Controlling levonorgestrel binding and release in a multi-purpose prevention technology vaginal ring device

Abstract

Despite a long history of incorporating steroids into silicone elastomers for drug delivery applications, little is presently known about the propensity for irreversible drug binding in these systems. In this study, the ability of the contraceptive progestin levonorgestrel to bind chemically with hydrosilane groups in addition-cure silicone elastomers has been thoroughly investigated. Cure time, cure temperature, levonorgestrel particle size, initial levonorgestrel loading and silicone elastomer type were demonstrated to be key parameters impacting the extent of levonorgestrel binding, each through their influence on the solubility of levonorgestrel in the silicone elastomer. Understanding and overcoming this levonorgestrel binding phenomenon is critical for the ongoing development of a number of drug delivery products, including a multi-purpose technology vaginal ring device offering simultaneous release of levonorgestrel and dapivirine - a lead candidate antiretroviral microbicide - for combination HIV prevention and hormonal contraception.

Mechanical testing methods for drug-releasing vaginal rings

“…The DPV+LNG slab samples cured under the same conditions as the DDU-4320 product specification provided a value of 11.50  0.55 Shore A. In this case, the lower durometer value may be attributable to inhibition of the silicone elastomer curing reaction as a result of irreversible covalent binding of the LNG molecules to the addition-cure silicone elastomer system (Murphy et al, 2016).…”

Matrix and reservoir-type multipurpose vaginal rings for controlled release of dapivirine and levonorgestrel

“…Various release media have been used for in vitro release testing of dapivirinereleasing rings during the past twelve years of development, including simulated vaginal fluid (SVF; a substantially aqueous, non-buffered medium), various buffer systems, aqueous media incorporating surfactant(s), and various organic solvent/water mixtures (Fetherston et al, 2013a(Fetherston et al, , 2013bMalcolm et al, 2005;R. Karl Malcolm et al, 2012;Murphy et al, 2016aMurphy et al, , 2016bMurphy et al, , 2014Woolfson et al, 2006). SVF is unquestionably the most physiologic medium here, but it affords very low in vitro release of dapivirine (in the order of low micrograms per day) even when relatively large volumes (> 100 mL) are used, due to the poor aqueous solubility of dapivirine.…”

“…Koetsawang et al, 1990aS. Koetsawang et al, , 1990bMishell et al, 1975;Murphy et al, 2016b). Recently, as part of continued efforts to develop a MPT vaginal ring offering simultaneous release of DPV and LNG, we reported on various formulation strategies to reduce the extent of LNG binding to addition cure silicone elastomer materials (Murphy et al, 2016b).…”

“…Koetsawang et al, , 1990bMishell et al, 1975;Murphy et al, 2016b). Recently, as part of continued efforts to develop a MPT vaginal ring offering simultaneous release of DPV and LNG, we reported on various formulation strategies to reduce the extent of LNG binding to addition cure silicone elastomer materials (Murphy et al, 2016b). Here, we report for the first time assessment of the preclinical feasibility of matrix-type and reservoir-type silicone elastomer vaginal rings offering continuous release of both DPV and LNG for at least 60 days and preferably at least 90 days in quantities anticipated to offer clinical effectiveness.…”

Pipeline for contraceptive development

“…Low dose LNG rings had been used previously in studies conducted by WHO and were shown to be effective in women who weighed less than 80 kg but had higher failure rates in higher weight women (43). The current design of the Dapivirine/LNG ring is to find a dose of LNG that will inhibit ovulation (44). Early phase clinical studies of the rings are ongoing.…”