Abstract
The objective of this study was to develop a nontoxic and noncontraceptive vaginal drug delivery vehicle for lipophilic anti-human immunodeficiency virus (HIV) microbicides. Three representative poorly water-soluble novel broad-spectrum anti-HIV microbicides, PHI-113, PHI-346, and PHI-443, were evaluated in 11 different solvent systems. Based on their solubility profiles, a novel nonspermicidal self-emulsifying gel (viz Conceival) composed of pharmaceutical excipients, sorbitol, polyethylene glycol 400, polysorbate 80, microcrystalline cellulose, xanthan gum, and water was optimized. Conceival enhanced the solubility of these poorly water-soluble (<0.001 mg/mL) anti-HIV drugs by at least 150- to 270-fold. Conceival was evaluated in vivo in the New Zealand white rabbit model for the preservation of sperm function based on pregnancy outcome and the potential for vaginal irritation following single and multiple intravaginal applications, respectively. Conceival administered intravaginally immediately prior to artificial insemination with semen had no adverse effects on subsequent reproductive performance, neonatal survival, or pup development when compared with untreated control group. Histologic evaluation of vaginal tissues of rabbits exposed intravaginally to Conceival for 14 consecutive days revealed lack of epithelial, submucosal, and vascular changes at the gel application site (total irritation score <3 out of a possible 16). These findings indicate that Conceival has potential to become a clinically useful, safe noncontraceptive vaginal vehicle for lipophilic microbicides.
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