| Purpose:Ticagrelor is a new type of antiplatelet drug.It is a reversible adenosine diphosphate(ADP)P2Y12 receptor inhibitor.It is active,has rapid onset of action,and has a high platelet inhibition rate.However,due to its poor solubility,its bioavailability is low.Therefore,in this study,it was prepared into nanosuspension to increase the solubility and dissolution rate of the drug.However,nanosuspension does not have long-term stability.Therefore,in this study,ticagrelor was prepared into pellets to improve the long-term stability and bioavailability of the drug,and it is more suitable for industrial production after being prepared into pellets.Methods:The in vitro analytical method of ticagrelor was established by UV and HPLC,and the linearity,precision and recovery of the two analytical methods were investigated.Sodium lauryl sulfate(SDS)was used as a stabilizer to prepare ticagrelor nanosuspension by a combination of precipitation and high-pressure homogenization.Under this method,the effects of stirring time,number of homogenization cycles,homogenization pressure,ratio of water phase to oil phase,ratio of tegrarol to stabilizer and concentration of tegrarol on particle size(Size),dispersion index(PDI)and potential were investigated.To characterize the nanosuspension,it was freeze-dried.X-ray diffraction(XRD)and infrared spectrum scanning(IR)were used to analyze the crystal form and structure respectively.The saturation solubility and dissolution in vitro were investigated by UV,and the stability of nanosuspension was investigated from the appearance,size and PDI.With PVP-K30 as binder,the nanosuspension was sprayed on the surface of the blank core by the bottom spraying technology of fluidized bed,HPMC was used as isolation material and talcum powder as anti adhesion agent to pack isolation coat.With the dissolution of the pellets as the main index,the effects of the amount of adhesive,the weight gain of the isolated coating and other factors on the quality of the pellets were investigated.The surface morphology of the two kinds of pellets was observed by scanning electron microscope(SEM)to ensure the coating effect,and the stability of the isolated coated pellets was investigated by the influencing factors experiment.The rats were used as the model animal.The drug concentration in the plasma of rats after administration was determined by high performance liquid chromatography(HPLC),and the preliminary pharmacokinetics study was carried out to investigate the drug release and absorption of ticagrelor in rats.Results:The standard curve established by UV method has a good linearity in the concentration range of 5-30 μg/ml,and the standard curve established by HPLC has a good linearity in the concentration range of 10-150 μg/ml.both analytical methods have high sensitivity and good reproducibility.Through the prescription screening,the best prescription was determined as ticagrelor:SDS=10:1,water phase:organic phase=10:1,and the concentration of ticagrelor was 8 mg/ml;the best process was stirring for 30 min,homogenization pressure was 1200 bar,homogenization cycle times was 15 times.The mean Size was 166.13±4.21 nm,PDI was 0.16±0.02,potential was-42.43±1.36 mV measured by the Malvern particle size analyzer.The results of IR and XRD show that the structure of the nanosuspension is unchanged and the crystal form is not transformed.The results of in vitro dissolution showed that the dissolution rate of tegrarol was increased significantly after the nanosuspension was prepared compared with the drug substance and the original drug,that is,the release rate reached 85%in 5 min.The preliminary stability results show that the suspension can keep stable within one month,but its particle size increases significantly after three months.Taking the dissolution of pellets in vitro as the evaluation index,the technology and prescription of pellets were screened by single factor experiment.The content of the drug loaded pellets was uniform,and the pellets covered with the isolation coat were smooth and round;The results of dissolution showed that the release rate of the pellets covered with isolation coat reached 85%in 45 min,which was significantly higher than that of the drug substance and the original drug in different pH;The preliminary stability test results show that the pellets are stable at high temperature,light and relative humidity of 75%,and the moisture absorption is serious at 92.5%.The results of pharmacokinetic studies in rats showed that the Tmax of ticagrelor pellets was 1 h,the Cmax was 0.90±0.17 μg/mL,and the AUC0-∞ was 5.35±1.07 μg.h/mL,compared with the bulk drug(Tmax was 1.5 h,Cmax was0.50±0.01 μg/mL,AUC0-∞ was 2.82±0.15 μg·h/mL),the peak time was shortened,the blood concentration was increased,and the relative bioavailability was improved significantly.Conclusion:The prepared ticagrelor nanosuspension increased the dissolution rate of the drug significantly,and the saturation solubility after lyophilization was improved significantly.The ticagrelor loaded pellets covered with the isolation coat were smooth and round,compared with the crude drug and the original drug,the dissolution was significantly improved.The preliminary results of pharmacokinetic study showed that the peak time was shortened and the bioavailability was improved after ticagrelor was prepared into pellets. |
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