Development and Evaluation of Nanoparticles-in-Film Technology to Achieve Extended In Vivo Exposure of MK-2048 for HIV Prevention

Abstract

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.

Innovations in monoclonal antibody-based multipurpose prevention technology (MPT) for the prevention of sexually transmitted infections and unintended pregnancy

“…An HIV integrase strand transfer inhibitor, MK-2048, used for HIV prevention, was incorporated into poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and the nanoparticles were delivered in a PVA—PEG (polyethylene glycol) film to female macaques. This new delivery system introduced more drug to the vaginal mucosa, and PK studies indicated sustained release for up to 3 weeks in vaginal secretions ( 87 ). This approach could potentially be used to extend the release of MPT mAbs at mucosal surfaces.…”

Pharmacological advances in anti‐retroviral therapy for human immunodeficiency virus‐1 infection: A comprehensive review

“…This compound applied as a vaginal ring has the same administration route as DPV and is presently being developed as a nanoparticle film to sustain delivery (Figure 13). 103 The search for the novel INSTIs continues where a novel scaffold, compound 44, a 4-phenylpiperidine derivative amenable to chemical modification, was identified using the High-Throughput Screening.…”

“…This compound applied as a vaginal ring has the same administration route as DPV and is presently being developed as a nanoparticle film to sustain delivery (Figure 13). 103 …”

The Potential of Films as Transmucosal Drug Delivery Systems

“…In the search carried out in PubMed referring to the last 5 years of publications, several articles were found about films for vaginal administration. The most cited applications were prevention of HIV transmission [124][125][126][127][128], candidiasis [129][130][131], vaginal microbial infections [132][133][134], cervical cancer [135], and genital herpes [136]. However, these studies only dealt with drugs for local action or did not indicate the site of action and therefore were not considered in the present review.…”