CN109069413B - 用于治疗阴道真菌感染的葡萄糖酸δ-内酯 - Google Patents
用于治疗阴道真菌感染的葡萄糖酸δ-内酯 Download PDFInfo
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- CN109069413B CN109069413B CN201780020670.1A CN201780020670A CN109069413B CN 109069413 B CN109069413 B CN 109069413B CN 201780020670 A CN201780020670 A CN 201780020670A CN 109069413 B CN109069413 B CN 109069413B
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Abstract
本发明涉及用于阴道给药的药物制剂,其中该制剂包含药学上可接受的赋形剂和葡萄糖酸δ‑内酯,其中葡萄糖酸δ‑内酯以制剂的5至99wt%的量存在。本发明还涉及根据本发明的药物制剂用于预防或治疗泌尿生殖系统真菌感染。此外,本发明涉及葡萄糖酸δ‑内酯(式(III))用于预防或治疗真菌感染。
Description
发明领域
本发明涉及用于治疗阴道真菌感染的阴道给药的药物制剂。特别地,本发明涉及用于治疗外阴阴道念珠菌病的阴道给药的药物制剂。
发明背景
阴道微生物组是一种具有不同比例和数量的各种微生物的复杂混合物的动态系统,其依赖于产生乳酸的细菌以维持弱酸性环境(通常pH 3.5至4.5)。阴道微生物菌群的任何突然变化都会增加阴道pH值,从而为阴道病原体的形成创造更有利的环境,阴道病原体在pH值大于5时生长最佳。因此,阴道中微生物菌群的不平衡可导致阴道感染,这是每年影响大部分育龄妇女的一种病症。
阴道念珠菌感染是一个常见问题,有时会影响大多数女性(大于75%),但对许多女性(8%)而言,其是更大、更麻烦和反复发作的问题。症状包括瘙痒、疼痛或刺激、阴道组织变红和肿胀、排尿和性交疼痛,通常为粘性白色和块状凝乳样排出物(如茅屋芝士)或正常至稀薄和水样的排出物。白色念珠菌(Candida albicans)是最常见的病原体,通常以较少的量存在于阴道、口腔、消化道和皮肤上而不引起感染,但是当正常菌群发生变化,例如在抗生素治疗后,念珠菌可过度生长并发生感染。然而,由于与生殖器感染相关的社会心理学耻辱,在很大程度上被不完全了解关于外阴阴道感染的发生。
白色念珠菌的毒力是由浮游细胞向菌丝的转化介导的。菌丝形式即丝状细胞具有由念珠菌素(candidalysin)(破坏阴道的上皮细胞的细胞毒素肽毒素)介导的侵入组织并诱导炎症的能力(Moyes等人,Nature,2016,532,64)。
念珠菌在阴道粘膜中存在的糖原上茁壮成长,并且怀孕期间增高的雌激素水平对粘膜的影响以及还有妊娠期间弱化的免疫系统也促进了感染。避孕药、月经以及其他压力因素可产生类似的效果。糖尿病是另一种常见的促进因素。
在通过拭抹阴道的阴道检查后建立诊断,以获得排出物样品,在其上进行所谓的湿涂片或湿敷的显微镜检查,加入KOH以裂解上皮细胞并使念珠菌菌丝可视化。对于有复发或持续症状的女性,应该获得阴道培养物,因为较少见的念珠菌属,如光滑念珠菌(Candidaglabrata)或克鲁斯念珠菌(Candida krusei),需要不同的药物。自我诊断可能并不可取,因为在一项研究中,只有11%的女性准确诊断出自己的感染;先前感染过的女性仅稍微更准确一些(35%),这导致昂贵的治疗,并产生潜在的不良反应[D.G.Ferris等人Obstet.Gynecol.2002,99,419-425]。
对于持续的病症,治疗包括阴道乳膏或片剂如益康唑醇(econazol)、克罗咪唑(clomitrazol)、咪康唑、噻康唑或丁康唑,持续1-3天或7-14天;但对于持续或复发感染常推荐使用氟康唑。氟康唑也可每周或每隔一周进行给药,持续3-6个月,以预防复发感染。然而,尽管氟康唑的副作用是轻微且不常见的,但这些副作用可能包括胃部不适、头痛和皮疹。氟康唑与许多药物发生相互作用,并且由于可能对胎儿造成伤害的潜在风险,因此不建议在怀孕期间使用。可能产生对药物的抗性,在这种情况下可以使用伊曲康唑(itrakonazol),但其也不能在妊娠期间使用。
