In Vitro Dissolution And Relative Bioavailability In Beagle Dogs Of Metformin Hydrochloride Oral Preparations

Bioequivalence and in vitro dissolution test were two basic methods to evaluate the quality consistency of solid dosage forms.If a good correlation between in vitro dissolution and in vivo absorption had been established,in vivo absorption could be predicted from in vitro dissolution data,which would not only reduce bioinequivalence risk,but also save a lot of resources and greatly improve the development efficiency of new preparations.In this article,metformin hydrochloride was selected as a model drug,the in vitro dissolution and relative bioavailability in beagle dogs of metformin hydrochloride oral preparations were studied.Objective: This paper is to evaluate the quality of commercial metformin hydrochloride oral preparations by in vitro dissolution and in vivo absorption tests and compare the relative bioavailability of different dosage forms.For enteric-coated formulations with higher bioinequivalence risk,in vitro dissolution and bioequivalence studies were conducted to provide a reference for clinical rational medication,and develope an in vitro dissolution method which can discriminate the inherent quality of enteric–coated preparations effectively.Methods:1 By rotating basket method,the in vitro dissolution tests of commercial metformin hydrochloride preparations with different release rate were conducted in different dissolution media;Four preparations which included an immediate-release tablet(A),an enteric-coated capsule(B),an imported sustained-release tablet from India(C)and a domestic sustained-release tablet(D)were given to 12 healthy beagle dogs according to an simplified four-way crossover design at a single oral dose of 500 mg.The wash period was 7 days.The plasma concentrations of metformin were determined by HPLC-UV.Thepharmacokinetic parameters and the relative bioavailability were calculated by DAS 2.1.1 software on the basis of noncompartmental model analysis.2 By rotating basket method,the in vitro dissolution tests for 7enteric-coated preparations of metformin hydrochloride were conducted in pH1.2 hydrochloric acid solution,p H 4.5 acetate buffer solution,pH 6.0 and pH6.8 phosphate buffer solution,respectively.Three preparations which showed significant difference in dissolution curves were given to six beagle dogs according to a three-way crossover design at a single oral dose of 500 mg under fasting or fed conditions,respectively.The bioequivalence and food effects on the absorption of the tested preparations were evaluated.Results:1 Dissolution tests of metformin hydrochloride preparations with different release ratesThe dissolution results of immediate-release tablet,enteric-coated capsule,and sustained-release tablets of metformin hydrochloride were all met the criteria of Chinese pharmacopoeia(2015)for each preparation.The dissolution curve similarity factor f2 between any two metformin hydrochloride sustained-release tablets were more than 50.2 Relative bioavailability of metformin hydrochloride oral preparations with different release rate in beagle dogsThe main pharmacokinetic parameters of preparation A,B,C and D were as follows: Tmax were(1.18 ± 0.45),(2.11 ± 0.96),(1.95 ± 0.65)and(2.48 ±1.04)h;Cmax were(17.7 ± 7.2),(12.91 ± 7.13),(6.96 ± 1.91)and(7.14 ± 2.06)?g·mL-1;t1/2were(4.31 ± 1.82),(5.45±2.81),(7.26 ± 3.11)and(4.96 ± 2.51)h;AUC0-24 h were(58.30 ± 18.70),(48.75 ± 24.16),(35.21 ± 9.61)and(40.59 ±13.56)?g·h·mL-1,respectively.The relative bioavailability of preparation B,C and D compared to A were(87.18 ± 34.46)%,(68.23 ± 19.83)% and(73.93 ±19.45)%,respectively.3 Dissolution tests of metformin hydrochloride enteric-coated preparationsAll tested metformin hydrochloride enteric-coated preparations hardlyreleased in hydrochloric acid solution(pH 1.2)and acetate buffer(pH 4.5)within 2 h.Three preparations(I,J and K)showed significantly different dissolution results in both p H 6.0 and pH 6.8 phosphate buffer,but the difference was more obvious in pH 6.0 phosphate buffer and all preparations released more than 75% of metformin within 45 min in pH 6.8 phosphate buffer.The dissolution curve similarity factor f2 between any two tested preparations were less than 50.4 Bioequivalence of metformin hydrochloride enteric-coated preparationsThe main pharmacokinetic parameters of preparation I,J and K in 6healthy beagle dogs at a single dose of 500 mg metformin hydrochloride under fasting condition were as follows: Tmax were(1.63 ± 0.86),(1.96 ± 0.90)and(2.83 ± 1.66)h;Cmax were(15.87 ± 9.30),(18.06 ± 6.96)and(13.49 ± 10.42)?g·mL-1;AUC0-24 h were(48.79 ± 26.98),(71.18 ± 49.73)and(46.74 ± 17.88)?g·h·mL-1,respectively.The drug concentration under fed condition was too low to calculate the pharmacokinetic parameters.The relative bioavailability between two preparations were(148.3 ± 38.4)%(J/I),(121.1 ± 77.2)%(K/I)and(83.2 ± 46.8)%(K/J).There was no bioequivalence between any two enteric-coated preparations calculated with Cmax or AUC0-t parameters.Conclusions:1 The bioavailability of metformin hydrochloride immediate-release tablet(A)is higher than that of enteric-coated capsule(B)and sustained-release tablets(C and D).2 Significant differences of dissolution curves and in vivo absorptions showed high risk of bioinequivalence for metformin hydrochloride enteric-coated preparations,and quality consistency evaluation should be strengthened for these preparations.3 Food has significant effects on the absorptions of metformin hydrochloride enteric-coated preparations,the bioavailability was much higher under fasting condition,especially for enteric-coated tablets.So metformin hydrochloride enteric-coated preparations should be administered under fasting condition.4 In vitro dissolution curves of metformin hydrochloride enteric-coated preparations in pH 6.0 phosphate buffer can discriminate their in vivo absorptions,but comprehensive in vitro and in vivo correlations is needed to study further.