CN1761461A - 治疗早泄的组合物和方法 - Google Patents
治疗早泄的组合物和方法 Download PDFInfo
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- CN1761461A CN1761461A CNA2004800070579A CN200480007057A CN1761461A CN 1761461 A CN1761461 A CN 1761461A CN A2004800070579 A CNA2004800070579 A CN A2004800070579A CN 200480007057 A CN200480007057 A CN 200480007057A CN 1761461 A CN1761461 A CN 1761461A
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Abstract
本发明涉及治疗早泄的组合物和方法,其中所述组合物包括外用麻醉剂、剪切变稀的聚合物增稠剂、亲脂性成分、水以及缓冲体系,所述亲脂性成分选自C1-C8脂肪醇、C8-C30脂肪酯、液态多元醇及它们的混合物,所述缓冲体系使所述组合物的pH值缓冲至约3-约7.4的范围;将所述组合物用于阴茎口处。
Description
相关申请的交叉引用
本申请要求2003年3月21日提交的美国临时申请No.60/456,604和2003年3月21日提交的申请No.60/456,813为优先权申请。上述申请的全部内容都以引用方式并入本文。
发明背景
早泄(PE)是男性性功能障碍中最常见的一种,美国男性多至30%患有该病。根据心理失调的诊断和统计指南(Diagnostic and Statistical Manual ofMental Disorders,fourth edition(DSM-IV,1994)),早泄的诊断标准是:A.在进入之前,之时或不久之后的微小性刺激导致经常性、反复性早于愿望之前的射精。临床医生需考虑影响兴奋期持续时间的多种因素,如年龄、性伙伴的新鲜感或状态和最近性行为的频率。B.明显导致沮丧和俩人之间困难的行为。C.PE不单单是一种物质(如药物)的直接生理结果或通常的医学病症。美国精神病学协会,心理失调的诊断和统计指南,第四版,Washington,DC:美国精神病协会(1994)。
早于愿望之前的射精是指缺乏主动控制的射精。在PE的一些定义中,缺乏主动控制主要是指无法顾及进入时间的长短、动作的次数多少或伙伴是否达到高潮。实际上,PE经常被定义为,进入后至射精的时间为1分钟至7分钟,尽管对于最少时间的定义还没有统一。根据经验,在对110名终身遭受PE的男性进行研究发现,利用秒表进行测时,其中90%的进入阴道至射精的潜伏期(IELT)小于1分钟,参见Waldinger,M.D.,The neurobiologicalapproach to premature ejaculation,J.Urol.,2002,168:2359-2367。
最近神经生理学研究提出射精反射包括两种反射:龟头-迷走神经反射,该反射促使精液到达后尿道(Shafik,A.,The mechanism of ejaculation:theglans-vasal and urethromuscular reflexes.Arch Androl.199841(2):71-8)。第一种反射由生殖感受器引发,然后通过阴部神经到达骶骨索,最终到达缘叶和视丘下部。第二种反射是从尿道开始传导到射精中心(片断S2-4)。阴部副交感神经的输出管纤维将信号传导到神经中枢,这些信号导致神经传递素的释放,通过会阴肌肉的去极化翻译成节奏性的收缩而导致射精。上述反射之一或全部的功能不良都会导致射精紊乱。
PE的一个理论假设是当性兴奋达到某一阈值或调整好的某一水平时,发生射精行为。基于该假设,阈值较低的男性的IELT应该较短。但,该假设没有说明阈值是通过中枢神经系统的突触相互作用而进行的中枢性调整,还是通过外周神经调整的传入的感觉信号。二者都可以是治疗靶点。
外用(topical)麻醉剂已被应用于阴茎以阻断体觉传入神经元的传导。例如,在一个公开指导的非盲试验中,11名患有早泄的无器官性疾病或勃起障碍的健康已婚男性施用利多卡因-丙胺卡因霜。试验患者在性交前30分钟涂上2.5gm的霜剂,然后用安全套套上阴茎。11名中有九名患者有明显改进(Berkovitch,等Efficacy of prilocaine-lidocaine cream in the treatment ofpremature ejaculation.J Urol.1995154(4):1360-1)。
中枢神经系统的脊髓或脊椎水平上的阈值设定机理(threshold settingmechanism)得出了几种药理学方法。很多都是5HT再摄取抑制剂。一种非选择性5HT再摄取抑制剂三环结构的抗抑郁药氯米帕明(chlomipramine)已被用于治疗PE。几种选择性5HT再摄取抑制剂(SSRIs)也已被用于治疗PE,包括氟西汀(fluoxetine)、帕罗西汀(paroxetine)和舍曲林(sertaline)。但,5HT再摄取抑制剂通常具有不利的副作用。见McCullough,A.R. & Melman,″Ejaculatory Disorders,″pp.351-370 in Mulcahy,J.J.,ed.,Male Sexual Function:A Guide to Clinical Management,Humana Press,Totowa,NJ,2001。
在很多患者中,PE与勃起功能障碍(ED)并存,这是影响治疗选择性的一个因素,但任何一个问题都没有完全一致性。在一项研究中,87名PE患者被分为两组:原发PE组和用西地那非治疗ED的PE组(Chia,S.,Managementof premature ejaculation--a comparison of treatment outcome in patients with andwithout erectile dysfunction.hit J Androl.200225(5):301-5)。两组患者都在预定的性交时间前4个小时施用50mg舍曲林。用西地那非治疗后的ED患者中的28名都患有PE。在治疗前,PE和PE+ED组的射精潜伏期没有显著差别(分别为46和34.6秒)。但,采用舍曲林治疗6个月后,两组的射精潜伏期存在显著差别(PE和PE+ED组分别为247.2和111.6秒)。该项研究表明选择性5HT再摄取抑制剂(SSRIs)对于原发PE患者具有疗效,与用西地那非治疗ED的患者的疗效不相同。在另一个以安慰剂为对照的双盲交叉试验中,另一种SSRI,氟西汀对于早泄男性患者和/或勃起功能障碍的研究发现,PE+ED组的射精潜伏期明显延长(p=0.03),PE组和PE+ED组都有疗效(p=0.007),而不仅仅是PE组,见Haensel,S.M.,等Fluoxetine and prematureejaculation:a double-blind,crossover,placebo-controlled study.J ClinPsychopharmacol.199818(1):72-7。Chia,2002的研究报道ED患者可发展成PE,有其他报道长期的PE患者不会发展成ED(Waldinger,2002,p.2364)。
前列腺素E1是前列腺酸,一种具有20个碳原子的脂质酸的衍生物,,由下列通式表示:
该物质可购得,如购自Chinoin Pharmaceutical and Chemical Works Ltd.(匈牙利的布达佩斯),其产品名称为″Alprostadil USP,″;Phannacia & Upjohn,其产品名称为″Caverject″。前列腺素E1与α-环糊精混合可以得到OnoPhannaceuticals(Japan)的产品alprostatil alfadex,以及Schwarz Pharrna(Germany)的注射形式产品″Edex″或″Viradex″。
在一种可商购的产品形式(MUSE,Vivus,Menlo Park CA)中,前列地尔(alprostadil)以小球形式施用,该小球借助敷药器被沉积在尿道中,该敷药器具有长为3.2cm直径为3.5mm的孔洞(Padma-Nathan,H.,等,N.Engl.J.Med.,336:1-7(1997),参见图1)。Padma-Nathan等对家庭治疗群进行了研究,32.7%的患者(给药的占10.8%)接受MUSE@后抱怨阴茎疼痛,5.1%经受轻微尿道损伤,有分别为3.3%和1.0%的患者接受安慰剂作对照。这些副作用的报导频率在随后的研究中各有不同:有17-23.6%的患者给予MUSE后感到阴茎疼痛,有1.7%给予安慰剂作对照,4.8%的患者有轻微尿道出血(Peterson,C.A.,等,J.Urol.,159:1523-1528(1998))。在一项对欧洲人种的研究中,31%MUSE的患者感觉阴茎疼痛或灼烧感,4.8%有轻微尿道出血,有2.9%有严重的睾丸疼痛(Porst,H.,Int.J.Impot.Res.,9:187-192(1997))。经受MUSE治疗的患者能够产生至少足以进行性交的勃起的比例是43%(Porst,1997),65.9%(Padma-Nathan等,1997)和70.5%(Peterson等,1998),不过公开的评论已暗示在后两项研究中,患者响应的比例在30-40%之间更合适(Benson,G.,J.Urol.,159:1527-1528(1998)。
据报导,尿道内给予1mg卵磷脂脂质体中的前列腺素E1,其存在于1ml的聚氧乙烯乙二醇中,比海绵腔体内注射前列腺素E1的效果差(Englehardt,P.F.,等,British J.Urology,81:441-444,1998)。没有ED患者接受脂质体制剂获得完全的阴茎变硬,25名患者中只有6名达到足以进入阴道的勃起。相反,海绵腔体内注射前列腺素E1能够导致足以进入阴道的勃起,或相同的25名患者中有23名阴茎完全变硬。作者提示前列腺素E1在尿道间的作用可能是由前列腺素E1扩散而引起,首先被扩散到海绵体分开部分,然后进入海绵体内。
最近,将包括至少一种促渗剂的外用PGE1组合物应用于阴茎口内(intrameatal或meatal)已显示出是治疗勃起功能障碍所采用的海绵体内注射或尿道用栓剂的一种非侵入型替代法(见美国专利号6,323,241和美国已公布的专利2003/0220292,其内容在此被全文引用)。阴茎口内应用是将药物施用于阴茎顶端,并由此进入舟状窝内。给药时,须将阴茎竖起,并将阴茎口张开,将药物滴入舟状窝中而无需将药物容器置入阴茎口内。
发明概述
在一个实施方式中,本发明提供了一种外用(topical)组合物,其包括外用(topical)麻醉剂;聚合物增稠剂,其选自剪切变稀的多糖胶和剪切变稀的聚丙烯酸聚合物;亲脂性组分,其选自C1-C8脂肪醇、C2-C30脂肪酯、液态多元醇和这些物质的混合物;水和缓冲体系,缓冲体系使组合物的pH为约3至约7.4,优选为约3至约6.5。在一个优选的实施方式中,组合物进一步包括合适的血管活性前列腺素,其选自PGE1、PGA1、PGB1、PGF1α、19-羟基-PGA1、19-羟基-PGB1、PGE2、PGA2、PGB2、19-羟基-PGA2、19-羟基-PGB2、PGE3、PGF3和这些物质的混合物。在更优选的实施方式中,血管活性前列腺素选自前列腺素E1、前列腺素E2、其药学可接受的盐、其低级烷基酯和这些物质的混合物。更优选地,血管活性前列腺素为PGE1。血管活性前列腺素的典型含量为约0.1mg至约0.5mg。
在另一个优选实施方式中,组合物进一步包括促渗剂,其选自(N-取代的氨基)-链烷酸烷基酯、2-(N,N-二取代的氨基)-链烷酸烷基酯、(N-取代的氨基)-链烷醇链烷酸酯、(N,N-二取代的氨基)-链烷醇链烷酸酯、其药学可接受的盐及这些物质的混合物。
在优选实施方式中,外用麻醉剂为氨基酰胺局部麻醉剂,其选自利多卡因(lidocaine)、布比卡因(bupivacaine)、甲哌卡因(mepivacaine)、地布卡因(dibucaine)、普罗比卡因(propivacaine)、依替卡因(etidocaine)、妥卡尼(tocainide)、其药学可接受的盐及这些物质的混合物。在一个尤其优选的实施方式中,局部麻醉剂选自多卡因(lidocaine)、布比卡因(bupivacaine)、达克罗宁(dyclonine)、其药学可接受的盐以及这些物质的混合物。在一个实施方式中,外用麻醉剂的含量为组合物重量的约0.01至约4wt%。在另一个实施方式中,外用麻醉剂的含量为组合物重量的约0.01至约10wt%。
