Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc.
Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc.
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DOI：
10.1016/j.jconrel.2011.08.006
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发表时间：
2011-12-10
期刊：
影响因子：
--
通讯作者：
Malcolm RK
中科院分区：
文献类型：
--
作者：
Forbes CJ;Lowry D;Geer L;Veazey RS;Shattock RJ;Klasse PJ;Mitchnick M;Goldman L;Doyle LA;Muldoon BC;Woolfson AD;Moore JP;Malcolm RK
以羟乙基纤维素(HEC)和聚丙烯酸(如Carbopol®)为基础的水性半固体聚合物凝胶在阴道给药方面有着悠久的历史。然而，尽管它们无处不在，但由于较差的粘膜保留率和较差的水溶性活性物质的溶解度有限，它们的临床表现往往不佳。这些问题与阴道艾滋病毒杀菌剂特别相关，因为许多主要候选药物的水溶性很差，而且主要目标是开发一种性交独立的、每天一次的凝胶产品。在这项研究中，我们报告了一种非水性硅橡胶凝胶用于HIV-1进入抑制剂马拉韦罗的阴道给药。体外流变学、注射性和保留性研究表明，与传统的HEC水凝胶相比，硅胶的性能有所增强，而在段塞模型中对凝胶的测试证实，这种凝胶没有粘膜刺激性。恒河猴单剂量阴道注射马拉韦罗硅凝胶后的药代动力学研究表明，与含有相同马拉韦罗负荷的HEC凝胶相比，阴道液、阴道组织和血浆中的MVC水平更高且持续时间更长。结果表明，非水性硅胶有潜力作为阴蒂独立的阴道HIV杀菌剂的配方平台。
Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.
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