CN1444926A - 生物粘着性药物释放系统 - Google Patents
生物粘着性药物释放系统 Download PDFInfo
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- CN1444926A CN1444926A CN02127087A CN02127087A CN1444926A CN 1444926 A CN1444926 A CN 1444926A CN 02127087 A CN02127087 A CN 02127087A CN 02127087 A CN02127087 A CN 02127087A CN 1444926 A CN1444926 A CN 1444926A
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Abstract
本发明涉及一种新的pH基本为中性的阴道药物释放系统,适于在阴道腔内缓和地释放具有治疗活性的物质。此阴道药物释放系统包含pH基本为中性的乳剂,此乳剂内有含有两相的药球,内相为水溶相,外相为水不溶相或膜,其中水溶性的内相含有一或多种治疗活性药物。本阴道药物释放系统的一个新的方面是内部的水溶相含有酸性缓冲相。
Description
发明所属技术领域
本发明涉及一种新的pH基本为中性的阴道药物释放系统,适于在阴道腔内缓和地释放具有治疗活性的物质,以优化与治疗活性物质相关的治愈率。阴道药物释放系统包含pH基本为中性的乳剂,此乳剂内有含有两相的药球,内相为水溶相,外相为水不溶相或膜,其中水溶性的内相含有一或多种治疗活性药物。本阴道药物释放系统的一个新的方面是内部的水溶相含有酸性缓冲相,它可以为等渗、高渗或低渗。本发明还涉及一种用这些药物释放系统治疗阴道疾病的方法。
发明的背景技术
药物的一个主要类别是用于妇科生殖系统以诊断、预防、减缓、处置及治愈疾病,及防止或促进妊娠。通常这包括活性药物直接释放到阴道腔及其周围。
因为阴道腔处于使其成为疾病和感染的目标的条件下,实现这些治疗剂的释放的系统通常为凝胶、泡沫、霜剂、栓剂和快速溶解的片剂等剂型。这些释放系统,无论制备的配方和方法如何,已证明它们在阴道腔内按控制方式以3个小时或更长的周期释放活性剂的能力方面有一些困难。在延长的时间周期内向此区域释放活性剂是十分困难的。
阴道腔含有分泌腺而显示水性环境,其分泌液产生在4.5-5.5范围内的酸性pH。由于温暖、湿润和黑暗,阴道的环境有助于细菌、真菌、酵母和其他微生物的生长。另外,从生理结构看阴道是月经碎片、性交的残余精液和不良细菌、真菌、酵母及其它微生物的出入通道。例如在性交或在月经棉条插入时,阴道腔也有相当程度的物理变形。
有药物特性的活性剂已被开发,并被批准用于治疗阴道腔的病痛及防止妊娠。这些活性剂包括抗真菌剂、杀精子剂等。然而,由于已知释放系统的不足,难于达到这些活性剂的最优的潜在效果。目前批准或进而适用于阴道腔内的系统在持久释放药物活性剂方面显示出一些困难。对于与美感有关的系统,例如酸化剂和除臭剂也是这样。
现在作为阴道释放系统的大多数凝胶、泡沫剂、霜剂、栓剂和片剂几乎在塞入阴道腔内后立即分解,并在阴道壁有极小的生物粘附。这被认为是由于它们的水混溶性和/或它们在37℃(体温)缺乏物理稳定性。因此,它们由于活性剂快速、不受控制的释放而显示有限的效果。另外,常规的剂型通常有泄漏和滴漏。为使这些快速泄漏减小到最小程度,最常规的剂型是在夜间病人临睡前以俯卧位给药。
一种改进的释放系统将活性剂输送到发挥作用、吸收的部位,或以预定方式使用。这与常规的需要频繁重复给药以达到活性剂的理想水平的立即释放系统形成对照。改进的释放系统的一个优点是,因为阴道腔内的药物水平保持在恒定的等级,所以每天的给药次数少于常规的系统。另外,现有技术的控制释放系统不影响治疗疾病所需的总天数。
改进的药物释放系统的制剂可以采用乳剂。乳剂通常有高的自由能量保护屏障。特别地,本领域将有相对高的水与油的比例,并有高的自由能的乳剂称为“高内相乳剂”(“HIPE’s”)。 HIPE’s已用于多种用途,例如燃料、农业喷雾剂、纺织品印刷、食品、家庭和工业清洁、化妆品和药品,及灭火剂。HIPE’s也用于制备聚合物泡沫类材料。例如,参见美国专利U.S.Patent No.3,988,508(“Lissant”);和美国专利U.S.PatentNo.5,189,070(“Brownscombe等”),将每个都全文结合于此作为参考。
已知HIPE’s的最突出的特点是:在胃肠道和/或消化道的乳剂型分解,并失去内相能量,这使乳剂在粘膜上融合成连续的膜。
本领域已知一些用于输送药物的控制释放乳剂。例如,全文结合于此作为参考的美国专利U.S.Patent No.5,298,246(“Yano等”),公开了通过口服给药促进亲脂性药物吸收能力的水包油型乳剂。通过加入磷酸钠等渗缓冲液(pH7.0)使乳剂保持稳定。
全文结合于此作为参考的美国专利U.S.Patent No.5,622,657(“Takada等”),公开了一种制备能延续释放的微粒制剂的方法。这些制剂可以包括油包水型乳剂,并可以通过阴道给药。
全文结合于此作为参考的美国专利U.S.Patent No.5,733,939(“Fuhrman等”)公开了治疗包括阴道粘膜的粘膜炎症,炎症的常规的药物释放剂型。这些参考文献讨论了有连续气态或液态碳氟化合物相和不连续的水相的凝胶类乳剂。
全文结合于此作为参考的美国专利U.S.Patent No.5,840,744(“Borgman”)公开了一种治疗细菌性阴道炎的非流动的甲硝唑组合物。可以用缓冲剂将此公开的甲硝唑组合物调节到酸性pH。此参考文献讨论了油包水型乳剂,其中甲硝唑和缓冲盐溶解或悬浮在油相组分中。
全文结合于此作为参考的美国专利U.S.Patent No.5,993,846(“Friedman等”),公开了一种用于例如阴道粘膜的粘膜表面的乳剂。特别地,Friedman公开了有增进的生物粘附性质的含药的水包脂质型乳剂。
全文结合于此作为参考的美国专利U.S.Patent No.6,191,105(“Ekwuribe等”),公开了自由型和/或共轭稳定化的治疗剂的微乳液剂。微乳剂包含油包水乳剂。Ekwuribe公开,可以根据鼻粘膜和眼对所给药物的耐受性,总体上调节乳剂的pH。Ekwuribe还讨论了所公开制剂的阴道给药。
全文结合于此作为参考的美国专利U.S.Patent No.6,294,550(“Place等”),公开了一种治疗女性性机能障碍的常规药物输送形式。此参考文献讨论了阴道给药的油包水乳剂。
然而,本文记载的药物输送系统的广泛使用受到以下因素的限制:(1)已知系统需要毒性量的佐剂或抑制剂;(2)不能得到适宜的低分子量治疗剂;(3)已知系统显示差的稳定性和不充分的保存期;(4)已知系统难于制备;(5)已知系统不能保护活性剂;(6)已知系统会有害地改变活性剂;(7)已知系统不能允许或促进活性剂的吸收;和/或(8)已知系统不能在充分延长的期间内释放活性剂。
