CN1225581A - α阻断剂的应用,尤其是百里胺和/或其衍生物通过龟头透粘膜途径治疗阴茎勃起功能障碍 - Google Patents
α阻断剂的应用,尤其是百里胺和/或其衍生物通过龟头透粘膜途径治疗阴茎勃起功能障碍 Download PDFInfo
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Abstract
本发明涉及对治疗阴茎勃起功能障碍有效的活性化合物的应用,更具体地涉及不同制剂的α阻断剂,通过龟头透粘膜途径治疗哺乳动物,特别是人类的勃起功能障碍。
Description
本发明涉及对阴茎勃起功能障碍有效的化合物的应用,更具体地涉及不同药物组合物制剂的α阻断剂,通过龟头透粘膜途径治疗勃起功能障碍。本发明尤其涉及百里胺和/或其衍生物的应用,特别是脱乙酰百里胺(DAM)和/或单去甲基脱乙酰百里胺(MDAM)作为所述药物组合物的主要成分。这样的阴茎透粘膜制剂允许治疗各种临床表现的雄性阴茎勃起功能障碍,所用的百里胺及其衍生物,尤其是DAM在此类给药方式中显示出良好的耐受性。
阴茎勃起功能障碍发生于大约4-9%的男性人口中,当该病涉及慢性疾病时,其百分比还要升高。事实上,20%为住院病人及表现为慢性阻塞性肺病的患者,55%为糖尿病患者以及38-40%为肾功能不全而需透析的患者。此外,美国的一项最新的流行病学研究报道,在40岁男性人口中,52%患有轻度、中度以及重度阴茎勃起功能障碍。
勃起生理机制的最后阶段是海绵体坚硬和阴茎海绵体膨胀。这与血液动力学现象:动脉血流增加结合有静脉血流明显减少有关。受髓质上和髓质神经控制以及雄激素分泌调节的这些复杂现象依赖于组织和血管因素。海绵体平滑肌细胞以及大量的递质也起着重要作用。其中有些递质尚未鉴定。
在这一机理中,勃起组织起着重要作用。实际上,勃起不仅仅依赖于动脉血管扩张,以及随后的海绵体的充填,而且主要是由于海绵体环平滑肌纤维松弛,从而使得血液渗透到海绵体内并通过白膜对侧静脉的挤压来压迫而实现的。
通过体外实验和在人体内实验中使用海绵体内注射以揭示勃起的神经-药理学的技术诀窍方面取得了进展。这些数据证实了神经介质在勃起生理学中的药物动力学作用。去甲肾上腺素,作为交感神经系统的介质,引起平滑肌纤维的收缩,相反,α阻断剂引起其松弛,乙酰胆碱,作为副交感神经系统的介质,控制平滑肌纤维的松弛,此种控制似乎主要是通过非胆碱能、非肾上腺素能末梢和海绵体内皮诱导氧化氮和血管-活性肠肽(VIP),P物质和降血钙素-基因-相关肽(CGRP)来实现的,此外,还包括平滑肌纤维的直接作用。PGE1,很可能是在阴茎内通过血管内皮合成的,对平滑肌细胞具有直接的松弛作用,它可通过降低去甲肾上腺素的释放调节抗-勃起肾上腺素能紧张度。α-肾上腺素能受体的密度10倍于β-肾上腺素能受体,其中又以α-1肾上腺素能受体占绝大多数。最近,肾上腺素能α-1受体又被分为3个亚型:α-1-a-d、α-1-b和α-1-c,它们很可能在不同程度上涉及到人类海绵体和平滑肌细胞的收缩。
对于阴茎勃起障碍,可采用不同的给药途径,如口服给药、海绵体内给药(ⅡC)及尿道内途径。
事实上,此类治疗的一种方式尤其是使用育亨宾碱盐酸盐,但它相对于勃起本身,更加涉及到性行为。它对神经系统的作用表现为一系列可能的副作用:如神经过敏、兴奋、震颤、眩晕、头痛、恶心、呕吐、腹泻、起立性低血压。盐酸曲唑酮虽显示出效果,但却引起勃起时间延长并伴有嗜睡、起立性低血压和皮疹。
使用硝基衍生物和米诺地尔类物经透皮途径治疗阴茎勃起功能障碍起始于八十年代,最近使用罂栗碱和前列腺素El进行治疗。由这些临床试验得到了关于阴茎动脉的血流量及阴茎的尺寸的Dopler记录,但并没有给出令人信服的临床结果。并报道了一些常见的血管类型的副作用,从理论上讲,在生殖器官上涂抹凝胶或乳膏似乎不会产生多大效果,因为皮下静脉网络的吸收导致试验药物扩散到全身血液循环中,而不会仅仅分布于海绵体中。
