الفهرس 
Lipid Drug Delivery Systems for Brain TargetingOnly 14 pages are availabe for public view
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Abstract
Lipid drug delivery systems for brain targeting
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 of this 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 studies in both plasma, and brain,
brain drug targeting efficiency determinations and histopathological examinations were
performed, on Wister albino rats, for the selected intranasal 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
GalHBr than from cationic and 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 absolute drug 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.Conclusion
The present study revealed that solid lipid nanoparticles can be considered as suitable
drug carrier system for nasal delivery of galantamine hydrobromide. These systems
provide brain drug targeting, thus more predictable brain drug levels with consequent
possible reduction of GalHBr side effects would be achieved.
Keywords: Intranasal, Solid lipid nanoparticles, Alzheimer, Galantamine
hydrobromide, Pharmacokinetic studies.