McBride John W, Boyd Peter, Dias Nicola, Cameron David, Offord Robin E, Hartley Oliver, Kett Vicky L, Malcolm R Karl
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
Envigo, Huntingdon, Cambridgeshire, UK.
J Control Release. 2019 Mar 28;298:1-11. doi: 10.1016/j.jconrel.2019.02.003. Epub 2019 Feb 4.
Antiretroviral-releasing vaginal rings are at the forefront of ongoing efforts to develop microbicide-based strategies for prevention of heterosexual transmission of the human immunodeficiency virus (HIV). However, traditional ring designs are generally only useful for vaginal administration of relatively potent, lipophilic, and small molecular weight drug molecules that have sufficient permeability in the non-biodegradable silicone elastomer or thermoplastic polymers. Here, we report a novel, easy-to-manufacture 'exposed-core' vaginal ring that provides sustained release of the protein microbicide candidate 5P12-RANTES, an experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. In vitro release, mechanical, and stability testing demonstrated the utility and practicality of this novel ring design. In a sheep pharmacokinetic model, a ring containing two ¼-length excipient-modified silicone elastomer cores - each containing lyophilised 5P12-RANTES and exposed to the external environment by two large windows - provided sustained concentrations of 5P12-RANTES in vaginal fluid and vaginal tissue between 10 and 10,000 ng/g over 28days, at least 50 and up to 50,000 times the reported in vitro IC50 value.
抗逆转录病毒释放阴道环处于正在进行的开发基于杀微生物剂策略以预防人类免疫缺陷病毒（HIV）异性传播的努力的前沿。然而，传统的环设计通常仅适用于在不可生物降解的硅氧烷弹性体或热塑性聚合物中具有足够渗透性的相对强效、亲脂性和小分子重量药物分子的阴道给药。在此，我们报告了一种新型的、易于制造的“暴露核心”阴道环，它能持续释放蛋白质杀微生物剂候选物5P12-RANTES，这是一种实验性趋化因子类似物，可有效阻断HIV CCR5共受体。体外释放、机械和稳定性测试证明了这种新型环设计的实用性和可行性。在绵羊药代动力学模型中，一个含有两个四分之一长度赋形剂修饰硅氧烷弹性体核心的环——每个核心含有冻干的5P12-RANTES，并通过两个大窗口暴露于外部环境——在28天内阴道液和阴道组织中5P12-RANTES的浓度持续保持在10至10,000 ng/g之间，至少是报道的体外IC50值的50倍，最高可达50,000倍。
