Studies On Improving Bioavailability Of Daidzein And Total Flavones Of Hippophae Rhamnoides L.by Nanosuspension Technology

Purpose: The flavonoids component of traditional Chinese herbal medicines has multiple pharmacological activities such as dilatation of coronary artery,anti-inflammatory,anti-oxidation and anti-estrogen,etc.However,its poor water solubility leads to low oral absorption,which limits its therapeutic effect.In this study,daidzein and total flavones of Hippophae rhamnoides L.nanosuspension,which were the insoluble flavonoid components of traditional Chinese medicine,were developed to improve their solubility and oral absorption.The purpose is to preliminarily explore the adaptability and feasibility of nanosuspension technology in improving the solubility and bioavailability of flavonoids components of traditional Chinese medicine.Methods: Daidzein and total flavones of Hippophae rhamnoides L.nanosuspension were prepared by solvent-antisolvent precipitation-high pressure homogenization method,and the prescription factors(type of solvent,drug concentration,solvent antisolvent ratio,type of stabilizer,concentration of stabilizer)and process parameters(pressure and number of homogeneous),etc.were investigated to obtain preparation process of nanosuspension.Then,the nanosuspension was characterized by SEM,PXRD,and FT-IR.Afterward,the saturation solubility,stability,in vitro dissolution,cytotoxicity,and in vivo pharmacokinetics of nanosuspension were evaluated.Results:Daidzein nanosuspension prepared with HP-?-CD,soy lecithin,HP-?-CD: soy lecithin,TPGS,TPGS: SBE-?-CD,SDS,HPMC E5: SDS was obtained.The seven daidzein nanosuspension presented relatively regular shapes and homogenous sizes with particle size of 360-600 nm,and were physically stable and biocompatible.Additionally,the saturation solubility of daidzein in nanosuspension was 2.39-6.38 times higher compared to that of coarse daidzein,and the amount of daidzein released from nanosuspension was significantly higher than that of the pure drug.Consequently,when the daidzein suspension was used as reference preparation,the relative bioavailability of daidzein nanosuspension in rats was 163.06%-219.68%.In particular,daidzein nanosuspension prepared with steric stabilizers and electrostatic stabilizers as co-stabilizer(HPMC E5: SDS)has the highest solubility and oral bioavailability,which is an optimal formulation.Similarly,the total flavones of Hippophae rhamnoides L.nanosuspensions stabilized with SDS,Soluplus,P407,PEG-6000 and HP-?-CD,with particle size of 130-200 nm,were obtained.The saturated solubility of quercetin,kaempferol and isorhamnetin in nanosuspension were increased by 7.87-24.06 times,7.30-26.58 times,and 59.08-85.60 times,respectively,and the dissolution rate is also significantly improved.Additionally,when the total flavones of Hippophae rhamnoides L.was used as reference preparation,the relative bioavailability of quercetin,kaempferol and isorhamnetin in nanosuspensions was 95.90%-128.8,77.13%-385.21%,120.04%-411.50%.In addition,total flavones of Hippophae rhamnoides L./HP-?-CD inclusion complex and nanaosuspension stabilized HP-?-CD was prepared.The solubility of quercetin,kaempferol and isorhamnetin in the inclusion compound was 6.24 times,7.14 times and 1.36 times higher than that of the corresponding nanosuspension,and the oral relative bioavailability of these three flavonoids after oral administration of the inclusion compound in rats was 2.09-7.49 times,compared with corresponding nanosuspension.Additionally,crystal form and intermolecular interactions of the drug are different in these two formulation,indicating that HP-?-CD can be used not only as an inclusion compound preparation,but also as a stabilizer for nanosuspension.Conclusions:In this study,the daidzein and total flavones of Hippophae rhamnoides L.nanosuspension was prepared,which can effectively improve the water solubility and oral bioavailability of them.Obviously,nanosuspension technology is an effective and feasible approach to improve the oral absorption of poorly soluble flavonoids of traditional Chinese medicines,which also will provide reference for development and application of related formulations of flavonoids components.