JP2009167110A - Sarpogrelate hydrochloride-containing oral preparation excellent in stability in unpacked state - Google Patents
Sarpogrelate hydrochloride-containing oral preparation excellent in stability in unpacked state Download PDFInfo
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- 229950005789 sarpogrelate Drugs 0.000 title claims abstract description 32
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
- 238000005469 granulation Methods 0.000 description 29
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 6
- 235000012239 silicon dioxide Nutrition 0.000 description 6
- 239000012085 test solution Substances 0.000 description 6
- 229920003114 HPC-L Polymers 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
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- 235000010355 mannitol Nutrition 0.000 description 5
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 238000005096 rolling process Methods 0.000 description 2
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 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
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 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 1
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- 208000021328 arterial occlusion Diseases 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 229950008138 carmellose Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
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- 239000002552 dosage form Substances 0.000 description 1
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- 238000007908 dry granulation Methods 0.000 description 1
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- 230000037406 food intake Effects 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
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Abstract
Description
本発明は、塩酸サルポグレラート含有経口投与製剤に関する。 The present invention relates to a preparation for oral administration containing sarpogrelate hydrochloride.
塩酸サルポグレラートは５−ＨＴ２レセプターに対する選択的拮抗作用を有しており、慢性動脈閉塞症に伴う潰瘍、疼痛および冷感等の虚血性諸症状の改善薬として臨床現場で用いられている。
塩酸サルポグレラートを有効成分とする製剤はアンプラーグ錠（登録商標）として市販されており、最終包装形態において安定性に問題は認められない。
しかしながら、塩酸サルポグレラートは加湿することで加水分解することが知られている。
そこで市販製剤について無包装状態での安定性について検討したところ、４０℃・７５％ＲＨの条件下無包装状態で２ヶ月間保存すると、加水分解物が主薬含量に対して３〜４％程度生成することが判明した。
近年、外来患者のコンプライアンスの向上を目指して一包化調剤を実施する病院が増加したこと、自動錠剤包装機の普及により開封後の製剤の取り扱いが増加したこと、また長期投与処方が飛躍的に増加しているなどの理由で無包装状態において安定性に優れた製剤開発が求められている。
本製剤については、崩壊剤を製剤中に配合することで市販製剤と同等の溶出性を担保しながら小型化する方法が特開２００７−５６０１１号に示されている。
しかしながら、同文献には速い溶出性と包装状態における良好な保存安定性が示されているものの、無包装状態の安定性については触れられていない。
また、塩酸サルポグレラート含有経口投与製剤の無包装状態の安定性を改善する方法として、市販製剤に配合されているステアリン酸Ｍｇをステアリン酸Ｃａに変更する方法が特開２００７−１４５７３３号に示されているが、小型化が不充分である。
このように、製剤を十分に小型化しながら無包装状態において安定な塩酸サルポグレラート含有経口投与製剤の例はまだ示されておらず、一包化調剤に対応可能な無包装状態においても安定であり、かつ服用性に優れた塩酸サルポグレラート含有経口投与製剤の開発が望まれていた。
塩酸サルポグレラート含有経口投与製剤については、製剤の小型化を目指し錠剤中の薬物含量を増加させると、原薬の溶解度特性が製剤からの溶出挙動に影響を及ぼし、特に日局崩壊試験法第１液では主薬のゲル化が生じるため、速やかな溶出挙動を示す経口投与製剤を提供することが困難であった。
前述の特開２００７−５６０１１号においては、崩壊剤である水に不溶性のセルロース誘導体を製剤中に配合することで市販製剤と同等の溶出性を担保しながら小型化する方法が示されている。
しかしながら本発明者らが検討した結果、同公報に開示する水に不溶性のセルロース誘導体は無包装状態では水を多量に吸収した状態になり、塩酸サルポグレラートの加水分解が促進され安定性に悪影響を及ぼすことが判明した。
Sarpogrelate hydrochloride has a selective antagonism against 5-HT 2 receptor, and is used in clinical practice as an ameliorating agent for various ischemic symptoms such as ulcer, pain and cold feeling associated with chronic arterial occlusion.
A preparation containing sarpogrelate hydrochloride as an active ingredient is commercially available as Amprag tablets (registered trademark), and no problem is observed in stability in the final packaging form.
However, it is known that sarpogrelate hydrochloride hydrolyzes when humidified.
