CN1250221C - 女性性功能紊乱的治疗 - Google Patents
女性性功能紊乱的治疗 Download PDFInfo
- Publication number
- CN1250221C CN1250221C CNB998044423A CN99804442A CN1250221C CN 1250221 C CN1250221 C CN 1250221C CN B998044423 A CNB998044423 A CN B998044423A CN 99804442 A CN99804442 A CN 99804442A CN 1250221 C CN1250221 C CN 1250221C
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- Prior art keywords
- apomorphine
- blood flow
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- dosage form
- vaginal
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Abstract
舌下给予脱水吗啡剂型能够改善人类女性性功能紊乱而没有明显的不需要的副作用。给予脱水吗啡可以增加神经刺激性阴蒂海绵体血流和阴道壁血流,以增强女性阴蒂勃起和阴道充血。优选维持脱水吗啡血浆浓度不高于约5.5ng/ml。
Description
发明领域
本发明涉及改善女性性功能紊乱的剂型和方法。更具体地说,本发明涉及含有脱水吗啡的组合物在改善女性性功能紊乱方面的用途。
发明背景
脱水吗啡是已经广泛用作催吐剂、镇静剂、抗帕金森氏病药物和行为改善剂的选择性多巴胺受体激动剂。最新研究和临床研究证实,脱水吗啡在男性具有表现为阴茎勃起的勃起作用。此前尚没有研究脱水吗啡对女性性功能的影响。
女性也可能发生随年龄而增加的并与存在心血管疾病高危因素和绝经有关的性功能紊乱。据认为引起男性阴茎勃起的某些血管和肌肉机制是女性生殖反应中的相似血管性因素。已知女性性觉醒(aroulsal)伴随使阴道充血和增加阴道润滑作用的动脉血流入;而且已知会阴肌肉有助于阴蒂勃起。
器质性或精神性因素或上述综合因素引起女性性功能紊乱。女性性功能紊乱包括不能达到或维持性兴奋的阴道润滑-肿胀反应直到性活动结束。已知器质性女性性功能紊乱与引起血流灌注不足、阴道充血不足和不完全阴蒂勃起的血管性障碍部分相关。
女性性功能紊乱不像男性性功能紊乱那样得到广泛研究。部分原因是获得志愿女性患者困难和历来认为女性性功能紊乱是性欲高潮(orgasmic)相关性的(性欲高潮延迟性的或非性欲高潮性的)或性欲性的,因此缺乏合适的动物模型。
已充分确立了New Zealand White雄性家兔用作阳萎动物模型的用途。最近研究报道了New Zealand White雌性家兔也是合适的较经济的研究女性性功能紊乱的血管病理学的动物模型,并且已经证明阴道充血和阴蒂勃起取决于血液灌注。参见例如Park等,“血管性女性性功能紊乱:阴道充血不足和阴蒂不完全勃起的血流动力学基础”,International Journal of Impotence Research,9,(1),27-37(1997年3月)。
在医学上治疗血管性性功能紊乱时,女性患者需要减轻性活动引起的不适或紊乱。对于精神性性功能紊乱的治疗而言,也可以使用有助于患者的精神性性治疗。
此前已证明脱水吗啡的口服生物利用度非常低。参见例如,Baldessarini等,述于Gessa等(编辑),
Apomorphine and Other Dopaminomimetics,Basic Pharmacology,
1,219-228,Raven Press,N.Y.(1981)。
最近,关于男性的研究表明,只要实现明显勃起应答所需要的脱水吗啡的剂量不会伴随恶心和呕吐或其它严重的副作用如低动脉压、潮红和出汗,口服给予脱水吗啡可以用来诱导精神性男性阳痿患者的勃起。参见美国专利第5,624,677和E1-Rashidy等和Heaton等,Urology,
45,200-206(1995)。脱水吗啡在人类患者产生勃起反应的具体机制虽然不完全清楚,但是据认为是通过刺激大脑正中视叶前区中的多巴胺受体的中枢性作用。
现在已经发现某些脱水吗啡控释传递系统可以提供切实可行的改善女性性功能紊乱的治疗用途,同时减少副作用的可能性。
