CN1315177A - 用特定血浆浓度水平的阿朴吗啡治疗性功能障碍的方法 - Google Patents
用特定血浆浓度水平的阿朴吗啡治疗性功能障碍的方法 Download PDFInfo
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- CN1315177A CN1315177A CN00137440A CN00137440A CN1315177A CN 1315177 A CN1315177 A CN 1315177A CN 00137440 A CN00137440 A CN 00137440A CN 00137440 A CN00137440 A CN 00137440A CN 1315177 A CN1315177 A CN 1315177A
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- apomorphine
- patient
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- plasma concentration
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Abstract
公开了给予患者阿朴吗啡以治疗性功能障碍同时减少不需要的副作用的方法。用这种方法,患者血浆阿朴吗啡浓度可高达10ng/ml。该浓度可有利地实现仅有15%以下的如此治疗患者出现呕吐。给药方法是经鼻、吸入到肺或口服摄取。
Description
本发明涉及将阿朴吗啡给予患者治疗性功能障碍、同时减少不需要的副作用的方法。用这种方法,患者血浆阿朴吗啡浓度高达10ng/ml。该浓度的治疗患者仅有15%以下患者出现呕吐。给药方法为鼻内、吸入到肺或口服摄取给药法。
人类男性和女性性反应产生于心理、激素、生理因素等复杂的相互作用。正在努力寻求提供有效的简便疗法,该简便疗法不需要恒定给药方案甚或多剂给药达到所需要的效果、是非侵袭性的并且可根据要求以及对正常性刺激反应产生快速的预期的性能力。
对于男性,已经提出包括各种治疗阳萎的外用设备的治疗方法,如压脉器(tourniquet)(参阅美国专利第2,818,855号)。另外,一定时间以来应用阴茎插入物,如绞链式或固体棒以及可膨胀的弹簧驱动式或水压式模型。
另外,药物治疗是已知的。例如美国专利第4,127,118号公开的方法,该方法通过局部注射血管扩张药、特别是肾上腺素能阻断剂或平滑肌松弛剂以影响和促进勃起,从而治疗男性阳萎,以及美国专利第4,801,587号公开应用软膏解除阳萎。该软膏包含血管扩张剂罂粟碱、肼苯哒嗪、硝普钠、苯氧苄胺或酚妥拉明和有助于主要药剂通过皮肤吸收的载体。美国专利第5,256,652号公开了血管扩张剂的水性组合物的应用,如罂粟碱与羟丙基-β-环糊精的组合物。
阿朴吗啡对阳萎或性功能障碍的作用已有广泛的研究和报道。然而,已证实阿朴吗啡口服生物利用度很差。参见例如Baldessarini等,载于gessa等编辑,阿朴吗啡和其它多巴胺类似物,Basic Pharmacology,第1卷,Raven Press,N.Y.(1981),第219-228页。
因此,使用阿朴吗啡治疗性功能障碍的功效因为生物利用度低和不需要的副作用而降低。提高生物利用度导致药物血浆浓度升高和不需要的副作用增加。因此,迄今已用阿朴吗啡特定浓度参数和/或特定给药方法限定性治疗性功能障碍以克服该问题。
例如美国专利第5,945,117号公开阿朴吗啡用于改善女性性功能障碍。美国专利第5,624,667、5,888,534、5,770,606、5,985,889和5,994,363号也已公开阿朴吗啡用于改善男性勃起功能紊乱。美国专利第5,624,667号中,制剂中可以加入薄荷调味剂以削弱一些局部呕吐受体。美国专利第5,888,534号公开缓释舌下含片。据认为,上述缓释片可减少不需要的阿朴吗啡药物副作用。通过逐渐适应阿朴吗啡可减少阿朴吗啡的副作用,如美国专利第5,994,363号所公开。WO 98/31368已公开,当患者首先用多潘立酮预治疗时,以阿朴吗啡快速释放口服制剂治疗阳萎。WO99/27905公开用某些阿朴吗啡鼻制剂治疗勃起功能紊乱。
美国专利第5,770,6065和5,985,889号公开阿朴吗啡舌下用药维持血浆浓度不高于5.5ng/ml,这样可减少不需要的副作用。并且,‘889专利指出虽然在飞行员研究3号(Pilot Study 3)中评估了阿朴吗啡水性鼻内喷雾剂,但是仅一例患者出现严重副反应导致终止进一步实验,因此,认为仍需要可靠和相对安全的剂型制剂。
