US 20090311321A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0311321 A1 Mimura et al. (43) Pub. Date: Dec. 17, 2009
(54) ORAL DISINTEGRATING TABLET HAVING (30) Foreign Application Priority Data MLASKED BITTERTASTE AND METHOD FOR PRODUCTION THEREOF Aug. 8, 2006 (JP) ...... 2006-215146 (75) Inventors: Kazuki Mimura, Nagano (JP); Publication Classification Yasuhiro Takeda, Nagano (JP); (51) Int. Cl. Ken Kanada, Nagano (JP) A69/20 (2006.01) Correspondence Address: A63L/403 (2006.01) SUGHRUE MION, PLLC (52) U.S. Cl...... 424/465; 514/412 2100 PENNSYLVANIA AVENUE, N.W., SUITE 8OO (57) ABSTRACT WASHINGTON, DC 20037 (US) The present invention provides an orally disintegrating tablet containing mitiglinide calcium hydrate. The tablet has (73) Assignee: KISSE PHARMACEUTICAL reduced bitterness and quickly disintegrates in the mouth, CO.,LTD., Matsumoto-shi (JP) while exhibiting rapid dissolution in the digestive tract. The bitterness-masked orally disintegrating tablet comprises: (a) (21) Appl. No.: 12/376,161 mitiglinide calcium hydrate; (b) microcrystalline cellulose; (c) at least one masking agent selected from the group con (22) PCT Fled: Aug. 3, 2007 sisting of aminoalkyl methacrylate copolymer E. polyviny (86) PCT NO.: PCT/UP2007/065228 lacetal diethylaminoacetate, an ethyl acrylate-methyl meth acrylate copolymer, and ethyl cellulose; (d) a Sugar or a Sugar S371 (c)(1), alcohol; and (e) at least one selected from corn starch and (2), (4) Date: Feb. 3, 2009 partially pregelatinized starch. US 2009/03 11321 A1 Dec. 17, 2009
ORAL DISINTEGRATING TABLET HAVING 0012 Patent literature 5: A pamphlet of International Pub MLASKED BITTERTASTE AND METHOD lication 2002/002083 FOR PRODUCTION THEREOF DISCLOSURE OF THE INVENTION TECHNICAL FIELD 0013 The inventors of the present invention conducted studies on orally disintegrating tablets containing mitiglinide 0001. The present invention relates to a bitterness-masked calcium hydrate. The studies found that mitiglinide calcium orally disintegrating tablet containing mitiglinide calcium hydrate produces a strong bitter taste during administration. hydrate, and a method for preparing Such tablets. Because the orally disintegrating tablets are designed to quickly disintegrate in the mouth, the influence of bitterness BACKGROUND ART becomes a big factor when the active ingredient has a bitter taste. It was also found that, because the mitiglinide calcium 0002 Mitiglinide calcium hydrate (chemical name: (+)- hydrate does not easily dissolve in water, simply disintegrat Monocalcium bis(2S,3a,7a-cis)-O-benzylhexahydro-y-oxo ing the tablet in the mouth is not sufficient to rapidly dissolve 2-isoindolinebutyratedihydrate) has an activity to improve the compound in the digestive tract. Under these circum stances, the inventors of the present invention conducted stud postprandial hyperglycemia in type-2 diabetes mellitus. The ies to provide a mitiglinide calcium hydrate-containing orally mechanism of action involves binding to the Sulfonylurea disintegrating tablet having reduced bitterness and capable of receptors of the pancreatic B cells to inhibit ATP-dependent rapidly dissolving in the digestive tract. K" channel currents and thereby promoting insulin secretion 0014 Various methods have been proposed to reduce bit (see Non-Patent Document 1, for example). terness, using, for example, a flavoring agentoragel-forming 0003 Mitiglinide calcium hydrate is commercially avail anionic polymer (see Patent Document 3, for example), and a able as a tablet preparation, intended for oral administration water-insoluble polymer (see Patent Document 4, for in a single dose of 5 to 20 mg for adults, three times a day. example). The inventors of the present invention applied Mitiglinide calcium hydrate is taken immediately before each these techniques to mitiglinide calcium hydrate. However, a meal, or more preferably within 5 minutes before meal, sufficient masking effect could not be obtained with the addi because absorption is slow and the efficacy attenuates in tion of a flavoring agent or a gel-forming anionic polymer. postprandial administration. In order to provide an insulin Adding a water-insoluble substance reduced bitterness, but secretagogue capable of quickly exhibiting its action after the dissolution of the drug was delayed in this case. A method administration, there have been developments of mitiglinide is proposed in which the masking effect is provided by spray calcium hydrate-containing preparations that can rapidly dis drying a mixture of a bitter drug and an insoluble polymer (see Patent Document 5, for example). However, this tech Solve in the digestive tract. nique is not applicable to mitiglinide calcium hydrate, 0004. There have also been developments of solid prepa because of the strong water repellency of mitiglinide calcium rations that can quickly disintegrate or dissolve in the mouth, hydrate. in an effort to provide a dosage form readily administrable to 0015 The inventors of the present invention further con the elderly, children, and patients having a problem with ducted intensive studies on orally disintegrating tablets using Swallowing, or a dosage form that does not require water for a water-insoluble Substance as a masking agent. As a result, it administration. was found that an orally disintegrating tablet having consid 0005 WO2003/61650 discloses an orally disintegrating erably reduced bitterness and capable of rapidly dissolving in tablet containing (a) mitiglinide calcium hydrate, and (b) the digestive tract can be obtained when it includes a granu granules of co-spray dried lactose and starch (see Patent lated material formed from mitiglinide calcium hydrate, Document 1, for example). However, WO2003/61650 does microcrystalline cellulose, and a water-insoluble Substance. The inventors of the present invention also found that an not disclose anything about a bitterness-masked orally disin orally disintegrating tablet having an appropriate hardness tegrating tablet of mitiglinide calcium hydrate. and capable of quickly disintegrating in the mouth can be 0006 WO00/71117 discloses an immediate-release obtained when it is prepared from Such a mitiglinide calcium medicinal composition for oral use, containing mitiglinide hydrate-containing granulated material, a Sugar or a Sugar calcium hydrate as an active ingredient (see Patent Document alcohol, and at least one selected from corn starch and par 2, for example). However, the medicinal composition dis tially pregelatinized starch. The present invention was closed in WO00771117 is an immediate-release tablet for the accomplished based on these findings. digestive tract such as the stomach, and the publication does 0016 Specifically, the present invention provides: not disclose anything about tablets that can quickly disinte grate in the mouth, nor does it disclose bitterness-masked 0017. 1 a bitterness-masked orally disintegrating tablet, orally disintegrating tablets. comprising: (a) mitiglinide calcium hydrate as a bitter active ingredient; 0007. Non-Patent literature 1: Ohnota H. et al., J. Phar (b) microcrystalline cellulose; macol. Exp. Then, 1994, vol. 269, p. 489-495 (c) at least one masking agent selected from the group con 0008 Patent literature 1: A pamphlet of International Pub sisting of aminoalkyl methacrylate copolymer E. polyviny lication 2003/61650 lacetal diethylaminoacetate, an ethyl acrylate-methyl meth 0009 Patent literature 2: A pamphlet of International Pub acrylate copolymer, and ethyl cellulose; lication 2000771117 (d) a Sugar or a Sugar alcohol; and 0010 Patent literature 3: JP-A-4-235.136 (e) at least one selected from corn starch and partially prege 0011 Patent literature 4: JP-A-2004-339071 latinized starch; US 2009/03 11321 A1 Dec. 17, 2009
