Ex Parte Easson et al

Patent Trial and Appeal BoardNov 22, 2016

13383061 (P.T.A.B. Nov. 22, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 13/383,061 01109/2012 23599 7590 11/25/2016 MILLEN, WHITE, ZELANO & BRANIGAN, P,C 2200 CLARENDON BL VD. SUITE 1400 ARLINGTON, VA 22201 James Easson 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. MERCK-3918 2426 EXAMINER PURDY, KYLE A ART UNIT PAPER NUMBER 1611 NOTIFICATION DATE DELIVERY MODE 11/25/2016 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): docketing@mwzb.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte JAMES EASSON, WALTER HAMM, and GUENTER MODDELMOG 1 Appeal2015-003210 Application 13/383,061 Technology Center 1600 Before ERIC B. GRIMES, MELANIE L. McCOLLUM, and RICHARD J. SMITH, Administrative Patent Judges. McCOLLUM, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. Â§ 134 involving claims to a composition for the production of tablets. The Examiner has rejected the claims as obvious. We have jurisdiction under 35 U.S.C. Â§ 6(b). We affirm. STATEMENT OF THE CASE Claims 1, 6-19, and 22 are on appeal (App. Br. 2). 2 Claim 1 is representative and reads as follows: 1 Appellants identify the real party in interest as Merck Patent GmbH (App. Br. 1). 2 Claims 20 and 21 are also pending but have been withdrawn from consideration (App. Br. 2). Appeal2015-003210 Application 13/383,061 1. Directly compressible composition for the production of tablets, which consists of 50 - 85% by weight of anhydrous calcium hydrogenphosphate, 10 - 40% by weight of mannitol and 5 - 20% by weight of sorbitol. Claims 1, 6-19, and 22 stand rejected under 35 U.S.C. Â§ 103(a) as obvious over Yokoi et al. (WO 99/55373 Al, Nov. 4, 1999) (hereinafter "Yokoi")3 in view of Sheth et al. (US 3,134,719, May 26, 1964) (hereinafter "Ranchhordas" for consistency with the Examiner and Appellants) and Reiff et al. (US 4,507,511, Mar. 26, 1985) (hereinafter "Reiff') (Ans. 2). The Examiner relies on Y okoi for teaching "a powdered composition for using in tablets or granules the composition consisting of calcium hydrogen phosphate and a sugar alcohol such as fructose, xylitol, mannitol, erythritol and sorbitol" (id.). The Examiner finds: "The calcium hydrogen phosphate is present in an amount of between 99.5-40% by weight and the sugar alcohol is present in an amount of between 0.5-60% by weight .... Specific weight ratios of calcium hydrogen phosphate:erythritol mixtures include 85:15, 75:25 and 65:35." (Id.) "The Examiner acknowledges that Y okoi fails to explicitly teach a combination of at least two saccharides" (id. at 6). However, the Examiner finds "that Y okoi should [not] be interpreted as only teaching including one saccharide" (id.). In addition, the Examiner concludes that, "assuming that Appellant[s are] correct in their assertion that Yokoi teaches including 'a' 3 The Examiner relies on a machine translation of Yokoi (Ans. 2). Appellants rely on a corresponding European Patent Application, EP 1 008 353 Al, published June 14, 2000 (copy attached), as an English language translation (App. Br. 2). We will refer to this European Patent Application as Yokoi EP. 2 Appeal2015-003210 Application 13/383,061 saccharide, ... it would still be obvious to modify Y okoi to where two or three saccharides are included in the composition, rather than just the one, all while still working with the weight range of saccharide required" (id.). The Examiner relies on Ranchhordas and Reiff for teaching features of dependent claims (id. at 4). ANALYSIS Y okoi discloses "[ s ]pray-dried powders containing calcium hydrogen phosphate and saccharides having excellent powder-fluidity and compression-moldability, being quickly disintegrated/dissolved when put into the oral cavity or water in the form of ... tablets" (Yokoi, Abstract). As the saccharide, Y okoi discloses "sugar alcohols such as erythritol, mannitol, sorbitol, xylitol and the like" (Y okoi EP i-f 29). Y okoi also discloses a combining ratio of "0.5 ~ 99.5 % by weight of calcium hydrogen phosphate to 99.5 ~ 0.5 % by weight of erythritol as an example of saccharide, more preferably, 40 ~ 99 .5 % by weight of calcium hydrogen phosphate to 60 ~ 0.5 % by weight of erythritol" (id. i-f 19). In view of these disclosures, we conclude that the Examiner has set forth a prima facie case that it would have been obvious to include 10 - 40% by weight of mannitol and 5 - 20% by weight of sorbitol (Ans. 6-7). Appellants argue that "[ t ]here is no fair suggestion in Y okoi of compositions which combine calcium hydrogenphosphate with two different saccharides and particularly with the specific saccharides mannitol and sorbitol and in the specific amounts as claimed" (App. Br. 4). We are not persuaded. 3 Appeal2015-003210 Application 13/383,061 We agree with Appellants that Y okoi does not expressly teach a combination of two different saccharides. However, we note that the Abstract of Y okoi does refer to "saccharides" (Y okoi, Abstract). In addition, we agree with the Examiner that it would have been obvious to combine two saccharides (Ans. 6). "[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980). With regard to the specific saccharides mannitol and sorbitol in the specific amounts claimed, we note that Y okoi discloses both of these saccharides (Yokoi EP i-f 29). In addition, Y okoi discloses including saccharide in an amount of "60 ~ 0.5 % by weight" (id. i-f 19). We agree with the Examiner that it would have been obvious to use mannitol and sorbitol and to apportion them within the disclosed amount (Ans. 6). Appellants also argue that Y okoi fails to suggest a "composition which 'consists of' three components, i.e., (1) the anhydrous calcium hydrogen phosphate, (2) mannitol and (3) sorbitol" (App. Br. 4). We are not persuaded. As noted by the Examiner, "Example 1 of Y okoi provides a composition that consists of calcium hydrogen phosphate (85%) and erythritol (15%) (variant of the sugar alcohol taught by Yokoi) and Example 5 consists of calcium hydrogen phosphate ( 50%) and erythritol (50%)" (Ans. 6; see also Yokoi EP i-fi-155-58). As discussed above, we conclude that it would have been prima facie obvious to replace the erythritol with mannitol and sorbitol, which would result in a composition consisting of anhydrous calcium hydrogen phosphate, mannitol, and sorbitol. 4 Appeal2015-003210 Application 13/383,061 In addition, Appellants argue "that the evidence of record showing unexpected advantages of the claimed invention further supports nonobviousness" (App. Br. 6). We are not persuaded. In particular, Appellants argue that "a tabletted composition consisting of co-spray-granulated calcium hydrogenphosphate anhydride, mannitol and sorbitol in the weight ratio 90:5:5 - i.e., in amounts outside the claimed range - exhibits a[] greatly increased and disadvantageous disintegration time" (id. at 7). We note that the Specification discloses: Whereas a tabletted composition consisting of co-spray- granulated calcium hydrogenphosphate anhydride, mannitol and sorbitol in the weight ratio 90 : 5 : 5 [(product H)] exhibits an enormously increased disintegration time of up to more than 3600 sec with increasing hardness of between 30 and 139 N, the compositions according to the invention have only disintegration times in the range from about 140 sec to about 670 sec, in spite of increasing hardness, apart from disintegration times of about 1100 to 2200 sec for pressed compositions prepared from a co- spray-granulated composition comprising 85% by weight of calcium hydrogenphosphate anhydride and 10% by weight of mannitol and 5% by weight of sorbitol [(product G)]. (Spec. 28-29, 30 (Table 1).) We do not agree that this statement indicates, nor have Appellants clearly pointed to additional evidence indicating, that product G, which is the closest embodiment to product H that is within the scope of claim 1, is unexpectedly superior as compared to product H. See, e.g., Spec. 32, Table 3 (product G has disintegration times of 1113 to 2200 sec; product H has disintegration times of 529 to >3200 sec). Moreover, we note that Y okoi specifically discloses "a series of compositions wherein the combining ratio of spherical calcium hydrogen phosphate to erythritol is 85 : 15 ~ 50 : 50" (Y okoi EP i-f 57). Thus, Y okoi 5 Appeal2015-003210 Application 13/383,061 specifically discloses ratios of calcium hydrogen phosphate to saccharide within the ranges recited in claim 1. Appellants also argue: The evidence provides a side-by-side comparison of the properties of compositions according to the invention (compositions C-G) containing the combination of the two distinct specific saccharides, i.e., mannitol and sorbitol in the amounts as claimed, versus compos1t10ns which are representative of Y okoi -- i.e., containing only a single saccharide (see compositions A and B, containing only mannitol or only sorbitol, respectively) . . . . The data is clearly representative of the distinction of the claimed invention from Y okoi at the point of novelty, i.e., the use of two specific saccharides in particular amounts rather than a single saccharide. The data demonstrate that the claimed compositions provide an advantageous combination of ease of compressibility while still resulting in tablets with high hardness, low ejectability requirements, low drying loss, low friability and good disintegration properties. (App. Br. 6.) We agree with the Examiner that the most relevant