CN1346274A - 含睾酮十一酸酯和蓖麻油的制剂 - Google Patents
含睾酮十一酸酯和蓖麻油的制剂 Download PDFInfo
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Abstract
本发明公开了一种用于口服给药的胶囊形式的药物制剂,其包含作为活性成分的溶于药物上可接受的液体载体中的睾酮十一酸酯,其特征在于液体载体含有至少50%(按重量计)的蓖麻油。选择蓖麻油作为液体载体同时选择睾酮十一酸酯作为雄激素有利于含有约200－250mg/mlTU的溶液。对于任何可口服给药的睾酮溶液来说,这是一项新成果。溶液中还可以含有亲脂性表面活性剂,如丙二醇单月桂酸酯。
Description
本发明属于用于口服给药的雄性激素制剂领域。鉴于用于男性避孕和男性HRT(激素替代治疗)制剂的开发，此类制剂已经获得了新的关注。在这两种情况中，雄激素可被特别用作内生睾酮的替代。因此，例如，在男性HRT中，给予雄激素以缓解因年龄导致的(部分)雄激素缺乏的不良效应。雄激素也同样可以用于妇女，例如在绝经后的妇女中进行雄激素替代治疗。
雄激素的口服制剂很少，唯一有市售的口服天然睾酮产品是睾酮十一酸酯(TU)的油酸溶液。该产品在不同的国家注册了各种商品名，如Andriol和Restandol，它是一种含有40mg溶解于油酸的TU的软明胶胶囊制剂。为了在血中达到并保持可接受的睾酮水平，应每日服用3-4粒这种胶囊。涉及这样大量的单独给药的方案不很适合于TU作为一种可接受的HRT产品的实际应用，更不用说在避孕时人们会以这种方式接受它了。
本发明试图通过提供能被人体很好吸收的口服活性雄激素制剂来解决这一问题。特别地，本发明试图提供比上述已知TU制剂具有更高浓度的TU的制剂。
为了实现这些和其它目标，本发明提供了用于口服给药的胶囊形式的药物制剂，其包含作为活性成分的溶于药物上可接受的液体载体中的睾酮十一酸酯，其中的液体载体为蓖麻油。尽管在一个实施方案中，蓖麻油可以是唯一的液体载体，也有可能将蓖麻油与其它液体载体组合。然而，如果需要，蓖麻油是液体载体的主要成分，即其占所述载体的50％(按重量计)以上。
选择蓖麻油作为液体载体同时选择睾酮十一酸酯作为雄激素有利于每ml可含有约200-250mg TU的溶液。这相当于每ml含大约127-137mg睾酮。对于任何可口服给药的以任何形式存在的睾酮溶液来说，这是一项新成果。因此，本发明的一个方面包括用于口服给药的胶囊形式的药物制剂，其含有作为活性成分的溶于药物上可接受的液体载体中的睾酮十一酸酯，其浓度为200-250mg/ml。
人们注意到，Exp.Clin.Endocrinol.Diabetis 105 Suppl.1，21，1997和Eur.J.Endocrinol.123：514-9(195)中提到一种浓度为250mg/mlTU的蓖麻油可注射溶液。然而，这不能带来获得相似水平的TU口服给药的可能性。这些是药物制剂不同的领域，而且，直接进入肌肉的注射液不能用作为经口服途径给药的模型。另外，更加令人吃惊的是，显然蓖麻油是适合于这种类型的给药的适宜载体，因为其正常的能力是作为缓泻药。当然，这与本发明中的用途是完全相反的，本发明的目的是使一些物质(在这里是TU)进入并被人体吸收，而不是通过诱导排泄使之离开人体。因此，完全出乎意料的是，结果证明蓖麻油对于TU口服给药来说是一种非常适合的载体，TU能被很好地吸收。
本发明还包括睾酮十一酸酯用于制备口服溶液形式的药物的用途，其中的睾酮十一酸酯溶解于药物上可接受的液体载体中，其特征在于液体载体含有至少50％(按重量计)的蓖麻油。另一个方面，本发明涉及一种包括给予需要补充雄激素的人类男性或女性睾酮十一酸酯的治疗方法，其特征在于经口服给予载体溶液形式的睾酮十一酸酯，后者含有至少50％(按重量计)的蓖麻油。为了获得最佳的TU给药，优选在用餐时或饭后马上服用该胶囊。
在所有上述方面中，优选地，除了TU和蓖麻油之外，该胶囊中还可含有如WO97/40823和WO95/24893中公开的添加剂。最优选地是，将制剂基于蓖麻油与亲脂性表面活性剂的特定组合上，因为这种组合可以提供用于溶解TU的液体载体，从而生成可以最有利于淋巴吸收的最稳定的制剂。因此，优选的制剂是这样一种制剂，其中TU溶解于含有50-70％(按重量计)蓖麻油及30-50％(按重量计)HLB值小于10的亲脂性表面活性剂，任选地，0-20％(按重量计)亲水性表面活性剂的液体载体中，其中的液体载体基本上不含游离脂肪酸，并且含有不超过10％(按重量计)的乙醇。合适的HLB值小于10的亲脂性表面活性剂对于本领域技术人员来说是已知的。