CN109843272A - 度他雄胺和他达拉非的口服胶囊复合制剂 - Google Patents
度他雄胺和他达拉非的口服胶囊复合制剂 Download PDFInfo
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Abstract
本发明涉及一种胶囊复合制剂,其包含由式I表示的度他雄胺、由式II表示的他达拉非、具有8至10个碳原子的脂肪酸酯衍生物、和基于聚山梨醇酯或聚氧乙烯甘油酯的表面活性剂,其中两种药物均被溶解。
Description
技术领域
本发明涉及包含难溶性药物度他雄胺和他达拉非、作为油成分的具有8至10个碳原子的脂肪酸酯衍生物、和表面活性剂的口服胶囊复合制剂。本发明涉及增加难溶性药物度他雄胺和他达拉非两者的溶解性从而提高它们的溶出速率的复合制剂。
本发明涉及透明的基于自乳化药物递送系统的胶囊制剂,其中度他雄胺和他达拉非联合以使对前列腺增生的治疗效果最大化,并且所述透明的基于自乳化药物递送系统的胶囊制剂可以以自乳化方式形成乳液以快速溶解这两种难溶的药物。在该制剂中,自乳化药物递送系统包含度他雄胺、他达拉非、油成分和表面活性剂,并且如果需要,还包含溶剂。油成分是具有8至10个碳原子的脂肪酸酯衍生物,并且可以改善度他雄胺和他达拉非两者的溶解度。表面活性剂可以基于为度他雄胺和他达拉非提供良好的溶解性的聚山梨醇酯或聚氧乙烯甘油酯。油与表面活性剂的混合重量比可以是95:5至70:30,以配制透明的自乳化药物递送系统。通过该系统,可以改善度他雄胺和他达拉非的溶解度,因此也可以提高溶出速率。
背景技术
前列腺是男性生殖器官。前列腺增大在老年男性中相当普遍,并且随着年龄的增长更容易发展,特别是在40岁之后。增大的前列腺会增加尿道阻力,这可能导致排尿功能障碍,称为良性前列腺增生。前列腺增生的主要原因是伴随衰老而来的男性性激素睾酮的变化。众所周知,在老年时,睾酮水平降低,而睾酮的代谢产物二氢睾酮(DHT)导致前列腺增大。
用于前列腺增生的代表性药物包括5-α还原酶抑制剂和磷酸二酯酶(PDE)5抑制剂。
美国专利第5,565,467号公开了由式I表示的度他雄胺,即5-α还原酶抑制剂(IUPAC名称:17β-N-(2,5-双(三氟甲基))苯氨基甲酰基-4-氮杂-5α-雄甾-1-烯-3-酮)可用于治疗良性前列腺增生、前列腺癌和男性脱发。5-α还原酶抑制剂阻止睾酮转化为二氢睾酮(DHT),从而减少DHT并抑制前列腺生长。
<式I>
度他雄胺是水难溶性的,其在商业上可作为0.5mg软胶囊获得。是软胶囊形式的产品,其中,0.5mg度他雄胺溶解于349.5mg的辛酸/癸酸的甘油单酯和甘油二酯与丁基苯甲醇的混合物。
他达拉非(化学名:6R-反式-6-(1,3-苯并二氧杂环戊烯-5-基)-2,3,6,7,12,12a-六氢-2-甲基吡嗪[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮)是PDE5抑制剂,其由式II表示,并被开发为治疗性功能障碍的药物,但仅在剂量为5mg的情况下每日施用以用于前列腺增生的治疗。
<式II>
对于中度至重度尿路症状,推荐将两种药物分子的联合疗法作为比单一疗法的更有效的治疗选择。
然而,度他雄胺和他达拉非均为难溶性药物。此外,度他雄胺在商业上以软胶囊制剂的形式而可获得(0.5mg软胶囊),他达拉非在商业上以丸剂的形式而可获得(5mg丸剂)。两种药物的制剂彼此不同。因此,需要开发一种复合制剂,该复合制剂可以一起含有两种不同的药物,同时可以增加两种难溶性药物的溶解度。
