JP2022056798A - Azilsartan-containing pharmaceutical preparation - Google Patents
Azilsartan-containing pharmaceutical preparation Download PDFInfo
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- JP2022056798A JP2022056798A JP2020164739A JP2020164739A JP2022056798A JP 2022056798 A JP2022056798 A JP 2022056798A JP 2020164739 A JP2020164739 A JP 2020164739A JP 2020164739 A JP2020164739 A JP 2020164739A JP 2022056798 A JP2022056798 A JP 2022056798A
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- azilsartan
- coating layer
- light
- polyvinyl alcohol
- acceptable salt
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- 239000005485 Azilsartan Substances 0.000 title claims abstract description 22
- 229960002731 azilsartan Drugs 0.000 title claims abstract description 22
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 11
- 239000011247 coating layer Substances 0.000 claims abstract description 28
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 20
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 10
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 claims description 10
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 7
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 7
- 239000003826 tablet Substances 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 9
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
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- 210000000214 mouth Anatomy 0.000 description 2
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 239000003861 C09CA09 - Azilsartan medoxomil Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960001211 azilsartan medoxomil Drugs 0.000 description 1
- QJFSABGVXDWMIW-UHFFFAOYSA-N azilsartan medoxomil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C=3NC(=O)ON=3)C(OCC)=NC2=CC=CC=1C(=O)OCC=1OC(=O)OC=1C QJFSABGVXDWMIW-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 238000004587 chromatography analysis 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
- 238000009792 diffusion process Methods 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000002401 inhibitory 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
- 239000010410 layer Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
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- 239000000203 mixture Substances 0.000 description 1
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- 229920000642 polymer Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
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- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、有効成分としてアジルサルタンまたはその薬学的に許容される塩を含有する、安定性に優れた医薬製剤に関する。 The present invention relates to a pharmaceutical preparation having excellent stability, which contains azilsartan or a pharmaceutically acceptable salt thereof as an active ingredient.
一般に、光に不安定な薬物の固形製剤化に関して、遮光剤を含む被覆を施すことによる光安定性向上方法は公知である（例えば、特許文献１、特許文献２）。
しかしながら、被覆される薬物と被覆層に用いる基剤やそれに含有される遮光剤等の組み合わせによって、実際には薬物の光安定性に対する効果には違いがある。
また、経管投与される錠剤や、口腔内で崩壊させて服用される錠剤等では、被覆層の基剤が素早く崩壊することが望ましく、そのような基剤の例としては、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やポリビニルアルコールなどが公知である（例えば、特許文献３、特許文献４）。
In general, a method for improving light stability by applying a coating containing a light-shielding agent is known for solid preparation of a drug that is unstable to light (for example, Patent Document 1 and Patent Document 2).
However, the effect of the drug on the photostability actually differs depending on the combination of the coated drug, the base used for the coating layer, the light-shielding agent contained therein, and the like.
Further, in tablets administered by tube or tablets that are disintegrated and taken in the oral cavity, it is desirable that the base of the coating layer disintegrates quickly, and examples of such bases are polyvinyl alcohol and polyethylene. Glycol graft copolymers, polyvinyl alcohol and the like are known (for example, Patent Document 3 and Patent Document 4).
高血圧症の治療薬であるアジルサルタン（化学名：２－エトキシ－１－｛［２’－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル］メチル｝－１Ｈ－ベンゾ［ｄ］イミダゾール－７－カルボン酸）は、光に不安定な薬物として知られている。
特許文献５は、被覆層（コーティング層）に糖アルコール、遮光剤及び基剤（コーティング剤）を配合し、アジルサルタンの光安定性を改善した粒子状固形製剤について開示するが、基剤による光安定性への影響については言及していない。
また、被覆層中の糖アルコールは必須条件となっている。
Azilsartan (chemical name: 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl), which is a therapeutic drug for hypertension. -4-yl] methyl} -1H-benzo [d] imidazole-7-carboxylic acid) is known as a light-labile drug.
