CN103083325B - 治疗女性性功能障碍的包含他达拉非的药物剂型 - Google Patents
治疗女性性功能障碍的包含他达拉非的药物剂型 Download PDFInfo
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Abstract
本发明提供治疗女性性功能障碍的包含他达拉非的药物剂型。本发明涉及女性性功能障碍领域。特别是涉及睾丸酮或其类似物与他达拉非的组合物对患有女性性功能障碍(如女性性唤起障碍(FSAD)或女性性欲障碍(FSDD))的女性受试者的性健康的影响。本发明进一步涉及睾丸酮或其类似物与能够至少部分抑制平滑肌收缩的化合物(例如,一种能够至少部分抑制肾上腺素能紧张度的化合物)的组合物的影响。本发明还披露了在治疗女性性功能障碍中的其它组合疗法。
Description
本申请是申请日为2006年11月10目的题为“治疗女性性功能障碍的包含他达拉非的药物剂型”的中国专利申请No.200680049093.0的分案申请。
技术领域
本发明涉及女性性功能障碍领域。特别涉及睾丸酮或其类似物与他达拉非(tadalafil)的组合物对患有女性性功能障碍(如女性性唤起障碍(FSAD)或女性性欲障碍(FSDD))的女性患者的性健康的影响。本发明进一步涉及睾丸酮或其类似物与能够至少部分抑制平滑肌收缩的化合物(例如,一种能够至少部分抑制肾上腺素能紧张度((adrenergic tone)的化合物)的组合物的影响。本发明还披露了在女性性功能障碍治疗中的其它组合疗法。
背景技术
女性性功能障碍(FSD)指的是性功能的各种紊乱或缺陷,包括对性行为缺乏兴趣、在获得或保持性冲动上反复失败、在充分唤起(arousal)后不能获得性高潮。最近的研究估计,在美国,43%的女性受到性功能障碍的困扰1。性欲低(22%患病率)和性唤起问题(14%患病率)属于女性性功能障碍的最常见类型。这些类型便于为研究人员和临床医学家给出可行性定义以及可普遍采纳的专业词汇。然而,假定这些障碍彼此完全不同可能是不正确的。个案研究和流行病学研究都表明,这些障碍可以交迭(重叠,overlaop)并且可能是相互依赖的。在某些情况下,有可能辨别出引起其它障碍的原发性障碍,但是在许多情况下,这是不可能的。
在多项研究中已经示出,选择性5型磷酸二酯酶(PDE5)抑制剂改善了患有勃起障碍的男性的勃起功能,使平均起来接近于正常功能15。在阴茎中,由神经和内皮释放的一氧化氮(NO)诱导产生环磷酸鸟苷(cGMP)。cGMP是放松平滑肌的主要机制,是诱导勃起所必不可少的。这种核苷被磷酸二酯酶水解,由此,阴茎海绵体中的主要活性应归因于PDE5。因此,在性刺激过程中,NO/cGMP在勃起功能上的作用将通过PDE5-抑制剂被增强。两性的外生殖器具有共同的胚胎学起源。最近,已经发现阴蒂由勃起组织复合体(complex)构成,其包埋在阴道前壁中(O’connel等1998)。阴蒂勃起和阴道前壁与女性性唤起及性反应密切相关。近期已表明-昔多芬(sildenafil)-一种PDE5-抑制剂-改善了性功能障碍女性的性能力。此外,最近发现鼠阴蒂的平滑肌松弛和充血是由与阴茎勃起中相同的胞内和胞外机制引起的(Gragasin等,2004)。
尽管在男性和女性中,在生殖器反应中涉及相似的专门化脉管机制,但是阴道搏动振幅(VPA)的增大不能被认为等同于勃起。对勃起来说一个必要但不充分的条件是动脉扩张以及导致的增加的血流。在阴茎中,有海绵体(主体)(二个)以及包含小的不规则间隔(compartment)(脉管空间)的尿道海绵体(一个)。海绵体窦状壁中的平滑肌通常在活跃的交感(肾上腺素能)紧张度的控制下强力收缩。阴茎海绵体的平滑肌松弛引起充血和间隔扩大,其将伴随着勃起。尽管还不知道确切的机制,但是认为交感神经支配(交感神经分布,sympathetic innervation)以及副交感神经驱动(drive)的NANG(非胆碱能非肾上腺素能)神经支配(一氧化氮)都是阴茎海绵体平滑肌松弛中的主要介质。在阴茎中,血管的交感神经支配是稀疏的,尽管小梁平滑肌充分地被该系统支配。相反,阴茎的血管充分地被副交感神经系统支配,而该系统对小梁平滑肌的神经支配是稀疏的。因此,周围神经系统的这两部分对与勃起发生相关的过程具有相对独立的作用。阴茎动脉扩张的起始以及随后流向海绵状组织的血流的增加是由副交感神经系统调节的(这种胆碱能活性增加的起始取决于大脑的信号)。