CN1197388A - 用于口服给药的药物组合物 - Google Patents
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Abstract
本发明涉及用于口服给药的药物组合物。所述组合物包括:选自植物油、动物油或矿物油的液态载体油,悬浮剂,均化剂,表面活性剂,它们与药物的活性成分以及一种或多种药物学上可接受的赋形剂或载体相混合。本发明的组合物应用于不溶于或仅略溶于水和油中的药物,这些药物选自二乙酰大黄酸、大黄酸或它们在药物学上可接受的一种盐。
Description
本发明涉及用于口服给药的药物组合物，更具体而言是涉及用于人或动物之药物产品的活性成分的药物组合物，该活性成分不溶于或仅略溶于水和油中，例如二乙酰大黄酸(diacerein)、大黄酸或它们的盐，本发明的组合物使它们的生物利用度得以提高。
二乙酰大黄酸描述于法国专利A-2,508,798中，其药理性质多年来已广为人知，并已被允许用作非甾体抗炎药，用于治疗如关节炎的疾病。但是，二乙酰大黄酸实际上不溶于水和醇中，这对其给药，特别是注射给药是一个缺陷。而且在口服给药时，二乙酰大黄酸不能完全被消化道吸收，并且由于此不完全吸收性可产生不令人希望的副作用，例如轻泻作用。
在文献中已提出各种的衍生物、药物组合物和药物制剂来改进二乙酰大黄酸或其他不溶于或仅略溶于水中的药物的性质。例如EP-A-243,968专利描述了水溶性的二乙酰大黄酸钾盐，该盐可用在非胃肠道给药的制剂中。
EP-A-598,337专利描述了包括不溶于或仅略溶于水中的药物活性成分的组合物，该活性成分是掺入交联聚合物、表面活性剂和油中，此组合物可提高生物利用度。US-A-5,225,192专利描述了制备快速溶解药物的方法，该方法包括将药物掺入交联聚合物颗粒中，该聚合物颗粒不溶于但可以溶涨于水中，使所述药物与有机溶剂相接触，然后真空干燥。
本发明的目的是提供适用于人或动物用药之活性成分的药物组合物，其包括不溶于或仅略溶于水和油中的药物，特别是二乙酰大黄酸、大黄酸或它们的一种盐，该药物组合物可口服给药，并使活性成分更块、更完全地在体内吸收，而且提高生物利用度，减少或消除上述副作用。
本发明的目的还有一种新型的基于二乙酰大黄酸、大黄酸或二乙酰大黄酸或大黄酸盐的药物组合物，该组合物可以糯米纸囊剂或明胶囊剂的形式口服给药，而且与常规制剂相比具有更高的生物利用度。
本发明的药物组合物可口服给药，包括上述不溶于或仅略溶于水和油中的药物，这些药物选自二乙酰大黄酸、大黄酸或它们在药物学上可接受的一种盐，所述组合物的特征在于包括：
-选自植物油、动物油或矿物油的液态载体油，
-悬浮剂，
-均化剂，
-表面活性剂，它们与药物的活性成分以及一种或多种药物学上可接受的赋形剂或载体相混合。
可用于本发明的药物学上可接受的盐例如是二乙酰大黄酸或大黄酸的钠或钾盐。
用于本发明之组合物的液态载体油可选自植物油(例如花生油、大豆油或葵花油)、矿物油(例如石蜡)以及动物油。其可包括一种或多种中等链长的甘油三酯。在此所用术语“中等链长”是指优选包含8-12个碳原子的直链或支链。无需赘言，也可复合使用多种甘油三酯。用于本发明之药物组合物中的中等链长的甘油三酯例如是精馏(fractionated)椰子油。
用于本发明组合物中的悬浮剂可以是在室温下为固态或半固态的任何油，例如是氢化植物油、蜡(例如蜂蜡)或凝胶剂(例如二氧化硅)。根据本发明，优选使用全部或部分氢化的植物油，例如氢化大豆油。
表面活性剂可以是阴离子型或非离子型的表面活性剂，但优选选自聚烷基山梨糖醇酐酯、聚氧乙烯山梨糖醇酐衍生物的非离子型表面活性剂，例如聚羟基乙基山梨糖醇酐的单油酸酯，如缩聚山梨醇油酸酯80(吐温80)或Span。这些表面活性剂在制药领域中是已知的，并可市售得到。
均化剂可从本领域中通常使用的试剂中选择。根据本发明，大豆卵磷脂优选使用，其优点是既可起到均化作用又可使所用的各组份流体化。
根据本发明之组合物中的各组份的量可根据所希望的作用以及药物活性成分来调节。
对于二乙酰大黄酸和大黄酸，特别有利的是使用包括以下组份的组合物：5-25wt％、优选5-10wt％的均化剂，和5-25wt％、优选10-15wt％的表面活性剂，这是以各组份及活性成分的总重来计算的。
液态载体油和悬浮剂的重量比在8∶1-2∶1之间，优选接近4∶1。这两个组份在室温或加热条件下于制备组合物的过程中混合在一起，以形成糊剂或软膏剂。该温度可根据所用组份的性质来调节。
将药物制剂中各种常规赋形剂和添加剂加至药物活性成分中，根据制药中常用的技术将上述组份与药物活性成分混合在一起。
例如，液态载体油为中等链长的甘油三酯，悬浮剂是氢化大豆油，均化剂是大豆卵磷脂，此时的方法优选按以下方式进行：将甘油三酯加热至约65-70℃，将大豆油熔化在其中，然后在冷却至室温后添加大豆卵磷脂和非离子型表面活性剂，在标准型的混合器中均化该混合物，之后加入二乙酰大黄酸，继续均化混合物10-30分钟。
根据本发明的组合物优选为软明胶胶囊或硬明胶胶囊的剂型，其每单位中包含例如20-50mg的的活性成分。
根据常规的制药技术制备软和硬明胶胶囊，该胶囊可包括例如包含各种添加剂如甘油、二氧化钛或氧化铁的明胶基囊壁。对于明胶胶囊的壁来说，优选的是包括将组合物与可导致活性成分降解的湿气隔开的物质。可使用硅油，例如二甲基硅油。
