s.
[01 !Jc6j In;, prdurvd <.'mbodimrnl lil<." mdh•xl of prtp<>ring
a su;,1~inv:I rdcis·.; ft>rmul31ion compt·i&:s londing 3.ppwxi-
1m1tdy J.26 kg, of guul l 50 R!"M and a chopper spc·~d of
.1boui :moo RPM. Tlw mixing and dioppiag spec;ds 1rnoy
!lx:ri he inu..:as-cll w abmil 200 RPM aull :·«JO(} RPM rec;pec,
!ivdy for ahuu! llv~ rnirnJ1.es whik i:!IX'l.!l 49 kg of wakr ;m;
3dikd !o !h<.: mixn tx;nl.erils. Tht'. mixt'.r may b~ nm for !wn
~.ddiii·.)1Ml minuks !o ·.:t>mpkt.; grnauhlii•Ja. In 11 furlhu
prdcrrd cmbud.im<.:nl. th<: ~tlul. off lor lb~ 11.1ix~r 1-J;id i:> "'-''
In 21 hlnw;;l!s.
[0!07) TIJ<: \Vd gnrnuJ;Hioa may b<.' rn1pllcd intr> a thiid
ht:d [:{1w! ;md pl:i.:eJ in!n a lluiJ hell drya ?;t;\ hl a dryei ~ir
!low of \)(l(l ( 'H>'I ~nJ ar1 in kl !t:mper;1!ur<.: uf ;,buul SP° C
In ahuut 5.5" C. Bn!il !h,; mHlet kmp;;nlurn im:r<.:a-.es ;it a rnk
uf 1° C. ~x:r minut•.;, Th..: air !fow may !b<.:a be (b.:.r;.:35;.:d tr•
600 CFM, and di;; rnk1 io:mp•:rnt1m: may b;; d~;;r~ased lo '13°
{'. 1mtil iht: gr;inu);Jlion I,'< drit:d In il moi"dimcnl, ml ;1g,itn1or in lh<.: l'lu1d b<:d bowl rrniy
h<.: rnn int<.'.rn1iiwmly dut·i11g dryi11g. Tb<.· dt·kd granu!i:1ion
ma;; bt' p~s..~;;:J lfimugh a mill Jll!cd witb ;i ,,uilabk .'i<:rC<.:fl
si,:r. ,,., !fi;>l nol mnr<:: th3rl 3.hnut }0% uf i.h" rt'.~,ti!ting
grnm1h1ion <.'Om<.:s ilm::i11gb ;1 100 mc:sh S>:'rc:c:n anti nol nw.r"
lh;:n ,1bou1 JO% uf th<: r<::<1.d1in1; grz.mJbtiun .is rcwino:d ou ::i.
HJ m,;,;[J M:n:t:fl, In une pre!'err<::d cmhndim;;;ril., ihe zlri<:d
granul:ilic,n m20y ht'. r;i:.;,it'.d through a mill H11t:d with a O. HllY
si.-:e :~neen ~l ,., mill .>peed uf ;iboul 'iOO lo ~houl 1'.iUO Ri-'M
;rnd it 'iff<.:W fed rntc of 3lxn1f 35 lu abou! ,i5 rt PM. Tht:
rv,·,1liing &cr<.·<.:nl:d grn1whi1iou i:" abuul f})fi f;U3.ifrn<.:sw ;rnd
i~ calkd (J {;uaifcntc:ill DC (Dir-cd Cmr1press1.::.d) h<.:1eir1
tH 0.7 kg nf
magnesmm skarnk, ;rnd ul
5 kg ;Jf Mdh<••.:d LWM, ah·:rnt 15 J;g lu abmtt :'. .. 1.5 kg of
CubGpo!® 'J74P, .'lml .'tDO\I( 4t> ;'; lO about 240;;, or <:o!ornnl
ail\l :. high ~he3f mix~r. if :11 !hb lime W3fcr is lo be ad(k\i,
1.bc;a abom 1 k::; 10 3.hout t.5 kg, of magne;sium slf:arn!<: ;,,
add;;d 3S ',>,•dl. Tbt rngredwr11"' mav h1.: mixed rm ahuul !en
l·:' 3hrnH I.:? m.imik.> ;J.l a mixing sp;:ed of about l 'i() I< Pl>·{ "nd
,l ,;boppt:r 'iJK•.:d of ;lbPul 20ilO RPM. Tb(: mixing ;uJd
d1upping &[X:<.'.d'i m;,y llK:n ix: im;r<.'.a.;;,:.'.d !o abom 10G RPM
anJ 3000 Ri-'M, n~s1x:divdy, for ahnul llv( rnirrnk:~ wlitk
uptirnially ;ihrnil :'.9 kg t;i' walt:r HE :dded Jn lhc mixer
~milem:;. Ir rio ;va!n j,., added, !ber1 fE,m ab:ml ! kg lu alxrnl
J 5 kg or m:igu~»;ium sl.c~rnrc ·::iln b·~ add-~d a! rtiis 1im~. Th;;
rnix<.:r nrny bt rnn for trn ;1ddi!ioaa! minut<.:s lo <:ompld<:
grarml:H1011. l n ;i fun her pre fnn.cd embudirnenl, lh~: shu! l•ff
for tht: flllX\:T bad is ;.,d tll :! ! kiluwal\s.
[0I01}j The wd grarnJLHron may I~ emptied inln 3 fluid
hed h;iwl ,md pl;m:.ll inln a llHiJ heJ dryer'\>~! lu a llryer air
tlow of 900 cnv! ~rld ii[] inkl t·~mp·~rnt\Jr•: of :1h<.>ll1 ,",~:'' c
to ;i.bou14B" C un1il th<.' otJt!d t<.:rnptrn1Hr<.~ lm:r.:J.''-';, ,Harn;;;
of I" C p~r mim.ik .. Th~ 3i.r How may thrn b~ -;kcr<:3'i<:d 10
(,(l() CFM, ~fld
mutl: tbr.n O.Y?i. ln MJO!ber 11rcfrrrtd 1;mh<:li.iimrnL lb<.: out kt
tcmpcra!\lf<.: i~ ';U !o l Cll(·Off of ,k( C {n yd ed !hm1J""fi a mill ihkd '-'·ith ;,: sui!ablt :><.:re,on
siz,; ;;o lh;11 not more tb<1n om l i.V1. uf !he resu!l.ing grmrnlalirn1 1>, rdain<.:d nri a
Jn mt'.s!J :;neen ln (;ne prcforred i.~mbixlimrnl, lht tlri;.~d
grnrmla1.:on may be pa~s.c:d !IH011:;h ,~ mill tilted wiib B ;.iz;:
screen of 3hout lU09" !o ;1bnut U.l2S" :11 n miH ~p~~d of
al,,J\11 500 !u abom lSIJO RPM and <1 ;;,c;r<.~'N fen[ rat•: of ahoul
.1'i lo :;hrnll cJ"i RPM.
[OlHi] Tb<.· ;1;sul1ing furnmJa1ion> rnJy further Ix wm-
prL'i.',cd m1 a iabkl um1pr<:>,>KH mprmrria!e ·wcigh1,
'>1zc, 3.nd "Imp<: dq:o:ndins un lhv dt'itf<.~d d1)c;;1i,;c :>lr1:rn;1b uf
l~bki. !ii une cmbrnHmcw, these u1b!us rn:1y h1r1ll~r he
Jo;{,k:d into a ;.~0<11in:; µ<1a i1ml !ilrn coal.l.'.d wi;ll Op<:dry
'r"S·~·7l-1 (suppllt;.;l by CJlurnm, lrn:.) ;md air dri,;d in !he
pan.
[Ol! ! ] !n ar1olfH~r <::ml-.uJirncrJl, lhe methud uf prqiaring ;;
:m:-1.aini::d r~kl!'<: formul;;Jinn ,;ompri'i<'..~ blrndirig the drug:;,,
llydwpbilk p0Jymtr. \V?.\.:r insolHbk polym<.or, <:nd miy
phamw,;.~11tiea.I ;iddit[v<:s. Tb•., re:>oll.ing bknd may then lw
cnmrn:sst"d imo lilhld:; arid, if des.irnd. film ,;,,;;1t.d wilh cl
pmtt:dive coating which rarally di:.;:;olve;; ;;r di:;per:;>.o;; in
g~s!ric jm•:<::~. !rJ a prdeffeJ nrihudimt:ni of such;; metlitKI,
almui U\1 kg of Ciirnifcnc~in DC (;ilx>lJI 9Y::t purny}, 3111'.l\ll
1.(i kg of M<:llKKd El OM, allot•! LJ kg, uf Cad:ioplol 'J74P
;rnd 1lxml o.:n:< kg of a n>lurnnl such a"' Em<.:13ld Gn:•~.n
I ~ke nr FH&C 1ll UE Nu. ; may he lo.oded intn ,; W rnhil·
fo•.>t V Blrndn. Th~ in:;rcdirnls nuy ht bknd<:tl 11_-.r about 20
minuks al wllid1 1it111.· ;,ho,iul 0.6 kg of magn<.'.~.ium sl.t:irnw
may k added lo Ibo.: Mrndcd aigrdirnh. This mixnir·~ may
Ix; blrnded for ;ihnut ;;no!hn Ill minutes. Th<.: resuliirig
forrnu[;,tiun rn~y tunhei be cmnprcc,!'--tJ rn1 ;: ubkl cnm-
US 2003/0215508 Al
pre:;_~or m~.diinc usirJg ln-;>lifl."' in furm ;;,hh'.l!i. The l.-0hle1-;
ffrny b,, i1ny apprupriai<.'. wdgb1, :>iz1.:, and sbap-.; dcprndiog
on lh·:: dcsir•:d dnsa1;c sin:ngtb ot the 1abk1. These tilhkts
may fmthc; he ];iadcd inlo ~ <:Palin!<: pan ;,nd lllm coal.<.d
'>,',·ilh Opadry Y-S"~'"71'1 (suppfood by Cnl<.m:ufl, !nc.) 3ri.;J air
dt·inl in lb1.o p3.n.
[O! 12] One emhndimrnt uf the invnition w;et> the ((>11nw-
ing gcn<.'.rnl mdbods of rnanufac!11rin::;. To make th<.:
Guaif<.:n·~,;in OC (95':?;,I inrcrrnv:halc grarn1 !ii1iun is nm·
dtirlcd. The gr;rnuLHor t>. charged wi1ll piritied 'Nlkr USP
Tht: guaiCwesin USP :s added in10 l!H~ ;;pnulatnr. Ne;;I the
liydroxypmpy! mdbvkdJu!u.'.<: USP (Mdbucd ll OM) is
add<:tL Tb(: gn,1ik11i:;;in in1crmcdi;1!l is dried wil!i Ibo.: ;iif
ink1 !cmpna!iw,: &:t :ibuut ::;~ C., lJ!lti! Jh:; ,1ir om!d wrn·
p,;.1alun: re1d1ed appmximakly •l!<'' (·.A ;.;arnpk may >h,,n
he Lilien for tfl·prrn:;:.!~~ >.:tHJl.wl ks!ing (moi"lun; ~.ri,ilysis).
J\f1er the rrw.t~r~1~! IeacfH::-r ;_he ~argcl Fnoi.~tuE~ k;~ . ..-~], di._.~
charg<: llK: bk:nd aml pru<:<:d to rnilling. Th<.'. dri1.'d grnrnJ-
!atwn [;; rhrn add!.'.d !o di<.: milling madi1m: ;im] tb<.: milling
prnt:ess inillakd. !\ga[n a s;;mple may bi: taken f[;r in-
pmn:"" C'>ntml k;;.,Jin:;: (rnl.cn.3.! ih colkctcd into tunl libn dnims, dmihk-
!in.::d wdli p!a:>,ic hng,<. aml conlaimng ;; 'ksir.1.,mll poudJ
bctwecn rti·~ i.nncr and oi1l<.:r pListi.:: b:igs, th(:n I r;rnsfrm:d to
hl.:riding. Tlie hai.:bi.:s Mt: blended iri a 60-cu. fuot blender
1<.-.r ;;! lea .. "t I 0 rninuks. Ag;;rn, a s;impk may ht: Liken r,,r
in-pro'-'''"' con1rnl tt'.&tin~ (dc:;cfipliun, moisture, hknd HVill:-'
3tld ;;[eve ;,r13!ys1s}. Th~ hmi I siev~. 11rn1lv;;[;; for rnJ!kd
Gu;,il'.;;ne.~ir; nc prefr.r;,hly \>/ill he :l!i fulhw:;: nnl. ITH.lf<:: 1.h;m
;,lxrn! 2: 1_o JO',:!,. n:.!airi,,d on a lil-rm:sh .<:t:ieen \2.UO mm), 1Jot
k!;s 1 h:in dhnut SO t n 60'/; re Mind ori Hm 2:0" m"sh 1hro1i gh
WO·!!l~~h ~i.:rccno> {l 50 ,wn), nm k:.;s lh" 1brough i1. HJ(.>-m-.:"b S<.'.rc1.:n. 3.lld not rnorc th;1n ahom
h-::Off;.;. wilt [Els:~ !brnugh a l·10-m.::-Ji .'«:n:(;fl (10fi pm)
\.\'lit:fl at leiZ<.'. in ibc rnng.;o of fmrn abom
2 mm to abotll ISO pm, this faci!itaks bolll pro(:css:ibillty
and achi<.'.vcm.:rn of th<.' ck1>irct1 in vivo rck;1S1.' pwti!r>; for
lh.: singh: w!il)' anJ enmbin;ifi(m Jrngs ·:kscnkd her~'rn.
·nw fin;,] Gu~ifr.n.:.<,ifl !)( · (9S•'X.} grami!aurni t~ culk.:1.nJ
i1110 12red tihcr drnms, dotiilk-hncd with do~bk:-lirn:d with
pfa::,1i(' h«ss and • ..:onti(:c:tnl poi1d1 bdw1.•1.'ll th1.•
irn1~r ;111d O'.l!(:t pl3slic !ngs.
[{HU] Jn on•: rn1bodim<.:nt the imm~diak rdessc lilyn is
pmd11cvJ iicemding io lhc foi!owing gnicral pmi:--:durc&.
Tilt: rdt:ased c:om110nenh, c;u;:if,:nesifl DC (9S'.:·~J arn.i
mi<."n>crysl~lJin.: cd!uloS<.:, Ni· {Avtcd11I 2(1
miimk:~ .. Tbrn sndium <;\;irch g!ycola!r.~. NF (Exp!oi<1b!'.ii-'), i:'.
added lo lh!ear;ile, NI·", i~.added Jn the hkmler and hkmfod
k·E appmxinrnkly ari ;;:ddi1i,1na! 10 mim1l.:". Sampk may
lhr.:n l:x:. 1akt.'n br in-prnn:ss nmtro! !<.:sting (dcs;;rip!jt>JJ.
hknd ass;iy nnd ~it'.'v'<:: amllysi.~).
[{lll4] !non~ ·~mhodimc1i1 lh~ ~tht;lltl•~.d ro.:Jc3s;; by•A is
produ1;·1.•d according !o lh<.: fo!ki-,ving g'°na,i.! pm<->..:dm·.;•s.
The rclea>.<:d mmpollrnh, Cmiifrnesir1 I)(· (9''..<,;) and ps~'U·
dnq1hedriflc0 !!CL USP, previnusly s.i::ree11td lhwu;;h a No.
10 .'<:n.ou1, nn: \W'.iglK'.d and blrnded for !rn rnirn11.<.:s '""it h
bydrox~'prupyl m:;!bykdlu!o&;, USP (.M~1ho<.:d E!OM),
Cirbnm<.:r 934P and Ille appmprrak o.:olornnt (fl) & C Ecd
Nn. 4'l alum[mim lakt: dyt: fl:ir PO{) mg g1iaifem:stll/l20 mg
1w..:11doephcd,im: liCl uhkh (>r !'D & C Ydlow No. 6
11
Nov, 20, 2003
alu.mi.mim J:ih dy~ fur Mill mg g1J:iifenesin160 mg p.'.lll ten rninlllt'i.
A1~nin, s:irupb; may k ti1k1;n for 1t1-prnc~;;~ mntrol t1;sli11g
{ dcscr[pt:on, si<:vc ;:,na iy~.is, mid blend ;:,s;;~y for bo1 h
guaifcw:::~in aud p~'-'.uduepbedrillt: l!Cl). 'fahkt Cmripre-;.<;imi
inv,1lved lo:iding ,;;.ch b1wd (lR ;1.rnl SI<) in1P it-; rcspt:div<:
btippcr c•n tile hi-bycr iahlo cornprc;;<.in amJ 30 mg dr.:x1mmd!J,;rphan HBr
t;ib!us. Thi: <:<)fllpun<.:nt;; for th1; imm1;di:t11; rdcasc hyn (!R
l;;yer) for bulli slmnglh 1<1hlds mprnicnb
fnr the ~11.'-'l~iw:J rek:i.'I:'. !ayer (SR layer) kr hmh s!iUli,"Jh
lahkt~ nr!.'. ~lsn idcntic3!.
[O! 16] i'or 1 h~ SR byer tfor 1200 mg p1:tifene:ly :>1.'f<0<0n<.'d through <1
2(Hnesb c;<."rcrn}, ;ire grn1wbtd tngc!hcr wirb <:arl)(•ffl(;r
9.~'1 P, bydmxypmpyl methykdl1ih•:;;.: (Methncel t .. lOM),
anJ J·'D&{' hlll'.:" #l, afominum [;-ke ( l J. J ~'"'() u:;ing puriJicJ
w~(er 3.s lhc grnmi!atrng thi id in ;1 Dny rnix·~r. Th·~· '.Vcl mm;.,;
is c',·rn!y sprc<1d oo!o pap<.:r-liEK:d irny:> aml dri.:d in a drying,
ovrn :-'<:t a! !09.:t JU° L for appmxirirnltly 2'i b-:imcs m1lil !lie
average mni.~1.u;;;c l>. rm! murt: than L'.'i'.:i.. H1( p;rn:•.:.c,-, for 111<~
SR layer for 6{)0 mg g1rn.ikne:;in ;md .10 mg dn1x 'Nilh the t::>:o;pt1Ufl or lh<~ dyt: USing .1 Fitzplltfid: Mill tltt•.;d \Villi a
IU2'i" ruunJ-bllk Y~Tceri, knivi::~ forward al ;i "fa~l" :;peed.
The grnmil;Hinr; i~ fed iriH> lhe mill iit;ing :rn :rntom;:lic
f;;du. The :>ix s11blnt1< ( li2.04 kg p<.~r subloi... ::;rnm1lillccl,
dri.d, mid millcd 3S tkscrihed 3bovc:j <1r1; tb<.011 l'knr.kd
tog;;thvr in a (JlJ-ttJ. fool bh:ndu wi11J magnv:>illrn skarnl<:
rm kn mim1k:;.
[OH7] Fof lh<; IR Lul and dcxlw1m;t!10-
rph;,r1 !!Br (pte'•iou,.Jy screened lhwugh a 20-me"li :-nR: (Mctlm<:d E.tC!',.-1) thing
[llJrilkd w.>::irrrnkly 2{,
bour,;; 111ilil ill;;; :iwr:·1g~ moisl11re is not rnnrc lhan l.U'X Thi:
IR hyu pn:"''"''"'' is lh1.• Mm1; for bolb Hbkt stru1glh>.. Tlw
dncd ;,;rarrnb!im1 is p~s.>;1.::d lbmug:h a Swem eq11ipped with
W-mesh :;.;:n:<:n" Th<' gr3.mll3.tiori n.,Utinetl on the W-mo:sh
screen is rnilkd using n fitzpntnck f'.Ail! titt<:t1 wilh n tU25"
mund-bok .~r>:;·.;11, kniv~s foi~.vMd <p·.xd. Th<.:
grarwlalion it; fd rnto \t1;.: mill 11>.ing ;m atHorrrniic f<;1;d<:r.
The mined materi;;J rs l3ler hkrnJctl wirh the malerial lh:u
pas"l:'.d lbwugb lb<~ l 0-rne~b .'J.;;t, gr:rnt1h1<'d, dri.ed. ;rnd milkd 3:< '-ks>:rih<:d
alx>v<.~) MC then hkndc:d tog_;;1hcr :fl a (i{) cu.-foot blcmk;
\V.ith rnngncsillrn s1c~rn1c for f<.:n mint1lcs. Each blend is lhcn
!li~d.:J intn lht:ti r.:>{X:<:liw huppcL~ ~nd cmnpn;:~~;;d irHn
hi-byn Llhlds.
[{HHJ:] T;;hlds uimpri:;ing ;; :i: ta:)!;:ts
Vi<:r•~ compared against rrmJifit:d rd<:'.a&: Li!Jkls lmrnulal.:d
wiHmul ,;.;;;y![,, re>.irJ {ll'rnmp!e l). ~mJ llm~i;; comrrn:rn,dly
avail3hk l;ih!ds, nm: bt:ing an imr:iedi;il<.: release forrmi ]a.
1ion ;,nd ihc ot!Kr 1w0 lKing moditkd n:kd~· fonrn1Luinns
T:::t:.l;;i;. ·:omprisrng lhl) s11"-tain._:d H;kasc: fornrnlaiinn dtm ·
(Jn'i\f:Jllcd it slr;\';<;f., mon; nmtrn!led r<::k3""' ur guail.{;nesin
m··er a lweh;~. 1l'llll pniml lhafl any of !he .;ilh<.:r labkb. (.~e
e.g., Exnmpk ! and '2, and FIGS. ~ aml 5).
[OH9] ln the 1r1 v[yo k:-,tin;;, sernm com:efli.ralirnl'i (ir
subj;:cts laking t;ibkls comprising the: siislainc:d rdc:a:'.<.:
rormt1!ai.inn 1,vcn.: compared \vitb sc,;nim -.:0ncl•nl.ra1.i,1ns of
nihj\:cls !3king imm\:di:nc: rcbicot: guaifrrn:sin tnbkh :ind
modilied rd<.:3.S<.: guilii',;ne.>in t;1bk1s furmuLiied wilhour
auy!i;: resin {> 3nJ FIG. 6). 'fahkb. cumpri:;~
ing lh~ sustained rdcas;c fumwlil1ion demonsU&kd
improved s11slrnp3red to the ;Jtha lwt•
for1rn.d~rinn:-,. J\Jditimial!y, in the suhjecb !~king \,itikb
nlr:ipri~ing th,· susl;itn<:d rekas•» forr:iublotni, it lnnk longer
for guaifon'.'sio !u appear in th" blood :;.lr'.'Rm rnd th;.:
1rnninrnrn gu:tikncsin s;;nim conc·~n1rnrion {C,.".,J W3."- less
lh<'mbimxl »vitll a P')f1ion
or ill] inm1cdi;1h; fd<.::t.'i<.'. form\lfaJ~;)l] in il modifo;d r<.:ka:';c,;
pmducL ln ~ prd.:m~d !Ombodirnenl, 'il k.asl one adJi1im1al
drug um I}<;; preS<.::nl within I be sust:;m;;d rde~se !i>rrnulillinn,
!Ile,; imm<.:dt3lc rc:ka"<: formul3Jion. o; boih dqK:mJing, upon
111·~ d~sirc:d clkcr. \Vllen using dnigs &pp.roved by 1b;; Foml
and Drug /ulminis!rn!ion (FDA), lilc: Sll@oined rdeast: ror-
mulaliun, immediate. 1ekase rur1rnilatimi, m both m1y h<::
formlliakd l.U mimic lilt' b!tiocJ .'MUlll pmii\e ur the ;;ddi-
ll<)Jlfll drug 3S (kf'.Cdl'•Cd in tile dinie:ll documcnls Hied with
lil·.; FDA or ''-" rcll3! drug.
l 0122] The rnodifo;tl n:ka&; foffm•lii!ion can he in I.he:
form of bi-13ycr<.::d 1:1bkls, capsuk;. trnviug '' c<,irnbwahon ,,r
ht:ad;; or grarniks nf immediate rdt:3.~ fc,rmuLHirm and
su:~laim:d n::kas<.: fornmlallon, m a t;'!bk! whtreill the sus·
l;i.i11d rdc3.se k>rrnub!ion cornpri'>'~s :i core 1hs1. isco3rcd by
;1 !ay<:f of !b<: imrm:dui\,_· n:kns;..: formlllRlion. Fo1 purpose of
illus!rnti,m ,mly., the invrnrinn will b;; dt''£rilied in detail in
lb.: nrnkxl .;,r lt1t. bi-l;iycrnJ 1,1bkl err1bndirn~nl.
[ml::r1 Th<: immc:d13k rdease k·rr:iuL11inn may cumpri:;t·
guatfoncsin ;;nd v:,
12
Nov. 20, 2003
l1Jhrinml.s, culnr;rnl~, bimk>s. glidants, surt'a<:e 3divt 3g<:.nls,
pre<.;..~f'o'Hli','<.'.$, siabili:1:u1>, 3$
di3.k rck8.'i<.' foy-.;r 1;ornprises r:! ki•f'l !wn dnigs. lo ll mur<.e
prckrn;d unbodium
starch gl y~·ulak, ;rnd rmlgn.:sium ~,\,;arc.lt:. ln amllt1<:'.r 1T1ori:
[Jf~ft'fH'd emh(Xliment, ;m immedi<'.k rde;i:;e !'ormul:iliPfl
-::omprist:s g·i1aift:rn::sin. 31 ka:~t Plk ;Jddi!lr>n3l dnig, m ii:ru-
~-ryst3JJim cdlufosc, l:Jydroxypwpyl mdhyk<,l!ulos-.;,
;;odium swn:h glycoh1·~, anJ rr1agne>,iurn ,,i,e,;.rak. lr1 yd
.rnn!ber Jlrd'em~d <.:rnhmlirn<.:nl, ;rn immedi;;le rdeaSi11 5'.1<
hydmxypmpyl EJ<.:I hykdh1b>e, :ibrnJl .'\'.:(; lo :ihoJJI w.:{.
.'kill in lhc ~rt. TIK
re,;u!1a1g l::lblcl compri.'-"Cs 1b·~ 1v,o portions comprc:';..;,ed
;igairist one :>1:. pnrl.iun
in th<.: cculcr c:oat;;d by lbe inmivfok ;de&"-<: pnr,
compr<.:.s:;;.:d ag;im~l i>llt: <:nolhn ;;n th;iJ 1he LK<.: of t:a,;h
puftion is <:xpos;:;cl.
l:ill2~q !n <'< pref<:rred mt'lhnd ofrn;rnufat:t1Jring lhe bi-layt:r
lablcts. 3 ';iisl3iu·~d r~kn'>'; fomn1farion is prq,3.r-:;d accord·
ing tn <.'it!H:1· ~ ·w;;t grMm1'11ion t•f dry gran\llatiun mdhod ~:;;
d~:«:rrht:d 3huvt:. '111<:: immedrat;; rekase formufa\i·:in r:iay bt'
prepared hy :;imply blrnding !he gu3ilt:rr,;:;in '>''itb 3ny ph;ir.
ru:k"\:lllk:li Jddi!ivcs. ff 8\ lt:, lh.:fl ;,;Jd,.>J w 1.bc irign.o-
J[enls anJ blended rm· ~h(>l!l kfl rr1on~ minute~ I.() make all
imnK,diaK rdc;,s;;. formulation. p,_.,nions (if the su:>l;1in:mr mM:hirn; '.'.<'. !n nri,; t:mhodiment, lhc,:e lidc jui~v<
fUU'5] The: Ubklf' may be: m3dt with Ml)' r:n io ut guaikn ·
<.esin !(i al k;isl on<: additimial drug 'lvhid1 r1.::o;ulh rn ;, bknxl
pmfilc: demorNrating appmprrnk !lierapeulic dT,·d -:JY!'.l.
<.:Xkndt:d lir:ie rt;ri"()f; /<.s di-;.:,'.llS'ied 3hPV of g1rnifeflt'.Sifl HJ iH kas1 Ufl. ab"'lll 8:11'> al'<)lJ! 12: l by ,_,,,,,ighL \Vl:J•.;!l
pn:f'<:El\ in !he inimcdiJk'. rdc;isc by<.:c !be a1lKHrnt o{ the >~I
kasl one nddi1ional dnig f'boukl he &uffi.dcnt w 111n1d1 the
Jwg Edt:ae;e proi'ik: of !lie addiriorrnl drug ~vilhin !be su:~Â
!ained r,;k~ .. -;;;: rrofilc.
[IH27] !n a j!rd'crrcJ i~mbudim<.:ril, !In: iabkls art: mad<:
wilh :;ny fiHlO of _\\ll;JJ[';;m;sio in [J.'itlldt1cpht:drinc whid1
n;,c;~lls in a bluud pm(d;;: dcmm1s1rn1ing a1ipm;iri;1k d1torn-
pc11tic dk·.:-l 011(:f <.::. A"> di&eu<><;<;d
:tlmvc, the p&etJ(focph<.:drim:. i:> prcscnl i!l an iilllOlin! f'llfli-
cielll !u mimic lh~: blood ""mm pmllk of !b,· cc.mmcrcrally
;J'i (>f !013 l gu;iikn<.:,;.in to p;;eu·
do;;prH;drine is ahrnil .l: I 10 ;1lmu1 10· J, more prefer;ihly
alx,ul l: l le· 2S: l, arnJ mrn•:: prdeE ably abuu! ZO: l by weigbL
AJtc.rn:nivdy, 1be r3!io of gus.ifoncsin to f6ci1do·~phcdrine is
,~!mu! 8: l 1.0 abl'lll 12: l i'y wcigll!. ln ,1n0ihcr <:mlxidimcm
lbc p~<::mbephedfim: i:; nrily prcscri! m th<: immc1fo!l<: n:ka"I in nf g<«lil'<:ne:;in In ckx1rnmdhnrph~.n which
resul!s in a bluud pmlik dcrnm1~,lrnling appmprial<:: th1:rn-
pcutic dk·::l diS<:ll<><;ed
Jhivc. the dcximmtl liorpbil!l is pr1:>;;~1ll 1n a11 :1moum suffi-
cit'.fll In mimic lh,; bloc{] .sernm pmli!e of !hc commerU?, lly
aY3i[;il;k fornrnllllim1 llr lhv drug aml flOl lu exceed it!<:
mnimiim do!-ie ;iprmvnl hy !he FD/\ for Jht'. lre20lrrn:nt.
f'E"<.:vi:ntion, or a1m:hurn1ion of~ partin1lar illncs,..; or dt"'-'fl&e.
!n on~, ·~mhodimclll, !ll;; ri1oio of tolal 1 ;uaff<.:n•~i;in to de:\·
!rnmc1.bnqihan is :1hout I: I l.u ?,bout :~fr!, mur<:: prdn:ihly
alx,ul l: l lo 2): L arnJ mnE pr<:rt:Eahly abuut ZO: 1 hy wcig.h!.
AJ1cnu1ivdy, tbv rn!if, of guaifoll(csin to d<.:xtromdlmr;ibi1n
i~ ;1b01n K:l !n 1ibolll I2: 1 by weight.
[IH2'1J The labld:; m?,y he m::dc wilh J.flY rnlin ni" sus·
mined n;ln~<: iu imm<.:Jin!v r<.:kasc fornwlllion wlJiZ'h
r·~i;iil!s in :o blond protilc dcmuns1rn1fog ;ippmpri@.: ih;;ra·
p<:ul i<: dft:c:1 nva l'. xlemled ii mt: period:;. !fl nrn: emb, HJi-
m<:nl, the bi.l;iyer lahlds compr\sc pt:;1frn<:siri dislrlrni<:d
·wiHiin 1.hc s•-<-' 3brnH l· 110abom10:L rno1·c
prdernbly 3boul ! . l lu ahour l: i 'i by ;veigtll, prd:Crnblv lbin d1s!nbu1':d wnhin 1hr: suo>taincd rdc.tri ir1 <.c IRyu
[01.:Ml] Th<: rn.bki:> mll or
with tht: 1iddi1innal drug only in itii..: imrncdia!;; rckili;'~·
l<·nrnila!ion. Opliofl?,lly, rh,; lahld"< m:;y bt: matk wi!b at
!c;i:4 '-'il< 1:JJiliPnal drng distribuleJ will1ir1 tbt s11staim::ll
Nov, 20, 2003
rde,!>it'. l.'nrmt1l;,1iun ;md 1.h1<1incd rdc~.se fonm1·
la!inn ;rnd imm~·diak tde:1~1:: formuhtim1 v-'hu·;;in ihto rnlto
or ;iddirional drng lfl the SR lo additinml drug in IJK lR is
,ibom !:t !o <•bt(: pi;;forably
abolll 1: l !o ab(o,1 I 1: L
[ll!Jlj !nun;; prcforro.:d cir1bodi11!i.:tll of m kg uf Cuhnpul \J74P, , Ah0u1 0.{J kg Ddiul!l SlMCi:J g!y:...··d~it: lllE a.bout hveuly
rninu!es. /'1.ppmximatdy 0 I ks of magnesium skank riiay
th;.;n l>l ;oddcd mid hlrndillg <.:ontim1<~.d for abou1 :rntl'd hl mak<~. bi-!11ycr
t:;hk1;; wberciri ahrnJ! 75% ni" t'.:<., wo:igh :obmll 0.77.9 gr:im.-; :md hav,c ;, h, 1_;.Alu·,vcd l)y dq:rng.
.. \!><.Jul OA8 kg of magnesium .~ltmak may 1J1<0fl he ?,Jdcd Mid
bkm.lifl"' u1ritinw;d for :JhrnJ! ::nolhn 1r.n mim11t:; 1.n prnp«rc
!bl: immedi"lc ;ck;asc forrnu!atiun. Tbo:: !\YO for:m1laiiom;
rn;1.y then b·.; compr,::;s,~d lu nuke bi-!uy;;r tJbk;,o, wllcr·.;in
abuut 75%· of cacti t. v•cigh nbom ! 5 . .1 1;ram-> and have a
lwrdnns rnnge of ahuL<\ 15-35 SCU. hi ;n101b.:r prefone.d
emhrnJrm,ml, 6Wl mg l.abkts are muml aml abm1t ~/' im:h in
diilm<.'.l\.'r, al_'<)lli_ {l '.':2 inch-0.16 inch in thkkrn.''~. '-Vdt;h
abot1I 7.65 gnm~ and h;ivc :1 lwrdnes." nngc o{ :1h011\ 15-65
SdJ.
[lH3J J The immedial<.'. rdc:a~.c pt>rtion or the bi-lay,;r t.1bk1
i'> furmul:ll<.:d l.O d[,.sr.in 1s dosed ~','<.:ry four honrn ov"r ;J J 1 hour period
[Ul34] The s11>.r:1in~d ri:k:1s-~ portion 1;;;1s wll"n o:po.'>.:d 1u
m,'.<.Jia of low pH "l!O\Ving, th': susll!im:d rdca>. in Cf•lllrnlkd bin~vail3bility
uvu :rn <:xkndi;d lime pnind {_i.t:. eight lo lwt:lvo: or mme
hours) ..:;iu,..ing !ho: rablel lo pm·,-id•,, ~c:>:lrnded lherapt·llti·~·
di:i.:cl A"- shown iu Ex:in1pk (:. '1[](1 HGS, \.I :smi HI, ihl'.
iialf-lifc o[ tb<: ;11odi1ied ftkH'-<.~ hi-bycr l:im3tdy IJ;iff or
a 1200 mg 111bkL Thu~, w[tholll adjusl.ing or changing th"
<:ornpusi1.imi ur !lie ,,~.0,!airn:0d re-kase frnrnula!iun ()j bi-la ye;
;;ibl•.'L a lower cki:;age ~lfeflgl h gunrn "'Om:cJJ!rnlion profile lhiol is
zpproximz.tdy dir<;ctly propon ion~l to I hat of 3. highn
dns:tge strrngl.h gu;,if,;n,,_sir-1 lahl.el. As fmlha dem·;;nslrakd
in Lx?,mple 7 and F~C. H, !he hi-byer ublet:; ri::sul!nl in
ltrnl th.: C,""" anJ Alf( ·i,.f uf a ! 200 mg t~bk! admin["-;:_,;n::d
lt' voln1H<.:Cf'i w!w had h"cn fosring aud !hi.: C',.,"x and i\UC;,,r
of a l'.':Ofl mg, rnhkt admrnis1crc.d 10 vohitJlc:c:r~ wllc> lrnd
·~·,:x1s.urncd a high fal HK'al wtre apj'rnxirrrntdy <.:quivakcn!.