此外,海绵体白膜的存在及其阻力导致采用注射器局部注射各种血管-活性药剂。此类海绵体内的临床效果事实上延长更久。但是,结果显示有50%的病人由于心理原因或其副作用而停止了此种治疗。最大的困难是接受此种治疗的心理障碍,并且据报道有多种副作用:恶心、呕吐、眩晕、低血压、头痛、心动过速、面部潮红或阴茎皮肤灼烧感。还报道了其它一些严重的副作用,如阴茎异常勃起(priapsis)或海绵体的纤维化。在某些情况下,由于整个勃起过程伴有疼痛以至无法进行性关系。
鉴于阴茎内注射ⅡC的有效性和局部用药的非侵入性,尿道内途径成为一种有利的方式。此种用药途径的效果可能是阴茎海绵体膜的粘性和粘膜吸收能力的结果。这据信是由于使用龟头粘膜的敏感受体,起初是副交感神经和躯体运动神经中枢的反射作用在海绵体形成一定的膨大之后是可能的。通过海绵体吸收能膨大而不带来造成严重障碍的副作用的物质,可通过反射作用导致完全硬化。
尽管尿道内途径显示出令人满意的结果,但此种途径对大约50%的病人而言,仍存在着一定的障碍,其中一些病人又返回到原先的ⅡC途径。而且,尿道内给药途径也给女方带来不愉快的感觉,因为她们通过阴道途径被动地接受了活性化合物。这会感到不便的并可能引起副作用。
本发明通过非侵入性疗法并经简便的用药途径使用对阴茎勃起功能障碍有关的活性化合物如百里胺和/或衍生物的性质,从而解决了上述难题。
本发明涉及使用此类衍生物,尤其是脱乙酰基百里胺(DAM),以便获得一种经龟头透粘膜途径治疗哺乳动物,尤其是人类阴茎勃起功能障碍的药物。
百里胺(DCI)或称肾上腺素能阻断剂或(6-乙酸基百里氧基)乙基二甲胺盐酸盐为具有式:C16H25NO3.HCl的α阻断剂。不管采用何种给药途径(口服、ⅡC、静脉内或透皮),百里胺都从未在全身循环中发现过。其母体化合物被立即转化和水解为它的两种代谢产物:DAM和MDAM。百里胺可以认为是一种药物前体,其后它的两种代谢产物经硫代和葡萄糖醛结合。
就其对去甲肾上腺素的作用效果而言,DAM和MDAM为竞争剂,具有与母体药物相同的活性,但作为α阻断剂,DAM的活性比MDAM稍强。此外,硫代结合物也显示出α阻断剂的活性,但强度稍弱一些。
百里胺于1965年以30mg剂量的片剂(PLANTIER Laboratories)在法国上市。百里胺主要用作治疗年龄较大人群的心理行为障碍,肢端循环疾病(或肢端综合症)和更年期开始时血管疾病的处方药。1989年又以120mg片剂(用以治疗功能性前列腺肥大(DEBAT Laboratories))和经Ⅳ途径的10mg冻干制剂(用以治疗尿道颈张力过强的膀胱排泄疾病(DEBAT Laboratories))上市。1990年法国专利2666507提出经透皮使用百里胺(贴剂)治疗年龄较大人群的心理行为障碍,脑循环或外周循环疾病。雷诺氏病以及前列腺瘤引起的泌尿系统疾病。1992年,用以引起勃起的ⅡC制剂(ASTA-MEDICA Laboratories)上市,而在1993年,120mg剂量的口服制剂(FOURNIER-DEBATLaboratories)由于其与剂量依赖性及病人依赖性有关的肝毒性(FOURNIER-DEBATLaboratories)而被迫撤出市场。
根据本发明的应用,即通过龟头透粘摸方法使用治疗勃起机能障碍的化合物,尤其是例如百里胺或其衍生物的α阻断剂,可以改善有日常勃起障碍的男人及其配偶的心理状态和情绪。到目前为止,在有效治疗阴茎勃起功能障碍的疗法中,要么是海绵体内途径,并非没有危险的侵入性模式,要么是口服途径,因使用抗焦虑药和抗抑郁药而伴有这些药物自身的副作用,要么是尿道内途径,很难为病人接受,以至有些病人又回到侵入性的给药途径。此外,在阴茎勃起功能障碍病人中采用龟头透粘膜给药代表了科学和医学的进步。采用这种给药方式对阴茎勃起功能障碍病人给予百里胺衍生物可以使阴茎完全坚硬或部分坚硬并持续几分钟。
龟头透粘膜给药途径不仅使用舒适,而且有效地解决了阴茎勃起功能障碍病人的生理问题。龟头粘膜为海绵体的组织延续。通过龟头透粘膜给予本发明所列举的化合物,特别是百里胺或其代谢产物之一,这些活性化合物能扩散到海绵体组织并导致其膨大。如此按前述机理引发了勃起过程。
已经证实,百里胺及其衍生物,尤其是DAM能够渗透粘膜,因而可以单独使用而无须其它的龟头粘膜透过剂或渗透剂。尽管如此,百里胺及其衍生物仍优选与一种或几种能溶解这些活性成分并促使其透过粘膜的赋形剂组合使用。
