Preparation And Pharmacokinetic Study Of HYSA Phospholipid Complex Loaded Self-Emulsifying System

Objective Hydroxysafflor yellow A is one of the main active ingredients of Chinese traditional medicine safflower,who has a variety of pharmacological effects such as anticoagulation,anti-oxidation,expanding coronary artery,reducing blood pressure,relieving myocardial ischemia,immunosuppressive and brain protection.Low oral bioavailability of HSYA greatly limits the development of oral preparations,due to its strong water-solubility and poor fat-soluble properties.Therefore,the products on the market are mainly based on injections.In order to solve the disadvantage of poor oral absorption of hydroxysafflor yellow A,the hydroxysafflor yellow A phospholipid complex was obtained by reacting HSYA with soybean lecithin in this study.And the phospholipid complex was prepared into a self-microemulsifying drug delivery system to future increase the oral bioavailability of hydroxysafflor yellow A.So as to provide some research ideas and foundation for the development of oral preparations in the future.Methods Through the single-factor experiment,the recombination rate was used as the evaluation standard.The solvent evaporation method was used to examine the recombination rates under different reaction solvents,reaction times,reaction temperatures,drug concentrations,and drug/lipid ratios,and the optimal conditions for the preparation of hydroxysafflor yellow A phospholipid complex（HSYA-PC）were determined.Characaterization of the complex by infrared spectroscopy（FT-IR）,X-ray diffraction（XRD）and differential scanning calorimetry（DSC）.The composition and proportion range of each prescription in the blank self-microemulsion were obtained by the preparation of the emulsification grade test and the pseudo-ternary phase diagram.Central composite design（CCD）surface method was used to optimize the preparation of hydroxysafflor yellow A phospholipid complex self-microemulsifying drug delivery system（HSYA-PC-SMEDDS）with particle size and drug loading as response values.The particle size and Zeta potential were evaluated and the effects of different dilution media and times on HSYA-PC-SMEDDS.In addition,the HSYA-PC-SMEDDS was encapsulated in an enteric capsule shell and its in vitro dissolution in different dissolution media was measured.Finally,the pharmacokinetics of HSYA-PC-SMEDD in SD rats was investigated by intragastric administration with HSYA aqueous solution as a control group.Results The single factor experiment results showed that when the reaction solvent is absolute ethanol,the reaction time was 2h,the reaction temperature was 40°C,the drug concentration was 2 mg/m L,and the ratio of drug to lipid was 1:3,the preparation conditions of HSYA-PC were the most excellent.The recombination rate of the best process was（98.14±0.95）%,and infrared spectroscopy,X-ray diffraction and differential scanning calorimetry demonstrated that the complex formed between HSYA and soybean lecithin did not generate new chemical bonds.The result of emulsifying grade test showed that the blank SMEDDS composed of Ethyl oleate,Tween 80 and Transcutol^?P could form homogeneous,stable and clear solution with light-blue rapidly.Meanwhile,HSYA-PC showed well solubility in the medias mentioned above,（2.30±0.21）mg/g,（1.36±0.25）mg/g and（83.03±6.65）mg/g,respectively.Final prescription of SMEDDS was 12.93%of Ethyl oleate and 87.07%of mix-surfactant which composed of Km value at 1.01:1,predicting that the particle size and drug loading were 13.98 nm and 25.18 mg/g while the practically measured were（14.38±0.24）nm and（24.19±0.74）mg/g.Their bias were 2.86%and-3.93%,respectively.Furthermore,the particle size of HSYA-PC-SMEDDS had not almost changed when dispersed in various medias.Whereas,the Zeta potential was increasing when concentration of H⁺increased.After encapsulated in enteric capsule,the accumulative release of HSYA-PC-SMEDDS could reach（88.75±2.31）%in p H 6.8phosphate solution but only（21.61±4.36）%,（6.03±1.08）%and（29.18±5.16）%in p H4.5 acetate solution,p H 1.2 HCl and water,repectively.The pharmacokinetics result demonstrated that HSYA-PC-SMEDDS group’s C_maxwas（1.28±0.62）μg/m L,AUC_0→tand AUC_0→∞were（430.99±151.46）min?μg/m L and（502.69±138.96）min?μg/m L,which increased remarkbly compared with HSYA control group.Its oral relative bioavailability was 292.61%,however,the T_max was almost unchanged.Conclusion The lipid solubility of HSYA has improved remarkbly when prepared into phopholipid complex,further prepared into SMEDDS and it could both disperse in aqueous solution and increase the oral relative bioavailability in rats.