CN1289071C - 曲马朵物质在制备用于延缓男性射精的药物中的用途 - Google Patents
曲马朵物质在制备用于延缓男性射精的药物中的用途 Download PDFInfo
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- CN1289071C CN1289071C CNB028099281A CN02809928A CN1289071C CN 1289071 C CN1289071 C CN 1289071C CN B028099281 A CNB028099281 A CN B028099281A CN 02809928 A CN02809928 A CN 02809928A CN 1289071 C CN1289071 C CN 1289071C
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
Abstract
本发明提供了延缓射精的方法。该方法包括在性交前对男性给药有效量的曲马朵物质。该方法特别用于治疗早泄。
Description
发明领域
本发明涉及延缓射精的方法。本发明特别涉及通过给药曲马朵物质延缓射精的方法。
发明背景
早泄是虚弱的性功能障碍。这种功能障碍可以导致不能插入或持续性交且可以对患者产生心理上的损害。早泄还可能损害成功生殖。
对早泄的治疗包括心理疗法、局麻药和应用装置。所有这些治疗方法均存在显著的缺陷。心理疗法仅有益于一少部分患者且需要不可能对所有患者均可得到的特定治疗学家。此外，心理疗法不可能缓解因非心理原因而导致的早泄。麻醉剂可以减少组织的敏感性，由此减少性交的快感。此外，局麻药可能被转入到性配偶体内且由此也会减少其敏感性和快感。就装置而言，它们可能较为笨拙、不易使用且使用时令人为难。装置极为显眼且显示出患病配偶最好将其隐藏的特定条件。另外，装置可以对一个或两配偶产生刺激。
已经描述了通过全身给药某些抗抑郁药化合物(包括氟西汀、舍曲林、帕罗西汀)治疗早泄的方法。参见美国专利US 4,507,323、US 4,940,731、US5,151,448和US 5,276,042和Rosen等的J.Clin.Psychopharmacol.，19，67-85(1999)。然而，这些抗抑郁药可能并非对所有患者有效且其副作用可以阻止治疗或影响患者的依从性。疾病情况或与其它药物的不良相互作用可以禁忌使用这些化合物或要求较低剂量，而这些低剂量可能对延缓射精发生无效。
美国专利US 6,037,360中描述了通过给药某些5-羟色胺兴奋剂和拮抗剂治疗早泄的方法。在该专利中将5-羟色胺兴奋剂定义为模拟5-羟色胺对其受体中的至少一种的作用的化合物并将5-羟色胺拮抗剂定义为阻断5-羟色胺对其受体中的至少一种的作用的化合物。优选5-羟色胺5HT3受体拮抗剂(例如奥丹司琼、麦角生物碱、格拉司琼、甲氧氯普胺、曲美苄胺、托烷司琼、多拉司琼、巴他必利和扎考必利(zacropride))和5-羟色胺5HT4兴奋剂(例如西沙必利和D-麦角酰二乙胺)。令人遗憾的是，这些化合物具有可以禁止其应用的副作用(例如麦角生物碱和D-麦角酰二乙胺)或具有有限的功效(例如甲氧氯普胺等；参见PCT申请WO 95/13072)。
因此，显然存在对其它治疗早泄方法的需求。特别存在对不需要特定心理疗法的、可以便利而没有困难地使用且不包括与现有治疗方法相关的难题的早泄治疗方法的需求。
曲马朵是起中枢作用的合成止痛化合物。其作用方式尚未得到完全了解。从动物试验中看出至少两种互补机制可以适用：(1)母体化合物(曲马朵)和O-脱甲基化的M1代谢物与u-阿片类受体结合；和(2)对去甲肾上腺素和5-羟色胺重吸收的抑制作用较弱。阿片类的活性是由于母体化合物的低亲和性结合和M1代谢物与u-阿片受体的高亲和性结合所导致的。在动物模型中，M1在产生止痛作用中的功效高于曲马朵6倍以上且在u-阿片类结合方面高于曲马朵200倍以上。已经证实因为曲马朵具有某些其它阿片类止痛作用而在体外抑制去甲肾上腺素和5-羟色胺重吸收。这些机制可以独立地产生曲马朵的总体止痛分布。
