Study On The Construction And Evaluation Of Nano-micelles For The Delivery Of Poorly Soluble Drugs

A poorly-water-soluble drug was restrict in application with low bioavailability due to the poorly soluble, while the micelle drug delivery system was focus on development in solving it. The thesis presented here focuses mainly on the preparation and evaluation on solubilization and effect in vivo of polymer-lecithin-sodium cholate mixed nano-micelles applied for SLB, which is combined single molecular polymeric micelle with lecithin/bile salt low molecular micelle. It will be divided into four parts as follows:Part one: ReviewThe advanced progresses of micelles, a new carrier of pooly-water-soluble drug, are described, including physico-chemical properties, the carrier materials, preparation methods, the mechanism on solubilization and the applications in fields of drug delivery, which of course, may be regarded as a basis for our succeeding research.Part two: Formulation of nano-micelles and evaluation in pharmaceuticsIn this part, we choose the organic solvent, polymeric carrier, and suitable proportion of SLB/lecithin based on the pre-tests accrording to the clarity, stability and diameters of nano-micelles. We make sure of the best ratio between lecithin and sodium cholate are 4 to 3 by pseudo-triphasic figures of lecithin/sodium cholate binary micelles, and the final ratios, 1～2:4:3:3, between SLB, lecithin, sodium cholate and polymer are confirmed by another pseudo-triphasic figures of ternary micelles.The ternary nano-micelles were prepared for the studies on the shape, size, stability, drug content and release behavior in vitro. The results showed that most of the particles of nano-micelle were spherical and were distributed symmetrically. The average diameter of nano-micelle is 61．2nm, and the zeta potential is-44．8mV. The ultraviolet spectrophotometer were used to determin the drug content and 4．19mg·ml^-1 SLB were in nano-micelles. No any changes had been observed after three months in stability test conditions. The release behavior has been studied by dialysis method. Datas showed that the accumulative releasing ratio has a compact relation with pH value of the release mediums. In pH 7．4,60% of SLB were released in 72 hours. Part three: Evaluation on solubilization of nano-micellesThe solubility of SLB in binary micelles and ternary micelles was determined, furthermore, the effect on solubilization of nano-micelles prepared by different polymers was compared by solubilities and triphasic figures in order to expain the relationship between solubilization and struture of polymers. We draw the same conclusion that ternary micelles were better than binary micelles on the capability of solubilization, as well as the same results showed that the sequence on effect is respectively K30>K17>K90 in povidone and F108>F127>F98>F88>F68 in Pluronic. It indicated that the solubilization effect is related to the proportion of hydrophobic block. The prolonging of hydrophobic block leaded to the better solubilization on drugs.Part four: Evaluation in vivo of nano-micellesDistribution of SLB control preparation, binary micelle and ternary micelle were studied by HPLC in mice. The results showed that the amount in micelles were double than those in control preparation.Then, we evaluated the bioavailability of micelle preparations based on the blood concentration data in dogs. The concentration data were fitted with compartment model and non-compartment model respectively in so as to make the studies on relative bioavailability, bioequivalence and correlation in vitro and in vivo. The results showed micelle preparations prolonged the T_max, C_max and MRT, AUC of free-SLB in binary and ternary micelle is 228．2±57．5% and 309．9±104．1% respectively, as well as AUC of total-SLB in binary and ternary micelle is 130．6±30．7% and 258．4±29．8% respectively. The two one-side test results showed that ternary micelle have better bioavailability than binary micelle and control preparation. The absorption fraction in vivo has good correlation with accumulative releasing ratio in vitro so that the quality of micelle preparations can be reflected in vitro.