Abstract
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.