能够溶解百里胺及其衍生物的赋形剂优选选自:
-脂肪酯如十四烷酸异丙酯、对羟基苯甲酸甲酯钠盐,己二酸二辛酯或乙二酸二异丙酯,
-醇如十六醇、苄醇、Mygliol812、Labrafac、Labrifil、Transcutol、聚乙二醇。
此外,能够促进百里胺衍生物透过粘膜的赋形剂包括优选选自N-甲基-吡咯烷酮、吡咯烷酮和N-N-二甲基甲苯甲酰胺。
所有这些赋形剂可以单独使用或与多种其它赋形剂组合使用。
优选百里胺衍生物与这些赋形剂的重量比在1-20%(w/w)范围内,更优选在5-10%范围内。
在本发明中,所述制剂可以是膏剂、洗剂、软膏或凝胶。
本发明还涉及一种至少能够覆盖阴茎龟头粘膜的装置,所述装置的内部与所述粘膜接触的部分涂有上文所述应用中的药物。该装置优选为避孕套。此种给药方式不仅能使活性成分长久涂抹于粘膜上,而且可以作为一道屏障以保护女性配偶的阴道粘膜。因此,当大量使用该药物时,避免了给女方带来副作用。
DAM的透膜特性
根据Franz的细胞扩散模型,用母猪阴道粘膜进行体外DAM的粘膜穿透试验。通过使百里胺盐酸盐脱乙酰化(由SIGMA供应REF.M.51-54)来制备DAM,然后通过乙醚萃取并过硅胶柱纯化。在体外试验前经NMR验证DAM结构。
将DAM溶于Mygliol/乙醇50/50或3/97(vol/vol)(v/v)的混合物中。然后将50mgDAM喷涂在粘膜上。24小时后,测定已透过粘膜的DAM的量。结果显示,当DAM最初在50/50(w/w)的乙醇-Mygliol溶液中时,初始剂量中有60%透过粘膜。对于3/97(w/w)的乙醇-Mygliol溶液来说,有41%的初始剂量的DAM透过粘膜。
在相同的试验条件下,对大鼠皮也进行了同样的试验,结果表明,对于在3/97(w/w)和50/50(w/w)的乙醇-Mygliol混合液中的DAM溶液来说,分别有4%-8%的初始剂量透过粘膜。
在这些体外结果证实了DAM,尤其是与一种或多种药物可接受赋形剂共用的凝胶、洗剂或膏剂形式的DAM的可以透粘膜施药后,又对病人在龟头粘膜上施用此种剂型的药物,研究了其体内效果。
制剂的实施例
给出下列实施例用于说明本发明,而不对其范围构成限制。
a)凝胶的制备
实施例1
将6g DAM加入到50g丙二醇,42g二甘醇单乙醚(Transcutol)和1g羟丙基甲基纤维素中混合。然后加入0.5g对羟基苯甲酸甲酯钠盐作为防腐剂。
实施例2
将12g DAM和40g Mygliol812混合。然后将300g Mygliol凝胶用反絮凝器匀化3分钟。
实施例3
将10g DAM和4g Carbopol940于100ml水中混合。然后加入16ml10%氢氧化钠溶液中和。
实施例4
将10g DAM和80g甘油和1g Carbopol940混合。用1g三乙醇胺中和。
实施例5
将10g DAM、4g甲基纤维素和80g水混合。
b)乳膏剂的制备
实施例6
于70℃将50g甘油一硬脂酸酯和850g凡士林熔化,然后冷却至40℃。在搅拌下加入100g DAM。
c)洗剂的制备
实施例7
将100g DAM和900g Mygliol812混合以获得含10%DAM的洗剂。
涂有不同药物制剂并覆盖于阴茎粘膜的装置的制备
特别包含本发明应用的装置是避孕套。避孕套内部涂上包含用于治疗阴茎勃起功能障碍的所述化合物的组合物,例如百里胺和/或其代谢产物中的一种,尤其为上述制剂。脂肪族化合物如石蜡产品也可与制剂结合作为活性产物,尤其是百里胺及其衍生物的溶剂。
临床试验和结果
5位截瘫病人志愿参加与安慰剂组对照的双盲试验。这些试验使用了含有下述组分的凝胶:
DAM 2.00g
丙二醇 18.00g
TranscutolGattefosse 13.00g
羟丙基甲基纤维素 0.30g
对羟基苯甲酸甲酯钠盐 0.05g
试验方案为:
·将0.5-1ml凝胶涂抹到双盲条件下病人的龟头粘膜上。
·按摩阴茎约1分钟。
·在没有其他刺激的情况下观察药理作用,然后任选在第二次刺激后观察药理作用。
·对勃起度进行评价:0(无勃起),1(仅膨大),2(部分坚硬的勃起),3(坚硬勃起)。
·临床试验及所获结果如下:
表1
病人生日 | 损伤程度 | 测试产品 | 结果 |
