Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK.
Department of Molecular and Clinical Pharmacology, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK.
Eur J Pharm Biopharm. 2019 May;138:30-36. doi: 10.1016/j.ejpb.2018.05.015. Epub 2018 May 17.
Oral drug administration remains the preferred approach for treatment of HIV in most patients. Maraviroc (MVC) is the first in class co-receptor antagonist, which blocks HIV entry into host cells. MVC has an oral bioavailability of approximately 33%, which is limited by poor permeability as well as affinity for CYP3A and several drug transporters. While once-daily doses are now the favoured option for HIV therapy, dose-limiting postural hypotension has been of theoretical concern when administering doses high enough to achieve this for MVC (particularly during coadministration of enzyme inhibitors). To overcome low bioavailability and modify the pharmacokinetic profile, a series of 70 wt% MVC solid drug nanoparticle (SDN) formulations (containing 30 wt% of various polymer/surfactant excipients) were generated using emulsion templated freeze-drying. The lead formulation contained PVA and AOT excipients (SDN), and was demonstrated to be fully water-dispersible to release drug nanoparticles with z-average diameter of 728 nm and polydispersity index of 0.3. In vitro and in vivo studies of SDN showed increased apparent permeability of MVC, compared to a conventional MVC preparation, with in vivo studies in rats showing a 2.5-fold increase in AUC (145.33 vs. 58.71 ng h ml). MVC tissue distribution was similar or slightly increased in tissues examined compared to the conventional MVC preparation, with the exception of the liver, spleen and kidneys, which showed statistically significant increases in MVC for SDN. These data support a novel oral format with the potential for dose reduction while maintaining therapeutic MVC exposure and potentially enabling a once-daily fixed dose combination product.
口服给药仍然是大多数患者治疗 HIV 的首选方法。马拉维若（MVC）是首个上市的共受体拮抗剂，可阻止 HIV 进入宿主细胞。MVC 的口服生物利用度约为 33%，这受到较差的通透性以及与 CYP3A 和几种药物转运体的亲和力的限制。虽然每日一次的剂量现在是 HIV 治疗的首选方案，但当给予足以实现 MVC（特别是在与酶抑制剂共同给药时）的高剂量时，体位性低血压会限制剂量，这在理论上令人担忧。为了克服低生物利用度并改变药代动力学特征，使用乳液模板冷冻干燥生成了一系列 70wt%MVC 固体药物纳米颗粒（SDN）制剂（含有 30wt%的各种聚合物/表面活性剂赋形剂）。主导配方包含 PVA 和 AOT 赋形剂（SDN），并被证明完全可分散在水中以释放药物纳米颗粒，其 Z 均直径为 728nm，多分散指数为 0.3。SDN 的体外和体内研究表明，与常规 MVC 制剂相比，MVC 的表观渗透性增加，大鼠体内研究表明 AUC 增加了 2.5 倍（145.33 与 58.71ng·h·ml）。与常规 MVC 制剂相比，在检查的组织中，MVC 的组织分布相似或略有增加，除了肝脏、脾脏和肾脏，SDN 中的 MVC 显示出统计学上的显著增加。这些数据支持了一种新的口服剂型，具有减少剂量的潜力，同时保持治疗性 MVC 暴露，并可能使每日一次的固定剂量组合产品成为可能。
