Study On Preparation And Pharmacokinetic Evaluation Of Solid Lipid Nanoparticles Of Venlafaxine And Its Effect On P-Glyprotein Expression In Brain

AimsThe aims of this present study was to prepare and evaluate the pharmacokinetic feature of solid lipid nanoparticles of venlafaxine, the effect of solid lipid nanoparticles of venlafaxine on P-Glyprotein expression in brain was further investigated after long-term administration.Methods(1) The solid lipid nanoparticles of venlafaxine were prepared by emulsion with a high temperature-low temperature curing, the encapsulation efficiency, particle size distribution, zeta potential and morphology were evaluated and characterized. The stability of solid lipid nanoparticles of venlafaxine was evaluated under the condition of room temperature and 4℃ for 0.1.2,3 and 4 months.(2) The prepared solid lipid nanoparticles of venlafaxine, venlafaxine water solution, venlafaxine with blank nanoparticles, and venlafaxine plus Verapamil were given to mice by single-dose oral administration. Plasma and brain were collected at different time points. HPLC method was used to measure the concentration of venlafaxine in plasma and brain. The concentration-time curve and pharmacokinetic parameters of venlafaxine was analized by DAS 1.0 software.(3) The prepared solid lipid nanoparticles of venlafaxine, venlafaxine water solution, venlafaxine with blank nanoparticles, and venlafaxine plus Verapamiwere given to mice for 7 days,14 days and 21 days, respectively. Plasma and brain were collected at 2 hours after the last drug administration, and HPLC method was used to measure the concentration of venlafaxine in plasma and brain.(4) To investigate the effect of long-term venlafaxine administration on p-glycoprotein transporter expression in brain, mice were given solid lipid nanoparticles of venlafaxine, venlafaxine water solution, venlafaxine with blank nanoparticles, and venlafaxine plus Verapamil for 7 days.14 days and 21 days, respectively. Brain tissue were collected and prepared for Western blot analysis.Results(1) The morphology of the prepared solid lipid nanoparticles of venlafaxine shows spherical or ellipsoidal; the average particle size is 180.4±13.46 nm; the Zeta potential is -18.5±0.98 mV; and the encapsulation efficiency is (74.9±3.2)%. Under the condition of room temperature and 4℃, the above parameters of the solid lipid nanoparticles of venlafaxine did not show significant alteration during 4 months’ evaluation.(2) After single-dose drug administration, the main pharmacokinetic parameters of solid lipid nanoparticles of venlafaxine are improved significantly with Tmax 60 min and Cmax 467.21 mg/L; and the venlafaxine concentration in brain was also elevated significantly when compared to that of venlafaxine.(3) After oral administration of solid lipid nanoparticles of venlafaxine for 7 days,14 days and 21 days, the concentration of venlafaxine in brain is 443.28,436.29, and 421.17 mg/L, respectively; the plasma concentration is 3328.64,3286.17, and 3246.28 mg/L, respectively. Concerning the brain/plasma ratio of venlafaxine concentration, significant difference (P<0.05) was found in solid lipid nanoparticle group when compared to the rest of groups, and after 7 days,14 days and 21 days drug administration, the brain/plasma value is 0.133,0.133, and 0.130, respectively. (4) Concerning the p-glycoprotein transporter expression in brain, no significant difference was found between solid lipid nanoparticle-treated group and saline group after long-term (7,14, and 21 days) venlafaxine administration; while the brain p-glycoprotein transporter expression was significantly increased in the rest of venlafaxine treated groups (P<0.05).Conclusion(1) With the method of emulsion with a high temperature-low temperature curing, the prepared solid lipid nanoparticles of venlafaxine show spherical nanoparticles with good encapsulation efficiency and stability.(2) Comprared to venlafaxine, the solid lipid nanoparticles venlafaxine prolong the residence time in the brain and plasma, improve the drug distribution in brain, and increase the bioavailability of venlafaxine.(3) After long-term drug administration, the concentration of venlafaxine in plasma and brain and the brain/plasma value were significantly improved in solid lipid nanoparticles venlafaxine-treated group when compared to that of other groups.(4) Long-term administration of solid lipid nanoparticles venlafaxine did not affect p-glycoprotein transporter expression of brain, while long-term administration of venlafaxine water solution, venlafaxine with blank nanoparticles, and venlafaxine plus Verapamil all significantly increased the expression of p-glycoprotein expression in brain.