CN1874762A - 含类视色素的软明胶胶囊用新型配制剂 - Google Patents
含类视色素的软明胶胶囊用新型配制剂 Download PDFInfo
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Abstract
本发明公开了一种含类视色素的软明胶胶囊用新型药物配制剂。本发明配制剂包含用包含作为活性成分的类视色素、天然植物油、部分氢化的天然植物油和中链甘油三酯的填充物填充的软明胶胶囊。任选地，本发明配制剂还包含天然蜡。在特别优选的实施方案中，软明胶胶囊包含与上述填充物组合的胶囊外壳中的猪明胶。
Description
本发明总体上涉及软明胶胶囊形式的类视色素(retinoid)新型药物配制剂。
类视色素是结构上与维生素A相关的一类化合物，包括天然和合成化合物，已经发现它们在临床上对皮肤疾病、肿瘤疾病和免疫疾病有用。
类视色素的活性被认为通过细胞核类视色素受体如已知的类视色素受体RARα、β和γ或RXRα、β和γ介导。类视色素的活性可以为激动活性或对抗活性。具有受体激动活性的类视色素与受体结合并激活受体，然而，具有受体对抗活性的类视色素与受体结合但不激活它们。
已经发现在临床上有用的类视色素的具体实例例如为已知在痤疮治疗中有效的全反式维生素A酸，可在严重痤疮的情况下使用的13-顺式维生素A酸(见Rmpps Chemie Lexikon，1987)或9-顺式维生素A酸，9-顺式视黄醛和9-顺式维生素A及其衍生物，据说它们在1型辅助性T细胞介导的免疫疾病的治疗中是临床有效的(WO 99/09969)。
类视色素或其药用衍生物通常可以局部给药或全身给药。
类视色素的口服药物制剂例如由EP-A-0 552 624 A1、WO 00/25772和WO 99/24024已知，并描述为片剂、小药囊、吸入用气雾剂、软明胶胶囊和硬明胶胶囊。
优选的口服剂型为软明胶胶囊，因为这种材料在消化道中易于溶解。对软明胶胶囊的综述例如在Soft Gelatin Capsules Development，Tabibi，S.E.和Gupta，S.L.，编辑：Liu，Rong，Water-Insoluble Drug Formation(2000)，第609-633页，Interpharm出版，Buffalo Grove，Ill.，美国中给出。此外，这些制剂一般是优选的，因为它们掩盖了活性药物成分本身可能带有的令人不愉快的味道和令人反感的臭味。它们也可以保护活性成分免受氧和光引起的降解。
EP-A-0 552 624 A1例如公开了具有由5-50mg 9-顺式维生素A酸，1-3份油和1-5份蜡混合物组成的填充物配制剂的软明胶胶囊。
此外，WO 99/24024公开了含有20mg活性类视色素化合物，0.028mgDL-α-生育酚，4.2mg氢化蓖麻油，56.00mg辛酸/癸酸/硬脂酸甘油三酯和199.772mg中链甘油三酯的特定的含类视色素软明胶胶囊制剂。
然而，这个配制剂的关键缺点在于由于在超过5℃的温度下长期储存后形成膜而呈现非常慢的溶解速率。这个现象随着药物制剂的储存温度的升高而增强。此外，在水性介质中，观察到形成不可分散填充物，有时观察到形成针状体。
基于现有技术的这种情况，本发明的目的是提供一种改进的含类视色素的药物软明胶胶囊配制剂，该配制剂具有明显改进的溶解性能和/或没有表现出形成膜和/或形成不可分散填充物或针状体的趋势。
根据本发明，提供了一种根据权利要求1的新型药物配制剂，它包含用包含作为活性成分的类视色素、天然植物油、部分氢化的天然植物油和中链甘油三酯的填充物填充的软明胶胶囊。
本发明配制剂显示出优异的溶解特性并且没有形成膜或不可分散填充物或针状体，而这在先前使用的在上述WO 99/24024的第19页，第14行以及随后各行中所述的配制剂中观察到了。
在本发明优选实施方案中，填充物另外包含天然蜡，尤其优选黄蜡以提高它的粘度并为了防止悬浮的药物在胶囊内沉淀。
还优选的是，填充物也可以含有抗氧化剂，一方面为避免活性化合物的氧化，另一方面也为避免天然油的氧化，因此提高了配制剂的稳定性。
可用于本发明配制剂的天然植物油优选选自豆油、玉米油、向日葵油、菜子油、亚麻子油、芝麻油、橄榄油、椰子油、花生油、红花油、蓖麻油和棉籽油或这些油中的两种或更多种的混合物。尤其优选豆油，因为它被很好耐受并被广泛接受。
部分氢化的天然植物油也可以选自上述油。
中链甘油三酯通常选自含8-10个碳原子的饱和脂肪酸的甘油三酯，尤其选自辛酸甘油三酯和/或癸酸甘油三酯。
抗氧化剂优选选自DL-α-生育酚、丁基羟基甲苯(BHT)和丁基羟基苯甲醚(BHA)。
软明胶胶囊的外壳通常包含明胶、一种或多种增塑剂以及水。
增塑剂优选选自甘油、山梨糖醇、丙二醇以及这些组分的混合物。更优选地，增塑剂包含甘油和山梨糖醇的混合物。增塑剂的重要性在于向软明胶胶囊提供弹性。