所以,需要给予阿朴吗啡的替代用药方法,以提供需要的生物利用度,同时将不需要的副作用减至最小。
我们现已发现其它给药途经可提供比传统舌下治疗获得的生物利用度高而且不会产生成比例增加的不需要的副作用,这与本领域技术人员了解的原理相反。
本发明涉及用阿朴吗啡治疗性功能障碍患者同时减少不需要的副作用的方法。用这种方法患者血浆的阿朴吗啡浓度高达10ng/ml。更具体地讲,本发明涉及一种治疗性功能障碍患者的方法,该方法包括:
给予患者治疗有效量的阿朴吗啡或其药学上可接受的盐,给药方法为鼻内、吸入到肺或口服摄取给药;
其中所述患者的阿朴吗啡血浆浓度高达10ng/ml;
其中所述浓度实现如此治疗的患者出现呕吐的小于15%。
本发明还涉及一种治疗性功能障碍患者的方法,包括:
给予所述患者治疗有效量的阿朴吗啡或其药学上可接受的盐;
其中所述患者血浆阿朴吗啡浓度高达10ng/ml;
其中所述浓度实现如此治疗的患者出现呕吐的小于15%;
前提是给药方法不是舌下给药法。
通过鼻内、吸入到肺或口服摄取给予所述吗啡。
鼻内给药可以通过使用鼻喷雾剂、滴鼻剂、凝胶剂、悬浮剂、软膏、乳膏或散剂来完成。
“经口摄取”或“口服摄取”在此用于说明药物将主要经嘴吞服到胃;这样嘴是进入部位但不是主要吸收部位。这样,术语“经口摄取”或“口服摄取”在此用于区别嘴是进入部位而吸收主要发生在胃的口服吸收与嘴既是进入部位又是吸收部位的口粘膜用药,或区别于嘴是进入部位但是嘴和粘膜是吸收部位的快速溶解片剂的口服用药。阿朴吗啡可以以溶液剂、悬浮剂、滴剂、凝胶剂、片剂、颗粒剂、喷雾剂(sprinkle)、丸剂、散剂或胶囊剂的形式经口摄取。
对于实践本发明的任何方法,所述性功能障碍可是勃起功能紊乱。所达到的浓度无明显副作用如呕吐。具体地说,这种浓度的治疗患者出现呕吐的小于15%。这种治疗性功能障碍的方法可用于男性和女性。对于实践本发明的任何方法,阿朴吗啡血浆浓度可优选为约从0.1ng/ml到约0.7ng/ml。目前最优选阿朴吗啡血浆浓度为约从0.5ng/ml到约5ng/ml。
本发明还涉及一种治疗性功能障碍患者的方法,包括:
鼻内给予所述患者治疗有效量的阿朴吗啡或其药学上可接受的盐;
其中在所述患者达到的阿朴吗啡血浆浓度高达10ng/ml。
对于鼻内给药途经,阿朴吗啡可以以鼻喷雾剂、滴鼻剂、凝胶剂、悬浮剂、软膏剂、乳剂或散剂给药。
本发明还涉及一种治疗性功能障碍患者的方法,包括:
口服摄取给予所述患者治疗有效剂量的阿朴吗啡或其药学上可接受的盐;
其中在所述患者达到的阿朴吗啡血浆浓度高达10ng/ml。
对于口服摄取,阿朴吗啡可以以溶液剂、悬浮剂、滴剂、凝胶剂、片剂、丸剂、散剂、颗粒剂、喷雾剂或胶囊剂的形式给药。
本发明还涉及一种治疗性功能障碍患者的方法,包括:
经吸入到所述患者肺部给予治疗有效量的阿朴吗啡或其药学上可接收的盐;
其中在所述患者达到的阿朴吗啡血浆浓度高达10ng/ml;
所述吸入给药的传递设备或方法可包括剂量测量吸入仪、干粉末吸入仪、溶液或悬浮液的雾化和/或取得同样效果的其它任何系统。
男性性功能障碍的形式是勃起功能紊乱。正常勃起的出现是阴茎血管协调过程的结果。这通常通过是神经系统激发并包括阴茎血管舒张以及平滑肌松弛及其动脉血管充血。动脉血流导致海绵体膨大。海绵体膨大使静脉血流出受阻,从而维持阴茎高血压足以使阴茎坚硬。阴茎的肌肉也辅助产生和维持阴茎坚硬。勃起也可通过性的想象或幻想在神经系统中枢性诱发,并且通常通过反射机制局部再增强。勃起机制在本质上与女性阴蒂是相似的。
阳萎或男性勃起功能紊乱定义为不能达到和维持有效的性勃起完成性交。任何一例阳萎可产生于心理异常(精神性)、全身性生理异常(器质性)、神经性紊乱(神经性)、激素缺乏(内分泌性)或以上综合因素。其它阳萎可是激素性、先天性、血管性或局部因素(partial ability)。
然而这些描述是不完全准确的。目前没有诊断或治疗阳萎的标准方法。本文所用的精神性阳萎定义为没有明显占主要地位的器质性基础的的功能性阳萎。其特征为对一些刺激不能产生勃起反应(如手淫、自发遗精、自发性早晨勃起(spontaneous early morning)、色情视觉刺激等),但另一些刺激(如配偶或配偶关心(spousal attention))能产生勃起反应。
女性也可能发生随年龄而增加并与存在心血管疾病高危因素和绝经有关的性功能障碍。据认为引起男性阴茎勃起的某些血管和肌肉机制与女性生殖反应中的血管性因素相似。已知女性性唤起(arousal)伴随使阴道充血和增加阴道润滑作用的动脉血流入,而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障碍。女性性功能障碍包括不能达到或维持性兴奋的阴道润滑-膨胀反应直到性活动结束。已知器质性女性性功能障碍与引起血流灌注不足、阴道充血不足和阴蒂勃起障碍的血管性异常部分相关。
