| Ebastine is an alkaloid anti-allergic drug and it belongs to the second-generation H1 receptor antagonist.It is clinically used to treat allergic rhinitis,urticaria,bronchial asthma,eczema,and pruritus.Currently listed as a regular release tablets,each oral 10 mg,1 or 2 times a day.Ebastine is a poorly soluble drug,tablet dissolution is limited,and allergic diseases are acute and require rapid relief.Ebastine can be made into quick-acting preparations to meet the fast-acting drug requirements.In this experiment,Ebastine Drop Pills were prepared using a water-soluble matrix,and quality inspections and pharmacokinetic experiments were performed.The main research contents and results of this paper are as follows:1.Pre-prescription studyUV method and HPLC method were used to analyze the content of Ebastine.The results showed that Ebastine has a good linear relationship with absorbance in the concentration range of 1.68～15.12 μg/mL when using UV method,and the regression equation is Y=0.0499X+0.0041,R2=0.9993.Ebastine also showed a well linear relationship with the peak area in the concentration range of 1.68～33.60 μg/mL when using HPLC method,and the regression equation is Y=8584.1X+2376.2,R2=0.9994.The specificity of UV and HPLC methods was good,and other components were not interfered;the RSDs of precision and stability were less than 2%;the recoveries of the samples were all greater than 97%,and the RSD values were less than 2%,which met the requirements.The high-temperature and high-humidity tests were conducted on the drug substance,and the stability of the main drug and auxiliary materials was investigated.The results of the content determination showed that Ebastine had a good thermal stability at 60 ℃,and RH 80%and 25 ℃ The moisture absorption under the condition of is less than 0.2%;there is no interaction between the main drug and the substrate at 60 ℃.The roundness of the dropping pills and the dissolution time limit were used as evaluation indicators.Based on the single factor effect test,the ratios of drug to matrix were selected:1:7,1:5,1:3,PEG 4000:PEG 6000 ratio 1:3,1:1,3:1,melting temperature 75 ℃,80 ℃,85 ℃ for optimization tests.2.Formulation process optimizationOn the basis of single-factor investigation,Box-Behnken response surface optimization method was adopted to optimize the preparation process of dripping pills.The cumulative dissolution index Q of 5 min and 30 min was the evaluation index,the proportion of drug and matrix,the proportion of matrix PEG 4000:PEG 6000,and the melting temperature were the influencing factors.The results showed that:the optimal prescription was the ratio of drug to the matrix was 1:3.4,the ratio of matrix PEG 4000 to PEG 6000 was 1:0.41,the melting temperature was 84 ℃.3.Quality evaluationX-ray powder diffraction(XRD),differential scanning calorimetry(DSC),scanning electron microscopy(SEM),infrared spectroscopy(IR),etc.were used for the analysis of Ebastine dripping pills.The experimental results showed that the characteristic peaks of Ebastine in the XRD pattern were significantly weakened,the absorption peaks of the main drug in the DSC spectrum disappeared,the peak intensity of the main drug in the IR spectrum was significantly weakened,and the main drug and matrix were fully fused in the SEM image.These proved that Ebastine was present in the dripping pill in the form of non-crystals;the formulation of the dripping pills prepared by the optimal prescription was evaluated by visual inspection,weight difference,roundness,and content determination.The test showed that the dripping pills were milky white,consistent with weight difference and roundness requirement which was 0.90±0.03.Ebastine Dripping Pills are also stable and reproducible;Compare the dissolution rate with the commercial Ebastine tablets,it showed that Ebastine dripping pills had the characteristics of fast dissolution and complete dissolution.the stability test showed that the dropping pills were no significant change in appearance and content at a temperature of 40 ℃and a relative humidity of RH 55%± 5%for 6 months,which proved the optimal formulation of the prepared dropping pills was stable.4.Preliminary study of pharmacokineticsThis paper established HPLC method for determination the Carebastine which is the metabolites of Ebastine in biological samples.The chromatographic conditions were as follows:column:Symmetry C18(5m,4.6mmx250mm);mobile phase:methanol-water = 30:70;Column temperature:25 ± 5 ℃;Flow rate:0.9 ml/min;Detection wavelength:210 nm;Injection volume:20 μL;The results showed the R2 of Carebastine was 0.9993 within the range of concentration 0.05～10 μg/mL in rat plasma.The intraday and inter-day precision RSD values were all less than 7%and the room temperature stability,freeze-thaw stability RSD values were all less than 7%.The average recovery rate was greater than 95%and RSD values were less than 6%.The minimum detection concentration was 12.5 ng/mL.The methodological study above proved that the method has high accuracy and good feasibility.Rats were given gastric gavage at 3 doses of 1.8 mg/kg,2.7 mg/kg,and 3.6 mg/kg respectively.DAS2.0 software was used for data processing to obtain the corresponding pharmacokinetic parameters:The t1/2kα which means drug absorption half-life in rat drug plasma were 0.678±0.361 h,1.031 ±0.25 h,and 0.924±0.147 h respectively.The distribution half-life t1/2αwere 1.025±0.716 h,1.950±0.927 h,and 1.806±1.569 h respectively.The elimination half-life t1/2β were respectively 11.178± 4.364 h,11.178±3.368 h and 11.585±2.346 h.The peak plasma concentrations were 2.333±0.516 h,2.500±0.548 h and 2.167±0.408 h respectively.The peak plasma concentrations were 0.639±0.027 μg/mL,0.940±0.025 μg/mL and 1.259±0.033 μg/mL.The elimination rate CL/F were 2.072±0.217 L/h/kg,2.302±0.397 L/h/kg and 2.099±0.170 L/h/kg.The area under the concentration time curve AUC0-24 were 6.987±0.360 μg·h/mL,10.245±1.187 μg·h/mL and 13.800±0.517 μg·h/mL respectively.The results of this experiment showed that the pharmacokinetics of Ebastine dripping pills were in line with the characteristics of the two-compartment model.After administration,the drug had a rapid distribution in rats;a wide range of distribution,a slow elimination rate,a low clearance rate,and a long average residence time.Bioequivalence evaluation was performed on self-made Ebastine dripping pills and commercially available tablets.The main pharmacokinetic parameters Cmax,Tmax,AUC0-t,AUC0-∞.were analyzed by analysis of variance,double-sided t-test and(1-2%)confidence intervals for statistical analysis of equivalence.The results showed that there was a significant difference between the two different formulations(P<0.01).The relative bioavailability F obtained with AUC0-∞.as the calculation parameter was(106.2%to 140.9%)%,indicating that the two formulations were not bioequivalent in rats.Compared with the commercially available tablets,the self-made Ebastine dripping pills showed the main characteristics of rapid release,rapid distribution,slow elimination,and high peak concentration. |
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