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.

Figure 1. Administration of oxytocin powder formulation to the sheep lung.

Screen images taken (A) prior to; (B) during and (C) 2 min after pulmonary administration of the oxytocin powder formulation above the first bronchial bifurcation.

Figure 2. Images of oxytocin particles.

Scanning electron micrographs of unprocessed oxytocin and oxytocin loaded carrier particles; (A) unprocessed commercial oxytocin (x 375); (B) oxytocin formulated as an ultrafine dry powder with the glycine-leucine-mannitol carrier (x 5000). (C) Well-dispersed aerosolised plume of ultrafine particles emitted from an insufflator.

Figure 3. Ex vivo assessment of oxytocin induced uterine smooth muscle contractions.

Effects of applied oxytocin on smooth muscle contractility ex vivo using (A) human (n=8) and (B) ovine (n=8) uterine tissue samples. Contraction was normalized as % of the response to high potassium (HiK) in PSS.

Figure 4. Ex vivo assessment of oxytocin induced tracheal smooth muscle contractions.

Effects of applied oxytocin on smooth muscle contractility ex vivo using ovine (n=5) tracheal tissue samples. Contraction was normalized as % of the response to acetylcholine (ACh) in PSS.

Figure 5. Representative electromyograph uterine activity over time in response to oxytocin administration.

Representative electromyograph (EMG) activity over time (min) recorded in vivo from the uterine smooth muscle of sheep (n=8). (A) spontaneous activity during parturition and prior to oxytocin administration; (B) activity following pulmonary administration of 200 IU (nominal dose) of oxytocin prepared as an ultrafine spray-dried powder and; (C) activity following IM injection of 10 IU of oxytocin solution. Oxytocin dose and time of administration are indicated (OT = oxytocin).

Figure 6. Parameters derived from electromyograph uterine activity in response to oxytocin administration.

Electromyograph (EMG) parameters derived from group EMG profiles outlining; (A) time of onset; (B) duration of initial burst of activity; (C) number of activity bursts per 30 min and; (D) total duration of activity bursts. Data was collected immediately postpartum (PP) and after pulmonary (airway, 200 IU) or IM (10 IU) administration of oxytocin to ewes. Data presented as mean ± SD, n=8.