另一方面,本发明提供了一种治疗早泄的方法,其包括向阴茎口内施用一种组合物,该组合物包括血管活性前列腺素、外用麻醉剂、促渗剂、选自多糖胶和聚丙烯酸聚合物的聚合物、选自C1-C8脂肪醇、C2-C30脂肪酯、液态多元醇和这些物质的混合物的亲脂性组分、水和酸性缓冲体系。在优选的实施方式中,血管活性前列腺素选自前列腺素E1、前列腺素E2、其药学可接受的盐、其低级烷基酯和这些物质的混合物。血管活性前列腺素的典型含量为约0.1mg至约0.5mg。
在某些优选实施方式中,外用麻醉剂为氨基酰胺局部麻醉剂,其选自利多卡因(lidocaine)、布比卡因(bupivacaine)、甲哌卡因(mepivacaine)、地布卡因(dibucaine)、普罗比卡因(propivacaine)、依替卡因(etidocaine)、妥卡尼(tocainide)、其药学可接受的盐及这些物质的混合物。在尤其优选的实施方式中,局部麻醉剂选自多卡因(lidocaine)、布比卡因(bupivacaine)、达克罗宁(dyclonine)、其药学可接受的盐以及这些物质的混合物。在其它优选实施方式中,外用麻醉剂包括达克罗宁(1-(4-丁氧苯基)-3-(1-哌啶基)-1-丙酮)。尤其是,所包括的外用麻醉剂为组合物重量的约0.01至约10wt%。在其它实施方式中,外用麻醉剂的含量为组合物重量的约0.01至约4wt%。
在优选实施方式中,剪切变稀的多糖胶为半乳甘露聚糖胶或修饰的半乳甘露聚糖胶。优选修饰的半乳甘露聚糖胶为修饰的瓜儿豆胶。在优选的实施方式中,促渗剂为2-(N,N-二甲氨基)-丙酸十二烷基酯或其药学可接受的盐。在优选的实施方式中,亲脂性组分至少包括一种C8-C30脂肪酯。在一个优选的实施方式中,亲脂性组分包括至少一种甘油酯,其选自甘油一酸酯、甘油二酸酯、甘油三酸酯及这些物质的混合物。在另一个实施方式中,亲脂性组分至少包括一种甘油酯,其选自甘油一油酸酯、甘油三油酸酯、三豆蔻酸甘油酯、三硬脂酸甘油酯、及其混合物。通常,缓冲体系使组合物的pH值在约3至约7.4的范围内,优选为约3至约6.5。在某些实施方式中,组合物进一步包括乳化剂,其选自蔗糖酯、聚氧乙烯山梨醇酯、长链醇、和甘油酯。适宜地,乳化剂至少包括一种甘油酯,其选自甘油一酸酯、甘油三酸酯、三豆蔻酸甘油酯、三硬脂酸甘油酯、及这些物质的混合物。任选地,组合物进一步包括芳香剂。在一些实施方式中,组合物进一步包括多至约5%组合物重量的桃金娘烯醇(myrtenol)。适宜地,组合物进一步包括防腐剂。
在一个实施方式中,多糖胶为剪切变稀的多糖胶,优选为半乳甘露聚糖胶或修饰的半乳甘露聚糖胶。优选修饰的半乳甘露聚糖胶为修饰的瓜儿豆胶。在一个实施方式中,促渗剂为2-(N,N-二甲氨基)一丙酸十二烷基酯或其药学可接受的盐。在一个实施方式中,亲脂性组分至少包括一种C8-C30脂肪酯。在一个优选的实施方式中,亲脂性组分包括至少一种甘油酯,其选自甘油一酸酯、甘油二酸酯、甘油三酸酯及这些物质的混合物。在另一个实施方式中,亲脂性组分至少包括一种甘油酯,其选自甘油一油酸酯、甘油三油酸酯、三豆蔻酸甘油酯、三硬脂酸甘油酯、及其混合物。通常,缓冲体系使组合物的pH值在约3至约7.4的范围内,优选为约3至约6.5。在某些实施方式中,组合物进一步包括乳化剂,乳化剂选自蔗糖酯、聚氧乙烯山梨醇酯、长链醇和甘油酯。适宜地,乳化剂至少包括一种甘油酯,其选自甘油一酸酯、甘油三酸酯、三豆蔻酸甘油酯、三硬脂酸甘油酯、及这些物质的混合物。任选地,组合物进一步包括芳香剂。在一些实施方式中,组合物进一步包括多至约5%组合物重量的桃金娘烯醇。适宜地,组合物进一步包括防腐剂。
发明详述
定义
除非另有说明,本申请,包括说明书和权利要求书中所使用的以下术语具有下述定义。必须要指出,本文说明书以及权利要求中,如果没有详细指出例外,单数型的“一个”以及“该(这一)”也包含复数的内容。
“阴茎口内”或“阴茎口”是指将药物用于阴茎顶端,并由此进入舟状窝内。给药时,须将阴茎竖起,并将阴茎口张开,在无需将药物容器置入阴茎口内的情况下将药物滴入舟状窝中。
“射精潜伏期延长剂量”是指能有效延长阴道内射精潜伏期的时间至2分钟的剂量。
除非特别说明,“烷基”是指单键直链或支链的饱和烃基,其仅含有碳原子和氢原子,具有1-20个碳原子。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、异丁基、仲丁基、叔丁基、戊基、正己基、辛基、十二烷基、十四烷基、二十烷基等。
除非特别说明,“低级烷基”是指单键直链或支链的饱和烃基,其仅含有碳原子和氢原子,具有1-6个碳原子。低级烷基的实例包括但不限于甲基、乙基、丙基、异丙基、叔丁基、正丁基、正己基等。
“低级烷氧基”是指-O-R,其中,R为如上定义的低级烷基。低级烷氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基等。
“卤素”是指基团氟、溴、氯和/或碘。
“任选”是指以下描述的情况或情形可能但不需要发生,以及包括发生的情况或情形以及没有发生的情况和情形。例如,“任选的键”是指该键可以存在也可以不存在,该描述包括单键、双键或三键。
“药学可接受的”是指在制备药物组合物中可被利用的,即在生物上安全、无毒、合乎要求的,包括在兽药上和人类药物应用上可接受的。
化合物的“药学可接受的盐”是指一种如上定义的药学上可接受的盐,其具有母体化合物的预期药理活性。这种盐包括:
1.与无机酸形成的酸加成盐,所述无机酸为如盐酸、氢溴酸、氢氟酸、氢碘酸、三氟醋酸、硫酸、硝酸、磷酸、硼酸等;或与有机酸形成的酸加成盐,所述有机酸如乙酸、苯磺酸、苯甲酸、樟脑磺酸、对氯苯磺酸、肉桂酸、柠檬酸、环戊烷丙酸、乙磺酸、1,2-乙基二磺酸、甲酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、羟基乙酸、己酸、庚酸、邻-(羟基苯甲酰基)苯甲酸、羟基萘甲酸(hydroxynaphtoic acid)、2-羟基乙磺酸、乳酸、十二烷基硫酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、4-甲基二环[2.2.2]辛-2-烯-1-羧酸、4,4′-亚甲基双(3-羟基-2-烯-1-羧酸)、粘康酸、2-萘磺酸、草酸、3-苯基丙酸、内酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、酒石酸、叔丁基乙酸、对-甲苯磺酸、三氟甲磺酸、三甲基乙酸等;或
2.母体化合物中的一个酸性质子被一种金属离子取代所形成的盐,所述金属离子例如为碱金属离子、碱土金属离子或铝离子;或与有机碱或无机碱形成的配合物,可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇、甲胺、乙胺、羟乙胺、丙胺、二甲胺、二乙胺、三甲胺、三乙胺、乙二胺、羟乙胺、吗啉、哌嗪和胍等。可接受的无机碱包括氢氧化铝、氢氧化铵、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠和肼。优选的药学可接受的盐是与盐酸、三氟醋酸形成的盐。
“患者”是指哺乳动物和非哺乳动物。“哺乳动物”是指哺乳纲的任何动物,其包括但不限于人类、非人类灵长目动物,如黑猩猩以及其它猿类和猴类;畜牧动物,如牛、马、绵羊、山羊和猪;家养动物,如兔、狗和猫;实验室动物,包括啮齿类,如大鼠、小鼠和豚鼠等。非哺乳类的实例包括但不限于鸟类等。术语“患者”并不限定年龄或性别。
“治疗有效量”是指当给患者施用以治疗某种疾病时,能足以治疗该疾病的化合物的量。“治疗有效量”依据化合物、所治疗疾病状况、疾病的严重程度、患者年龄和健康状况、给药途径和给药形式、医生或兽医的判断准确度等各因素所决定。
本发明的术语“药理学作用”包括接受治疗的患者获得预期目的治疗效果。在一个优选实施方式中,药理学作用是指接受治疗的患者的血管痉挛症状得到防止、减轻或减小。例如,药理学作用是指接受治疗的患者的血管痉挛得到防止或减轻。
“病状”是指任何疾病、症状、征兆或适应症。
疾状的“治疗”包括:
1.预防疾病,即,使可能发展成或倾向于发展成该疾病的临床症状没有得到发展,从而还没有形成或表现出疾病的症状,
2.抑制疾病,即,抑制疾病或其临床症状的发展,或
3.减轻疾病,即,使疾病或其临床症状暂时或长期得到减轻。
“前药”是指化合物的药理学非活性形式,其必须在体内代谢后转变成药理学活性形式才产生所需的药理学作用。给药后,在生物体液或酶的参与下,药理学非活性形式的化合物在体内转变成药理学活性形式。尽管很多化合物最初在肝脏中进行代谢,但其它组织和器官,尤其是肺也能不同程度地进行代谢。前药可改善生物利用度,使不良特性,如苦味得到掩盖,可改善溶解度以适于静脉内使用或使化合物被运送到特定靶位。本发明的化合物包括前药形式。
在一个优选的实施方式中,药物组合物包括外用麻醉剂、血管活性前列腺素、剪切变稀的聚合物增稠剂、亲脂性组分、水和缓冲体系,该缓冲体系使组合物的pH值为约3至约7.4,优选为约3至约6.5。优选的血管活性前列腺素选自前列腺素E1、其药学可接受盐、其低级烷基酯及这些物质的混合物。在优选的实施方式中,组合物进一步包括促渗剂,其选自(N-取代的氨基)-链烷酸烷基酯、2-(N,N-二取代的氨基)-链烷酸烷基酯、(N-取代的氨基)-链烷醇链烷酸酯、(N,N-二取代的氨基)-链烷醇链烷酸酯、其药学可接受的盐及这些物质的混合物。
在另一个优选实施方式中,药物组合物包括外用麻醉剂、剪切变稀的聚合物增稠剂、亲脂性组分、水和缓冲体系,所述的亲脂性组分,其选自选自C1-C8脂肪醇、C2-C30脂肪酯、液态多羟基化合物和这些物质的混合物,所述的缓冲体系使组合物的pH为约3.0至约7.4。在某些实施方式中,组合物进一步包括促渗剂,促渗剂选自(N-取代的氨基)-链烷酸烷基酯、2-(N,N-二取代的氨基)-链烷酸烷基酯、(N-取代的氨基)-链烷醇链烷酸酯、(N,N-二取代的氨基)-链烷醇链烷酸酯、其药学可接受的盐及这些物质的混合物。
已经发现,包括前列腺素E1和外用麻醉剂的半固体组合物对施用于紧邻阴茎口的天然开阔区域中是有利的,导致有效治疗早泄。
本发明适用的半固体组合物和促渗剂的详细描述见美国专利6046244、6118020和6323241,将这些文献的教导都引用于本申请中。
血管活性前列腺素是指作用同外周血管扩张剂的前列腺素,包括天然的前列腺素,如PGE1、PGA1、PGB1、PGF1a、19-羟基-PGA1、19-羟基-PGB1、PGE2、PGA2、PGB2、19-羟基-PGA2、19-羟基-PGB2、PGE3、PGF3a;天然前列腺素的半合成或合成的衍生物,包括卡波前列素缓血酸胺、地诺前列素缓血酸胺、地诺前列酮、脂前列腺素(lipoprost)、吉美前列素、甲烯前列素(metenoprost)、硫前列酮和噻前列素。前列腺素E1和前列腺素E2是尤其优选的用于本发明方法和组合物的血管活性前列腺素。
另外,两种或多种血管活性剂的同时给药是理想的,并且在某些情形下显示出协同作用。已经发现哌唑嗪和前列腺素E1的组合在这点上是特别有益的。
