| The objective of the present study was to prepare chitosan hydrochloride, Tween-80, PEG20000, borneol/mentholum eutectic mixture multiple-coated nasal polylactic acid nanoparticles for intranasal delivery (M-PLA-NP). The aims are to enhance the uptake amount of drugs in target organ, evaluated aniracetam M-PLA-NP stability preliminarily in vitro, in vivo studies and evaluation aniracetam on M--PLA-NP brain targeting efficiency.Firstly, the HPLC methods were established for Galanthamine Hydrochloride determination. Owing to the solubility of Galanthamine Hydrochloride, the NP were prepared by using the multiple emulsion (w/o/w) combine with high-pressure homogenizer technique. Thus the NP prepared using optimized parameters had a percentage drug entrapment of49.55%, drug loading of3.54%. Zeta potential was3.24mv and size85.47nm, with a polydispersity index of0.170.Due to the lower encapsulation efficiency and drug loadings of galantamine hydrobromide PLA-NP and unable to meet the requirements, the aniracetam has been choice as a model drug and the HPLC methods were established for aniracetam determination. Aniracetam achieved a good separation without interference, which provided analysis methods for subsequent experiments.In preparation of aniracetam M--PLA-NP, owing to the high solubility of aniracetam in organic solvent and in order to increase the brain targeting efficiency of aniracetam, the solvent diffusion-evaporation combined with magnetic stirring method has been chosen as one of the most appropriate method for the encapsulation of aniracetam. Then, the promote penetration modification, long cycle modification with PEG-2000, modification of inhibit P-glycoprotein in brain capillary endothelial cell membrane’s drug efflux function, modification of biological adhesion has been done for the nanoparticles by the magnetic stirring method. Different formulation variables such as the ratio of the drug and PLA, concentration of Poloxamer188as stabilizer, the aqueous phase volume, nanoparticles volume after rotary evaporated, ethanol:acetone ratio were varied. Only one parameter was changed at a time in each set of experiments. Thus the NP prepared using optimized parameters had a percentage drug entrapment of96.40%, drug loading of11.57%and size145.6nm. The size145.6nm, with a polydispersity index of0.077and the zeta potential was20.4mv. The NP in the lysozyme solution is stable and within2h,70.03%drug release occurred from PBS solution. Demonstrated that the NP prepared using optimized parameters had good drug entrapment, drug loading, generally spherical appeared to be smooth and in vitro/vivo environment is stable etc.To evaluation the brain targeting effencicy and systemic absorption of the M-PLA-NP the Sprague-Dawley rats have been used to in vivo studies. Evaluation of the aniracetam distribution in different organs such as, heart, liver, spleen, lung, kidney, brain, plasma following nasal administration of multiple coated aniracetam loaded PLA-NP and aniracetam suspension. The data suggested that the targeting efficiency of M-PLA-NP was about5.67folds compared with the aniracetam suspension in the brain, the relative targeting efficiency of M-PLA-NP was about5.19folds compared with the aniracetam suspension in the brain. The concentration ratio efficiency of M-PLA-NP was about3.21folds compared with the aniracetam suspension in the brain. However, the distribution of aniracetam in the spleen or liver in M-PLA-NP group was lower than that of aniracetam solution. The result demonstrated that the M-PLA-NP changed the drug distribution in rat and showed good brain targeting property.In summary, the M-PLA-NP in vitro/in vivo environment is stable, indicating sustained release in vitro drug release studies and showed good brain targeting property in vivo studies. So the M-C-PLA-NP is a novel brain targeting agent for nasal drug delivery. |
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