Preparation And Transdermal Absorption Of Nanomete Gels Preparations Of L-tetrahydropalmatine

Objective:This project intends to use the method of transdermal drug delivery to develop l-tetrahydropalmatine（l-THP）liposomes with a certain drug load,uniform particle size,good stability and good transdermal absorption characteristics and make gel.The characteristics of transdermal absorption of liposome gel were tested to provide reference for the application of l-THP for external use.Methods:1.A Ultra Performance Liquid Chromatography（UPLC）method was established for l-THP analysis.l-THP was detected by UV detector,and lecithin and cholesterol in liposome were detected by evaporative light scattering detector.Liposomes were prepared by thin film dispersion-high pressure homogenization method.With drug loading,particle size,particle size distribution index（PDI）and Zeta potential as indexes,the preparation technology and prescription ratio were compared by orthogonal experiment,and the optimal prescription and preparation technology were selected to prepare l-THP liposome gel and its stability was investigated.2.l-THP liposome gel was coated on the skin of rats,and the blood concentration of 0-24 h was measured by liquid mass combination technique.The drug time curve was fitted to calculate the pharmacokinetic parameters of l-THP transdermal administration.3.Metabolism of l-THP in rat liver and skin tissue was compared by S9system metabolism experiment.4.l-THP liposome gel and emulsion were coated on Strat-M（?）artificial membrane using Franz diffusion cell to test the transmission rate of l-THP within 24 hours.Results:1.A UPLC method for the determination of lecithin,cholesterol and l-THP in liposomes was developed.According to single factor investigation and orthogonal experiment,the optimal liposome formulation and preparation process were as follows:mass ratio of phosphatidylcholine,l-THP and cholesterol was 10:3:1,the concentration of phosphatidylcholine hydration was 10 mg/m L,and the raw material was dissolved in dichloromethane by thin film dispersion method.Hydration time was 3 hours,ultrasonic power was 250W,2 minutes.Then l-THP liposome was prepared by high pressure homogenizer.The encapsulation rate of l-THP liposome was 18.79%,the drug loading was 4.33%,the average particle size was 68.56 nm,the PDI was 0.27,and the Zeta potential was-41.27 m V.l-THP liposome gel prepared with optimal prescription liposome showed good stability for 45 days at storage conditions of 4℃and 30℃.2.In the transdermal absorption experiment of rats,the peak time of l-THP in blood of liposome gel group was 1.2hours,the maximum concentration(C_max)was 0.16μg/m L and t_1/2 was 64hours,and the maximum concentration of l-THP in emulsion group was1.2 hours,C_max was 0.10μg/m L and t_1/2 was 9 hours.The AUC_（0-24）under the plasma concentration curve of liposome gel was 2.3 times that of emulsion.3.S9 metabolism experiment:The metabolic rate of l-THP PBS solution in liver S9 system was 0.0067μg/m L/min,and that in skin S9system was 0.0027μg/m L/min.The metabolic rate of l-THP in liver S9system was 2.5 times that in skin.The metabolic rate of l-THP liposome solution in liver S9 system was 0.0032μg/m L/min,which was similar to that in skin S9.4.The results of in vitro artificial membrane permeation test showed that the cumulative permeability per unit area of l-THP emulsion was higher than that of l-THP liposome gel.When the in vitro permeation time reached 24 hours,the area unit cumulative permeability Q_n of l-THP liposome gel and l-THP emulsion were 0.05 mg/cm² and 0.08mg/cm²,respectively.Conclusions:1.l-THP liposomes were successfully prepared by thin film dispersion method and high pressure homogenization method.The preparation process was simple and good repeatability.The prepared l-THP liposomes had good drug loading,particle size,PDI,and Zeta potential,and had good stability at 4℃and 30℃for 45 days.2.Compared with l-THP emulsion,l-THP liposome gel can improve the bioavailability of l-THP and is a promising preparation for l-THP.3.The metabolic rate of l-THP in liver S9 model was 2.5 times that in skin in vitro,suggesting that l-THP was less affected by metabolic enzymes during percutaneous absorption.