虽然外阴阴道念珠菌病通常不会危及生命,但它可能或多或少是慢性的,会降低生活、性生活、工作的质量以及集中注意力的能力;其可最终导致抑郁。一种慢性病症可导致使人衰弱的前庭炎,这可能非常难以治疗。有证据支持通过前列腺素产生引起的过度炎症可导致过早宫缩和早产。早产新生儿随后可能面临侵入性念珠菌感染,这是最严重的医院感染之一,导致比细菌感染更高的发病率和死亡率,特别是在新生儿重症监护病房。
即使使用静脉注射棘白霉素(echincandin)治疗,人们也越来越关注日益增加且广泛发生的抗真菌药物的耐药性。针对女性特定疾病的治疗是一个相对不发达的领域,在没有有效治疗的情况下,外阴阴道感染造成众多且部分隐藏的问题。特别危险的是糖尿病患者,特别是怀孕的糖尿病患者。在怀孕期间使用的无害治疗可以证明在预防早产方面也是最有价值的。
外阴阴道念珠菌病的替代建议治疗包括使用乳酸(参见WO 2008/119518)和乳酸菌(参见WO 2008/071783),其长期用于治疗细菌性阴道病。然而,乳酸在影响外阴阴道念珠菌病方面的效果差很多。
如本领域所公认的,尽管有治疗进展,但是外阴阴道念珠菌病因此仍然是世界范围内的常见问题,影响社会的所有阶层[J.D.Sobel.Lancet,2007,369,1961-1971]。
因此需要针对外阴阴道念珠菌病的新的药物制剂。本发明旨在提供一种针对外阴阴道感染问题的简单、便宜、环境友好的解决方案。
发明内容
因此,本发明旨在通过提供用于阴道给药的药物制剂来单独或任何组合地减轻、缓解、消除或避免本领域中的一个或多个上述缺陷和缺点,其中该制剂包含药学上可接受的赋形剂和葡萄糖酸δ-内酯(式(III)),
其中葡萄糖酸δ-内酯以制剂的5至99wt%(重量/重量)的量存在。已经表明,这种组合物减少了不同念珠菌的生物膜的存在,并且此外,其还对几种念珠菌具有细胞毒性作用。葡萄糖酸δ-内酯(GDA)在室温和体温下是固体,因此适合用作例如阴道片剂、薄片剂(disc)或栓剂或阴道栓(vagitorium)中的活性成分。
根据一个实施方案,葡萄糖酸δ-内酯以制剂的10至70wt%的量存在。葡萄糖酸δ-内酯可以以制剂的20至70wt%的量存在。葡萄糖酸δ-内酯可以以大于50wt%,例如大于60wt%,例如大于70wt%,例如大于75wt%,例如大于80wt%的量存在。这种组合物具有快速释放有效剂量的葡萄糖酸δ-内酯的优点。
根据另一个实施方案,该组合物包含不大于10wt%,优选不大于5wt%的水。这种组合物具有保质期长并保护葡萄糖酸δ-内酯免于水解的优点。
根据一个实施方案,药物制剂还包含选自以下组成的组中的抗真菌剂:咪康唑、特康唑、异康唑、芬替康唑、氟康唑、制霉菌素、酮康唑、克霉唑、布康唑、益康唑、噻康唑、伊曲康唑、5-氟尿嘧啶和甲硝唑。这种组合物的优点是,在感染不仅由对葡萄糖酸δ-内酯敏感的物种引起,而且还必须用另一种抗真菌剂进行治疗的情况下,它是有效的。
根据一个实施方案,药物制剂包含载体、填充剂和/或缓冲剂或pH调节剂。
根据另一个实施方案,配制该药物制剂以在给药例如阴道内插入后经延长的时间段,例如经至少4小时、经至少6小时、经至少8小时或经至少24小时释放根据式(III)的化合物。这具有延长治疗效果的优点。此外,可延长组合物给药之间的时间间隔。
根据另一个实施方案,药物制剂被配制为卫生棉条、阴道栓、阴道气溶胶、阴道杯、阴道凝胶、阴道插入物、阴道贴剂、阴道环、阴道海绵、阴道栓剂、阴道乳膏、阴道乳液、阴道泡沫、阴道洗剂、阴道软膏、阴道粉末、阴道洗涤剂、阴道溶液、阴道喷雾剂、阴道悬浮液、阴道片剂、阴道棒、阴道薄片剂、阴道装置及其任何组合,或其中药物制剂存在于卫生用品,例如卫生棉条、卫生巾、失禁垫或尿布、或卫生护垫上。
根据另一个实施方案,将药物制剂配制成为阴道栓、阴道插入物、阴道环、阴道栓剂、阴道片剂、阴道棒或阴道薄片剂。
根据一个实施方案,药物制剂具有减少或预防念珠菌形成生物膜的能力。生物膜是一组微生物,其中细胞彼此附着。这些细胞通常粘附在表面,例如粘膜表面上。在生物膜中生长的微生物细胞在生理上不同于同一生物体的所谓的浮游细胞,其是可在液体培养基中漂浮或游动的单细胞。念珠菌具有形成生物膜的能力。当减少或预防了生物膜形成时,个体念珠菌细胞不能再附着于例如阴道的粘膜上。因此,预防了进一步的感染,并且不再形成生物膜的念珠菌细胞由例如阴道排出。
