Formulation Development and Evaluation of Freeze-dried Aviptadil Injection using Mannitol as Cryoprotectant

Abstract

physiological effects that have been well-documented, including anti-inflammatory, immune-modulatory, anti-hypertensive, enhancement of cardiac contractility, vasodilation, and fostering immune-neuroendocrine connection. Aviptadil (AVP) is the name of the vasoactive intestinal polypeptide’s synthetic version. Aims and Objectives: The main goal of this work was to create a novel, stable, lyophilized version of aviptadil injection. The stability of aviptadil is of utmost importance due to its classification as a polypeptide, recommended storage condition of -20°C, and susceptibility to degradation in aqueous solutions. To achieve this, the aviptadil injection was processed using freeze-drying technology with the addition of mannitol, serving as a bulking and cryoprotectant agent, within an aqueous solvent system. The choice of cryoprotectant and solvent system was based on factors such as the drug substance’s solubility, stability, and feasibility in the manufacturing process. During the development of the formulation, the bulk solution underwent evaluation to assess the effects of process time, temperature, and compatibility with the materials it came into contact with. Results and Discussion: The incorporation of mannitol, a sugar alcohol, led to the stability of the bulk solution for up to 24 hours before lyophilization when stored at temperatures between 2 and 8°C. Moreover, enhanced stability was observed post freeze-drying. The lyophilization process was meticulously optimized, taking into account critical quality attributes such as description, active drug content, pH of the reconstituted solution, reconstitution time, moisture content, and color absorption percentage. The bulk solution demonstrated compatibility with various materials employed in manufacturing the drug product, such as stainless-steel vessels, polyethersulfone (PES) and polyvinylidene difluoride (PVDF) membrane filters. Notably, when the drug product bulk solution was kept refrigerated for up to 24 hours, there were no appreciable changes in the critical quality features found. The optimized freeze-dried product successfully meets the quality target product profile (QTPP)’s preset acceptance criteria. Conclusions: The stabilization of AVP injection was successfully achieved through the implementation of the lyophilization process with mannitol as the cryoprotectant. The envisaged injectable formulation proves to be safe and showcases its economic viability, convenience, and overall safety in the preparation methods. These findings strongly support the viability of the freeze-dried formulation as a technically sound solution for ensuring the stability of aviptadil as a drug substance within the freeze-dried injectable dosage form. This formulation warrants more research due to its potential to treat patients with conditions such acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, and sarcoidosis.