comparison appears to be between product E and products A and B, because these products each contain 30% of either mannitol (product A), sorbitol (product B), or a combination of the two (product E) (Ans. 7-8). In addition, the evidence clearly provides differences between these products (Spec. 32). However, we agree with the Examiner that Appellants have not provided sufficient evidence indicating that the combination is unexpectedly superior, particularly over the full scope of claim 1 (Ans. 8). In the Reply Brief, Appellants argue: [T]he fact that composition B has about the same hardness as composition E when compressed at 5 or 10 kN does not refute the fact that composition E is superior to composition B. 6 Appeal2015-003210 Application 13/383,061 Composition E is still superior because it can achieve higher hardness at higher compressing forces, provides tablets with lower friability, better disintegration properties4 and lower tablet ejection force than composition B. (Reply Br. 3.) However, even if we assume that the Specification demonstrates that composition E is superior to composition B, Appellants have not demonstrated that the results are unexpectedly superior. "Attorney's argument in a brief cannot take the place of evidence." In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). Appellants also argue that, "[ w ]hile it is true that the hardness property for composition G is not improved over compositions A and B, composition G is significantly improved over compositions A and B ... with respect to the combined properties of hardness, friability, disintegration and ejection force" (Reply Br. 4). However, upon review of the data provided in Specification Table 3, it is not clear to us why this is the case. CONCLUSION The evidence supports the Examiner's conclusion that Y okoi, Ranchhordas, and Reiff suggest the product of claim 1. We therefore affirm the obviousness rejection of claim 1. Claims 6-19 and 22 have not been 4 Specification Table 3 demonstrates that product E has a slower disintegration time than product B (Spec. 32). Appellants refer to the "longer extended release disintegration times" as an advantage (Reply Br. 3). However, the Specification states that the "tablets of the compositions according to the invention have very short disintegration times compared with the pure substance" (Spec. 28; see also App. Br. 7 ("tablets of the compositions according to the invention maintain advantageous short disintegration times")). Thus, it is not clear from the record that longer disintegration times are necessarily superior. 7 Appeal2015-003210 Application 13/383,061 argued separately and therefore fall with claim 1. 37 C.F.R. Â§ 41.37(c)(l)(iv). TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. Â§ 1.136(a). AFFIRMED 8 Application/Control No. Applicant(s)/Patent Under Reexamination 13/383,061 James Easson et al. Notice of References Cited Examiner Art Un it n ..... ,.,. ..... -I ..... .i: -I od!::jO:: I UI I Purdy, Kyle 1600 U.S. PATENT DOCUMENTS DOCUMENT * SOURCE** DOCUMENT NO. DATE NAME CLASS SUBCLASS APS OTHER D A D D D B D D D c D D D D D D D E D D D F D D D G D D D H D D D I D D D J D D D K D D D L D D D M D D FOREIGN PATENT DOCUMENTS DOCUMENT * SOURCE** DOCUMENT NO. DATE COUNTRY NAME CLASS SUBCLASS APS OTHER D N EP 1 008 353 A1 06/14/00 Yokoi et al. D D D 0 D D D p D D D Q D D D R D D D s D D D T D D NON-PATENT DOCUMENTS DOCUMENT * DOCUMENT (Including Author, Title Date, Source, and Pertinent Pages) SOURCE** APS OTHER D u D D D v D D D w D D D x D D *A copy of this reference 1s not being furnished with this Office action. (See Manual of Patent Exam1n1ng Procedure, Section 707.05(a).) **APS encompasses any electronic search i.e. text, image, and Commercial Databases. U.S. Patent and Trademark Office PT0-892 (Rev. 03-98Notice of References Cited Part of Paper No. 16 111111111111111111111111111111111111111111111111111111111111111111111111111 (19i ' Europaisches Patentamt European Patent Office (11) EP 1 008 353 A1 Office europeen des brevets (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: 14.06.2000 Bulletin 2000/24 (2 Â·1) Application number: 99917131. 7 (22) Date of filing: 23.04.1999 (84) Designated Contracting States: CH DE FR GB iT U (30) Priority: 24.04.1998 JP 11543198 29.07.1998 JP 21421398 (I1) Applicant: FUJI CHEMICAL INDUSTRY CO., LTD. Nakaniikawa-gun, Toyama 930-0397 (JP} (72) Inventors: â€¢ YOKO!, Shinichiro Fuji Chemical Industry Co., Ltd. Nakaniikawa-gun Toyama 930-0397 (JP) (51) lnt.Ci. 7: A61K47/04, A61K47/26, A61K9/20, A61 K "1/00, A23L 1/03, COi B 25/32 (86) International application number: PCT/JP99f02175 (87) International publication number: WO 99/55373 (04.11.1999 Gazette 1999/44} â€¢ NISHIMURA, Yoshihiro Fuji Chemical ind. Co. ltd. Nakaniikawa-gun, Toyama 930-0397 {JP) â€¢ TANAKA, Nobukazu Fuji Chemical Industry Co., Ltd. Toyama 930-0397 (JP) â€¢ IKUSHIMA, Heiji Fuji Chemical Industry Co., Ltd. Nakaniikawa-gun Toyama 930-0397 (JP) Cl 4) Representative: Albrecht, Thomas, Dr. Kraus, Weisert & Partner Patent- und Rechtsanwa!te Thomas-Wimmer-Ring 15 80539 Munchen (DE) (54) SACCHARIDE-CONTAINING COMPOSITIONS (57) Spray-dried powders containing calcium hydro-Â· gen phosphate and saccharides having excellent pow- der-fluidity and compressionÂ·moldability. being quickly disintegratedidissolved when put into the orai cavity or water in the form of granules, tablets, etc., being useful as fillers. cornpressionÂ·-moldability irnprovers, disinte- gration aids, administration-facilitating agents, solubiliz- ers in the oral cavity, etc. and being applicable to drugs, foods, etc. Printed by Xerox (UK) tlus1ness Ser/ices 2.16.7 (Hm;)/3.6 EP 1 008 353 A1 Description TECHNICAL FIELD 5 [0001] The present invention relates to spray-dried powders containing calcium hydrogen phosphate and a saccha- ride which have a good powder-fluidity and a high compression moldability, which are quickly disintegrated and dis- solved when put in the oral cavity or water in the form of granule, tablet, etc,, which are useful as excipient, compression moldabiiity-increasing agent, disintegration aid, administration-improver, intraoral quick dissolubie agent, etc., and which can be used in medicines, foods, etc. 10 BACKGROUND TECHNOLOGY [0002] Calcium hydrogen phosphate has been used in medicines, foods, etc. as a reinforcing agent for calcium and phosphorus components, an antacid, an excipient for pharmaceutical formulation, for example as an excipient for tablet, 1" a diluting agent for tablet or capsule preparation or as anti-caking agent. Calcium hydrogen phosphate has been utilized as an excipient for medicines, cosmetics, foods, etc. owing to its low hygroscopicity, inertness, littie reactivity with med .. icines and no discoioration being caused by itself. [0003] Calcium hydrogen phosphate has generaiiy been prepared by precipitating it from a slurry of lime and phos- phoric acid which has been heated above 80 'C. However, the precipitated calcium hydrogen phosphate is a fine pow- 20 der having a high density and a very' small binding property in itself and hence it couid not be applied to direct cornpaction process of tabletting without incorporating into it a binder such as starch orÂ· the like (Japanese Patent Appli- cation Laid-Open No. Sho 62-36010 gazette). [0004] That is, the hitherto used calcium hydrogen phosphate taking forrn of plate crystal particle of 10 pm or rnore is known to be inferior in binding property and lacking in suitability to be used as an excipient. In order to avoid the prob- 25 lem as stated above, various processes have been proposed for imparting moldability to calcium hydrogen phosphate For example, there is a process for changing the shape or the crystal form of calcium hydrogen phosphate into other one. As the specific example, calcium hydrogen phosphate is pulverlized into fine granules to give it molding property (Japanese Patent Application Laid-Open No. Sho 62-36010). Also, as disclosed in the present applicant's Japanese Patent Application Laid-Open No. Hei 6-298505 gazette, Japanese Patent Application Laid-Open No. Hei 7-118005 30 gazette (Patent No. 2700141 ), U.S. Patent No. 5,486,365 specification (1996), European Patent No. 0 644 156 B 1 (1998) and Japanese Patent Application No. Hei 8-293251 (Japanese Patent Application Laid-Open No. Hei 10-120408 gazette), there are some processes wherein a prismatic or scaly crystal formed calcium hydrogen phosphate is spray- dried thereby the crystal form is converted into spherical one to impart the moldability to it. More specifically, a process is wherein the starting material, phosphoric acid is reacted with an alkaline calcium compound or an alkaline metal 35 phosphate is reacted with a calcium compound in the presence of a polyvalent organic acid having a coordination ability to prepare calcium hydrogen phosphate composed of primary particies having a prismatic crystal of 0.1 -- 1 Âµm in par- ticle size thereby the moldability is imparted to it [0005] Another process is wherein the prismatic calcium hydrogen phosphate obtained by the above process or calcium hydrogen phosphate having monoclinic crystalline structure is further subjected to hydrothermal treatment to 40 convert into a scaly calcium hydrogen phosphate having a specific surface area of 20 -- 60m2/g, a static apparent spe- cific volume of 5 ml/g or more, a primary particle diameter of 0.1 ~ 5~tm and an average agglomerated secondary par- ticle