阿朴吗啡((R)-5,6,6a,7-四氢-6-甲基-4H-二苯并-[de,g]-喹啉-10,11-二酚)可用下式表示:,并以游离碱形式或作为酸加成盐存在。对于本发明目的来说,优选阿朴吗啡盐酸盐,然而,也可以用其它药学上可接受的部分形式的阿朴吗啡。
可用与无机酸或有机酸产生的药学上可接受盐形式的阿朴吗啡。术语“药学上可接受的盐”是指这样的盐:在可靠的医学判断范围内,适用于与人类和低等动物组织接触而没有不适当的毒性、刺激性、过敏反应等并具有相称的合适利益/风险比的盐。药学上可接受盐是本领域众所周知的。例如S.M.Berge等,药学上可接受盐的详细描述,载于J.Pharmaceutical Sciences,1997,66:1以及下列等。这类盐在本发明化合物的最后的分离和提纯过程中或使游离碱官能团与适合的有机酸反应分离,从而原位制备。典型的酸加成盐包括但非仅限于乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐(camphorate)、樟脑磺酸盐、二葡萄糖酸盐(digluconate)、甘油磷酸盐、半硫酸盐(hemisulfate)、庚酸盐(heptanoate)、己酸盐、延胡索酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(异硫代硫酸盐)、乳酸盐、马来酸盐、甲磺酸盐、烟碱酸盐(nicotinate)、2-奈磺酸盐、草酸盐、棕榈酸盐(palmitoate)、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸酯、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。此外,用以下物质季铵化碱性含氮基团:低级烷基卤的所述物质例如甲基、乙基、丙基和丁基氯、溴和碘;二烷基硫酸盐如二甲基、二乙基、二丁基和二戊基硫酸盐;长链卤如葵基、月桂基、肉豆蔻基和硬脂酰氯、溴和碘;芳烷基卤例如苯甲基和苯乙基溴和其它。因此获得可溶于水或油或可分散的产品。可用于形成药学上可接受的酸加成盐的酸的实例包括无机酸如盐酸、氢溴酸、硫酸和磷酸以及有机酸如草酸、马来酸、琥珀酸和柠檬酸。
美国专利第5,756,483号已公开阿朴吗啡鼻内制剂用于治疗帕金森氏病。美国专利第5,939,094号已公开阿朴吗啡经皮给药;而美国专利第5,866,164号已公开胶囊型阿朴吗啡。
阿朴吗啡为多巴胺受体激动剂,当皮下给予约5mg剂量时明确用作催吐剂。对于本发明目的,阿朴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,该细胞兴奋作用可能是包括5-羟色胺、多巴胺和催产素的神经传导的级联刺激的部分。
按照本发明的阿朴吗啡能以鼻喷雾剂、滴鼻剂、悬浮剂、凝胶剂、软膏剂、乳剂或散剂给予。所述鼻组合物也可用鼻塞和鼻海绵给予。
散剂可用鼻吹入器给予。散剂也可以以将其置于胶囊中的形式使用。将所述胶囊放进吸入或吹入设备。用针头穿过胶囊,在胶囊顶部和底部打孔,通入空气吹出粉剂颗粒。散剂也可用惰性气体喷射或悬浮在液体有机流体中。
本发明提供用含阿朴吗啡及其药学上可接受的盐和生理耐受稀释剂的药用组合物治疗性功能障碍的方法。本发明包括将阿朴吗啡及其药学上可接受的盐与一种或多种无毒的生理可耐受或可接受稀释剂、载体、辅助剂、媒介物(在本文统称为稀释剂)配制成组合物,供鼻内传递或以固体或液体形式口服给药。
这些组合物也可含有辅助剂如防腐剂、湿润剂、乳化剂和分散剂。可通过各种抗菌剂和抗真菌剂保证防止微生物的作用,例如对羟基苯甲酸酯、氯代丁醇、苯酚、山梨酸等。此外最好包含等张剂如糖、氯化钠等。
除所述活性化合物外,悬浮制剂可包含悬浮剂如乙氧基化异硬酰醇类、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝(aluminummetahydroxide)、膨润土、琼脂和黄蓍胶或这些物质的混合物等。
