Preparation And Evaluation Of Self-microemulsifying Drug Delivery System For Hesperidin

Hesperidin (HDN) is the flavanone derivatives, namely, hesperetin-7-0- rutinoside. It has been many Pharmacological activities, such as its anti-oxygen, anti-inflammatory, maintaining normal blood vessels osmotic pressure, increasing capillary toughness, lowering blood pressure, protecting cardiovascular, anti-tumor, and so on. As a weak acid, due to insoluble in water, its solubility was about 20μg/L in water, which leads to the low oral bioavailability. Currently, HDN is listed only tablets and capsules, to limit its efficacy and clinical applications.Self-microemulsifying drug delivery system (SMEDDS) is mixtures drug, oils, nonionic surfactant and co-surfactant, consisting of isotropic, homogeneous liquid mixture of clarity, after oral administration in the gastrointestinal under slight peristalsis, spontaneously form a diameter less than 100nm in the O/W microemulsion. As a new-fashioned drug delivery system, it has many advantages such as absorbed r- apidly, well stability, accuracy dosage, convenient administration, simple prepared, suitable for mass production. It is mainly used as vehicle for indissoluble drugs, to improve their dissolution and oral bioavailability. So it has great prospect and application value. HDN self-microemulsifying drug delivery system would be prepared, to improve the solubility, in order to improve its oral bioavailability and meet the requirement for clinical use. The main research was as follows four parts:1 establishment assay method of HDNHPLC method of HDN was established for assay. The regression equation is A=32.393C-43.603 (r=0.9996,n=7), which is linear over the range of 2.54～76.2μg/ml. Its recovery, precision, stability all met the requirement of technology.2 Prescription design and optimization of HDN-SMEDDS2.1 The balance solubility of HDN in different excipients was assayed, selected the higher ones. According to the results, IPM was chose as the oil,Cremophor EL35 as the nonionic surfactant, PEG400 as the co-surfactant.2.2 Pseudo-three rounds phase diagrams, oil(IPM)-mixed surfactants(CremophorEL35/ PEG400)-Water, were constructed by water-dropping method, to identify the efficient self-emulsification region, which was IPM(30%～40%)and mixed surfactants(Km=1:1, 60%～70%).2.3 Setted to10%, 20% and 30% three levels of the oil content in the SMEDDS, and changed at each level of surfactant and co-surfactant ratio, to optimize HDN-SMEDDS prescription, the best prescription is: the oil phase (IPM): surfactant (Cremophor EL35): co-surfactant (PEG400) = 10%: 45%: 45%, drug loading of 15 mg/g.3 Quality evaluation and dissolution study of HDN-SMEDDS in vitro3.1 HDN-SMEDDS milk drop in transmission electron microscopy was showed spherical uniform distribution and the average size of 22.91nm, particle size distribution is uniform.3.2 The influence of different temperature, diluted medium and dilution of HDN-SMEDDS efficiency of micro-emulsification was investigated; the results show that the dilution medium and dilution of HDN-SMEDDS not effect efficiency of micro-emulsion, but the temperature would effect it a little.3.3 The stability of HDN-SMEDDS at room temperature and influencing factor were studied, the results show that the stability of HDN-SMEDDS met quality standards. 3.4 HDN crude drug as the control, using direct release method to inspection HDN-SMEDDS in vitro dissolution behavior, the results show that the HDN-SMEDDS dissolution increased significantly at 10min, the basic release complete and its cumulative dissolution was 85.9%; the dissolution of HDN in water is very small and its cumulative dissolution of 20.6%.4 In situ intestinal absorption kinetics of HDN-SMEDDS in rat4.1 HPLC method of HDN-SMEDDS and phenol red as signal in circulation intestinal fluid was developed for assay. The regression equation is A=35.163C-8.563(r=0.9999, n=6); A=18.717C-19.154(r=0.9993, n=6), which is linear over the range of 4～60μg/ml. Its recovery, precision, stability all met the requirement of technology.4.2 Used HDN suspension as the reference agent, the absorption of HDN-SMEDDS was researched in duodenum, jejunum, ileum, colon, using in situ intestinal absorption in rats, and the influences of this test were investigated. It was stable for HDN-SMEDDS in circulation intestinal fluid, and it was almost no physical adsorption on the intestines. There was existed invariably absorption saturation of HDN-SMEDDS over the range of 15～60μg/ml. The results identified that HDN-SMEDDS and HDN suspension could be absorbed in the whole intestinal segments.The jejunum and ileum were the main absorption segments by passive diffusion with First-order kinetics. Compared to HDN suspension, the absorption rate constants and average absorption percentage of HDN-SMEDDS in the all intestinal segments were higher significantly (P<0.01). It can be seen SMEDDS could significantly increase the absorption in rats'intestine.