Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GF, UK.
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Eur J Pharm Biopharm. 2019 May;138:92-98. doi: 10.1016/j.ejpb.2018.04.009. Epub 2018 Apr 21.
Suboptimal adherence to antiretroviral (ARV) therapy can lead to insufficient drug exposure leading to viral rebound and increased likelihood of resistance. This has driven the development of long-acting injectable (LAI) formulations which may mitigate some of these problems. Maraviroc (MVC) is an orally dosed CCR5 antagonist approved for use in patients infected with CCR5-trophic HIV-1. MVC prevents viral entry into host cells, is readily distributed to biologically relevant tissues and has an alternative resistance profile compared to more commonly used therapies. This makes a MVC LAI formulation particularly appealing for implementation in Pre-Exposure Prophylaxis (PrEP). A 70 wt% MVC-loaded nanodispersion stabilised with polyvinyl alcohol (PVA) and sodium 1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT) was prepared using emulsion-templated freeze-drying. In vitro release rate studies revealed over a 22% decrease in MVC release rate constant across a size selective membrane compared with an aqueous solution of MVC (<5% DMSO). Pharmacokinetic studies in rats were subsequently carried out following intramuscular injection of either the nanodispersion or an aqueous MVC preparation (<5% DMSO). Results demonstrated over a 3.4-fold increase in AUC (1959.71 vs 567.17 ng.h ml), over a 2.6-fold increase in MVCs terminal half-life (t½) (140.69 vs 53.23 h) and MVC concentrations present up to 10-days. These data support development of a MVC LAI formulation with potential application in HIV therapy or prevention.
抗逆转录病毒 (ARV) 治疗的依从性差可导致药物暴露不足，从而导致病毒反弹和耐药性增加。这促使人们开发了长效注射 (LAI) 制剂，这些制剂可能会缓解其中的一些问题。马拉维若（MVC）是一种口服 CCR5 拮抗剂，已被批准用于感染 CCR5 嗜性 HIV-1 的患者。MVC 可阻止病毒进入宿主细胞，容易分布到生物学相关组织中，与更常用的治疗方法相比，其耐药谱不同。这使得 MVC LAI 制剂特别适合用于暴露前预防 (PrEP)。使用乳液模板冷冻干燥法制备了一种负载 70wt% MVC 的纳米分散体，该纳米分散体由聚乙烯醇 (PVA) 和 1,4-双（2-乙基己氧基）-1,4-二氧丁烷-2-磺酸钠 (AOT) 稳定。体外释放率研究表明，与 MVC 的水溶液（<5%DMSO）相比，经过尺寸选择膜后，MVC 的释放率常数降低了 22%以上。随后在大鼠中进行了肌肉内注射纳米分散体或水性 MVC 制剂（<5%DMSO）后的药代动力学研究。结果表明，AUC（1959.71 比 567.17ng.h ml）增加了 3.4 倍，MVC 的终末半衰期（t½）（140.69 比 53.23h）增加了 2.6 倍，MVC 浓度可维持长达 10 天。这些数据支持开发一种 MVC LAI 制剂，该制剂可能在 HIV 治疗或预防方面具有应用潜力。