有用的鼻内制剂包含稳定剂和表面活性剂。其中药学上可接受的表面活性剂包括聚氧乙烯蓖麻油衍生物,如聚氧乙烯-甘油-三聚蓖麻酸酯(也称为聚氧乙烯35蓖麻油(CREMOPHOR EL)或聚氧乙烯40氢化蓖麻油(CREMOPHOR RH40),它们均可得自BASF公司;聚氧乙烯(20)脱水山梨醇一脂肪酸酯,如聚氧乙烯(20)脱水山梨醇单月桂酸酯(TWEEN80)、聚氧乙烯单硬酯酸酯(TWEEN 60)、聚氧乙烯(20)脱水山梨醇一棕榈酸酯(TWEEN 40)或聚氧乙烯(20)脱水山梨醇一月桂酸酯(TWEEN20),所有均可得自Wilmington DE的ICI Surfactants;聚甘油酯,如聚甘油油酸酯;和聚氧乙基化橄榄油(LABRAFIL,可得自Gattefosse公司)。优选表面活性剂为药用组合物重量的约0.01%到10%之间。
药学上可用的稳定剂有抗氧化剂,例如亚硫酸钠、焦亚硫酸钠、硫代硫酸钠、甲醛次硫酸钠、二氧化硫、抗坏血酸、异抗坏血酸、硫代甘油、巯基乙酸、半胱氨酸盐酸盐、乙酰半胱氨酸、棕榈酸抗坏血酸酯、氢醌、没食子酸丙酯、去甲二氢愈创木酸、丁基化羟甲苯、丁基化羟基苯甲醚、α-生育酚和卵磷脂。所述稳定剂优选为所述药用组合物的约0.01%-5%(重量)。
其它物质中也可应用螯合剂如乙二胺四乙酸、其衍生物及其盐、二羟乙基甘氨酸、柠檬酸和酒石酸。
保持合适的流动性,例如应用包衣物质如卵磷脂、在分散剂的情况下保持所要求的颗粒大小以及应用表面活性剂。
口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这样的固体剂型中,活性化合物可与至少一种惰性的、药学上可接受的赋形剂或载体混合,如柠檬酸钠盐或磷酸二钙,和/或a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;b)粘合剂如羧甲基纤维素、藻酸盐、明胶、聚乙稀吡咯烷酮、蔗糖和阿拉伯树胶;c)保湿剂(humectant)如甘油;d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐和碳酸钠;e)缓释剂溶液如石蜡;f)吸收加速剂如季铵化合物;g)湿润剂如鲸蜡基醇和一硬脂酸甘油酯;h)吸收剂如高岭土和膨润粘土和i)润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、聚乙二醇固体、月桂基硫酸钠及其混合物。在胶囊剂、片剂和丸剂的情况下,所述剂型也可含有缓冲剂。
相似类型的固体组合物也可用作用赋形剂如乳糖或乳糖(milk sugar)和高分子量聚乙二醇等装填的软明胶胶囊和装填的硬明胶胶囊的填充物。
固体剂型的片剂、锭剂、胶囊剂、丸剂和颗粒剂可用包衣和壳如肠溶包衣和药学制剂领域众所周知的其它包衣制备。它们可以任选含有遮光剂,也可以为这样的组合物使得它们任选以缓释方式仅在或优选在胃肠道的某一部分释放活性成份。可用的包埋成分(embedding composition)的实例包括聚合物和蜡。
所述活性化合物也可是微胶囊形式,若合适,可含有上述一种或多种赋形剂。
口服给药的液体剂型包括药学上可接受的乳剂、溶液剂、悬浮剂、糖浆剂和酏剂。除所述活性化合物外,液体剂型可包括本领域常用的稀释剂如水或其它溶剂;增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1-3-丁二醇、二甲基甲酰胺、油(特别是棉子油、花生油、玉米油、胚芽油(germ oil)、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨醇脂肪酸酯及其混合物。
除惰性稀释剂外,所述口服组合物可包含辅助剂,如湿润剂、乳化剂和悬浮剂、甜味剂、调味剂和香料。
所述药物也可以以脂质体的形式给药。如本领域所知,脂质体通常产生自磷脂或其它脂质物质。脂质体由单层或多层水合液晶分散到含水介质中形成的。可用能够形成脂质体的任何无毒的生理可接受的并可代谢的脂质。脂质体型的本发明组合物除了所述药物外,还可含有稳定剂、防腐剂、赋形剂等。优选的脂质是天然和合成磷脂和磷脂酰胆碱(蛋黄素),单独或一起使用。
形成脂质体的方法是本领域已知的。参见例如Prescott,Ed.,细胞生物学方法,第XIV卷,Academic Press,New York,N.Y.(1976),第33页,以及下列等。
根据给药途径或药物制剂减少阿朴吗啡不需要的副作用在下文实施例中详细描述。提供这些实施例是为了描述本发明的实施方案和用途,而不是限制本发明,除非在所附权利要求书中对其另有说明。
实施例1
用狗研究比较鼻内给药与传统舌下给药途径对阿朴吗啡不需要的副作用的减小作用。已证实狗是研究的合适模型,如美国专利第5,994,363号实施例3所公开。已证实阿朴吗啡舌下给药片剂在狗的生物利用度与人相同给药途经的生物利用度相当。已知狗对阿朴吗啡诱发呕吐的敏感性是人的5-10倍。
