ORCID
0009-0009-9641-1325 (Doncel)
Document Type
Article
Publication Date
2025
DOI
10.1016/j.jconrel.2024.11.062
Publication Title
Journal of Controlled Release
Volume
377
Pages
842-854
Abstract
Pre-exposure prophylaxis (PrEP) has emerged as a prominent approach for the prevention of HIV infections. While the latest advances have resulted in effective oral and injectable product options, there are still gaps in on-demand, event-driven, topical products for HIV prevention that are safe and effective. Here we describe the formulation development of a dual-compartment topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) that may be administered when needed, vaginally or rectally, pre- or post-coitus, for flexible HIV prophylaxis. Specifically, we describe the lab-scale formulation development, preclinical mucosal safety and pharmacokinetics (PK) testing in rabbits, long-term stability, and scale-up clinical manufacturing of the lead TAF/EVG (20 mg/16 mg) inserts, which are currently in clinical stages of development. As designed, the inserts are small, discreet and portable, offering a number of promising attributes, such as simple and robust direct-compression manufacturing, fast initial disintegration/dissolution, and suitable mechanical strengths showing low hardness (<8 kg), friability (<1 %), and moisture content (<1 %). The inserts initiated disintegration quickly (~ ≤ 15 min) providing full in vitro release (>90 %) of TAF and EVG within 60 min of dissolution. The lead insert was selected from formulation prototypes that met the evaluation criteria for manufacturability and characterization, together with a dose-ranging PK study in non-human primates. Successful technology transfer for clinical development of the lead TAF/EVG (20 mg/16 mg) insert was confirmed under cGMP conditions. Based on the 12 months (lab-scale) and 24 months (clinical batch) stability data, the TAF/EVG inserts are projected to have a long shelf life of over 2 years, if stored at or below 30 °C/65 % RH. Overall, these newly designed topical inserts have formulation properties that enable stable storage and fast release of the antiretroviral payload from a small, portable and discreet dosage form. They are safe and effective when applied vaginally or rectally, before or after coitus, providing the basis for a new method of flexible on-demand HIV prevention for cisgender and transgender women and men. The TAF/EVG inserts are currently the most clinically advanced on-demand topical product, as attested by their completed and ongoing clinical trials.
Rights
© 2024 The Authors.
This is an open access article under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License.
Data Availability
Article states: "Data will be made available on request."
Original Publication Citation
Agrahari, V., Peet, M. M., Chandra, N., Ramalingam, P., Gupta, P. K., Jonnalagadda, S., Singh, O. N., McCormick, T. J., Doncel, G. F., & Clark, M. R. (2025). Formulation development of dual-compartment topical inserts combining tenofovir alafenamide and elvitegravir for flexible on-demand HIV prevention. Journal of Controlled Release, 377, 842-854. https://doi.org/10.1016/j.jconrel.2024.11.062
Repository Citation
Agrahari, V., Peet, M. M., Chandra, N., Ramalingam, P., Gupta, P. K., Jonnalagadda, S., Singh, O. N., McCormick, T. J., Doncel, G. F., & Clark, M. R. (2025). Formulation development of dual-compartment topical inserts combining tenofovir alafenamide and elvitegravir for flexible on-demand HIV prevention. Journal of Controlled Release, 377, 842-854. https://doi.org/10.1016/j.jconrel.2024.11.062
Appendix A. Supplementary Data
Included in
Chemicals and Drugs Commons, Equipment and Supplies Commons, Obstetrics and Gynecology Commons, Viruses Commons