diameter of 2 ~- 10 p.m or wherein said scaiy calcium hydrogen phosphate is spray-dried for convertion into spherical one for imparting the moldability to it Or further another process is wherein the scaly calcium hydrogen phos .. phate and a ceiiulose derivative such as sodium carboxymethylceiiulose, methylcellulose, hydroxyethyl cellulose or the 45 like as a binder are incorporated into a suspension to be spray-dried for preparing a spherical material having more functional property. [0006] Also, a process was reported for imparting the moldability to calcium hydrogen phosphate by adding binders such as starch, polyacrylic acid and the like to it [0007] However, these calcium hydrogen phosphates hitherto used cannot yet be said to have a completely satis- 50 factory charateristic properties as excipient, and therefore there has been required further improvement to be achieved in a easy handling including molding property and physical property of powders. DISCLOSURE OF THE INVENTION 55 [0008] An object of the present invention is to provide a powdery composition containing calcium hydrogen phos- phate and a saccharide which have a good powder-fluidity and a high compression moldability, which are quickly disin- tegrated and dissolved when put in the oral cavity or water in the form of granule, tablet, etc., which are useful as excipient, compression moldability-increasing agent, disintegration aid, administration-improving agent, intraoral quick 2 EP 1 008 353 A1 dissoluble agent, etc., and which can be used In medicines, foods, etc. [0009] 1';,,s a result of having ardently studied in order to solve the foregoing object, the present inventors have found that a powdery composition which rnay be obtained by spray-drying a suspension comprising water rnediurn, calcium hydrogen phosphate and a saccharide has greater moldability, taking feeling and water inducting ability or water 5 adsorbability (calcium hydrogen phosphate itself which is present in the composition has a micro-porous structure for water inducting or water adsorbing structure and further the composition obtained through spray-drying has numerous and fine cavities which become water conducting structure) in comparison with spray-dried preparation of calcium hydrogen phosphate alone. The present invention was completed based on this finding. [0010] That is, the invention involving claim 1 is a powdery composition containing a saccharide and calcium hydro- 10 gen phosphate which has been prepared by spray-drying a suspension comprising water medium, calcium hydrogen phosphate and a saccharide, the invention involving claim 2 is a composition containing a saccharide and calcium hydrogen phosphate wherein calcium hydrogen phosphate present in the suspension to be spray-dried is a scaly cal- cium hydrogen phosphate, the invention involving claim 3 is a composition containing a saccharide and calcium hydro- gen phosphate wherein the saccharide is erythritol, the invention involving claim 4 is a process for preparing a spherical 1" and powdered composition containing a saccharide and calcium hydrogen phosphate which is characterized by spray- drying an aqueous suspension comprising calcium hydrogen phosphate and a saccharide, the invention involving claim 5 is an excipient comprising as the main ingredient the composition containing a saccharide and calcium hydrogen phosphate as claimed in claim i, 2 or 3, the invention involving claim fi is a compression moldability-Â·improving agent for a pharmaceutical formulation which comprises as the main ingredient the composition containing a saccharide and 20 calcium hydrogen phosphate as claimed in claim 1, 2 or 3, the invention involving claim 7 is a disintegration aid com- prising as the main ingredient the composition containing a saccharide and calcium hydrogen phosphate as claimed in claim 1, 2 or 3, the invention involving claim 8 is an administration-improving agent comprising as the main ingredient the cornposition containing a saccharide and calcium hydrogen phosphate as claimed in claim 1, 2 or 3, the invention involving claim 9 is an intraoral instantaneous (quick) dissoluble agent comprising as the main ingredient the composi- 25 tion containing a saccharide and calcium hydrogen phosphate as claimed in claim i, 2 or 3. and the invention involving claim 10 is an intraoral instantaneous (quick) dissoluble agent which is characterized by containing further a saccharide in addition to the composition containing a saccharide and calcium hydrogen phosphate as claimed in claim 1. 2 or 3. [0011] The followings illustrate a powdery composition containing calcium hydrogen phosphate and a saccharide which may be prepared by spray-drying a suspension comprising water medium, calcium hydrogen phosphate and a 30 saccharide according to the present invention (hereinafter, referred to as "the composition") in detail. [0012] The composition has superior moldability to either the spray-dried product resulted from an aqueous sus- pension of calcium hydrogen phosphate alone or one resulted from an aqueous suspension of saccharide alone. For example, when compressed into a tablet form, there may be obtained a tablet having higher hardness than the tablet made from the spray--dried product of calcium hydrogen phosphate alone or saccharide alone. Even when it is mixed 35 with other excipient, the lowering in hardness is little. Also, the spray-dried product comprising calcium hydrogen phos- phate alone has particular rough feeling to the tongue when being laked. Contrary thereto, the composition of the present invention has no rough feeling and has refreshing sweetness, thus taking feeling is remarkably improved. In general, the use of a sugar alcohol gives refreshing sensation when it is put in the oral cavity. Among sugar alcohols, especially erythritol and xylitol are preferred. 40 [0013] On the other hand, when an aqueous soiution of saccharide is spray-dried or when it is spray-dried in the state of a medicine being dispersed or dissolved therein is spray--dried, the primary particles of saccharide formed by spray-drying melt partially at the heat temperature during spray-drying and subsequently the melted saccharide adheres to the inner wail of a spray dryer or an aggregation occurs through the mo!ten state of saccharide. For this rea-- son, not only the yield (recovery yield) of the spray-dried material is reduced but also the fluidity is not said to be good 45 owing to unevenness in the particle size. [0014] By preparing and spray-drying an aqueous suspension of a saccharide in the presence of calciurn hydrogen phosphate or an aqueous suspension of a saccharide, a medicine and/or other antacids in the presence of calcium hydrogen phosphate, there may be achieved advantages that not only saccharide does not melt, but also there may be obtained in a high yield composition containing saccharide having the desired particle size and a good fluidity. indeed, 50 as a means to prevent a saccharide from being molten during spray--drying, for example to lower the inlet and outlet temperatures as the spay-drying condition is considered. In this case, it can not be said to be efficient because the treat- ment time becomes long and this impairs the feature of the spray-drying process that the drying may be conducted instantaneously and continuously in a large amount. [0015] The composition involving in the present invention is an amorphous white powdery material which may be 55 obtained by suspending calcium hydrogen phosphate in an aqueous solution of a saccharide e.g. erythritol and then spray-drying the suspension, for exam pie under the condition of an inlet temperature of about 250 "C and an outlet tem- perature of fiO ~ 120 Â°C, preferably 70 ~ 90 Â°C for example with a nozzle or a disk spray--dryer according to the conven .. tionai manner. 3 EP 1 008 353 A1 [0016] The particle size of the composition involving in the present invention is not particularly limited. There may be obtained one having the desired particle size by varying the preparing condition such as the particie size, the amount concentration of saccharide to be used. The calcium hydrogen phosphate to be used in the present invention may be 5 either dry or wet powdery one which may be obtained by filtering the calcium hydrogen phosphate formed by the reac- tion (hereinafter, referred to as ''undried product"). The dry product may be obtained by spray-drying the undried prod- uct having a primary particle size of 0.1 -- about 1 jt described in ,Japanese Patent No. 2700i 41 or Japanese Patent Application No. Hei 8-293251 (Japanese Patent Application Laid-Open No. Hei 10-120408 gazette). Also, as to the undried product its suspension may be used as it is, and mixed with an aqueous solution or a suspension comprising a 10 saccharide, and the mixture may be subjected to spray-drying, thereby obtaining spherical particles. [0017] That the composit;on has an excellent moldability may be evidenced e.g. by a corn starch load test etc according to the conventional manner. For example, when the hitherto used calcium hydrogen phosphate is com- pounded with 20 % of corn starch and compressed into a tablet form under a pressure of 3000 kg, the hardness of the resultant tablet decreases by about 50 % as cornpared with that of control tablet where no corn starch is added. Con- 1" trary thereto, the composition of the present invention is still significantly excellent in moldability even when combined with 30 % of corn starch. Also, in case where the composition of the present invention has been used for tabletting, the residuai wall surface pressure and maximum release force are smaller than those of the spray-dried product of calcium hydrogen phosphate alone, and its action toward a punch and a die of tabletting machine becomes small so that the improvement in the tabletting suitability can be realized (see Examples described later). 