可按表1所列的剂量和三种不同的制剂通过滴入鼻内给予药物,每6只狗一组。每只狗的鼻内剂量为在0.2ml体积中的2mg。将狗轻度麻醉以免发生喷嚏反射。在每一指定时间检查狗的呕吐情况。表中列出在特定时间所述试验组狗中出现呕吐的狗的数量。例如表中的2/4表示在给定时间4只狗的一组中2只出现呕吐。这些资料与以前研究获得的资料相似,其中4只狗为一组,监测各种途径给药后在相同的时间间隔后出现呕吐的情况。SL代表舌下给药,SC代表皮下给药。
表1
阿朴吗啡鼻内给药后狗发生呕吐的原始资料比较
给定时间呕吐发生率(分钟) | |||||||||
治疗 | 剂量/狗(mg) | 0 | 5 | 8 | 10 | 15 | 20 | 30 | 60 |
SCa | 0.4 | - | - | 4/4 | - | 2/4 | - | - | - |
SL片a | 2 | - | - | - | - | 1/4 | - | 1/4 | - |
经口给予a | 2 | - | - | - | - | - | - | - | - |
研究1 | |||||||||
鼻内1b | 2 | 3/6 | - | - | - | - | 2/6 | - | - |
鼻内2c | 2 | 3/6 | - | - | - | - | 1/6 | 1/6 | - |
鼻内3d | 2 | - | - | - | 4/6 | - | 1/6 | - | - |
SCe | 1 | - | 1/6 | - | 4/6 | 1/6 | - | - | - |
a=资料来源于美国专利第5,994,363号的实施例3研究
b=1%药物(10mg/ml)、5%聚氧丙烯/聚氧乙烯嵌段共聚物(PLURONIC F127)
和1%焦亚硫酸钠(稳定剂)的水溶液制剂
c=1%药物(10mg/ml)、15%聚氧丙烯/聚氧乙烯嵌段共聚物(PLURONIC F127)
和1%焦亚硫酸钠(稳定剂)的水溶液制剂
d=1%药物(10mg/ml)、15%聚氧丙烯/聚氧乙烯嵌段共聚物(PLURONIC
F127)、0.6%羟丙基甲基纤维素(METHOCEL K100LV,生物粘合剂)和1%
焦亚硫酸钠(稳定剂)的水溶液制剂
e=0.04%药物(0.4mg/ml)和1%焦亚硫酸钠的水溶液制剂。
上表1中提供的原始资料分析如下表2。相对于生物利用度为100%的皮下给药,测量生物利用度。Cmax为最大血浆浓度;Tmax为从给药到达到最大血清浓度的时间;平均副作用强度(AS)以一定时间内出现呕吐总数除以所研究的狗数目计算,用百分数来表示。AS/Cmax测量相对于最大血药浓度的副作用强度。AS/Cmax值高表示在所述受试体系相对于药物量的副作用(在此以呕吐测量)比更高。而且,AS/Cmax值低表示在所述受试体系相对于药物量的副作用比更低。所以,希望AS/Cmax值低。还需注意的是,在狗的50%AS约等于在人的5%AS,由于狗比人的敏感性高得多。
表2显示在同一剂量水平鼻内给药较舌下给药的Cmax和生物利用度明显增高。然而,与传统方式相反,副作用强度并不成比例地增加。表2最后一栏说明这一点。所以,鼻内给药比舌下给药产生意想不到的更有效的生物利用度而没有产生相应高的副作用。
表2阿朴吗啡鼻内给药后狗发生呕吐的原始资料比较分析
治疗 | 剂量/狗(mg) | Tmax(hr) | Cmax(ng/ml) | 生物利用度(%) | 平均强度(%) | AS/Cmax |
SCa | 0.4 | 0.25 | 8.46 | 100 | 150 | 17.7 |
SL片a | 2 | 0.38 | 7.75 | 13.5 | 50 | 6.5 |
经口给予a | 2 | 0.35 | 0.40 | 3.9 | 0 | 0 |
研究1 | ||||||
鼻内1b | 2 | 0.17 | 139.2 | 150.8 | 83 | 0.6 |
鼻内2c | 2 | 0.27 | 161.4 | 126.9 | 83 | 0.5 |
鼻内3d | 2 | 0.17 | 1152.6 | 105.8 | 83 | 0.5 |
SCe | 1 | 100 | 100 |
a=资料来源于美国专利第5,994,363号的实施例3研究
b=1%药物(10mg/ml)、5%聚氧丙烯/聚氧乙烯嵌段共聚物(PLURONIC F127)和1%焦亚硫酸钠(稳定剂)的水溶液制剂
c=1%药物(10mg/ml)、15%聚氧丙烯/聚氧乙烯嵌段共聚物(PLURONIC F127)和1%焦亚硫酸钠(稳定剂)的水溶液制剂
d=1%药物(10mg/ml)、15%聚氧丙烯/聚氧乙烯嵌段共聚物(PLURONICF127)、0.6%羟丙基甲基纤维素(METHOCEL K100LV,生物粘合剂)和1%焦亚硫酸钠(稳定剂)的水溶液制剂
