Development and Preclinical Investigation of Physically Cross-Linked and pH-Sensitive Polymeric Gels as Potential Vaginal Contraceptives

This study explored the development of cross-linked gels to potentially provide a physical barrier to vaginal sperm transport for contraception. Two types of gels were formulated, a physically cross-linked iota-carrageenan (C(i)) phenylboronic acid functionalized hydroxylpropylmethyacrylate copolymer (PBA)-based (C(i)-PBA) gel, designed to block vaginal sperm transport. The second gel was pH-shifting cross-linked C(i)-polyvinyl alcohol-boric acid (C(i)-PVA-BA) gel, designed to modulate its properties in forming a viscoelastic, weakly cross-linked transient network (due to C(i) gelling properties) on vaginal application (at acidic pH of ~3.5–4.5) to a more elastic, densely cross-linked (due to borate-diol cross-linking) gel network at basic pH of 7–8 of seminal fluid, thereby acting as a physical barrier to motile sperm. The gels were characterized for dynamic rheology, physicochemical properties, and impact on sperm functionality (motility, viability, penetration). The rheology data confirmed that the C(i)-PBA gel was formed by ionic interactions whereas C(i)-PVA-BA gel was chemically cross-linked and became more elastic at basic pH. Based on the screening data, lead gels were selected for in vitro sperm functionality testing. The in vitro results confirmed that the C(i)-PBA and C(i)-PVA-BA gels created a barrier at the sperm-gel interface, providing sperm blocking properties. For preclinical proof-of-concept, the C(i)-PBA gels were applied vaginally and tested for contraceptive efficacy in rabbits, demonstrating only partial efficacy (40–60%). Overall, the in vitro and in vivo results support the development and further optimization of cross-linked gels using commercially available materials as vaginal contraceptives.