对于二乙酰大黄酸，其不溶于水和乙醇中，而仅略溶于碳酸盐溶液和四氢呋喃中，根据本发明的组合物可明显改善其药代动力学性质。具体而言，与常规的硬明胶胶囊剂的组合物相比，在口服给药包含本发明之组合物的软或硬明胶胶囊时，可观察到溶解速率显著提高，达致最大浓度。
使用包含38mg剂量之二乙酰大黄酸的本发明胶囊组合物在人身上进行临床研究，并与包含50mg剂量的二乙酰大黄酸常规药剂(硬明胶胶囊)相比，其结果见下表。
对比表
| 硬明胶胶囊 | 本发明 | |
| Cmax(mg/ml)Tmax(h) | 2.07±0.574.30±1.65 | 4.38±1.341.30±0.48 |
可以看出，根据本发明的组合物可提供明显增高的血清浓度(Cmax)，增加到两倍多，而时间却更短(Tmax)，从4.3小时缩短至1.3。而且还观察到，AUC(曲线下的面积)值增加25％多。这些结果表明所用活性成分(二乙酰大黄酸)的生物利用度明显增加。
为进一步说明本发明以下给出根据本发明的组合物以及用于口服给药的药剂的实施例，这些实施例并非限制本发明的范围。
实施例1
制备组合物，其包含：中等链长的甘油三酯 156mg氢化大豆油 38mg大豆卵磷脂 14.5mg吐温80 43.5mg
在盘式混合器中在该组合物中仔细地混入38mg的二乙酰大黄酸(400转/分钟；30分钟)，然后以常规方式灌入胶囊中，该胶囊包括明胶、甘油、纯水以及Anidrisorb，并添加有二氧化钛和氧化铁。
实施例2
与实施例1相同的组合物，包含38mg二乙酰大黄酸，灌入明胶囊中，该胶囊的囊壁组份包括实施例1中的各组份以及约15wt％的二甲基硅油。
实施例3
制备包含30mg剂量之大黄酸钠盐的硬明胶胶囊，使用以下组份：精馏椰子油 140mg大豆油 35mg大豆卵磷脂 10mgSpan(山梨糖醇酐酯) 30mg
将上述组份与30mg大黄酸钠盐仔细混合，然后装入常规市售类型的硬明胶胶囊中，该胶囊的壁是明胶制成的。
Claims (12)
1、可口服给药的药物组合物，其包括不溶于或仅略溶于水和油中的药物，这些药物选自二乙酰大黄酸、大黄酸或它们在药物学上可接受的一种盐，所述组合物的特征在于包括：
-选自植物油、动物油或矿物油的液态载体油，
-悬浮剂，
-均化剂，
-表面活性剂，它们与药物的活性成分以及一种或多种药物学上可接受的赋形剂或载体相混合。
2、如权利要求1的组合物，其特征在于，所述液态载体油是一种或多种8-12个碳原子的中等链长的直链或支链甘油三酯。
3、如权利要求1的组合物，其特征在于，所述悬浮剂是完全或部分氢化的植物油。
4、如权利要求3的组合物，其特征在于，所述氢化植物油是氢化大豆油。
5、如权利要求1的组合物，其特征在于，所述表面活性剂是非离子型的表面活性剂，其选自聚烷基山梨糖醇酐酯和聚氧乙烯山梨糖醇酐衍生物。
6、如权利要求1的组合物，其特征在于，所述均化剂是大豆卵磷脂。
7、如前述任一权利要求的组合物，其特征在于，相对于各组份和活性成分的总重，其包含5-10wt％的均化剂，和10-15wt％的表面活性剂。
8、如前述任一权利要求的组合物，其特征在于，所述液态载体油与悬浮剂的重量比在8∶1-2∶1之间。
9、如权利要求1-8之一的组合物，其特征在于，其是软明胶胶囊剂型。
10、如权利要求1-8之一的组合物，其特征在于，其是硬明胶胶囊剂型。
11、如权利要求9和10的组合物，其特征在于，所述软或硬明胶胶囊的壁包含二甲基硅油。
12、如前述任一权利要求的组合物，其特征在于，所述的药物活性成分是二乙酰大黄酸。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL1003503A NL1003503C2 (nl) | 1996-07-04 | 1996-07-04 | Farmaceutische samenstelling voor orale toediening. |
| NL1003503 | 1996-07-04 |
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| Publication Number | Publication Date |
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| CN1197388A true CN1197388A (zh) | 1998-10-28 |
| CN1196477C CN1196477C (zh) | 2005-04-13 |
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| CNB971908419A Expired - Fee Related CN1196477C (zh) | 1996-07-04 | 1997-06-30 | 用于口服给药的药物组合物 |
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| US (1) | US5952383A (zh) |
| EP (1) | EP0862423B1 (zh) |
| JP (1) | JP4209467B2 (zh) |
| KR (1) | KR980009519A (zh) |
