| Chewing gum preparation (CGP), which bases on water-insoluble materials, is a special formulation of oral cavity immediate-released system. With some simple machonnement, CGP-loaded drug can be released, dissolved in saliva and finally absorbed through cavity, the whole drug delivery system is completed in oral cavity with no additional water. To pocess such good advantages, CGP is especially suitable for patients who have difficulty in swallowing, and significantly improves the compliance of the elder and younger patients in clinical.Dextromethorphan(DH) is the d-isomer of the codeine analog of levorphanol and one of the widely used antitussives. With the equivalent action to codeine, DH has no such disadvantages of codeine as analgesia,sedation and addiction, and will not inhibit the respiratory center and secretion of respiratory tract mucosa at therapeutic dose. With low adverse reactions, DH is a safe and effective antitussive for clinical use. While the t1/2 of DH is only 2-3 hours, as a result, DH should be given 3-4 times a day in clinical and it tastes bitterly. To research and develop DHCGP can offer a convenient and tasty DH formulation for clinical use and expand drug delivery systems for DH at the same time.In this study, DH is taken as the model drug. Molecular inclusion technology is exploited to mask the bitterness of DH. DHCGP is prepared by sheeting law. The characters and the pharmacokinetic studies of DHCGP are invested in both vivo and vitro.Method:1. The inclusion complex was prepared by grinding method, the suitable molar inclusion proportion is determined by continuous variation method and bitter evaluation method, and the optimal formulation is obtained by ordinal optimization method, and confirmed by microscope observation, differential scanning calorimetry, solubility test and computer simulation methods.2. DHCGP was prepared by press tablet, and optimized by orthogonal experiment. The dissolution studies were carried out according to a dissolution test apparatus of China pharmacopoeia (2005 edition, paddle method). And the concentration of DH in vitro is determination by UV method.3. Studing the preliminary stability.4. Establishing quantitative method of DH in vivo by RP-HPLC.5. Studying the pharmacokinetic of DH in rabbit, fitting the compartment model by 3P97 software and calculating pharmacokinetic parameters and the various pharmacokinetic parameters by SAS software.Results:1. The drug loading and the entrapment efficiency were determined as 9.83% and 92.10%, respectively. The inclusion complexes can completely mask the bitterness of DH and improve the compliance.2. The concentration of DH in the optimized preparation is 101.71%, the content uniformity is 97.0%, and DHCGP releases 97.08% by15min.3. The preliminary stability studies indicated that DHCGP is unstable is stable in high temperature and illumination experiment and not stable in humidity test. Away from light, DHCGP is stable for at least 12 month at 25 ±2℃, 60%±10%RH.4. Establishing the quantitative method of DH in vivo by RP-HPLC. It shows that the precision,accuracy and reproducibility are good. The concentration and the peak area linear relationship are fine. The range of the linear was 1.0~1000 ng.mL-1, inter-precision and intra-precision are smaller than 15%, the absolute returns-ratio is 83.63%, the relative returns-ratio is 109.9%.5. The pharmacokinetic studies showed that DHCGP and market product conform to the weight of 1/C2 single compartment model. The Cmax of DHCGP is 95.45 ngmL-1 lower than the market product, and the Tmax is 1.83h retards 0.8h compared to the market product, AUC0→∞is 488.76ng.mL-1.h higher than the market product 110 ng.mL-1.h, the results indicated that CGP can absorbs rapidly, release sustainable and steadily and pocess high bioavailability.Conclusion:We had prepared DHCGP, a new drug delivery system of DH, which tastes tasty, absorb quickly, release sustainably and stably, and process high bioavailability. Moreover, this new drug delivery system of DH provides valuable prospects for the research and development of antitussives. |
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