e=0.04%药物(0.4mg/ml)和1%焦亚硫酸钠的水溶液制剂。
实施例2
与传统舌下给药途经相比,采用实例1的实验方法获得关于吸入给予阿朴吗啡对不需要的副作用的减轻作用的信息。通过在每只狗的气管制作的孔将溶液直接引入狗的肺,代表沉积在肺的给予的雾化药物。研究结果见表3。
表3
吸入给予阿朴吗啡后狗发生呕吐的原始资料比较
给定时间的呕吐发生率(分钟) | |||||||||
治疗 | 剂量/狗(mg) | 0 | 5 | 8 | 10 | 15 | 20 | 30 | 60 |
SCa | 0.4 | - | - | 4/4 | - | 2/4 | - | - | - |
SL片a | 2 | - | - | - | - | 1/4 | - | 1/4 | - |
经口给予a | 2 | - | - | - | - | - | - | - | - |
研究2 | |||||||||
吸入1b | 0.5 | - | 4/5 | - | - | - | - | - | - |
吸入2c | 1 | 5/5 | - | - | - | - | - | - | - |
吸入3d | 2 | 5、5 | - | - | - | - | - | - | - |
a=资料来源于美国专利第5,994,363号的实施例3研究
b=0.05%药物(0.5mg/ml)和1%焦亚硫酸钠(稳定剂)的水溶液制剂;每只狗1ml
c=0.1%药物(1mg/ml)和1%焦亚硫酸钠(稳定剂)的水溶液制剂;每只狗1ml
d=0.2%药物(2mg/ml)和1%焦亚硫酸钠(稳定剂)的水溶液制剂;每只狗1ml
下表4显示上表3提供的原始资料分析。在相同剂量水平以及在低剂量水平时将药物给予到肺,其生物利用度较舌下给药高。然而,与传统方式相比,副作用强度并不随之成比例增加。表4最后一栏说明这一点。因此,吸入给药比舌下给药产生更有效的生物利用度而不会产生相应增高的副作用。特别值得注意的是,该给药方法能使Cmax相对于剂量成比例地增加,是一种意外现象,同时降低AS/Cmax,也是一种意外现象。
表4
吸入给予阿朴吗啡后狗发生呕吐的原始资料比较分析
治疗 | 剂量/狗(mg) | Tmax(hr) | Cmax(ng/ml) | 生物利用度(%) | 平均强度(%) | AS/Cmax |
SCa | 0.4 | 0.25 | 8.46 | 100 | 150 | 17.7 |
SL片a | 2 | 0.38 | 7.75 | 13.5 | 50 | 6.5 |
经口给予a | 2 | 0.35 | 0.4 | 3.9 | 0 | 0 |
研究2 | ||||||
吸入1b | 0.5 | 0.17 | 15.2 | 67.2 | 80 | 5.3 |
吸入2c | 1 | 0.17 | 31.5 | 62.7 | 100 | 3.2 |
吸入3d | 2 | 0 17 | 65.1 | 63.9 | 100 | 1.5 |
a=资料来源于美国专利第5,994,363号的实施例3研究
b=0.05%药物(0.5mg/ml)和1%焦亚硫酸钠(稳定剂)的水溶液制剂;每只狗1ml
c=0.1%药物(1mg/ml)和1%焦亚硫酸钠(稳定剂)的水溶液制剂;每只狗1ml
d=0.2%药物(2mg/ml)和1%焦亚硫酸钠(稳定剂)的水溶液制剂;每只狗1ml
实施例3
与传统舌下给药途经或口服给药途经比较,采用实施例1的实验方法获得关于当经口给予各种阿朴吗啡制剂时减小不需要的副作用的信息。试验制剂以溶液通过管或以胶囊形式直接引入狗的胃。研究结果见表5。
表5经口给予阿朴吗啡后狗发生呕吐的原始资料比较
给定时间的呕吐发生率(分钟) | |||||||||
治疗 | 剂量/狗(mg) | 0 | 5 | 8 | 10 | 15 | 20 | 30 | 60 |
SCa | 0.4 | - | - | 4/4 | - | 2/4 | - | - | - |
SL片a | 2 | - | - | - | - | 1/4 | - | 1/4 | - |
经口给予a | 2 | - | - | - | - | - | - | - | - |
研究3 | |||||||||
经口给予1b10mg/ml管饲法 | 10 | - | - | - | - | - | - | - | 15 |
经口给予2c20mg/ml管饲法 | 20 | 2/5 | - | 3/5- | - | - | - | - | - |
