Preparation, characterization and in-vivo efficacy study of glatiramer acetate (GA)-hydrogel-microparticles as novel drug delivery system for GA in RRMS

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Abstract
Relapsing Remitting Multiple Sclerosis is a chronic Central nervous system autoimmune disease. There is no absolute treatment for MS and the available remedies are called disease modifying therapies (DMTs). Glatiramer acetate (GA) is one of the FDA approved DMTs. Currently, injection-site problems and unfavorable daily injection are the most common milestones in administration of GA. So that, the design of improved drug delivery systems with sustained release profile seem necessary and helpful in order to minimize GA adverse effects and improve patients’ compliance. In this study, we have manufactured a novel chitosan-PLGA (poly (lactic-co-glycolic acid)) hydrogel-microparticles containing GA by double emulsion method. Hydrogel-microparticles’ properties including size, morphology and GA loading were investigated. In-vitro drug release was studied during 30 days. In vivo efficacy of GA-hydrogel-microparticles was evaluated in experimental autoimmune encephalomyelitis (EAE) as an established animal model for MS. Pathological studies were performed through H&E (Hematoxylin and Eosin) staining of brain, spine, liver, skin and kidney tissues. Luxol fast blue staining of brain tissue was also done. The obtained results were applied for safety and efficacy evaluations. GA loading and Entrapment efficiency (EE %) of 60% and 95% were achieved, respectively. In- vitro release studies confirms a sustained release profile for GA-hydrogel-microparticles. Mean clinical scores and mean body weights obtained from EAE animal model for GA-hydrogel-microparticles were compared to the outcomes achieved from conventional Iranian brand-generic injection solution of GA (Copamer®, 20 mg/ml). EAE outcomes and pathological studies confirm similar therapeutic efficacy with longer dosing intervals possibility, improved safety through decreased adverse effects and elimination of site injection reactions for GA-hydrogel-microparticles. Further studies on pharmacokinetic and pharmacodynamics in human volunteers are still required to thoroughly examine different aspects of this newly developed GA- hydrogel-microparticles.

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