0018 2 a bitterness-masked orally disintegrating tablet, soluble acrylic polymer. Examples of the stomach-soluble comprising: polymer include methyl methacrylate-butyl methacrylate a granulated material including: dimethylaminoethyl methacrylate copolymers such as ami (a) mitiglinide calcium hydrate as a bitter active ingredient; noalkyl methacrylate copolymer E (For example, Eudragit (b) microcrystalline cellulose; and EPO, Roehm Pharma Gmbh: Eudragit E100, Roehm Pharma (c) at least one masking agent selected from the group con Gmbh), and stomach-soluble polyvinyl derivatives such as sisting of aminoalkyl methacrylate copolymer E. polyviny polyvinylacetal diethylaminoacetate (for example, AEA, lacetal diethylaminoacetate, an ethyl acrylate-methyl meth Sankyo). Examples of the water-insoluble cellulose ether acrylate copolymer, and ethyl cellulose; include ethyl celluloses (for example, Ethocel STD10FP. (d) a Sugar or a Sugar alcohol; and Dow Chemical Company), and aqueous dispersions of ethyl (e) at least one selected from corn starch and partially prege latinized starch; cellulose (for example, Aquacoat, FMC). Examples of the 0019. 3 an orally disintegrating tablet according to 1 or water-insoluble acrylic polymer include dispersion liquids of 2, wherein the Sugar or the Sugar alcohol is lactose or ethyl acrylate-methylmethacrylate copolymer (for example, D-mannitol; Eudragit NE30D, Roehm Pharma Gmbh). Among these 0020 4 an orally disintegrating tablet according to 1 or masking agents, the stomach-soluble polymer, capable of 2, wherein the Sugar or the Sugar alcohol is D-mannitol; rapidly dissolving in the stomach, is preferable in terms of 0021 5 an orally disintegrating tablet according to 1 or masking effect and solubility. In the same respect, aminoalkyl 2, wherein the masking agent is at least one selected from methacrylate copolymer E and polyvinylacetal diethylami aminoalkyl methacrylate copolymer E and polyvinylacetal noacetate are most preferable. As required, these masking diethylaminoacetate; agents may be used in a combination of two or more. 0022 6 an orally disintegrating tablet according to 2. 0030. When a water-insoluble substance is added as a wherein the granulated material is obtained by granulating a masking agent, the property of the tablet to disintegrate and mixture of mitiglinide calcium hydrate and microcrystalline disperse suffers, which, in turn, lowers the dissolution prop cellulose while spraying at least one masking agent selected erty of the tablet, or the drug dissolution from the drug from the group consisting of aminoalkyl methacrylate containing particles of the disintegrating tablet. It is therefore copolymer E. polyvinylacetal diethylaminoacetate, an ethyl required that the water-insoluble substance be added in such acrylate-methyl methacrylate copolymer, and ethyl cellulose; amounts sufficient to reduce bitterness in the mouth but not 0023 7 an orally disintegrating tablet according to 2. detrimental to the rapid dissolution of the drug in the digestive wherein the granulated material has an average particle diam tract. In an orally disintegrating tablet of the present inven eter of 60 to 150 um: tion, the content of the masking agent, though it depends on 0024 8 a bitterness-masking particle for orally disinte the type of masking agent, is generally about 1 to about 100 grating tablets, parts by weight, preferably about 5 to about 50 parts by the particle including: weight, and more preferably about 10 to about 50 parts by (a) mitiglinide calcium hydrate; weight, with respect to 100 parts by weight of mitiglinide (b) microcrystalline cellulose; and calcium hydrate. (c) at least one masking agent selected from aminoalkyl meth 0031. As mentioned above, the mitiglinide calcium acrylate copolymer E. polyvinylacetal diethylaminoacetate, hydrate-containing preparation is administered immediately an ethyl acrylate-methyl methacrylate copolymer, and ethyl before meal, and preferably, rapidly dissolves upon adminis cellulose; tration to improve postprandial hyperglycemia. It is therefore 0025 9 a bitterness-masking particle according to 8. desirable in an orally disintegrating tablet of the present wherein the bitterness-masking particle has an average par invention that the tablet rapidly dissolves in the digestive ticle diameter of 60 to 150 um; tract, particularly in the stomach, after having disintegrated in 0026 10 a method for preparing a bitterness-masked the mouth. The mitiglinide calcium hydrate has a calcium salt orally disintegrating tablet, of carboxylic acid as a functional group within the molecule, 0027 the method comprising the steps of: making it soluble in an alkaline pH range, and insoluble (1) granulating a mixture of mitiglinide calcium hydrate and toward the neutral to acidic pH. It is therefore preferable that microcrystalline cellulose while spraying at least one mask an orally disintegrating tablet of the present invention rapidly ing agent selected from the group consisting of aminoalkyl dissolve in the stomach and water. methacrylate copolymer E. polyvinylacetal diethylaminoac 0032. In an orally disintegrating tablet of the present etate, an ethyl acrylate-methyl methacrylate copolymer, and invention, microcrystalline cellulose, after the disintegrating ethyl cellulose; and tablet is disintegrated in the mouth, improves the wetting and (2) compression-molding the granulated material obtained in dispersibility of the mitiglinide calcium hydrate in the diges the granulating step, after mixing the granulated material with tive tract, and particularly in the stomach, to thereby improve a Sugar or a Sugar alcohol, and at least one selected from corn the dissolution property of the mitiglinide calcium hydrate. starch and partially pregelatinized starch; and Examples of the microcrystalline cellulose used in an orally 0028 11 a method according to 10, wherein the granu disintegrating tablet of the present invention include Ceolus lation in the granulating step is performed by a high shear PH-101, PH-102, PH-301, PH-302, F-20, and KG-802 granulating method. (Asahi Kasei Chemicals Corporation), which may be used in 0029 Preferably, the masking agent used for an orally a combination of two or more. The content of microcrystal disintegrating tablet of the present invention is water-in line cellulose in an orally disintegrating tablet of the present soluble, and delays the dissolution of the drug in the mouth. invention is generally about 10 to about 500 parts by weight, Examples of Such masking agents include a stomach-Soluble and preferably about 30 to about 300 parts by weight, with polymer, a water-insoluble cellulose ether, and a water-in respect to 100 parts by weight of mitiglinide calcium hydrate. US 2009/03 11321 A1 Dec. 17, 2009