20 [0018] The composition of the present invention enables the moldability of calcium hydrogen phosphate and the capacity of loading or mixture of drugs to increase, and it enables the wall surface friction to decrease. [OOH!] The combining ratio of calcium hydrogen phosphate to saccharide such as erythritol in the composition of the present invention is not particularly limited. However, 0.5 - 99.5 % by weight of calcium hydrogen phosphate to 99.5 -- 0.5 % by weight of erythritol as an example of saccharide, more preferably, 40 Â·-- 99.5 % by weight of calcium hydro- 25 gen phosphate to 60 ~ 0.5 % by weight of erythritol. [0020] Even by increasing the compression tabletting pressure, any effect by varing of the foregoing combining ratio on the residual wall surface pressure can not be seen. This suggests avoidance of the influence of the foregoing com- bining ratio on the tablet troubles such as sticking etc. [0021] In direct compression tabletting of the composition alone of the present invention, when compression tablet- 30 ting pressure of 500 kgf is applied there may be obtained a tablet having a hardness of 5 -- 7 kg. Also, although the increase in the tablet hardness by application of high compression tabletting pressure is observed, any prolongation in the disintegration time is not recognized. [0022] The results such as apparent density/tap density, water content, particle size distribution, stability, etc. which may be obtained by using the composition of the present invention lie within the normal range for the excipient to be 35 generally conducted in a direct tabletting procedure and rather indicate a good compression moldability, fluidity, taking feeling and whiteness. [0023] Also, since the composition of the present invention has a little friction resistance there can be avoided the troubles derived from the abrasion of a punch and a die in the tablet machine which is usually used in the tabletting. [0024] The followings illustrate a process for preparing the composition of the present invention. 40 [0025] The composition of the present invention may be obtained as an amorphous white powder by suspending calcium hydrogen phosphate in an aqueous solution of a saccharide and then spray .. drying the suspension for example under the condition of an inlet temperature of 200 Â°C and an outlet temperature of 100 'C for exampie with a nozzle or a disk spray-dryer according to the conventional manner. [0026] As to the particle size of the composition, it rnay be adjusted as desired by properly selecting the suspension 45 concentration, spray operation, drying condition, etc, as stated previously. [0027] As calciurn hydrogen phosphate which may be used in the present invention, for exarnple calciurn hydrogen phosphate ''ATS'' (a trade name, a product of Rhone-Poulenc Co., Ltd., "DiTAB" (a trade name, a product of Nikken Chemical Co., Ltd.), "GS Calica" (a trade name. a product of Kyowa Chemical Co., Ltd.), a spherical calcium hydrogen phosphate "Fujicalin SG'' (a trade name, a product of Fuji Chemical Industry Co., Ltd.), a scaly calcium hydrogen phos- 50 phate "Fujicalin" (a trade name, a product of Fuji Chemical Industry Co., Ud.), or the calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate obtained by the known process may be employed. Anhydrous calcium hydro- gen phosphate may be either calcium dihydrogen phosphate or calcium secondary phosphate. Calcium hydrogen phosphate may be used in combination with anhydrous calcium hydrogen phosphate. A spherical calciurn hydrogen phosphate "Fujicalin SG" and a scaly calcium hydrogen phosphate "Fujicalin" are preferred. 55 [0028] Also, the spherical calcium hydrogen phosphate which may be obtained by spray-drying the foregoing scaly calcium hydrogen phosphate is hardly soluble in water and neutral, and does not react with the main ingredient, and therefore it is not adversely affected on the main ingredient and the formulation. And, it is easy to handle owing to its good fiuidity and miscibility. Furthermore, it has a good affinity to water so that it is easily suspensible in water and a 4 EP 1 008 353 A1 slurry preparation may be conducted conveniently and simply. [0029] 1';,,s the saccharide, there are monosaccharide, oligosaccharide and polysaccharide. For example, sugar a!coho!s such as erythritol: rnannitol; sorbitoL xylitol and the like, rnaltitol: rnalt!lose: !actito!l spray-dried lactose, granu- lar lactose, anhydrous lactose, lactose, refined sucrose, reducing maltose, thick malt syrup, cane sugar (sucrose), fruit 5 sugar (fructose), arabitol, erythrose, glucose, fructose, xylose, arabinose and the like may be taken. [0030] The composition of the present invention may be used, when being spray-dried, in combination with inor- ganic or organic solid carriers for formulation which has been conventiona!!y used in the preparation of medicines, for example starches or celluloses such as crystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, hydroxypropylstarch, sodium carboxymethylstarch, sodium croscarmellose. calcium car- 10 boxymethyicelluiose and the like. [0031 l The selection of the l\ind and amount of saccharide to be added may be adequately made depending on the objects of the main ingredient and the formulation, for exarnple the improvement in molding property and disintegration, intraoral disintegratable formulation suited to therapeutic region for the aged person, and the like. Also, the particle size of saccharide may be adjusted as desired. Sugar alcohols such as erythritol, sucrose, fruit sugar (fructose), xylitol, 1" mannitol, arabitol and the like are easily soluble in water and hot ethanoi, and they may be used as the solution or the suspension. The amount used of sugar alcohols is not particularly limited. [0032] In case of non-caiory saccharides such as erythritol and xylitol, it is especially desirable to use them in the anti .. diabetic formulation. [0033] Also, erythritol, xylitol, etc. may be preferably used in the intraoral instantaneous (quick) dissoluble ibnnula- 20 tion owing to their taste with refreshing sensation (cooling sensation). [0034] The composition of the present invention comprising saccharaide and calciurn hydrogen phosphate can be molded into tablets by the known processes. The tablts may be obtained by direct compression tabletting the composi- tion alone or in combination with one or rnore of pharmaceutically active ingredients, in addition with binders, disinte- grants, colorants, flavoring agents, diluents, lubricants etc. The tablets may be molded into any forms as desired 25 including circular, e!!iptic and caplet-like forms irrespective of the size and shape. [0035] The composition of the present invention may also be used as a filler in powderes, fine granules, granules, capsules, etc .. or as an absorbent for oily materials such as fragrances. [0036] The composition of the present invention may be rnolded in the forms which are suitable for oral or non-oral administration in combination with inorganic or organic solid carriers for ibrmulation which have been conventionally 30 used in the preparation of medicines, for exarnple excipients such as starch, crystalline cellulose, hydroxypropyl meth- ylcellulose, calcium carboxymethylcellulose, hydrogenated oil, talc and the like; binders such as acacia, hydroxypropyl cellulose, aiginic acid, gelatin. polyvinyl .. pyrrolidone, partially alpha starch and the like; lubricants such as stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oil and the like; disintegrants such as modified atarch, calcium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymeth .. 