因此,本发明人进行了研究以开发一种复合制剂,其中两种难溶性药物度他雄胺和他达拉非的溶解度得到改善,其中两种药物的溶出可在30分钟内完成,并且该复合制剂可以容易地制备。结果,发明人发现,作为油成分的具有8至10个碳原子的脂肪酸酯衍生物和作为表面活性剂的聚山梨醇酯或聚氧乙烯甘油酯必须形成混合物以制备透明的基于自乳化药物递送系统的复合制剂。
发明内容
技术问题
本发明的实施方式涉及提供一种包含度他雄胺和他达拉非的基于自乳化药物递送系统的复合制剂,所述度他雄胺和他达拉非在初始溶出和总体溶出速率方面得到改善以快速起效,并且所述复合制剂中两种药物在胶囊中处于溶解状态。
技术方案
根据本发明的一种实施方式的复合制剂是透明的基于自乳化药物递送系统的复合制剂,其包含由式I和II表示的度他雄胺和他达拉非、具有8至10个碳原子的脂肪酸酯衍生物、和表面活性剂:
<式I>
<式II>
根据本发明的另一种实施方式的胶囊制剂包含透明的基于自乳化药物递送系统的复合制剂。
前述内容仅是说明性的,并不旨在以任何方式进行限制。除了以上描述的说明性方面、实施方式和特征之外,通过参考附图和以下详细描述,其他方面、实施方式和特征将变得显而易见。
发明的有益效果
本发明的实施方式可提供透明的基于自乳化药物递送系统的复合制剂,该复合制剂完全溶解难溶性药物度他雄胺和他达拉非,以提高其溶出速率。
附图说明
图1是示出根据本发明的实施方式制备的复合制剂的内容物的照片图像。
图2是示出在实施例和比较例的制剂之间比较的溶出试验结果的图。
具体实施方式
根据本发明的基于自乳化药物递送系统的复合制剂包含式I的度他雄胺和式II的他达拉非、由具有8至10个碳原子的脂肪酸酯衍生物组成的油、和基于聚山梨醇酯或聚氧乙烯甘油酯的表面活性剂,以及如果需要,还可以包含作为溶剂的聚氧乙烯。
基于自乳化药物递送系统的复合制剂中的药学活性成分度他雄胺和他达拉非都是难溶性药物,并且可以通过在自乳化药物递送系统中使用具有8至10个碳原子的脂肪酸酯衍生物和基于聚山梨醇酯或聚氧乙烯甘油酯的表面活性剂来增加溶解度。作为自乳化药物递送系统中的油成分,具有8至10个碳原子的脂肪酸酯衍生物可以大大增加主要成分度他雄胺和他达拉非的溶解度,并且可以完全溶解水溶性差的药物并且导致外观清澈。具有8至10个碳原子的脂肪酸酯衍生物的实例包括辛酸甘油酯/癸酸甘油酯和丙二醇单辛酸酯。如在试验例1中所评估的,这些油为两种药物提供了远高于其他油的溶解度。此外,可以证实由于度他雄胺和他达拉非均完全溶解,复合制剂中的内容物具有透明性质。
试验例1示出了度他雄胺和他达拉非在各种油中的溶解度。从表5的数据可以理解,度他雄胺和他达拉非不太可能溶解在蓖麻油、大豆油和聚氧乙烯6杏仁油中,但具有8至10个碳原子的脂肪酸酯衍生物表现出对度他雄胺的溶解度为至少10倍,对他达拉非的溶解度为4倍。
基于溶解度测试结果,使用脂肪酸酯衍生物作为改善自乳化药物递送系统中难溶性药物的成分,使得度他雄胺和他达拉非可以完全溶解以形成透明的复合制剂。基于制剂的总重量,油可以特别以70至95重量%的量使用。例如,当油的用量大于95重量%时,难以进行自乳化。另一方面,当油的量小于70重量%时,其他成分可使胶囊膜硬化而延迟胶囊的崩解。