相应地,现在提出的发明一方面提供一种pH基本为中性的阴道药物释放系统,其中包含pH基本为中性的乳剂,乳剂中有具有两相的药球,内相为含有一或多种治疗性活性药物的酸性缓冲的水溶相,外相为水不溶相或膜。本阴道药物释放系统的优点在于它为在阴道腔内释放治疗性活性药物提供了一种改进方式,其延长的释放周期长达168小时。相应地,药物释放系统优化了药物释放效率、药物治疗效果和治疗性活性药物产生的治愈率。本系统可以采用能方便地引入阴道腔内而不易从此体腔渗出的多相液体或半固体的形式。另一个优点是能缩短活性剂的治疗周期。
从说明书和权利要求书可以清楚地展示本发明的这些和其他方面。
发明概述
本发明的主题涉及一种由pH基本为中性的乳剂构成的pH基本为中性的阴道药物释放系统,其中的乳剂有具有两相的药球,以及制备和使用此阴道药物释放系统的方法。
更特别地,本发明的主题涉及一种pH基本为中性的阴道药物释放系统,其含有:
一种pH基本为中性的乳剂,它有具有两相的药球,内相为水溶相,外相为水不溶相或膜;
所述的内部水溶相包含含有一或多种治疗活性药物的酸性缓冲相,其中酸性缓冲相包含独立的或与其它的缓冲剂结合的一或多种所述治疗活性药物;
其中酸性缓冲相为等渗、高渗或低渗。
本发明主题的另一实例是pH基本为中性的阴道药物释放系统,其中包含:
一种pH基本为中性的乳剂,它有具有两相的药球,内相为水溶相,外相为水不溶相或膜;
所述的内部水溶相包含含有一或多种微粉化的治疗活性药物的酸性缓冲相,其中酸性缓冲相包含独立的或与其它的缓冲剂结合的一或多种所述微粉化的治疗活性药物;
其中酸性缓冲相为等渗、高渗或低渗;并且
其中微粉化的治疗活性药物具有在0.1微米至小于60.0微米范围内的颗粒大小,
其中酸性缓冲相使治疗活性药物的效果最大化;并且
其中酸性缓冲相的量足以中止阴道粘膜的炎症和瘙痒症状。
本发明主题的另一实例是pH基本为中性的阴道药物释放系统,其中包含:
一种pH基本为中性的乳剂,它有具有两相的药球:内相为水溶相,外相为水不溶相或膜;
所述的内部水溶相包含其本身pH约为2.0至约6.0的酸性缓冲相和治疗活性药物,其中酸性缓冲相包含独立的或与其它的缓冲剂结合的治疗活性药物。
本发明主题的另一实例是治疗阴道疾病的方法,包括:给病人施用pH基本为中性的阴道药物释放系统,其中包含:
一种pH基本为中性的乳剂,它有具有两相的药球:内相为水溶相,外相为水不溶相或膜;
所述的内部水溶相包含含有一或多种治疗活性药物的酸性缓冲相,其中酸性缓冲相包含独立的或与其它的缓冲剂结合的一或多种所述的治疗活性药物;
其中酸性缓冲相为等渗、高渗或低渗;并且
其中的治疗活性药物具有在0.1微米至小于60.0微米范围内的颗粒大小。对发明的详细描述
在此处用于描述有药球的乳剂,术语“药球”指用高剪切均化作用制备的圆形药球。另外,此处描述的药球有两相:内部包含酸性缓冲相的水溶相和外部的水不溶相或膜。
本发明的药物释放系统为“pH基本中性”,即整体上pH基本是中性,因为这些药物释放系统的水相不连续,所以不能测定其pH。因此,在完整的情况下,这些药物释放系统不显示pH值。只有构成即刻药物释放系统的药球的缓冲内相有非中性(酸性)的可测定的pH值。
关于本文的药球,术语“平均直径”是用粒径分析器-例如使用可以从Micromeritics(Norcross,Ga.)市售得到的SediGraph5100-得到的值。另外,可以通过测定用光学显微镜得到的照片中的至少100个药球的直径确定平均直径。
关于本文记载的乳剂的连续相、相间的组分或悬浮介质所用的术语“油”,是指这些介质具有疏水性因而不能与亲水相混溶。此术语不意味这些相必须由油组成或包括油。
此处使用的术语“稳定”或“稳定化的”指形成的药球在储藏过程中或在阴道给药时基本上能抵抗不希望的降解。
术语“生物相容的”指当单独或与pH控制剂配合引入病人组织中时,脂质体或聚合物不产生任何程度不能接受的毒性,包括变应原性反应和病态。优选地,脂质体或聚合物是惰性的。
此处使用的术语“微粉化的”指在约0.1微米至小于60.0微米的粒径范围。微粉化的治疗活性药物促进阴道释放系统的效能,因为它们接近包裹微粉化颗粒的药球载体的最优体积。
本发明的主题为阴道释放系统。此系统的特点是它们在延长的时间周期内以改进的方式向特定位置-阴道腔释放治疗活性药物,使药物治疗效果及药物释放效能达到最大的能力。此系统能生物粘附在上皮组织,并由至少两相构成。在阴道腔内,此系统在延长的停留时间里保持其完整性并显示物理稳定性。
如上所述,阴道腔产生有益于细菌、真菌、酵母和微生物生长的水性环境。现有技术的系统由于它们的水可混合性、缺乏生物粘附性或在37℃的阴道环境内缺乏物理稳定性而不能使治疗这些状况的效果最优化。此处定义的“阴道腔”不仅包括阴道,还包括任何另外的临近组织或表面。这些临近的组织或表面包括女性泌尿生殖道的任何部分,例如尿道口、子宫颈、子宫、外阴、输卵管、膀胱、结肠、肛门、直肠、卵巢、输尿管和输卵管。“释放系统”是为安全方便地释放精确剂量的所述治疗活性药物,而对治疗活性药物起溶解、悬浮、增稠、稀释、乳化、稳定、防腐、保护、着色、调味和风味作用使其制成可接受的和有效的制剂的非活性组分的组合。
本发明的阴道药物释放系统适于向阴道内缓和地释放治疗活性药物。这些阴道药物释放系统包含pH基本为中性的乳剂,它含有明确限定了外部水不溶相或膜和内部水溶性相的药球,内部的水溶相包含含有治疗活性药物的酸性缓冲相,其中的酸性缓冲相包含独立的所述治疗活性药物或它与另外的缓冲剂的结合。
典型地,本发明使用的药球有约0.1微米-约100微米的直径。在一优选实施例中,药球有约0.1微米至约60微米的粒径。在一特别优选的实施例中,药球有约0.5微米至约55微米的粒径。
本发明药球的外部由生物相容性的脂质体或聚合物材料构成,其中特别优选生物相容性脂质体。对于生物相容性脂质类材料,优选双亲性或疏水性组合物。双亲性组合物指既有亲脂性(疏水性)又有亲水性的物质的任何组合物。
天然和合成的磷脂是在制备本发明所用的药球的外表时作为乳化剂的脂质的例子。它们含有亲水性的带电荷的磷酸“端部”基团,连接到疏水性的长的碳氢尾上。此结构允许磷脂形成单一的双分子层(单层)排列,其中所有水不溶性碳氢尾相互接触,使高电荷的磷酸酯头部区域自由地与极性的水环境接触。可以理解的是能形成一系列同心的双分子层,即寡层和多层,这些排列也在本发明要求的范围之内。特别地,磷脂和磷脂的酯增加本发明的乳剂的稳定性。当使用主动治疗性活性药物时这点有特别的重要性。
制备本发明药球的壁最有用的稳定化化合物一般是有疏水/亲水特点使其能在水性介质存在下形成双层结构的化合物。因此,水、盐水或一些其他水性介质,以下通常称为稀释剂,可以形成本发明药球的外表,在此处这些形成双层的化合物作为稳定化化合物。
本发明优选的有用的双亲性的或疏水性的材料选自矿物油、脂质材料、中性脂肪、脂肪酸、脂肪酸酯、植物油、维生素油(vitamin oils)、果实的油、鱼油、来源于植物或动物的任何其它的油及其组合。根据本发明主题特别优选的脂质是磷脂。
本发明产生的药球的稳定性可以归因于由高剪切均化方法得到的药球所显示的非牛顿物理性质。高剪切均化方法的其它显著的特点是高的表面自由能和药球间的亲合力。
根据本发明的主题,在制备的药球中不必使用辅助的稳定化添加剂,即使这是可以选择的,并且这些辅助的稳定化剂是本领域普通技术人员已知的。
作为制备本发明药球的稳定化化合物的生物相容性聚合物可以是天然、半合成或合成的。
此处使用的术语聚合物指包含2个或多个重复的单节单位的化合物,优选有10或更多的重复单节单元。