它们包括脂肪酸单-和/或二甘油脂以及其中甘油中剩余的游离羟基基团可被酯化的脂肪酸单-和/或二甘油脂，例如它们的乙酸酯、琥珀酸酯、乳酸酯、柠檬酸酯和/或酒石酸酯；脂肪酸丙二醇单-和/或二酯；蓖麻油或氢化蓖麻油的乙氧基化物(低乙氧基化物含量，HLB＜10)；环氧乙烷与脂肪酸或脂肪酸甘油酯反应形成的酸和酯的乙氧基化物；脂肪酸脱水山梨醇酯；不饱和聚乙二醇化甘油酯(如果HLB＜10)；脂肪醇乙氧基化物(如果HLB＜10)；聚氧乙烯-聚氧丙烯共聚物和嵌段共聚物(如果HLB＜10)。优选地，亲脂性表面活性剂的使用量为液体载体35-45％(按重量计)。优选的亲脂性表面活性剂是丙二醇单月桂酸酯。任选的亲水性表面活性剂对本领域技术人员来说也是已知的。任何药物上可接受的亲水性表面活性剂(即HLB值＞10的表面活性剂)都可以用于本发明。该制剂中还可以含有少量的其它添加剂，例如，抗氧化剂，如d-α-生育酚、BHA、BHT；共溶剂，如乙醇和Transcutol(二甘醇单乙醚)；增塑剂，如丙二醇等。
通过已知方法，例如WO 95/24893中所描述的方法可以容易地制备本发明制剂。可用已知技术来制备包裹该制剂的胶囊。优选的是明胶软胶囊，例如Andriol，但任何药物上可接受的软壳或硬壳材料都可以用来制作胶囊壁。在《工业药学理论与实践》(Lachman和Leibermann编，第二版，Henry Kimpton Publishers，London出版)一书中公开了使用软明胶包囊的方法。液体填充的硬壳包囊方法公开于《硬胶囊-发展与技术》(K.Ridgeway编，PharmaceuticalPress 1987年出版)。
下文中的实施例将进一步说明本发明。
实施例
将下列成分加入到合适的混合器(Unimix)中并加热至40℃：
蓖麻油BP 53份(按重量计)
丙二醇单月桂酸酯 35份(按重量计)
睾酮十一酸酯(TU) 12份(按重量计)
待完全溶解后，使用标准设备将生成的溶液填充到330ml软明胶胶囊中。得到一个稳定的制剂，从中TU可被很好地口服吸收。
Claims (8)
1.用于口服给药的胶囊形式的药物制剂，其包括作为活性成分的溶于药物上可接受的液体载体中的睾酮十一酸酯，其特征在于液体载体包含至少50％(按重量计)的蓖麻油。
2.权利要求1所述的药物制剂，其特征在于唯一的液体载体是蓖麻油。
3.权利要求1所述的药物制剂，其特征在于液体载体进一步含有30-50％(按重量计)HLB值小于10的亲脂性表面活性剂。
4.权利要求3所述的药物制剂，其特征在于亲脂性表面活性剂为丙二醇单月桂酸酯。
5.前述权利要求中任一项中所述的药物制剂，其特征在于睾酮十一酸酯的溶解浓度为200-250mg/ml。
6.睾酮十一酸酯用于制备口服溶液形式的药物的用途，其中的睾酮十一酸酯溶解于药物上可接受的液体载体中，其特征在于液体载体含有至少50％(按重量计)的蓖麻油。
7.治疗方法，其包括给予需要补充雄性激素的人类男性睾酮十一酸酯，其特征在于睾酮十一酸酯是以载体溶液的形式经口服给药的，后者含有至少50％(按重量计)的蓖麻油。
8.用于口服给药的胶囊形式的药物制剂，其含有作为活性成分的溶解于药物上可接受的液体载体中的睾酮十一酸酯，溶解浓度为200-250mg/ml。
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| EP99302581.6 | 1999-04-01 | ||
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| CN109700763A (zh) * | 2011-01-26 | 2019-05-03 | 阿勒根公司 | 用于治疗眼科病症的雄性激素组合物 |
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| US11433083B2 (en) | 2010-11-30 | 2022-09-06 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
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| GB9907715D0 (en) * | 1999-04-01 | 1999-05-26 | Scherer Corp R P | Pharmaceutical compositions |
| JO2505B1 (en) * | 2003-03-14 | 2009-10-05 | باير شيرنغ فارما اكتنجيسيلشافت | Pharmacy methods and formulations for obtaining acceptable serum testosterone levels |
