(M0930-11-72) Drug-Free Bioresponsive Hydrogel for On-Demand Contraception

Purpose: The incidence of unintended pregnancies in the United States is the highest among Western industrialized countries. As current contraceptive methods do not appear to deliver the desired impact and/or gender norms limit women’s ability to access/use existing preventive tools, the challenge of the future is to develop innovative, women-controlled contraceptive technologies that are affordable and socially acceptable. Nonsteroidal contraceptive products generally offer the benefit of fewer side effects and the convenience of adapting the use of these women-initiated prevention technologies to the changes that occur over a woman’s reproductive life (i.e., on-demand contraception). The purpose of this research is to explore an innovative drug-free bioengineering concept that maintains a physiologically protective vaginal environment upon exposure to semen, thereby resulting in contraceptive efficacy.

Methods: Hydration of equivalent amounts of Carbopol 974P (CP) and polyvinylpyrrolidone (PVP) resulted in a 4% (w/w) hydrogel that was used for this study. Viscoelastic and mucoadhesive gel properties in the presence and absence of vaginal fluid simulant, pH 4.2 (VFS), and/or seminal fluid simulant, pH 7.7 (SFS) were quantified using the TA-XT Plus Texture Analyzer. In parallel, buffer capacity of the gel phase was measured using a DeltaTrak® ISFET pH probe. Migration rate and motility of human sperm before and after interaction with the CP/PVP hydrogel were used as in vitro contraceptive efficacy endpoints. Experiments were performed at least in triplicate. To assess safety and contraceptive efficacy of this drug-free hydrogel in vivo, gross pathology and pregnancy rate of female New Zealand rabbits (n=10 per treatment group) after artificial insemination were compared in the presence and absence of a vaginal 2 mL dose of the CP/PVPV gel. The spermicidal VCF® gel was used as positive control. A statistically significant difference (p < 0.05) between treatment groups was assessed by one-way analysis of variance or two-sided Student’s t test for pairwise comparison.

Results: Upon exposure to alkaline SFS, viscoelastic properties of the CP/PVP hydrogel sharply increased resulting in a 68% greater work of shear measured at a volumetric gel/fluid ratio of 1:1 (5.11±0.25 N×s vs. 3.05±0.01 N×s for gel only). Further addition of SFS appeared to dilute the gel structure, which was quantified by the continuous reduction in the work of shear from 5.11±0.25 N×s to 3.85±0.21 N×s at a volumetric gel/fluid ratio of 1:4. The pH value of the gel phase measured under those conditions increased from pH 3.6 to 5.6. In comparison to the marketed spermicidal VCF® gel, mucoadhesive properties of the CP/PVP gel phase were ~4.5-fold greater (5.80±0.17 N×mm vs. 1.30±0.22 N×mm, respectively). The number of human sperm capable of traversing a CP/PVP gel barrier was significantly reduced by 73%. More importantly, the motility of sperm cells that were able to overcome the CP/PVP gel barrier was < 20%. Intravaginal application of the CP/PVP hydrogel formulation in female rabbits did not affect mortality and only resulted in transient clinical observations. In comparison to sham-treated animals, a 2 mL dose of the CP/PVP gel reduced in vivo pregnancy rate to 0%, while the same dose of the marketed spermicidal VCF® gel resulted in a pregnancy rate of 22%.

Conclusion: The non-hormonal CP/PVP hydrogel demonstrates bioresponsive properties after exposure to alkaline seminal fluid, which significantly augments natural physical and chemical contraceptive barriers of the vaginal cavity. As a consequence, sperm movement is severely restricted resulting in contraceptive efficacy in vitro and in vivo. The promising results from preliminary safety assessments in the rabbit model support further development of this innovative bioengineering concept as a drug-free, women-controlled on-demand contraceptive.

Acknowledgements: NIH and Bill & Melinda Gates Foundation