发明概述
给予脱水吗啡增强神经性刺激的阴蒂海绵体内血流和阴道壁血流,它们分别与增强女性阴蒂勃起和阴道充血有关。
通常含有约2-约12mg、优选约2-约8mg脱水吗啡的舌下脱水吗啡剂型可有效使女性产生性准备,而不会诱发明显恶心或其它不需要副作用。优选在性活动前15-20分钟舌下给予。维持脱水吗啡血浆浓度不高于约5.5ng/ml、优选约0.3-约4ng/ml、更优选约1-约2ng/ml,以在性活动期间维持足以维持性交期间的阴道充血、与其相关的阴道润滑和阴蒂勃起的脱水吗啡血液循环血清水平和中脑组织水平,但是低于诱发明显恶心的剂量。
图的简述
在附图中:
图1是图示安慰剂和每公斤体重的静脉内脱水吗啡量为0.05、0.1、0.2、0.3和0.4mg时,神经刺激前和后脱水吗啡对雌性家兔阴蒂血流(ml/分钟/100g组织)的影响的条形图;
图2是图示安慰剂和每公斤体重的静脉内脱水吗啡量为0.05、0.1、0.2、0.3和0.4mg时,神经刺激前和后脱水吗啡对雌性家兔阴道壁血流(ml/分钟/100g组织)的影响的条形图;和
图3是图示静脉内脱水吗啡对雌性家兔体循环动脉压(舒张压和收缩压)影响的图。
优选实施方案详述
脱水吗啡可以用下式表示:
并以游离碱形式或酸加成盐存在。对于本发明目的来说,优选脱水吗啡盐酸盐;然而,也可以用它的其它药学上可接受的部分。本文所用术语“脱水吗啡”包括游离碱型的该化合物或其药学上可接受的酸加成盐。除了所述盐酸盐外,其它可接受的酸加成盐包括氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乳酸盐、柠檬酸盐、酒石酸盐、水杨酸盐、琥珀酸盐、马来酸盐、葡萄糖酸盐等。
已知脱水吗啡当皮下给予约5mg剂量时是具有催吐剂用途的多巴胺激动剂。对于本发明目的,脱水吗啡或类似作用的多巴胺受体激动剂以足以兴奋患者中脑区细胞而仅具有最小副作用的剂量给予。据信该细胞兴奋作用是可能包括5-羟色胺和催产素有关的神经传导的级联刺激的部分。
从关于的男性的研究知道,可以刺激男性患者中脑区的多巴胺受体至足以通过舌下给予脱水吗啡以维持脱水吗啡血浆浓度不高于约5.5每毫升纳克(ng/ml)而引起勃起的程度。
根据在人类(帕金森氏病)和动物中进行的脱水吗啡盐酸盐研究的文献报道,脱水吗啡在女性和男性中的药代动力学相同。所以,已知剂量的脱水吗啡在男性中的作用发生及持续时间(类似于动物)也适用于女性。
在雌性家兔研究中发现脱水吗啡静脉内剂量每公斤约100微克(μg/kg)体重最适于对神经刺激阴道和阴蒂血流产生血管性作用。对于女性,与该剂量相关的最适剂量约为1/10或10μg/kg体重。在舌下含片剂型时,脱水吗啡的生物利用度约为皮下给予脱水吗啡盐酸盐的13%。假如女性平均体重约70公斤,脱水吗啡的有效性准备剂量约76μg/kg或约5.3mg片。因此,约2mg-约12mg的剂量范围将使女性产生性准备(即性刺激时阴蒂勃起和阴道充血)。
舌下给予优选在性活动前约2-约10分钟的时间范围或更长时间给予,优选约15分钟-约20分钟。在此时间范围内舌下给予的脱水吗啡剂量范围优选为约25μg/kg体重-约80μg/kg体重。
说明性优选的舌下给予剂型列于下表1中。
表1
150mg无水吗啡盐酸盐舌下含片
3-mg片剂
脱水吗啡盐酸盐 2.00%(重量)
甘露醇 66.67%(重量)
抗坏血酸 3.33%(重量)
柠檬酸 2.00%(重量)
Avicel PH102 15.00%(重量)
甲基纤维素Methocel E4M 10.00%(重量)
天冬甜素 0.67%(重量)
硬脂酸镁 0.33%(重量)
4-mg片剂
脱水吗啡盐酸盐 2.66%(重量)
甘露醇 66.00%(重量)
抗坏血酸 3.33%(重量)
柠檬酸 2.00%(重量)
Avicel PH102 15.00%(重量)
甲基纤维素E4M 10.00%(重量)
天冬甜素 0.67%(重量)
硬脂酸镁 0.33%(重量)
%(重量)
5-mg片剂
脱水吗啡盐酸盐 3.33%(重量)
甘露醇 65.34%(重量)
抗坏血酸 3.33%(重量)
柠檬酸 2.00%(重量)
Avicel PH102 15.00%(重量)
甲基纤维素E4M 10.00%(重量)
天冬甜素 0.67%(重量)
硬脂酸镁 0.33%(重量)
需要时以及为了促进吸收,并由此提高生物利用度,现在设计的剂型除了含有片剂赋形剂外还含有β-环糊精或β-环糊精衍生物如羟丙基-β-环糊精(HPBCD)。含有HPBCD的说明性剂型示于下表II和III。
