JP4874797B2 - Film coated tablets - Google Patents
Film coated tablets Download PDFInfo
- Publication number
- JP4874797B2 JP4874797B2 JP2006527889A JP2006527889A JP4874797B2 JP 4874797 B2 JP4874797 B2 JP 4874797B2 JP 2006527889 A JP2006527889 A JP 2006527889A JP 2006527889 A JP2006527889 A JP 2006527889A JP 4874797 B2 JP4874797 B2 JP 4874797B2
- Authority
- JP
- Japan
- Prior art keywords
- film
- coated tablet
- compound
- tablet according
- coating layer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000007941 film coated tablet Substances 0.000 title claims description 63
- 239000003826 tablet Substances 0.000 claims description 61
- 239000000203 mixture Substances 0.000 claims description 44
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 40
- 229940126062 Compound A Drugs 0.000 claims description 39
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 39
- 239000011247 coating layer Substances 0.000 claims description 34
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 34
- 238000009472 formulation Methods 0.000 claims description 33
- 239000000126 substance Substances 0.000 claims description 32
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 28
- -1 glyceryl fatty acid ester Chemical class 0.000 claims description 23
- YPELFRMCRYSPKZ-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxy-N-({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)benzamide Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 YPELFRMCRYSPKZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000001087 glyceryl triacetate Substances 0.000 claims description 20
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 20
- 239000004014 plasticizer Substances 0.000 claims description 20
- 229960002622 triacetin Drugs 0.000 claims description 20
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 235000011187 glycerol Nutrition 0.000 claims description 13
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 12
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 claims description 11
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- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 claims description 11
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- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 claims description 11
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- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 claims description 8
- GOJCZVPJCKEBQV-UHFFFAOYSA-N Butyl phthalyl butylglycolate Chemical compound CCCCOC(=O)COC(=O)C1=CC=CC=C1C(=O)OCCCC GOJCZVPJCKEBQV-UHFFFAOYSA-N 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
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- 239000001856 Ethyl cellulose Substances 0.000 claims description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 5
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- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims description 4
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- 238000013110 gastrectomy Methods 0.000 claims description 3
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 claims 4
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- 238000000576 coating method Methods 0.000 description 20
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- 229960004085 mosapride Drugs 0.000 description 16
- 238000004806 packaging method and process Methods 0.000 description 15
- 238000000354 decomposition reaction Methods 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
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- 238000004519 manufacturing process Methods 0.000 description 9
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- 239000000047 product Substances 0.000 description 7
- 238000013112 stability test Methods 0.000 description 7
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- 229910052791 calcium Inorganic materials 0.000 description 1
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- 235000001465 calcium Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 229950008138 carmellose Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011086 glassine Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- KVKIQHMTGSGTFO-UHFFFAOYSA-N mosapride citrate dihydrate Chemical group O.O.OC(=O)CC(O)(C(O)=O)CC(O)=O.CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 KVKIQHMTGSGTFO-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000123 paper Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229940068917 polyethylene glycols Drugs 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 102000007739 porin activity proteins Human genes 0.000 description 1
- 201000007847 postgastrectomy syndrome Diseases 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Images
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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Description
本発明は、４−アミノ−５−クロロ−２−エトキシ−Ｎ−［［４−（４−フルオロベンジル）−２−モルホリニル］メチル］ベンズアミドまたはその生理学的に許容される塩を含有するフィルムコーティング錠に関する。 The present invention relates to a film coating comprising 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof. Regarding locks.
（±）−４−アミノ−５−クロロ−２−エトキシ−Ｎ−［［４−（４−フルオロベンジル）−２−モルホリニル］メチル］ベンズアミド（以下、「モサプリド」ということがある。）は、選択的セロトニン４受容体アゴニストであり、良好な消化管運動促進作用を有する（米国特許第４，８７０，０７４号公報）。また、モサプリドまたはその生理学的に許容される塩は、逆流性食道炎、胃切除後症候群、その他の消化器症状の治療薬としても有用である。
モサプリドを含有する固形製剤としては、米国特許第４，８７０，０７４号公報の実施例２４５にクエン酸モサプリドを含有するフィルムコーティングされていない錠剤が記載されている。前記錠剤は、クエン酸モサプリド、コーンスターチ、乳糖、結晶セルロース、ヒドロキシプロピルセルロース、軽質無水ケイ酸およびステアリン酸マグネシウムを含有する固形製剤である。
クエン酸モサプリド・２水和物は、慢性胃炎に伴う消化器症状の改善を目的として既に実用化されている。クエン酸モサプリド（無水物）として２．５ｍｇまたは５ｍｇ（モサプリドとして１．７２ｍｇまたは３．４４ｍｇ）含有する錠剤は、日本では「ガスモチン」なる商標名のもとに市販されている。市販の錠剤は、モサプリドが苦味を呈する薬物であることから、フィルムコーティング錠の形態をとっており、さらに、長期保存下における副産物の生成および着色を防ぐため、アルミ包装が施されている。(±) -4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter sometimes referred to as “mosapride”) It is a
As a solid preparation containing mosapride, a non-film-coated tablet containing mosapride citrate is described in Example 245 of US Pat. No. 4,870,074. The tablet is a solid formulation containing mosapride citrate, corn starch, lactose, crystalline cellulose, hydroxypropyl cellulose, light anhydrous silicic acid and magnesium stearate.
Mosapride citrate dihydrate has already been put into practical use for the purpose of improving gastrointestinal symptoms associated with chronic gastritis. Tablets containing 2.5 mg or 5 mg as mosapride citrate (anhydride) (1.72 mg or 3.44 mg as mosapride) are commercially available in Japan under the trade name “Gasmotin”. Commercially available tablets are in the form of film-coated tablets because mosapride is a bitter drug, and is further provided with aluminum packaging to prevent the formation and coloring of by-products under long-term storage.