0033. The sugar or sugar alcohol used in an orally disin 0041. Examples of the fillers include rice starch, potato tegrating tablet of the present invention is preferably highly starch, magnesium aluminometasilicate, anhydrous calcium water-soluble, and exhibits low moldability. Examples of phosphate, precipitated calcium carbonate, calcium silicate, Such Sugars and Sugar alcohols include: Sugars such as lac calcium lactate, and ethyl cellulose. Examples of the binders tose, glucose, Sucrose, and fructose; and Sugar alcohols such include hydroxypropyl cellulose, hydroxypropylmethyl cel as D-mannitol, erythritol, and Xylitol. Lactose and D-manni lulose, polyvinylpyrrolidone, dextrin, methyl cellulose, poly tol are preferable for their pleasant sweet taste exhibited vinyl alcohol, Sodium alginate, aminoalkyl methacrylate during administration. Of these, D-mannitol is particularly copolymers, and polyethylene glycols. Examples of the lubri preferable for its ability to provide a pleasant, cooling sensa cants include magnesium Stearate, calcium Stearate, talc, light tion, while having an appropriate hardness and facilitating the anhydrous silicic acid, Sucrose fatty acid esters, and sodium tablet to quickly disintegrate. Stearyl fumarate. Examples of the Sweeteners include Aspar 0034 Examples of the lactose used in an orally disinte tame(R), Saccharine sodium, dipotassium glycyrrhizinate, Ste grating tablet of the present invention include Tablettose 70, via, thaumatin, acesulfame K, and Sucralose. Examples of the Tablettose 80, Tablettose 100 (Meggle), Pharmatose 100M, acidulants include citric acid, tartaric acid, malic acid, and Pharmatose 200M, Impalpable (DMV), and FAST-FLO (For ascorbic acid. Examples of the foaming agents include most). Among these examples, the direct tableting lactose Sodium bicarbonate, Sodium carbonate, and calcium carbon Tablettose 70, Tablettose 80, Tablettose 100 (Meggle), FAST ate. Examples of the flavoring agents include L-aspartic acid, FLO (Formost), and Pharmatose 100M (DMV) are prefer Sodium chloride, magnesium chloride, Sodium citrate, cal able. Examples of the D-mannitol used in an orally disinte cium citrate, L-sodium glutamate, and sodium bicarbonate. grating tablet of the present invention include Mannit P (Towa Examples of the other flavoring agents include orange oil, Kasei Kogyo), PEARLITOL 25C, PEARLITOL 50C, lemon oil, menthol, and various kinds of flavoring agent PEARLITOL 100SD, PEARLITOL 200SD, and PEARLI powders. Examples of the colorants include: food dyes such TOL 400DC (Roquette). as food yellow 5, food red 2, and food blue 2: yellow ferric 0035. As required, these sugars or sugar alcohols may be oxide; red ferric oxide; and caramel dyes. used in a combination of two or more. Further, the Sugar and 0042. The following describes a method for preparing an Sugar alcohol may be used in combination. orally disintegrating tablet of the present invention. 0036. In an orally disintegrating tablet of the present 0043. A method for preparing an orally disintegrating tab invention, the content of Sugar or Sugar alcohol is about 10 to let of the present invention includes the steps of: about 95 parts by weight, preferably about 30 to about 90 (1) granulating a mixture of mitiglinide calcium hydrate and parts by weight, and more preferably about 40 to about 90 microcrystalline cellulose while spraying at least one kind of parts by weight, with respect to 100 parts by weight of the masking agent selected from the group consisting of ami tablet. noalkyl methacrylate copolymer E. polyvinylacetal diethy 0037. In an orally disintegrating tablet of the present laminoacetate, an ethyl acrylate-methyl methacrylate copoly invention, corn starch and partially pregelatinized starch are mer, and ethyl cellulose; and used to help the tablet quickly disintegrate in the mouth, and (2) compression-molding the granulated material after mix to give an appropriate hardness to the tablet. Examples of the ing it with a Sugarora Sugar alcohol, and at least one selected partially pregelatinized starch used in an orally disintegrating from corn starch and partially pregelatinized starch. tablet of the present invention include Starch 1500 (Colorcon 0044. In a method for preparing an orally disintegrating Japan, cold-water solubles: 10 to 20 weight%), PCS (Asahi tablet of the present invention, the granulated material Kasei Chemicals Corporation, cold-water solubles: less than includes microcrystalline cellulose and a water-insoluble 10 weight%), LYCATABC (Roquette, cold-water solubles: polymer to mask the bitterness of the mitiglinide calcium less than 10 weight%), and Fibose (Nippon Starch Chemical hydrate and provide rapid drug dissolution. Further, by the Co., Ltd.). Among these, Starch 1500 (Colorcon Japan, cold compression molding of the granulated material mixed with a water solubles: 10 to 20 weight%) is preferable. Sugar or a Sugar alcohol, and at least one selected from corn 0038. In an orally disintegrating tablet of the present starch and partially pregelatinized starch, the tablet is suffi invention, the content of corn starch is about 2 to about 40 ciently hard and quickly disintegrates in the mouth. parts by weight, and preferably about 5 to about 30 parts by 0045. The following specifically describes each step of a weight, with respect to the total weight of the preparation. In preparing method of the present invention. an orally disintegrating tablet of the present invention, the content of partially pregelatinized starch is about 0.5 to about (Granulating Step) 10 parts by weight, and preferably about 1 to about 5 parts by 0046 Mitiglinide calcium hydrate contained in an orally weight, with respect to 100 parts by weight of the tablet. disintegrating tablet of the present invention has low fluidity, 0039. The content of mitiglinide calcium hydrate in an in addition to being very adherent and water-repellent. This orally disintegrating tablet of the present invention is not makes it difficult to directly granulate the mitiglinide calcium particularly limited to, but generally about 1 to about 20 parts hydrate using a solution or Suspension of the masking agent as by weight, and preferably about 2 to about 10 parts by weight, a liquid binder. Further, when a mixture of mitiglinide cal with respect to 100 parts by weight of the tablet. cium hydrate and an excipient such as D-mannitol is used to 0040. An orally disintegrating tablet of the present inven prepare an orally disintegrating tablet by compression mold tion may include appropriate amounts of a variety of additives ing after granulating the mixture using the masking agent as used for production of preparations, provided that they do not a liquid binder, the resulting tablet suffers from low dissolu interfere with the effects of the present invention. Examples tion, though it can mask the bitterness. As a result of intensive of such additives include fillers, binders, lubricants, sweeten studies, the inventors of the present invention found that the ers, acidulants, foaming agents, flavoring agents, and colo bitterness-masking effect and rapid drug dissolution can be rantS. realized at the same time, when a mixture of mitiglinide US 2009/03 11321 A1 Dec. 17, 2009 calcium hydrate and microcrystalline cellulose is granulated ing agent through a spray nozzle, after thoroughly mixing the using the masking agent as a liquid binder. mitiglinide calcium hydrate and microcrystalline cellulose 0047 Regarding