The Study Of Solid Self-microemulsifying Drug Delivery System(S-SMEDDS) For Oral Delivery Of Cyclovirobuxinum D And In Vivo Pharmacokinetic Study Of Voriconazole Injection

Cyclovirobuxinum D is an alkaloid which extracted and refined from buxus in1970sby Chinese researchers. Using it as a raw material, Huangyangning tablets, acardiovascular drug, were developed and applied in treatment of cardiovascular disease,such as angina, coronary heart disease, arrhythmia, cardiac insufficiency. Thirty years ofclinical application showed that Cvb-D had a strong curative effect and low toxicity, withbroad application prospects. However, due to poor aqueous solubility, the bioavailabilityof Cvb-D is very low and need for multiple doses in clinical, likely to cause bloodconcentration "peak-valley" phenomenon and result in instability efficacy and poor patientcompliance. To overcome these shortcomings and improve the oral bioavailability, solidself-microemulsifying drug delivery system of Cvb-D was studied in this paper. SMEDDScan significantly improve the oral bioavailability of the insoluble drug and received moreand more attention. The main research results are as follows:The preformulation study of Cvb-D was taken. A high performance liquid phasemethod was established for analysis of Cvb-D. The method was comprehensivelyvalidated and then applied in determination of the saturated solubility of Cvb-D in waterand the apparent oil-water partition. The results showed that Cvb-D has low watersolubility and better liposolubility, suggesting that use SMEDDS to increase its solubilityand gastrointestinal dissolution can improve the bioavailability.The Cvb-D liquid self-microemulsifying drug delivery system was prepared.Saturated solubility of Cvb-D in different lipids and surfactants was determined andpriority choose the materials of better solubility, combined with the compatibility ofmaterials and build pseudo-ternary phase diagram to screen the prescriptioncomponents.On this basis, combined with the self-emulsifying properties(includingemulsifying time, particle size, zeta potential, etc) and stability of the prescription,the optimized formulation of the liquid SMEDDS was determined as follows: Oleic acid:WL1349=2:1,EL:Transcutol P=2:1,(Oleic acid+WL1349):(EL+Transcutol P)=6:4. Theparticle size of microemulsion after self-emulsifying was70nm with a nearly sphericalshape.The cvb-D solid self-microemulsifying drug delivery system was prepared. Solidself-microemulsion was prepared by spray-drying with HPMC as a solid carrier. Theobtained solid self-emulsifying microemulsion exhibited good redispersion performanceand could form a fine emulsion spontaneously with a droplet size of100nm whendispersed in the water under gentle agitation, indicating that the self-emulsifying abilitywas kept in solid SMEDDS. Observation with TEM showed that the microemulsionparticles formed after self-emulsifying are nearly spherical. SEM showed the solid powderis irregular spherical with different degrees of surface pitting. X-ray diffraction showedthat Cvb-D is amorphous form in the solid SMEDDS.The pharmacokinetics study of itraconazole injection was carried out in rats. Theconcentration-time curve was established, and relevant pharmacokinetic parameters wereobtained.In summary, the obtained Cvb-D solid SMEDDS provides a new direction for thedevelopment and utilization of Cvb-D, and the preliminary in vivo pharmacokinetics studyof itraconazole injection provides the theoretical basis for the development of its products.