本発明の課題は、モサプリドまたはその生理学的に許容される塩を含有するフィルムコーティング錠において、アルミ包装等の保護包装を施さなくても保存安定性に優れた速溶性のフィルムコーティング錠を提供することにある。
本発明者らは、かかる課題を解決すべく鋭意検討したところ、フィルムコーティング錠において被覆層を形成する際に必要と考えられている特定の可塑剤の種類によって、モサプリドの分解を促進するもの、およびモサプリドの分解を抑制する（または分解に影響を及ぼさない）ものがあることを見いだした。
そこで、まず、可塑剤を除去したフィルムコーティング組成物を用いてフィルムコーティング錠を製造することを試みたところ、意外にも、長期保存においてもアルミ包装を施さなくてもモサプリドの分解が抑制され、且つ製剤への着色が抑制されることを見いだし、本発明を完成した。
さらに、本発明者らが、研究を重ねた結果、モサプリドの分解を抑制できるまたは分解に影響を及ぼさない特定の製剤化成分を含むフィルムコーティング組成物を用いて製剤化すると、製造に支障を来たすことなく、長期保存においても、アルミ包装を施さなくてもモサプリドの分解が抑制され、且つ製剤への着色が抑制されることを見いだし、本発明を完成した。
即ち、本発明は、４−アミノ−５−クロロ−２−エトキシ−Ｎ−［［４−（４−フルオロベンジル）−２−モルホリニル］メチル］ベンズアミドまたはその生理学的に許容される塩を含有する速溶性のフィルムコーティング錠であって、可塑剤を実質的に含まないか、もしくは、特定の製剤化成分を含む被覆層で被覆することを特徴とするフィルムコーティング錠を提供する。
より具体的には、以下の発明を提供するものである。
項１： ４−アミノ−５−クロロ−２−エトキシ−Ｎ−［［４−（４−フルオロベンジル）−２−モルホリニル］メチル］ベンズアミド（以下、「化合物Ａ」という）またはその生理学的に許容される塩を含有する速溶性のフィルムコーティング錠であって、
（ａ）化合物Ａまたはその生理学的に許容される塩を含有する素錠および
（ｂ）該素錠の表面に、可塑剤を実質的に含まないか、もしくは、トリアセチン、フタル酸ジエチル、セバシン酸ジブチル、クエン酸トリブチル、セバシン酸ジエチル、グリセリン脂肪酸エステル、アセチル化モノグリセライド、クエン酸アセチルトリエチル、クエン酸アセチルトリブチル、モノステアリン、ソルビタンモノラウレート、フタル酸ジオクチル、ブチルフタリルブチルグリコレートおよび中鎖脂肪酸トリグリセリドからなる群から選ばれる特定製剤化成分を少なくとも１種含む被覆層
を有するフィルムコーティング錠。
項２： 可塑剤を実質的に含まない被覆層を有する項１に記載のフィルムコーティング錠。
項３： トリアセチン、フタル酸ジエチル、セバシン酸ジブチル、クエン酸トリブチル、セバシン酸ジエチル、グリセリン脂肪酸エステル、アセチル化モノグリセライド、クエン酸アセチルトリエチル、クエン酸アセチルトリブチル、モノステアリン、ソルビタンモノラウレート、フタル酸ジオクチル、ブチルフタリルブチルグリコレートおよび中鎖脂肪酸トリグリセリドからなる群から選ばれる特定製剤化成分を少なくとも１種含む被覆層を有する項１に記載のフィルムコーティング錠。
項４： 特定製剤化成分が、トリアセチン、フタル酸ジエチル、セバシン酸ジブチル、クエン酸トリブチル、セバシン酸ジエチル、グリセリン脂肪酸エステル、アセチル化モノグリセライド、クエン酸アセチルトリエチルおよびクエン酸アセチルトリブチルからなる群から選ばれるものである項３に記載のフィルムコーティング錠。
項５： 特定製剤化成分が、トリアセチン、フタル酸ジエチル、セバシン酸ジブチルおよびクエン酸トリブチルからなる群から選ばれるものである項３に記載のフィルムコーティング錠。
項６： 特定製剤化成分が、トリアセチンである項３に記載のフィルムコーティング錠。
項７： 特定製剤化成分の含有量が被覆層中約０．１〜約３０重量％である項３に記載のフィルムコーティング錠。
項８： 化合物Ａの生理学的に許容される塩が化合物Ａのクエン酸塩の２水和物である項１〜７のいずれかに記載のフィルムコーティング錠。
項９： 化合物Ａまたはその生理学的に許容される塩の含有量が素錠中、化合物Ａに換算して約０．５〜約７０重量％である項１〜８のいずれかに記載のフィルムコーティング錠。
項１０： 前記フィルムコーティング錠を容器中、４０℃、７５％ＲＨの開栓条件下で６ヶ月保存したときの化合物Ａの類縁物質の生成量の割合が、高速液体クロマトグラフ法で測定した面積百分率で約１％以下である項１〜９のいずれかに記載のフィルムコーティング錠。
項１１： 項１に記載のフィルムコーティング錠および当該フィルムコーティング錠に関する記載物を含む商業パッケージであって、当該フィルムコーティング錠を消化管運動機能促進、胃切除後症状の改善または胃食道逆流症の予防もしくは治療に使用することができるまたは使用すべきである記載を、該パッケージ上または該パッケージ内の記載物に含む商業パッケージ。
本発明のフィルムコーティング錠は、上記特徴を有しているので、アルミ包装などの保護包装を施さなくても化合物Ａまたはその生理学的に許容される塩が分解されにくく、安定な状態で保存することができる。さらに、本発明のフィルムコーティング錠を服用した場合、苦味を感じることもない。An object of the present invention is to provide a fast-dissolving film-coated tablet that is excellent in storage stability without being subjected to protective packaging such as aluminum packaging in a film-coated tablet containing mosapride or a physiologically acceptable salt thereof. There is.
The present inventors diligently studied to solve such problems, and promote the degradation of mosapride by the type of a specific plasticizer that is considered necessary when forming a coating layer in a film-coated tablet, And some found to inhibit (or do not affect) the degradation of mosapride.
Therefore, first, when trying to produce a film-coated tablet using a film coating composition from which the plasticizer has been removed, surprisingly, the decomposition of mosapride is suppressed without applying aluminum packaging even in long-term storage, And it discovered that coloring to a formulation was suppressed and completed this invention.
Furthermore, as a result of repeated research, the present inventors have hindered production when formulated with a film coating composition containing a specific formulation component that can suppress or do not affect the degradation of mosapride. Thus, even in long-term storage, it was found that the decomposition of mosapride was suppressed and the coloring of the preparation was suppressed without applying aluminum packaging, and the present invention was completed.
That is, the present invention contains 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof. A fast-dissolving film-coated tablet is provided which is coated with a coating layer which is substantially free of a plasticizer or contains a specific formulation component.
More specifically, the following invention is provided.
Item 1: 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter referred to as “compound A”) or a physiologically acceptable product thereof A fast-dissolving film-coated tablet containing a salt,
(A) an uncoated tablet containing Compound A or a physiologically acceptable salt thereof, and (b) a surface of the uncoated tablet substantially free of a plasticizer, or triacetin, diethyl phthalate, sebacic acid Dibutyl, tributyl citrate, diethyl sebacate, glyceryl fatty acid ester, acetylated monoglyceride, acetyl triethyl citrate, acetyl tributyl citrate, monostearate, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate and medium chain fatty acids A film-coated tablet having a coating layer containing at least one specific formulation component selected from the group consisting of triglycerides.
Item 2: The film-coated tablet according to Item 1, having a coating layer substantially free of a plasticizer.
Item 3: Triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glyceryl fatty acid ester, acetylated monoglyceride, acetyl triethyl citrate, acetyl tributyl citrate, monostearin, sorbitan monolaurate,
Item 4: The specific formulation component is selected from the group consisting of triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid ester, acetylated monoglyceride, acetyl triethyl citrate and acetyl
Item 5: The film-coated tablet according to Item 3, wherein the specific formulation component is selected from the group consisting of triacetin, diethyl phthalate, dibutyl sebacate and tributyl citrate.
Item 6: The film-coated tablet according to Item 3, wherein the specific formulation component is triacetin.
Item 7: The film-coated tablet according to Item 3, wherein the content of the specific formulation component is about 0.1 to about 30% by weight in the coating layer.
Item 8: The film-coated tablet according to any one of Items 1 to 7, wherein the physiologically acceptable salt of Compound A is a dihydrate of the citrate salt of Compound A.
Item 9: The film according to any one of Items 1 to 8, wherein the content of Compound A or a physiologically acceptable salt thereof is about 0.5 to about 70% by weight in terms of Compound A in the uncoated tablet. Coated tablets.
Item 10: The area measured by high performance liquid chromatography when the film-coated tablet was stored in a container at 40 ° C. and 75% RH for 6 months and the amount of the compound A related substance was generated. Item 10. The film-coated tablet according to any one of Items 1 to 9, which is about 1% or less as a percentage.
Item 11: A commercial package comprising the film-coated tablet according to Item 1 and a document relating to the film-coated tablet, wherein the film-coated tablet is used to promote gastrointestinal motility function, improve symptoms after gastrectomy or gastroesophageal reflux disease A commercial package containing a description on or in the package that can or should be used for prevention or treatment.
Since the film-coated tablet of the present invention has the above-mentioned characteristics, compound A or a physiologically acceptable salt thereof is hardly decomposed and stored in a stable state without applying protective packaging such as aluminum packaging. be able to. Furthermore, when the film-coated tablet of the present invention is taken, no bitterness is felt.
図１は、本発明の化合物Ａ−ａ（化合物Ａのラセミ体）のクエン酸塩と各種成分との接触試験の結果を示すグラフである。
図２は、実施例１と比較例１で得られた製剤の安定性試験の結果を示すグラフである。
図３は、実施例１と比較例１で得られた製剤の安定性試験の結果を示すグラフである。
図４は、実施例２と比較例２で得られた製剤の安定性試験の結果を示すグラフである。
図５は、実施例２と比較例２で得られた製剤の安定性試験の結果を示すグラフである。FIG. 1 is a graph showing the results of a contact test between a citrate of compound Aa (racemic compound A) of the present invention and various components.