the granulating step, use of a fluidized using a high shear granulating method. bed granulating method or a tumbling fluidized bed granulat 0.052 Generally, in a high shear granulating method, vari ing method causes a problem in that, owning to the high ous factors are known to influence ease of granulation. Some adherence of the mitiglinide calcium hydrate, the drug in the of the examples include the method of adding the liquid flowing air adheres to the upper part inside the granulating binder, the concentration of the liquid binder, the amount of apparatus, causing the drug to granulate separately from the liquid binder added, granulation time, the number of blade microcrystalline cellulose. The resulting granulated material rotations, and the number of cross Screw rotations. is therefore bulky and friable, which causes the granulated 0053. The method of adding the liquid binder, the amount material to break during the compression molding. That is, a of liquid binder added, granulation time, and the number of sufficient bitterness-masking effect cannot be obtained in blade rotations and cross screw rotations in a high shear tablets prepared by a fluidized bed granulating method or a granulator are particularly important in a preparing method of tumbling fluidized bed granulating method. When a spray the present invention. The liquid binder is added preferably drying granulating method is used, the high water-repellency by a spray method, because the proportion of coarse particles of the mitiglinide calcium hydrate prevents formation of a increases in a falling-drop method. The rotation speed of the spray solution of mitiglinide calcium hydrate and masking blade and the cross Screw in the high shear granulator is agent. In a preparing method of the present invention, the preferably about 15 to about 600 rpm for the blade, and granulating step is preferably performed by making a mixture preferably about 180 to about 3,600 rpm for the cross screw, of mitiglinide calcium hydrate and microcrystalline cellulose though it depends on the manufacturing scale. Regarding the using a high shear granulating method, and granulating the amount of liquid binder added, the average particle diameter mixture while spraying a solution or dispersion of the mask of the granulated material generally increases as the amount ing agent as a liquid binder. of liquid binder is increased, and decreases when the granu 0048. The solvent used to dissolve or suspend the masking lation time becomes excessively long. In a preparing method agent is not particularly limited to, but includes alcohols such of the present invention, the amount of liquid binder added as ethanol and methanol; methylene chloride; toluene; methyl and the granulation time are appropriately adjusted according ethyl ketone; water; and mixtures of these. Ethanol and water to Such factors as the manufacturing scale, the type of mask are preferable. The ethyl acrylate-methyl methacrylate ing agent, and the type of solvent used to dissolve or Suspend copolymer (for example, Eudragit NE 30D, Roehm Pharma the masking agent, so as to produce a granulated material Gmbh) and ethyl cellulose (for example, Aquacoat, FMC) are having an average particle diameter of about 60 to about 150 commercially available in the form of an aqueous dispersion, lm. and may be used by being diluted with water, as required. The 0054 The granulated material may be further coated with aminoalkyl methacrylate copolymer E, which is water-in a masking agent to such an extent that the dissolution of the soluble, may be used as an aqueous solution by being dis drug from the preparation is not overly delayed. The coating Solved in acidic water (pH of 5 or less), or an aqueous disper step does not particularly limit the method of production, and sion by being mixed, in any proportion, with at least one kind methods such as a fluidized bed coating method, a tumbling of plasticizer selected from sodium lauryl sulfate, stearic fluidized bed coating method, a Wurster coating method, and acid, triethylcitrate, diethyl sebacate, and dibutyl sebacate. a melt coating method may be used. The coating step can 0049. The liquid binder of masking agent may addition further improve the bitterness-masking effect. ally include additives used for production of preparations, provided that it is not detrimental to the bitterness-masking (Mixing Step) effect and dissolution properties. Examples of such additives 0055. In a preparing method of the present invention, the include: binders such as hydroxypropyl cellulose, hydrox mixing step proceeds by mixing the mitiglinide calcium ypropylmethyl cellulose, polyethylene glycol, and polyvi hydrate-containing granulated material, prepared in the nylpyrrolidone; colorants such as red ferric oxide, yellow granulating step, with (a) a Sugar or a Sugar alcohol, and (b) at ferric oxide, food dyes, and caramel dyes; and Surfactants least one selected from corn starch and partially pregelati Such as Sodium laurate. Sucrose fatty acid esters, diethyl seba nized starch. cate, cetanol, Polysorbate 80, and Macrogol 400. 0056. When the sugar used in a preparing method of the 0050. In an orally disintegrating tablet of the present present invention is for direct tableting, mixing and compres invention, the average particle diameter of the granulated sion molding of (a) the mitiglinide calcium hydrate-contain material is preferably about 60 to about 150 lum, and more ing granulated material, (b) Sugar, and (c) corn starch can preferably about 60 to about 120 um. When the average form a tablet of appropriate hardness that can quickly disin particle diameter of the granulated material is below 60 um, a tegrate in the mouth. sufficient bitterness-masking effect cannot be obtained. 0057 When the sugar alcohol used makes it difficult to Above 150 lum, rapid drug dissolution suffers. In the present perform the direct mixing and compression molding with the invention, the “average particle diameter means a 50% par mitiglinide calcium hydrate-containing granulated material, ticle diameter (weight-based median size). The 50% particle it is desirable that the sugar alcohol be granulated beforehand diameter can be measured with a particle distribution mea to improve fluidity and ease of feeding. For example, when suring sifter (for example, sonic sifter L-3PS, Seishin Enter D-mannitol is used as a Sugar alcohol, a partially pregelati prise Co., Ltd.). nized Starch, and particularly a partially pregelatinized starch 0051. In a preparing method of the present invention, the having about 10 to about 20 weight% of cold-water solubles, granulating step is preferably performed by granulating a and specifically Starch 1500 (Colorcon Japan, cold-water mixture of mitiglinide calcium hydrate and microcrystalline solubles: 10 to 20 weight%) are preferably used as a granu cellulose while spraying a solution or dispersion of the mask lation binder, because they reduce the incidence of tableting US 2009/03 11321 A1 Dec. 17, 2009