除止痛外，已经描述了曲马朵在治疗尿频和尿失禁(参见美国专利US6,090,856)和在治疗咳嗽、支气管炎和普通感冒(参见美国专利US 3,652,589和US 3,830,934)中的应用。现有技术中没有曲马朵可以用于延缓射精的教导或提示。
发明概述
本发明提供了延缓射精的方法。该方法包括对在性交前对男性给药有效量的曲马朵的步骤。
附图简述
附图1曲马朵的立体异构体。
本发明优选实施方案的详细描述
本文所用的术语″早泄″指的是一种性功能障碍，其中男性不能控制足以使配偶满意程度的射精过程。一般来说，早泄指的是在性交前或性交过程中使用最低程度的刺激就可持续或再发性射精。该术语既包括″先天″或″终生″早泄、也包括″原发性″或″获得性″早泄。具体的定义包括：(i)插入前射精或插入后摩擦10-20次内射精；(ii)少于1-2分钟内射精；和(iii)如果女性不存在性欲高潮障碍的情况，那么射精50％的时间快于女性能够达到性欲高潮的时间。例如参见：美国专利US 6,037,360和US 5,151,448；Male lnfertility andSexual Dysfunction，356页(Springer-Verlag 1997)；Diagnostic and StatisticalManual of Mental Disorders(American Psychiatric Association 1994)。然而，可用本发明的方法治疗定义的早泄。
本文所用的″延缓射精″指的是接受曲马朵物质的男性能够控制射精过程以便防止在一定时间内射精，该时间应长于未接受曲马朵物质时男性一般经历的时间。就患有早泄的男性而言，预计男性能够将射精过程控制到足以使其配偶较为满意或完全满意的程度。″延缓射精″并不意味着完全防止射精。
本文所用的术语″曲马朵物质″指的是2-[(二甲氨基)甲基]-1-(3-甲氧基苯基)-环己醇(″曲马朵″)和曲马朵的所有药物上可接受的形式和衍生物。该术语特别包括N-氧化物衍生物(″曲马朵N-氧化物″)和O-脱甲基衍生物(″O-去甲曲马朵″)。该术语还包括曲马朵及其衍生物的溶剂合物、多晶型物和药物上可接受的酸加成的盐。该术语进一步包括上述物质中任意一种的立体异构体，包括各个立体异构体(包括各个对映体)和立体异构体混合物(包括外消旋物)。
曲马朵的立体异构体如图1中所示。看起来存在有关曲马朵各个立体异构体的命名法的文献中存在一定差异。就本申请而言，根据曲马朵分子内环己烷环上的二甲氨基和羟基的相对位置对曲马朵的″顺式″和″反式″立体异构体进行命名。正如图1中所示，R，R和S，S对映体在本文中称作″顺式″异构体，而R，S和S，R异构体在本文中称作″反式″异构体。另外正如图1中所示，曲马朵的R，R异构体在本文中称作″+″顺式异构体，而S，S异构体称作″-″顺式异构体。目前可以理解R，S和S，R异构体不是旋光的。
目前优选曲马朵及其酸加成盐、特别是盐酸盐。甚至更优选(±)顺式-曲马朵、其酸加成盐、特别是盐酸盐和各个对映体。
曲马朵、曲马朵N-氧化物和O-去甲曲马朵的制备方法是众所周知的。例如参见：美国专利US 3,652,589、US 3,830,934、US 5,223,541、US 5,336,691、US 5,723,668、US 5,728,885和US 5,874,620，将这些公开文献的全部内容引入本文作为参考。曲马朵还可以商购自Gruenenthal GmbH，Aschen，Germany。
通过本领域中众所周知的常规方法，使用药物上可接受的基本上无毒的有机酸和无机酸制备药物上可接受的酸加成盐。这类酸包括盐酸、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、苯二甲酸、烟酸等。优选盐酸且盐酸曲马朵是最优选的实施本发明的化合物。