Patent Document 5 discloses a particulate solid preparation in which a sugar alcohol, a light-shielding agent and a base (coating agent) are blended in a coating layer (coating layer) to improve the photostability of azilsartan. No mention is made of its impact on stability.
In addition, sugar alcohol in the coating layer is an essential condition.
本発明は、有効成分としてアジルサルタンまたはその薬学的に許容される塩を含有し、安定性に優れた医薬製剤の提供を目的とする。 An object of the present invention is to provide a pharmaceutical preparation containing azilsartan or a pharmaceutically acceptable salt thereof as an active ingredient and having excellent stability.
本発明に係る被覆錠剤は、ポリビニルアルコール及び遮光剤を含有する被覆層を有し、アジルサルタンまたはその薬学的に許容される塩を含有することを特徴とする。
本発明者らは、被覆錠剤の速やかな崩壊性の観点から、被覆層の基剤としてポリビニルアルコール又は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を選択し、被覆層に遮光剤を含有させてアジルサルタンの光安定性について確認したところ、実際には基剤によりアジルサルタンの光安定性が大きく相違することを知見した。
The coated tablet according to the present invention has a coating layer containing polyvinyl alcohol and a light-shielding agent, and is characterized by containing azilsartan or a pharmaceutically acceptable salt thereof.
From the viewpoint of rapid disintegration of the coated tablet, the present inventors select polyvinyl alcohol or polyvinyl alcohol / polyethylene glycol / graft copolymer as the base of the coating layer, and impregnate the coating layer with a light-shielding agent to obtain azilsartan. After confirming the photostability, it was found that the photostability of azilsartan actually differs greatly depending on the base.
本発明においては、アジルサルタンまたはその薬学的に許容される塩のみを有効成分として含有することが好ましく、有効成分が２種以上含有された、いわゆる配合錠でないことが好ましい。 In the present invention, it is preferable that only azilsartan or a pharmaceutically acceptable salt thereof is contained as an active ingredient, and it is preferable that the tablet is not a so-called combination tablet containing two or more kinds of active ingredients.
本発明における遮光剤は、酸化チタン、三二酸化鉄、黄色三二酸化鉄からなる群から選択される１種以上であることが好ましい。 The light-shielding agent in the present invention is preferably at least one selected from the group consisting of titanium oxide, iron sesquioxide, and yellow iron sesquioxide.
本発明に係るアジルサルタン含有医薬製剤は、被覆層にポリビニルアルコール及び遮光剤を含有することで、光安定性に優れた医薬製剤を提供し得る。 The azilsartan-containing pharmaceutical preparation according to the present invention can provide a pharmaceutical preparation having excellent photostability by containing polyvinyl alcohol and a light-shielding agent in the coating layer.
本発明に係る医薬製剤の有効成分は、アジルサルタン（化学名は２－エトキシ－１－｛［２’－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル］メチル｝－１Ｈ－ベンゾ［ｄ］イミダゾール－７－カルボン酸）またはその薬学的に許容される塩である。 The active ingredient of the pharmaceutical preparation according to the present invention is azilsartan (chemical name is 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3). -Il) biphenyl-4-yl] methyl} -1H-benzo [d] imidazole-7-carboxylic acid) or a pharmaceutically acceptable salt thereof.
アジルサルタンまたはその薬学的に許容される塩は、公知の方法により製造したものを使用してもよいし、市販品を使用してもよい。
薬学的に許容される塩としては、薬理学上許容できる塩であれば特に制限はなく、アジルサルタンメドキソミルなどが例として挙げられる。
アジルサルタンまたはその薬学的に許容される塩の含有量としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、錠剤あたり１０質量％～４０質量％の範囲が例として挙げられる。
As the azilsartan or a pharmaceutically acceptable salt thereof, those produced by a known method may be used, or commercially available products may be used.
The pharmaceutically acceptable salt is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include azilsartan medoxomil.
