title: Development and evaluation of a thermoreversible ovule formulation of stampidine, a novel nonspermicidal broad-spectrum anti-human immunodeficiency virus microbicide.
abstract: Stampidine [2',3'-didehydro-2',3'-dideoxythymidine 5'-[p-bromophenyl methoxyalaninyl phosphate], a prodrug of stavudine (STV/d4T) with improved anti-HIV activity, is undergoing development as a novel nonspermicidal microbicide. Here, we report the stability of stampidine as a function of pH, preparation of a novel thermoreversible ovule formulation for mucosal delivery, its dissolution profile in synthetic vaginal fluid, and its mucosal toxicity potential as well as systemic absorption in the rabbit model. Stampidine was most stable under acidic conditions. Stampidine was solubilized in a thermoreversible ovule formulation composed of polyethylene glycol 400, polyethylene glycol fatty acid esters, and polysorbate 80. Does were exposed intravaginally for 14 days to an ovule formulation with and without 0.5%, 1%, or 2% stampidine corresponding to 1 x 107- to 4 x 107-fold higher than its in vitro anti-HIV IC50 value. Vaginal tissues harvested on Day 15 were evaluated for mucosal toxicity and cellular inflammation. Additionally, does were exposed intravaginally to stampidine, and plasma collected at various time points was assayed by analytical HPLC for the prodrug and its bioactive metabolites. Stampidine did not cause mucosal inflammation. The vaginal irritation scores for 0.5-2% stampidine were within the acceptable range for clinical trials. The prodrug and its major metabolites were undetectable in the blood plasma. The marked stability of stampidine at acidic pH, its rapid spreadability, together with its lack of mucosal toxicity or systemic absorption of stampidine via a thermoreversible ovule may provide the foundation for its clinical development as an easy-to-use, safe, and effective broad-spectrum anti-HIV microbicide without contraceptive activity.
authors.affiliation: Drug Discovery Program, Department of Reproductive Biology, Parker Hughes Institute, St. Paul, Minnesota 55113, USA. odcruz@ih.org
authors.forename: Osmond J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: Peter
authors.initials: P
authors.lastname: Samuel
authors.forename: Barbara
authors.initials: B
authors.lastname: Waurzyniak
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054306:Dideoxynucleotides; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D006678:HIV / Q000187:drug effects / Q000472:pathogenicity; D006863:Hydrogen-Ion Concentration; D006965:Hyperplasia; D007700:Kinetics; D011817:Rabbits; D012995:Solubility; D013089:Spermatocidal Agents / Q000494:pharmacology; D018119:Stavudine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014621:Vagina / Q000187:drug effects / Q000473:pathology / Q000821:virology; D014627:Vaginitis / Q000139:chemically induced / Q000473:pathology
chemical_list: D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D013089:Spermatocidal Agents; C472384:stampidine; D013938:Thymidine Monophosphate; D018119:Stavudine