为了延缓射精，在性交前对男性给药有效量的曲马朵物质。所谓″有效量″指的是无毒性、但足以延缓射精的曲马朵物质用量。有效剂型、给药方式和给药时间以及剂量可以根据经验决定且进行这类确定属于本领域技术人员的范畴。优选在性交前不久口服单剂量。特别地，已经发现用于延缓射精的(±)顺式-2-[(二甲氨基)甲基]-1-(3-甲氧基苯基)-环己醇盐酸盐的有效剂量为约10-约50毫克(mg)，优选约15-约35mg，最优选约25mg，在性交前约30-约60分钟经口服给药。然而，本领域技术人员应理解剂量可以随所用曲马朵的特定形式、给药途径、给药时间选择、所给药的任何其它药物的一致性、男性是否患有早泄和早泄情况的严重程度、患者年龄、大小和情况等医学领域中公知的因素的不同而改变。一般来说，适宜的剂量是有效延缓射精而没有毒性的最低剂量的化合物用量。然而，剂量、给药途径等可以由护理的临床医师在声医学判断范围内决定。
可以通过任意合适的给药途径给药曲马朵物质，包括经口服、鼻部、直肠、非肠道(例如静脉内、皮下或肌内)、局部(即转运至皮肤或粘膜)、经皮(即使药物经皮肤转运入血流)、跨粘膜(即使药物经粘膜组织转运入血流)、海绵窦内(即注入阴茎海绵体之一或两体)和尿道内(即转运入尿道)。高度优选口服给药。
尽管能够单独给药曲马朵物质，但是优选将其以药物制剂(组合物)形式给药。该药物组合物包括曲马朵物质作为活性组分并混有一种或多种药物上可接受的载体和任选的一种或多种其它化合物、药物或其它物质。每种载体必须是在与该制剂中其它组分相容且对服用该组合物的男性而言是无害的意义上″可接受的″。药物上可接受的载体在本领域中是众所周知的。通过本领域技术人员所公知的常规方法将所述的活性组分配制成药物上可接受的剂型而与选择的给药途径无关。例如参见：Remington′s PharmaceuticalSciences。
适合于口服给药的本发明制剂可以是胶囊、扁囊剂、丸剂、片剂、粉剂、颗粒剂形式或为含水或非水液体溶液或混悬液或水包油或油包水液体乳剂或酏剂或糖浆剂或为锭剂(使用惰性基质，诸如明胶和甘油或蔗糖和阿拉伯胶)等，它们各自含有预定量的活性组分。优选的口服给药剂型是片剂和胶囊。
在用于口服给药的本发明固体剂型(胶囊、片剂、丸剂、锭剂、粉剂、颗粒剂等)中，将活性组分与一种或多种药物上可接受的载体、诸如柠檬酸钠或磷酸二钠和/或下列物质中的任意一种混合：(1)填充剂或补充剂，诸如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和/或硅酸；(2)粘合剂，诸如：例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶；(3)湿润剂，诸如甘油；(4)崩解剂，诸如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些硅酸盐和碳酸钠；(5)溶解阻滞剂，诸如石蜡；(6)吸收促进剂，诸如季铵化合物；(7)润湿剂，例如鲸蜡醇和甘油单硬脂酸酯；(8)吸附剂，诸如白陶土和硼润土粘土；(9)润滑剂，诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠及其混合物；和(10)着色剂。就胶囊、片剂和丸剂而言，所述的药物组合物还可以包括缓冲剂。相似类型的固体组合物可用作使用诸如乳糖以及高分子量聚乙二醇等这样的赋形剂的软胶囊和硬胶囊中的填充剂。
可以通过任选与一种或多种辅助组分压制或模压制备片剂。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(例如羟基乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂制备压制片剂。可以通过在合适的机器上模压用惰性液体稀释剂湿润的粉状化合物混合物来制备模压片。
可以任选地给本发明药物组合物的片剂和其它固体剂型，诸如锭剂、胶囊、丸剂和颗粒剂刻痕或使用制药领域中众所周知的诸如肠溶包衣材料和其它包衣材料这样的包衣材料和壳体包衣。还可以将它们配制成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释放分布的活性组分的缓释或控释、其它聚合物基体、脂质体和/或微球的制剂。例如还可以通过截留细菌的滤膜过滤给它们灭菌。这些组合物还可以任选含有遮光剂且可以是它们仅仅或优选以延缓方式任选在胃肠道中的某些部位上释放活性组分的组合物。可以使用的包埋物质(compositions)的实例包括聚合物和蜡。活性组分还可以是微囊形式。