适宜的非内生性荷尔蒙血管扩张剂包括但不限于:硝化甘油、硝酸异山梨酯、丁四硝酯、硝酸戊酯、硝普酸钠、吗多明(molsidomine)、林西多明氯化水合物(linsidomine chlorhydrate)(″SIN-1″)和S-亚硝基-N-乙酰基-d,l-青霉胺(″SNAP″);氨基酸,例如L-精氨酸;长效和短效α-阻断剂,例如苯氧基苯沙明、双卞胺(dibenamine)、多沙唑嗪(doxazosin)、特拉唑嗪(terazosin)、酚妥拉明、苯甲唑啉(tolazoline)、哌唑嗪(prazosin)、曲马唑嗪(trimazosin)、阿夫唑嗪(alfuzosin)、坦索罗辛(tamsulosin)和吲哚拉明(indoramin);血管舒张的天然草药组合物和其生物活性提取物,例如gosyajinki-gan,Satureja obovata,白花前胡(bai-hua qian-hu),lipotab,saiboku-to,长春乙酯(vinpocetine),银杏叶(Gingko biloba),虎耳草(bacopa),绞股蓝七叶胆(Gynostemma pentaphyllum),绞股蓝总皂甙(gypenosides),吴茱萸(Evocia rutaecarpa),吴茱萸次碱(rutaecarpine),去氢吴茱萸碱(dehydroevodiamine),丹参(dan-shen),丹参根(salviae miltiorrhizae radix),柴胡(shosaikoto),大枣(Zizyphi fructus),人参以及它们的混合物(美国专利6,007,824);麦角生物碱类,如麦角胺和麦角胺类似物,例如,乙酰二氢麦角胺(acetergamine),巴西麦角林(brazergoline),溴麦角脲(bromerguride),氰麦角林(cianergoline),德勒够腈(delorgotrile),地舒勒近(disulergine),麦角新碱马来酸盐(ergonovine maleate),麦角胺酒石酸盐,乙舒麦角(etisulergine),麦角腈(lergotrile),麦角酸酰二乙胺,美舒麦碱(mesulergine),甲麦角林(metergoline),甲基麦角胺(metergotamine),尼麦角林(nicergoline),培高利特(pergolide),普罗麦角(propisergide),丙麦角脲(proterguride)和特麦角脲(terguride);抗高血压药,如二氮嗪,肼苯哒嗪(hydralazine)和米诺地尔(minoxidil);血管舒张剂,例如尼莫地平(nimodepine),吡那地尔(pinacidil),环扁桃酯,双嘧达莫(dipyridamole)和异克舒令(isoxsuprine);盐酸氯丙嗪(chlorpromazine);氟哌啶醇(haloperidol);育亨宾(yohimbine);氯哌三唑酮(trazodone);天然存在的前列腺素,例如PGE1,PGA1,PGB1,PGF1α,19-羟基-PGA1,19-羟基-PGB1,PGE2,PGA2,PGB2,19-羟基-PGA2,19-羟基-PGB2,PGE3,PGF3α;天然前列腺素半合成的或合成的衍生物,包括碳前列缓血酸胺(carboprost tromethamine),地诺前列缓血酸胺,地诺前列酮,脂前列腺素(lipoprost),吉美前列素(gemeprost),甲烯前列素,硫前列酮和噻前列素;和血管活性肠肽。
前列腺素E1是本领域所熟知的。对于其药理活性、副作用和正常剂量范围在不同的文献中都有引用。例如,Plzysician′s Desk Reference,51 st Ed.(1997),The Merck Index,12th Ed.,Merck & Co.,N.J.(1996),和Martindale The ExtraPharmacopoeia,28th Ed.,London,The Pharmaceutical Press(1982)。前列腺素E1以及其它在此引用的化合物都包括其药学可接受的衍生物以及其生理相容的盐和酯。
本发明药物组合物中血管活性前列腺素如前列腺素E1的含量是治疗有效量,并根据具体血管活性前列腺素、所需剂量、剂型(如栓剂或外用药剂)进行必要的调整。本发明中所用术语“前列腺素”通常指前列腺素游离酸和其药学可接受的衍生物,例如包括PGE1、其药学可接受衍生物,如PGE1和其药学可接受盐和低级烷基酯(术语低级烷基是指含有1-4个碳原子的直链或支链烷基)。组合物通常包含组合物总重量的0.001%-1%的血管活性的前列腺素,如前列腺素E1,尤其是0.05%-1%,优选为0.1%-0.5%。
当与血管活性前列腺素联合使用时,哌嗪基喹唑啉抗高血压药,如哌唑嗪的使用量为每单位剂量约0.1mg至约2.0mg,该使用量依据具体哌嗪基喹唑啉抗高血压药的效力以及所使用血管活性的前列腺素的类型和剂量而定。血管活性前列腺素和哌嗪基喹唑啉的剂量和比例可以由本领域普通技术人员根据常规进行确定,而无需试验。
在优选实施方式中,外用组合物至少包括一种局部麻醉剂。适宜的局部麻醉剂包括适用于外用的麻醉剂,其包括,但不限于:氨布卡因(ambucaine)、阿莫拉酮(amolanone)、盐酸阿米卡因(amylocaine hydrochloride)、阿替卡因(articaine)、benoxinate、本坐卡因(benzocaine)、贝托卡因(betoxycaine)、苯柳胺酯(biphenamine)、布比卡因(bupivacaine)、布他卡因(butacaine)、氨苯丁酯(butamben)、布坦卡因(butanilicaine)、丁胺卡因(butethamine)、butoxycaine、卡铁卡因(carticaine)、盐酸氯普鲁卡因(chloroprocainehydrochloride)、古柯乙烯(cocaethylene)、可卡因(cocaine)、环美卡因(cyclomethycaine)、盐酸地布卡因(dibucaine hydrochloride)、二甲卡因(dimethocaine)、盐酸地哌冬(diperodon hydrochloride)、达克罗宁(dyclonine)、ecgonidine、芽子碱(ecgonine)、氯乙烷、依替卡因(etidocaine)、β-优卡因(eucaine)、尤普罗辛(euprocin)、非那可明(fenalcomine)、福莫卡因(fomocaine)、盐酸海克卡因(hexylcaine hydrochloride)、羟丁卡因(hydroxytetracaine)、对-氨基苯甲酸异丁酯、甲磺酸亮氨卡因(leucinocainemesylate)、左沙屈尔(levoxadrol)、利多卡因(lidocaine)、甲哌卡因(mepivacaine)、美普卡因(meprylcaine)、美布卡因(metabutoxycaine)、氯甲烷、麦替卡因(myrtecaine)、纳依卡因(naepaine)、奥他卡因(octacaine)、orthocaine、奥昔卡因(oxethazaine)、对乙氧卡因(parethoxycaine)、盐酸非那卡因(phenacaine hydrochloride)、苯酚、皮珀罗卡因(piperocaine)、匹多卡因(piridocaine)、聚多卡醇(polidocanol)、普莫卡因(pramoxine)、丙胺卡因(prilocaine)、普鲁卡因(procaine)、丙泮卡因(propanocaine)、丙美卡因(proparacaine)、丙哌卡因(propipocaine)、盐酸丙氧卡因(propoxycainehydrochloride)、假可卡因(pseudococaine)、吡咯卡因(pyrrocaine)、罗哌卡因(ropivacaine)、水杨醇、盐酸丁卡因(tetracaine hydrochloride)、托利卡因(tolycaine)、三甲卡因(trimecaine)、佐拉敏(zolamine)及这些物质的混合物。
通常,有少数例外,局部麻醉剂含有亲脂基团(大多数为芳香结构)、中间链和亲水基团(通常为氨基)。局部麻醉剂可按照结构进一步分为醇类和烷基醚类(如,氯丁醇、苄醇、saligenine和pistocaine)、胺、氨基醇、氨基烷醚(如,普莫卡因和dimethisoquine)、氨基酮类(如法立卡因(falicaine))、羧酸酯(如,苯坐卡因、普鲁卡因和parophoxycaine)、羧酸酰胺(如,利多卡因和地布卡因)、氨基甲酸酯(如diperodone)以及脒和胍(如芬那卡因(phenacaine)和茴胍卡因(guanicaine))。参见Buchi,J.,and Perlia,X.,″Structure-ActivityRelations and Physico-Chemical Properties of Local Anesthetics.Part I.Relationsbetween Chemical Structure and Local Anesthetic Activity,″pp.39-130 inInt.Encycl.Pharm.Therapeut.,Local Anesthetics,Vol.I,Pergamon Press,NewYork,1971。
在优选的实施方式中,局部麻醉剂分子结构由叔胺与中间链取代的芳香环相连而构成。在一些实施方式中,中间链包括一个羰基和一个或多个烷基。中间链可进一步包含酯键或酰胺键。适宜的氨基酰胺局部麻醉剂包括利多卡因、布比卡因、甲哌卡因、地布卡因、普罗比卡因(propivacaine)、依替卡因和妥卡尼。适宜的氨基酯局部麻醉剂包括普鲁卡因、氯普鲁卡因、丁卡因、异卡因(isocaine)、苯坐卡因和单卡因(monocaine)。在中间链既含有羰基又含有一个或多个烷基的实施方式中,优选的局部麻醉剂为达克罗宁、1-(4-丁氧苯基)-3-(1-哌啶基(piperidynyl))-1-丙酮。
优选的局部麻醉剂是能维持适度麻醉时间的麻醉剂,更优选地是具有长时间麻醉效果的麻醉剂。例如,普鲁卡因和氯普鲁卡因的作用持续时间短。利多卡因、甲哌卡因和丙胺卡因的作用时间适中。适宜的长效局部麻醉剂包括罗哌卡因、丁卡因、布比卡因和依替卡因。
外用麻醉剂为组合物总重量的约0.01-约20wt%,优选为约0.01-约10wt%。当然,外用麻醉剂的适宜浓度随具体麻醉剂和其他组分的不同而不同。例如,适宜浓度包括苯坐卡因为约1-约20wt%,地布卡因为约0.25-约2.5wt%,利多卡因为约0.01-约10wt%,丁卡因为约0.25-约1wt%。在一个实施方式中,组合物包括约约2.5-约5wt%的利多卡因。在另一个实施方式中,组合物包括约0.5-约1.0wt%的盐酸达克罗宁。
如果只单独起作用,前列腺素制剂所包括的大多数药物都不能足够渗透到皮肤中而达到其它给药途径所达到的药物浓度水平。为了解决该问题,外用药物制剂通常包含皮肤促渗剂。皮肤促渗剂也称为促吸收剂、促进剂、辅料、增溶剂、促吸附剂等。无论如何称谓,该物质是用于促进药物经皮吸收的。理想的促渗剂不仅能增加药物经皮吸收而且不会刺激皮肤、使皮肤过敏或损伤皮肤。而且,理想的促渗剂在适用剂型(如,霜剂或凝胶剂)上不应该对身体有副作用。
从促进药物经皮渗透的作用角度出发,对大量化合物进行了评价。参见,如,Percutaneous Penetration Enhancers,Maibach h.I.and Smith H.E.(eds.),CRCPress,Inc.,Boca Raton,FL.(1995),该文献研究了各种皮肤促渗剂并进行了试验测试,以及Büyüktimkin,N.,等,Chemical Means of Transdermal DrugPermeation Enhancement in
Transdermal and Topical Drug Delivery Systems,Gosh,T.K.,等,(eds.),Interpharm Press,Inc.,Buffalo Grove,IL.(1997)。前列腺素外用组合物适用的促渗剂在美国专利号为4,980,378、5,082,866和6,118,020中公开。利用这些促渗剂输送前列腺素的外用组合物在美国专利号为6,046,244、6,323,241、6,414,028和6,489,207中公开。
本发明的外用组合物可以包括一种或多种促渗剂。本发明的优选促渗剂为乙醇、丙二醇、甘油、月桂酸乙酯、棕榈酸异丙酯、豆蔻酸异丙酯、月桂氮卓酮(AzoneTM)、二氧戊环(在美国专利号为4,861,764中有描述)、大环酮、HP-101、唑烷酮、可生物降解的促渗剂(在Wong等的美国专利号为4,980,378和5,082,866中有描述,如2-(N,N-二取代的氨基)链烷酸烷基酯(例如,N,N-二甲氨基异丙酸十二烷基酯(DDAIP)),N,N-二取代的氨基烷醇链烷酸酯),及这些物质混合物。促渗剂的含量足以促进血管活性的前列腺素如前列腺素E1的渗透。具体含量根据所需释放速率和具体前列腺素E1的剂型而不同。通常,渗透剂的含量为组合物总重量的约0.1至约20wt%,优选为约0.5至约10wt%,更优选为约0.25至约5wt%。
通常,适宜的促渗剂可以是上述所列物质,也可以是亚砜、醇、脂肪酸、脂肪酸酯、多元醇、酰胺、表面活性剂、萜、链烷酮(alkanones)、有机酸及这些物质的混合物。参见Chattaraj,S.C.and Walker,R.B.,PenetraionEnhancer Classification,pp.5-20in Maibach,H.I.,and Smith,H E.,(eds.),Percutaneous Penetration Enhancers.,CRC Press,Inc.,Boca Raton,FL(1995),以及Buyuktimkin,N.,等,Chemical Means of Transdermal Drug PermeationEnhancement,in Gosh,T.K.,等,(eds.)