表II
含有羟丙基-β-环糊精的脱水吗啡盐酸盐舌下含片
mg/片
脱水吗啡盐酸盐 4.0
HPBCD 5.0
抗坏血酸 10.0
PEG8000 39.5
甘露醇 39.5
天冬甜素
2.0
总计 100
表III
含有β-环糊精的脱水吗啡盐酸盐舌下含片
mg/片
脱水吗啡盐酸盐 5.0
β-环糊精 20.0
抗坏血酸 5.0
甘露醇 68.9
硬脂酸镁 1.0
D&C 10号黄Aluminum Lake
0.1
总计 100
以控制的溶出率传递脱水吗啡能够避免或延迟发生恶心,以便提供足以使阴道和阴蒂充血而不诱发恶心的脱水吗啡的循环血清水平和中脑组织水平。当脱水吗啡以或接近上述剂量范围的较高剂量给予时,通过同时给予神经节剂(神经节反应的抑制剂)如烟碱或盐酸山梗菜碱可以减少恶心发生的可能性。为此,脱水吗啡与神经节剂的重量比范围约10至约1。
其它可以与脱水吗啡联合使用的止吐剂有抗多巴胺剂如胃复安以及酚噻嗪类如氯丙嗪、甲哌氯丙嗪、哔哌吗嗪(pipamazine)、硫乙哌丙嗪、氮羟哌丙嗪盐酸盐等。此外,合适的止吐剂还有:5-羟色胺(5-HT)拮抗剂如多潘立酮、奥旦西隆(可市售获得其名称为Zofran的盐酸盐)等;组胺拮抗剂如盐酸氯苯丁嗪、盐酸苯甲嗪、茶苯海明等;副交感抑制剂如东莨菪碱等;以及其它止吐剂如甲磺哌丙嗪、三甲氧苯酰胺、苯奎胺盐酸盐、盐酸地芬尼多等。
含有烟碱的剂型和含有多潘立酮的剂型列于下表IV中。
表IV
含有止吐剂的盐酸脱水吗啡舌下含片
mg/片
盐酸脱水吗啡 5.0
抗坏血酸 5.0
甘露醇 67.9
硬脂酸镁 1.0
烟碱 1.0
β-环糊精 20.0
D&C 10号黄Aluminum Lake
0.1
总计 100.0
mg/片
盐酸脱水吗啡 5.0
抗坏血酸 5.0
甘露醇 58.9
硬脂酸镁 1.0
多潘立酮 10.0
β-环糊精 20.0
D&C 10号黄Aluminum Lake
0.1
总计 100.0
优选的舌下含片剂型在至少约2分钟、但是优选低于约10分钟的时间范围内溶解。然而,需要的话溶出时间可以更长,只要能够维持必需的脱水吗啡血浆浓度。对于现在设计的剂型在水中的溶出时间更优选约3分钟至约5分钟。
以下实施例进一步采用合适的雌性动物模型说明脱水吗啡对雌性动物阴道和阴蒂血流的血管性作用。
方法
静脉内给予苯巴比妥麻醉New Zealand White雌性家兔(n=6,约3.5-4kg)。将20号血管导管植入右侧颈动脉内以测定体循环动脉压。进行腹部中线切口,解剖至阴道和阴蒂的盆神经分枝。用置于至阴道和阴蒂的盆神经分枝附近并连接至Grass SD-9刺激器的Harvard超小型电极进行神经刺激。用直接置入阴蒂海绵休组织和阴道壁内并连接至激光多普勒流量计的激光多普勒流量探针测量阴蒂海绵体和阴道壁血流。
刺激至阴道和阴蒂的盆神经分枝的前后分别记录基础动脉血压和阴蒂以及阴道壁血流。此后,以剂量反应方式(0.05mg/kg、0.1mg/kg、0.2mg/kg、0.3mg/kg和0.4mg/kg)经耳静脉给予脱水吗啡。神经刺激前后分别记录给予脱水吗啡对动脉血压和阴蒂以及阴道血流的影响。
结果
1.脱水吗啡对阴蒂海绵体内血流的影响
刺激至阴道和阴蒂的盆神经分枝引起阴蒂海绵体血流显著增加。静脉内给予脱水吗啡不会影响基础阴蒂海绵体内的血流。静脉内给予0.05mg/kg-0.2mg/kg浓度的脱水吗啡引起神经刺激诱发的阴蒂海绵体最大血流的增加并呈浓度依赖性,如图1所示。具体来说,与给予脱水吗啡前的观察到的结果相比,0.1mg/kg、0.2mg/kg和0.3mg/kg的脱水吗啡引起统计学上具有显著性的神经刺激诱发的阴蒂海绵体内最大血流的增加(图1)。
2.脱水吗啡对阴道壁血流的影响
静脉内给予脱水吗啡不会影响基础阴道壁血流。0.05mg/kg和0.2mg/kg浓度的脱水吗啡引起神经刺激诱发的阴道壁最大血流的增加并呈浓度依赖性,如图2所示。与给予脱水吗啡前的观察到的结果相比,静脉内给予0.1mg/kg和0.2mg/kg的脱水吗啡引起统计学上具有显著性的神经刺激诱发的阴道壁最大血流的增加(图1)。
0.4mg/kg浓度的脱水吗啡在神经刺激诱发的阴道壁血流增加时,产生副作用。
3.脱水吗啡对体循环动脉压的影响
脱水吗啡剂量增加对动脉舒张压的影响示于图3。静脉内给予脱水吗啡引起动脉舒张压浓度依赖性的中度降低,同时对动脉收缩压的影响最小。
结论
