CN101657101A - 并存早泄和勃起功能障碍的治疗 - Google Patents
并存早泄和勃起功能障碍的治疗 Download PDFInfo
- Publication number
- CN101657101A CN101657101A CN200880011802A CN200880011802A CN101657101A CN 101657101 A CN101657101 A CN 101657101A CN 200880011802 A CN200880011802 A CN 200880011802A CN 200880011802 A CN200880011802 A CN 200880011802A CN 101657101 A CN101657101 A CN 101657101A
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- China
- Prior art keywords
- tramadol
- inhibitor
- pharmacy
- pde5 inhibitor
- erectile dysfunction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
本发明提供一种治疗并存早泄和勃起功能障碍的方法。特别地，所述方法包括给药有效量的曲马多物质和有效量的磷酸二酯酶抑制剂。本发明还提供药物组合物，其包括药学可接受的载体、曲马多物质和磷酸二酯酶抑制剂。本发明进一步提供试剂盒，其包括曲马多物质和磷酸二酯酶抑制剂。
Description
相关申请
本申请交叉引用2007年2月12日提交的美国临时专利申请号60/889,369。该在先申请的全部内容被认为是随后申请内容的一部分，且将其在此引入作为参考。
发明领域
本发明涉及一种在人类男性中治疗并存早泄和勃起功能障碍的方法。所述方法包括向所述男性给药曲马多(tramadol)物质和磷酸二酯酶抑制剂。本发明还涉及药物组合物，其包括曲马多物质和磷酸二酯酶抑制剂。本发明进一步涉及试剂盒，其包括曲马多物质和磷酸二酯酶抑制剂。
发明背景
早泄是最常见形式的男性性功能障碍，估计22-38％的男性患有早泄。其是一种使人虚弱的性功能障碍，其导致不能插入或持续性交，且可对患者引起心理损害。早泄也可能损害生育成功。
勃起功能障碍也是一种常见形式的男性性功能障碍，估计5-15％的男性患有勃起功能障碍。勃起功能障碍的患病率随年龄和某些医学病症如心脏病、高血压和糖尿病而增加。
男性通常患有早泄和勃起功能障碍。已经报道了约25至约45％患有早泄的男性也患有勃起功能障碍(Fasolo等人，J.Sex.Med.，2：376-382(2005)；Shabsigh和Perelman，J.Sex Res.，Volume 43，Number 1(2006年2月)；Porst等人，European Urology，51(3)：816-824(2007年3月；在线公布于2006年7月)，并且超过一半患有勃起功能障碍的男性也患有早泄(Shabsigh和Perelman，J.Sex Res.，Volume 43，Number 1(2006年2月))。与单独患有早泄或勃起功能障碍的那些男性相比，同时患有早泄和勃起功能障碍的男性的生活质量和性愉悦的得分更低。
发明概述
本发明提供一种在人类男性中治疗并存早泄和勃起功能障碍的方法。特别地，所述方法包括在性活动之前的有效时间，向所述男性给药有效量的曲马多物质和有效量的磷酸二酯酶抑制剂。
本发明还提供药物组合物。所述组合物包括药学可接受的载体、曲马多物质和磷酸二酯酶抑制剂。
本发明进一步提供试剂盒，其包括曲马多物质和磷酸二酯酶抑制剂。所述试剂盒可以包括一个或多个容器，每个同时包含曲马多物质和磷酸二酯酶抑制剂。替代性地，所述试剂盒可以包括容纳曲马多物质的容器和容纳磷酸二酯酶抑制剂的不同的容器。
附图说明
图1显示了曲马多的立体异构体。
本发明优选实施方案的详细说明
在此使用的术语“早泄”是指一种性功能障碍，其中男性不能控制足以使配偶和/或他自己满足程度的射精过程。早泄指的是性交期间在插入前或插入后不久，使用最小刺激就可持续或再发性射精和/或比期望较早地出现射精，引起配偶的一方或双方痛苦。参见Montague等人J.Urol.，172：290-294(2004)；Diagnostic and Statistical Manual of Mental Disorders，第4版，American Psychiatric Association，Washington，D.C.(2000)。该术语包括“先天性”、“终生性”、“原发性”和“获得性”早泄。
尽管已经提出了多种具体标准用于诊断早泄，然而没有一个标准或一组标准被普遍接受。具体提出的标准包括：(i)插入前射精或在插入后抽插十至二十次内射精；(ii)少于1-2分钟内射精；和(iii)如果女性不存在性高潮功能障碍的情况，那么早于女性能够达到性高潮的时间的50％射精。参见，例如美国专利号6,037,360和5,151,448；Male Infertility and Sexual Dysfunction，第356页(Springer-Verlag 1997)；Diagnostic and Statistical Manual of MentalDisorders(American Psychiatric Association 1994)。最近，通过秒表测量的阴道内射精潜伏时程(intravaginal ejaculatory latency time，‘IELT’或‘IVELT’)少于2分钟与痛苦或交媾困难(interpersonal difficulty)的证据的组合在临床研究中被用于诊断早泄。参见，Pryor等人，Lancet，368(9539)：929-937(2006年9月9日)。