Thu:>, ;, bi-l;iye: l:ihld ;;r the inv<:ntion d~mrm:,Jrd1es . we;·~ ohlJ in<:d for combi1111Hon forrmda:icHl'>
I<:« instan\.Oe as (k~nih<:d in Exam pk:; S-?. l.
[0136 J Scv<.eral o:irnbiirn.lion formu!at1vns ·wcr~ i1lw ..::um-
par~d lu uimrnc;;,;ial <.liugs for btc-avaibbtlt!y. hir in:-;l:>m:('.,
Ex;1mpk ii t.;hu'>'··;; 1 hree h;,1ch>.'.:> .;-,f I ht: l '.WO mg girnifen1:sin.·
(i{l mg dcxtrom,:i1]0rpii;m HDr \vhi1.~h 'NU<: di:-;~t>lvtd to
di.:knni11•;; lhc ,'Tr a J2 hour pi.:ri:.;d. ·n11: rcka~d ;urnmnl c•r
14
Nov. 20, 2003
dex!mmethnrphlal Vi>,:iglll
o( d~xlmmdhorphzn prior lo d.is.5.olul ion. Alkr J ho:1r ahou I
'!t'i'X ru .17<:;; uf lh.: dexlrnrne:JJl•rplrnn b<>d dis..>oknL J\fler
2 hnurs.. lb<: abm1! s·:.is-r tn 60',:;. had tfo;suked, aner 6 hrnir:;
7'.\'k to 7(i'X had di&<;olvd, and alkr 12 ho\lrs abou1 .0:6~{ to
:'{')'/(. by wdghl (if lh\; dex1:ort1•~-lhtirph;m hzd di:;solvc!L
Tlm5.. lb<.~ fo;mub1ioos of ibc invcmi0n r<.:prod•.1:.::1hly rdti1f'1;
dl'x!torndhmpban -:JVt:t tim.:. (M:•cc, FlG. 11). \"lhik,
<:x~mpk 9, t'nr ins1;1nc;; d<:monslr:iles 1h" in vivo bin;,v'1il-
,ibili!y c•f a S!J&t;,incd rdc:ts(: ;;-,u:nknc;,in '"ilh dcxlromo.:tlw-
rphan.
fU137] Vuious cil guaifrnc:>in/ps;;udoephcdfit1c
;.;omµ1J'ii!ions W<.'.f<;.c ;,bn cxm1iincd !o tk-tcmiinc i.h1:ir di.%0-
lllli.on r,,;..,s and b.in<:v3.ifabihty. E:>:zmpk;; Hl ~ml l L pwvid<.:
;i l(1;mu!:t1 ions or gi_1aifw;;:;in and pww.lnq1hedrirn: in the
su~t;_'BfH:J n.:h::;_i9:: purnuu of a biwh1y~n:U labk:L Rc.suiV~
d1.:mon,trak'.d lh11! ~~>mbining 111·.; drugs in10 a "-iugk rnbkl
;·iccording l<) rnclhods ()[' !he i11vc111io11 dtd WJ( dfoc! th<.:ir
di:;sdutiun pm!lk Of !heir in vivo rek;tse pml\k
[Ul3~] Th1: iwn pm:oryp" luti; uf n~rnpk ! : shuwed
s[milar 111 v itrn rdc;~sc to 1rn1rk<.'.t l\-foci m.:x T'" and S11d;, fed@.
In paiiicu!a, hurllJ!atiorJ B (lnl PBOl~K6!) pwduo.:ed c·pli-
m:!l hto~v;,[fahili!y for hulh guaifrncc.in and p~..:-11<.b:plitÂ
drinc nnd w;i'> thc;drnc ti<..<.:d in ';i1b.'icqncnt hi<.1a~·:iibbili1y
'i!lldi~,~ ..
[ll!J9j Exampk l .l compared cornhin:Hi!>n pmducw fur
gu; <:ommnciJl
Muci nexrn mid Sud:i f;.;.;J@ l?. Dom. The l.?00/ J.?O mg
slr(,n_s!h show<.'.d bio<.''Jllt'-«t PBO-M65A3) fo; :~1.;;-.ady-sldk liiuava:l;ibility in
Ml 11 day 1w1tl'-d~ily do.'><.: rc1')rn<.:. "!fo~ lest fonrn1fotion w3;.
hiocquivaknl {"vitilrn !he t«.l-1'.':5 1/i rna;c 'Nilh J l/f>'ii. ·.xin-
lklt:nl'i:: intcr C""''' for
gu:iifrnesin hlll W<-l'i for I he ps.t!U!.k)0-125~'.i rn11gc.
[fH42] l'.xampk 1 (i G)ffl[-'Hl'd >,illgk·d(>c' M11<:inl'X '" , de1m:-us!n1le
1b1 ihe ph of g11;1ifone'iifl wd p.-;;,:11<.b:ph<:·
tlrine f>[\; tl!Ufkclnl wi!h regard (O buth AlJC'inf ~ml cm.ox tn
the prcscucc or nb.S<.orK"<.' of 011c ,'l1JO!il1.:r (r,.ulls oi' 1J1<.: ulh~r
exarnpk~ wb1ch demnflstratt. hineqiii'Hkm:e fi:Jr; ht: ;;nmhi·
na!ion k·rmul;'mp;1n·.d I ht binrmt1 l;i r inn, enfl1a irn ng hi>l h gu;i ll'.o ntsin arnJ de : Hui_ oflrK• fkf<:,rcn..::<.'.. Mll'-'lil<-'X,
iu h:'rr11s of C'"'"', AUCn .. : -:Jr ;\lJC;,,r·
l0145] Dcx1rnmdhorphan bydmlxomidr.: in the <.'X!-"·'ri-
m-cn!al tahkl was ;ilsn fr>und !o ht' hio·~quivaknl lu hu!h '.lO
mg dtxlmrnelbllrph:w hyJmbmmid~- cv<~rv 6 hour.',, and 20
mg evti-y 4 hmw;, iu krms (;I' C'"'"" J\UC,._, (;r :\UC,._,-.
[lll46] Exarnpk :10 r.:umparcd the rdaliv•: !ii(lava:fahi!ity
of gu<1ifrncsin nml dn:lwrndhorplwn from au c:th !!,Uilit<:nc<:.iH MKI d1.,xtmmc:hw-
plm1 hll k:cv1in2; lh~ coni;11rnp1.!on ot" a hi1;h fat med as
<:orr1pM<"d ln following an ovemigh! fast. Th<:re was mi fond
;_cjfo.;:l (;l) !he ab;.;>rp1 ton or guaifom;;;m frnm lh-c experinhofl·
!al l~hkl. Thcr,, wa<:. an <.•.111.,<.'l of food 01i tlw mt<; of
::lh.'illrp1wn or (l,;xtromdilorphan fwm lb<.: <::xp..:rimclllal lilh-
!d fnmmlalinn (;i ~m;\ll in,Teil:>'~ in 1h,; r;ilt ot" :tlxmrptin:lrnmdhurph;in i"mm afl expcrimt'.flial
formulation ~•on1'lifling hl cornpM;;d t'(:f)' r1 hours, ;md ?.P mg evay ,j hunr&, rn t.:.rni;;
uf C.,,"~ ;md AUC,._ wilhin xnr;,:_ lo l 25S1.
[{114!'1] Th;;s'-' stiidi!.'.s demonstrnk !ll~' cr.~,(: 1.~ornpoÂ
n<.:Ell nH1y b'-' f·:)tmub!<.:d 1u mimi·::- 1.bc blood :;~,mm protik of
gu;,iE:ne.~io dfld upli•,)[]ally the :iddi1.ional drng(sj <\s
de!;crihed in the diflical ll may bt: fuur:d at
htl p: ,:wv-Av. fda. ;~r 2,463:t:Hl13., ;i T,'""' of t15, -u!l w a rn~ximum
15
Nov, 20, 2003
xerum ('.On'.'.e!1lrntiun {C,,,,., I ;mdinr ltm(c nr ma>:imum S!Orllm
COllCelllt"alJO!l (Tmo.J cquivakn! (O !h<.'. C,.,"x ub(Jt!K'.d 'Nh<:n
lb•. firs\ •,)t lbff<.: do;;t.s >Jf a standard irnmcdh:t~- rdcasc
frnrm1L1!iun lrnving one third lh':' amrnrnl or gt.atfrnt."in [:-;
dosed ;;vny fnur hrn1I"> nver ;i 12 h>:iuf pt:firnL ln nlher
word<:., 1[1-., s.usrninv:I rckaS<; fonrn.iLt!ion rd;;ascs bo1!J !lw
gtui.knesiu ;rnd Jl k:asr one addi1ilm3l drn:; al a .';irnil3r nk
1.0 lhc commcn:i;,lly available fornwbtioll, !h<.'Icby prnvid-
ing_ a lhernpc11!in1lly dfocti·~e amuunl uf f}:>lh drug.~. Alltt·
fl~l.ivei.y, th<;: p;ir;;mders m:ty he GlklliWdi"<:. sud1 as 1ho8.: pr·~,;·.nk:d !!~-rein whcr•. cq1ijvakno.:c JS
tkkrmin(:d from iht meJ11 a:1d Ml 80-115% rnn l\C with a
90'.:i: cmifiJ<.:nn'. kvd and/or om: "laudaid dtvrn!iut~ frnm !fit
rne;m. Tht pMamttns m;,y al"1:1 Ii;;: <.:akulakd frum in Yi"·u
!;\mJies such as Ihm«'. pr-c:;i:nred herein when:. equivm !he lll<.'.dimi and :iu 80-125'.;i rJng<.'. wi!h a
•)(t'ii. cont1dcm:i; kvcl iind.-\Jr on!.'. slaw.ford ckvi~!ion from I hi;
rnedi~n. Du('. lo 1 h~ extreme vari;1bi1il\" f'or dex:mmdhm-
plnn, a:~ recognized hy 1.he fl)/\ and lb<;; ir1herrnt variability
of m;;~si.ir.in,_; pbsma ,;,~rum kv!.'.h a1 !hi.: picogr:om lcvd tlic
<.:(j\I i'v' :1 knee ~.;, de t•Armncd from ltK- mcw end ot lb~ ('""'" for p.'<.:lJ -
d•xpb•xlr[ur.: is prdcrJbly gn:alu ihan 150 ng.-ml, mor<.0
preferably l7'i ng;ml., rmm:: ptd,Tahly :mo ngiml., Mid
mw'I prd_:_,r:ihly 2S{I ng/rn! deptrnJing nn the fr_irnrnhilion.
Tb<.'. high rnd of lh<.'. C . .,,,x fc·,r p<-n1docphdrinc is pir.:frrahly
ks.s than 50\.> 11g;rnL more pid.;rnbly 45(! ng/mL mof<.'.
prdcral)Jy 40(l ng/mL, ~nd mos! prekrnbly 375 n:>mi..
dq1.;;nding on lh<-' fnrmula!inn. Fur ngm1!. :rnJ 250 ng/m! ., WO ng/m!. and 225
ng/m l ., J 25 ng/m ! and .?00 ng/m C mid J <;O ng/m l ;ind I &<
n:;/mL
[O! 53 j Ali.erm1t1vdy, !ht low end of the C"'" for dex-
1rorm:1.1Juq!bm1 i> pn.:krnbly grcarer than 3840 pg/mL, mmJlm<~lll !he Jow end of [[i(.
c,,," for dexlrnmd hurphan is prekrably greakr th;m j 300
pgiml, mor"' prtkrnbiy l 550 pg:rnL, mor" prdcr.1bl:-1
l ,860 pg/mL rnor·: prdcr3b!y 2,170 pg:mL, mnr~ pr(;kf·
:ibly 2,41'0 p!!,/mi., :md mof;l f''~r<::rilb!y .?,790 11i;;/ml.
dep~uding on !he i'offm1latiur1. Th" higJi "nd c-!' the Cm,,, for
d<::xtr,•mdlmrphi'1ll is preforahl.y !;;:;,,; lh<'t'.t:I whidi i~ pfaen no1 met
by Yat·iln:il drng(:;) <"r holh i~ prekrahly bdween ~W'i arnJ
125''/f. of !h<: fDA roppnwcd mo.Jl, more prd<.:r3.bly b(;tvic<.:n
90?;. :rnd ! ! 5()(, mid mn~t prd·~rnbly be1ween 95"1(. ;md
ll5%. Th<:&: rn:1g<:s do not have to 1dJll&t conrnwosuu:!dy,
th:;! is tu s;iv iht: m.;;;m may fnr iri:;l;mn: prd't:rahl:• be
l1ctwn, Thl'. C,,,;,, r~ngt ii>r t:ilht:r a 1200 or a 6{)0
mg tahld m~y be :¥~kd•.od fmm '>0 r1g/mL ;;ml l'iO ng 'rnL,
SO W!/mL 3nd l 1S ug;mL, 60 n~;.,mL, CS ngiml., 70 n,;:ml.
:tml 125 ng:mL, HO ng/111L and 125 ng,mL, h<.:t\v;;1.:11 35
ng/mL ;ind 75 ngiml.., 40 ng:mL and 70 ng'mL, 45 ng/ml..
aml 6i rJg,m!, aml 50 D!>,:m! .rnd 60 ng,'ml,
[m.55] Altern;ilivdv. th" low <.:ml d th<.: C. , tor pw~!J·
dnephedrine i;; prrf'i~rahly ,<,:m3kf lhari 7': '~'.~im! , milrt'
JHefrrably 100 rig/ml., muh' wekrahly l:b ng/ml., aml
16
Nov, 20, 2003
mos! prel'<::rhedrin1.' is pidtrnbly
lcscs th~n 30(! JliVmL mor<.: p.rdcrnbly 250 n2;.'mL, more
prdenh!y 22S ng/m! ,, ;,nd mo;;! pn:fu~h!y .200 r1g,ml.
depeDding ()fl th.;; l<>rm1ilatior:, Th;; c"''" range [;:ir either a
110 mg, or (1() m:; rnbkt may h<.: sd<;<:kd from 75 u:;:rn!. ; prdt:r;;bh· gr,;iller tti;rn l ,llSO
pg:·'~! , mm,; preler;;hly l,:0:50 pg/rr;l.,~ m(;re prd'nably
1,450 pg/mL rnon.' prc•fornhly LG50 pg:ml, and most
prekrably l ,8SO Pn pruv[dc a T'""" f<.ir
ci!hcr !J,tniknesiri, lh<.: addl!iou;il dru,:;(s) ur boih wh:d1 is
prdenh!y hdw<::<::n i'lfVii :;nd l.?S'1 (;r the Fili\ :ir·rmved
me;m, mm~ pn:Jcrnb!y !>dwern 9U"k Mid l l.S'i;,, mid 1T1osl
pre lt:r3.bly hr.lwi'.,:fl 95S{ :md l l 5'.:i. Tbet.;;: rarip'.s do nu!
have to adjusl <.:ommeo;;urn1;;Jy, 1lrn! [s to say tll<: lll<.'Rll nuy
for inslMJc<.: pt·d··.;rnbly lxo b.;;;\11 •. ;,;n 90'} Mld J.25"k of !hr
fl)/\ mean d!Op<::nding ()fl lbe {ormu!~iiun. Alkrna1.ivdy, !lie
kw end nl' lht: T,,," tor guail'l.:uesin it.; prc:ler;;hly grnakx lh, more prcf·.;rnbly 0.'}
hours., mori:: preferably J..O hour~. mid mtk>t prdcrnbly l l
l1t•i1rs ckpending oo the fornwlMion. TIJ<: bigb (:nd of !!w
T for guailerJ-;:'c;in i" prdenhlv k;;.<; dnn 3.0 huurs. mme
r~fenblv 25 hnllrs, mor" jlf<:'.t'~rnb!y 2.25 hou~, ilnd mo:>!
prdenbly 2 h(•lJrn dq:.;;nding nt1 lb( fornHiln1inn. The T,,·,,x
rnngc may at"'.l [l<; <;<..:b;:t<.'d from bdwc.cn 0,6 !lours .tml 3 0
bllmC», 0.8 huurs ~fld 25 boms, 0.9 hu1m-; Mid 2.2:'> hows, ! 0
hrnir,; 3.ml 2 hom:;, .wd l. I. hP
[0158] AJ!cnrn1i-_·tty, the !ow !'.Ud uf lb~ T"'" for p."l:l.!,
dnq:·hedfiric is prder~h!y grr.f ihc T"''" for
p~:udu.;;ph-;;!Jrin~ i:; prd~rably les.s !h:rn '} 0 hc·llr~, more
prckrab!y 8.'i hours, mme pn:fonbiy 8.0 hmJrs, ;md mo;;l
prekrnl:-ly 75 hours dcpcnding on itic ti1rmuL1lion, Tile
T rnogs rn1y <1!so he <;<,:kcKd frnm hdw<:<:n 3. 75 hotirs mid
9:·ff!J.,,m;>, t.O brnir:; ::nd 8..~ h·.>t1rs, .:l-.2S h1mr:-. and H.0 llly 5.85 hour<> 0cp1.,nding
on lhc formu!dlion. Tll;; high ;;ml of lhc T"'"" i::)r do:-
!wrm:lbmphan ]c; jHdera!ily le~°' lhan 10.6 bouL'<, mort:
pre E: rnbly 9 .!-'. hom.~. mo rt- pre lt:rahly '.l. J hrni r.,;, mnn: pref -
1.:rnh!y 8.8 hour:;;, mon; pn:fornbly 85 ho11n~, mor\;: prd<.'.rably
78 hours aud n1(:.-;1 pn.:l'ernb!y 7.2 hout'; dqJendin~~ on lhl
fornmlMion. T!J<.'. T,,.,,x range m~y also be s.;k;,;wcl .trom
b,;tw<:<:fl f'..2 hullr~ and 9.7 holirs, 6.7 hmm; :.md ?i.8 brnm;,
<1.7 hourn arnJ 7 7'. hours, aod 7.75 hmm; :rnd 8.:". bnur-; f(lr
a (10 mf~ tabkL Th<.: T.,,," rnngto may also lx: s::lcdtd frnrn
hd'-'-'•.xn 4.6 !wur& <11Jd 7.25 h::>11rs, 5.2 how" Mld (!5 hour&,
S 2 bums am.I 'U< boul'i, am.I 5.k buu1'i arn.l 1'.'i hours (or .t
1{) m.~ lahler.
[!Ii 60] h1rnmfaliom; o( 1.bt: inw:nlion prni) or hnth whkh _i,
prdcrnbly lx:twc<.:ri 8\l'X aml l2S';~. of the flJ;\ ,;.pprnv<:d
!ll<-'.&!l, ll10f\.' prs:fornbJy bt!W<.o<.'.ll l)(i'/f and 11)~:~., and :TIC"il
pr<.:krnlily lidw<.:<.:Jl r;-y;;. 3nd l !5',l. Tllcs;; rang<.:~ dn t101
hav;; In adjust ,_:nmnit:fl:mr;;tely, rh:tl i:.; lo :.;;;y the mt'"-fl m;;y
f..,r w:-;l:rnct: pr<:frnihly !'"' h:h>.'tTn 9(l'-_/,, anJ l 2)1.:{. (lf rb':
FD/~ m·~an dq)(·rnfaig un 1bc forrmila1iotL Alt<.0rn~1!vcJ.y. 1ti~
kw,- rnd or lb<.: AUCu,r fur guaifom:sin is pn::fornb!y g,reMn
1b;m -'<.GOU hr-r1ivmL, mor~ pr~knbly S,(il]() llr-ngdni.., nwr<.0
prdernblv 5,500 hr-ng-'ml , ~nd mo,,! prd'aably 6,(}00 b;·-ng<
ml (kpcmlirig t•n the [(>rmulatinn. Tht high rnd nf lhc
AUC'"' for g,tmi!cn<:»ill i:.; prcfornhly k"s than l250f! hHig.:
mL mor<.0 pr~krnbly J.0,00-0 hr-ngimL, mor(; prekrJbly
9500 hr-rig/mi , «rn.1 mos! prdcr:i.bh· 9Jl(JO hr-nr,;_/ml.
Jcp~uding (:.JJ rile f.:irmularion. l'm a !200 mg !abl<.:t lh<::
.-\UC"' r;;ngt: may ht: .'.w uid o! !h;; AUC;.,1 for p;;;~;1-
do<.·ph1.,drin\;• i:> pn::frr~bly i;;r1.03.kf th11n 2,500 hr-n:;..-ml, more:
prdn;1bly '.2,fiOO br-ng/mi., mot" pn.'.fornb!y 3,''..00 h:-rig/
ml., ~;rnJ mns! prdc:ahly :>,7'.'iO hr-ng/ml ckpcmling (!fl tile
fornm!a1.ion. Tbt.'. high t.:ml of !ht: AUC,,,r fur p~.cuth.:pht.>
drin(; ;" pr•:forn:_,ly kss ihan 6,(100 ll.r-11g/rnL, more prd~rÂ
:tbly 5,8UO br-ng'mL mot"'-' prekrnbly 5,500 hr-ngimL and
m\lsl prder;;hly s,ono hr·n~:m!' tkpt:mling un ;he formula-
ll('ll. l'ot a l 20 mg. lahk! the AUC,.,1 may ]-y~ -;ekci,;d l"mn1
hclwccn 2,500 hnig:mL and 6,(l(l{l IJr-ng/rnL. 2.800 tw-ngi
mL :tml 5.800 hHigimL, ?>.500 hr-ngimL ,•tnd 5.500 lu-11g/
ml., and '.\7'i0 'ir-ng:rnl. rnJ :=i,lKl(l hHigimL l·or a 60 mg
!J.ble! I.he AUC;.,r m<':ol
prdn;,bly T!O,[~]il hr-ng/ml. depernliog •im the fmmulMion.
For '" (l(i m::; i.~bk1 lh<.' AUCi,,,- nuy Ix 'idcc1d frorn tx'.l"W<:1.'n
256Ji{JO hr·nf~imL and •1HO,WK~ hr-ngimL, 288Ji<'.JO llr-rif~
mi.. aml ~\(JO,IJOO hr-ng- mL, 1tl8J~i<'.l pg.imL and ::nn,noo
hr-ng/ml ., ;rnd 320,000 hHJ~im[. and 360,UOO hr-ngnnl ..
hir 3. 1() mg 1~hkl the AUC;,,,· mt'twecn
J')2,noo hr-n::_~irnl :uid :wo,rn~1 hr-n 2~.:mL :::10,nnn ill"·ng.
rnL MJd 270JIOO ilr-ng/ml, 216,0UU lu-ng/mL aml 24{),IJ(~)
hr-ng/rnl., am.l 2~0,000 hr-ng/n1l and 270,0HO b;-ng.mL ln
crnntbcr t:mhndiml'.fl\ the kvw <:rnl of lhtc .!\UC,,.r J(;r (k>:·
lrumcl!1orphari i~ p1cforai:-ly gJcak; !hafl l'i,OllO hHigimL,
rnorc pr(;knb.!y J.8,0:JO hr·ni'/rnL, mur~ prd•:rnbly 2L0l~:;
llr-ng/mL, more prdcrnbly '.::4,00U hr-ng/ml, ;rnd most
pnofonbly '.~7,rnlo hHig'ml. 'kp<:nJing on I.bl'. f,irn1tda1ion.
Th,; high o:ml ol the AUC10r (or J::xlrmnelborph«r1 i:-, prel-
enhly le:;:.; tli:rn '16,9{)1] hr-ng.-mi., mme prelt'.rahly '1'.,0lKr
hr-ng:rnL, nwn.'. p;dcrably 41,(~JO llf-ng/rnL, nwrc: pr1,~forÂ
ahly J9,rn.10 tir-ng/mL. mor<.: prd~:n1bly J6,0UU llr-ngimL
crnd mo,;t prefornbly 1.\0rnl hr-ng-'ml. depemhng on I he
form u[;11 il
prcfcrnbly h-.;tw<.'.<.'.IJ BO'T ~lld l 25'» of lhc FDA :tpprov<:d
rn1:an. mcir<: prdu~bly lxtw<:tfl 9lYX :md J.J :VT, and moM
rrefenbly hetweeri iJ.'5 1/;. am) JI 5'X-. ThcS<:: ll! ;;.J_iusl :.:mrimens11n1dy, !tm! is \o c;1y the mean may
for !nsl3ll<.:'~ pri:krnb!y be h<:lW(;rn 901:;. 31ld l257' ,if !Ile
FDA mean \kp(;ndi11g on Hw formul' 9,000 br-ng/ml., and ITIO'il
prs:-f<:rnbly 8,500 hr-ng.:mL ck:p<.:nding on 1h" formu!J1iou.
For a J.100 rng lablu 1be t\UC0 __ , m:iy [><: sdu.:kd frorn
i·H.olW((il 3,2(~] ht·-ngot11L nnJ U.,150 hr-tigJrnL, 3,7l~J ht·-ng ·
ml. rnd 10,'.i(!{) fi1,rig/rnl., -i,OPO hr-ng-'ml. and 9,SOll lir-ng'
ml., '1,2'50 hr,ng.'ml. arn.1 -:J,(fOO hr-ng/ml., arnJ 4;'\00 br-ng:
mi.. z.nd 8,5(1{l ht"-ng.imL For " 600 mg !abkt !be AUC,._,
mzy li·~ '"'-kdt:d from bdw·~~:11 J.,6(1{) hr·n~VrnL and 5.615
lH--llgimL, l ,850 hr-ng:mL and 5,25•} hr--ng/ml., :?:Jl-00 ilr-n1~·
mi. ;md -'l-.}'iO lir-ng/mi ., ?, l :'.5 hr-ng/mi. ;md 4501) lir-ng:
mL, ;mJ 2,:2:}{) br-ng .. 'mi. rnd -~2'i0 br-ng.'rnl..
[ll!!\-11 t\lkrm1tivdy, the ln\'. tnd nf \h,; AUC0 ., for p«;e<1-
do(;ph(;d!lfl<.: i& prd;::rnbly :;reilln 1lrnu 2,urn~ hr-ng'mL more
pn.:fornbly 2.:200 h.r·ni;/mL, run.r-~ prd~rzbly 2.5Ull hr·u:!,'
rn!, :-;1 pdcn1bly 5,0lK) ht·-ug ·
rnl. dt:prnding uri !lie fommlatwrL hH a l'.20 mg tahkt tile
i\UC,,., m;,y he w.kcwd fr·;>m hc'.IW~t:n ?,OOH hr-og:ml ;-
lwmrthorphan i.~ pn.:krnb!y :;rcJt1:·r rllan 59,00{l hr-n:;i__.'mL
moff. pr-cfon1.hly l l 9,(lOO hr-ngiml ., 11wr<: prdcr;ihJy-· l 43,
(100 hr-ng/mi., mmt'. pkfornbly 162,!)(]0 hr-ng/mL, mure
pn:fornb!y t VJ,000 llr-n:;im l, mor1.• prnf<.'.ral.-:-Jy ·-rn1,iJUO tir-
rn>mL, rnor<.: prekrab.ly I 9(1,0{>0 hr--ng.·mL, mur<.: pr;;kraf:.Jy
202,(~K_J hr-ng/mL, and mos! pn::krnbly 214,000 llr-ng/ml
dq:irndmg t do;.lrumdtmrph;m is prefer;;\+,; k:,,,., limn -175,lltl\) hr-n;~>
mL, mure prdenbly .~61!,000 llr-ngJmL, more prd'enbh
33 75(KJ llr-ng/ml, mor~ prd(:Hbiy 33'.Ui«l hr-og/mf~,
rmm: prdentbly J09,{)(fl br-ng/rnL, mor~ prdcnbl•; ](~J,
(1{)0 br-ng/ml . mon: pn:fernbly 2X6,0(1{! hr-og/m[ ; more
prder;ihly 2'70,000 hMig/m! , :rnd mo:;l pn.:.f..,rnbly 262,0UO
br-ng;mL d<.:prnding lHl 111'' f<.,rnrnfa!it•n For ~1 (;0 ml; (abk1
lb;; />i.U C~ __
1
may be S<.:kd~d from [:,~lW!.'.rn :216,0f!O hr- ng/
mf. :md D7,Sff0 hr-ogimL, 24\0-HO hr-ng/ml. and .10(},(){)j)
lir-ngirni ., 2·B,ODO hr-11~'m!. and :no,ouo br-n~/rnl ., rnJ
17(1,000_hf-ng/mL "'id :A)OJiOO hr-n1VrnL For a Ji) mg ralik1
i!J<.e ;\llCc-t lllhY I_>;,~ .'1":kdccd fmrn lxhv;:rn !62Jt!)(l !Jr-Ill(/
mL and 250,0(}0 hr-ng:mt, li-:2,i.l(\IJ hr-ng/mL Mld 230,U{i"l
lir-rig/rnL, .lK?,000 hr-n;;.:-ml. :md :m::O,(l-00 lir-0~_1m[, ~ml
W2Jl(l{l hr'n\!,iml. !lmmdhorphO hr-ogimL, ;;-nd most
prd<.,rnbly ~~3,c1rn~ hr-ngirnl dqx:ndin;;; on Ill<.'. fornrnl3.1ion,
[Oi 66] l·um:mlalioris ,.Jf !ht:- invenlinri prnvillo.: a AU(· kr
1:ithn gu<1ilen~sin. tbe ;11.klilion:;] mmt:n:mr;lidy, 1.h:H is 10 sily iii<:: mean m;;y
for tfl!il'.!ll•:X prcfrrably b<.~ hel\V<.'.<.'.ll f;·(f<"ii, and 125'7.'- of lb~•
FDA m,;;,n dq)(:ndiug un the fonrnihtiou. Altern3fr~cly. lh~
k•w '~nd of 1.h<.: A!.Jl',., for gumfu\1:sir: i'; pr"<.:frr:1b!y grcatn
!h;;n ';,(l(l{l ht-ng/rnl , mur<.: prt:for;ibly 5fifl0 hHigirn! , more
prdcrnbly 6000 h;-n!,!/mL, and tm~',l prd,.:rnhly n50IJ br-ng.
mL ckrx;ndi11i; ~·11 !he fomwl?,li<)lL Tht: hii;h ,;:nd of tk
ADC. ft>r gu.'lifom:&in is prckrnbly k'iS 1ban 9(1{10 lir-ng/mL
rmm; prdernbh- 87SO hr-nglrnl., mm<:: pr,;f.:rnbly 82'i() In"
ng.·m[ ., ,ind mo.~! prd';;;rahly 8(1(1{) hr-ng.,ml. <.kp;:nding nn
lh<: (;>rmubtinn_ The ALIC,_, k-r ;i 1 :'.!~.l mg tablet ma~' h<.:'-
sdecl<.'.d from bctwe;;n 5!HJO hr-ug rnL 0 ilr-n:<~:mL
5600 hf- nw'111 L 3fld 8750 hr- n;?jm L, (A)U{) hr E](l /mi. 3.W 1
~om br-ng/m l .. ;md 65(1{) hr-rig,.'~!. and 8.750 hr-n;i'./ml :. Th~
ALIC_" fnr a ()(j{) mg labkl rnoiv bt: '"°'k,_·1nl from bdwecn
2,500 llr--ngimL and '1,S0-0 lir-r;1;·rnL 2,t-li.l!crnativdy, lh<.'. [ow .. ;nd of tlw AlJC. .. for p:><.,11-
dn~phcdrin~· i-;, prckrnbly gr1:atu thafl 2J on hr-ng ... mL, rnnr<~
prder;;hly ?,4()0 hr-ng/mi., mnrn prekrnhly 2,6SO hr-nf;;.'
ml., anJ fll(!St ptekrahly 2,800 hHig/ml ckpernJirig p;i 1.lie
18
NO\/, 20, 2003
form ii Llt iori. Th<:: high wd of !h·., !<. lJ C._, ror Jit;,:mloephi:drint:
L-;, prd<.:rnbly kK« 1han 5.5(1{) tir-ng,··m L, more p.rdn;1b!y
5,(ll~i hr-ng/rnL, more prdcrably 4,50(! hr-m.>JHl L, and most
prcfcrnhly 4,000 hr··tlt,~1mL (kp<.'.ilding Oll !he rr.rnrn la lion.
Tb<:: i\UC,, l'nr a J :co mg !ablet rmy he ;;;:kctt:d from
helvt..,cr1 2,W{) br-11,;-'ml. and S,'iOO hr";1g.'mL, 2;WO iir-ng'
niL 2nd SJl(~l hr-n1~·mL 2,650 hr-n1~-'mL 3nd 4,WO hr-n1~:
mL, a.nd 2,800 hr-ng/rnL 4,000 llr-11:;/mL Tbc AUC._, fur a
60 mg t~bk1 m:iy be sdci:icd from hctwe<.:ll LUSO IJr-m;imL
and 2,2'i0 hr-rJgiml , l ,200 hr-ri:o;imL ;,rid 1,'iHD lir-ngi'ml..
1,32S br-ng:mL and 2,?:'<0 hr-og-ml ., ~ml 1,400 bH1~ mi.
2.000 hr-ngimL, -
[!lit.RI :'\H~rnalivdy., lht: lmv rnd ('r the A.UC i<>r .;lex·
ln_>mt!horph;rn is prefornb!y ;;n:awr lban o7,750,hr-11~:ml
more prcf;;rahly .l05,(~l{l l;r~H!/mL, mor-~ prd<~.rnbl~ Go'.
(l(j{) hr-ng/rnL mc>n: prdcr:1bly 131,rn:Ki hr-n.s.'mL: more
prekrahlv ! 40,(){K) br-nglml.. ~ml mos! prdt:rably !58,0(~]
lJr-ng/rnl. dep;:nding, (HJ !be fornmJallO[]. "!li.: high <.:rnJ Df !hi~
!<,UC., !i)t d<.:xlrorntlhorpb3n ES prd'crnbly k,;.;;; rhan 2fi3,0UO
llH1g/mL, more, prnfrrnbly 245,{l(!{J br-flg/mL mor<.: prcf<.'.t'-
;ibly 22!-UHJO hr-ngimL, ni..in.: prdcrnhly 220/KI{) hr-ng. mL,
more prefer;;hly '.l0,(1()0 hr-n:S;mL, mtff<' pr;.;fer;!biy. \97,
0(~) hr-ng,·mL ;ind 11mH pr;.;!'t'.rably l'n.ooo hr-~1~..-mL
dcp<.~ndiug uil 1b-~ formubl ion. Thv AlJC,
0
for 3 ()1:f mg ;tblct
nuy he i;dec1cccl from buw~rn J '10,{J(I{) hr--rn),iml and 210.
nm; hr-n_~,ml, J '175H{) lir-ng:mL :md 197/fOO hr-ogiml:
h7,')00 hr-ng/rnL and li'i,O(I!) iiHig/mL, and 17S,{)(10
hr-ng/rnl. :rnd l 97,0rnl lir-ng/mi.. '!1i;; .-'\UC, I'm a .10 fll'<.'kd<:d from bd'Nt<.:n WSH)O.llr-n~/ml ;:rid
J.6S,rnl0 hr-n;,~,..mL, J.20,riOO hr-ng/mL i111d 149.o(i(i llr-m~
mL, l 20,000 hr·ng, mL .rnd LT.",O(~f hH!KimL, .rnd \12,0tlO
hr-rig/ml. arid 1 ~9,0i:Ki h[·ng/m! .. !n arnilh-~r <:mbc-Jirnem I ri~
k11.v <.:ll(I of rh~ AUC" for--.;k: hr-ng/mL 11101<.' pr;;frrh!y 22,800 hr-
ng/rn L, mc,n; pfffornbly 2{, ,600 hr-ng,'m l, more prcfornh[y
:m,son hHigimL, ;rnd i:1Dsl prtfornbly J'1,(l\)l) hH1g1mi_
dep<.:rn.liog m1 lh~ t'nrrnuiatioo. Tb<:: ht,,;h <.:nd llfthc :'\UC fnr
dcxlrnrnc1tiorp!un is pn:fornbly ks" '[tun 57,{J(l{l hr-n~);nL,
nwrc prdr:ubly 5.1,0:io hr-ng/rnL mor<.0 preferably .. <(},5!0
hr-ng-'rnl ., more prel;.;tably 4'i,60l) h;-nK-:ml . and musl
prekr:obl_,, -il.800 hr-ngimL ckpemling cm-lhtc fonnul;iliori.