根据本发明的第二方面,提供了根据上述的药物制剂,其用于预防或治疗泌尿生殖系统真菌感染。
葡萄糖酸δ-内酯可以作为药物制剂中的活性成分存在。
根据一个实施方案,泌尿生殖系统真菌感染是外阴阴道真菌感染。
根据另一个实施方案,泌尿生殖系统真菌感染是外阴阴道念珠菌病。
还根据另一个实施方案,外阴阴道念珠菌病是由白色念珠菌、光滑念珠菌、克鲁斯念珠菌和/或热带念珠菌(Candida tropicalis)引起。
根据本发明的第三方面,提供了葡萄糖酸δ-内酯(式(III)),
其用于预防或治疗真菌感染。
根据一个实施方案,真菌感染是泌尿生殖系统真菌感染。
根据一个实施方案,泌尿生殖系统真菌感染是外阴阴道念珠菌病。
根据另一个实施方案,外阴阴道念珠菌病是由白色念珠菌、光滑念珠菌、克鲁斯念珠菌和/或热带念珠菌引起。
此外,本发明的各种实施方案的有利特征在以下从属权利要求中限定并在详细描述内。
发明详述
据估计,人类中大约80%的病原体感染与生物膜的形成,即病原体与细胞壁以及其他病原体细胞结合的复杂三维结构的形成有关。已经表明,外阴阴道念珠菌感染需要生物膜的形成[M.M.Harriott,E.A.Lilly,T.E.Rodriguez,P.L.Fidel,M.C.Noverr,Microbiology,2010,156,3635-3644]。此外,生物膜的形成也使抗真菌的效率降低了10-100倍。
鉴于生物膜形成在外阴阴道念珠菌感染中的重要性,认为生物膜测定适合于评估羟基化羧酸在靶向外阴阴道念珠菌感染中的效果。根据本领域中的报道,发现在生物膜测定中,乳酸具有靶向外阴阴道念珠菌感染的中等活性(参见下面的实验部分)。由于生物膜的形成依赖于pH和可替代的碳水化合物源的出现两者,因此了解到乳酸对生物膜的形成具有一些作用并不奇怪。此外,一些其他羟基化的C2-C5羧酸也提供类似的作用。认为它们的作用与其酸化作用有关,因为更强的酸提供某种程度上更强的作用。
令人惊奇地发现,相比于密切相关的C3和C5类似物(即分别为甘油酸和木糖酸),多羟基化的C6羧酸,例如葡萄糖酸在减少生物膜形成方面具有优异的效果。甚至更令人惊讶地发现,相比于酸性更强的羟基化羧酸(例如柠檬酸),多羟基化的C6羧酸,例如葡萄糖酸也是优异的。
而其他羟基化羧酸的作用似乎仅仅是由于它们的酸性(降低pH值以妨碍生物膜的形成),多羟基化的C6羧酸例如葡萄糖酸对于生物膜形成的作用在pH<7时就已经很明显。因此,似乎多羟基化的C6羧酸例如葡萄糖酸对于生物膜形成的作用不仅与其酸性有关,而且化合物本身,或更确切地说是其相关的δ-内酯也提供了作用。
在本领域中,已经证明由假单胞菌菌株AN5产生的D-葡萄糖酸对由真菌小麦全蚀病菌变种tritici(Gaeumannomyces graminis var.tritici)引起的小麦全蚀病具有作用(R.Kaur等人,Phytochemistry 67(2006)595-604;还参见WO 00/44230A1)。作者提出了假单胞菌菌株产生的D-葡萄糖酸和其他抗真菌剂例如吩嗪-1-羧酸(phenanzine-1-carboxylic acid)(PCA)和2,4-二乙酰基间苯三酚(DPG)抑制全蚀病真菌的能力必须至少部分是由于它们降低小麦根际的pH值的能力。
不受任何理论的束缚,葡萄糖酸的存在可能有利于浮游细胞而不是生物膜形成念珠菌,因为多羟基化的C6羧酸,例如葡萄糖酸可以被念珠菌和磷酸戊糖途径中的其他真核细胞使用。
在水溶液中,葡萄糖酸(GA,CAS 526-95-4)与葡萄糖酸-δ-内酯(GDA,CAS 90-8-2)和葡萄糖酸-γ-内酯(GGA)处于平衡状态。葡萄糖酸难以作为固体结晶产物生产,并且通常作为50%水溶液提供。
尽管这种水溶液可用于提供用于阴道给药的液体药物制剂,例如阴道乳膏、阴道凝胶;但水溶液不太适合用于提供用于阴道给药的固体药物制剂,例如阴道片剂、阴道栓剂或阴道环。
为了解决这个问题,本发明人研究了在制备固体药物制剂中使用葡萄糖酸-δ-内酯(GDA)的可能性。令人惊讶的是,本发明人发现GDA本身即内酯本身对不同念珠菌的生物膜形成具有影响。进一步的研究表明,GDA对生物膜形成和念珠菌活力的影响与葡萄糖酸的作用相当,表明GDA本身作为活性化合物起作用。
