title: Modified silicone elastomer vaginal gels for sustained release of antiretroviral HIV microbicides.
abstract: We previously reported nonaqueous silicone elastomer gels (SEGs) for sustained vaginal administration of the CCR5-targeted entry inhibitor maraviroc (MVC). Here, we describe chemically modified SEGs (h-SEGs) in which the hydrophobic cyclomethicone component was partially replaced with relatively hydrophilic silanol-terminated polydimethylsiloxanes (st-PDMS). MVC and emtricitabine (a nucleoside reverse transcriptase inhibitor), both currently under evaluation as topical microbicides to counter sexual transmission of human immunodeficiency virus type 1 (HIV-1), were used as model antiretroviral (ARV) drugs. Gel viscosity and in vitro ARV release were significantly influenced by st-PDMS molecular weight and concentration in the h-SEGs. Unexpectedly, gels prepared with lower molecular weight grades of st-PDMS showed higher viscosities. h-SEGs provided enhanced release over 24 h compared with aqueous hydroxyethylcellulose (HEC) gels, did not modify the pH of simulated vaginal fluid (SVF), and were shown to less cytotoxic than standard HEC vaginal gel. ARV solubility increased as st-PDMS molecular weight decreased (i.e., as percentage hydroxyl content increased), helping to explain the in vitro release trends. Dye ingression and SVF dilution studies confirmed the increased hydrophilicity of the h-SEGs. h-SEGs have potential for use in vaginal drug delivery, particularly for ARV-based HIV-1 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: Clare F
authors.initials: CF
authors.lastname: McCoy
authors.forename: Diarmaid J
authors.initials: DJ
authors.lastname: Murphy
authors.forename: A David
authors.initials: AD
authors.lastname: Woolfson
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Abbey
authors.initials: A
authors.lastname: Evans
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
authors.forename: R Karl
authors.initials: RK
authors.lastname: Malcolm
mesh_terms: D000282:Administration, Intravaginal; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage / Q000737:chemistry*; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000737:chemistry*; D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D003510:Cyclohexanes / Q000008:administration & dosage / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry*; D005260:Female; D005782:Gels / Q000008:administration & dosage / Q000737:chemistry*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D000077592:Maraviroc; D012826:Silicone Elastomers / Q000008:administration & dosage / Q000737:chemistry*; D014230:Triazoles / Q000008:administration & dosage / Q000737:chemistry; D014621:Vagina / Q000187:drug effects; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000891:Anti-Infective Agents, Local; D044966:Anti-Retroviral Agents; D003510:Cyclohexanes; D003692:Delayed-Action Preparations; D005782:Gels; D012826:Silicone Elastomers; D014230:Triazoles; D014622:Vaginal Creams, Foams, and Jellies; D002482:Cellulose; C002283:hydroxyethylcellulose; D000077592:Maraviroc
keywords: HIV/AIDS; HIVmicrobicides; antiinfectives; drug delivery systems; formulation; gels; rheology; silicone elastomer; sustained release; viscosity