[ 0169] F<~rmu bl \(•ns nt 1 h<.: i rwrnl ion prov id~ r he-th 'Nhich i.~
p;derahlv hd~vt:t:ll 80·'./i a1Jd !2S'l. of !h~ FDA appmv•:eJ
muin, murc pr>.:len1bly bdwl'.(il r;l)?i mid ll5':i, and mosl
pn:fcrnbly bdVi<.:efl \l5'X and J 15%. Th~s<.: rnn~1.'.c; du uo!
tiav<.e 10 djus! ;,·omrn<:n;;;ur3.ldy, 1!J:.ii i:> !u c;av 1hc-mcM1 rn:rv
for ins!ari;;~' prd..,rnbly l-x; b~lw"rn 9\Vi:0 a;id l2'i'f<· ol lh~
FDA mean d~p.;;ndini; r(. pr~fornhly .t J
hnm:~, mut<.: pr<.:krdbl.y J .. 1 hom,.,, ~nd rm»,f pn'.J"t,r:ihly l 4
ht;:-; tb;in "!.~''i liuur:~, rnon~
prder:obly .'J.0 bou!':';, more prckr3bly 5.ti bn1.H", nnd mos!
prd<:rably '.\5 lmurs dqlcoding <:>fl ih~ fornm!a1.ion. Thi; Tl'."'
for a 12(~.l mg tabk< r1iay [1s: :-;,:kck.J fr um bt:twc.:r: 0.7 liom"
and 7.'.lS hour!'., 0.'.l bn;1rs .rnd h.O hrn.1r:i, [. l !;uurs ::ml S.O
hu1.1r;;;. 1.3 hour;;; am.I 3.5 hourc;, and l A holJm mid ~~.5 ho1.11-s.
The T,.~ fur ;i 6rn~ mg i<1blci may he ;,.;;k<.:tccl from b<.:twe1.·11
0.35 hmm and :-1.63 h<.iurs, 0.45 hotirs and ."\.O ilrnir:>, O.SS
hmm; arid .'2.5 hnurs, 0.65 hum~ ~ml l ,75 hn1irs, ~rnl fl.70
hums ;,,1J J .'/'.> liuurs.
US 2003/0215508 Al
[017lJ] i\11.<'mativdy, !he low erid of !h<' T, .. , r.;,r r""'t1-
do1:phcdrinc [·; prnf<.'.Hbly grcai<.a· !h;rn ~;.2 hotHS, rnot"c
pn:frrnbly 3.6 !lotus, more prdcr:ohly 4.il lio\1rs, more prcf-
crnbly 4.2 huur:~, ar1d mus! jHeft:r;1hly ·1.5 bw.m; dqiemling
<.m lht: form1ilatim1. Th<' hi_<,:h end uf lh<' T,.;c fur f'Oi!'.UdOt:)lht:-
dt·inc is prcfrrab!y kss ihan 8 0 huurs, mon; rrdct\lbly 7.5
hotios. more pn.:frrnbly 7.0 huur;., :ind Jll<)Sl prcfcrnbly 6.25
lloufs dcp1.,nding 011 tile fomrnlaiion Th.:o T1 .,:: for a 120 mg
!ahld may lie .'.<:!tctcu rmrn rY~!Wttu 3.2 huurs am] KO
hours, ~,.fl hrnJP.i ;iml 7.'. hour:;, 4.0 hom:; ;rnd 7.U hrnw;, 4 .. '!
llom:> Mid C>.25 linurs, ;rnd :JS butm;. ;:wd 6.25 hours. Th1: T, .-:
fot· r, CM mg tabk1 may lK :>dcctcd lr:Jm lx~t-w<:<.'ll 1 6U hours
aml ·1 0 huw'i. t .liO hrn.1r:-, rnd 3.7:; bDUl'i. '.LO huw'i ;;rid J5
hrnw;, 2. J huuroi and ~,. L> hmm;, and 2 .. ?S buurs aml ·'· 1.1
hmirs.
[017! J i\l1.erm1livdy, the lnw erid nf !ht: T, _, for tkx-
!ron·1tthoqi!rnn i.~ prd(.;r;;hly gr..:ak:; !frnn 4.6 hour'>, n1on·
iw.:fornb!y 5.C> llo\HS, m, mor:: prdcrahly 13.0 ho1w;, mor.: p1d-
ernb.!y .l.3.0 bours, mor<.: preferably J.2 J. tiuurs, murc prd-
<.:rably t l .75 hurns., rnon; pn:forah!y ! J .2 hou1s, and mo:-.l
prefor;;hly !O .. ?. hour:; dept:ndillg nn !b;; formubliun. Tht
T .• for a GO mg !~bkt may Ix: sckd1.'d from hl'.l\'/<.:Cl1 'YA
ti(iurc; mid l4.7 rmllr:-;, Hi.6 llnurs :md LL?. lloms. Hl.6 hourn
:rnd 11.75 hnu.P.;, alld 1 J .7S hour.~ MJd 1 :~ .. ? hm1~. The T, ·~
fc.r a 60 mg labk.I may be :.;i:kd.:d from bdweeri 1.0 hours
ciissc,.J ft1ribcr in lh<~ 1:xampks whid1 fl•llow
EXAMPl LS
[01731 ["ht: inventinfl i.s fonher uellrit:d by rde1,;nce !d the
r(,Jl;n1.: takc'n priur 10 dosing and M
SJY~tihc inlerv ol' being drawll
Th~ plasma wa,; scparnl~d, lransfnr;;u !u a polyprupykwc:
IJJbt, frnzell ;,i. -.7.0'' C. or hdnw itmJ s!ored frrn'.tcll urili[
h!.'.ing shipp<.:d for drng 1mily,sis. Th<.: pLisnt-:t ,;.3mpk" W!.'.ro,o
lil•.;n ,urnlyz1.'d !)y a foll:/ vs.lid~_[l:;J l-lf'LC mdlmd. This
r.:,c;:illing J!lasma Gir1..-n1lrn.liur1 v !im!O d3ta Wis u:;ing ll()fl-cump:tr! men l;i 1 all;; lv:;i:.;
;vilh \Vimmnlill J .'.'>.
[ 0175] \Vhen ll<::ce.-;:;;ory, vultmkeP.; wa<' lhrn gi·,·rn <' lh·.:m under ibc :51lidy) prior lo bo,oitig
crot;s<.:d-<;~·cr \o lb;;; n~1il tr<.::ttm~nl gnrnp. Gcn1,;rnlty, lh·~Â
subJt'.cb Wl'.ighed v.•ililin ! '.'i"i(·, nr lht:ir itk;I Hndy \Vcighl ;;:;
Jdlm.:u hy lbs: 1 %'.\ Mdwpulitw Lifo durL
19
Nov, 20, 2003
[0176] A batd1 uf susl1im:d rdea.'.<: gu~ifon1:Csin !ahkh,
LU!Nu. 7LB-3lFC with tht ro!b"•ing comrr.;siliori w:i:;
prepared:
(5;.~;1ifi::r: . .i.::s.i11 !X."
:t-kl!m-·~::! l·!d:'iA
E~~~ts-ri!d f11c":>:f! Lr1h~
Yfa~rw~.;ii~ :~;~c<~m~c
Opa·J••,' ~~·· ~~-3-7-fL:;
J :·1);) 111g
:mm~
[ill 77] i\notlw.r b:11d1 of s\1;.Utincd re bis<: gua ikn<.:sin
tnbkK Loi No. 7lB-3?FC '"ith ihc fo!k-wing CC•fflfX'lsi!ion
w ;is prer:u-t:d:
< Cmli lcM~f-iri ~ ?; '
'>1·,l'wcd E!O\j
(":,ch•.ll'nl 974P
E1!-:-;::i;1l·~ G!~<:1j L;"(kr;;
\.-fogm;'.,,,;l~!H S~~;:~~~\~~::
Op;iJ: ,. Y-S-.<-'?i'-1
: ::~·in rn~
)\1 m,~
~5 r!1,G
~~ mg
~~.~ mr.
L\.;.i:1 m~
[017~1 .S.ii< l~bk1~ fo.Jrn Lot 7U3-.3J.FC :tnd .,;1x l3bk1s
from Loi 7U3-32f( w,;.f.: K:;Kd for in vitrc- gtJaif,,n,"ul
rcblf"'-' its.in,; an A·::idi{fay;; dis.'>:lhJtion (sligti11y mnd[lied
USP 23/NT lN..-:.71 l >Drng tkkM.c u,:.ir1g /\pp<>rnlus 2). Six
dissdutinn "'·'';w.l:i of" USP (:al1hlu!ion k'.~!. ·1 r1e p1Jdks wcr~' Y.'.I
1.0 mt;lle at')() RPM aml I;luwlv lnwaed in!n l.ht: ve,:.:;;:h. Oll<::
rnblu of lol 7Lil-?d wa;, lh<.:i; dwpptd into eacb ~·c'V;d.
[OI79J A! 11l,; .'d and tlllo.:rcd (boo•.igh a W micoon polyc!hylcm:
lihn ioln gbs.' l !Pl .C vial:;, lmrnedi;ilely :;i'ler 1.he lwn h-:,<1r
;.;ampk,~ 'vlei~' withJrnwn, 22'} ml. uf 0.2M Midtum p!EJS,
rh:;tc uih;,:-;i;: wa,; added lo i;ad1 \'tS."<':l !u incrtasc !he
solu!i(>n pl I 10 2bou! 6.tl. Th!.'. di.S';ollllton w~s run for kn
;idddition.d al. lb\:' four, ;;ighl li.l, anu 12 hum inltrvats. 'l11c
IHkn:d ;;,;mrk:> \Wm !.hen n:n Oll ;m !lP! C m dekrmirit:
p':n:" m gi1 <1ifon1.,,;in r<;kn:;,,d.
[Orn!!] Th<: same dis:-Rllutirni le~ling, prc·\.xxlme w;;c; pcr-
fnmK'd fo.x lot 7LB<'1>2 fC. Th<.' lots g.w<: dis;;.:,fu1ion prt>iik«
shown bdow and depict<.:d in fl(;, 4.
fOHH] Lo1 7LB-.1J
Ve~::---.,d
~;a. : :H. ~ "'· . i hr, <~ ~I'. ;11 ht . J~ :H.
:r> 3~ 55. n ::-::i ~;-.:
ory ,""·(.." _=;..;. ?S Kl -~~)
US 2003/0215508 Al Nov. 20, 2003
20
-C0!lllllllCd
\(1.:s:~·,,:!
!"<:l·, l !H. .. Ii;. 1.r. ;,-.:: h•. ]l) :H, 1: I•··
.::."/ _Aj:(j ·r.:-. )(~ K~
.+ ,, 3_; 4; ,.~ 7"::, /(;
5 -~~:;; _1-,i:, s.~ 7 .... c:i $•::
{ ~ .'4 ?,\. ·H 11 Kl [',I
A\'{'"/l~~e ..'.-t:, ]t •.. < SL: }:'.II /'-)_? .;J;:t,2
[Ol81J Lot 7LB<~2fC
\.'i::~::'-d
".\n. I hr. ' h• {~ In. {,' er. Jr: :H 1:· ":.
:s 3D e :'"~ ~': (:.-Ui
: ::.1 JS -I~ 5~: td ()(;
-~ ::'..i"' ]~ ~5 :~~~ \J5 ;'°}(.,'
-1- :·-t .''5 .+:: S-t ~-~n ~~s
:'> 24 3!) u ~'~ 5': l·-1
" :::_1 _1.4 ,=!:~ 50 5:-; :-s:
,4;,,·c11:;_~,: _,4_:. 3c:, ' -t.c.i: 54.3 ;i·} .~ ()4.5
[{1183] B(>ih t•.mrwb1ioo~ ;.k:motislrated ;;us!;tined n.:ka:>c..:
or guailem'.sin DV\'.f ;; I.? hour jlt:rind. l .ul 71 .B·_FFC d<:m·
urn-J1;; ied idrnlir:al rdi::;;se pmpttlte_, lo Lui 'lLB>vct rck;isc th3.n Loi
7l .B-.'i I FC. compri!;ing Me1.hm:d !_'. HJM «ml no C:1rbnpnl
'.17.:lP. !\ .sluwer rck;;;;i; rnlt: ill vtim trmi~];;Je.s lo a skwer,
mof<.' <:ontrnlkd rdtR"-' 'Nith lon~.<-'l' drng ;irtion in vivo-.'l
fovorabk charnu..:rii;tic for pbumaL"tlll i<.:al pruduch cnH-
lainillg ;1 high conn:fllnliun ;Jf afl aclivto in_i.;redit:nl wilh '1
shm! half-life (..:. g. guJi f<:nl'.sin ).
Exampk l
[{11841 A dissoli1tioo smdy was nm to ''0mp,w:. disR.1lminn
pmlik:s uf lms 7i.B-32H' and 7!.B-'.\1H' wilb rnm:n!ly
~;~;
,'lv1ii[;,bk gu. ~.m.t;,im:d reb1S1: labkl:~,
mJMlB!I) LA. :rnd DlHl!\TUSS, war. suhjected lo th1;
S;J.rllt'.· Jis~;;:iluli(l[l sl11dy ~s Jt.'fo.:fd.:~J rur [oh 71. B-J l i c am]
7!.B-.'12.FC in Ex;,mpk l ::huve. Th~ fn!ln'Ning i!; ;, summ J:Jn ~):-:
[i!Ul:'\j 'lhL immcdi31!.'. rel!.'. ii;;~ 0.rg;rnidin rck:tc;i.:d JOO'.~:. uf
gu3ifcn<.:sin ·~onk!ll within tb·~' tirs! hoiir ot dissollltiO[L ·rb<.:
t>1-·l1 L'Ornmndal sw;t;1in<.:d rdc<1g·~ fonw; ·~kmonÂ
;;lrated a sbwu n~k;i~ ni' guaili;m~sill. However, huth lhe
Iiumihid l ./~ :md D1n:t1uss released gu3ifem:sin mil.re raridly
than either Loi 7LB-J J FC <.>r 7LB-.'.'.1FC putict1Ll.rly ;1ficr
1ti-~ d)0ll hour inlLrv::J. Holli l-fomibid LA Hid D1Ju1uss
would, !h<:rdon.:, <.~xhibi1 a fao1n· ml<.: of rd",i::"; -3nd lfrns a
;;burl.er J[v"d !hen1peuli\.'. dfrcl in Vi\·'ll.
[01§:6] The ill viYu hd1;,·,-irn c-f HJ.0,lained rek~.-;.e !abl.:b d
l .ul 7! B-.>J re mid i.rn. 7l .ll-1.'FC frnm EK:;mple J "'"'""
compared 10 ibe in 'ilYt> l>drnv[ur of ml immcdi-3lc t'd<.'.asi..:
timm1l:ilinn (OrgMiidin NR). The open-bbd swdy in'-·,1lv~.d
') il<.'uhj;,;d w11>< kirrnk and 1hc r<:mainJi:r "'""-" rm.le. Ead1
suhy.;ct n;,,,,,iwd <.:i1l1cr one 120{) mg, dos-;: of 7lB-3lfC
71J~ ror } dose!;).
[!Jl~7] Th<.: r'"~uh" d th<.: pharnu•.:t>kindic parnmckrs
Mlaly"i.'. an~ lk.,,nibeC.'.:C -~·~1 "i'.:.:1 -Lh·~ k+Jn . .:.::i-
7Ll3·.'JfC J.5(, ~1::'-4,f;5 _;1,{)S_;s:_i :'..Ii S::9J.71
"i'l IL'li'C l.'.c) .r;o: ·>1 ·1 H:· !'-: :u,1 ~rr>~- :.;_:t
IL[I. J2['(' u.-/~ r~~~5. ~'~~ .~O.~-! JJ ~;, l>·= 5J.'.L<5
7l.8·'.'fC l.l.R' i ~ t5 .~.~it; Sx7.~.4v ~.'~;.(} 0:"~''0.J.1
-:~.B-.~_?H :.IJO ~.:?~'..I J[) -;·;:: ~. _:~~ 5.~) ~h"' :.-;i~,
Oi·;:p1;ildjr~ '.':r.. .:).5~ i : ~ .il)))r~ .:::1·-):.;J,q.; i~33l> ~i{!.:y?.Uf\
\. )rg;~;1 iJ!r~ "~- 4.:':i 3N. j 7_~}l; 059~·t2~ 0.73 <;1~14 .. t1S
of ~r~:rnidir: >.;E i~-~10 :'l('.j()() (_)~~~) ?~ llXI LJ5 .. if;_''.)!
7ULlifC 3.1)7 ,~;~.:.Jr 4~,:;;;_l.?4 ,\.=::9 5--t'\,"l:, Iii
-r~.B-:;._~M 1.'.'' !Hiit:.1!1-) .:..~:,HJ __ :.t; _-.,_-;-; ]frfo.:t.'~-'J
Ofgitnldjr~ >:R ], .,.,-:: _2~~<_:.ll ~I ~!\:•.;f).t:S il.ct.1 -i~.1~ j . ):~
7l_l}.3JfC.'JR :)5 A-' :.t. .. :!;f) ~::;·)_()! 4-'1a.:·.7 7t.~.Js
·11 Ii<', ::FC. II< I l.•1 < ol-l. 0~'. '{\.\,' I :g:;: G~i-~>_1
[OH!~] Suhjixl<> gi,..-1.:n th.-: 1200 rn;; fornmlatit>JJ 7LB-
:~2n · r.:;,clicd rn;,xirnurn plasm;, gu;,iF~rK:.-
hr-ng/rnl.. n-11~ sub_ieds r,;ivcr1 foilrmblitm /l _H-J !H.'
US 2003/0215508 Al
r<:~d1<'.d maximllm plasma o;,u;1ikri<'siri cnm:~mr~1.inn.s nt~2 l
ngimL i11 l.67 hours and lwd Rf! AUCr
0
r of 5453 llr--ng. mL
The subi·~·::-is given the im1n-~rfo11c rde<1sc formulation.
Orgrrnidrn Nit r<.:ad1•~.d rna:<:nmd dn-;e ;-,J. 4 bntir>) <'.llll l:i~d ;m /'.UC,,.f
of 7'f'i2 lu·ng_!mL !fo; (W'.l con!m[kd H'..ka:;..: rom1JJfo;ttms
di::moos1rn1cd susiained rdc3.sc in 1t1111 their lrnlf--liw;; \vnc.:
!0n~\t:r, 5.77 hour~ for the.: 7LR32FC <1ml 3.:'lJ buurs: foi the
7LB<;l FC <.xirnp;,rtd 10 (U;: hours for !ht inmwdiat<.~ rd0.'lS(;
forn11Jbtion, Orgrrn[dit1 NR.
l0189] Buth fornrnlaliom 7LB--J::!FC(wilb bulb M•.:tbt>~'.cl
E-1 OM and C1rbopol 9741') ~nd 7LB--3 lFC i\vi1h Mpul '.l74P, h;id 1.h~ kmgt:,;t
lrnff lifr <>.! 'i:n boufa wilb lb':: hu~~e2;t ;\UC,.,f bclwn:ri tti':
\'ND ,~u,,t;iim:d r-::ka""' formulati'->fl, ! lnwev<::r. hoih su,;t;·,iri..:d
rdc~'it forrm1l~tiuns bav<.~ '' C""'' k:os 1bm1 !rntf of 1JK Cm,,~
of 1h·~ immcdi:tic n.:k;is<.: Orpnidin NR.
Ex~rnpk: 4
[Ol90] Tbnx: d1ffncn! ~ur;uin~d r~k;i.s;,; l;ihkl !c-1s of
gt•aik 111.·sin n!on<.: Vi<:i<.e prcpuc.J:
i:n ! ~ 11 i) i •'or mu b1 iorJ i ---- t :.'.00 mg SR; ii) l ·'nrmub-
1 km Il----4(MJ mg rn am] 8..00 mg SR; and iii) for·
mu!atio.m Hl-<:100 mg m. and i_i00 mg SR.
c~~lx•pD! ';74P
l'.1r!.;! 1·,1lci G~.:.:~ft Lak~
\.h~m.::-,iu.;;; St-.:o~~-~H-.:
Fni f1.mk1~;0~! i
\°'./cj~_rM pn L1"hkt
1:•c,H m~
'~l m~
:-'.O mt~
-·~ rn~
[lll9J1 BE--L3ycwd 'fabk!s (S11;;t:uw.:d ik]<;,·isc.: and Jrnm<.:-
dil.i_;;{'-;A~~ iNr::,,c:• ~: . ~ f .;, '-"flll)_;
[Oi'IR] Su~iaintd l'ormub1ions [J all.13.incd
Fornrnhlioti l. Tb<: !u!f--hws nf bc•l_i:J Sus1aif:(,() Fornmlaiio<1
(] irnd HI wnc reduced from ihc h~lf-hk or Sw;;;iind
[:nrmufalion !. Tht:"Jtion study wa~ mu 10 cnrnp:lrl' di~.<,d11!ion
pmliksoffornm!"tir:in L fonrnJ!"tion !! and f,Hmu!Jlion Ill
rHcpareJ a~ ddino:J in lxarnpk 4 above, ;mJ Formula1irn1
IV. a h[-bv<'r l;ihkl Jn: wi.th .?i.1-0 mg [I{ ;md WOO m~ Si<
rr~r:m:d with the fulhwiflg cnrnp:.,;[li,;n:
Gu~ik11c~i1l DC
M tc-Hx;·~··,'~l;~!!jf1 r_: { · c!!uirn...i:
(,..\\.'i.Cd)
~-·.~-·'F'IJ l;~linn C'\,.
Woi.~1\1 I'"' Tobi
CGr.!pn1~t1:ls ')k:lght :;.c~· T;~t-l.::~i
'-c.d;~:m .S~tffct. C1~\·c~·1j;w: ;-i.:; m~
(!·:x:·~:,: .. ld~) .
:~ht~l\J:S.(•.•m s~>::11,~~>: .j mg
-: lin i k ~?.::·.sir:. Df'
Vklhc"''·I I· ;11>,i
c,~~1xipo! ';7--:.r
Em-: 1·,1id {ig;::.":!1 L1k~
::\bgm.::-,i~~~:: ~-)1~;~··~n~
V;~ro;o-,1..1l:1tinn i'/
\Vi:..:;g.!1~ p-.:r J·<)t}kt
Ju-S.~ mg
~~ m~
!~j mr
~~.J. mg
:-:...7 mg
[0201 J Th·l :"! -t(; ;;~
4 ~IL 4.' ·>5 .::.:~ --!-t~ ,, ~[. 51' 7(1 (d s.1
0 ht', s~ --;:.:.. .f)\~ UJ
Ill hr "· "~ "i'n {1~·.
i:: hr. t·{· ;_rnwlillhm ['i/ tuo. :< rnlc of
r·.;ka·.;;.: wbid1 v»as Lt&t•.;r !ban formul~ii•Jn I, compri:>ing tw
irrnrn.:diak: rdta .. ~<: b!rnd, bur ;,ln\.V<:f !h;m h•mrnlafrm ll~;rnll
Form1Jlatiun m. huth cnmpri.>iog rnnr<: immetfote rd"'°·~"
bknd ibm1 Forrmih1ii0n !V.
Exampk 6
l 0104] The in vive., lxol'rnvior of Fonm•b1ion IV bi-!3v0r<.:d
rnb!d><. pr<.:par-::<1 il:> d<.:~ribcd abovi.: 1r1 [>;3mpk S: Wi•$
<.:ompcired In ;m imm,;di<\te rd":t!>t: formllhtlino (Orgarndin
NR). Hit opcn·labd, mullipk Ju;:t, r::1JdumiI of ;;gc: with :i ran;;i.: of I 9 yc3r;; !o 50 Y'~·M$
of age. Tli·.; subj,;ds wdg)lcJ HlJ.77ot19J(l !bs. Tli·.; subjeds
weK plK~,J inlo um; uf two ln:alm-.;n! grnups. Grullp I
nx:eived hirmulMinn iV L!hkt ;vii I: ?.40 ml nC wakr afkr
:rn uv1:mighl !a;;! •:very 12 hours ti.ir 5 Jays :rnJ 3 ,..[r!gk Jo»<:
ou d;iy (J. Group 1 rei.,1.'.iv<.:d 'WU m1; of Org3nidin NR (2x200
mg labk1s} wilh 140 mL t>f w:w:r cvav 4 llo\Jr'> for 5 davs
~rnd one ..jO() mg d;i;;t; CV•.:ry !'our home< i(:.r a lottl c-i' :'• do~:;
ll[l d;iy 6.
[ff!OSJ Blmid samples (5 ml with srnlit1m her::rin ;;:.;
::.min,agulrnl) \.\">:re laken prior !u U(l:;ing un Jays l, 4, "i, aml
22
Nov, 20, 2003
6. On lhly J, <;.dditi;in:ol bl.mv..l ~:impk:< ('i ml. wilh .'!:Jdium
hcpnrin as ;1nli<.'0;1g11bnl} wc:r<.: al:.;o obtained JJ 0.5, 0.75, l.
J .5, 2, 3. '1, 4.5, "l 75, 5, 55, 6, 7, S, t>S, x 75, 9, 9.5, JO 1<
aml l2 b(ltii:< a!lt[ th~' inili;,l do:.;c;_ On lhy 6, ;iddilion:il
blood sampk:.; (5 m!. with ."iJdium hep;irin as 2w1icn?,g1ilaol)
w1.ot\: 3lS<..> obt~in<:d al O 5, 0.75, L 1.5. 1, ~\ 4, 4.5, 4, 75, 5,
55, 6, 7, 8, 8.5, ts.75, 9, 95. W, l l. l1. [4, Hi. rnd 21< ho1us
a flcr tile ini1ial do;;e:.
[0204] Tti~ rcsull'> ut 1h<.: pll;im13cukindi<: p;ir<1mdc.rs
a@lysi:; an.: bd0vi,
[0.207 j Av·.;rn(';.•.;d T<.'.>ling-11 T\vdn;-Hour !nk"rvals
ACC. ,,
r,,,.,, •l~..1-">, \:lf-;ri~ . ~- ... ' Al"< jii!
Foj •ll '.J L~ti.f~J! n~u (:i~'!nLi ::"!L; ii::,. I (!~1-1~~·1nU
;.,k,'Hl O!·~~ ~~!di fl ~.R l.VJ ::::~;(,~(.:)~ ;_:Ut~l '),' ()_?~~ ;:::~2t~.s ~
~vk·;!!l F·:1rn1ul,1l!rn~ !"/ I .r::i 2 ~ i L_=:-.:e.:1,x
[020~] Tti~ r·~;.;iil!,:; of the 1..:s1ing ax~ dcpi<:i·~d in flG. 9.
[tl209] Sl1:ady S!ak fr,..ling
ALC .. ,.
Tt: blcrnl, ill in lh<: immcdic11<:
t'cka&: formulaiion and WO{J mr: t>f l'.ll3ifon;.:sin in !!w
.sustained rdc;i;;;.; fonmibii(lfl r<.:suJ(,:; in a ·i,1bk1 whii.:IJ ddJv-
en; :t high :itofllfll l:Onl'.Cfllral[on in 3 snort pt:riud oi' !im1;, ytol
m:iin!ains ~n dkdivc: conccnlrnttun d' gu11ikr1(sin in tbe
hi.om! ';trci1m for a foll 1wdvc holll"'i.
E1rnrnpk 7
[ll21.2j i\ i;rncly wa:< pvrformcd 10 V>rnmin\: lh<~. rd:Hivc
b[o3vaihbih1y ,.,f tv'ing·.; :-ilrcngth:> of rnndilkd
rde:·>:>t- gu;'.ir1 fonnuhitiun>. of !h•.o iw;cnlron JS wdl a:<
the dfcd of rood on th<' rd;1tiw bim\v;,iLlhilily nC:: guai.!<:11-
e::.in funrm laiion ot' 1 be lw,·1.,niion in 11orn1n!, h;; ;;llby mak
;1mL'oc· ti.'.mak: volHuJccn;. 'l\v.;i lx-1l·.:hc> uf r.tuikncs.iu bi-
];1y•.;f !~blc:.tC>, on<.e \•OB mg ;md om; J 20{'; rng:~v<.:n: pn.:pMtd.
[02Bj lmnJ<.xli31t Rdcas;.: Layvr
~>l~i:~itetj-=~jr. O('
\·~k:rc1..:Tt~u~:: i r!t' {"i,::!!ul~,:~·~
l,iWi.:~: rmn:;
6UO mg T;;tt·,:i::~
'1.?/t~:~h:
~:·e; :.:'.d1J~t;~1~~ T,-.,::dt~s
~J.H." k~
11.7:' kg
1::n:1 n1r T:.hH
'~1el:::~1
pel' rn:uJ•~l "fobkt;
US 2003/0215508 Al
~c{li·.·~n S~:Hd~ Cdy•:Dbtt
(b:pbt;;b,i
~;~.i;r.c_·-,~um ~;lcar:m:
n~!•~if.:::ri::sif1 ; a
~]ydrc}:y~·n:-p~:! ~echyi
Ci:;:! 1~~1n1(:" (\k~hrl'-..·~! E 30\,1 ~
(··~~!lorn.:.:' (( '•~-:-hcp.:-1: q ~· ·i~~ f
FD&<. l°''\·I' :-<0. J
Ah.: :Hil'ii) :,, r.:~ke D::·=
'.-,1,!gi:c.;:-.:m11 ~;tuir;ac..:
(;{~~ 111g T,~:)kl
\\'"gl,1
~~HD m~ T;ihk(
\Vt_~r;!~~
:x r :{~).il·(il) T~1Mt:H
iii~.:·;· k;e
:.;.:.: hg
I '·' k~
()_3.3 kf,
L~'!G it1~ ~.foM·.:l
Weig ill
ll.H: ':~
I ~'.(:·B ;11~ -i:1hk-1
\\'r:.i;;!~l
1x:r 1"11.l>l]ll T.oMw,
i~!_--;. ='. i kl.:_
:..:.~.1~: t,~
j __ ~_') kµ
n .. ~J k~
[ll2~5] The 600 mg aml L'.;JO mg l,kr<:J lu vo!unk, in lb~: [;isling .~lak (d-.uul lU liuur>,
jlrt'.·dn~; 1rnlrl voh1nK<.crs ;\ftcr J hig/1 fol
!11<.~&l (<.~,!mJy wvu!v~:d 27 bcallby vduntc.:r'i
hdv•i<.::<:fl lhe <:gt:s <'r JM aml "i'), Tht: :n vo!unl.eer:> wt'.re
diYirkli inki 3 !teatmefll ~rnup-;, 9 iixx:iviflg tht· 60() mg
l:ibkL 9 r1:cciving 1 ti~ J.:W!i mg rnblc! \Vlii k: fos1i.ni;, :md 9
recdvint\ a 1100 mg iabld afa~r <.:ons11ming ;\ ilig.b fa1 mehki wbik fa,,ring in PnirnJ
?.) /\lkr u1mpktiori of P;;rind .'., 1!1,; volunteer;:; v.ere
cms.V;;'U·OYtcr ag;1i1J inln lh<:ir :\rd an.is an; lic~died hc.:low and w fl(;, H.
23
Nov, 20, 2003
r""" c..,"' /1,_t"( '1· ' -~.' .. At'{'~!lC
fo;-;rouul!lti.n1~ (:1r,) (1~g/~1Jt ' (lH- ri~l~."1nLJ .n:· 74~.~,;:r~ .~.3J NJ.~.f,J
h~'.>led
~Y1·::11n DK> !llf' F'1crnll cm1crnlalion witb lime, llicfr b;1lt-lifo wa.~
cnmpmm is.;::d.
[0219] The 1200 mg rnhkl uc.:mon>Jt;;,ted !hat lb,; hi-byn
t;1bkis nl' lho: inveilinri gr,;aily rtdm:t lh<: foud <:lli.'<:l m
bio,ivailJbili1y and f'<:rnm coneenlfRii0n t>f gu<>ifcnc<:.in. Tiw
C '""~ of lh·~ ] 200 mg Utb kt ;i.;lm .in isle rd ~tier ii h igli fal mc:d
(ft:d lat/kl) W<:>, ;ibnui !02',:{ of t!1~ ('"""· of I.be \2\)(> fll~
t;;hk1 ;idminiskrnd a!'t<:r Casting (faskd l;ihkl). The.: A!JC,. i::
of th<0 t:.Wfl mg fed lohlcl was Jbm1r Jcd l»bkl,
Eirnmpk 8
ro2:wj In :Ul exam pk d" ii Ct>mbi1rn1ion drug formul~1ion,
two hat~h<,.\ nl g1i;;i!';;nesin/dn;1.rnm;;1horphan !!Br hi·Lly;;r
t;1!>kls were prt:par.:u: i) 600 m~' :<.n mg dc,xltorndhrnpb;rn
am] ii) J 200 mg/fli! mg. !fl lht :m m:~ d-ox!mmc.:thnrph;rn
rnbk1 7.5 mg \VR<:. w[1hin Hw imm<.cdi:oK rck:i.s<: i;1y~.f Rlld
'.225 mg withiu 1lit: sust:oin~d rek&s~ l.3.y<:L The 60 mg
dexlrumelbnrph·!!et!1orpf1an 11B!
C;!!"l-•1 .. •poC '.'f.:..1-P. ~.;~
\~;Cr(XT1,-:<.[;;,:: lw~ {'dh.11~),SL~
t ~hr;vxcl E lll~l 1
D&C Yc:lluw '\ci. lU
A1mni~~~~Jii t~~k:: (I +---J :).'~;- i
\1ag<~e-~;l11rj ""::~i::an~:e
{,,Ji!iil·r1t-s.jf•, (.':~p
De:xi ,,._~,~~-::lhD1rh•1 ri i lB~
:N)H ;;;g,·.?op f!~g
W<.:~~' po<
~f)U.~)lK~ lr~: ... ;G~~ {~)
! (1 ! .rn~
.i,50
l:.(14
N;n :"'!~~ ~o ;;--;•~;
\\o'it."~?iH p~1
,:;:.:o~~,;rn! t;--1::.1~~~- {kg;
...:.:-;_tJ-q
: .. 1f ~
! 2;1q r~·1~,·~~n mg
\\-'i::.it~hl jW~
jl)).IJUI) >:Neto (l,;,;J
iii l.i"I
J...~:n
5.iill
l.'.I)
1.d
~:'.:in 1o1g;•"':iB m~
'-..Vcj,~!~!. fie~
~ ·!OJKltl i«illeh (!;,;I
US 2003/0215508 Al
St:•.Ji~~~B s~arc:! ( i!ycol:!l.L.
