JP2022074105A - Linagliptin-containing granule and pharmaceutical composition - Google Patents
Linagliptin-containing granule and pharmaceutical composition Download PDFInfo
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- JP2022074105A JP2022074105A JP2021176998A JP2021176998A JP2022074105A JP 2022074105 A JP2022074105 A JP 2022074105A JP 2021176998 A JP2021176998 A JP 2021176998A JP 2021176998 A JP2021176998 A JP 2021176998A JP 2022074105 A JP2022074105 A JP 2022074105A
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- linagliptin
- granules
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- pharmaceutical composition
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- BYUMYPPGJBLEIS-UHFFFAOYSA-N acetic acid;propane-1,2,3-triol Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.OCC(O)CO BYUMYPPGJBLEIS-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
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- 229960001126 alginic acid Drugs 0.000 description 1
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- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
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- 239000011648 beta-carotene Substances 0.000 description 1
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- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
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- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
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- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000004503 fine granule Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
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- 239000003205 fragrance Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
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- 239000001087 glyceryl triacetate Substances 0.000 description 1
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- 229920000578 graft copolymer Polymers 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
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- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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- 230000001771 impaired effect Effects 0.000 description 1
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
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- 230000000873 masking effect Effects 0.000 description 1
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000003921 oil Substances 0.000 description 1
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- 238000004806 packaging method and process Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
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- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
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- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
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- 229960002477 riboflavin Drugs 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
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- 229920003109 sodium starch glycolate Polymers 0.000 description 1
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- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- 239000012086 standard solution Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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- 239000000811 xylitol Substances 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Abstract
Description
本発明は、リナグリプチンを含有する顆粒及びこの顆粒を含む医薬組成物であって、服用時に感じるリナグリプチンの苦みが抑えられており、リナグリプチンの安定性が向上しており、さらにリナグリプチンの溶出性が良好な顆粒及び医薬組成物に関する。 The present invention is a granule containing linagliptin and a pharmaceutical composition containing the granule, in which the bitterness of linagliptin felt at the time of administration is suppressed, the stability of linagliptin is improved, and the elution of linagliptin is good. Linagliptin and pharmaceutical compositions.
リナグリプチンは、下記構造を有する薬物であり、２型糖尿病の治療薬として用いられている。
リナグリプチンを含む製剤としては、トラゼンタ錠（登録商標）（日本ベーリンガーインゲルハイム社）が市販されている。トラゼンタ錠は、添加物として、Ｄ－マンニトール、部分アルファー化デンプン、トウモロコシデンプン、コポリビドン、ステアリン酸マグネシウム、ヒプロメロース、酸化チタン、タルク、マクロゴール、三二酸化鉄を含む錠剤である（非特許文献１）。 As a preparation containing linagliptin, Trazenta Tablets (registered trademark) (Japan Boehringer Ingelheim Co., Ltd.) is commercially available. Trazenta tablets are tablets containing D-mannitol, partially pregelatinized starch, corn starch, copolyvidone, magnesium stearate, hypromellose, titanium oxide, talc, macrogol, and iron sesquioxide as additives (Non-Patent Document 1). ..
また、特許文献１は、リナグリプチンは従来汎用されている多くの賦形剤と反応して製剤中で変性するが、リナグリプチンを、マンニトール、アルファー化デンプン、トウモロコシデンプン、コポリビドン、ステアリン酸マグネシウムと共に打錠すれば、その安定性が向上することを教えている。また、この素錠に、ヒプロメロース、酸化チタン、タルク、ポリエチレングリコール、酸化鉄を含むコーティングを施した錠剤を開示している。 Further, in Patent Document 1, linagliptin reacts with many conventionally used excipients and is denatured in the formulation, but linagliptin is tableted together with mannitol, pregelatinized starch, corn starch, copolyvidone, and magnesium stearate. It teaches that if it does, its stability will improve. Further, the present invention discloses a tablet in which a coating containing hypromellose, titanium oxide, talc, polyethylene glycol, and iron oxide is applied to the uncoated tablet.
また、特許文献２は、リナグリプチンに結合剤を添加せずに、無水リン酸水素カルシウム、マンニトールのような希釈剤、デンプン、クロスポビドン、デンプングリコール酸ナトリウム、クロスカルメロースナトリウムのような崩壊剤、ステアリン酸マグネシウム、タルクのような潤滑剤を添加して直接圧縮して錠剤を製造すれば、製造工程が少なく、生産性が良いことを教えている。また、この素錠に、ヒプロメロース、酸化チタン、タルク、ポリエチレングリコール、酸化鉄を含むコーティングを施した錠剤を開示している。 Further, Patent Document 2 describes an anhydrous calcium hydrogen phosphate, a diluent such as mannitol, a disintegrant such as starch, crospovidone, sodium starch glycolate, and croscarmellose sodium, without adding a binder to linagliptin. It teaches that if tablets are manufactured by adding lubricants such as magnesium stearate and starch and directly compressing them, the number of manufacturing steps is small and the productivity is good. Further, the present invention discloses a tablet in which a coating containing hypromellose, titanium oxide, talc, polyethylene glycol, and iron oxide is applied to the uncoated tablet.
また、特許文献３は、リナグリプチンは湿潤環境下で不安定であるが、マンニトール、コポリビドン、ステアリン酸マグネシウムを含む錠剤とすれば、リナグリプチンの安定性が向上することを教えている。また、この素錠をヒプロメロース、二酸化チタン、タルク、ポリエチレングリコールを含む被覆層でコーティングしたものを開示している。 Further, Patent Document 3 teaches that linagliptin is unstable in a moist environment, but the stability of linagliptin is improved by using a tablet containing mannitol, copolyvidone, and magnesium stearate. Further, the present invention discloses a tablet coated with a coating layer containing hypromellose, titanium dioxide, talc, and polyethylene glycol.
上記の従来のリナグリプチン含有錠は、そのまま嚥下する普通錠である。
近年、高齢者、小児の患者などの、錠剤を嚥下するのが困難な患者でも服用し易い錠剤として、口腔内の水分で速やかに崩壊する口腔内崩壊錠が求められている。
The above-mentioned conventional linagliptin-containing tablet is a normal tablet that is swallowed as it is.
In recent years, there has been a demand for an orally disintegrating tablet that rapidly disintegrates with water in the oral cavity as a tablet that is easy to take even for patients who have difficulty swallowing the tablet, such as elderly patients and pediatric patients.
しかし、リナグリプチンは苦みがあるため、口腔内崩壊錠とするには、苦みをマスキングすることが必要である。一般に、薬物含有顆粒をコーティング層で被覆したコーティング顆粒を打錠することで薬物の不快な味がマスキングされた口腔内崩壊錠を製造することが行われている。しかし、顆粒をコーティングすると、薬物の溶出性が低下し易いため、溶出性の低下を抑制しながらマスキングすることが必要である。
また、特許文献１、３が教える通り、リナグリプチンは製剤中で不安定な薬物であるため、その安定性を確保する必要がある。上記従来の錠剤は、素錠に遮光剤を含むコーティング層を設けることで、リナグリプチンの光安定性を確保しているが、口腔内崩壊錠をコーティングすると、口腔内崩壊性が低下する場合が多いため、製剤設計の自由度が低下する。
However, since linagliptin is bitter, it is necessary to mask the bitterness in order to make it an orally disintegrating tablet. Generally, an orally disintegrating tablet in which the unpleasant taste of a drug is masked is produced by tableting the coated granules in which the drug-containing granules are coated with a coating layer. However, when the granules are coated, the elution of the drug tends to decrease, so it is necessary to mask while suppressing the decrease in the elution.
Further, as Patent Documents 1 and 3 teach, linagliptin is an unstable drug in a pharmaceutical product, so it is necessary to ensure its stability. In the above-mentioned conventional tablets, the photostability of linagliptin is ensured by providing a coating layer containing a light-shielding agent on the uncoated tablet, but coating the orally disintegrating tablet often reduces the orally disintegrating property. Therefore, the degree of freedom in formulation design is reduced.