然而,没有平滑肌的松弛就不会勃起。交感紧张的降低以及随之发生的平滑肌松弛对于勃起的起始表现为相对独立的先决条件。因此,响应于骶副交感神经支配的活性增加以及交感神经通路的活性降低而发生阴茎勃起。在阴茎中,由NANG神经以及内皮释放的一氧化氮(NO),诱导产生环单磷酸鸟苷(cGMP)。cGMP是松弛平滑肌的主要机制,对诱导勃起是必不可少的。NO的产生和释放可受到交感神经支(sympatheticbranch)活性降低的影响,例如通过产生的副交感神经支的异型抑制(heterotropic inhibition)的降低,其通过相同的神经节后交感神经节介导。
为了治疗女性性障碍,具有或多或少效果的大量不同的疗法已经被提出并且应用。这些疗法不是没有完全成功就是由于副作用很难被接受。本发明提供了治疗性物质的多种新组合物,优选以特别适宜的给药方案给出,在这种方案中组合物是有效的且没有严重的副作用。
发明内容
因此,本发明提供了睾丸酮或其类似物与他达拉非的组合物在制备用于治疗女性性功能障碍的药物中的应用,其中所述睾丸酮或其类似物以及他达拉非基本上同时释放并且其中所述睾丸酮或其类似物是这样提供的,即在已给受试者的血液循环中存在睾丸酮或其类似物的峰值(最大值,peak)。根据本发明的这个部分,尽管不认为其受理论限制,但对中枢神经系统以及周围系统的作用还是需要的,其中到达中枢神经系统的信号由睾丸酮或其类似物(具有相同类型的活性)提供而周围信号则由他达拉非提供。根据本发明,游离睾丸酮的水平应该为游离睾丸酮血浆水平的峰值,至少约为0.010nmol/L,该峰值通常出现在睾丸酮给药后的1至20分钟之间。在该血浆睾丸酮峰值后约3.5至5.5小时,出现睾丸酮的有效峰(effect peak),也就是说,睾丸酮对于性功能障碍女性的生殖器唤醒的作用存在时滞。直到最近,认为他达拉非应该在几个小时后在睾丸酮已经在治疗FSD中至少部分有效后给药。然而,现在披露了睾丸酮或其类似物与他达拉非可以基本上同时释放(导致他达拉非的作用与睾丸酮的作用交迭)以及这就形成了对FSD的治疗。
术语“基本上同时”应该理解为是指优选地睾丸酮或其类似物与他达拉非互相之间在30分钟内在待治疗的受试者体内释放,优选25-30分钟,更优选20-25分钟,甚至更优选15-20或10-15分钟,并且最优选两种化合物互相之间在5至10分钟内在受试者体内释放。
取决于睾丸酮或其类似物的制剂并且取决于他达拉非的制剂,存在不同的可能性。例如,睾丸酮(或其类似物)以及他达拉非都配制为在给药后几个小时(例如两个小时)后释放活性化合物(即,迟释),以这种方式它们基本上同时释放,例如相互之间在30分钟内。如果以此方式配制睾丸酮(或其类似物)以及他达拉非,则必须在性行为之前至少3-4.5小时加上释放时间(在本实例中为2小时)使用该制剂。技术人员应该清楚,取决于性行为所使用/花费的时间量,该制剂给药的准确时机是有可能变化的。这些变化包含于本发明中。然而,还可以这样配制睾丸酮(或其类似物)以及他达拉非,使它们基本上都在给药后即基本上同时释放。在这种情况下,必须在性行为前大约3-4.5小时使用该制剂。而且,睾丸酮(或其类似物)以及他达拉非可以被分别配制(在这种情况下,制剂可同时使用或相继使用)或者化合物可配制在一种以及相同的制剂中,在这种情况下这些化合物被同时使用。技术人员应该清楚,可以在本发明的范围内对该剂型进行各种改变。在优选的实施方式中,同时给药或者使用睾丸酮(或其类似物)以及他达拉非,从而降低了忘记使用其中一种化合物(完全忘记或未按时使用)并因此增大了有效治疗变化的风险。然而,明确的是,如果待治疗的女性受试者在用药方面是非常准确的,睾丸酮(或其类似物)以及他达拉非也可以按时分开使用。在上述实施方式中,必须注意有效成分(即,他达拉非以及睾丸酮)释放是这样的,即它们基本上同时释放。
现在我们知道他达拉非的作用存在12-36小时,也可以首先释放他达拉非且随后释放睾丸酮。优选地,睾丸酮在他达拉非的作用开始减弱(即大约在12-24小时后)之前至少3-4.5小时释放。