Transdermal and Topical Drug Delivery Systems,Interpharm Press,Inc.,Buffalo Grove,IL(1997)。适宜的亚砜包括二甲亚砜、癸基甲基亚砜及其混合物。适宜的醇包括乙醇、丙醇、丁醇、戊醇、己醇、辛醇、壬醇、正癸醇、2-丁醇、2-戊醇、苄醇、辛醇、癸基醇、月桂醇、2-月桂醇、肉豆蔻醇、十六烷醇、硬脂醇、油醇、亚油醇(linolyl alcohol)、亚麻醇(linolenyl alcohol)及这些物质的混合物。适宜的脂肪酸包括戊酸、庚酸、壬酸、己酸、癸酸、月桂酸、肉豆蔻酸、硬脂酸、油酸、亚油酸、亚麻酸、辛酸、异戊酸、新戊酸、新庚酸、新壬酸、三甲基己酸、新癸酸和异硬脂酸及这些物质的混合物。
适宜的脂肪酸酯包括正丁酸异丙酯、正己酸异丙酯、正癸酸异丙酯、豆蔻酸异丙酯、棕榈酸异丙酯、豆蔻酸辛基十二醇酯、乙酸乙酯、乙酸丁酯、乙酸甲酯、戊酸甲酯、丙酸甲酯、癸二酸二乙酯、油酸乙酯、月桂酸乙酯及这些物质的混合物。适宜的多元醇包括1,3-丙二醇、聚乙二醇、乙二醇、二甘醇、三甘醇、双丙二醇、甘油、1,2-丙二醇、山梨醇、葡聚糖、丁二醇、戊二醇(pentanediol)、己三醇(hexanetriol)及这些物质的混合物。
适宜的酰胺包括脲、二甲基乙酰胺、二乙基甲苯酰胺、二甲基甲酰胺、二甲基辛酰胺、二甲基癸酰胺、1-烷基-4-咪唑啉-2-酮、吡咯烷酮衍生物、环酰胺、环六亚甲基月桂酰胺及其衍生物、二乙醇胺、三乙醇胺及这些物质的混合物。适宜的吡咯烷酮衍生物包括1-甲基-2-吡咯烷酮、2-吡咯烷酮、1-月桂基-2-吡咯烷酮、1-甲基-4-羧基-2-吡咯烷酮、1-己基-4-羧基-2-吡咯烷酮、1-月桂基-4-羧基-2-吡咯烷酮、1-癸基-硫乙基-2-吡咯烷酮(HP-101)、1-甲基-4-甲氧羰基-2-吡咯烷酮、1-己基-4-甲氧羰基-2-吡咯烷酮、1-月桂基-4-甲氧羰基-2-吡咯烷酮、N-环己基吡咯烷酮、N-二甲氨基丙基吡咯烷酮、N-椰油烷基吡咯烷酮、N-牛油脂肪烷基吡咯烷酮、N-(2-羟甲基)-2-吡咯烷酮的脂肪酸酯、及这些物质的混合物。适宜的环酰胺包括1-十二烷基氮杂环庚-2-酮(月桂氮卓酮,Azone)、1-香叶基氮杂环庚-2-酮、1-法呢基氮杂环庚-2-酮、1-香叶基香叶基氮杂环庚-2-酮、1-(3,7-二甲基辛基)氮杂环庚-2-酮、1-(3,7,11-三甲基辛基)氮杂环庚-2-酮、1-香叶基氮杂环己-2-酮、1-香叶基氮杂环戊-2,5-二酮、1-法呢基氮杂环戊-2-酮、及这些物质的混合物。
适宜的表面活性剂包括阴离子表面活性剂、阳离子表面活性剂、非离子表面活性剂、胆汁和卵磷脂。适宜的阴离子表面活性剂包括月桂酸钠、月桂基硫酸钠及这些物质的混合物。适宜的阳离子表面活性剂包括溴化十六烷基三甲基铵、溴化十四烷基三甲基胺、氯化苄烷铵、氯化十八烷基三甲基铵、氯化十六烷基吡啶、氯化十二烷基三甲基铵、氯化十六烷基三甲基铵、及这些物质的混合物。适宜的非离子表面活性剂包括α-氢-ω-羟基-聚(氧乙烯)-聚(氧丙基)聚(氧乙烯)嵌段共聚物、聚氧乙烯醚、聚氧乙烯山梨醇酯、脂肪酸聚乙二醇酯、及这些物质的混合物。适宜的α-氢-ω-羟基-聚(氧乙烯)-聚(氧丙基)聚(氧乙烯)嵌段共聚物包括泊洛沙姆231、182和184、及这些物质的混合物。适宜的聚氧乙烯醚包括4-月桂醚(Brij 30TM)、(Brij 93TM)、(Brij 96TM)、20-油醚(Brij 99TM)、及这些物质的混合物。适宜的聚氧乙烯山梨醇酯包括单月桂酸酯(Tween 20TM,Span 20TM)、单棕榈酸酯(Tween 40TM)、单硬脂酸酯(Tween60TM)和单油酸酯(Tween 80TM)、及这些物质的混合物。适宜的脂肪酸聚乙二醇酯包括8-氧乙烯硬脂酸酯(8-oxyethylene stearate ester(Myrj 45TM))、(Myrj51TM)、40-氧乙烯硬脂酸酯(Myrj 52TM)及这些物质的混合物。适宜的胆汁盐包括胆酸钠、月桂胆酸钠、羟基乙酸钠、脱氧胆酸钠及这些物质的混合物。
适宜的萜类包括D-柠檬油精、α-蒎烯、β-enrene、a-松油醇、松油烯-4-醇、香芹醇、香芹酮、蒲勒酮、薄荷酮(piperitone)、孟酮(menthone)、薄荷醇、香叶醇、氧化环己烯、氧化柠檬油精、α-氧化蒎烯、氧化环戊烯、1,8-桉叶油素、依兰油、茴香油、土荆芥油、桉叶油、及这些物质的混合物。适宜的链烷酮(alkanone)包括N-庚烷、N-辛烷、N-壬烷、N-癸烷、N-十一烷、N-十二烷、N-十三烷、N-十四烷、N-十六烷、及这些物质的混合物。适宜的有机酸包括柠檬酸、琥珀酸、水杨酸、水杨酸酯(包括甲基、乙基和丙基二醇衍生物)、酒石酸、及这些物质的混合物。
在一个优选的实施方式中,促渗剂为2-(N-取代的氨基)-链烷酸烷基酯、(N-取代的氨基)链烷醇链烷酸酯或其混合物。为便于参考,2-(N-取代的氨基)-链烷酸烷基酯和(N-取代的氨基)链烷醇链烷酸酯可归为一组,标记为烷基(N-取代的氨基)酯。
适于本发明的2-(N-取代的氨基)链烷酸烷基酯如下式所示:
其中n是约4-约18范围内的整数;R选自氢、C1-C7烷基、苄基和苯基;R1和R2选自氢和C1-C7烷基;R3和R4选自氢、甲基和乙基。
优选的是(N,N-二取代的氨基)链烷酸烷基酯,如(N,N-二取代氨基)-乙酸的C4-C18烷基酯和(N,N-二取代氨基)-丙酸的C4-C18烷基酯和其药学上可接受的盐和衍生物。具体的2-(N,N-二取代氨基)-链烷酸烷基酯包括2-(N,N-二甲氨基)-丙酸十二烷基酯(DDAIP);
和2-(N,N-二甲氨基)-乙酸十二烷基酯(DDAA);
2-(N,N-二取代氨基)链烷酸烷基酯是已知的。例如,2-(N,N-二甲氨基)-丙酸十二烷基酯(DDAIP)得自Steroids,Ltd.(Chicago,IL)。此外,如Wong等的美国专利No.4,980,378中所描述的,2-(N,N-二取代氨基)-链烷酸烷基酯可由更易得到的化合物合成,该文献不同程度地列于此以作参考。如其介绍,2-(N,N-二取代氨基)-链烷酸烷基酯易于经两步合成而制备。在第一步中,氯代乙酸长链烷基酯通常在合适的溶剂(如氯仿)中,通过相应的长链烷醇与氯甲酸氯甲基酯等在存在合适的碱(如三乙胺)的条件下反应制备。反应描述如下:
其中R,R3,R4和n如上定义。反应温度选自约1O℃至200℃或者回流温度,优选室温。可使用溶剂,也可不使用溶剂。如果使用溶剂,可以选择宽范围的有机溶剂。碱的选择同样不是很重要。优选的碱包括叔胺,例如三乙胺、吡啶等。反应时间一般为约1小时至3天。
在第二步中,氯代乙酸长链烷基酯与合适的胺根据如下路线缩合:
其中n,R,R1,R2,R3和R4如前定义。过量的胺反应物一般用作碱,反应在合适的溶剂(如醚)中容易进行。尽管温度可以改变,但第二步优选在室温下进行。反应时间通常从约1小时至几天。可以采用常规的纯化技术,很容易得到用于药物化合物的酯。
适宜的(N-取代的氨基)-链烷醇链烷酸酯通过以下化学式表示:
其中n是约5至约18范围内的整数;y是0至约5范围内的整数;R1,R2,R3,R4,R5,R6,和R7选自氢、C1-C8烷基和C3-C8芳基;R8选自氢、羟基、C1-C8烷基和C3-C8芳基。(N-取代的氨基)-链烷醇链烷酸酯的制备及其作为促渗剂的应用在已公布的PCT国际申请WO95/09590中公开,其在此被参考引用。
优选的是(N-取代的氨基)-链烷醇链烷酸酯,如C5-C18羧酸酯和其药学上可接受的盐。示例性具体的(N,N-二取代氨基)-链烷醇链烷酸酯包括1-(N,N-二甲氨基)-2-丙醇十二烷酸酯(DAIPD);
1-(N,N-二甲氨基)-2-丙醇豆蔻酸酯(DAIPM);
1-(N,N-二甲氨基)-2-丙醇油酸酯(DAIPO);
(N,N-二取代氨基)-链烷醇链烷酸酯易于通过相应的氨基链烷醇和月桂酰氯在三乙胺存在的条件下反应制备。溶剂,例如氯仿是可有可无的,但是优选有溶剂。例如在氯仿中在三乙胺存在的条件下,1-(N,N-二甲氨基)-2-丙醇可与月桂酰氯反应生成1-(N,N-二甲氨基)-2-丙醇月桂酸酯(DAIPD)。
促渗剂的含量足以促进血管活性前列腺素如前列腺素E1的渗透。具体含量根据所需释放速率和具体前列腺素E1的剂型而不同。通常,渗透剂的含量为组合物总重量的约0.1至约10wt%,优选为约0.5至约10wt%。
此外,如果需要,也可添加其它已知的透皮促渗剂,例如,二甲亚砜(DMSO)、二甲基乙酰胺(DMA)、2-吡咯烷酮、N,N-二乙基-间甲苯酰胺(DEET)、1-十二烷基氮杂环庚-2-酮(AzoneTM,Nelson Research的注册商标)、N,N-二甲基甲酰胺、N-甲基-2-吡咯烷酮、巯基乙酸钙、噁唑烷酮、二氧戊环衍生物、月桂氮卓酮衍生物和大环类促进剂,如大环酮。
天然的和修饰的多糖胶也是组合物的一种重要成份。适宜的代表性胶属于天然的和修饰的半乳甘露聚糖胶类。半乳甘露聚糖胶是包括D-半乳糖和D-甘露糖单元的碳水化合物聚合物,或这类聚合物的其它衍生物。组合物中的半乳甘露聚糖种类很多,根据其来源而不同。半乳甘露聚糖胶特征为(1→4)连接为直链结构的β-D-甘露吡喃糖单元。和主链发生(1→6)连接的单一成员α-D-甘露吡喃糖基(manopyranosyl)单元作为侧链存在。半乳甘露聚糖胶包括瓜儿豆胶,其是在两种豆科植物(Cyamposis tetragonalobus和psoraloids)的种子胚乳研磨成粉而得,以及刺槐豆胶,其是在carobtree(ceratonia siliqua)的种子胚乳中发现的。适宜的修饰的多糖胶包括天然的或取代的多糖胶的醚,如羧甲基醚、乙二醇醚和丙二醇醚。取代的多糖胶的示例为甲基纤维素。
其它适宜的代表性胶包括瓜儿豆胶、角叉胶、达瓦树胶(ghatti gum)、刺梧桐树胶、鼠李聚糖胶(rhamsan gum)和黄原胶。本发明的组合物可以包括各种胶的混合物或胶和酸性聚合物的混合物。
胶,尤其是半乳甘露聚糖胶是熟知物质。参见,例如,IndustrialGums:Polysaccharides & Their Derivatives,Whistler R.L.and BeMiller J.N.(eds.),3rd Ed.Academic Press(1992)and Davidson R.L.,Handbook of Water-SolubleGums & Resins,McGraw-Hill,Inc.,N.Y(1980)。大多数的胶是可购得的,其形式多种,通常是粉末状,便于用在食品和外用组合物中。例如,刺槐豆胶的粉末可购自Tic Gums Inc.(Belcam,MD)。
当组合物中添加多糖胶时,多糖胶的含量是组合物总重量的约0.1%-约5%,优选为0.5%-3%。在一个优选实施方式中,多糖胶的含量为2.5wt%。示例的组合物在下述实施例中给出。
可选择性添加的多糖胶是聚丙烯酸聚合物。通常的聚丙烯酸聚合物通常被称作“卡波姆”(″carbomer″)。卡波姆是与聚链烯基聚醚轻度交联的聚丙烯酸聚合物,可从B.F.Goodrich Company(Akron,Ohio)购得,商品名称为″CARBOPOLTM″。尤其优选的卡波姆是被称作″CARBOPOL 940″的物质。
适用的其它聚丙烯酸聚合物是可购得的名为″PemulenTM″(B.F.GoodrichCompany)和″POLYCARBOPHILTM″(A.H.Robbins,Richmond,VA)的聚合物。PemulenTM聚合物是丙烯酸C10至C30烷基酯和一个或多个丙烯酸、甲基丙烯酸单体或者它们与蔗糖烯丙醚或季戊四醇烯丙醚交联的简单酯的共聚物。POLYCARBOPHILTM促渗剂是丙烯酸与联乙烯二醇的交联物。
如果组合物中添加聚丙烯酸聚合物,则其含量占组合物总重量的约0.5%-约5wt%。
半固体组合物具有适宜的粘度从而使组合物存留在舟状窝内。半固体组合物能够表现牛顿流变学特征或非牛顿流变学特征。在一些优选实施方式中,本发明的半固体组合物表现了非牛顿流变学特征,即表观粘度由施加到组合物的剪切速率所决定。优选的组合物具有“剪切变稀”的流变学性质。本发明所用“剪切变稀”是指随着剪切速率的提高,表观粘度(剪切应力与剪切速率的比例)明显降低,无论是表观粘度的显著降低不随时间改变(假塑性)、随时间改变(触变性),还是与屈服应力相关,其中屈服应力被定义为在流动开始之前必须超越的应力,(Bingham plastics and generalized Bingham plastics)。参见Harris,J.,& Wilkinson,W.L.,″Non-newtonian Fluid,″pp.856-858 inParker,S.P.,ed.,McGraw-Hill Encyclopedia of Physics,Second Edition,McGraw-Hill,New York,1993。组合物适宜的粘度范围为约5,000厘泊(cps)至约20,000cps,优选为约7,000厘泊(cps)至约13,000cps。
在某些优选的实施方式中,血管活性前列腺素从药物储库中释放一段时间。应该认为,血管活性前列腺素从经阴茎口施用的半固体组合物中一段时间的释放是从药物储库释放的一种类型。在其它类型中,血管活性前列腺素可以从包括已置入其它部位的其它聚合物载体的组合物中释放出来。
另一种重要的组分是亲脂性组分。本发明的“亲脂组分”是指既亲脂又亲水的物质。药学领域普通技术人员会理解一个化合物的亲脂性是利用分配系数与其它化合物相比较的常规定性方法而确定的。分配系数是国际纯粹和应用化学联合会(IUPAC)所定义的,其为在不同种类的体系(两相)的平衡状态时,物质在两相中的分配比值;在恒定温度下,相同物质分子在两相中的浓度(或严格的说是活性)的比值是常数。