BO-JE07-08-76 | 截瘫D4-D5 | DAM:0.5mlDAM:1ml安慰剂:0.5ml | 勃起度3持续7分钟勃起度3持续15分钟(勃起消失,按摩30秒后再勃起15分钟)勃起度0 |
MA-CE29-05-79 | 截瘫D11-D12 | DAM:0.5mlDAM:1ml安慰剂:0.5ml | 勃起度3持续8分钟勃起度3持续7分钟(勃起消失,按摩30秒后再勃起15分钟)勃起度0 |
FE-DI05-02-72 | 截瘫D8-D9 | DAM:0.5ml安慰剂:0.5ml | 勃起度2持续3分钟按摩时勃起度2,之后0 |
MI-AI06-03-56 | 截瘫D4-D5 | DAM:1ml安慰剂:0.5ml | 勃起度0勃起度2持续2分钟 |
HE-MI23-09-56 | 截瘫D4-D5-D6 | DAM:1ml安慰剂:1ml | 勃起度2持续3分钟按摩时勃起度1,之后0 |
在该临床试验的所述试验条件下,5位接受治疗的病人中有4位在阴茎龟头粘膜按摩透粘膜给予DAM后显示出药理上可测量的勃起。临床试验期间未观察到副作用。动脉血压和脉搏未出现明显变化。
Claims (10)
1.一种或多种涉及治疗哺乳动物,尤其是人的勃起机能障碍的化合物,尤其是α阻断剂化合物的应用,以得到一种用于龟头透粘膜方式治疗的药物。
2.权利要求1的应用,其特征在于该化合物是百里胺和/或其衍生物之一,尤其是脱乙酰百里胺(DAM)。
3.权利要求1或2的应用,其特征在于该化合物与一种或多种药物上可接受的赋形剂结合使用,所述的赋形剂可以溶解所述的化合物和/或促进所述化合物透过粘膜。
4.权利要求3的应用,其特征在于所述可以溶解化合物的药物上可接受的赋形剂选自:
-脂肪酸酯例如肉豆蔻酸异丙酯、对羟基苯甲酸甲酯钠盐、己二酸二辛酯或己二酸二异丙酯;
-脂肪醇,例如鲸蜡醇、苯甲醇、Mygliol812、Labrafac、Labrifil、Transcutol和聚乙二醇。
5.权利要求3的应用,其特征在于所述可以促进化合物透过粘膜的药物上可接受的赋形剂选自:N-甲基吡咯烷酮、吡咯烷酮、N,N-二甲基甲苯甲酰胺。
6.权利要求3-5中任一项的应用,其特征在于所述化合物的存在量相对于所述赋形剂而言,其重量比为1-20%,优选为5-10%。
7.权利要求1-6中任一项的应用,其特征在于该药物呈膏状、洗剂、膏剂或凝胶的形式。
8.权利要求1-7的应用,其特征在于所述呈凝胶形式的药物中各组分的比例如下:
-2.00克脱乙酰百里胺、-18.00克丙二醇、-13.00克Transcutol、-0.30克羟丙基甲基纤维素和-0.05克对羟基苯甲酸甲酯钠盐。
9.用于覆盖至少龟头粘膜的装置,其特征在于:在其与所述粘膜接触的内部涂有根据权利要求1-8的药物。
10.根据权利要求9的装置,其为避孕套。
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US6469065B1 (en) | 1996-02-02 | 2002-10-22 | Nitromed, Inc. | Nitrosated and nitrosylated α-adrenergic receptor antagonist, compositions and methods of use |
US7087240B1 (en) | 1998-06-25 | 2006-08-08 | Lavipharm Laboratories Inc. | Device and method for the treatment of erectile dysfunction |
NZ509031A (en) * | 1998-06-25 | 2002-10-25 | Lavipharm Lab Inc | A disk formed from a filmogenic polymer carrying a therapeutic agent selected from a stabiliser, a solubiliser, an enhancer and a plasticiser |