failures and provide a tablet of appropriate hardness that can (paddle method) in the dissolution test of the Japanese Phar quickly disintegrate in the mouth. macopoeia, Fourteenth Edition. 0058. The granulation of the sugar alcohol can be per 0066. A mitiglinide calcium hydrate-containing orally formed, for example, by granulating a mixture of (a) a Sugar disintegrating tablet of the present invention is generally alcohol and (b) corn starch using a partially pregelatinized taken in a mitiglinide calcium hydrate dose of 5 to 20 mg for starch as a binder. In the granulation of the Sugar alcohol, (1) adults, three times a day immediately before each meal, and a granulated material including (a) a Sugar alcohol, (b) corn preferably 5 minutes before each meal. starch, and (c) partially pregelatinized starch may be prepared first and a remaining part of corn starch may be added and ADVANTAGEOUSEFFECTS OF THE mixed thereafter, or alternatively (2) the entire amount of corn INVENTION starch may be added and mixed after preparing a granulated. 0067. An orally disintegrating tablet of the present inven material including (a) a Sugar alcohol and (b) partially prege tion masks the bitterness attributed to the mitiglinide calcium latinized starch. hydrate, and quickly disintegrates in the mouth, making it 0059. The granulation of the sugar alcohol may be per easier for patients to take. Further, because an orally disinte formed by common wet granulating methods, such as, for grating tablet of the present invention rapidly dissolves in the example, a high shear granulating method, a fluidized bed digestive tract after having disintegrated in the mouth, it can granulating method, a tumbling fluidized bed granulating effectively suppress postprandial hyperglycemia. Further, the method, and an extrusion granulating method. Preferably, a bitterness-reduced, orally disintegrating tablet of the present high shear granulating method and a fluidized bed granulat invention is easy to handle because it is sufficiently hard to ing method are used. withstand damages encountered during the course of distri 0060. After preparing a mixture of the mitiglinide calcium bution. hydrate-containing granulated material with (a) a Sugar or a Sugar alcohol, and (b) at least one selected from corn starch BEST MODE FOR CARRYING OUT THE and partially pregelatinized starch, additives Such as lubri INVENTION cants, foaming agents, Sweeteners, flavoring agents, fluidiz ers and flavoring agents may be added as required. 0068. The following describes the present invention in 0061. In an orally disintegrating tablet of the present more detail based on Examples, Comparative Examples, and invention, the compression molding can be performed using, Test Examples below. Note, however, that the invention is not for example, a single punch tableting machine or a rotary limited in any ways by the following descriptions. tableting machine. The punch pressure is generally 1 to 60 kN/cm, and preferably 3 to 30 kN/cm. EXAMPLES 0062 An orally disintegrating tablet of the present inven Measurement of Particle Distribution tion, produced as above, has an appropriate hardness, and can quickly disintegrate in the mouth with its bitterness masked. 0069. A particle distribution was measured to determine a Further, an orally disintegrating tablet of the present invention 50% particle diameter (weight-based median size) by sifting, exhibits rapid drug disolution in the digestive tract after hav using a sonic sifter (model L-3PS, Seishin Enterprise Co., ing disintegrated in the mouth. Further, an orally disintegrat Ltd.). ing tablet prepared by a preparing method of the present Test Example 1 invention is suited for industrial production, because it is free of tableting failures during the compression molding. Bitterness Test 0063. To provide a sufficient bitterness-masking effect, an 0070. Each tablet prepared in Examples 1 to 5 and Com orally disintegrating tablet of the present invention preferably parative Examples 1 to 6 was put in the mouth of five healthy has an average score of less than 2.0 in the bitterness test males. The tablet was gently rolled on the tongue until it described below. disintegrated, and furthermore was kept in the mouth for 30 0064. The disintegration time of an orally disintegrating seconds. Then, bitterness was scored according to Table 1, tablet of the present invention in the mouth is generally within and the average was taken. 60 seconds, preferably within 40 seconds, and more prefer ably within 30 seconds, though it depends on the size or TABLE 1 thickness of the tablet. The hardness of an orally disintegrat None ing tablet of the present invention is generally 30 N or more, Almost none and preferably 50 N or more. Slightly bitter 0065. An orally disintegrating tablet of the present inven Bitter tion preferably has good dissolution properties in the first Very bitter fluid (pH of about 1.2), equivalent of stomach pH, and in Extremely bitter purified water. Specifically, the drug dissolution rate of an orally disintegrating tablet of the present invention is prefer ably 85% or more after 15 minutes when a dissolution test is Test Example 2 conducted at a rotation speed of 50 rpm using the first fluid (pH of about 1.2) as a test fluid according to method 2 (paddle Dissolution Test method) in the dissolution test of the Japanese Pharmaco 0071. Each tablet prepared in Examples 1 to 5 and Com poeia, Fourteenth Edition, and more preferably 85% or more parative Examples 1 to 6 was conducted a dissolution test to in both the first fluid (pH of about 1.2) and purified water as determine dissolution rate after 15 minutes. The test was test fluids after 15 minutes when a dissolution test is con performed at a paddle rotation speed of 50 rounds per minute ducted at a rotation speed of 50 rpm according to method 2 (rpm) using 900 mL of purified water or 900 mL of the first US 2009/03 11321 A1 Dec. 17, 2009 fluid as test fluids, according to method 2 (paddle method) in aspartame (Ajinomoto Co., Inc.) were mixed using a V the dissolution test of the Japanese Pharmacopoeia, Four blender (DV-1, Dalton Co., Ltd.). The resulting mixed pow teenth Edition. der was lubricated with 28 g of calcium stearate (Nitto Chemical Industry Co., Ltd.) and 14 g of light anhydrous Test Example 3 silicic acid (Adsolider 101, Freund). The resulting lubricated Oral Disintegration Test powder was compression-molded with a rotary tableting machine (HT-X20SS, Hata Iron Works Co., Ltd.: tablet 0072 Each tablet prepared in Examples 1 to 5 was put in weight, 150.0 mg. die and punch, 10x5 mm; table rotation the mouth of five healthy males. The tablet was gently rolled speed, 30 rpm; punch pressure, 6.9 kN) on the tongue until it disintegrated, and the time required to disintegrate the tablet was measured and averaged. Example 2 Test Example 4 0078 Hardness Test 0073. The hardness of each tablet prepared in Examples 1 Mitiglinide calcium hydrate: 10.0 mg Microcrystalline cellulose: 25.0 mg to 5 was measured using a hardness meter (TS-75N. Okada Polyvinylacetal diethylaminoacetate: 1.5 mg Seiko Co., Ltd.). D-mannitol: 73.7 mg Partially pregelatinized starch: 2.4 mg Example 1 Corn starch: 32.4 mg Redferric oxide: 0.005 mg 0074 Aspartame: 2.0 mg Calcium Stearate: 2.0 mg Light anhydrous silicic acid: 1.0 mg
