Date of Award
2024
Document Type
Dissertation
Degree Name
Philosophy (Ph.D)
Department
Pharmaceutical Sciences
First Advisor
Ketankumar Patel
Second Advisor
Sandra E Reznik
Third Advisor
Abu T.M. Serajuddin
Abstract
Annually, preterm birth (PTB) affects fifteen million infants, posing a significant risk of infant mortality and lifelong disability. Among various triggers, it is well-established that infection-associated oxidative stress and inflammation can induce preterm labor. There is no FDA approved medication for the prevention of PTB except tocolytics which provide marginal benefit at a later stage. Scarcity of therapeutic intervention and unmet medical need propelled us in investigating a novel drug molecule. Our current research is focused on investigating the potential of Edaravone (EDA), an FDA-approved antioxidant and anti-inflammatory medication, in delaying preterm labor and improving neonatal outcomes. Our goal is to develop and optimize a translational parenteral dosage form – an injectable nanosuspension of EDA (EDA-NS) for in vivo evaluation. EDA-NS formulation is developed through a dual centrifugation nano-milling process. During its preparation, we evaluated various stabilizers, including bovine serum albumin (BSA), lecithin, poloxamer-407, and hyaluronic acid, both individually and in combinations. Notably, formulations stabilized with hyaluronic acid and poloxamer-407 exhibited phase separation, while stable nanoformulations were prepared using BSA, either alone or in combination with lecithin. To enhance the EDA stability, we explored freeze-drying method. The final EDA-NS formulation, stabilized with 10% BSA, demonstrated a particle size of 253.2±8.9 nm. Furthermore, the release profile indicated controlled drug release, with approximately 44.7 ± 4.5% released within 24-hour period via Fickian diffusion. The formulation exhibited acceptable injectability and remained stable when stored under refrigerated and room temperature conditions for at least one month. In vitro studies on trophoblast cells or macrophages revealed that the formulation effectively reduced levels of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and NF-κB and increased iκBα levels, all while maintaining cell viability. These findings suggest that the formulation is efficacious as well as safe. In vivo experiments, using LPS-induced preterm labor model in timed pregnant CD1 mice, demonstrated delayed labor, improved pup weight, enhanced organ differentiation, and favorable morphological features. Collectively, our research highlights the effectiveness of subcutaneous EDA-NS in preventing LPS-induced preterm labor in vivo. Further, in vivo investigations with higher doses are warranted to optimize the dose.
Recommended Citation
Sarvepalli, Sruthi, "ROLE OF EDARAVONE NANOSUSPENSION IN PRETERM LABOR AND BIRTH OUTCOMES" (2024). Theses and Dissertations. 715.
https://scholar.stjohns.edu/theses_dissertations/715