(T1030-10-55) Development of Vaginal Thermosensitive Hydrogel for Enhanced Local Progesterone Delivery

Purpose: Progesterone (P4) plays a crucial role in maintaining normal female physiological functions and has a wide range of therapeutic applications, including the prevention of preterm birth, treatment of infertility caused by inadequate luteal phase, and hormone replacement therapy for menopausal individuals. The increasing prevalence of infertility in recent years has highlighted the need for improved P4 formulations. Currently, the main P4 products in clinical use are oral capsules, such as Prometrium^®, and vaginal gels, such as Crinone^®. Clinical trials have demonstrated the limitations of oral route compared to vaginal administration for uterine P4 supplementation. However, the available progesterone vaginal products, such as Endometrin^® and Crinone^®, have been on the market for more than 15 years and share similar drawbacks, including poor patient compliance, local discomfort, and messiness after dosing. These challenges necessitate the development of a new formulation that can achieve enhanced mucus penetration, longer dosing intervals, and improved bioadhesion. The primary objective of this research is to develop an innovative vaginal delivery platform for progesterone and establish a series of characterization methods to ensure product quality control.

Methods: To deliver P4 with poor water solubility, we applied high pressure homogenize and probe sonication and nanoprecipitation to reduce the P4 particle size. Besides, forming a P4-cyclodextrin complex or liposome can also be a good strategy to solubilize the P4. Chitosan and Pluronic F127 have been widely used for formulation of thermosensitive hydrogels and we verified their effectiveness in vaginal delivery. A Franz cell release test was performed to test the permeability and release profile at 37 ℃. The gelation temperature and time were determined by the TA instrument HR2 Rheometer in oscillation mode. The bio adhesion was measured by Brookfield CT3 texture analyzer in compression mode.

Results: Progesterone suspension, liposome, cyclodextrin complex were made and quantified. It shows that F127 gel can achieve a sustained release of about 20% of P4 after 24 hours while the free P4/CD released 80% of it within a short time (Figure.1A). However, the P4 liposome in F127 gel can no longer maintain its sustained release (Figure.1B). Although F127 based formulation became more adhesive at 40 ℃ after its transition into gel form (Fig 2 A, B), all current in-house formulation is less adhesive than the commercial long-lasting vaginal gel Replens^® (Fig 2 C, D).The rheology test shows current F127 formulation has a relatively low T_gel around 25 ℃ (Fig 3 A, B) and chitosan gel shows a high T_gel over 40 ℃ (Fig 3 C). And these two gels show different rheological behavior during the sol-gel transition process.

Conclusion: Characterization methods for vaginal gel were established and tested for different bench made samples and Crinone^®. Our new progesterone hydrogel can achieve local controlled release with good bioadhesion, which is also a very promising vaginal delivery platform for other poorly soluble hormone or antifungal drug.