Studies On Puerarin Self-Microemulsifyevg Drug Delivery System And Solidfication

Puerarin, a traditional Chinese medicinal herb, known as isoflavone compound is extracted from kudzuvine root of leguminous plant. Called7,4’-Dihydroxy-8-C-glucosy-lisoflavone. Puerarin has low solublility in water.SMEDDS is isotropic mixtures of an oil, surfactant, co-surfactant and drug, which creates fine droplets of emulsion (<100nm), when under gentle agitation following dilution by aqueous phases at surrounding temperature (usually37℃).SMEDDS can increase the solubility of the drug significantly. In this study, we prepared the puerarin SMEDDS and enhanced the release rate and bioavailability of puerarin in vivo by increasing the solubility of the drug.With the development of the material and manufacture process, there are more and more resechers focus on the solidification of SMEDDS, and it needs the solidification of self-emulsifying ingredients into suitable solid material to form various solid dosage forms include self-emulsifying microspere, self-emulsifying pellets, self-emulsifying tablets and so on.Alginates are natural polysaccharides extracted from brown sea weed and plant cell walls. Alginate is a linear copolymer consist of mannuronic acid and guluronic acid. Sodium-alginate can crosslink with divalent cation (calcium cation) to form calcium alginate gel of non-toxicity, insoluble in water or acid and adequate strength.In this study we prepare puerarin SMEDDS into alginate-calcium gel beads in order to avoid the drawbacks of liquid dosage, combine the advantages of SMEDDS with those of solid dosage forms and enhance the bioavailability and clinical efficacy of drug.Part I Studies on puerarin self-microemulsifying drug delivery systemUV method of puerarin was developed for assay. The wavelength of the peak is305nm. The regression equation was A=0.0231C+0.0351, r0.9996, which was linear over the range of5.0～35mg·L-1. At the same time, its precision, recovery all met the requirement of technology.The basic components of the formulation were screened by investigating the equilibrium solubility of puerarin in different oils, surfactants, and co-surfactants and drawing pseudo ternary phase diagrams to indentify the area of microemulsion in different prescription combine equilibrium solubility and pseudo-ternary phase diagrams to get the optimal formulation of puerarin SMEDDS, MCT was used as oil, Cremophor RH40was used as surfactant and Transcutol P was used as co-surfactant, meanwhile drawing pseudo-ternary phase diagrams in different Km. The result of oil percentage ranges from10%to40%, km ranges from2to5.A central composite design (CCD) was used to opitimize the prescription of the Pu-SMEDDS. The average partical size and equilibrium solubility in different prescription were taken as dependent variables, and the oil percentage and surfactant to co-surfactant ratio (Sur/Co-s ratio) as the independent variables. The best formulation composed of ODO-Cremophor RH40-Transcutol P(17.5%:55%:27.5%). The average partical size is21.51nm. The polydispersity is0.075. In the study of release in vitro, the drug release rate of SMEDDS is faster than puerarin suspension in the medium of0.1N HC1. The stability experiment indicated that puerarin-SMEDDS could be kept stable at room temperature for3months.HPLC method of puerarin was employed to determine puerarin in rat plasma, which met the requirement of technology. After oral administration, the concentration of puerarin in plasma The regression equation was y=49.414x+2.67, r=0.9994, which was liner over the range of0.0125～5.0μg·ml-1. After oral administration compared to the puerarin suspension, the values of Cmax and AUC(0-24) from puerarin SMEDDS resulted in a2.04-and2.3-fold increase in vivo respectively compared with the puerarin suspension. As a result, we could enhance the oral bioavailability of puerarin by SMEDDS. Part Ⅱ the solidification of liquid Pu-SMEDDSDripping method was used to prepare the puerarin SMEDDS calcium-alginate gel beads. A central composite design (CCD) was used to investigate the influence of factors (sodium-alginate concentration, calcium chloride concentration, curing time) on the responses including entrapment effciency and droplet size of the beads after emulsion. The optimum preparation as follows:1.61%concentration of sodium alginate.32.09%concentration of calcium chloride,16.15min of calcification,73.74%entrapment effciency, the average partical size is56.89nm.We study the release property of the calcium-alginate gel beads in vitro. The release percentage of puerarin from the SMEDDS was faster than that of from the gel beads in phosphate buffer (pH6.8). The DSC curve suggest puerarin existed in amorphous state in the beads and no interaction occurred between the puerarin and other excipient. We study the pharmacokinetics of SMEDDS gel beads. The values of Cmax and AUC(0-12) from puerarin SMEDDS Ca-alginate gel beads resulted in a3.2-and2.22-fold increase in vivo respectively compared with the puerarin gel beads.