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