The content of azilsartan or a pharmaceutically acceptable salt thereof is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the range of 10% by mass to 40% by mass per tablet is given as an example. Be done.
本発明における医薬製剤は、被覆層を有する錠剤であり、その製造工程（例えば、造粒、混合、打錠、コーティング等）は、公知の装置（流動層造粒機、撹拌造粒機、乾式造粒機、転動造粒機、拡散式混合機、速崩錠成型機、ロータリー打錠機、パン型コーティング機、ドリップ型コーティング機等）を適宜利用でき、その製造方法は公知の製造方法であれば特に限定されない。
本発明における被覆層とは、フィルムコーティング層であり、被覆層の厚みとしては特に制限はなく、目的に応じて適宜選択できる。
本発明の医薬製剤における被覆層の含有量は、例えば、素錠部に対して５．０質量％以下であり、３．０質量％以下が好ましく、２．０質量％以下がより好ましい。
被覆錠剤は、例えば、口腔内崩壊錠であってもよいし、口腔内で崩壊しない、いわゆる普通錠であってもよい。
The pharmaceutical preparation in the present invention is a tablet having a coating layer, and the manufacturing process thereof (for example, granulation, mixing, tableting, coating, etc.) is a known device (fluidized bed granulator, stirring granulator, dry type). A granulator, a rolling granulator, a diffusion type mixer, a quick-breaking lock molding machine, a rotary tableting machine, a pan-type coating machine, a drip-type coating machine, etc.) can be appropriately used, and the manufacturing method thereof is a known manufacturing method. If so, it is not particularly limited.
The coating layer in the present invention is a film coating layer, and the thickness of the coating layer is not particularly limited and can be appropriately selected depending on the intended purpose.
The content of the coating layer in the pharmaceutical preparation of the present invention is, for example, 5.0% by mass or less, preferably 3.0% by mass or less, and more preferably 2.0% by mass or less with respect to the uncoated tablet portion.
The coated tablet may be, for example, an orally disintegrating tablet or a so-called ordinary tablet that does not disintegrate in the oral cavity.
被覆層に含有されるポリビニルアルコールとしては、ポリ酢酸ビニルをけん化して得られる重合物であればよく、例えば、ポリビニルアルコールの平均重合度が２００～３５００、好ましくは３００～２２００、あるいは、けん化度が６５ｍｏｌ％以上、好ましくは７８％以上、より好ましくは７８ｍｏｌ％～９６ｍｏｌ％（部分けん化物）である。
なお、平均重合度及びけん化度は、ＪＩＳ Ｋ ６７２６に従って測定可能である。
被覆層に含有されるポリビニルアルコールの含有量は、例えば、被覆層中２０質量％以上、好ましくは２６質量％以上である。
The polyvinyl alcohol contained in the coating layer may be a polymer obtained by saponifying polyvinyl acetate. For example, the average degree of polymerization of polyvinyl alcohol is 200 to 3500, preferably 300 to 2200, or the degree of saponification. Is 65 mol% or more, preferably 78% or more, and more preferably 78 mol% to 96 mol% (partially saponified product).
The average degree of polymerization and the degree of saponification can be measured according to JIS K 6726.
The content of polyvinyl alcohol contained in the coating layer is, for example, 20% by mass or more, preferably 26% by mass or more in the coating layer.
被覆層に含有される遮光剤としては、酸化チタン、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、食用黄色５号、食用赤色１０２号が例として挙げられ、酸化チタン、三二酸化鉄、黄色三二酸化鉄が好ましい。
これらは、１種単独で使用してもよいし、２種以上を併用してもよい。
Examples of the light-shielding agent contained in the coating layer include titanium oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, edible yellow No. 5 and edible red No. 102, and titanium oxide, iron sesquioxide, and yellow. Iron sesquioxide is preferred.
These may be used alone or in combination of two or more.
