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®), 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.
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Forbes
authors.forename: Deborah
authors.initials: D
authors.lastname: Lowry
authors.forename: Leslie
authors.initials: L
authors.lastname: Geer
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Mark
authors.initials: M
authors.lastname: Mitchnick
authors.forename: Laurie
authors.initials: L
authors.lastname: Goldman
authors.forename: Lara A
authors.initials: LA
authors.lastname: Doyle
authors.forename: Brendan C O
authors.initials: BC
authors.lastname: Muldoon
authors.forename: A David
authors.initials: AD
authors.lastname: Woolfson
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: R Karl
authors.initials: RK
authors.lastname: Malcolm
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D003510:Cyclohexanes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000737:chemistry; D005260:Female; D005782:Gels / Q000737:chemistry; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D000077592:Maraviroc; D012826:Silicone Elastomers / Q000737:chemistry*; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014621:Vagina / Q000187:drug effects / Q000378:metabolism*; D014622:Vaginal Creams, Foams, and Jellies / Q000737:chemistry*
chemical_list: D003510:Cyclohexanes; D003692:Delayed-Action Preparations; D005782:Gels; D023581:HIV Fusion Inhibitors; D012826:Silicone Elastomers; D014230:Triazoles; D014622:Vaginal Creams, Foams, and Jellies; D000077592:Maraviroc