Long-acting biodegradable implant for sustained delivery of antiretrovirals (ARVs) and hormones

• DOI: 10.1016/j.jconrel.2021.10.021
• Publication Date: 2021-10-21T21:54:42Z
• Authors: Linying Li; Gregory J. Gatto; Rhonda M. Brand; Sai Archana Krovi; Mackenzie L. Cott...; Chasity Norton; Ariane van der St...; Leah M. Johnson
• Keywords: HIV Infections; Levonorgestrel; Hormones; 12. Responsible consumption; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Anti-Retroviral Agents; Pregnancy; Absorbable Implants; Humans; Female

Women worldwide confront two major reproductive health challenges: the need for contraception and protection from sexually transmitted infections, including Human Immunodeficiency Virus (HIV). Multipurpose Prevention Technologies (MPTs) that simultaneously prevent unintended pregnancy and HIV could address these challenges with a single product. Here, we developed a long-acting (LA) subcutaneously administered and biodegradable implant system that provides sustained delivery of contraceptive and antiretroviral (ARV) with zero-order release kinetics. The MPT system involves two implants comprising an extruded tube of a biodegradable polymer, poly(ε-caprolactone) (PCL). Each implant is filled with a formulation of progestin [levonorgestrel (LNG) or etonogestrel (ENG)], or a formulation of a potent ARV [tenofovir alafenamide (TAF), or 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA)]. We demonstrated sustained in-vitro release of LNG, ENG, and EFdA from the implant system for 13-17 months, while maintaining high stability of the drugs (>99%) within the implant reservoirs. We further elucidated the controlled release mechanism of the implant and leveraged several tunable parameters (e.g., type and quantity of the excipient, PCL properties, and implant wall thickness) to tailor the release kinetics and enhance the mechanical integrity of the MPT implant. The optimized MPT showed sustained in-vitro release of ENG and EFdA over 1 year while maintaining a high level of formulation stability and structural integrity. The MPT implant system was further evaluated in a preclinical study using a rodent model and demonstrated sustained release of EFdA (6 months) and ENG (12 months) with high stability of the drug formulation (>95%). This manuscript supports the continued advancement of LA delivery systems for MPTs.