Research Of Xiongbing Self-emulsion Dripping Pill And The Evaluation System

1 ObjectiveThis research is the sub-item of the project "The Construction and Evaluation of local PK/PD Model's on chinese medicine by Microdialysis Technique" (No.30873443). To study the preparation of XiongBing(XB) Self-emulsion dripping pill, the formula is made up of Chuanxiong, ligustrazine, borneol and to establish the quality standards. Observing the release characteristics in vitro and pharmacokinetic characteristics in vivo in SD rats with micro-dialysis technology. And to further descripe dynamic characteristics of the new formulations with XB microemulsion for the reference.2 Methods2.1 Refining process research of ChuanXiong alcohol extractionTo establish the determination method of FA by HPLC.Purifing alcohol extraction solution of ChuanXiong by using macroporous adsorption resin and studying the influence factors of purification process, in oder to enrich FA in greatest extention and provide stability intermediates for the prepration of XB self-emulsion dripping pill.2.2 Preparation of Xiongbing Self-microemulsion drug delivery system (XB SMEDDS)The XB SMEDDS was prepared by using the methods of titration to prepare the Pseudo-ternary phase diagram. The size, solubility of XB ME is tested. Researching the preparation technology influence the ability of self-mircroemulsion and molding by testing emulsification rate,to decide the formular and preparation method.2.3 Preparation of XB SEDDS dripping pillThe study was made on the basis of screening the marix refrigerant, proportion of the drug and marix; To optimizate the molding technics,the proportion,dripping speed and space, temperature was tested. With the hardness,trailing degree,spherical degree,self-micro-emulsion rate,to decide the suited condition of moulding technics.2.4 Quality Assessment of XB SEDDS dripping pillStudy the appearance,the size distribution,self-microemulsion rate,dissolution time and the stability of XB SEDDS dripping pill. To establish the TLC and the determination method of the main components of it.2.5 The study of release characteristics in vitro of XB SEDDS dripping pillStudy release characteristics of it by simulate physiological environment in different medium and different conditions. The study was made on appearance characters,the size distribution,viscosity Observing the influence of self-microemulsion pocess and molding of ME to forecast micro emulsion result in vivo.2.6 Pharmacokinetics of XB SEDDS dripping pillWith the micro dialysis technology to determinate the concentration of drug concen-tration in blood and brain of SD rats,draw concentra-tion-time curve. Data was processed by DAS2.1 software,fitting the best compartment model.Prepared with Xiong Bing ME,to Clariflying pharmacokinetic characteristics of pill.3 Results3.1 Refining process research of ChuanXiong alcohol extractHPD-100 macroporous adsorption resin was wet packing.the ratio of diameter and height was 1:8, Chuan xiong ethanol-extraction fluid (concentration of it was 0.5 kg.L-1), the ratio weight of resin and drug was 2:1, with the speed of 2 BV.h-1 to adsorption, stewing 2 h,with 2 BV water of pH 3.0 to clean impurities by 10 BV. h-1.Garnish with 10 BV 50%ethanol by 8 BV.h-1.Collect eluent desorption, parallel three copies, vacuum drying,weighing,determinate the content of FA, calculated the ratio of dried solid and the FA content, the ratio of dried solid were 2.07%,2.02%,2.04%, average 2.04%, RSD is 1.25%; The FA transfer rate 83.67%,84.65%,86.09%, average 84.80%, RSD is 1.44%, the content of solid respectively in the FA 33.19,34.09,33.58 mg.g-1, average 33.62 mg.g-1, RSD is 1.34%, FA greatly enriched and the content stablely, they can provide stable intermediates for preparation. 3.2 Preparation of XB SMEDDSThe result indicated that the TMP has a strong solubility in Ethyl Oleate, emulsifier and assistant emulsifiers. Microemulsion ternary phase diagram shows that the Ethyl Oleate /EL-35, OP (1:1)/glycerol, anhydrous ethanol (6:1) combination (Km= 1.5:1) has a large dairy region. To research the particle size, viscosity, stability based on the ternary phase diagram. The preparation method of Xiongbing microemulsion:ChuanXiong 500g, TMP 2.5 g, borneol 0.5 g, the ratio of Ethyl Oleate, EL-35, OP, glycerol, alcohol is 10:18:18:21:3.3.3 Preparation of XB SEDDS dripping pillBy orthogonality test select the suited condition of moulding technics of dropping pill, make the scale of medicine and radicle is 1:3(the raito of PEG4000 and PEG6000 is (1:1), the temperature of drugs is 80℃,the speed of droping is 45 d.min"1.3.4 Quality Assessment of XB SEDDS dripping pillThe product is tan dripping pill in 25℃.Testing three batches of XB SEDDS dripping pill,the self-microemulsion time 8 min15 s,8 min35 s,8 min9 s;the particle size are 43.0 nm, 45.1 nm,44.3 nm, RSD 2.15%, distribute uniformly. average viscosity is 2.83 mPa-s, RSD = 1.87%. The study of TLC and the content concentration required that the containing of TMP is not less than 0.30 mg, ferulic acid is not less than 0.04 mg, borneol is not less than 0.06 mg of 1 XB SEDDS dripping pill. The stability of the preparation was studied,and the results showed that the product was stable. The appearance is in good shape,suitable hardness,even color;the average size and self-emulsifying rate aren't significant change; active ingredient content is stable.3.5 Release characteristics in vitro of XB SEDDS dripping pillThe release degree is similar in artificial intestinal juice, artificial gastric juice and water. Inthis three different medium, dissolving degrees in 20 min are more than 95%, dissolving faster. Based on the investigation the factors of influence, we can predict, it will not be influenced by different medium and diluted times,can self-emulying well.3.6 Pharmacokinetics of XB SEDDS dripping pillDrug concentration data when processed by DAS2.1 software, the Pill group and microemulsion group all showed one-compartment model after orally administration. The AUC, Cmax of pill in the blood and brain wasn't great different with microemulsion, which showed pills had good efficacy and bio-Utilizatio. But T1/2,MRT0-∞were significantly different in blood and brain.MRT0-∞respectively was 1.21,1.13 times of microemulsion, T1/2 was 1.24,1.19 times of microemulsion,indicating that elimination rate of the pill was slower than the microemulsion in the blood and brain, and drug residence time was longer in vivo.4 ConclusionIn this study, enriching and purifying FA in greatest extention by macroporous resin. which provide stability intermediates for the prepration of XB self-emulsion dripping pill. The preparation process of the pill is feasible, testing is convenience, and quality is stability. SEDDS can effectively improve the solubility of insoluble drugs,and the stability of liquid instability. After self-emulsilying in the gastrointestinal tract, small size and distrbusite uniformly can increase inclusion, improve drug absorption.It had good bioavailability, long residence time, which extended treatment,which showed great research value and development prospects of the new drug delivery systems.