Construction and evaluation of berberine/piperine co-loaded self-microemulsion drug delivery system
OBJECTIVE To prepare berberine/piperine co-loaded self-microemulsion drug delivery system(BBR/PIP-SMEDDS),evaluate its physicochemical properties,in vitro release and pharmacokinetic characteristics.METHODS The drug loading mass ratio of berberine(BBR)and piperine(PIP)in the preparation was determined by the everted intestinal sac method.The oil-phase,emulsifier and co-emulsifier were determined by solubility detection,compatibility evaluation and pseudo-ternary phase diagram,respectively.The formulation of blank self-microemulsion drug delivery system(SMEDDS)was optimized and verified by central composite design-response surface methodology with the amount of oil-phase and the mass ratio of emulsifier to co-emulsifier as factors,and the comprehensive score of particle size and Zeta potential as response value.According to the optimal prescription,BBR/PIP-SMEDDS was prepared by adding excessive BBR and PIP raw materials under magnetic stirring,and its physicochemical properties,in vitro release behavior and pharmacokinetic characteristics in rats were investigated.RESULTS The drug loading mass ratio of BBR and PIP was 1∶1.The optimal prescription included oil-phase(ethyl oleate)accounted for 18.54％,emulsifier(Tween-80)accounted for 52.16％,and co-emulsifier(polyethylene glycol 400)accounted for 29.30％.Three verification experiments showed that the average particle size of blank SMEDDS was(16.49±0.49)nm;the Zeta potential was(-16.22±0.77)mV;the comprehensive score was 0.97,the relative deviation of which from the predicted value(0.95)was 2.11％.The prepared BBR/PIP-SMEDDS was an oil-in-water microemulsion,which was a golden yellow oily liquid with a spherical shape.The average particle size was(32.90±0.38)nm,and the Zeta potential was(-19.17±0.70)mV.The encapsulation efficiency of BBR was(90.44±0.88)％,and the drug loading was(10.18±0.17)mg/g.The encapsulation efficiency of PIP was(87.48±1.13)％,and the drug loading was(9.41±0.17)mg/g.BBR/PIP-SMEDDS had good stability at low temperature(4 ℃)in the dark,centri-fugation and dilution.The results of in vitro release showed that the cumulative release percentage of BBR in simulated intestinal fluid for 24 h was significantly higher than that of the raw drug after the preparation of SMEDDS.The pharmacokinetic results in rats showed that the peak concentration and area under the drug-concentration time curve(AUC0-t)of BBR/PIP-SMEDDS were 4.61 and 7.07 times higher than those of the raw drug respectively,and the relative bioavailability was 707.484％.CONCLUSIONS BBR/PIP-SMEDDS is successfully prepared,and the in vitro release and bioavailability of the preparation are greatly improved compared with the raw material.
berberinepiperineself-microemulsion drug delivery systempreparation optimizationphysicochemical propertiesin vitro drug releasepharmacokinetics
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