Jonkman-de Vries J D, Rosing H, Talsma H, Henrar R E, Kettenes-van den Bosch J J, Bult A, Beijnen J H
Department of Pharmacy, Slotervaart Hospital/Netherlands Cancer Institute, Amsterdam.
Invest New Drugs. 1998;16(2):99-111. doi: 10.1023/a:1006041024109.
The aim of this study was to develop a stable parenteral dosage form for the investigational cytotoxic drug [Arg6, D-Trp79,MePhe8]-Substance P [6-11] (Substance P Antagonist G; Antagonist G). Antagonist G bulk drug was structurally and analytically characterized. The drug exhibits excellent aqueous solubility, although relatively poor aqueous stability characteristics. Lyophilization was, therefore, selected as the manufacturing process. Differential scanning calorimetry studies were conducted to determine the freeze-drying cycle parameters which resulted in a stable, lyophilized formulation of Antagonist G. The prototype, containing 50 mg Antagonist G per vial, was found to be the optimal formulation in terms of solubility, length of the freeze-drying cycle, stability, and dosage requirements in the planned phase I clinical trials. Quality control of the freeze-dried formulation showed that the manufacturing process does not change the integrity of Antagonist G. Shelf life studies demonstrated that the formulation is stable for at least 3 years, when stored at 2-8 degrees C in a dark environment. Oxidative degradation products of Antagonist G were isolated and structurally characterized by mass spectrometry, nuclear magnetic resonance spectroscopy, and infrared spectroscopy.
本研究的目的是为研究用细胞毒性药物[Arg6，D-Trp79，MePhe8]-P物质[6-11]（P物质拮抗剂G；拮抗剂G）开发一种稳定的肠胃外剂型。对拮抗剂G原料药进行了结构和分析表征。该药物具有出色的水溶性，尽管其水稳定性相对较差。因此，选择冻干作为生产工艺。进行了差示扫描量热法研究，以确定冻干循环参数，从而得到稳定的拮抗剂G冻干制剂。在计划的I期临床试验中，每瓶含50 mg拮抗剂G的原型制剂在溶解度、冻干循环时长、稳定性和剂量要求方面被认为是最佳制剂。冻干制剂的质量控制表明，生产工艺不会改变拮抗剂G的完整性。货架期研究表明，该制剂在2-8℃黑暗环境中储存时至少3年稳定。通过质谱、核磁共振光谱和红外光谱对拮抗剂G的氧化降解产物进行了分离和结构表征。
