Evaluation of the Factors Contributing to Levonorgestrel Binding in Addition Cure Silicone Elastomer Vaginal Rings

Karl Malcolm, Diarmaid Murphy, Clare McCoy, Peter Boyd, Sandeep Kumar, Susan Fetherston, Andrew Brimer, Jonathon Holt, Wendy Blanda, Brid Devlin, Jeremy Nuttall, Chris Gilmour, Tiffany Derrick

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Abstract

Background: Following progress of the dapivirine (DPV)-releasing silicone elastomer (SE) vaginal ring (VR) into Phase III clinical studies, there is now interest in developing next-generation rings that additionally provide contraception. Levonorgestrel (LNG) is a safe and effective progestin that is being widely considered for use as a hormonal contraceptive agent in future multipurpose prevention technology (MPT) products. Although LNG has previously been incorporated into various controlled release SE devices, minimal attention has focused on its propensity to irreversibly react with addition cure SE systems. Here, for the first time, we investigate this LNG binding phenomenon and outline strategies for overcoming it.
Methods: VRs containing various loadings of DPV and LNG were manufactured and in vitro release assessed. Different LNG-only SE samples were also prepared to assess the following parameters: (i) addition cure vs. condensation cure SEs; (ii) different types of addition cure SEs; (iii) mixing time, (iv) cure temperature, (v) cure time; and (vi) LNG particle size. After manufacture, the LNG-only samples were assayed for total drug content using a solvent extraction method. The SE curing reaction and the LNG binding reaction was probed using nuclear magnetic resonance (NMR) spectroscopy. Results:
Under certain drug/formulation/processing conditions, LNG was not recoverable from VRs. Further studies using non-ring samples showed that: (a) the phenomenon was only observed with addition cure SEs (and not condensation cure SEs); (b) the extent of binding was dependent upon the type of addition cure SE; (c) micronised LNG showed significantly greater binding than non-micronised LNG; (d) the extent of binding correlated with increased mixing time, cure time and cure temperature.
Conclusions: Careful control of the API characteristics, the SE composition, and the manufacturing conditions will be necessary to establish a practical VR formulation for controlled release of LNG.
Original languageEnglish
Publication statusPublished - 29 Oct 2014
EventHIV R4P - HIV Research for Prevention - Cape Town, South Africa
Duration: 28 Oct 201431 Oct 2014
http://hivr4p.org/

Conference

ConferenceHIV R4P - HIV Research for Prevention
CountrySouth Africa
CityCape Town
Period28/10/201431/10/2014
Internet address

Keywords

  • vaginal ring
  • MPT
  • silicone elastomer
  • levonorgestrel

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    Malcolm, K., Murphy, D., McCoy, C., Boyd, P., Kumar, S., Fetherston, S., Brimer, A., Holt, J., Blanda, W., Devlin, B., Nuttall, J., Gilmour, C., & Derrick, T. (2014). Evaluation of the Factors Contributing to Levonorgestrel Binding in Addition Cure Silicone Elastomer Vaginal Rings. Poster session presented at HIV R4P - HIV Research for Prevention, Cape Town, South Africa. http://hivr4p.org/program/posters/posters-theme