Sustained Release Formulation Of Theophylline, Salbutamol Compound

In this paper, orthogonal design was used to select the optimized synergic ratio of theophylline and salbutamol in guinea pigs using 0.2% solution of acetylcholine chloride and 0.1% histamine as asthma inducing agent and probability sum method as well as variance analysis based on the inhibiting rate of the asthma incubation difference in the maximum effects (360 seconds) before and after drugs. As the results shown, there was a significant synergy between theophylline and salbutamol and the best synergic effect was found at the ratio of 75:1 between theophylline and salbutamol. The recommend daily dose is 300 mg for theophylline and 4 mg for salbutamol. Based on the daily dose and the optimized synergic ratio, the pharmacokinetics and pharmacodynamics of theophylline and salbutamol were studied on guinea pigs by both the separate and combined use of these two drugs. According to the results determined by HPLC, at the recommended dose as clinically used, there were no significant difference in both the pharmacokinetic parameters and the AUC whether these two drugs were used separately or simultaneously. This means that no interference exists between these two drugs in their pharmacokinetics. As the results from the correlation between pharmacokinetics and pharmacodynamics shown, for theophylline and salbutamol when used alone, there was a linear relationship between the asthma incubation difference and logarithm of drug concentration. But for there two drugs when used in combination, a complex relation was found between the asthma incubation difference and logarithm of drug concentration. This means that for these two drugs when used in combination, not only the drug concentration but also the drug-ratio is of influence on the asthma incubation difference.Based on the synergy of theophylline and salbutamol and optimized synergic ratio of drugs as well as the recommended dose, two-layer tablet was prepared with HPMC as the release controlling material. Uniform design method as well as the fraction method was applied for the formulation optimization. The in vitro drug release of the two-layer tablet from the optimized formulation followed Higuchi plot. According the absorption kinetics and bioavailability in healthy volunteers at single dose, the relative bioavailability of theophylline and salbutamol was 98.2% and 98.7% respectively. There was a point to point or level A correlation between the percent of in vitro drug release and in vivo drug absorption for both theophylline and salbutamol. The fluctuation percentage at the steady state after multiple dose were 0.48% and 0.59% for theophylline and salbutamol respectively. This means the slow release property for these two drugs.Considering the therapeutic use of the two drugs for asthma that frequently attacks around 4 o' clock early at morning, the multiparticular slow release pellets containing theophylline and salbutamol whose therapeutic effect lasts for 24 hr were prepared bylayering method in centrifugal rotary coater. In the preparation of the naked core, the powder layering method and suspension layering method were used and compared. According to the results, the naked core by powder layering method is of smooth appearance but bad in sphericity. For the core by suspension layering is of good sphericity but rough in appearance. Varied technology and materials were used for the coating of the pellet. Among them are the organic solution of EC, Aquacoat and Eudragit NE 30 D. A satisfied controlled release can be achieved with smaller amount of EC solution than with Aquacoat and Eudragit NE 30, However, the advantage of Aquacoat and Eudragit NE 30 D as compared with EC is its less sticky property as coating materials. Eudragit NE 30 D can obtain the simultaneous controlled release of theophylline and salbutamol at a proper amount.According to the bioavailability and absorption kinetics of the slow release pellets of theophylline and salbutamol in healthy volunteers, the relative bioavailability of theophylline and salbutamol are 108.2% and 104...