FIG. 2 is a graph showing the results of the stability test of the preparations obtained in Example 1 and Comparative Example 1.
FIG. 3 is a graph showing the results of the stability test of the preparations obtained in Example 1 and Comparative Example 1.
FIG. 4 is a graph showing the results of the stability test of the preparations obtained in Example 2 and Comparative Example 2.
FIG. 5 is a graph showing the results of the stability test of the preparations obtained in Example 2 and Comparative Example 2.
本発明の第１の態様は、化合物Ａまたはその生理学的に許容される塩を含有する素錠、および該素錠の表面に、可塑剤を実質的に含まない被覆層を有する速溶性のフィルムコーティング錠である。前記フィルムコーティング錠は、長期保存においてもアルミ包装等の保護包装を施さなくても有効成分である化合物Ａの分解が抑制され、且つ製剤への着色が抑制される効果を奏するものである。
フィルムコーティングされたフィルムコーティング錠は、通常コーティング層（被覆層）に可塑剤を含んでおり、そして当該可塑剤は、有効成分と反応しないと考えられてきた。しかしながら、本発明者らの研究によって、特定の可塑剤、具体的には、ポリエチレングリコール、ポロキサマー、ポリソルベート、ポリオキシエチレン硬化ヒマシ油、グリセリン等と、化合物Ａまたはその生理学的に許容される塩とが接触すると、化合物Ａの分解を促進させることがわかった。具体的には、以下の参考例において示すように、本発明における化合物Ａまたは生理学的に許容される塩と上記成分とを接触させると非常に多くの分解物（類縁物質）が生成されることが判明した。また、一方では化合物Ａの分解を抑制する可塑剤があることも判明した。
そこで、通常被覆層に含まれるべき可塑剤を実質的に含まないコーティング層で被覆すると、長期保存においても化合物Ａの分解が抑制されることが判明した。
本態様における「可塑剤を実質的に含まない」とは、化合物Ａと接触した場合に当該化合物Ａの分解を促進させる作用を有する可塑剤だけでなく、化合物Ａの分解を抑制する（または影響を及ぼさない）可塑剤を含まないことをいう。ここで、可塑剤としては、ポロキサマー、ポリソルベート、プロピレングリコール、ポリエチレングリコール、グリセリン、ポリオキシエチレン硬化ヒマシ油、トリアセチン、フタル酸ジエチル、セバシン酸ジブチル、クエン酸トリブチル、セバシン酸ジエチル、グリセリン脂肪酸エステル、アセチル化モノグリセライド、クエン酸アセチルトリエチル、クエン酸アセチルトリブチル、モノステアリン、ソルビタンモノラウレート、フタル酸ジオクチル、ブチルフタリルブチルグリコレート、中鎖脂肪酸トリグリセリド等が挙げられる。
本発明の第２の態様は、化合物Ａまたはその生理学的に許容される塩を含有する素錠、および該素錠の表面に、特定製剤化成分を少なくとも１種含む被覆層を有する速溶性のフィルムコーティング錠である。前記フィルムコーティング錠は、被覆層に特定の製剤化成分を配合したことにより、コーティング工程が円滑に進行し、長期保存においてもアルミ包装等の保護包装を施さなくても有効成分である化合物Ａの分解を促進させないかまたは分解が抑制され、且つ製剤への着色が抑制される効果を奏するものである。また、製造においても支障を来たすこともない。
特定製剤化成分
本態様における「特定製剤化成分」としては、トリアセチン、フタル酸ジエチル、セバシン酸ジブチル、クエン酸トリブチル、セバシン酸ジエチル、グリセリン脂肪酸エステル、アセチル化モノグリセライド、クエン酸アセチルトリエチル、クエン酸アセチルトリブチル、モノステアリン、ソルビタンモノラウレート、フタル酸ジオクチル、ブチルフタリルブチルグリコレート、中鎖脂肪酸トリグリセリドが挙げられる。これら化合物は、一般的には可塑剤として製剤に配合されるものである。また、これら化合物の中には、分散剤、光沢化剤、安定化剤、界面活性剤などとして製剤に配合されるものもある。
従って、特定製剤化成分の少なくとも１種、具体的には、トリアセチン、フタル酸ジエチル、セバシン酸ジブチル、クエン酸トリブチル、セバシン酸ジエチル、グリセリン脂肪酸エステル、アセチル化モノグリセライド、クエン酸アセチルトリエチル、クエン酸アセチルトリブチル、モノステアリン、ソルビタンモノラウレート、フタル酸ジオクチル、ブチルフタリルブチルグリコレートおよび中鎖脂肪酸トリグリセリドからなる群から選ばれる少なくとも１種の成分を被覆層に配合することが好ましい。これにより、化合物Ａの分解がさらに抑制され、被覆層がより強くなり、錠剤の滑り（流動性を含む）もよい。好ましくは、トリアセチン、フタル酸ジエチル、セバシン酸ジブチル、クエン酸トリブチル、セバシン酸ジエチル、グリセリン脂肪酸エステル、アセチル化モノグリセライド、クエン酸アセチルトリエチルおよびクエン酸アセチルトリブチルであり、より好ましくはトリアセチン、フタル酸ジエチル、セバシン酸ジブチルおよびクエン酸トリブチルである。
これら特定製剤化成分の含有量は、被覆層中、約０．１〜約３０重量％、好ましくは約２〜約２５重量％、とりわけ、約７〜約２０重量％が好ましい。
以下、本発明の第１および第２の態様に共通する特徴および成分を説明する。
本発明にかかわるフィルムコーティング錠の「速溶性」とは、第１４改正日本薬局方に記載の溶出試験（３７℃、パドル法、５０回転／分、溶媒９００ｍｌの水）において、３０分後の溶出率が約８５％以上であることを意味するものである。前記溶出率は、好ましくは９０％以上、より好ましくは９５％以上である。
化合物Ａまたはその生理学的に許容される塩
本発明にかかわる化合物Ａ、即ち、４−アミノ−５−クロロ−２−エトキシ−Ｎ−［［４−（４−フルオロベンジル）−２−モルホリニル］メチル］ベンズアミドは、下記式：
また、化合物Ａはフリー体であってもよいし、その生理学的に許容される塩であってもよい。塩としては好ましくは酸付加塩がよい。たとえば有機酸の付加塩としては、ギ酸塩、酢酸塩、乳酸塩、アジピン酸塩、クエン酸塩、酒石酸塩、フマル酸塩、メタンスルホン酸塩、マレイン酸塩等が挙げられ、無機酸の付加塩としては、塩酸塩、硫酸塩、硝酸塩、リン酸塩等が例示できる。この中でも特にクエン酸塩が好ましい。さらに、化合物Ａまたはその生理学的に許容される塩は、溶媒和物であってもよく、水和物および非水和物であってもよい。好ましくはクエン酸塩の水和物がよく、とりわけクエン酸塩・２水和物が好ましい。
上記化合物Ａまたはその生理学的に許容される塩は、例えば、米国特許第４８７００７４号公報に記載の方法またはこれに準じる方法によって製造することができる。
素錠
「素錠」は化合物Ａまたはその生理学的に許容される塩単独であってもよいが、一般的には、他の製剤化成分を配合してなる。これら他の製剤化成分は、配合しても不都合がなく、且つ、配合の必要性があるものならばいずれでもよい。例えば、結合剤、賦形剤、流動化剤、崩壊剤などがその例として挙げられる。
化合物Ａまたはその生理学的に許容される塩の含有量は、化合物Ａに換算して、素錠中、約０．０１〜約９０重量％、好ましくは、約０．５〜約７０重量％、より好ましくは、約０．５〜約５０重量％、さらに好ましくは、約０．５〜約３０重量％である。
結合剤
結合剤の具体例としては、アラビアゴム、デンプンのり、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、プルラン、ゼラチン、エチルセルロース、メチルセルロース、カルメロースナトリウム、デキストリン、ポビドンなどが挙げられる。好ましくは、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポビドンなどが挙げられる。結合剤の配合量は、錠剤の硬度を維持し、且つ消化管内での崩壊に支障のない量であればよく、通常素錠中約０．５〜約１０重量％、好ましくは、約１〜約７重量％程度である。
賦形剤
賦形剤の具体例としては、乳糖、デンプン、マンニトール、結晶セルロース、ショ糖、エリスリトール、トレハロース、無水リン酸水素カルシウム、硫酸カルシウムなどが挙げられ、乳糖、デンプン、マンニトール、結晶セルロース等が好適である。その配合量は、通常、素錠中約５〜約９７重量％、好ましくは、約１０〜約８０重量％程度である。
流動化剤
流動化剤の具体例としては軽質無水ケイ酸、メタケイ酸アルミン酸マグネシウムなどが挙げられ、軽質無水ケイ酸が好ましい。その配合量は、通常、素錠中約０．０１〜約１０重量％、好ましくは、約０．１〜約５重量％程度である。
崩壊剤
崩壊剤としては、低置換度ヒドロキシプロピルセルロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン等が例示できる。この中で、低置換度ヒドロキシプロピルセルロースにおいてそのヒドロキシプロポキシル基含量は、通常は約５〜約１６重量％であるが、好ましくは約７〜約１６重量％であるものが使用され、より好ましくは約１０〜約１６重量％であるものが使用される。崩壊剤の配合量は、通常、素錠中の約２〜約３０重量％、好ましくは、約５〜約２５重量％程度である。
その他、ステアリン酸マグネシウム、ステアリン酸亜鉛、ステアリン酸カルシウムなどの滑沢剤等の製剤化成分を必要に応じて配合してもよい。
素錠は、上記製剤化成分を適宜組み合わせ、常法に従い、圧縮成型することにより製造できる。これら成分の中でも、賦形剤として乳糖およびデンプン、結合剤としてヒドロキシプロピルセルロース、流動化剤として軽質無水ケイ酸、崩壊剤として低置換度ヒドロキシプロピルセルロース、滑沢剤としてステアリン酸マグネシウムを選択するのが好ましい。
被覆層
上記特定製剤化成分以外に被覆層に含まれる成分としては以下のものが挙げられる。
フィルム基剤
フィルム基剤としては、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、メチルセルロース（ＭＣ）、エチルセルロース（ＥＣ）などのセルロース誘導体、ポリビニルアルコール（ＰＶＡ）、ポリビニルピロリドン（ＰＶＰ）などのビニル高分子類、メタアクリル酸コポリマーなどのアクリル高分子などが例示できる。好ましくは、ＨＰＭＣが例示できる。被覆層中のフィルム基剤の濃度としては、可塑剤を含まない被覆層の場合、約５〜約１００重量％、好ましくは約３０〜約１００重量％、とりわけ、約５０〜約９８重量％が好ましい。また、特定製剤化成分を含む被覆層の場合、約５〜約９９．９重量％、好ましくは約３０〜約９８重量％、とりわけ、約５０〜約９３重量％が好ましい。
