Preparation And Evaluation Of Solid Dispersion Of Daidzein Phospholipid Complex

Objective:Daidzein?7,4'-diphenol hydroxyisoflavone,DD?also known as daizeol,is a major component of soybean isoflavones?SIF?and has estrogen-like effects.However,DD is poor in water solubility and fat solubility,affecting its absorptionin the intestine,resulting in low oral bioavailability.Phospholipid complexes are relatively stable intermolecular complexes formed by the transfer of drugs and phospholipid molecules by charge transport.The combination of poorly soluble drugs and phospholipids helps to improve the affinity of the drug with the cell membrane,thereby improving the bioavailability of the drug.However,PLC has strong hydrophobicity and poor dispersibility in water.Therefore,the use of solid dispersion technology to prepare PLC into a solid dispersion can effectively improve the hydrophilicity of PLC,thus further improving the oral bioavailability of poorly soluble drugs.This project utilizes DD as a model drug to establish a solid dispersion of phospholipid complex?PLC-SD?,aiming to improve the oral bioavailability of DD,in order to apply the phospholipid complex and solid dispersion technology to SIF and the feasibility of other flavonoids provides a basis for research.Methods:1.To optimize the formulation and preparation process of DD-PLC by orthogonal design method,and to screen the solid dispersion of DD-PLC with dissolution as the evaluation index.DD-PLC-SD prescription and preparation process;the phase is characterized by differential scanning calorimetry?DSC?,infrared spectroscopy?IR?,X-ray diffraction?XRD?,and scanning electron microscopy?SEM?.2.Establish a high performance liquid chromatography?HPLC?method for the determination of DD content.The in vitro dissolution properties of DD-PLC and DD-PLC-SD were investigated by measuring the apparent solubility,oil-water partition coefficient and dissolution.3.Establish a rat model of extracorporeal rectal sac,and use cumulative absorption?Q?,absorption rate constant?Ka?and drug absorption rate?V?as evaluation indicators to investigate DD,DD-PLC and DD-PLC-SD.Absorption characteristics of the jejunum,ileum,and colon.4.Establish analytical method for determination of DD in rat plasma by HPLC method.Pharmacokinetics and bioavailability of DD-PLC and DD-PLC-SD in rats after oral administration as a reference.Conduct an evaluation.Results:1.The optimal preparation process of DD-PLC is:tetrahydrofuran is the reaction solvent,the concentration of DD is 2.5mg/ml,the ratio of DD to phospholipid is 1:3.5,the reaction temperature is 55?,and the reaction time is 1 h.Under this condition,DD and the recombination rate of phospholipids reached 94.18±0.91%.The optimal preparation process of DD-PLC-SD is:povidone-K30?PVP-K30?as the carrier,the mass ratio of DD-PLC to PVP-K30 is 1:3,and the stirring time is 1 h.The characterization results of DSC,IR,XRD and SEM indicated that DD-PLC and DD-PLC-SD were successfully prepared.2.Compared with the drug substance,the solubility of DD-PLC-SD in water and n-octanol increased by about19.3 times and 6.7 times,respectively the oil-water partition coefficient increased by about 8.4 times;the results of in vitro dissolution experiments showed that the dissolution rate of DD-PLC-SD was significantly higher than that of the drug substance under the three pH conditions.The cumulative dissolution rate of DD-PLC-SD in PBS buffer at pH=6.8 reached within 1 h more than 75%,and the cumulative dissolution rate of the drug substance within 3 hours under the same conditions is less than 20%.Compared with the crude drug,the solubility,oil-water partition coefficient and dissolution of DD-PLC were also improved,but the improvement was not as significant as DD-PLC-SD.3.The Ka of the DD-PLC-SD group was significantly higher than that of the drug-drug group?P<0.05?,and the Ka of the jejunum and ileum of the DD-PLC group was significantly higher than that of the crude drug group?P<0.05?;the Ka of the jejunum and colon in the PLC-SD group was significantly higher than that in the DD-PLC group?P<0.05?.The Q and V data at each time point showed that the absorption effects of DD-PLC and DD-PLC-SD in different intestinal segments were better than those of the drug substance,and the effect of DD-PLC-SD was better than that of DD-PLC.4.The established HPLC method for the determination of DD content in rat plasma,plasma endogenous substances without interference,methodological investigation in line with biological sample testing requirements.he pharmacokinetic study showed that the pharmacokinetics of DD,DD-PLC and DD-PLC-SD in rats were consistent with the one-compartment model,and the peak times(t_max)of the three were?116.67±15.16?min.,?43.39±11.28?min and?36.67±9.10?min,the peak concentrations(c_max)were?0.17±0.09??g/ml,?0.39±0.06??g/ml and?0.68±0.04??g/ml,and the relative bioavailability?F_r?of DD-PLC was476.6%,the F_r of PLC-SD is 925.5%.It can be seen that after the DD is made into PLC or PLC-SD,the absorption rate in the rat body is obviously accelerated,the bioavailability is significantly improved and the PLC-SD has higher bioavailability than the PLC.Conclusion:This topic successfully constructed and evaluated DD-PLC-SD.The solid dispersion of DD into a phospholipid complex can significantly improve its dissolution properties and intestinal absorption,thereby greatly improving oral bioavailability.The results of the study indicate that the reconstitution of the solid dispersion on the basis of the phospholipid complex helps to further improve the oral bioavailability of DD.This study provides a basis for the feasibility of applying phospholipid complex and solid dispersion technology to soybean isoflavones and other flavonoids.