用于本发明化合物口服给药的液体剂型包括药物上可接受的乳剂、微乳剂、溶液、混悬液、糖浆剂和酏剂。除活性组分外，所述的液体剂型还可以含有本领域中常用的稀释剂，例如水或其它溶剂、加溶剂和乳化剂，诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1，3-丁二醇、油(特别是棉子油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和失水山梨醇脂肪酸酯及其混合物。
除惰性稀释剂外，所述的口服组合物还可以包括佐剂，诸如湿润剂、乳化剂和悬浮剂、增甜剂、调味剂、着色剂、香料、增稠剂和防腐剂。
混悬液除含有活性组分外还可以含有悬浮剂，例如乙氧基化异十八烷醇类、聚氧乙烯山梨糖醇和山梨糖醇酯类、微晶纤维素、偏氢氧化铝(aluminummetahydroxide)、硼润土、琼脂和黄蓍胶及其混合物。
可以将用于直肠给药的本发明药物组合物制剂制成栓剂，可以通过将本发明的一种或多种化合物与一种或多种适宜的非刺激性赋形剂或载体混合来制备所述的栓剂，所述的赋形剂或载体例如包括可可脂、聚乙二醇、栓剂蜡或水杨酸盐，且所述的栓剂在室温下是固体、而在体温下是液体且由此在直肠中熔化而释放所述的活性组分。
用于活性组分局部、经皮或跨粘膜给药的剂型包括粉剂、喷雾剂、软膏、糊剂、霜剂、洗剂、凝胶、溶液、贴剂、滴剂和吸入剂。可以在无菌条件下将活性组分与药物上可接受的载体和与任意缓冲剂或可能需要的抛射剂混合。
软膏、糊剂、霜剂和凝胶除含有活性组分外还可以含有赋形剂，诸如动物脂肪和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅氧烷、硼润土、硅酸、滑石和氧化锌或其混合物。
粉剂和喷雾剂除含有活性组分外还可以含有赋形剂，诸如乳糖、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。喷雾剂可以另外含有常用抛射剂，诸如氯氟烃类和挥发性未取代的烃类，诸如丁烷和丙烷。
还可以使用通用的经皮药物转运系统，即经皮贴剂，通过皮肤转运所述的活性组分，其中在用作固定在皮肤上的药物转运装置的层状结构内一般含有所述的活性剂。在这类结构中，活性组分一般包含在上部的裱背层下的层或″储蓄器″内。层状装置可以含有单一储蓄器或可以含有多个储蓄器。在一种实施方案中，所述的储蓄器包括用于在药物转运过程中使所述系统与皮肤固定的药物上可接受的接触粘合剂物质的聚合物基质。合适的皮肤接触粘合剂物质的实例包但不限于聚乙烯类、聚硅氧烷类、聚异丁烯类、聚丙烯酸酯类、聚氨基甲酸酯类等。另一方面，含药物的储蓄器和皮肤接触粘合剂作为独立和不同的层存在，在这种情况中，储蓄器下的粘合剂可以是如上所述的聚合物基质或可以是液体或水凝胶储蓄器或可以采用其它形式。
在用作所述装置上表面的这些层中的裱背层起层状结构的主要结构部分的作用并给所述装置提供许多柔韧性。应对为裱背材料选择的材料进行选择以使它基本上不能透过活性组分和存在的任意其它物质。裱背层可以是封闭的或不封闭的，这取决于是否需要皮肤在药物转运过程中水化。裱背层优选由柔性弹性材料片或薄膜制成。适合于裱背层的聚合物实例包括聚乙烯、聚丙烯、聚酯类等。
在储存过程中和应用前，层状结构包括释放垫。应用前立即将该层从装置中取下以暴露其基底表面、药物储蓄器或分离的接触粘合剂层，使得该系统可以固定在皮肤上。所述的释放垫应由不透过药物/载体材料制成。
可以使用本领域中公知的常规技术，例如通过使粘合剂、药物和载体的液体混合物在裱背层上成型、随后层压释放垫而制成经皮药物转运装置。类似地，可以使粘合剂混合物在释放垫上成型，随后层亚裱背层。另一方面，可以在没有药物或赋形剂存在的情况下制备药物储蓄器且然后通过在药物/载体混合物中″浸渍″加载药物储蓄器。