| CN (1) | CN1196477C (zh) |
| AT (1) | ATE275945T1 (zh) |
| AU (1) | AU3263197A (zh) |
| BR (1) | BR9706537A (zh) |
| CA (1) | CA2231342C (zh) |
| DE (1) | DE69730688T2 (zh) |
| ES (1) | ES2230608T3 (zh) |
| IL (1) | IL123336A (zh) |
| MX (1) | MX9801727A (zh) |
| NL (1) | NL1003503C2 (zh) |
| PL (1) | PL189358B1 (zh) |
| WO (1) | WO1998001118A1 (zh) |
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| DE69941966D1 (de) * | 1998-02-13 | 2010-03-11 | Nutramax Lab Inc | Mittel und Verfahren zum Schutz, zur Behandlung und Reparatur von Bindegewebe |
| US6956048B2 (en) | 1999-03-31 | 2005-10-18 | Pharmacia & Upjohn Company | Pharmaceutical emulsions for retroviral protease inhibitors |
| US20020128317A1 (en) * | 2001-01-23 | 2002-09-12 | Laboratories Negma | Treatment of pathological conditions characterized by an increased IL-1 level |
| CA2533013C (en) * | 2003-07-17 | 2011-07-26 | Banner Pharmacaps, Inc. | Controlled release preparations |
| GB0317869D0 (en) * | 2003-07-30 | 2003-09-03 | Disperse Ltd | Improved drug delivery system |
| JP5096658B2 (ja) * | 2003-10-06 | 2012-12-12 | 株式会社三協 | 生物学的利用能を向上させたソフトカプセル |
| US7775245B2 (en) | 2005-04-08 | 2010-08-17 | Air Products And Chemicals, Inc. | Secure loop system and method for supply and delivery of product contained in a carrier |
| GB0523041D0 (en) * | 2005-11-11 | 2005-12-21 | Cyclacel Ltd | Combination |
| GB0526419D0 (en) * | 2005-12-23 | 2006-02-08 | Cyclacel Ltd | Formulation |
| GB0622479D0 (en) * | 2006-11-10 | 2006-12-20 | Sosei R & D Ltd | Novel salts and their therapeutic use |
| GB0625283D0 (en) * | 2006-12-19 | 2007-01-24 | Cyclacel Ltd | Combination |
| US10265265B2 (en) | 2007-03-15 | 2019-04-23 | Drug Delivery Solutions Limited | Topical composition |
| CN101371823B (zh) * | 2007-03-19 | 2010-09-15 | 上海慈瑞医药科技有限公司 | 二乙酰大黄酸缓释胶囊的制备工艺 |
| EP2008651A1 (en) | 2007-06-26 | 2008-12-31 | Drug Delivery Solutions Limited | A bioerodible patch |
| US8821924B2 (en) * | 2007-09-14 | 2014-09-02 | Wockhardt Ltd. | Rhein or diacerein compositions |
| FR2920991A1 (fr) * | 2007-09-14 | 2009-03-20 | Wockhardt Ltd | Composition a base de diacerheine pour le traitement de l'arthrose |
| US20100285114A1 (en) * | 2007-09-27 | 2010-11-11 | Rahul Dabre | Pharmaceutical compositions of rhein or diacerein |
