Study On The In Vitro Dissolution And Pharmacokinetic For Solid Dispersants Of Ursolic Acid

Objective To establish a method for determinating the dissolution in vitro and blood concentration in rats in vivo of ursolic acid?UA?,which was in physical mixture?PMs?and solid dispersants?SDs?capsules,respectively.To investigate the dissolution of them in vitro and pharmacokinetic behavior in rats.The SDs was prepared for improving the bioavailability of UA by optimizing the prescription composition and production process of SDs.Methods A method of HPLC was applied to research the dissolution characteristics of UA,PMs and SDs in vitro.The chromatographic conditions:column:SinoPak-C₁₈ column?4.6mm×250 mm,5.0?m?;the mobile phase:methanol-0.1%phosphoric acid?v:v?88:12??;flow rate:1.0 mL/min;210 nm as detection wavelength;injection volume:10?L.A HPLC-MS method was established to determine the concentration of UA in rat plasma.The chromatographic conditions for the detection method:Stationary Phase,SinoPak-C18 column?4.6 mm×250 mm,5.0?m?;the mobile phase A:methanol,the mobile phase B:0.02%triethylamine;the elution conditions:73%¹00%of mobile phase A and 27%⁰%of mobile phase B for 0 min²0 min.The flow rate was 0.5 mL/min,and the injection volume was 10?L.The mass spectrometry conditions:SIM?Selective ion monitoring?as the acquisition mode;negative as ion polarity;ionization with electro spray ion source;m/z 455.7 for UA as detecting objects;N₂ volume flow:35.0 L/min;heating temperature:350?.DAS 2.0 pharmacokinetic software was found by the Chinese Pharmacology Society and used to process the pharmacokinetic data.And study the pharmacokinetic behavior of UA,PMs and SDs in rats in vivo.The SDs containing hydroxypropyl methyl cellulose?HPMC?,sodium lauryl sulfate?SLS?and NaHCO₃ was prepared by solvent method.Differential scanning calorimetry?DSC?and X-ray powder diffraction?XRD?were used to characterize the SDs.The dissolution rate of SDs in pH 6.8 buffer solution for 120 min was used as an evaluation index to determine the optimum material ratio of SDs.Results The HPLC method has a good linearity in the range of 10.00⁶40.0 ng/mL with an R₂ of 0.9981.The RSD values of precision were all less than 1.90%.The average extraction recoveries for SDs of low,medium and high concentrations were 92.9%,94.6%and 93.3%,and the RSD values were less than 1.80%.The average extraction recoveries for PMs of low,medium and high concentrations were 97.0%,98.0%and 97.2%,and the RSD values were less than 1.20%.The HPLC-MS method for the determination of UA content has a good linearity in the range of 10.0⁶40.0 ng/mL with an R₂ of 0.9981.The RSD values of intra day and inter day precision were all less than 10.0%.The average extraction recoveries of low,medium and high concentrations were all greater than 80.0%.The dissolution study results in vitro showed that the UA did not dissolve out in the four dissolution media.The cumulative dissolution of the SDs was 33.58%⁵2.14%,and the cumulative dissolution of the PMs was 5.16%²9.85%.The cumulative dissolution of the PMs in the pH 1.2 buffer solution is 5.16%,which is far less than the 43.98%of SDs.The SDs of UA was prepared by a solvent method.When the ratio of UA,HPMC,SLS and NaHCO₃ was 1:1:4:0.4,the dissolution of SDs was highest in a buffer solution of pH6.8 at120 min.The SDs was characterized by DSC and XRD methods.The results showed that UA was change the crystalline structure to amorphous form in the SD formulations by the solvent method.The pharmacokinetics behavier of UA,PMs and SDs in rats were in line with the one-compartment model.The relative bioavailability of the PMs and the SDs was about 168.7%,when the UA was used as reference.And the Cmax of the the SDs was1.31-fold greater than the PMs.Conclusions This article prepared the SDs of UA successfully.The method of HPLC is accurate,reliable and specific,and it is suitable for the determination the dissolution of UA,SDs and PMs.The HPLC-MS method has good accuracy and specificity,and could be used to study the pharmacokinetic behavior of UA,PMs and SDs in rats by determination the concentration of bug.The dissolution rate of the SDs in vitro was significantly higher than the UA and PMs.The PMs and SDs significantly improved the bioavailability of the UA in rats,and the pharmacokinetic behavior of SDs is better than the PMs.