Study On The Preparation And Tissues Distribution Of Sinomenine Long-circulating Nanoparticles

Object:Sinomenine is a fat-soluble alkaloid and only slightly soluble in water,which lead to the pharmaceuticals is not easily absorbed in vivo,besides,the clinical application of sinomenine is limited for its short biological half-life.In this study,sinomenine was selected as a model drug,safe and non-poisonous polymer materials was used as carrier materials to prepare stable,small-sized,sustained and controlled release long-circulating nanoparticles,and to study the pharmacokinetic behaviour of sinomenine long-circulating nanoparticles in rats and the tissue distribution characteristics in mice,which will provide new method and dosage forms for the therapy of tumor.Methods:On the basis of the pilot experiments,SIN-PLGA-NP was prepared by the nano-precipitation method,the entrapment efficiency and drug-loading rate of nanoparticles was determined by using the sephadex column chromatography.Using single-factor experiments and the central composite design-response surface methodology to optimize the prescription and preparation technology.On this basis,choosing PEG₂₀₀₀-PLGA amphiphilic block polymer as carrier materials.Three batches of SIN-PEG₂₀₀₀-PLGA-LCN was prepared according to this optimal prescription and technology,and evaluate the encapsulation efficiency,drug-loading,size and Zeta potential indicators of long-circulating nanoparticles.Subsequently,freeze dry process were optimized with appearance,colour and redispersibility as the evaluation index,then we investigated the preliminary stability of the freeze-dried powder.After the SIN-PEG₂₀₀₀-PLGA-LCN were intravenously administered through tail vein of rats and mice,we investigated the pharmacokinetics behaviour of sinomenine in rats and the tissue distribution characteristics in mice.Results:The optimum prescription and process were as follows:the mass ratio of SIN to PLGA was 1.4:10;the ratio of organic phase to water phase was 2.2:10;the concentration of the RH40 was 0.7%.The average encapsulation efficiency was 83.93%,and the average drug loading was7.39%,the average particle size of nanoparticles was 104.8nm.SIN-PEG₂₀₀₀-PLGA-LCN was prepared according to this optimal prescription and technology,its average entrapment efficiency was81.10%,and the average drug loading was 7.43%,the average particle size of nanoparticles was 126.1nm.In freeze drying study,6%mannitol was using as cryoprotectant,the freeze-dried powder of SIN-PEG₂₀₀₀-PLGA-LCN had good appearance and redispersibility,and there were no obvious changes before and after freeze-dried.The results of preliminary stability experiments indicated that the appearance,size,Zeta potential,the average entrapment efficiency and drug loadings of freeze-dried powder had no obvious change after storing at 4?for 3months.From the study of pharmacokinetic behaviour in rats,the T1/2?,AUC_?0-t?and CL of SIN-PEG₂₀₀₀-PLGA-LCN group were 1.20,2.28;1.74,3.15;0.58,0.34 times higher than those of SIN-PLGA-NP group and SIN solution group.From the study of tissue distribution characteristics in mice,the Ce and Re of SIN-PEG₂₀₀₀-PLGA-LCN group were all larger than 1,and the Re of liver was 3.36.Conclusion:The prepared SIN-PEG₂₀₀₀-PLGA-LCN had small size as well as high entrapment efficiency and drug loading,and obviously prolonged circulation time of drug in vivo.Moreover,it also prominently changed the distribution of drug in vivo,and showed better liver targeting.