Dual-responsive ionic liquid based foam-to-gel for precision vaginal delivery of progesterone

Vaginal progesterone administration represents the preferred route for luteal phase support in assisted reproductive technology due to the uterine first-pass effect. However, its therapeutic efficacy is limited by poor aqueous solubility and low transmucosal penetration. This study aimed to develop an ionic liquid-based foam-to-gel system (IL-FOAM) for enhanced vaginal delivery of progesterone. The IL-FOAM was formulated using choline oleate to improve drug solubility, propellants for foam formation, and Poloxamer 407 (P407) to enable temperature- and pH-responsive gelation. Key findings demonstrated that choline oleate increased progesterone solubility by 1031-fold. The IL-FOAM exhibited rapid foam expansion, uniform ejection, and complete foam-to-gel transition under vaginal physiological conditions. Using a 3D-printed vaginal model, the system achieved complete vaginal coverage within minutes and maintained gel retention for up to 24 h. Ex vivo studies revealed that the mucosal penetration ratio of IL-FOAM was approximately 3-fold higher than that of the commercial product Crinone®. In Sprague-Dawley rats, IL-FOAM demonstrated superior uterine targeting efficiency (85.96%) compared to intramuscular injection (5.43%), with favourable safety profiles in both in vitro and in vivo evaluations. In conclusion, the dual-responsive IL-FOAM offers a promising strategy for vaginal progesterone delivery with enhanced solubility, prolonged retention, and improved uterine targeting, providing new insights for luteal phase support in assisted reproductive technology. STATEMENT OF SIGNIFICANCE: Existing luteal support for Assisted Reproductive Technology (ART) is challenged by the poor solubility and retention of vaginal progesterone. We presented an ionic liquid-based foam-to-gel system (IL-FOAM) to address these limitations. This formulation strategy leverages ionic liquids to enhance drug solubility and permeation, while the foam mechanism ensures extensive distribution and prolonged retention. Our study demonstrates that IL-FOAM significantly improves uterine bioavailability, offering a potent and sustained therapeutic option that overcomes the drawbacks of current formulations for infertility treatment.