此处使用的术语半合成聚合物指在一些方面经过化学修饰的天然聚合物。适用于本发明的示例性的天然聚合物包括天然产生的多糖。这些多糖包括例如阿拉伯糖、果糖、脱氧半乳聚糖、半乳聚糖、聚半乳糖醛酸、葡聚糖、甘露聚糖、木聚糖(例如菊粉)、果聚糖、岩藻依聚糖(fucoidan)、角叉菜胶、半乳卡洛糖、果胶酸、果胶、直链淀粉、出芽短梗霉聚糖(普鲁兰)、糖原、支链淀粉、纤维素、右旋糖酐、石脐素、壳多糖、琼脂糖、角质素(keratan)、软骨素(chondroitan)、皮肤素(dermatan)、透明质酸、海藻酸、黄原胶、淀粉,和各种其它天然均聚物或杂聚物,例如含有一或多个以下醛糖、酮糖、酸或胺的化合物:赤藓糖、苏阿糖、核糖、阿拉伯糖、木糖、来苏糖、阿洛糖、阿卓糖、葡萄糖、甘露糖、古洛糖、艾杜糖、半乳糖、塔罗糖、赤藓酮糖、核酮糖、木酮糖、阿洛酮糖、果糖、山梨糖、塔格糖、甘露糖醇、山梨糖醇、乳糖、蔗糖、海藻糖、麦芽糖、纤维二糖、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酸盐、天门冬氨酸、谷氨酸、赖氨酸、精氨酸、组氨酸、葡糖醛酸、葡糖酸、葡糖二酸、半乳糖醛酸、甘露糖醛酸、葡糖胺、半乳糖胺、神经氨酸及其天然存在的衍生物。
适用于本发明的示例性的半合成聚合物包括羧甲基纤维素、羟甲基纤维素、羟丙甲基纤维素、甲基纤维素和甲氧基纤维素。
适用于本发明的示例性的合成聚合物包括聚乙烯(例如聚乙二醇、聚氧乙烯和聚乙烯对苯二酸酯)、聚丙烯(例如聚丙二醇)、聚氨基甲酸酯(例如聚乙烯醇(PVA)、聚氯乙烯和聚乙烯吡咯烷酮)、包括尼龙的聚酰胺、聚苯乙烯、聚合乳酸、氟化碳氢化合物、氟化碳(例如聚四氟乙烯)、聚甲基异丁烯酸酯及其衍生物。
可以用于制备本发明药球的外相或膜的另外的脂质或油包括但不限于:脂肪酸;溶血脂质(lysolipid);有饱和及不饱和脂质的卵磷脂,包括二油酰基卵磷脂、二豆蔻酰基卵磷脂、二-十五酰基卵磷脂、二月桂酰基卵磷脂、二棕榈酰基卵磷脂(DPPC)、二硬脂酰基卵磷脂(DSPC);磷脂酰乙醇胺,例如二油酰基磷脂酰乙醇胺和二棕榈酰基磷脂酰乙醇胺(DPPE);磷脂酰丝氨酸;磷脂酰甘油;磷脂酰肌醇;鞘脂类,例如神经鞘磷脂;糖脂(glycolipids),例如神经节苷脂GM1和GM2、葡萄糖脂(glucolipids);硫脂类;糖鞘脂(glycosphingolipids);磷脂酸,例如二棕榈酰基磷脂酸(DPPA);DHA;ω-3油;ω-6油;低芥子酸菜籽油;橘油;氢化植物油;矿物油;玉米油;棉籽油;花生油;芝麻油;大豆油;棕榈油;硬脂酸;花生四烯酸;油酸;含有聚合物例如聚乙烯醇的脂质,即PEG-基化脂质、壳多糖、透明质酸或聚乙烯吡咯烷酮;有磺化单-、二-、寡-或多糖的脂质;胆固醇、胆固醇硫酸酯和胆固醇偏琥珀酸酯(cholesterol hemisuccinate);维生素E偏琥珀酸酯;有连接醚和酯的脂肪酸的脂质;聚合脂质(本领域已知的多种);二乙酰磷酸酯;三十二烷磷酸酯;硬脂酰胺;心磷脂;有长度为6-8碳的短链脂肪酸的磷脂;有不对称酰基链的合成磷脂(例如,有一个6碳的酰基链和另一个12碳的酰基链);神经酰胺;包括非离子表面活性剂微囊(niosomes)的非离子脂质体,例如聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇、聚氧乙烯脂肪醇酯、聚氧乙基化脱水山梨醇脂肪酸酯、甘油基聚乙二醇羟基硬脂酸酯、甘油基聚乙二醇蓖麻油酸酯、乙氧基化豆甾醇、乙氧基化海狸油,聚氧乙烯-聚氧丙烯聚合物和聚氧乙烯脂肪酸硬脂酸酯;甾醇脂肪酸酯,包括胆固醇硫酸酯、胆固醇丁酸酯、胆固醇异丁酸酯、胆固醇棕榈酸酯、胆固醇硬脂酸酯、羊毛甾醇醋酸酯、麦角甾醇棕榈酸酯,和植物甾醇正丁酸酯;糖酸甾醇酯,包括胆固醇葡萄糖醛酸化物,羊毛甾醇葡萄糖醛酸化物,7-脱氢胆甾醇葡萄糖醛酸化物,麦角甾醇葡萄糖醛酸化物,胆固醇葡萄糖酸酯,羊毛甾醇葡萄糖酸酯,和麦角甾醇葡萄糖酸酯;糖酸和醇的酯,包括月桂基葡萄糖醛酸化物,硬脂酰葡萄糖醛酸化物,肉豆蔻酰葡萄糖醛酸化物,月桂基葡萄糖酸酯,肉豆蔻酰葡萄糖酸酯,和硬脂酰葡萄糖酸酯;糖和脂肪酸的酯,包括蔗糖月桂酸酯、果糖月桂酸酯、蔗糖棕榈酸酯、蔗糖硬脂酸酯、葡萄糖醛酸、葡萄糖酸、糖质酸(saccharic acid)和多糖醛酸;皂甙,包括萨洒皂角苷配基(sarsasapogenin)、菝葜配基(smilagenin)、常春藤皂甙元、齐墩果酸和毛地黄毒苷配基;甘油,和包括以下种的甘油酯:甘油二月桂酸酯、甘油三月桂酸酯、甘油二棕榈酸酯、甘油三棕榈酸酯、甘油二硬脂酸酯、甘油三硬脂酸酯、甘油二肉豆蔻酸酯,和甘油三肉豆蔻酸酯;长链醇,包括正癸基醇、月桂醇、肉豆蔻醇、鲸蜡醇和正十八烷醇;6-(5-胆甾烯-3β-基氧)-1-硫代-β-D-吡喃半乳糖甙;双半乳糖甘油二酯;6-(5-胆甾烯-3β-基氧)己基-6-氨基-6-去氧-1-硫代-β-D-吡喃半乳糖甙;6-(5-胆甾烯-3β-基氧)己基-6-氨基-6-去氧-1-硫代-α-D-吡喃甘露糖甙;12-(((7′-二乙基氨基香豆素-3-基)羰基)甲氨基)-硬脂酸;N-12-(((7′-二甲基氨基香豆素-3-基)羰基)甲氨基)十八烷酰基-2-氨基棕榈酸;胆甾醇基(4’-三甲基氨基)丁酸酯;N-琥珀酰二油酰磷脂酰基乙醇胺;1,2-二油酰基-sn-甘油;1,2-二棕榈酰基-sn-3-琥珀酰基甘油;1,3-二棕榈酰基-2-琥珀酰甘油;1-十六烷基-2-棕榈酰基-甘油磷酸乙醇胺(glycerophosphoe thanolamine)和棕榈酰基高半胱氨酸和/或它们的组合。
本发明pH基本为中性的阴道药物释放系统还可以含有其它赋形剂,选自:润滑剂、清洗剂、除臭剂、湿润剂、软化剂、增塑剂、粘合剂、乳化剂、稳定剂、溶剂、生物可吸收材料、增溶剂、抗微生物防腐剂、稀释剂、助流剂、悬浮剂、延迟释放剂(extended-release agents)、包衣剂、吸附剂、崩解剂、螫合剂,及其混合物和组合。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性润滑剂选自:硬脂酸钙、低芥子酸菜籽油、甘油基棕榈酸硬脂酸酯、氢化植物油、氧化镁、矿物油、泊咯沙姆、聚乙二醇、聚乙烯醇、苯甲酸钠、月桂基硫酸钠、硬脂酰基富马酸钠、硬脂酸、灭菌的玉米淀粉、滑石粉、硬脂酸锌及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性湿润剂选自:甘油、丙二醇、山梨醇、甘油三乙酸酯及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性软化剂选自: 鲸蜡硬脂醇、羊毛脂、矿物油、凡士林、十六烷基酯蜡、胆固醇、甘油、甘油基单硬脂酸酯、异丙基肉豆蔻酸酯、异丙基棕榈酸酯、卵磷脂及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性增塑剂选自:羊毛脂、矿物油、凡士林、苯甲酸苄酯、三氯叔丁醇、二乙基邻苯二甲酸酯、甘油、聚乙二醇、山梨醇、甘油三乙酸酯、二乙基癸二酸酯、三乙基柠檬酸酯、巴豆酸、丙二醇、丁基邻苯二甲酸酯、二丁基癸二酸酯、海狸油及其混合物。显然,增塑剂的性质可以是疏水性和亲水性的。