(T0930-11-74) Microbicide-Containing SMART Gel for Female-Controlled Multipurpose Prevention

Purpose: Global health statistics underscore that unintended pregnancy and a variety of sexually transmitted infections (STIs), including HIV, gonorrhea, chlamydia, and trichomoniasis, represent the primary sexual and reproductive health risks for women and adolescent girls. As awareness of the need to simultaneously address these interlinked risks has increased, innovative multipurpose prevention technologies (MPT) are being designed to deliver multifaceted reproductive health prevention, largely focused on contraception and prevention of STIs. The purpose of this research is to explore a novel, non-hormonal, microbicide-containing SMART (= System Mute until Activation by Remote Trigger) hydrogel design for future development as a female-controlled, on-demand MPT.

Methods: A SMART hydrogel containing 0.5% (w/v) metronidazole (MTZ) was fabricated using conventional sol-to-gel transformation. Viscoelastic and mucoadhesive properties of the MTZ-loaded SMART hydrogel 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. Buffer capacity in the presence of SFS was measured using a DeltaTrak ISFET pH probe. MTZ release from the microbicide-containing SMART hydrogel in VFS was quantified in vitro using a validate HPLC method. Compatibility of the MTZ-SMART gel with the human cervicovaginal homeostasis was assessed in vitro using quantitative release of the proinflammatory biomarker IL-1α from bioengineered human vaginal tissue colonized with Lactobacillus crispatus after a 24 hr gel exposure. Experiments were performed at least in triplicate and results compared to the marketed spermicidal VCF™ gel. A statistically significant difference (p < 0.05) between treatment groups was assessed utilizing a one-way analysis of variance or a two-sided Student’s t test for pairwise comparison.

Results: Upon interaction of the microbicide-containing SMART hydrogel with SFS, viscoelastic gel properties significantly increased, resulting in a 114% greater work of shear measured at a volumetric gel/fluid ratio of 1:1 (6.05±0.10 N×s vs. 3.62±0.10 N×s for gel only). The pH value of the gel phase measured under those conditions remained below pH 6.0. In comparison to the marketed spermicidal VCF™ gel, mucoadhesive properties of the MTZ-loaded SMART hydrogel were 15-fold greater (4.47±0.04 N×mm and 0.30±0.06 N×mm, respectively). Kinetic drug release measurements in VFS revealed the presence of MTZ concentrations after 60 s that were in excess of the minimum inhibitory concentration reported for this antibacterial drug after vaginal administration in vivo. IL-1α concentrations released from bioengineered human vaginal tissue colonized with Lactobacillus crispatus into the media after a 24 hr incubation period with the spermicidal VCF™ gel were >2.3 ng/mL. In contrast, media concentration of this proinflammatory cytokine following a 24 hr incubation with the MTZ-SMART gel was ~95-fold reduced (24.5±3.9 pg/mL), which was comparable to media control.

Conclusion: Increased viscoelastic properties of the metronidazole-containing SMART hydrogel design after exposure to alkaline seminal fluid, combined with its demonstrated buffer capacity, are predicted to significantly augment natural physical and chemical contraceptive barriers of the vaginal cavity. In addition, mucoadhesive properties exceeding those of the marketed spermicidal VCF™ gel product are positive indicators for favorable end-user adoption. Most importantly, the presence of predicted pharmacodynamically effective microbicide concentrations after 60 s and the promising vaginal safety profile measured in vitro suggest that this non-hormonal, microbicide-containing SMART hydrogel design meets critical MPT performance endpoints.

Acknowledgements: NIH Foundation, Bill & Melinda Gates Foundation