JP6304751B2 - Warfarin-containing solid preparation and method for producing the same - Google Patents
Warfarin-containing solid preparation and method for producing the same Download PDFInfo
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- 239000007787 solid Substances 0.000 title claims description 27
- 238000002360 preparation method Methods 0.000 title claims description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 14
- 229960005080 warfarin Drugs 0.000 title description 11
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 title description 11
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 claims description 15
- 229960000883 warfarin potassium Drugs 0.000 claims description 15
- 239000012535 impurity Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- 239000011248 coating agent Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 5
- 239000004503 fine granule Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 claims description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims 3
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims 3
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 claims 2
- 239000000945 filler Substances 0.000 claims 1
- 238000005286 illumination Methods 0.000 claims 1
- 239000008187 granular material Substances 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 208000001435 Thromboembolism Diseases 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 235000019501 Lemon oil Nutrition 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 230000023555 blood coagulation Effects 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
- 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
- 239000002775 capsule Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000008120 corn starch Substances 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
- 238000000354 decomposition reaction Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 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
- 230000001771 impaired effect Effects 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000010501 lemon oil Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 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
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 238000003860 storage 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
- 239000005720 sucrose Substances 0.000 description 1
- -1 sucrose fatty acid ester Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、光照射下での不純物の増加が抑制されたワルファリン含有固形製剤に関する。 The present invention relates to a warfarin-containing solid preparation in which an increase in impurities under light irradiation is suppressed.
ワルファリンは血液凝固阻止に有用な成分であり、１９６２年に錠剤が発売されてから血栓塞栓症の治療及び予防に広く使われている。 Warfarin is a useful component for preventing blood coagulation and has been widely used for the treatment and prevention of thromboembolism since the introduction of tablets in 1962.
ワルファリンは血栓塞栓症を発症した患者が治療及びその再発予防に長期的に服用するものであるが、薬効が非常に強いために、服用する患者の血漿中濃度を測定しながら微調整し、適切な服用量を決定する必要がある。しかしながら、長年に渡り市場には錠剤しか存在せず、医療機関では錠剤を分割または粉砕し、服用量の調整を行わざるを得なかった。そこで当出願人らは、医療機関における服用量の調整を簡便化できるように、２００９年に細粒剤の販売を開始した。 Warfarin is for patients with thromboembolism who take it for treatment and prevention of recurrence for a long time. The appropriate dose needs to be determined. However, for many years, there were only tablets on the market, and medical institutions had to divide or crush the tablets and adjust the dosage. Therefore, the applicants started selling fine granules in 2009 so that the adjustment of doses in medical institutions can be simplified.
上市されている錠剤や細粒剤には、ワルファリンのカリウム塩であるワルファリンカリウムが使用されている。ワルファリンカリウムを含有する製剤の特性として、光照射下での不純物の増加が公知であるが、特に細粒剤の場合は表面に露出するワルファリンカリウムの面積が錠剤と比較して非常に大きく、光照射下での安定性はより悪いものとなっている。医療機関での細粒剤の分包時や患者がその分包品を保管する際に、光に曝されることでワルファリンカリウムの分解が進むことから、分包時からその保管に至るまで極度の遮光包装を行う必要性が生じている。 Warfarin potassium, which is a potassium salt of warfarin, is used in tablets and fine granules that are marketed. As a characteristic of formulations containing warfarin potassium, an increase in impurities under light irradiation is known, but in the case of fine granules, the area of warfarin potassium exposed on the surface is very large compared to tablets, and light Stability under irradiation is worse. When fine granules are packaged in medical institutions or when patients store their packages, warfarin potassium is decomposed by exposure to light. There is a need to perform light shielding packaging.
このような状況を改善する試みは多々行われており、例えば「（１）ワルファリンカリウムを含有する核と、（２）三二酸化鉄を含有し、前記核を被覆する被膜とを含む医薬組成物」（特許文献１）が報告されている。しかしながら、顆粒を被覆剤でコーティングする物理的な遮光は複数工程を必要とし、またコーティングは非常に緻密に行う必要があるため、長時間を要するものである。 Many attempts have been made to improve such a situation. For example, “(1) a pharmaceutical composition comprising a core containing warfarin potassium and (2) a coating containing iron sesquioxide and coating the core. (Patent Document 1) has been reported. However, the physical shading that coats the granules with a coating agent requires a plurality of steps, and the coating needs to be performed very densely, and therefore takes a long time.
