Establish Formulation System Of Self-microemusifying And Study On Preparation Of Self-microemusifying Capsule For Silibinin

Purposes: Silymarin is active component of fruit of silybummarianum, one compositae plant. Silibinin is the main composition of silymarin flavonoid mixtures, the most content, the strongest activity and pharmacological action. Today, silymarin has become one cosmopolitan liver protectant with certain curative effect. Many kind of silymarin preparation have been widely used to cure acute hepatitis, chronic hepatitis, cirrhosis and so on. But, silymarin is indissolvable drug with solubility only 0.0404mg/mL and has poor bioavailability which influence the clinical curative effect. Besides silymarin, 40% newfound lead compounds are lipid soluble, a great quantity traditional Chinese medicine ingredient such as puerarin, rutoside, oleum curcumae wenchowensis, taxinol and so on are low water-solubility medicines.Self-emulsifying drug delivery system, (SEDDS) is a newfashioned drug delivery system. It also named self-microemulsifying drug delivery system, (SMEDDS), when the emulsion particle size is smaller than 100 nm. It is main used as vehicle for indissolvable medicines to raise orally absorption. But, SMEDDS is a new-type of administration system and administration technology without unified and integrated quality control standard in internal and abroad, and the formulation design depend most on experience. In this treatise, Puerarin(PUE), Indomethacin(IDM) and Zedoary Turmeric Oil (ZTO) were chosen as model drugs to establish the quality controlling standard, research the regularity between the character of drugs and the formulations. Silibinin was chosen as model drugs to research the vitro and vivo evaluation of SMEDDS.Methods: (1) The regularity between drugs peculiarity and formulations of self-microemulsifying. Puerarin(PUE), Indomethacin(IDM) and Zedoary Turmeric Oil (ZTO) were chosen as model drugs. The optimization composition and the ratio of PUE-SMEDDS, IDM-SMEDDS and ZTO-SMEDDS including oil, emulsifier and co-emulsifier were studied by orthogonal design and pseudo ternary phase diagrams and the co-dissolving situation of Pre-microemulsifying concentrate(PMC), the emulsifying efficiency(the emulsifying speed, the degree of emulsifying), the stability in 24h after emulsifying(the float oil in water surface, the drug sediment) were used as estimating index. Also, the dissolution rate of model drugs SMEDDS were compared with market product or self-made product.(2) study and research of SLB-SMEDDS. The solubility and O/W coefficient of distribution in different ratio and different pH of n-octyl alcohol– distilled water of SLB in 25℃were determined by ultraviolet spectrophotometry.The optimization composition and the ratio of SLB-SMEDDS, including oil, emulsifier and co-emulsifier were studied rthogonal design and pseudo ternary phase diagrams and the co-dissolving situation of PMC, the emulsifying efficiency (the emulsifying speed, the degree of emulsifying), the stability in 24h after emulsifying(the float oil in water surface, the drug sediment) were used as estimating index just as before stated. The vitro dissolution were compared with the self-made granula capsule, and stability was studied, also.The pharmacokinetics of SLB-PMC capsule in rat was investigated by high efficiency liquid chromatograph and was compared with self-made SLB suspension. The data of concentration in plasma with time was processed with 3p97 pharmacokinetics procedure and was fitted with model of compartment.(3) Studied the SLB phospholipid complex-SMEDDS. SLB was prepared into phospholipid complex by single factor investigation and orthogonal design. The solubility and O/W coefficient of SLB phospholipid complex were determined. Further, the SLB phospholipid complex was formulated into SMEDDS.Results: (1) The regularity between drugs peculiarity and formulations of self-microemulsifying. Besides PUE, IDM, ZTO, the optimum public formulations of PUE-SMEDDS, IDM-SMEDDS and ZTO-SMEDDS were composed of tween80, ethyl oleate and PEG400, with the particle sizes of 14.2nm, 18.0nm and 66.7nm after emulsifying. The dissolutions of the optimum formulations of PUE-PMC, IDM-PMC and ZTO-PMC in artificial gastric juice(artificial intestinal juice) were >95% in 20 min and higher than the comparison tablet or capsule.(2) Study and research of SLB-SMEDDS. The solubility of SLB was 33.8μg/mL and the balanced time of SLB in n-octyl alcohol- distilled water was 6 h. The o/w coefficient of distribution of SLB were multiplication following the raising of water layer ratio. When n-octyl alcohol: distilled water was 1:6, the coefficient of distribution was 3.87.The coefficient of distribution was multiplication firstly following the raising of pH, when the pH was 5.0, it went to the peak 8.2, then it decreased.The optimum formulations of SLB-SMEDDS were composed of SLB, Labrafac Lipophile WL 1349, Cremophor RH40 and PEG400, with the ratio 3.85:16.15:60:20. The particle size was 14.2nm after emulsifying. The dissolution of SLB-PMC in artificial gastric juice and artificial intestinal juice were both >95% in 16 min and the self-made SLB granulation capsule was almost not dissolution. The appearance and content of SLB-SMEDDS were almost not change in three month by keeping in 4℃or room tempreture, color gradually turned to deepen and content decreased a little in 15 days by keeping in (4500±500) Lx highlight-struck accllerated text.The data of concentration in plasma with time of SLB-PMC and SLB-suspension were best fitted with first-order absorption one compartment model. The Cmax of SLB-PMC and SLB-suspension were 0.70μg/mL and 0.104μg/mL, respectively. The AUC of SLB-PMC was 11.7 times higher than SLB-suspension and the relative bioavailability was 1265.22%.(3) Studied the SLB phospholipid complex-SMEDDS. The best productive condition of SLB phospholipid complex were 50℃reaction temperature, 2h reaction time, the ratio of SLB and phospholipid was 1:2. the complex ratio was 100% following above to prepared. The solubility and O/W coefficient of distribution of SLB phospholipid complex were 126.3μg/mL and 166.64, respectively. the optimum formulations of SLB phospholipid complex-SMEDDS were composed of complex, ethyl oleate, tween80 and propylene glycol, with the ratio of 12:30:45:13. The dissolution of t SLB complex-PMC in artificial gastric juice was >80% in 36 min.Conclusions: The SMEDDS public formulation system established in this research fits with indissolvable drugs having different solubility and O/W coefficient of distribution. It would gotten good result when the formulation ratio was adjusted according to different drugs, with the formulation uniform and the total amount changeless. This public formulation system has applied for patent(the application accepted number is 200810025617.3 ).The estimated indexes were allround and quantification by applying several indexes combined evaluation style for SMEDDS formulation design and it will have some demonstrated effect for evaluating SMEDDS scientific and overall.The vitro dissolution of indissolvable drugs with different solubility and o/w coefficient of distribution were all notable higher than comparison tablet(capsule). The vivo bioavailability of SLB-PMC was far higher than the self-made suspension. The research demonstrated SMEDDS can effectively raise the absorption in vivo of indissolvable drugs and the preparation technology is simple. SMEDDS is one of new technology and new dosage form of preparations with good applied prospect.