Therefore, we examined the stability of the commercial preparation in the unwrapped state, and when it was stored for 2 months in the unwrapped state at 40 ° C. and 75% RH, the hydrolyzate produced about 3 to 4% of the active ingredient content. Turned out to be.
In recent years, there has been an increase in the number of hospitals that carry out single-packed preparations aimed at improving the compliance of outpatients, the increased handling of preparations after opening due to the widespread use of automatic tablet packaging machines, and a dramatic increase in long-term prescriptions. There is a demand for development of a formulation having excellent stability in a non-packaging state because of an increase in the number of reasons.
Japanese Patent Application Laid-Open No. 2007-56011 discloses a method for reducing the size of this preparation by incorporating a disintegrant in the preparation while ensuring the same dissolution property as that of a commercially available preparation.
However, this document does not mention the stability in the unwrapped state, although it shows fast dissolution and good storage stability in the packaged state.
Japanese Patent Laid-Open No. 2007-145733 discloses a method for improving the stability of a non-packaging state of a sarpogrelate hydrochloride-containing oral administration preparation by changing Mg stearate mixed in a commercial preparation to Ca stearate. However, miniaturization is insufficient.
Thus, an example of an orally administered preparation containing sarpogrelate hydrochloride that is stable in an unwrapped state while sufficiently miniaturizing the preparation has not yet been shown, and is stable even in an unwrapped state that can be used for a single-packed preparation, In addition, development of an oral administration preparation containing sarpogrelate hydrochloride that is excellent in ingestion has been desired.
For oral dosage forms containing sarpogrelate hydrochloride, increasing the drug content in the tablet with the aim of miniaturizing the dosage form affects the dissolution characteristics of the drug substance, especially the dissolution of JP Since gelation of the active ingredient occurs, it has been difficult to provide an orally administered preparation that exhibits rapid dissolution behavior.
In the above-mentioned JP-A-2007-56011, there is shown a method for reducing the size while ensuring the dissolution property equivalent to that of a commercially available preparation by blending a water-insoluble cellulose derivative as a disintegrant into the preparation.
However, as a result of studies by the present inventors, the water-insoluble cellulose derivative disclosed in the publication is in a state in which a large amount of water is absorbed in the unwrapped state, and hydrolysis of sarpogrelate hydrochloride is promoted, which adversely affects stability. It has been found.
本発明は、無包装条件下における保存安定性に優れ、従来の市販の経口投与製剤と同様に速やかな溶出速度を示す小型化された塩酸サルポグレラート含有経口投与製剤を提供することを目的とする。 An object of the present invention is to provide a miniaturized sarpogrelate hydrochloride-containing oral administration preparation that is excellent in storage stability under non-packaging conditions and exhibits a rapid dissolution rate in the same manner as conventional commercial oral administration preparations.
本発明者らは、水を多量に吸収する性質をもつ水に不溶性のセルロース誘導体を使用しないで速やかな薬物の放出を得るために検討を重ねた結果、本発明に至った。
本発明に係る無包装状態での安定性に優れた塩酸サルポグレラート含有経口投与製剤は、結合剤として水溶性セルロース誘導体を含有するが、崩壊剤としての水に不溶性のセルロース誘導体を含有していないことを特徴とする。
本発明において、結合剤として用いる水溶性セルロース誘導体の配合量は、製剤質量の０．５質量％から３質量％とすることが好ましい。
配合量が０．５質量％より少ない場合、十分に造粒が進まず製造時にスティッキング等の打錠障害が発生し商品価値が著しく損なわれ、さらには製造が困難となるため好ましくない。
また、結合剤の配合量が３質量％より多い場合、製剤からの薬物の放出速度が遅延し充分なバイオアベイラビリティを確保できない可能性があるため好ましくない。
また、本発明に用いる水溶性セルロース誘導体は、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロースのいずれかであることが好ましい。
本発明においては、結合剤として水溶性のセルロース誘導体に加えて賦形剤、滑沢剤などの経口投与可能な医薬品添加剤が使用できる。
賦形剤としては、乳糖、Ｄ−マンニトール、バレイショデンプン、トウモロコシデンプン、リン酸水素カルシウム、軽質無水ケイ酸、クエン酸などが挙げられる。
また、滑沢剤としてはステアリン酸マグネシウム、ショ糖脂肪酸エステル、硬化油、タルクなどが挙げられる。
本発明では製剤の小型化が可能であり、製剤あたり塩酸サルポグラートを４０〜９５質量％含有している。
