Fully synthetic injectable depots with high drug content and tunable pharmacokinetics for long-acting drug delivery

Abstract Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy outcomes, and both long-acting implants injectable depot systems are being developed to improve patient adherence. Here, we describe platform exploits new mechanism for formation controlled release. The is polymeric prodrug synthesized from monomers incorporate ARV drug tenofovir alafenamide (TAF) with degradable linkers be designed control release rates. synthetically incorporated into homopolymer or block designs exhibit high weight percent (wt%) also hydrophobized in these segments drive upon injection. Drug converts those more hydrophilic pendant groups via linker cleavage, this proceeds, polymer chains losing hydrophobicity then disassociated released over time provide dissolution mechanism. We show TAF depots copolymers homopolymers. They different linkers, example faster slower degrading p-hydroxybenzyloxycarbonyl (Benzyl) ethyloxycarbonyl (Alkyl) respectively. Diblock of p(glycerol monomethacrylate)-b-p(Alkyl-TAF-methacrylate) monomethacrylate)-b-p(Benzyl-TAF-methacrylate) were first characterized mouse subcutaneous injection model. alkylcarbamate design (TAF 51 wt%) showed excellent sustained profiles key metabolite (TFV) skin plasma 50-day period. Next, wt% 73% was same p(Alkyl-TAFMA) exhibited TFV blood 60 days, TFV-DP concentrations peripheral mononuclear cells (PBMC) found at least 10-fold higher than clinically suggested minimally EC90 protective concentration 24 fmol/106 cells. These reports parent dosing observed PBMC. IVIS imaging rhodamine labeled degradation coincided Finally, polymers stability accelerated six-month period, exceptional solubility 700 mg/mL DMSO formulation solvent. reservoir potential well year mg/day may not require cold chain storage global health world delivery applications.