本発明は、リナグリプチンを含有する顆粒及びこれを含む医薬組成物であって、リナグリプチンの苦味がマスキングされており、またリナグリプチンの光安定性が向上しており、さらにリナグリプチンの溶出性が良好である顆粒及び医薬組成物を提供することを課題とする。 The present invention is a granule containing linagliptin and a pharmaceutical composition containing the same, wherein the bitterness of linagliptin is masked, the photostability of linagliptin is improved, and the elution of linagliptin is good. It is an object of the present invention to provide granules and pharmaceutical compositions.
本発明者は、上記課題を解決するために鋭意研究を重ね、リナグリプチン含有顆粒及びそれを含む医薬組成物において、リナグリプチンをアミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆することにより、リナグリプチンの苦みがマスキングされると共に、コーティングされているにも拘らずリナグリプチンの溶出性が実用上十分であることを見出した。また、リナグリプチンの光照射による分解が抑制されることを見出した。
本発明は、上記知見に基づき完成されたものであり、下記〔１〕～〔１０〕を提供する。
The present inventor has conducted extensive research to solve the above problems, and by coating linagliptin with a coating layer containing an aminoalkylmethacrylate copolymer E in linagliptin-containing granules and a pharmaceutical composition containing the same, the bitterness of linagliptin can be reduced. It was found that the elution of linagliptin was practically sufficient despite being masked and coated. It was also found that the decomposition of linagliptin by light irradiation was suppressed.
The present invention has been completed based on the above findings, and provides the following [1] to [10].
〔１〕 リナグリプチンを含む成分がアミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆されている、リナグリプチン含有顆粒。
〔２〕 リナグリプチンと賦形剤の混合物が、アミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆されている、〔１〕に記載のリナグリプチン含有顆粒。
〔３〕 リナグリプチンと賦形剤と結合剤を含む造粒物が、アミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆されている、〔１〕に記載のリナグリプチン含有顆粒。
〔４〕 コーティング層の含有量が、被覆される全成分の１重量部に対して０．０５～１．５重量部である、〔１〕～〔３〕の何れかに記載のリナグリプチン含有顆粒。
〔５〕 さらに、酸化鉄を含む、〔１〕～〔４〕の何れかに記載のリナグリプチン含有顆粒。
〔６〕 〔１〕～〔６〕の何れかに記載のリナグリプチン含有顆粒を含む医薬組成物。
〔７〕 医薬組成物が錠剤である、〔６〕に記載の医薬組成物。
〔８〕 錠剤が口腔内崩壊錠である、〔７〕に記載の医薬組成物。
〔９〕 さらに崩壊性顆粒を含む、〔８〕に記載の医薬組成物。
〔１０〕 さらに酸化鉄を含む、〔６〕～〔９〕の何れかに記載の医薬組成物。
〔１１〕 （ａ）リナグリプチンと添加物の混合物に、アミノアルキルメタクリレートコポリマーＥを含むコーティング層材料を供給しながら、造粒及びコーティングする工程を含むか、又は（ｂ）リナグリプチンと添加物の混合物を予備造粒した後、得られた造粒物をアミノアルキルメタクリレートコポリマーＥを含むコーティング層材料で被覆する工程を含む、リナグリプチン含有顆粒の製造方法。
〔１２〕 リナグリプチン含有顆粒又はリナグリプチン含有顆粒を含む医薬組成物において、リナグリプチンを含む成分をアミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆することにより、リナグリプチンの溶出性低下を抑制しながら、リナグリプチンの苦みをマスキングする方法。
〔１３〕 リナグリプチン含有顆粒又はリナグリプチン含有顆粒を含む医薬組成物において、リナグリプチンを含む成分をアミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆することにより、リナグリプチンの光安定性を向上させる方法。
[1] Linagliptin-containing granules in which a component containing linagliptin is coated with a coating layer containing an aminoalkyl methacrylate copolymer E.
[2] The linagliptin-containing granule according to [1], wherein the mixture of linagliptin and the excipient is coated with a coating layer containing the aminoalkylmethacrylate copolymer E.
[3] The linagliptin-containing granule according to [1], wherein the granule containing linagliptin, an excipient and a binder is coated with a coating layer containing an aminoalkyl methacrylate copolymer E.
[4] The linagliptin-containing granule according to any one of [1] to [3], wherein the content of the coating layer is 0.05 to 1.5 parts by weight with respect to 1 part by weight of all the components to be coated. ..
[5] The linagliptin-containing granule according to any one of [1] to [4], further containing iron oxide.
[6] A pharmaceutical composition containing the linagliptin-containing granules according to any one of [1] to [6].
[7] The pharmaceutical composition according to [6], wherein the pharmaceutical composition is a tablet.
[8] The pharmaceutical composition according to [7], wherein the tablet is an orally disintegrating tablet.
[9] The pharmaceutical composition according to [8], further comprising disintegrating granules.
[10] The pharmaceutical composition according to any one of [6] to [9], further containing iron oxide.
[11] (a) the mixture of linagliptin and the additive comprises the steps of granulating and coating while supplying the coating layer material containing the aminoalkylmethacrylate copolymer E, or (b) the mixture of linagliptin and the additive. A method for producing linagliptin-containing granules, which comprises a step of coating the obtained granulated product with a coating layer material containing an aminoalkylmethacrylate copolymer E after pre-granulation.
[12] In a pharmaceutical composition containing linagliptin-containing granules or linagliptin-containing granules, by coating the component containing linagliptin with a coating layer containing an aminoalkylmethacrylate copolymer E, the bitterness of linagliptin is suppressed while suppressing the decrease in elution of linagliptin. How to mask.
[13] A method for improving the photostability of linagliptin by coating a component containing linagliptin with a coating layer containing an aminoalkyl methacrylate copolymer E in a linagliptin-containing granule or a pharmaceutical composition containing linagliptin-containing granules.
本発明の医薬組成物は、リナグリプチンを含む成分がアミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆された顆粒を含むため、リナグリプチンの苦みが効果的にマスキングされている。この医薬組成物は、崩壊させても顆粒がコーティングされているため、リナグリプチンの苦みを感じない又は感じ難い。従って、口腔内崩壊錠とするのに適している。
また、リナグリプチン含有顆粒がコーティングされているにも拘らず、リナグリプチンの溶出性に優れるため、リナグリプチンの予定した薬効が十分に得られる。
また、リナグリプチンは製剤中で不安定な薬物であるが、本発明の医薬組成物は、光照射によるリナグリプチンの分解が低減している。従って、遮光包装などのコスト高な包装材を使用する必要がない。
Since the pharmaceutical composition of the present invention contains granules in which the component containing linagliptin is coated with a coating layer containing the aminoalkyl methacrylate copolymer E, the bitterness of linagliptin is effectively masked. Since the granules of this pharmaceutical composition are coated even when disintegrated, the bitterness of linagliptin is not felt or is difficult to feel. Therefore, it is suitable for making an orally disintegrating tablet.
In addition, despite the fact that the linagliptin-containing granules are coated, the elution of linagliptin is excellent, so that the expected medicinal effect of linagliptin can be sufficiently obtained.
Further, although linagliptin is an unstable drug in the pharmaceutical product, the pharmaceutical composition of the present invention reduces the decomposition of linagliptin by light irradiation. Therefore, it is not necessary to use a costly packaging material such as light-shielding packaging.