WO2018073821A1 (en) * | 2016-10-18 | 2018-04-26 | Vasolead (2012) Ltd. | Compositions and methods for treating erectile dysfunction |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4801587A (en) * | 1987-03-02 | 1989-01-31 | Gene Voss | Impotence ointment |
US5256652A (en) * | 1987-11-12 | 1993-10-26 | Pharmedic Co. | Topical compositions and methods for treatment of male impotence |
FR2666507A1 (fr) * | 1990-09-07 | 1992-03-13 | Sarget Lab | Compositions pharmaceutiques pour l'administration topique de moxisylyte et de desacetyl moxisylyte et leurs utilisations en therapeutique. |
BR9203277A (pt) * | 1992-08-21 | 1994-03-01 | Cesar Roberto Dias Nahoum | Utilizaccao de drogas eretogenicas e respectivas metodologias de aplicacao |
US5565466A (en) * | 1993-08-13 | 1996-10-15 | Zonagen, Inc. | Methods for modulating the human sexual response |
US5741511A (en) * | 1995-04-12 | 1998-04-21 | Sam Yang Co., Ltd. | Transdermal drug delivery device for treating erectile dysfunction |
-
1996
- 1996-05-15 FR FR9606105A patent/FR2748658B1/fr not_active Expired - Fee Related
-
1997
- 1997-05-13 EP EP97924075A patent/EP0906093A1/fr not_active Withdrawn
- 1997-05-13 AU AU29662/97A patent/AU2966297A/en not_active Abandoned
- 1997-05-13 CN CN 97196485 patent/CN1225581A/zh active Pending
- 1997-05-13 WO PCT/FR1997/000837 patent/WO1997042946A1/fr not_active Application Discontinuation
- 1997-05-13 TR TR1998/02324T patent/TR199802324T2/xx unknown
Also Published As
Publication number | Publication date |
---|---|
TR199802324T2 (xx) | 2001-01-22 |
FR2748658B1 (fr) | 2000-08-18 |
FR2748658A1 (fr) | 1997-11-21 |
AU2966297A (en) | 1997-12-05 |
EP0906093A1 (fr) | 1999-04-07 |
WO1997042946A1 (fr) | 1997-11-20 |
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