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性粘合剂选自:阿拉伯胶、海藻酸、羧甲基纤维素、羟乙基纤维素、羟丙基纤维素、糊精、乙基纤维素、明胶、液体葡萄糖、氢化植物油、羟丙基甲基纤维素、硅酸铝镁、麦芽糖糊精、甲基纤维素、聚氧乙烯、聚甲基丙烯酸酯、聚维酮、藻酸钠、淀粉、玉米醇溶蛋白、丙烯酸和甲基丙烯酸的共聚物、药用釉(pharmaceutical glaze),树胶,例如瓜尔胶,和乳的衍生物,例如乳清,及淀粉,及本领域技术人员已知的其他常规粘合剂。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性稳定化剂选自:阿拉伯胶、白蛋白、聚乙烯醇、海藻酸、膨润土、羧甲基纤维素、羟丙基纤维素、硅胶、环糊精、甘油基单硬脂酸酯、羟丙基甲基纤维素、硅酸铝镁、丙二醇、丙二醇藻酸酯、藻酸钠、蜡、黄原胶及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性溶剂选自:乙醇、苯甲酸苄酯、玉米油、棉籽油、二乙基邻苯二甲酸酯、乙基油酸酯、甘油、葡萄糖糠醛(glycofurol)、异丙醇、异丙基肉豆蔻酸酯、中链甘油三酯、矿物油、花生油、聚乙二醇、碳酸异丙烯酯、丙二醇、芝麻油、豆油、甘油三乙酸酯及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性增溶剂选自:氯化苯甲烃铵、海狸油、环糊精、聚氧乙烯醚、甘油基单硬脂酸酯、卵磷脂、泊咯沙姆、聚山梨醇酯、聚氧乙烯硬脂酸酯、脱水山梨醇酯、硬脂酸及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性抗微生物防腐剂选自:苯甲酸、EDTA、酚酸、山梨酸、苯甲醇、异丙醇、氯化苯甲乙氧铵、溴硝丙二醇、尼泊金丁酯、溴化十六烷基三甲铵、氯己定、三氯叔丁醇、氯甲酚、甲酚、羟苯乙酯、甘油、亚胺脲(imidurea)、尼泊金甲酯、苯酚、苯氧基乙醇、乙酸苯汞、硼酸苯汞、硝酸苯汞、山梨酸钾、丙二醇、尼泊金丙酯、苯甲酸钠、丙酸钠、山梨酸、乙基汞硫代水杨酸钠及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性稀释剂选自:磷酸钙、硫酸钙、羧甲基纤维素钙、纤维素、醋酸纤维素、葡萄糖结合剂(dextrates)、糊精、葡萄糖、果糖、甘油基硬脂酸棕榈酸酯(glycerylpalmitostearate)、高岭土、乳糖醇、乳糖、碳酸镁、氧化镁、麦芽糖醇、麦芽糖糊精、麦芽糖、微晶纤维素、聚甲基丙烯酸酯、粉状纤维素、预胶化淀粉、硅酸化微晶纤维素、氯化钠、山梨醇、淀粉、蔗糖、糖、滑石、氢化植物油及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性助流剂选自:麦芽糖醇、聚合葡萄糖、蔗糖及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性悬浮剂选自:海藻酸、膨润土、卡波姆(carbomer)、羧甲基纤维素、羟乙基纤维素、羟丙基纤维素、微晶纤维素、糊精、明胶、瓜尔胶、黄原胶、高岭土、硅酸铝镁、麦芽糖醇、甲基纤维素、聚山梨酯(polysorbate)、聚维酮、藻酸丙二酯、藻酸钠、脱水山梨醇酯、黄芪胶及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性延迟释放剂选自:角叉菜胶、醋酸纤维素、甘油基单硬脂酸酯、玉米醇溶蛋白及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性崩解剂选自:海藻酸、羧甲基纤维素钠、羟丙基纤维素、微晶纤维素、硅胶、交联羧甲基纤维素钠(croscarmellose sodium)、交联聚维酮(crospovidone)、硅酸铝镁、甲基纤维素、波拉克林(polacrilin)、聚维酮、藻酸钠、羟乙酸淀粉钠、淀粉及其混合物。
根据本发明主题,可以作为其他赋形剂的非限定性的示例性螯合剂选自:EDTA、苹果酸、麦芽酚及其混合物。
本发明主题的一个重要的特色是当药物释放系统作为一个整体基本是中性时,内部的水溶相由酸性缓冲相构成,酸性缓冲相含有独立的或与附加的缓冲剂结合的一或多种治疗活性药物。在内相建立酸性pH缓冲剂已显示能增强其中结合的抗真菌剂和其他抗菌剂的功效。此增强的功效可能是缓冲组分扩散在阴道腔中并将阴道分泌物的pH值缓冲调节到大约4.5的结果。在阴道穹隆的生理最佳pH,此pH对通常的病原体是有害的,例如属于真菌病原体的假丝酵母属,和属于细菌病原体的肠球菌属(Enterococci)。另外,因为4.5或在此值附近的pH对于阴道环境是最佳的,此pH也能帮助消除炎症、瘙痒和见于其他急性感染性疾病中的不适。结果,本发明的组合物能优化对这些病原体的治疗效果。
正常地,对阴道穹隆施以酸性组合物将刺激阴道腔引起严重的不适。相应地,本发明主题确定为pH基本为中性的阴道药物释放系统。只有构成此释放系统的药球的缓冲内相是酸性的。因为将缓冲系统螯合在药球壁内,药球的整个酸性缓冲内相将不刺激阴道腔。因此,酸性缓冲液不直接与阴道内壁接触。如果试图测定乳剂的pH值,内相开始释放之前不会产生pH值读数,所以形成一个pH基本为中性的药物释放系统。
本发明pH基本为中性的药物释放系统的另一优点是内部酸性缓冲相的酸性缓冲组分慢慢从药球的内相释放,即释放周期长达约168小时。这避免了对周围组织的突然的酸性刺激。这对于高度炎症和感染的阴道腔具有特别的重要性。
相应地,药球的内部酸性缓冲相有正电荷,其本身pH小于6.0。在一个优选实施例中,酸性缓冲相本身pH为约2.5-约5.5。在一个特别优选的实施例中,酸性缓冲相本身的pH为约3.5-约5.0。
酸性缓冲相可以使用的优选的缓冲溶液由弱酸和此酸的盐或弱碱和此碱的盐构成。本发明可以使用的缓冲系统优选的非限制性例子选自:醋酸/醋酸钠或醋酸钾,氯化铵/氢氧化铵,苯甲酸/苯甲酸钠或苯甲酸钾,硼酸/硼酸钠,柠檬酸/磷酸氢二钠,柠檬酸/柠檬酸钠或柠檬酸钾,乳酸/乳酸钠或乳酸钾,钠或钾的一元或二元磷酸盐,邻苯二甲酸氢钾/氢氯酸,琥珀酸/琥珀酸钠或琥珀酸钾,和酒石酸/酒石酸钠或酒石酸钾。
另外,本发明的释放系统为治疗活性药物提供约0.1小时至约168小时的释放速率。在另一优选实施例中,本发明的释放系统为治疗活性药物提供约0.1小时至约72小时的释放速率。
本发明主题影响治疗活性药物释放速率的另一方面是在克分子渗透压浓度的宽范围内调整药球酸性缓冲相的渗透压的能力。相应地,药球的缓冲相可以为等渗、高渗或低渗。制备具有可变渗透压的药球的能力是使用本发明pH基本为中性的阴道药物释放系统的另一优势。
在一优选实施例中,药球的酸性缓冲相是等渗的。等渗的酸性缓冲相将有与生物组织相同的渗透压,等于300±10毫渗克分子(milliosmol)/升。等渗酸性缓冲相通过扩散从药球中释放治疗活性药物。相应地,有等渗酸性缓冲相的药球可以在一次用药后持续数天或数周提供治疗活性药物的缓慢的释放。
在另一优选实施例中,药球的酸性缓冲相是高渗的。高渗酸性缓冲相有高于生物组织的渗透压,即高于300±10毫渗克分子(milliosmol)/升。高渗酸性缓冲相通过药球的破裂从药球中释放治疗活性药物。相应地,治疗活性药物在给药后约5分钟至约60分钟内持续释放到作用部位。