层状经皮药物转运系统还可以含有皮肤渗透促进剂。即因为皮肤固有的对某些药物的透性可能过低而不能使治疗水平的药物通过适当大小的未破损皮肤面积，所以必需与这类药物共同给药皮肤渗透促进剂。合适的促进剂在本领域中是众所周知的。
还可以通过鼻部气溶胶或吸入剂给药本发明的药物组合物。按照药物制剂领域中众所周知的技术制备这类组合物，和可以使用苄醇或其它适宜防腐剂、提高生物利用度的吸收促进剂、诸如碳氟化合物或氮的抛射剂和/或其它常用加溶剂或分散剂制备这类组合物的盐水溶液。
用于局部药物转运的优选制剂是软膏和霜剂。软膏是一般基于凡士林或其它凡士林衍生物的半固体制剂。含有选择的活性剂的霜剂是如本领域中公知的粘性液体或半固体乳剂，它可以是水包油型也可以是油包水型。霜剂基质是耐水洗的且含有油相、乳化剂和水相。有时也称作″内″相的油相一般由凡士林和诸如鲸蜡醇或十八烷醇这样的脂肪醇组成；尽管并非必要，水相通常在体积上超过油相且一般含有润湿剂。霜剂中的乳化剂一般是非离子型、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，所用的具体软膏或霜剂基质是提供最佳药物转运的基质。作为使用的其它载体或赋形剂，软膏基质应是惰性的、稳定的、无刺激性且无敏感性。
用于口含给药的制剂包括片剂、糖锭、凝胶等。另一方面，可以使用本领域技术人员所公知的跨粘膜转运系统进行口含给药。
适合于非肠道给药的药物组合物包括活性组分与一种或多种药物上可接受的无菌等渗水溶液或非水溶液、分散液、混悬液或乳浊液或可以在使用前再溶解成无菌可注射溶液或分散液的无菌粉末或其它固体形式，它们可以含有抗氧化剂、缓冲剂、使所述制剂与指定接受者血液等渗的溶质或悬浮剂或增稠剂。
可以用于所述药物组合物的适宜含水和非水载体的实例包括水、乙醇、多元醇类(诸如甘油、丙二醇、聚乙二醇等)及其适宜混合物、诸如橄榄油这样的植物油和诸如油酸乙酯这样的可注射有机酯类。例如可以通过使用诸如卵磷脂这样的表面包衣材料、就分散液而言通过维持所需颗粒大小且通过使用表面活性剂来维持合适的流动性。
这些组合物还可以含有佐剂，诸如湿润剂、乳化剂和分散剂。另外需要在组合物中包括等渗剂，诸如糖、氯化钠等。此外，可以通过包含诸如一硬脂酸铝和明胶这样的延缓吸收的试剂使可注射药物剂型延长吸收。
在某些情况中，为了延长活性组分的作用，需要延缓来自皮下或肌内注射剂的活性组分吸收。这一目的通过使用具有低水溶性的结晶或无定形物质的液体混悬液来完成。活性组分的吸收率取决于其溶出率且依次取决于晶粒大小和晶形。另一方面，通过将药物溶解或悬浮在油载体中实现非肠道给药的活性组分的延缓吸收。
通过在诸如聚交酯-聚乙醇酸交酯这样可生物降解的聚合物中形成活性组分的微囊基体来制备可注射的缓释型制剂。根据活性组分与聚合物的比例和所用特定聚合物的性质的不同，可以控制活性组分的释放率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酐)。还通过使活性组分进入与身体组织相容的脂质体或微乳剂来制备缓释可注射制剂。例如，可以经阻止细菌的滤膜过滤给可注射物质灭菌。
可以通过使用注射器或任意其它适宜装置进行海绵体内注射。可以用于同时注入海绵体的本文所用的皮下注射器的实例描述在美国专利US4,127,118中。通过将针头置于各背侧静脉一侧并插入海绵体来进行对阴茎背面的注射。
可以以适合于经尿道药物转运的药物制剂的形式给药活性组分。该制剂含有一种或多种选择的载体或赋形剂，诸如水、硅氧烷、蜡、矿脂、聚乙二醇、丙二醇、脂质体、诸如甘露糖醇和乳糖这样的糖和/或各种其它物质，其中特别优选聚乙二醇及其衍生物。需要在尿道剂型中混入经尿道渗透促进剂。合适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、癸基甲基亚砜、聚乙二醇单月桂酸酯、甘油单月桂酸酯、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(商购自Nelson Research&Development Co.，Irvine，Calif.，商品名为Zone)、SEPA(商购自Macrochem Co.，Lexington，Mass.)、醇类(例如乙醇)、洗涤剂(诸如Tergitol、Nonoxynol-9和TWEEN-80)等。经尿道制剂可以另外包括一种或多种有效抑制可能在尿道中存在的降解药物的酶的酶抑制剂。正如药物制剂与转运领域技术人员可以理解的，其它任选的成分包括赋形剂、防腐剂(例如抗氧化剂)、螯合剂、加溶剂(例如表面活性剂)等。