上記フィルム基剤および上記特定製剤化成分以外の被覆層に追加してもよい成分としては、例えば、酸化チタン、三二酸化鉄のような着色剤（被覆層中の含有量：約０．１〜約５０重量％）、タルクのような固着防止剤（被覆層中の含有量：約０．１〜約５０重量％）、軽質無水ケイ酸のような光沢化剤（被覆層中の含有量：約０．１〜約１０重量％）などが挙げられる。その他必要に応じて、適宜製剤化成分を配合してもよい。
被覆層の形成工程は、上記記載の一種または二種以上のフィルム基剤（またはフィルム基剤および特定製剤化成分）を選択し、これを水またはエタノール等の有機溶媒、好適には、水に溶解もしくは懸濁させて製した液状組成物（コーティング液）を素錠のうえに噴霧することにより実施できる。また、コーティング液には、必要に応じて上記着色剤、固着防止剤あるいは光沢化剤などを配合してもよい。
本発明のフィルムコーティング錠は、長期保存においても安定である。従って、本発明のフィルムコーティング錠を容器に収納し、容器中、４０℃７５％ＲＨの開栓条件下で６ヶ月保存したときに、類縁物質の生成量（総類縁物質量）を高速液体クロマトグラフ法で測定した場合、面積百分率でのその総類縁物質量の割合は約１％以下である。約０．６％以下であるのが好ましい。類縁物質の生成量（総類縁物質量）とは、化合物Ａの分解生成物、製造時の中間体、製造時の不純物等の総量であって、後述する高速液体クロマトグラフ法による測定条件で検出可能な総量を意味する。面積百分率とは、後述する高速液体クロマトグラフ法で得られた総ピーク面積に占める類縁物質の合計ピーク面積の割合を％で示した数をいう。
前記高速液体クロマトグラフ法での測定条件は、実施例に記載の通りである。
本発明のフィルムコーティング剤は、消化管運動機能促進、胃切除後症状の改善または胃食道逆流症（ＧＥＲＤ）の予防もしくは治療に好適に用いられる。A first aspect of the present invention is a fast dissolving film having an uncoated tablet containing Compound A or a physiologically acceptable salt thereof, and a coating layer substantially free of a plasticizer on the surface of the uncoated tablet. It is a coated tablet. The film-coated tablet has the effect of suppressing the decomposition of the compound A, which is an active ingredient, and suppressing the coloration of the preparation even if it is not subjected to protective packaging such as aluminum packaging even during long-term storage.
Film-coated film-coated tablets usually contain a plasticizer in the coating layer (coating layer), and it has been considered that the plasticizer does not react with the active ingredient. However, according to the inventors' research, specific plasticizers, specifically, polyethylene glycol, poloxamer, polysorbate, polyoxyethylene hydrogenated castor oil, glycerin and the like, and compound A or a physiologically acceptable salt thereof, It was found that the decomposition of the compound A was promoted when contacted. Specifically, as shown in the following Reference Examples, when a compound A or a physiologically acceptable salt in the present invention is brought into contact with the above components, a large number of decomposition products (related substances) are generated. There was found. On the other hand, it was also found that there is a plasticizer that suppresses the decomposition of Compound A.
Thus, it has been found that when the coating layer that does not substantially contain the plasticizer that should normally be contained in the coating layer is coated, the decomposition of the compound A is suppressed even during long-term storage.
In the present embodiment, “substantially free of plasticizer” means not only a plasticizer having an action of promoting the decomposition of the compound A when brought into contact with the compound A, but also suppresses (or influences) the decomposition of the compound A. Does not contain a plasticizer. Here, as the plasticizer, poloxamer, polysorbate, propylene glycol, polyethylene glycol, glycerin, polyoxyethylene hydrogenated castor oil, triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid ester, acetyl Monoglycerides, acetyl triethyl citrate, acetyl tributyl citrate, monostearate, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate, medium chain fatty acid triglycerides and the like.
According to a second aspect of the present invention, there is provided an undissolved tablet containing compound A or a physiologically acceptable salt thereof, and a fast dissolving composition having a coating layer containing at least one specific formulation component on the surface of the uncoated tablet. Film-coated tablet. In the film-coated tablet, the compounding component is blended with the coating layer, so that the coating process proceeds smoothly, and even in long-term storage, the compound A which is an active ingredient can be used without protective packaging such as aluminum packaging. Degradation is not promoted or degradation is suppressed, and the coloring of the preparation is suppressed. In addition, there is no problem in manufacturing.
Specific formulation component In this embodiment, “specific formulation component” includes triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid ester, acetylated monoglyceride, acetyl triethyl citrate, acetyl citrate Examples include tributyl, monostearin, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate, and medium-chain fatty acid triglycerides. These compounds are generally blended into a preparation as a plasticizer. In addition, some of these compounds are blended in the preparation as a dispersant, a brightener, a stabilizer, a surfactant and the like.
