Study On Absorption Mechanism Of Pueraria Flavones Self-microemulsifying Drug Delivery Systems

Self-microemulsifying drug delivery system(SMEDDS)is a development drug carrier with the broad application prospect,but plenty of surfactants used in SMEDDS can cause gastrointestinal mucosal irritation and systemic toxicity.Hence,how to decrease the dosage of surfactant to reduce the toxicity of microemulsion is difficult in the process of preparation under the properties of microemulsion is guaranteed.In this study,Pueraria flavones(PF)were selected as the model drug.Sodium taurocholate(NATC)and Cremophor?RH 40 were used as surfactants to prepared a SMEDDS containing bile salts(PF-SMEDDSNR),in order to reduce the cell toxicity,enhance bioavailability as well as increase intestinal absorption of PF.In the present study,HPLC method of puerarin in gastric perfusate,intestinal perfusate and rat plasma was established.The results showed that the selected HPLC conditions were simple and endogenous impurities had good separating degree with puerarin.Rat in situ single-pass intestinal perfusion experiment showed that the rank order of Ka and Peff values was PF-SMEDDSNR > PF-SMEDDS without bile salts(PF-SMEDDSR)> PF-Solution in four individual intestinal segments(duodenum,jejunum,ileum and colon).Intestinal absorption of PF had the character of saturated which indicated that intestinal transport of PF might be through the medium carrier transport.PF-SMEDDSNR,PF-SMEDDSR and PF-Solution could be absorbed in whole intestinal segments.Higher Ka and Peff values were in the duodenum segment than other individual intestinal segments of PF-Solution,while for PF-SMEDDSNR and PF-SMEDDSR,the higher Ka and Peff values were in the ileum,which indicated that different mechanisms between SMEDDS and solution.SMEDDS could be explained by rich collection of lymph nodes in the ileum and transferring through lymphatic transport.In situ single-pass stomach perfusion experiment results showed that both PF-SMEDDSNR and PF-Solution had absorbed in the stomach,but PF-SMEDDSNR was significantly higher than PF-Solution(*p < 0.05),which indicated SMEDDS can promote the absorption of PF in the stomach.Pharmacokinetic study in rats manifested that Cmax and AUC0-24 h of PF-SMEDDSNR were remarkably higher than those of PF-Solution(*p < 0.05),the oral relative bioavailability was 257.00%.The results manifested that SMEDDS could contribute to the oral absorption of PF.The effects of P-glycoprotein inhibitor,carrier inhibitor,and adenosine triphosphate inhibitor on Ka and Peff values in the ileum were determined.Meanwhile,cycloheximide model was used to evaluate the lymphatic transport mechanism of SMEDDS.The results showed that intestinal absorption of PF-SMEDDSNR presented P-gp-dependent and carrier-dependent,but no energy consumption.The absorption behaviour of PF-SMEDDSNR was coincided with lymphatic transport which transfered by pinocytosis.Hence,in vivo absorption of PF-SMEDDSNR may through lymphatic transport.Under the condition of lymph-cannulated and non-lymph-cannulated,the Cmax and AUC0-24 h of PF-SMEDDSNR were 1.67 vs.4.46 ?g/mL and 438.50 vs.618.67 ?g·min/mL respectively.While for PF-Solution,the Cmax and AUC0-24 h of PF-SMEDDSNR were 1.03 vs.1.23 ?g/mL and 192.29 vs.240.73 ?g·min/mL respectively.The oral relative bioavailability was 228.04%.The absorption of PF-Solution has no significant difference between lymph-cannulated and non-lymph-cannulated,while the absorption of PF-SMEDDSNR performed significant difference at 5?15?30?60 min compared with lymph-cannulated group(*p < 0.05 and **p < 0.01).The results confirmed that lymphatic transport was one of the reasons for microemulsion promoting oral bioavailability of drugs.Biological safety results showed that compared with Cremophor?RH 40,using Cremophor?RH 40 : NATC =(1 : 1)as surfactant in SMEDDS have a higher cell viability and lower LDH release.That was,NATC possessed good biological safety from the results which NATC could reduce cell toxicity from Cremophor?RH 40 in SMEDDS to some extent.