| US8784869B2 (en) | 2003-11-11 | 2014-07-22 | Mattern Pharma Ag | Controlled release delivery system for nasal applications and methods of treatment |
| EP1530965B1 (en) | 2003-11-11 | 2006-03-08 | Mattern, Udo | Controlled release delivery system of sexual hormones for nasal application |
| US20060140820A1 (en) | 2004-12-28 | 2006-06-29 | Udo Mattern | Use of a container of an inorganic additive containing plastic material |
| US8492369B2 (en) | 2010-04-12 | 2013-07-23 | Clarus Therapeutics Inc | Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same |
| RU2623206C2 (ru) * | 2005-04-15 | 2017-06-22 | Кларус Терапьютикс, Инк. | Фармацевтические системы доставки для гидрофобных лекарственных средств и композиций, их содержащих |
| MX2009003654A (es) | 2006-10-04 | 2009-04-22 | M & P Patent Ag | Sistema de suministro por liberacion controlada para la aplicacion nasal de neurotransmisores. |
| GB0818473D0 (en) | 2008-10-08 | 2008-11-12 | Probio Nutraceuticals As | Composition |
| US11304960B2 (en) | 2009-01-08 | 2022-04-19 | Chandrashekar Giliyar | Steroidal compositions |
| KR101607034B1 (ko) * | 2010-04-12 | 2016-03-28 | 클라루스 쎄러퓨틱스, 아이엔씨. | 경구 테스토스테론 에스테르 제형 및 이를 포함하는 테스토스테론 결핍을 치료하는 방법 |
| GB201006200D0 (en) * | 2010-04-14 | 2010-06-02 | Ayanda As | Composition |
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| US20120148675A1 (en) | 2010-12-10 | 2012-06-14 | Basawaraj Chickmath | Testosterone undecanoate compositions |
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| JP6723166B2 (ja) * | 2014-06-19 | 2020-07-15 | ソルラル ファーマ エーピーエス | 親油性の化合物の固体経口剤形 |
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| CN1102095A (zh) * | 1993-10-30 | 1995-05-03 | 浙江医科大学 | 长效雄激素类制剂——十一酸睾丸注射液 |
| GB9608719D0 (en) * | 1996-04-26 | 1996-07-03 | Scherer Ltd R P | Pharmaceutical compositions |
| SE9700642D0 (sv) * | 1997-02-24 | 1997-02-24 | Kronvall Stefan Med Ab | Medel och sätt för förebyggande och behandling av det metabola syndromet |
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