Therefore, at least one specific formulation component, specifically triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid ester, acetylated monoglyceride, acetyl triethyl citrate, acetyl citrate It is preferable that at least one component selected from the group consisting of tributyl, monostearin, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate and medium chain fatty acid triglyceride is blended in the coating layer. Thereby, decomposition | disassembly of the compound A is further suppressed, a coating layer becomes stronger, and the slip of a tablet (including fluidity | liquidity) is also good. Preferably, triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid ester, acetylated monoglyceride, acetyl triethyl citrate and acetyl tributyl citrate, more preferably triacetin, diethyl phthalate, Dibutyl sebacate and tributyl citrate.
The content of these specific formulation components is preferably about 0.1 to about 30% by weight, preferably about 2 to about 25% by weight, especially about 7 to about 20% by weight in the coating layer.
Hereinafter, features and components common to the first and second aspects of the present invention will be described.
“Fast dissolution” of the film-coated tablet according to the present invention means dissolution after 30 minutes in the dissolution test (37 ° C., paddle method, 50 rotations / minute, solvent 900 ml of water) described in the 14th revised Japanese Pharmacopoeia. It means that the rate is about 85% or more. The elution rate is preferably 90% or more, more preferably 95% or more.
Compound A or a physiologically acceptable salt thereof Compound A according to the invention, ie 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl Benzamide has the following formula:
Compound A may be a free form or a physiologically acceptable salt thereof. The salt is preferably an acid addition salt. For example, organic acid addition salts include formate, acetate, lactate, adipate, citrate, tartrate, fumarate, methanesulfonate, maleate, etc. Examples of the salt include hydrochloride, sulfate, nitrate, phosphate and the like. Of these, citrate is particularly preferable. Furthermore, Compound A or a physiologically acceptable salt thereof may be a solvate, a hydrate or a non-hydrate. Citrate hydrate is preferred, and citrate dihydrate is particularly preferred.
The above compound A or a physiologically acceptable salt thereof can be produced, for example, by the method described in US Pat. No. 4870074 or a method analogous thereto.
The uncoated tablet “uncoated tablet” may be Compound A or a physiologically acceptable salt thereof alone, but generally comprises other formulation ingredients. Any of these other formulation ingredients may be used as long as there is no inconvenience even if they are blended and there is a necessity for blending. For example, binders, excipients, fluidizing agents, disintegrating agents and the like can be mentioned as examples.
The content of Compound A or a physiologically acceptable salt thereof is about 0.01 to about 90% by weight, preferably about 0.5 to about 70% by weight in uncoated tablets, in terms of Compound A, More preferably, it is about 0.5 to about 50% by weight, more preferably about 0.5 to about 30% by weight.
Specific examples of the binder binders are acacia, starch paste, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, pullulan, gelatin, ethylcellulose, methylcellulose, carmellose sodium, dextrin, povidone and the like. Preferably, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, etc. are mentioned. The amount of the binder may be any amount that maintains the hardness of the tablet and does not hinder disintegration in the gastrointestinal tract, and is usually about 0.5 to about 10% by weight in the uncoated tablet, preferably about 1 to About 7% by weight.
Specific examples of excipient excipients include lactose, starch, mannitol, crystalline cellulose, sucrose, erythritol, trehalose, anhydrous calcium hydrogen phosphate, calcium sulfate, etc., lactose, starch, mannitol, crystalline cellulose, etc. Is preferred. The amount is usually about 5 to about 97% by weight, preferably about 10 to about 80% by weight in the uncoated tablet.
Specific examples of the fluidizing agent fluidizing agent include light anhydrous silicic acid and magnesium aluminate metasilicate. Light anhydrous silicic acid is preferred. The blending amount is usually about 0.01 to about 10% by weight, preferably about 0.1 to about 5% by weight in the uncoated tablet.
Examples of the disintegrant disintegrant include low-substituted hydroxypropylcellulose, carmellose calcium, croscarmellose sodium, crospovidone and the like. Among them, the hydroxypropoxyl group content in the low-substituted hydroxypropyl cellulose is usually about 5 to about 16% by weight, preferably about 7 to about 16% by weight, more preferably Is about 10 to about 16% by weight. The compounding amount of the disintegrant is usually about 2 to about 30% by weight, preferably about 5 to about 25% by weight in the uncoated tablet.
In addition, formulation ingredients such as lubricants such as magnesium stearate, zinc stearate and calcium stearate may be blended as necessary.
An uncoated tablet can be manufactured by combining the said formulation component suitably, and compression-molding according to a conventional method. Among these ingredients, lactose and starch as excipients, hydroxypropylcellulose as binder, light anhydrous silicic acid as fluidizing agent, low substituted hydroxypropylcellulose as disintegrant, and magnesium stearate as lubricant Is preferred.
Coating layer In addition to the above-mentioned specific formulation component, examples of the component contained in the coating layer include the following.
Film base As the film base, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylcellulose (EC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), etc. Examples thereof include acrylic polymers such as vinyl polymers and methacrylic acid copolymers. Preferably, HPMC can be exemplified. The concentration of the film base in the coating layer is about 5 to about 100% by weight, preferably about 30 to about 100% by weight, especially about 50 to about 98% by weight in the case of the coating layer containing no plasticizer. preferable. In the case of a coating layer containing a specific formulation component, it is preferably about 5 to about 99.9% by weight, preferably about 30 to about 98% by weight, especially about 50 to about 93% by weight.
Examples of components that may be added to the coating layer other than the film base and the specific formulation component include colorants such as titanium oxide and iron sesquioxide (content in the coating layer: about 0.1 to 0.1). About 50% by weight), anti-sticking agent such as talc (content in coating layer: about 0.1 to about 50% by weight), brightening agent such as light anhydrous silicic acid (content in coating layer: About 0.1 to about 10% by weight). In addition, you may mix | blend a formulation component suitably as needed.
In the step of forming the coating layer, one or two or more types of film bases described above (or film base and a specific formulation component) are selected, and this is added to an organic solvent such as water or ethanol, preferably water. It can be carried out by spraying a liquid composition (coating solution) prepared by dissolving or suspending on an uncoated tablet. Moreover, you may mix | blend the said coloring agent, sticking prevention agent, or a brightener with a coating liquid as needed.
The film-coated tablet of the present invention is stable even during long-term storage. Therefore, when the film-coated tablet of the present invention is stored in a container and stored in the container for 6 months under an opening condition of 40 ° C. and 75% RH, the amount of related substances generated (total related substance amount) is determined by high performance liquid chromatography. When measured by the graph method, the percentage of the total related substances in area percentage is about 1% or less. It is preferably about 0.6% or less. The amount of related substances generated (total amount of related substances) is the total amount of decomposition products of compound A, intermediates during production, impurities during production, etc., and is detected under measurement conditions by high-performance liquid chromatography described below. It means the total amount possible. The area percentage refers to a number indicating the percentage of the total peak area of related substances in the total peak area obtained by high performance liquid chromatography described later in%.
The measurement conditions in the high performance liquid chromatographic method are as described in the examples.
The film coating agent of the present invention is suitably used for promoting gastrointestinal motility function, improving symptoms after gastrectomy, or preventing or treating gastroesophageal reflux disease (GERD).