一个报告建议将具有IELT少于1分钟的男性具有“明确性”早泄，具有IELT为1至1.5分钟之间的男性具有“可能性”早泄，而早泄的严重程度(如“无症状”、“轻度”、“中度”和“重度”)应当根据有关心理学问题来定义。Waldinger等人，J.Sex.Med.，2(4)：498-507(2005)。已经开发了用于诊断早泄的多个自填式(self-reported)结果调查问卷，也称为患者-报道式结果(patient-reported outcomes)。参见Althof等人，Urol.Clin.North Am.，34(4)：581-589(2007年11月)。所述早泄诊断工具(PEDT)是一种此类调查问卷。最近，证实和表明得分9和10为“可能性”早泄，得分等于或大于11诊断为早泄。参见Symonds等人，Eur.Urol.，52：565-573(2007)和Symonds等人，Int.J.Impot.Res.，19：521-5(2007)(包括调查问卷文本)。该调查问卷评价了控制不足、早泄频率、最小性刺激、痛苦和交媾困难。目前，本发明人认为用于诊断早泄的最好的标准是短IELT(short IELT)加PEDT的得分为9或更高。短IELT的准确定义预期是可变的，取决于地理区域和/或文化差异，其可根据经验确定。对于美国而言，目前本发明人认为短IELT的最好定义是使用秒表测量时，大于50％的性交尝试的IELT少于2分钟。
在此使用的术语“勃起功能障碍”是指持续的或周期性的不能获得和/或保持足以允许令人满意的性交或性活动的阴茎勃起。在本文中，“勃起功能障碍”也用于指部分的、暂时性的或阵发性的阴茎不能勃起。
勃起功能的国际指数(International Index of Erectile Function，IIEF)的勃起功能(EF)域(domain)已被开发出来，并且被批准作为基于患者的调查问卷，其现在被广泛地用于诊断勃起功能障碍。IIEF的EF域以高度灵敏性和特异性地证实了试验的可靠性和正确性。特别地，得分为25或更低的男性归类为患有ED，得分高于25的男性归类为未患有ED(灵敏性＝0.97；特异性＝0.88)。进一步，根据对IIEF勃起功能问题的反应可以将勃起功能障碍分类为五个诊断类别：没有勃起功能障碍(得分26-30)；“轻度”勃起功能障碍(得分22-25)；“轻度-至-中度”勃起功能障碍(得分17-21)；“中度”勃起功能障碍(得分11-16)；和“重度”勃起功能障碍(得分6-10)。参见Rosen等人，Int.J.Impot.Res.，14(4)：226-244(2002年8月)和Rosen等人，Urology，49：822-830(1997)(包括IIEF调查问卷文本和EF问题的鉴定)。称为男性性健康目录(Sexual Health Inventory for Men，SHIM)的另一种小类的IIEF也被开发出来，并且被批准作为诊断工具，其现在被广泛地用于诊断勃起功能障碍。得分为21或更低的男性归类为患有ED，得分高于21的男性归类为未患有ED(灵敏性＝0.98；特异性＝0.88)。进一步，根据对SHIM问题的反应可以将勃起功能障碍分类为五个诊断类别：没有勃起功能障碍(得分22-25)；“轻度”勃起功能障碍(得分17-21)；“轻度-至-中度”勃起功能障碍(得分12-16)；“中度”勃起功能障碍(得分8-11)；和“重度”勃起功能障碍(得分5-7)。参见Rosen等人，Int.J.Impot.Res.，14(4)：226-244(2002年8月)(鉴定SHIM问题)和Rosen等人，Urology，49：822-830(1997)(包括IIEF调查问卷文本)。因此，可以使用EF得分和/或SHIM得分诊断勃起功能障碍，也可以使用这些得分评价勃起功能障碍的严重性。
在此使用的术语“并存(comorbid)”指两种疾病同时存在于或发现于同一人中。“并存早泄和勃起功能障碍(comorbid premature ejaculation anderectile dysfunction)”指早泄和勃起功能障碍同时存在于或发现于同一男性中，即，单个男性遭受、倾向于遭受早泄和勃起功能障碍两者或具有遭受这两者的病史。
在此使用的术语“曲马多物质”是指2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)-环己醇(“曲马多”)和曲马多的所有药学可接受的形式和衍生物。特别地，该术语包括N-氧化物衍生物(“曲马多N-氧化物”)和O-去甲基衍生物(“O-去甲曲马多”)。该术语还包括曲马多及其衍生物的溶剂合物、多晶型物和药学可接受的酸加成盐。该术语进一步包括前述物质中任一一种的所有立体异构体，包括单个立体异构体(包括单个对映异构体)和立体异构体的混合物(包括外消旋体)。
曲马多的立体异构体示于图1中。关于曲马多的单个立体异构体的命名体系在文献中似乎存在一些差异。对于本申请的目的而言，曲马多“顺式”和“反式”立体异构体的命名是参照曲马多分子内环己烷环上的二甲基氨基和羟基取代基的相对位置进行的。如图1所示，R，R和S，S对映异构体在本文中称为“顺式”异构体，而R，S和S，R异构体在本文中称为“反式”异构体。又如图1所示，曲马多的R，R异构体在本文中称为“+”顺式异构体，而S，S异构体称为“-”顺式异构体。目前理解R，S和S，R异构体不是光学活性的。
目前优选的是曲马多和其酸加成盐，特别是盐酸盐。更优选的是(±)顺式-曲马多、酸加成盐，特别是盐酸盐，和单个对映异构体。
制备曲马多、曲马多N-氧化物和O-去甲曲马多的方法是众所周知的。参见，例如美国专利号3,652,589、3,830,934、5,223,541、5,336,691、5,723,668、5,728,885和5,874,620，将这些文献的全部内容引入本文作为参考。曲马多也可以是从一些来源，包括Gruenenthal GmbH，Aschen，Germany市售可获得的。
