Construction And Evaluation Of Self-emulsifying Drug Delivery System Of Saponins Of Sanguisorba Officinalis

Objective:To construct a self-emulsifying drug delivery system（SEDDS）for improving the solubility and oral bioavailability of S.saponins,and to evaluate its preparation process,quality standards,intestinal absorption kinetics,pharmacokinetics and pharmacodynamics.Methods:1.Construction of S.saponins SEDDS.The solubility of the Ziyuglycoside I in the S.saponins was used as the index.The oil phase,emulsifier and co-emulsifier with the best solubility were screened by single factor experiment.The selected excipients were matched to construct the ternary phase diagram.The final oil phase,emulsifier and co-emulsifier were determined by the size of the area of the milk formation.Furthermore,the D-optimal mixing test design was adopted,with the drug loading of the Ziyuglycoside I,the particle size of the self-emulsifying system and the polydispersity coefficient were used as indicators,the best formulation of S.saponins SEDDS were preferred.2.Establishment of quality assessment.The microscopic morphology,in vitro release,stability and inclusion state of the S.saponins SEDDS were used as evaluation indexes to evaluate its quality,respectively.3.Evaluation of intestinal absorption kinetics.In the rat single-pass intestinal perfusion method,the absorption percentage（A%）,absorption rate constant（Ka）and apparent absorption coefficient（Papp）of the drug were used as evaluation indexes to compare absorption of the S.saponins SEDDS,and the S.saponins raw materials in duodenum,jejunum,ileum and colon.4.Pharmacokinetic evaluation.The pharmacokinetic parameters and the in vivo bioavailability of Ziyuglycoside I in rats after oral administration of S.saponin SEDDS and S.saponin were used to evaluate the improvement of oral bioavailability of S.saponins by SEDDS.5.Pharmacodynamic evaluation.The bone marrow suppression mouse model was established by cyclophosphamide.The number of white blood cells,hematopoietic stem cells and the apoptotic rate in peripheral blood were detected to evaluate the therapeutic effect of S.saponins modified by SEDDS on bone marrow suppression.1.The optimal prescription for the optimally selected S.saponins SEDDS is:Obleique CC497-Tween-20-Transcutol P=0.25:0.45:0.30（m:m:m）,the drug loading is 23.93 mg·g^-1,and the average particle size is（207.92±2.13）nm,Zeta potential is（38.84±0.18）mV.2.The in vitro release results showed that the release rate of S.saponins SEDDS was significantly higher than that of S.saponins.3.The results of intestinal absorption kinetics showed that the A%,Ka and Papp values of the Ziyuglycoside I in the four intestinal segments significantly increased compared with the drug group（P<0.05）,of which the duodenum A%increased by 11.7 times,Ka increased by 2.1 times,Papp increased by 29 times;A%of jejunum increased by 3.2 times,Ka increased by 3.6 times,Papp increased by 3 times;A%of colon increased by 3.6 times,Ka increased by 11.3 times,Papp increased by 7 times;A%of ileum increased by 4.2times,Ka increased by 5.7 times,and Papp increased by 5.5 times.These findings indicated that SEDDS can significantly increased the absorption of S.saponins in the intestines.4.Pharmacokinetic results showed that the absolute bioavailability of oral S.saponins SEDDS（21.94±4.67）%was 6.94 times higher than that of Ziyuglycoside I（3.16±0.89）%.5.Pharmacodynamic results showed that the number of white blood cells in the model group significantly decreased compared with the normal group（P<0.05）,the number of bone marrow hematopoietic stem cells and bone marrow DNA content significantly decreased（P<0.01）,and the apoptotic rate of hematopoietic stem cells significantly increased（P<0.01）.Compared with the model group,the number of leukocytes in the SEDDS group significantly increased（P<0.05）,the number of hematopoietic stem cells and bone marrow DNA content significantly increased（P<0.01）,and the apoptotic rate of hematopoietic stem cells significantly decreased（P<0.01）.Compared with the drug group,the number of white blood cells in the SEDDS group significantly increased（P<0.05）,the number of hematopoietic stem cells and bone marrow DNA content significantly increased（P<0.01）,and the apoptotic rate of hematopoietic stem cells significantly decreased（P<0.01）.Conclusion:The S.saponins SEDDS was successfully accepted.This system not only effectively promoted the absorption of S.saponins in the gastrointestinal tract,but also improved its oral bioavailability,and its therapeutic effect on myelosuppressive mice.