前述の事情より、本発明の目的は、ワルファリン含有固形製剤の光照射下での不純物の増加を抑制し、医療機関や患者が保管する際の包装を簡素化することである。また、それと同時に、製剤を製造する工程が複雑且つ長時間を要するものでは実用性が損なわれるため、簡易な製造方法で課題を解決することも本発明の目的である。 In view of the above circumstances, an object of the present invention is to suppress an increase in impurities of a warfarin-containing solid preparation under light irradiation, and to simplify packaging when stored by a medical institution or patient. At the same time, it is an object of the present invention to solve the problem with a simple manufacturing method because the practicality is impaired if the process for producing the preparation is complicated and takes a long time.
本発明者らは、上記課題を解決すべく鋭意研究した結果、溶媒を使用しない製造方法を選択することでワルファリンカリウムの光照射下での分解を抑制できることがわかった。すなわち、本発明はワルファリンまたはその塩を含有し、溶媒を使用せずに製造される固形製剤及びその製造方法に関する。 As a result of diligent research to solve the above problems, the present inventors have found that decomposition of warfarin potassium under light irradiation can be suppressed by selecting a production method that does not use a solvent. That is, the present invention relates to a solid preparation containing warfarin or a salt thereof, which is produced without using a solvent, and a method for producing the same.
本発明によれば、ワルファリン含有固形製剤の医療機関及び患者の保管条件を簡素化できるものである。 ADVANTAGE OF THE INVENTION According to this invention, the medical institution of a warfarin containing solid formulation and the storage conditions of a patient can be simplified.
本発明は、ワルファリンまたはその塩を含有し、溶媒を使用せずに製造される固形製剤である。その形態は特に限定されることはなく、例えば錠剤、カプセル剤、細粒剤、散剤などが挙げられる。 The present invention is a solid preparation containing warfarin or a salt thereof, which is produced without using a solvent. The form is not particularly limited, and examples thereof include tablets, capsules, fine granules, powders and the like.
本発明に用いられるワルファリンまたはその塩は医薬品として用いられるいずれのものを用いてもよい。また、その含有量は特に限定されることはないが、好ましくは０．０１〜５０重量％である。 As warfarin or a salt thereof used in the present invention, any of those used as pharmaceuticals may be used. The content is not particularly limited, but is preferably 0.01 to 50% by weight.
本発明の固形製剤は、固形製剤に一般的に用いられる種々の添加剤を含んでもよく、賦形剤、結合剤、崩壊剤、滑沢剤、甘味剤、香料などが挙げられる。 The solid preparation of the present invention may contain various additives generally used in solid preparations, and examples thereof include excipients, binders, disintegrants, lubricants, sweeteners, and fragrances.
賦形剤としては、例えば乳糖水和物、無水乳糖、Ｄ−マンニトール、トウモロコシデンプン、結晶セルロース、無水リン酸水素カルシウムなどが挙げられる。 Examples of the excipient include lactose hydrate, anhydrous lactose, D-mannitol, corn starch, crystalline cellulose, anhydrous calcium hydrogen phosphate, and the like.
結合剤としては、例えばヒドロキシプロピルセルロース、ヒプロメロース、ポビドン、ポリビニルアルコール、カルメロースナトリウムなどが挙げられる。 Examples of the binder include hydroxypropylcellulose, hypromellose, povidone, polyvinyl alcohol, and carmellose sodium.
崩壊剤としては、例えばカルメロース、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、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が挙げられる。 Examples of the disintegrant include carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, and partially pregelatinized starch.
滑沢剤としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、軽質無水ケイ酸、、マクロゴール、ショ糖脂肪酸エステル、フマル酸ステアリルナトリウムなどが挙げられる。 Examples of the lubricant include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, macrogol, sucrose fatty acid ester, sodium stearyl fumarate and the like.