35 ylstarch and the like; nonionic su1iactant, etc. [0037] The ibrms which are suitable for oral administration include tablets, capsules, powders, fine granules, gran- ules or their sugar coating, film coatings and the like. Ones which are suitable for local application include an ointrnent, a suppository, a plaster or a patching agent. absorbent for cream and viscosity-increasing agent. a gel, etc. [0038] The intraoral instantaneous (quick) dissolvable agent of the present invention is an intraorÂ·al quick dissoluble 40 formulation which contains the composition of the present invention as a functional excipient and which may be pre- pared by the general direct compression tabletting method. [0039] For preparing the tablets, the composition of the present invention may be used in combination with saccha- rides vvh!ch have been usua!!y used. [0040] This formulation may be obtained from the corn position of the present invention or one wherein an adequate 45 saccharide and other additives have been further incorporated by direct compression tableting with a tabletting tester. [0041] In case where the tablets are prepared using the composition of the present invention, the combining ratio is not particularly limited. For the moldability, however, it is desirable to incorporate 5 % by weight -- 99 % by weight, preferably 10 % by weight -- 70 % by weight of the composition per tablet weight. For giving a refreshing sensation to the oral cavity, it is preferable to incorporate 40 % by weight Â·-- 99 % by weight of the composition per tablet weight. For 50 preparation of intraorai instantaneous (quick) dissoluble agent. it is preferable to incorporate 50 % by weight -- 95 % by weight of the composition per tablet weight. [0042] The obtained tablets are instantaneous (quick) dissoluble. As a result of disintegration test conducted under condition not to chew them in the oral cavity, there may be prepared ones which are disintegrated within 1 rninute. in addition, by combining the composition of the present invention with an adequate saccharide, there can be conveniently 55 and simply obtained tablets having a disintegration tirne of i minute or less in all cases. The compression tabletting pressure and the tablet hardness are varied depending on the kind and amount of the composition to be used and not particularly limited. For example, by application of a pressure ranged 100-- 1000 kg there can be obtained a tablet hav .. ing a hardness of 1. i -- 14.5 kg. In case where disintegrants which have been generally used are added to the compo- 5 EP 1 008 353 A1 sition of the present invention, the disintegration time may be further shortened (see Exambles described later). [0043] In case where the composition which may obtained in the present invention is used as an excipient etc. for pharmaceutical preparation, the examples of its pharrnaceuticaiiy active ingredient include peripheral nervous system agent, antipyretic, anaigesic anti-infiammatory agent, central nervous system drugs such as hypnic sedative, psychic 5 and nervous system agent, etc.: peripheral nervous system agents such as skeletal muscle relaxants, autonomic nerv- ous system agents, etc.; cardiovascular and circulatory system agents such as cardiotonics, anti-arrhythmic drugs, diu- retics, vasodilators: respiratiry system agents such as bronchodilators, antitussives, etc.; gastrointestinal system agents such as digestive, intestinal function-controiiing agent, antacids, etc.; metabolic drugs such as hormones, anti- histaminic agents, vitamins, etc ; antiÂ·-ulcer agents, antibiotics, chemotherapeutic agents, crude drug-Â·extracts and the 10 iike. [0044] The composition of the present invention is suitable for use as an excipient ;n ( 1) medicines for the aged per- son, for example cardiovascular and circulatory system such as hypotensive drugs: antilipidemics and the like, (2) med- icines having poor moldability, or (3) medicines having bad taste such as bitter taste. [0045] The kind of a pharmaceutically active ingredient is not particularly limited in the present invention. As spe- 1" cific examples of the pharmaceuticaiiy active ingredient, there may be taken an active agent for cold remedy, an active agent for rhinitis and the like. Examples of the active agent for cold remedy include antipyretic, analgesic, anti-inflam-Â· matory agent, vasodiiators, antihistaminic agents, antitussives, expectorants, antitussive expectorants, vitamins, Chi- nese medecine extracts and the like. Examples of an active agent for the active agent for rhinitis include sympathomimetics, sympatholytics, anti-allergenic agents, anti-inflammato1y agents and the like. Examples of antipy- 20 retie, analgesic anti-inflammatory agents include aniline derivatives such as acetaminophen, phenacetin, lefetamine hydrochloride and the like; salicylic acid derivatives such as ethenzamide, sasapyrine, methyl saiicylate, phenyl sali- cylate, sodium salicylate, choline salicylate, aspirin, aspirin aluminum and the like; pyrazolone derivatives such as iso- propylantipyrine, sulpyrin, phenylbutazone, ketophenylbutazone, antipyrine, aminopyridine and the like; propionic acid derivatives such as ibuprofen, ketoprofen, oxaprozin, naproxen, fenoprofen calcium, tiaprofenic acid and the like; phe- 25 nylacetic acid derivatives such as fenbufen, diclofenac sodium, anfenac sodium and the like; indoleacetic acid derivaÂ·Â· lives such as indomethacin, indomethacin farnesil, proglumetacin maleate, sodium tolmetin and the like; anthranilinoacetic acid derivatives such as mefenamic acid, fiufenamic acid. tolfenamic acid and the like; oxicam deriv- atives such as piroxicam, arnpiroxicam, tenoxicam and the like; benzydamine hydrochloride, epirizole (mepirizole), tinoridine hydrochloride, tiaramide hydrochloride, etc., anti-inflammatory enzyme preparations, serrapeptase, lysoxyme 30 chloride and the like. These antipyretic, analgesic anti-infamrnatory agents may be used singly or in combination of two or more. [0046] Examples of bronchodilators include ephedrine hydrochloride, dl-Â·methylephedrine hydrochloride, dlÂ·-methyl- ephedrine hydrochloride saccharinate, isoprenaiine hydrochloride, isoproterenol sulfate, methoxyphenamine hydro- chloride, orciprenaline sulfate, chlorprenaline hydrochloride, trimetoquinol hydrochloride, salbutamol sulfate. terbutaline 35 sulfate, hexoprenaline sulfate, formoterol fumarate, fenoterol hydrobromide, procaterol hydrochloride, pirburol hydro- chloride, clenbuterol hydrochloride, mabuterol hydrochloride, xanthine derivatives such as aminophylline, theophylline, diprophylline, proxyphylline and the like; anti-cholinergics such as flutropium bromide, oxitropium bromide and the like. Examples of antihistaminic agents include ethanolamine antihystaminic agents such as diphenhydramine and the like; propylamine antihystaminic agents such as dl-chloropheniramine maleate, d-chloropheniramine maleate and the like; 40 phenothiazine antihystaminic agents such as alimemazine tartrate, isothipendyi hydrochloride, promethazine hydro- chloride, mequitazine, and the like: diphenylpyraline. carbinoxamine maleate. clemastine fumarate, iproheptine hydro- chloride, homochlorcyclizine hydrochloride, cycloheptazine hydrochloride, dimetindene maleate, triprolidine hydrochloride, etc. [0047] Examples of antitussives include codeines such as codeine phosphate, dihydrocodeine phosphate and the 45 like; dextromethorphan hydrobromide, cloperastine, noscapine dimemorfan, oxeladin, pentoxiverin citrate, eprazinone hydrochloride, clobutinol hydrochloride, isoaminile citrate, forninoben hydrochloride, clofedanol hydrochloride, ben- properine phosphate, hydrocotarnine hydrochloride, sodium dibunate, etc. [0048] Examples of expectorants include potassium guaiacolsulfonate: cysteine derivatives such as carbocysteine, L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride, acetylcysteine and the like; bromhexine, ambroxol 50 hydrochloride, etc. Examples of antitussive expectorants include guaiphenesin, tipepidine, oxymethebanol, aiioclamide hydrochloride, carbetapentane citrate, trimetoquinol hydrochloride, methoxyphenamine and the like. Some of the phar- maceutically active ingredients exemplified as antitussives, expectorants and antitussive expectorants described above show antititussive and/or expectorant actions. Examples of vitamins include vitamin B1, its derivatives or salt thereof such as fursultiamine, fursultiamine hydrochloride, prosultiamine, octotiamine, tiaminedisulfide, bisbentiamine, bisbu- 55 tythiamin, bisibutiamine, benfotiamine, cetotiarnine hydrochloride and the like; vitamin B2, its derivatives or salts thereof such as riboflavin, sodium riboflavin phosphate, sodium flavin-adenine-dinucieotide, riboflavin lactate and the like; vita- min C, etc. [0049] The drugs in the present invention may aiso include pharmacologically acceptable salts of the forgoing 6 EP 1 008 353 A1 drugs with an inorganic or an organic acid. Examples of an acid include hydrochloric acid, phosphoric acid, sulfuric acid, etc., tannic acid, citric acid, fendizoic acid, hibenzic acid, citric acid, etc. [0050] Exarnples of Chinese rned!cine extract include licorice, cinnarnon, puerariae radix, apricot kernel: bup!euri radix, ginger, ginseng, dried orange peel, pinelliae tuber and the like. 5 [0051] Exarnples of sympathomirnetic agents (o:-receptor stimuiants) which constitute drugs for rhinitis include decongestands such as phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, phenylephrine hydro- chloride and the like. Examples of parasympatholytics include beiiadonna alkaloids and the like. Examples of anti .. aller-Â· gic and anti-inflammatory drugs include tranexamic acid and the like. These active ingredients may be used singly or in combination of two or more. 10 [0052] If necessary, the active ingredients described above may be used in association with caffeines such as anhydrous caffeine, caffeine sodium benzoate, caffeine citrate, caffe;ne (monohydrate) and the like; minerals and amino acids thereof such as magnesium hydroxide, magnesium oxide, magnesium carbonate, magnesium siiicate, aiuminium sulfate, synthetic hydrotalcite [Alkamac (a trade name)j, synthetic aluminium silicate, dihydroaluminium aminoacetic acid salt, aluminium hydroxide gel, magnesium alumina metasilicate, rnagnesiurn alurnino silicate, aluminium hydrox- 1" ide-caicium hydrogen phosphate co-precipitate, sucralfate and the like. [0053] The features of the composition obtained by the present invention are shown as follows: there can be taken (1) improvement in the moldability of a tablet, (2) improvement of fluidity in tabletting (specifaclly, direct compression molded tablet has a good homogeneity with respect to the ingredient content), (3) improvement in taking feeling (refreshing sensation and/or cooling sensation), (4) improvement in disintegration property and (5) usefulness as 20 intraoral instantaneous (quick) dissoluble tablet. 