以下、本発明を詳細に説明する。
（１）リナグリプチン含有顆粒
本発明のリナグリプチン含有顆粒は、リナグリプチンを含む成分がアミノアルキルメタクリレートコポリマーＥを含むコーティン層で被覆された顆粒である。
顆粒は、リナグリプチン粉末自体を被覆したものであってもよく、リナグリプチンと添加物の混合物を被覆したものであってもよく、リナグリプチンと添加物の混合物を一旦造粒した後に被覆したものであってもよい。中でも、リナグリプチンと添加物の混合物を被覆した顆粒、及びリナグリプチンと添加物の混合物を一旦造粒した後に被覆した顆粒が好ましい。
Hereinafter, the present invention will be described in detail.
(1) Linagliptin-containing granules
The linagliptin-containing granules of the present invention are granules in which a component containing linagliptin is coated with a coating layer containing an aminoalkylmethacrylate copolymer E.
The granules may be coated with the linagliptin powder itself, may be coated with a mixture of linagliptin and an additive, or may be coated with a mixture of linagliptin and an additive after being granulated once. May be good. Of these, granules coated with a mixture of linagliptin and an additive, and granules coated with a mixture of linagliptin and an additive after being granulated are preferable.
リナグリプチン
リナグリプチンには、Ａ型、Ｂ型、Ｃ型、Ｄ型、Ｅ型（以上、特許第５３２３６８４号に記載された結晶）、Ｆ型、ＡＬ型等の複数の結晶型が存在するが、何れも用いることができる。中でも、ＡＬ型が好ましい。
Linagliptin Linagliptin has a plurality of crystal types such as A type, B type, C type, D type, E type (above, the crystal described in Japanese Patent No. 5323684 ), F type, AL type and the like. Can also be used. Of these, the AL type is preferable.
リナグリプチンの粒度分布は、Ｄ５０が１μｍ以上、中でも３μｍ以上、中でも５μｍ以上であることが好ましい。また、Ｄ５０が２０μｍ以下、中でも１５μｍ以下、中でも１０μｍ以下であることが好ましい。この範囲であれば、本発明の効果が得られる。
リナグリプチンのＤ５０は、レーザー回折式粒度分布測定装置（マスターサイザー３０００；Ｍａｌｖｅｒｎ製）を用いて測定し、算出した値である。レーザー回折式粒度分布測定装置で測定した粒度分布は、機器の種類にほとんど影響されない。
The particle size distribution of linagliptin preferably has a D50 of 1 μm or more, particularly 3 μm or more, and particularly preferably 5 μm or more. Further, it is preferable that D 50 is 20 μm or less, particularly preferably 15 μm or less, and particularly preferably 10 μm or less. Within this range, the effect of the present invention can be obtained.
D50 of linagliptin is a value measured and calculated using a laser diffraction type particle size distribution measuring device (Master Sizar 3000; manufactured by Malvern). The particle size distribution measured by the laser diffraction type particle size distribution measuring device is hardly affected by the type of equipment.
添加物
添加物は、顆粒の製造に使用されるものであればよく、賦形剤、結合剤、崩壊剤、滑沢剤ないし流動化剤、着色剤、香料、甘味剤、保存剤ないしは防腐剤などが挙げられる。添加物は、１種又は２種以上を組み合わせて使用できる。
中でも、リナグリプチンと賦形剤の混合物を被覆して顆粒とすることが好ましく、中でも、結合剤溶液を用いるなどして、リナグリプチンと賦形剤の混合物を予備造粒した造粒物を被覆して顆粒とすることが好ましい。
Additives Additives may be those used in the production of granules, excipients, binders, disintegrants, lubricants or fluidizers, colorants, fragrances, sweeteners, preservatives or preservatives. And so on. Additives can be used alone or in combination of two or more.
Above all, it is preferable to coat the granules with a mixture of linagliptin and an excipient to form granules, and above all, coat the granules prepared by pre-granulating the mixture of linagliptin and an excipient by using a binder solution or the like. It is preferably granules.
賦形剤としては、マンニトール（特に、Ｄ－マンニトール）、マルチトール、ソルビトール、キシリトール、エリスリトール、ラクチトールのような糖アルコール；乳糖水和物、白糖、マルトース、果糖、ブドウ糖、トレハロースのような糖類；デンプン、アルファー化デンプン、部分アルファー化デンプンのようなデンプン類；結晶セルロースのようなセルロース類；デキストリン；デキストラン；グリセリン脂肪酸エステル；メタケイ酸アルミン酸マグネシウム、合成ヒドロタルサイトのような無機粉体などが挙げられる。
中でも、マンニトール、乳糖水和物、部分アルファー化デンプン、結晶セルロースが好ましく、マンニトールがより好ましい。
Excipients include sugar alcohols such as mannitol (particularly D-mannitol), martitol, sorbitol, xylitol, erythritol, lactitol; lactose hydrate, sucrose, maltose, fructose, starch, sugars such as trehalose; Starches such as starch, pregelatinized starch, partially pregelatinized starch; celluloses such as crystalline cellulose; dextrin; dextran; glycerin fatty acid ester; magnesium aluminometasilicate, inorganic powder such as synthetic hydrotalcite, etc. Can be mentioned.
Among them, mannitol, lactose hydrate, partially pregelatinized starch, and crystalline cellulose are preferable, and mannitol is more preferable.
結合剤としては、コポリビドン；ポビドン；メチルセルロース、エチルセルロース、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース（ヒプロメロース）、クロスカルメロースナトリウムのようなセルロース類；デンプン；ゼラチン；寒天、アルギン酸、アルギン酸ナトリウム、トラガント、キタンサンガム、アラビアゴム、プルラン、デキストリンのような増粘多糖類；ポリビニルアルコール－ポリエチレングリコールグラフトコポリマー；カルボキシビニルポリマー；ポリエチレンオキサイド；ポリオキシエチレン硬化ヒマシ油；Ｎ－イソプロピルアクリルアミド及び／又はアクリルアミドのＮ位に疎水性を有する基を導入した誘導体を含む高分子；ポリオキシエチレン－ポリオキシプロピレングリコール；ポリビニルアルコール（部分けん化ポリビニルアルコールを含む）；塩基性（メタ）アクリレートコポリマー；ポリエチレングリコールなどが挙げられる。
予備造粒に用いる結合剤としては、コポリビドン、ポビドン、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（ヒプロメロース）が好ましく、コポリビドンがより好ましい。
Binding agents include copolyvidone; povidone; methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (hypromerose), celluloses such as croscarmellose sodium; starch; gelatin; agar, alginic acid, sodium alginate. Thickening polysaccharides such as Tragant, Kitansan gum, Arabica rubber, Plulan, Dextrin; Polyvinyl alcohol-Polyethylene glycol graft copolymer; Carboxyvinyl polymer; Polyethylene oxide; Polyoxyethylene hydrogenated castor oil; N-Isopropylacrylamide and / or acrylamide Polymers containing derivatives having a hydrophobic group at the N-position; polyoxyethylene-polyoxypropylene glycol; polyvinyl alcohol (including partially saponified polyvinyl alcohol); basic (meth) acrylate copolymers; polyethylene glycol and the like. Be done.
As the binder used for pre-granulation, copolyvidone, povidone, hydroxypropyl cellulose and hydroxypropylmethyl cellulose (hypromellose) are preferable, and copolyvidone is more preferable.
崩壊剤としては、クロスポビドン；カルボキシメチルセルロース（カルメロース）、カルメロースナトリウム、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、結晶セルロースのようなセルロース類；デンプン、アルファー化デンプン、部分アルファー化デンプン、カルボキシメチルスターチナトリウム、カルボキシスターチナトリウム、ヒドロキシプロピルスターチのようなデンプン類；デキストリン；ケイ酸カルシウム；クエン酸カルシウム；軽質無水ケイ酸などが挙げられる。 Disintegrants include crospovidone; carboxymethyl cellulose (carmellose), carmellose sodium, carmellose calcium, low substitution hydroxypropyl cellulose, croscarmellose sodium, celluloses such as crystalline cellulose; starch, pregelatinized starch, partial alpha. Starches such as modified starch, sodium carboxymethyl starch, sodium carboxystarch, hydroxypropyl starch; dextrin; calcium silicate; calcium citrate; light anhydrous silicic acid and the like.