甘味剤としては、例えばアスパルテーム、アセスルファムカリウム、スクラロース、タウマチン、サッカリンナトリウムなどが挙げられる。 Examples of the sweetener include aspartame, acesulfame potassium, sucralose, thaumatin, and saccharin sodium.
香料としては、例えばｌ−メントール、レモンオイル、ペパーミントオイルなどが挙げられる。 As a fragrance | flavor, 1-menthol, lemon oil, peppermint oil etc. are mentioned, for example.
本発明の固形製剤は溶媒を使用しない製造方法であればいずれを選択してもよく、例えば直接打錠法、乾式造粒法などが挙げられる。また、製造工程も特に限定されることはなく、例えば造粒、整粒、混合、打錠などを行い固形製剤とすることができる。 Any solid preparation of the present invention may be selected as long as it is a production method that does not use a solvent, and examples thereof include a direct tableting method and a dry granulation method. Moreover, a manufacturing process is not specifically limited, For example, granulation, granulation, mixing, tableting, etc. can be performed and it can be set as a solid formulation.
本発明で得られる固形製剤は、室内散乱光下（約４００ｌｘ）に７日間放置した時の不純物の増加量が、総量として１％以下である。 In the solid preparation obtained in the present invention, the amount of increase in impurities when left for 7 days under room scattered light (about 400 lx) is 1% or less as a total amount.
ポリ袋にワルファリンカリウム１２．３６ｇ、乳糖水和物５，７６３ｇ、ヒドロキシプロピルセルロース１８０ｇ及びステアリン酸マグネシウム７．５ｇを入れ、１分間混合した。乾式造粒機を使用して混合品をフレークとし、粉砕機で粉砕して細粒剤を得た。 A plastic bag was charged with 12.36 g of warfarin potassium, 5,763 g of lactose hydrate, 180 g of hydroxypropylcellulose and 7.5 g of magnesium stearate and mixed for 1 minute. The mixture was made into flakes using a dry granulator and pulverized with a pulverizer to obtain a fine granule.
（比較例１）
流動層造粒機に乳糖水和物２９ｋｇを入れ、水８．１ｋｇにワルファリンカリウム約６０ｇ及びヒドロキシプロピルセルロース９００ｇを溶解させたものを噴霧後、乾燥した。得られた造粒物を篩及び粉砕機を用いて整粒後、混合し、細粒剤を得た。(Comparative Example 1)
A fluidized bed granulator was charged with 29 kg of lactose hydrate, sprayed with about 60 g of warfarin potassium and 900 g of hydroxypropylcellulose dissolved in 8.1 kg of water, and then dried. The obtained granulated product was sized using a sieve and a pulverizer and then mixed to obtain a fine granule.
（試験例１）
光照射下での安定性の評価
室内散乱光下（約４００ｌｘ）に細粒剤を７日間放置し、放置前後の不純物の量を確認した。不純物の量を確認する試験は、日本薬局方「ワルファリンカリウム」の純度試験法を基に設定した方法で実施し、不純物の総量を細粒剤中のワルファリンに対する百分率として求めた。(Test Example 1)
Evaluation of stability under light irradiation The fine granule was allowed to stand for 7 days under indoor scattered light (about 400 lx), and the amount of impurities before and after being left was confirmed. The test for confirming the amount of impurities was carried out by a method set based on the purity test method of Japanese Pharmacopoeia “Warfarin Potassium”, and the total amount of impurities was determined as a percentage of warfarin in the fine granules.
実施例１及び比較例１の試験例１による評価結果を表１に示す。 Table 1 shows the evaluation results of Test Example 1 of Example 1 and Comparative Example 1.
表１の結果より、比較例１に対して実施例１では不純物の増加が著しく抑制された。本発明の有効性が確認された。 From the results in Table 1, the increase in impurities was remarkably suppressed in Example 1 compared to Comparative Example 1. The effectiveness of the present invention was confirmed.
Claims (16)
The manufacturing method of the solid formulation of any one of Claims 9-15 which does not contain ferric oxide and yellow ferric oxide.
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