Development and Evaluation of a Thermoreversible Ovule Formulation of Stampidine, a Novel Nonspermicidal Broad-Spectrum Anti-Human Immunodeficiency Virus Microbicide1
- 1 December 2003
- journal article
- Published by Oxford University Press (OUP) in Biology of Reproduction
- Vol. 69 (6) , 1843-1851
- https://doi.org/10.1095/biolreprod.103.019182
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 × 107- to 4 × 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.Keywords
This publication has 41 references indexed in Scilit:
- Potent dual anti-HIV and spermicidal activities of novel oxovanadium(V) complexes with thiourea non-nucleoside inhibitors of HIV-1 reverse transcriptasePublished by Elsevier ,2003
- Structural Requirements for Potent Anti-Human Immunodeficiency Virus (HIV) and Sperm-Immobilizing Activities of Cyclohexenyl Thiourea and Urea Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase1Biology of Reproduction, 2002
- Considerations and development of topical microbicides to inhibit the sexual transmission of HIVExpert Opinion on Investigational Drugs, 2002
- The global impact of HIV/AIDSNature, 2001
- Novel Thiourea Compounds as Dual-Function MicrobicidesBiology of Reproduction, 2000
- Novel Derivatives of Phenethyl-5-Bromopyridylthiourea and Dihydroalkoxybenzyloxopyrimidine Are Dual-Function Spermicides with Potent Anti-Human Immunodeficiency Virus ActivityBiology of Reproduction, 1999
- Synthesis, characterization and preclinical formulation of a dual-action phenyl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07) with potent anti-HIV and spermicidal activities.Molecular Human Reproduction, 1999
- WHI-05, a novel bromo-methoxy substituted phenyl phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activityContraception, 1999
- Aryl Phosphate Derivatives of Bromo-Methoxy-Azidothymidine Are Dual-Function Spermicides with Potent Anti-Human Immunodeficiency VirusBiology of Reproduction, 1998
- The Efficiency of Male-to Female and Female-to-Male Sexual Transmission of the Human Immunodeficiency VirusEpidemiology, 1994