滑沢剤ないし流動化剤としては、ステアリン酸、ステアリン酸塩（ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸アルミニウム、ステアリン酸亜鉛など）、フマル酸ステアリルナトリウム、モノステアリン酸グリセリン、パルミトステアリン酸グリセリン、ラウリル硫酸ナトリウム、ポリエチレングリコール、タルク、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、酒石酸ナトリウムカリウム、カルナウバロウ、Ｌ－ロイシン、ポリエチレングリコール、硬化油、ケイ酸化合物（軽質無水ケイ酸、メタケイ酸アルミン酸マグネシウム、含水二酸化ケイ素、合成ケイ酸アルミニウムなど）、酸化チタンなどが挙げられる。 Examples of the lubricant or fluidizer include stearic acid, stearate (magnesium stearate, calcium stearate, aluminum stearate, zinc stearate, etc.), sodium stearyl fumarate, glycerin monostearate, glycerin palmitostearate, etc. Sodium lauryl sulfate, polyethylene glycol, talc, glycerin fatty acid ester, sucrose fatty acid ester, sodium potassium tartrate, carnauba wax, L-leucine, polyethylene glycol, hardened oil, silicic acid compound (light anhydrous silicic acid, magnesium aluminometasilicate, water-containing) (Silicon dioxide, synthetic aluminum silicate, etc.), titanium oxide, etc. may be mentioned.
着色剤としては、黄色三二酸化鉄、三二酸化鉄、黒酸化鉄のような酸化鉄、酸化チタン、食用タール色素、天然色素（βカロチン、リボフラビンなど）などが挙げられる。中でも、黄色三二酸化鉄、三二酸化鉄が好ましい。
リナグリプチン含有顆粒に着色剤を配合すれば、リナグリプチンの光安定性が一層向上する。
Examples of the colorant include yellow iron sesquioxide, iron sesquioxide, iron oxide such as black iron oxide, titanium oxide, edible tar pigments, and natural pigments (β-carotene, riboflavin, etc.). Of these, yellow iron sesquioxide and iron sesquioxide are preferable.
If a colorant is added to the linagliptin-containing granules, the photostability of linagliptin is further improved.
甘味剤としては、スクラロース、マンニトール、ショ糖、アスパルテーム、ステビア、アセスルファムカリウムなどが挙げられる。 Examples of the sweetener include sucralose, mannitol, sucrose, aspartame, stevia, acesulfame potassium and the like.
コーティング層
コーティング層に含まれるコーティング剤としては、アミノアルキルメタクリレートコポリマーＥ、エチルセルロース、アンモニオアルキルメタクリレートコポリマーが挙げられる。アミノアルキルメタクリレートコポリマーＥは、オイドラギッドＥ（オイドラギットＥ１００、オイドラギットＥＰＯなど；樋口商会）のような市販品を利用できる。エチルセルロースは、エトセル（日本カラコン）、エトセルプレミアム（ダウ・ケミカル日本）、ＡｑｕａｌｏｎＥＣ（アイエスピー・ジャパン）などの市販品を利用できる。アンモニオアルキルメタクリレートコポリマーは、オイドラギットＲＬＰＯ、オイドラギットＲＳＰＯ（樋口商会）のような市販品を利用できる。
Coating layer Examples of the coating agent contained in the coating layer include aminoalkyl methacrylate copolymer E, ethyl cellulose, and ammonioalkyl methacrylate copolymer. As the aminoalkyl methacrylate copolymer E, a commercially available product such as Eudragit E (Eudragit E100, Eudragit EPO, etc .; Higuchi Shokai) can be used. As ethyl cellulose, commercially available products such as Etocell (Japan Colorcon), Etocell Premium (Dow Chemical Japan), and AqualonEC (AISP Japan) can be used. As the ammonioalkyl methacrylate copolymer, commercially available products such as Eudragit RLPO and Eudragit RSPO (Higuchi Shokai) can be used.
コーティング層は、本発明の効果を損なわない範囲で、可塑剤、結合剤、流動化剤ないしは滑沢剤、着色剤、甘味剤などの添加物を含有することができる。添加物は、１種又は２種以上を組み合わせて使用できる。 The coating layer may contain additives such as a plasticizer, a binder, a fluidizing agent or a lubricant, a coloring agent, and a sweetening agent as long as the effects of the present invention are not impaired. Additives can be used alone or in combination of two or more.
可塑剤としては、ポリエチレングリコール、プロピレングリコール、グリセリン、トリアセチン（グリセリン三酢酸）のようなグリセリン脂肪酸エステル、流動パラフィン、ソルビタンモノラウレート、モノステアリン酸グリセリン、クエン酸トリエチル、クエン酸トリブチル、フタル酸ジエチル、フタル酸ジブチル、セバシン酸ジエチル、セバシン酸ジブチル、ポロキサマー、ポリオキシエチレン硬化ヒマシ油などが挙げられる。
結合剤、流動化剤ないしは滑沢剤、着色剤、甘味剤は、顆粒の添加物として例示したものが挙げられる。
Plasticizers include glycerin fatty acid esters such as polyethylene glycol, propylene glycol, glycerin, triacetin (glycerin triacetic acid), liquid paraffin, sorbitan monolaurate, glycerin monostearate, triethyl citrate, tributyl citrate, diethyl phthalate. , Dibutyl phthalate, diethyl sebacate, dibutyl sebacate, poroxamar, polyoxyethylene hydrogenated castor oil and the like.
Examples of the binder, fluidizing agent or lubricant, coloring agent, and sweetening agent include those exemplified as additives for granules.
コーティング層の含有量は、被覆される全成分（リナグリプチン及び場合により配合される添加物の合計量）の１重量部に対して、０．０５重量部以上が好ましく、０．１重量部以上がより好ましく、０．２重量部以上がさらにより好ましい。この範囲であれば、リナグリプチンの苦みが十分にマスキングされ、またリナグリプチンの光安定性が十分に向上する。
また、コーティング層の含有量は、被覆される全成分の１重量部に対して、１．５重量部以下が好ましく、１．２重量部以下がより好ましく、１重量部以下がさらにより好ましい。この範囲であれば、リナグリプチンの溶出性が十分になる。
The content of the coating layer is preferably 0.05 part by weight or more, preferably 0.1 part by weight or more, based on 1 part by weight of all the components to be coated (total amount of linagliptin and optionally compounded additives). More preferably, 0.2 parts by weight or more is even more preferable. Within this range, the bitterness of linagliptin is sufficiently masked, and the photostability of linagliptin is sufficiently improved.
The content of the coating layer is preferably 1.5 parts by weight or less, more preferably 1.2 parts by weight or less, still more preferably 1 part by weight or less, based on 1 part by weight of all the components to be coated. Within this range, the elution of linagliptin is sufficient.
粒子サイズ
コーティング層で被覆後のリナグリプチン含有顆粒の粒径は、特に限定されないが、Ｄ５０が１２０～２００μｍ程度、中でも１４０～１８０μｍ程度であればよい。本発明において、顆粒のＤ５０は、第１７改正日本薬局方の粒度測定法のふるい分け法（ロボットシフターＲＰＳ－０１；セイシン企業社製）で粒度を測定し、算出した値である。ふるい分け法で測定した粒度分布は、機器の種類にほとんど影響されない。
The particle size of the linagliptin-containing granules after being coated with the particle size coating layer is not particularly limited, but may be about 120 to 200 μm for D50 , and particularly about 140 to 180 μm. In the present invention, D50 of the granule is a value calculated by measuring the particle size by the sieving method (robot shifter RPS-01; manufactured by Seishin Corporation) of the 17th revised Japanese Pharmacopoeia. The particle size distribution measured by the sieving method is almost unaffected by the type of equipment.