本発明における被覆層には、ポリビニルアルコール、上記遮光剤以外にこの分野で通常使用される添加剤を含めることができる。
例えば、添加剤としては、タルク、デキストリン、トウモロコシデンプン、乳糖水和物、バレイショデンプン、結晶セルロース、軽質無水ケイ酸などを適宜組み合わせて使用することができる。
In addition to polyvinyl alcohol and the above-mentioned light-shielding agent, the coating layer in the present invention may contain additives usually used in this field.
For example, as the additive, talc, dextrin, corn starch, lactose hydrate, potato starch, crystalline cellulose, light anhydrous silicic acid and the like can be appropriately combined and used.
本発明に係る医薬製剤には、有効成分であるアジルサルタンまたはその薬学的に許容される塩、上記被覆層以外に、この分野で通常使用される添加剤、例えば、賦形剤、結合剤、崩壊剤、着色剤、滑沢剤、ｐＨ調整剤、界面活性剤、安定化剤、酸味料、香料、流動化剤などを含めることができる。
例えば、賦形剤としては、乳糖水和物、Ｄ－マンニトール、結晶セルロース、トウモロコシデンプン、バレイショデンプン、軽質無水ケイ酸、含水二酸化ケイ素、無水リン酸水素カルシウム、炭酸カルシウムなどを適宜組み合わせて使用することができる。
結合剤としては、ポリビニルアルコール、ヒドロキシプロピルセルロース、ポリエチレングリコール、ヒプロメロース、メチルセルロース、ポビドン、エチルセルロースなどを適宜組み合わせて使用することができる。
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、クロスカルメロースナトリウム、カルメロース、カルメロースカルシウム、クロスポビドン、デンプングリコール酸ナトリウム、部分アルファー化デンプンなどを使用することができる。
着色剤としては、黄色三二酸化鉄、三二酸化鉄、食用タール色素、天然色素などを使用することができる。
In addition to the active ingredient azyl sartane or a pharmaceutically acceptable salt thereof, the pharmaceutical preparation according to the present invention includes additives commonly used in the art, such as excipients and binders. Disintegrants, colorants, lubricants, pH regulators, surfactants, stabilizers, acidulants, fragrances, fluidizers and the like can be included.
For example, as an excipient, lactose hydrate, D-mannitol, crystalline cellulose, corn starch, potato starch, light anhydrous silicic acid, hydrous silicon dioxide, anhydrous calcium hydrogen phosphate, calcium carbonate and the like are used in an appropriate combination. be able to.
As the binder, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, hypromellose, methyl cellulose, povidone, ethyl cellulose and the like can be appropriately combined and used.
As the disintegrant, low-degree-of-substitution hydroxypropyl cellulose, croscarmellose sodium, carmellose, carmellose calcium, crospovidone, sodium starch glycolate, partially pregelatinized starch and the like can be used.
As the colorant, yellow iron sesquioxide, iron sesquioxide, edible tar pigment, natural pigment and the like can be used.
以下、本発明を具体的に説明するが、本発明はこれら実施例に限定されるものではない。 Hereinafter, the present invention will be specifically described, but the present invention is not limited to these examples.
アジルサルタンを含有する被覆錠剤（実施例１～３及び比較例１～３）を、以下に示す方法により製造した。
＜製造方法＞
アジルサルタン、黄色三二酸化鉄（黄色三二酸化鉄、癸巳化成株式会社製）及び乳糖水和物（Ｐｈａｒｍａｔｏｓｅ２００Ｍ、ＤＦＥ ｐｈａｒｍａ社製）を撹拌造粒機（ＦＭ－ＶＧ－５０、株式会社パウレック製）に投入し、７０％エタノール水溶液に溶解させたポリビニルアルコール（ゴーセノールＥＧ－０３Ｐ、日本合成化学工業株式会社製）を液滴し、練合した。
得られた練合末を、速崩錠成型機（ＥＭＴ－１８、エーザイ株式会社製）を用いて打圧１５０Ｎで打錠し、直径８．５ｍｍの素錠部を得た。
得られた素錠部をコーティング機（ＨＣ－ＬＡＢＯ、フロイント産業株式会社製）に投入し、精製水に溶解させたポリビニルアルコール又は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（コリコートＩＲ、ＢＡＳＦジャパン製）、分散させたタルク（Ｔａｌｃ，ｅｘｔｒａ ｆｉｎｅ ｐｏｗｄｅｒ、メルク株式会社製）及び酸化チタン（酸化チタンＡ－ＨＲ、フロイント産業株式会社製）を噴霧し、被覆錠剤（実施例１～３及び比較例１～３）を得た。
Coated tablets containing azilsartan (Examples 1 to 3 and Comparative Examples 1 to 3) were produced by the methods shown below.
