Subdermal implants for HIV prevention with increased dapivirine release rates

Dapivirine (DPV) is an antiretroviral drug used for prevention of sexually acquired HIV infection in the form of a monthly matrix-type silicone elastomer vaginal ring. As part of efforts to develop longer acting antiretroviral products for HIV pre-exposure prophylaxis (PrEP), we previously reported reservoir-type DPV-releasing silicone elastomer subdermal implants. These early prototypes were constrained by relatively low DPV daily release rates (7-14 µg/day), which are likely too low to prevent sexual transmission of HIV. Here, we report in vitro formulation development of next-generation implant formulations as part of efforts to increase DPV release rates. Three strategies were evaluated-(i) reservoir-type implants fabricated from medical-grade silicone tubing comprising a core containing DPV solubilised in a liquid polyethoxylated castor oil (Kolliphor® EL), (ii) dip-coated reservoir rods, comprising a matrix-type silicone core and a relatively thin (∼0.33-0.66 mm) drug-free, silicone elastomer, rate-controlling membrane applied by dip coating, and (iii) simple matrix-type silicone elastomer rods. Replacing the conventional silicone elastomer core of the implants with Kolliphor® EL increased DPV solubility and enhanced steady-state flux ∼1.5-fold. Dip-coated implants provided mean daily release rates of 19-41 µg/day. Matrix-type implants lacking a rate-controlling membrane delivered up to 185 µg/day. While these release rates represent a substantial improvement over first-generation devices, it remains uncertain whether they would produce systemic concentrations sufficient for HIV prevention, given dapivirine's relatively low potency and the absence of a local delivery advantage with subdermal administration. Nonetheless, the findings are useful in demonstrating the feasibility of designing silicone-based implants, illustrating how core composition, membrane geometry, and release conditions influence DPV release from silicone subdermal implants, and providing a basis for future in vivo pharmacokinetic and preclinical evaluation.