用于软胶囊外壳的明胶优选为尤其是来自猪皮的猪明胶。
根据本发明，发现当胶囊外壳中的猪明胶与本发明填充物配制剂组合使用时，对药物配制剂的溶解特性有意想不到的协同增效作用。该作用在将牛明胶与本发明填充物组合时或将猪明胶与先前的WO 99/24024使用的填充物组合时没有观察到。然而，本发明填充物与牛明胶的组合也优于牛明胶与旧填充物的组合。
此外，在这个配制剂中使用猪明胶还具有的优点在于它避免了使用牛明胶带来的监管问题，即牛传染性海绵状脑病(bovine transmissiblespongiform encephalopathies)的出现。
在药物配制剂中作为活性成分含有的类视色素可以选自维生素A、视黄醛、维生素A酸及其衍生物。具体的实例为全反式维生素A、全反式维生素A酸、13-顺式维生素A酸和9-顺式维生素A酸。类视色素也可以药用衍生物如盐、酯或药物前体的形式存在。
在软明胶胶囊中含有的填充物优选包含约50重量％至80重量％，尤其是约60重量％至70重量％，特别优选约62重量％至64重量％的天然植物油，约15重量％至35重量％，尤其是约20重量％至30重量％，特别优选约24重量％至25重量％的氢化天然植物油，以及约3重量％至20重量％，尤其是约6重量％至12重量％，特别优选约8重量％至9重量％的中链甘油三酯。
在填充物还包含天然蜡的情况下，填充物优选包含约1重量％至10重量％，尤其是约3重量％至6重量％，特别优选约4重量％的天然蜡，最优选黄蜡。
由于上述的填充物和胶囊外壳之间在体外溶解特性上的协同增效作用，根据本发明特别优选的药物配制剂为包含软明胶胶囊外壳和填充物的配制剂，软明胶胶囊外壳含有猪明胶、甘油、山梨糖醇和水，填充物含有作为活性成分的类视色素，尤其是9-顺式维生素A酸，豆油，氢化豆油，中链甘油三酯，黄蜡和DL-α-生育酚。
如果需要的话，也可以加入其它药用添加剂如着色剂、矫味剂、稳定剂、乳化剂等等。
参考如下非限制性实施例更详细叙述本发明。
实施例
按照与cGMP规范一致的如下概述的标准生产方法而制备根据现有技术的软明胶胶囊和根据本发明的软明胶胶囊。在黄光和惰性气氛(氮气)中进行各个生产步骤(合适的话)。
为生产填充物，将填充物的甘油三酯和油组分称重加入合适的不锈钢容器中，加热至最高70℃，并在恒速搅拌下冷却至室温。如果应用的话，将抗氧化剂如DL-α-生育酚加入所得混合物中，然后将其在室温下搅拌约30分钟。
随后，将类视色素如9-顺式维生素A酸加入上述共混物中并搅拌直至得到均匀的悬浮液。在惰性气体和减压下，将悬浮液储存在不锈钢容器中，紧紧密封并避光直至胶囊化。
然后在旋转式染色机(rotary dye machine)上将均匀悬浮液包入胶壳，这在现有技术(例如见Bauer，K.H.等人，Lehrbuch der PharmazeutischenTechnologie，第6版，第343-348页，Stuttgart，1999)中是众所周知的。
对比例1(批料A)
按照如上概述使用如下用于填充物和胶壳的组分而制备如在WO99/24024中所述的现有技术软明胶胶囊配制剂：
旧填充物：
| 化合物 | mg/胶囊 |
| 阿利维A酸(9-顺式维生素A酸) | 20.00 |
| DL-α-生育酚 | 0.028 |
| 氢化蓖麻油 | 4.200 |
| 中链甘油三酯(Miglyol812，MCT) | 199.772 |
| 辛酸/癸酸/硬脂酸甘油三酯(Softisan378，合成甘油三酯) | 56.00 |
Miglyol812和Softisan378由Sasol，Witten，德国得到。DL-α-生育酚来自Roche Vitamins，Sisseln，瑞士。氢化蓖麻油和阿利维A酸由Hoffmann La-Roche，Basel，瑞士提供。
胶囊外壳：
| 化合物 | mg/胶囊 |
| 牛明胶 | 80.85 |
| 甘油(98-101％) | 24.53 |
| 液体非结晶山梨糖醇 | 15.09* |
| 纯化的水 | 13.33** |
| 铁红(E 172) | 0.595 |
| 铁黄(E 172) | 0.595 |
(*以干物质计算，**干燥后壳中的计算量)
在实施例和对比例中，所有的明胶都由DGF Stoess，Eberbach，德国得到；甘油来自Uniquema，Emmerich，德国；液体非结晶山梨糖醇来自Merck，Darmstadt，德国；铁红和铁黄由BASF，Ludwigshafen，德国得到；黄蜡来自Kahl，Trittau，德国。豆油及部分氢化的豆油来自Florin，Muttenz，CH。
对对比例1的现有技术配制剂进行溶解测试。发现Miglyol812/Softisan378/氢化蓖麻油的混合物在溶解测试中出现问题，因为在升高的温度下储存之后形成膜。在40℃下1星期后，填充物在溶解测试中已经由肉眼可见的薄膜覆盖。此外，观察到不可分散的填充物的小块。