:"F !Ex:>:deh>
\~i;~roc· v~;~,~~~ir.·~ C.:.·: ~·-·~rn·•·-:.:
(i\:.·i~d ['[!llL I
\fr1l1·x) d1.,pkt<.~d in FIG. 12.
l'Bt:J.(L'lt <'dini·:".r:.1 b~it..:b) l'lfll·!P3 ['fl<~m3
nlm:<::ntrntinri nf g<«1il't:rn:t>in, dexumm:thmph::ri !!Hr, arnJ
llx: riwubulik Jextrrn ph;m. HGS. B~ 1.5 ill uslrale lb<:,
pfosnrn con·~'~ntrntion frn <.:ad1 drug or mtt~bolitt in iwo
fnnmibtinns, Fomrnbtion Band Fornmlation C, durin~, a '.'.4
hom period. lmm<::di;;Je!y ;if !mmdia,dy nlkr adrninistr:uion, :;u11ifom;s1n pli1snu
eouecntrntion never dti.:r<.:a~d to k;;~ 1l1an '.!00 n~>,iml. nvn
12 hrnirs. Thae.
l0225] Funrwfationf' B and {' of F!C" B, <:xllibit<.~d
gu;ii knesin rdeao:t protiks simifor tn lh0 rtfor·~J.1<:<.: forniu·
latimi. Th•.: rnfcrem:;: form1J1atinfl fm fl.C. D was Fo;-mu-
l;i1iun !V ill Lxampk S. FnrmuL;1iun B comprised T,1<;;
guaifon":-,in bv wL:igbL J .. k'l hy V-"•;'.igb1. i:k:ri. /-,ccordingly, the cnmhin;{fimi fo:m1J-
!;i1.1uw; of tilt: lllV~·lllim1 Jjd llPl tnl;:rfrn; wi1.b I h(; r<:k~st: or
gu:iikncsin. ln p~rlkubr, 3.!kr l1 tim1r> Fomwfa1ion C
f<.:ka.".;<;d il grc:tkf clo9.: of stH\tf<.aKSill liJmJ the r...-fcrvilCC
frnmu!allOfl.
[0226 J Ft>rmu lr.1ion~. B :1J1d l' c-f HG, 1.3 \V<:.rc compar·.;d
-:tgaim;1 ;i rcttrcrn:c eousi.s\ing d' Ml <.::n WJ>-,
24
Nov, 20, 2003
ctrried lJIJ[ ;n dd!Om1in.;; Ilic l~h,rvim nt' ~u,iilt::ie.sin-dexÂ
trt>m<:lhorph;rn formu!;i1iolls of ihc i1w0n!i0n ::~, comp;1r0cl tG
scparnldy 3dmiuist<.:rcd <.:ombinaliou furmub1ions ot' dcx·
lromcrhnrpban. Formnbt1cms B iorid (' tlild lun~'.Of dcx·
trumcihorplian ;d..:.tt.sc proli:ks tb3n lh<.: tl:f1.,r•.;llflucnlr?,fimis rs !iJ mrmufaiinn
and Formu!a1io11s Band C' of ~·1G, 14 W<:rv p!onccl in FIG,
1.5. Gcn•:rally, tlw rormubli•.;ns nhibit~d sirnibr dn:lrnr·
ph3.!1 ;;0nc<:111rn1i0ns, wi1h Formul~ (' -.cxilibi1[ng the; ht:;;htsl
dcxtwrph:rn \lf:" FIE, l 5 dvmoll-
;.;lrates tb;,( I.he rummJ;:tirn1~ uf llJe invcll\ion Cl'ffll.atr1ing
,i;u::ifrnes1fl dn riul. inbihi1 the relt:<"X'. nt' (kxrmmeibnrphafl,
,;,., Jdt:i1rnncd hy ffll:;LS\Hing tile pre:Â¥,mT nl lb<:: mdJbo'lilc
de xlmrph;; n.
[022SJ /\ slmly was pt:&>rmtcd lo examrne lhe rdativtc
hw;iv~ibhihJ;; or a SUSt~ineJ [ek;i:~ i;;u3ifone,,,jn \'.'Jlil d;;x-
lfOttJCl.hOfphan fonntibitOll of tlJ<.' fovcnt:cm Wi111 llOWWl~
healthy m,1k ,tml"or fctm.k voluflt'.'n":>. A lnKh uf gnc'lifon-
tsin ~ml dtxirnrn!)lhorvb3n h·l'lyn l~hkt. l2f(l mg, wai;
pn:pMnl a behaviors d th.o nno mg 1ablct
adrnillfat(:n:d lt> vc.!uniccr> in !he fas1in:;; stitW (;,bom W
bcmm pr·>dosc until ;ibom 'l bours alkr do~ing) w;os dtK:r·
min<::d. Th;: np.;;n-l;ihd :;lmly involvlllnl<.0<.:f wv~.; i!dminiswr1.~d om; dt>.'.;<; of ill<.: <•ppmpri~.1".
tnhlt1 drld ih!).!J monitor~d (W<.:r a l 6 hour period.
[02311] llkJod .<;arnpks (1 ml. with sodiJJm h·q1Jm1 as
;rnl.i<:(iagu!anl) were oaken .Iboul om; ho1;r priur li' dosin;; ;,nd
al sp<.:dlk irw~rval.~ tip l.o [6 botir .. ~ fot"lcr d;>sing (at u.::5, 05,
n.75, L 15, 1, 3, 4, (J, K W, 12, 14, and Hi hours). Th<:
rrnults ol' the pti:mnK\;kinciii.: p;iram~tcrs an;;lyc:i'; for
gu.3.ii"em'.»in im:lud<:: ;1 T,,,"~ nl 1 . .t'I hr, C.,,,,x !.ng:rnl.) of?. I ':.lo,
AlJC,).J: {bH11C,/mL) of 8"702, T,., llf Lr~ t1J~ .. , mid w
·\UC,,, {hr-ng.'ml .) of RTP .. 5. Tbr. r<::~Hlls uf 1h,: ph;irmaco-
kindi·~' paramder." an;ilysis for 1.le:f 5 {)hi:;, C,,,"x (pgirnL) of 5157, AU( 'n., ·' (hq1gm11,}
of 74'.:09. TJ : ot 7 .93 Im;., ;nid au A.UC«,r (hr·p,vmL} of
750H1.
[ll2J1j !n ;inuthcr <.::cm1plc of ;:i ;;;)mbinnli;>n J'ormulal1on,
1.wu haldi;;;s of guailrnesin-p.wudueph<:drin,, I!( ·1 bi-layer
t;,hkls, m1~, 60() mi;; and m1e l 20ll mg, wtTe prqi;,i;~d i11 !ln:
folki'<>;ing arn('fln!:''·
US 2003/0215508 Al
l•ilfi ~Ht"'...'-lil"J ~:i:i£
\'-"/"::,i_f:li~. p..: :·
(\:·mprH1r.21ar~ J.(J(;:11nn lt~Hd.~ (~.g~
f•:..:~ifrncsln rx· ().'~--,~) l.~7.-:~·t)
F·:c:~~·..l·:1G1::
c~rl-'iop.·1: 9l4r". "~'
FD.<:C Yellow '.<~. ';
;\b•ni1~~a~ f ~k-::- (!5--!:-.;•~rf
~-...:it1gf1.f·~ imn Sl,o;~:1i;~~c·
l~.~r;i.frn('~[t-1 lX' ('6 > ~
\1 i;;.:Hx..:rvs~~!!!r~c t··,,.:: l~!m,.•_·
(A'-'i·rd r"UJH2 ~
~.;t~Ui:..:~11 s~arc~ (i!yc~jl,tl-L
\fago:oc!-.•'•.H11 ~lct~nw.:. ~<; ..
::.:.;.
IU-l
151'
i>i1n :nµ;u~ 'fi_~
\Vd~l1~ p-::-·•
3,n;,1]')(11,,_0,l<:h (J:.f'
; ::(:-1~ :~~g .. ·J::n~,1~.
wetgl!t ::·e:·
1"
i>lllil·Mi1'-
( ... ~!in~(..·~1l ~Ol!' S~I 50
l; "' ..-:_~.~/ ;-fi ~' 12 I" ;n 9~~ S)L,
[i.113.5] The in vivo bdl~Vi•Jr or lhi.: J10fo mg j!,Uiiit'rncs.iu
;~ml l :::o mg pS<.:I1clocphrdrim: tabk1 'N;~s swdicd by tw,_c.3:;11f-
i11g lh~ pLii;rna conc-..:ntrn1ioll of i;tin w<::rt:
dis~)lvcd lt> ckt,:fmiiw !Ile ;;mount of ps.;uduq1h(•drin<.'. HCl
rdcJ'-<.~d nvcr I irnc:. Gcn~r;d!y, rhc furmulalion~ bad l:?:OO mg
of ;;u:iifem:,;in .:rxl l 20 mg p.>eudncphedrirn: !!Cl :rnd v.ne
studi,·d nw:r <> J ::'. hum puic.J_ ·nie n::k;,;n( or
di:-;f'O.l!vi.'.d ps@doq1h;:;driu~ HCI in c«nfr;ic>I lo the lot;1I
wdgh1 ,;f psnido·.;ph<.'.dftfl<.' HCl !lrior to di">olu1iun. Atkr l
brnn .tbnul 43'-''- to 4'i'l uf lh(; p.~euduephi~drin" I !Cl hm.l
dissolved. Arter :J hours the abmH SWi;. I<; 6W'i dissolved,
af!er f> hours 82'.;:. l'-' X9~f !iaJ d1s.'ioi<;,·u, and afl;;r 12 liuurs
;1ho11! fJ6'X. 10 97··x by W·~iglll of the pseud·:x:pb·~ddni.'. HCI
lrnd dissc·lvcd. (S<.:t HG, Hi)_
[0236] Tim''' [r,rmublt(,ns of g,u3.ifoa,,~.in. two <.:onrninitig
.:rn addi1 ional drug, !:r.';•~;1doephi.:drirn.:. •,vuc compar;;d lu
dcinrnlne whe!hn mi ;iddirirma! drug a!focrs 1he rek;i:;t·
11wfik of gu;ij(;;ne,;ir1. f!(;S_ fl-iS il!u:cJult lbs: pbsma
25
Nov. 20, 2003
nm,:enlnlinn foreadi dmg(!"nrrnul:ilion Jl ,md !-ormul:Jlinri
C) during d 14 hour period_ I1mm:clt;Hdy afwr ndminis1Hiim1
1ti,, phsrn,, concrnl.r:Hion •J! gu3[fonc~in pc3ks in aboul >.<::parnt1.· St1dafv:I® L1
hum formula!im1 avctilabk !rmri l'll;:e1 lnc 201 Tabor Rlrnd,
Tvforri~ Plain.~, NJ., 07<:>'\0. The rd'erem:" l"nrmuh;_tinri 'N:ts
<.:umpm·.:d lo h:·i-mula1im1 B mpfi'i-'.'.d a siis111.iuc>
ypn>pyl rn<:thyktllulrne, rnJ l.2'{ by wt:igtH. ('arbupu!@
opnl® 'J74E
Furrmila!ion:> B and C ;;xllibi1nl :;;im1l<>r bd1:1vior !o i'-1.'.p;i -
rntely atlmini"tered rnrmul:llions, lhu-; tbmun:S studied lP d;;;l,;1min,; wb~-lh::1 1.hi: (llrmulatinn:c. uf
tbt: invrnl ion inl~rfort:d \Yith lhe f<.:ki>f:t: protik of p.'ll'.H-
dtlq>hc:drin·-~- Th<.'. psuidocph,~drinc pl;1s11i;, 1:oncrntrn1ioa;;
rm lhe rmmufa!irnl'i or FIG< 17 Wt!<: pluucd OV<:[ a :_:,j brnH
period .'\:; ilh1slr:i1'~lJck•;:;pht:drin1: Jtl eompa-
rithk nr bt:lln rnka.«e Jlmfik:.; than fr·,rmuLHrmis nmlaining
[l'i>~udoqibs::d:int a!on.:.
Exampk ll
[0239] A "1udy w:t~. performed !o ~xJmini.'. !h~ rd;1l.iv1;
b10av3ibhil11y of SiJ'il:lincd n:kil'>'~ gu<1iknl:sin wi1t1 P-'ll'.ll -
do<.:phr.dria·.; fornmlatinll>i of ilK inv~mion ill nt>rnul, vo!-
Lmh:<:fa. 1\ b;i1.:b o( guaif,;rit,sHJ ;md psc:uduepht:dHm~ hi·
layer 1_ahkts, J .WU m's, w:t:; pr~p;ored :1c>x,rdi11g 10 ib<::
i:ompo~.iHon tk"''rihcd abt•Ve for [;i;:,1mpk W.
1:02 vt•luu!;;~:rs in the fo:;I iug "lat-.: (abof11 W hoiH-~
prc-do.S<.o umil ;,bou! 4 hours af1;;r dosing,)\\'<.'.!'<: ;;ornprored.
Th,~ OJ!rn-!flhti :c.tfldy involved 29 ht:alHiy ">'Diunk<~r»
hdweeri 1h~ ;;g~s ul" 18 aml "JS_ The 2'.l vulullieer:; -;./ne
dtvided in lo !wll !rt"~!m-cnt ;,;mups, half rec~iving, lhi: ! 200
rng rabkt white fastinf; for Pc:.riod J of the: lri3L Each
vt>lumeu w~:.; ndminls!cr"d om; dG-'1: of tile appmpriak
1.abld and then mm1ilored uv•:;r ;i l h bom pei·irnl
[0241] Bb1d sampks (7 rnL with ;;.xlii1rn h;:;paw1 3;;
;rn!koaguLmq wne taken 3bnut i>m: tmur pmir f(; dusillf,'; ~rnl
al spi:cilk inkrvab up !o 16 huui.,, ,
US 2003/0215508 Al
0.7i, I, l 5, 2~ ), '1, Ii, Ii, 1.0, 12, 1'1, ,rnd J(i h'-mr~). The
rcs·1ili'> of th<: plrnrmn,:okinclic parn111u;;r-; arrnlysi~. fo;
,;uaifoo·~sin irn:hidc ~ T"""· of IAH IH, C,.,,,~ (ni~rnL} ot' 2.! 96,
AUC0 _,: (hr-ng;'mL) uf !'702, T; .~ or l .32 brs., anJ ~n
AUC,,, (hr-ngimi_} of :iTH.'i: Th-c :esu[I;, ul' l~e ph:trm3C< in
IJ";ilthy v•.ilunk<:r:-. [n an op-.;n l"hd, siugk d•.:>&:. rn.mlom-
ized, 3-way cro~sov~'r swdy i.n J 5 <;11bjects.
[ti243 J Tbc su b11:1:u; 'Ncrc rnnJ0m izod mid placed ink' Of1<.:
of 1.br<.:<.: lrc;1trn-~nt groups (;roup Awa:> given Ft>rmt1!;1tion
;\, one 1200 mg conlrulkd rde.m;e guaikm::sin pmlk!ct
(Mucinex) plus ;i l :'.O mg nmlniikd rnka"'-' p;;;.;udm:pht·
dt·ino bydmd1loride prodl1c! (Sud;,kd-11 l!GDr) with 240
mL of W3kr ,irtu ;in ,1vcm!d1! t;isl. Grullp !l n:cciv'°d
Form1Jlatimi IJ (lot PBl\J-K6l), ari lher oxpcrimenrnl <.'O!llrolb.1 r-;;k,ft<.1.· liob-
!!Ot cum~ining 12().0 mg g>nifrm:sw and l :w mg ps;:udwqibi~.Â
drin.: hydmd1lnritk v.··i1 h _7.4(1 ml. of Willer Jfter MJ nv.orrngbi
f:osl. Tllcrc w;'<. al k"<.i a 7-Jay wa>.lwiot bctween do><:s.
[fl244] Tlu: vPlunlr.tTh «v;;;nged :::6.4::t l{J.')7 yr,;,;>; ni' :tge
(Mo.:aut;Stamlafd Dcviumb w!th
3 rang;;; nf l!fi. w :'..'l_?. pounds. Sn·en wt:f<: m:ik (47'~;'..) arnJ
Lcigbl r.:mak (:d'X-,). fon (67'k) of !b~' .':llh_J<:d.~ twJ a lllrg<.:-
rrnmf.'. sid { l 0 rn! , ~odmm
liepa;in ;rnlicoag~l;inl} .,,.;<,s obfaineJ al the following lirn<~0,:
Pn; dnsc, 05, 0.75, I, 1.5, 2, -:;, 4, 6, fi., IO, 1?.., 14, 10 ;rnd
14 hours P'..l'i! dG&;
[i.tU~q ~it1b.io.:•;ls given l WO mg of gu:iikm;s1.n :Vi g;u;iif~nÂ
osin ER (f<.: f,:rem:<.~) n:ad1eJ a l ',,,
00
,, d 184 7 ngiml in 0. 78
l1011rs :wd had 3!1 /\ UC,"r of 7?Al2 hr .. ugimL Sul~i<:cts g.ivcn
! 2(10 mg gu;iil{;rJ<:.c;in as l'unmili1lion ll 1e;;died ~ Z '""''' of
! 7X4 ng/ml_ ( 10~'1 or tb;n ot' I he refaem:c) in (U·Q hum
(H3'7f ..-,f 1ha1 ,,f !h" rdi:n;nc1.') and had an AUC,.,,. of 7(j{12
hr-rn>,..m! { W'J'.:i t•f lhnl of 1hc rcfrrrnce) Sul~;t:Us giv-~n
I :mo mg gtMii.t:ne.sin as l:omrn];-,J,ion c rt,tch;;;d 3. c""'-' or
!154 ng:ml_ (6'.'i'k of tbal uf !ht refrT!Orice) in J.::'.2 huur';
( J 79•)'5 ni' 1.11,H ol' I h~ rtfrr"ll-'<') arid bad ;rn !\UC,,, 1 or 7P.H
hr-ug·mL (WW~ of 1trn! of 1b;,; rcforf.'.uee).
[0246] Subied:o giv;,;n 120 mg P-"~lluo~ptiedrint hydro-
dtlofick 8S Suchl'cd .. J.2 liour (rd<.:rcw:·~) readied :1 c""" ,,r
300 ngm1L (mca11:tslm1dard d..:viallt>n) in 6 hc;i1rc; and hi•d Ml
AUC,"r uf ,pJO bHig:mL. Sul>_iects givrn i.20 mg P"~IJ·
dnq1hedririe hydrrn:hloride a~ h;rmufa!inn n reat:h"d a. c, or
ws ng,:mL ('l'!':'i of tha! or tbc Kfof<.'!l(;(;J in (i hours ( l01 1l
of1Ju1 of the rdcr<.:11c<:) Jlld lud an AUC;.,[ of444') hr-ni;/mL
(WW;:: uf ;bat ot lti•~ rdcrcn;;c). S\1bjc:c!s ,~rvcn 120 mg
p!;..;;udoepht:-:Jrim: hydrrn:hlnrid;;; as Furnrn lalif 2'i6 ng/ml. (:if lhJ.l ul" lh<-' ret<.'rr-n<.·e) «ml hM.l ;m ,.\UC;.,1 nf 444':1
l1r-ngirnL ('J71l of 1hn1 d lh<.~ rcfon:nn:).
(0247] Tbe pla:~ma cnnccri!r~!im1~ of gu.iil'em::~tn M<:
depicled t<• fIC. 19. Tht r-c:;ulting pb;irmacukintlk dat;i is
sbuwn in 'fab!!Oc, l lhwugh '1. Tb.: rrrn.1:irnurn ph~rna con-
<:cntrntions of f~tHlJkn1:,..in flll -
i:rntnnion vs. lilll<.'. curve (AUC,.,,- 'Nios 7~'i02:t281:·6.4 llr-n!!,_·
mL. The m;iximllm pbxm20 ·~nn•.:;;nlfalinns c·I' g1i3ifrntsin
follnv-··ing a l 200 rng oral Jo.~<: a,_, i:ormula1.ion B w.:1e
l 71-14±5-l-'l.9 ng/ml' { l (l?..9.1';;.:tJ6.'i7'i!;. or ihat of !lit rnfer·
encl.'. fomrn[al;oU) '1nd 01.:CllUcd in {ic:~'.::t0.2/ hollrS
(U2c78<::f:t4.l.29'it !hat •Jf tile .rdcr<:ncc formul3tion}. -rhi:
rcsulling !\UC\,.i w2s 7602±2491.8 llr-ng!mL
{ 1(}f(('.7' .. f.-;_:::>.9y:;: of ltrnl <>i' lti-c )'('. frn-: lll't fwm u bli1 )fl!. 'rht:
m21ximum pb:im-vi th :--;u.;_bfrd :.='. E~k.iir ~·:·1 '.'\1:.r•md ":/~:i::~m.::e:-1
Subjt'.~t
>-1-::-~n
\1-!.."Ji'1f~
3tr1~,i11rn
~ k'\.·c,~i.i.:-·"
~A;~~J.arJ
t: ~ re '
,~~ \.'\"
\1,Jx: ;~~kl I!!
\-1ii~i:m~f·"'
Si.1bjt,.·t
.\1<""
\1 • .::-Ji;1f•
:,;1,,.:.,hrd
p~"\;;~\,_j•:•il
~l•~~JarJ
Firer
('~
' v
\1:rxi ;)"HJ rn
\.jji~i:m~fi"'
,1,{_'['1H At'C,,~s
J',..,., (IF· \.'>r- !-hlf-lik
(t~g_ 1rnL1 '.h•i 1'5t~'i1:.U :lf' .... ~~; t ~ (lirl
~6-!? n:;~ iHJ ·;xi~ L~.l)_)
~s_::;o it7".1 577~) :·;}\\)_~ -'·-2l
{:.;.::).n.?. n.:·,~ ::7'),;.4: -?Xfi{i.J'; :·;).'
~ ~;_::. __ ~ ~ !W!l 7'4.fi_:~-7 7N;_\l~ 0.55
_".!..,/_}.:-; J.55!~ _:]_q ll 3~_~;1 5:}_si..:t
3B--!-7 n.7,'j: 7 J4.' 1.-:=.n.~ 2 .. {.q
~ 5.~o u.rs ST"rr, 5mJ~1 ~.~l
'iAHl.l 2
·•,'ju~~~f~ne-1ir. Ph;irn1.1c:0k~1-1::~i::::- V:11:a·::.)i::::. Folk·-~".'ir:.g th<..-'
/\J··11!!1i:~lf,1litrn ~,{ : =~}~; :~~.;;: (;'Ll,1il'i.:-ai:s.in ;~·1U L]; :~:~
P\c'~:r.k1 -;~j.'lh-r:d 1·: :~1..' { f '1'dv.'I: :~kn:'._;z. 0.59
; ~~~-f_r; n_q7 N}...:-. ?! ()~ie . .:.: O.J ~i
,::;c~.g~ _~3.r}7 -' \)i _:;~_·p;) _.rr_(O
IKilii ir.r< ~ .. ~n _.:;·1~-~~'. I ~:"
Jl..'..0 II.'. .:<15 "~{n~1 ],!{
(~it;dl<{a;_;r_,;
(l.:l1J'l
1·~3.~ .. t~
-=~~>}-~~
14,.;.-;
P.>.9:=
3<:.J:A,:t
IS1.%
..:0-1,\:•8
( ··:r~~1rn i11:c
(t.:t1fl
I ?~.~;(:
J.:,3 __ ,,,,
-t'i.4':'
l.<.:_,
~g_:~\'i
~:o~, 'l.:
~·H oj
US 2003/0215508 Al
[0249]
~!eH
~1(:d~:1ri
Ss ri ~.~h ~ .-:..:.
D~,·i.al.i·J~~
St;~~~d~i d
~~r~o;
"'~CV
~·{i:lXiJll~~ff1
\1lr~ji-.-•um
l0250]
{)u,~ikr.csir, Ph;~r'1)?.c~-.~;ir:c~i;_: i./;1ri;)hk~. Vnll'.)v.·ing ~toe
/\.io::ff11ni~:.t~•t~·=·!1 nf ~ ~~}. i r:.~~ (1;,,;;~ii~r.t'~,!:1 ;H·~iJ l ~O mg
!:\;c•Jotiol:[J-~·r_xJrii:i: HyJ~~K·~.:,_~!-·d-L" a:· F·:i"•m~!<{li(.rl (' '-'-~
HS1
Jil.'1'
) ~'. ~ .~;!
7Ni
;\.·:·•r.•ri! \f1lur:lc•~f:'r,
ihrl
~-kl
[), ·15 J15?
[)_IS ·'E.ll;~
t} . .'lH)
:.:u::.s?
j'Jt\U:'\
.\4 __ ,,
L~·r·t_i;.~
"+:A~
llE~,i_o ai" n~~r~ift:'f•f_!";;!l} f'h.t~(ff!~~..:0ki~1.;:H;__' ~~!r:.bks. Fo!!o1J;!i1~ the
AJrn i r1·s~1 'i'ior1 of l ::rr.:J f'•g (i~;1jkf:r_.::~·,-..~ cii:J : =:iq rjjg
p.,_:'":LKk~...:-pht>:~.!'is~~· H;·dsG·chl1)~itlt' r1~ r.:..~i:nuhtifff! B ( ~·-;r.~p<•~.td k·
l~"J .:-1:.' ~he t~::fnco:o1:c ~:nrnm:'1:!o-:-t w \."cr~n;)~ ·,,.;:,1:1mi::co:-. ?'-:,~
:-.1.~.t~;l
JA,_.Ji:rn
Sl<~ ~' d::111;~
l).-:.:\·i:iJ.i•'i'O]o
~l;if!J.lr,,,
!,~·Â
!1£..'irtl.)
1U~JJ?
;1)n_45
Le.I.hi.I
1-lc,::'~lik
('ill
(_)fJ5J
5~l. "ft,
f_rS ul
!7.5J
C~c,mu:~,·~
(!_:: .. ,
-~ ·h. '.!l)
~ I . 1' _.
~::.:A
j] ~-· :15
[OZSJ.] The phsr1u <.~)rK"~ntrnlion~ of pscudocpb·~drin.._ ;ir,,_.
dq.lidvd in FiG, ZO. Tlv.~ rcsu!ling phMm11<:okindk da1'l is
shc-wn in ·fabks 'i lhmllgh 9. Th~· maximum pla~,m~ nm"
,;-~r11r;i 1\rn1s uf p:.;t1__;duq1h.:tlrim: foHuwing ;_i l :20 mg urnl
dose ;is Sud2!1ed" 12 Hour {n::ferem;;;} wue .1(XL~>:t9 L44
!lf/mL and (IOU l~h4L77Sf uf Iha! ul" the :eforrnce
formul~linnj. ·llH: r.:.!iun). H1~
ro;;:;1il!i11g :\UC,"r was 4444:tl.'!l?..l hH-ig/ml.
(96.7:-;1,:{ ± ! 7.90',{ Df tlial uf tbc n:kr-.l'•-·d~'{"~1~t:~hi :1.:.- ~ 1 t.~rnl~h.-11~ iT!{"(i._- \,';}1:ri hie-, ;..·~)!!ov,·i T~~
~he: /i.,dmirn•,~wt;ncj of ! :n m~ P~.::11.::i:·eph·~d: me
HyJ;~:icl-!;1.~r~iJe ;wi!i !.:::r;n 111~, {~w1il"r..:rn:s:;~ <1~
r:'r:.1·:11ribtln~\ B !'.i · .. z .. ;!·m..-~j ~ ... bl\i~~J.e::~;~-"
/\l '{'i11!
7. 77
-~(".':;q
JJ.77
-c-1:1.t»
(r~g.'rn~)
/\t:.('11 o
ih:·-
ng:·~I: l ~
(hr
agif.-·~.)
!lolfl1fo
(~r)
c··:~~u;~:'HX'
(1:111)
\k;rn
:...-k:J~ai~
S-t:~~uarJ
rk-..·~;1~ion
:;1~:i<1.n-,J
Lrrc.r
';,-:j)
r._1..~)n
:'AH
.!n«n.~:i·
39N5.~b
94l1. ~.i.:::
-1<,:·iX'·
-1%!.I·'<
m?r.u-,j
u.27
(-,. -:-=·v 1~~.c: ,H._::~ ~3,..::2 .. :..-t.::~( HU•i
'"~4
-'-"'·
:...-~ax· •nu m -~ 7 ] n b(lfL=i. J 4 .:~,J'-:1 (.1.i17
[0253]
::1«
TAilLE 7
F~~:..::..:.J•:1!.'"phi:J1 ·, •!C F!~~m1-1:..:dki r~di::: '•/:iri;~h:r.2'.-i Fu!!~~wi1~;;
lht: .. ~.-.-::ni11i\~1~lint~ .:..1f l:-'.fl ~ng P.::.!'·11Jetrh~:i1!c·
HJ'd ~:x·~ : 1:·r·•k ~rn.::. ! ~t:H m_;.:, 'f lu..-ii !"•=r:o;i :-t c~.-,
·--------------~~Q~~ll~~l_:}§}.03!_~:--~';J __ ~·;·_!~(i}_(~~--":-'..~l~:3~~~~3!': ______________ _
::.·i_.:1
(
r\l."l II l
(I,,·"
nµ."rrd)
Al 'C"''
f!H-
:-t~i;r;oi.i
!b!f-lil.t
(;in
C:-::~1. r:.~ ~H~c:
(l :~r1
\.1-::-:i·HLI m -~-lj lU ( 1.:"0n. lt~ (0?56,{d
::...-~ii~ia~ur•• H>2 -=:31°>(J.(l! :~54_7q
''--'9
~-1-'
I ID
)), .. ;_i
·~.{)(;.
rn"
.=".3.~-t~
:".:.'.\.~]4
~i. l t·
_'l.n.~i~.
~f:J):'
1455
US 2003/0215508 Al
[0254]
1J\[IU-: ~
11.~l~c· ~~f P:~~1{k~c:)t1.;.;d~ii1t p:~~~t1sneei,!i~c-:;~\.': V;,1t~i~hk~::Â
F0llQWrng ~h~ Ad1~~::1ii:-~m~io;~ d Ll~ r."':.g ]~;;~..,_~d.:1sph~1jl'ii!e
ny-:.:·~~1__.-!~Curi;;..k ;~··K.l 1:'.()i1 mg (iuaikf,,__.~.,jr~ ,!;;.. Fcra~utnlrn~ B
{~0~1Jptn(~d hl th:"1l c;f tht R.::~(~rtr.(.:.; fon~~~1IJticm tD
+~:lrn1.'ll \bCun: .• ::::r~ (:",- i
~dOH
?vkei.·ia~ioa
~-;!.~;;i:hro!i
Er"-'·'
\·~;s;:! mum
\1 irw•~,1,1 m
ii •• ~ ••
(r.g'mL)
',l{!.J3
'-'4_7ct
:'.~)3~)
5-4:-::
-~D-~;:::
::!O .:!-0
{i~,q·_;
I',,,,_,
(hii
Ji)j ]]
J(ji)_<)f'
...t.! ,77
I I IC
·1 I .::.i
:·c;i
~s
At'c,H .-\c:cw1!-
(~r- (l-:~- !k!C-~,f.:: { -k~~fl~O:Or.:r
~o; . .'.'-t~ •.1;~.~:~/
;q,+_~.15 C:!J .c.1-
:'~.')I-, ::vAll
;.'.i__,.;.·i .:1,_.•1--1
i3't .~J? 1-•-: 7~
~[),•"-· -e {.!_)
TAB!.l: 9
fhrl
~_.:!< _1_1};'°}
!7.54
i.-.: ?'-.'
!~DA.;
fi~.L::
t} . .'lH)
y;_J
! 14)
v~~.1
lbt~c d f'~:c~s-dot'::·hedricff f':u-:.rnK1(,)k.ii~~l~·~ V,ln~-:.b!.e,
t-·ulk1..-., i1~g ~!1c ~.'lo,_.Jmiai:~~rn~ioa d J ::'.O i::g P:,r_.::..:J•:H..:pito:._U1·,,!c
Hy,J~·od~k Sil 7~ _\);'- lt> more dosdy mard1 tbc: rcfrn:ncc} aod Fornw-
!atiou B produces optimal r~,;udoqih·~ffinnali\y or r~mkx::ph-odrine.
[0258] The sub]i.'.t:ts were rnndomi1.ed mid plan:d inlt' um:
of 1hree lrr.:tlmr.nl grnup!i. Gnrnr l rec<:ivt:d Tre,itmenl .• '\" :t
1200 ,,;011tn_>llcd rdc;,;;,,; p13ifcm:::<[n pro;.h1ct (Mucino:} plus
a 110 mg conlrullcd rck.~SI.' p:seudu1:pb·.;drinc pmducl
(Sudaf;;d<:udoeph1:-
drim: bydrodiloridc 'Nith 240 ml l>f \Vaier nfli.:r an uv<.~rniglll
fof;t (_lcsl)_ Group 3 r·~c·~ivcd Tr·~;o1m;;ni C(PHO! -AJ.2A), Ml
cxpertmenl_;il rnnlrullcd rdem;e !~1mrnlalirni t:m1!:iining 600
mg g,uailern;:;in and 60 mg psrndrn:phedrine wirh ?AO ml. uf
wat<.:r afa:r <•n c>V<.:rnigh! fasl
[0259] Tbe rnluntcers ;tvernged 2'.t0i:i±7.0'i year;-, ,,f ;ige
IM<.~Rl1:t5rnm:fard D<:Vt<>lion) '.'-'ilh a rnng<: of rn )'C:ilfS !o 4,c;
Y':at'<. of hg•:. T!J<:y wcl'c 7U.S8:t:\O.S indi•.;s !3-11 w,th a rnng"
of 64 lo 75 im:h.;,.~. ·niey w<:igh<::d .l67.'l?:t?6. 14 poum}; 'Nilh
a rnn).!.t: ut' J l 4 !n 229 puumJ,.,, Twenly-t'nlli wer<-: rrrnle ((l7·:-;)
and iw1.,[v .. : fenrnk (3?i'X). Sixh:en ( 44~1} of 1h1.: suhjccts had
a farg1.' frnmv sizc, lhirtcen n0c:;.) [J~d a rnl.'dium fr«m<.: ;,nd
sev,;n ( 19':·;-) hall , 2, 3, '1, 6, K W, 12, 14. l 6 and 24 tfoub p::.:~l llos;; {Hll:
tnlal h!nod lo:>:', i'ur guaireflesin :wd p:;.;;udneph•.:dnm; ;maly,
sis will Ix ,1-50 mL\
[026!Jj Subjf kll-6] hr-ng.'ml .
S11hj•:cls giwu J.10/J mg guaifcn·~i;in :rnd l 20 [lJ'.,-,_ p.<.<.:11-
docph<.:drin<.~ hydro·.;hloride ~s Trr;8lmrnt B (T·.;sl) rc.'ld'Jd a
C.,,"x or rnn llgimL {98';,:, nr lh:ll ,,r lh;; rdemm-;,·} in L04
htlJJ[ (!¥Vi(. nr lhal c·r !h<: fckrem:<::} ;rnd had ;m AUCH---· of
8114 br ngimL {W J'X uf lb:H of !b·~ rdcr;..;n<.:1:) S11bj<:cJ<.
given (l{~J mg g113 [fcncsin ~nd 6{J mg p~o:udf 35{6 hr ng/m{, ( 46'} of
lhal nf r!K rckrrn<:c).
[021..ii] Sub_j<.'.ns given !1() rng pi'>::udoq_ilicdrinv bydrn-
diloride "-" St1Jafod@ 12 l iuur ;inJ 1200 mg gu:i\frn·~.<.in a.-.
Mucinex (Tr<::atmcnl A, R<::fr.r;;;n,:o-:} r<:<'<<'li<:d ,, mt:,:n C"m of
250 ngimL in (1 hour~- and ilad <111 i\UC,.,r of 3847 llr-JJg,:rnL
S11bjcds givrn l20 m1; pSl.'udocph<.:dr!n;; :md J.2(1{) mg
;;iJ:iikneo>in a·, ;,n expcrimelll.a] form1Jlation (Tre:t!menl IL
-fr;;!) re;ich>.-,d?, C•f ./.61 ng/m!, ( J 07';;'.. of lh;;[ oi' th<:: rd\:rnm:r_'p
in ''.· bmm; {8Y:1. uf !h~l nl tbc rderrnce) and bad an AUC;,,r
of .)884 br-ng· mL {J_O::>'k ot \hill ol' H1;: rd'u;;ncc), SuhJC<::I:-;
;;;iv<.:u (iO lll!!, p;;,,;u<.ka:pbvdtin<.'. hydmdiloridv ::.nd [;{I{) mg
i,::n1ifrnc,.,1u in an experimn1U! furmulallm1 (fn.:-;-i\m;;n! C)
re:odied 3 C,,,,,, or 1 c!-l n""m!. {'>cJ~:·>. ur Iha: or Formubtiun
lJ) io 5 bm1t-s ( !OO'k of Hl3l nf Forrm1l<1!ion BJ and h3d 3n
AlJC,Hr of 1968 hHig..-mL (50';;, of 1ha1 ,,f furnwfarion B}.
