论文标题:酮洛芬口服定时释放制剂的研制
Study on Ketoprofen Orally Delayed Release System
论文作者 潘新
论文导师 任麒,论文学位 硕士,论文专业 药剂学
论文单位 上海医药工业研究院,点击次数 95,论文页数 86页File Size4851k
2005-05-01论文网 http://www.lw23.com/lunwen_96736027/ 酮洛芬;定时释药;时滞时间;流化床;薄膜包衣
ketoprofen ; delayed release ; lag time; fluid bed ; film coating
口服定时释放制剂是近年来发展起来的一种新型释药系统。其能在经过特定的时滞之后,快速的释放药物,以实现最佳治疗。酮洛芬在临床上主要用于风湿性关节炎的治疗。本文以酮洛芬为模型药物,应用薄膜包衣技术,分别制备了定时释放片和定时释放微丸,以期满足临床上的用药需要。 本文建立了紫外分光光度法作为酮洛芬体外分析的方法,包括药物释放,含量测定和理化性质的研究等。溶解度研究结果表明,酮洛芬在水中和pH6.8磷酸缓冲液中的表观溶解度分别为O.2mg/mL和5.7mg/mL。为了方便膜处方研究,采用浇铸法制备了不同处方的乙基纤维素游离膜。通过测定并计算抗张强度、杨氏模量和渗湿系数,来预测不同膜处方对药物释放及制剂稳定性的影响。 制备了酮洛芬定时释放片,使其在晚间被口服而次同凌晨迅速释放药物。羧甲基淀粉钠被选作片芯中的崩解材料。乙基纤维素(EC)不溶于水,且溶解性不受pH变化的影响,被用作制剂外层包衣。根据游离膜实验结果,选择柠檬酸三乙酯(TEC)作为增塑剂。对包衣处方的组成和衣层厚度对药物释放的影响进行了考察。应用中心组合设计安排实验,以释药时滞(T_10%)和释药速率(T_10-90%,T_10-90%越小,释药速率越大)为指标,对包衣处方进行筛选。结果表明,EC和TEC用量对T_10%的影响都较显著。通过对EC用量的控制,即外层膜的厚度,可有效控制释药时滞。根据逐步回归拟合的方程,确定EC用量为5%,而TEC为膜材量的lO%,实际测得T_10%=5.6h,T_(10-90%)=0.72h,与拟合方程的预测值偏差小于8%。 设计制备了实验室用底喷式流化床,用于酮洛芬定时释放微丸的上药和包衣。对流化床的工艺因素和相关性能进行了考察,结果表明该装置适合于上药和包衣。该脉冲微丸由5层结构组成,从内而外分别是丸芯、药物层、溶胀层、阻滞层和水不溶性控释层。对影响药物时滞和释药速率的因素进行了考察,如内外层结构的厚度,增塑剂和致孔剂的用量等。结果表明,溶胀层仍起着重要作用,主要由其将外层胀裂而释放药物。一定范围内,增加外层EC膜用量、阻滞层用量和增塑剂用量都能延长时滞,而增加致孔剂的用量,能提早药物的释放。最终,
The present project was aimed to preparing a novel drug delivery system which could automatically release a desired amount of drug after the predetermined lag time. Ketoprofen has been mainly used for rheumatoid arthritis in clinical therapeutics. The objective of the study was to prepare and evaluate a delayed release tablets and pellets by film coating technique , using ketoprofen as model drug , which attempts to address clinically therapeutic requirements.In this study , UV spectrophotometry was developed for in vitro assay during the study of release , content and physico-chemical properties of ketoprofen . The studies on solubility showed that the equilibrium solubility in distilled water , pH6.8 phosphate buffer were 0.2mg/mL and 5.7mg/mL . Cast free films of ethylcellulose with different composition were prepared . The tensile strength , elastic modulus and permeability of free films were calculated to investigate the properties of preparation which was coated with the same film composition .The ketoprofen delayed release tablets was prepared and was designed to be administered at night and release its drug in the next early morning . Carboxymethyl starch sodium(CMS-Na) was selected as swelling material to make the tablet core. Ethylcellulose (EC) was used as the outer coating material which was insoluble in water and pH-independent . Triethyl citrate (TEC) was employed as the plasticizer . We investigated the effect of the composition and thickness of the coating film on drug release . The coating formulation was optimized by central composite design (CCD) , having the lag time (T10%) and the delayed release rate (T10-90%) as the evaluation standard . The result showed that the dosage of EC and TEC were both important factors to T10% . When the level of EC is 5% and TEC is 15% of EC respectively , T10%=5.6h , T10-90%=0.72h.A laboratory scale bottom spray fluid bed was designed and applied to the drug layering and film coating of ketoprofen delayed release pellets . The most significantprocess variables and other relevant quality standards were studied . The results showed that the equipment was quite suitable for drug layering and film coating . The timed release pellets consist of 5 laminar layers from the center to the outside :the core, the drug layer, the swelling agent layer , the block layer and the controlled layer . The factors which affect the lag time and drug release behavior were investigated, such as the thickness of the inner and outer layers, the amount of the plasticizer and pore-former, etc.. The results showed that the swelling layer played an important role in the formulation since the drug release is triggered by the destruction of the outer membrane. The lag time was prolonged in some degree with the increase of the outer layer or the block layer or the amount of plasticizer . And increase the amout of pore-former would speed the drug release after T|0<>/0. Eventually , the optimized pellets was prepared with Tio%=4-5h .The result of stability test showed that the delayed release tablets and pellets were unstable under high humidity condition , and were stable when exposed to strong light and hign temperature . The tablets and pellets are stable in 40 °C and RH75%. The next work is to investigate the release behavior in vivo and its correlation with in vitro .
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