还有另一优选实施例,药球的酸性缓冲相是低渗的。低渗酸性缓冲相有低于生物组织的渗透压,即低于300±10毫渗克分子(milliosmol)/升。低渗酸性缓冲相通过扩散和渗透从药球中释放治疗活性药物。相应地,在给药后治疗活性药物持续向作用部位释放至少约1小时。
相应地,在本发明主题的一个实施例中,酸性缓冲相有高于300±10毫渗克分子(milliosmol)/升的渗透压。在本发明主题的另一实施例中,酸性缓冲相有低于300±10毫渗克分子(milliosmol)/升的渗透压。本发明主题还有另一个实施例,酸性缓冲相有等于300±10毫渗克分子(milliosmol)/升的渗透压。
影响治疗活性药物释放速率的其它因素是各相中所含治疗活性药物的百分比、外膜的厚度、外相或膜中乳化剂的数量和性质、内相的pH、活性成分通过外相或膜的扩散性等。在阴道腔的生理环境中,表现出的全部化学和物理影响因素,包括分泌液、酶、pH、化学平衡、温度和身体运动产生的剪切力,影响系统破裂的速度。这些因素不以与已知系统相同的速度影响本系统的完整性。
本发明主题使用的治疗活性药物可以是任何被批准或已使用的用于处理、预防、治疗或减轻阴道、泌尿道、子宫或其它女性生殖器官的疾病或妊娠诱因、用于美容或化妆用途、用于诊断目的、用于全身药物治疗,或用于后代性别测定的药物。当通过释放到阴道表面的全部或部分区域而给药时,药剂必须有效。潜在的药剂由于获得政府批准或通常的使用而是众所周知的。在本发明的组合物中使用这些治疗活性药物将优化这些药物产生的治疗效果。
用于本药物释放系统的优选的治疗活性药物选自:抗真菌剂、抗细菌剂、抗微生物剂、抗病毒剂、杀精子剂、激素药物、抗阴道滴虫药、抗原虫药、抗支原体药物、抗逆转录病毒剂、核苷类似物、逆转录酶抑制剂、蛋白酶抑制剂、避孕药、磺胺药类(sulfadrugs)、磺胺类药物、砜类药物、保健剂、前生物剂、疫苗、抗体、肽制剂、蛋白质制剂、多糖药物、核酸、质粒、脂质体、碳氢聚合物、转基因细菌、酵母、化疗药、甾体药物、生长促进剂、性欲增强剂、雄激素物质、壳多糖衍生物、环境改善剂例如pH调节剂,及其混合物或组合。
在一优选实施例中,治疗活性药物是抗真菌剂。在一特别优选的实施例中,治疗活性药物是选自以下种类的抗真菌剂:硝酸布康唑、克霉唑、硝酸酮康唑、咪康唑(miconizole)、多烯抗真菌剂、制霉菌素、两性霉素B、匹马菌素、硝酸奥昔康唑、硝酸特康唑、噻康唑、氟三唑(flutrimazole)、吲康唑(intraconizole)、丙烯胺、特本萘芬(terbenafine)、布替那芬、阿莫罗芬、萘替芬、葡康唑(gluconazole)、唑类、益康唑、voriconizole、氟康唑、泼洒康唑(posaconazole)、硫康唑、diction双苯并咪唑(diction bisbenzimidazoles)、葡聚糖合成抑制剂、echinacandins、anidulafungin、caspofungin、micafugin、抗结核药、间苯基砜(diaphenylsulfone)、环匹罗司、卤普罗近、tolnatane、十一碳烯酸酯及其混合物和组合。
在另一优选实施例中,治疗活性药物是抗菌剂。在一特别优选的实施例中,治疗活性药物是选自如下种的抗菌剂:克林霉素、磺胺类药物、红霉素、克拉霉素、阿齐霉素(azythromycin)、四环素、多沙霉素(doxacline)、甲硝唑、大环内酯类、酮大环内酯类(ketolide)、喹诺酮、头孢菌素、碳青霉烯、青霉素、庆大霉素、爪蟾抗菌肽(magaininpeptides)、dalbavancin、雷莫拉宁、iseganan、头孢西丁、头孢曲松、三氯醋酸及其混合物和组合。
还有另一优选实施例,治疗活性药物是抗病毒剂。在一特别优选的实施例中,治疗活性药物是选自如下种的抗病毒剂:喷昔洛韦、阿昔洛韦、更昔洛韦、膦甲酸盐、缬昔洛韦、pleconaril及其混合物和组合。
还有另一优选实施例,治疗活性药物是杀精子剂。在一特别优选的实施例中,治疗活性药物是杀精子剂壬苯醇醚-9(nonoxyl-9)。
在另一优选实施例中,治疗活性药物是生长促进剂。在一特别优选的实施例中,治疗活性药物是选自细胞因子构成的组的生长促进剂。
还有另一优选实施例,治疗活性药物是表面活性药物。在一特别优选的实施例中,表面活性药物是磷酸克林霉素。
还有另一优选实施例,治疗活性药物是雄激素物质。在一特别优选的实施例中,雄激素物质选自达那唑、睾酮及其混合物和组合。
本发明药物释放系统的内部水溶相的治疗活性药物是微粉化物质,其颗粒大小在约0.1微米-小于60微米范围内。在一优选实施例中,治疗活性药物的颗粒大小为约0.1微米-约15微米。相应地,在本发明的药物释放系统中可以使用可溶性和微溶性药物。
对本释放系统显示的微溶性治疗活性药物-例如布他康唑(butaconazole)、克霉唑和氟曲马唑-效能上增强的可能的解释被认为是,与随着相对水不溶性药物粒径的降低,而显现溶解速率增加有关。认为内部水溶相中微粉化的治疗活性药物可以根据存在于内相之外和内相中的治疗活性药物数量之间平衡的改变迅速调整。快速溶解能够快速重建此平衡。不经过微粉化,必须经过一段时间重新建立平衡,在感染部位产生低水平量的可扩散的治疗活性药物。
在本发明主题的另一实施例中,外部水不溶相或膜在酸性缓冲相之外含有附加的治疗活性药物。在一个优选实施例中,将外相或膜中的附加的治疗活性药物微粉化,其颗粒大小为约0.5微米-小于60.0微米。在另一实施例中,外相或膜中附加的治疗活性药物不经过微粉化。还有另一实施例,外相或膜中的附加治疗活性药物是微粉化和不经过微粉化的。
在本发明主题的一个优选实施例中,酸性缓冲相中和酸性缓冲相之外的微粉化药物与未微粉化的药物的比例为约0.1至约1,000。
可以用常规的涂药器或其他敷层、喷雾器、泡沫器或气溶胶装置或给药技术领域普通技术人员已知的任何可能的装置将本发明药物释放系统用于阴道腔内。
或者,本系统在生理温度,约37℃是可变形的,它们不会像在先技术的系统那样失去其完整性。不同于已知系统,这些释放系统没有在置入阴道腔后从其中渗漏的特点。因为这些系统在延长的时间周期内破裂,它们的非水性成分以低于通常剂型的速率从阴道腔吸收或释放。
本发明主题的示例性的释放系统包括但不限于分散体、固体、悬浮液、软膏、泥敷剂(膏状物)、膏剂、粉末、药丸(ovules)、栓剂、泡沫剂、敷料、霜剂、溶液、液体、冻胶、喷雾剂、凝胶剂、片剂(包括速溶片剂)、棉塞、海绵剂、药枕、膨胀剂(puffs)和贴剂。
本发明主题还涉及治疗阴道疾病的方法,包括给病人使用本发明所述的pH基本为中性的阴道药物释放系统。特别地,阴道疾病包括以下引起的感染:假丝酵母、肠球菌、链球菌、葡萄球菌、尿路病原体、大肠杆菌(E.coli)、克雷白氏杆菌属、梭菌、动弯杆菌(Mobiluncus species)、加德纳氏菌属(Gardnerella)、普雷沃氏菌(Prevotella species)、假单孢属细菌、原虫、支原体属(mycoplasm)、衣菌属(Chlamydia)、HIV、HPV、疱疹(herpes)、非特异性阴道炎(nonspecific vaginitis)、淋病奈瑟氏球菌(N.gonorrhoeae)、阴道毛滴虫、砂眼衣原体,及其混合和组合。
