| Salbutamol is the first choice to treat asthma which is a frequent disease. Commercially available salbutamol sulfate is a racemate that contain R-optimal enantiomers and S-bad enantiomers.S-bad enantiomer lack of pharmacological activity and has toxicity. R-salbutamol can be gained by chiral resolution. Compared with its racemate, R-salbutamol can significantly improve the curative effect and reduce toxicity. As a new drug, a levosalbutamol sulfate tablet in the clinical trials is going to be completed in China. However, levosalbutamol sulfate tablets metabolize fast in vivo. Therefore patients need to take the medicine three times a day, which lead to poor patient compliance. We study on the preparation of levosalbutamol sulfate controlled-release tablets with extended drug effect time and lower peak concentrations. The main contents of our study are as follows:We used the skeleton slow-release technology to prepare levosalbutamol sulfate controlled-release tablets, and optimize its preparation conditions by single factor experiments and orthogonal test. By investigating the effect of different tabletting method and excipients doing on drug release rate, we can finally chose the best preparation conditions(53% of hydroxypropyl methyl cellulose(HPMC) as sustained-release matrix material, 22% of lactose as filling agent and 18% of pregelatinized starch as adhesive agent with direct power compressing method). The content and release rate of levosalbutamol sulfate controlled-release tablets were determined by high performance liquid chromatography(HPLC). The results showed that the drug dissolution in 2 h, 4 h, 8 h were 46%, 67% and 93% respectively. It had a simillar dissolution curve with the drug “Vo Spire”(f2>50) that was on sale in foreign country.With the fitting of drug release model, we can deduce that the release mechanism of our levosalbutamol sulfate controlled-release tablets with Ritger-Peppas model.The stability of levosalbutamol sulfate controlled-release tablets was evaluated by stress test(high temperature, high humidity and strong light) and three months accelerated test(40℃±2 ℃of temperature, 75%±5% of relative humidity).The result showed that its content, related substances and dextroisomer conformed to the requirement of limit.We established and validated the detection and analysis technique of levosalbutamol in biological samples using UPLC-MS/MS. The pharmacokinetics of beagle dogs after taking the levosalbutamol sulfate controlled-release tablets(4mg) had been studied and compares with the reference levosalbutamol sulfate tablets. Our results showed that the AUC value of sustained release tablets and conventional tablets were 305.50±29.23h·μg·ml-1 and 302.71±49.91h·μg·ml-1, half-life period were 3.41±0.89 h and 2.47±0.65 h, peak concentration were 42.20±6.59μg×L-1 and 78.86±14.59μg×L-1 respectively.The relative bioavailability of sustained release tablets was 107.73%.Conclusion:The release test result of in vitro of levosalbutamol sulfate controlled-release tablets was in line with the demand of the Chinese Pharmacopoeia, which was similar with the salbutamol sustained release tablets in forgin country. In vivo experiments of dogs showed that the controlled-release tablets had longer residence time in the body, obvious extended half-life, and obvious decrease on peak concentration(Cmax). The relative bioavailability of the controlled-release tablets was 107.73% which show the similar abosortion with the conventional tablet. |
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