静脉内给予0.1mg/kg、0.2mg/kg和0.3mg/kg浓度的脱水吗啡引起神经刺激诱发的阴蒂海绵体最大血流的显著增加。静脉内给予0.1mg/kg和0.2mg/kg浓度的脱水吗啡引起阴道壁血流的显著增加。静脉内给予脱水吗啡所观察到的主要副作用是舒张压的中度降低。判定最适剂量为约0.1mg/kg。
采用雌性家兔动物模型进行的研究表明阴蒂勃起和阴道充血的血液动力学机制取决于阴蒂海绵体和阴道壁平滑肌的松弛作用。已知女性在性兴奋期间阴道血管充血必然伴有阴道润滑和外生殖器的肿胀。因此,脱水吗啡提高雌性家兔阴蒂血流被判定为增强人类女性阴蒂勃起的指标,而脱水吗啡提高阴道血流被判定为增强女性阴道润滑和增加阴道充血的指标。
已知盐酸脱水吗啡的剂量范围是种属依赖性的。人类有效剂量约为动物的1/10。因此,基于雌性家兔研究的静脉内给予的已知最适剂量约0.1mg/kg,与其相关的人类女性有效剂量应该约为0.01mg/kg。因为已知舌下给予脱水吗啡约为皮下给予脱水吗啡的13%生物利用度,所以约76μg/kg或约5.3mg片剂的剂量能够对70kg体重的女性产生显著的性准备(性刺激时产生阴蒂勃起和阴道充血)。所以,约2-约12mg、优选约2-约8mg、更优选约4-约6mg的剂量范围足以使女性产生性准备而不会诱发明显的恶心。
前述讨论和所报道的研究用来说明本发明而不是用来限制本发明。甚至在本发明精神以及范围内的其它变化仍是可能的且对本发明技术人员而言是显而易见的。
Claims (6)
1.脱水吗啡或其药学上可接受的酸加成盐在制备用于刺激人类女性中脑区的多巴胺受体的舌下药用剂型中的用途,所述剂型能改善所述女性性功能紊乱,引起阴蒂勃起和阴道充血的,其剂量足以使阴蒂内血流和阴道壁血流增加但是低于诱发明显恶心的量。
2.按照权利要求1的用途,其中所述剂型含有约2mg至约12mg脱水吗啡或其酸加成盐。
3.按照权利要求1的用途,其中酸加成盐是脱水吗啡盐酸盐。
4.按照权利要求1的用途,其中所述剂型包括β-环糊精或β-环糊精衍生物。
5.按照权利要求4的用途,其中所述β-环糊精衍生物为羟丙基-β-环糊精。
6.按照权利要求1的用途,其中所述剂型包括甘露醇和抗坏血酸作为赋形剂。
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US09/016,252 US5945117A (en) | 1998-01-30 | 1998-01-30 | Treatment of female sexual dysfunction |
US09/016252 | 1998-01-30 |
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CN1313742A CN1313742A (zh) | 2001-09-19 |
CN1250221C true CN1250221C (zh) | 2006-04-12 |
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CNB998044423A Expired - Fee Related CN1250221C (zh) | 1998-01-30 | 1999-01-28 | 女性性功能紊乱的治疗 |
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US (2) | US5945117A (zh) |
EP (1) | EP1056419A4 (zh) |
JP (1) | JP2002501875A (zh) |
KR (1) | KR20010040477A (zh) |
CN (1) | CN1250221C (zh) |
AR (1) | AR017976A1 (zh) |
AU (1) | AU752928B2 (zh) |
BG (1) | BG64667B1 (zh) |
BR (1) | BR9908038A (zh) |
CA (1) | CA2322289A1 (zh) |
CO (1) | CO4970819A1 (zh) |
CR (1) | CR5959A (zh) |
DZ (1) | DZ2714A1 (zh) |
GC (1) | GC0000096A (zh) |
GT (1) | GT199900013A (zh) |
HK (1) | HK1040901B (zh) |
HN (1) | HN1999000015A (zh) |
