Formulation Research Laboratory, CMC Division, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan.
Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
Int J Pharm. 2019 Jun 10;564:237-243. doi: 10.1016/j.ijpharm.2019.04.042. Epub 2019 Apr 16.
Liposomal anticancer drugs have been developed with improved clinical effects and reduced side effects. We have developed a PEGylated liposomal formulation of oxaliplatin that has anticancer effects in animal models of colorectal cancer with a favorable toxicity profile. To move this formulation into clinical development, a formulation that is stable during long term storage is needed, which has similar pharmacokinetics and therapeutic activity against solid tumors to the original formulation. In this study, we found that PEGylated liposomal oxaliplatin showed no changes in particle size after long term storage (12 months at 2-8 °C), but phospholipid degradation had occurred. Hence, the stored formulation had compromised membrane integrity, resulting in decreased in vivo circulation times of the liposomes. To improve the stability during long-term storage, a screening study to obtain an appropriate stabilizer was carried out. The buffer 2-morpholinoethansulfonic acid (MES) attenuated not only phospholipid degradation but also oxaliplatin degradation, unlike most other excipients. After 12 months storage at 2-8 °C in the presence of MES only slight degradation of phospholipids in PEGylated liposomal oxaliplatin occurred, resulting in similar in vivo pharmacokinetic profiles of the encapsulated oxaliplatin to the original formulation. Long term stability of PEGylated liposomal oxaliplatin was achieved by addition of MES, resulting in long circulation half-lives in vivo, a property which would be expected to lead to increased suppression of tumor growth and reduced side effects. Our formulation may now be suitable for clinical development.
脂质体抗癌药物的临床疗效得到改善，副作用降低。我们开发了一种聚乙二醇化脂质体奥沙利铂制剂，在结直肠癌动物模型中具有抗癌作用，且毒性谱良好。为了将该制剂推向临床开发，需要一种在长期储存过程中稳定的制剂，该制剂具有与原始制剂相似的药代动力学和对实体瘤的治疗活性。在这项研究中，我们发现聚乙二醇化脂质体奥沙利铂在长期储存（2-8°C 下 12 个月）后粒径没有变化，但磷脂降解已经发生。因此，储存的制剂膜完整性受损，导致脂质体体内循环时间缩短。为了提高长期储存过程中的稳定性，进行了筛选研究以获得合适的稳定剂。缓冲液 2-吗啉乙磺酸（MES）不仅能减轻磷脂降解，还能减轻奥沙利铂降解，与大多数其他赋形剂不同。在 2-8°C 下仅添加 MES 储存 12 个月后，聚乙二醇化脂质体奥沙利铂中的磷脂仅略有降解，导致包封奥沙利铂的体内药代动力学特征与原始制剂相似。通过添加 MES 实现了聚乙二醇化脂质体奥沙利铂的长期稳定性，导致体内长循环半衰期，这有望增加对肿瘤生长的抑制作用和减少副作用。我们的制剂现在可能适合临床开发。