根据本发明主题可以治疗的另外的阴道疾病包括所有形式的子宫内膜异位、宫外子宫内膜异位、子宫内膜炎、癌症、卵巢囊肿、输卵管炎、子宫纤维瘤、其他生殖器病毒性疾病、生殖器疣及其混合性疾病和组合。
可以用各种为剪切混合提供充分的高剪切力的装置制备本发明的药球。市场上可以得到多种这些装置,包括微流体化器-例如生物技术发展公司制造的“French”型压片机,或提供足够高剪切力的其他装置。
Micro Vesicular Systems,Inc.,Vineland,N.J.开发了一种制备本发明药球特别有用的装置,在美国专利U.S.Patent No.4,895,452中有进一步描述,将其全文结合于此作为参考。
此装置有一个基本为圆筒形的混合室,此混合室有至少一个正切向定位的进料口。一或多个入口将水不溶相导向储存室,至少一个其他的入口将水溶相连接到储存室。
通过泵-例如容积泵将不同相送入圆筒形混合室中,并以在混合室中形成湍流的方式交汇。通过轴向固定的排放孔将药球排出。
在水溶相混合室中,生物活性治疗剂与稀释剂混合。在水不溶相混合室中加入起稳定作用的化合物。然后在筒形混合室中加入表面活性剂,按约30,000转/分钟(“rpm”)的转速混合两相。
本发明使用的一些非限制性的表面活性剂的例子包括琥珀辛酯钠、月桂基硫酸钠、溴化十六烷基三甲铵、聚氧乙烯脂肪酸酯和脱水山梨醇酯。
本领域普通技术人员不经过过度的试验可以改变高剪切均化的转速产生基本相同的发明而不超出本发明公开的范围。而且,当本发明公开的内容与现有技术已知的信息结合时,参考本发明公开的内容,本领域技术人员将很清楚制备这些pH基本为中性的药物释放系统的制备方法。本发明的理论
不将本发明的理论限制为任何特定的理论,为有本发明药球的乳剂的新机理建立了一些可能的解释。
根据脉冲乳剂现象理论(“PEP”),治疗活性药物从药球的酸性缓冲相中的释放依赖于环境pH或周围环境中存在的酶的种类。根据pH依赖性模型,药球在适合的环境pH条件下停留于阴道粘膜内层并释放生物活性治疗剂。
根据酶依赖性模型,生物学存在的酶可以触发或阻止停留/释放过程。例如,阴道腔中的脂肪酶可以触发将治疗剂释放到阴道腔而通过粘膜吸收的停留/释放过程。
粘膜停留囊理论假设显著的吸收仅发生在粘膜上皮。可能药球仅与粘膜基层或粘液本身接触。停留/释放过程仅发生在粘膜表面。通过停留/释放过程,螯合在小囊中的生物活性药物通过粘膜基底膜扩散,并进入血液而分配。
对停留/释放过程的另一个解释是药球与粘膜之间的范德华(VanderWaal)相互作用力。范德华力是一个分子受另一个分子的作用而产生的暂时的偶极。此物理吸引力与代替汽车窗附着贴的附着于玻璃的塑料贴采用的“静态附着”相似。范德华力可以触发停留和随后的释放。
本领域的普通技术人员将认识到本发明的特定的理论不局限于上述理论的任何一种,或者可以是上述理论的组合,或包括尚未阐明的理论,并绝不局限于实施本文公开的发明的能力。
下述实例是对本发明优选实施例的说明,并不能解释为对本发明的限制。所有聚合分子量是平均分子重量。除非另外说明,所有百分比基于最终释放系统或所制备制剂的重量百分数,其总和等于重量的100%。实施例
甲硝唑和克林霉素示例性说明在设计有效的阴道药物释放系统方面遇到的问题。可以用任何数量的技术方便地改变甲硝唑和克林霉素的药物性质,但它们的物理化学性质限制阴道释放系统的设计。
用本发明pH基本为中性的阴道药物释放系统制备以下实例。实施例I
表I
组分 | 数量%w/w |
纯化水 | 24.676 |
甘油 | 47.250 |
冰醋酸 | 0.225 |
醋酸钠 | 0.200 |
氯化钠 | 0.750 |
尼泊金甲酯 | 0.090 |
尼泊金丙酯 | 0.035 |
尼泊金丁酯 | 0.024 |
蔗糖 | 8.000 |
甲硝唑 | 0.750 |
矿物油 | 13.000 |
聚乙二醇(30)二聚羟基硬脂酸酯 | 5.000 |
可以用各种本领域已知的为剪切混合提供充分的高剪切力的装置制备本发明的药物释放系统使用的药球。Micro VesicularSystems,Inc.,Vineland,N.J.开发了一种特别有用的装置,在美国专利U.S.Patent No.4,895,452中有进一步描述。根据最终需要的产品确定采用的温度。在制备药球前测定药球的内部水溶解相的pH以保证pH在前述临界pH范围内。
用以下方法制备这些实施例中记载的制剂:
用纯化水将甲硝唑和内部水溶相另外的成分混合。在第二容器中将外部水不溶相或膜中的成分混合。将内部水溶相缓慢加入外部水不溶相或膜中,同时用叶片-圆盘搅拌器将两相混合直至内相完全加入到外相中并得到所需的粘度。根据最终所需的产品确定混合速度。实施例II
可以用例I的方法制备具有下述配方的磷酸克林霉素释放系统。
表II
组分 | 数量%w/w |
纯化水 | 24.676 |
甘油 | 45.200 |
冰醋酸 | 0.225 |
醋酸钠 | 0.200 |
氯化钠 | 0.750 |
尼泊金甲酯 | 0.090 |
尼泊金丙酯 | 0.035 |
尼泊金丁酯 | 0.024 |
蔗糖 | 8.000 |
磷酸克林霉素 | 2.800 |
矿物油 | 12.000 |
聚乙二醇(30)二聚羟基硬脂酸酯 | 6.000 |
如上描述了本发明,显然同一发明可以有多种方式的变化。这些变化不应认为偏离了本发明的实质范围,所有这些改变应包括在以下权利要求的范围之内。
Claims (57)
1.一种pH基本为中性的阴道药物释放系统,其中包含:
pH基本为中性的乳剂,它有具有两相的药球:内部的水溶相,和外部的水不溶相或膜;
所述的内部水溶相包含含有一或多种治疗活性药物的酸性缓冲相,其中酸性缓冲相包含独立的或与其它的缓冲剂结合的一或多种所述的治疗活性药物;
其中酸性缓冲相为等渗、高渗或低渗。
2.权利要求1所述的组合物,其中的治疗活性药物是微粉化的,并具有在约0.1微米至小于60微米范围内的粒径。
3.权利要求2所述的组合物,其中的治疗活性药物具有在约0.1微米至小于约15微米范围内的粒径。
4.权利要求1所述的组合物,其中的药球具有在约0.1微米至约100微米范围内的粒径。
5.权利要求4所述的组合物,其中的药球具有在约0.1微米至约60微米范围内的粒径。
6.权利要求5所述的组合物,其中的药球具有在约0.5微米至约55微米范围内的粒径。
7.权利要求1所述的组合物,其中的酸性缓冲相其本身pH小于6.0。
8.权利要求7所述的组合物,其中的酸性缓冲相其本身pH为约2.5至约5.5。
9.权利要求8所述的组合物,其中的酸性缓冲相其本身pH为约3.5至约5.0。
10.权利要求1所述的组合物,其中的治疗活性药物选自:抗真菌剂、抗细菌剂、抗微生物剂、抗病毒剂、杀精子剂、激素药物、抗阴道滴虫药、抗原虫药、抗支原体药物、抗逆转录病毒剂、核苷类似物、逆转录酶抑制剂、蛋白酶抑制剂、避孕药、磺胺药类、磺胺类药物、砜类药物、保健剂、前生物剂、疫苗、抗体、肽制剂、蛋白质制剂、多糖药物、核酸、质粒、脂质体、碳氢聚合物、转基因细菌、酵母、化疗药、甾体药物、生长促进剂、性欲增强剂、雄激素物质、壳多糖衍生物、环境改善剂例如pH调节剂,及其混合物或组合。
11.权利要求10所述的组合物,其中的治疗活性药物是选自细胞因子构成的组的生长促进剂。
