| Epliepsy is a brain dysfunction diseases,which is often repeatedly and suddenly broken out.Drug therapy is the preferred way to treat eplilesy,which is effective on about 70% of patients.But there are about one-third of patients who has drug resistance.And now it cannot effectively control the seizures with drugs.Therefore,it is particularly necessary to research the antiepileptic drugs,which have better efficacy and better safety.Retigabine is a new antiepileptic drug,mainly for adjunctive treatment of epilepsy partial seizures on the adults over the age of 18.Its mechanism of action is about voage-gated potassium channel(KCNQs),the main role is regulate M-type potassium current [IK(M)] by way of KCNQ2/3 channel.Gastric retention floating tablets is a sustained-release formulation,also known as floating drug delivery system.The density of the formulation is lower than gastric,so the formulation can float on top of the gastric.And the gastric emptying impact less on its residence time in the stomach,the drug contained release slowly with certain rules in the float process.Retigabine easily dissolved in the stomach,but with the PH increased,the solibility greatly reduced,so the bioavailability of Retigabine in the ordinary tablets is only 60%.The gastric floating tablets of is good for Retigabine to release in the stomach,promote the absorption in the small intestine and improve the bioavailability.The content of this article is as follows:Objective: Evaluating the pharmacokinetics and bioequivalence of Retigabine gastric floating sustained release tablets and Retigabine regular tablets in rabbits and beagle dogs, then comparing the correlation in vivo of retigabine gastric floating sustained release tablets in beagle dogs, building the quality evaluation criteria.Methods:Establish a HPLC/MS/MS method for the determination of plasma concentrations after single-dose and multiple-dose oral administration of both Retigabine gastric floating sustained release tablets and Retigabine regular tablets in rabbits and beagles,then make an An equivalent test using analysis of variance and two one-sided t-test. Simulate the plasma concentration-time data of Retigabine using DAS 2.1.1 pharmacokinetic program,then select the appropriate compartment model to automatically calculate the relevant parameters.In vitro release behavior was researched by the release assay, the similarity factor was used to evaluate the similar of release rate in the sustained-release tablets and regular tablets.Calculate the cumulative absorption rate in vivo with the Wagner-Nelson equation. Research the in vivo correlation by in vitro release percentage and in vivo absorption percentage in the same time points of the test products.Results: The pharmacokinetic parameters of rabbits after a single dose oral administration showed that the Tmax of sustained-release tablets and regular tablets were respectively(7.6±2.966)h and(4.2±3.493)h; Cmax were(2.656 ± 0.009) mg / L and(2.777±0.94) mg/L;AUC(0~24h) were(35.673±14.11) mg.h/L and(26.899±9.41)mg.h/L;MRT(0~24h) were respectively(12.478 ± 3.709)h and(8.665 ± 1.217)h.The relative bioavailability was 132.40% of test product and reference product in single dose.The pharmacokinetic parameters of rabbits after a multiple-dose oral administration showed that the Tmax of sustained-release tablets and regular tablets were respectively( 10.8±7.694) h and(7.8±3.213)h;Cmax were(2.369±1.108) mg/L and(3.198±0.925)mg/L;AUC(0~24h) were(41.41±29.27)mg.h/L and(45.06±30.767)mg.h/L;AUCss were respectively(32.923±18.86)mg.h/L and(11.601±6.82)mg.h/L;DF were(1.542±0.57)and(1.989±1.05);MRT(0~24h) were(14.03±3.189)h and(13.044±1.985)h;Cmin were respectively(0.40 ±1.015)mg/L and(0.845 ±1.40)mg/L mg/L; Cav were(1.372±0.786)mg/L and(1.989±1.053)mg/L.The pharmacokinetic parameters of beagle dogs after a single dose oral administration showed that the Tmax of sustained-release tablets and regular tablets were respectively(7.25±0.689)h and(1.833±0.516)h; Cmax were(0.307±0.2) mg/L and(0.328±0.059) mg/L;AUC(0~24h) were(3.511±2.509) mg.h/L and(1.995±1.471)mg.h/L;MRT(0~24h) were(11.258 ± 0.979)h and(6.788 ± 2.613)h.The relative bioavailability was 181.55% of test product and reference product in single dose.The pharmacokinetic parameters of beagle dogs after a multiple-dose oral administration showed that the Tmax of sustained-release tablets and regular tablets were respectively(7.333±0.516)h and(2.083±3.649)h; Cmax were(0.788±0.336) mg/L and(0.794±0.086) mg/L;AUC(0~24h) were(13.997±8.46) mg.h/L and(16.139±1.279)mg.h/L; AUCss were(11.36±6.88)mg.h/L and(3.48±0.68) mg.h/L; Cmin were(0.376±0.17) mg/L and(0.358±0.12)mg/L; DF were respectively(0.918±0.18)and(0.89±0.223); MRT(0~24h) were(14.27±2.319)h and(16.922±0.74)h.Similarity factor for the two formulations is 10.65,Retigabine in sustained release tablets is in line with compartment model in vivo. The correlation coefficient of in vitro release percentage and in vivo absorption percentage is 0.9658.Conclusion: In the single administration test of rabbit, AUC(0~24h),Cmax,Tmax and MRT(0~24h) were test by two one-sided t-test.The results showed that there was no significant difference in AUC(0~24h) of both formulations,proving the extent of absorption was equal. The Tmax and MRT sustained-release tablets were longer than conventional tablets, Cmax lower than conventional tablets,indicating that there is a certain release effect in the sustained-release tablets without the burst phenomenon.In the multiple dose oral administration, AUC(0~24h) of both formulations has no significant differences, proving that it was bioequivalence.DF of test formulation is smaller than the DF of reference formulation, indicating that the fluctuation coefficient of gastric floating sustained release tablets is smaller than that of the conventional tablets, while Cmax had no significant differences in the multiple doses and single dose, saying Retigabine had no no accumulation in vivo. In the pharmacokinetics research of beagle dogs, bioavailability was 181.55%, indicating that it was bioequivalence, Tmax a significant difference in the test formulation and the reference formulation, there were significant differences in Tmax of test preparation and reference formulations, indicating Retigabine gastric floating sustained release tablets had sustained-release effective. In multiple doses,AUC(0~24h) had no significant difference,indicating it was bioequivalence,but there was no significant difference in Cmax and Cmin.DF in the gastric floating sustained release tablets was smaller than in the conventional tablets, indicating the plasma concentration fluctuation coefficient of sustained-release tablets was smaller than that of conventional tablets. In vitro release behavior of two formulations was different, in vivo absorption fraction in Beagle dogs was correlated to vitro release. |
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