【作者】 许建辰；

【导师】 赵康；

【作者基本信息】 天津大学 ， 应用化学， 2008， 博士

【摘要】 口腔崩解给药系统作为一种新型制剂,近年来有大量产品上市,已成为研究热点。然而,该剂型存在生产费用高;产品稳定性差;口味不良;临床应用仅作速释制剂等问题。因此,本论文在处方和工艺研究的基础上进行掩味和缓释系统的探索,为这一新剂型的开发应用提供技术上的支持和理论上的参考。首先,使用新型协处理材料,粉末直接压片工艺,制备口崩片。使用理化性质不同的三种模型药物(5-羟基色氨酸、法莫替丁和对乙酰氨基酚)考察处方及工艺,得到最优处方为模型药物24.5%,协处理材料60%,HPMC 7.5%,PVP 5%,柠檬酸1%,富马酸硬脂酸钠2%。一定量聚合物的添加改善了系统的润湿性,增加了溶出度。以法莫替丁为模型药物,制备并比较了三种掩味系统(掩味颗粒、掩味包衣颗粒和喷雾干燥掩味微球),评价其掩味效果。得到结论,喷雾干燥微球口感口味理想,一步操作,工艺可控,是最佳的掩味系统。通过星点法试验设计,数学模型拟合,参数最优化计算,确定喷雾干燥工艺为:进口温度110℃;引风量90%;法莫替丁:Eudragit EPO?:微粉硅胶:PEG 400 =1:2:1:0.2;固体含量为34 mg/ml;流速为7 ml/min。制得掩味微球的包封率为61.56%。掩味口崩片口味得到明显改善,口感良好,口内1 min崩解,SEM观察证明微球压片后结构保持完整。喷雾干燥制备对乙酰氨基酚缓释微球。压片制得体外12h释放的缓释口崩片,释放符合一级动力学,口腔内1 min崩解,DSC证明药物以无定型态存在,SEM证明微球形态完整。对制得的产品进行稳定性实验,证明以上各制剂稳定性良好,但须防潮保存。最后,体内药动学研究表明法莫替丁掩味口崩片生物利用度提高,tmax缩短,具有速释特征。对乙酰氨基酚缓释口崩片的Cmax显著下降,tmax显著延长,体内释放具有缓释特征。综上所述,本文应用新型协处理材料粉末直压工艺制得性质理想的口崩片,喷雾干燥微球即可以作为掩味手段也可以制备缓释系统。使用上述技术可以开发缓释口腔崩解给药系统,为该系统的研究和开发提供了新的思路,有一定的研究价值。更多还原

【Abstract】 Orally disintegrating tablet (ODT) is a new strategic tool for Drug delivery system. Many ODT products have come to global market, and the researches are moving rapidly. In this paper, we focused on the formulation and process design, as well as the development of taste masking system and extended release system. The investigation aimed to provide practice and theory on the drug delivery system.In this paper, the co-processed excipient (Pharmaburst Powder) was applied to prepare ODTs by direct compression. Three model drugs with different physicochemical properties (5-hydroxytryptophan, famotidine, and acetaminophen) were used and evaluated. The final formulation was model drug 24.5%, the co-processed material 60%, HPMC 7.5%, PVP 5%, citric acid 1%,SSF 2%. The additions of polymer improve the wettability and dissolution.Three different taste masking systems (granulation, coating granulation and spray-dried microspheres) were prepared and evaluated. The conclusion was the spray-dried microspheres can not only improve the taste and mouth feel but also one step process and easy to control. So the spray-dried microsphere was the best taste masking system. The microspheres were produced by spray drying a mixture of the famotidine with polymer (drug:Eudragit EPO?:glidant:PEG 400=1:2:1:0.2). The spray process was optimized using a central composite design and the final parameters were inlet temperature 110℃; aspirator setting 90%; solid concentration 34 mg/ml; flow rate 7 ml/min. The encapsulation efficiency was 61.56%. SEM proves the integrated structure of the tabletted microspheres. The taste masking ODTs can disintegrate in buccal cavity within 1 min.For preparation of the extended release microspheres, the mixture of Eudragit RS 30D? and acetaminophen was spray dried. The ODTs with the microspheres can extend the release to 12h and follow the first order release kinetics. The tablet with microspheres can disintegrate in buccal cavity within 1 min. DSC proved the drug completely entrapped in the polymer matrix.The stability test demonstrated the acceptable stability of the final products. However the storage of the products should keep in dryness.In vivo the taste masking famotidine ODTs improved the bioavailability and exhibited fast release profile. And the extended release acetaminophen ODTs exhibited the extended release profile.In conclusion, we prepared the good quality ODTs by direct compression. Spray-dried microspheres can be applied as taste masking or the extended release system. The investigation has important meaning for the future research and product development.更多还原