製造方法
リナグリプチン粉末へのコーティングは、常法に従い、流動層コーティング機、ワースター式流動層コーティング機、遠心流動コーティング機、転動流動コーティング機などの装置を用いて行えばよい。
Manufacturing Method The coating on the linagliptin powder may be carried out by using an apparatus such as a fluidized bed coating machine, a worster type fluidized bed coating machine, a centrifugal fluidized coating machine, and a rolling fluidized coating machine according to a conventional method.
リナグリプチンと賦形剤（特に、Ｄ－マンニトール）などの添加物の混合物に、コーティング剤を含むコーティング層材料を供給しながら、造粒及びコーティングすることもできる。例えば、常法に従い、リナグリプチンと添加物を転動流動造粒コーティング装置などの造粒コーティング装置に投入し、コーティング剤を含む分散液又は溶液を噴霧することにより、造粒・コーティングすればよい。さらに、必要に応じて、整粒、乾燥させればよい。 Mixtures of linagliptin and additives such as excipients (particularly D-mannitol) can also be granulated and coated while supplying a coating layer material containing a coating agent. For example, according to a conventional method, linagliptin and an additive may be added to a granulation coating device such as a rolling flow granulation coating device, and a dispersion liquid or a solution containing a coating agent may be sprayed to granulate and coat. Further, if necessary, the grains may be sized and dried.
リナグリプチンと賦形剤（特に、Ｄ－マンニトール）などの添加物の混合物を予備造粒した後に、コーティング剤を含むコーティング層材料で被覆することもできる。この場合、先ず、リナグリプチンと添加物を混合し、例えば、結合剤溶液を供給しながら造粒すればよい。湿式造粒法としては、流動層造粒法、撹拌造粒法、転動造粒法、押出造粒法、破砕造粒法、練合造粒法、連続直顆粒化法、複合型流動層造粒法などが挙げられ、乾式造粒法としては、乾式複合造粒法、圧片造粒法、ブリケット造粒法、溶融造粒法などが挙げられる。中でも、結合剤の溶液を噴霧しながら湿式造粒することが好ましい。さらに、必要に応じて、整粒、乾燥工程を加えることもできる。
コーティングは常法に従い行えばよい。
A mixture of linagliptin and an additive such as an excipient (particularly D-mannitol) can also be pre-granulated and then coated with a coating layer material containing a coating agent. In this case, first, linagliptin and the additive may be mixed, and for example, granulation may be performed while supplying a binder solution. Wet granulation methods include fluidized layer granulation method, stirring granulation method, rolling granulation method, extrusion granulation method, crushing granulation method, kneaded granulation method, continuous straight granulation method, and composite type fluidized layer. Examples thereof include a granulation method, and examples of the dry granulation method include a dry composite granulation method, a slab granulation method, a briquette granulation method, and a melt granulation method. Above all, it is preferable to perform wet granulation while spraying a solution of the binder. Further, if necessary, a sizing and drying step can be added.
The coating may be performed according to a conventional method.
（２）医薬組成物
本発明の医薬組成物は、上記説明したリナグリプチン含有顆粒を含む製剤であればよく、顆粒剤、細粒剤、カプセル剤、ドライシロップ、リナグリプチン含有顆粒を含む錠剤、特に口腔内崩壊錠などが挙げられる。
錠剤中では、リナグリプチン含有顆粒の形状は打錠前と異なるが、本発明では、このような場合も、リナグリプチン含有顆粒を含む錠剤に該当する。
(2) Pharmaceutical Composition The pharmaceutical composition of the present invention may be any preparation containing the linagliptin-containing granules described above, and is a granule, a fine granule, a capsule, a dry syrup, a tablet containing linagliptin-containing granules, particularly an oral cavity. Examples include disintegrating tablets.
In the tablet, the shape of the linagliptin-containing granules is different from that before tableting, but in the present invention, the tablet containing the linagliptin-containing granules also corresponds to such a case.
錠剤について説明すると、リナグリプチン含有顆粒だけを打錠したものであってもよく、リナグリプチン含有顆粒と添加物を打錠したものであってもよく、リナグリプチン含有顆粒、他の顆粒、及び必要に応じて添加物を打錠したものであってもよい。 The tablets may be tableted with only linagliptin-containing granules, tableted with linagliptin-containing granules and additives, linagliptin-containing granules, other granules, and optionally. The additive may be tableted.
添加物は、錠剤の製造に使用されるものであればよく、賦形剤、崩壊剤、結合剤、滑沢剤ないし流動化剤、着色剤、香料、甘味剤、保存剤ないしは防腐剤などが挙げられる。添加物は、１種又は２種以上を組み合わせて使用できる。具体例は、リナグリプチン含有顆粒について説明した通りである。
本発明では、リナグリプチン含有顆粒の他に着色剤を含むことが好ましく、これにより、リナグリプチンの光安定性が一層向上する。着色剤は、そのまま又は顆粒に含ませて配合することができる。
Additives may be those used in the manufacture of tablets, such as excipients, disintegrants, binders, lubricants or fluidizers, colorants, flavors, sweeteners, preservatives or preservatives. Can be mentioned. Additives can be used alone or in combination of two or more. Specific examples are as described for the linagliptin-containing granules.
In the present invention, it is preferable to contain a colorant in addition to the linagliptin-containing granules, whereby the photostability of linagliptin is further improved. The colorant can be blended as it is or in granules.
添加物の組成、特に崩壊剤や賦形剤の種類や量を調整したり、他の顆粒として崩壊性顆粒を用いることで、口腔内崩壊錠を得ることができる。口腔内崩壊錠とするための組成は、当業者であれば、適宜設計することができる。
崩壊性顆粒は、水分を吸って膨潤することで錠剤を崩壊させる顆粒であり、成分の組成、特に崩壊剤や賦形剤の種類や量を調整することで調製できる。崩壊性顆粒に着色剤を配合すれば、リナグリプチンの光安定性が一層向上する。
Orally disintegrating tablets can be obtained by adjusting the composition of the additive, particularly the type and amount of disintegrants and excipients, and using disintegrating granules as other granules. A person skilled in the art can appropriately design the composition for making an orally disintegrating tablet.
Disintegrating granules are granules that disintegrate tablets by absorbing water and swelling, and can be prepared by adjusting the composition of the components, particularly the type and amount of disintegrants and excipients. Adding a colorant to the disintegrating granules further improves the photostability of linagliptin.
（３）リナグリプチンの苦みのマスキング方法・光安定性向上方法
本発明は、リナグリプチン含有顆粒又はリナグリプチン含有顆粒を含む医薬組成物において、リナグリプチンを含む成分をアミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆することにより、リナグリプチンの溶出性低下を抑制しながら、リナグリプチンの苦みをマスキングする方法を包含する。
また、本発明は、リナグリプチン含有顆粒又はリナグリプチン含有顆粒を含む医薬組成物において、リナグリプチンを含む成分をアミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆することにより、リナグリプチンの光安定性を向上させる方法を包含する。
本発明方法において、リナグリプチン含有顆粒又は医薬組成物に含まれる成分の種類や量、リナグリプチン含有顆粒及び医薬組成物の諸特性は、本発明のリナグリプチン含有顆粒について説明した通りである。
(3) Method for Masking Bitterness of Linagliptin / Method for Improving Photostability In the present invention, in a pharmaceutical composition containing linagliptin-containing granules or linagliptin-containing granules, a component containing linagliptin is coated with a coating layer containing an aminoalkylmethacrylate copolymer E. Thereby, it includes a method of masking the bitterness of linagliptin while suppressing the decrease in the elution of linagliptin.