25 BRIEF EXPLANATION OF THE DRAWINGS [0054] Fig. 1 is a scanning electron microgragh (SEM) of the spray-dried product comprising calcium hydrogen phos- phate/erythritol (75/25 % by weight) obtained in Example 3. Fig. 2 is a SEM of the spray-dried product comprising calcium hydrogen phosphate/erythritol (75/25 % by weight) obtained in Example 6. 30 Fig. 3 is a SEM of the spray-dried product comprising calcium hydrogen phosphate/erythritol (75/25 % by weight) obtained in Example 7. Fig. 4 is a SEM of the spray-dried product comprising calcium hydrogen phosphate/erythritol (75/25 % by weight) obtained in Example 8. Fig. 5 is a SEM of the spray-dried product comprising calcium hydrogen phosphate/lactose (75/25 % by weight) 35 obtained in Example 9. 40 45 50 Fig 6 is a SEM of the spray-dried product comprising calcium hydrogen phosphate/lactose (50/50 % by weight) obtained in Example 10. THE BEST MODE FOR CARRYING OUT THE INVENTION [0055] The followings illustrate uses of the composition obtained in the present invention in detail. Example 1 : Preparation of a composition wherein the combining ratio of calcium hydrogen phosphate to erythritol is 95 :5 [0056] 10 Grams of erythritol was dissolved in 1 liter of water and to the aqueous solution under stirring was added 190 g of spherical calcium hydrogen phosphate CFujicaiin SG'') was added. The resultant suspension was spray-dried using a centrifuge .. type atomizer at an iniet temperature of 250 Â°C and an outlet temperature of 100 ~ 110Â°C to obtain '180 g of white spherical granular material. Examples 2 ~ 5 [0057] There were prepared a series of compositions wherein the combining ratio of spherical calciurn hydrogen phosphate to erythritol is 85 : 15 Â·- 50 Â· 50 in a similar manner as in Example 1. 55 [0058] The results are shown in table Â·1. 7 EP 1 008 353 A1 Table i Example No. Amount mixed of Cal- Arnount mixed of Erythri- 5 cium Hydrogen Phos- tol (% by weight) phate (% by weight) 2 85 3 75 25 10 4 65 35 1---------------5-------------- -----------------------50----------------------- -----------------------5-0----------------------- 1" Physico-chemical test: [0059] Tablets for "Corn Starch Load Test" were prepared from the compositions obtained in Examples 1 Â·- 5 for evaluation of the moldability of said compositions and the comparison test was conducted for the physical property such as the tablet hardness. The "Corn Starch Load Test" is a method to evaluate such moldability by adding the composition 20 of the present invention or calcium hydrogen phosphate to a corn starch which has no molding property in itself as how to extent that the resuitant mixture can be molded into a tablet form. Example 6 25 [0060] Calcium hydrogen phosphate ",<\TAB" (a trade name. a product of RhoneÂ·-Poulenc Co., Ltd. and erythritol 30 were used to prepare a specimen in a similar manner as In Example 1, and then tablets for corn starch load test were prepared similarly as in the above. Example 7 [0061] Calcium hydrogen phosphate "OiTAB" (a trade name, a product of Nikken Chemical Co., Ltd.) and erythritol were used to prepare a specimen in a similar manner as in Example 1, and then tablets for corn starch load test were prepared similarly as in the above. 35 Example 8 40 [0062] Calcium hydrogen phosphate "GS Calice" (a trade name, a product of Kyowa Chemical Co., Ltd.) and eryth- ritol were used to prepare a specimen in a similar manner as in Example 1, and then tablets for corn starch load test were prepared simiiarly as in the above. Preparation of a tablet [0063] 8 Grams of the total amount weighed with respect to a mixture of the composition obtained in Example 3, a corn starch (a product of Nippon Corn Starch Co., Ltd.) and rnagnesium stearate (a product of Nippon Oils & Fats Co., 45 Ltd.)in the combining ratio(% by weight) shown in the following table 2. 50 55 [0064] The composition obtained in Example 3 was used for Experimental Exampies 1 - 6. A scaly calcium hydro- gen phosphate "Fujicalin" which may be prepared by the process disclosed in Japanese Patent Application Laid-Open No. Hei 7-118005 as the hitherto used product was used for Experimental Examples 7 -- 12. And the compositions obtained in Examples 6 - 8 were used ibr Experimental Examples 13 Â·-- 15, respetively. Tabie 2 Exp. No. Composition Content (~10 by vv't.) Content of Corn Starch Magnesium Stearate (% (~{;by vvt.) by wt.) Example 3 99 0 2 Example 3 89 10 8 5 10 20 25 EP 1 008 353 A1 Table 2 (continued) i----E~-r;:-N;:--r-----------c-;;;;;;-~;;;;-;------------y---c-;;~-i~-;i-(~Yo--by--~;;:)-T--c;-;1;~1--;f-C;;:~--3-;~;:~h--T-~~~-9;~-;~;~-;;--31-;~-~~1-;-(-~/o-- (~!Q by vvÂ·t.) by vvt.) 3 Example 3 l9 20 4 Example 3 69 30 5 Example 3 59 40 6 Example 3 49 50 7 Hitherto Used Product 99 0 8 Hitherto Used Product 89 10 -----------9---------- ---;:;:ii~-;;:i;--u-~~-d-f;;:;d-~;1-- r---------------~79------------------- -----------------------2-0----------------------- ------------------------1-------------------------1 Hitherto Used Product ! 69 30 I __________ :_~--------- ---~::~-~=:_:~--~-==-~-~:-~~-:~-~-1------------------~=------------------- -----------------------~-~----------------------- ________________________ :: _________________________ ) 12 Hitherto Used Product i 49 50 1 I . .. ! ! 13 Example 6 99 14 Exampie 7 ! 99 Â·1 1 ------------------------------------------------------------------------t--------------------------------------------------------------------------------------------- ---------------------------------------------------! 15 Example 8 i 99 1 i ! : Note) As the hitherto used product in Experimental Examples 7 -~ 12, a scaly calcium hydrogen phosphate alone ! was used. ! -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------J [0065] Each of the components in the combining ratio shown in table 2 was placed in a dried polyethylene bag and the bag was sealed not so as to absorb rnoisure. After mixing sufficiently, the mixture was compressed into a tablet form using "Tabletting Tester-SK-02" (a trade name, a product of Sankyo Biotech Co., Ltd.) to estimate the relationship 30 betvveen the compression tableting pressure and the tab!et hardness. [0066] The tablets each weighing 600 mg and having a diameter of Â·1 i .3 mm were prepared at a tabietting velocity of 10 mm/min under compression tableting pressures of 500 kgf, 1000 kgf, 2000 kgf and 3000 kgf [0067] The results are shown in Table 3. 35 Table 3 Exp No. Compression Tabletting Pressure 500 kgf Â·1000 kgf 2000 kgf 3000 kgf 40 28.3 46.6 7Hl 2 7.9 20. 1 4i .0 54.fi 3 6.9 19.7 39.9 ! 57.3 45 ----------:;---------- --------4-_-8------1------1-4::7-------- -------35:7-------1-------49-:4------- 5 2.9 11.6 24.9 34.3 ----------~---------- ------1-~~-~------1-------2-~-:------- -------;;:~-----+------;~-~~------- 50 8 84 15.9 30.4 35.8 ----------=---------- --------~:_: ____ ) __________ ::=-------- _______ :_:_:~-------!-------==-:~------- 10 2.5 i 5.2 11.8 I 15.3 : ! 1 i 2.0 5.5 10.1 12.2 55 12 Â·1.0 34 8.-1 7.5 9 EP 1 008 353 A1 [0068] It can be seen frorn the results shown in table 3 that the tablets made from the composition of the present invention have higher hardness even under all compression tabletting pressures applied and significantly increased trol tablets made from the hitherto used product alone-formulation wherein the com starch content is the same as that 5 in the composition of the present invention. 10 1" 20 25 30 35 [0069] CD The residual wall surface stress (Pwr), 0 the release force and Q) the maximum release force of the above samples were measured using a 'Tabletting Tester-SK-Â·02" apparatus. Table 4 --R~~;ci-~~-1--v;;~ii--s~-;t.;;;~--s-i~-;;~~--fr-;~~~~--~;;~-1i-Tf.:9i~;;2) __________________ _ Exp. No. Compression Tabletting Pressure 500 kgf Â·1000 kgf 2000 kgf 3000 kgf 10"1 188 318 449 2 94 150 229 292 ----------~----------- ---------~~-------\--------2~-~-------- -----<-~-~------- -----<-~~------- 5 63 79 73 60 ----------~----------- -------1-~:-------1--------2~-~-------- --------4~-~------- -------5~~------- 8 122 197 321 427 9 106 I 164 250 302 ---------1-0--------- ---------93-------1--------1-:i-4 ________ --------1-9-3------- -------225------- 11 89 128 174 182 ---------~:--------- ---------~:-------\------<~-~-------- --------~~:------- -------:;~------- 14 59 101 194 284 [0070] As is apparent from the results shown in Table 4, the composition of the present invention gives tablets hav- ing less wall surface abrasion in all of the formulations and compression tabletting pressures applied, then better com- pression moldability as cornpared with the control calcium hydrogen phosphate alone wherein the corn starch content 40 is the same as that in the composition of the present invention. Table 5 Maximum Release Force (Pej) 45 Exp. No. Compression Tabletting Pressure ---------------------- --------------------.--------------------------------------------------------------------- 500 kgf ! 