可以按照许多不同方式、使用各种尿道剂型进行如PCT申请WO91/16021中解释的经尿道药物给药。例如，可以将药物从柔性管、压榨瓶、泵或气溶胶喷雾剂中导入尿道。药物还可以包含在在尿道中吸收、熔化或生物侵蚀的包衣层、丸粒或栓剂中。在某些实施方案中，药物包含在阴茎插入体外表面上的包衣层内。用于经尿道给药的药物转运装置描述在美国专利US 6,037,360和PCT申请WO 91/16021中。
正如本领域技术人员可以理解和如相关文献和药物教科书中所述的，可以将含有聚乙二醇或聚乙二醇衍生物的尿道栓剂用作尿道剂型且可以使用例如模压、加热成型等这样的常规技术便利地配制尿道栓剂。例如：参见Remington：The Science and Practiceof Pharmacy，第19版(Easton，PA：MackPublishing Co.，1995)，该文献中公开了尿道栓剂形式的药物组合物的典型制备方法。还优选尿道栓剂含有一种或多种有效增加活性组分在聚乙二醇或其它经尿道载体中的溶解度的加溶剂(例如非离子型、阴离子型、阳离子型或两性表面活性剂)。
需要将活性组分转运入提供控释或缓释所述活性剂的尿道剂型中。在这类情况中，所述的剂型一般包括生物相容的、可生物降解的物质，一般是可生物降解的聚合物。这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、清蛋白、明胶和淀粉。例如，正如PCT申请WO 96/40054中解释的，可以将这些和其它聚合物用于形成可生物降解的能够控制和延缓药物释放微粒，由此将所需的给药频率减少到最低限度。
尿道内的给药方法可以涉及″活性成分″转运机制，诸如离子电渗疗法、电穿孔或超声药物透入疗法。按照这种方式转运药物的装置和方法在本领域中是众所周知的。离子电渗疗法辅助的药物转运例如描述在PCT申请WO96/40054中。简单地说，借助于从外电极到尿道探子内包含或与尿道探条固定的第二个电极的电流通过尿道壁驱动所述的活性剂。
曲马朵物质的药物制剂可以存在于单位剂量或多剂量密封容器中，例如安瓿和小瓶中，且可以将它们保存在仅需要在应用前立即添加无菌液体载体、例如注射用水的冻干条件下。可以由上述类型的无菌粉剂、颗粒剂和片剂制备临时用注射溶液和混悬液。
已经描述了含有曲马朵物质的药物组合物和该药物组合物的制备方法。例如，参见美国专利US 3,652,589、US 3,830,934、US 5,223,541、US 5,591,452、US 5,601,842、US 5,728,885、US 6,017,963、US 6,090,856和US 6,156,342，将这些文献的全部公开内容引入本文作为参考。此外，生产含有曲马朵及其药物上可接受的盐的药物组合物并广泛销售它们。在美国，用于口服给药的(±)顺式-2-[(二甲氨基)甲基]-1-(3-甲氧基苯基)-环己醇盐酸盐以ULTRAM片剂形式商购自Ortho-McNeil Pharmaceutical，Inc.，Raritan，New Jersey 08869。每片ULTRAM含有50mg(±)顺式-2-[(二甲氨基)甲基]-1-(3-甲氧基苯基)-环己醇盐酸盐和许多非活性组分(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、聚山梨醇酯80、羟基乙酸淀粉钠、二氧化钛和蜡)。应理解在商品名ULTRAM下销售的曲马朵商品制剂由盐酸曲马朵的R，R和S，S异构体混合物组成。
实施例
实施例1：盐酸曲马朵延缓射精