因此,仍然在另一实施方式中,本发明提供了睾丸酮或其类似物与他达拉非的组合物在制备用于治疗FSD的药物中的应用,其中他达拉非在受试者中的释放或给药先于睾丸酮或其类似物,并且其中所述睾丸酮或其类似物可以被这样提供,即在已给药的受试者的血液循环中具有睾丸酮或其类似物的峰值。优选地,他达拉非先于睾丸酮或其类似物2-14小时,更优选4-12小时并且最优选6-10小时释放。这种方式对早晨的性行为是非常有利的。在希望进行性行为之前的夜晚,他达拉非以这种配方进行给药/使用,即在给药后即释放或在例如1小时内释放。睾丸酮可以被这样提供,即在6-10小时后释放。该释放被这样安排以使得在3-4.5小时后,患病(inquestion)女性被唤起并且作好性行为的准备。
睾丸酮优选以一种制剂给出,其中在已给药的受试者的血液循环中具有(持续时间短的)(高,也就是说正常睾丸酮血清水平增加10-100倍)睾丸酮的峰值。术语“持续时间短”是指睾丸酮血清水平的急剧增加,并且在给药后约1-20分钟得到睾丸酮血清水平的峰值。峰值血清水平迅速下降,并且在大约120分钟后睾丸酮血清水平恢复到睾丸酮给药前水平。因此,本发明提供一种应用,其中睾丸酮或其类似物以舌下制剂的形式提供,优选包含作为载体的环糊精的舌下制剂。适合的给药途径的其他实例为鼻黏膜(buco-mucosally)或鼻内,其也可以在环糊精制剂或其它常用赋形剂、稀释剂等的应用下实施。制剂的典型实例以羟丙基-β-环糊精给出,但是其他β-环糊精以及其他常用赋形剂、稀释剂等都在用于制备包含睾丸酮或其类似物的制剂(其基本上在一个短时突发内释放所有的睾丸酮)的技术领域范围内。所述突发通常是在给药后的短时间间隔内(例如60-120秒内,更优选60秒内),导致在1-20分钟后产生睾丸酮的血液峰值水平。在优选实施方式中,药物被设计为舌下给药,并且甚至更优选地所述组合物包括环糊精,如羟丙基-β-环糊精的。制备的睾丸酮样品的典型实例(用于睾丸酮0.5mg)包含0.5mg睾丸酮、5mg羟丙基-β-环糊精(载体)、5mg乙醇,以及5ml水,但是这些物质中的每一种的含量都可以更高或更低。
循环中的睾丸酮通常被SHBG(甾类激素结合球蛋白)以及白蛋白结合。重要的是,本发明中所定义的睾丸酮血浆水平峰值是以游离的睾丸酮存在并计算的,是不与白蛋白以及SHBG结合的部分。因此,给予的睾丸酮剂量应该足够高以饱和白蛋白以及SHBG(也就是说,睾丸酮的浓度必须足够高来克服SHBG或白蛋白造成的睾丸酮的全部结合),或者必须设计其它方法来避免与白蛋白或SHBG结合,例如SHBG上睾丸酮结合位点的竞争剂的使用。
对于本发明,给药途径的选择是那些最小侵入性(invasive)的(例如口服、鼻黏膜或者鼻内的)。性行为的动机不应受到侵入性给药途径的消极影响。
本发明还提供了多部件的试剂盒,包括至少一个含有睾丸酮或其类似物的药物组合物以及至少一个含有他达拉非的药物组合物,其中所述试剂盒进一步包括与所述组合物给药相关的说明,优选该试剂盒包括使得所述组合物基本上同时给药的说明,或者所述试剂盒包括使得他达拉非首先给药而睾丸酮随后给药的说明。
在优选实施方式中,所述包含睾丸酮的组合物被设计为在靶位上基本立即(例如在60秒内)释放全部睾丸酮。所述试剂盒优选包括在性行为前3.5-4.5小时使用含有睾丸酮的药物组合物以及含有他达拉非的药物组合物的说明。本领域技术人员可以明了,该多部件的试剂盒包括每种活性成分的有效量。多部件的试剂盒可以包括睾丸酮或其类似物的舌下制剂以及含有他达拉非的片剂或其他制剂。每份含有睾丸酮的药物组合物的睾丸酮的量为至少0.3mg睾丸酮以及至多2.5mg睾丸酮。取决于白蛋白以及SHBG的水平以及待治疗受试者的体重,更高或更低的剂量也可以是必不可少的。含有他达拉非的药物组合物包含至少5mg他达拉非以及至多20mg他达拉非。此剂量仍然可以随病人的体重而改变。由于上述理由,根据本发明的试剂盒可以进一步包含可与睾丸酮(或其类似物)竞争结合SHBG的化合物。
已知睾丸酮的化学名为17-β-羟基雄甾-4-烯-3-酮,其可以多种途径获得:可以从自然界分离和提纯或者用任何方式合成制备。术语“或其类似物”包括任何有用的睾丸酮代谢产物或前体,例如代谢产物二氢睾酮。如果使用睾丸酮的类似物,本文描述的时间范围应该进行一些改变,但本领域的技术人员在没有任何过度劳动下可以轻易地确定该改变。
他达拉非在化学上命名为吡嗪并[1′,2′:1,6]吡啶并[3,4-b]吲哚-1,4-二酮,6-(1,3-苯并二氧杂环戊烯-5-基)-2,3,6,7,12,12a-六氢化-2-甲基-(6R,12aR)-。除了活性成分,他达拉非,每一种片剂都含有下列成分:交联羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素、氧化铁、乳糖一水合物、硬脂酸镁、微晶纤维素、月桂基硫酸钠、滑石粉、二氧化钛以及三乙酸甘油酯。如上所述,该片剂这样服用或配制为例如缓释制剂。