经口给予3d胶囊 | 10 | - | - | - | - | - | - | - | - |
a=资料来源于美国专利第5,994,363号的实施例3研究
b=1%药物(0.5)和1%(0.5g)焦亚硫酸钠(稳定剂)的水溶液制剂
c=2%药物(1g)和1%(0.5g)焦亚硫酸钠(稳定剂)的水溶液制剂
d=10%药物(10mg)和90%(90mg)Avicel 101(微晶纤维素)的制剂
上表5中提供的原始资料分析如下表6。通过改变口服给药的制剂可控制生物利用度与不需要的副作用强度的关系。口服制剂2产生的生物利用度高于口服制剂1,口服制剂2产生的与生物利用度相关的副作用较口服制剂1轻。表6最后一栏说明这一点。还需要注意的是,不同的口服制剂产生不同的Cmax值。口服制剂2产生的Cmax几乎比舌下片剂高于4倍,而没有相应的呕吐加重。因此,根据制剂也可优化Cmax与副作用。
表6经口给予阿朴吗啡后狗发生呕吐的原始资料比较分析
治疗 | 剂量/狗(mg) | Tmax(hr) | Cmax(ng/ml) | 生物利用度(%) | 平均副作用强度(%) | AS/Cmax |
SCa | 0.4 | 0.25 | 8.46 | 100 | 150 | 17.7 |
SL片a | 2 | 0.38 | 7.75 | 13.5 | 50 | 6.5 |
经口给予a | 2 | 0.35 | 0.4 | 3.9 | 0 | 0 |
研究3 | ||||||
经口给予1b10mg/ml管饲法 | 10 | 0.13 | 4.21 | 1.83 | 20 | 4.75 |
经口给予2c20mg/ml管饲法 | 20 | 0.35 | 29.3 | 3.87 | 100 | 3.4 |
经口给予3d胶囊 | 10 | 0.19 | 1.75 | 1.16 | 0 | 8.6 |
a=资料来源于美国专利第5,994,363号的实施例3研究
b=1%药物(0.5g)和1%(0.5g)焦亚硫酸钠(稳定剂)的水溶液制剂
c=2%药物(1g)和1%(0.5g)焦亚硫酸钠(稳定剂)的水溶液制剂
d=10%药物(10mg)和90%(90mg)Avicel 101(微晶纤维素)的制剂
实施例4
本研究是测定各种剂量水平阿朴吗啡在人体的吸收。用剂量为2、4、5和6mg舌下片测试24例男性。在将药片置于舌下后立即从受试者获取血浆样品,接着以特定时间间隔取样本,最长至20分钟。20分钟后除去舌下仍未溶解的物质(如果有的话)。接着样本用高敏感性LC/MS/MS技术分析。血浆药物水平峰值分别接近0.70、1.25、1.70和1.91ng/ml,如表7所示。表中SD代表标准差。结果显示阿朴吗啡按剂量比方式吸收(Cmax和AUC(曲线下面积)与舌下片剂量呈线性增加)。因为已证实在人类通过舌下片给予6mg剂量可提供良好功效而副作用最小,所以给予6mg阿朴吗啡舌下片剂后所获得的血浆药物水平是有意义的性能指标。换句话说,在人类舌下给予片剂后的0到6ng/ml血浆药物浓度水平(用6mg片剂获得)是治疗性功能障碍功效好而副作用小的有意义的指标。据估计,相对于皮下给予对照,舌下片在人类的生物利用度为16-18%。
表7
阿朴吗啡在人体的药代动力学参数参数 2mg SL 4mg SL 5mg SL 6mg SL 1mg SCtmax(h) 均值 0.74 0.72 0.68 0.66 0.34标准差0.30 0.32 0.21 0.32 0.17Cmax(ng/ml)均值 0.70 1.25 1.70 1.91 3.22标准差0.37 0.80 1.32 1.22 1.67AUC(ng·h/ml)均值 1.23 2.37 2.92 3.60 3.39标准差0.48 1.06 1.50 1.73 1.09
2-4mg舌下阿朴吗啡片在人类的临床经验证实恶心发生率约13%及呕吐发生率约2%。能够预测的是,使药物水平达到0.25-5ng/ml范围而诸如呕吐的副作用小的任何制剂或给药技术可改善患者顺从性和这种化合物在治疗性功能障碍中的有效性。已证实狗对呕吐比人敏感得多,如前所述。因此,据认为,使狗的药物水平能够与舌下片可达到的药物水平相似而没有相应的呕吐发生的任何制剂或给药,在人类将具有优越的功效。本研究的鼻内、吸入至肺或口服制剂证实可实现该目的。
已证实在人类,相对于人体的皮下给药对照,舌下阿朴吗啡片的相对生物利用度约15%,在狗也同样如此。这提示狗是代表阿朴吗啡吸收的良好模型。已证实人类能很好耐受高达8mg的阿朴吗啡片剂。假设一个60kg的人和一个10kg的狗,8mg人体剂量与约1.33mg阿朴吗啡狗剂量非常相当。关于本研究,研究0.5-20mg/狗的剂量范围在狗产生的血浆药物水平与2mg舌下片在狗获得的血浆药物水平相当或更高而没有相应的副作用。以上实施例所研究的鼻内、吸入至肺或口服给药证实可达到该目的。