HU (1) | HUP0101268A3 (zh) |
IL (2) | IL137569A0 (zh) |
JO (1) | JO2085B1 (zh) |
MA (1) | MA26600A1 (zh) |
MX (1) | MXPA00007447A (zh) |
NO (1) | NO319821B1 (zh) |
NZ (1) | NZ506597A (zh) |
PA (1) | PA8467801A1 (zh) |
PE (1) | PE20000240A1 (zh) |
PL (1) | PL194350B1 (zh) |
SK (1) | SK11362000A3 (zh) |
TN (1) | TNSN99008A1 (zh) |
TR (1) | TR200002220T2 (zh) |
TW (1) | TW550069B (zh) |
UY (1) | UY25374A1 (zh) |
WO (1) | WO1999038467A1 (zh) |
ZA (1) | ZA99686B (zh) |
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1998
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1999
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- 1999-01-28 CN CNB998044423A patent/CN1250221C/zh not_active Expired - Fee Related
- 1999-01-28 ZA ZA9900686A patent/ZA99686B/xx unknown
- 1999-01-28 WO PCT/US1999/001776 patent/WO1999038467A1/en not_active Application Discontinuation
- 1999-01-28 NZ NZ506597A patent/NZ506597A/en unknown
- 1999-01-28 IL IL13756999A patent/IL137569A0/xx active IP Right Grant
- 1999-01-28 EP EP99905497A patent/EP1056419A4/en not_active Withdrawn
- 1999-01-28 HU HU0101268A patent/HUP0101268A3/hu unknown
- 1999-01-28 CA CA002322289A patent/CA2322289A1/en not_active Abandoned
- 1999-01-28 AU AU25644/99A patent/AU752928B2/en not_active Ceased
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- 1999-01-28 KR KR1020007008333A patent/KR20010040477A/ko not_active Application Discontinuation
- 1999-01-28 JO JO19992085A patent/JO2085B1/en active
- 1999-01-28 TR TR2000/02220T patent/TR200002220T2/xx unknown
- 1999-01-28 JP JP2000529203A patent/JP2002501875A/ja not_active Withdrawn
- 1999-01-28 HN HN1999000015A patent/HN1999000015A/es unknown
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- 1999-01-28 PL PL99342062A patent/PL194350B1/pl unknown
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2001
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