为了进一步增强本发明的多部件的试剂盒的效果,所述试剂盒可以进一步包括用于认知干预和刺激的装置(工具,mean)。这种信息可以呈现在任何数据载体上(纸、CD、DVD),被动的或相互影响的,或者其可以是至少部分地被设计用于所述认知刺激的目的的一种网页的链接。有时优选下意识地也就是潜意识地呈现所述认知刺激信息。
为了进一步增强本发明的试剂盒的效果,可以向试剂盒中加入一种物质,其刺激受试者体内边缘叶的多巴胺能通路。这种通路涉及相对不同种类的奖赏系统,其帮助提供与性行为有关的奖赏寻找(rewardseeking)的增强。这种化合物的实例是,阿朴吗啡,一种多巴胺D2激动剂;阿立哌唑,一种部分多巴胺D2激动剂;培高利特,一种非选择性多巴胺(DA)激动剂;普拉克索,一种与D2和D4受体相比更优选D3受体的新多巴胺受体激动剂;溴隐亭,一种非选择性多巴胺(DA)激动剂;盐酸罗匹尼罗,一种非麦角林(结构)多巴胺激动剂,在体外有相对高的特异性并且对D2和D3多巴胺受体亚型具有完全的内在活性;其与D3结合比与D2或D4受体亚型结合具有更高的亲和性;罗克吲哚,一种有效的(自身受体)-“选择性”D3多巴胺激动剂;卡麦角林,一种多巴胺D2激动剂;利舒脲,一种非选择性多巴胺(DA)激动剂以及自身受体拮抗剂;(+)-AJ 76,一种D3-优选的多巴胺(DA)自身受体拮抗剂;(+)-UH232,一种多巴胺能性传递刺激物,其可以优先拮抗多巴胺神经末梢的自身受体,也就是再摄取阻断剂;安非他酮,一种去甲肾上腺素、血清素以及多巴胺的神经摄取抑制剂;安咪奈丁,一种(相对)选择性的多巴胺再摄取抑制剂;GBR 12909(伐诺司林),一种多巴胺再摄取抑制剂;以及金刚烷胺,一种NMDA受体拮抗剂以及多巴胺再摄取抑制剂。
为了进一步增强本发明的试剂盒的效果,(可选择地)加入一种物质,其抑制中枢及周围肾上腺素能紧张度,即抑制或压抑中枢和外周细胞外的去甲肾上腺素浓度。位于中枢神经系统中的α2肾上腺素受体的激活产生了对交感神经紧张的抑制。这种化合物的实例是氯压定,一种α2肾上腺素受体激动剂;咪唑啉,一种部分α2肾上腺素受体激动剂;以及右旋美托咪定,一种α2肾上腺素受体激动剂。外周α1肾上腺素能受体的拮抗作用阻断了肾上腺素能紧张度(去甲肾上腺素)的效果。这种化合物的实例是哌唑嗪、莫西赛利(胸腺氧胺)、NMI-870、HMP12或酚妥拉明。
低性欲、性唤起问题以及受阻碍的性高潮都是心理药理学治疗的候选者。这些种类的性问题同样关联到人类性反应的三个阶段(性欲、性唤起和性高潮)(过渡的和交迭的),其由相对独立的神经递质功能来调节。传统上,动机性行为已经分为渴望和完成(consummatory)部分。针对获得奖赏和满意的活性属于渴望部分。基本的渴望诱导的过程是一种固有的脑功能,并且特别涉及对于奖赏的刺激的预测值。诱导性地相关信息的处理(也就是预测奖赏的刺激)引起了中脑-伏隔(meso-accumbens)多巴胺能(DA)系统(也就是伏隔核(NAS)支配的中脑腹侧被盖区(VTA)的DA神经元),中脑边缘多巴胺系统的一部分的活力增加。当预料涉及性交的奖赏时2,这个系统的活性在柔性趋向行为(flexibleapproachbehavior)过程中被增强。增强这些多巴胺能通路的活力促进了性诱导,特别是预想性行为3。其中,阿立哌唑是影响多巴胺能途径的药物的实例,并且其可以用来与睾丸酮或其类似物以及PDE5-抑制剂组合以影响性诱导和性行为。阿立哌唑是一种多巴胺D2受体和血清素5-HT1a受体的高亲和性的部分激动剂以及5-HT2a受体的拮抗剂。阿立哌唑被描述成一种多巴胺系统稳定剂,这是由于其对D2受体,尤其是突触前D2受体的部分对抗作用,因此其具有更高的亲和力。对位于多巴胺神经末梢的自身受体的刺激引起了多巴胺合成和释放的抑制。因此,在中脑-横卧DA系统的低多巴胺能状态中,阿立哌唑将会拮抗突触前D2受体,使得VTA中的NAS-突出DA神经核从自身抑制中释放出来。中间的前额皮质(mPFC)调解行为的抑制。mPFC中的多巴胺在行为抑制中发挥着重要的作用。