| Bronchial asthma is a chronic respiratory disease which threatens public health seriously,and its incidence rate has increased in recent years.?-Asarone?ARE?and anthocyanin play different roles in treating asthma through different mechanisms.The results of guinea pig asthma pre-experiment showed that the combination of?-asarone and anthocyanin are more effective in treating bronchial asthma than medication alone.Therefore,the compound preparation of the two drugs can not only play a synergistic role in the treatment of asthma,but also improve the patient's compliance.However,ARE with poor water solubility exhibits a poor absolute bioavailability.Anthocyanins can just be stable in acidic environment.These limit the progress of ARE-anthocyanin compound preparations.In this study,we developed?-Asarone phospholipid complex?ARE-PC?and anthocyanin gastric floating sustained-release tablets,in order to improve the oral bioavailability of ARE and solve the stability problem of anthocyanin after oral administration.This paper can also provide the experimental basis for further study of compound preparation.The main research contents are as follows:1)Preparation of?-asarone-phospholipid complex?ARE-PC?The ARE-PC was prepared through solvent evaporation.With the complexation efficiency as the evaluation index,we studied the effects of compound solvent,drug-lipid ratio,drug concentration,preparation time and temperature by using single factor experiments.Then ethyl acetate was chosen as compound solvent and the preparation time was 3 h.The drug concentration,drug-lipid ratio and preparation temperature were significant for influencing the complexation efficiency of ARE-PC.After that,a central composite design?CCD?was applied to design the experiments for optimization of ARE-PC.A response surface methodology as used to estimate the influence of drug-lipid ratio,the drug concentration,and preparation temperature on the complexation efficiency.Therefore,our final formulation and preparation are as follows:an appropriate amount of ARE and phospholipid at the mass ratio of 1:2 are dissolved in ethyl acetate and the concentration of ARE is 1.6 mg/m L.Then the solution is stirred magnetically for 3 h at 30?and preparation solvent is removed through rotary evaporation.Finally,the crude ARE-PC is dispersed in appropriate amount of water and filtered through a 0.45?m organic microporous filter membrane.After the filtrate is dried through rotary evaporation,ARE-PC is obtained.Three batches of ARE-PC samples were prepared according to the optimized optimal formulation process.The measured value of the compound rate was 96.12±0.90%with good repeatability and a small deviation from the predicted value of 95.26%,which indicated that the optimized preparation process was stable and feasible.Differential scanning calorimetry?DSC?,ultraviolet spectrum?UV?,X-ray powder diffraction?XRD?,Fourier transform infrared absorption?FT-IR?,and 1H-NMR were used to characterize and identify ARE-PC.The results showed that the ARE-PC was successfully prepared.It was speculated that the double bond in ARE and the X-H group at the polar end of the phospholipid molecule generated electrostatic interaction to form a complex.No new covalent bond was formed and ARE was dispersed in the phospholipid in an amorphous state.The plasma concentration of ARE was measured at different time points after intragastric administration of ARE and ARE-PC in mice,and the data was analyzed using DAS 2.0 pharmacokinetic software.The area under the average drug-time curve AUC?0-t?of the ARE group and the ARE-PC group were 64364.58?g/L*min and193927.93?g/L*min respectively,and AUC?0-??were 80170.53?g/L*min and19960.13?g/L*min respectively.The results indicated that ARE-PC can improve the oral bioavailability of ARE.The tissue distribution of ARE-PC was further investigated,and the results showed that after drug administration,ARE could be rapidly dispersed to all tissues of mice.The concentration of ARE in tissues was higher in ARE-PC group than that in ARE group.No significant improvement in liver suggested that ARE-PC may not increase the hepatotoxicity of ARE.In this part,ARE-PC was successfully prepared and oral bioavailability of ARE was improved.2)Preparation of gastric floating sustained release tablets of anthocyaninAnthocyanin gastric-floating sustained release tablets were prepared through the wet granule compression technique with the floatability and release of purple potato anthocyanin as evaluation indexes.HPMC,sodium bicarbonate and copovidone were selected respectively as the skeleton material,foaming agent,and adhesive.A central composite design was applied to design the experiments for optimization of tablet formulation.And a response surface methodology was used to estimate the influence of HPMC,sodium bicarbonate and copovidone.Therefore,our final gastric floating sustained-release tablet formulation consisted of 10%anthocyanin,19.08%HPMC,14.34%sodium bicarbonate,7.12%copovidone,48.46%lactose and 1%magnesium stearate.After wet granulation,tablet is obtained by pressing.The anthocyanin gastric floating sustained-release tablets prepared according to the best prescription have a bleaching time<5 min and a continuous bleaching time>11 h.ARE was released slowly in the tablets.In summary,ARE-PC that improved the oral bioavailability of ARE was prepared and anthocyanin gastric floating sustained-release tablets increasing the stability of anthocyanin was achieved as well in this paper. |
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