根据对比例1(批料A)的软明胶胶囊的溶解曲线如图1所示。即使在最佳溶解测试条件下，曲线在较高温度下变平坦，最可能是由上述作用引起的。在40℃下储存1个月后的试样的溶解速率很少超过20％(没有显示数据)。
实施例2(批料D)
通过上述方法使用如下组分而制备根据本发明的软明胶胶囊配制剂：
根据本发明的新填充物：
| 化合物 | mg/胶囊 |
| 阿利维A酸(9-顺式维生素A酸) | 20 |
| 豆油 | 162.00 |
| 部分氢化的豆油 | 65.00 |
| 中链甘油三酯(Migyol812) | 23.00 |
| 黄蜡 | 10.00 |
| DL-α-生育酚 | 0.028 |
胶囊外壳：
| 化合物 | mg/胶囊 |
| 猪明胶 | 82.0 |
| 液体非结晶山梨糖醇 | 22.3* |
| 甘油(98-101％) | 16.5 |
| 纯化的水 | 13.6** |
| 铁红(E 172) | 0.60 |
| 铁黄(E 172) | 0.60 |
(*以干物质计算，**干燥后壳中的计算量)
实施例3(批料C)
如实施例2制备根据本发明的另一种软明胶胶囊配制剂。然而，虽然填充物与实施例2的填充物相同，但胶囊外壳含有牛明胶而不是猪明胶，它的组成如下：
胶囊外壳：
| 化合物 | mg/胶囊 |
| 牛明胶 | 82.0 |
| 液体非结晶山梨糖醇 | 15.3* |
| 甘油(98-101％) | 26.4 |
| 纯化的水 | 14.6** |
| 铁红(E 172) | 0.60 |
| 铁黄(E 172) | 0.60 |
(*以干物质计算，**干燥后壳中的计算量)
实施例4(批料E)
使用实施例2的填充物制备根据本发明的另一种软明胶胶囊配制剂，不同之处在于仅存在5mg阿利维A酸并额外加入15mg豆油，并且胶囊外壳的组成如下：
胶囊外壳：
| 化合物 | mg/胶囊 |
| 猪明胶 | 82.0 |
| 液体非结晶山梨糖醇 | 16.5* |
| 甘油(98-101％) | 22.3 |
| 纯化的水 | 13.6** |
(*以干物质计算，**干燥后壳中的计算量)
发现根据实施例2-4的配制剂在高达30℃的温度下足以稳定至少12个月。
对比例5(批料B)
使用实施例2的胶囊外壳组合物制备另一种基于对比例1的旧填充物配制剂的软明胶胶囊配制剂。
进行实施例2-4(批料D、C和E)以及对比例5(批料B)的配制剂的溶解测试，样品在40℃/75％相对湿度(r.h.)下储存以加速检测各方案的溶解曲线的可能差异。实施例2-4的配制剂的溶解曲线如图2所示，对比例5的溶解曲线如图3所示。
使用旧填充物的对比例5的溶解曲线表现出与对比例1同样差的溶解性能，而实施例2-4的溶解曲线显示出明显改进的溶解特性。在同样的溶解测试条件下，根据本发明的新型配制剂在短时间内几乎将药物完全释放。即使在同样的加速储存条件下储存12个月后，也能够重现这些结果。
最后，在6个月的储存期间，测试了在对比例1以及实施例2的填充物配制剂中悬浮的活性组分的化学稳定性，并且测定了降解产物(包括的降解产物例如为13-顺式维生素A酸和全反式维生素A酸以及不明确的降解产物)的量。稳定性测试的对比结果如下表所示。
储存条件：6个月，40℃/75％r.h.
| 来自对比例1的填充物 | 来自实施例2的填充物 | |
| 降解产物的总量 | 1.49％ | 0.98％ |
从该表中可以看出，降解产物的总量可以从根据现有技术的配制剂的1.49％减至根据本发明配制剂的0.98％。
此外，如上所述也测试了仅含有5mg而不是20mg活性组分的对比例1和实施例2的填充物配制剂的稳定性，其中对比例1填充物配制剂含有15mg额外的豆油，实施例2的填充物配制剂含有15mg额外的Miglyol812。此时，降解产物的总量甚至可以从2.93％降至1.64％(对应下降了约50％)。
该改进的化学稳定性是本发明新型配制剂的另一个优点。
Claims (18)
1.类视色素药物配制剂，包含用含有作为活性成分的类视色素、天然植物油、部分氢化的天然植物油和中链甘油三酯的填充物填充的软明胶胶囊。
2.根据权利要求1的药物配制剂，其中填充物另外包含天然蜡。
3.根据权利要求1或2的药物配制剂，其中填充物另外包含抗氧化剂。
4.根据权利要求1-3中任一项的药物配制剂，其中天然植物油选自豆油、玉米油、向日葵油、菜子油、亚麻子油、芝麻油、橄榄油、椰子油、花生油、红花油、蓖麻油和棉籽油或这些油中的两种或更多种的混合物。
5.根据权利要求1-4中任一项的药物配制剂，其中天然植物油为豆油。
6.根据权利要求1-5中任一项的药物配制剂，其中中链甘油三酯选自含8-10个碳原子的饱和脂肪酸的甘油三酯，尤其选自辛酸和/或癸酸的甘油三酯。
7.根据权利要求2-6中任一项的药物配制剂，其中天然蜡为黄蜡。
