Abstract
Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries. The recommended treatment includes administration of oxytocin; however, oxytocin is a heat-labile protein, and it must be given as an intramuscular injection by skilled health care providers. To address these challenges, we developed a freeze-dried oxytocin fast-dissolving tablet (FDT) for sublingual (SL) needle-free administration. Using methods developed previously, we produced a robust FDT that maintained oxytocin stability at 40 °C, 75% relative humidity for 12 months. This formulation contains 9% sucrose, 1.5% (hydroxypropyl)methyl cellulose, 9% mannitol, 4% dextran, 1% carbomer, 1% sodium taurocholate, and 100 IU oxytocin. An in vitro study showed a > 30% reduction in tissue transepithelial electrical resistance after treatment with the oxytocin FDT, implying an increase in the permeability of the mucosal tissue to oxytocin. Anesthetized Yucatan miniature swine were administered a SL FDT, and blood was periodically collected for a pharmacokinetic study. Higher plasma concentrations were seen when larger SL doses were given. The maximum concentrations for SL and intramuscular doses in anesthetized pigs were 207 and 612 pg/mL, respectively. Whether the levels attained will be sufficient to elicit beneficial results in humans is yet to be determined. This study demonstrates the feasibility of our approach for developing a heat-stable oxytocin tablet that can be administered successfully via the SL route.
Highlights
Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries
Postpartum hemorrhage (PPH)—loss of ≥500 mL of blood from the genital tract within 24 h of the birth of a baby—is a major cause of mortality, morbidity, and long-term disability related to pregnancy and childbirth, with most deaths
Active management of the third stage of labor is the practice recommended by the World Health Organization (WHO) for reducing the incidence of PPH [2]; it consists of controlled cord traction, cord clamping, and administration of a uterotonic drug
Summary
Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries. The recommended treatment includes administration of oxytocin; oxytocin is a heat-labile protein, and it must be given as an intramuscular injection by skilled health care providers. To address these challenges, we developed a freeze-dried oxytocin fastdissolving tablet (FDT) for sublingual (SL) needle-free administration. If oxytocin is not available or if skilled birth attendants are not present, WHO recommends oral misoprostol (600 mcg) [3] This drug, has been associated with adverse side effects such as chills and fever (including hyperpyrexia), nausea and vomiting, diarrhea, and pain [4]. To address the challenges of heat instability and administration of oxytocin by injection, we conducted a feasibility study to develop a heat-stable, freeze-dried oxytocin fast-dissolving tablet (FDT) for sublingual (SL) needle-free. We explored SL absorption of oxytocin from the FDT in a pharmacokinetic study in mini pigs
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