Preclinical development of an injectable multipurpose prevention technology (MPT) formulation

Introduction: There is growing interest in the development of MPT products for women that combine hormonal contraception with HIV prevention. Since long-acting injectable (LAI) contraceptive products are already widely used by women in countries where HIV infection is highest, and efforts are ongoing to develop injectable antiretroviral formulations, there is strong rationale for combining a progestin and antiretroviral drug in a single injectable product. Here, we report preclincial development of a LAI aqueous suspension product containing the antiretroviral rilpivirine (RPV) and the progestin medroxyprogesterone acetate (MPA).
Materials and Methods: RPV was milled to produce an aqueous nanosuspension, and then reformulated with commercial micronised Depo-Provera® to produce the MPT test product (~90mg/mL RPV; ~45mg/mL MPA). Suspension formulations were characterized for particle size, charge, pH, osmolality, drug concentration, and by thermal analysis. The lead candidate MPT formulation and its separate controls (Depo-Provera® and RPV-only nanosuspension) were sterilised and then administered intramuscularly in cynomolgus monkeys for 90-day pharmacokinetic evaluation, with quantification of MPA/RPV in vaginal fluid/blood plasma by UPLC-MS/MS.
Results: All test formulations were confirmed sterile and stable over three months, and the separate agents had the following Dv(50) values: RPV ~114 nm; MPA ~ 10.6 μm. Plasma concentrations of RPV and MPA in macaques decreased from ~100 ng/mL to ~0.1 ng/mL, and over time periods ranging from 25–70 days depending upon the formulation (Figure 1). RPV vaginal fluid concentrations decreased from ~100 ng/g to ~2 ng/g over up to 40 days.