Study On Hawthorn Leaves Flavonoids Solid Self-emulsifying Granules

Objective：Hawthorn Leaves Flavonoids has significant efficacy in treatingcardiovascular diseases. It has better curative effects in reducing blood pressure,lowering blood fat and increasing cardiac blood flow for human. Because of its poorlywater solubility and low oral bioavailability, its clinical application is limited.self-emulsifying drug delivery system is one of the technologies to improvedissolution rate and oral bioavailability, so it is really a meaning thing to prepareHawthorn Leaves Flavonoids solid self-emulsifying granules (HLF-SSEG).Methods：The solubility of Hawthorn Leaves Flavonoids in several surfactantsand co-surfactants and oils were determined, Ternary phase diagram of SMEDDS(several surfactants and co-surfactants and oils) were drawn to the area ofemulsification. The compositions of HLF-SMEDDS were selected. The formulationwas optimized by using central composite design-response surface methodology.Independent variables were surfactant (X1) and co-surfactant (X2) and oil(X3), whileresponse variables were self-microemulsifying time, mean particle size and Zetapotential. The dissolution of optimized SMEDDS was determined. Different solidaccessories were selected to absorb and release SMEDDS. Solid carrier effect on thesolubilization capacity and conductivity in SMEDDS were investigated. There-dispersion and dissolution of the proportion of different prescription rate werestudied. The size and zeta potential, DSC scan and X-diffraction were examined.Vitexia-rhamnoside of HLF-SSEG was determinated by HPLC. Accelerated testingand long-term stability was used to study the stability of HLF-SSEG. Thepharmacokinetics test of HLF-SMEDDS in rat was studied by LC-MS-MS method.Results： A method UV for quantization of Hawthorn Leaves Flavonoids was established． Rutin was selected as standard substance, and the linear range was12~72μg/mL (r=0.9997). The recovery was100.63%,99.30%,100.33%.The solubility experimental results reveals Tween80and Labrasol as surfactant,Transcotol P and PEG400as co-surfactant, Castoroi, ethyloleate and ethylol as oils.Tertiary phase diagrams were constructed to determine the greater area ofemulsification. By using central composite design-response surface methodology, thebest formulation was Tween80-Transcotol P-ethyloleate with weight ratio of47:39:13.The particle size was50nm, self-micro-emulsifying time was29.5s and Zetapotential was-17.3mv; the dissolution was more than80%in20minute. Theoptimized formulation was starch: lactose: mannitol (1:3:0.5:0.5). After dispersed, theaverage particle size was169.3±7.6nm. The dissolution was89.5%in30min.To establish the method for content determination of Vitexia-rhamnoside inhawthorn leaves flavonoids solid self-emulsifying Granules, the column wasDiamonsil-C18(200mm×4.6mm,5μm). The mobile phase consisted oftetrahydrofunan-methanol-acetonitrile-2.8%acetic acid (114:9:9:748). The linearrange of Vitexiarhamnoside was19.8～198μg/mL (r=0.9994). The recovery was100.77%，100.99%and100.97%. The concent of Vitexia-rhamnoside in threebatches HLF-SSEG is12.18mg/g，12.16mg/g and11.96mg/g.The accelerate test and long-term stability test showed that the content andappearance of HLF-SSEG did not change significantly in12months. Thepharmacokinetics experiments showed that Cmaxof SMEDDS and referencesuspension were413.33±91.22ng/mL and155.33±31.09ng/mL, tmaxwere40.0±8.66and100.0±17.32min respectively, As compared with suspension, and the relativebioavailability of HLF-SMEDDS was179.24%.Conclusions：The central composite design and response surface methodology isuseful for the formula optimizati on of HLF-SMEDDS. The prediction accuracy ofthe established model is good. HLF-SSEG is easy to prepare and its quality is stable.The dissolution and bioavailability of HLF were improved by SSEG. The evaluationmethods are simple and accurate to be used in the quality control HLF-SSEG.