本発明においては、公知の方法により塩酸サルポグレラート含有経口投与製剤を製造することが可能であり、例えば直接打錠法、乾式造粒法、流動層造粒法、撹拌造粒法、転動流動層造粒法、押出し造粒法、溶融造粒法などが挙げられ、好ましくは流動層造粒法、撹拌造粒法、転動流動層造粒法、押出し造粒法が挙げられ、より好ましくは撹拌造粒法が挙げられる。
例えば流動層造粒法を用いる場合には、塩酸サルポグレラート、賦形剤などを混合した粉体に対して本発明に係る結合剤溶液を噴霧して造粒を行う。
また、撹拌造粒法を用いる場合には、塩酸サルポグレラート、賦形剤などを混合した粉体に対して本発明に係る結合剤溶液を投入して造粒を行い、造粒品を得る。
また、塩酸サルポグレラート、賦形剤および結合剤などを混合した粉体に対して精製水を投入して造粒を行い、造粒品を得ることも可能である。
これらの方法で得られた造粒品に対して滑沢剤などを混合し打錠することで目的とする錠剤を得ることができる。
また、本発明では上記のとおり製した錠剤に対して、原体由来の苦味のマスキングを目的としてフィルムコーティングすることも可能である。
本発明においてフィルムコーティングに使用できる添加剤は、通常フィルムコーティング錠を製する際に使用されるものを用いることができ、ヒプロメロース、ヒドロキシプロピルセルロースを用いることが望ましい。
また、フィルムコーティング層中には、可塑剤やタルク、酸化チタン、色素などを配合することができる。
As a result of repeated investigations to obtain a rapid drug release without using a water-insoluble cellulose derivative having a property of absorbing a large amount of water, the present inventors have reached the present invention.
The oral administration preparation containing sarpogrelate hydrochloride having excellent stability in a non-packaging state according to the present invention contains a water-soluble cellulose derivative as a binder, but does not contain a water-insoluble cellulose derivative as a disintegrant. It is characterized by.
In the present invention, the blending amount of the water-soluble cellulose derivative used as the binder is preferably 0.5% by mass to 3% by mass of the formulation mass.
When the blending amount is less than 0.5% by mass, granulation does not proceed sufficiently and tableting troubles such as sticking occur at the time of production, the commercial value is remarkably impaired, and the production becomes difficult.
Further, when the amount of the binder is more than 3% by mass, it is not preferable because the release rate of the drug from the preparation may be delayed and sufficient bioavailability may not be ensured.
The water-soluble cellulose derivative used in the present invention is preferably any of hydroxypropyl cellulose, hypromellose, and methyl cellulose.
In the present invention, orally administrable pharmaceutical additives such as excipients and lubricants can be used as a binder in addition to a water-soluble cellulose derivative.
Examples of the excipient include lactose, D-mannitol, potato starch, corn starch, calcium hydrogen phosphate, light anhydrous silicic acid, citric acid and the like.
Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, hydrogenated oil, talc and the like.
In the present invention, it is possible to reduce the size of the preparation, and 40 to 95% by mass of salpoglaate hydrochloride is contained per preparation.
In the present invention, it is possible to produce an oral administration preparation containing sarpogrelate hydrochloride by a known method. For example, direct tableting method, dry granulation method, fluidized bed granulation method, stirring granulation method, rolling fluidized bed Examples thereof include a granulation method, an extrusion granulation method, a melt granulation method, etc., preferably a fluidized bed granulation method, a stirring granulation method, a rolling fluidized bed granulation method, and an extrusion granulation method, more preferably. A stirring granulation method may be mentioned.
For example, when the fluidized bed granulation method is used, granulation is performed by spraying the binder solution according to the present invention to a powder mixed with sarpogrelate hydrochloride, excipient, and the like.
When the stirring granulation method is used, granulation is performed by adding the binder solution according to the present invention to a powder mixed with sarpogrelate hydrochloride, excipient, and the like to obtain a granulated product.
Further, it is possible to obtain a granulated product by granulating by adding purified water to a powder mixed with sarpogrelate hydrochloride, an excipient and a binder.
The target tablet can be obtained by mixing a lubricant and the like with the granulated product obtained by these methods and then tableting.
In the present invention, it is also possible to film-coat the tablets produced as described above for the purpose of masking the original bitterness.