示例性的mPFC-DA的抑制作用是抑制中脑-横卧的DA系统;mPFC-DA的高胞外浓度抑制中脑-伏隔DA活性,通过去抑制,mPFC-DA的低胞外浓度激活中脑-横卧DA活性。因此,可以想象,FSD中的多巴胺能作用并不仅限于中脑-伏隔DA,而可扩展到mPFC-DA,其中,虽然通过伏隔(accumbal)DA的抑制或通过其它与FSAD有关的认知或情感因子的抑制,FSD症状伴随着高活力的mPFC-DA而增强。然后,阿立哌唑的部分对抗作用将通过mPFC中突触前D2受体的激动,从而抑制DA在这个区域的释放而对FSD的减轻(综合症)具有积极的效果。预期的性奖赏将产生生殖器的唤起,其中,至少与三种重要的神经递质有关:乙酰胆碱、去甲肾上腺素以及一氧化氮。乙酰胆碱和一氧化氮都促进男性的勃起和女性的润滑和隆突。去甲肾上腺素抑制男性勃起和女性的润滑和隆突。性高潮,人类性反应的完成(consummatory)状态受到下游的脊柱去甲肾上腺素能纤维和生殖器的神经支配的促进,并且受下游的脊柱血清素能性纤维的抑制。
该多部件的试剂盒对于受到任何形式的FSD困扰的任何个体都是有效的,它是通过心理或生理或它们的组合而引起的。因此,其对于因为其它药品和/或药物,如SSRI’s-而具有FSD的受治者、受到性腺机能减退等等困扰的受试者同样是有效的。
采用结合有他达拉非的一定剂量的睾丸酮的疗法产生了脑部和身体功能的改变,其将产生对性刺激、生殖器唤起以及可能的主观感受之间的积极联系的认识。此外,用睾丸酮和他达拉非的组合物治疗FSD优选通过“激发感应(approach induction)”疗法来增强。为了引起更加持久的心理的改变,在与性相关的刺激下由睾丸酮与他达拉非激活的身体中枢系统需要被感知并且需要与积极的快感度结合或与行为趋向系统(behavior approachsystem)的激活结合。通过将注意力集中在生殖器唤起上的身体反应的感知通过睾丸酮成为可能(藉此,生殖器唤起通过他达拉非被协同地增强)并且可以通过口头指导而被加强。在FSD患者的群体中不能确保积极的快感度。为了达到积极的快感度,患者可以在药物的有效阶段(也就是,在摄取睾丸酮之后至少3个小时)受到积极的刺激。这些正面的动机性刺激由患者的优选性交人的快乐表情的印象构成,有可能包括伴侣的表情。这些表情的印象潜在存在,使得行为趋向系统以一种不显眼的方式被激化。
FSD的治疗可以包括创造一种氛围,在其中,患者尝试将生殖器唤起与积极的快感度或行为趋向系统的激活相联系。这需要对生殖器唤起的诱导(通过性刺激和他达拉非),对性刺激以及对生殖器唤起的持续关注(使用睾丸酮可能达到)以及行为趋向系统的激活(通过潜意识存在的快乐表情的印象)。
本发明进一步提供了一种用于治疗受到女性性功能障碍困扰的女性的方法,通过向所述女性提供他达拉非与睾丸酮或其类似物的组合物。
除了通常使用睾丸酮(或其类似物)以及PDE5-抑制剂和特殊情况下使用他达拉非,具有至少一种其它化合物的睾丸酮(或其类似物)组合物同样适用于治疗FSD。PDE5-抑制剂替换物的一个实例是通常至少能够部分抑制平滑肌收缩的化合物,并且优选至少能够部分抑制(或压抑)肾上腺素能紧张度的化合物。可以看出抑制或减缓肾上腺素能紧张性可导致:(i)在肾上腺素受体上可用的去甲肾上腺素的量的减少(例如通过抑制去甲肾上腺素合成或通过自受体激动抑制去甲肾上腺素的释放)和/或(ii)突触后肾上腺素受体上可用的去甲肾上腺素的效果的降低(例如通过阻断突触后肾上腺素能受体),和/或(iii)突触后肾上腺素受体活性的效果的降低(例如,通过干扰去甲肾上腺素的下游)。因此,在另一个实施方式中,本发明提供了睾丸酮或其类似物与能够至少部分抑制肾上腺素能紧张度的化合物的组合物在制备用于治疗FSD的药品中的应用,其中,所述睾丸酮或其类似物这样提供,即在已经给药的受试者的血液循环中存在睾丸酮或其类似物的峰值。在一个优选的实施方式中,所述能够至少部分抑制肾上腺素能紧张度的化合物是α1-肾上腺素受体拮抗剂,如哌唑嗪、莫西赛利(胸腺氧胺)、NMI-870、HMP12或酚妥拉明、或α2肾上腺素受体激动剂,如可乐定(一种α2肾上腺素受体激动剂)、咪唑啉(一种部分α2肾上腺素受体激动剂)或右旋美托咪定(一种α2肾上腺素受体激动剂)。能够至少部分抑制平滑肌收缩的化合物的实例是Rho激酶拮抗剂、神经肽Y拮抗剂或血管紧张素II拮抗剂。
睾丸酮(或其类似物)适合的浓度和制剂如上所述。