Mitiglinide calcium hydrate: 10.0 mg Total: 150.0 mg tablet Microcrystalline cellulose: 25.0 mg Polyvinylacetal diethylaminoacetate: 1.0 mg D-mannitol: 76.5 mg 0079 50 g of mitiglinide calcium hydrate and 125 g of Partially pregelatinized starch: 2.5 mg microcrystalline cellulose (Ceolus PH-101, Asahi Kasei Corn Starch: 30.0 mg Chemicals Corporation) were mixed using a high shear Red ferric oxide: 0.005 mg Aspartame: 2.0 mg granulator (FM-VG-01, Powrex Corporation). For granula Calcium Stearate: 2.0 mg tion, a solution prepared by dissolving 7.5 g of polyvinylac Light anhydrous silicic acid: 1.0 mg etal diethylaminoacetate (AEA, Sankyo) in 67.5 g of 90 weight% ethanol was sprayed onto the mixture using a two Total: 150.0 mg tablet fluid spray nozzle at a feed rate of 7.5 g/min. Here, the mixture was granulated for a total of 11 minutes at a blade rotation 0075 1,000 g of mitiglinide calcium hydrate and 2,500 g speed of 600 rpm, and a cross screw rotation speed of 2,000 of microcrystalline cellulose (Ceolus PH-101, Asahi Kasei rpm. The wet granulated material was dried with a tray drier Chemicals Corporation) were mixed using a high shear (DSB80HPT, Seiwa Rikou), and put through a sieve having a granulator (FM-VG-25, Powrex Corporation). For granula 500. 82 m opening. The resulting sieved granulated material tion, a solution prepared by dissolving 100g of polyvinylac containing mitiglinide calcium hydrate (a-2) had a 50% par etal diethylaminoacetate (AEA, Sankyo) in 1,150 g of 90 ticle diameter of 119.4 um. weight% ethanol was sprayed onto the mixture using a two 0080 0.73 g of sieved granulated material containing fluid spray nozzle at a feed rate of 250 g/min. Here, the mitiglinide calcium hydrate (a-2), 1.57 g of the fluidized bed mixture was granulated for a total of 15 minutes at a blade granulated material (b-1) prepared in Example 1, 0.6 g of corn rotation speed of 250 rpm and a cross screw rotation speed of starch, and 0.04 g of aspartame (Ajinomoto Co., Inc.) were 2,000 rpm. The wet granulated material was dried with a tray mixed in a plastic bag. The resulting mixture was lubricated drier (DSB80HPT, Seiwa Rikou), and sized using a mill with with 0.04 g of calcium stearate (Nitto Chemical Industry Co., a screen having a 0.55 mm opening (ND-30S, Okada Seiko Ltd.) and 0.02 g of light anhydrous silicic acid (Adsolider Co., Ltd.). The resulting sized granulated material containing 101, Freund). The resulting lubricated powder was compres mitiglinide calcium hydrate (a-1) had a 50% particle diameter sion-molded with a single punch tableting machine (N-30E, of 75.5um. Okada Seiko Co., Ltd.: tablet weight, 150.0 mg; die and 0076 Separately, 1,200 g of D-mannitol (Mannite P, Towa punch, Ø 7 mm; punch pressure, 6 kN). Kasei Kogyo), and 40g of corn starch (Nihon Shokuhin Kako Co., Ltd.) were charged into a fluidized bed granulator (LAB Example 3 1, PoWrex Corporation). Then, a dispersion liquid, prepared by dispersing 40 g of partially pregelatinized starch (Starch 0081 1500, Colorcon Japan) and 0.08g of red ferric oxide in 360 g of purified water, was sprayed through a spray noZZle to granulate. The resulting granulated material was sized using Mitiglinide calcium hydrate: 10.0 mg Microcrystalline cellulose: 25.0 mg a mill with a screen having a 1.5 mm opening (P-02S, Dalton Aminoalkyl methacrylate copolymer E: 1.3 mg Co., Ltd.) to obtain a fluidized bed granulated material (b-1). Lactose: 77.0 mg 0077 504 g of sized granulated material containing D-mannitol: 1.7 mg mitiglinide calcium hydrate (a-1), 1,141 g of fluidized bed Corn starch: 30.0 mg granulated material (b-1), 385 g of corn Starch, and 28 g of US 2009/03 11321 A1 Dec. 17, 2009
bed drier (LAB-1, Powrex Corporation), and put through a -continued sieve having a 500 um opening. The resulting sieved granu Aspartame: 2.0 mg lated material containing mitiglinide calcium hydrate (a-4) Calcium Stearate: 2.0 mg had a 50% particle diameter of 77.1 um. Light anhydrous silicic acid: 1.0 mg I0086) 152 g of sieved granulated material containing Total: 150.0 mg tablet mitiglinide calcium hydrate (a-4),308g of lactose (Tablettose 80, Meggle), 120g of corn starch (Nihon Shokuhin Kako Co., 0082 300 g of mitiglinide calcium hydrate and 750 g of Ltd.), and 8g of aspartame (Ajinomoto Co., Inc.) were mixed microcrystalline cellulose (Ceolus PH-101, Asahi Kasei using a V blender (DV-1, Dalton Co., Ltd.). The resulting Chemicals Corporation) were mixed using a high shear mixture was lubricated with 8 g of calcium stearate (Nitto granulator (FM-VG-10, Powrex Corporation). For granula Chemical Industry Co., Ltd.) and 4 g of light anhydrous silicic tion, a solution prepared by dissolving 39 g of aminoalkyl acid (Adsolider 101, Freund). The resulting lucricated pow methacrylate copolymer E (Eudragit E 100, Roehm Pharma der was compression-molded with a rotary tableting machine Gmbh) in 351 g of 90 weight% ethanol was sprayed onto the (Correct 12HUK, Kikusui Seisakusho Ltd.: tablet weight, mixture using a two-fluid spray nozzle at a feed rate of 78 150.0 mg; die and punch, 10x5 mm; table rotation speed, 30 g/min. Here, the mixture was granulated for a total of 10 rpm; punch pressure, 9.8 kN). minutes at a blade rotation speed of 354 rpm, and a cross screw rotation speed of 2,000 rpm. The wet granulated mate rial was dried with a tray drier (DSB80HPT, Seiwa Rikou), Example 5 and sized using a mill with a screen having a 0.5 mm opening (P-02S, Dalton Co., Ltd.). The resulting sized granulated 0087 material containing mitiglinide calcium hydrate (a-3) had a 50% particle diameter of 86.3 um. 0083. 145.2 g of sized granulated material containing Mitiglinide calcium hydrate: 10.0 mg mitiglinide calcium hydrate (a-3), 308g of lactose (Tablettose Microcrystalline cellulose: 25.0 mg 80, Meggle), 6.8 g of D-mannitol (Mannit P. Towa Kasei Ethyl cellulose: 0.9 mg D-mannitol: 74.2 mg Kogyo), 120 g of corn starch (Nihon Shokuhin Kako Co., Partially pregelatinized starch: 2.4 mg Ltd.), and 8 g of aspartame (Ajinomoto Co., Inc.) were mixed Red ferric oxide: 0.005 mg using a V blender (DV-1, Dalton Co., Ltd.). The resulting Corn starch: 32.4 mg mixture was lubricated with 8 g of calcium stearate (Nitto Aspartame: 2.0 mg Chemical Industry Co., Ltd.), and 4 g of light anhydrous Calcium Stearate: 2.0 mg silicic acid (Adsolider 101, Freund). The resulting lubricated Light anhydrous silicic acid: 1.0 mg powder was compression-molded with a rotary tableting Total: 149.9 mg/tablet machine (Correct12HUK, Kikusui Seisakusho Ltd.: tablet weight, 150 mg. die and punch, 10x5 mm; table rotation speed, 30 rpm; punch pressure, 9.8 kN). I0088 70 g of mitiglinide calcium hydrate and 175 g of microcrystalline cellulose (Ceolus PH-101, Asahi Kasei Example 4 Chemicals Corporation) were mixed using a high shear granulator (FM-VG-01, Powrex Corporation). For granula 0084 tion, a solution prepared by dissolving 6.4 g of ethyl cellulose (STDIOFP, Dow Chemical Company) in 73.6 g of 99.5 weight % ethanol was sprayed onto the mixture using a two-fluid Mitiglinide calcium hydrate: 10.0 mg spray nozzle at a feed rate of 10 g/min. Here, the mixture was Microcrystalline cellulose: 25.0 mg granulated for a total of 9 minutes at a blade rotation speed of Ethyl acrylate-methyl methacrylate copolymer: 3.0 mg 600 rpm, and a cross screw rotation speed of 2,000 rpm. The Lactose: 77.0 mg Corn starch: 30.0 mg wet granulated material was dried with a fluidized bed drier Aspartame: 2.0 mg (LAB-1, Powrex Corporation), and sized using a mill with a Calcium Stearate: 2.0 mg screen having a 0.5 mm opening (P-02S, Dalton Co., Ltd.). Light anhydrous silicic acid: 1.0 mg The resulting sized granulated material containing