药学可接受的酸加成盐通过本领域众所周知的常规方法，使用药学可接受的基本上无毒的有机和无机酸制备。此类酸包括盐酸、硝酸、硫酸、磷酸、氢溴酸、乙酸、丙酸、马来酸、丙二酸、琥珀酸、柠檬酸、酒石酸、苹果酸、苯甲酸、水杨酸、邻苯二甲酸、烟酸等。优选的是盐酸，而曲马多盐酸盐对于实施本发明是最优选的化合物。
磷酸二酯酶(PDEs)是一类参与第二信使核苷酸cAMP和cGMP代谢的胞内酶。目前，PDEs被分为十一个主要的家族，I-XI型。所述家族的成员在其组织、细胞和亚细胞分布以及它们与cAMP和cGMP途径的连接方面不同。例如，在海绵体中发现了III型PDE(PDE3)、IV型PDE(PDE4)和V型PDE(PDE5)，PDE5的量最大。
“磷酸二酯酶抑制剂”是一种能够选择性地或非选择性地抑制或降低PDE活性的试剂。用于本发明的适宜的PDE抑制剂包括在美国专利号5,250,534、5,859,006、6,140,329、6,362,178、6,403,597、6,469,012、6,821,975、6,943,166和6,943,171中公开的那些抑制剂，将其全部公开的内容引入本文作为参考。制备PDE抑制剂的方法是已知的。参见，例如，美国专利号5,250,534、5,859,006、6,140,329、6,362,178、6,403,597、6,469,012、6,821,975、6,943,166和6,943,171。用于本发明的PDE抑制剂优选地为PDE3、PDE4和/或PDE5的抑制剂。更优选地，且所述PDE抑制剂为PDE5的选择性抑制剂。更优选地，所述抑制剂为西地那非(sildenafil)、伐地那非(vardenafil)和/或泰地那非(tadalafil)，和它们药学可接受的形式(例如盐、溶剂合物、立体异构体(单个异构体和异构体的混合物)等)。最优选地，所述抑制剂为西地那非柠檬酸盐(例如，西地那非柠檬酸盐；Pfizer)，伐地那非盐酸盐(例如，
伐地那非HCl；Schering-Plough)和/或泰地那非(例如，
LillyICOS)。
为了治疗并存早泄和勃起功能障碍，在性活动之前的有效时间，向男性给药有效量的曲马多物质和有效量的磷酸二酯酶抑制剂。所述两种药物可以同时或者以任何顺序依次给药。它们可以按照相同的或不同的给药方式分别给药，或者它们可以按照单一给药途径在单一剂型中组合给药。优选的是在性活动之前口服单剂量的每种药物。“有效量”指无毒、但足以延缓射精和降低勃起功能障碍的发生率或严重性的两种药物中每种的用量。“有效时间”是指在性活动之前必须给药两种药物的每种以便有效地延缓射精和降低勃起功能障碍的发生率的时间范围。(±)顺式盐酸曲马多的有效量为约1mg至约250mg，优选约10mg至约200mg，更优选约25mg至约150mg，性活动前约30分钟至约24小时口服给药。
西地那非柠檬酸盐的有效量为约5mg至约500mg，优选约25mg至约100mg，在性活动之前约30分钟至约4小时口服给药。伐地那非盐酸盐的有效量为约1mg至约100mg，优选约5mg至约20mg，在性活动之前约30分钟至约2小时口服给药。
泰地那非的有效量为约1mg至约100mg，优选约5mg至约20mg，在性活动之前30分钟至约36小时口服给药。然而，本领域技术人员应当理解剂量将随如下因素而改变：施用的曲马多的具体形式和施用的具体磷酸二酯酶抑制剂、给药途径、给药时间、正在给药的任何其他药物的性质、早泄和勃起功能障碍病症的严重性、患者的年龄、大小和病症，以及医学领域已知的类似因素。一般而言，适宜的剂量是会有效地延缓射精和降低勃起功能障碍的发生率或严重性而没有毒性的最低剂量的化合物的用量。然而，该剂量、给药途径等将由主治医师在合理的医学判断范围内确定。有效剂型、给药方式和时间，和剂量可以凭经验确定。
在此使用的“延缓射精”是指正在接受治疗的男性能够控制射精过程，以便在一定时间内防止射精，而该时间长于未接受治疗的男性一般经历的时间。预期男性能够将射精过程控制到足以使其配偶比较满意或非常满意的程度。“延缓射精”并不是指完全防止射精。
在此使用的“降低勃起功能障碍的发生率”是指预防勃起功能障碍或减少勃起功能障碍的发生次数。在此使用的“降低勃起功能障碍的严重性”是指降低了按照由EF和/或SHIM得分测量的勃起功能障碍的严重性(即，EF或SHIM得分增加)。
曲马多物质和磷酸二酯酶抑制剂可以通过任一适宜的给药途径给药，包括口服、鼻部、直肠、肠胃外(例如静脉内、皮下或肌内)、局部(即递送至皮肤或粘膜)、透皮(即使药物穿过皮肤递送至血流)、经粘膜(即使药物穿过粘膜组织递送至血流)、海绵窦内(即注射入阴茎的海绵体之一或两体)和尿道内(即递送至尿道)给药。高度优选口服给药。
尽管能够单独给药曲马多物质和磷酸二酯酶抑制剂，但是优选地将其以药物制剂(组合物)给药(分别或以组合)。该药物组合物包括作为活性成分的曲马多物质、磷酸二酯酶抑制剂，或两者，混有一种或多种药学可接受的载体，以及任选地与一种或多种其它化合物、药物，或其它物质。每种载体必须是与该制剂中其它成分相容并且对将服用该组合物的男性而言是无害的意义上“可接受的”。药学可接受的载体是本领域众所周知的。不用考虑所选择的给药途径，通过本领域技术人员已知的常规方法将活性成分配制成药学可接受的剂型。参见，例如Remington’s Pharmaceutical Sciences。