12.权利要求1所述的组合物,还含有赋形剂,选自:润滑剂、清洗剂、除臭剂、湿润剂、软化剂、增塑剂、粘合剂、乳化剂、稳定剂、溶剂、生物可吸收材料、增溶剂、抗微生物防腐剂、稀释剂、助流剂、悬浮剂、延迟释放剂、包衣剂、吸附剂、崩解剂、螫合剂,及其混合物和组合。
13.权利要求10所述的组合物,其中的治疗活性药物选自:硝酸布康唑、克霉唑、硝酸酮康唑、咪康唑、多烯抗真菌剂、制霉菌素、两性霉素B、匹马菌素、硝酸奥昔康唑、硝酸特康唑、噻康唑、氟三唑、吲康唑、丙烯胺、特本萘芬、布替那芬、阿莫罗芬、萘替芬、葡康唑、唑类、益康唑、voriconizole、氟康唑、泼洒康唑、硫康唑、dictionbisbenzimidazoles、葡聚糖合成抑制剂、echinacandins、anidulafungin、caspofungin、micafugin、抗结核药、间苯基砜、环匹罗司、卤普罗近、tolnatane、十一碳烯酸酯及其混合物和组合。
14.权利要求10所述的组合物,其中的治疗活性药物是选自以下种的抗菌剂:克林霉素、磺胺类药物、红霉素、克拉霉素、阿齐霉素、四环素、多沙霉素、甲硝唑、大环内酯类、酮大环内酯类、喹诺酮、头孢菌素、碳青霉烯、青霉素、庆大霉素、爪蟾抗菌肽、dalbavancin、雷莫拉宁、iseganan、头孢西丁、头孢曲松、三氯醋酸及其混合物和组合。
15.权利要求10所述的组合物,其中的治疗活性药物是选自以下种的抗病毒剂:喷昔洛韦、阿昔洛韦、更昔洛韦、膦甲酸盐、缬昔洛韦、pleconaril及其混合物和组合。
16.权利要求10所述的组合物,其中的治疗活性药物是杀精子剂壬苯醇醚-9。
17.权利要求10所述的组合物,其中的雄激素物质选自达那唑、睾酮及其混合物和组合。
18.权利要求1所述的组合物,其中的外部水不溶相或膜在酸性缓冲相外含有附加的治疗活性药物。
19.权利要求18所述的组合物,其中外相或膜中的附加的治疗活性药物是微粉化的,并具有在约0.5微米至小于60.0微米范围内的粒径。
20.权利要求18所述的组合物,其中外相或膜中的附加的治疗活性药物是未微粉化的。
21.权利要求18所述的组合物,其中外相或膜中的附加的治疗活性药物是微粉化和未微粉化的。
22.权利要求21所述的组合物,其中酸性缓冲相中和酸性缓冲相之外的微粉化药物与未微粉化的药物的比例为约0.1至约1,000;其中治疗活性药物的释放速率为约0.1小时至约168小时。
23.权利要求1所述的组合物,其中的酸性缓冲相具有高于300±10毫渗克分子/升的渗透压。
24.权利要求1所述的组合物,其中的酸性缓冲相具有低于300±10毫渗克分子/升的渗透压。
25.权利要求1所述的组合物,其中的酸性缓冲相具有等于300±10毫渗克分子/升的渗透压。
26.权利要求1所述的组合物,其中的治疗活性药物是表面活性药物。
27.权利要求26所述的组合物,其中的表面活性药物是磷酸克林霉素。
28.一种pH基本为中性的阴道药物释放系统,其中包含:
pH基本为中性的乳剂,它有具有两相的药球:内部的水溶相,和外部的水不溶相或膜;
所述的内部水溶相包含含有一或多种微粉化的治疗活性药物的酸性缓冲相,其中酸性缓冲相包含独立的或与其它的缓冲剂结合的一或多种所述的微粉化的治疗活性药物;
其中酸性缓冲相为等渗、高渗或低渗;并且
其中微粉化的治疗活性药物具有在0.1微米至小于60.0微米范围内的粒径,
其中酸性缓冲相使治疗活性药物的效果最大化;并且
其中的酸性缓冲相的量足以中止阴道粘膜的炎症和瘙痒症状。
29.权利要求28所述的组合物,其中的酸性缓冲相带正电荷,其本身pH在约2.5-约5.0之间。
30.权利要求28所述的组合物,其中的治疗活性药物选自:抗真菌剂、抗细菌剂、抗微生物剂、抗病毒剂、杀精子剂、激素药物、抗阴道滴虫药、抗原虫药、抗支原体药物、抗逆转录病毒剂、核苷类似物、逆转录酶抑制剂、蛋白酶抑制剂、避孕药、磺胺药类、磺胺类药物、砜类药物、保健剂、前生物剂、疫苗、抗体、肽制剂、蛋白质制剂、多糖药物、核酸、质粒、脂质体、碳氢聚合物、转基因细菌、酵母、化疗药、甾体药物、生长促进剂、性欲增强剂、雄激素物质、壳多糖衍生物、环境改善剂例如pH调节剂,及其混合物或组合。
31.权利要求30所述的组合物,其中的治疗活性药物是选自细胞因子构成的组的生长促进剂。
32.权利要求28所述的组合物,还含有赋形剂,选自:润滑剂、清洗剂、除臭剂、湿润剂、软化剂、增塑剂、粘合剂、乳化剂、稳定剂、溶剂、生物可吸收材料、增溶剂、抗微生物防腐剂、稀释剂、助流剂、悬浮剂、延迟释放剂、包衣剂、吸附剂、崩解剂、螫合剂,及其混合物和组合。
33.权利要求30所述的组合物,其中的治疗活性药物是抗真菌剂,选自:硝酸布康唑、克霉唑、硝酸酮康唑、咪康唑、多烯抗真菌剂、制霉菌素、两性霉素B、匹马菌素、硝酸奥昔康唑、硝酸特康唑、噻康唑、氟三唑、吲康唑、丙烯胺、特本萘芬、布替那芬、阿莫罗芬、萘替芬、葡康唑、唑类、益康唑、voriconizole、氟康唑、泼洒康唑、硫康唑、dictionbisbenzimidazoles、葡聚糖合成抑制剂、echinacandins、anidulafungin、caspofungin、micafugin、抗结核药、间苯基砜、环匹罗司、卤普罗近、tolnatane、十一碳烯酸酯及其混合物和组合。
34.权利要求30所述的组合物,其中的治疗活性药物是选自以下种的抗菌剂:克林霉素、磺胺类药物、红霉素、克拉霉素、阿齐霉素、四环素、多沙霉素、甲硝唑、大环内酯类、酮大环内酯类、喹诺酮、头孢菌素、碳青霉烯、青霉素、庆大霉素、爪蟾抗菌肽、dalbavancin、雷莫拉宁、iseganan、头孢西丁、头孢曲松、三氯醋酸及其混合物和组合。
35.权利要求30所述的组合物,其中的治疗活性药物是选自以下种的抗病毒剂:喷昔洛韦、阿昔洛韦、更昔洛韦、膦甲酸盐、缬昔洛韦、pleconaril及其混合物和组合。
36.权利要求30所述的组合物,其中的治疗活性药物是杀精子剂壬苯醇醚-9。
37.权利要求30所述的组合物,其中的雄激素物质选自达那唑、睾酮及其混合物和组合。
38.权利要求28所述的组合物,其中外部水不溶相或膜在酸性缓冲相外含有附加的治疗活性药物。
39.权利要求38所述的组合物,其中外相或膜中的附加的治疗活性药物是微粉化的,并具有在约0.5微米至小于60.0微米范围内的粒径。
40.权利要求38所述的组合物,其中外相或膜中的附加的治疗活性药物是未微粉化的。
41.权利要求38所述的组合物,其中外相或膜中的附加的治疗活性药物是微粉化和未微粉化的。
42.权利要求41所述的组合物,其中酸性缓冲相中和酸性缓冲相之外的微粉化药物与未微粉化的药物的比例为约0.1至约1,000;其中治疗活性药物的释放速率为约0.1小时至约72小时。
43.权利要求28所述的组合物,其中的酸性缓冲相具有高于300±10毫渗克分子/升的渗透压。
44.权利要求28所述的组合物,其中的酸性缓冲相具有低于300±10毫渗克分子/升的渗透压。
45.权利要求28所述的组合物,其中的酸性缓冲相具有等于300±10毫渗克分子/升的渗透压。
46.权利要求28所述的组合物,其中的治疗活性药物是表面活性药物。
47.权利要求46所述的组合物,其中的表面活性药物是磷酸克林霉素。