[UZ62] Blood ( W mL, _<,odium bcp>1tin 3nlicoagubnl) w;t:~
nbtaind 3l lh<: fo!bwirw 1.im1:,o,: Poo:-<.kh~. O.S, 0.75" l, l.5,
Z, 3, '1, (l, H, 10, 12,-[1, 16 and 2~ hour:; p·:>sl duM:.
Biuequiv1lcfa'~' w;;s e:omined bl:lw<:tll lhe !esl ( [j-~:;;lm~'nl
B--gt1aifcw,:1vphcdritK: byrJwdi!nridc o;p<.'.fi-
fllin or pscud·,-:.q)he;Jr[nc hydmcbloi icl<: <.'.i;p1:rlmc1,la! fr•rrm1-
latinn) ~ml lhc rd'n~m:e (Tr<:almrnl C-----g;u.aifrm::;in or
p-;eudn"ph<:drirn: hydmdilurid~ ref:C:rnnn: l'nrm1ih'. nr g:uaifonesw following;)_ l '.200 rn;s ma! do:.;,::
US 2003/0215508 Al
:i." Miicim:x ;wd l 20 mg p:-;cmlncphedrirn: hydmd1lnr;d,; "'
S11dafod® 12 Hllllf wi;r(; l ()4iJ:ti381) ng>mL wd ocn1m;·d in
O 77;;:0.2'.": hoiJr,;. The- m;;1.il:ing are;1 !Jrnkr rhc pfasm,1 cnn-
•:"n1t;Hi•_m vs. ! une eu1:vo:: (AUC;,,,- W.<: "" -lh:almrn! B wen: lkl:h9{)0
11~/ml (9-". l 'ii,i:JS.kS·i. uf ihat uf the n:len:nn; furmu L!1iu11)
and ocrnrn::J rn 1 Al-·bJL,19 hm1rs {J-JCf_;,:_±65.Y;;-. lh<>l Qf lfi•o.
rdncncc formobl!<.>ll). Tile r•.:su!ting AUC,"1 'N~s
8l:?A:t_;(l77 br ng/mL{J.Ol ~f:t l q_j~·i of 11Jat ol' Jh•.; rd\.:rrnc(;
fornmlatinn). The mm::inrnm pLtsma con.:-.;ntrnti,1ns of
g\iaiknl:sin t'tlllnwing 3 (10U mg (>ml dose ;is Tr":nmerlt ('
Wt'. re 920:!::4..'! l ng.:ml _ (''l4 .. 1'/h_?0.2"! nf lhal nr I he rd~rrnce
f-:Jrmuialinn) and ou:mruJ in {L99±0A6 limirs { l 16'il--:J.:78.F.:~:
ih«l or I hl: reJen:no,, t'nrmul.n} Tht: resul1ing i\U(\,r 'Nils
3:'i6'i±l•M2 br"ng/m! ('1'.i.f'..'X--.i:W.2':-1-. uftlial ,_;ftbe rekremx
formn lai_ion }.
[0264]
:\h::1
~frdi.~11!
Sl;~f!Jar.J]LE l l
1-10::'-lik
(:irl
Ci
\iut1ifc~i•_'":~jf~ P~·~:1::;1cnki~~c~.~1...: Vd!-,~:~ic.;s F::.:ilk·"·'~··~1g.
~j,~i; Ad~rw"!.~st1;Hl·:.::1:1 ·=·f l 2(:(J mg b~c.·Hfr.: ~1t.:: 1 -!.i1 :~a..:I L~J) !Hg
P~~~ud~ph:.::di in-:: Uydrcd1b; id.;; H~• i: a !:x~-..;:~·i;r1~r:.l~1!
h~-·,F••Jl: ;~ p: ~r~ :'!'!!1K'.·~.1k i i':.f:f ~i..': V;i 1 is~l.., ks F~"'.'! 1 ~..,\"};; ~1 g
tl1e A_.,_~;n~flist,;~c.i1_:.1} of tJ}~1 ,ng Glt)!~~1}~;:i.1~ at·1.:. tJ} ·B~
P:-.c.;~·:d~K'f1h-LJri7~l:" H)·J,oc~.;,_~··i·Jr..: ln ~CC7~~;~: \.'.:1!-:_. 01i;<.;\..·r:-
IT1\:<"<~1<1>:1il r· ~
'-
0
1:;.13:-._
(r.i~/mf.J
i\l "{ -11 ~ ;\l "C~llC
(11•- \'»-
n~-ff1~.; •lµ:r:~l ~
1blf-life
(_rir1
Clc-::1r.~:H>:
(L·~n1
JL'
.14 . .'
~bt;o o~ (~lt.;~!f~nc-1ir:. Ph~~! n1a:.::okiri·~~i ... ~ '·./~1 i::-1::.~r;;.::o ;~cilk·""' !i~~
~~:e ,·\!..! 1=.u mg
P~i..::~~di..x:-ph·fd 1·~:].~~ f {y;;;,,A:h!n·~·idc' :1~ fnc !'!!ll hi~HJ! [t
c~;a1p ... 11r..:J ~o tbt1L uf ~!;{:" Rd;<.;CCl"~i_X' h~r;~mblini;
~Trc;iHmT,l i\ ~ ~;::. "'.\~~,r;-rm: \bl~~nkc;s. (~." .. ~
:\~~ ·:.·v
[026/j
c,""-'
(B~:fnU
AlT'I~•
(fic-
ng..-rc.l)
ll)1
) )~ jt;(,
6.~.3- .~1L;o;
Al·t~;"i
(:H-
a_g'i~!L)
"11
!lln
l'U
_l 3J
\9.1
D\IR.E l4
!btf-lil-,
(!l1) il:hrl
:·-t~
rc~t!I:• ·=·f {j~);-:i te1~~;:,.jf~ Pt~,)! t11.a.;."'>~.·kil}C~ [.: Vtl! ;~1b]1:>~ ralbwin.~
iii:-:-~ Ad111i1~~-;.:,~~1;1;1~ 0f cnn 111g (lt1;1if;;rw:;,ii~ ;1.t~d ::.~J '1J~ Ps..:.-ud~--;-,-:::..:)~~·J1·!:l.;:'
---------------~~~~~~~c;:~~:;;~~;~:~:L~;~~:;;~~~;~~~~:;~~:l~;~~:~~~~;:;:~:~.(·:~:.-~:-~:~~---------------
.\k!!!I
\kd!c~1~
:-;1;!-:-t{l,inJ
Dt,,-!,~~i:)rJ
:.;l.r;.;~{.Li1·iJ
f·ni:·f
·~-CV
l ..... .tiJ.'.'.~~
(n~/mLJ
]J(,
3t}1
-/~~. "i
i\L(.11, ;\l"{'~"c
ih;- ('"-
ng:ri' ~ .) ;)µ·r:~ l ~
~~5 .'.< -15.'~
-t.1-,') 4~ u
Ill.<· l:J..:
:·::4
f bi(C]ifr
(rir·1
Ck:1 fi~ ~H.:t:
(1..-liri
]]•l
J:-l
l 02M!] Th•: pfosma ,_.,_,ncc:nlrn!il>W, of P'"';udo,:phnlrin<.: ::r<.:
utpided in fIC. 22. The n:>,uhillg pbamu;.;ukin~ti<.: data 1;:-.
:>huwn in -fabk;-; l 'i lhrnug:h 19. The maximum p!«sriM
concr;n!(3Jinn;; of psn1d1xphdrim: followtng::. l2f> rng ornl
dt>&.' 3_s Svd;:f<.od® 12 !!0111· mid 1200 mg gl1<1ifrm:<>i11 ,1;;
Mudnc:e: (fn.:;timrnt A. ilt:f;;n;nce) wcr1: 250:.t:?J.4 ng:mL
aml occurred in o.:!9:d 76 tinurn. The n:sullillg t\lJC,,, 1 W3S
:\K.:17±.IJ W hr~ng/mi . The ma;i,:irmm1 plasma conn;rnra!iun:-;
US 2003/0215508 Al
or p,;eud.uqJhcdrim: l"n!kw .. irig a 120 mg uni! doS<' d" ;m
cxptt"irnrnul fornrnb1ion (Tr<0a!1w:111 Bl '"''n: 163:tSR5
11g1mL (J07'l.:dS::y:·; of rb:H ol tbc rdcru1cc formu!a1inn)
and occurred in 5.lb:l.78 bour:< (.'15.?.?i:t3L5'/i. ·:if !!rn! of
lhe rderence furnmlatinfl). Tbe f<::sullmg /\UC;,,, w;i:;
.188'1:l:c9 l l br-11g/mL ( 10.1'~'1±?.0.,?.<;i.. nf th;11 n! the fer.;:rrnce
l(·nrmlatioD}. Th<: m;ixiflHl[]l rh>ma cnn,;rnlrnlinnsofrs"IJ-
docph·:drin<: fo!kw.··ing a 60 m~; ornl dnsc a:< ;JH o;po:ri.mcnuil
formulation (Trca1mc11t Ci w<.:rc l.4h:303 n:~m1L
(53.5%:t6.51'!f of !ti;11 of Formub1ion H) and ucc1irrcd in
4 .94± l .6D hrnJr:; (995'/i :t:'.!.5.9~f of lha! uf Forrnubl iun H).
Tht: re,;u!I iflg 1\UC,,,r '-'';;:; J 9n:i:l:c477 hr-n,-,:/ml.
(5{L)';·;:o:-8.77Si oflhJI d hwmufarinn ll).
'[AHLE 15
Psr;;'Jdo~~rh..:~~~·iri-:: p·;K1~,.,~r~i;oklc,.;:lt:: t,.~-.1~1m~~~e1~, r: o; !·:·\\'[;~g
d~{: "'~d:nC~1l·1~11~~i'Jr. of J2[· :ng r~-el1d 0,,:.1~pho..:Jr~·1:e- ih·..;;~··:•1..:Morid~ ~t~;
Su.J,1f.i:J ~~) J~ Horn ~i:J !.=':PH •n~ (~u;.i.~f-:..T1~:-i!1 :{;· \fo...:.incx t•:1 -:.~nn-,··~l
'1./.::ih.:~il::-·"=~;:) {TH~:i"~~:n.i.~t~; ..-"'.)
'.vie~"
\k-di~1lj
~.;~_~i:J,!r.J.
f.X:.>,,'!J.~[.~,:~
SG~f·~bid
l'I•····
·~;.-. f'V
[0169]
C6n:;
tr:~mC
'i.J(,
.·\l-Ci, (
(!H-
ri~·"°'' ~ _;
i\l-C;q:
(l;;-
'1µ_.'ml)
TAHU.'. l6
Jb:,.1;ro
{:irl
C'k:11~,,-1~i·:.m
.: =-ci F•~~ ~·~;{·•J1Jo::p~r:drlr:c H~\'~l:-~'ch:,:.ro-.::e rir:{I ~ =-nn m!; (~Ll,,'!d.~[:J;~
:<~-~1 !".~;~j Vnlu:n-c:c:~'.-i. rTt·c~.:~t m~:1H Ci
Cm.:i.:~
lr:~m1.)
H!
U·l
3f)_J
t\l·c·i· i
(!H-
ri~'i"Jo1'~.)
i\(!(\1;
(I;;·.
'1~.'ml)
ll<•'·'·lck
{h1 I
C'!.::~;i i~ r:.~~.:
(1 hr)
:l• .. ;,,
~{>.~
1·~.5:~
30
Nov, 20, 2003
P~·::uUot:"::-h~xkicii.. ~·~;~-:-m:~·:.:,:ikir.cli·: P~r.1mclt:~s. i1nllc1\'i,.')flf
~h"=: "~.;~:rii~li::-M:i~!n:l of {)q f:.'!t_"; P-:.-tl1-:~n.::1>l-!c":Js~~~t Hy'-hD•..'.!·!!c .. rfrk: (md
rv.m m~.! ~ -~~;ff:~?c~.i11 i11 "'' Lxp.:.:ri•nf:'!1~;.)~ ~o,-,,m,_~;,~~:(~!: ~o
________________________ 0:_·~~~~~~=:_l~--Y.!~·J.~3!~s.:_o;-.:~-f~~~~~!~~~~~j:_"!_l __ ~~j_ _______________________ _
:St:~~JarJ
E~1l-:-i
[0271]
c,,,..,
fo~"!./n1LJ
IJ~?
.:1 5
i\CC 11 ,
(h:-
ri~;,1JU
l5.J
.•\l '{"illl
{'ir
·l&'l~":.t ~
TABLE rn
!Mt.life
(!lf) (l.d11'i
I.I:
Rci~io ul' L~·r...: F::•,,1.:.ur1
St~;_;_,{hl'd
!·m:·f
·~-CV
c·L<.1-'h
(1~~/mf.)
i\l.<"11,
ih;-
n~·"'1-;j.)
lri'i
I!':
:.9. ~·~·
;\l.°{'~llC
\1'<·
;)g'r:~ l ~
;,n
_:(Jl
·=-~ ~- l ~)
T/'\ULE J')
f bitC] ifo
(ilfJ
[~_)')
t!~.s
{-.:c::1ff~~H.x~
(1..'nrl
Iii I
·~·,",'..!
H.c·c~ici a~ PsVJ<..lot;.•hcd!;a~ f'l"i8.l'~H::l<..1-:--ki:1.e~j.: f\1rnmtk:r~
t:.;.-.i:~-1;,;,Jn~ ~;-.-'-- .i\~!:-e?i!li,;.,~rnlinn l~r f,~~ r:~.? P~cm.l.;.•c;-.•n.:.:1Jrio;c
f-fyci~-t)d~i~~·jJ,r_.: O'.aJ t1(lH •nf (~:._:;-ijfi:··x.~:~!!l a~, ,11~ ~~-1.,'_pcrC;~~c.:f·~-!mlio:tl.
E:omple l4
!:027.t I Tht dl;.:;:ls or ;i high rat mnl (l[] lh<: bimnifahility
t>l ;i cornbin<>linr1 ((>rrnubJi(>n ·,;,·n<~ h::>.tnL Thi: bio~v<>ibbi!-
US 2003/0215508 Al
\ty nl' '' POH mg guaifrm,t>in ;md l :m m\\ P,;t:uduqJhdrirJ,.
Hydmcilloridc rormulaiion volunh;•.;rs \Vfl:< ;.ximp&r•xi t•.; f<.'.f-
crcrK>:; drug bio:ivaibbihty !n l l?:OO-mg
;.ximr~··llvd-r;.:lv!lsc g11aifrucsin produd (Muc:im::x) ;md 120
mg ps-;ud(}:;ptiulrin" hydm:;hloridc (Sudafod@ l2 Huur)
\Vilil 14n ml of w'1!n, JO mwiJl(;o:; alkr !he b1:gtnm!lg of the
•.xim;t1mp1im1 nl d (W rnl., >;<1dimn heparin a1Jii·~:ua;,:utim) was
uhlaim:J mg
gua[kn~.-:;in as .1.n <.oxperimnlls.l E:>rnntl~!ion (fo,,n!m(:n\ 8)
rcad1;:;d :ridc 3S Sudaf-.,d® 12 Hour (Rcf·.;rtnc,;) rc:ch1xl ;. of tlrnl of til<.' Rd<: rem:<.') an,: ll;1d
:w Alit.rnr of 3521" IJt·-ng,:'rnL (%.Y~ d !hat of tlic Rd<.'f-
rnce).
[0279] /\Jdilionally, liiu'~qui·,-akmx Jat~ w:is ('Xan1ir1nl
!Jci \'-1·~·~ n th<: lLsl grm1 p (fr•;;,i men t B-----_uno m;~ guii i frncs.i u
and 110 mg p.<.1:t1do1:phcdrinc hydrud1ludde !ls an c;: of giizikn~sin ar1:
(kptc:kd in FIG. 13. Tlw 1':c;i1 Hing p!iarnrncukinctic:: d3J<1 Mc;
din,,vo in T3bt...:.s 20 1lmough 12. ·n11: mm::imum pb;o.rrn
l'.oricen!rn!inr:,; uf girnifem:,;in roHnwill~ it 1 ?.UO mg nrn1 dn:,ullin\\ ~rt;i und.:1 1_hc pbsnrn rnr1-
.;;.;mlra tinn vs. I rm<: cuf','<' (_,-\UC;,,,, was !-<067:t.?fiii1 hr·w~ :mi ..
The l\H.Xim um phc;ma i:ouccntH.tion,:; uf f;ll Bifrnesin fol !uw-
ing 3 J_20lHng oral do8:: :ts rn cxp<:.rimrnlal [ormu l.11iun
(Trca1mrn1_ B) ..,,,,,~~, Hi4(J:!:(80 ng/inl {"79 1;? :i:J J .S'X- c·f th1:
Ri;l:i..'.n:nc'' forrnu!atiou} mxl occum:d in l .l'.i4:i:O .':)18 hours
( l l 8% ±.M'i.W!i- (ir 1_he !frletem.x formubtion). The r~su!ting
AUC;nf Wit.'< 7661:t.?8M lir-1Jg_/m!. {9.Y/i-:!: ! 7.fi'::f- nr that ()r
!b-.: Refc[t:nc;; l-:mnt1btionj.
31
Nov, 20, 2003
T.'\BLE 20
~~:;~··ld1c:,ln Pha1nn.i..:ckfro,,,:~ic Far;~ro•i..:~cP~ h..:·Bo\viri~
lh.::~ Ad:ni11~'.'>~ff~~~cn~ nf L"'.CJu ::i:i~, GKtllf:;1<::-.~~i r1~ :i.·hi.:.'~;~<::1'
t\:fm:.! wi~h ~ :.1~ ;)~l~ ~;-';. .:::udmT1~f:d6-:-K f!>·d~od•;nriJc
·~~- Sotld<1~~;{ ~~ Hid~-Ei.t \·ft~tl (Tr<:<:i~~<:
(r.i~imf.J
' "'' n~iff1 ~ .,: i);;.'r:~ l ' ,_llfJ
:'.:'UI ]/5 0r;-},~; ~U61 L:-'.:':
:.'.1-!f) l ' :: [ ~ ;Jlli:O t~19(. U.(J-~J
f_}5;:_: ;_~k :::. {~ :·11} 2.:-1·:~3 ~ui:=:;
!"l')f; IU~4 ~t(•.:} ;..! (°};~ 0 l!li'
~),.' "''.:: J: .. i ''·" ~.l.J
'lABl.L21
~ cl!;);f,-:_: m·~;ir: Pl:c~rm,i~:nh'1'di:~ P~1.1"11"i1H~lcr:, ~\:.I krv.·in._i:
1he .. \{j rfr i~!s;;-r,.-ili•:•1 i:·f l ::on :n.~ < Clo!.f..;:-t~c--,i1~ ar1•j j ::n ~n.~
(! . .-llTJ
J6B
J,\,_,
,,~_1
.I I
"~··"
Ps.i:: ~~d,1-:: i)hf\..:.:·~~;r: r £:·d~D..:liloc id~~ ~:l <~~; E~pi::~ ~ m:::~n:.:.1J f c.;, .,~~; :~~in·r1
l•_I >~u1rn;d \;,~lm;[{:r_'l'.-. FdCu.~i1l:; ~~~ n~1~:-itrn1pl;1;CI or a Mjt!~'-L!! Mud
"Tu.~:;-~~~n~~::i R T!'.":::-.l ~
At·c,, , At·cl"i
Tm.lo·~ (1,,- (hi- !blf-ljfr C:<:'J.l~~ :H~t
~;LlhJ<~.;:t (r~~;.'m~ I i ~·: n~;'cr~ l ~g,-•";;o• j.) (~r) (l .'hr)
\1~3r1 ~ t1-;<; j .;.l1 l6lJ ~i\_1!.\3 J. rn ll'l
\kd:;:ii~ 3.;;~n ::.ot; 747-> 74~>;"5 ]1)7 .IH.1
~l:•oJ;uJ ()'-..lt) 1;.~;;> ~~ C(> ~~~: • ..+ ~t ?'::.l_ ~ -,· -r ~-. ,• ,\~
Dn·~~1~i~·:c1
:;1o:idord lW 1),Hll '1t0 -!9j ;;_u, .. lJ. ~~
I HCC
1'i~ \. ...... 1v' -!-J.') 4~.-'i J7.P .'H s~-..~. ~: .. -;
102821
R.;~~~'~ ~j' ( ;~:·~~f.:.. ri:: ~in ~;-'~;1r;n:~c,!ki~K I i1~ s::.:ir;tmc~~~rs. ~ .. .:~: : .......... , .. ;!":~
~he /\.Jmii:i:~~rn~ioa d J ::'.Oil :n~ {iuaiicr~!.'S.if· ,rnJ ~=:iil ;n~
Psr.i:-d-:-_1(:rrl~i::d :·ir:.c-~ n·.:d1-:-J1,:h:_;_,, iJ-c: :1) n'> of p:-,,;udo,:phnlrin" ::r"
dtpidcd iri f~(;, 24, Tb.c f'~S•.Jlling pbmmarnbnd1c dala ait:
!;huwn in -fabks .'1 lhrnt1g:h ?S Th<: m;>ximum p!asm;i.
conccn!(3Jions of ~1"<.'.'.ld(>,~ph<:rlrin1: foHo»vtng !l 120 mg ornl
d'-'"'' as Sudaf..xl® 12 Hour (Rdu<.'llC<.') \VHS 2!18:t69 7
n1;.--rnL and nccurrd rn 6.3tfa:L2li hm1rs. lti~' rc:>i1lling
i\UC wa:; _1f.._\6:t940 hr-ng<'ml .. The m::ximum pla,;m;i
conc;'r'itnlir1n>. or psrndl'~Thedrint !{1Jtuwwg & 1 ?0 n1g <'Lil
US 2003/02 J 5508 A I
do&: ;;:.; ao <;xp<::rimt111.;-1[ fnrmulal.inn (Tn::dm•.:TJI. ll} \'-'"'
174:t 7~L~ ng:mL ( w~·Vii'~'urrcd l1l 'tSU:tl..2.": hour;;
(765',~:i;2::u(.I o! lhM of th;; Rdi.:n.:m;;; formubtioll}. H1(
rc;;iil!ing,AUC,., 1 was 3'.i'.';t':o:%2 hr-ng/rnL (91150i :t1L7'ii of
!trnl of !h<.: Rd(;[<'fl<:<~ formuhliunj.
TAllLl D
t ' . .;;c ,_,_,foep :-F.: dii nc ~; :c;) fF•i!C·~-. ~;ind i.;.' t; 11•:m~c~.::-1:--, ~ · ! ! !ov;•" ~~
~h~ A~h'i.':.i:~i::tt'Jtir~•' .:..~f L'.o r;.;.g P:~f\~J·-.·c-p!~~drn~f: HyJi·~pJ~lm~Je
)S S'.Xi)ft:d ::_.:: C !four Along v:~th L.::Uu r~l.? L•;,;1ii~en~~i1i ):S. ~~hicin-tx
~_,_ .. '.\:~i~ma! Vol~~r1H:.-1.::~:~ Fon~~~.,.·ii~g d~o:._ (\;i::~ui::pLiof· ~1C :~ B;_[:lb·
f:11 ~·.-i.i::-;i! (TH:~f~~ :H~~<~I ;.\. f{.:.;fo1·{:~H.~('.)
..-u.-c
1
) , Al'C1,I'
cm.r; TG.J5X liH- (e:·- [fae!"-lik cit:~~~~~;~;:
~;lil--r_!.-:.:~~L (r.:l~;m~ .,~ (ho fl):;,.":nl rl~ m!_J \on (I ~f)
\fr:~•;I ~:{~-"' I~. ~'.;,;j .;J(,: .!.{)3\~ ~-~" •• <.'1.•J
~'· ieo;:l 1) I~ .:'. ~~{! 6,00 ::23.~ JS~:: •l t/"( ""1"1 .:.1,1
Sl;~f·darJ 1'9.7 I.:'!; N~7 ~_1~' i.r:a 7.~5
n~;-"'·~1il·J~~
~1-~l~(bi .. : I~- l (), ~ 1 ~I H"l ltd IJ.lOI-~ L:)kCc; c:~~.: r~~·:~rn~ !..::.~
h-1~~•.r\-..·!r:g ~he /i.,Jr:~i~i"",~f,l-Hicri nl L'.(l ilcg nl F:-..-:.:m!n-.2p~x·,Jro1oe
Uyd!cx:M.or!.d.:: ;:1fi_J i:)JQ :ng G,~dife:H:s.ir1 in ~~r:
S1~bjc1.I
?v~-.:1~~1
\.kdi:~I~
~.;hii:J:ir.J.
D;;;,,,'!a~[.~,:~
Sl~1f·1:hcd
1'1.-,,-.-
·~;., CV
Eli.r.:r~ 1n~i;t;~j r:nrn1i:b~in:l m S".rrnnl \-'.~"J:11~r::-~.:..',;:,
F•;jlk•\1,:ii:g lfK. (\~CJ:-,~Cllj1~j.;~f· ~:·l" ;~ Hi8b
F:i! 'vit;:: i'"Ltc::t:m:;il 6. T:o:>e'
t\~ ·ci.
' i\l'(\1:
( .mci.:~ -~~.::-. ;:h<- (I;;- lb.:_:-lik
(r:g;mC.) (bn rig_/•H~ " "~.'ml I (hn
=74 4.1'>'! x:7J _V).='.~ :-i.=6
:'.ii~ 4.lln ~tfJ~ }~:,; :;; .. 1;
-;~·-;; l.=~; ~/{1 ii.;.·,:? u;i
J~.2 O,~_.U1 J -le~ l 1J~: (I !?'..:
" ~(.,1) :ci;~ ~7 .. ~ !'!.+ ··'-'-
T\Hl.1_· ,?5
Ck;.ii~ii;c-:
(! 'hr;
j\l_I)
:-~ ·'
B.~:~
L-U
:·,~-.~
J.h~i·· •·f fs.:.,~'~:d-:-y,;p:wdii~H~ Pk11w.:H.·okl1w~t ... · P:1r:1:n{'cu;;
Fnlb ... ..-ir~~ \h·-:.: Adm•-"i)!~H•~:.i.~-·" •:·f 1 ;o ;;--;•~; Ps.c•_•rhc::-·:,;:dri:-tc
HyJ l'r:chla; td.e ari•J .t~nd 1~-:.g ~ (\:r:i(ents.ia ia ;ii~ E;,.;r1r:wnen~al
f.fnmj11c-~:.lo.~ (\.rm~_r:;11',:-;:(! ~,_..~ ~h~'·~: cfT,r".'.;tt~k .. il A (R::fr::·~·~n.:-:::J ff; :-'nrplion -:;r ~u;nk11e:l.'.(j\li'-'Gkm 1u lh<.: kst fonm:bliun .in th<: prescm;~. uf :c
hrgh fol mnl wilh a 9",r;;. nmli(km.:t'. inllTval hch<.'c<::n 6"/ ,9'X-
and X l }Vii. Th<:: exleril d ::hsmptino d guaifrncsiri from I ht:
i:xixnm1.:nuiJ 1;ibk1, n.~ a.<.scs.."-':d by AUC,",- is l:quiv~lrn1 tu
th(; 11,:sf fornrnl;i1ion in \he pn::!'ien<:<: ()f n higb for rw~;iL
l tU!ri] l n (Tilldw-;iun, llJ,; r,
ihte Rdcr,;n;,:,: l'ormub1io11t;; ·v-.'ht:r<'. in Ml oprn-l:lbd, mulliplc-do.';c.
rnndomiz-t:d., 1--'v1:iy-crtn&>'iCf f't!Jdy m'ing 36 >.11b.it:th. Thi.'.
Sl!i.l_l(;tTs wu~· rafldornJy placed ir1lu tlfle uf lwo tri::;;\m;;nl
grnujh Gmup l 1ec:t:ivi::d a 12(){) mi,; eumwlh-J0[dt:a~
gu;tikm::>in _prnclt1d (Mui:in1:x) phi>. iu m1d 120 rng ps...'udoc:phdrirn.o llydrnch!orid';
Wtlh :!4{) ml. of Wi\kr ;Jfle;- :rn OV<::rnl_\',tll. fas! J.mJ . :ttkr lh~ li1f't do'Y~ (t20Al hours t<.:ndy-s!at•o plasm a
:;;u3_ifrncw1 rnnc<.:lllration c·f FJ.':t'\ ll;'/ff>L ( lf(i"A: of !he
Rd<.a-rnn: fnm1l.lb!iun) a:. 0.9b buur~ a!'i<::t th<: bsl dos.:
{120.9(i bou;:-; Jfler lhc lir:-;I llM
ps.:,udoq>IJ .. ;drin~ ,x,nccnlrntion ot 3D l ng/mL al 4.R9 hours
al'ler \ht: !a:;l Vas l73 ng/ml,,
US 2003/0215508 Al
[0291 J The flh;mJ rhsm;J. G'.'fJ<:<.mtrnlmns or guaifon •. :;;i n are
d;;pi·::lcd in §'!h. 25 The rcstill irn; ph~1.rma"-r1J.::inciii: d3.U ar\'.
sfxrnm in T~bks 2{:• 1tirough W. /'.! sk;ody s!~k. rhc s1Jbj0ds
g]v,;;1 LW.0 mg g,u3.ikncsiJJ ''"Try 11 hours .• ,rrrn gll,iifow~:~in <:01-icentra!i(>ll ol 1 flc;r !h<.: firs! doS<;) and the
s1cady-st:11c i\UC (/\UC_J w:;,; 7:::o9:t.1746 hr-nr,JmL /u
Sl<'ady "tale, ih" -;uhjeds gi\'en I :'.00 mg g1;:Jif<'m:sin every
l ?. linuP.;. 3.~ ;m o:rnim;;n!;tl labkt forrrmLH1m1 t'ur l 1 do:;~s.
;<.cari:J,;d 3_ sl<.eady-srnlx rn3ximum plasnu guaiknc;,,jn ruil-
C<.:t11ra1wn (>f t l.i83± l OI 9 ng/rnL ( 103'/i '1:19.6'!; ot the Hd-
er.;;;nce Munnex) in 0.96 l:Jintrs±ll 645 hnm !° ~l Do.::t"';; nf L~UU r."...~ gi.F1.l.fr:.:r:.c.::in
,~,, \1~1,.:-i1~-L_-i.._ ;:o.·x..l 1~n ;ni! P·~~·LtJ, ... erh-::-J1~YK' H•,'!h!~>l-~idu[i CV
[0193]
Sl.1 ... hf;:-d ® J ~ n.-..1o11:· ;_;_'; -~,U
i~~ CC"".~ -i::·,:10: Cu:.~-. 'l',J:,1:-; (.~A··, C ;1_.,~_.;:
Sub.ic.;.:t {!;;-n.E . ."1••l-i (:1g/1;;f .i (r1~ "'; : {'111 (n~,":.:L~
1k'"' :nt::'. I I"/ jq_,...,_~ 1':i % ~..tte
\je{1i)t~ 0·1{j') JuU ' l5U l'.'') :15 ''~·1
su~f!Jar r-v (J~ ~::: 'i-tS. 5J.·1 ~·1.~J.~ 6:.. f
R~1~i~,- ~-,f Gll~tlk;ws.i~1 ::.~t..1.J~·-s~~1!t. Ph~ll!Wiu"'.1b1'i.('.~i-;,
! 1 ~;o;1m~·tc;;,. h-,j ~·•\vi r;~ : t.f: /;,,;_: ~~~ri!;o...~r.~I io·.n ·~·f J i j J:osf:s. ;,f ; ?r ;\) mt~
{1m1!f"1::1Cr·,i!": :rnci l~(l mt-: P:--.....-l!Jn;_,·p~:•...'"Jiin;: HyU1nd1!'.J~ldr.:
ln (''1 f.:, ... pi::i·im~;:1~~;iJ ("l;r.m1ktti.:.~11 :i:>n".;p:1~;,;d !\1
H_,~fr-:-:::io:: ~-nrnmi:;: i•"•ilo:>. w :"-.k·n•1~~ \.·;-:,:1rn~co::T:--, J,...;. ~
s~ih'..:~:t !),t'C'~,::. Cu~n::-. rMX\. C,.:-.,.·b.•SJ1....:.+b
).-.;<..::xa I 14 5:~[) Jf)J. 11)(1 11~
'.'i-,1::-:J~·dri:~c~bri;Jf:
~ub_:·e:c~
St•1~,i11rn
i)...:YC;ji,im1
S:iI~!Hford
[jm'
c,~ \.'\"
Ii: :rn Exf1!.."n•11;'.;nt!~ h_•(ffl'l.l:<-l~lo11 Cum[h~~tU ln
g~:fr:1~;1~r.:,,; f,_~1·:nuk1j i\n~~ ~n ~c:1·:11.r~i V-:-.ih~!'!k-t~'l ( ""~ 1
At"C:::..~. [" cm.I:". T,., ... ,
n l) E' ::1)_(1 'lA"':~
-!-.57 Lcll 5.lil (>-!}.'<~
=--~'--; !29 ::--:_c OA'-!c{
(~A'~T-~.\,-,;r-
;~lk~
4.-.;.r,
,, '
[029$ J The 1JJ<.'.;~il plas11M conccniHiion of Ps;.,:-i1clocpb':-
drine 3r;; .'iflO\Vn in FIG. 16. -.:.h<. r~st111ing pharm,i;;nkindic
datn ar·~ shown in 'fol:·ks 29 1tirniwJi 3 J .. At s103dv slat>;;, !Ii~:
;;uhi-cds givcn J .?O mg psemluq:ihedm1-c bydm._·h!nride, ~:<
S11da!"cdi)\1 12 l !uur, cvc;ry l2 ~K>llr.'i for ! t (lo;;c,;., n:ad1cd ;i
.~l<:ady-sl~l.: rn;n:imum Jlla.',m'1 pst:udu;;;p!it:J;irie c;inccr11_ra-
tion of .'16b:77.7 ng,..mL ill 4.~l) hour.<, :t114 hotH 10!kr !!w
fat.;I dot~ ( l 24Y«J hu1Jr0> -;:). Th<.: ;\UC,., Wits
~1'):'.X±XD:'. br-ngimL At t>k3.dy 'ii<\!!:, th" "~uhjeds givrn L?O
rng pc;i;i1dn0pti~drin<.: tiydrod:Jur.id~ ~very J 2 hours, ~is 3!!
t'.Xpenment:ll l:ibkl fo1nmbtiuu fnr J [ doSK. .. ~, E<:Jdic:d :!
sKndy-s\ak m3xirnum p!nsml!r'>-:t l .35 lKiurs ~;Jt;.:r tll<.' last
du"" ( 1.?4. lO hrnir.~ llfkr lh<' JiP.;I dnw., 99.-lS-,'..<~.09~:0. Th1;;
AUC,~ w;1s 35S(b'l98 br-ng;rnL {_!02'-X:tJ9.(i';~ ).
