Study On Preparation Of Baicalein Solid Dispersion By Hot-Melt Extrusion Technology And Its Evaluation In Vivo And In Vitro

Baicalein（Baicalein,BA）has a variety of pharmacological effects and has attracted more and more people’s interest.However,BA has poor water solubility and high melting point,resulting in low oral bioavailability.This study intends to use hot-melt extrusion technology to prepare a solid dispersion of baicalein to increase the solubility of baicalein,thereby improving the bioavailability of BA,and to improve the pharmacokinetics of the solid dispersion of baicalein and the span of Caco-2 cells.Membrane transport and preliminary pharmacodynamics were evaluated.This article first established the HPLC detection method for content determination,and finally selected the hydrochloric acid solution containing 0.05%sodium ascorbate and 0.5%SDS with pH=1.2 and the phosphate containing 0.05%sodium ascorbate,0.5%SDS and pH=6.8 through experimental screening.Buffer is used as the dissolution medium of BA solid dispersion in vitro,and a method for determining solubility is established at the same time.According to solubility parameters and literature reports,we initially screened PVP-VA64,Eudragit EPO and PEG 6000 among the commonly used carriers.Poloxamer P 188 was used as the plasticizer.According to BA:Carrier:P188=4:15:1 ratio,set rotation speed 50r·min-1,hot-melt process parameters of 170 ℃ throughout the region to prepare three solid dispersions of baicalein,PVP-VA64 was selected as a carrier by in vitro dissolution screening,and TPGS was selected at the same time As a plasticizer.Orthogonal experiments were designed to optimize the hot-melt extrusion process and prescription,and finally the speed was 50r·min-1,the temperature section was set to 140-170℃ gradient section,the drug loading ratio was 1:6,and the plasticizer content was The baicalein solid dispersion prepared under the condition of 10%showed the best solubility.Differential scanning calorimetry（DSC）and X-ray diffraction（XRD）analysis show that baicalein has been completely transformed into an amorphous state in the solid dispersion.Scanning electron microscopy（SEM）shows that BA solid dispersions are mostly irregular blocks.The surface is loose and porous;Fourier transform infrared（FTIR）indicates that there is an intermolecular hydrogen bond between baicalein and the carrier.In the 6-month accelerated stability test,the cumulative dissolution rate of BA within 120 minutes did not change significantly,and it was in an amorphous state with high physical stability.In the transmembrane transport experiment of Caco-2 cells,an in vitro method for detecting the content of BA in cells was established,which has high accuracy and good repeatability.The results of cell transmembrane transport showed that the Papp values of 20μg/mL BA,BA-PVP-VA64 and BA-PVP-VA64-TPGS were 1.126×10^-5,1.966×10^-5,4.231×10^-5,respectively.Compared with BA,the Papp values of BA-PVP-VA64 and BA-PVP-VA64-TPGS were significantly increased（p<0.01）,which increased by 1.75 and 3.76 times,respectively.The two solid dispersions of 10 μg/mL increased by 1.46 and 2.64 times respectively（p<0.01）;the B and C of 5 μg/mL increased by 1.4 times and 2.31 times（p<0.01）,respectively,indicating that the solid dispersion can be significantly improved Improve the transmembrane transport of BA.TPGS inhibits the activity of P glycoprotein and increases the membrane permeability of BA.In the rat pharmacokinetic study,the Cmax of the drug substance was（8.13±1.15）μg/mL,Tmax was（1.5±0.58）h,AUC0-24h was（71.97±26.92）μg·h/mL,solid dispersion The Cmax of the body is（23.09±5.79）μg/mL,the Tmax is（1.1±0.55）h,and the AUC0-24h is（207.4±27.36）μg·h/mL.Compared with the bulk drug group and the physical mixture group,BA solid The dispersion group had higher AUC0-24h（p<0.05）,Cmax（p<0.05）and shorter Tmax,and the bioavailability in rats was increased by about 2.88 times.In the pharmacodynamic experiment of CUMS mice,the model group showed obvious depression-like behaviors（decreased sucrose intake and exercise capacity,increased fixed time of forced swimming and tail suspension）after 28 days of CUMS stimulation.Baicalein and its solid dispersions（20,40mg/kg）can significantly reverse these changes（p<0.05）,but there is no significant difference between them（p>0.05）.Therefore,the solid dispersion prepared by this subject can significantly improve the water solubility of BA and promote the penetration of BA,thereby increasing its bioavailability.