<Manufacturing method>
Azil sartane, yellow sesquioxide (yellow sesquioxide, manufactured by Ayumi Kasei Co., Ltd.) and lactose hydrate (Pharmatose200M, manufactured by DFE pharma) in a stirring granulator (FM-VG-50, manufactured by Paulek Co., Ltd.) Polyvinyl alcohol (Gosenol EG-03P, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) dissolved in a 70% aqueous ethanol solution was added dropwise and kneaded.
The obtained kneaded powder was locked with a rapid breaking lock molding machine (EMT-18, manufactured by Eisai Co., Ltd.) at a pressing pressure of 150 N to obtain an uncoated portion having a diameter of 8.5 mm.
The obtained uncoated tablet was put into a coating machine (HC-LABO, manufactured by Freund Sangyo Co., Ltd.) and dissolved in purified water, or polyvinyl alcohol or polyvinyl alcohol / polyethylene glycol graft copolymer (Coricoat IR, manufactured by BASF Japan). Dispersed talc (Talc, extra fine powder, manufactured by Merck Co., Ltd.) and titanium oxide (titanium oxide A-HR, manufactured by Freund Sangyo Co., Ltd.) are sprayed and coated tablets (Examples 1 to 3 and Comparative Examples 1 to 3). ) Was obtained.
上記実施例１～３及び比較例１～３における被覆錠剤を比較評価した処方例を、下記の表１に示す。
［試験例］
得られた被覆錠剤（実施例１～３及び比較例１～３）に、曝光試験機（ＰＴＨ－４００ＮＣ－Ｄ、株式会社日本医化器械製作所製）を用いて、２５℃６０％ＲＨ下、１２０万ｌｘ・ｈｒの光を照射した。
曝光前又は曝光後の検体について、高速液体クロマトグラフィー（Ｃｈｒｏｍａｓｔｅｒ、株式会社日立ハイテクサイエンス製）により測定し、相対保持時間が約０．２８の分解物Ａの量を求めた。
液体クロマトグラフィーによる測定条件を、下記に示す。
[Test example]
The obtained coated tablets (Examples 1 to 3 and Comparative Examples 1 to 3) were subjected to an exposure tester (PTH-400NC-D, manufactured by Nippon Ika Kikai Seisakusho Co., Ltd.) at 25 ° C. and 60% RH. It was irradiated with 1.2 million lx · hr of light.
The sample before or after exposure was measured by high performance liquid chromatography (Chromatography, manufactured by Hitachi High-Tech Science Co., Ltd.), and the amount of decomposition product A having a relative retention time of about 0.28 was determined.
The measurement conditions by liquid chromatography are shown below.
