Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia ; Biotechnology Research Laboratories, Department of Physiology, Monash University, Clayton, Australia.
PLoS One. 2013 Dec 23;8(12):e82965. doi: 10.1371/journal.pone.0082965. eCollection 2013.
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.
世界卫生组织推荐催产素作为预防和治疗产后出血最有效的子宫收缩剂。由于需要经过培训的医疗保健提供者进行静脉注射，并且药物溶液需要冷藏储存，这限制了催产素在发展中国家的应用。在这项研究中，开发了一种喷雾干燥的催产素超细制剂，其最佳粒径直径（1-5μm）有助于通过肺部进行气溶胶输送。使用甘露醇、甘氨酸和亮氨酸作为载体，制备了一种催产素粉末制剂，其体积平均粒径为 1.9μm。使用高效液相色谱-质谱法测定了制剂中的催产素含量，发现喷雾干燥后含量不变。利用人体和羊的子宫组织进行的体外收缩性研究表明，喷雾干燥前后催产素的生物活性没有差异。对产后绵羊进行肺部（体内）给予催产素后，子宫肌电图（EMG）活动与正常阴道分娩后（产后 0-12 小时）立即观察到的情况非常相似。与肌肉注射相比，向产后绵羊肺部给予催产素干粉制剂导致的 EMG 反应通常相似，但肺部给予（129±18 秒）比肌肉注射（275±22 秒）更快地引起子宫 EMG 活动。这是第一项研究表明，催产素作为肺部气溶胶化粉末全身吸收后具有引发子宫活动的潜力。雾化催产素有可能为资源匮乏环境中的产后出血提供一种稳定且易于管理的输送系统，以有效预防和治疗产后出血。