以下に実施例を挙げて本発明をより具体的に例示するが、本発明は、これらの実施例に限定されるものではない。
以下の実施例等において、化合物Ａのラセミ体を化合物Ａ−ａと、また、化合物Ａ−ａのクエン酸塩二水和物を化合物Ａ−ｂと定義し、Ａ−ｂは、大日本製薬（株）製のものを使用した（平均粒子径約７μｍ）。
ポリエチレングリコール１５００はナカライテスク（株）製の「ポリエチレングリコール１５００」を、ポリエチレングリコール４００は丸石製薬（株）の「マクロゴール４００」を、ポリエチレングリコール６０００は日本油脂株式会社製の「マクロゴール６０００」を、ポリソルベート８０はナカライテスク（株）製の「ポリオキシエチレンソルビタンモノオレエート」を、ポロキサマー１８８は、ＢＡＳＦジャパン（株）製の「プルロニックＰＥ６８００」を、グリセリンは和光純薬工業株式会社製のものを、ソルビタンモノラウレートはナカライテスク（株）製のものを、フタル酸ジエチルは和光純薬工業（株）製のものを使用した。また、モノステアリンはナカライテスク（株）製のものを、トリアセチンは有機合成薬品工業株式会社製のものを使用した。
乳糖は、ＤＭＶ社製の「ＰｈａｒｍａｔｏｓｅＲ ２００ｍｅｓｈ」を使用した。デンプンは日本食品加工株式会社製の「コーンスターチ」を使用した。軽質無水ケイ酸は、日本アエロジル株式会社製の「Ａｅｒｏｓｉｌ（登録商標） ２００」を使用した。ヒドロキシプロピルセルロースは、日本曹達株式会社製の「日曹ＨＰＣ Ｌ」を使用した。低置換度ヒドロキシプロピルセルロースは、信越化学工業株式会社製のＬ−ＨＰＣ（ＬＨ−１１）」を使用した。ステアリン酸マグネシウムは、太平化学産業株式会社製の植物由来の「ステアリン酸マグネシウム」を使用した。ヒドロキシプロピルメチルセルロースは，信越化学工業株式会社製の「ＴＣ−５ＲＷ」を使用した。酸化チタンは石原産業株式会社製の「酸化チタン」を使用した。タルクは日本タルク株式会社製のものを使用した。
参考例
化合物Ａ−ｂと各種成分（ポリエチレングリコール６０００、ポリエチレングリコール１５００、ポリエチレングリコール４００、ポリンルベート８０、ポロキサマー１８８、グリセリン、ソルビタンモノラウレート、フタル酸ジエチル、モノステアリン、トリアセチン）との配合変化試験を行った。即ち、ガラス容器に化合物Ａ−ｂと各種成分を重量比で１：１になるような割合で配合し、密栓後６０℃、１ヶ月の保存試験をおこなった。配合の際に溶解しない場合には、懸濁または接触状態においた。比較例としてガラス容器に化合物Ａ−ｂのみいれ、密栓後、同様に６０℃、１ヶ月の保存試験をおこなった。１ヶ月経過後、類縁物質の生成量（総類縁物質量）を測定した。類縁物質の生成量は、高速液体クロマトグラフ法（面積百分率）で測定した。尚、総類縁物質量とは、化合物Ａ−ａの分解生成物、製造時の中間体、製造時の不純物等の総量を意味する。試料の調製は、上記ガラス容器に水：メタノールを１：９の割合で加え２０分間振り混ぜた後、遠心分離し、上澄液を得ることによって行った。使用したカラムは、Ｄｅｖｅｒｏｓｉｌ ＯＤＳ−７（野村化学）であり、移動相はクエン酸ナトリウム緩衝液（ｐＨ３．４）／メタノール／アセトニトリル混液（２４：９：７）を用いた。測定波長は、２７４ｎｍであった。
面積百分率は、（類縁物質の合計ピーク面積／総ピーク面積）×１００の計算式により求めた。
結果を図１に示す。化合物Ａ−ｂと、ポロキサマー１８８、ポリエチレングリコール類、ポリソルベート８０またはグリセリンとを混合すると、類縁物質が生じ、分解が促進されることが判明した。一方、化合物Ａ−ｂと、ソルビタンモノラウレート、フタル酸ジエチル、モノステアリンまたはトリアセチンとを混合すると、化合物Ａ−ｂ単独とほぼ同等または単独で保存するよりも分解が抑制されることが判明した。
実施例１ フィルムコーティング錠の製造
（１）素錠の製造
（２）被覆層の形成
上記（１）で得た素錠４００ｇ（約３１００錠分）をハイコーター（ＨＣ−ＬＡＢＯ型、フロイント産業）に投入し、コーティング液を噴霧して乾燥後のコーティング量が１錠あたり５．００ｍｇになるようコーティングした。コーティング終了後、ハイコーター内で乾燥を行い、目的のフィルムコーティング錠を得た。
比較例１
実施例１（１）で得た素錠に１錠あたり表３に記載の被覆を施したフィルムコーティング錠を以下のようにして製造した。
実施例１（１）で得た素錠４００ｇ（約３１００錠分）をハイコーター（ＨＣ−ＬＡＢＯ型、フロイント産業）に投入し、コーティング液を噴霧して乾燥後のコーティング量が１錠あたり５．００ｍｇになるようコーティングした。コーティング終了後、ハイコーター内で乾燥を行った。
試験例１ 安定性試験
実施例１および比較例１で得た錠剤を（１）ガラス瓶密栓で４０℃７５％ＲＨにて６ヶ月間保存、または（２）ガラス瓶開栓で４０℃７５％ＲＨにて６ヶ月間保存し、一定時期ごとに類縁物質の生成量（総類縁物質量）、色相変化を調べた。類縁物質の生成量は、錠剤２錠に水１ｍｌおよびメタノール９ｍｌを加えて参考例に記載の方法によって試料を調製し、参考例に記載の高速液体クロマトグラフ法（面積百分率）で測定し、色相変化は目視により判定した。
結果を図２（ガラス瓶密栓）および図３（ガラス瓶開栓）および表４（ガラス瓶密栓）および表５（ガラス瓶開栓）に示す。
上記結果が示すように、４０℃、７５％ＲＨの条件下において、本発明のフィルムコーティング錠は、安定性に優れたものであった。従って、本発明のフィルムコーティング錠は、個別に包装（例えば、ＰＴＰ包装など）されていない状態で一定量保存すること、いわゆるバラ包装も可能である。それゆえ、本発明のフィルムコーティング錠は、簡易な形態で包装（例えば、グラシン紙、薬包紙などによる包装）された形で、または服用時毎にひとまとめにするワンドースパッケージの形でも患者に処方できる。
試験例２ 苦味マスキング試験
上記実施例１で得られた錠剤の苦味マスキング試験を行った。即ち、化合物Ａ−ｂと比較して、不快な味の遮蔽効果があるか否かを３名のパネラーによって試験した。その結果、実施例の錠剤は明らかに遮蔽効果があり、不快な味は全く感じられなかった。
実施例２ フィルムコーティング錠
表６に示す処方に従い、１錠あたり化合物Ａ−ａを１．７２ｍｇ含む素錠を製造し（１錠あたり８０ｍｇ、円形錠、直径６．５ｍｍ）、これに表７の組成からなるコーティング液でもって、実施例１と同様にコーティングし、目的とするフィルムコーティング錠を製造した。
実施例２で得た素錠に１錠あたり表８に記載の組成の被覆を施してフィルムコーティング錠を製造した。
実施例２で得た素錠４００ｇ（約５０００錠分）をハイコーター（ＨＣ−ＬＡＢＯ型、フロイント産業）に投入し、コーティング液を噴霧して乾燥後のコーティング量が１錠あたり３．００ｍｇになるようコーティングした。コーティング終了後、ハイコーター内で乾燥を行った。
試験例３ 安定性試験
実施例２および比較例２で得た錠剤を（１）ガラス瓶密栓で４０℃７５％ＲＨにて６ヶ月間保存、または（２）ガラス瓶開栓で４０℃７５％ＲＨにて６ヶ月間保存し、一定時期ごとに類縁物質の生成量（総類縁物質量）、色相変化を調べた。類縁物質の生成量は、試験例１と同様にして測定し、色相変化は目視により判定した。
結果を図４（ガラス瓶密栓）および図５（ガラス瓶開栓）および表９（ガラス瓶密栓）および表１０（ガラス瓶開栓）に示す。
その結果、本発明のフィルムコーティング錠は、６ヶ月保存した後であっても、開栓・密栓のいずれの条件であっても、類縁物質の生成量（総類縁物質量）は基準値（１％）以下であった。また、色相変化も認められず安定であった。
実施例１（１）で得た素錠に１錠あたり表１１に記載の被覆を施したフィルムコーティング錠を以下のようにして製造した。
実施例１（１）で得た素錠４００ｇ（約３１００錠分）をハイコーター（ＨＣ−ＬＡＢＯ型、フロイント産業）に投入し、コーティング液を噴霧して乾燥後のコーティング量が１錠あたり５．００ｍｇになるようコーティングした。コーティング終了後、ハイコーター内で乾燥を行った。
試験例４ 安定性試験
実施例３で得た錠剤を（１）ガラス瓶開栓で４０℃７５％ＲＨにて１ヶ月間保存し、類縁物質の生成量（総類縁物質量）の生成量を試験例１と同様にして測定した。その結果、どちらの錠剤も安定であった。
試験例５ 溶出試験
実施例１の錠剤を用いて、第１４改正日本薬局方に記載の溶出試験（３７℃、パドル法、５０回転／分、溶媒９００ｍｌの水）に従い溶出試験を行った。その結果、３０分後の溶出率は、９８．５％であった。EXAMPLES The present invention will be illustrated more specifically with reference to the following examples, but the present invention is not limited to these examples.