C1-C8脂肪醇、C2-C30脂肪酯及其混合物可作为亲脂性组分。示例的适宜醇为乙醇、正丙醇和异丙醇,适宜的脂为乙酸乙酯、乙酸丁酯、月桂酸乙酯、丙酸甲酯、豆蔻酸异丙酯和棕榈酸异丙酯。本发明中的术语“脂肪醇”包括多元醇,如甘油、丙二醇和聚乙二醇。在一个实施方式中,醇和酯的混合物是优选的,尤其是乙醇和月桂酸乙酯的混合物是优选的。
在一些实施方式中,亲脂性组分包括至少一种液态多元醇。在优选的实施方式中,液态的多元醇为聚乙二醇,其选自聚乙二醇200、聚乙二醇400和聚乙二醇600。当包含聚乙二醇时,组合物中聚乙二醇的含量为组合物总重量的约1-约25wt%。优选地,聚乙二醇为聚乙二醇400(PEG400)。聚乙二醇400的含量为组合物总重量的约1-约25wt%,优选为约3-约20wt%。
在一个实施方式中,C2-C30脂肪酯及包括亲脂性组分的混合物包括甘油的C8-C30脂肪酯,其选自甘油一酸酯、甘油二酸酯、甘油三酸酯及它们的混合物。适宜的脂肪酯包括饱和脂肪酸甘油酯、不饱和脂肪酸甘油酯及它们的混合物。适宜的饱和脂肪酸包括己酸、辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、二十二酸和二十四烷酸。适宜的不饱和脂肪酸包括油酸、亚麻油酸和亚麻酸。适宜的甘油酯包括甘油一油酸酯、甘油三油酸酯、三豆蔻酸甘油酯和三硬脂酸甘油酯,优选为三豆蔻酸甘油酯。
所需亲脂性组分的浓度依其它各因素而变,如所需半固体的稠度和所需皮肤渗透的效果。适宜的亲脂性组分的浓度占组合物总重量的0.5%-40%。优选的外用组合物包含的亲脂性成分的浓度占组合物总重量的7%-40%。
当采用脂肪醇和脂肪酯的混合物时,醇的适宜含量为0.5%-10%。在一个优选实施方式中,醇的含量占组合物总重量的5%-15%,而脂肪酯占2%-15%。在另一个优选实施方式中,醇的含量占组合物总重的0.5%-10%,而脂肪酯占0-10%。
亲脂性组分的浓度依其它因素而改变,如所需半固体的稠度和所需皮肤渗透的效果。优选的外用组合物包含的亲脂性组分占组合物总重量的7%-40%。当采用脂肪醇和脂肪酯的混合物时,优选的醇含量占组合物总重量的5%-15%,而脂肪酯占2%-15%。
可选择性加入的,但优选是加入的组分是乳化剂。尽管不是关键因素,适宜的乳化剂通常的亲水-亲脂平衡常数大于10。蔗糖酯,具体为硬脂酸蔗糖酯,能够作为组合物中的乳化剂。硬脂酸蔗糖酯是熟知的乳化剂,其能够从各种商业途径获得。当使用乳化剂时,硬脂酸蔗糖脂占组合物总重量的比例优选为至多约2%。硬脂酸蔗糖酯乳化剂的优选含量也可以用乳化剂与多糖胶的重量比例表示。优选乳化剂与胶的比例为1-6,最优选1-4,可以产生预期的半固体稠度和分层阻力。
也适用的其它乳化剂包括聚氧乙烯山梨醇酯、长链醇,优选为鲸蜡硬脂醇(cetostearyl alcohol)以及脂肪酸甘油酯。适宜的聚氧乙烯山梨醇酯包括单月桂酸酯(Tween 20TM,Span 20TM)、单棕榈酸酯(Tween 40TM)、单硬脂酸酯(Tween 60TM)和单油酸酯(Tween 80TM)及它们的混合物。优选的脂肪酸甘油酯包括甘油一油酸酯、甘油三油酸酯、三豆蔻酸甘油酯和三硬脂酸甘油酯。
本发明包括酸性缓冲体系。酸性缓冲体系有助于维持或缓冲组合物的pH落在预期的范围内。本文使用的术语″缓冲体系″或″缓冲剂″指溶质试剂或试剂,当它们溶于水溶液时,能够稳定该溶液,使溶液中加入酸或碱时pH值(或者氢离子浓度或活度)不发生大的变化。阻止pH值离开上述范围内的起始缓冲pH值发生变化的上述溶质试剂或试剂是公知的。尽管有许多其它合适的缓冲剂,但已经证明了磷酸钾一水合物对本发明的组合物具有有效的作用。
药物组合物的最终pH值可以在生理相容的范围内变化。必要的是最终pH值不能刺激人的皮肤。在没有违背这一限制条件下,可以选择既促进活性物质的稳定性又能调节所需稠度的pH值。在一个实施方式中,优选的pH值为约3.0-约7.4,更优选为约3.0-约6.5,最优选为约3.5-约6.0。
组合物的其余组成是水,而且是必须纯化后的水。组合物包含的水占组合物总重量的约50%-约90%。水的具体含量要求不严,只要其能够调节其它组成以获得所需稠度和/或浓度。
前列腺素E1稳定剂、着色剂、流变学改进剂和防腐剂的添加量不能过度限制前列腺素E1的皮肤渗透性或对所需半固体稠度不利。
半固体药物组合物的预期剂型为霜剂、凝胶剂、软膏剂、胶状悬浮液及类似剂型,也包括但不限于适用于透皮贴剂及类似装置的组合物。上述所列组成可以以能够制备稳定组合物的任何顺序和方式进行混合,以制得包括均匀分散于半固体制剂中的前列腺素E1的稳定组合物。制备该组合物的一种可行方法包括将多糖胶(或聚丙烯酸聚合物)均匀分散于预先混合的水/缓冲液中,然后充分匀化(混合)所得混合物,该混合物为“部分A”。如果需要加入乳化剂,则在分散多糖胶之前将乳化剂加入到水/缓冲液中。可以采用任何适宜的方法调节部分A的pH值以达到可使用的程度,例如,加入浓磷酸或氢氧化钠的方法。
单独地,在搅拌下,将前列腺素E1溶于亲脂性组分中,该亲脂性组分可以是多种醇、多种酯或醇与酯的混合物,然后,加入促渗剂。或者,当亲脂性组分包括醇和酯时,前列腺素E1在加入促渗剂之前可先溶于醇中,然后再加入酯。无论采取何种方法,得到的混合物都为“部分B”。最后步骤是在持续混合下,将部分B缓慢加入(如,逐滴加入)部分A中。
得到的外用组合物表现出没有过量施用药物而使前列腺素E1的渗透性和生物利用度得到改善,减少了皮肤伤害和相关的感染,增加了剂型的可选择范围。这些组合物可用前列腺素E1长时间地治疗外周血管疾病、男性阳萎和其它疾病,而避免了低生物利用度和其它传输途径相关的快速化学降解。前列腺素E1在用于患者皮肤的外用组合物中的应用使得前列腺素E1能够预先确定持续给药量,避免了通过注射途径的一次或多次给予较大剂量而产生的不良作用。通过维持持续的剂量速率,前列腺素E1在患者靶组织中的浓度能够更好地被维持在最佳治疗范围内。
在一个实施方式中,组合物包括占组合物总重量约0.01%-约5%的修饰的多糖胶;约0.001%-1%的前列腺素,其选自PGE1、其可药用盐、其低级烷基酯及它们的混合物;约0.5%-约10%的DDAIP或其盐;约0.5%-约10%的低级醇,其选自乙醇、丙醇、异丙醇及它们的混合物;约0.5%-约10%的酯,其选自月桂酸乙酯、肉豆蔻酸异丙酯、月桂酸异丙酯及它们的混合物;和酸性缓冲液。优选的组合物也包括至多约2%的硬脂酸蔗糖酯。
组合物还任选地包括至多约5%乳化剂。优选地,组合物包括至多约2%的乳化剂。适宜的乳化剂包括聚山梨醇酯,如Tweens、甘油一油酸酯、甘油三油酸酯、三豆蔻酸甘油酯和三硬脂酸甘油酯。优选的乳化剂为三豆蔻酸甘油酯。
本发明的实施在下述实施例中描述。这些实施例意欲举例说明本发明而不是限制其保护范围。组合物中不会负面影响前列腺素E1的作用的变化对于本领域技术人员是显而易见的,这些变化也在本发明的保护范围内。例如,其它着色剂、抗微生物防腐剂、乳化剂、芳香剂、前列腺素E1稳定剂及类似物质的成份也可包括在组合物中,只要使所得组合物仍保持上述所需特性。当添加防腐剂时,其加入量通常为约0.05%-约0.30%。适宜的防腐剂包括对羟基苯甲酸甲酯类(甲基PABA)、对羟基苯甲酸丙酯类(丙基PABA)和丁基羟基甲苯(BHT)。适宜的香精和芳香剂是本领域已知的;适宜的芳香剂为至多占组合物总重量的约5%的桃金娘烯醇,优选为约2%的桃金娘烯醇。如果需要,本发明的组合物也可以包括少量,约0.01%-约4%重量比的外用麻醉剂。外用麻醉剂包括利多卡因、达克罗宁、地布卡因、及其可药用盐和混合物。在一个优选实施方式中,外用麻醉剂为占组合物重量约0.5%的达克罗宁。在另一个优选实施方式中,外用麻醉剂为占组合物重量约2.5至约5wt%的利多卡因。
药物制剂优选以单位剂量形式存在。该形式的制剂被分成包含适量活性成份的单位剂量。单位剂量形式为包装的制剂,含有具体量的药物制剂的包装为如硬塑料投放器或软包装。
本发明的另一方案是提供在一适宜容器中包含如上所述的治疗早泄的组合物的产品,优选的容器为如美国专利No.6,224,573中公开的容器,如投放器,以及标签说明书。或者,该容器可以是具有适宜大小孔的管,如尖端伸出的管、袋、包或可挤压的瓶,这些容器可以以任何适宜材料制得,如硬塑料或软塑料。
标签说明书可以是小册子、产品包装上的标签或与该包装有关的标签。
标签说明书用于指导早泄患者在阴茎口给予本发明组合物,指导患者垂直握住阴茎、使阴茎口(meatus)张开并将组合物置入舟状窝内而不要将容器放入口内,需在性交前约5-30分钟时给药。打印的标签说明书是用于描述本发明的组合物用于治疗早泄的方法。标签说明书是本发明的一个重要方面,因为在组合物被批准任何用途之前,必须得到可靠的国家管理机构如美国食品药品监督管理局的批准才可投入市场。部分步骤包括提供最终销售的药物组合物的标签。标签可以包括对组合物的定义和一些其它内容,如临床药理、作用机理、药物耐受、药代动力学、吸收、生物利用度、禁忌症等,还提供必需剂量、给药途径和用途。因此,当药品通过市场到达患者手中,带有投放器的组合物和治疗说明书的结合才是合理应用药物的重要环节。因此,治疗说明书根据前述治疗方法而描述其用途。
舟状窝提供了适于使用半固体药物组合物并使药物停留的天然开阔部分。当将半固体药物,如本发明的组合物,置于阴茎口中时,会很好地阻碍药物从该部位、阴茎口和尿道的狭窄出口流出。流动的被阻碍与通道横截面积和长度成比例。因此,适宜选择的粘度的半固体药物会处于窝内,从而便于如血管扩张剂的活性成份的吸收。组合物粘度的适宜范围为约5,000cps-约20,000cps,优选为约7,000cps-约13,000cps。在优选实施方式中,所选择的组合物的粘度使施用的组合物的约90%-约99%保留在舟状窝中达约30分钟,优选为约93%-约98%,最佳为超过98%的组合物能保留在舟状窝中达约30分钟。
单位剂量的活性成份含量范围在0.01mg-1g,具体含量根据具体应用和血管活性前列腺素的效力而定。例如,当血管活性的前列腺素是前列腺素E1,其含量为约0.05mg-约0.8mg,优选为约0.1mg-约0.5mg,而在另一个实施方式中,为约0.2mg-约0.3mg。如果需要,组合物也可包含其它相容性治疗剂,如抗高血压药哌嗪基喹唑啉。
半固体血管活性前列腺素组合物应在性交前约2-30分钟,优选性交前约10-20分钟时用于阴茎的舟状窝中。
除非特别说明,每个组合物都是通过常规混合所述各种成份而制备的。
实施例1
示例性组合物
组合物A如下制备。通过在5份的乙醇中溶解0.4份的前列腺素E1(Alprostadil USP)而得到A部分。然后,将2.5份(N,N-二甲氨基)-丙酸十二烷基酯与醇-前列腺素E1溶液相混合,随后加入5份月桂酸乙酯。
B部分先从制备pH值为5.5的水/缓冲液开始。水/缓冲液通过将足量磷酸一氢钾加入纯水中得到0.1M溶液而制备得。用强碱溶液(1N氢氧化钠)和强酸(1N磷酸)将水/缓冲液的pH调节至5.5。缓冲液占总组合物的约80份。所有份都为重量份。
在缓冲液中加入0.5份的月桂酸乙酯。然后,将刺槐豆胶(以粉末形式)分散到缓冲液中,用搅拌器件搅匀。表1为成份列表。
所得组合物为适用于皮肤的易涂抹半固体物,不需要如贴片和粘合带等支承装置。组合物既均匀又不易分层。
表1:外用前列腺素E1组合物
成分(wt%) | A | B | C | D | E | F | G | H | L |
预水化的刺槐豆胶预水化的修饰的瓜儿豆胶水/缓冲液(pH5.5)硬脂酸蔗糖酯前列腺素E1DDAIP乙醇月桂酸乙酯利多卡因 | 3-810.50.1555- | 3-810.50.2555- | 3-810.50.3555- | 3-810.50.4555- | 3-810.50.4555- | 3-810.50.5555- | 3-810.50.4510-- | -381-0.32.5533 | -381-0.32.5532.5 |
其余示例的组合物B-H,按照表1所列成份以相同的方法制备得。如上所述,在其它实施例中,如组合物H,组合物可包含修饰的多糖胶,适宜为修饰的半乳甘露聚糖胶,如修饰的瓜儿豆胶。也可以用聚丙烯酸聚合物代替多糖胶。
示例性组合物L是一种适宜的组合物,其包括射精潜伏期延长量的外用麻醉剂,在该实施例中为组合物总重量的2.5%的利多卡因。
实施例2
含有利多卡因的组合物的安全性筛选研究
根据选入标准和排除标准,选了8名患者进行6周单盲试验。选入标准为男性,年龄20-55,具有稳定的异性关系,每周不低于1次性交次数,有超过3个月的PE(早泄)病史,射精潜伏期小于2分钟和/或性交后的性满足率低于50%。排除标准为:身体检查出现不正常,包括生殖器检查、血象或化验不正常、实验室化验结果显示肝脏和肾功能不正常、睾丸激素不正常、泌乳刺激素不正常、泌尿生殖器道感染,如前列腺炎、尿道炎或附睾炎,神经失调或具明显的心理障碍而需要精神病学上的治疗以及服用了任何可能改变性行为的抗抑郁剂、酒精或药物滥用者、低血压或6个月内患有心肌梗塞、心力衰竭或心绞痛者。
对患者共进行4次访问:筛选调查(给药前两周)、调查1(开始给药)、调查2(给药后3周)、调查3(给药后6周)。在前两周内,治疗前对射精潜伏期时间(ELT)进行测时(至少测两次)。给每名患者两种前列地尔(Alprostadil)霜剂,每种都含有1mg的前列腺素E1。每种霜剂都包含3个剂量,每剂量含约0.3mg。告知患者在性交前5-20分钟时将外用霜剂涂到阴茎头(即阴茎口)。
基本功效的不同体现在用秒表测定的ELT。患者的满意程度记录在患者日记中。患者按照要求使用研究用药物,被告知24小时内不能使用超过一个剂量的约0.3mg,每周不能使用少于一个剂量。在研究结束时,研究人员根据射精潜伏期、性满足率、全部功效评价和副作用记录来分析药物的效力和安全性。射精潜伏期延长至2分钟以上的被认为是临床上的有效。参与患者的整体数据见下表2。
表2总人员数据
范围 | 平均值 | |
年龄体重身高饮酒史吸烟史 | 25-64岁62-79公斤163-187cm5(62.50%)3(37.50%) | 41.25岁67.38公斤169.25 |
患者的PE史总结于表3中。
