Abstract
Oxytocin is recommended by the World Health Organisation as the most effective uterotonic for the prevention and treatment of postpartum haemorrhage. The requirement for parenteral administration by trained healthcare providers and the need for the drug solution to be maintained under cold-chain storage limit the use of oxytocin in the developing world. In this study, a spray-dried ultrafine formulation of oxytocin was developed with an optimal particle size diameter (1-5 µm) to facilitate aerosolised delivery via the lungs. A powder formulation of oxytocin, using mannitol, glycine and leucine as carriers, was prepared with a volume-based median particle diameter of 1.9 µm. Oxytocin content in the formulation was assayed using high-performance liquid chromatography-mass spectroscopy and was found to be unchanged after spray-drying. Ex vivo contractility studies utilising human and ovine uterine tissue indicated no difference in the bioactivity of oxytocin before and after spray-drying. Uterine electromyographic (EMG) activity in postpartum ewes following pulmonary (in vivo) administration of oxytocin closely mimicked that observed immediately postpartum (0-12 h following normal vaginal delivery of the lamb). In comparison to the intramuscular injection, pulmonary administration of an oxytocin dry powder formulation to postpartum ewes resulted in generally similar EMG responses, however a more rapid onset of uterine EMG activity was observed following pulmonary administration (129 ± 18 s) than intramuscular injection (275 ± 22 s). This is the first study to demonstrate the potential for oxytocin to elicit uterine activity after systemic absorption as an aerosolised powder from the lungs. Aerosolised oxytocin has the potential to provide a stable and easy to administer delivery system for effective prevention and treatment of postpartum haemorrhage in resource-poor settings in the developing world.
Highlights
Postpartum haemorrhage (PPH), usually defined as the loss of >500 mL of blood within 24 hours of birth, occurs in more than 10% of all births and is most commonly attributed to uterine atony [1]
There was no significant difference (p>0.05) in the contractile activity of human (Figure 3A) versus ovine (Figure 3B) uterine smooth muscle to cumulative increases in oxytocin alone or oxytocin reconstituted from the spray-dried powder formulation (p=0.99 for human, and p=0.92 for sheep, n=8), again demonstrating no loss in oxytocin potency after spray-drying
The similarities in responses suggested that exogenous oxytocin delivered by either route would elicit a contractile response similar to that produced by endogenous oxytocin released during delivery of the lamb
Summary
Postpartum haemorrhage (PPH), usually defined as the loss of >500 mL of blood within 24 hours of birth, occurs in more than 10% of all births and is most commonly attributed to uterine atony [1]. The alternate parenteral uterotonic, ergometrine, is unstable at elevated temperatures and even more so when exposed to light [7,8]. Such cold-chain requirements present difficulties in developing countries where: (i) poor supply chain management, lack of infrastructure and local practices are often inadequate to maintain product stability [9]; (ii) many women give birth in rural facilities or at home where the supply of medical provisions, e.g., needle, syringes and alcohol swabs, required for injection are unavailable or inconsistent; and (iii) there are shortages of or limited access to skilled birth attendants or medical personnel to safely administer the injection [10]
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