The present invention also provides a method for improving the photostability of linagliptin by coating a component containing linagliptin with a coating layer containing an aminoalkylmethacrylate copolymer E in a pharmaceutical composition containing linagliptin-containing granules or linagliptin-containing granules. Include.
In the method of the present invention, the types and amounts of the components contained in the linagliptin-containing granules or the pharmaceutical composition, and various properties of the linagliptin-containing granules and the pharmaceutical composition are as described for the linagliptin-containing granules of the present invention.
以下、実施例を挙げて、本発明をより詳細に説明するが、本発明はこれらに限定されない。
（１）試験方法
光照射後の総類縁物質の定量
各錠剤をシャーレに静置し、室温下、４０００ｌｕｘ／時間の光を１２．５日間照射した。総照射量は１２０万ｌｕｘである。
錠剤５個に、溶解剤としてメタノール／水混液（４：１）４０ｍＬを加えた後、フィルターでろ過して試料溶液を得た。
試料溶液１０μＬにつき、次の条件の液体クロマトグラフィーにより総類縁物質を定量した。
検出器：紫外吸光光度計
カラム：内径４．６ｍｍ、長さ１５ｃｍのステンレス管に３μｍの液体クロマトグラフィー用オクタデシルシリル化シリカゲルを充填する。
カラム温度：３０℃付近の一定温度
移動相Ａ：ｐＨ４．０の酢酸塩緩衝液
移動相Ｂ：メタノール／アセトニトリル混液（１：１）
Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
(1) Test method
Quantification of all related substances after light irradiation
Each tablet was allowed to stand in a petri dish and irradiated with light at 4000 lux / hour for 12.5 days at room temperature. The total irradiation amount is 1.2 million lux.
To 5 tablets, 40 mL of a methanol / water mixed solution (4: 1) was added as a solubilizer, and then filtered through a filter to obtain a sample solution.
For 10 μL of the sample solution, the total related substances were quantified by liquid chromatography under the following conditions.
Detector: Ultraviolet absorptiometer Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm is filled with 3 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 30 ° C. Mobile phase A: Acetate buffer solution with pH 4.0 Mobile phase B: Methanol / acetonitrile mixed solution (1: 1)
溶出試験
第１７改正日本薬局方に規定される溶出試験法第２法に従い、溶出試験を行った。パドルの回転数を５０回転／分に設定し、試験液は、ｐＨ４．０のマッキルベイン緩衝液（クエン酸-リン酸塩緩衝液）９００ｍＬを使用した。錠剤１個をベッセルへ投入し、１５分後に各ベッセルから１０ｍＬずつサンプリングし、フィルターでろ過して試料溶液を得た。
試料溶液及び標準溶液１０μＬにつき、次の条件の液体クロマトグラフィーによりリナグリプチンを定量した。
検出器：紫外吸光光度計
カラム：内径４．６ｍｍ、長さ１０ｃｍのステンレス管に５μｍの液体クロマトグラフィー用オクタデシルシリル化シリカゲルを充填する。
カラム温度：３０℃付近の一定温度
移動相：ｐＨ４．０の酢酸塩緩衝液／アセトニトリル混液（３：１）
測定値からリナグリプチン溶出率を算出した。各例について、錠剤３個の溶出試験を行い、リナグリプチンを定量し、溶出率を算出し（ｎ＝３）、平均値を算出した。
Dissolution test The dissolution test was conducted in accordance with the second dissolution test method specified in the 17th revised Japanese Pharmacopoeia. The rotation speed of the paddle was set to 50 rpm, and 900 mL of McIlvaine buffer (citric acid-phosphate buffer) having a pH of 4.0 was used as the test solution. One tablet was put into a vessel, and after 15 minutes, 10 mL was sampled from each vessel and filtered through a filter to obtain a sample solution.
Linagliptin was quantified by liquid chromatography under the following conditions with respect to 10 μL of the sample solution and the standard solution.
Detector: Ultraviolet absorptiometer Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 10 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 30 ° C. Mobile phase: Acetate buffer / acetonitrile mixed solution with pH 4.0 (3: 1)
The linagliptin elution rate was calculated from the measured values. For each example, an dissolution test of 3 tablets was performed, linagliptin was quantified, the dissolution rate was calculated (n = 3), and the average value was calculated.
服用感の評価
各錠剤につき、官能試験を行った。訓練された４名のパネルが、各錠剤を口に含んで崩壊させた後、吐き出した。錠剤が崩壊したときの味、ざらつき感、吐き出した後の味（服用後の後味に相当）、及び総合的な印象を、ビジュアルアナログスケール（ＶＡＳ）を用いてスコア化した。崩壊時の味、服用後の後味、総合評価は、「０」が非常に悪い、「１００」が非常に良いことを示す。また、口中での崩壊時間を測定した。４名の評価値の平均値及び標準偏差を算出した。
Evaluation of dosing feeling A sensory test was performed on each tablet. A panel of four trained people put each tablet in their mouth, disintegrated it, and then spit it out. The taste when the tablets disintegrated, the feeling of roughness, the taste after exhalation (corresponding to the aftertaste after taking), and the overall impression were scored using a visual analog scale (VAS). The taste at the time of disintegration, the aftertaste after taking, and the overall evaluation indicate that "0" is very bad and "100" is very good. In addition, the disintegration time in the mouth was measured. The average value and standard deviation of the evaluation values of the four subjects were calculated.
顆粒の粒度分布測定
第１７改正日本薬局方の粒度測定法のふるい分け法（ロボットシフターＲＰＳ－０１；セイシン企業社製）で、リナグリプチン含有顆粒の粒度を測定し、Ｄ５０を決定した。
Measurement of Granule Particle Size Distribution The particle size of linagliptin-containing granules was measured by the sieving method (Robot Shifter RPS-01; manufactured by Seishin Corporation) of the 17th revised Japanese Pharmacopoeia particle size measurement method, and D50 was determined.
リナグリプチンの粒度分布測定
レーザー回折式粒度分布測定装置（マスターサイザー３０００；Ｍａｌｖｅｒｎ製）を用いて測定し、Ｄ５０を決定した。
Particle size distribution measurement of linagliptin Measurement was performed using a laser diffraction type particle size distribution measuring device (Master Sizar 3000; manufactured by Malvern), and D50 was determined.
（２）リナグリプチン含有口腔内崩壊錠の製造
表１に組成を示す各口腔内崩壊錠を下記のようにして製造した。
実施例１
リナグリプチン（ＡＬ型結晶；Ｄ５０ ５．７５μｍ）、及びＤ－マンニトールを流動層造粒乾燥機に投入し、アミノアルキルメタクリレートコポリマーＥ（オイドラギットＥ１００）、及びタルクを含水エタノールに分散した分散液を噴霧し、造粒及び乾燥して、薬物含有顆粒を得た。
別に、Ｄ－マンニトール、エチルセルロース、及び軽質無水ケイ酸を流動層造粒乾燥機に投入し、トウモロコシデンプン、及びクロスポビドンを含む分散液を噴霧し、造粒及び乾燥して、崩壊性顆粒を得た。
前記薬物含有顆粒、前記崩壊性顆粒、アスパルテーム、軽質無水ケイ酸、エチルセルロース、及びペパーミントミクロンを拡散式混合機を用いて混合し、続いて、ステアリン酸マグネシウムを加えて混合し、打錠用粉末を得た。この打錠用粉末を錠剤プレス機で打錠し（打錠圧力：７ｋＤ）、リナグリプチンを５ｍｇ含有する口腔内崩壊錠を得た。
(2) Production of Orally Disintegrating Tablets Containing Linagliptin Each orally disintegrating tablet whose composition is shown in Table 1 was produced as follows.
Example 1
Linagliptin (AL type crystal; D 50 5.75 μm) and D-mannitol were put into a fluidized bed granulator, and the dispersion liquid in which aminoalkylmethacrylate copolymer E (Eudragit E100) and talc were dispersed in hydrous ethanol was sprayed. Then, granulation and drying were performed to obtain drug-containing granules.