1 000 kgf 2000 kgf 3000 kgf 10.9 19.8 37.5 54.9 50 ----------=---------- ________ ::~ ____ J ______ 2~-~~------- -------=~~-~------- -------~-=:-~------- 3 7.6 '11.0 15.7 18,3 4 6.4 10.1 10.6 11 0 5 5.9 7.6 7.7 7.5 55 6 7.3 6.9 6.2 5.6 7 30.3 43.7 74.5 92.6 EP 1 008 353 A1 Table 5 (continued) r----------------------------~~~-~i~~-~~~--Fi~i-;~~-;-F;;:;~--(f;~j) _____________________________ J Exp. No. Compression Tabletting Pressure 5 500 kgf 1000 kgf 2000 kgf 3000 kgf 8 173 27.2 44.9 61.0 9 13.9 20.6 31.2 37.0 10 ---------~-~--------- _____ 2_~-:~-----1------~-~:-~------- --------~::_: _______ . ------~-=:-~------- 11 iOO 14.2 17.1 17.4 i2 8.9 11 7 i 2.6 11.4 13 5.6 130 29.5 48.1 1'> 14 7.0 14.3 28.9 41.8 i5 5.6 11.5 24.3 39.5 [0071] The composition of the present invention gives tabiets having less realease force as compared with the cal- 20 cium hydrogen phosphate alone-formulation. Experimental Examples 16 -- 19 [0072] As a sample, 10 g of each recipe weighed which comprises 97 % by weight of the spray-dried product 25 wherein the combining ratio of a spherical calcium hydrogen phosphate "Fujicalin SG" to erythritol is 95 : 5. (Example Â·1), 85: 15 (Example 2), 75: 25 (Example 3) or 65: 35 (Example 4), 2 % by weight of sodium croscarmellose and 1 % by weight of magnesium stearate (a product of Nippon Oils & Fats Co., Ltd.) , and was mixed in a dried polyethylene bag to prepare a specimen for a tabletting tester, which was molded into tablets for Experimental Examples 16 - 19. 30 35 40 45 50 55 [0073] Table 6 Exp. No. Amount of Composition Sodium Croscarmellose Magnesium Stearate (% 16 17 18 19 in each of Examples (% bywt.) (Example 1) 97 (Example 2) 97 (Example 3) 97 (Example 4) 97 (%bywt.) bywt.) 2 2 2 2 Test for the relationship between compression tabletting pressure and the tablet hardness was conducted according to a similar manner as in the above. Tabie 7 Exp. No. Compression Tabletting Pressure 500 kgf 1000 kgf 2000 kgf 3000 kgf 16 6.4 '13.6 27.1 38.9 17 7.4 16.3 33.4 49.1 18 8.7 20.6 40.0 57.2 19 6.1 '16.5 40.3 56.0 [0074] As can be seen from the results shown in Table"?, in considering the combining ratio of erythritol to calcium 11 EP 1 008 353 A1 hydrogen phosphate application of the compression tabletting pressure of 500 kgf results in the formation of tablets having sufficient hardness required as the plain tablets even in all of the combining ratios, and the tablet hardness [0075] The compositions of Experimental Examples 16 -- 19 for the residual wail surface stress was tested in a sim- 5 liar rnanner as previously stated. [0076] As a result, there was recognized a slight effect of the disintegrant on the residual wall surface stress, but there was not recognized any effect of the combining ratio of erythritol to calcium hydrogen phosphate on it. [0077] The compositions of Experimental Examples 16 ~- 19 for the maximum reiease force was tested in a similar manner as previously stated. 10 [0078] As a result, there was not recognized any effect of the disintegrant on the reiease force but there was shown a tendency to diminish effect of the combin;ng ratio of erythritol to calcium hydrogen phosphate on it. Disintegration test: 1" [0079] According to the method of the Japanese Pharmacopoeia, three tablets in each test were immersed in the 20 25 30 35 40 first liquid of the ,Japanese Pharmacopoeia, and the time required for the form of the tablet to be completely disinte-Â· grated was measured. [0080] [0081] Exp. No. 16 Tabie 8 Compression Tabletting Pressure 500 kgf 1 000 kgf 2000 kgf 3000 kgf 1.7 i .7 2.Â·1 1.3 1.3 1.3 1.1 1.2 1.1 1.0 1.1 1.2 ------------------------------------------+--------------------- --------------------------------------------- 17 "7 I 3 2 2 2 3 1 ~:~ ,.:1 3.1 2. i 3:0 3.8 3.2 3.0 3.1 ------------------------------------------+---------------------- --------------------------------------------- 18 6.0 .:1 5.4 3.8 6.0 6.1 5.5 4.4 5.6 ---------------------- --------~:~ _____ J _______ ~~-~-------- --------~:-~--------- ---------~:~-------- 19 69 I 49 62 i:;7 _ili_;_j_ Disintegration time in the table is shown in minute. Aithough there was recognized a tendency to extend the disintegration time with decrease in the amount 45 compounded of calcium hydrogen phosphate or with increase in the amount compounded of erythritol. there was not recognized any effect of the rnolding pressure on it. 50 [0082] In synthesizing the evaluation results of the moldability and the disintegrabliity, it can be seen that an improvement in the moldability and adjustment of the disintegrating property may be made by the combining ratio of saccharide to calcium hydrogen phosphate. (Evaiuation of taking feeling) [0083] A tongue test by six volunteers (three men and three wornen) in the Company was carried out. Tablets pre- pared by application of a compression tabletting pressure of 500 kg to the formulation of Experimental Example 19 were 55 used as sampies, and their taste, aftertaste, cooling sensation, taking feeling and intraorai dissolution property were evaluated by ranking of "Good" "Ordinal" and "Bad". Tablets consisting of calcium hydrogen phosphate ".ATB" alone were used as control. 12 5 10 Sample Tablet Tested Control Â·rabiet Taste and After- taste (Number of Person) EP 1 008 353 A1 Table 9 Cooling Sensa- tion (Number of Person) Taking Feeling (Number of Per- son) Slight sweet taste Preferable owing Gradually dis- and refreshing aftertaste ( 6 per- sons) Tasteless (6 per- sons) to cooling sensa- tion (5 persons) solved in the mouth and not sticky (6 per- sons) None (6 persons) Adhered to teeth and tongue (5 persons) lntraoral (Disinte- gration) Dissolu- tion Property Dissolved (disinte- grated) within 1-Â·2 rninutes Dissolved (disinte- grated) within i minute Total Evaluation Excellent Siighyly bad [0084] Furthermore, the kind and amount of the disintegrant are selected in the combination with the composition of the present invention and followed by forming into a tablet having a sufficient hardness range required as an indus- 20 trially feasible tablet, thereby instantaneously (quickly) dissoluble tablets suited to the intended use and tablets having the general disintegration degree may be obtained. Examples 9 -- 1 0 25 [0085] 1'!,, spherical calcium hydrogen phosphate "Fujicalin SG" and lactose in the following formulations were spray-Â· 30 35 40 45 dried in a similar manner in Example 1 to prepare the respective calcium hydrogen phosphate-lactose compositions which are designated as samples for Examples 9 ~ i 0. Table 10 Example No. Amount of Calcium Amount of Lactose(% by Hydrogen Phosphate(% wt.) by vvt.) g 75 10 50 50 Cornparative Exarnple 1 [0086] Calcium hydrogen phosphate and magnesium stearate were combined so as to become 99 % by weight and i % by weight, respectively and the mixture was formed into tablets in a similar manner as stated previously. Cornparative Exarnple 2 [0087] Lactose and magnesium stearate were combined so as to become 99 % by weight and 1 % by weight, respectively and the mixture was formed into tablets in a similar manner as stated previously. [0088] 1'!,, series of tests were conducted using samples for Examples 9 ~ 10 and Comparative Examples 1 ~ 2 to evaluate the relationship between the compression tabletting pressure and any of the tablet hardness, the residual wall 50 surface stress and the maximum release force. Table 11 55 Examole No. Compression Tabletting Pressure ! ---------------------------------------------------- -------------------- -----------------------,----------------------- ----------------------~ 500 kgf 1000 kgf ! 2000 kgf 3000 kgf ! Example 9 122 194 328 394 EP 1 008 353 A1 Table Â·11 (continued) i---------------E~-;;~~-pi~--N;:Â·------------rÂ·----------c;;-~P-~~-;;;;-~-=r~-;;i~!ii~\1--P~-~~~~-~~--------------] 500 kgf 1 000 kgf ! 2000 kqf 3000 kgf I - 5 ___ ::~_'.:~~:=--~-~--------------------------- ______ ::.~=------- --------~-~-~-------1--------~=~------- -------=-==-------- Comparative Example 1 131 215 ! 361 496 I Comparative Example 2 95 141 285 343 10 [0089] A test was conducted to evaluate the relationship between a compression tabletting pressure and the hard- ness of the resultant tablets. [0090] From the results shown in the above tabie, the hardness of the tablets made from the spray-dried lactose- calcium hydrogen phosphate composition is higher than that of tablets made from lactose alone. Thus, it could be con- 1" firmed that the composition of the present invention where lactose is concerned increases moldability. [0091] Also, the residual waii surface stress was tested in a similar manner as stated previously. Table 12 20 Example No. Compression Tabletting Pressure 500 kgf 1 000 kgf 2000 kgf 3000 kgf 25 ---:;~~~~;~--~0--------------------------- ----<-~~------ --------~-:~--------\--------~~-~-------- --------~~-~------- Comparative Example 1 131 215 361 496 ---~~::_:~~-~~-:'.~=--~~:::_:~~-:_: ____ ---------=-~------ ________ ::_::: _____ ___! ________ :~-=-------- --------=~-=------- 30 [0092] The calciurn hydrogen phosphate-lactose composition decreases in the residual wall surface stress. 45 [0093] [0094] Table 13 r -------------------------------------------------------------------------------------------------------------------------------------------------1 Maximum release force test ---~~~~~~~-~~~~--:~~~~;~-~---- --------~~-------- ---------~-;---------\---------~-~--------- ---------~;--------- The maximum release force was tested in a similar manner as stated previously. With respect to raiease force, the calcium hydrogen phosphate-lactose composition decreases in the resid- ual wall surface stress. 