包含曲马多物质的药物组合物和制备该药物组合物的方法已经公开。参见，例如美国专利号3,652,589、3,830,934、5,223,541、5,591,452、5,601,842、5,728,885、6,017,963、6,090,856和6,156,342，将其全部内容引入本文作为参考。而且，包含曲马多和其药学可接受的盐的药物组合物已在世界范围内制备并销售。在美国，用于口服给药的(±)顺式-2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)-环己醇盐酸盐可从Ortho-McNeil Pharmaceutical，Inc.，Raritan，New Jersey 08869以ULTRAM片剂获得。每个ULTRAM片剂包含50mg的(±)顺式-2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)-环己醇盐酸盐和大量的非活性成分(玉米淀粉、羟丙基甲基纤维素、乳糖、硬脂酸镁、微晶纤维素、聚乙二醇、聚山梨酯80、淀粉羟乙酸钠、二氧化钛和蜡)。应当理解以商品名销售的曲马多的市售制剂包括曲马多盐酸盐的R，R和S，S异构体的混合物。
包含磷酸二酯酶抑制剂的药物组合物和制备该药物组合物的方法也已被公开。参见，例如美国专利号5,250,534、5,859,006、6,140,329、6,362,178、6,403,597、6,469,012、6,821,975、6,943,166和6,943,171，将其全部内容引入本文作为参考。适宜的磷酸二酯酶抑制剂也是商业可获得的，例如来自Pfizer(
西地那非柠檬酸盐)、Schering-Plough(
伐地那非HCl)和Lilly ICOS(
秦地那非)。
适于口服给药的本发明的制剂可以是胶囊、囊片(cachets)、丸剂、片剂、粉剂、颗粒剂或在水性或非水性液体中的溶液或悬浮液，或水包油或油包水液体乳剂、或酏剂或糖浆剂、或锭剂(pastilles)(使用惰性基质，如明胶和甘油，或蔗糖和阿拉伯胶)等，它们各自包含预定量的活性成分。优选的口服给药形式是片剂和胶囊。
在用于口服给药的本发明的固体剂型(胶囊、片剂、丸剂、糖衣片(dragees)、粉剂、颗粒剂等)中，将活性成分与一种或多种药学可接受的载体混合，所述载体如柠檬酸钠或磷酸二钙，和/或任一种下述载体：(1)填充剂或增容剂，如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸；(2)粘合剂，如例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶；(3)保湿剂，如甘油；(4)崩解剂，如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、海藻酸、某些硅酸盐，和碳酸钠；(5)溶解阻滞剂(solution retardingagents)，如石蜡；(6)吸收促进剂，如季铵化合物；(7)润湿剂，如例如鲸蜡醇和甘油单硬脂酸酯；(8)吸附剂，如高岭土和膨润土；(9)润滑剂，如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠，及其混合物；和(10)着色剂。就胶囊、片剂和丸剂而言，所述药物组合物还可以包括缓冲剂。类似类型的固体组合物可用作使用如乳糖或乳糖以及高分子量聚乙二醇等这样的赋形剂的软填充的明胶胶囊和硬填充的明胶胶囊中的填充剂。
片剂可以通过任选地与一种或多种助剂压制或模压而制备。压制片可以使用粘合剂(例如明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如淀粉羟乙酸钠或交联羧甲基纤维素钠)、表面活性剂或分散剂而制备。模压片可在适宜的设备中将用惰性液体稀释剂润湿的粉末化合物的混合物模压而制备。
本发明的药物组合物的片剂及其它固体剂型，如糖衣片、胶囊、丸剂和颗粒剂可以任选地刻痕或使用包衣或壳，如肠溶衣和药物制剂领域众所周知的其它包衣制备。还可以将它们配制以提供活性成分的缓慢或控制释放，其中使用了例如不同比例的羟丙基甲基纤维素(以提供所需的释放分布)、其它聚合基质、脂质体和/或微球。它们可以例如通过截留细菌过滤器(bacteria-retaining filter)过滤来杀菌。这些组合物也可任选地包含遮光剂，且可以是它们仅仅或优先地在胃肠道的某些部位释放活性成分的组合物，任选地以延缓方式。这些组合物也可以是仅仅或优先地以某一顺序释放活性成分的组合物(例如，一种在另一种之前、一种立即释放和另一种随时间释放，两种都随时间释放但释放分布不同等)。可以使用的包埋组合物的实例包括聚合物和蜡。活性成分还可以是微囊化形式。
用于口服给药本发明的化合物的液体剂型包括药学可接受的乳剂、微乳剂、溶液、混悬剂、糖浆剂和酏剂。除了活性成分之外，所述液体剂型可以包含本领域常用的惰性稀释剂，如例如水或其它溶剂、增溶剂和乳化剂，如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1，3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油(germ)、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨醇的脂肪酸酯，及其混合物。
除了惰性稀释剂之外，所述口服组合物还可以包括助剂，如润湿剂、乳化剂和助悬剂、甜味剂、调味剂、着色剂、芳香剂、增稠剂和防腐剂。
除了活性成分之外，混悬剂可以包含助悬剂，如例如乙氧基异硬脂醇(ethoxylated isostearyl alcohols)、聚氧乙烯山梨醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝(aluminum metahydroxide)、膨胀土、琼脂和西黄蓍胶，及其混合物。
用于直肠给药的本发明的药物组合物的制剂可以以栓剂存在，其可以通过将活性成分与一种或多种适宜的无刺激性赋形剂或载体混合制备，所述赋形剂或载体包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯，且所述栓剂在室温下为固体，但在体温下为液体，因此其在直肠融化并释放活性成分。
