Application Of Central Composition Design For Optimization The Formulation And Processing Of Potassium Chloride Sustained-released Tablets

The purpose of this investigation was to study the sustained release tablets using potassium chloride (KCl) as model drug ,and acrylic resin (Eudragit RS100 and Eudragit RL100) as coating materials. While screen of the formulation and prescription often need to investigate the influence of composition and process factors on dosage. CCD(central composite design)was used to optimize experiments design and connect with the optimum method of RSM (response surface methodology). The new method used for the design and development of the formulation can avoid the shortcoming of the traditional test method.KCl sustainted release tablets are potassium supplements, indicated for treatment of hypoklemia which is one of the common electrolyte disturbance disease symptom. KCl is available in a variety of dosage forms. Liquid forms provide for rapid absorption of potassium ion (K~+), but also have an unpleaseant taste;common tablets can irritate the GI tract, result in GI injury such as esophagitis, gastric ulcer, gastric bleeding etc, but the K.C1 sustainted release tablets can avoid or minimize these side effect.The objective of the present study was to optimize the formulation of KCl sustainted release tablets using CCD and RSMd. KCl sustaintedrelease tablets were prepared with povidone as core matrix material and Eudragit RL100 and RSI00 as coating material. While Eudragit RL100 is high permeable material and Eudragit RSI00 is impenetrable material, the dissolution rate we desired should be obtained if we adjust the proportion of two polymer. The central composite experiment design consisting of a two level full factorial design superimposed on a star design was employed for developing the sustained tablets. In the study the ratio of polymers (Xl)and coat weight (X2) that affect the drug release rate were chosen as the indepentdent variable. The percentage of drug release after 2,4 and 8h was selected as the dependent variable(Y). Nine experiments were performed according to the design. SAS and Matlab software were used for statistical analysis including multivariant linear regression and response surface analysis respectively. The mathematical models were tested for their significance using analysis of variance (ANOVA). Results were considered significant when the corresponding P values were less than 0.05. Two- and three-dimensional contour diagrams visualizing the simultaneous effect of the causal factors on the response at each time point were established. Response surface analysis using the contour diagrams was utilized to select the coating formulation variables, required to select the desired percent of drug release at each time point. A release profile with 25% KC1 released after 2h,55% released after 4h and 80% drug released after 8h was targeted. Two-dimensional contour diagrams were superimposed and the overall coating formulation variables that can simultaneously fulfill the release requirements at all the time points were estimated.An optimum formulation for sustained tablets was established. The formulation was comprised of the ratio of Eudragit RL100 and RSI00(57:43), and coat weight 2%~2.5%. Further we developed the formulation, including on scale-up three batch sample. The resultsshowed the experiment of percent drug released after 2,4 and 8h were close to the predicted values.Three batch of samples were made on a manufacturing scale and used for stability test. The samples was tested such as influence factor test(high temperature,high humidity and photostability),and 6 months accelerated testing and 24 months long term testing. The overall quality of the batchs of the drug meet to the specification in the all duration. It's scenitific and trust that central composition design was applied to optimize the formulation and processing. This optimal method is efficient and foreseeable, and can guide manufacturing.The relative bioavailability of potassium chloride sustained-release tablets was studied in healthy volunteers and the bioequivalence of the two kinds of potassium chloride sustained-release tablets was evaluated. A single 3000mg(500mg/tablet) dose were administered The relative bioavailability was represented by the cumulative amount of potassium ion(K+)e xcreted in urine 48h after drug administration. The results of the RT(reference tablet) and TT(test tablet) were as follow:Aco-48h(cumulative urinary excretion from 0-48h) were 26.63±5.71mEq and 26.46±6.72 mEq;Vmax(maximal rate of urinary excretion) were 2.85±1.10 mEq.h'1 ^Q 2.64±1.12 mEq.li'1;Tmax (time of maximal urinary excretion) were 5.50±2.42 fP 5.60±1.96 h, respectively;The bioequivalence of the two formulations was 99.2%. The results evaluated by ANONA and two one-side t test indicated there was no significant difference between the two formulations and they were bioequiovalent.