本领域的技术人员应该明了,以上提及的化合物(例如提及的肾上腺素受体拮抗剂)必须以这种方式服用和释放,即它们的作用与睾丸酮的作用至少部分一致,也就是所述化合物的作用必须在睾丸酮(或其类似物)释放后存在3.5-5.5小时。本领域的技术人员基于所述化合物的药理动力学可以容易地确定所述化合物适合的制剂以及适合的浓度。
PDE5是副交感神经链的一部分,并且PDE5的存在引起了对平滑肌松弛的抑制以及随后的平滑肌组织的收缩。通过PDE5抑制剂对PDE5的抑制是一种能够治疗FSD的途径。然而,通过使用如有机硝酸盐(例如作为鸟苷酸环化酶刺激物的硝化甘油)、K+通道开放剂(例如BMS-2231321)、PGE1激动剂(例如前列地尔或前列腺环素)或血管活性肠多肽(VIP)激动剂(例如阿肽地尔))的化合物或通过给药一氧化氮(例如通过吸入)或L-精氨酸谷氨酸盐(NO的前体),同样可能促进副交感神经诱导的应答(也就是促进了平滑肌的松弛)。
本发明进一步提供了睾丸酮(或其类似物)与任意上述化合物(例如能够至少部分地抑制或压抑肾上腺素能紧张性的化合物)组合,与PDE5抑制剂,如伐地那非、昔多芬或他达拉非或其它任何已知的PDE5抑制剂组合的应用。PDE5抑制剂的数量还在扩大,以下是非限制性实例:E-4021、E-8010、E-4010、AWD-12-217(苯氮嘌呤酮)、AWD 12-210、UK-343,664、UK-369003、UK-357903、BMS-341400、BMS-223131、FR226807、FR-229934、EMR-6203、Sch-51866、IC485、TA-1790、DA-8159、NCX-911或KS-505a。其它的实例可以在WO 96/26940中找到。
如上所述,他达拉非可以这样的方式给药,其与睾丸酮同时释放。然而,也可以以下对伐地那非或昔多芬所描述的方式提供。
伐地那非或昔多芬优选以这样的方式提供,即它们的最大(peak)效果至少部分地与睾丸酮的效果交迭。为了获得这种交迭,首先提供睾丸酮(优选作为舌下制剂)而伐地那非或昔多芬优选在睾丸酮给药后约1.5-2.5小时提供,甚至更优选地,即Cmax出现在血浆游离睾丸酮峰值后的约3到4小时。这可通过例如昔多芬或伐地那非持续释放形式,或通过迟释制剂来实现。
一个典型的口服给药伐地那非的实例以伐地那非盐酸盐(vardenafil HCl)示出,其化学命名为哌嗪,1-[[3-(1,4-二氢-5-甲基-4-氧基-7-丙基咪唑并[5,1-f][1,2,4]三嗪-2-基)-4-乙氧苯基]磺酰]-4-乙基-,一盐酸盐。除了活性成分,伐地那非HCl、每种片剂还包含微晶纤维素、交聚维酮、二氧化硅(胶体)、硬脂酸镁、羟丙甲纤维素、聚乙二醇、二氧化钛、黄氧化铁以及红氧化铁。另一个实例以枸橼酸西地那非示出,其化学命名为1-[[3-(6,7-二氢-1-甲基-7-氧基-3-丙基-1H吡唑啉酮[4,3-d]嘧啶-5-基)-4-乙氧苯基]磺酰]-4-甲基枸橼酸哌嗪。除了活性成分、枸橼酸西地那非,每种片剂还包含下列成分:微晶纤维素、无水磷酸氢钙、交联羧甲基纤维素钠、硬脂酸镁、羟丙甲纤维素、二氧化钛、乳糖、三醋汀、以及FD&C蓝色#2铝色淀。
每种含有睾丸酮的药物组合物的睾丸酮含量为至少0.3mg睾丸酮和至多2.5mg睾丸酮。依赖白蛋白和SHBG水平以及待治疗患者的体重,更高或更低剂量可能是必不可少的。包括PDE5抑制剂的药物组合物包括至少25mg昔多芬(或5mg伐地那非,或5mg他达拉非)和至多100mg昔多芬(或20mg伐地那非,或20mg他达拉非),或相当剂量的其它PDE5抑制剂。此外,这些剂量可以根据患者的体重改变。出于已经在上文给出的这个原因,根据本发明的试剂盒可以进一步包括能够与睾丸酮或其类似物竞争结合SHBG的化合物。
上面提及的化合物的组合物(例如睾丸酮(或其类似物)与能够至少部分抑制肾上腺素能紧张性的化合物以及可选择的PDE5抑制剂)可以作为试剂盒的部件(part)便利地包装在一起,优选附有怎样以及何时对独立的(或组合的)的化合物给药的说明。
这种试剂盒可以进一步包括,对于充分性刺激的适当状态中将注意力指向生殖器唤起的认知干预的方法,或通过潜意识感受受试者优选性交人的快乐表情的印象诱导行为趋向系统或积极快感度的激活的认知干预的方法。或者多部件的试剂盒可以进一步包括多巴胺途径(dopamine pathway)的激动剂。