因此,本发明的一个实施方案涉及用于阴道给药的药物制剂,其包含根据式(III)的化合物,即葡萄糖酸-δ-内酯(GDA)
此外,药物制剂包含药学上可接受的赋形剂以提供制剂。在本文中,“药学上可接受的”是指这样的赋形剂,其在所用的剂量和浓度下,不会在其施用的受试者中引起任何不希望的作用。此类药学上可接受的赋形剂是本领域熟知的。它们可选自以下组成的组:载体;稀释剂;粘结剂;崩解剂;流动改进剂;pH调节剂;稳定剂;粘度调节剂;防腐剂;胶凝剂或溶胀剂;表面活性剂;乳化剂;悬浮剂;用于栓剂、栓或阴道栓的基质;用于乳膏、软膏、凝胶、洗剂(lotion)、洗涤剂(shampoo)、泡沫、喷雾剂等的基质。如本领域技术人员所认识到的,药学上可接受的赋形剂的具体选择取决于具体的形式或制剂,例如剂型。本领域技术人员可以在各种教科书(例如Remington:The Science and Practice of Pharmacy)中找到指导,以提供合适的药学上可接受的赋形剂。这种药物制剂可用于治疗和/或预防外阴阴道真菌感染。
药学上可接受的赋形剂可以是亲脂性或亲水性载体。亲脂性载体的实例是蜡、油、肉豆蔻酸异丙酯、固体甘油三酯和可可脂。亲水性载体的实例是甘油、丙二醇和聚氧乙二醇。
此外,赋形剂可以是填充剂。填充剂的实例包括糖类,例如乳糖、麦芽糖和海藻糖。其他二糖如蔗糖、乳果糖、纤维二糖等也可适用于本发明的上下文。在本发明的组合物中,二糖通常有助于组合物的合适结构。糖类也可用作冻干助剂。
在水溶液中,根据式(I)的化合物与相应的内酯例如δ-内酯和γ-内酯处于平衡状态。
因此,药物制剂的活性成分可包含少量的酸(参见式(I))和/或葡萄糖酸-γ-内酯。
根据一个实施方案,根据式(III)的化合物在药物制剂中部分以其非带电质子化形式作为酸(式(I))例如葡萄糖酸存在,部分作为相应的加成盐,即共轭碱,例如葡萄糖酸盐存在。因此,葡萄糖酸可用于缓冲药物制剂。可以选择其非带电质子化形式的酸与共轭碱之间的比例,以在给药时提供合适的pH,例如3.5至4.5。因此,药物制剂可以在给药后恢复阴道中的正常生理pH。然而,考虑到式(III)化合物已经在pH 6.5或更低时具有的活性,不必恢复pH就可向药物制剂提供其作用。然而,优选药物制剂在给药时具有6.0或更低,例如5.0或更低的pH。给药后,药物制剂应优选提供不低于3.0,更优选不低于3.5的pH。
虽然可使用其非带电质子化形式的相应酸和/或相应的加成盐(即共轭碱)形式的根据式(III)的化合物向药物制剂提供pH调节性质,药物制剂可包含另外的缓冲剂或pH调节剂。这种缓冲剂或pH调节剂可以是药学上可接受的缓冲剂,其适于将pH调节至约3至约5,例如3.5至4.5。缓冲剂或pH调节剂的实例包括乳酸、乙酸、柠檬酸、丙二酸、磷酸、酒石酸、马来酸等及其相应的共轭碱,即乳酸盐、乙酸盐、柠檬酸盐、丙二酸盐、磷酸盐、酒石酸盐和马来酸盐。
此外,药物制剂还可以单独或组合地包含一种或几种药学上可接受的盐,例如琥珀酸盐、赖氨酸盐、环丙酸盐、戊酸盐、半琥珀酸盐、丁酸盐或氨丁三醇盐。
药物制剂包含药学活性量的根据式(III)的化合物。根据优选的实施方案,药物制剂包含至少5wt%,例如至少10wt%、15wt%、20wt%、25wt%、30wt%、40wt%、50wt%、60wt%或75wt%的根据式(III)的化合物。此外,药物制剂可包含不大于99wt%,例如不大于95wt%、90wt%、80wt%、75wt%、70wt%、60wt%或50wt%的根据式(III)的化合物。因此,药物制剂可包含5wt%至99wt%的根据式(III)的化合物。如本领域技术人员所公认的,该范围可以基于上述指定的上限和下限量来缩小,例如10至95wt%、10至80wt%、15至90wt%、20至75wt%、30至70wt%。药物制剂可包含40wt%至90wt%的根据式(III)的化合物。该药物制剂可包含50wt%至80wt%的根据式(III)的化合物。药物制剂可包含60wt%至70wt%的根据式(III)的化合物。
