Development of a mucoinert progesterone nanosuspension for safer and more effective prevention of preterm birth

Preterm birth (PTB) is a significant global problem, but few therapeutic options exist. Vaginal progesterone supplementation has been demonstrated to reduce PTB rates in women with a sonographic short cervix, yet there has been little investigation into the most effective dose or delivery form. Further, vaginal products like progesterone gel often contain excipients that cause local toxicity, irritation, and leakage. Here, we describe the development and characterization of a mucoinert vaginal progesterone nanosuspension formulation for improved drug delivery to the female reproductive tract. We compare the pharmacokinetics and pharmacodynamics to the clinical comparator progesterone gel in pregnant mice and demonstrate increased vaginal absorption and biodistribution via the uterine first-pass effect. Importantly, the unique plasma progesterone double peak observed in humans, reflecting recirculation from the uterus, was also observed in pregnant mice with vaginal dosing. We adapted a mouse model of progesterone withdrawal that was previously believed to be incompatible with testing the efficacy of exogenous progestins, and are first to demonstrate efficacy in preventing preterm birth with vaginal progesterone in this model. Further, improved vaginal progesterone delivery by the nanosuspension led to increased efficacy in PTB prevention. Additionally, we identified histological and transcriptional evidence of cervical and uterine toxicity with a single vaginal administration of the clinical gel that are absent after dosing with the mucoinert nanosuspension formulation. We demonstrate that a progesterone formulation that is designed for improved vaginal progesterone absorption and vaginal biocompatibility could be more effective for PTB prevention.