s salatin - Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran .Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.Department of pharmaceutics faculty of pharmacy of medical tabriz unive
j barar - Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran.Department of pharmaceutics faculty of pharmacy of medical tabriz university sciences tabriz iran
m barzegar jalali - Department of pharmaceutics faculty of pharmacy of medical tabriz university sciences tabriz iran
kh adibkia - Department of pharmaceutics faculty of pharmacy of medical tabriz university sciences tabriz iran.Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
m jelvegari - Department of pharmaceutics faculty of pharmacy of medical tabriz university sciences tabriz iran.Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Background and Objective: Alzheimer,s disease (AD) is a progressive neurological disorder that commonly leads to the damage of memory, reasoning, and thinking skills. Delivery of drugs to the brain is a challenging issue owing to the presence of the highly selective blood brain barrier (BBB) [1,2]. Intranasal administration of pharmaceutical compounds is gaining considerable attention as an alternative route for direct drug delivery to the brain, bypassing the BBB. However, insufficient therapeutic efficacy of drugs via this route due to the mucociliary clearance exhibits a major challenge for development of de novo formulations. This shortcoming can be overcome by simultaneous utilization of a nanoparticulate delivery system with a polymeric gel network [3]. Therefore, the aim of the present study was to develop erodible in-situ gel forming system of poloxamer 407® (P407) as promising platforms, capable of prolonging rivastigmine hydrogen tartrate (RHT) release from the embedded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs).Materials and Methods: RHT was received as a kind sample from tofigh-daru, engineering research company (Tehran, Iran). PLGA (50:50, Resomer® RG 503 H, MW 24,000-38,000) and P407 (Pluronic®F-127, MW 9,840-14,600) were purchased from Sigma-Aldrich (St. Louis, USA). All other solvents and reagents not listed above were purchased in highest grade available. PLGA NPs containing RHT were formulated by changing the drug to polymer ratios using nanoprecipitation technique [4]. They were finally embedded in P407 gel forming matrix and analyzed in terms of gelation temperature, loading efficiency, and in vitro drug release [5]. The cytotoxicity of NPs was evaluated on A549 cell line using MTT assay. Cellular uptake of the NPs was also measured by fluorescence microcopy and flow cytometry analyses.Findings: The mean particle size of PLGA was found to be between 75.14 to 173 nm. A linear dependence of sol-gel temperature (Tsol-gel) on the P407 concentration was observed, and a P407 content of 18% was selected. The loading efficiency of all gel nanoformulations was found to be in the range between 100.22-104.31%. In vitro drug release studies showed a sustained release from the all formulations over period of 24 h, primarily by Fickian diffusion (P<0.05). The RHT-loaded NPs showed a suitable cytocopatibility on A549 cells with a time-dependent increase in cellular uptake. Besides, nanoformulations showed higher amount of drug permeated than plain drug gel.Conclusion: It is concluded that the prepared gel-based nanoformulation can be used as a useful drug delivery system for the brain delivery of RHT through the nasal administration. Further studies recommended to investigate in detail the mechanism of uptake of RHT NPs in nasal epithelial cells, biodistribution as well as in vivo fate of NPs.

PLGA, BBB, Rivastigmine, Nanoparticle, Hydrogel, Nasal, Poloxamer