Formulation of Injectable Prolonged-Release Glatiramer Acetate Microsphers

Abstract

Introduction: Glatiramer acetate (GA) is a newly emerged therapeutic peptide to reduce the frequency of relapses in multiple sclerosis (MS). Despite its good performance in controlling MS, it is not widely used due to daily or biweekly subcutaneous injections due to rapid degradation and body clearance. Therefore, implant design with sustained release leads to prolonged biological effects by gradually increasing drug exposure and protecting GA from rapid local degradation. Aim: This study aimed to optimize the preparation and evaluation the 1-month injection formulation of peptide microspheres with high encapsulation percentage and zero-order release behavior to achieve a successful sustained-release product using emulsion techniques. Methods: In this study by modifying different emulsion methods, PLGA type, surfactant concentration, drug/polymer ratio, drying processes, stirring method, and other variables in preliminary studies the final formulation achived. The release kinetics were studied through mechanistic kinetic models such as zero-order, Weibull, Higuchi, etc. In this study, all challenges for easy scale-up, methodological detail, and a simple, feasible setup in mass production were discussed. Results: The final and improved formulation was obtained by 1:6 drug/PLGA, 0.5% w/w polyvinyl alcohol, and 0.75% w/w NaCl in the external aqueous phase, 1:10 continuous phase to dispersed phase ratio, and without any surfactant in the primary emulsion. The final freeze-dried particles presented a narrow-distributed size of 1-10 µm with 7.29% ± 0.51 drug loading and zero-order release behavior with appropriate regression correlation (R2 98.7), complete release, and only 7.1% initial burst release. Conclusion: To achieve improvement in patient compliance through better and longer efficacy, designing the parenteral sustained release microspheres of this immune modulator is a promising approach that should be considered.