In the following Examples and the like, the racemate of Compound A is defined as Compound A-a, and the citrate dihydrate of Compound A-a is defined as Compound Ab, where Ab is Dainippon Pharmaceutical Co., Ltd. The product made by Co., Ltd. was used (average particle diameter of about 7 μm).
Polyethylene glycol 1500 is “Polyethylene glycol 1500” manufactured by Nacalai Tesque, polyethylene glycol 400 is “Macrogol 400” manufactured by Maruishi Pharmaceutical, and polyethylene glycol 6000 is “Macrogol 6000” manufactured by NOF Corporation. Polysorbate 80 is "Polyoxyethylene sorbitan monooleate" manufactured by Nacalai Tesque, poloxamer 188 is "Pluronic PE6800" manufactured by BASF Japan, and glycerin is manufactured by Wako Pure Chemical Industries, Ltd. The sorbitan monolaurate was manufactured by Nacalai Tesque, and the diethyl phthalate was manufactured by Wako Pure Chemical Industries. Monostearin was manufactured by Nacalai Tesque, and triacetin was manufactured by Organic Synthetic Chemical Industry Co., Ltd.
As the lactose, “Pharmacato R 200 mesh” manufactured by DMV was used. As the starch, “Corn Starch” manufactured by Nippon Food Processing Co., Ltd. was used. As the light anhydrous silicic acid, “Aerosil (registered trademark) 200” manufactured by Nippon Aerosil Co., Ltd. was used. As the hydroxypropyl cellulose, “Nisso HPC L” manufactured by Nippon Soda Co., Ltd. was used. Low substituted hydroxypropyl cellulose used was L-HPC (LH-11) manufactured by Shin-Etsu Chemical Co., Ltd. As the magnesium stearate, plant-derived “magnesium stearate” manufactured by Taihei Chemical Industry Co., Ltd. was used. As the hydroxypropyl methylcellulose, “TC-5RW” manufactured by Shin-Etsu Chemical Co., Ltd. was used. As the titanium oxide, “Titanium oxide” manufactured by Ishihara Sangyo Co., Ltd. was used. Talc manufactured by Nippon Talc Co., Ltd. was used.
Reference Example A compound change test between compound Ab and various components (polyethylene glycol 6000, polyethylene glycol 1500, polyethylene glycol 400, porin rubate 80, poloxamer 188, glycerin, sorbitan monolaurate, diethyl phthalate, monostearin, triacetin) went. That is, Compound Ab and various components were blended in a glass container at a ratio of 1: 1 so that a storage test was conducted at 60 ° C. for 1 month after sealing. If it did not dissolve during compounding, it was in suspension or contact. As a comparative example, only Compound Ab was placed in a glass container, and after sealing, a storage test was similarly conducted at 60 ° C. for 1 month. After 1 month, the amount of related substances produced (total amount of related substances) was measured. The amount of related substances produced was measured by high performance liquid chromatography (area percentage). The total amount of related substances means the total amount of decomposition products of compound Aa, intermediates during production, impurities during production, and the like. The sample was prepared by adding water: methanol in a ratio of 1: 9 to the glass container and shaking and stirring for 20 minutes, followed by centrifugation to obtain a supernatant. The column used was Deverosil ODS-7 (Nomura Chemical), and the mobile phase used was a sodium citrate buffer (pH 3.4) / methanol / acetonitrile mixture (24: 9: 7). The measurement wavelength was 274 nm.
The area percentage was determined by a calculation formula of (total peak area of related substances / total peak area) × 100.
The results are shown in FIG. It has been found that mixing compound Ab with poloxamer 188, polyethylene glycols, polysorbate 80 or glycerin produces related substances and promotes degradation. On the other hand, it was found that when compound Ab was mixed with sorbitan monolaurate, diethyl phthalate, monostearin or triacetin, decomposition was suppressed more than when it was almost the same as compound Ab alone or stored alone. .
Example 1 Production of film-coated tablets (1) Production of uncoated tablets
(2) Formation of coating layer
400 g (about 3100 tablets) of the uncoated tablet obtained in (1) above is put into a high coater (HC-LABO type, Freund Sangyo), and the coating amount after drying by spraying the coating solution is 5.00 mg per tablet. It was coated to become. After coating, the film was dried in a high coater to obtain the desired film-coated tablet.
Comparative Example 1
Film-coated tablets in which the uncoated tablets obtained in Example 1 (1) were coated as shown in Table 3 per tablet were produced as follows.
400 g (about 3100 tablets) of the uncoated tablets obtained in Example 1 (1) were put into a high coater (HC-LABO type, Freund Sangyo), and the coating amount after drying by spraying the coating solution was 5 per tablet. Coated to 0.000 mg. After coating, drying was performed in a high coater.
Test Example 1 Stability Test The tablets obtained in Example 1 and Comparative Example 1 were (1) stored for 6 months at 40 ° C. and 75% RH in a glass bottle cap, or (2) opened to 40 ° C. and 75% RH by opening the glass bottle. The product was stored for 6 months, and the amount of related substances produced (total amount of related substances) and hue change were examined at regular intervals. The amount of the related substance produced was measured by the high performance liquid chromatographic method (area percentage) described in the reference example by adding 1 ml of water and 9 ml of methanol to 2 tablets, and measuring the color by hue. The change was judged visually.
The results are shown in FIG. 2 (glass bottle stopper), FIG. 3 (glass bottle stopper), Table 4 (glass bottle stopper) and Table 5 (glass bottle stopper).
As the above results show, the film-coated tablet of the present invention was excellent in stability under the conditions of 40 ° C. and 75% RH. Therefore, the film-coated tablet of the present invention can be stored in a certain amount without being individually packaged (for example, PTP packaging), so-called rose packaging. Therefore, the film-coated tablet of the present invention can be prescribed to patients in a simple packaged form (for example, wrapped in glassine paper, medicine wrapping paper, etc.), or in the form of a one-dose package that is packaged together every time it is taken. .
Test Example 2 Bitterness Masking Test The tablet obtained in Example 1 was subjected to a bitterness masking test. That is, it was tested by three panelists whether or not there was an unpleasant taste shielding effect as compared with the compound Ab. As a result, the tablets of the examples clearly had a shielding effect, and no unpleasant taste was felt at all.
Example 2 Film-coated tablets According to the formulation shown in Table 6, uncoated tablets containing 1.72 mg of compound Aa per tablet were produced (80 mg per tablet, round tablet, diameter 6.5 mm). With the coating liquid having the composition, coating was performed in the same manner as in Example 1 to produce the target film-coated tablet.
The uncoated tablets obtained in Example 2 were coated with the composition shown in Table 8 per tablet to produce film-coated tablets.
400 g (about 5000 tablets) of the uncoated tablet obtained in Example 2 is put into a high coater (HC-LABO type, Freund Corporation), and the coating amount after drying by spraying the coating solution is 3.00 mg per tablet. Coated so that After coating, drying was performed in a high coater.