As the additive that can be used for film coating in the present invention, those usually used when producing film-coated tablets can be used, and it is desirable to use hypromellose or hydroxypropylcellulose.
Moreover, a plasticizer, a talc, a titanium oxide, a pigment | dye, etc. can be mix | blended in a film coating layer.
塩酸サルポグレラート含有経口投与製剤において、結合剤として水溶性セルロース誘導体を使用し、さらに崩壊剤である水に不溶性のセルロース誘導体を添加しないことで無包装状態において安定であり、かつ服用性に優れた小型化された塩酸サルポグレラート含有経口投与製剤を得ることができる。
これにより、一包化調剤や開封後の製剤の取り扱い性およびコンプライアンスが向上する。
A small size that is stable in an unwrapped state by using a water-soluble cellulose derivative as a binder and not adding a water-insoluble cellulose derivative as a disintegrating agent in an oral administration preparation containing sarpogrelate hydrochloride and having excellent dosing properties An oral administration preparation containing sarpogrelate hydrochloride can be obtained.
Thereby, the handleability and compliance of the packaged preparation and the preparation after opening are improved.
以下に実施例、比較例を示し詳細に説明する。
しかしながら本発明はこれらによって限定されるものではない。
図１の表に示す処方の製剤（実施例１，２および比較例１，２）を流動層造粒法にて製した。
塩酸サルポグレラート、Ｄ−マンニトール（マンニットＰ、東和化成工業製）、バレイショデンプン（精製乾燥殺菌馬鈴薯澱粉、松谷化学工業製）を流動層造粒機（ＦＬ−ｍｉｎｉ、フロイント産業製）に投入し、実施例ではヒドロキシプロピルセルロース（ＨＰＣ−Ｌ、日本曹達製）、クエン酸（小堺製薬製）溶液、比較例ではポリビニルアルコール（ゴーセノール、日本合成化学工業製）、クエン酸（小堺製薬製）溶液、もしくはポビドン（コリドンＫ３０、ＢＡＳＦジャパン製）、クエン酸（小堺製薬製）溶液を噴霧した後、乾燥、整粒して流動層造粒品を得た。
この流動層造粒品と軽質無水ケイ酸（アドソリダー−１０１、フロイント産業製） 、ステアリン酸マグネシウム（ステアリン酸マグネシウム−Ｓ、日本油脂製）を混合後、直径７．５ｍｍ（実施例１、比較例１，２）もしくは直径６．５ｍｍ（実施例２）の杵を用いて打錠して塩酸サルポグレラートを５０ｍｇ含有する製剤を得た。
Examples and comparative examples will be described below in detail.
However, the present invention is not limited to these.
Formulations (Examples 1 and 2 and Comparative Examples 1 and 2) having the formulations shown in the table of FIG. 1 were produced by a fluidized bed granulation method.
Sarpogrelate hydrochloride, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo), and potato starch (refined and dried sterilized potato starch, manufactured by Matsutani Chemical Industry) were added to a fluidized bed granulator (FL-mini, manufactured by Freund Sangyo). In Examples, hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda), citric acid (manufactured by Kosuge Pharmaceutical), in comparative examples, polyvinyl alcohol (Gosenol, manufactured by Nippon Synthetic Chemical Industry), citric acid (manufactured by Kosuge Pharmaceutical), or After sprayed with povidone (Kollidon K30, manufactured by BASF Japan) and citric acid (manufactured by Kominato Pharmaceutical), it was dried and sized to obtain a fluidized bed granulated product.
After mixing the fluidized bed granulated product with light anhydrous silicic acid (ADSOLIDER-101, manufactured by Freund Corporation) and magnesium stearate (magnesium stearate-S, manufactured by NOF Corporation), a diameter of 7.5 mm (Example 1, comparative example) 1, 2) or a tablet with a diameter of 6.5 mm (Example 2), and tableted to obtain a preparation containing 50 mg of sarpogrelate hydrochloride.
実施例１，２、比較例１，２で製した製剤および市販製剤（５０ｍｇ錠）を４０℃・７５％ＲＨ・無包装条件下で２ヶ月間保存した。
保存した製剤について類縁物質量（加水分解物）を測定し、類縁物質量の主薬含量に対する含有割合を求めた。
結果を図２の表に示す。
なお、市販製剤はポリビニルアルコールを含有している。
実施例１および実施例１の処方から製剤を小型化した実施例２では、比較例１，２と比較して安定性試験後の製剤中の類縁物質量が１／２程度であった。
The preparations prepared in Examples 1 and 2 and Comparative Examples 1 and 2 and commercially available preparations (50 mg tablets) were stored for 2 months at 40 ° C./75% RH / non-packaging conditions.