| ATE551990T1 (de) * | 2007-09-27 | 2012-04-15 | Wockhardt Ltd | Selbstemulgierende pharmazeutische zusammensetzungen von rhein oder diacerein |
| CA2709236A1 (en) | 2007-09-27 | 2009-04-02 | Wockhardt Research Centre | Pharmaceutical compositions of rhein or diacerein |
| US20100018107A1 (en) * | 2008-07-22 | 2010-01-28 | Christensen Kurt L | Method and means for controlling the population of mosquitoes in a non-toxic manner |
| US9987226B2 (en) * | 2010-12-10 | 2018-06-05 | Ns Technologies Pty Ltd | Methods for forming miniemulsions and use thereof for delivering bioactive agents |
| ES2736256T3 (es) | 2011-03-14 | 2019-12-27 | Drug Delivery Solutions Ltd | Composición oftálmica |
| EP2793854B1 (en) | 2011-12-23 | 2015-12-16 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Formulations of flurbiprofen and diacerein |
| EP3542788A1 (en) | 2018-03-19 | 2019-09-25 | MC2 Therapeutics Limited | Topical composition comprising calcipotriol and betamethasone dipropionate |
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| ZA761627B (en) * | 1976-03-16 | 1978-01-25 | C Friedmann | Improvements in or relating to the treatment of arthritis |
| US5225192A (en) * | 1988-10-17 | 1993-07-06 | Vectorpharma International S.P.A. | Poorly soluble medicaments supported on polymer substances in a form suitable for increasing their dissolving rate |
| IT1189097B (it) * | 1986-05-02 | 1988-01-28 | Proter Spa | Sali di diacetilreina e loro impiego terapeutico nel trattamento dell'artrosi |
| IT1197316B (it) * | 1986-10-01 | 1988-11-30 | Proter Spa | Formulazione galenica ad uso orale di derivati della reina a lento rilascio per impiego terapeutico |
| IT1230566B (it) * | 1988-10-17 | 1991-10-28 | Vectorpharma Int | Farmaci poco solubili supportati su sostanze polimeriche in forma atta all'aumento della velocita' di dissoluzione |
| EP0519428B1 (en) * | 1991-06-21 | 2000-09-20 | Takeda Chemical Industries, Ltd. | Cyclodextrin compositions with fumagillol derivates |
| IT1256386B (it) * | 1992-11-13 | 1995-12-04 | Luigi Boltri | Composizioni farmaceutiche comprendenti un farmaco,una sostanza polimerica reticolata,un olio ed un agente tensioattivo |
| GB9316923D0 (en) * | 1993-08-13 | 1993-09-29 | Lilly Industries Ltd | Pharmaceutical compounds |