所引用的所有参考文献通过引用结合到本文中。
本发明通过以上描述和实施例进行了说明。以上描述为非限制性的说明,因为对本发明进行的无数改变对本领域技术人员而言将是显而易见的。因此其本意是本发明包括在所附权利要求书范围及精神内的这样的各种改变。
可对本文所述的本发明组合物、本发明方法的操作和方案进行各种改变而未偏离以下权利要求书所定义的本发明基本原理和范围。
Claims (19)
1.治疗性功能障碍患者的方法,该方法包括:给予所述患者治疗有效量的阿朴吗啡或其药学上可接收盐;其中所述患者的阿朴吗啡血浆浓度高达10ng/ml;其中低于15%的达到所述浓度的治疗患者出现呕吐;前提是:不是舌下给药。
2.权利要求1的方法,其中所述阿朴吗啡通过鼻内给药。
3.权利要求2的方法,其中所述阿朴吗啡以鼻喷雾剂、滴鼻剂、凝胶剂、悬浮剂、软膏、乳剂或散剂给药。
4.权利要求1的方法,其中所述阿朴吗啡通过口服摄取给药。
5.权利要求4的方法,其中所述阿朴吗啡以溶液剂、悬浮剂、滴剂、凝胶剂、片剂、颗粒剂、喷雾剂(sprinkle)、丸剂、散剂或胶囊剂给药。
6.权利要求1的方法,其中所述阿朴吗啡通过吸入到肺给药。
7.权利要求6的方法,其中所述阿朴吗啡通过剂量计量吸入仪、干粉末吸入仪、雾化溶液或雾化悬浮液给药。
8.权利要求1的方法,其中所述性功能障碍是勃起功能障碍。
9.权利要求1的方法,其中所述患者是女性。
10.权利要求1的方法,其中所述阿朴吗啡在所述患者的血浆浓度为约从0.1ng/ml到约7ng/ml。
11.权利要求1的方法,其中所述阿朴吗啡在所述患者的血浆浓度为约从0.5ng/ml到约5ng/ml。
12.治疗性功能障碍患者的方法,该方法包括:
给予所述患者治疗有效量的阿朴吗啡或其药学上可接受的盐,给药方法为鼻内、吸入至肺或口服摄取给药法;
其中所述阿朴吗啡在所述患者达到的血浆浓度高达10ng/ml;
其中15%以下达到所述浓度的治疗患者出现呕吐。
13.权利要求12的方法,其中所述阿朴吗啡以鼻喷雾剂、滴鼻剂、凝胶剂、悬浮剂、软膏、乳剂或散剂通过鼻内给药。
14.权利要求12的方法,其中所述阿朴吗啡以溶液剂、悬浮剂、滴剂、凝胶剂、片剂、丸剂、散剂、颗粒剂、喷雾剂或胶囊剂口服给药。
15.权利要求12的方法,其中所述阿朴吗啡通过剂量计量吸入仪、干粉末吸入仪、雾化溶液或雾化悬浮液吸入到肺给药。
16.权利要求12的方法,其中所述性功能障碍是勃起功能障碍。
17.权利要求12的方法,其中所述患者是女性。
18.权利要求12的方法,其中在所述患者的所述阿朴吗啡血浆浓度为约从0.1ng/ml到约7ng/ml。
19.权利要求12的方法,其中在所述患者的所述阿朴吗啡血浆浓度为约从0.5ng/ml到约5ng/ml。
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US6566368B2 (en) * | 1994-04-22 | 2003-05-20 | Pentech Pharmaceuticals, Inc. | Apomorphine-containing dosage form for ameliorating male erectile dysfunction |
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US20040018237A1 (en) * | 2002-05-31 | 2004-01-29 | Perricone Nicholas V. | Topical drug delivery using phosphatidylcholine |
US7591999B2 (en) * | 2003-03-04 | 2009-09-22 | Mitsubishi Tanabe Pharma Corporation | Powdery preparation for nasal administration |
US20040204439A1 (en) * | 2003-04-14 | 2004-10-14 | Staniforth John Nicholas | Composition, device, and method for treating sexual dysfunction via inhalation |
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