50 1';,, process for preparing an intraoral instanteneous (quick) dissoluble (disintegratable) agent [0095] It was prepared by direct compression tabletting of a mixture of the composition of the present invention and saccharide using a tabletting tester. [0096] In the following Examples Â·11 - 13, there was used the composition obtained in Example 4 wherein a sus- 55 pension comprising 65 % of calcium hydrogen phosphate and 35 % of erythritol was spray-dried. 14 EP 1 008 353 A1 Example Â·11 [0097] A spray-dried povvder obtained in Exarnple 4, !actose and rnagnes!urn stearate vvere co!nbined so as to be 60 % by weight, 39 % by weight and Â·1 % by weight, respectively and mixed together. Thereafter, tablets each weighing 5 500 mg (tablet diarneter:11.3 mm) were obtained. The relationship between moiding pressure and hardness, and intraoral disintegration property (without chewing) are shown in the foilowing table. 10 Molding Pressure (kg) 100 200 500 800 Table 14 Hardness (kg) 1. 1 1.2 2.6 4.5 lntraoral Disintegration Time (min) Within 1 minute Within 1 minute Within 1 minute Within 1 minute 20 Example 12 [0098] A spray-dried powder obtained in Example 4, erythritol and magnesium stearate were combined so as to be 60 % by weight, 39 % by weight and 1 % by weight, respectively and mixed together. Thereafter, tablets each weighing 500 mg (tablet diameter:11.3 mm) were obtained. The relationship between moiding pressure and hardness, and 25 intraoral disintegration property (without chewing) are shown in the foilowing table. 30 35 Molding Pressure (kg) 200 500 800 Example Â·13 Table 15 Hardness (kg) Â·1.5 3. 1 intraorai Disintegration Time (min) Within 1 minute Within Â·1 minute \tVith~n 1 m~nute [0099] A spray-dried powder obtained in Example 4, erythritol, AC-di-sol and magnesium stearate were corn- 40 pounded so as to be 60 % by weight, 34 % by weight, 5 % by weight and 1 % by weight, respectively and mixed together. Thereafter, tablets each weighing 500 mg (tablet diameter:11.3 mm) were obtained. The relationship between molding pressure and hardness, and intraoral disintegration property (without chewing) are shown in the following table. 45 50 [0100] Molding Pressure (kg) 500 750 1000 Table 16 Hardness (kg) 1.5 2.5 3. 1 lntraoral Disintegration Tirne (min) Within 1 minute Within 1 minute Within 1 minute From the results shown in the above, the intraoral disintegration time is within 1 minute, thus showing suffi- 55 cient disintegration property [instantaneously (quickly) dissolution property] even when !abetting was done under mold- ing pressure required generally to impart a necessary hardness to a tablet. 15 EP 1 008 353 A1 Example Â·14 [0101] To 500 rr1! of vvater under stirring vvas added i 20 g of erythritol and then 30 g of a!d!oxa, 60 g of rnagnesiu!n alumina silicate "Neusilin A" (a trade name, a product of Fuji Chemical Industry Co., Ltd.) and 36 g of scaly calcium 5 hydrogen phosphate "Fujicalin" were added thereto, followed by stirring and subjected to dispersion treatment with Mycolloider. The resultant suspension was spray-dried at an inlet temperature of 250 'C and an outlet temperature of 81 Â°C to obtain 183 g of powders (77.4 % recovery). 10 Example 15 [0102] To 500 ml of water under stirring was added 120 g of xylitoi and then 30 g of aidioxa, 60 g of magnesium aiumino silicate "Neusilin A" and 36 g of scaly calcium hydrogen phosphate "Fujicalin" were added thereto, foiiowed by stirring and subjected to dispersion treatment with Mycolloider, The resultant suspension was spray-dried at an inlet temperature of 250 Â°C and an outiet temperature of 91 "'C to obtain 129 g of powders (54.2 % recovery). Example 16 [0103] To 500 ml of water under stirring was added 120 g of sorbitol and then 30 g of aldioxa, 60 g of magnesium alumino silicate "Neusilin A" and 36 g of scaly calcium hydrogen phosphate "Fujicalin" were added thereto, followed by 20 stirring and subjected to dispersion treatment with rv1ycolloider. The resultant suspension was spray-dried at an inlet temperature of 250 Â°C and an outiet temperature of 90 Â°C to obtain 129 g of powders ( 40.5 % recovery). Comparative Example 3 25 [0104] To 420 ml of water under stirring was added 120 g of erythritol and then 30 g of aldioxa, 60 g of magnesium aiumina silicate "Neusilin .A" were added thereto, followed by stirring and subjected to dispersion treatment with l\ilycol- loider. The resultant suspension was spray .. dried at an inlet temperature of 250 Â°C and an outlet temperature of 90 Â°C to obtain 136 g of powders (66 % recovery). 30 Cornparative Exarnple 4 [0105] To 420 ml of water under stirring was added 120 g of xylitol and then 30 g of aldioxa, 60 g of magnesium alumino silicate "Neusilin A" were added thereto, foilowed by stirring and subjected to dispersion treatment with Mycol- loider. The resultant suspension was spray .. dried at an inlet temperature of 250 Â°C and an outlet temperature of 72 ~ 35 82 Â°C to obtain 16. 1 g of powders (7.9 % recovery). Comparative Example 5 [0106] To 420 ml of water under stirring was added Â·120 g of sorbitol and then 30 g of aldioxa, 60 g of magnesium 40 aiumino silicate "Neusilin .A" were added thereto, followed by stirring and subjected to dispersion treatment with l\ilycol- loider. The resultant suspension was spray-dried at an inlet temperature of 250 Â°C and an outlet temperature of 75 -- 80 'C to obtain 21 .2 g of powders (1 Â·1.5 % recovery). [0107] The yields of the saccharide-containing compositions obtained in Examples 14 -- 16 were as shown in table 17. 45 [0108] For comparison, the results prepared without adding calcium hydrogen phosphate are shown in Compara- tive Examples 3 -- 5. 50 Example Â·14 Example 15 55 Example 16 Comparative Exampie 3 Table 17 Saccharide Calcium Hydrogen Phos- Yield (%) phate Erythritol Xylitol 54.2 Sorbitol 40.5 Er;thritol 66.0 16 EP 1 008 353 A1 Table 17 (continued) i----------------------------------------------------r-s-;;~~h-~~1ci~--Tc~-i;1~;:;;-;:;yd-~;-;~-~-Ph;-~~-r-y1~ici--(-~;~-i---1 phate 5 Comparative Example 4 Xylitol - 7. 9 Comparative Example 5 Sorbitol - 11.5 [0109] It can be seen that the yield may be significantly improved by spray-drying in the prsence of calcium hydro- 10 gen phosphate. INDUSTRIAL APPLICABILITY [0110] According to the present invention, there can be provided a powdery composition containing calcium hydro- 1" gen phosphate and saccharide which has characteristic properties such as (1) improvement in the moldabiiity of a tab- let, (2) improvement in fluidity (specifaclly, direct compression molded tablet has a good homogeneity in the ingredient content), (3) improvement in taking feeling [refreshing sensation (cooling sensation)], (4) improvement in disintegration property, (5) disintegration property required for intraoral instantaneous (quick) dissoluble tablet and the like. [0111] The composition of the present invention may be obtained by a simple and convenient process wherein a 20 suspension comprising water medium, calcium hydrogen phosphate and a saccharide is spray-dried. Also, as the com- position having the desired particle size rnay be prepared by altering the spray-drying condition properly, it is able to be flowed into the dies of high speed tabletting machine without causing bridging which occurs often with fine powders. Furthermore, it may be obtained as a hornogenious particie in a large amount in a short time. The composition of the present invention has features that it is non-hygroscopic and stable under the normai condition and that it has little fric- 25 lion coefficient and that it is soft and has a good stability of particle. 30 35 40 45 50 55 [0112] The composition of the present invention is useful as an excipient, etc. Claims 1. 2. '.l 4. 5" li 7" 8. 9. 10. A composition containing a saccharide and calcium hydrogen phosphate which is in a powdery forrn and which is prepared by spray-drying a suspension comprising water medium, calcium hydrogen phosphate and a saccharide The composition as claimed in ciaim 1 wherein calcium hydrogen phosphate present in the suspension to be spray- dried is a scaly calcium hydrogen phosphate The composition as claimed in claim 1 wherein the saccharide is erythritol. A process for preparing the composition as claimed in claim 1 which is characterized by spray-drying a suspension comprising water medium, calcium hydrogen phosphate and a saccharide. f\n excipient comprising as the main ingredient the composition as claimed in any of claims 1 -- 3. A compression moldability-improving agent of a phamaceutical preparation which comprises as the main ingredi-Â· ent the cornposition as claimed in any of claims 1 ~Â· 3. A disintegration aid comprising as the main ingredient the cornposition as claimed in any of claims 1 ~Â· 3. A taking feeling-improving agent comprising as the main ingredient the composition as claimed in any of claims 1 - 3. An intraoral instantaneous (quick) dissoluble agent comprising as the main ingredient any one of the composition as claimed in any of claims 1 - 3. The intraoral instantaneous (quick) dissoluble agent as claimed in claim 9 which is characterized by containing fur- ther a saccharide. Fig~ 1 ~ I l ~ EP 1 008 353 A1 ... Â·Â·Â·Â·Â·-Â·--Â·Â·--Â·Â·' ....... ' ... Â·'-Â·----------------Â·" --------------------1 ! ~ l l ' j t ; ' ' ~:::_~:~,:~---~~--... ~~ .... , ..,, ............................. -.............. ; ............. __ ..... """"_Â·Â·-....Â·Â·Â·Â·Â·Â·-Â·Â·Â·" ..................... ,, ....................... -.... .,,.,,.,,.,. ... J. r- ! ! i i ! I I ! i l EP 1 008 353 A1 . 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