在基于自乳化药物递送系统的复合制剂中,表面活性剂用于使油成分在水中稳定地乳化以形成乳液。优选的是在与油成分混合时使度他雄胺和他达拉非透明,并且在与水接触时形成纳米乳液的表面活性剂。其中,最优选的是对两种药物表现出高溶解度并且可以配制具有8至10个碳原子的脂肪酸酯衍生物的自乳化体系的表面活性剂。表面活性剂的实例包括聚山梨醇酯和聚氧乙烯甘油酯,所述聚山梨醇酯例如氧基山梨醇酐脂肪酸酯,即聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60和聚山梨醇酯80,所述聚氧乙烯甘油酯例如PEG 6辛酸甘油酯/癸酸甘油酯(Acconon CC-6TM)、PEG 8辛酸甘油酯/癸酸甘油酯(LabrasolTM)。相关专利(韩国专利公开第10-2016-0023962号)中引入的表面活性剂(例如聚氧乙烯硬脂酸酯、聚氧乙烯蓖麻油、泊洛沙姆等)由于其对度他雄胺和他达拉非的溶解度低而难以应用于形成透明胶囊。因此,这些表面活性剂不同于本发明的表面活性剂,不能用于本发明。换句话说,适用于本发明目的的表面活性剂可包括聚山梨醇酯和聚氧乙烯甘油酯中的至少一种。油和表面活性剂可以优选以95:5至70:30的重量比使用。
在这方面,本发明人进行的相平衡研究表明,表面活性剂和油成分丙二醇单辛酸酯的混合物相互混合,在水中稳定且宽的区域内形成乳液。
由于少于5%的表面活性剂对度他雄胺和他达拉非的溶解度低,因此不可能将所得制剂制成具有适合施用的尺寸的胶囊制剂。另外,当表面活性剂的用量大于30%时,表面活性剂可能会使胶囊膜硬化,从而降低药物的质量,例如稳定性。
进一步地,可以在胶囊中使用辅助增溶剂(例如聚乙二醇)以增强两种药物的溶解。此外,本发明的制剂还可进一步包含用于口服施用的药学上可接受的添加剂,例如抗氧化剂,优选丁基羟基甲苯。
此外,本发明的实施方式提供了一种制备基于自乳化药物递送系统的组合物的方法,包括以预定重量比将度他雄胺和他达拉非与具有8至10个碳原子的脂肪酸酯衍生物和基于聚山梨醇酯或聚氧乙烯甘油酯的表面活性剂混合的步骤,以及溶解度他雄胺和他达拉非。根据该方法,将度他雄胺和他达拉非与脂肪酸酯衍生物和表面活性剂混合以获得透明液体。
本发明的另一种实施方式提供了填充有基于自乳化药物递送系统的制剂的口服胶囊制剂,所述制剂包含度他雄胺和他达拉非、油成分和表面活性剂。使用自动旋转式胶囊装载器,可将制剂包封在由明胶、琥珀酰化明胶和增塑剂(甘油、山梨糖醇)制成的胶囊中以制备软胶囊制剂。
此外,可以通过使用用于液体填充的硬胶囊填充机将基于自乳化药物递送系统的复合制剂装载到硬胶囊中来制备胶囊制剂。
根据一些实施方式的口服胶囊制剂包含基于自乳化药物递送系统的复合制剂,其中度他雄胺和他达拉非以增强的溶解度被溶解并且保证了药物的增加的溶解速率高于软胶囊AVODART和商业上可获得的CIALIS丸剂。参考图2,观察到基于自乳化药物递送系统的复合制剂显示出比对比例更高的溶出速率。
在下文中,将参考实施例和对比例详细描述根据本发明的实施方式的复合制剂。然而,这不限制本发明的范围。
实施例1至8
以如下表2所示的量向配备有搅拌器的5L制备容器中添加油和表面活性剂,搅拌混合物,在此期间缓慢添加0.5g度他雄胺并完全溶解。然后,添加0.5g他达拉非并完全溶解。将所得混合物进一步与0.1g丁基羟基甲苯一起搅拌,以形成透明的基于自乳化药物递送系统的复合制剂。单独地,使用典型的明胶、增塑剂等制备软明胶胶囊膜,如表1所示。将增溶制剂填充到软胶囊中以产生软胶囊制剂。
表1
成分 | 重量% |
琥珀酰化明胶 | 71.17 |
浓缩甘油 | 20.16 |
二山梨醇(Disorbitol)溶液 | 8.67 |
总计 | 100% |
表2
实施例9至16
以如下表3所示的量向配备有搅拌器的5L制备容器中添加油和表面活性剂,搅拌混合物,在此期间缓慢添加0.5g度他雄胺并完全溶解。然后,添加5g他达拉非并完全溶解。将所得混合物进一步与0.1g丁基羟基甲苯一起搅拌,以形成透明的基于自乳化药物递送系统的复合制剂。单独地,使用典型的明胶、增塑剂等制备软明胶胶囊膜,如表1所示。将增溶制剂填充到软胶囊中以产生软胶囊制剂。
