| Objective The nicotinate-curcumin ester has poor water solubility and low bioavailability.The subject will be made into nanoparticles,and the optimal preparation process,technological parameter,quality evaluation,biopharmaceutics,and pharmacokinetic properties of the nicotinate-curcumin ester nanoparticles will be explored in order to increase Bioa vailability of nicotinate-curcumin esters.Methods(1)C18 column(250mm×4.6mm,5?m)was used at 30?using the mobile phase of acetonitrile–0.5%acetic acid glacial(65:35)with a flow rate of 1.0m L·min-1;The UV detection wavelength was 280 nm;The number of theoretical plates exceed4000;the resolution is not less than 1.5 and symmetry factor is between 0.96 and1.03.(2)The nanoparticles prepared by film ultrasonic method,Establishing an HPLC method for the determination of nicotinate-curcumin ester and choosing the entrapment efficiency of nicotinate-curcumin ester as evaluating indicators,the optimal exci pient formul a was selected through the Box-Bebnken reponse surface design of three factors at three levels,Including the content of stearic acid,lecithin and the concentration of tween-80?With particle size and the entrapment efficiency of evaluation indexes,through the orthogonal design test,the 95% confidence interval overlapping method,statistical analysis,optimum dispersion,ultrasonic membrane of nicotinate-curcumin esters of high rate of small particle size,coating process parameter.(3)The nicotinate-curcumin ester were dissolved in p H buffer solution in 1.2-7.8 The high performance liquid chromatography(HPLC)method was used to detect the equilibrium solubility of nicotinate-curcumin ester in various solutions.The apparent oil/water partition coefficients of drugs in the octanol-water and octanol-buffer solution systems were measured by shaking-flask method.(4)A high performance liquid chromatography method for the determination of nicotinate-curcumin esters in rabbits was developed and methodological inves-tigations were conducted.A HPLC method was established for the determination of curcumin con-tent in rabbits.The pharmacokinetic study was carried out with rabbit blood drug concentration method,and the rabbits were randomly divided into 2 groups,each group of 3 rabbits.Blood concentrations were determined at different times.The drug curve was plotted.The blood drug concentration changes over time,and the peak time and peak concentration were found.Statistical moments were ob tained.According to the zero-order moment method in the statistical moment method,The 95% confidence interval method was used to process the experimental results and the difference was compared.the AUC of the nicotinate-curcumin esters and its nanoparticles were calculated and the results were processed by 95% confidence inter val method.Results(1)The results of build HPLC experiment shows that the standard curve regression equation of nicotinate-curcumin esters is y=9756x-28.239(r = 0.9996),a good linear relationship was shown within the range of 5.2?145..6 ?g / m L,both of them was not interfered by the negative control and was stable within 48 hours,the precision of instrument and repeatability also meet the standards of quantitative analysis.Nicotinate-curcumin ester and its nanoparticles average recovery was100.1% ?100.9%,with RSD of 1.260%?0.9950%respectively(n=9).(2)The results of the optimized preparation process shows that under the condition of 80 mg of stearie acid,150 mg of lecithin and 20 m L of tween-80(0.6%);Preparation of double nicotinate-curcumin optimum parameters of solid lipid nanoparticle as: bath temperature40?,tomato type bottle rotation speed 80 r/min.The average particle size of solid lipid nanoparticles was 107.8 nm,and the dispersion index(PDI)was 0.583,and the encapsulation rate was 68.91%.(3)The equilibrium solubility and apparent oil-water partition coefficients of nicotinate-curcumin ester experiment shows that the solubility of nicotinate-curcumin ester in p H6.8 is the largest,The apparent oil-water partition coefficient of the nicotinate-curcumin ester in p H 1.2,p H 5.8,p H6.5,and p H 7.8 were lg Pap values falling in favor of the absorption range of the drug in vivo(lg Pap = 1.69-1.98).But in the p H 2,5,6.8,the lg Pap value is greater than 2,It has strong lipophilicity.(4)The results of the determination of nicotinate-curcumin ester in vivo by high performance liquid chromatography(HPLC)showed that the standard curve regression equation of nicotinate-curcumin ester is y=-50.377+2.1383x(r = 0.997,n=8),a good linear relationship was shown within the range of 0.084?525 ?g / m L.The nicotinate-curcumin ester and its nanoparticles in rabbit body of pharmacokinetic experimental results show that the nicotinate-curcumin ester raw materials and nanoparticles have two tmax,suggests that there is a enterohepatic circulation;The bimodal tmax of nicotinate-curcumin ester is shorter than the bimodal tmax of nanoparticles,indicating that the nicotinate-curcumin ester nano-particles have sustained-release effect.The difference between the two peak values of the first blood drug concentration is statistically significant.The concentration of the nicotinate-curcumin esters drug substance is higher than that of the nanoparticles;The difference in the second blood drug concentration peak value is not statistically significant.The AUC of the nicotinate-curcumin esters nanoparticles was significantly higher than that of the drug substance,and the average AUC of the nicotinate-curcumin esters nanoparticles was 2.49 times the average value of the raw material AUC.The results showed that the nicotinate-curcumin estersr made of nanoparticles can significantly improve the bioavailability of nicotinate-curcumin esters.The nicotinate-curcumin esters were not metabolized to curcumin during transport in vivo.Concusions The nicotinate-curcumin esters nanoparticle increases the equilibrium solubility of the drug substance and improves the dissolution rate of the drug substance.The nanoparticles are more likely to be absorbed in the gastrointestinal tract than raw materials;Both nanoparticles and the drug have enterohepatic circulation.The rabbit pharmacokinetics experiment shows that both the nanoparticle and nicotinate-curcumin esters have the enterohepatic circulation;The bioavailability of nicotinate-curcumin esters was improved by nanoparticles improving the pharmacokinetics;The preparation of nanoparticles with the nicotinate-curcumin esters has a slow release effect. |
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