8.根据权利要求3-7中任一项的药物配制剂，其中抗氧化剂选自DL-α-生育酚、丁基羟基甲苯(BHT)和丁基羟基苯甲醚(BHA)。
9.根据权利要求1-8中任一项的药物配制剂，其中胶囊外壳包含明胶、一种或多种增塑剂以及水。
10.根据权利要求9的药物配制剂，其中增塑剂选自甘油、山梨糖醇、丙二醇以及这些组分的混合物。
11.根据权利要求9或10的药物配制剂，其中增塑剂包含甘油和山梨糖醇的混合物。
12.根据权利要求9-11中任一项的药物配制剂，其中明胶为猪明胶，尤其是来自猪皮的猪明胶。
13.根据权利要求1-12中任一项的药物配制剂，其中类视色素选自维生素A、视黄醛、维生素A酸及其衍生物。
14.根据权利要求1-13中任一项的药物配制剂，其中类视色素为9-顺式维生素A酸。
15.根据权利要求1-14中任一项的药物配制剂，其中填充物包含约50重量％至80重量％，尤其是约60重量％至70重量％，特别优选约62重量％至64重量％的天然植物油，约15重量％至35重量％，尤其是约20重量％至30重量％，特别优选约24重量％至25重量％的氢化天然植物油，以及约3重量％至20重量％，尤其是约6重量％至12重量％，特别优选约8重量％至9重量％的中链甘油三酯。
16.根据权利要求2-15中任一项的药物配制剂，其中填充物包含约1重量％至10重量％，尤其是约3重量％至6重量％，特别优选约4重量％的天然蜡。
17.根据权利要求15或16的药物配制剂，其中天然植物油为豆油。
18.根据权利要求16或17的药物配制剂，其中天然蜡为黄蜡。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102612375A (zh) * | 2009-09-15 | 2012-07-25 | Qlt股份有限公司 | 含有在脂质媒介物中的9-顺式-视黄酯的药物制剂 |
| CN107157966A (zh) * | 2017-06-14 | 2017-09-15 | 程刚 | 一种纳米包裹视黄醛祛痘凝胶及其制备方法 |
| CN109512795A (zh) * | 2018-12-24 | 2019-03-26 | 浙江安宝药业有限公司 | 维生素a软胶囊 |
| CN112618509A (zh) * | 2019-09-24 | 2021-04-09 | 重庆华邦制药有限公司 | 一种维a酸软胶囊及其制备方法 |
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| US8541469B2 (en) * | 1997-08-23 | 2013-09-24 | Glaxo Group Limited | Treatment of cell-mediated immune diseases |
| EP1461935B1 (en) | 2001-12-26 | 2007-03-14 | Research In Motion Limited | User interface and method of viewing unified communications events on a mobile device |
| US20080112987A1 (en) * | 2006-11-10 | 2008-05-15 | National Starch And Chemical Investment Holding Corporation | Coating for oxygen sensitive materials |
| US20110280960A1 (en) * | 2008-12-04 | 2011-11-17 | Juris Rubens | Thick pine needle extract composition for capsulation |
| RU2622763C2 (ru) | 2010-04-19 | 2017-06-19 | Новелион Терапьютикс Инк. | Лечебная схема и способы лечения или уменьшения нарушений зрения, связанных с дефицитом эндогенных ретиноидов |
| NZ629267A (en) | 2012-03-01 | 2016-11-25 | Quadra Logic Tech Inc | Therapeutic regimens and methods for improving visual function in visual disorders associated with an endogenous retinoid deficiency |
| CN102716103B (zh) * | 2012-07-02 | 2013-12-18 | 西安力邦制药有限公司 | 2,2′,6,6′-四异丙基-4,4′-二联苯酚软胶囊制剂及其制备方法 |