在存在PDE5抑制剂的情况下,PDE5结合到cGMP并且抑制钙通道的关闭以及钾通道的打开(也就是抑制平滑肌的超极化),因此,其抑制平滑肌松弛。PDE5和cGMP之间的交互作用是通过PDE5的GAF-AN-端结构域(其是药物开发的潜在靶点)的交互作用完成。在另一个实施方式中,本发明提供了睾丸酮或其类似物与能够至少部分抑制GAF-A域和cGMP(例如GAF-A阻断剂)之间交互作用的化合物的组合物在制备用于治疗女性性功能障碍的药物中的应用,其中所述睾丸酮或其类似物这样提供,即在已经给药的受试者的血液循环中存在睾丸酮或其类似物的峰值。例如,GAF-A阻断剂的存在将至少部分地阻止PDE5结合cGMP,产生平滑肌细胞松弛。
适合的睾丸酮(或其类似物)制剂已在上文给出。
本领域的技术人员应该明了,能够至少部分抑制GAF-A域与cGMP(例如GAF-A阻断剂)交互作用的化合物必需以这样的方式服用和释放,即其作用至少部分地与睾丸酮的作用相一致,也就是说所述化合物的作用必须在诱导的睾丸酮(或其类似物)血浆峰值后存在3.5-5.5小时。本领域的技术人员基于所述化合物的药物动力学能够容易地确定所述化合物的适合的制剂以及适合的浓度。
下面的非限制性实例将更加详细地解释本发明。
具体实施方式
实验部分
实验1:环糊精-结合的睾丸酮给药结合他达拉非给药对患有FSD的女性响应性爱影片片段的VPA的效果。
在双盲试验中,根据交叉设计随机分配安慰剂,一组16个患有女性性功能障碍(FSD)的女性,在4个间隔的实验日,将仅接受他达拉非(10mg)、仅接受舌下环糊精-结合的睾丸酮(0.5mg)、接受组合的他达拉非和舌下环糊精-结合睾丸酮(分别为10mg&0.5mg)或安慰剂。在给药后立即测量、以及在给药后4小时测量响应与无性爱影片片段和性爱影片片段的阴道搏动幅度。这4个实验日将(至少)间隔3天时间。在整个给药过程中,受试者将接受一个包含他达拉非或者安慰剂的胶囊,以及一个含有或不含睾丸酮(其是无味的)的液态环糊精混悬剂。两者同时服用。舌下环糊精-结合的睾丸酮效果的时间滞后(约4小时)将与高的(约>95%的他达拉非的Cmax)他达拉非的血清浓度交迭(他达拉非的Tmax为2小时;T1/2=17.5小时)。
在实验期间,受试者必须插入卫生棉条状的阴道探针(一种光体积变化描记仪),以测量VPA。然后,受试者将要观看10分钟的无性爱片段,随后是5分钟性爱影片片段。在这些基准测量后,受试者接受上述四种药物组合物之一。服用药品后,观看另一套无性爱(5分钟)以及性爱(5分钟)影片片段。然后移除阴道探针。4小时后,将会进行响应无性爱(5分钟)以及性爱(5分钟)影片片段的另一个VPA测量。在整个实验日里,将监测血压(仰卧以及站立)、心率、呼吸率以及体温。
筛选调查将先于实验。在此筛选随访中,受试者接受Flevo医院妇科住院医师almere的谈话以及检查,以诊断FSD并确定参与研究的适合性。受试者将被要求填写调查表;女性性功能指标(FSFI)。筛选受试者,以排除有如下情况的受试者:怀孕期或母乳喂养、阴道感染、阴道及/或外阴重大手术、未被检出的重大妇科疾病或未说明的妇科疾病。测量体重、身高、血压(仰卧以及站立)。测试心血管状态并且检查心电图(ECG)是否有显著异常。
有内分泌、神经或精神疾病病史和/或治疗史的受试者,将进行标准血液化学及血液学检测。在实验前一天晚上和当天,要求参与者不能饮酒或使用精神药物。不检测处于月经期的受试者。
实验2:环糊精-结合的睾丸酮给药结合哌唑嗪给药对患有FSD的女性响应于性爱影片片段的对VPA的效果。
在双盲试验中,依据交叉设计随机分配安慰剂,一组16个患有女性性功能障碍(FSD)的女性,在4个间隔的实验日,将仅接受哌唑嗪(0.5mg)、仅接受舌下环糊精-结合睾丸酮(0.5mg)、接受组合的他达拉非和舌下环糊精-结合睾丸酮(分别0.5mg&0.5mg)或安慰剂。在给药后立即测量以及在给药后4小时测量响应于无性爱影片片段和性爱影片片段的阴道搏动幅度。这4个实验日将(至少)间隔3天时间。在整个给药过程中,受试者将接受一个包含哌唑嗪或者安慰剂的胶囊,以及一个含有或不含睾丸酮(其是无味的)的液态环糊精混悬剂。舌下环糊精-结合睾丸酮效果的时间滞后(约4小时)将与高的(约>95%的哌唑嗪Cmax)哌唑嗪的血清浓度交迭(哌唑嗪Tmax为1-2小时;T1/2=2-3小时)。因此,哌唑嗪必须按这样的方式给药,即哌唑嗪Cmax在血浆游离睾丸酮达峰后3至4小时产生。因此,哌唑嗪必须在舌下睾丸酮给药后约2.5小时给药,或者必须对哌唑嗪进行修饰以使其在给药后约2.5小时释放,或者使Cmax在血浆游离睾丸酮达峰后3到4小时产生。