The amount of the related substance (hydrolyzate) was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in the table of FIG.
The commercial preparation contains polyvinyl alcohol.
In Example 2 in which the preparation was miniaturized from the formulations of Example 1 and Example 1, the amount of related substances in the preparation after the stability test was about ½ compared to Comparative Examples 1 and 2.
図３の表に示す処方の製剤（実施例３〜５）を撹拌造粒法にて製した。
塩酸サルポグレラート、Ｄ−マンニトール（マンニットＰ、東和化成工業製）、バレイショデンプン（精製乾燥殺菌馬鈴薯澱粉、松谷化学工業製）を撹拌造粒機（ＶＧ−０１、パウレック製）に投入し、ヒドロキシプロピルセルロース（ＨＰＣ−Ｌ、日本曹達製）、クエン酸（小堺製薬製）溶液、またはヒプロメロース（ＴＣ−５ＥＷ、信越化学製）、クエン酸（小堺製薬製）溶液、もしくはメチルセルロース（ＳＭ−４、信越化学製）、クエン酸（小堺製薬製）溶液を撹拌しながら投入し造粒を行った。
造粒終了後、流動層造粒機（ＦＬ−ｍｉｎｉ、フロイント産業製）を用いて乾燥、整粒して撹拌造粒品を得た。
この撹拌造粒品と軽質無水ケイ酸（アドソリダー−１０１、フロイント産業製） 、ステアリン酸マグネシウム（ステアリン酸マグネシウム−Ｓ、日本油脂製）を混合後、直径６．５ｍｍの杵を用いて打錠して塩酸サルポグレラートを５０ｍｇ含有する製剤を得た。
The preparations (Examples 3 to 5) having the formulations shown in the table of FIG. 3 were produced by the stirring granulation method.
Sarpogrelate hydrochloride, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo), and potato starch (refined and dried sterilized potato starch, manufactured by Matsutani Chemical Industry) were added to an agitating granulator (VG-01, manufactured by Paulek) and hydroxypropyl. Cellulose (HPC-L, manufactured by Nippon Soda), citric acid (manufactured by Kosuge Pharmaceutical), or hypromellose (TC-5EW, manufactured by Shin-Etsu Chemical), citric acid (manufactured by Kosuge Pharmaceutical), or methylcellulose (SM-4, Shin-Etsu Chemical) And citric acid (manufactured by Kominato Pharmaceutical Co., Ltd.) were added with stirring to perform granulation.
After completion of granulation, the mixture was dried and sized using a fluidized bed granulator (FL-mini, manufactured by Freund Corporation) to obtain a stirred granulated product.
This stirred granulated product is mixed with light anhydrous silicic acid (Adsolider-101, manufactured by Freund Corporation) and magnesium stearate (magnesium stearate-S, manufactured by Nippon Oil & Fats), and then tableted using a 6.5 mm diameter punch. Thus, a preparation containing 50 mg of sarpogrelate hydrochloride was obtained.
比較例３として図４の表に示す処方の製剤を撹拌造粒法にて製した。
塩酸サルポグレラート、結晶セルロース（セオラスＰＨ１０１、旭化成ケミカルズ製）、カルメロース（ＮＳ−３００、五徳薬品製）を撹拌造粒機（ＶＧ−０１、パウレック製）に投入し、ヒドロキシプロピルセルロース（ＨＰＣ−Ｌ、日本曹達製）、クエン酸（小堺製薬製）溶液を投入した後、乾燥、整粒して撹拌造粒品を得た。
この撹拌造粒品と軽質無水ケイ酸（アドソリダー−１０１、フロイント産業製）、ステアリン酸マグネシウム（ステアリン酸マグネシウム−Ｓ、日本油脂製）を混合後、直径６．５ｍｍの杵を用いて打錠して塩酸サルポグレラートを５０ｍｇ含有する製剤を得た。
As Comparative Example 3, a preparation having the formulation shown in the table of FIG. 4 was produced by the stirring granulation method.
Sarpogrelate hydrochloride, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) and carmellose (NS-300, manufactured by Gotoku Pharmaceutical) were introduced into a stirring granulator (VG-01, manufactured by Paulek), and hydroxypropylcellulose (HPC-L, Japan). Soda) and citric acid (manufactured by Kosuge Pharmaceutical) were added, dried and sized to obtain a stirred granulated product.