液体クロマトグラフィー測定条件
検出器：紫外吸光光度計（測定波長：２５０ｎｍ）
カラム：内径３．０ｍｍ、長さ１０ｃｍのステンレス管に３．５μｍ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した。
カラム温度：２５℃付近の一定温度
移動相Ａ：水／酢酸（１００）混液（１０００：１）
移動相Ｂ：アセトニトリル
移動相の送液：移動相Ａ及び移動相Ｂの混合比を、下記の表２に示すように制御した。
流量：アジルサルタンの保持時間が約２１．８分になるように調整した。
面積測定範囲：溶媒ピークの後からアジルサルタンの保持時間の約２．８倍の範囲
Column: A stainless steel tube having an inner diameter of 3.0 mm and a length of 10 cm was filled with 3.5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 25 ° C Mobile phase A: Water / acetic acid (100) mixed solution (1000: 1)
Mobile phase B: acetonitrile Mobile phase feed: The mixing ratio of mobile phase A and mobile phase B was controlled as shown in Table 2 below.
Flow rate: The retention time of azilsartan was adjusted to about 21.8 minutes.
Area measurement range: Approximately 2.8 times the retention time of azilsartan after the solvent peak
結果を表３に示す。
表３の結果から、実施例１と比較例１は遮光剤である酸化チタンの添加量が同量であるにも関わらず、基剤としてポリビニルアルコールを使用した実施例１が、基剤として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を使用した比較例１よりも光照射による分解物Ａの生成抑制効果が高く、実施例２と比較例２、実施例３と比較例３においても同様の結果となった。
また、実施例１～３は、素錠部に対する被覆層の含有量がそれぞれ１．０質量％、２．０質量％、３．０質量％であり、いずれも光照射による分解物Ａの生成抑制効果が高かった。
このことは、アジルサルタンの光安定性について、遮光剤の含有量や被覆層の厚み以外に、被覆層に用いる基剤との組み合わせも重要な要素であることを明らかにした。
なお、比較例１～３の結果から、素錠部に対する被覆層の含有量による影響も認められているが、基剤としてポリビニルアルコールを用いた場合には、素錠部に対する被覆層の含有量は３．０質量％以下でよく、１．０質量％でも充分に分解物Ａの生成を抑制していた。
From the results in Table 3, although the amount of titanium oxide as a light-shielding agent added to Example 1 and Comparative Example 1 was the same, Example 1 using polyvinyl alcohol as a base was made of polyvinyl as a base. The effect of suppressing the formation of decomposition product A by light irradiation is higher than that of Comparative Example 1 using the alcohol, polyethylene glycol, and graft copolymer, and the same results are obtained in Example 2 and Comparative Example 2, and Example 3 and Comparative Example 3. rice field.
Further, in Examples 1 to 3, the content of the coating layer with respect to the uncoated portion was 1.0% by mass, 2.0% by mass, and 3.0% by mass, respectively, and all of them produced decomposition product A by light irradiation. The inhibitory effect was high.
This clarified that the combination with the base used for the coating layer is also an important factor for the photostability of azilsartan, in addition to the content of the light-shielding agent and the thickness of the coating layer.
From the results of Comparative Examples 1 to 3, the influence of the content of the coating layer on the uncoated portion was also recognized, but when polyvinyl alcohol was used as the base, the content of the coating layer on the uncoated portion was observed. May be 3.0% by mass or less, and even 1.0% by mass sufficiently suppressed the formation of decomposition product A.
以上のことから、被覆層にポリビニルアルコール及び遮光剤を含有することで、アジルサルタン含有医薬製剤の光安定性を向上できることが明らかとなった。
このように、ポリビニルアルコールを被覆層の基剤として使用することで、口腔内崩壊錠や普通錠（経管投与する場合等）の速やかな崩壊も期待できる。
From the above, it was clarified that the photostability of the azilsartan-containing pharmaceutical preparation can be improved by containing polyvinyl alcohol and a light-shielding agent in the coating layer.
As described above, by using polyvinyl alcohol as the base of the coating layer, rapid disintegration of orally disintegrating tablets and ordinary tablets (when administered by tube, etc.) can be expected.
Claims (3)
アジルサルタンまたはその薬学的に許容される塩を含有する被覆錠剤。 It has a coating layer containing polyvinyl alcohol and a light-shielding agent, and has a coating layer.
Coated tablets containing azilsartan or a pharmaceutically acceptable salt thereof.
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