Study On The Preparation Of Hydroxypropylmethylcellulose Matrix Tablets Containing Gliclazide Complexed With Hydroxypropyl-β-cyclodextrin

Background and objectiveGliclazide(GZ), (1-〔3-azabicyclo(3.3.0)oct-3-yl〕-3-p-tolylsulphonylurea )is a second generation sulfonylurea of oral hypoglycemic agents used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). In genernal GZ has a better glycemic control and can reduce development of diabetic complications. But as oral dosage forms the major drawback in the therapeutic application and efficacy of GZ is its very low aqueous solubility because of its hydrophobic nature, so its bioavailability has a great interindividual variation. Furthermore, hypoglycemia is the other disadvantage of GZ. Since cyclodextrins (CDs) can form complexes with numerous molecules, improving their bioavailability and their biological properties, the objective of this paper is to prepare the GZ's complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) and then to develop the preparation of sustaind-release matrix tablete with hydroxypropylmethylcellulose (HPMC). Sustained release formulations have been introduced into drug therapy with advantages of reducing the frequence of administrationduring the day, and decreasing the fluctuations of serum levels in view to obtain better therapeutic efficacy and diminished toxicity.Materials and MethodsThe molar ratio 1:1 of GZ: HP-β-CD was decided in the production of complex and the GZ complex was obtained by spray-drying and identified by phase solubility study, solubility test, infrared spectrophotometry and thermal analysis. The solubility of complex was used as an indicator, the conditions of preparation were investigated with the orthogonal test and analyzed by ANOVA and multiple linear regressions. The stability of GZ in the inclusion complex was determined by high-performance liquid chromatography (HPLC), and then the optimized conditions of preparation were determined.Matrix tablets composed of GZ-HP-β-CD complex and HPMC were prepared by direct compressing method. The influence of HPMC viscosity grade and HPMC percentage on the release profile of matrix tablet were evaluated in vitro. The release pattern was analyzed in various mathematical models. Then the pharmacokinetic parameters of sustained-release matrix tablets in dogs (n=5) were evaluated by a randomized cross-over study and compared with the pure drug suspension. Blood samples were obtained simultaneously and the concentration of GZ in which were analyzed by HPLC.Results: Spray-drying method could be used in the preparation of the GZ-HP-β-CD inclusion complex with 1:1 stoichiometry, as demonstrated by Phase solubility studies and other method. Inclusion complex lead to a higher solubility and dissolution rate; It was found that the increasing reaction temperature and time could enhance the solubility of GZ, while dripping-rate of GZ solution had a negative effect. Combining stability test, the optimal conditions were 45℃, 6h and 0.5ml/min dripping-rate(accord with 3gGZ) .In this condition, GZ's water solubility increased up to eight-fold compare with that of the pure drug .In order to modificate the release of GZ, a sparingly water-soluble drug, we used hydroxypropyl-β-cyclodextrin as hydrophilic matrices. All matrix formulations in vitro displayed a sustained-release profile when compared to the reference formulation. As in the Higuchi model, the release kinetics of the matrix formulation may be square root time dependent(correlation coefficients, r≥0.997), The value 0.612～0.643 of the release exponents indicated that the release in according with anomalous or non-Fickian release, i.e. the drug release proceeded by diffusion as well as erosion of the polymer. An increasing sustained effect occurred with increasing viscosity grades and increasing HPMC percentages.Evaluation in vivo showed that matrix tablets containing the GZ-HP-β-CD inclusion complex presented a significantly higher bioavailability (1.40times) and longer Tmax than that of the pure GZ suspension. Conclusion:Spray-drying method could be used in the preparation of the GZ-HP-β-CD inclusion complexes...