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1996
- 1996-07-04 NL NL1003503A patent/NL1003503C2/nl not_active IP Right Cessation
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1997
- 1997-06-30 AT AT97928275T patent/ATE275945T1/de not_active IP Right Cessation
- 1997-06-30 EP EP97928275A patent/EP0862423B1/fr not_active Expired - Lifetime
- 1997-06-30 BR BR9706537-4A patent/BR9706537A/pt not_active IP Right Cessation
- 1997-06-30 ES ES97928275T patent/ES2230608T3/es not_active Expired - Lifetime
- 1997-06-30 US US09/029,073 patent/US5952383A/en not_active Expired - Fee Related
- 1997-06-30 AU AU32631/97A patent/AU3263197A/en not_active Abandoned
- 1997-06-30 DE DE69730688T patent/DE69730688T2/de not_active Expired - Fee Related
- 1997-06-30 JP JP50472298A patent/JP4209467B2/ja not_active Expired - Fee Related
- 1997-06-30 PL PL97325282A patent/PL189358B1/pl not_active IP Right Cessation
- 1997-06-30 WO PCT/EP1997/003405 patent/WO1998001118A1/fr active IP Right Grant
- 1997-06-30 CN CNB971908419A patent/CN1196477C/zh not_active Expired - Fee Related
- 1997-06-30 IL IL12333697A patent/IL123336A/xx not_active IP Right Cessation
- 1997-06-30 CA CA002231342A patent/CA2231342C/fr not_active Expired - Fee Related
- 1997-07-16 KR KR1019970033100A patent/KR980009519A/ko not_active Application Discontinuation
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Also Published As
| Publication number | Publication date |
|---|---|
| NL1003503C2 (nl) | 1998-01-07 |
| BR9706537A (pt) | 1999-12-28 |
| EP0862423A1 (fr) | 1998-09-09 |
| ATE275945T1 (de) | 2004-10-15 |
| IL123336A (en) | 2001-03-19 |
| JPH11512115A (ja) | 1999-10-19 |
| PL189358B1 (pl) | 2005-07-29 |
| EP0862423B1 (fr) | 2004-09-15 |
| KR980009519A (ko) | 1998-04-30 |
| IL123336A0 (en) | 1998-09-24 |
| MX9801727A (es) | 1998-11-30 |
| CA2231342C (fr) | 2008-04-08 |
| ES2230608T3 (es) | 2005-05-01 |
| WO1998001118A1 (fr) | 1998-01-15 |
| US5952383A (en) | 1999-09-14 |
| CN1196477C (zh) | 2005-04-13 |
| JP4209467B2 (ja) | 2009-01-14 |
| CA2231342A1 (fr) | 1998-01-15 |
| AU3263197A (en) | 1998-02-02 |
| DE69730688T2 (de) | 2005-09-22 |
| PL325282A1 (en) | 1998-07-20 |
| DE69730688D1 (de) | 2004-10-21 |
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