Study On Solid Dispersion System Of Breviscapine With PVP And Poloxamer 188

Breviscapine?BRE?is mainly used for the treatment of cardiovascular diseases,anti-tumor and cerebral infarction.However,its poor solubility in acidic solution and poor stability in alkaline solution result in low bioavailability and poor efficacy after administration.It is desirable to design a suitable formulation to improve the dissolution of BRE.Aiming at these problems,solid dispersion was selected to improve its solubility in acidic solution and dissolution in acidic dissolution media.Preformulation studies of BRE were investigated.The solubility of BRE in different organic solvents and different pH phosphate buffered saline?PBS?,the oil-water partition coefficient and the stability of BRE in different pH buffers were investigated.The solubility of the drug in aqueous solution was only 0.16?g/mL and the solubility in methanol and ethanol was satisfactory.The oil-water partition coefficient of BRE was-1.846.BRE was stable in acidic solution but unstable in alkaline solution.The concentration of BRE in the high humidity conditions was slightly lower.Solid dispersion was prepared to improve the low solubility of BRE.First of all,according to the solubility and thermodynamic parameters,PVP K30 and poloxamer188 were screened as carriers and sodium acetate?NaAc?was selected as alkalizer.The preparation parameters of the solid dispersion was investigated according to the orthogonal experiment,and the optimal combination of the PVP K30:poloxamer 188:NaAc was selected as 8:1:1.Solid dispersion containing BRE was characterized to understand the physical state of drug in SD and the interaction between drug and carrier.BRE solid dispersion showed no drug crystallisation under the observation of SEM.XRD and DSC results further demonstrated that the drug existed in amorphous form in the solid dispersion.The FTIR results showed that hydrogen bond was formed between the hydroxyl groups of BRE and the carbonyl group of the carrier PVP K30.The dissolution of BRE from the solid dispersion was investigated in pH 1.2 simulated gastric fluid.The dissolution profiles of the drug were composed of two stages,namely the initial stage controlled by polymer dissolution and the platean stage governed by the physicochemical properties of drug.The dissolution curves fit the Weibull model and the fitting constant R² is 0.997.The results of the stability test of the BRE solid dispersion indicated that the BRE still existed in the amorphous state in the BRE solid dispersions after 30 days of storage.In the high humidity condition,the BRE solid dispersion absorbed moisture and the content decreased to a certain extent.Therefore,BRE solid dispersion should be stored in a dry environment.The efficacy of BRE solid dispersion on cell proliferation in vitro were investigated.HepG2 cells were used to investigate the inhibitory effect of BRE solid dispersions.The results of MTT showed that the cell growth inhibition rate?P<0.05?was dose and time dependent in the range of 6.25-100?g/mL.After 48 h,the IC₅₀ of BRE solid dispersion was determined as 19.34?g/mL.These results showed that the application of PVP K30,poloxamer 188 and NaAc as a combination of carriers was able to effectively improve the dissolution in acidic solution of BRE from SD.In vitro dissolution experiments showed that solid dispersion on HepG2 cell proliferation was effective than BRE.The above research has laid a solid foundation for the application and development of BRE preparations.