Lipid Drug Delivery Systems for Brain Targeting

Abstract

Purpose: The objective of this thesis was to develop Galantamine hydrobromide (GalHBr) solid lipid nanoparticles (SLNs) for intranasal administration for brain targeting and bypassing the blood brain barrier (BBB) with the desired drug concentration at the site of action. The lipidic particles and the route of administration can enhance the drug delivery to the brain ofthis hydrophilic drug. Methods:Screening of different components used in fabrication of plain solid lipid nanoparticles (SLNs) was done in a preliminary study where, different types and concentrations of lipids and surfactants were tested. The unloaded SLNs were characterized for their particle size, polydispersity index and zeta potential. Optimized formulations were selected to prepare GalHBr loaded SLNs [anionic SLNs, cationic SLNs and chitosan coated SLNs]. GalHBr loaded SLNs were characterized viz: dynamic light scattering (DLS), entrapment efficiency, transmission electron microscopy (TEM) differential scanning calorimetry (DSC)and drug release in phosphate buffer saline. Biological investigations including pharmacokinetic studiesin both plasma,and brain, brain drug targeting efficiencydeterminations andhistopathological examinations were performed, on Wister albino rats, for the selectedintranasal GalHBr SLNs: Results The optimized unloaded SLNs were composed of 7.5% lipid (Precirol®ATO5 or Compritol®888ATO or GMS) with variable surfactant concentrations (3,5,7,10%) of Brij®78 or Tween80.These formulations were used for the preparation of GalHBr loaded SLNs using hot high shear homogenization method in the presence of sodium deoxycholate (SDC). According to the factorial design experiment for optimization of anionic GalHBr loaded SLNs and stabilized with various surfactant combinations, it was deduced that increasing the surfactant concentration from 3 to 10% had significantly decreased the mean PS and the ζ potential of SLNs but insignificantly affected EE%. Besides, the results also showed that all SLNs carried negative charge due to the presence of SDC.Cationic SLNs were successfully prepared after the addition of 0.56% SA. They all showed lower mean PS and EE% compared to their alternative anionic SLNs. To increase residence time of cationic SLNs, SLNs were successfully prepared by addition of 0.15% low molecular weight CS. CS-SLNs showed larger mean PS and PDI, higher positive ζ values while lower EE% compared to their alternative cationic SLNs. The in vitro release studies of GalHBr from anionic, cationic and CS SLNs revealed a more sustained release of GalHBrthan from cationicand anionic SLNs. Electron microscope examination confirmed that all particles were spherical in shape with smooth surface with no obvious particle aggregation except with CS-SLNs which showed reversible aggregation. The DSC study confirmed the solid nature of all SLNs at room temperature and the formation of drug SLN with a uniform matrix engulfing the hydrophilic GalHBr in case of F20 and its analogs. The values of absolutedrug bioavailability following intranasal drug solution, chitosan SLNs, anionic SLNs and cationic SLNs were found to be 94.18%, 93.94%, 56.62% and 22.25% respectively. Drug brain targeting efficiency was found to be higher for anionic and cationic SLNs indicating better drug deposition in brain after their intranasal administration. The main GalHBr transport pathway to rat brain for anionic and cationic SLNs was found to be the olfactory route, while for IN solution and chitosan SLNs, the drug transport was achieved via systemic circulation. Histopathological examinations revealed that none of severe signs such as sloughing of epithelial cells or hemorrhage were detected in any of the tested rats.