Pulmonary Delivery of an Ultra-Fine Oxytocin Dry Powder Formulation: Potential for Treatment of Postpartum Haemorrhage in Developing Countries

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.

The prevention and treatment of postpartum haemorrhage: what do we know, and where do we go to next?

“…Inhaled oxytocin powder may provide an alternative, but may also have many of the same issues with its use. 56 …”

Heat-Stable Dry Powder Oxytocin Formulations for Delivery by Oral Inhalation

“…In addition, evaluation of off-target effects, such as the potential for OT to stimulate contraction of the airways, would also be conducted. Encouragingly, a recent study published by Prankerd et al (5) showed that pulmonary administration of oxytocin as a dry powder to postpartum sheep lead to authentic response of uterine tissue and no contractile responses to oxytocin in isolated airway tissue.…”

“…It undergoes rapid degradation to inactive products when exposed to elevated temperature and therefore requires storage below 25°C (3,4). Due to interest in reducing maternal death related to postpartum hemorrhage in developing countries, numerous efforts have been recently reported in the literature to develop stable OT formulations (5)(6)(7).…”

“…The lungs provide a large surface area for drug absorption (80-100 m 2 /adult), avoid first pass metabolism, and can allow a rapid onset of therapeutic action. In particular, an inhaled dry powder OT formulation was shown to provide a more rapid onset of action than an intramuscular injection (5).…”

The Novelty of Inhalable Medications: Interest, Use, and Impact of Inhalant Medications in Low-Resource Settings

“…9 The inhalant form of oxytocin that is under development is described as an innovative, heat-stable, and low-cost form of oxytocin that could help manage PPH treatment in resource-poor settings. 10,11 Such a novel approach is needed for women who do not deliver in facilities that have appropriate interventions for PPH.…”