男性配偶在性交前约30-60分钟服用剂量为10mg和10mg以上的曲马朵物质明显延缓了射精。例如，观察到一般男性受试者在性交前30-60分钟口服剂量为25mg的盐酸曲马朵(50mg ULTRAM片的一半，Ortho-McNeilPharmaceutical，Inc.，Raritan，New Jersey)将射精延缓了至少10-15分钟。在50-100mg剂量下观察到了类似的作用。然而，发生瞌睡、头晕、口干和轻度兴奋感(阿片类作用)，而在100mg剂量下，有时没有出现射精/性欲高超。从这些观察结果中可以推断剂量为10-50mg的曲马朵物质、优选15-35mg、最优选25mg可以明显延缓射精且可以用于治疗(预防或减轻)早泄。
Claims (12)
1.曲马朵物质在制备用于延缓男性射精的药物中的用途。
2.权利要求1所述的用途，其中所述的曲马朵物质是曲马朵或其药物上可接受的盐。
3.权利要求2所述的用途，其中所述的曲马朵物质是(±)顺式-曲马朵或其药物上可接受的盐。
4.权利要求3所述的用途，其中曲马朵物质是顺式-曲马朵的(+)-对映体或其药物上可接受的盐。
5.权利要求3所述的用途，其中曲马朵物质是顺式-曲马朵的(-)-对映体或其药物上可接受的盐。
6.权利要求3所述的用途，其中所述的曲马朵物质是(±)顺式-曲马朵盐酸盐。
7.权利要求1-5中任意一项所述的用途，其中所述药物是适于口服给药的。
8.权利要求6所述的用途，其中所述药物是适于口服给药的。
9.权利要求1-5中任意一项所述的用途，其中所述的男性患有早泄。
10.权利要求6所述的用途，其中所述的男性患有早泄。
11.权利要求7所述的用途，其中所述的男性患有早泄。
12.权利要求8所述的用途，其中所述的男性患有早泄。
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-
2002
- 2002-03-15 ES ES02721427T patent/ES2265495T3/es not_active Expired - Lifetime
- 2002-03-15 DE DE60211689T patent/DE60211689T2/de not_active Expired - Lifetime
- 2002-03-15 PT PT02721427T patent/PT1397126E/pt unknown
- 2002-03-15 JP JP2002572952A patent/JP4377585B2/ja not_active Expired - Fee Related
- 2002-03-15 CA CA2758923A patent/CA2758923A1/en not_active Abandoned
- 2002-03-15 WO PCT/US2002/007928 patent/WO2002074241A2/en active IP Right Grant
- 2002-03-15 AT AT02721427T patent/ATE326957T1/de active
- 2002-03-15 CN CNB028099281A patent/CN1289071C/zh not_active Expired - Fee Related
- 2002-03-15 NZ NZ528935A patent/NZ528935A/en not_active IP Right Cessation
- 2002-03-15 EP EP02721427A patent/EP1397126B9/en not_active Expired - Lifetime
- 2002-03-15 US US10/098,826 patent/US6974839B2/en not_active Expired - Fee Related
- 2002-03-15 KR KR1020037012090A patent/KR100908350B1/ko not_active IP Right Cessation
- 2002-03-15 MX MXPA03008372A patent/MXPA03008372A/es active IP Right Grant