表3PE史
患者 | PE史时间(月数) | ELT(秒) | 性交频率(每周) | PE率(%) | 以前的治疗 | 病因 |
12345678 | 142631805231912 | NA30-506018020-30306030-60 | 0-11.5221-221-21 | 50504050100303350 | 50mg西地那非24-50mg西地那非无中药50mg西地那非无25mg西地那非25-50mg西地那非 | 心理性心理性心理性伴随ED器质性伴随ED伴随ED伴随ED |
表4给出了每个患者的结果。原始和给药后的平均ELT(±SE)分别为1.03±0.19和1.39±0.39分钟(p>0.05)。8名患者中的4名ELT没有变化。只有一名患者,使用了霜剂后,平均ELT超过2分钟,从2分钟改善为4分钟。在研究起点至研究终点之间,身体的检查结果没有明显变化。所有患者的副作用都小且无需药物治疗。在研究结束时,安全分析表明研究用的药物在治疗早泄中是安全的。少数患者的ELT没有明显延长。
表4患者结果:前列地尔的研究(0.3mg/剂)
患者 | 年龄 | 给药前的ELT(分钟) | 给药后的ELT(分钟) | 副作用 |
12345678 | 6445274425394640平均SDSE | 110.521.20.51.50.51.030.540.19 | 11141.30.81.50.51.391.100.39 | 尿道轻微疼痛尿道轻微疼痛尿道轻微疼痛---尿道轻微疼痛尿道轻微疼痛>0.05 |
实施例3含有前列地尔和利多卡因的组合物的临床研究
对44名患者进行更大规模的临床研究,其中43名患者完成了研究。总人员数据见表5。
研究中采用单位剂量投放器。每次使用的投放器的含量为75mg霜剂中含有0.4%的前列地尔(300mcg)/利多卡因(2.5%)。两次给药的最小间隔为24个小时。患者每周用药不少于两次。
表5总人员数据
范围 | 平均值 | |
年龄体重身高饮酒史吸烟史 | 21-53岁60-100公斤159-185cm15(34%)4(18%) | 37岁74.18公斤172.93 |
前两周,收集PE患者的原始射精潜伏期时间(ELT)(>2次)。给所有患者最小的4个剂量霜剂。告知患者在性交前5-20分钟时将外用霜剂涂到阴茎头(即阴茎口)。正如秒表所测,主要的功效变化是ELT。记录患者和性伙伴的满足程度。临床功效基于患者的日记由医生进行评价。
患者各组的总数据见表6。
表6PE史总结
范围 | 数量 | 百分比 | |
致病类型病因 | 后天的自成年环境型普通型器质性心理原因伴有ED其它 | 271773772980 | 61.438.69.184.115.965.918.180 |
患者的PE史总结于表7中。
表7PE史
患者 | 患PE的时间(月) | ELT(秒) | 性交频率(每周) | PE发生频率(%) | 类型 | 治疗史 | 病状 | 病因 |
12345678910111213141516171819202122232425262728293031323334353637 | 246388361648248996726210361610301203618060165120120609648729618036488438852 | 805030090703040152080050457530703570306060909012060903060120120606060606030 | 13-41223134311141251-21-211-21231123321-223210-10.5 | 9510090100908510080100901001009590857570858010080100801001001001001005050901001001008095100 | 普通型普通型普通型普通型环境型环境型普通型环境型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型普通型环境型环境型普通型普通型普通型普通型普通型普通型普通型 | 曲唑酮50mg,bid曲唑酮50mg,bidBaiyoujie20mg,qd中药中药中药中药中药 | 后天的自成年起后天的自成年起后天的后天的后天的自成年起后天的后天的后天的后天的后天的自成年起后天的后天的后天的后天的后天的后天的自成年起后天的自成年起自成年起自成年起自成年起自成年起自成年起自成年起自成年起自成年起自成年起自成年起自成年起后天的后天的后天的 | 心理性心理性心理性心理性心理性心理性心理性心理性心理性心理性混合性心理性混合性心理性混合性心理性心理性心理性混合性心理性器质性器质性心理性器质性器质性器质性器质性心理性心理性心理性器质性心理性心理性心理性心理性心理性伴有ED |
38394041424344 | 942861132144 | 3045606030200 | 2223220-1 | 1009010070100100100 | 普通型普通型普通型普通型普通型普通型环境型 | 性交前施用氯米帕明25mg性交前施用氯米帕明25mg | 后天的后天的后天的后天的自成年起后天的后天的 | 心理性伴有ED伴有ED心理性心理性心理性伴有ED |
在前列地尔/利多卡因的霜剂治疗组中,原始和给药后的平均(±SE)ELT分别为0.89±0.08和3.12±0.36分钟,净增长为2.23±0.36分钟(p<0.001)。参见表8,其中所示结果单位为秒。所有患者的ELT延长至2分钟以上的占53.5%(23/43)。患者和其性伙伴达到性满足的为72.1%(31/43)和67.4%(29/43)。研究人员评价的临床疗效为72.1%。所有副作用都轻微且通常是暂时的局部充血疼痛或发热。
表8射精潜伏期(秒)
患者 | 给药前ELT(秒) | 给药后ELT(秒) | 延长的时间(秒) |
123456789101112131415161819202122 | 8050300907030401520800504575303570306060 | 803004515011045522545210290145110503601606019590306060 | 025015150203851955195270651100315853016020000 |
23242526272829303132333435363738394041424344平均标准偏差 | 909012060903060120120606060545130303560712616053.530.8 | 909060012090306030030012012090505299375146409206372141109329189142.0 | 004806000018018060603045124834511637414630111593329136140.2 |
对患者性满足率的治疗效果:9名患者(20.93%)为显著改善,22名患者(51.16%)为改善,12名患者(27.91%)为没有变化。对患者性伙伴的性满足率的治疗效果:9名(20.93%)为显著改善,20名(46.51%)为改善。
将总疗效定义为射精潜伏期延长≥2分钟且性满足率为显著改善或改善。24名患者(24/43)满足上述标准,临床有效率为55.8%。
医生评价临床疗效为62.79%(27/43)。完成研究的43名患者中的31名表示该研究所用药物改善了他们的早泄状况。
表9结果总结
射精潜伏期超过2分钟 | 58.14% |
患者的性满足率患者的性满足率总疗效研究人员作出的临床疗效评价患者的总疗效评价 | 72.09%67.44%55.80%62.79%72.09% |
实施例4
含有达克罗宁的示例性组合物
示例性组合物PDC1如下制备。通过在5份的乙醇中溶解0.4份的前列腺素E1(Alprostadil USP)而得到A部分。然后,将0.5份(N,N-二甲氨基)-丙酸十二烷基酯.HCl与醇-前列腺素E1溶液相混合,随后加入2.5份月桂酸乙酯和外用麻醉剂。
B部分先从制备pH值为5.5的水/缓冲液开始。水/缓冲液通过将足量磷酸一氢钾加入纯水中得到0.1M溶液而制备得。用强碱(1N氢氧化钠)和强酸(1N磷酸)将水/缓冲液的pH调节至5.5。缓冲液为总组合物的约81份。或者,用磷酸和氢氧化钠调节组合物的pH。加入适量的纯化水。所有份数都是基于组合物总重的重量份。
在缓冲液中加入0.5份的月桂酸乙酯。然后,将预先水化的修饰的瓜儿豆胶(以粉末形式)分散到缓冲液中,用搅拌器件搅匀。表10为成份列表。
所得组合物为适用于皮肤的易涂抹半固体物,无须承载物如帖剂和粘附带。组合物既均匀又不易分层。
表10:外用含前列腺素E1和达克罗宁的组合物
成分(wt%) | PDC1 | PDC2 | PDC3 | PDC4 | PDC5 | PDC6 | BLC2 | BLC3 |
预水化的修饰的瓜儿豆胶水/缓冲液(pH5.5)前列腺素E1盐酸达克罗宁利多卡因DDAIP HCl乙醇月桂酸乙酯 | 381040.5-2.553 | 3810.41.0-2.553 | 38101.0-2.553 | 3810.4--2.553 | 381---2.553 | 381-1.0--53 | 381--5.02.553 | 381--5.0-53 |
其余示例的组合物按照表10所列成份以相同的方法制备得。此外,发现组合物在瓜儿豆胶和DDAIP HCl浓度低时也有疗效,见表11。
表11:前列腺素E1和达克罗宁的其它外用组合物
成分(wt%) | DD1 | DD2 | DD3 | DD4 | DD5 | DD6 | DC1 | DC2 |
预水化的修饰的瓜儿豆胶前列腺素E1盐酸达克罗宁利多卡因DDAIP HCl乙醇月桂酸乙酯 | 2.50.40.500.553 | 2.50.41.000.553 | 2.501.000.553 | 2.50.4000.553 | 2.50000.553 | 2.501.00053 | 2.5005.00.553 | 2.5005.0053 |
用磷酸和氢氧化钠调节组合物的PH。加入适量的纯化水。
实施例5达克罗宁组合物的临床研究
含PGE1和外用麻醉剂的外用组合物在治疗早泄中的疗效研究是采用双盲、交叉和随机性的临床研究。根据患者的选入标准/排除标准,选择了30名患者。在收集和评价患者一般数据和性功能数据的筛选准备后,开始4周的双盲试验研究。在研究中进行两次附加调查(给药后的第2周末和第4周末)。研究人员根据秒表测出的射精潜伏期时间(ELT)的变化、患者和其性伙伴的性满足率、副作用来评价药物的效力和安全性。研究期间,每名患者使用8次前列地尔霜剂。临床样本由NexMed Pharmaceuticals(Zhong Shan),Ltd.提供。患者施用的药物根据使用需要包装在投放器中。要求患者24小时内不能使用超过一个剂量,每周使用不能少于一个剂量。在研究中患者不能进行其它PE治疗。对其它疾病的治疗可以继续。要求所有患者在患者日记中记录性行为状况。
对每名患者进行共4次调查:筛选调查(给药前两周)、调查1(开始给药)、调查2(给药后2周)、调查3(给药后4周)。在前两周内,治疗前对射精潜伏期时间(ELT)进行测时(至少测两次)。在调查1和调查2的两次调查中分别给每名患者含有活性霜剂的各4个共8个投放器。施药后患者应返回汇报外用组合物治疗PE的安全性和疗效。一个半月后完成研究。
告知患者阴茎口用药是指将药物用在阴茎头而进入舟状窝内,垂直握住阴茎、使阴茎口张开并将药物滴入舟状窝内而不要将容器放入口内。
患者组一般特征描述见表12。
表12患者一般数据
患者数 | % | |
年龄分布20-3031-4041-50>50过敏史Y/N饮酒史Y/N吸烟史Y/N患PE的时间(月):平均(最短,最长)年龄范围(年):产均(最小,最大)身高范围(cm):平均(最低,最高)体重范围(kg):平均(最轻,最重) | 1312140//3011//199//2149.1(9,150)46.6(28,62)174.4(165.0,182.0)75.9(62.0,67.0) | 3.310.040.046.70/10036.7/63.330/70 |
研究组的各患者的特征见表13。所有患者的PE分为后天的和普通型。每名患者在治疗前ELT都小于80秒,PE发生率为80-100%。
表13PE史
患者 | 患PE的时间(月) | 治疗前ELT(秒) | 性交频率(每周) | PE发生频率(%) | 治疗史 | 病因 |
123456789101112131415 | 5664213049925150205416113883737 | 6370389517970493158543613666 | 11-210-11210-111-21-211-221-2 | 80909010010080901001008595100858090 | 曲唑酮50mg,tid中药性交前30分钟施用氯米帕明25mg中药 | 心理性心理性心理性伴有ED心理性心理性心理性器质性心理性心理性心理性心理性伴有ED心理性心理性 |
161718192021222324252627282930 | 543532304835577422184933477497 | 163765435865803543706945504835 | 11221-31-2111211-312-31 | 1001008010095809010010010080909590100 | 中药中药中药/壮阳药(口服)中药/壮阳药(口服) | 心理性器质性伴有ED心理性器质性心理性伴有ED心理性伴有ED心理性伴有ED伴有ED心理性心理性心理性 |
主要测量值是ELT,由患者用秒表测量。每次治疗的延长时间为治疗前的ELT和治疗后的ELT之差。各患者数据见表14。
表14ELT的延长
患者 | 组合物 | |||||||
PDC1 | PDC2 | PDC3 | PDC4 | PDC5 | PDC6 | BLC2 | BLC3 | |
