(T0930-07-46) Biodegradable, Hormone-Free Thermoresponsive Vaginal Gels for On-Demand Contraception Using Low-pH Block Copolymer Systems

Purpose: Despite longstanding demand, innovation in female contraceptive technology remains limited.¹ Most current options rely on systemic hormonal regulation, often accompanied by undesirable side effects such as mood disturbances, metabolic changes², and gastrointestinal discomfort.³ This highlights a critical need for alternative, woman-controlled, non-hormonal contraceptive modalities that are safe, effective, and suitable for as-needed use. Existing vaginal drug delivery forms—gels, creams, and aerosols face challenges such as insufficient mucosal penetration and rapid expulsion due to natural clearance mechanisms. We report on a novel platform of biodegradable, hormone-free, low-pH reverse thermo-responsive gels designed to overcome key limitations of current vaginal contraceptive formulations. These formulations consist of a reverse thermo-responsive block copolymer gelator which in solution has low pH. At room temperature, the formulations exist in a sol state, allowing for facile intravaginal administration and thorough dispersion into the vaginal rugae. Upon contact with body temperature, the sol undergoes a phase transition into a gel, promoting prolonged mucosal retention and sustained local acidification. In addition, with time, the gelators would degrade to lactic acid which helps maintain a low pH and therefore acts as a natural spermicide. By maintaining the vaginal pH within the spermicidal range of 3.5–5.0, the lactic acid-enriched gel creates an inhospitable environment for sperm, supporting effective, non-hormonal, on-demand contraception.

Methods: Two series of biodegradable, reverse thermos-responsive gel formulations were prepared using amphiphilic block copolymers: Poly(lactide-co-caprolactone)-b-Poly(ethylene glycol)-b-Poly(lactide-co-caprolactone) (VG1) and Methoxy Poly(ethylene glycol)-b-Poly(caprolactone) (VG2). These polymers were dissolved in water under cold conditions with gentle shaking in a mechanical shaker until a clear solution was achieved. Final polymer concentrations were optimized to ensure solutions could be prepared in a short time (overnight) and that sol-to-gel transitions took place at physiological temperatures. To characterize gelation behavior, the sol form of each composition was transferred to screw-cap vials and gradually heated in a water bath. The vials were inverted at every 1 °C increment, and the gelation temperature was recorded as the point at which the sol ceased to flow and adhered to the bottom of the inverted vial. Erosion studies were conducted by allowing ~2 g of the sol to gel in vials at 37 °C for 10 minutes. Simulated vaginal fluid (SVF, pH 4.2, 10 mL) pre-equilibrated to 37 °C was gently layered over the gel surface. The vials were placed in a thermostatic shaker (37 °C, 100 rpm), and at designated intervals, the medium was removed, the vial surface was dried, and the remaining gel weight was recorded. The medium was replaced with fresh, pre-warmed SVF after a 10-minute equilibration period. This cycle was repeated until the gel fully eroded. Data was collected in triplicate to evaluate gel integrity and erosion kinetics.

Results: Both formulations exhibited sharp sol-to-gel transitions. The gelling temperature of the VG1 and VG2 compositions were 37.5 °C and 37.8 °C respectively which is close to human body temperature. Sols of both the polymers of VG1 and VG2 sols were acidic having a pH of 3.8 and 3.65 respectively (Table 1.) Both gels returned back to their sol forms in about 2 minutes at room temperature. Figure 1 shows sol to gel transition of a representative vaginal gel of VG2 polymer. Figure 2 shows erosion of a representative thermos-responsive gel, VG2 in simulated vaginal fluid. After 7 days at 37 °C, >20% of the gel was still intact. Erosion of the hydrogel slowed down as time progressed. Erosion results indicate that a substantial portion of the polymer remains for an extended period of time thereby maintaining an acidic environment for extended periods.

Conclusion: The in-vitro data of thermo-reversible gels were very encouraging as potential vaginal gels (VGs). The formulations of the two vaginal gels were acidic (~pH 3.6) sols at room temperature and formed gels at body temperatures. Both VGs thereby create an acidic and unfavorable environment for sperm. Both gels also demonstrated extended erosion times. Erosion testing revealed that hydrogels formed from VG1 and VG2 copolymers had prolonged residence time in SVF, attributed to slower degradation of the lactide-caprolactone backbone. Across all systems, sustained pH maintenance within the spermicidal range (3.5–5.0) was observed throughout the erosion duration. The ability to modulate gel erosion through polymer structure provided a tunable approach to balance retention with clearance. This study demonstrates the feasibility of using biodegradable block copolymers to formulate thermos-responsive, low-pH vaginal gels capable of forming stable in situ depots upon administration. These gels show promise as non-hormonal, user-controlled contraceptives, addressing both biological and practical limitations of existing delivery technologies. Further optimization and in vivo validation are ongoing.

References: 1. “Better Birth Control Could Exist, But It Wouldn’t Pay for Big Pharma,” Naomi Kresge and Cynthia Koons, Bloomberg Businessweek, August 8, 2019.
2. Association of hormonal contraceptive use with adverse health outcomes: an umbrella review of meta-analyses of randomized clinical trials and cohort studies. JAMA Netw Open. 2022;5(1). Brabaharan S.; Veettil SK.; Kaiser JE.; Osman M.; Langan SM.; Prasad V.; Siemieniuk RA.; Thorlund K.; Agoritsas T.; Guyatt GH.; Mustafa RA.
3 . Four Decades of research on Hormonal Contraception. Perm J. 2005 Winter; 9 (1): 29-34. Petitti, D. B.; Sidney, S.

Acknowledgements: I thank Dr. Sangita Ghosh for advice and Dr. Ravi Mahalingam for providing laboratory space


Table 1. Properties of Vaginal Gels VG1 and VG2 Prepared from Poly(lactide-co-caprolactone)-b-Poly(ethylene glycol)-b-Poly(lactide-co-caprolactone) (VG1) and Methoxy Poly(ethylene glycol)-b-Poly(caprolactone) (VG2)


Figure 1. Vaginal Reverse Thermal Gel with Methoxy Poly(ethylene glycol)-b-Poly(caprolactone) copolymers (VG2): before and after 37 degree C


Figure 2. Erosion of VG2 Polymeric Thermo-responsive Gel in Simulated Vaginal Fluid