Flunarizine-loaded microparticles for the prophylaxis of migraine

Abstract

The World Health Organization has listed migraine as the sixth most disabling disorder globally and the most disabling of all neurological disorders. Flunarizine (FZ) is considered a first-line prophylactic treatment for migraine in several guidelines. For this purpose, treatment courses of 2-3 months are necessary and once proven effective, the course of treatments may continue for 6-12 months or even more. In this work we have developed and characterized a new controlled delivery system consisting of flunarizine-loaded microparticles using a mixture of PLGA 502H and PLGA 502 as polymer. To obtain the optimum formulation a two-factor five-level central rotatable composite 2 (2) + star design was employed. The independent variables analyzed were the amount of flunarizine and the ratio PLGA 502H:PLGA502. The selected formulation from the experimental design showed good yield of production, high encapsulation efficiency (91.9 +/- 1.74%), and released the drug at a constant rate for 14 days with mean zero-order release constant of 168.98 mu g FZ/day/10 mg microspheres. Sterilization by gamma-irradiation of the formulation did not produce any modifications on the surface characteristics of the microparticles. Particle size, loading efficiency, X-ray diffraction patterns, and controlled release of FZ from PLGA microparticles were not affected by the sterilization procedure used. Storage of FZ-loaded microparticles for 18 months at 5 degrees C or 6 months at 30 degrees C/65RH did not affect the release behavior of the drug. Cell viability and ROS production was analyzed in SKN-AS, T47 and PC3 cells after exposure to different concentrations of flunarizine (80, 120 and 180 mu M) released in vitro from the sterilized selected formulation without statistically significant differences found with respect to control cells.