mitiglin Total: 150.0 mg tablet ide calcium hydrate (a-5) had a 50% particle diameter of 68.9 lm. 0085 50 g of mitiglinide calcium hydrate, and 125 g of I0089 0.7182 g of sized granulated material containing microcrystalline cellulose (Ceolus PH-101, Asahi Kasei mitiglinide calcium hydrate (a-5), 1.5818 g of fluidized bed Chemicals Corporation) were mixed using a high shear granulated material (b-1) prepared in Example 1, 0.6 g of corn granulator (FM-VG-01, Powrex Corporation). For granula starch, and 0.04 g of aspartame (Ajinomoto Co., Inc.) were tion, 125 g of a 12 weight% ethyl acrylate-methyl methacry mixed in a plastic bag. The resulting mixture was lubricated late copolymer dispersion liquid (Eudragit NE30D, Roehm with 0.04 g of calcium stearate (Nitto Chemical Industry Co., Pharma Gmbh) was sprayed onto the mixture using a two Ltd.), and 0.02 g of light anhydrous silicic acid (Adsolider fluid spray nozzle at a feed rate of 5 g/min. Here, the mixture 101). The resulting lubricated powder was compression was granulated for a total of 60 minutes at a blade rotation molded with a single-punch tableting machine (N-30E, speed of 600 rpm, and a cross screw rotation speed of 2,000 Okada Seiko Co., Ltd.: tablet weight, 149.9 mg; die and rpm. The wet granulated material was dried with a fluidized punch, Ø 7 mm; punch pressure, 5.5 kN). US 2009/03 11321 A1 Dec. 17, 2009
granulator (FM-VG-01, Powrex Corporation). For granula TABLE 2 tion, 140 g of ethanol was sprayed onto the mixture using a two-fluid spray nozzle at a feed rate of 9.3 g/min. Here, the Example 1 Example 2 Example 3 Example 4 Example 5 mixture was granulated for a total of 18 minutes at a blade 50% particle 75.5 119.4 86.3 77.1 68.9 rotation speed of 600 rpm, and a cross screw rotation speed of diameter 2,000 rpm. The wet granulated material was dried with a tray (Lm) Bitterness 1.2 1.2 1.4 1.6 1.8 drier (DSB80HPT, Seiwa Rikou), and put through a sieve (score) having a 500 um opening. The resulting sieved granulated Oral 23 24 19 18 22 material containing mitiglinide calcium hydrate (a-6) had a dis 50% particle diameter of 82.6 um. integration 0.095 1.4 g of sieved granulated material containing time (Sec) Hardness (N) 60 62 51 57 65 mitiglinide calcium hydrate (a-6), 3.24 g of the fluidized bed Dissolution 92.5 86.3 90.8 94.7 93.0 granulated material (b-1) prepared in Example 1, 1.2 g of corn rate (%, starch (Nihon Shokuhin Kako Co., Ltd.), and 0.04 g of aspar purified tame (Ajinomoto Co., Inc.) were mixed in a plastic bag. The water) Dissolution 97.2 96.2 97.5 87.O 92.1 resulting mixture was lubricated with 0.08g of calcium stear rate (%, ate (Nitto Chemical Industry Co., Ltd.), and 0.04 g of light first fluid) anhydrous silicic acid (Adsolider 101, Freund). The resulting lubricated powder was compression-molded with a single punch tableting machine (N-30E, Okada Seiko Co., Ltd.: Comparative Example 1 tablet weight 150.9 mg; die and punch, Ø 7 mm; punch pres sure, 9.8 kN). 0090 Comparative Example 3 0096 120g of mitiglinide calcium hydrate was charged in Mitiglinide calcium hydrate: 10.0 mg Granules of co-spray dried lactose and starch: 135.0 mg a high shear granulator (FM-VG-01, Powrex Corporation), Aspartame: 2.0 mg and a solution, prepared by dissolving 6 g of polyvinylacetal Calcium Stearate: 2.0 mg diethylaminoacetate (AEA, Sankyo) in 69 g of 90 weight% Light anhydrous silicic acid: 1.0 mg ethanol, was sprayed onto the mixture using a two-fluid spray nozzle. However, the granulation was failed because the Total: 150.0 mg tablet mitiglinide calcium hydrate was not stirred in the granulator. 0091. A tablet was prepared according to the method Comparative Example 4 described in Example 1 of WO2003/61650. 0092 0.2 g of mitiglinide calcium hydrate, 2.7 g of gran O097 ules of co-spray dried lactose and starch (Starlac, Meggle), and 0.04 g of aspartame (Ajinomoto Co., Inc.) were mixed in a plastic bag. The resulting mixture was lubricated with 0.04 Mitiglinide calcium hydrate: 10.0 mg g of calcium stearate (Nitto Chemical Industry Co., Ltd.) and D-mannitol: 25.0 mg 0.02 g of light anhydrous silicic acid (Adsolider 101). The Ethyl acrylate-methyl methacrylate copolymer: 2.6 mg resulting lubricated powder was compression-molded with a D-mannitol: 72.6 mg Partially pregelatinized starch: 2.4 mg single punch tableting machine (N-30E, Okada Seiko Co., Red ferric oxide: 0.005 mg Ltd.: tablet weight, 150.0 mg. die and punch, a 7 mm; punch Corn starch: 32.4 mg pressure, 6 kN). Aspartame: 2.0 mg Calcium Stearate: 2.0 mg Comparative Example 2 Light anhydrous silicic acid: 1.0 mg 0093 Total: 150.0 mg tablet 0.098 70 g of mitiglinide calcium hydrate, and 175 g of Mitiglinide calcium hydrate: 10.0 mg D-mannitol (Mannit P. Towa Kasei Kogyo) were mixed using Microcrystalline cellulose: 25.0 mg a high shear granulator (FM-VG-01, Powrex Corporation). D-mannitol: 75.9 mg For granulation, 60 g of a 30 weight% ethyl acrylate-methyl Partially pregelatinized starch: 2.5 mg methacrylate copolymer dispersion liquid (Eudragit NE30D, Corn starch: 32.5 mg Red ferric oxide: 0.005 mg Roehm Pharma Gmbh) was sprayed onto the mixture using a Aspartame: 2.0 mg two-fluid spray nozzle at a feed rate of 10.9 g/min. Here, the Calcium Stearate: 2.0 mg mixture was granulated for a total of 6.5 minutes at a blade Light anhydrous silicic acid: 1.0 mg rotation speed of 600 rpm, and a cross screw rotation speed of 2,000 rpm. The wet granulated material was dried with a Total: 150.9 mg tablet fluidized bed drier (LAB-1, Powrex Corporation), and sized using a mill with a screen having a 0.5 mm opening (P-02S, 0094 50 g of mitiglinide calcium hydrate and 125 g of Dalton Co., Ltd.). The resulting sized granulated material microcrystalline cellulose (Ceolus PH-101, Asahi Kasei containing mitiglinide calcium hydrate (a-7) had a 50% par Chemicals Corporation) were mixed using a high shear ticle diameter of 79.4 um. US 2009/03 11321 A1 Dec. 17, 2009
0099 0.7512 g of sized granulated material containing mitiglinide calcium hydrate (a-7), 1.5488 g of the fluidized -continued bed granulated material (b-1) prepared in Example 1, 0.6 g of Lactose: 78.7 mg corn starch, and 0.04 g of aspartame (Ajinomoto Co., Inc.) Corn starch: 30.0 mg were mixed in a plastic bag. The resulting mixture was lubri Aspartame: 2.0 mg cated with 0.04 g of calcium stearate (Nitto Chemical Indus Calcium Stearate: 2.0 mg try Co., Ltd.) and 0.02 g of light anhydrous silicic acid (Ad Light anhydrous silicic acid: 1.0 mg solider 101, Freund). The resulting lubricated powder was compression-molded with a single punch tableting machine Total: 150.0 mg tablet (N-30E, Okada Seiko Co., Ltd.: tablet weight, 150.0 mg; die and punch, Ø 7 mm; punch pressure, 5.5 kN). 