Zhu Changcheng, Lal Manjari
Medical Devices and Health Technologies, PATH, Seattle, WA 98121, USA.
Pharmaceutics. 2022 Apr 28;14(5):953. doi: 10.3390/pharmaceutics14050953.
The work reported here focuses on an evaluation of a novel heat stable formulation of a uterotonic peptide drug oxytocin involving stability testing under elevated temperatures and toxicokinetic response generated by sublingual (SL) administration in rabbits. The formulation was thermotolerant, maintaining the potency of oxytocin in the form of a fast-dissolving tablet at the end of 2-year storage at 30 °C/65% relative humidity with less than 5% loss in oxytocin content based on analytical high performance liquid chromatography (HPLC). The toxicokinetic results in rabbits showed that the fast-dissolving tablet was safe without any reactogenicity or toxicity associated with SL administration or the excipients present in the formulation. The SL route elicited rapid absorption of oxytocin in plasma within 5 min of administration although lower than intramuscular (IM) administration. IM resulted in area under the curve (AUC) values approximately 5 times higher than SL oxytocin. However, due to the limitations encountered during SL administration in an anesthetized rabbit model, the relevance of heat stable oxytocin formulation that has the flexibility to be adapted in different formats may warrant a human clinical study to determine whether therapeutically relevant plasma levels for treating postpartum hemorrhage can be generated via alternate non-injectable routes of administration.
本文报道的工作重点是评估一种新型子宫收缩肽药物催产素的热稳定制剂，包括在高温下的稳定性测试以及兔舌下给药产生的毒代动力学反应。该制剂具有耐热性，在30℃/65%相对湿度下储存2年后，以速溶片形式存在的催产素效力得以维持，基于高效液相色谱（HPLC）分析，催产素含量损失小于5%。兔的毒代动力学结果表明，速溶片是安全的，与舌下给药或制剂中存在的辅料无任何反应原性或毒性。舌下给药途径在给药后5分钟内可使血浆中的催产素快速吸收，尽管低于肌肉注射给药。肌肉注射导致的曲线下面积（AUC）值约为舌下催产素的5倍。然而，由于在麻醉兔模型中进行舌下给药时遇到的限制，具有多种剂型适应性灵活性的热稳定催产素制剂可能需要进行人体临床研究，以确定是否可以通过替代非注射给药途径产生治疗产后出血的相关血浆水平。
