| Flupirtine Maleate is a new type of central non opioid analgesic,which is located in the brain stem,is a selective nerve potassium channel open agent,mainly with pain relief,muscle relaxation and nerve protection triple efficacy,and will not produce tolerance and dependence.At present,the domestic listed dosage forms of flupirtine maleate are often-released capsules.However,for the treatment of pain emergency,the ideal drug should be both effective and long time to maintain a stable and efficient blood concentration,for this purpose,this experiment was prepared with polyethylene glycol(PEG)6000 and single stearic acid Glycerol(GMS)as the carrier for the preparation of flupirtine maleate slow-release solid dispersion agent.The main contents and results of the experiment are as follows:1.Preparation of flupirtine maleate solid dispersion agent(1)The experimental investigation of flupirtine maleate properties,hygroscopicity and raw materials melting point determination of flupirtine maleate sustained-release solid dispersion by ultraviolet spectrophotometry in drug content preparation,and methodological study.The results show that flupirtine maleate has white floc crystallization,melting point one hundred seventy-one degrees Celsius to one hundred seventy-five degrees Celsius,soluble in methanol,ethanol,water and 0.1 mol/l hydrochloric acid solution,and in the study of flupirtine maleate humidification,the weight gain is less than 0.2%after 24 hours under RH80%condition,without wetting.Selected 345 nm is a quantitative wavelength,flupirtine maleate in the 0.1M HCL,in the study of 1.9mg/mL?16.2mg/mL concentration range in a good linear relationship,the determination of specificity,precision,day stability and recovery are in line with the requirements.(2)In this experiment,the cumulative release degree was used as the study index the factors influencing the cumulative release of solid dispersions were selected:The quality ratio of drug to carrier,the ratio of excipients(the ration of polyethylene glycol andglycerol ester of mono-stearic acid isone to one,one to two and one to four respectively)and the melting temperature of solid dispersions(three horizontal eighty degrees Celsius,ninety degrees Celsius,one hundred degrees Celsius)Three factors,the response surface test is used to optimize the process.The process parameters were determined as follows:the mass ratio of drug to carrier is one point five,polyethylene glycol 6000 and Glycerol ester of mono-stearic acid ratio is one to two,and the melting temperature of the prepared solid dispersions is Ninety degrees Celsius.(3)The dissolution properties of the similarity factor between self-made flupirtine maleate solid dispersion preparation with foreign listed flupirtine maleate sustained-release tablets in vitro.The results showed that f2 = 43.2,not between the 50?100,showed that the dissolution of the two formulations was not similar in vitro.However,the cumulative release rate of the self-made flupirtine maleate solid dispersion agent in 0.75 h was 33%,there was no phenomenon of sudden release,60%of drug release time was about three hours,the time of release 90%was about ten hours,and the drug release was slow.Compared with the flupirtine maleate sustained-release tablets,the cumulative release curve shows that the homemade flupirtine maleate solid dispersion agent can reach the flat-topped time later,the slow release effect is better,and the self-made preparation can maintain the effective concentration for a long time.(4)The model of drug release in vitro byzero-stage drug release model,first-release model and Higuchi model,the results showed that the self-made slow-release solid dispersion agent was more suitable for the first release model.2.Flupirtine maleate solid dispersion agent phase and stability characterization(1)The agent phaseof flupirtine malcate sustainedsolid dispersionwas characterized by Scanning electron microscope,Infrared spectrum and X-ray diffraction,and the presence of flupirtine maleatein solid dispersions was investigated.The results show that the raw material flupirtine maleate crystals are clearly visible under Scanning electron microscope,the crystal particles can also be seen in the physical mixture of flupirtine maleate and matrix material,but the crystal particles are not observed in the flupirtine maleate solid dispersion,thus the flupirtine maleate is dispersed in the carrier by amorphous state.It was observed that the main telescopic vibration peaks of flupirtine maleate sustained-release solid dispersion and glycerol ester of mono-stearic acid were similar,while the two characteristic peaks of flupirtine maleate were weakened In X-ray diffraction spectra,raw materials of flupirtine maleate have three characteristic diffraction peaks in 8.8 °,17.44° and 18.18 °.The characteristic peaks of flupirtine maleate are still present in the spectra of the physical mixtures of flupirtine maleate and matrix materials,while in the spectrum of the slow-release solid dispersion of flupirtine maleate,the original intensity of each diffraction peak is greatly weakened,and it is inferred that the flupirtine maleate is in micro-crystalline form in the slow-release solid dispersion.(2)The stability of flupirtine maleate sustained-release solid dispersion preparation was investigated by accelerated and long-term tests,and the results showed that:in the accelerated experiment,the appearance,drug content and drug release of slow-release solid dispersions were not significantly changed under 40 ?±2 ?,RH75±5%condition.In the long run,at room temperature,the appearance,drug content and drug release of slow-release solid dispersion agent showed no obvious changes,which suggested that Flupirtine maleate sustained-release solid dispersion preparation had good stability under sealing condition.3.Bioequivalence of homemade Flupirtine maleate sustained-release solid dispersion preparation and foreign flupirtine maleate sustained-release tabletsI was involved in the early establishment of the ratplasma flupirtine maleate in the HPLC detection method for chromatographic conditions:chromatographic column:Symmetry C18(5?m,4.6× 250 mm),mobile phase:methanol:water=fifty:fifty(?/?),with 1mol/l formic acid ph value to 6.70;column temperature:twenty fivedegrees Celsius;flow rate:0.5 ml/min;detection wavelength:320 nm;Sampling quantity:20 ?L.Flupirtine maleate has a good linear relationship(R2>0.9991)in the 0.015?-5.00 ?g/ml concentration range of rat plasma.The method has good specificity,RSD is less than 6%,the stability rsd is less than 6%,the recovery rate is more than 90%,all meet the relevant testing requirements,and can be used for the determination of flupirtine maleate in plasma samples.This method was used to evaluate the bioequivalence of self-made Flupirtine maleate sustained-release solid dispersion preparations and foreign flupirtine maleate sustained-release tablets,and to analyze the bioequivalence of the main pharmacokinetic parameters Cmax,Tmax,AUCo-t,AUC0-? using the method of variance analysis,double unilateral t test and(1-2?)%confidence interval,The results showed that there were significant differences(P<0.01)between the two different kinds of flupirtine maleate.In AUC0-?.the value of flupirtine maleate sustained-release tablets in foreign markets was(30.897±1.387)?g·h/ml,Flupirtine maleate sustained-release solid dispersion preparation was(76.079±3.906)?g·h/ml,relative bioavailability was(246.811 ± 19.884)%,In the 80.0%?125.0%range of reference preparation,it is indicated that the two formulations are not bioequivalence in rats,but the bioavailability of self-made Flupirtine maleate sustained-release solid dispersion is greater than that of foreign flupirtine maleate sustained-release tablets.Flupirtine maleate solid dispersion formulations prepared in this experiment has a good storage stability and good dissolution characteristics,and can achieve good long-term release requirements.And the formulation made Flupirtine maleate sustained-release solid dispersionachieved rapidly effective blood concentration,while being able to quickly analgesic effect slow release of the drug to maintain effective blood concentration lasting,sustained release to achieve a better effect,to extend the duration of analgesia.Vivo pharmacodynamics study and clinical application of this experiment Flupirtine maleate sustained-release solid dispersion formulation of the foundation. |
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