| The objective of this study was to prolong the time of drug action, reduce the frequency of administration, improve the bioavailability, and reduce its adverse reactions through the method of Pharmaceutics. This study prepare a kind of N1014-nanostruetured lipid carriers(N-NLC) and carry out system evaluation of N-NLC in vivo and in vitro. N imodipne was the second generation of dihydropyridine calcium antagonists,which shows very slight water solubility and present low oral bio-availability. N1014 for injection using a certain concentration of ethanol as solvent has intensive stimulation. In order to reduce the adverse effect, increase the solubility of the drug, and enhance bioavailability of drug in vivo, N-NLC was prepared.In this study, a ultraviolet spectrophotometry(UV) which was simple and feasible was developed to determine the concentration of N1014 in vitro, and analysed the method validation. Then, the entrapment efficiency and drug-loading were determined by mini-column centrifugation, which was considered as a simple, high accuracy and reproducible way.A novel high speed shearing emulsification-cool solidification method was study to prepare N-NLC. As shown in result, as the shear speed and time of emulsification were 8000 rpm and 15 min, respectively, the NLC particle size was small, and the size distribution was narrow. Using singer factor experiments to investigate the influence factors of the quality of the MND-NLC. In the experiment, the stability and entrapment efficiency were taken as the evaluation index. And the type of solid lipid, the type of liquid lipid, the type of emulsifier, the ratio of mixed emulsifier, and the ratio of drug to lipid were taken as the influence factors. The N-NLC of stabilization and high encapsulation efficiency be acquired, if solid lipid Compritol 888 ATO and liquid lipid isopropyl myristate were lipid carrier, and Tween-80/Cremophor EL were emulsifiers. Subsequently orthogonal design experiments, with the criteria of particle size, were performed to optimize the prescription of the N-NLC.The lyophilized N-NLC powder was also developed. Effects including the freeze-dried protective agent types, the adding methods and the amount of the freeze-dried protective agent were studied on the quality of the frozen dry products. The results showed that 8% of trehalose as freeze-dried protective agent can be prepare lyophilized N-NLC injectable powder with well reconstitution.The properties of N-NLC were studied in order to make sure the quality of it. The surface morphology of N-NLC was observed by transmission electron microscope, the particle size, PDI and Zeta potential of N-NLC were determined by laser particle size analysis. The appearance of N-NLC was spheroidal with mean particle size of( 76.9±6.7 nm), PDI of(0.294±0.032) and Zeta potential of(-23.22±0.56 m V). The encapsulation efficiency of N-NLC were( 94.2±0.6%). The freeze-dried N-NLC powder were investigated by DSC. The results showed that crystallization characteristic of N1014 was amorphous or molecular dispersion in lipid matrix.The HPLC methods were developed for the determination of N1014 in rabbit plasma. The results of N-NLC and N1014 injection of commercial products after rabbits’ ear-rim acricular vein i.v. administration were compared. The pharmacokinetic parameter data was evaluated by statistical moment. The t1/2α, t1/2β, and AUC after administration of N-NLC were 1.26、1.62、1.70 times, repectively, Compared with the commercial products. By Student’s test, statistically significant differences were found in the main pharmacokinetic like t1/2α, t1/2β, and AUC between two groups indicating that to some extent N-NLC can improve the drug concentration of rabbit plasma, prolong the time of drug action, and increase the bioavailability in rabbit. |
PDF Full Text Request