Separately, D-mannitol, ethyl cellulose, and light anhydrous silicic acid are put into a fluidized bed granulator dryer, sprayed with a dispersion containing corn starch and crospovidone, granulated and dried to obtain disintegrating granules. rice field.
The drug-containing granules, the disintegrating granules, aspartame, light anhydrous silicic acid, ethyl cellulose, and peppermint micron are mixed using a diffusion mixer, and then magnesium stearate is added and mixed to obtain a tableting powder. Obtained. This powder for tableting was tableted with a tablet press (tablet pressure: 7 kD) to obtain an orally disintegrating tablet containing 5 mg of linagliptin.
実施例２
崩壊性顆粒の製造時に、分散液に三二酸化鉄を分散させた他は、実施例１と同様にして、口腔内崩壊錠を得た。
Example 2
Orally disintegrating tablets were obtained in the same manner as in Example 1 except that iron sesquioxide was dispersed in the dispersion during the production of disintegrating granules.
実施例３
実施例２において、薬物含有顆粒の製造時に、アミノアルキルメタクリレートコポリマーＥを増量した。また、薬物含有顆粒と崩壊性顆粒の成分量を表１に示すように変更した。その他は、実施例２と同様にして、口腔内崩壊錠を得た。
Example 3
In Example 2, the amount of aminoalkyl methacrylate copolymer E was increased during the production of the drug-containing granules. In addition, the component amounts of the drug-containing granules and the disintegrating granules were changed as shown in Table 1. Orally disintegrating tablets were obtained in the same manner as in Example 2.
実施例４
実施例２において、薬物含有顆粒の製造工程で、アミノアルキルメタクリレートコポリマーＥ含有分散液を用いた造粒の前に、リナグリプチン（ＡＬ型結晶）及びＤ－マンニトールを湿式高せん断造粒機に投入し、コポリビドンを水に溶解した造粒液を噴霧し、造粒及び乾燥して、予備造粒末を得る工程を加えた。また、崩壊性顆粒の成分量を表１に示すように変更した。その他は、実施例２と同様にして、口腔内崩壊錠を得た。
Example 4
In Example 2, in the process of producing drug-containing granules, linagliptin (AL-type crystal) and D-mannitol are charged into a wet high-shear granulator before granulation using the aminoalkylmethacrylate copolymer E-containing dispersion. , A step of spraying a granulation solution in which copolyvidone was dissolved in water, granulating and drying to obtain a pre-granulated powder was added. In addition, the amount of the components of the disintegrating granules was changed as shown in Table 1. Orally disintegrating tablets were obtained in the same manner as in Example 2.
実施例５
実施例４において、薬物含有顆粒の製造時、アミノアルキルメタクリレートコポリマーＥを増量した他は、実施例４と同様にして、口腔内崩壊錠を得た。
Example 5
In Example 4, an orally disintegrating tablet was obtained in the same manner as in Example 4, except that the amount of the aminoalkyl methacrylate copolymer E was increased during the production of the drug-containing granules.
実施例６
実施例４において、薬物含有顆粒の製造時に、アミノアルキルメタクリレートコポリマーＥを減量した。また、薬物含有顆粒と崩壊性顆粒の成分量を表１に示すように変更した。その他は、実施例４と同様にして、口腔内崩壊錠を得た。
Example 6
In Example 4, the amount of aminoalkyl methacrylate copolymer E was reduced during the production of the drug-containing granules. In addition, the component amounts of the drug-containing granules and the disintegrating granules were changed as shown in Table 1. Orally disintegrating tablets were obtained in the same manner as in Example 4.
比較例１
Ｄ－マンニトール、エチルセルロース、及び軽質無水ケイ酸を流動層造粒乾燥機に投入し、トウモロコシデンプン、及びクロスポビドンを含む分散液を噴霧し、造粒及び乾燥して、崩壊性顆粒を得た。
リナグリプチン（ＡＬ型結晶；Ｄ５０ ５．７５μｍ）、前記崩壊性顆粒、アスパルテーム、軽質無水ケイ酸、エチルセルロース、及びペパーミントミクロンを拡散式混合機を用いて混合し、続いて、ステアリン酸マグネシウムを加えて混合し、打錠用粉末を得た。この打錠用粉末を錠剤プレス機で打錠し（打錠圧力：７ｋＮ）、リナグリプチンを５ｍｇ含有する口腔内崩壊錠を得た。
Comparative Example 1
D-mannitol, ethyl cellulose, and light anhydrous silicic acid were put into a fluidized bed granulator dryer, sprayed with a dispersion containing corn starch and crospovidone, granulated and dried to obtain disintegrating granules.
Linagliptin (AL-type crystal; D50 5.75 μm), the disintegrating granules, aspartame, light anhydrous silicic acid, ethyl cellulose, and peppermint micron are mixed using a diffusion mixer, and then magnesium stearate is added. It was mixed to obtain a powder for tableting. This tableting powder was tableted with a tablet press (tablet pressure: 7 kN) to obtain an orally disintegrating tablet containing 5 mg of linagliptin.
比較例２
トラゼンタ錠（リナグリプチン５ｍｇ含有）を比較例２の錠剤とした。
Comparative Example 2
Trazenta tablets (containing 5 mg of linagliptin) were used as the tablets of Comparative Example 2.
参考例１
実施例４において、アミノアルキルメタクリレートコポリマーＥに代えてエチルセルロースを用いた。また、薬物含有顆粒と崩壊性顆粒の成分量を表１に示すように変更した。その他は、実施例４と同様にして、口腔内崩壊錠を得た。
Reference example 1
In Example 4, ethyl cellulose was used instead of the aminoalkyl methacrylate copolymer E. In addition, the component amounts of the drug-containing granules and the disintegrating granules were changed as shown in Table 1. Orally disintegrating tablets were obtained in the same manner as in Example 4.
参考例２
実施例５において、アミノアルキルメタクリレートコポリマーＥに代えてエチルセルロースを用いた。また、薬物含有顆粒と崩壊性顆粒の成分量を表１に示すように変更した。その他は、実施例５と同様にして、口腔内崩壊錠を得た。
Reference example 2
In Example 5, ethyl cellulose was used instead of the aminoalkyl methacrylate copolymer E. In addition, the component amounts of the drug-containing granules and the disintegrating granules were changed as shown in Table 1. Orally disintegrating tablets were obtained in the same manner as in Example 5.
（４）評価結果
服用感及び崩壊時間の官能評価結果を表２に示す。また、総類縁物質の定量、溶出試験の結果を表３に示す。
表２が示す通り、本発明のコーティング顆粒を用いて製造した実施例１～４の口腔内崩壊錠は、リナグリプチンをコーティングしていない比較例１の口腔内崩壊錠に比べて、口腔内で崩壊させたときの味及び服用後の後味の何れも優れていた。
また、本発明のコーティング顆粒を用いて製造した実施例１～４の口腔内崩壊錠の口腔内での崩壊時間は３０秒以下（最大平均値：２２．５秒）であり、リナグリプチンをコーティングしても十分な崩壊性を有していた。
また、リナグリプチンをエチルセルロースを含むコーティング層で被覆した参考例１、２の口腔内崩壊錠は、服用感、崩壊時間ともに、実施例１～４の口腔内崩壊錠と同等であった。
As shown in Table 2, the orally disintegrating tablets of Examples 1 to 4 produced using the coated granules of the present invention disintegrate in the oral cavity as compared with the orally disintegrating tablets of Comparative Example 1 not coated with linagliptin. Both the taste when linagliptin was allowed and the aftertaste after taking the drug were excellent.
