Preparation Of Flavoxate Hydrochloride Sustained-release Tablets

PurposeThe ordinary flavoxate hydrochloride(FX)tablet has short half-life period,and its concentration in plasma reaches the peak very soon,therefore the side effects of the tablet are enhanced on the human body.In addition,the tablet or capsule needs to be taken 3 to 4 times a day.It is not convenient for patients.However,the sustained-release tablet made of FX with proper processes can reduce the taking times,increase patient compliance,and provide reference for industrial production.Methods The best preparation processes and prescription were selected according to the releasing rate of FX in different prescription and process conditions.The wet granulation technique was used to prepare tablets.Sugar content,HPMC viscosity and HPMC dosage were used as factors,the overall desirability of every index was used as evaluation indicator,and the Central Composite Design Response Surface Methodology was used to optimize the prescription of preparations.The HPLC methodology to determine the concentration of FX and the relevant substances was established,and the quality was evaluated through investigation on the content and stability of the relevant substances of self-made tablets.The HPLC methodology to determine the concentration of active metabolites of flavoxate hydrochloride(MFCA)in plasma was established,the self-made FX sustained-release tablets(Spec.: content at 200 mg)were used as a tested preparation,and the commercially available FX tablets(Spec.:content at 200 mg)were used as a reference preparation.Then the drug concentration in plasma at different time points were measured,the drug concentration graph was drawn,and the pharmacokinetic parameter wascalculated,with the experimental method of two preparations of six rabbits and double cycle oral medication.ResultsAccording to the investigation on each release and optimization of central composite design response surface methodology,the best prescription composition was determined—68.44 mg of HPMC-4000,4.60 mg of HPMCAS,and 19.60 mg of sugar.The FX and the relevant substances were well separated,and the self-made sustained-release tablets met the specification of the China Pharmacopoeia 2015 about the quality limitation of the relevant substances.The experiment of pharmacodynamics on rabbits showed that the main pharmacokinetic parameters of the reference preparation and the tested preparation were Cmax(4.31±0.76)μg·m L-1,(2.81±0.31)μg·m L-1,Tmax(1.00±0.00)h,(8±0.00)h,AUC0~t(20.36±2.66)μg·m L-1*h,(22.94±0.31)μg·m L-1*h,AUC0~∞(22.52±1.911)μg·m L-1*h,(23.46±0.43)μg·m L-1*h,and the relative bioavailability was Fr:(110.27±10.80)%.ConclusionsThe preparation of FX sustained-release tablets is easy and practicable.After the optimization of prescription,the deviation between the predicted and measured value is less than 5%.The mathematic model established by the central composite design response surface methodology has accurate predictability.The pharmacodynamics experiment results showed that the pharmacokinetic parameters of self-made FX sustained-release tablets and commercially available FX tablets are obviously different in Tmax 、 Cmax and AUC0~t.As the pharmacokinetics experiment results found,the Tmax of FX sustained-release tablets is distinctly delayed and the Cmax of that is reduced in comparison with commercially available FX tablets.The bioavailability is thereby improved and it provides a reference for industrial production,achieving the experimental goal.