根据另一个实施方案,该药物制剂包含葡萄糖酸-δ-内酯(III)和任选但非必需的葡萄糖酸(I)。在这样的实施方案中,制剂中葡萄糖酸-δ-内酯(III)和葡萄糖酸(I)的摩尔比可以是至少9:1(III:I),优选至少49:1(III:I),更优选至少99:1(III:I)。由于葡萄糖酸-δ-内酯(III)将水解成葡萄糖酸(I),因此药物制剂中高比例的葡萄糖酸-δ-内酯(III)可能是优选的。根据这样的实施方案,药物制剂可包含少于1wt%的葡萄糖酸(I),例如少于0.1wt%、0.05wt%、0.01wt%、0.005wt%或0.001wt%的葡萄糖酸(I)。
在阴道插入药物制剂后,内酯将暴露于引起水解的水性条件。由于水解不是即时的,药物制剂将在延长的时间段内释放根据式(III)的化合物,从而延长其作用。此外,根据式(I)的化合物可以作为游离酸或作为其共轭碱释放,因此增强了降低pH的效果。阴道的pH可以在3.5至4.5之间变化,并且在真菌或细菌感染的情况下,其可以升高到高于4.5。
此外,如技术人员所认识到的,药物制剂可以配制用于延长释放,进一步延长作用。该药物制剂可以配制成在经阴道插入后在延长的时间段,例如经至少4小时、经至少6小时、经至少8小时或经至少24小时释放根据式(III)的化合物。
此外,除了充当活性成分之外,葡萄糖酸-δ-内酯(III)还可以充当填充剂和/或载体以促进包含葡萄糖酸-δ-内酯(III)的组合物配制在药物制剂(例如半固体或固体药物制剂)中。
除赋形剂之外,药物制剂还可包含另外的抗真菌剂。抗真菌剂可选自以下组成的组:咪康唑、特康唑、异康唑、芬替康唑、氟康唑、制霉菌素、酮康唑、克霉唑、布康唑、益康唑、噻康唑、伊曲康唑、5-氟尿嘧啶和甲硝唑。每剂量的抗真菌剂的量可以为0.1mg至2000mg。根据式(III)的化合物和这种另外的抗真菌剂可以以协同方式起作用。
有时,但并非总是如此,外阴阴道真菌感染也涉及细菌感染。由于其酸性,葡萄糖酸将提供类似于乳酸对细菌感染的作用的作用。因此,此外,葡萄糖酸-δ-内酯(III)也可对细菌感染有作用。然而,优选用一种或多种另外的抗菌剂补充药物制剂。根据一个实施方案,药物制剂因此包含一种或多种抗菌剂。抗菌剂可选自以下组成的组:克林霉素、四环素、阿莫西林、氨苄青霉素、红霉素、强力霉素、洛美沙星、诺氟沙星、afloxam、环丙沙星(ciproflaxin)、阿齐霉素、头孢噻肟(cefltoxine)。抗菌剂的量可以为每剂量5mg至1000mg。
此外,药物制剂可包含一种或多种病原体-抗粘附剂。如已经讨论的,外阴阴道真菌感染涉及生物膜形成和真菌与阴道粘膜的粘附。根据一个实施方案,药物制剂因此包含一种或多种抗粘附剂,以预防病原体例如真菌的粘膜粘附。抗粘附剂可以是用作预防粘附的屏障的试剂,或是用作导致已粘附的微生物解粘附的试剂。导致解粘附的抗粘附剂的实例可以是甘露糖、乳糖、木糖醇和其他糖醇。
药物制剂优选配制成给药至阴道,例如阴道内给药。根据一个实施方案,药物制剂因此配制为卫生棉条、阴道栓、阴道气溶胶、阴道杯、阴道凝胶、阴道插入物、阴道贴剂、阴道环、阴道海绵、阴道栓剂、阴道乳膏、阴道乳液、阴道泡沫、阴道洗剂、阴道软膏、阴道粉末、阴道洗涤剂、阴道溶液、阴道喷雾剂、阴道悬浮液、阴道片剂、阴道棒、阴道薄片剂、阴道装置及其任何组合。优选地,药物制剂被配制为阴道栓、阴道气溶胶、阴道杯、阴道凝胶、阴道环、阴道海绵、阴道栓剂、阴道乳膏、阴道乳液、阴道泡沫、阴道洗剂、阴道软膏、阴道洗涤剂、阴道溶液、阴道喷雾剂、阴道悬浮液、阴道片剂、阴道棒或阴道薄片剂;更优选配制为阴道栓、阴道插入物、阴道环、阴道栓剂、阴道片剂、阴道棒或阴道薄片剂。药物制剂还可以是液体制剂,例如阴道气溶胶、阴道凝胶、阴道乳膏、阴道乳液、阴道泡沫、阴道洗剂、阴道软膏、阴道洗涤剂、阴道溶液、阴道喷雾剂、阴道悬浮液或其任何组合。
根据可替代但不太优选的实施方案,药物制剂存在于卫生用品例如卫生棉条、卫生巾、失禁垫或尿布、或卫生护垫上。
药物制剂可进一步配制以在给药例如阴道插入后用于延长释放,即在延长的时间段,例如经至少4小时,经至少6小时,经至少8小时或经至少24小时释放根据式(III)和/或(I)的化合物。根据式(I)的化合物可以作为以其非带电质子化形式的酸和/或作为相应的共轭碱释放。此外,如已经概述的,制剂可以以未水解的形式释放葡萄糖酸δ-内酯。通过配制用于延长释放的药物制剂,药物制剂将在更长的时间内发挥其作用。这可有益于恢复阴道中的正常状况和治疗和/或预防外阴阴道真菌感染。
如已经详述的,用于阴道给药的包含根据式(III)的化合物的药物制剂