- 2002-03-15 CA CA2440920A patent/CA2440920C/en not_active Expired - Fee Related
- 2002-03-15 AU AU2002252361A patent/AU2002252361C1/en not_active Ceased
- 2002-03-15 DK DK02721427T patent/DK1397126T5/da active
-
2003
- 2003-10-16 ZA ZA2003/08067A patent/ZA200308067B/en unknown
-
2005
- 2005-02-07 HK HK05101017A patent/HK1068549A1/xx not_active IP Right Cessation
- 2005-09-01 US US11/219,322 patent/US20060106113A1/en not_active Abandoned
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2006
- 2006-08-23 CY CY20061101166T patent/CY1107478T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA03008372A (es) | 2004-11-12 |
| DE60211689D1 (de) | 2006-06-29 |
| CA2440920C (en) | 2012-01-24 |
| KR100908350B1 (ko) | 2009-07-20 |
| CA2440920A1 (en) | 2002-09-26 |
| CY1107478T1 (el) | 2013-03-13 |
| JP2004532828A (ja) | 2004-10-28 |
| US20060106113A1 (en) | 2006-05-18 |
| DK1397126T5 (da) | 2007-05-21 |
| ES2265495T3 (es) | 2007-02-16 |
| NZ528935A (en) | 2004-10-29 |
| WO2002074241A3 (en) | 2003-12-24 |
| AU2002252361C1 (en) | 2006-03-30 |
| CA2758923A1 (en) | 2002-09-26 |
| KR20040052490A (ko) | 2004-06-23 |
| DE60211689T2 (de) | 2007-01-11 |
| EP1397126A2 (en) | 2004-03-17 |
| ZA200308067B (en) | 2005-03-30 |
| US6974839B2 (en) | 2005-12-13 |
| WO2002074241A2 (en) | 2002-09-26 |
| EP1397126A4 (en) | 2005-02-16 |
| EP1397126B1 (en) | 2006-05-24 |
| EP1397126B2 (en) | 2006-05-31 |
| JP4377585B2 (ja) | 2009-12-02 |
| DK1397126T3 (da) | 2006-10-02 |
| AU2002252361B2 (en) | 2005-09-08 |
| US20020132857A1 (en) | 2002-09-19 |
| EP1397126B9 (en) | 2007-02-21 |
| ATE326957T1 (de) | 2006-06-15 |
| HK1068549A1 (en) | 2005-04-29 |
| CN1520289A (zh) | 2004-08-11 |
| PT1397126E (pt) | 2006-10-31 |
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