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 Johan 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

    40 Citations (Scopus)

    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.
    LanguageEnglish
    Pages161-169
    JournalJournal of Controlled Release
    Volume156
    Issue number2
    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

    Keywords

    • Vaginal HIV microbicide
    • Silicone elastomer gel
    • Sustained release
    • Macaque pharmacokinetics
    • Slug mucosal irritation
    • Rheology

    Cite this

    Forbes, Claire J. ; Lowry, Deborah ; Geer, Leslie ; Veazey, Ronald S. ; Shattock, Robin J. ; Klasse, Per Johan ; 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.
    @article{3f1c1d624aab4823bda81e10a9c9a1aa,
    title = "Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc",
    abstract = "Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol{\circledR}), 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.",
    keywords = "Vaginal HIV microbicide, Silicone elastomer gel, Sustained release, Macaque pharmacokinetics, Slug mucosal irritation, Rheology",
    author = "Forbes, {Claire J.} and Deborah Lowry and Leslie Geer and Veazey, {Ronald S.} and Shattock, {Robin J.} and Klasse, {Per Johan} and Mark Mitchnick and Laurie Goldman and Doyle, {Lara A.} and Muldoon, {Brendan C.O.} and Woolfson, {A. David} and Moore, {John P.} and Malcolm, {R. Karl}",
    year = "2011",
    month = "12",
    day = "10",
    doi = "10.1016/j.jconrel.2011.08.006",
    language = "English",
    volume = "156",
    pages = "161--169",
    journal = "Journal of Controlled Release",
    issn = "0168-3659",
    publisher = "Elsevier",
    number = "2",

    }

    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 Johan; 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

    TY - JOUR

    T1 - Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

    AU - Forbes, Claire J.

    AU - Lowry, Deborah

    AU - Geer, Leslie

    AU - Veazey, Ronald S.

    AU - Shattock, Robin J.

    AU - Klasse, Per Johan

    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

    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.

    AB - 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.

    KW - Vaginal HIV microbicide

    KW - Silicone elastomer gel

    KW - Sustained release

    KW - Macaque pharmacokinetics

    KW - Slug mucosal irritation

    KW - Rheology

    U2 - 10.1016/j.jconrel.2011.08.006

    DO - 10.1016/j.jconrel.2011.08.006

    M3 - Article

    VL - 156

    SP - 161

    EP - 169

    JO - Journal of Controlled Release

    T2 - Journal of Controlled Release

    JF - Journal of Controlled Release

    SN - 0168-3659

    IS - 2

    ER -