具有减少或甚至预防念珠菌形成生物膜的能力。此外,此类药物制剂可具有减少或甚至溶解由念珠菌形成生物膜的能力。
如已经详述的,葡萄糖酸δ-内酯(III)因此可用于预防或治疗泌尿生殖系统真菌感染,例如外阴阴道真菌感染。因此,一个实施方案涉及如本文所公开的药物制剂,其用于预防或治疗泌尿生殖系统真菌感染,例如外阴阴道真菌感染。通常,泌尿生殖系统真菌感染是外阴阴道念珠菌病,其涉及念珠菌例如白色念珠菌、光滑念珠菌、克鲁斯念珠菌和热带念珠菌的感染。
外阴阴道念珠菌感染是念珠菌在阴道中过度生长,导致炎症相关的症状,如瘙痒、疼痛或刺激,阴道组织变红和肿胀、排尿和性交疼痛,通常为粘性白色和块状凝乳样排出物或正常至稀薄和水样的排出物。
类似地,本发明的一个实施方案涉及葡萄糖酸δ-内酯用于制备如本文所公开的药物制剂的用途,该药物制剂用于治疗和/或预防泌尿生殖系统真菌感染,例如外阴阴道真菌感染。通常,泌尿生殖系统真菌感染是外阴阴道念珠菌病,其涉及念珠菌例如白色念珠菌、光滑念珠菌、克鲁斯念珠菌和热带念珠菌的感染。
而另一个实施方案涉及预防和/或治疗泌尿生殖系统真菌感染(例如外阴阴道真菌感染)的方法,包括给予需要这种预防和/或治疗的哺乳动物(包括男性)治疗有效量的如本文所公开的药物制剂。通常,泌尿生殖系统真菌感染是外阴阴道念珠菌病,其涉及念珠菌例如白色念珠菌、光滑念珠菌、克鲁斯念珠菌和热带念珠菌的感染。
根据本文实施方案的药物组合物可以以药学有效剂量给药于患者。“药学有效剂量”是指足以产生与其给药的病症相关的所需效果的剂量。确切剂量可取决于给药方式、病症和/或疾病的性质和严重程度以及一般病症,例如患者的年龄和体重。
根据一个实施方案,本文公开的药物组合物以每天至少一次进行给药,持续至少一周,但也可以使用其他剂量方案。
当在本文中使用时,“预防/预防”不应解释为意指在使用根据本文公开的实施方案的化合物或药物组合物实现了预防之后,不再发生病症和/或疾病。此外,该术语也不应被解释为意指在这样的使用以预防所述病症之后,所述病症至少在某种程度上不会再发生。与之相比,“预防/预防”旨在表示即使在这样的使用情况下发生了待预防的病症,该病症的严重度会低于没有这种使用时。
根据一个实施方案,治疗还包括预处理,即预防性治疗。
尽管以上已经参考特定的说明性实施方案描述了本发明,但是并不意图将本发明限于本文所阐述的特定形式。应当理解,上述实施方案的任何组合都落入本发明的范围内。与之相比,本发明仅由所附权利要求所限制,并且除了上述具体实施方案之外的其他实施方案同样可落入所附权利要求的范围内。
在权利要求中,术语“包含/包含”不排除存在其他物质或步骤。另外,尽管各个特征可包括在不同的权利要求中,但是这些特征可以有利地组合,并且包含在不同的权利要求中并不意味着特征的组合是不可行和/或不利的。另外,单数引用不排除多个。术语“一”(a)、“一(an)”、“第一”、“第二”等不排除多个。短语“至少一个”或“一个或多个”指1或大于1的数字,例如1、2、3、4、5、6、7、8、9或10。
附图的简要说明
图1示出了GDA在蒸馏水(实心圆圈)、pH 4的缓冲液(实心方块)、pH 5的缓冲液(实心方块)和pH 7的缓冲液(实心圆圈)中水解的旋光度的变化。
图2示出了在具有磷酸盐缓冲液(实心圆圈,虚线)的pH值为2.6-6.6或具有GDA(实心方块,实线)的基本培养基中经归一化的白色念珠菌的生物膜形成。生物膜是在24小时后测量,用结晶紫进行染色。
图3a示出了用GDA处理的经归一化的白色念珠菌的生物膜形成。在37℃下将GDA颗粒加入pH 3.71(10mL)的缓冲溶液中。在1、2、3、4、5、6和24小时后取样(4mL)并加入新的缓冲溶液(4mL)。将样品用生物膜培养基稀释50倍,并在24小时后测量生物膜形成的量。
图3b示出了用GDA处理的经归一化的光滑念珠菌的生物膜形成。在37℃下将GDA颗粒加入pH 3.71(10mL)的缓冲溶液中。在1、2、3、4、5、6和24小时后取样(4mL)并加入新的缓冲溶液(4mL)。将样品用生物膜培养基稀释50倍,并在24小时后测量生物膜形成的量。
图4a示出了用不同浓度的GDA处理24小时后,白色念珠菌和光滑念珠菌的生物膜的活力。用XTT进行生物膜染色。在485nm处测量光密度。斜纹表示白色念珠菌的数据。实心黑色柱表示光滑念珠菌的数据。
