Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

Claire J. Forbes, Deborah Lowry, Leslie Geer, Ronald S. Veazey, Robin J. Shattock, Per J. Klasse, Mark Mitchnick, Laurie Goldman, Lara A Doyle, Brendan C.O. Muldoon, A. David Woolfson, John P. Moore, R. Karl Malcolm

Research output: Contribution to journalArticle

Abstract

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.
Original languageEnglish
Pages (from-to)161-169
Number of pages9
JournalJournal of Controlled Release
Volume156
Issue number2
Early online date12 Aug 2011
DOIs
Publication statusPublished - 10 Dec 2011

Fingerprint

HIV Fusion Inhibitors
Silicone Gels
Silicone Elastomers
Anti-Infective Agents
HIV-1
Gels
carbopol 940
Intravaginal Administration
HIV
Gastropoda
Water
Macaca mulatta
Solubility
Pharmacokinetics
maraviroc
Pharmaceutical Preparations
hydroxyethylcellulose

Bibliographical note

© 2011, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

Keywords

  • intravaginal administration
  • animals
  • cyclohexanes
  • delayed-action preparations
  • female
  • gels
  • HIV fusion inhibitors
  • HIV infections
  • HIV-1
  • humans
  • macaca mulatta
  • silicone elastomers
  • triazoles
  • vagina
  • vaginal creams
  • foams
  • jellies

Cite this

Forbes, C. J., Lowry, D., Geer, L., Veazey, R. S., Shattock, R. J., Klasse, P. J., ... Malcolm, R. K. (2011). Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc. Journal of Controlled Release, 156(2), 161-169. https://doi.org/10.1016/j.jconrel.2011.08.006
Forbes, Claire J. ; Lowry, Deborah ; Geer, Leslie ; Veazey, Ronald S. ; Shattock, Robin J. ; Klasse, Per J. ; Mitchnick, Mark ; Goldman, Laurie ; Doyle, Lara A ; Muldoon, Brendan C.O. ; Woolfson, A. David ; Moore, John P. ; Malcolm, R. Karl. / Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc. In: Journal of Controlled Release. 2011 ; Vol. 156, No. 2. pp. 161-169.
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Forbes, CJ, Lowry, D, Geer, L, Veazey, RS, Shattock, RJ, Klasse, PJ, Mitchnick, M, Goldman, L, Doyle, LA, Muldoon, BCO, Woolfson, AD, Moore, JP & Malcolm, RK 2011, 'Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc', Journal of Controlled Release, vol. 156, no. 2, pp. 161-169. https://doi.org/10.1016/j.jconrel.2011.08.006

Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc. / Forbes, Claire J.; Lowry, Deborah; Geer, Leslie; Veazey, Ronald S.; Shattock, Robin J.; Klasse, Per J.; Mitchnick, Mark; Goldman, Laurie; Doyle, Lara A; Muldoon, Brendan C.O.; Woolfson, A. David; Moore, John P.; Malcolm, R. Karl.

In: Journal of Controlled Release, Vol. 156, No. 2, 10.12.2011, p. 161-169.

Research output: Contribution to journalArticle

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AU - Forbes, Claire J.

AU - Lowry, Deborah

AU - Geer, Leslie

AU - Veazey, Ronald S.

AU - Shattock, Robin J.

AU - Klasse, Per J.

AU - Mitchnick, Mark

AU - Goldman, Laurie

AU - Doyle, Lara A

AU - Muldoon, Brendan C.O.

AU - Woolfson, A. David

AU - Moore, John P.

AU - Malcolm, R. Karl

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PY - 2011/12/10

Y1 - 2011/12/10

N2 - Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

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