Further, the disintegration time in the oral cavity of the orally disintegrating tablets of Examples 1 to 4 produced using the coated granules of the present invention was 30 seconds or less (maximum average value: 22.5 seconds), and linagliptin was coated. However, it had sufficient disintegration property.
In addition, the orally disintegrating tablets of Reference Examples 1 and 2 in which linagliptin was coated with a coating layer containing ethyl cellulose had the same feeling of administration and disintegration time as the orally disintegrating tablets of Examples 1 to 4.
また、表３が示す通り、リナグリプチンの光照射による分解は、リナグリプチンをアミノアルキルメタクリレートコポリマーＥを含むコーティング層で被覆することにより低減し、さらに三二酸化鉄を配合することにより一層低減した。また、リナグリプチンをコーティングしているにも拘わらず、溶出性はトラゼンタ錠（比較例２）と同等であった。 Further, as shown in Table 3, the decomposition of linagliptin by light irradiation was reduced by coating the linagliptin with a coating layer containing the aminoalkyl methacrylate copolymer E, and further reduced by adding iron sesquioxide. Moreover, despite being coated with linagliptin, the dissolution property was equivalent to that of Trazenta tablets (Comparative Example 2).
また、実施例１～６の製造に用いたリナグリプチン含有顆粒のＤ５０を測定した結果、１６０～１８０μｍであった。 Moreover, as a result of measuring D50 of the linagliptin-containing granules used in the production of Examples 1 to 6, it was 160 to 180 μm.
表４に組成を示す口腔内崩壊錠を下記のようにして製造した。
製造例１、２
リナグリプチン（ＡＬ型結晶；Ｄ５０ ５．７５μｍ）、及びＤ－マンニトールを湿式高剪断力造粒機に投入し、ポリビニルアルコール（部分ケン化物）の水溶液を噴霧して造粒し、流動層造粒乾燥機にて乾燥し、予備造粒末を得た。
アミノアルキルメタクリレートコポリマーＥのエタノール溶液と、三二酸化鉄及びタルクの水分散液とを混和して得た造粒液を、予備造粒末に噴霧、乾燥して、薬物含有顆粒を得た。
別に、Ｄ－マンニトール、エチルセルロース、及び軽質無水ケイ酸を流動層造粒乾燥機に投入し、三二酸化鉄、トウモロコシデンプン、及びクロスポビドンを水に分散させた分散液を噴霧し、造粒及び乾燥して、崩壊性顆粒を得た。
前記薬物含有顆粒、前記崩壊性顆粒、アスパルテーム、軽質無水ケイ酸、エチルセルロース、及びペパーミントミクロンをポリエチレン袋内で混合し、さらにステアリン酸マグネシウムを混合し、ロータリー式打錠機で打錠し、リナグリプチンを５ｍｇ含有する口腔内崩壊錠を得た。
Production Examples 1 and 2
Linagliptin (AL type crystal; D 50 5.75 μm) and D-mannitol are put into a wet high shear granulator and sprayed with an aqueous solution of polyvinyl alcohol (partially saponified) to granulate and granulate the fluidized bed. It was dried in a drier to obtain a preliminary granulated powder.
A granulation solution obtained by mixing an ethanol solution of aminoalkylmethacrylate copolymer E with an aqueous dispersion of iron sesquioxide and talc was sprayed on the pre-granulation powder and dried to obtain drug-containing granules.
Separately, D-mannitol, ethyl cellulose, and light anhydrous silicic acid were put into a fluidized bed granulator / dryer, and a dispersion liquid in which iron sesquioxide, corn starch, and crospovidone were dispersed in water was sprayed, and granulation and drying were performed. Then, disintegrating granules were obtained.
The drug-containing granules, the disintegrating granules, aspartame, light anhydrous silicic acid, ethyl cellulose, and peppermint micron are mixed in a polyethylene bag, further mixed with magnesium stearate, and tableted with a rotary tableting machine to obtain linagliptin. An orally disintegrating tablet containing 5 mg was obtained.
表５に組成を示す口腔内崩壊錠を下記のようにして製造した。
製造例３
リナグリプチン（ＡＬ型結晶；Ｄ５０ ５．７５μｍ）、Ｄ－マンニトール、及び軽質無水ケイ酸を湿式高剪断力造粒機に投入し、ヒドロキシプロピルセルロースの水溶液を噴霧して造粒し、流動層造粒乾燥機にて乾燥し、予備造粒末を得た。
アミノアルキルメタクリレートコポリマーＥのエタノール溶液とステアリン酸カルシウムのエタノール分散液、三二酸化鉄の水分散液とを混和して得た造粒液を、予備造粒末に噴霧、乾燥して、薬物含有顆粒を得た。
別に、Ｄ－マンニトール、エチルセルロース、及び軽質無水ケイ酸を流動層造粒乾燥機に投入し、三二酸化鉄、トウモロコシデンプン、及びクロスポビドンを水に分散させた分散液を噴霧し、造粒及び乾燥して、崩壊性顆粒を得た。
前記薬物含有顆粒、前記崩壊性顆粒、アスパルテーム、軽質無水ケイ酸、エチルセルロース、及びペパーミントミクロンをポリエチレン袋内で混合し、さらにステアリン酸カルシウムを混合し、ロータリー式打錠機で打錠し、リナグリプチンを５ｍｇ含有する口腔内崩壊錠を得た。
Production example 3
Linagliptin (AL type crystal; D 50 5.75 μm), D-mannitol, and light anhydrous silicic acid are put into a wet high shearing force granulator and sprayed with an aqueous solution of hydroxypropyl cellulose to granulate and form a fluidized bed. It was dried in a grain dryer to obtain a preliminary granulated powder.
A granulation solution obtained by mixing an ethanol solution of aminoalkylmethacrylate copolymer E with an ethanol dispersion of calcium stearate and an aqueous dispersion of iron sesquioxide is sprayed onto the pre-granulated powder and dried to obtain drug-containing granules. Obtained.
Separately, D-mannitol, ethyl cellulose, and light anhydrous silicic acid were put into a fluidized bed granulation dryer, and a dispersion liquid in which iron sesquioxide, corn starch, and crospovidone were dispersed in water was sprayed, and granulation and drying were performed. Then, disintegrating granules were obtained.
The drug-containing granules, the disintegrating granules, aspartame, light anhydrous silicic acid, ethyl cellulose, and peppermint micron were mixed in a polyethylene bag, further mixed with calcium stearate, locked with a rotary tableting machine, and 5 mg of linagliptin was added. Orally disintegrating tablets containing were obtained.
製造例４
製造例３において、リナグリプチンを含む予備造粒末中のＤ－マンニトール、及び軽質無水ケイ酸の配合量を変えた他は、製造例３と同様にして、リナグリプチンを５ｍｇ含有する口腔内崩壊錠を得た。
Production example 4
In Production Example 3, an orally disintegrating tablet containing 5 mg of linagliptin was prepared in the same manner as in Production Example 3, except that the blending amounts of D-mannitol and light anhydrous silicic acid in the pre-granulated powder containing linagliptin were changed. Obtained.
本発明の医薬組成物は、リナグリプチンの苦みがマスキングされているため、口腔内崩壊錠として好適に使用できる。また、リナグリプチンは製剤中で不安定であることが知られているが、本発明の医薬組成物は、リナグリプチンの分解が抑制されている。さらに、リナグリプチンがコーティングされているにも拘わらず、溶出性が良好である。従って、本発明の医薬組成物は実用性が高いものである。 Since the pharmaceutical composition of the present invention masks the bitterness of linagliptin, it can be suitably used as an orally disintegrating tablet. Further, linagliptin is known to be unstable in the pharmaceutical product, but the pharmaceutical composition of the present invention suppresses the decomposition of linagliptin. Furthermore, despite being coated with linagliptin, it has good elution. Therefore, the pharmaceutical composition of the present invention is highly practical.
Claims (13)
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