TAH!.E _?9
P~.!·u;Jrn:pt.c~Jr!f!c St.:::•!d:,-::-;~.-i.H.: ~)t.ri-:-m:t.:.'nki :l.:::I i..:
v-~~~{~Bi:h..:l~ Fcl!u ....... 11~.;; ~h; .·\Jmii:f;.[n~l~)a oC c] n:~S(:"~ nl'
J :·t:: ;"g P~c::..::d·:)~;p:h-~dt·:~ie- th·.;~~·-,~·Mo; ~Jc: :r~s. ".';-:..~J~k.;:.: :~ ~ -~ l k~t1 r
;;_;HJ c.:rn: r.;g: (,;_;~!f~'::ii;,:s.in ;~;.; ;i.A11~:iri.::::.. In ~\,;rr.~;;_: '...,'nhx•Joi;~nf' -
_______________________________ L~£~5_~)l~~~~-~~--CI~~~~~~-!)~~-~-------------------------------
S.ubie·~t
S·k11n
'>1di'"'
''il~< <~;~,] ; :u
:•1.-1 ~-!) _ _:} =' l.5 UI .'4-·1
F:.,..._·u-!ofm)! Vci;•.'i1~c~ii; -
.n·.::.·nm~n~ B ··£e1d 1
A~-{"'::.~ r'm;ll. ("'r;.1,:x rffi:E A'.'l..:~"'Lr_·~
S.ubje..:i (l~i- :1g:'f.~t) ( ~1~.'~H L) (!~~':nLf (!lfJ (;igi«'Li
:\1..::in _:;,550 JI~ _1()5 ;:.uo 2')U
\•kd!c«'. ?,,-.i;1~r:.} nn -"S'I !:~~.no ~0.~
~l<~":llii~~; Ph<1n;;1·~1..:ok.in~::tl;;
P~1r~~~n~~tc····~ F·:·ll'J'virJg \ho: Alir·~J·H<,,t;·~1tiG1~ .;1f J ~ Oci::..re~ ot
i.-::O i~~g Pr-..L'.~~u~-".::ph;Jrjf•r_.; HyJ•·:1.__bic~iJ{:' ;~f·.d !~()H mg C1LrnikN.:::-.•1i
11~ ~H1 E:q;:::-iiffv.::r~;;iJ fes;~HJ!:itlfl·~~ c.-.l':.~p:1~;::d l\) :{;:;:~kr<:::'H:t
!~hrnm!.'1.: ii-i'i)~ l,:; :\.~-·•r.•ri! \Jf;.:1rn~c.::-1;-; f"; ~
Suh.i.-:~·t ,\tT·~~::. t"u.!.1.' Tm~.-( {'_..3.,"l,}_ :.WJ j•i.c
n__.,:ia\i•1•1
$! ;i f!.tfa ~ ,j .'-.. 'J 4.7.~ _'l;_.(i:· iD and p~mJoephedfi ne hydmd1 lnmk.
[0299] !n ;mulhr:r sludy drng intn:Jdinfl f'•:lleDlia! fc,r
<:ornbim!ion urng:o. w~~ e:rnmim:d. Tbe inkraclirni ptiterJli~l
for 12rn1 mg gua [l'cntf'tfl ::nd J :w mg l':;etidocpbcdr.!t1c
Hydmcilloridc 'Nas .:ndocphi:-
dt"in.-: producl (Sti<.bkd(l{) 12 Hour) 'Nilh 240 mL ,_,r room-
knq11:nlun; 'f.':ikt .1fln 311 ;wemight fa~.L ()wl!p ('received
a ! 200 mg gtrntfl!owing ltir1cs: Prc: dof'!:, 05, 0.75, L 1.5,
1, :\ 4, 6. 8, JO, 12, l4, l(; ~nd 24 hnurspos1 duSI.' (th·~ l,',·as-450 m! .}.
[{13021 Sub_i1:d~ given l 200 mg uf guaifon•~i;in a~ Mucrn"x
(Tr<::a1m<::nt /\., Rd~r<::m:<:) reached .1 C,,,,x nr .?Jl09 n_"'iml. in
0.::\9 tmurs arJJ had an i\UC;,,c l'f KUC: hHighnL Subjtcts
,;iv~n .l20fl mg guaifi::u~osi.n ss f\,fo,~in~;.; along wi1.ti co mg
P&:udoephcdrin<.: llydweh!Nidc a:'; Sud<:frd'E' 12 Hmu
(Tr<::atment C, -\:;;:;!} reach,xl a Cm,,x tif l 989 flg_imL ( lli.1-':Y;-. c·I'
!b~l of the 1<:frr<.iw.:) Jfl 0.84 bt11.1r { HWii. nl 1_hal uf tb<:
rdnwce} aml h~d ~n AUC;,,,· nf ~4)S2 i1H1gim!. !. JOO':;'.. d
lhlll of 1b1.: n;t\.'r<:JJn:).
[0303] Sttbiech giwn J20 mg p~u(berhedrine hydro-
cehioridc ar,. Suthlf•xl@ 12 Hour· (Trc<01m<.:nl B, R<:fu,:n1,:.;;)
rc1.chcd a C""'x of 29<:1 ng/mL in 6 boi1r". alld had Ml A!Jl',,,r
ut ,1505 hr ng:mL. Suh.Jce1s given I '.W mg psctiducpbdnw~
hytlmi.:hloritk ;::; Sud:;l':::d@ J '.! l !nur, ~long \Vllh i . .?00 mg
gua1fr.nesin a,, M;Jcim:x (Trtalrn,n1:1
('O!l<.:<.:nlf'J.liunc; ut' g;1aif<.:w:sin fo!kwting a GOO mg om! closi.:
'•ing a I :'.O(J m,-,: nr;il dm;e as Mut:inex
aiullg witb 120 mg ps.-:udocpbcdrinc llydrudilorid<.'. {Tt"<:al-
rn·~n( C, 0 fosi'l wer~ t 9119:t~63 ugirnL ( 102 .. '.\Y.7c-:d l iHJ?i uf
th3J of ibc rdcr<.'.l11x fc,rmula1_icin} mid o('('Urr<:d in 0 . .':4:?:0.3 l
hour& (103 94'/i,:tJS -~l\<;t di,r- !bll.--li[c C]c-~,ll'l:.!H>"::
c't~g_'rnL1 tJ~·:· "~ it~L) ~1g-·i;~ L ~ (~Jj l (l:l-! 11.>::;-i
l:H"::Oi'
~·;- C\l ~i,_77 4t°L79 -t~l._:;,s _.,(_/_\);;-,'. ~3~;-~~ .:.Ut/:..:
[030.5]
TABLE 39
-:. il1J!f~ne-1ir. i")h~~j rna:..::0J.-i;g~i::::- 1~~u.;~_;,11.ett.j·• F·::.lla"~·i1l:;:
lht Adi~~i11.l'.~~i;!l~('1i nf L"'.Cll; ~<<:-:; Ci-tJJ.ltc~~(::-.i:-s A!nt(&~ \:c'ith : ::n f:~g
~.;i.::-..u .. drxr~::.Jriri.:: H>"di~)~·~:r)T•rk ~o '\nrnHI
-------------------------------~~!-~:~:~~::~.r~~~~::::::.~_:;~--~~-~-------------------------------
~\.k.J•t)f:
:.;l<-:.;~-rh1·iJ
[k-,:~ ;~~ ioci
~i;:.'1d;.11·d
~·:in~~
c,."'-'
c'n~_:'mLJ
i r1~ ~
~f,_1_J.~ .•
r,.,"
t.h:·!
il."4
n.i'"'
ll31
;\L( ·ri-~
(l>Y-
1~g;m_L)
79-:__-;,
.i.-1r.-H'~-'
_:>;_:<,_~ 7
;\~··c;..,c
/hr- ihlf-lil·c ~··:c;~T-OOH~C
;1};;i~ll ~ (!lfJ (L:hri
:,11s,;
\:,}~j
-'·-'~4
l:'_;;_:
US 2003/0215508 Al
TAJlLE 40
R~1!i-:-.i .,.-~f GtHifr;~o::s(<~ Pru~!'W1~.;,;.,.-_1bi~.:.:;i.,; Priun1.:~h.:~·:1
F·:•ll1::;.\1 • .'~;~~ th.c: A.dmlfibt:·~t~mi [If L:n~1 ill~ G~i,:-1jte.1ec-~!1
/\l 0:1··q~. \-Vi"li~ J :'.H a1g P:~~u.J,_~1:pl1-::-J~ inc H_~·Jr~~ddorik"" ;il::.:n ~n:; ·;q ~()[)_~-,1 !::cl.Iii> 1:'~-"" 11::,_.::1
~de(il-)l~ •J::-.·r,,- JO<..i l03.J·1 i~JL-i 1 ]Iii 4J ~i~:.32
Sl;~f·dar CV .~~-j-~{,< .'-i,<)~ 3 ?,~·:: ~;.:,()$ nL~; _: t).~) 3
TAllLL 41
;•,1i;:;t~·.focph~di !ft.:.:: Ph;_~!f:!,1cci!~ii~ c~i..:..'. P ;i!')fl.1;t: tt::!"~
r-nlkY~Yl11g ~~1·_· i'\Jm~~1i-::.B<-1~;(_•~ 1.:!' I :::C• f!~g P~i:..:~tbcp;~cciri~~t:
flnJ1·.:x:!-:i('r!d'-:' ~--.. '.'-.:c•im~I \t·l,.i1~:x:i;i:-. tTn~,~~~!~~r.~ B:
!\\'(
" '
i\t-C'1·1;
c"}"" f~~w. (hr- (I;;·. lfa:f.lik Ck:,11 ~ r..i._~.~
~:;ul>jc·~l p~g, rnC .'• {bi ~ r1g.'•n l _ ~ i1p..'rnl.) {:1r1 (L fl r ~
\1rn:i 2(JS,;-:;: ~) .. 17 4'r4 45n.; f;i,1.r·:: :·J l)f~
\~.:-di~1r, 297.5 )) -~~:J '~~! 3~) 5.d -- ::u
::;i::.;;i:brl.! 73. _ _::::-.; ;>.i.::: ;c;47 ~ 2 :-;~f L+: 7"
f).;;,,·ia([:_);~
Sl;,f~dacc: I : .. 'Ii< r;_3~ 177 - !J iL~.-} I.:':'
j"'.r:-o;
':;., ('V ..::~;_'{() -~j.L.t ..1.l>.0~ '":,? '15 ~J,.:.·:3 31lJ,C)
[tiJOlfl Th<.: pbsm'< of pscudcx.:ph·~drin1.- ;Jr~Â
di::pk1ed in HG. 28 Th<: ret.;1Jloing pharrma:okiridi,; dal1i is
,;lx··wn rn 'Hi.bk:-; ,12 H1wugb 1)'.L !11<~ rrrnxirnurn pla~ma
cowxn!nHion~ l>f Jl"'-~uJ0rrh1xlri11c following ;, l20 mg on,[
do!';C ;1s SudafocW:: 11 lilnir (Trc;Hmc11l rt RdbcncC:~ .__,,<.:r•~
. ?95./0ct:TL?."i ng,.·mi. 3mJ occurrtd in 6.\7:0:-l.'l.'? h(;JJrli. Thr;
K.:! 2:i0 hr"flg/ml _ '!'hi:: rn1xiriwm
pfasma cnn·~·.:ri!rn.linnx nf p>«'.ud<.>t:]Jhcdririe f<.:·lluwi.ng a 120
mg urai ;.kw;.; h~" St•dafud® J 2 Ho11r akaig '8ilh J 2((> mg
:;11aifon·~';in ;,..; Mucino; (fo.:~trn~ni C, '!hr) \Ver~
289.J::t TUi ! ng/mi _ !, 98.4l'-'f.:tl1. T!'Yr. uf lbat of thc rdcr-
cmx forrn1Jla1iuri) :~nifr·1~l:"!-.i~~ ~o S\.irw::l \'f_i.h·::Ht{:!·~- (Ti-e::c~~~~~tr.1. C;
t\t·c·i· < i\(!(\1;
Cm,:i.:~ T!.!.l~::. (!H- - (hr- !Mf-lil'c ( ":r:;\w i11X~
S-ub_:·~c~ (r,~:mu (h,·: ng/mU :lf'/l~~L i U11) il:lll')
St•1•,ihrn 1J._~ :· n.:·6 JM .~.:::>:' O,.::.; .:.n
!'.ffY•'
•;- CV .'.t.8:.'. ;::r~•,74 -~7. 7~ .!<<).~)_=; -~;-:. 7,; :·:<.;)q
[0309]
!{;-~~i·:1 °:1f P~,:eli(k•r:y!io::;Jiiii:::. Ph~11':1E~:C:cbi~::':ic P~~j)metet:·
fa!!nv.-(1j.:S t!'·r~ .-\ . J.o;i1lstjt~~ .. ;1::.f1 1~.r J21) ;iig Ai.:..wg -~'-'i~h L~~!U mg
( i._._~i~ fcr1c:-.::1 H~ d11.:·:..:hk1rici._- CuMr-11-LJ ~o l 2(1 rj10 P:-,cudn~ .. ·pb._-j; i !1{'.
Alon-:.: ~o ~'-~<1mil V.;_~j:..::~1bt;'.~ r·~.;-.·.
,\['I_
" ' ;\l 'C~"c
{_"L..IJ.X TmJ:~, (h-- (:,,_ fblr.Clifr Ck~1 rn :H.:r:
:-;1.1hic.:1 (n~/mf.J ""'' n~;""' ~ .) i)g.·r:~l ' (rir1 (1 . ."0TJ
\·k!!!1 'J0Ai J 1.J: . .1. :1 -~ '-!;L~ iJ;t:~~J ~~)J.Jl: luJ.:-Y~
\J.:j;, .. : ';~Ail ji)o) 9u:):) (}( ')] 97.~il l•!:.i.1
:..;t;~aci,nd ;~_77 3:-u~s 1_1_15 !5 . .:~ j()_"-) l5_i"j{;
Di:::;,·ic~~i;:})J
SU;.Ol1hr~! ~:-;CT b. -;._:;..
.,
::_:-;~ ;;_H ~/[;
f·:n1:.·i-
,-;- CV '' 1_0 i.s.:i:~} IJ.:/.' J 5 ~'-' :(J.~! 3,;;,~-::,5
[03HJJ In ndu;;ioo, thoo pb<:nmF.~okindics of gu-1if<.'Jl<.'.Stn
anll [.'hl'.UUll\:')lb<~drin<: hyllmdilu1id~ ~rt 1rna!frdd by !bt:
prcscn<.:<.: ut· ,'lbsen'-''' of oiK' MJO!htt·.
Ex:tmr•k 17
[03 !! J In ehlrnidt wilh 2'1() ml. nf wain,
J(l rninu«:s at'lcr l!k beginning of th" consumption of n
high-far. !>n:akfast {'!b;t).
[0.313] BJc.ud (JO mL, wdium hepMin anliwagulanl) wa.~
ob1aincd <1! ill;:; foUmving rim<:~;: Pre do.'<.:. O.S, {J7-"'~ l, l.5,
1, '.$, ·t. 6, fl, 10, 12, l-'1-, Hi anu 2~ brn.1n-; [)(,_,,[ dU!-«5 (tlie total
hkiod k»'>' for ,;;irnik n<0stn and p.-:;,::11docphcdrinc ~naly:;i:> wa;o;
3(~J mL) Suhjo.'.d;; ::;ivtn J1(J{) m::; of gt1~ik1K,~it1 &ml l.20
mg p:i
i,;ivcri LWO mg_ gu;1it'ent:sir1 ;rnJ 120 m~ j!.'i<:lld('·q1[-1,.0Jrint
liydrochkirid1; ~~' ;rn 1.'.xµcrimc:1l.r,[ fonm:LHion ( lhill uf the Rderenu:)
and !rnd w AUt ·,d uf 74{J'J hr-ng/mL {'·.14. J ~'·' of lhJ.l ,_,f lh<::
R<:frn.:mx).
[OJHJ SubJC~'i~ giv•.;!l 120 mg p';n1do;;phcdrim.> hydro-
chk>ridc 35 Ml cxp;;;irn<»nlal formu!a1iun ;,fl..;r Ml OV(•rnigln
L;:;i (Tr;;;;I men! 1\, Hdaen~·e) reacht:d ~ pL;:'.ma p;;.;;udc-t0phl'.·
drirn· C.""" nr ?J~3 ng/mf. in 'L6 hours a!ld li:id :m /\UC1,., 1 of
37,16 ilr-n1~irnL S1ibj('.cls :;•,ivcn ! ~O mg ps;;•.iducph<.:drinc:
hyd.rncllbrid<.: a:> an ~xpcrimcnt:d. k>m11Jb1!ion foHvwin 1~ the
<.:OU';umplim1 ol ~ bigb-fal m<:al (Tn:al1T1<.:'.lJ( B, ·l!:st) rc3dJ,'!J
3 pbsma P">-•UdPcpli;;driw.: c"'"' or 3!.>I ng.'mL ( inw.:;: or 1h;11
of lh::: Rdi:rrncc) in S.77 hours ( 137'/i ol' rha1 • .. if 1hc
R.:l'cn~nu.:) and had an ALIC r of 361~) br-r1~/ml {\)9'X. or
!trnl of !ht: R1:k[e:io~_). «· ~
[KH5] Tbe. plasma nmcenlnlic·ns c-1' guaifcn~sin me
Jqiickd in FIG. 29. Tile r.c.~ulling pharnrncokim:lic d1la me
>'.hown w Tabk.s 4'1 1hn.nigh 41], Th;.c nrnxinwm plitsnu
corn:<:r1ffalions l'f gu;1iknt:&in k>!Jowing 1200 mg g!l<•ifcn-
e:c.in and J20 mg p.St'.UJuqib~:;_l;int iJy;Jrod1Joridc ~fl.er ~n
u;;crnigh! fas! W'<"-W !E'i7:t:83~ ngirnL {McanISlar1tfard
D<:vi (2:< W.li i:IS7'T 1ha1 of lhc
Rd~n.:ncc for:mJfatiou}, Th~ rc:suliing .'\Uc ... , Wil:>
7469±:',2!7 hr·rigjml ('M.l'H·:t:23.l'k '.if tha! u!' rh~ R,.cfrr·
uice l'ornmlallrni).
TABLE 4,,1
(~u<~~Cl:f•c.:.;;..if~ Pb-11m'1c1.~li1~c.;lj,_:_ Poinii~;c.;l,__.1x. h~!!cvt!n£
tht Ad~-;.~::,:c:~:;..i~i')'1 of 1 ::tJO ~1l!; r~1<;)k~1-::.::.J1~ ~f1d J ::n •1l:t;
~·\c;:_;(_hwrtonir::1c Mi.-fJm~:~j~·i-;-i.Jc iri •~:1 !·x~·r:m{";)l:~! h~;r:~~ci~;Jio·.n : .. ~
:'.\-(~f:rn~; \'-.)b!1~-.:i.::·~, t\l-~cr ;rn O\t.";i::g~1~
~.;ut1ic·~t
\.fr:;~:l
\1.:~li:ll'l
~-;H-.;;i:bro!i
!)\; ;,,· i~I( [.~1,'
::-;l:;;r;rfar1,.]
Ei:··y
·.;" ('\I
[~l.H6]
S1Jflic·.:I
\.k;~:l
\fr,J:oii
~.;hii:d:ii.J
D;::,.·!a~l•J;~
[-\~s\ ,.T~;:-;'llcrn.·,1~ A.. Rt f.::r~r1 .. ·f:- ~
r\l'Ci, < Al·r'l' 1:
r-oo::.x rJ~IJ.'> !h<· q·.,. !!«if.Me
(i~g."rnC {bH c1g.'•nl.) !l~ ml.) ('1r1
:SS? 3.Hi~ '~~~;J aJ42 l.S:'
W.':J o. 1~:u ,')~:::~ -~:'-q ].I,.~
8_J;:-.,: 0.5~2 J5t)J JS\!~! n_.,n:
H•: o.lnn C.C)() ;,()'.; \I 1 '?~ ~
15 5.5.n LU ->.';.II .li>.C
G•.~~iff: :l•:>;i11 P!1 ~·~ •n;:~~-'b 11(:"~ :~~ F:1~~11~~(;V.t~·-,
h~ClO'l/~0:01; I~:: :\,Jmir:ir-.1 O,JSi;rn ni' l.!()i; r:~µ
(n!~ilk;s::~isJ r~~Kl ; :·l) :~~:;; Pu::..:d-:-1~;-ph{:d1~:H'=
Hvdmd1k • .-iJ(~ iri <~~? !·x:-x.'•i1w.:N:d h~rf'.~lll;.)ii•·.n sn
~-·:1fi::J~: \XJ-l~"1L-t::l:•', t\hl:f ~he Curn-u1~~[~lfcr1
of,\ !li di-f'ol \k.i l (Ti c,11 mrnl 13, T~0 ll
t\t·c·i· < i\(!\\1:
Cm.:i.:~ T!.!.l~::. (!H- i:1i.:·- 11<::.:.1ck
lr:~m1.) C:bn ri~'i)Jo~.) '1:;_.'ml I {h1 I
!.''''' .H!' .'10.' ~.:_H~(; t ,,, __ .... .1
11~i~1 .I}) (_,~~~:.: {J~~;-i ],] ~
f}9] .!:} _;;a:' J~lf n_~Q.J
Ck.E~irir.i.~~
(L fie)
)~.I)
t-U>
(1_ .. fo
I .•1'
•C/.11
C'!1:~;1 i~ r:.~~.:
(1 hr)
1:':\. 1)
3{.;>;
7.8()
36
Subjt-::-~
:i'tO:ldO!\J
I Her
1\. \. ...... ,.,.,
Nov. 20, 2003
-r.Su.tlt'i..:r.{:.;i~ Ph:~•r-•a~cl·:iroi..:lL: P;~qm~l{T::,
Fnll.:..J·,:._·i11g ~h,o;: ,~,.-;~:nlni.')H:perrment;;J l(;rmulatilm fmulation) arnJ uccmr;;d i!l 5.77:t! .7H lint1rs
iL:rt~;;:.J:(> L9'k of llrnl of the Rd'cr1:1-,c;: fmmublion). Tile
~esullmg />UC,.,,'""'~-" ~MO:t96.1 hr·!lg:m I .('!9.0~:i :!:~!0 .. 1 'f u f
th3.t uf ilx Hckrrnc<: forrmdal1ou).
TABLE 47
P:-.i.:-11dc{ pho.:: . .-i ri<~ ~~~;~r:-:~:h. nki ~;.I .r: ~'~~arn.:i:;r:...
f-'{1-]].;1\\ lt(g ~he.:- A·d :~~~•ti~ tni;i.0;1 <;f J :·o ;~~g \)f
~·\c;_;df:!-'.:rhcdr~:1{: :h'·Jmd1k••iJc z~J ; ?r~\l
(fl~;.~f~!~e-iil~ il~ ::rn Exp~!jf•Iet~:al rcJml1!::-LH01~ ~G· 'Son~~.:-1":
\·bh~l!lf.c":~:!-. A.b;-r HI( (},'.;i:~i~ ... ,,h~ L~'S~ cr~tl~l:lH~;~j A. Rtfr:·t:HX~l
Al't I I· ~ ,.:\l'C,;...,l
l ~UJ,):.0: j.mJ:~, iii;- ('"· H"lf·li1·,, (";caro~:u::.:.
:"1.1hjc.::S (i~~;'mf.J : '"' n~(ff'i ~ .,~ 01µ/r.~l ' \. ~lf.J (1 :hr1
}.-ji;;::Hl .'.~.!- 4.~~l; J477 .''74G .'.llJ :·"ti,.~
\1;.:d:t~r. =~t.~:. -LOii 1'·;.~ ::.:'"':.=· t.<1.: =·?. )
Sl<~atl-11·1J 79J_} :.:'Ii ifr:~ (,'~17 Lilt• (o!_()_':S
Dt\'ic~~i.0~1
US 2003/0215508 Al
P:,L~c.cio·:::pl-:c-:Jfir-1_.: rl}af:-tHt:ckiri·:::L!t: Far:~r-•1_.;~.::_:-p~
Fo!!' .... "\'~~~g !hf~ A1d~11i11!:-::.~;1•i~Gf1 f>f 3,~n sfig ·.;!"
r"s..:.:;_;fj'.)c:1h:xlr:-:-H.: f!>·droc~;ori.:Jc :111J J.?lJ\l
{;rniifl.'.at:-.ii~ ii~ ar~ Exp·.::-r;•n-L""aU~ h_•m11.Ani~;;1 ~o :-.,·(1rnk1l
v .... ~lu1M~er:-. Ant~ ·~~~ 0'1.'~;r:~ld;l f~1.:;_t (T:~Jtr1it~1l A. R<:f!:'ic:r;..:..-,.:.i
~;l1hj·-:.:~~L
~it<~~~ d::l ! d
b;·,:.,
•"{· CV
Slib.k:..:L
\b;"
\:J.e{l~JI~
S~;if!J<1r- 1'1'.:·- [foC!'-lik
(r.g.'m ~ ' (ho ".~·:nl !1~ ml J \'111
I .''.7 '1.:'61 JS:: l 7J 11.!-~:'
~{';_~ _.,_.\K ::d =:~_(J- ~L~
TA.DU, 4R
c~·X:l~ ... foeph~Di !fl{'; Ph~~tf•"'.o.,lC:Ol~!!'• e;~j_.:.:; P~~~')fll<:! ter:~
r.11!!~>i,·1:ir1g ~hr_: /\Jv .. •!ix.trt1~.i~_•!'1 !~c ! =:'.fl i-.-·~ 1.°':'l.
P"~c~!(3,~{·phcJ•iw·~ ti:·{lrn.;.·;-i!o;id:: ;~w~ ! ::€~() mµ
gt1~1jkB..;:!;ii~ ii~ ~tn [x1).el'~me.'1U~! Fnrnm!aH01
C k~E~~\t."~;
(I :;lf)
;.3~
:'tl.5
t',J :++;1:.'l·~n«C Vl.Arn;li:..:•_·1::. A~lt:r Co;,~,u:•~pl :c~~ • ..1f ;i H;gn +'- d,,·_ lbi!-1.t'" -CIJ:!~jj:1f~1_::e
(f·g_.'m~.) (l"~n !l~.':~d ~1g,"mL1 ('HI lf ::ir)
. :;,\ l ~ ;'.-'.}~I J.:~I ;_' :;.iy(')~~ .1 1:.4 ::H.~{
~'?..; (,,un :<15~ _:;._t5~; -·U5 :.:.s.~
:.-:t;A L7{; 9;5 iJt1_::, u;r, 7_f) j
J.< ,, ~). 3~ ~f; b-i 1.\.1:'- I) ;t;o ~ .3{i
~(i.i' j0,9 ::rJ.'i 2:;3 ~~-'-' :.·l, ~'
TAHU:. '19
R,1~i{_::. ot [':·;e'•.••::k:i.ej•:wd~i:~c: f>li111!',l::ti..'•:·:~1~e\[, ~'a.l~!:~Klr;;i::,
Fnlk'~~·ir1g \b!.'" i\ L~7 'J0,~)
:_lf_~_q {j_j 'i Jr).<
~·.'!.e{l1,11~ l'l'i LJ..:; (_i{,, q :J~.9 -~~ -l Ji).·1
Sl;~f·Jacd j~-~ c!_(; ?r/_:..; ~B_l 17 : !D '
o~;t.·~1ll"m
Ssrir:d;~r.::. :. --- !IH' _\_{'1; ?' .~l} ~:.'n -~_.:-;::
Eroo;
r,, CV 17.J 4S .. ' ::;"1 .:1J.." J8. ' _\(),!,
[{~32:l] The mt<· of ah:.;.;>qirinn nf gu;lifonesifl rrc•rn lhc
t X[1<:ri m<::n lal rormula!illn, ;,;; d:i.'>'.;,''S<:U by ( ·m.w i>. not
hioequ i.v d lent to I ho:: "\i::sl rnJTnu!:1i ion in (he prn:;,;,n<:<: of :i
high-LH meal. Tb<.' <.:xt<.~rn of Jbsc·qliion of g11aifcm::>in from
lh<.: np<.:ri.m·~n!al !abk!, ;l"< 3S-';('.f,•.::d by AUC c,.,-. is cquiv.:iknt
!ll !he ·J{;,,[ frnrmifation in t!ie jite»<:rn:-. (lr ~ hi;;h"fat m<:~L
[UJ.22] Tb1.: r3ti.: ;:nd >.:xli.:El\ of p:;;~i.idoqitidr ini.: :obsorptiou
fr;im lht'. <.:xperimt'.nl~l l(iJTnublitm w;is hi;x:quivaknt lo lh«
Rdn<::1Ke i'<>rn1ubli<'ll in iht [HC.->ern.x uf a high-fol m;;aL
37
Nov. 20, 2003
[OJ13J !n cnm:luxirni, the r;t1<:: uf guaifon1;;xi.n .-,h.•in abrnplinri i:~ biu,,-qut;··;iler1l !u thi~ Rdcrrnce formuh1-
tilm ifl the prt~t'.m:e nC ;i hi""h"fat mtfphan W3.s <:(•i11par<.:d \i:> rdi:rvnn: gn..: 6 liour,; fatl.'..r ["fr~atmrn! C], ·while
tbe: oihcr half r<.:ccivctl '.W mg d1:xtrnm<.:ch0rpban ;.~very LJ
tJUUfS !i>r lhn:l~ dn-.ex [Trea!menl DH with 24{) ml nf'A·al<;r,
afler rn O'lernight fosl. (imup 4 n~e<:.iv.;;;J :i,o mg of deK 0
lromdhorphan bydrohwm!dc in a rducni.:;: immcdi;lle-
rcluu.,,;: liq11id fonmilalbn a1.:;;·ordin!!, !n 2 difkr.:n! de:;;ing
[tgimes {on<: half ul flit'. volm1Jte[s n:c,,-i·,•eu J5 mg uf
dexlmrnethnrrhm1.,1l10rµhm1 1;vny 4 lwur,; E)f !!ll"<."-~ do'il.::> [Tn.:;;tmctJ! F]I
\Vitb 240 rnL (•f ''':ilu. nf!,;r all ov•Anigtll fa;;t. Thc>:';c «llhJC<:I:~
that received ]0 mg dex!mmethmphJn hydmhmmide in ilflt
lH:almtrll rx:nud n:•:eivtd 15 mg dex1.rnmtthcirplrnn m
;rnolher !r•,;;nl mcm p<.0riod; ;;!mibdy, ili,1sc I hat rci:i:iv<.0d 20
rng J1:x!romdllnt"pl:rn11 in ooc !r.::Mm0m peri,>d Kcdv<.~d tO
mg dn:lr•.Jmc1tiorplrnn in« sub~q11<.:nl treatmrnl. P'~riod. hi
th ix exp~'nrn<:enl 1.h<:rt w;i:-; ;i l ,J,day washmil lid w·eni do>.es.
[0316] Blood {7 ml, sodium hq,Mit1 dlll.ico3_;;,ilm1l) w.t;;
ubMined al !be fo!k>wing limt·.~: Pr<:-duse. il.'.\ 0.7:\ L 1.:i,
?., . .,_ .:1, 5, 6, 7, ti, ·:_i, lO. JI, ) 2, l.:1, JtL, .'4. ·.>6, ..JR, 7!. ;imJ
')(, llour~. po;;t do~c (tll<.: !uttl bloocl !n>f' for g;irnifone.;;in mid
dcx!rurn'J!horph gi~·..,n 1200 rngofi;.uBifoncsrn :ts Mut:incx
(rd<.:n:ncc, Trca1mrlll B) r<.:achf 1145
ngimL in () 9 boms and h~u a rm;;,r1 AUC;,,,- 8'i'i3 hr-ng_'
mL. Sub1~,:I!; _l.,';iV<:n L?.0{) mg _;;u;iffcnesifl ;J:-; ;m nrnimenl:1 crn1raini1Jg (10 mg (k:\Jwrr1-drmrph:rn
hydrobromiCh<.~d a m(:,Hl tkli:!r01ll<.:1lJorpl:Ja11 C"'"x of 4711 pg'rnl jo
<'! .1 hrnm; rnd !nd a nk:trl t\UC"'' or i>2655 l:Jr·rg mi ..
S1ihj.;;Us giv-cn (A) mg tl-cxtmmdhi>fJJhan hvdmhmmid". as
.~o mg ever,· ~ hmw; (Tn:i1Jm,;n\ D) n:~tched a mean tkx-
tromd!iorprrn1i C,,,," o[' 334:1 pg:ml.. .in 7 hours nnd li;1d :1
m<.:an AUC,"r ut' -·l4(j8J hqig:mL. 5ubi·~·::1s giv<.:n JO mg
dnlr·::>rn-~I tiorplrnu llvdmbromidc 3.s J.5 mg ;;v<.:rv (:. boors
(Tn:almt:nl E) reat:h-cd a mt::on dn:1r;imdhorph;rn C""'' d.
.?.l:-lO rg/mi. in r: hmm; aml h;i.d a rrn;:m AUC;,,, nf 40T!4
hr-rg'mL Suhjed;; .~ivrn .]{) mg dexlrnmdhurrh;m hydri>·
hrnmi<.k i1s JO mg ~V<.:ty 4 hours (Treatment F) rc3dJ<.:d 3
m<.:afl d·~Xtr1>rncdmrphan C""''· •.Ji.' J.2Jk• p,;:ml. in 7.7 hour:>
3ml bml :o m;;3n /\UC;,,,- of 20U·i hq:-,;:mL
[1JJ29] The 1ib,.:.rn;; G>rit:enlr:1linn:-, 1.if g.uciiknesin i:-, ;.,fJ:ds givrn 12.G{l mg of gtw[fcn-
vsin R> Mucincx (Tn:atmrn1 B) n:;wbtd ;1 1w:~.n Coax of
?.l45:0c.9<.l7 ng:mi. (Me:m:0c.Sl;.i.mbnl Deviafom_l in O.'Jl:d)..'l
hnuL~ aod bad an .Al.IC;,,r or 895}±..J?.7.J hr-n.i;/m! .. Suhj~ds
giyen 1200 mg guaifrm:sin .1s an .;;xpaim<'n!al fi.,rn1iJl.ilion
T.t±K.? 71!1} of lh;;t or Mu.,:inex) f 1lrn1 of
M!lctocx). The';~ datil [mfo:a1c th3.t ill·~ pli;irnrncoki.n•:l ic~ of
:,",ti"il'-.·n"sin nn: ;wt nlf.;:.:.::Kd by th<.: pi<::>.C!K'<-' of ;.kxtr0mc1hc.-
rrhao.
TAJlLE 5\1
{~Lt:iirr..:1;~~i1~ P!1ar;n:it:CJUr~r..:~i...:: P<1r:if!~t:~..-::-n, t'·-~!!1: .. '!,vi;1g
th~· Admi~\~S.lc:~l~C't~ nf -~ >11) '"t;'. G~i~;-~C.::.:-H:-s.i~ ,,'!d.~[:J;~
•'-.CCi..__, P,i_;('i!I~
Ca~:~"'·- ~-rfl,lX 1.br ·' (f, .. , H;;::· We
(r.~:m~.) (ho:-i ri~.'ml .) !l:?."mf_) (on
:u: .. i.11 ~?l't ~:~!(d L'J
18.'li ;5t; 75!fl 1734 ll)N
3.?-:)~ [).{,! 47',j --P,;;.:;; J ...
=:_:;;7_1:; tLJ: :-.:55 :..;54 il.2U
{1r/JJ7 4~~-~..;N 545:: _:;4_=1 H5.~~!
TAHlJ:: 'ii
( ill<1"ifr:r: ::.,.,in ~::.~;~r~;.)D::kir.c~ !~: Pt~no;-;-;(~~cr~ ~,.;;~~ •:·\'·-'i!l~
l~·r...: AJu1jf,·:x.tra\i·:1f• ·A ~.:'fl() mi. Ci: .. :x°C1,.:.!x>;l1~ ~~ ~~.ru
997 q_5~: .l:1·}o.-t ~~12 -1 .. ~:~
{~C·uinii:c-~
(I ~r)
j :Ill
!55
'i}.~i ".
~ r:..:il
5:.5~)
C'!.::~;i i~ r:.~~.:
(1 hr)
3·;1
JJ(.
9ci .. 2~,
38
St•1•,ihrn
!'.ffY•f
•;-cv
[OJJ1j
Nov, 20, 2003
TABLE 5 l-i:omim1cd
( •1..ni !l:.:-~<..s.ici Fri;~fV·~:..c~~::i f1::.:-lic F;~•J.mt-'H.:fa ;..;.Ji ic"'<';"~
~1lt r\-:~r1i.l1~~:::,~!':1l~n1~ .Jf .l:'.(!-:J mg (~l'<~ik:~.;;-'='~~1 :;-don~
~o :-..;~-:ml;il \-i:_·,;un~cF~ ... T1c;ilrrn~f"(~ B
or 'o:o•rih I r:~<1x
(r,~:mu (h,·:
.•\CC'I H Al 'C;.,~
(hr ~ (er •
ng/mU ag·'l~~Li
T . \B!.t: 5:?