用于局部、透皮或经粘膜给药活性成分的剂型包括粉剂、喷雾剂、软膏剂、糊剂、乳膏、洗剂、凝胶剂、溶液、贴剂、滴剂和吸入剂。将所述活性成分可在无菌条件下与药学可接受的载体，以及任一种缓冲液，或可能需要的推进剂混合。
所述软膏剂、糊剂、乳膏和凝胶剂除了包含活性成分之外，还可以包含赋形剂如动物和植物脂肪、油、蜡、石蜡、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇、硅氧烷、膨润土、硅酸、滑石和氧化锌，或其混合物。
粉剂和喷雾剂除了包含活性成分之外，还可以包含赋形剂如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末，或这些物质的混合物。喷雾剂可以另外包含常规推进剂比如氯氟烃类和挥发性未取代的烃，如丁烷和丙烷。
活性成分还可以使用常规透皮药物递送系统(即透皮贴剂)通过皮肤递送，其中活性成分典型地包含在充当固定在皮肤上的药物递送装置的层状结构内。在此类结构中，所述活性成分典型地包含在上部背层下面的层或“储库”内。所述层压装置可以包含单一储库，或者其可以包含多个储库。在一个实施方案中，所述储库包括在药物递送期间起固定系统至皮肤作用的药学可接受的接触粘合性物质的聚合物基质。适宜的皮肤接触粘合性物质的实例包括，但不限于，聚乙烯、聚硅氧烷、聚异丁烯、聚丙烯酸酯、聚氨酯等。替代性地，包含药物的储库和皮肤接触粘合剂作为独立的和分离的层存在，在这种情况下，储库下面的粘合剂可以是如上所述的聚合物基质，或者其可以是液体或水凝胶储库，或者可以采用其它形式。
在充当装置的上表面的这些层中的背层起到层状结构的主要结构元件的作用，并提供给所述装置许多弹性。应当对选择用于背层材料的材料进行选择以便其基本上不能透过活性成分和存在的任何其它物质。背层可以是封闭的或未封闭的，取决于皮肤是否需要在药物递送期间水化。背层优选地由柔性弹性材料片或薄膜制备。适于背层的聚合物的实例包括聚乙烯、聚丙烯、聚酯等。
在贮存期间和应用前，层状结构包括释放垫(liner)。在应用前立即将该层从装置上除去以暴露其基底面，药物储库或单独的接触粘合剂层，以便该系统可以固定到皮肤上。所述释放垫应当由药物/载体防渗材料制成。
可以使用本领域已知的常规技术制造透皮药物递送装置，例如通过将粘合剂、药物和载体的液体混合物浇铸在背层上，接着层压该释放垫。类似地，可以将粘合剂混合物浇铸在所述释放垫上，接着层压背层。替代性地，可以在不存在药物或赋形剂的情况下制备药物储库，然后通过“浸渍”在药物/载体混合物中载药。
所述层压透皮药物递送系统还可以包含皮肤渗透促进剂。即因为皮肤固有的对某些药物的渗透性可能太低而不能使治疗水平的药物通过合理大小的未破损皮肤区域，所以必须与此类药物共同给药皮肤渗透促进剂。适宜的促进剂是本领域众所周知的。
本发明的药物组合物也可以通过鼻腔气雾剂或吸入给药。此类组合物根据药物制剂领域中熟知的技术制备，且可以将其制备成在生理盐水中的溶液，使用苯甲醇或其它适宜的防腐剂、增加生物利用度的吸收促进剂、推进剂比如碳氟化合物或氮气和/或其它常规增溶剂或分散剂。
用于局部药物递送的优选的制剂为软膏剂和乳膏。软膏剂是典型地基于凡士林或其它石油衍生物的半固体制剂。包含选择的活性剂的乳膏为如本领域已知的水包油型或油包水型的粘性液体或半固体乳剂。乳膏基质是耐水洗的(water-washable)，且包含油相、乳化剂和水相。所述油相有时也称为“内”相，通常包含凡士林和脂肪醇如鲸蜡醇或硬脂醇；所述水相(尽管不是必须的)通常在体积上超过油相，且通常包含湿润剂。乳膏制剂中的乳化剂通常是非离子型、阴离子型、阳离子型或两性表面活性剂。正如本领域技术人员可以理解的，所用的具体软膏或乳膏剂基质应当是提供最佳药物递送的基质。作为使用的其它载体或赋形剂，软膏基质应当是惰性的、稳定的、无刺激性的和非致敏的。
用于口腔给药的制剂包括片剂、锭剂、凝胶剂等。替代性地，可以使用如本领域技术人员已知的经粘膜递送系统进行口腔给药。
适于肠胃外给药的药物组合物包括活性成分与一种或多种药学可接受的无菌等渗水性溶液或非水性溶液、分散液、悬浮液或乳液、或在使用之前可以重构成无菌可注射的溶液或分散液的无菌粉末或其它固体形式，其可以包含抗氧剂、缓冲剂、使所述制剂与指定接受者的血液等渗的溶质或助悬剂或增稠剂。
可以用于所述药物组合物的适宜的水性和非水性载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)，和其适宜的混合物、植物油如橄榄油，及可注射的有机酯如油酸乙酯。例如，适宜的流动性可以通过使用包衣材料如卵磷脂，在分散液的情况下通过保持期望的粒径和通过使用表面活性剂而保持。
这些组合物还可以包含助剂如润湿剂、乳化剂和分散剂。其还可需要在所述组合物中包括等渗剂，如糖、氯化钠等。另外，可以通过包含延缓吸收的试剂如单硬脂酸铝和明胶来延长可注射药物形式的吸收。
在某些情况下，为了延长活性成分的作用，需要减慢来自皮下或肌内注射的活性成分的吸收。这可通过使用具有低水溶性的结晶或无定形材料的液体悬浮液来完成。活性成分的吸收率则取决于其溶出速率，而溶出速率又取决于晶体大小和结晶形式。替代性地，通过将药物溶解或悬浮在油性载体中实现肠胃外给药活性成分的延缓吸收。
可注射的贮库(depot)形式通过在可生物降解的聚合物如聚交酯-聚乙醇酸交酯中形成活性成分的微胶囊基质制备。根据活性成分与聚合物的比例，和所用具体聚合物的性质，可以控制活性成分的释放速率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。可注射的贮库制剂还可通过使活性成分包裹入与身体组织相容的脂质体或微乳剂中制备。例如，所述可注射的物质可以通过截留细菌过滤器的过滤灭菌。
海绵体内注射可以通过使用注射器或任一其它适宜的装置进行。可用于同时注入海绵体的本文有用的皮下注射器的实例描述在美国专利号4,127,118中。通过将针置于各背侧静脉一侧并将其插入至海绵体来进行对阴茎背面的注射。