Test Example 3 Stability Test The tablets obtained in Example 2 and Comparative Example 2 were (1) stored for 6 months at 40 ° C. and 75% RH in a glass bottle cap, or (2) opened to 40 ° C. and 75% RH by opening the glass bottle. The product was stored for 6 months, and the amount of related substances produced (total amount of related substances) and hue change were examined at regular intervals. The amount of related substances produced was measured in the same manner as in Test Example 1, and the hue change was visually determined.
The results are shown in FIG. 4 (glass bottle stopper), FIG. 5 (glass bottle stopper), Table 9 (glass bottle stopper) and Table 10 (glass bottle stopper).
As a result, the film-coated tablet of the present invention has a reference amount (1) of the amount of related substances generated (total amount of related substances) regardless of whether the film-coated tablets are stored for 6 months or not. %) Or less. Moreover, the hue change was not recognized and it was stable.
Film-coated tablets in which the uncoated tablets obtained in Example 1 (1) were coated as shown in Table 11 per tablet were produced as follows.
400 g (about 3100 tablets) of the uncoated tablets obtained in Example 1 (1) were put into a high coater (HC-LABO type, Freund Sangyo), and the coating amount after drying by spraying the coating solution was 5 per tablet. Coated to 0.000 mg. After coating, drying was performed in a high coater.
Test Example 4 Stability Test The tablets obtained in Example 3 were (1) stored for 1 month at 40 ° C. and 75% RH by opening the glass bottle, and the amount of related substances produced (total amount of related substances) was tested. Measurement was performed in the same manner as in Example 1. As a result, both tablets were stable.
Test Example 5 Dissolution Test Using the tablets of Example 1, a dissolution test was performed according to the dissolution test described in the 14th revised Japanese Pharmacopoeia (37 ° C., paddle method, 50 revolutions / minute, 900 ml of solvent water). As a result, the elution rate after 30 minutes was 98.5%.
本発明のフィルムコーティング錠によれば、アルミ包装などの保護包装を施さなくても化合物Ａまたはその生理学的に許容される塩が分解されにくく、安定な状態で保存することができる。また、生産においても支障をきたすこともない。更に服用時に苦味を有することもない。
以上、本発明の具体的な態様のいくつかを詳細に説明したが、当業者であれば示された特定の態様には、本発明の教示と利点から実質的に逸脱しない範囲で様々な修正と変更をなすことは可能である。従って、そのような修正および変更も、すべて後記の請求の範囲で請求される本発明の精神と範囲内に含まれるものである。
本出願は、日本で出願された特願２００４−２２０８６４（出願日：２００４年７月２８日）を基礎としており、その内容は本明細書に包含されるものである。According to the film-coated tablet of the present invention, compound A or a physiologically acceptable salt thereof is not easily decomposed and can be stored in a stable state without carrying out protective packaging such as aluminum packaging. Moreover, there is no trouble in production. Furthermore, it does not have a bitter taste when taken.
Although several specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that various modifications may be made to the specific embodiments shown without departing from the teachings and advantages of the invention. It is possible to make changes. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the invention as claimed in the following claims.
This application is based on Japanese Patent Application No. 2004-220864 (filing date: July 28, 2004) filed in Japan, the contents of which are incorporated herein.
Claims (15)
（ａ）化合物Ａまたはその生理学的に許容される塩を含有する素錠および
（ｂ）該素錠の表面に、可塑剤を実質的に含まないか、もしくは、トリアセチン、フタル酸ジエチル、セバシン酸ジブチル、クエン酸トリブチル、セバシン酸ジエチル、グリセリン脂肪酸エステル、アセチル化モノグリセライド、クエン酸アセチルトリエチル、クエン酸アセチルトリブチル、モノステアリン、ソルビタンモノラウレート、フタル酸ジオクチル、ブチルフタリルブチルグリコレートおよび中鎖脂肪酸トリグリセリドからなる群から選ばれる特定製剤化成分を少なくとも１種含む被覆層
を有するフィルムコーティング錠。4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter referred to as “compound A”) or a physiologically acceptable salt thereof A fast-dissolving film-coated tablet containing
(A) an uncoated tablet containing Compound A or a physiologically acceptable salt thereof, and (b) a surface of the uncoated tablet substantially free of a plasticizer, or triacetin, diethyl phthalate, sebacic acid Dibutyl, tributyl citrate, diethyl sebacate, glyceryl fatty acid ester, acetylated monoglyceride, acetyl triethyl citrate, acetyl tributyl citrate, monostearate, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate and medium chain fatty acids A film-coated tablet having a coating layer containing at least one specific formulation component selected from the group consisting of triglycerides.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006527889A JP4874797B2 (en) | 2004-07-28 | 2005-07-27 | Film coated tablets |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004220864 | 2004-07-28 | ||
| JP2004220864 | 2004-07-28 | ||
| JP2006527889A JP4874797B2 (en) | 2004-07-28 | 2005-07-27 | Film coated tablets |
| PCT/JP2005/014149 WO2006011637A1 (en) | 2004-07-28 | 2005-07-27 | Film-coated tablet |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPWO2006011637A1 JPWO2006011637A1 (en) | 2008-05-01 |
| JP4874797B2 true JP4874797B2 (en) | 2012-02-15 |
Family
ID=35786372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006527889A Expired - Fee Related JP4874797B2 (en) | 2004-07-28 | 2005-07-27 | Film coated tablets |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP4874797B2 (en) |
| KR (1) | KR101045508B1 (en) |
| CN (1) | CN1993131B (en) |
| HK (1) | HK1107258A1 (en) |
| TW (1) | TW200605920A (en) |
| WO (1) | WO2006011637A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5700367B2 (en) * | 2010-05-06 | 2015-04-15 | 高田製薬株式会社 | Paroxetine-containing oral film coating |
| JP2012201597A (en) * | 2011-03-23 | 2012-10-22 | Nihon Generic Co Ltd | Solid preparation comprising mosapride |
| CN106943369B (en) * | 2016-01-07 | 2020-06-26 | 江苏豪森药业集团有限公司 | Pharmaceutical composition of mosapride citrate and preparation method thereof |
| WO2017170854A1 (en) | 2016-03-31 | 2017-10-05 | 大日本住友製薬株式会社 | Film-coated tablet having high chemical stability of active ingredient |
| CN106214657B (en) * | 2016-09-06 | 2018-04-06 | 江苏豪森药业集团有限公司 | Thin membrane coated tablet of mosapride citrate and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63264467A (en) * | 1986-04-30 | 1988-11-01 | Dainippon Pharmaceut Co Ltd | Benzamide derivative |
| US6676933B2 (en) * | 2001-05-23 | 2004-01-13 | Osmotica Corp. | Pharmaceutical composition containing mosapride and pancreatin |
| WO2003011256A1 (en) * | 2001-07-30 | 2003-02-13 | Sun Pharmaceutical Industries Limited | Oral controlled release pharmaceutical composition of a prokinetic agent |
-
2005
- 2005-07-27 CN CN2005800254806A patent/CN1993131B/en not_active Expired - Fee Related
- 2005-07-27 TW TW094125369A patent/TW200605920A/en unknown
- 2005-07-27 KR KR1020077003645A patent/KR101045508B1/en not_active IP Right Cessation
- 2005-07-27 JP JP2006527889A patent/JP4874797B2/en not_active Expired - Fee Related
- 2005-07-27 WO PCT/JP2005/014149 patent/WO2006011637A1/en active Application Filing
-
2007
- 2007-11-26 HK HK07112896.3A patent/HK1107258A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2006011637A1 (en) | 2008-05-01 |
| CN1993131B (en) | 2010-10-13 |
| WO2006011637A1 (en) | 2006-02-02 |
| TW200605920A (en) | 2006-02-16 |
| CN1993131A (en) | 2007-07-04 |
| HK1107258A1 (en) | 2008-04-03 |
| KR20070046117A (en) | 2007-05-02 |
| KR101045508B1 (en) | 2011-06-30 |
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