This stirred granulated product is mixed with light anhydrous silicic acid (ADSOLIDER-101, manufactured by Freund Corporation) and magnesium stearate (magnesium stearate-S, manufactured by Nippon Oil & Fats), and then tableted using a 6.5 mm diameter punch. Thus, a preparation containing 50 mg of sarpogrelate hydrochloride was obtained.
実施例３，４，５、比較例３で製した製剤および市販製剤（５０ｍｇ錠）を４０℃・７５％ＲＨ・無包装条件下で２ヶ月間保存した。
保存した製剤について類縁物質量（加水分解物）を測定し、類縁物質量の主薬含量に対する含有割合を求めた。
結果を図５の表に示す。
実施例３，４，５では比較例３および市販製剤に比べて、２ヶ月間安定性試験後の製剤中の類縁物質量は１／３〜１／２程度であった。
The preparations prepared in Examples 3, 4, 5 and Comparative Example 3 and the commercially available preparation (50 mg tablet) were stored for 2 months under the conditions of 40 ° C., 75% RH and no packaging.
The amount of the related substance (hydrolyzate) was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in the table of FIG.
In Examples 3, 4 and 5, the amount of related substances in the preparation after the stability test for 2 months was about 1/3 to 1/2 compared to Comparative Example 3 and the commercially available preparation.
図６の表に示す処方の製剤（実施例６，７）を撹拌造粒法にて製した。
塩酸サルポグレラート、Ｄ−マンニトール（マンニットＰ、東和化成工業製）、バレイショデンプン（精製乾燥殺菌馬鈴薯澱粉、松谷化学工業製）を撹拌造粒機（ＶＧ−０１、パウレック製）に投入し、ヒドロキシプロピルセルロース（ＨＰＣ−Ｌ、日本曹達製）、クエン酸（小堺製薬製）溶液を撹拌しながら投入し造粒を行った。
造粒終了後、流動層造粒機（ＦＬ−ｍｉｎｉ、フロイント産業製）を用いて乾燥、整粒して撹拌造粒品を得た。
この撹拌造粒品と軽質無水ケイ酸（アドソリダー−１０１、フロイント産業製）、ステアリン酸マグネシウム（ステアリン酸マグネシウム−Ｓ、日本油脂製）を混合後、直径６．５ｍｍの杵を用いて打錠して塩酸サルポグレラートを５０ｍｇ含有する製剤を得た。
The preparations (Examples 6 and 7) having the formulations shown in the table of FIG. 6 were produced by the stirring granulation method.
Sarpogrelate hydrochloride, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo), and potato starch (refined and dried sterilized potato starch, manufactured by Matsutani Chemical Industry) were added to an agitating granulator (VG-01, manufactured by Paulek) and hydroxypropyl. Cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and citric acid (manufactured by Kosuge Pharmaceutical Co., Ltd.) were added with stirring to perform granulation.
After completion of granulation, the mixture was dried and sized using a fluidized bed granulator (FL-mini, manufactured by Freund Corporation) to obtain a stirred granulated product.
This stirred granulated product is mixed with light anhydrous silicic acid (ADSOLIDER-101, manufactured by Freund Corporation) and magnesium stearate (magnesium stearate-S, manufactured by Nippon Oil & Fats), and then tableted using a 6.5 mm diameter punch. Thus, a preparation containing 50 mg of sarpogrelate hydrochloride was obtained.
実施例６，７で製した製剤および市販製剤（５０ｍｇ錠）の溶出試験を日本溶出試験法第２法（パドル法）に従って実施した（試験液：日本薬局方崩壊試験液第１液（ｐＨ１．２）、試験液量：９００ｍＬ、パドル回転数：５０ｒｐｍ）。
結果を図７の表に示す。
実施例６，７の製剤はともに、市販製剤と同等の速やかな溶出挙動を示した。
The dissolution test of the preparations prepared in Examples 6 and 7 and the commercial preparation (50 mg tablet) was carried out according to the Japanese dissolution test method method 2 (paddle method) (test solution: Japanese Pharmacopoeia disintegration test solution solution 1 (pH 1. 2) Test solution volume: 900 mL, paddle rotation speed: 50 rpm).
The results are shown in the table of FIG.
Both the preparations of Examples 6 and 7 showed rapid dissolution behavior equivalent to that of the commercially available preparation.
