PHARMACEUTICAL DEVELOPMENT OF A PARENTERAL LYOPHILIZED FORMULATION OFTHE INVESTIGATIONAL ANTITUMOR NEUROPEPTIDE ANTAGONIST [ARG(6), D-TRP(7,9), MEPHE(8)]-SUBSTANCE P (6-11)

The aim of this study was to develop a stable parenteral dosage form f or the investigational cytotoxic drug [Arg(6), D-Trp(7.9), MePhe(8)]- Substance P {6-11} (Substance P Antagonist G; Antagonist G). Antagonis t G bulk drug was structurally and analytically characterized. The dru g exhibits excellent aqueous solubility, although relatively poor aque ous stability characteristics. Lyophilization was, therefore, selected as the manufacturing process. Differential scanning calorimetry studi es were conducted to determine the freeze-drying cycle parameters whic h resulted in a stable, lyophilized formulation of Antagonist G. The p rototype, containing 50 mg Antagonist G per vial, was found to be the optimal formulation in terms of solubility, length of the freeze-dryin g cycle, stability, and dosage requirements in the planned phase I cli nical trials. Quality control of the freeze-dried formulation showed t hat the manufacturing process does not change the integrity of Antagon ist 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 environme nt. Oxidative degradation products of Antagonist G were isolated and s tructurally characterized by mass spectrometry, nuclear magnetic reson ance spectroscopy, and infrared spectroscopy.