活性成分可以以适于经尿道药物递送的药物制剂给药。所述制剂包含一种或多种选择的载体或赋形剂，如水、硅氧烷、蜡、凡士林、聚乙二醇、丙二醇、脂质体、糖如甘露醇和乳糖，和/或多种其它物质，聚乙二醇及其衍生物特别优选。需要在尿道剂型中加入经尿道渗透促进剂(transurethralpermeation enhancer)。适宜的经尿道渗透促进剂的实例包括二甲亚砜、二甲基甲酰胺、N，N-二甲基乙酰胺、癸甲基亚砜、聚乙二醇单月桂酸酯、甘油单硬脂酸酯、卵磷脂、1-取代的氮杂环庚-2-酮类，特别是1-正-十二烷基环氮杂环庚-2-酮(可以以商标
从Nelson Research & Development Co.，Irvine，Calif获得)、
(可从Macrochem Co.，Lexington，Mass.获得)、醇类(例如，乙醇)、洗涤剂(如
Nonoxynol-
和TWEEN-
)等。经尿道的制剂可以另外包括一种或多种有效地抑制可能在尿道中存在的降解药物的酶的酶抑制剂。药物制剂和递送领域的技术人员会知道其它任选的组分包括赋形剂、防腐剂(例如抗氧剂)、螯合剂、增溶剂(例如表面活性剂)等。
经尿道药物给药(如在PCT申请WO 91/16021所述的)可以按照许多不同的方式利用多种尿道剂型来进行。例如，可以将药物从柔性管、塑料挤瓶、泵或喷雾剂引入尿道。药物也可以包含在于尿道吸收、熔化或生物侵蚀的包衣、丸剂或栓剂中。在某些实施方案中，药物包含在阴茎插入外表面的包衣内。用于经尿道给药的药物递送装置描述在美国专利号6,037,360和PCT申请WO 91/16021中。
包含聚乙二醇或聚乙二醇衍生物的尿道栓制剂可用作尿道剂型，且可以使用常规技术例如压模、加热成型等方便地配制，正如本领域技术人员所理解的以及在相关文献和药物教科书中所描述的那样。参见，例如，Remington：The Science and Practice of Pharmacy，第19版(Easton，PA：Mack PublishingCo.，1995)，其中公开了制备尿道栓剂形式的药物组合物的典型方法。还优选的是尿道栓剂包含一种或多种有效地增加活性成分在聚乙二醇或其它经尿道载体中的溶解性的增溶剂(例如，非离子型、阴离子型、阳离子型或两性表面活性剂)。
可能需要以提供控制释放或持续释放所述活性剂的尿道剂型递送活性成分。在这种情况下，所述剂型典型地包括生物相容的、可生物降解的物质，典型地是可生物降解的聚合物。此类聚合物的实例包括聚酯、聚氰基丙烯酸烷基酯、聚原酸酯、聚酐、白蛋白、明胶和淀粉。如例如在PCT申请WO96/40054中阐述的，这些和其它聚合物用于提供能够控制释放和持续释放药物、从而最小化所需给药频率的可生物降解的微粒。
尿道内给药的方法可以涉及“活性”递送机制，如离子电渗疗法、电穿孔或超声透入疗法。以此类方式递送药物的装置和方法是本领域众所周知的。离子电渗疗法辅助药物递送例如描述在PCT申请WO 96/40054中。简而言之，利用从外部电极至尿道探子内或固定在其上的第二电极的电流驱动所述活性剂穿过尿道壁。
所述药物制剂可存在于单剂量或多剂量密封容器(例如安瓿、小瓶和泡罩包装)中，并且可以保存在冷冻干燥的条件下，仅需要在使用前立即加入无菌液体载体，例如注射用水。即配注射溶液和混悬剂可以由如上所述类型的无菌粉末、颗粒剂和片剂制备。
本发明还提供试剂盒，其包括曲马多物质和磷酸二酯酶抑制剂。所述试剂盒可以包括一个或多个容器，每个包含曲马多物质和磷酸二酯酶抑制剂。在此情况下，曲马多物质和磷酸二酯酶抑制剂优选地包含在相同的药物组合物中。替代性地，所述试剂盒可以包括容纳曲马多物质的容器和容纳磷酸二酯酶抑制剂的不同容器。适宜的容器包括管、安瓿、小瓶、瓶子、箔包(foilpackets)、多孔盘和模压的泡罩包装。所述试剂盒也包括用于给药曲马多物质和磷酸二酯酶抑制剂来治疗并存早泄和勃起功能障碍的说明。所述容器优选地包含在包装如盒子中。所述说明可以附着或打印在容器之一上，可以打印在包装内单独的纸片上，或可以附着或打印在包装上。
应当注意“一个”或“一种”实体指一个或多个(一种或多种)那些实体。例如，“一个容器”指一个或多个容器。
实施例
实施例1
由泌尿科医师评价具有长久早泄和勃起功能障碍史的51岁异性恋男性，泌尿科医师确定其早泄为“严重的”(秒表证实的阴道内射精潜伏时程少于1分钟，早泄诊断工具(PEDT)得分为15)，并存病症“轻度至中度”勃起功能障碍(勃起功能的国际指数(IIEF)勃起功能(EF)得分为21)。
最初，用选择性的5-羟色胺重吸收抑制剂(SSRI)药物治疗受试者；然而，SSRI治疗在治疗早泄方面仅仅部分有效，且没有改善其勃起功能障碍。由于功效低和无法忍受的副作用，受试者停止了所有了SSRI药物。在性交前给药西地那非柠檬酸盐(
)50mg稍微改善了勃起功能障碍，但没有减轻严重的早泄，其继续引起受试者和其性配偶的显著的情感痛苦。
在本发明的发明人之一的秘密建议下，所述泌尿科医师接着开处方盐酸曲马多，说明在性交前约3小时自我给药曲马多100mg和西地那非柠檬酸盐50mg的组合。结果被描述为“不可思议的”，受试者仅仅抱怨过度延缓的射精(“远大于10分钟”)和偶尔的性快感缺失。这些过度延缓射精和性快感缺失的中度不良事件不是永久的，在减少盐酸曲马多的剂量至50mg之后就不再有报道。现在，受试者报道该组合“显著地良好地作用”，并且在性交前给药盐酸曲马多50mg和西地那非柠檬酸盐50mg成功地治疗了他的早泄和勃起功能障碍的并存病症。
Claims (19)
1.一种治疗人类男性中并存早泄和勃起功能障碍的方法，其包括在性活动之前的有效时间，向所述男性给药有效量的曲马多物质和有效量的磷酸二酯酶(PDE)抑制剂。
2.权利要求1的方法，其中所述曲马多物质是曲马多或其药学可接受的形式，且所述PDE抑制剂是PDE3、PDE4或PDE5抑制剂。
3.权利要求2的方法，其中所述PDE抑制剂是PDE5抑制剂。
