| Flupirtine maleate is a new non-steroidal analgesic that acts on the central nervous system and it is effective in the treatment of acute and chronic pain,including increased muscle tone pain,joint disease such as osteoarthritis,tension-type headache,cancer pain,dysmenorrhea,orthopedic surgery,orthopedic surgery or post-injury pain.Flupirtine maleate has fewer adverse reactions and is generally not serious.The most common adverse reactions are fatigue,long-term use is not tolerant and dependent,and side effects are related to dose.When the treatment is complete,side effects will disappear on their own.At present,the commercial dosage is ordinary capsules,oral administratsion of 100mg,3-4times a day,the maximum daily dose of 600mg,there is no other domestic formulations listed.Because of its poor solubility in water,and the dissolution ratse of drugs is low,the less research for the drug.Domestic and foreign scholars have prepared flupirtine maleate maleate sustained-release tablets,oral solid quick release dosage form and study its pharmacokinetic characteristics.There is no other dosage form to research.Flupirtine maleate is less than the existing dosage forms,it is difficult to meet the needs of clinical medication,it is necessary to develop a safe and efficient new form of flupirtine maleate.On the basis of successful preparatsion of flupirtine maleate sustained-release solid dispersions,the method for the determination of flupirtine maleate in biological samples of HPLC was established.After administratsion of flupirtine maleate sustained-release solid dispersions,through the determination of the concentratsion of the index components of vivo concentratsion in rats and the concentratsion of main organs in mice,to study the flupirtine maleate sustained-release solid dispersions dynamic feature and in vivo distribution in animal,to provide an experimental basis for the research and development of oral flupirtine maleate sustained-release solid dispersions dosage forms.The main research contents and results are as follows:1.To establish a method for the determination of flupirtine maleate in biological samples of HPLCChromatographic condition:chromatographic column:Symmetry C18(5?m,4.6×250mm);the mobile phase of acetonitrile water,methanol:water=70:30(V/V)?adjusting the pH to 6.70 with 1mol/L formic acid;column temperatsure was 25?;flow ratse was 0.5ml/min;detection wavelength was 320nm;sample size was 20?l.By using acetonitrile as the solvent of protein in plasma and tissues of precipitated protein,flupirtine maleate in rats plasma from 0.015?5pg/ml concentratsion range,in different tissues of mice heart,liver,spleen,lung,kidney and brain in 0.064?21.33?g/g concentratsion all showed a good linear relationship(R2>0.9991).This method has good specificity,precision,stability and recovery ratse are in accordance with the relevant requirements,can be used for the determination of germacrone in biological samples.2.Study on pharmacokinetics and tissue distribution of flupirtine maleate sustained-release solid dispersionsDetermination of rats blood drug concentratsion to study the pharmacokinetics of flupirtine maleate sustained_release solid dispersions in ratss,the ratss were administered with three doses(9mg/kg,27mg/kg,54g/kg),the data were processed by two compartment model,and the pharmacokinetic parameters were determined.The peak time of the three groups were(3.318±0.308)?(3.326±0.548)?(3.333±0.516)h;the peak blood concentratsion as follows0.740±0.031)?(1.825±0.083)?(4.014±0.183)?g/ml;the half-life of drug absorption t1/2k?.in rats plasma was(0.837±0.364)?(0.835±0.055)?(0.831±0.057)h;the distribution half lives t1/2? were(4.463± 1.984)?(4.477±2.186)?(4.474±2.429)h;the elimination half lives t1/2? were(6.417±3.155)?(6.333±0.326)?(6.332±0.329)h;The elimination ratses CL/F were(1.004±0.034)?(1.202±0.035)?(1.546±0.017)ml/h/kg;the area of time-blood drug concentratsion under the curve AUC0-t were(8.244±0.198)?(21.624±0.453)?(45.134±0.803)?g·h/ml.Mice were administered flupirtine maleate sustained-release solid dispersions by 78mg/kg,HPLC determination of flupirtine maleate concentratsion in mice(heart,liver,spleen,lung,kidney and brain)in 2,4,8,12,24h.Comparison of drug distribution in different tissues,frozen sections of mice tissues after administratsion of the same dose,observated of a large number of fresh tissue sections of mice by fluorescence microscopy,comparatsive analysis of the statistics of flupirtine maleate in the organization general distribution trend.The result is same as the flupirtine maleate in sustained-release solid dispersions components in various tissue distribution of quantitative analysis by HPLC.There were significant differences in the distribution of different time points in each tissue after administratsion.The distribution of drug in each tissue changed with time.And reached the maximum value at 4h,the amounts of flupirtine maleate in various tissues,liver>brain>kidney>heart>spleen>lung.3.Study on the bioequivalence evaluation of flupirtine maleate sustained-release solid dispersions and flupirtine maleate commercial capsulesThe bioavailability evaluation of flupirtine maleate sustained-release solid dispersions and flupirtine maleate commercial capsules were evaluated.The bioequivalence of two formulations was evaluated by variance analysis,two-one side t test and(1-2?)%confidential internal to Cmax?Tmax?AUC0-t?AUC0-?.The results showed that there were significant differences between the two different formulations(P<0.01).The relative bioavailability F was(144.388± 18.400)%calculated by AUC0-?,and out of the range of 80.0%?125.0%.Flupirtine maleate sustained-release solid dispersions with slow release,slow distribution and elimination than commercial capsules.4.Study on the pharmacodynamics of flupirtine maleate sustained-release solid dispersions Mice were administered physiological saline,flupirtine maleate sustained-release solid dispersions by 13mg/kg,39mg/kg,78mg/kg)and flupirtine maleate commercial capsules by 78mg/kg.Using mice hot plate method and acetic acid writhing method to study the effect of each group of drug analgesia.The results showed that each treatment group was significantly different from that of saline control group(P<0.05).The ratse of increase of pain threshold(36.14%?61.47%)and writhing inhibition ratse(19.71%?49.97%)in the high dose sustained-release solid dispersion group were lower than those in the commercial capsules group(P<0.05)(45.85%?85.53%),(28.82%?54.00%),in 0.5?2h.But after 4 hours,the ratse of increase of pain threshold(95.38%)and writhing inhibition ratse(81.64%)in the high dose sustained-release solid dispersion group(85.53%)and the writhing inhibition ratse(72.16%)were the highest in the commercial capsules group after 2 hours of administratsion.The ratse of writhing inhibition was maintained at(15.42%?81.64%)and(12.23%?95.38%)of sustained-release solid dispersion group,(1.02%?48.47%)and(9.84%?68.77%)of commercial capsules group.The two analgesic models indicated that the rapid analgesic effect of fluprofen commercial capsules was higher than that of the same dose sustained-release solid dispersions before 2 hours,but reached the maximum efficacy at 2h.After the analgesic effect of its rapid decline in the sustained-release solid dispersion group analgesic effect decreased,reflecting the superiority of sustained-release analgesia.At the same time,the ratse of increase of pain threshold and the ratse of writhing of mice were gradually increased with the increase of the dose of the sustained-release solid suspension group.The results showed that the greater the dose,the more obvious the analgesic effect. |
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