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Andrographolide derivatives ISA,which was synthesized by our group,was a structuremodifications of andrographolide.The preliminary study found that the compound had strong anti-tumoreffect.However, the efficacy of the play might be restricted due to its poor water solubility,the lowbioavailability.In order to increase the solubility of ISA,improve its bioavailability,ISA loaded bile salt-phosphatidylcholine-mixed micelles （ISA-BS/PC-MM）,which took sodium deoxycholate and soya lecithin as a carrier,were prepared by film dispersion method in this study.Based on the results of single factor experiments,selecting drug dosage, carrier ratio and carrier concentration as examine factors which was the most influential factors,taking the drug concentration,encapsulation efficiency anddrug loading as evaluation index,the formulation was optimized by the central composite design-response surface method.Finally established optimization formulation of ISA-BS/PC-MM:when the hydration volume was10mL,the drug dosage was10mg, carrier ratio was3.47,carrier concentration was16.73mg·mL-1.The drug concentration,entrapment efficiency,drug loading,average diameter,multi-phase dispersion coefficient and Zeta potential of the optimized ISA-BS/PC-MM were （0.87±0.03） mg·mL-1,（86.34±1.23）%,（4.87±0.78）%,148.3nm,0.294and-32.9mV.The release behaviors in vitro of micelles were studied by dialysis method.Compared with ISA suspension liquid,the drug release of ISA-BS/PC-MM was more quick.The release characteristics of ISA suspension liquid and ISA-BS/PC-MM were all fitted with Rither-Peppas equation and the drug release mechanism was diffusion release.By intragastric administration in rats of ISA suspension liquid and ISA-BS/PC-MM accor ding to the dose of18.4mg·kg-1（with ISA plan）, the Plasma concentration was determined at0.25,0.5,1,2,3,4,6,8,12h.Adopting3P87pharmacokinetic program processing data, the pharmacokinetic characteristics in rats were investigated.The results showed that the concentration of ISA in plasmaafter intragastric administration of ISA suspension liquid and ISA-BS/PC-MM was in accord with two-compartment model.Compared with ISA suspension liquid,ISA-BS/PC-MM increased the absorption rate constant and Cmax,shortened Tmax,these said that the drug release of ISA-BS/PC-MM wasmore quick,and it was helpful for drug absorption;the elimination half-life and MRT were prolonged,the volume of distribution and clearance rate were reduced,these prompted that micelles could effectively prolong drug circulation in blood;AUC was increased,it showed that micelles could effectively improve bioavailability of ISA.By intragastric administration in mice of ISA suspension liquid and ISA-BS/PC-MM according to the dose of36.8mg·kg-1（with ISA plan）, the drug concentration of various tissues was determined at0.25,0.5,1,2,3,4,6,8,12h.Adopting3P87pharmacokinetic program processing data, thetissue distribution characteristics in mice were investigated,and targeted evaluation.The results showed that compared with ISA suspension liquid,the distribution of drug in plasma,lung and kidney significantly increased,but distinct decreased in heart,liver and spleen after intragastric administrationof ISA-BS/PC-MM.Especially the most obvious increase was in lung,it Showed certain lung targeting effects and prompted that micelles was helpful for the treatment of lung cancer;but the distribution of drug in heart was reduced, it prompted that micelles could reduce cardiac toxicity of drug.In summary,ISA loaded bile salts-phosphatidylcholine-mixed micelles could increase drugsolubility,improve the bioavailability of drug,and enhance the targeting of drug in lung,reduce cardiac toxicity.So it was expected to become a new drug delivery system of ISA and had good applic ation prospect.
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