0104 300 g of mitiglinide calcium hydrate, and 750 g of microcrystalline cellulose (Ceolus PH-101, Asahi Kasei Comparative Example 5 Chemicals Corporation) were mixed using a high shear granulator (FM-VG-10, Powrex Corporation). For granula 01.00 tion, a solution prepared by dissolving 39 g of aminoalkyl methacrylate copolymer E (Eudragit E 100, Roehm Pharma Gmbh) in 351 g of 90 weight% ethanol was sprayed onto the Mitiglinide calcium hydrate: 10.0 mg Microcrystalline cellulose: 25.0 mg mixture using a two-fluid spray nozzle at a feed rate of 133.3 Polyvinylacetal diethylaminoacetate: 1.2 mg g/min. Here, the mixture was granulated for 3 minutes at a D-mannitol: 74.1 mg blade rotation speed of 600 rpm and a cross screw rotation Partially pregelatinized starch: 2.5 mg speed of 2,000 rpm. At the same rotation speeds, the mixture Red ferric oxide: 0.005 mg Corn starch: 32.5 mg was further granulated for 1 more minute while spraying 100 Aspartame: 2.0 mg g of 90 weight 96 ethanol using a two-fluid spray nozzle at a Calcium Stearate: 2.0 mg feed rate of 100 g/min. The wet granulated material was dried Light anhydrous silicic acid: 1.0 mg with a fluidized bed drier (LAB-1, Powrex Corporation), and Total: 150.3 mg tablet sized using a mill with a screen having a 0.5 mm opening (P-02S, Dalton Co., Ltd.). The resulting sized granulated 0101 50 g of mitiglinide calcium hydrate, and 125 g of material containing mitiglinide calcium hydrate (a-9) had a microcrystalline cellulose (Ceolus PH-101, Asahi Kasei 50% particle diameter of 217.0 Lum. Chemicals Corporation) were mixed using a high shear 0105 145.2 g of sized granulated material containing granulator (FM-VG-01, Powrex Corporation). For granula mitiglinide calcium hydrate (a-9), 314.8g of lactose (Tablet tion, a solution prepared by dissolving 6 g of polyvinylacetal tose 80, Meggle), 120g of corn starch (Nihon Shokuhin Kako diethylaminoacetate (AEA, Sankyo) in 69 g of 90 weight% Co., Ltd.), and 8 g of aspartame (Ajinomoto Co., Inc.) were ethanol was sprayed onto the mixture using a two-fluid spray mixed using a V blender (DV-1, Dalton Co., Ltd.). The result nozzle at a feed rate of 3.3 g/min. Here, the mixture was granulated for a total of 24 minutes at a blade rotation speed ing mixture was lubricated with 8 g of calcium stearate (Nitto of 600 rpm, and a cross screw rotation speed of 2,000 rpm. Chemical Industry Co., Ltd.), and 4 g of light anhydrous The wet granulated material was dried with a tray drier silicic acid (Adsolider 101, Freund). The resulting lubricated (DSB80HPT, Seiwa Rikou), and put through a sieve having a powder was compression-molded to prepare a tablet (tablet 500 um opening. The resulting sieved granulated material weight, 150.0 mg. die and punch, 10x5 mm; table rotation containing mitiglinide calcium hydrate (a-8) had a 50% par speed, 30 rpm; punch pressure, 9.8 kN). ticle diameter of 57.2 um. 0102 1.448 g of sieved granulated material containing TABLE 3 mitiglinide calcium hydrate (a-8), 3.16 g of the fluidized bed Com. Com. Com. Com. Com. granulated material (b-1) prepared in Example 1, 1.2 g of corn Example 1 Example 2 Example 4 Example 5 Example 6 starch (Nihon Shokuhin Kako Co., Ltd.), and 0.04 g of aspar SO% 82.6 79.4 57.2 217.0 tame (Ajinomoto Co., Inc.) were mixed in a plastic bag. The particle resulting mixture was lubricated with 0.08g of calcium stear diameter ate (Nitto Chemical Industry Co., Ltd.), and 0.04 g of light (Lm) anhydrous silicic acid (Adsolider 101, Freund). The resulting Bitterness 2.6 2.6 1.O 3.0 1.2 (score) lubricated powder was compression-molded with a single Dissolution 96.3 98.8 81.0 97.9 68.7 punch tableting machine (N-30E, Okada Seiko Co., Ltd.: rate (%, tablet weight, 150.3 mg; die and punch, Ø 7 mm; punch purified pressure, 6 kN). water) Dissolution 53.3 97.9 704 99.8 92.3 rate (%, Comparative Example 6 first fluid) (0103)
INDUSTRIAL APPLICABILITY Mitiglinide calcium hydrate: 10.0 mg Microcrystalline cellulose: 25.0 mg 010.6 An orally disintegrating tablet of the present inven Aminoalkyl methacrylate copolymer E: 1.3 mg tion has an appropriate hardness and quickly disintegrates. Further, because it rapidly dissolves in the digestive tract, an US 2009/03 11321 A1 Dec. 17, 2009 orally disintegrating tablet of the present invention is useful as 7. The orally disintegrating tablet according to claim 2, a therapeutic agent for type-2 diabetes mellitus. wherein the granulated material has an average particle diam 1. A bitterness-masked orally disintegrating tablet, com eter of 60 to 150 um. prising: 8. A bitterness-masking particle for orally disintegrating (a) mitiglinide calcium hydrate as a bitteractive ingredient; tablets, (b) microcrystalline cellulose; the particle including: (c) at least one masking agent selected from the group (a) mitiglinide calcium hydrate; consisting of aminoalkyl methacrylate copolymer E. (b) microcrystalline cellulose; and polyvinylacetal diethylaminoacetate, an ethyl acrylate (c) at least one masking agent selected from aminoalkyl methyl methacrylate copolymer, and ethyl cellulose; methacrylate copolymer E. polyvinylacetal diethylami (d) a Sugar or a Sugar alcohol; and noacetate, an ethyl acrylate-methyl methacrylate (e) at least one member selected from corn starch and copolymer, and ethyl cellulose. partially pregelatinized starch. 9. The bitterness-masking particle according to claim 8. 2. A bitterness-masked orally disintegrating tablet, com wherein the bitterness-masking particle has an average par prising: ticle diameter of 60 to 150 lum. a granulated material including: 10. A method for preparing a bitterness-masked orally (a) mitiglinide calcium hydrate as a bitteractive ingredient; disintegrating tablet, (b) microcrystalline cellulose; and the method comprising the steps of (c) at least one masking agent selected from the group (1) granulating a mixture of mitiglinide calcium hydrate consisting of aminoalkyl methacrylate copolymer E. and microcrystalline cellulose while spraying at least polyvinylacetal diethylaminoacetate, an ethyl acrylate one masking agent selected from the group consisting of methyl methacrylate copolymer, and ethyl cellulose; aminoalkyl methacrylate copolymer E, polyvinylacetal (d) a Sugar or a Sugar alcohol; and diethylaminoacetate, an ethyl acrylate-methyl meth (e) at least one member selected from corn starch and acrylate copolymer, and ethyl cellulose; and partially pregelatinized starch. (2) compression-molding the granulated material obtained 3. The orally disintegrating tablet according to claim 1, in the granulating step, aftermixing the granulated mate wherein the Sugar or the Sugar alcohol is lactose or D-man rial with a Sugar or a Sugar alcohol, and at least one nitol. member selected from corn starch and partially prege 4. The orally disintegrating tablet according to claim 1, latinized starch. wherein the Sugar or the Sugar alcohol is D-mannitol. 11. The method according to claim 10, wherein the granu 5. The orally disintegrating tablet according to claim 1, lation in the granulating step is performed by a high shear wherein the masking agent is at least one selected from ami granulating method. noalkyl methacrylate copolymer E and polyvinylacetal 12. The orally disintegrating tablet according to claim 2, diethylaminoacetate. wherein the Sugar or the Sugar alcohol is lactose or D-man 6. The orally disintegrating tablet according to claim 2, nitol. wherein the granulated material is obtained by granulating a 13. The orally disintegrating tablet according to claim 2, mixture of mitiglinide calcium hydrate and microcrystalline wherein the masking agent is at least one selected from ami cellulose while spraying at least one masking agent selected noalkyl methacrylate copolymer E and polyvinylacetal from the group consisting of aminoalkyl methacrylate diethylaminoacetate. copolymer E. polyvinylacetal diethylaminoacetate, an ethyl acrylate-methyl methacrylate copolymer, and ethyl cellulose.