图4b示出了用不同浓度的GDA处理48小时后,白色念珠菌和光滑念珠菌的生物膜的活力。用XTT进行生物膜染色。在485nm处测量光密度。斜纹表示白色念珠菌的数据。实心黑色柱表示光滑念珠菌的数据。
图5示出了GDA对白色念珠菌和光滑念珠菌的成熟生物膜的影响。将成熟的生物膜(生长48小时)与GDA在37℃孵育5小时,然后将系列稀释的细胞接种在YPD板上以估计细胞存活率。
图6a示出了未经处理的白色念珠菌在pH 7.0的基本培养基中的生物膜发展的微流体研究。未经处理的细胞主要形成菌丝。
图6b示出了在基本培养基中用x50最终浓度的GDA水解产物pH 3.8处理的白色念珠菌的生物膜发展的微流体研究。GDA的添加导致白色念珠菌主要以酵母而不是菌丝形式生长。
材料和方法
葡萄糖酸-δ-内酯
从商业供应商获得固体葡萄糖酸-δ-内酯(GDA,CAS 90-8-2)。
生物膜形成测定
在37℃下在完全培养基YPD(0.5%(重量/体积)酵母提取物、1%(重量/体积)蛋白胨、2%(重量/体积)葡萄糖)或由YNB(酵母氮源,不含氨基酸和硫酸铵,FORMEDIUMTM,CYN0505)组成且补充有0.5%(重量/体积)的硫酸铵、0.2%(重量/体积)的葡萄糖和100mM的L-脯氨酸的基本培养基中使酵母菌株生长。如果需要,使用2%(重量/体积)的琼脂来固化培养基。液体基本培养基(YNB(酵母氮源,不含氨基酸和硫酸铵,FORMEDIUMTM,CYN0505;补充有0.5%的硫酸铵,0.2%(重量/体积)的葡萄糖和100mM的L-脯氨酸)用于生物膜测定(生物膜培养基)。
在pH对生物膜的影响的实验中(下面的实施例2),使用最终浓度为0.25M的不同磷酸钾缓冲液或通过向生物膜培养基中添加GDA来获得pH值(2.6至6.6)。
酵母菌株
生物膜形成实验中使用的菌株描述于表1中。
表1.用于生物膜实验中的酵母菌株
生物膜的测量
如[K.Scherz et al.,G3(Bethesda),2014,4,1671-1680.I.Serrano-Fujarte etal.Biomed Res Int.2015;2015:783639]所述,在液体培养物中测量生物膜,并进行了以下修改。在生物膜测定之前,酵母培养物在液体YPD培养基中生长24小时,直到通过离心(1699×g)沉淀静止期细胞,用无菌水洗涤,并将细胞以0.2OD600/ml的最终浓度进一步接种到测试生物膜培养基(YNB(酵母氮源,不含氨基酸和硫酸铵),补充有0.5%的硫酸铵,0.2%的葡萄糖和100mM的L-脯氨酸,pH 7.0)中,并在37℃恒温箱中在96孔平底聚苯乙烯微量滴定板(Sigma Aldrich,培养板,CLS3596-50EA)中孵育72小时。在确定的时间点,将结晶紫(HT901-8FOZ;Sigma Aldrich)以0.05%的最终浓度添加到培养基中。此外,测量总生物量。细胞染色24小时后,用200·l水洗涤板孔4次以除去浮游细胞(该细胞不是生物膜的一部分),然后将生物膜干燥并溶解在200·l 96%的乙醇中。使用BMG LABTECH的FLUOstar OPTIMA读板器在OD560下进行总生物量和结晶紫生物膜染色测量。将结晶紫生物膜测量归一化为总生物量(OD560生物膜/OD560总生物量)。
实施例
实施例1-葡萄糖酸-δ-内酯(GDA)的水解
在水溶液中,葡萄糖酸-δ-内酯(GDA)与葡萄糖酸(GA,CAS 526-95-4)处于平衡状态。在37℃下将GDA(200mg)加入到蒸馏H2O(20mL),pH 4的缓冲液,pH 5的缓冲液或pH 7的缓冲液中。测量旋光度和pH随时间的变化。,在37℃,钠D线,C=10mg/mL,路径长度=10cm下测量旋光度。GDA的旋光度约为66°。葡萄糖酸的旋光度约为5°[D.T.Sawyer,J.B.Bagger,J.Am.Chem.Soc.,1959,81,5302-5306]。该实验表明,GDA缓慢水解成GDA和GA的混合物(图1)。平衡是pH依赖性的,并且在所有缓冲条件下都存在相关的GDA浓度。
实施例2-白色念珠菌在不同pH下的生物膜形成
从图2中可以看出,GDA对白色念珠菌的生物膜形成有很强的影响,而磷酸盐缓冲液的影响则不太明显。此外,GDA在pH值升高约至少6时也表现出强烈的影响,而缓冲液的影响在pH 5时就已经减弱。