在这些实验性实例中,使用哌唑嗪迟释(2.5小时)制剂。
在实验期间,受试者必须插入卫生棉条状的阴道探针(一种光体积变化描记仪),以测量VPA。然后,受试者将要观看10分钟的无性爱片段,随后是5分钟性爱影片片段。在这些基准测量后,受试者接受上述四种药物组合物之一。服用药品后,观看另一套无性爱(5分钟)以及性爱(5分钟)影片片段。然后移除阴道探针。4小时后,将会进行响应无性爱(5分钟)以及性爱(5分钟)影片片段的另一个VPA测量。在整个实验日里,将监测血压(仰卧以及站立)、心率、呼吸率以及体温。
筛选调查将先于实验。在此筛选随访中,受试者接受Flevo医院妇科住院医师almere的谈话以及检查,以诊断FSD并确定参与研究的适合性。受试者将被要求填写调查表;女性性功能指标(FSFI)。筛选受试者,以排除有如下情况的受试者:怀孕期或母乳喂养、阴道感染、阴道及/或外阴重大手术、未被检出的重大妇科疾病或未说明的妇科疾病。测量体重、身高、血压(仰卧以及站立)。测试心血管状态并且检查心电图(ECG)是否有显著异常。
有内分泌、神经或精神疾病病史和/或治疗史的受试者,将进行标准血液化学及血液学检测。在实验前一天晚上和当天,要求参与者不能饮酒或使用精神药物。不检测处于月经期的受试者。
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Claims (11)
1.他达拉非与睾丸酮或二氢睾酮的组合物在制备用于治疗女性性功能障碍的药物中的应用,其中,所述他达拉非先于所述睾丸酮或二氢睾酮释放,或者他达拉非与睾丸酮或二氢睾酮基本上同时释放,并且其中所述睾丸酮或二氢睾酮以包含环糊精的舌下、鼻黏膜或者鼻内制剂提供,使得在已给药的受试者的血液循环中提供持续时间短的睾丸酮的峰值,其中提供所述睾丸酮或二氢睾酮使得实现至少0.010nmol/L的游离睾丸酮的峰值血浆水平,且其中所述睾丸酮或二氢睾酮在性活动之前3-5.5小时释放。
2.根据权利要求1所述的应用,其中所述睾丸酮或二氢睾酮与他达拉非彼此在30分钟内释放。
3.根据权利要求1所述的应用,其中所述他达拉非先于所述睾丸酮或二氢睾酮2-14小时释放。
4.根据权利要求1所述的应用,其中所述药物作为多部件的试剂盒提供,所述多部件的试剂盒包括至少一种含有睾丸酮或二氢睾酮的药物复合物以及至少一种含有他达拉非的药物复合物。
5.根据权利要求1所述的应用,其中所述药物作为包括他达拉非和睾丸酮或二氢睾酮的药物复合物提供。
6.根据权利要求1-5中任一项所述的应用,其中提供0.3mg至2.5mg睾丸酮以及5mg至20mg他达拉非。
7.一种多部件的试剂盒,包括至少一种含有睾丸酮或二氢睾酮的药物复合物以及至少一种含有他达拉非的药物复合物,其中所述试剂盒进一步包括所述复合物基本上同时给药或先于睾丸酮或二氢睾酮给药他达拉非的说明,并且其中所述睾丸酮或二氢睾酮以包含环糊精的舌下、鼻黏膜或者鼻内制剂提供,使得在已给药的受试者的血液循环中提供持续时间短的睾丸酮的峰值,其中提供所述睾丸酮或二氢睾酮使得实现至少0.010nmol/L的游离睾丸酮的峰值血浆水平,且其中所述睾丸酮或二氢睾酮在性活动之前3-5.5小时释放。
8.一种药物复合物,包括他达拉非和睾丸酮或二氢睾酮,所述复合物提供活性成分的基本上同时释放,或者提供他达拉非先于睾丸酮或二氢睾酮的释放,使得睾丸酮或二氢睾酮与他达拉非的峰值效应至少部分重叠,并且其中所述睾丸酮或二氢睾酮以包含环糊精的舌下、鼻黏膜或者鼻内制剂提供,使得在已给药的受试者的血液循环中存在持续时间短的睾丸酮的峰值,其中提供所述睾丸酮或二氢睾酮使得实现至少0.010nmol/L的游离睾丸酮的峰值血浆水平,且其中所述睾丸酮或二氢睾酮在性活动之前3-5.5小时释放。
9.根据权利要求8所述的药物复合物,其中所述睾丸酮或二氢睾酮作为舌下制剂提供。
10.根据权利要求9所述的药物复合物,其中睾丸酮或二氢睾酮以包含环糊精的舌下或鼻黏膜制剂提供。
11.根据权利要求8-10中任一项所述的药物复合物,其中提供0.3mg至2.5mg睾丸酮以及5mg至20mg他达拉非。
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