1234567891011121314151617181920 | 182415287611092211708125913728617724915910415463155247292 | 2673903324111930118538229162326217199841348453165167242 | 25736026266418660269972246117269591292941310592202 | 2773603721114921122056184112326197259741046933115147252 | 22732028716-1151190-9189-825614219412-161423512157 | 187310262-441211501161-320611721934-924332513182 | 207220212-94102100639-81861172699-16-1623516152 | 24737030791591711906189112296187259841291344395207232 |
21222324252627282930 | 22580195197240181450275102100 | 1756035162160161375260127105 | 135102752790111345200112155 | 1553016014719517144521067140 | 11530-35273011280160715 | 13560-352714051305180210 | 12510-5-30211851206215 | 175859515711010133523017275 |
总值平均值 | 5853195 | 5355179 | 4378146 | 5248175 | 280193 | 290897 | 214872 | 4898163 |
结果总结于表15和16中。无论是基于治疗后的ELT,还是基于根据治疗前ELT所计算出的每名患者的延长值,或是基于患者组的治疗前的平均ELT(表15),甚或是基于患者获得ELT>2分钟的比值(表16),各种治疗疗效等级相同。含有PGE1的组合物获得的ELT延长时间最长,其中,包含达克罗宁以及PGE1的组合物的ELT延长时间更长。含局麻药而不含PGE1的组合物(BLC3,PDC3和PDC6)比空白对照PDC5获得更长的ELT延长时间。促渗剂DDAIP的存在使不含PGE1的1%达克罗宁组合物的疗效略微增加,但在不含PGE1的5%达克罗宁组合物中也看到了相反作用。
表15ELT结果总结
组成 | 时间的延长 | ||||||
PGE1 | 达克罗宁 | 利多卡因 | DDAIP | 编号 | 治疗后的ELT | 患者自身 | 患者之间 |
0.40%0.40%0.40%---- | 0.50%1.00%--1.00%1.00%-- | ---5.00%--5.00% | 是是是否是否是是 | PDC1PDC2PDC4BLC3PDC3PDC6PDC5BLC2 | 245229225213193150141118 | 1951801751631431009168 | 195179175162146979372 |
表16结果:治疗后ELT>2分钟的患者比例
给药前的给药后的ELT的延长 治疗后ELT>2分钟的患者比例
ELT | ELT | 时间 | 患者 | % | |
PDC1PDC2PDC4BLC3PDC3PDC6PDC5BLC2 | 5050505050505050 | 245229225213193150141118 | 195179175162146979372 | 2824232222141311 | 93.380.076.773.373.346.743.336.7 |
偏差分析(ANOVA)显示治疗组合物之间的偏差比组合物之间的偏差更显著。见表17。
表17ANOVA结果
偏差来源 | SS | Df | MS | F | P值 | F crit |
组合物之间组合物内总值 | 450692.66252268693.8332719386.496 | 7232239 | 64384.6669778.8527 | 6.68407155 | 4.2E-7 | 2.049195 |
利用配对t检验对各种治疗效果进行评价。分析结果见表18。
表18延长(ELT)数据的t检验分析总结
组成 | 配对t检验平均值的显著差异(P=0.05) | ||||||||||
PGE1 | 达克罗 | 利多卡因 | DDAIP | 编号 | PDC5 | PDC2 | PDC3 | PDC4 | PDC6 | BLC2 | BLC3 |
0.40%0.40%0.40%----- | 0.50%1.00%--1.00%1.00%-- | ---5.00%---5.00% | 是是是否是否是是 | PDC1PDC2PDC4BLC3PDC3PDC6PDC5BLC2 | 显著显著显著显著显著显著-显著 | NS- | 显著显著- | 显著NS-显著 | 显著显著显著显著- | 显著显著显著显著显著- | 显著NSNSNS显著显著 |
对ELT>2分钟的患者比例进行Chi Square分析(表19),得出疗效等级相同。
表19对潜伏期(ELT)数据的Chi square分析总结
组成 | P值,配对Chi Square比较 | ||||||||||
PGE1 | 达克罗 | 利多卡因 | DDAIP | 编号 | PDC5 | PDC2 | PDC3 | PDC4 | PDC6 | BLC2 | BLC3 |
0.40%0.40%0.40%----- | 0.50%1.00%--1.00%1.00%-- | ---5.00%---5.00% | 是是是否是否是是 | PDC1PDC2PDC4BLC3PDC3PDC6PDC5BLC2 | 0.00020.0100.0020.0200.0390.1940.791 | 0.222 | 0.0800.584 | 0.5190.5590.260 | 0.0120.1840.0580.432 | 0.0010.0200.0040.0710.301 | 0.1360.7810.3900.7870.2920.038 |
在研究结束时,根据射精潜伏期时间分析所研究药物的疗效和安全性。将首要疗效定义为射精潜伏期时间达到2分钟以上并同时显著改善或者改善了性满足率。其次疗效分别通过射精潜伏期时间和性满足率(改善或显著改善)进行评价。研究结束时,对30名有评价价值的患者进行临床疗效评价和安全分析。给药后对患者性行为的其次疗效(射精潜伏期、性满足)以及首要疗效的分析结果列于表20。
表20疗效结果总结(患者百分比、根据首要疗效划分等级)
PDC1 | PDC4 | PDC2 | BLC3 | PDC3 | PDC6 | BLC2 | PDC5 | |
射精潜伏期>2分钟性满足伙伴的性满足首要疗效成分 | 93.386.780.083.3 | 76.783.380.077.0 | 80.076.773.370.0 | 73.370.063.367.0 | 73.373.370.063.0 | 46.773.370.053.0 | 36.750.056.740.0 | 43.366.766.736.7- |
PGE1达克罗宁利多卡因DDAIP | 0.4%0.5%-是 | 0.4%--是 | 0.4%1.0%-是 | --5.0%否 | -1.0%-是 | -1.0%-否 | --5.0%是 | ---是 |
所有患者都完成了该研究。共用药240次。共有47次(19.6%)表现出副作用。所有副作用都与研究用的药物有关。其中的45次(95.7%)为轻微程度作用,2次为中等程度。所有副作用都是暂时的。所有副作用都是阴茎、尿道或腺体疼痛。
测试组合物治疗PE的首要疗效从高到底是:PDC1>PDC4>PDC2>BLC3>PCD3>PDC6>BLC2>PDC5。
疗效结果表明分别含PGE183%、70%和77%的PDC1、PDC2和PDC4比其它不含PGE1的组合物的疗效明显。含PGE1而不含麻醉剂的PDC4的疗效为77%,说明PGE1具有治疗早泄的作用。
PDC5为空白对照组合物,其仅含DDAIP和霜剂的基质。PDC5治疗早泄的疗效最差。
对于只含外用麻醉剂为活性成分的组合物PDC3、PDC6、BLC2和BLC3,尽管这些组合物的首要疗效比空白对照组合物PDC5的疗效好,但比含有PGE1的组合物的疗效差。透皮促渗剂DDAIP对含有外用麻醉剂而不含PGE1的外用组合物疗效的影响依据所使用麻醉剂而变化。
含有0.5%达克罗宁和0.4%PGE1的组合物PDC1在本项研究中表现出最好的疗效(83%)。含有1.0%达克罗宁和0.4%PGE2的组合物PDC2的疗效其次,为70%。
实施例6 含有布比卡因的组合物的临床研究
进行随机、双盲、安慰对照临床研究。根据下述选入标准/排除标准选择患者。90名患者满足患者选入和排除标准,随机按比例分布在研究中。在研究结束时,对89名有评价价值的患者进行临床疗效评价和安全分析。
签署告知同意书后完成筛选表。在收集和评价患者原始数据的筛选准备中,给药前至少纪录4次原始数据,其包括射精潜伏期时间(ELT)和患者的满足率。筛选后,患者开始4周的双盲研究试验。在研究中进行两次附加调查(给药后的第2周末和第4周末)。
表21给出了安慰剂组合物和测试组合物的组成成分,测试组合物包括组合物总重的0.4wt%前列腺素E1以及0.75wt%的盐酸布比卡因。
表21:安慰剂组合物与含前列腺素E1和盐酸布比卡因的组合物
成分(wt%) | 安慰剂测试组合物 |
预水化的修饰的瓜儿豆胶前列腺素E1盐酸布比卡因DDAIP HCl乙醇月桂酸乙酯 | 2.5 2.50 0.40 0.750.5 0.55 53 3 |
用磷酸和氢氧化钠调节组合物的PH。加入适量的纯化水。
安慰剂组和研究组的首要疗效存在显著差异。安慰剂组和研究组的ELT和患者伙伴的满足率存在显著差异。安慰剂组和研究组的满足率没有显著差异。
主要疗效包括用秒表测得的从进入阴道至射精的射精潜伏期的时间、患者和他们的性伙伴的满足率、渴望程度以及临床疗效,临床疗效的定义为射精潜伏期超过2分钟且性满足率比筛选时提高了20%以上。
根据选入/排除标准选择具有至少3个月的早泄史的患者。共选择了90名患者,分成各研究小组。在检查身体时,90名患者都没有发现有不正常现象。与1名患者失去联系,但其它患者都没有中断研究。89名患者完成了本项研究。患者人员数据见表22。
表22患者人员基本数据
范围 | 平均值 | |
年龄分布体重分布身高分布患PE的时间(月)过敏史:2(青霉素1,磺饮酒史:44(48.9%)吸烟史:37(41.1%)药物滥用史:0 | 27-6252-90kg159-185cm3-135胺1) | 4373kg174cm31 |
患者的PE治疗史根据药物治疗和非药物治疗的分类进行总结。90名中有18名(20%)接受过药物治疗,没有患者接受过非药物治疗。
患者的非PE疾病史总结于表23中,其中列举了患有最常见的5种疾病的患者数。
表23有非PE疾病史的患者
可评价的患者 | 患者数90 | %100 |
心血管系统内分泌系统胃肠道系统泌尿系统免疫系统 | 32111 | 3.332.221.111.111.11 |
选入标准:男性,年龄20-60,患有PE并影响其性生活;射精潜伏期小于2分钟和/或性交后的性满足率低于50%;具有稳定的异性关系,每周至少性交1次。
排除标准:身体检查出现不正常,包括生殖器检查、血象或化验不正常、实验室化验结果显示肝脏和肾功能不正常、睾丸激素不正常、泌乳刺激素不正常、泌尿生殖器道感染,如前列腺炎、尿道炎或附睾炎,神经失调或具明显的心理障碍而需要精神病学上的治疗以及服用了任何可能改变性行为的抗抑郁剂、酒精或药物滥用者、6个月内患有低血压、心肌梗塞、心力衰竭或心绞痛者。
对每名患者共进行4次调查:筛选调查(给药前两周)、调查1(开始给药)、调查2(给药后2周)、调查3(给药后4周)。
在调查1和调查2的两次调查中分别给每名患者含有活性霜剂的各4个共8个剂量。用药后重复访问以观察外用组合物治疗早泄的安全性和疗效。患者阴茎口用药。两个月后完成研究。在研究中患者不能进行其它PE治疗。对其它疾病的治疗可以继续。要求所有患者在患者日记中记录性行为状况。
要求患者每次用药间隔最小为24小时,每周用药不能少于一次。研究结束后,患者将任何没有使用的临床物品送回到临床试验点。
首要疗效被定义为射精潜伏期时间延长至不少于2分钟并同时性满足率改善了20%(用药后的满足被定义为性满足获得改善或显著改善)。其次疗效通过射精潜伏期时间(ELT)和性满足率进行评价。同时还需要评价患者伙伴的性满足率。临床有效被认为是射精潜伏期时间延长到不少于2分钟。临床有效被认为是性满足率改善了20%。使用了至少4次药物的患者才纳入疗效评价中。
表24射精潜伏期时间
可评价的患者 | 给药前的射精潜伏期 | 给药后的射精潜伏期 | ELT的平均延长值+SD | t | p | |
安慰剂测试品 | 3059 | 6577 | 115209 | 49.9±47.0130.1±86.8 | 4.72 | <0.001 |
接受安慰剂组合物(安慰剂组)和接受包括0.4wt%前列腺素E1以及0.75wt%的盐酸布比卡因的测试组合物(研究组)的患者之间的ELT存在显著差异。见表24。性满足分析结果总结于表25中。
表25性满足
可讦价的患者 | 性满足率的改善 | 安慰剂组患者 | % | 研究组患者 | % | X2 | P |
30 | 100 | 59 | 98.33 | ||||
患者患者的伙伴 | ≥20%<20%≥20%<20% | 17131416 | 56.6743.3346.6753.33 | 45144613 | 76.2723.7377.9722.03 | 3.628.87 | 0.0570.003 |