实施例3-使用GDA在体内条件模型中形成生物膜
将GDA颗粒(2.5g,一式两份样品)在37℃下加入pH 3.71(0.5MKH2PO4/正磷酸,10mL)的缓冲溶液中。在固定时间点(1、2、3、4、5、6和24小时)取样(4mL)并加入新的缓冲溶液(4mL)。将样品用生物膜培养基稀释50倍(参见上文),并如上所述在24小时后测量生物膜形成的量。如图3a所示,释放的GDA显著降低了白色念珠菌中生物膜形成的量。此外,颗粒的水解似乎足够慢以提供至少长达24小时,以及可能更多的预防作用。光滑念珠菌的作用不太明显(图3b)。
表2.在体内条件模型中用GDA处理的白色念珠菌和光滑念珠菌的生物膜形成。1小时后取样,用生物膜测定培养基稀释50倍,24小时后测量生物膜形成量。
结果示出,在GDA存在下,白色念珠菌和光滑念珠菌的生物膜形成减少。除了生物膜形成减少外,GDA还可能影响白色念珠菌和光滑念珠菌成熟生物膜的活力。
实施例4-用GDA处理的白色念珠菌和光滑念珠菌的成熟生物膜的活力。
通过用XTT染色细胞来评估用GDA处理后的白色念珠菌和光滑念珠菌的生物膜在不同浓度和不同时间段的活力。XXT是用于定量细胞活力和细胞毒性的比色测定法。该测定基于四唑盐XTT的裂解,该转化仅发生在活细胞中。将成熟的生物膜暴露于GDA 24小时。然后用PBS洗涤细胞2次,之后加入XTT反应混合物。30分钟后,在485nm处测量光密度。
XTT测定示出,在孵育24小时后光滑念珠菌的活力已大大降低(图4a)。对于白色念珠菌的作用不太明显,但48小时后清晰可见(图4b)。
此外,在37℃下将白色念珠菌和光滑念珠菌的成熟生物膜(在YNB,0.2%的葡萄糖,100mM的脯氨酸中生长48小时)与不同浓度(0.05-0.5g/ml)的GDA一起孵育。为此目的,除去生物膜培养基(YNB,0.2%的葡萄糖,100mM的脯氨酸)并加入GDA,其中GDA以0.05、0.1、0.2和0.5g/ml的浓度溶解在水中。在与GDA孵育5小时或73小时后,将5·l细胞以系列稀释(1:10至1:1000)铺板在琼脂培养基YPD上以估计细胞存活率。将铺板的细胞在37℃孵育24小时并目测分析。来自用水处理的成熟生物膜的细胞用作对照。发现GDA降低了白色念珠菌和光滑念珠菌的细胞活力,特别是在高浓度下。在0.2和0.5g/ml的浓度下在孵育5小时后,对于白色念珠菌和光滑念珠菌,细胞活力降低约100倍。与0.5g/ml的GDA一起孵育73小时后,白色念珠菌的细胞活力降低约1000倍(数据未示出)。证实了光滑念珠菌对于GDA更敏感(图5)。
实施例5-生物膜发育的微流体研究
为了监测白色念珠菌的细胞形态,我们还使用显微镜和微流体学研究了生物膜的发育。接种酵母细胞后,在生物膜培养基(YNB,补充有100mM脯氨酸和0.2%葡萄糖,pH 7.0)孵育的第一个小时内开始形成菌丝。图6a示出5小时后未处理的细胞。在37℃下将GDA颗粒(2.5g)加入到pH 3.71的缓冲溶液(0.5M KH2PO4/正磷酸,10mL)中。1小时后取样,用生物膜培养基稀释50倍并加入白色念珠菌中。5小时后,大多数处理过的细胞是浮游的(图6b)。
实施例6-在GDA存在下不同念珠菌的活力
所研究的其他念珠菌对GDA也是敏感的(即使用XTT测定的细胞活力测量,参见实施例4)。但是,它们表现出不同的敏感度。白色念珠菌SC5314表现出最低的易感性,而克鲁斯念珠菌硅胶分离株A4-1(Candida krusei silicone isolate A4-1)表现出最高的易感性。GDA-毒性是通过细胞壁损伤介导的,因为与补充有渗透稳定剂(0.5M蔗糖)的细胞相比和与在这些培养基上的未处理的细胞相比,暴露于GDA的细胞在含有增白剂(calcofluorwhite)的培养基上具有更低的活力。表3总结了GDA所表现出的定性作用。
表3.不同的念珠菌对GDA的敏感性
总之,(i)GDA可以破坏由白色念珠菌和光滑念珠菌形成的成熟生物膜;(ii)在暴露于GDA后,白色念珠菌转化为酵母形式,而光滑念珠菌的活力降低;(iii)即使对其他菌株即热带念珠菌和克鲁斯念珠菌上,该作用也很明显。
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