表3
比较例1
使用商业产品0.5mg软胶囊,其对应于0.5mg度他雄胺。
比较例2
使用商业产品5mg丸剂,其对应于5mg他达拉非。
比较例3
以如下表4所示的量向5L制备容器中添加油。缓慢添加并完全溶解0.5g度他雄胺后,添加5g他达拉非并完全溶解。将所得组合物填充到硬胶囊中以制备口服硬胶囊制剂。
表4
试验例1:溶解度试验
测量度他雄胺和他达拉非在各种油中的溶解度,所述各种油包括大豆油、蓖麻油、聚氧乙烯6杏仁油、丙二醇单月桂酸酯、丙二醇单辛酸酯、辛酸甘油酯/癸酸甘油酯。在10mL小瓶中,在室温下用磁棒搅拌3mL油,在此期间添加约100mg的主要成分,然后以500rpm或更高的速度搅拌。搅拌24小时后,进行离心,取出由此形成的上清液,进行液相色谱,对溶解在油相中的主要成分定量。
表5
根据溶剂对度他雄胺和他达拉非的溶解度
主要成分在各种油中的溶解度在表5中给出。从表5中所示的溶解度结果可以理解,脂肪酸酯衍生物辛酸甘油酯/癸酸甘油酯和丙二醇单辛酸酯表现出对度他雄胺的溶解度为其他油对度他雄胺的溶解度的10倍或以上,对他达拉非的溶解度为其他油对他达拉非的溶解度的4倍或以上。
表6
根据表面活性剂的度他雄胺和他达拉非的溶解度
根据表面活性剂的溶解度测试结果总结在表6中。如表所示,聚氧乙烯甘油酯PEG6辛酸甘油酯/癸酸甘油酯和PEG 8辛酸甘油酯/癸酸甘油酯确保了对度他雄胺和他达拉非的高溶解度。
试验例2:溶出试验
对实施例15的软胶囊、比较例1和2分别使用的商业上可获得的制剂0.5mg软胶囊和5mg丸剂以及比较例3的硬胶囊进行比较例3的溶出试验。根据韩国药典溶出装置2进行溶出试验,其中使用1%十二烷基硫酸钠水溶液作为溶出介质,并将搅拌速度设定为50rpm。
如图2所示,本发明实施例中使用的口服软胶囊制剂增强了难溶性药物的溶解度,从而表现出比对比例1的AVODART、对比例2的CIALIS和对比例3的胶囊更高的溶出速率。
Claims (8)
1.一种口服胶囊复合制剂,包含:
由式I表示的度他雄胺;
由式II表示的他达拉非;
表面活性剂;和
具有8至10个碳原子的脂肪酸酯衍生物,
其中,所述衍生物溶解度他雄胺和他达拉非两者:
<式I>
<式II>
2.权利要求1所述的复合制剂,其中,所述衍生物是辛酸甘油酯/癸酸甘油酯或丙二醇单辛酸酯。
3.权利要求1所述的复合制剂,其中,所述表面活性剂包括聚氧乙烯山梨醇酐脂肪酸酯和聚氧乙烯甘油酯中的至少一种。
4.权利要求1所述的复合制剂,其中,所述脂肪酸酯衍生物的含量为70至95%。
5.权利要求1所述的复合制剂,其中,所述油与所述表面活性剂的混合重量比为95:5至70:30。
6.权利要求1所述的复合制剂,每个胶囊中包含0.5mg的度他雄胺和5mg的他达拉非。
7.权利要求1所述的复合制剂,其在施用后自发地在体内形成乳液。
8.权利要求1所述的复合制剂,其填充至胶囊的含量为400至1500mg的量。
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US20190224195A1 (en) | 2019-07-25 |
WO2018062831A1 (en) | 2018-04-05 |
TW201821065A (zh) | 2018-06-16 |
JP2019529498A (ja) | 2019-10-17 |
EP3518906A1 (en) | 2019-08-07 |
AU2017337767A1 (en) | 2019-04-18 |
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