| WO2018060866A1 (en) * | 2016-09-28 | 2018-04-05 | Dr. Reddy’S Laboratories Limited | Oral retinoid compositions |
| KR102108153B1 (ko) | 2017-07-05 | 2020-05-07 | (주)동구바이오제약 | 생체 이용률 및 안정성이 개선된 레티노이드를 함유하는 약제학적 조성물 |
| RU2744142C1 (ru) * | 2019-12-06 | 2021-03-03 | Общество с ограниченной ответственностью "Артлайф" | Композиция для профилактики грибковых заболеваний |
| CN113332258A (zh) * | 2021-06-30 | 2021-09-03 | 山东良福制药有限公司 | 维a酸硬胶囊及其制备方法 |
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| CA1282326C (en) * | 1984-12-14 | 1991-04-02 | Paul J. Jarosz | Pharmaceutical composition containing 13-cis vitamin a acid as the active ingredient |
| US5082661A (en) * | 1990-09-26 | 1992-01-21 | Elizabeth Arden Co., Division Of Conopco, Inc. | Odorless cosmetic compositions in gelatin capsules |
| ATE183924T1 (de) * | 1992-01-14 | 1999-09-15 | Hisamitsu Pharmaceutical Co | Cholesterinspiegelsenkendes mittel |
| CZ282548B6 (cs) * | 1992-01-22 | 1997-08-13 | F. Hoffmann-La Roche Ag | Farmaceutický přípravek |
| KR100274101B1 (ko) | 1992-01-22 | 2000-12-15 | 프리돌린 클라우스너, 롤란드 비. 보레르 | 9-시스 레틴산을 함유하는 약제학적 조성물 |
| CA2093577C (en) | 1992-05-07 | 2006-01-03 | Michael Klaus | Alkyl or alkoxy substituted s-heterocyclic retinoids |
| DE19603402A1 (de) * | 1995-02-24 | 1996-08-29 | Basf Ag | Weichgelatinekapseln |
| KR0173445B1 (ko) * | 1996-09-17 | 1999-02-01 | 이능희 | 화장료용 이중캡슐 및 이를 함유하는 화장료 조성물 |
| EP0908179A1 (en) | 1997-08-23 | 1999-04-14 | Werner Bollag | Treatment of cell-mediated immune diseases |
| AU749810B2 (en) * | 1997-11-12 | 2002-07-04 | Basilea Pharmaceutica Ag | Treatment of T-helper cell type 2 mediated immune diseases |
| PE20001227A1 (es) * | 1998-10-30 | 2000-11-06 | Hoffmann La Roche | Procesos para producir una composicion de isotretinoina |
| US6248354B1 (en) * | 1999-03-04 | 2001-06-19 | Allergan Sales, Inc. | Capsule system |
| US6468559B1 (en) * | 2000-04-28 | 2002-10-22 | Lipocine, Inc. | Enteric coated formulation of bishosphonic acid compounds and associated therapeutic methods |