!Mllil'c
U11)
( ··:r:;\w i11X~
il:IH)
5S .. l7
r~~I_; .. ,:-. 1.::·f \h~ (,'..~i.~~fo;;:!l~;-;.jn Ph.f~rr..~;1•:::,iki11~fr~· P~tr;~f\~,~~~i:-.
~o:ic,~..-tr~g ~~·-L ;\,_1,-nlni:..U;!l;nn ... -:-!' I :U~l m~ firniifr:~o:..:-.i~1 ii: ar~
Expc:lirn-:-:1~;,il T.;~h!,o;~~ ~dnr.g .._._,it!1 6~J m~, O(:X~1n1llt.~h~-:-q:1!~~;1
H'";;fr;:.hrc,midc ( ·nmp;ncd In (;~!_,i:'.:::ric:-,)n /\j.:~'l:: {'~()
:~;i.1bj"i::1,~t C•!!~X Tff~<"o; /\eC 1H Al'C;1~i 11;111' Lek (')i::at~~ .. H~c:
"'1·:'.5
f )r..:' ·i ti~. j~~!l
\t;~.'1d~11·.J S.41, lS .. ~ II 4 :".: 4.4.~ 7.J:, 4.!~~~
[jrc~
L\:. :.:·v ~~) .. ~~ 4b .. 'I ~~-~,4 ~..:. .. •7 h!.~3 ::3_;;1:
[O:U2] Th" plasm:i con,~·~ntr3tions of d.ox1mmcthorpb:m ii;
-;bowu in HG. 34. Tb·~ rtsul1ing pllarmacokin·~li-.; darn (;;
;;hnwn in [;ihli:ii 5} through (J l. Suhjeds give fl 60 m:~
dextmrnethnfrl-Em hydmhmmide as an ,;xpefimerila! fmm11·
lmion ;ibc• i::onl21inirn; !200 mg gu.:likncsrn (Trcatmrnl A}
rc3d1•;d a m<:;lll dcxtromcthorphinl C,m ... of :Jti'.l-1 :t61K1
pg,·rnL in '-i.U6.;:0.93 [l'.iut-,, and lrnd an ALIC,"' uf
6X1ti[:t:llZ906 tH 0 pgirnL Sl!bJl.'.Cts gJven 60 rng de>>
trt>mtlborp[rna bydrnbmmid<..' as 30 m::; every 6 lmtirs {Tn:al-
m"nt C) rci1>::llcd :< rnc:m dc:'/i x4'1.44'X. of lb;1! t>f Tn:al-
m,;m ;\_l Suhje.:1.~ given 60 mg dt::-J.'T:o:.'.l7.0G'l of tba! of iti-.; rdcrc1K1.'.) in 7.0i:tL93
hrnirs {X(I 02':f.t?.?.K1Sf. uf 1ha1 ur Tr-c;ilment A) ;rnd h;;d 15 mg twry (1 hour-; (Trratm<.:iH E.} f<;a::hnl a t·w:.rn
dexlmrnutiorphan C""'' of 2 l80x26SO pg·rn! {'i3.89')'
.;:17.6?.-'lf .. of lhill o( Treatrneol C) in K.\n:t2.'i2 hnt1r.~
{'Hi.l~'7.,:t24.8tl'ii of1i:Jal ofTr<.:J.!mull C} 3.lld lJ3d an AlJCiof
of 41B14:t62644 hr~pg/mL iS 1.73'/i.:o:l(i.77'!\, ,,f ih.-t l 'i;,."J: l ? .. 8.?·~{ ofltiill nfTrealmnil D} in 7 7'.h::?.4} hour-;
(1-"1-2.42··;; :;:G7.!:i1Y;.; of ilrnl of Trc,~!mu11 D) aml had ;;n
Al.IC,,, ot 6945:d6I58 llr-p~'/mL (:H32':t :tl6.37'!i o! lhM
ol -·fo:a1111l'.nf D). Thc,;,c darn .';t1g;;;~:f:t 1.hs! ill<.: plwrnrn<:oki-
m:ti'~' of d<.'.:>::lrumc! !mrplrn n an.' l im.'m ov.;; ilK rnng" e;l_ udkd
j)_·1.·l;Hi·.J~
S~lw~l-Lr~r~ T!·-:..-;i~i~:c.;f•l C
:i.-kr~ ~1
\1.:::fforn
S~1~r.d)!V
rx .. -. jd~i:::>:~
:;~ l..'.rl (Um
; <.' '.''~41)
l1 -k~ ~ -;3s
7,;;,9B
i.h~xlioi;.xihorplK~!! PJ1,i1i~·i:.--:.c-·:·ki1~e\i·: Par,1CV
f"f!.~<~};
(p~.'mf.)
T~<;•f.i
lh;f
Ii f .::' c: (:;I l'l~ ~H.~(~
(~n (1.-liri
"N:~ <' rn; ! .:::9.t~J Pd 7H :l'.1 '35 =:~en
9(n. : .. u ~c~~.: l·')l~?i :'.n.? ?,??4
T.'\m r :>8
l"b~!D of Oextrcm-:thccph,.-.!I f'h~rma·~Dki:~.;;-t~i.: P3camr.~t;·:'..
Folk:•','l,"ir1g ~b!_'- i\b~f:
Hydt·nbr,.-:01'1.i~di:: :;~s TH~I~~~nf:~~ A Comp~1.tcJ :v T\;'c- D-1.~~:-.s ·~.if J<) ~7~g
Si;.:: l-{;:.1sr;-. /~pC1;!!1 P~·;•g
__________ f_~·'.:"}_'~-~f_l?_L_l~~-br~~~-_(~~~~-'3~3~~~-C!-~--~?_i_~~~-';i_l~'-!~f_;~:~~i_:{l!~~~~~~-;~~~~-~!:_ _________ _
\ko;1
?-.. kiJ;·ai~
~1,,.,,hrJ
De:~.·~~1~i(:i1
3~)[:1.~~j (:n.~)2 ~:~.~_l_j ~.~. ]} ;(i},,~~:
~~~.~J:_~. ~<~_33 l?Jo..:i '?"i'.t~-! 1()1.11.:.'.
37.(){1 ~~-~J. ::J __ ;i..,I ~~-(_i3 j,';_ 7 !
l''~·'"'
J ::.··tt·5
~..H".f'.~e~~hi:.;rpku~
H:·,Jwb.-.:-.;nid~~ ti,_, T•.::::~Lm.:::ril A t nr:~r,- 3"m,ix fl.,~-"{ ,, , r\l.;(''i:I• fl: Ball L:fo ( k,11~••l1..):':'
'.vie~" 5J,-t{~l ·~~u.02'! _";.;_3:\ ) 1.-n 1)6_J._:<, ::'?~.:)4
~nJi:m -" ';) l<~l.(;I! S(Lf'O "!l ,,.i !lb . .::') ' j.) (_lO
0l(~~Ad'.l1•J ~ ~:.b:. :~-L'.~ iu;-1 [().7? H.'f< I ~··~~ ,:.J~
Dn ia~l~-10)
SG~f·~bid :~.ss tk~~ -i.Jo ~.:;:; _,,,.,, l·1.-!._';
Erco:
··;., CV :;:'. iii ~:'i_g() -'~'._1!U .~ ~' 'l.' I'. l'I ~·. : . ,,-
rph<.Jbjix\ o~n-l.1hd, single-dos;.:, :;;.ndornizcd,
-1~w;3y~lTOS .. ~}Vef ~lBdy.
[03+4] Th<: sub1et:t:; wcrc r;mdnmi,-.cd ;md plat:t:d inlc, mk
uf llm.:-e fr>.:almcrll gwnp". Grnup l fCc1:ivcd :i 1200-mg
40
Nov, 20, 2003
conlrulkd-rt.k<\'ie g1J3.ifon~sin prodm.:l {M1Ki.nt:x/ plus 60
1ng, of d.;:x!nm1dborphan hydrnbrumid<.: fadmini:"ln"<.'d '"' 30
mg <.'.'-'•:ry 6 llot1rs}, '
trome1borphan hyd1."hrnm1.d;; (adrnini:>l<..'.rsxl ,1s 20 mg '-'v'-'fY
4 hours}, \\lilb 240 mL o!' w:ih:r 3flcr an t
{Rcfon:nccj. Gmup 3 r1.'<.~<.~ivcd Rll <.~xpr:rirncm.r.! lS ;1
14-d&y W3SOOlJl b<.~l\li<.'<..'Jl do;;,;;;,
[tl34Sj Blood {7 mL. s-.ldi11rn hcpMiu nntkoagu lanl) w3s
nb1aill.:•d icl lb<.: fo!lmving !im.:s: Pr·.;-dc1s1.:, 0.5, (L 75, L L5,
:::, :~, 4, 45, 4J">, '}, 5.5, 6, 6.:", (:. "/'.\ 7, 75, 8, 9, !O, j 1, !2,
l4, If\ 24, 36, 48, 7.7 3.ml 96 ho1m; po~;l do:;-~ (the lolal blond
k:·:is fur gu;Hfr;ne~~n ;;nd J~;drorritlhur _ph;~n lH3aJy~~3f.; ·was. 609
rnL_l Suhj1::ds giv1;n 12(10 mg of gu,1lfrncsin ns Mucino:,
a lung '>'it!b Ml rng, dcxtrmn"1borptiM1 hydrohromid~ as two
}0-mg d<•s-t:s 6 hnurs aparl (Trt::itll 60 mg d<:xlmmt:!h(;rphan hydmhmmidc 3s _10 m:.,:
Vi;;k's Fonrn;L1 "14 Cough M<:di-.:im: •x·e!ld 30-rn;;
d('.:;lmrn•.,1tiorph2i1 hy.Jr,_;broarnk: ;,hi_-;.-~ {J ti..Jur:~ bl<::r {Tr<.:al-
m<:m /\, Rcfor;.;nc<:}, r<::oched a mt:mi ph:in e '1
l1t1i1rs ilf1cr t!u1 (Tr•' 3.ml h;1d ;rn ;\UC"' 1- nt' 7:0B6t)i1 I (1
hr-ng :;ivcn 11ilO mg of guhifrnt>ill a:'
Mll('i11<:x, a!on;; wiib 60 mg do:tn.>im:1llorp!rnn hydwbw-
rnid(.: "" 1tir<.:<.0 :20-mg doN::s ,1 llnm., apMl (Tr~hlm;.;n! B,
Rd<.:n::n~cc), r;;;;..:h<:d ;i mean pfa;;m?, guaifont:sin C""' uf
1 '?S'.h80~ ng/rni. in J _27:dl.833 hnnrs ;wd kid ;HI 1\Ui. ·;..,-of
US 2003/0215508 Al
76 l<\:0:3.'l'ni hr-r:g/m! ... Subj;;,:;,; "'ivc:.1kir.C!:.i.._· Prii ~r:.~t:i.-.:-r:=.. Po!! C\');~'1-g
lh~ ,-\dwifl~:O-:.l<::Hi<.:1f~ ·:·!" i .)JO !1~~ (:i',.~,ri~ffiit:srn
~.s :,,.~~ii~···~::x :~:.:n•g ;o;.·i~l-: '.~(; :n,µ ikx.l;omc:t.1,,rp~;~u ~~-\·dn)hmmi.:.k:
i:.~- _~H ·Hg Vt..:k~::, l~arm~:L· -!-1 Ccu:;1 .\i~:>::h.c~:1.c )ftci ~1 Se..:~11xl )~1- ing
!kxtrca10)K;i1>b~f· {fycimhrcmjJ!_'- l}oH_:: :"~ Hu~~·',
\~c~~(;
At~c·i· i
fhr'
ng.':nU
i\("(\1:
th.:·'
i1&-'fnL)
TAJlLE 61
r1:::' ;cro
(:ir1
t>~1)~fo1~ e·'"i 1~ P!1at·ar~r:cb!~i;;~lC P;--1j ;ifi_~c~eJ':: F·:·ll 1.:·'':';ng
~he .'\Jmi1~;H~·:ni~11; ol' i2tm ;1;g (j~::.:k:r1•..::.lr1
< '!it;1:~r:.~:;-,:Â
(L :ir:
:~:--. ~•Jei-:-t.::--. '1:ol"'.g .,..,i:~ i:.r) "'.t:J; ~ k~>.lo:-·::••nr:~l-:crph-lf'l Hy.Jwt-•,·::••nldc
J:. 2U rn[:.. Viet·~, f,_:~ :1H1k1 H ('.x:~h \t~:di.._, iii.-:.. ;~ s~c·~l~·J .)~- :ng
lX::·:~Y\)f!~-n:mrph:rn H;,·ffrnfi:"\"!r:~id.:.: Dos.-..: ~1 Hom::;. L.;w.;r r1r:{I t~ ; ;?ird
.2il-mg [kx.tr1..:·ineth.:i,1:tt·M": ih'~J!··:·hmmide D-:~.c -~ h•Jlli~ ,~fl-=r T!VJ.j \o:i
'.'\;J: inr1I V.:..J:11sH::-:,,;;~ - T1·c:r1~r.~c'1<( B H~::-;fi:::~.e;~\..-,o;~r
\i~~~:1
\1nforn
~.;s,<-li:J,!r.J.
r.x:. ,_, ;~1.~ t-~~; ~
::-;~,~o:od:~r-.J
i:r ~~=· !'
·> C"V
[034\1]
Tma;:._
(hn
in
l I~;
qj-{\:J;
Al'Ci•-i
(!ir,
ri~'"'~-)
45.:
A(·r-1_.,~·
I.I"'
"g.'ml)
TAllLl M
tfa:c lik
(hrl
\I i r.i i>h:1.r~;~1;ckir.<;: ).;: Pt~fi~r.•r:~crf>. ~;,,:.II 1:•\'-'Cr!fi
~he _.\Jmini',s.~afrJr:. m· L)JU m;? (-<~•:1~frsv;:si1·1
l'i :·
-l ! .. ~
;;_:.i":.~1g ... ..,~tC-i ~,n :ng D<::xtienH:'i~J·:"J!V;~~;_:.~ Uyd:\:-~~1· .. )ml~k i~1 r~:~
I 'r,r::rir:~cilol?.! hi~"i1l1Jl~Hin1o :o:. '.'"+~ornrnl ,.,.b!u-:-tlo:.r:li"i. - !"r.-:.::~lm·-:.:n: C (H:~l I
~i..:!-:-t
\~·..:Uia~
;:)l<1~1rfacd
l)-:.:\·ia~i~-1"
lrro:
'··.'·CV
C:n:~-<
r"r:.g."ml;
:·1m
·rrf~-lX
(h~ j
t\ l "{ ·~-\
{br •
~ig.'!HJ.)
i\t-C'1;11
(I,,,
i1g.'r1.iLJ
1fa::' 1ik
(:1<1
1.:r~
u;s
fl Sill
n.'~;f?
{~CL11nii:L-'"'~
(1.:l"i
41
Nov, 20, 2003
[0350) The rl:ism:t n>rn:rn!ratinm, or <.kJdrnm10l!iorph:rn
;lf·~ shown in flG •• %. The rcsiil.: <) [wur~ ]111cr 3.nd 3 ohird 20-mg dc;.;,tf(lll)c[!Jofj)!i;rn
llydrobromidc dose 1l IKHlrs alkr ih:u (fr<.:amidc, alollg with ! :::on mg gtnikn -
..:sin ill an :;xpnirn<.•nt;,! fornrnlmit>n (Tt'l:.'link,nt C Tv~t),
n:ad1;.;d 1 HK';rn p!J.~ma d<:X!mrr1dbOrj!lJan ('""" uf
74<'!".h!IJ.'2 pgimL ill (: •. J(f:t?..M hours ;111d bad ari ALIC;,, 1
of 3165>n:?: 7')(1975 br-pgiml
Oexl~·amo,h=.:i~pr.~j~ f>h,~;·1}},a.;..~okin~t,•: f'~i.r:.m~te~·s E~ollo'J.'i~1~
lb!.' i\J rff• '"' ;~w1 l i~-~ ·1 ,_, f J =:'Of) "'H ~ { ; tu! f._..1K-,,, i 1;
t~,~, ~,_..,:ir:c}; ..-\lorig i,i;,I~ (•() m.:; ! kr,i••:••m:Lh 0:'1~'"p~<~-:-t !-~~,.,J,._,-,:-.fi"?"i1li:k
1"•'., Jn mf. "'!i.;k'$ Fon:-...~cL~ -~ci Cm~gt: ,\1-cJi .. ~i.ri.; .:u~J ,:-~ ~;e,.:o;-...J JH- mg
!)exlro•r1•..:l!1o;pf~:~:"? Hy:.lr~~rn;'.;lC1~~·11:!,~a
Hyd~·.,.._1rc•.'i~"'!.~d.:.' ;1:--i Xi m~ Vii.:k's r-,_~1·;Ht1!~1 ~ C\J\•gh Mc.;:.:ii.:;1~f:. tMd ;:
S.::12cno..\ ""}~1-r("~~ ~:.t::x:.mm•2:l-:crr~v'"i1 Hydr~;hrnr.•·•k !k1,~.c ,.~ M"1·1._.r;.-,
Lal~i :H'i_d •i Third .::o-m~ ['x.::x~ff_1fi_~e~lwt·ph.11~ !]p)!··=·~.''i\:Or.~itfr
l°X)S.-t' ,~ Ifo~~!~ ,.J.Jc . .;:~ Th:1t :,_, '\:,-,1111;1[
:vk""
~..:d~oi1;
')i;:nd;.1r.J
lk1:,m!ori
3-u,;~J:lrd
E1J'I)!
,~.r (.\/
\'cl\wlecr~ - ·~."~c"l""·r~r:l I~ (Et~~'::rcn~:ci
{'i-,-•:!il!'1'l..:.~~1l c rn··~n
/\LC,r '
1\l-Ci, 1: Hoi!f
c.n;:}i. TJmi; (I,,· (I',. • I ifc Cl<:ci ""' ~"
~;~ihj.::;:t u-·~~:m~ .; (ho pg.:mC.1 ::·~.'mll t~~! U:~1;
'>k"" HK.' '.~. :..:; -~jJ.!')f) :-.!f,:"9=· ! '?J~ : i."i.t.i
~de(il-)l~ 2S.Si.i :_:,~,o ~-UY.I ~~9.SJ ,-:;.~-~ 1 ?•)D
Sl;~f·dar CV !65 4:.f~) :·,?n
[UJ5J] (h.:x1wrt1Uh<'!Vh~n hydwhro1nid~ 1:> widdy ret(>g-
ni7.t:tl as ;i highly -_.-;iri;;hlt: drug 2tmJ I hudi1re one c. a;.,
hioequi.v,ilent r;tlh~r th;rn lhc ch'-':>1c1[ ~:l,)'.4- lu l 7.S<;f. [n
;.xiw:l!1s1on, guaikn<.,sin in the 1:xpcrimu1rnl tabk1 i:o dearly
h.~(>quivalrnl h: 1!w1 of ihc Hd<.:rem>~, Mllc:imx. in l.<.:rn;,; nf
c·,.;:.x~ 1\L!( ·:J __ , or ~1.;._UC';) 1 r J.."1 th'-~ 9lFX·. v.:-nHdt:rio:e jntt:rv~cch~ a~c
all i:nrH;nm:d wilhin :'l{)~i lo l2'i'C1(.. D<::x!rmndhnrph;;n
bydrobromid<0 hi t!w c:qwrimn1t;,l rnbkt •.:an lxo consickr·.;d
hioqu[v,ilrnl ro bnth :~{) m~~ dcx(rumdbotphan hydrohm-
mick vvr:ry G hours, and :.W mg <:vvry 4 huurs, in term'> of
c .. ,,.~, Ali(·~--· c-r AUC;,,r as tb-c WVi( •:onlidl.'.un: inlcrvab mt.:
nlnlrnrnpk 20
[0354 J Tn dtlcrmim: the reb!ivt: hm;;vail;ihility high
f~I m-c;1J \Va'.' l"'lfflfME'.:J [p fc-Jk:-wirig 3.fl mnnigbl fa.;.,! in
11mrnal vulunkern ;m np<::n bb<-L :-;ingk du.'-<:, rnndnrniJ'.cJ,
1-w:iy ernsstw(:r f'liJdy <,v.:ts Gonduu<.:d in J6 subj~cts.
[iH.551 Th<- "rnli_i<:cb .,,·ere r;,wfomit:nl ar1u phccd int" ;;11c
or ;wo trcatm<.:lll gniups. Tr·~:11mcn1 A received a J.2(10 rng
guaikn1.o,in ~nd Gfl mg tkx1romr:ilmrptrn11 llydrohrornid<.'
·wi11J 140 rnL oJ' wakr aft>'.! ;m uvernii,;bl fa"l (Rder<.:ricc}_
Treatrn;:n! B tcc;oivcd '' !200 mg gi.rnifom:sin and d.:x-
lrnmdhorphan hydrnhmmidc •.~xperimcnlal lahkl wilh 240
ml of whc·lll. be!wten do&:.~.
[ill561 B!-:x>d (7 mL, wdium h<:pHin ~nlicc-11 2;1.dzrnr) 'N~s
nhl:iim:d ;ii the roHuwing lirr-,;:t>: Pr,;-dn:<<.:, 0 S, 0.7'i, 'J, ! .5.,
.?, _\ '1, :1, fl, X, to, 12, 1'1, [6, 2'1, ~~11, '1X, 72 20nd 96 lmur:;
po-;! dn'K (lb;: !ul~l blm1u lus.'-' (llr 1,p1aii"l.'.ri~:-;in ;rnd tkx-
1rome1.ll,xphin and 60 mg
dextrom<.:thorptrnn llydmbromitk following \tic 1:onm1mp-
1ion uf ;; high Lil mc3[ (Tri::3lmcrlt B, 'lbt} reached ;; me3D
C,.,.," '"r 182'.'i n~/ml _ {9S.O~i -')3 llr-ng_.-'ml (91.'l'::f d llnt of Tn:a1rm:nf A;.
l:ilJ57 j Suhjed-; given hO mg de:<:lrnmdhnrph:rn hydmhr<1-
mid;; rnd J 100 Ill!;. ~;<11nkno.;,:,iu in '111 o.;: hour:, ;rnd bad umplion cc·f ~ bigb fa! meat (Tn:almrnl R 'fos1) n::adJt:d a
mt';m do;!rnmdh1irphan ('""'~ uf J .?7S7 pg/mi_ (I ~s2'/i. uf
1.hal of T;e,1tmcril :\)in 5.74 lirnm, (HH'X, ut- tbal of ·rn~alÂ
mu1t <\}and had Ml AUC;,,,-of ,17106-1 br-p~imL (1.17'11. ot
t!ut ,_if Tr..:illlll!:i1t A)
i:ins1q Tht pk11l!ing pbarnrncok1m:1ic data i<. sho'Nll w
Tabks 68 lbrm1g.h 70. Subj,;ch gjv,;n I200 mg. (,f gu,'liti.:H-
c"w ar1u 60 mg dcxtnimelhc-rp!rnn hyumhmmiJt in an
<::xp-;;rimwlal liirm1ila!ion 1(-.Jlnwirig ;m nvemighl f?,:>I ffr<::al-
rnrnt :"., R·.;ftn:n<:e) f<.'HCllcd ,, lll!;3[] l',,,,-c or .2U30ztlfQ_
ug;mL (Memi:tSrnmfard i);;vi"1inn) iu J .6 I:d .. l5 hoim; ;md
liad mi AUC;.,r of 8 l 28:t~'497 lir-ng/rn L. Subjects given 12(Kt
mg of guatf,cncsiri and 60 mg (kxlmmt·tbmphart byJmbw-
midt in an Experimtri!al fornn1b1inn ;i.fo:r the L'i'n,;ump!frm
n( :thigh fat rw~.al lTrvatm<.:nl B, TL«!) rc;id1nl 3 mum C,.-,""
of 1825:;: 7[~·::1 n:;/mL (98 .W:{:i::40.Jt1< uf !!Ml ,,f Tru111w;nt A}
in 2.9:.\i:l .44 buw;., {:".:J.w.:-r.d6,1'X of !h;,l n( Trt:.;'() m.b !k.;_~r!~··n~lb•:i"•f1~·•~a HyiJri.~hm1~1lJc /\f~!_'-l l~·.i: (-~~·1:-.u•np~i._m
of ~I n~sl1 f;il \k,i.l C(JH!;"dl'cx: :o ;j~;il
l•o! !c:l.·i01l! :rn r: h;e-:-n~.rra hfii {'":.: )
Suh.i.-:~-t c.n;:li. TJmi; AL-C'b;-l At'C'!~)l <:.1r:IY Ck:1~,~~1i,;-~;
\kaa 9~~-1~ ~,_}N ~c .. (J ')~_~) 1~t __ .:... I j,_}
\~\:.tii;rn ~~J_H :'.'>II ;'<;~_~.~ ge,_:r, "f1-; 5 n.:.:
Std. !),,v, -t;J.J h:J ' ~~~:; :_:~.t.l1 l'-'.-i 2{;.~
SlJ. E1L j)_i)2 2lU -t_i)7 ~J15 ' _ _<;_':<. .:1J.1f) ··;;.. CV '!J.I (' ~)J .~ :CS.c• .?S.--!- .-c+A :J.5
[ill6l_J The pLi.srna con~'\~ntn11ion:3 »f do:twrnc1J10rplrnu i'>
f'.llO\VO in MG, 38. T!K rcstiHing phMm;:o...:llkincl.i;.; cfai_l<:t:b given 60 mg t'kx-
!mm<::l.hnrjlh.5S hours :tnd h~.d f·H::d V0lur1~.~-:;~c~
t•.~,,: :1:0\1..·C :~t.? ;~;;--; {h·cccig~·I. Fi~t - ·c·r•::i~r:x •ll /\ ( R·-:.: 1·,~P.:ci ... e I
i\l'C~ 1 '
Al"Ci..o 1 ~· lfali
Ca~:~-'- ~-rf~,1x (11• ·' '·"' ·' lilc {~Cc~inii:c.~ r":~~,'i!!l.; {hi~ 11~.mL) ::.g,·1~·iL1 (h:·: IL::.,,
hlT'.='. ~- :~~~ =1t'?h':'t"i ~i.:~~-1.:;, ! ~~ ~).X ~: ~{.~ ~
AJ2:; (>,I) 33:;'0 ~q ~3~- 8.~~ J2~i
:-;td. !),,,·, ;5.:}(•(; J,:;.; 7533 ~7 ·~·~?'.":fl~ !.?.:..; J,~5.~
~;ld. l'.rr ='. i'. 2-~~ O.i"~~l) 1::<1i<'•ll l<>'HI~ " I;
.... ,. i"V J-F; 5"1.0 2r]~ :c r)~. ·7 l-L'
Ti\Hl t 7,'!
~)>::x~ !'~) 1~~(;~ 1~,, ~ 1 , 1"1;1.1~ rc"t;".11· ·~ ~:r:,.:i:_, k J. i~· ti.... r :1 ~ ~1 Ii~(!: . .:.:-J ~-
~· 1-:-·~~n·.,, ..... icig. :.h.:: /\dmi;r;•~tr;ltic11o ·~,,f ~-i~) ilcg !)exlmm.:.l~~!-:-ph~·-"
flyJ,Db~o~iJld·::: ~••K; L~~:iq !"'!.~~ (t: .. :;~~r.;;i1t~:;.11~ ti..., ~o; mri! \~:..:liH'!~c:cj:-; .4~~.i::-;
~~c ~ '.·1~?..-1!r::::l:e11 nf :~ Ehg~ ;:.·,!~ /vh.:;1; - ro:-ci~mr;)I c; fH:.s.H
el,{T,H l·.C{'i~.; [folf
r·OJo~•!X J rn::i.~ (I~;
,- {~; ' lil'c ( ·k~~r..~r.r.:r
Sl1b.i·-·~L (r-·g·m~.:: (I'" pg/;11; l ~".!'g.'m1 I \I::; lL ·:1r)
).b::\ ; ::7:;\! ry, ·'''l , .. ;· 1 -l-7.)~(r~ !,\.~ :'.?-t{)
\~:x[~;m -~·~?(": -~-/~. !5 -~"h*fk ? . .::-g I IN
~ed. [1'C\', i ~'~) J ..} : .. ~7 },~,~-~-+') 9 )}4'"' 13. ~~- -~1}:}'.~
:,;td. lt<. 30:'.~ o .. x~ ... ~ 12?L~2:2 ~ {;~.2~5 - 3 -~~i l
~·.,:, CV 14('• 3{)_(} I'~·~ :!17 ~::-g 5 12'!
43
Nov, 20, 2003
TABLE 7J
Ifa:i.n nf Dt:dl'Glm:thG~:)kH1 Ph1~: m:1~~nti;~!:"li.e ri~~;ll!W~-t'."•'.:Â
Folk--1;;~!1~ ~he s\th~:~i1~i 1 ·H\1~i.c:-1~ :;:if in from tlic <.:xpciimcnt;tl rnhkt. Tbac [,;an
dfod or food on !he rnlc of C:•Jnd11~'kd in :;,0 :>vby:<.~K
[il3Mi I The. ">llhi·xls wrn.: r3udomiznl 3.nd pln·~m prndm:l (Mm:in<::KJ plus 60
mg OJ' dCX!nHlldborptmn hydwboumidc (:tJrnini~t<;r•~d ~S 30
mg ~very 6 hoim,) wifh 240 mL of '''lll<:r a!k:t an ovcrnighl
LN, ''l.mJ :.tg:iin t::> hour.-; btn rm ll lv-·dvc-h('.Uf dt,>.iflg
ptric.Js (Ta:alrm:nl J\, RdcrulCI.:). {imllp Z r{;t:t:ivt:d a 1200·
mg conlrolkd-Kka:;i; guaifom~sin prnducl (Muein1:x) plu,:;
60 mg of d<.:x!wm•'.lborplian hydrobmmitk (adrnini:>ttred ,'!.;;
20 mg ~:vny .j !wui:;} with :,:.10 m! of w~ta ;if!n ;m
u·ing ~>~:riod'> (Tn.oa1mcm B, R,.;krnn<.'-') (iruup C\ f<.~<.:dvsxl
1). Tti~.rc was n H-d~y wa~llmit l'·~lw'-'rn doss;s,
[031.il] Blood {7 ml, sodium !Jq..,Min anl.icG3,;;:1folll) w.<,:;
obtainl.'d al lb<.~ followins i.imcs: D~y l Pr(:-AJ.,f d;:isc:, Dily '1
Pn::"/\M dose :md lhv S Pre-/\M d;i,;1; for 20ll thre" lro;;;;Jm.;;nl
gm1Jps. 011 Day 6 Tr;::atme111 /\ 0>t1biet:t:> w<:re hkd ;,J
h;-[}Jsc, 0,5, 0.75, L J .5, 2. 3, 'I,:\ 6, 6.5. 6.7S, 7,7.5, 8.
'.\JO, H, J.2, I'l, 16, 24. 16. '18, 72, and 96 ho1ir;, post doS<.:.
rrcalmc;nl B subjccb wnc bkd a!: Pr,;.dnsc, (h, 0.7'i, l.
l .'i, ,?., _\ '1, 4.5., 4 7'>. 5, SS, 6, 7, !>, R.S, 8.75, 'l, (.i.S, 10, l 1.
L?:, l,( 16, 24, 36, 48, 72 ;ind % hour$ ]lO~I do&:. On rhy
6, Twatmc:n1 c SHhicct;. wcw bkd a!: Pre-doc;.::, n.:>, n.75, l,
1.'< ·~. _\ 4, S, 6, !', ·w. 1 '.', \ .J, l fl, 24, Vi. t .. !.i., '?2 ;mu 96 bom:~
[JU"l dU.'-.tfl
C,n,." of ! 935 ng_.trnL w L~l bnur:-; ::, 'iloug
1,',·ilh (ill mg dt:x\rnmd hurphafl hvdrobrnmiJt: as thrt:t: :m.mg
do:.;;.o:; cl hours :;p;;rl (Tr<::;;tm<::n! ll, Rd\::rnnce), r<::;Khed ;;
111;,;;;r1 s!1.0:1dy--stalc plas11rn gi111ifcn<.:;;in (_''"·'" t<; 6 llo1Jrs Luer (,Trc~!-Â
m-.;ni A, Rd;:;ruicc), rc;,,;h;.xl ;, m(:an <;ic,'ldy--s13.l<.: plnsrna
de:;:lmmd hnrphan C"'">· nC l 79f'\O p_giml. in -'iAn hour:s 2tl'lt'.r
1b,; [2H dme (J .'S hum>; ;;fkr lht'. ill'>I du:.;e), had a C,,,;,, c·I'
l H-·<-9 pgimL, 3. Cw>-. uf l 5 l67 pg/rnL aml ;rn AUC,;:_,,.,,, s"'"'
uf IC: J ;;parl. almig wil h LY~l mg c•f
f~U:llkn1:>.in 11s Mudncx {Trc:lfmcnl B, 11.efcn.:n1:c), rc11tb<:d
J rn;:;:m steady ·&l:11~ pl:lsma tkxtmmdhorphan C,,,." ,,r
!72'> 1 p;;_/ml. in 'i. afltt lb<" l~sl llu.<;<: ( l2fi hum·>,
af!t:r !be lirst lk"•Ci•:'), had B cmi1. u[ l l iJJ 1' pg_/rn! ,, a CAVF or
14097 ps;ml and cw AUC_,"_,,_,.,y "'""of 16916ft hr-pg.ml.
44
Nov. 20, 2003
Subje,·ls givrn 60 mg dexlmmdhurph~n hydr;{m;midt ;md
.U:rnl rn1;g:1a.ifcncsin 3S sn o:pi:rim1.:nrnl fomwfal:on (Tri::tl ·
rn<.:W C Tes!), n;3d1v:l ~ mean slc~-1.dy-;;t:n..- pla>.m:: do;.
tmmt:!hrnph;rn ('""''of l"?2L-l pg/ml. m S.JO hour;; Aln !ht:
l;;;;I du;;t: ( J 25 h;rnr:; ;ilkr !h<:: 1;rst do~), had;; C.,,;,, nl' 10978
p_i!,.-'tnL, n CAVE of l 4609 pg/mi.. mid :J.n AUC,,_,,._,, '"""' ot
175:109 ilr·pg!mL -
[1137~?] Th~ pla~m3. rnn<0rnlrnl iuns uf g1i3ifcm;~in <1r<.:
;;hown in f~CS. J9 o:im] ·Hl. "!fa: r~suhing pham1;Kokim:tic
data ;m: sliowll iri Tabks I~ 1.hmugh 76. Subjc;,;\;.. ;,;iv<:n ! 2(~)
mg tif guaifo:ncsin :is Mudno;, along with (iO mg di;x.
trlHticrhnrphau bydrobromidc ;is tvm JO-mg dos.;;s {i ilntH:>
apat"l ("lkalrn':'lll A, !Zelet·cnc<"), rcadiell a rncMI ,'i1r& ~fo.-r tile nml dose (LU hut11~ ,l
du~..:), bad a C,,,,,, ur 18.2± ! N.'.\ ng./r;i!., a C.w<- ut 601:!: l?\9
ng .. rnl and mi AUC,,,,,"i:.· "'"'· of 7 Ui:ix226o llr--ng,.-'mL
TABLE 74
°Sll:·dy··:S~alt (: LJ'1iicr~r_.::~· ·~ P~··~~ ma.;__·::Jki :~.;__ lj,~ f°(; s.~.'8
::i.1.u ~~nn l2J (lJ '~ 29:·' 2~~·1)~~
!_~_ ~) 7..J-1]. n.:-:s~ ' St-.~ \J7fr2
'!.?. I l~'.H II 1-\f) ,1,_.1 '!Jr•! 1 1-1'-!
~: 7' ~/ ~~x.1) U.l't!~ Jj_7 j':Jll ll~
T/-.,Bl.E 75
L,,
(hr '•
(i.27[)
~L~~: ii
0.1:' I
0.11::,-.