A组(安慰剂组)和B组(研究组)患者之间的性满足率没有显著差异。A组(安慰剂组)和B组(研究组)患者伙伴之间的性满足率具有显著差异。
首要疗效结果见表26。A组(安慰剂组)和B组(研究组)之间的首要疗效存在显著差异。
表26疗效测定
可评价的患者 | 安慰剂组患者数 | % | 研究组患者数 | % | X2 | P |
30 | 100.00 | 59 | 98.33 | |||
首要疗效 ELT≥2分钟其次疗效 患者满足率改善≥20%患者伙伴的满足率改善≥20% | 791714 | 23.3330.0056.6746.67 | 44504546 | 74.5884.7576.2777.97 | 21.3426.673.628.87 | <0.001<0.0010.0570.003 |
根据所有疗效的测定分析,安慰剂组和研究组之间的首要疗效、ELT以及患者伙伴的满足率都存在显著差异。安慰剂组和研究组之间的满足率没有显著差异。
完成研究的89名患者中有29名(32.58%)表现出副作用,其中6名(20.00%)是安慰剂组,23名(38.98%)是研究组。经研究人员确定,所有副作用都与研究用药物相关。安慰剂组和研究组之间的副作用没有显著差异。所有副作用都是轻微和暂时的。副作用的平均持续时间为18.85分钟。副作用持续的最长时间为46.88分钟。大多数副作用是阴茎、尿道或腺体疼痛和发痒。没有发现其他副作用。副作用的总结见表27。
表27副作用
总数 | 安慰剂组 | 研究组 | X2 | P | |||||
N | % | N | % | N | % | ||||
可评价的患者副作用副作用需要治疗的患者与本研究药物相关的副作用 | 总数轻微中度严重029 | 89292900032.58 | 98.8932.5832.580006 | 306600020 | 33.7202000023 | 59232300038.98 | 66.2938.9838.98000 | 3.263.26 | 0.0710.071 |
概括而言,对射精潜伏期时间、性满足率的分析显示了A组(安慰剂组)和B组(研究组)在治疗早泄中存在显著差异。施用研究用药物后,A组的9名患者(30%)和B组的50名患者(84.75%)的ELT延长至不低于2分钟。两组之间存在显著差异(表25)。
施用研究用药物后,A组(安慰剂组)的17名患者(56.67%)和B组(研究组)的45名患者(76.27%)性满足率得到了不小于20%的改善,两组之间存在显著差异。A组(安慰剂组)的14名患者(46.67%)和B组(研究组)的46名患者(77.97%)的伙伴的性满足率得到了不小于20%的改善,两组之间存在显著差异(表25)。
A组(安慰剂组)的7名患者(23.33%)和B组(研究组)的44名患者(74.58%)的ELT延长至不小于2分钟同时用药后的性满足率得到了不小于20%的改善。两组之间存在显著差异。
前述说明只用于对本发明进行举例说明,本发明的保护范围由权利要求书所限定。任何不背离本发明范围的变化和改变都在本发明范围之内。
Claims (44)
1.一种外用组合物,其包括:
外用麻醉剂;
聚合物增稠剂,其选自剪切变稀的多糖胶和剪切变稀的聚丙烯酸聚合物;
亲脂性成分,其选自C1-C8脂肪醇、C8-C30脂肪酯、液态多元醇及它们的混合物;
水;以及
缓冲体系,该缓冲体系使所述组合物的pH值缓冲至约3-约7.4的范围。
2.根据权利要求1所述的组合物,其进一步包括血管活性前列腺素,所述血管活性前列腺素选自PGE1、PGA1、PGB1、PGF1α、19-羟基-PGA1、19-羟基-PGB1、PGE2、PGA2、PGB2、19-羟基-PGA2、19-羟基-PGB2、PGE3、PGF3及它们的混合物。
3.根据权利要求2所述的组合物,其中,所述血管活性前列腺素选自前列腺素E1、前列腺素E2、它们的药学可接受盐、它们的低级烷基酯以及上述物质的混合物。
4.根据权利要求2所述的组合物,其中,所述血管活性前列腺素的含量为约0.1mg-约0.5mg。
5.根据权利要求2所述的组合物,其中,所述血管活性前列腺素的含量为约0.2mg-约0.3mg。
6.根据权利要求1所述的组合物,其中,所述外用麻醉剂为氨基酰胺局麻药,其选自利多卡因、布比卡因、甲哌卡因、地布卡因、普罗比卡因、依替卡因、妥卡尼、它们的药学可接受的盐及这些物质的混合物。
7.根据权利要求1所述的组合物,其中,所述外用麻醉剂为局麻药,其选自利多卡因、布比卡因、达克罗宁、它们的药学可接受的盐及这些物质的混合物。
8.根据权利要求1所述的组合物,其中,所述外用麻醉剂占组合物总重的约0.01wt%-10wt%。
9.根据权利要求1所述的组合物,其中,所述聚合物增稠剂为剪切变稀的聚丙烯酸聚合物。
10.根据权利要求1所述的组合物,其中,所述剪切变稀的多糖胶为半乳甘露聚糖胶。
11.根据权利要求10所述的组合物,其中,所述半乳甘露聚糖胶为修饰的半乳甘露聚糖胶。
12.根据权利要求11所述的组合物,其中,所述修饰的半乳甘露聚糖胶为修饰的瓜儿豆胶。
13.根据权利要求1所述的组合物,其进一步包括促渗剂,所述促渗剂选自(N-取代的氨基)-链烷酸烷基酯、2-(N,N-二取代的氨基)-链烷酸烷基酯、(N-取代氨基)-链烷醇链烷酸酯、(N,N-二取代氨基)-链烷醇链烷酸酯、它们的可药用盐及上述物质的混合物。
14.根据权利要求13所述的组合物,其中,所述促渗剂为2-(N,N-二甲氨基)-丙酸十二烷基酯或其药学可接受盐。
15.根据权利要求1所述的组合物,其中,所述亲脂性成分包括至少一种甘油酯,其选自一甘油酯、二甘油酯、三甘油酯及它们的混合物。
16.根据权利要求1所述的组合物,其中,所述亲脂性成分包括至少一种甘油酯,其选自甘油一油酸酯、甘油三油酸酯、三豆蔻酸甘油酯、三硬脂酸甘油酯及它们的混合物。
17.根据权利要求1所述的组合物,其中,所述组合物进一步包括乳化剂,其选自蔗糖酯、聚氧乙烯山梨醇酯、长链醇和甘油酯。
18.根据权利要求1所述的组合物,其中,所述乳化剂包括至少一种甘油酯,其选自甘油一油酸酯、甘油三油酸酯、三豆蔻酸甘油酯、三硬脂酸甘油酯及它们的混合物。
19.根据权利要求1所述的组合物,其中,所述组合物进一步包括至多占组合物总重量约5%的桃金娘烯醇。
20.根据权利要求1所述的组合物,其中,所述组合物进一步包括防腐剂。
21.根据权利要求14所述的组合物,其中,所述组合物进一步包括芳香剂。
22.一种治疗早泄的方法,包括将射精潜伏期延长剂量的半固体组合物用于阴茎口这一步骤,所述半固体组合物包括:
外用麻醉剂;
聚合物增稠剂,其选自剪切变稀的多糖胶和剪切变稀的聚丙烯酸聚合物;
亲脂性成分,其选自C1-C8脂肪醇、C8-C30脂肪酯、液态多元醇及它们的混合物;
水;以及
缓冲体系,该缓冲体系使所述组合物的pH值缓冲至约3-约7.4的范围。
23.根据权利要求22所述的方法,其中,所述组合物进一步包括含量为约0.1mg-约0.5mg的血管活性前列腺素,所述血管活性前列腺素选自PGE1、PGA1、PGB1、PGF1α、19-羟基-PGA1、19-羟基-PGB1、PGE2、PGA2、PGB2、19-羟基-PGA2、19-羟基-PGB2、PGE3、PGF3及它们的混合物。
24.权利要求22所述的方法,其中,所述血管活性前列腺素选自前列腺素E1、前列腺素E2、它们的药学可接受盐、它们的低级烷基酯以及上述物质的混合物。
25.根据权利要求22所述的方法,其中,所述血管活性前列腺素的含量为约0.2mg-约0.3mg。
26.根据权利要求22所述的方法,其中,所述外用麻醉剂为氨基酰胺局麻药,其选自利多卡因、布比卡因、甲哌卡因、地布卡因、普罗比卡因、依替卡因、妥卡尼、它们的药学可接受的盐及这些物质的混合物。
27.根据权利要求22所述的方法,其中,外用麻醉剂为局麻药,其选自利多卡因、布比卡因、达克罗宁、它们的药学可接受的盐及这些物质的混合物。
28.根据权利要求22所述的方法,其中,所述外用麻醉剂占组合物总重的约0.01wt%-约4wt%。
29.根据权利要求22所述的方法,其中,所述聚合物增稠剂为剪切变稀的聚丙烯酸聚合物。
30.根据权利要求22所述的方法,其中,所述聚合物为剪切变稀的多糖胶。
31.根据权利要求22所述的方法,其中,所述剪切变稀的多糖胶为半乳甘露聚糖胶。
32.根据权利要求22所述的方法,其中,所述剪切变稀的多糖胶为修饰的半乳甘露聚糖胶。
33.根据权利要求32所述的方法,其中,所述修饰的半乳甘露聚糖胶为修饰的瓜儿豆胶。
34.根据权利要求22所述的方法,其中,所述组合物进一步包括促渗剂,所述促渗剂选自(N-取代的氨基)-链烷酸烷基酯、2-(N,N-二取代的氨基)-链烷酸烷基酯、(N-取代氨基)-链烷醇链烷酸酯、(N,N-二取代氨基)-链烷醇链烷酸酯、它们的可药用盐及上述物质的混合物。
35.根据权利要求34所述的方法,其中,所述促渗剂为2-(N,N-二甲氨基)-丙酸十二烷基酯或其药学可接受盐。
36.根据权利要求22所述的方法,其中,所述亲脂性成分包括至少一种C8-C30脂肪酯。
37.根据权利要求22所述的方法,其中,所述亲脂性成分包括至少一种甘油酯,其选自一甘油酯、二甘油酯、三甘油酯及它们的混合物。
38.根据权利要求22所述的方法,其中,所述亲脂性成分包括至少一种甘油酯,其选自甘油一油酸酯、甘油三油酸酯、三豆蔻酸甘油酯、三硬脂酸甘油酯、及它们的混合物。
39.根据权利要求22所述的方法,其中,所述组合物进一步包括乳化剂,其选自蔗糖酯、聚氧乙烯山梨醇酯、长链醇和甘油酯。
40.根据权利要求22所述的方法,其中,所述乳化剂包括至少一种甘油酯,其选自甘油一油酸酯、甘油三油酸酯、三豆蔻酸甘油酯、三硬脂酸甘油酯及它们的混合物。
41.根据权利要求22所述的方法,其中所述组合物进一步包括至多占组合物总重量约5%的桃金娘烯醇。
42.根据权利要求22所述的方法,其中,所述组合物进一步包括防腐剂。
43.根据权利要求22所述的方法,其中,所述组合物进一步包括芳香剂。
44.根据权利要求1-21任意一项所述组合物在制备治疗早泄的药物中的应用。
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CN114767624A (zh) * | 2022-05-10 | 2022-07-22 | 南京唯创远医药科技有限公司 | 一种含4-丁氧基-β-哌啶基苯丙酮类化合物的药物组合物及其制备方法和应用 |
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- 2004-03-22 KR KR1020057017702A patent/KR101086147B1/ko not_active IP Right Cessation
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2014
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- 2014-08-20 US US14/463,966 patent/US9056044B2/en not_active Expired - Fee Related
- 2014-08-20 US US14/463,959 patent/US9060929B2/en not_active Expired - Fee Related
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114585410A (zh) * | 2019-08-15 | 2022-06-03 | 加尔祖研究教育科学和应用技术学院 | 尿道内药品剂型和装置 |
CN114767624A (zh) * | 2022-05-10 | 2022-07-22 | 南京唯创远医药科技有限公司 | 一种含4-丁氧基-β-哌啶基苯丙酮类化合物的药物组合物及其制备方法和应用 |
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US20150272875A1 (en) | 2015-10-01 |
WO2004084878A1 (en) | 2004-10-07 |
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US20040241245A1 (en) | 2004-12-02 |
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US9066854B2 (en) | 2015-06-30 |
AU2004224329A1 (en) | 2004-10-07 |
MXPA05009816A (es) | 2005-12-05 |
JP4667369B2 (ja) | 2011-04-13 |
KR20050119135A (ko) | 2005-12-20 |
CA2517828C (en) | 2016-10-04 |
US9060929B2 (en) | 2015-06-23 |
US20150011585A1 (en) | 2015-01-08 |
US9056044B2 (en) | 2015-06-16 |
CN1761461B (zh) | 2010-05-05 |
IL170467A (en) | 2012-04-30 |
US8841345B2 (en) | 2014-09-23 |
US20150011587A1 (en) | 2015-01-08 |
AU2004224329B2 (en) | 2009-07-09 |
KR101086147B1 (ko) | 2011-11-25 |
CA2517828A1 (en) | 2004-10-07 |
JP2006520801A (ja) | 2006-09-14 |
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