Design Development and Evaluation of In Situ Forming Implantable Durg Delivery System of Glibenclamide for the Treatment of stroke

Abstract

newline x newlineABSTRACT newlineCurrently, the only drug approved for the treatment of ischemic stroke is recombinant tissue plasminogen activator, a thrombolytic drug which has a limited time window for administration and increases the risk for subsequent hemorrhage. There is increased morbidity in stroke mainly due to cytotoxic edema development caused by the upregulation of sulfonylurea receptor 1-regulated NCCa-ATP channel for which no treatment is available. Glibenclamide, sulfonylurea receptor inhibitor is currently reported to be neuroprotective in stroke by reducing cytotoxic edema. As the worsening of neurological symptoms in stroke takes from 3-10 days post injury, there is a need to develop a system that would provide the release of glibenclamide for 10-15 days in order to effectively improve the neurological functions. In present research work, an attempt has been made to develop in situ forming implantable drug delivery system of glibenclamide by applying DoE and optimization techniques which on subcutaneous administration can prolong the release of drug for upto 15 days in a sustained manner. PLGA 50:50 was used as biodegradable polymer to develop the implantable system. Drug excipient compatibility studies were performed by using FTIR and DSC. Glibenclamide optimized ISFM formulation was evaluated for rheology, particle size, surface morphology and poly dispersity index. In vitro drug release studies and kinetics studies were performed for optimized formulation which showed minimum burst release i.e. 6.27 ± 1.11 % at 12 h and maximum release i.e. 98.92 ± 1.76 % on 15th day. newlineIn vivo pharmacodynamic and pharmacokinetics studies for glibenclamide optimized ISFM formulation were carried out in bilateral common carotid artery occlusion model of rat. Pharmacodynamic parameters including behavioral study, infarct volume, brain edema and histopathology of brain were studied. Results showed a significant improvement in neurological functions, infarct area and hemispheric swelling in glibenclamide ISFM treated animals as compared to diseased animals depicting the efficacy of long term ISFM formulation of glibenclamide for the treatment of stroke. From in vitro release studies and pharmacokinetic studies, it was concluded that release of glibenclamide was attained in sustained manner from ISFM for upto 15 days. Histopathology studies confirmed the biocompatibility of glibenclamide ISFM formulation. Conclusively, ISFM of glibenclamide is an newlinexi newlineeffective system of drug delivery to prolong the drug release for upto 15 days in an effective and sustained manner for preventing the neurological worsening in stroke. newlineKeywords: In situ forming microparticles, glibenclamide, stroke, ischemia, implants.