図８の表に示す処方の製剤（実施例８〜１０）を撹拌造粒法にて製した。
塩酸サルポグレラート、Ｄ−マンニトール（マンニットＰ、東和化成工業製）、バレイショデンプン（精製乾燥殺菌馬鈴薯澱粉、松谷化学工業製）を撹拌造粒機（ＶＧ−０１、パウレック製）に投入し、ヒドロキシプロピルセルロース（ＨＰＣ−Ｌ、日本曹達製）、クエン酸（小堺製薬製）溶液を撹拌しながら投入し造粒を行った。
造粒終了後、流動層造粒機（ＦＬ−ｍｉｎｉ、フロイント産業製）を用いて乾燥、整粒して撹拌造粒品を得た。
この撹拌造粒品と軽質無水ケイ酸（アドソリダー−１０１、フロイント産業製） 、ステアリン酸マグネシウム（ステアリン酸マグネシウム−Ｓ、日本油脂製）を混合後、直径７．５ｍｍの杵を用いて打錠して塩酸サルポグレラートを１００ｍｇ含有する製剤を得た。
The preparations (Examples 8 to 10) having the formulations shown in the table of FIG. 8 were produced by the stirring granulation method.
Sarpogrelate hydrochloride, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo), and potato starch (refined and dried sterilized potato starch, manufactured by Matsutani Chemical Industry) were added to an agitating granulator (VG-01, manufactured by Paulek) and hydroxypropyl. Cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and citric acid (manufactured by Kosuge Pharmaceutical Co., Ltd.) were added with stirring to perform granulation.
After completion of granulation, the mixture was dried and sized using a fluidized bed granulator (FL-mini, manufactured by Freund Corporation) to obtain a stirred granulated product.
This stirred granulated product is mixed with light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industries) and magnesium stearate (magnesium stearate-S, manufactured by Nippon Oil & Fats), and then tableted using a 7.5 mm diameter punch. Thus, a preparation containing 100 mg of sarpogrelate hydrochloride was obtained.
実施例８，９，１０で製した製剤および市販製剤（１００ｍｇ錠）を４０℃・７５％ＲＨ・無包装条件下で２ヶ月間保存した。
保存した製剤について類縁物質量（加水分解物）を測定し、類縁物質量の主薬含量に対する含有割合を求めた。
結果を図９の表に示す。
実施例８，９，１０では市販製剤に比べて、１ヶ月間安定性試験後の製剤中の類縁物質量は１／２程度であった。
The preparations prepared in Examples 8, 9, and 10 and the commercial preparation (100 mg tablet) were stored for 2 months under the conditions of 40 ° C., 75% RH and no packaging.
The amount of the related substance (hydrolyzate) was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in the table of FIG.
In Examples 8, 9, and 10, the amount of related substances in the preparation after the stability test for one month was about ½ compared to the commercially available preparation.
実施例８，９，１０で製した製剤および市販製剤（１００ｍｇ錠）の溶出試験を日本溶出試験法第２法（パドル法）に従って実施した （試験液：日本薬局方崩壊試験液第１液（ｐＨ１．２）、試験液量：９００ｍＬ、パドル回転数：５０ｒｐｍ）。
結果を図１０の表に示す。
１００ｍｇ錠の溶出挙動においても５０ｍｇ錠と同様に、実施例８，９，１０の製剤はともに、市販製剤と同等の速やかな溶出挙動を示した。
このように本発明は、無包装状態において安定であり、製剤の小型化に効果的であることが明らかになった。
The dissolution test of the preparations prepared in Examples 8, 9, and 10 and the commercial preparation (100 mg tablet) was performed according to the Japanese dissolution test method 2 (paddle method) (Test solution: Japanese Pharmacopoeia Disintegration Test Solution 1 ( pH 1.2), test solution volume: 900 mL, paddle rotation speed: 50 rpm).
The results are shown in the table of FIG.
Also in the dissolution behavior of the 100 mg tablet, as in the case of the 50 mg tablet, the preparations of Examples 8, 9, and 10 all showed rapid dissolution behavior equivalent to that of the commercially available preparation.
As described above, the present invention was found to be stable in an unwrapped state and effective for downsizing the preparation.
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| CN106580909A (en) * | 2016-12-21 | 2017-04-26 | 天津红日药业股份有限公司 | Solid drug composition containing sarpogrelate hydrochloride |
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