| WO2001095856A2 (en) | 2000-06-15 | 2001-12-20 | Chaconne Nsi Co., Ltd. | Urea derivative useful as an anti-cancer agent and process for preparing same |
| IN192188B (zh) | 2000-06-16 | 2004-03-13 | Ranbaxy Lab Ltd |
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2003
- 2003-11-03 EP EP03405788A patent/EP1527774A1/en not_active Withdrawn
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- 2004-10-28 KR KR1020067007881A patent/KR100856362B1/ko active Protection Beyond IP Right Term
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- 2004-10-28 AU AU2004290494A patent/AU2004290494B2/en active Active
- 2004-10-28 RU RU2006119326/15A patent/RU2344810C2/ru active
- 2004-10-28 JP JP2006537192A patent/JP4555827B2/ja active Active
- 2004-10-28 WO PCT/EP2004/012208 patent/WO2005048994A1/en active IP Right Grant
- 2004-10-28 BR BRPI0415634A patent/BRPI0415634B8/pt active IP Right Grant
- 2004-10-28 CN CN200480032140A patent/CN100594894C/zh active Active
- 2004-10-28 DK DK04790978T patent/DK1680096T3/da active
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- 2006-04-28 NO NO20061890A patent/NO339743B1/no unknown
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- 2009-12-17 US US12/640,325 patent/US8697122B2/en active Active
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- 2011-04-14 US US13/086,479 patent/US9084823B2/en not_active Expired - Lifetime
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- 2014-02-27 US US14/191,785 patent/US9084824B2/en not_active Expired - Lifetime
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- 2015-06-09 US US14/734,249 patent/US9399023B2/en not_active Expired - Lifetime
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102612375A (zh) * | 2009-09-15 | 2012-07-25 | Qlt股份有限公司 | 含有在脂质媒介物中的9-顺式-视黄酯的药物制剂 |
| CN107157966A (zh) * | 2017-06-14 | 2017-09-15 | 程刚 | 一种纳米包裹视黄醛祛痘凝胶及其制备方法 |
| CN109512795A (zh) * | 2018-12-24 | 2019-03-26 | 浙江安宝药业有限公司 | 维生素a软胶囊 |
| CN112618509A (zh) * | 2019-09-24 | 2021-04-09 | 重庆华邦制药有限公司 | 一种维a酸软胶囊及其制备方法 |
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