Engineering of Drug Formulations for the Prevention of Pre-Term Birth
- Type: Conference Presentation
- Conference Type: AIChE Annual Meeting
- Presentation Date: November 10, 2021
- Duration: 18 minutes
- Skill Level: Intermediate
- PDHs: 0.50
The vaginal route of drug administration results in more targeted local delivery to the cervix and uterus, reduces systemic side effects compared to intravenous or oral delivery, and requires less drug for an efficacious outcome . Vaginal drug administration is optimal for delivering drug to the female reproductive tract for a variety of womenâs health indications, including the prevention of preterm birth (PTB). Currently, the only approved therapy for the prevention of PTB is Makena, an intramuscular injection of 17-hydroxyprogesterone caproate . Recently, the FDAâs Center for Drug Evaluation and Research called for Makenaâs approved status to be revoked , meaning that new treatments are desperately needed. However, many vaginal products are not designed to overcome the cervicovaginal mucus (CVM) and tissue barriers for effective drug delivery to the reproductive tract . Here, we describe the formulation of mucoinert drug nanosuspensions via wet nanomilling for more effective drug delivery to the reproductive tract to prevent PTB. A selective progesterone receptor modulator (SPRM) was formulated for testing in an in vitro human myometrial cell assay to characterize effect on reducing contractility.
Drug nanosuspensions were formulated via wet nanomilling, during which drug was milled with a Pluronic block polymers to provide a mucoinert surface coating and particle stabilization. The zeta potential and size of the particles were characterized using a Zetasizer Nano. PHM1-41 human immortalized myometrial cells were embedded into a collagen matrix in a 24-well plate. Various concentrations of drug combinations were suspended in fetal bovine serum (FBS)-free media, then added on top of the collagen gels. The collagen gels were dissociated from the edges of the well, then imaged every 24 hours over the course of 96 hours to capture gel contraction over time. Images were then processed using Image J, and data was reported as a percentage of the time zero gel size.
The SPRM nanosuspension had a size of 224 ± 12 nm, zeta potential > -2.2 ± 0.7 mV, and PDI 0.17 ± 0.04. The collagen matrix tested with concentrations of SPRM show a dose-dependent reduction in contractility, which correlated with preliminary in vivo results showing prevention of inflammation-induced PTB. Importantly, cell viability was not negatively affected by SPRM nanosuspension at concentrations that were effective in preventing contraction. Additional in vivo testing in the animal model will confirm efficacy, as well as allow for elucidation of cellular mechanisms related to progesterone receptor expression.
About 10% of all live births in the United States are considered preterm . There are currently very few options for preventing PTB, particularly inflammation induced PTB. With the identification of new drugs for quiescing premature uterine contractility, we can continue to improve maternal and fetal care, particularly once labor begins. Understanding outcomes based on specific drug characteristics may also reveal mechanisms of PTB, which leads to deeper understanding in the field of how to prevent it.
- Ensign LM, Cone R, Hanes J. Nanoparticle-based drug delivery to the vagina: A review. J Controlled Release. 2014;190:500-14.
- Yu T, Chisholm J, Choi WJ, evo A, Pulicare S, Zhong W, et al. Mucus-Penetrating Nanosuspensions for Enhanced Delivery of Poorly Soluble Drugs to Mucosal Surfaces. Advanced healthcare materials. 2016;5(21):2745-50.
- Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003 Jun 12;348(24):2379-85.
- House M, Norwitz ER. Progesterone Supplementation does not PROLONG pregnancy in women at risk for preterm birth: What do we do now? MD Edge OBGYN. 2019 December;31(12):36-8.
- Zierden HC, Ortiz JI, DeLong K, Yu J, Li G, Dimitrion P, et al. Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth. Science Translational Medicine. 2021;13(576):eabc6245.
- FIGHTING PREMATURE BIRTH: THE PREMATURITY CAMPAIGN [Internet]. [cited 10/10/2020]. Available from: https://www.marchofdimes.org/mission/prematurity-campaign.aspx.
|AIChE Member Credits||0.5|
|AIChE Graduate Student Members||Free|
|AIChE Undergraduate Student Members||Free|