Tong Xin, Patel Sravan Kumar, Li Jing, Patton Dorothy, Xu Elaine, Anderson Peter L, Parikh Urvi, Sweeney Yvonne, Strizki Julie, Hillier Sharon L, Rohan Lisa C
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
Polymers (Basel). 2022 Mar 16;14(6):1196. doi: 10.3390/polym14061196.
MK-2048 is a second-generation integrase inhibitor active against HIV, which has been applied vaginally using ring formulations. In this work, a nanoparticle-in-film technology was developed as a discrete pre-exposure prophylactic product option against HIV for an extended duration of use. A film platform loaded with poly (lactic-co-glycolic acid) nanoparticles (PNP) encapsulating MK-2048 was engineered. MK-2048 PNPs were loaded into films that were manufactured via the solvent casting method. Physicochemical and mechanical properties, in vitro efficacy, Lactobacillus compatibility, in vitro and ex vivo permeability, and in vivo pharmacokinetics in macaques were evaluated. PNPs with a mean diameter of 382.2 nm and −15.2 mV zeta potential were obtained with 95.2% drug encapsulation efficiency. PNP films showed comparable in vitro efficacy to free MK-2048 (IC50 0.46 vs. 0.54 nM) and were found to have no impact on Lactobacillus. MK-2048 encapsulated in PNPs showed an increase in permeability (>4-fold) compared to the free MK-2048 in MDCKII cell lines. Furthermore, PNPs had higher ectocervical tissue permeability (1.7-fold) compared to free MK-2048. PNP films showed sustained drug levels for at least 3 weeks in the macaque vaginal fluid. This work demonstrates the synergy of integrating nanomedicine and polymeric film technology to achieve sustained vaginal drug delivery.
MK-2048是一种对HIV有效的第二代整合酶抑制剂，已通过环型制剂经阴道给药。在这项研究中，开发了一种纳米颗粒包埋于薄膜的技术，作为一种可延长使用时间的针对HIV的离散暴露前预防产品。设计了一种负载聚（乳酸-乙醇酸）纳米颗粒（PNP）包裹MK-2048的薄膜平台。将MK-2048-PNP负载到通过溶剂浇铸法制造的薄膜中。评估了其物理化学和机械性能、体外疗效、与乳酸杆菌的相容性、体外和离体渗透性以及猕猴体内药代动力学。获得了平均直径为382.2 nm、ζ电位为-15.2 mV的PNP，药物包封效率为95.2%。PNP薄膜显示出与游离MK-2048相当的体外疗效（IC50分别为0.46和0.54 nM），并且发现对乳酸杆菌没有影响。与MDCKII细胞系中的游离MK-2048相比，包裹在PNP中的MK-2048渗透性增加（>4倍）。此外，与游离MK-2048相比，PNP的宫颈外组织渗透性更高（1.7倍）。PNP薄膜在猕猴阴道液中显示出至少3周的持续药物水平。这项研究证明了整合纳米医学和聚合物薄膜技术以实现持续阴道给药的协同作用。
