| Objective: To prepare and study intra-gastric floating sustained-release tablets(SRT) of metformin hydrochloride, which could prolong absorbing-time in gastroentry, increase absorption and improve bioavailability of metformin hydrochloride. Methods: Hydroxypropyl methylcellulose (HPMC), hexadecanol(C16H34O) and NaHCO3 were taken as excipients to prepare metformin hydrochloride SRT by using dry granulating method. The effects of the viscosity of HPMC, preparing method, release conditions (release medium and stirring rate) on the dissolution behavior of metformin hydrochloride SRT were investigated. The best preparation was selected by orthogonal experiment design based on analysis of the above factors. Taking HPMC, hexadecanol, NaHCO3, and compressional pressure as 4 influencial factors, chosing 3 different levels respectively, 9 kind of preparations were made according to L9(34) orthogonal design table, determing respective release percents in vitro by dissolution test. The results of orthogonal experiment design were analysed by a method of comprehensive evaluation; evaluating guidelines including comprehensive release percent, the score of floating lag time, and the score of correlative coefficient for Higuchi equation.Floating lag time and sustained floating time were observed after metformin hydrochloride SRT were thrown into 0.1 mol·L-1HCl solution. Cylindrincal basket method was employed in the dissolution test according to C.P, 0.1 mol·L-1HCl solution was taken as release medium and samples were diluted by pH6.8 phosphate buffer . Metformin hydrochloride was determined by ultraviolet (UV) spectrophotometer at 233 nm wave-length. Comparing release percent of SRT and that of conventional tablets(CT) to investigate sustained-release property of SRT in vitro. The effects of high temperature, high humidity and radiancy on the stability of SRT were investigated. SRT were deposited 10 days at 60℃, relative humidity(RH)90% or 75% and (4500±500)lx respectively, samples at the fifth and the tenth day were analysed to investigate appearance, content and release percent of SRT.After oral administration of SRT(250 mg) and CT(250 mg) respectively, the concentration of metformin hydrochloride in rabbits plasma at certain sampling times were determined by high performance liquid chromatograph (HPLC). The pharmacokinetic parameters such as AUC0-∞,AUMC0-∞,MRT were calculated by a method of noncompartmental model, Cmax and tmax were recorded as observed. Unpaired t-test was used to all parameters except tmax to compare the parameters of SRT and CT, to which nonparametric Wilcoxon two-sample test was used. Calculated in vivo absorption of SRT(F in vivo) by using Wagner-Nelson formular, and the linear regression equation of F in vivo vs release percent in vitro (F in vitro) in 1~12 h was calculated.Results: The best preparation of metformin hydrochloride SRT composed from metformin hydrochloride 250 mg, HPMC 250 mg, hexadecanol 50 mg, NaHCO3 10 mg, and 4~8 kg compressional pressure.The SRT possessed superior floating property in vitro: floating lag time was less than 3 mins, sustained floating time was more than 12 hours. The SRT could hold consistent drug release rate within over 12 hours in 0.1 mol·L-1HCl, cumulative release percent was more than 75%. The kinetics of dissolution was followed to Higuchi equation: F=28.037t1/2+2.6697 (r=0.9956). No significant change was observed in appearance, content and release percent of SRT after high temperature and radiancy tests. The weight of SRT increased 1.46% and 2.43% under RH75% after 5 days and 10 days respectively; the weight of SRT increased 1.94% and 5.02% under RH90% after 5 days and 10 days respectively. The results of stability tests showed that it is easy to increase weight under high humidity.Pharmacokinetic research in rabbits showed metformin hydrochloride SRT had excellent sustained-release charater in vivo. There was no significance observed between the values of Cmax for SRT and that for CT, the values of Cmax were (3.70±0.68) μg...
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