48.一种pH基本为中性的阴道药物释放系统,其中包含:
pH基本为中性的乳剂,它有具有两相的药球:内部的水溶相,和外部的水不溶相或膜;
所述的内部水溶相包含其本身pH为约2.0至约6.0的酸性缓冲相和一或多种治疗活性药物,其中酸性缓冲相包含独立的或与其它的缓冲剂结合的一或多种所述的治疗活性药物。
49.权利要求48所述的组合物,其中的酸性缓冲相其本身pH在约2.5至约5.5之间。
50.治疗阴道疾病的方法,包括给病人使用一种pH基本为中性的阴道药物释放系统,其中含有:
pH基本为中性的乳剂,它有具有两相的药球:内部的水溶相和外部的水不溶相或膜;
所述的内部水溶相包含含有一或多种治疗活性药物的酸性缓冲相,其中酸性缓冲相包含独立的或与其它的缓冲剂结合的一或多种所述的治疗活性药物;
其中酸性缓冲相为等渗、高渗或低渗;并且
其中的治疗活性药物具有在约0.1微米至小于60.0微米范围内的粒径。
51.权利要求50的方法,其中的阴道疾病包括以下引起的感染:假丝酵母、肠球菌、链球菌、葡萄球菌、尿路病原体、大肠杆菌、克雷白氏杆菌属、梭菌、动弯杆菌、加德纳氏菌属、普雷沃氏菌、假单孢属细菌、原虫、支原体属、衣菌属、HIV、HPV、疱疹、非特异性阴道炎、淋病奈瑟氏球菌、阴道毛滴虫、砂眼衣原体,及其混合和组合。
52.权利要求50所述方法,其中的等渗酸性缓冲相通过扩散从药球中释放治疗活性药物。
53.权利要求50所述的方法,其中的治疗活性药物在用药后约0.1小时至约168小时内释放到作用部位。
54.权利要求50所述方法,其中的高渗酸性缓冲相通过药球的破裂从药球中释放治疗活性药物。
55.权利要求54所述方法,其中的治疗活性药物在用药后约5分钟至约60分钟内释放到作用部位。
56.权利要求50所述方法,其中的低渗酸性缓冲相通过扩散和渗透从药球中释放治疗活性药物。
57.权利要求56所述方法,其中的治疗活性药物在用药后持续向作用部位释放至少约1小时。
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US10/101,014 US6899890B2 (en) | 2002-03-20 | 2002-03-20 | Bioadhesive drug delivery system |
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CN2010105156408A Pending CN102048689A (zh) | 2002-03-20 | 2002-07-29 | 生物粘着性药物释放系统 |
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EP (1) | EP1494630A4 (zh) |
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KR (2) | KR20030076159A (zh) |
CN (3) | CN101045034A (zh) |
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CN110799198A (zh) * | 2016-11-30 | 2020-02-14 | 普罗生物瑞士股份公司 | 用于稳定阴道液的酸度和氧化还原状态的基于合适的生化组合物的泌尿生殖器医疗设备制剂 |
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- 2002-07-26 IT IT2002MI001660A patent/ITMI20021660A1/it unknown
- 2002-07-29 CN CNA2007101048008A patent/CN101045034A/zh active Pending
- 2002-07-29 CN CN2010105156408A patent/CN102048689A/zh active Pending
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110799198A (zh) * | 2016-11-30 | 2020-02-14 | 普罗生物瑞士股份公司 | 用于稳定阴道液的酸度和氧化还原状态的基于合适的生化组合物的泌尿生殖器医疗设备制剂 |
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Publication number | Publication date |
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CA2392473A1 (en) | 2003-09-20 |
US6899890B2 (en) | 2005-05-31 |
PT102854B (pt) | 2004-02-27 |
HUP0203102A3 (en) | 2004-06-28 |
US20030180366A1 (en) | 2003-09-25 |
JP2003286193A (ja) | 2003-10-07 |
CA2392473C (en) | 2007-09-18 |
CN101045034A (zh) | 2007-10-03 |
ITMI20021660A1 (it) | 2004-01-26 |
ZA200407535B (en) | 2006-06-28 |
AU2003218233A8 (en) | 2003-10-08 |
HU0203102D0 (zh) | 2002-11-28 |
JP4462818B2 (ja) | 2010-05-12 |
EP1494630A4 (en) | 2007-03-14 |
AU2003218233A1 (en) | 2003-10-08 |
AU2002300175B2 (en) | 2004-04-22 |
WO2003079981A2 (en) | 2003-10-02 |
RU2320322C2 (ru) | 2008-03-27 |
PT102854A (pt) | 2003-09-30 |
RU2004130870A (ru) | 2005-06-10 |
MXPA02006943A (es) | 2004-12-13 |
AR039037A1 (es) | 2005-02-02 |
CN102048689A (zh) | 2011-05-11 |
KR20030076159A (ko) | 2003-09-26 |
EP1494630A2 (en) | 2005-01-12 |
BR0202767A (pt) | 2004-05-25 |
AU2002300175A1 (en) | 2003-10-09 |
WO2003079981A3 (en) | 2003-11-06 |
KR20080098576A (ko) | 2008-11-11 |
HUP0203102A2 (hu) | 2004-05-28 |
FR2837389A1 (fr) | 2003-09-26 |
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