55,~
~~t.:.·~d:·-s~~~.;:: (i~!.:.;_o'~·.:.:o:of:~iO) f°:l!-<: '.· .. P:f :"'J'~\'!!'!~ L, T, .. ,
'.-)~1bic1...:~ f•{:':..'in ~ .f {ac:/1,.,f .) V!g_-'m! I (h· ' ~.~1g:•nL': (';-; \"c I (in '1 (h)
:~~Clf! -:.w'- :'"'~} ,, 19J.~i : :·1 {·,!~ _;p ~I ? I:\ :1 ·~11' I .L'.:'.
\·~ t•;l i~< <~ 1;~.~n _:.1,, I l'-'l') !~J ~~n:, :·":4 .~ ~ 7~" D.:'.:'.7 3.(iS
US 2003/0215508 Al Nov, 20, 2003
45
TABLE 75-<.:olllinucd
:;lc;)l:.h S~at{_ {iu;1ifr:r-1_;;Si 01 ~(f1,w·n:10Jklr.t:~k ~\n:m1ctt:rs. ~--oiici.•,:rnr
tl1~ Ai:.h1Jir.!'itt•~l.iGs1 Hf 3:,:t.ir) !!~g ~_i~:;~!f,·r..i::-s!:l 1~:S ~'1u.....--iit.:~x Ev<.:!'~' ! :.: Hl~lH~ fo; ; 3 n~.1::-it::::.
tH•1J {}i) •ng ~ ~n;1.-;:.01~;.:~h~1q-ifo;1:? j-f ;-·Jo;-~·1:.-..0;:.onifk t~,;-, .~(~ :1?~ \'id.: ·.s F.:·1rn1;_, :,, 44
E\~ry -l ~-h1._..!-s f,: .. r ::- !)u:.,..__.:.,. lo ~·2'n·~··oi: "Vi.1lu:~~c1,.:_rx.
~Tt·c~~1j111-:·1i( B. R.i::-fts.;,;l'K"'."\'.")
At'C -
ih>- f'i'.l:l.I ' w .• .:.: T(!J.i:s -c~-.·~i-:;i~
1)- p,f ~-;. S;,,o.:in£ l~ T,,
~;l1hj·-:.:~~L "£-'~rd (r~~«·n~ ) (ri:;:~nl I (h: I (r~~(ml I (<·,.: z' ·.~. ~ !er ': {hr)
~ild. :'.414 ·' l.'I i.3-7 ~)A-{;.~ 2~)_':;. ~-, ;-.·~J.4~ H.3G4 j ,,,~,
D<".
StJ. 4>; c:_;m Ill" OJ.}7<1 _:;,~-; ·- 12A l';.15 lt't~~-.; r;_~_=i..:::l•Jy-S~:1tf:- fn.J(,~fi'.;:r.e~'="i!~ Pl"ln1 :n;~~~('k~~;!'..·~!1,: P:1~(,nJ~~l~~r:;. ~~ ... :--11,;-.. o.·inr
dw /",dmir.iif>-i•;~lmr: o:' L~mr mg (~·-·~ikric1.,ir~ ;rnd f)O r:~g !) .. ::i-;ln:.riw~l-~·,:•f:-,:,.;rn
HyJ;~l~m;.;~~id•_· ;~ ;rn !-.:.!\.p-.:r:;m:~l<~i b°<1am.da1.i-:.1f! l .. ,-,_·1·y ; =: U,;ur:~ !fH l ! Dl~;S·..::~ w ;">i.]~-·~v:~i!
V-:-1!::cit~·£:!·s tT~-::ctm;:n~ ( ·. R::-~~~re:•,i:~·:
ii.l 'C ..
(~1- r·,J:ui ( _,6.•:-.: TJ!11~ t\.~'o:""l'.o!C~ ".):- p,f ~t. s\~.:irJ.~ L, r, .. ,
;Slitfj,__..::.:t n~.';n~ (r~~·'•n! ) (!1;,';nl I ~: h; I ( r~g.'rn1.:1 (°'' ., c: ......... ~
~k;;j 73,I:~ :::-:.2 I /CIC.) i:·: (il.1 ;:<"J:: J.l.'L'
:vi:e...-:li.11~ 1}9~;~ l~~- ! 1";"8) 1:J 5~:G :.'.'l'J 1~)~~-{J
Silo\vn in FH:~S. 41 mid 4:.:L Tbt: n:sultini; pllarirnico¥i-
1Jdic ·:lat:; :m: shmvu rn fahks Tf tbmugh 79. Suhi.cds ~iv<.:n
6{) mg lk:xlrn1rn:!lwrplrnn hyJml>wmidc a:o. 30 mg V:d; ,.,
Fnm1ul3 i'1Ol\lgh1'vkdidnc, akm~?, with J10:) rng gllaffcn·
<.o:>ill as Mucincx mid . afkr tht: iirsl dose
(5 OJ llrnw; 3ft·~r 1hc las1 dos;(°), !Dd a Cmio. ot J Ji)4iJ:t'.'.i-lllH
pg:mL., a C,', !tlno1~ 20-mg dm;c.', -;ir
\Iick's Fnrmul;; 44 Cough !vk-:fo:in" '1 hours 3pan, dlnng
1:!;c C) 1'!11)
ru.1.1 <_)_I
1).-li'' 0 ~;i
H. ! 77 t!.K=k:c~dy-s!ale phc<.mn d1:x-
l.rs.>1udhurpbau C,""~ ,,f i 715 !:':39562 pgm1L, a\ i2f•:!: l. 73
hPms a!'h:t 1.bc fir:~l duse (.S.9 l huur.<, Jft.:r lfK l;,,,,l dtw.:), had
" C,,,,,, [if l !O I Kt:.?6{)07 rgimL, 3 c,,VL pf l.iC'J7t11<;.17
pg mi Mld Ml AU{ ·,,,~·"''Y ""'''or l 69 l 60dfr'.·H9 tir-pg/ml .
S11bjv~ls gi\'nl (i(i mg d·~xtromdhnrphan tiydr•>br<:m1id<: ;1ud
12(;0 mg. g11aitt:nc<>i11 as an cxp<.:;irn<:i1Uol formufo1:0n \Tn.~cuÂ
mcnt C. 'les!), r<:~1ch•:d '1 mean slcady-f;t;,l<: pbsm~ do:-
trt>mc1horphan C,""" d l 71.D;,3370'.\ pg:mL «1 US:!: L61
hours {'>.JO hnms ;1fter th.c l3s1 dm;.,;), h:td ;i C,,,;,, ul'
JO·:PX:-t?..i71.1 pg/ml., a C.w~ nf i460'.lt10X04 rgiml. ~rnl
crn 1\UC._,,,,,<1, ""'''' d 175}09:d69651 tir-pg/m[ ..
TABl.E Tl
'.i!.t,ri>:)o. -:)~~~~~ L"1-.;;.::~r ... ~r:.~c::~~1·~·~~.,h011 PhJn!~,x·:..-,•.~ccl~~((." P;~~·,~fti.:?;:::-1:<.. FallD\1.'!!~g
~he _."\.Jro~~r.i~.lr;~fr-101 .A J :1 :d mg \ im;if.:::nc~.;r: :--c::.. Vl;_<..:!r:cx L» .t .. ,,.; J.~ tbm-s fnr j; l k1:-.c:-,
~~~1j rid i~~E !).;:x:1ar:.~e11· .. :·~ ::·h.-:.ri ik1:fr·~:·b!"=J1~~ ~J~ .J:-. ~~~ mg Yid:;.\ F1)l';·mjb
4--t [\<::";)'. -G [k~1K fo.:- 2;-: Dc~:."-:S. ;n ~-:-):'l"!!:i.I \·b!w~~t~:-~~ _(}H~1~;~~;f~!H .4. n~:fr;1.:w."':c:j
i\~:c;.. ...
(!1i· c.u.iir. c.:.liV·, 'l.'.UJ.i:-.. '
~~::, f' ~ :' ·,· S·,·•~~8 L,
·~'- .• ·.~0~
Suhil."1..:~ ~'":'" l.i {l'Jo'."'·,!
, (r<'·mfl (on IJ!~.:oil (•.·;-; (•".'-1 (hr , I .'
T l. ~
(or)
.:i~fr>Ji~ j;:_;}')C)..j j vi+9 ]!1i(.1() l~~ 15 j ~; 7 )i_ .. .:} ~~n.u ,1 !·13 -~,'.;)
\·hxJi;tW~Ji~lhD:.ph;~~~ f1yJ;.:_~homidc~ ("i.S .~rJ :H£ \lii::k~:::. f.:..J;m~:t:
:~4 ;>:cf'.,' ~ Umm, lnr ::~: !"J..:-.~ .. n, ~o '.": 'v'nj;xo~s::c•::;. r'Trc;1lm::11: ;~- ;{{·Co.:1·cr:cc~
Al.C__,_
Oir- >1:i>1 c,.. ..• r,.,", {~ l':f ~; ;)..,-..·iri~ L,
Slthy~ ... ~t l'!';mU (j:1_~;~nLf :p_:;:mu il1' I (~1~;mL) (i·: c:·-: i '"'
,,
Std. fJSn.?:.-:: 4) (I" ')
r,.,
(bf)
\'li,:_<{a ~ {1~; c ~}l; I l:);l{ I -;;_=:~ c lci \I'' ';
l 15J~)'-; Jl}));j j 7:L; i:s , ... l,f:') "i.~.f ~ l~i.f IJ.JL
Jf(}(,_l !~5:";j 4.155 1:5 J.j .-i:~) f_;A i=r, ll. I I.'·
)f/)r~:-=~1 :?-fi'JJ. ~~~t-;03. ].{;2 Jik·:i:.:
,, ,,
~;l•--~ n.oe
211 19Ci
1~".27
9.~-~
U>'l
~frf}
Nov, 20, 2003
[lB76 J !n c:midiisiori, i.;1i;i.itrn<'.siri i11 !h<: <.:X[Jcrtmenl~.l l, ni' C,..,,,, cwd AUC,,,. as lht. 90'.:i nmfak:w.:t' ink;·\'ab
.uc 3J] cllntaitK'.tl ·wi1hin 80'} 10 tl5'/. D..:x1romdhor;:•birn
llydrolxornidc in ibc <.'.Xf><:rimcni.nl 1.Rbk1 is biocquivaknl t0
b011J :w mg dl'Xlrom<:tburph;m ilydrul,wmid<.: ·.;•;1.,ry 0 botHS,
:rnd .?O mg .:v<:r:> 4 hnt1r.>, iri l.ernis ol' C"'"·' and . \UC •. ,. ~s lhK '' f "kill i n 1 be M1, van.< t ion:> i: nd
rmidilka!irnlS uf tach uf !ht di~dll.<.<:d <:mbudimenb Gill IJ<::
i;~.:''ill
h1: ;1ppar.:fll 10 tbn.~e or :~kill lfl th<· ;Ji! fnim con~,idna:.i(i;J c-r
Wb~! is daim<.:d i'i:
1. i\ drn.~ ddiv<;ry :.<:.
2. The drlJg dElivny uf daim l wha<:in ~ .. aid immnh;~h;
fd.::a.'>C µonion :lrc·mc11l01ptrno.
3. The system ,,f daim L wh;,:rcin lh~ rd<.:a~-·:.ldayiug
min the('""''· for gu;i[!:~r1-
csin i:; sd~clcd fmm hc;!weefl ! ,(t{JO n_\{..'ml _ ;md _\7i0
n;;m1L, 1,200 ngrmL ,'lml 3,50-0 ng.;mL, 1,'.\50 rn:;imL atKI
3/KlO n,;:mL :ind 1'150 ug/mL and ::,750 ng··rnL.
9. Th•.; ~.yst<:m tif chiim 6, \VlHA·cin '>'lid tHJtl dose 1orn1
cou1<1ins (J[} mg or dcxtrumdhorpti:rn.
10. Th" :.;y:;lern nt' ,;h1im 9, whcn:irJ (h;; C"'-'" ror ;.kx-
lmmi.!lhorph;;n ~~ :;elet:ted lmm between 9,600 Jl_<;-'ml ;;ml
!'i,U()O j!g/rnL, HU'!OO pg..-rnL and U,SOO pg/mL, W,l'lUO
pgimL aml 12,i)(O<) P!VrnL and J ::,OfKl pg.imL am! B,500
p;;;/mL
H. Tb•w syskm or daim 6, 'Nb·~r~in Silid \lrli.l doc;.; form
,;.;;ntilin-; 6(f{I mg of g1H:f'-km <··f dairn l l, wben;in lhc.: ('"""fur g1rnifor1-
cel!5;:k:li fmm b;;;hv\'.cn :-120 ng!ml ~nd l RlS ng 'rnL,
-100 ngimL Mid 1500 ng/m[ ., SCKl ng;mL y:.;km of "him 5, wtier<::in -;;;id lhn~p~ulic:; guJifcmc:-;io
wbld cunlaimng -100 mg ot gtwikne> ~deued frc-m lx:lwecn 3S ngimL aml 7:i ng/ml., 40
n_~/ml. :;ml 70 ng/mL, -'15 n_o;im!. and f,i ng/mL, ~nd 'JO
ngimL 311d (10 n;;;.·mL
IS. The sy: ,;;,~Jcct trom b\:lW<.:rn 50 ng.mL 3f1d 150 llg.·mL, 50
n,o;:m[ ;md l 2i n.\',•ml ., 60 ng/ml ., [ :'.5 ng_,ml ., 70 llg/ml. ;rnd
!ZS ngimi_, ;rn;J !«) ngimL and l2:i ng/mL.
47
Nov, 20, 2003
Hi. Tht: .sy-;k:m or daim 1.5, whnt:in ,;,iid unit do'i<:: t'nrrn
bas a C,,,;,, for ckx!mm<.:1borplrnn !hRl is bic"'-'(]Uiw:knt to !Ii<.:
[-'DA-spccih~d C,,,,,, for a long :ern ..J,000 hr-n_o;/m! ;rnd
l25UO hE·llg/mL 'i,(l{lO br·ng/rnL alld 10,000 hHig/mL,
_"i,i(lO hr·n\\:mi _ :md 'J,500 hr-ng.ml ., :rnd 1\000 hr-rJg.ml _
and y>-l.:m uf dairn 5. whn.: ;.;;:id 1wil uo.'>e form
nml;i.in:; 600 mg nr _<,:llrn' hr-ng/ml ..
zg_ Tht: .~y~km uf dairn .?J, wber<:in said uni! (b~ form
;;ontain-;; :10 mg of do:H•:.>mdhorµhm1.
29. The sy~!em nt claim 2'<, v.;ilcrt.:in 1hc !\UC,,., for
dex!mmethnrr!un i:; sekcb:J frnm hi'lweefl l 'l?.J)()(! hf"flg/
rnL ;md :mo,ouo hH1g/mL 21 l:-,000 fiHig/ml. a11d 270,m~:;
hr"flg'ml , '.'. 16,{)01) hr-ng/mL ;md ·"·'1n,OOH hr"ng/rn!., ;rnd
:240,0i:Jn hr-ogimL mid :::7U,{l00 h1-ng1mL
:m. Th<.: sys!<:m of claim 5. wllcn,·in ;;;,id th•wrnpeuti;:~!ly
dfoc1.w;;; k.vd i:c. m~asur;;d ac<:mdtrig lo /\,UC0 __ 1 •
JI. The sy:.;l<:m uf cl;;im ~(), whneifl s;iid lmil dose i'orm
C'mtair1:--, l 2f.IO mg or g11ailrnt:sir1.
Jl. The ~y,;tem ol' r.:Liim '.\I., wll~:rcin the Al){ "--· IC.lr
guaifom:sio is :;i,:lc;:t.<.'.d frum [J<:l'NCtrl J,::wn llr-ng/mL ~nd
H,'.:50 hr-nivmL :'\,70{> hr-ng/mL and W,500 llr-nivmL
4,000 hr-ngirnL arJd 9,SOtJ br-ngimL, ·~,:2',0 br-ngjml ar;J
9Jl(l0 hr"fl.~im! ., ;md 4,C.00 hr"ng/mL arnL f<,iOO hr·ngimL
J3, The "J!"l<.:m of claim 30, wh1crtin ~.Jid unit dos<: form
('OIJl:litVi (!0 mg of (kXlf<"rlldh01:i)hil!l.
3~. Tile sy:>ttm of dairn .B. wbrn:in th<: AliC,,_, for
dn!rmm·lt1nrphar1 i:~ :--.cb:!ed frorn Zl\>,(100 br·ng_1mL aflJ
.'B7,500 hr-rJg/ml _ 241,(1()() hr-ng/ml_ MJd ]0(1,lHlO hr-nu/
m! , 24~,(10() hf·flg,·m! 3ml ~70,000 hr·ng..-m!., ;rnd ?.70,0flO
hr-ng/mL and 3(1{UJOO hr-ng/mL
J-5. The syslem nt daim 30, wh.::.rc ;;aid unil dl«;c form
umLlins 600 mg n[' ~u:i.ifen;;~in.
36. Hit sysltm of ·:birn :b, ·wbtr<:ill tb1:k<:kd from h:l\':<'<'.ll l ,6110 hr-n_o;;'ml ;ind
5,625 br-og/mL i,850 hr-ogimL and 5,250 br-n:;>,:ml, 2,ot~~
llr-11g;rnL r.nd 4,75il hr-ng/mL 1,115 hr-ng/rnl and 4jf~'
hr-ng/rnL, arJd 2,2'i0 hr-r1g!rnL ar1d 4,2''..() br-ngnriL
J7. The ~;y:>km uf diirn ~{), wh~fdn s;iid lmir :thorpl'rnn is >ckc11xl from Hi2,ono llr-ni::/mL ;ff1d
1:'i(i.mfl hr-ngimL 182,rn~~ lir-nfJrnL 3nd 2'.<{L_Oh!l ll:-ng1
ml , 182,000 hr-rij/mL ;md 202,0{)0 hr-ng/rn! ., and 20.2,000
hH1g.·rn! aml 210,HOO hr-ng/mL
39. The :;yskm uf claim 5, \<.'hefdn said lher;Jf"'Hli,::tlly
d]b;;Jjy,; kvd i'i 1m:as\1rcd accnnlin;; tr.> />JJC,,.
40. Tb1.' system of daim 31.l, \Vb<.~Kin said tinil dos..: form
•:•.Jnl~i ns 1200 n1g ni' guaifem:strL
41 The syst:.:m uf ..:bim 40, wht:1eir1 !he ALIC .. kr
guiltF~rn:sin is ;>t;kded from bd'•Nt:o;fJ 5000 hHig/rnl. ;rn;J
90m hr-ng mt, 56{lil br--ngjmL and 8750 hr-ni:";,ur1L., 6fl(~)
llr-n~mL am:l &.lniJ !u-ngmL, and f.500 tu-ng,imL 3_11d 8150
hHl£/rn1 ..
4L Th;;; "ysh'.m of daim 39, w·h;;;r•:in said unil lklse ftmT1
,:ontilins hO mg or do:1mmel.hnrph:.rn.
4J_ The sysicm of cLiim 42, \Vhcrd11 !bv AUC ... _- fm
dcxtromdhorphu1 i" scku;;d from bdwt:•dl HOJKJIJ h:-ng/
ml afld 2?.0,00D hr-ng/ml., JS7,500 hr.rig/mi. ;rnd l97,0fl0
hHig·rnL, l'i7,'iOU br-rig.-'m! rnd 17'i/J{)0 hr-m;;rnL, and
l 7:\(("ll br--ng/mL am! 197,000 llr-n1VmL
44. The sysl<.'m nt' d:i.im JfJ. when; c•aid unil. dorit'. form
cc.nu.ins i::.no mg or ::;untf<.alvsin.
45. Tb<: system uf ·.·birn .:H, 'A'licr,;in !ht AUC_._ for
gu:>ifrne:-,in is :'ded\Od from heh>.~'eri 2,'.iOil hr-ng·m! and
4500 hr-ng/rnl ,.,. .?.,800 hr-ng/rnl. nid 4,37-1 hr·n<;,·'rn! ., UliJO
IJt·-ng/rnL 3.nd --1-,(lf;{J hr-ng/mL and 3,250 ilr-ng/rnL awl
-1,l 25 br-ng'rnL
46. The sy:>lem of ,:him _'\-:J, whneill s:iid urnt dost Corm
•:·:Jnh1rn:-: j0 mg ·:Jf {k>:lmme!tmrplrnri.
47. Tl.1<' t.;y:;l~rn of d.iirn 46, 'Nhndn !he ;\UC.,,. f::;r
dcxtromdhorph;:n is s;;ki;;;;d from buwt:;;n 105,000 h:-ng/
ml aml 165,000 hr-11gimL, 120,(KJO ilH1s,iml 311d 149.nfJO
11f-EE),.'mL, LW,000 hu1g/mL :rnd Ll2,BOi~ hr--ng:mL arnl
I ].?,mo hr·flg/m! .. arnl 149,rn:~l hr-ngiml ..
4fl. Hie syslt:-m uf ..-!aim '.i, wbn,;in s~id !h lmui;;, l .O bnuis :rnJ
1 llours, ::nd L l houl" and 2 hours.
51. Th1.o ~y~ .. icm of daim 48, wh<.:r1.,in :-;aid ;mil do;;..: form
·"·.;inl;;ins 60 mg of (h-xlmmelhorpirnri.
52. 'Hie 'Y"km nf '.'birn :'.'> l' wbcre·ill I.be r,,,"~ (;_1r ;k.x-
lmmt:thoq1h;rn is :;deckd fmm bclwt:ni fi.?. hour:; amJ '.l.7
houi":>, (,, 7 hollr:: .• wd R.R hout'ii, Ci.7 born<> mid 7.75 hotHs, and
7.7:'i hours :rnd 8.8 hours.
5.l Th;; sysKm ;if daim 48, 'Nil<.'.rc said unh doS<: torn1
crnilJins t'.00 mg of :<';1rn1knt:si1J.
54. The syskm ord:iim '>1 ... wh;:r..:in the T.,,,,,_ !'nr gu.iikfl-
esin is sdecbl !'mm hdwt:rn (U hrnm; am] l .'i hc·iirs, 0.4
hours and 1.25 hours, IJ--1-5 hGurn and L 13 b011rs, 0.50 hours
and l bunr, ;1rnl 055 hours .
55. "!ht sy:;Jem ('·f d;iim 4.'l, wh<0reifl s:iid llfltl dost: Corm
c•.Jnl;;ins :}O mg ·:Jf d•:-xlmmeltmrp!rnu.
:'iii. Tht: 'i)'>ikm of dc1im 55" \>/h,;n:ill 1_h,: T,.-.,,x t'nr de:<-
lfOill<:tborphRn i> 9..:kckd from htl.'Nt:tn 4.6 llours aml 7.25
hou;s, 5.1 lioiirs mid 6.5 !lours, 5.2 hours and 5.8 hours. and
'> 8 bum" ;tnll 6.'i boms.
57 The :;ysiem uf daim 4, whnein s~id lhef;ipt:uliully
dfociive kvd is meJ.'iurcll 3C<:in is s1.:ln:!<.'.d ft·,Jrn bd\\'l:l'.n 0.7 bouG and 7.25 hollrs, 0.9
liot1rs ~.nd 6.0 bou;s, 1.1 hour-; .'l11d 5 O hours, l J hoim; iHJd
.1.5 hrnirs, :rnd ·1 A hnufS ;md _n>.5 h\lur:;
till. '!let: ·'Y'km of dairn 57, wher<0in »did unit do~ t<>rm
c<.ml;Jtfloi 60 mg of d1;;xtmrndhmphiHL
6L The -;ysto:m of ddim f'Al, when:1n the T, -, fur dt:x-
1.rt>nKl.hurpbau is ~·:b.,l<.·.d tnmi bdw·.;~on 9.-'1 hours <:!ld l4.7
hs.1t1rs, W.6 ho-!lfs and 13.2 huur;;. lO.f.1 llours ~.nd U.75
hour:;, s.nd 11.75 hour:> am.I U.1. horns.
62. Th~' sy! btiur"i and J.O b(iurs, 0.)'i liuw" cind 2.5 homs. 0.fi'i
hoiin; and 1.75 hc•llrs, and O 70 ll0\1rs :tnd t.75 hoi1G.
6,;J. Till'. "J!"i<.'.Jll of daim 57, whertitJ ~.aid unit dose form
i:ontains ::w mg am;>um c.r <.kx!mrm:1hc .. rph~n.
6.5. Th1: <>y'ilCm ot daim 64. wll;,~rcin tbc T, 2 for dtx-
tromc1horpb;rn i> sckn..;d from how1:cn 7 .0 hot1r;; and H .0
hnm:~. 7.'J lwur:o and 9.9 hum;.., 7.9 hour.,, MKl ~ .f> hmH,.,, iilld
K8 bours arJd 9.9 hmir~.
6{;. Th~' Juig defo·1:1y syslcrn of dairn l, when~in !lie
imrn·~diak rd;:is'~ pon:i•Jn fonhi.:r comprL<.cs mi.::m.::ry.sl3!-
lillc cclluki&<.\ <;ifl lo the dcxtroml:lhurpban
is from allot1l <:l:l 1,, abuut J1:J. by wc.igbl ..
l'l9. Thi:: drug ddi\•<;;;<,' :;ys1x:m ufd:tim l, wher..:jn !he ralio
n( lhe irnmediale [l:lei!:t1st8it1i:d n.:kas·.; q113111ity of .Jcxtromct!J,,rplun is from
abt>ul l : ! !n :>hrni< l :::'..
72. The drng dd\v,;ry- :;y:-lem of d:iim I, wher<0111 :ii J;:;,;;1
ahuuJ 60'.k of !f1,; guairw<::.~in jl3rl1cks u:"iCd lo make !he uml
duS<.: form trnve a pu!ick ;;i;:.~ .in lhe ran1~~ of from 3bo111 .!SO
pm tu 1.0 mm.
73. TlK drug ddivl'.f)' sysl_<.'.m ;_if d.'lim L wb<.'l"<:in a unit
dos;; form has a ( ',,,"~ for guaikw~';in of :ti !cn.;;1 aboul l 9!.~}
llg.,...ml aml ~n /~lJCicit' I'm guaifrne:;in nl' 201 leas\ 70fl0
hHJ~'rnJ.
74. The drng ddivt:ry :;y.~1<0m nr d:tirn l, 'Nhnein ;j 1mi1
du~.:: form Ii;,;;~ C"'""' for guntfcncsin or M lcuSl l (~JO ng_iml
,1nd 1111 1\UC",r fr•r gu1oifcn..:;;i:1 of al J;;~;sl 3500 br-ng:rnl.
75. Th..: drug dd1vcry sy;;f(.:ffl of d1lirn L whcrcrn 3 irnil
dust: form ha~ a halt' Efe nf 201 lt'.:t:;t _'I hmlfs ;is det;;rmifled by
serum w~lysis.
US 2003/0215508 Al
76. The drug ddivay sy,;km of 1:h1im I, wh·;,n:ir. th,.
su~-;laimxl r1.ckm;;.; portion ''Ompris;.~s ;1lx>11t 7Y{ !u abotH '.iS'ii
hy wci0;h1 of gtuif~.ncsin, from 3bout ] '·'i· \U af:.•)UI J_:'i'Z: of
lkxlmmdhorphw, fmm ~hou! 05~-!. to 'iix>11l lOS{ nf 1_h"
hydmphih: polymer, arnJ ::boul O . .'i'?i lo ;ihuul .?.S<:~ wf claim J_, wb<.:rf.'.in tbc t1ni1
dose form comprist:s im1m;d[nt0 rdtilf'l:: and su1-m1in<.~d
rdeaS<.: jhirlwns <:adi <.:Uflljffi~<-: alml!irig ,.,uhslanlially planar
!ayus which rurm ll hi-bver tahkl.
711 Tt1'-' ,_lrn1;·, dclivay system c•f d:;n11 L wbcrcin lh·~·
(.];;x1romdhorph1:0 is bfoavJifobk 31 !rK~rnp<.~u!irnl!y dkc1iv0
!;;;;d for a! ka,.,! i·,,·c.:.[v,~ hntw< following a :-;ingk drn-.<:.
79. The dmg d~livny sy»km or daim i, wh-oreir. t!-w
sllslain(d r-ckase pm!im1 cr;mpric-;,;s from about 7';(;.; lll Hw:~
hy wd1;ht uf ;~1:aifru·~;-;in, {rum :oboi11 5% t<-' abuul l(V.~ by
\V<:iQ,hl ofdcxtmmcthoq:dna, ltum alx-iiil y.,- ;o Jh0\ll 6':.f of
lh-c hytlrm:ypmpvl c•.-:llulose, amJ rmm abrn1l 1 'k to alxml
! .S'X by wt:ighl of art acrylic resin,
80, The dmg delivery ,;ysl<:m (!]" daim l, whaein a unit
du:;;<.; form !us ;1 C,,"" for ;;uaifonvo;in frt>m ;ibolll lliOO tr•
25(~~ n1Vrl aml ;rn /'.lJ( ,.,,: for 1!,Udif.::ncs.in or 'iliou1 56(~r to
Cl750 hr-og/m1.
IU. Tbc drng delivery syslem c·f d~im l, whne[n a m1il
dose form ll'1" ;; C,.,,,~ for gu~ i!'<.0n<.:sin uf 1ibum 1mo 1.0 J15fi
ng/ml and an AUC,.,r for !:~linikncsiu or ~\,1)1.ll 2Wl0 10 '1.:\75
llc-ag/rnL
82. Hit: drn;.; ddt'!CiJ' ·'·YSkm or claim 1, wh-crein the 11nil
dn"'' furm n>rnpn-;e, oci3Jcd imm<.:diaw rok3.fi<: ;rnd SU'-'Utin'.'d rdcasc ponions.
83. Tb;; dnig dd i>'<.:ry i;yslo:m or d11im l, which L" 3.pprnxi-
miilely equ.3.ll)' elfodiv-o wheo adminisknxl In a pali<;;n! on
.:tum nmccnlrntion prntik <>f
HG.Ht
85. A drng prmlm:t i:omprisin;; :rn imm-cdia1.-c teka:-;r:.
pnnion uimpri:;ing :i giJailemo»ir. imd optiuo;1l.ly do:-
lromdh•xpba11 wlv.~rein gt1;1[kn0sin becomes biow,·n[lahh:: in
ihc suhj;.:<.:1 's s1c,n1<1d1; ,wd r. sw;1aim:d rcka.~ p>>rlioH com-
pri:>ing gu;1 iknc>
I !i·~ sustilin~d rd case guaifr ncsrn is abotil I: I lo ;il'l, lU t
1 : l 'i, I [i,; prod1rc1 f:>rff,·ide:; a. g<«1i It rn:;;in C,,,," in il
lrnm;m sub_jed <:ljUivakfll. 1.U tbe Cmn ui:-laim;d wtJ,:n
tho: Hf:'I of thr·~·~ doses of pccilicd immcdiillc
n:l<:rn fur '11 k3.:«I. lwdve
ht'llr" nfo,,,r ;' >.ingk dose ia :J. h11rnan ;..uhjcocl mxc·n:ling
le- :;.-~nim analysis and 'i tb·~rnp·~utic:Jlly dfo.:i.iv~
;imouol of !hr.- (kx!mrne!hnrph:tn.
49
Nov, 20, 2003
~f0c The drng prml1Jd ~'"''-'rding 1_0 dair.i 11.5, w h-on'. in I ht
imrm:diaK n:[<:<,&<.:; and sw-;1_ain<.~d n.:kasc: portion>. '--'ildJ c:om-
pri.Y..: nbunlng sub,;.1rnrially pfatnr fay·~rs wtiicl1 form ;,
hi-byn !ahkt.
87. Th;;: drug_ prndud accmding lo daim ?!'i, v,.!Jeffin !ht:
su;;!;;[m;d rek
di~.k rck$ '<'-~ porlion.
§K Tbc dn1c; pwdud aixording to daim .S5, v.vhnc.:in !!w
pnxhid comprl,.,~s ;1 .;;3ps11k wnl;i_ining immcdi:llc rde:isi.:
;rnd :-:ust:1i11ed rdeas-t: ptir!inri».
89. /\, rm:ttiuJ uf lr<:aling ;, ,.;ulij<:d in nt:cd ul- !•:mpmary
ri ;;nd coughin;.,:
--:omprisinc; ,'ldmioistcring to :-;aid subj<.~<.'.! ~ tb<.ornptllliraHy
dfodivc :m101rnl of one dnig delivery ;;y,;;crn :c.ccord1ng tP
daim ? ..
1W. Th1;; mdhml <->.n:nnling to <:him k()c, wh<'rnin Hm drng
J~li·,.'ery sy~1~n! is iiUnun3sk:rLd u::-1~Hy.
llL :\ m;;ihud ol' !r1,:a!ing a suhjed in rie•.od nr ttmpurary
t·cb;f from bro1J1:hi,n and coughing
(:(Hllpfi,.,ing ;idmiUJ:>lt:fU:g IO ';aid ;-;lJhjCCI 8 flicri1j)C\llic:J!l)'
dfoci.iv-c ammml nl' ,, rnndilkd rcka:>r. drn~ pmdud n-1m-
prising g11aifenl.'.;:i1J ;inli upi.tunaily :J-c.\trnmdlmrphan rn an
immo:dim.c n.:k;i_-;,; fomwhiti•.Jn aml '-Vbcrdn lh<.: guaikn<.0sin
l_wc0im;s bioav1;ifabk w the :-;tibj<.~ri's s10macb; <:nd a sus-
l_~ined n:k3&: porlion comprising a guaiktK~,in, (kX-
tmmelhwpban and a rekas.;;>ddil'.'"ing malrix,
wt1f.'.rcin lht rckf1,;.0-ddaying rnatri>; compri.~'-'' ;i liydro-
phi!i,- pdyma ~nd 3. wakr-insolu.ble [Y;lvma in ;i
W\:Cight rn!ill of byJrnpbtlic p-:J!ymu lll Wa(<:f 0 lll.Sllillbk
po Jyrncr l'wm n lxrn r I: I 10 ;ibom '}: J_,
v.·herdn tbe guaifrn-osin ha;, ;1 C,,,." in ;: hum3ri subj-od
equi11ah;n! ID !he Cmx {'hlain.:J when the llr-;! ur lbret
dnsc;; of ~ FDA-spcdlkd immedi:tlc rdcBs;,:' frnmJfa-
!ion !uving on;;- third HK amo11Jl( of gt1aifom:siJJ i:;;
dustu <:v•,·.ry (our hum;; ovt:r a l 2 IEmr pni'.)J, ;rnd
rd,;~:,1;;s lh<;:r;tf""Utic3.ll)' ~m:1:1 ive hinavai.Lihk. gu:tif,~11-
tsi11 do.s-: for al !e21:-;l hvdv,; IJOl1l); afkr a Mngk do,.,e in
a lrnnrnn '-'Hbjn;I an:ordi11,; l•J ~,ornrn am.!ysi~,;,
92. Adrug ddivcry ;,._y~tcm l.'ompri:>ing :< s11slaincd rdci!f'i;
portioH comprisio!!, _i;uairt:,n1.osia, dcx1mrnc11lorpllan nnd a
n::ko;_"<',ddayrng malri~: <.:umpii,.,iflg a hvdrnphilic pdymtE
;rnd ;1 W3.kr-lnsoluhle polymer; and im immediai-o rdea~-o
purtit>n compri:-;ing gt1aifcm:si11 and dnarom1:1borpbirn:
wherein 11J<.0 1 ;1rnd~:n·~"jo is hioava.il:tbk 31. a tho:rnprnlit:ally
dfoclivc kvd for i:l ka;-;! twd'v'c llo11rs accnrding to f".:tulll
:rnalysis following a singk do"<= arnl wher<:ir. 3 llnil do~
form rJern°:lr1:-.lrak:o a cm,,~ in a burn~n sub_ied ahuvi~ li,10
ug/m! wi1.l1 a f
0
,"" within 0.S hoim; ~Hid m<1inlains :1 C,,,,,,
ab(>vo 00 ng/ml fc;.r 3. p1.'ri1,id of 12 or mor<.: botJrs.