4.权利要求3的方法，其中所述曲马多物质是(±)顺式-曲马多或其药学可接受的盐，且所述PDE5抑制剂是西地那非或其药学可接受的形式、伐地那非或其药学可接受的形式、泰地那非或其药学可接受的形式，或两种或多种前述PDE5抑制剂的组合。
5.权利要求4的方法，其中所述曲马多物质是(±)顺式-曲马多盐酸盐，且所述PDE5抑制剂是西地那非柠檬酸盐、伐地那非盐酸盐、泰地那非，或两种或多种前述PDE5抑制剂的组合。
6.权利要求5的方法，其中所述PDE5抑制剂是西地那非柠檬酸盐。
7.药物组合物，其包括药学可接受的载体、曲马多物质和磷酸二酯酶(PDE)抑制剂。
8.权利要求7的组合物，其中所述曲马多物质是曲马多或其药学可接受的形式，且所述PDE抑制剂是PDE3、PDE4或PDE5抑制剂。
9.权利要求8的组合物，其中所述PDE抑制剂是PDE5抑制剂。
10.权利要求9的组合物，其中所述曲马多物质是(±)顺式-曲马多或其药学可接受的盐，且所述PDE5抑制剂是西地那非或其药学可接受的形式、伐地那非或其药学可接受的形式、泰地那非或其药学可接受的形式，或两种或多种前述PDE5抑制剂的组合。
11.权利要求10的组合物，其中所述曲马多物质是(±)顺式-曲马多盐酸盐，且所述PDE5抑制剂是西地那非柠檬酸盐、伐地那非盐酸盐、泰地那非，或两种或多种前述PDE5抑制剂的组合。
12.权利要求11的组合物，其中所述PDE5抑制剂是西地那非柠檬酸盐。
13.试剂盒，其包括：
(a)容纳曲马多物质和磷酸二酯酶(PDE)抑制剂的容器；或
(b)容纳曲马多物质的第一容器和容纳磷酸二酯酶(PDE)抑制剂的第二容器。
14.权利要求13的试剂盒，其中所述曲马多物质是曲马多或其药学可接受的形式，且所述PDE抑制剂是PDE3、PDE4或PDE5抑制剂。
15.权利要求14的试剂盒，其中所述PDE抑制剂是PDE5抑制剂。
16.权利要求15的试剂盒，其中所述曲马多物质是(±)顺式-曲马多或其药学可接受的盐，且所述PDE5抑制剂是西地那非或其药学可接受的形式、伐地那非或其药学可接受的形式、泰地那非或其药学可接受的形式，或两种或多种前述PDE5抑制剂的组合。
17.权利要求16的试剂盒，其中所述曲马多物质是(±)顺式-曲马多盐酸盐，且所述PDE5抑制剂是西地那非柠檬酸盐、伐地那非盐酸盐、泰地那非，或两种或多种前述PDE5抑制剂的组合。
18.权利要求17的试剂盒，其中所述PDE5抑制剂是西地那非柠檬酸盐。
19.权利要求13的试剂盒，其进一步包括使用曲马多物质和PDE抑制剂以治疗男性中并存早泄和勃起功能障碍的说明。
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| JP5528705B2 (ja) * | 2005-12-13 | 2014-06-25 | トリニティ ラボラトリーズ インコーポレイテッド | ヒトにおける早漏を治療するための方法 |
| US20070185145A1 (en) * | 2006-02-03 | 2007-08-09 | Royds Robert B | Pharmaceutical composition containing a central opioid agonist, a central opioid antagonist, and a peripheral opioid antagonist, and method for making the same |
| SG174079A1 (en) * | 2007-02-12 | 2011-09-29 | Dmi Biosciences Inc | Treatment of comorbid premature ejaculation and erectile dysfunction |
| AU2008216363B2 (en) * | 2007-02-12 | 2014-05-08 | Aytu Bioscience, Inc. | Reducing side effects of tramadol |
| US20100120780A1 (en) * | 2007-04-19 | 2010-05-13 | Chandra Ulagaraj Singh | Treatments for premature ejaculation in humans |
-
2008
- 2008-02-12 SG SG2011058682A patent/SG174079A1/en unknown
- 2008-02-12 KR KR1020157017473A patent/KR20150089085A/ko not_active Application Discontinuation
- 2008-02-12 NZ NZ579169A patent/NZ579169A/en not_active IP Right Cessation
- 2008-02-12 DK DK08729644.8T patent/DK2120570T3/da active
- 2008-02-12 ES ES08729644T patent/ES2384481T3/es active Active
- 2008-02-12 WO PCT/US2008/053710 patent/WO2008100926A1/en active Application Filing
- 2008-02-12 EP EP12167624A patent/EP2486927A1/en not_active Withdrawn
- 2008-02-12 BR BRPI0807282-5A2A patent/BRPI0807282A2/pt not_active IP Right Cessation
- 2008-02-12 AU AU2008216356A patent/AU2008216356C1/en not_active Ceased
