Development and Characterization of Effective Vaginal Tocolytic Nanoformulations for Prevention of Preterm Birth

Worldwide, over 15 million babies are born prematurely each year. Preterm birth (PTB) is the leading cause of morbidity and mortality in children under the age of 5. In addition to the health consequences of PTB, there are significant economic costs. In the US alone, it was estimated that at least 26 billion dollars was spent on healthcare for preterm infants and children each year. To solve the problem, progesterone and several tocolytics have been tested for the prevention of preterm birth. Systemic drug administration has several disadvantages including low concentration in target tissues and off-target side effects. For this reason, vaginal drug delivery has more potential since it could target directly to the female reproduce tract. Also, vaginal administrated therapies could take advantage of the uterine first pass effect which allow higher medicine uptake. Crinone® is a vaginally administered progesterone gel used off-label for the prevention of PTB. However, its lack of efficacy across heterogeneous populations has prevented the product from gaining FDA approval. We have previously shown that this lack of efficacy may be due to the formulation characteristics of Crinone® that make it non-ideal for vaginal delivery. The product is micronized and delivered in a hypertonic formulation. Our group has previously shown that the cervicovaginal mucus (CVM) barrier sterically and adhesively traps particles, preventing them from effectively delivering drug. Additionally, hypertonic formulations have been shown to cause tissue damage. In our previous studies, we developed a progesterone nanosuspension for safer and more effective treatment of PTB. With the experience, in this study, the tocolytics (Nifedipine and Indomethacin) were formulated into nanosuspensions too. We tested the biocompatibility of these nanosuspensions with CVM, as well as several other commonly used excipients in vaginal formulations. We demonstrated that F127, a triblock copolymer that is thought to be biocompatible material and has been increasingly used in the nanodrug delivery field, had no negative effect on vaginal microbiota remain. However, the vaginal administered product Crinone® had a negative effect on the vaginal microbiota. We additionally conducted a study to investigate gene expression changes based on oral or vaginal drug administration. The tocolytics (Nifedipine and Indomethacin) nanosuspension was shown to be potentially safer and more effective, however, more studies are needed. Finally, we developed a method for measuring ex vivo uterine contractions that could test the effectiveness in the treatment of preterm birth for various nanomedicines in our lab