Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers

Abstract

With a dapivirine-releasing vaginal ring having successfully completed late-stage clinical testing for HIV prevention and currently undergoing regulatory review, there is now growing interest in next-generation multipurpose prevention technologies that seek to combine antiretroviral and contraceptive drugs within a single product. Here, we focus on ongoing efforts to develop a silicone elastomer vaginal ring releasing both dapivirine and levonorgestrel. Specifically, we evaluate various strategies aimed at both better understanding and reducing the tendency of levonorgestrel to bind with the elastomer, including: (i) formulation and post-manufacturing strategies aimed at reducing the extent of levonorgestrel reaction with addition-cure silicone elastomers; (ii) evaluation of a simple silicone system to model the complex elastomer; (iii) use of model compounds representing the enone and ethinyl moieties of levonorgestrel to probe the mode of addition of levonorgestrel to addition-cure silicone elastomers; and (iv) solution and solid-state 13 C-NMR analysis to probe the structural features of the levonorgestrel-silicone system. The results demonstrate that both the enone and ethinyl groups within levonorgestrel undergo hydrosilylation reaction with hydrosiloxane groups in the silicone elastomer leading to binding. The results also highlight potential strategies for further optimising the dapivirine+levonorgestrel silicone vaginal ring formulation to ensure that the levonorgestrel is available for release.

Preferences regarding emerging HIV prevention technologies among Toronto men who have sex with men: a discrete choice experiment

“…The heterogeneity of preferences in these studies highlights the importance of developing a variety of PrEP formulations. Fortunately, there remains a rich pipeline of products in development for various populations, including rectal suppositories 35 , vaginal rings combining dapivirine with hormonal contraceptives 36 , and subdermal implants containing a variety of existing and forthcoming antiretroviral agents 37 .…”

The Vaginal Microbiota, Bacterial Biofilms and Polymeric Drug-Releasing Vaginal Rings

“…The presence of certain functional groups in the drug molecules can lead to cure inhibition and/or drug binding when using addition-cure silicone elastomer systems [132][133][134][135]. Although the condensation-cure crosslinking reaction is compatible with a much wider range of chemical functional groups, the alcohol by-product formed by the curing reaction can be problematic due drug dissolving in the alcohol and being deposited on the device surface during storage, both potentially impacting drug release kinetics.…”

The ins and outs of drug-releasing vaginal rings: a literature review of expulsions and removals

“…However, the tin catalyst used can be poisoned by certain chemical functional groups found in drug molecules. Addition-cure silicone elastomer systems are generally cured at higher temperatures (120-180 °C) and are compatible with a wider range of drug chemistries, although reaction and binding has been observed with drug molecules containing certain unsaturated moieties [64][65][66]. Other cure systems are also available from silicone suppliers, including those catalysed by peroxide species and UV light.…”