- 2008-02-12 KR KR1020147007397A patent/KR20140054312A/ko not_active Application Discontinuation
- 2008-02-12 MX MX2009008491A patent/MX2009008491A/es active IP Right Grant
- 2008-02-12 US US12/029,783 patent/US20080262094A1/en not_active Abandoned
- 2008-02-12 EP EP08729644A patent/EP2120570B1/en active Active
- 2008-02-12 KR KR1020097018878A patent/KR20090121315A/ko not_active Application Discontinuation
- 2008-02-12 CA CA2677690A patent/CA2677690C/en not_active Expired - Fee Related
- 2008-02-12 PL PL08729644T patent/PL2120570T3/pl unknown
- 2008-02-12 JP JP2009549684A patent/JP2010518167A/ja active Pending
- 2008-02-12 CN CN2008800118025A patent/CN101657101B/zh not_active Expired - Fee Related
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2009
- 2009-09-07 ZA ZA2009/06186A patent/ZA200906186B/en unknown
- 2009-12-15 HK HK09111745.6A patent/HK1132882A1/xx not_active IP Right Cessation
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2011
- 2011-09-28 US US13/247,387 patent/US20120018345A1/en not_active Abandoned
- 2011-09-28 US US13/247,347 patent/US20120022071A1/en not_active Abandoned
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2013
- 2013-12-20 JP JP2013264162A patent/JP2014077008A/ja active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103263435A (zh) * | 2013-05-17 | 2013-08-28 | 宋博 | 聚维酮碘的新用途 |
| CN103263435B (zh) * | 2013-05-17 | 2014-08-13 | 宋博 | 聚维酮碘的制药用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2120570A4 (en) | 2010-03-31 |
| KR20150089085A (ko) | 2015-08-04 |
| HK1132882A1 (en) | 2010-03-12 |
| WO2008100926A1 (en) | 2008-08-21 |
| JP2014077008A (ja) | 2014-05-01 |
| JP2010518167A (ja) | 2010-05-27 |
| EP2120570B1 (en) | 2012-05-16 |
| EP2486927A1 (en) | 2012-08-15 |
| KR20090121315A (ko) | 2009-11-25 |
| AU2008216356A1 (en) | 2008-08-21 |
| PL2120570T3 (pl) | 2012-10-31 |
| US20080262094A1 (en) | 2008-10-23 |
| AU2008216356C1 (en) | 2014-07-24 |
| SG174079A1 (en) | 2011-09-29 |
| KR20140054312A (ko) | 2014-05-08 |
| EP2120570A1 (en) | 2009-11-25 |
| NZ579169A (en) | 2012-05-25 |
| CA2677690A1 (en) | 2008-08-21 |
| ZA200906186B (en) | 2013-02-27 |
| CA2677690C (en) | 2012-05-15 |
| BRPI0807282A2 (pt) | 2014-04-29 |
| DK2120570T3 (da) | 2012-06-25 |
| MX2009008491A (es) | 2010-01-20 |
| CN101657101B (zh) | 2013-12-11 |
| US20120018345A1 (en) | 2012-01-26 |
| ES2384481T3 (es) | 2012-07-05 |
| US20120022071A1 (en) | 2012-01-26 |
| AU2008216356B2 (en) | 2014-04-03 |
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