Preparation and evaluation of injectable Rasagiline mesylate dual-controlled drug delivery system for the treatment of Parkinson’s disease

Abstract

<p>A microsphere–gel <i>in situ</i> forming implant (MS–Gel ISFI) dual-controlled drug delivery system was applied to a high water-soluble small-molecule compound Rasagiline mesylate (RM) for effective treatment of Parkinson’s disease. This injectable complex depot system combined an <i>in situ</i> phase transition gel with high drug-loading and encapsulation efficiency RM–MS prepared by a modified emulsion-phase separation method and optimized by Box–Behnken design. It was evaluated for <i>in vitro</i> drug release, <i>in vivo</i> pharmacokinetics, and <i>in vivo</i> pharmacodynamics. We found that the RM-MS-Gel ISFI system showed no initial burst release and had a long period of <i>in vitro</i> drug release (60 days). An <i>in vivo</i> pharmacokinetic study indicated a significant reduction (<i>p</i> < .01) in the initial high plasma drug concentration of the RM–MS–Gel ISFI system compared to that of the single RM–MS and RM–<i>in situ</i> gel systems after intramuscular injection to rats. A pharmacodynamic study demonstrated a significant reduction (<i>p</i> < .05) in 6-hydroxydopamine-induced contralateral rotation behavior and an effective improvement (<i>p</i> < .05) in dopamine levels in the striatum of the lesioned side after 28 days in animals treated with the RM–MS–Gel ISFI compared with that of animals treated with saline. MS-embedded <i>in situ</i> phase transition gel is superior for use as a biodegradable and injectable sustained drug delivery system with a low initial burst and long period of drug release for highly hydrophilic small molecule drugs.</p