酮洛芬24小时缓释片的制备与处方工艺优化
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摘要
酮洛芬是具有苯丙酸结构的非甾体类抗炎镇痛药物,具有明显的消炎、镇痛和解热作用,临床上主要用于类风湿性关节炎、风湿性关节炎、骨关节炎、强直性脊椎炎、急性痛风等的治疗。其普通口服制剂存在生物半衰期短(1.6～1.9 h)、有效血药浓度维持时间短等缺点,临床应用时需频繁给药(每天3～4次),对胃肠道又具有刺激性,长期服用会导致消化道溃疡、出血等症状。目前国内生产的酮洛芬制剂主要为普通片剂和肠溶胶囊,一日服药数次,患者顺应性不好,而且会带来对治疗效果和安全性的影响,因此开展酮洛芬缓释制剂的研究是很有必要的。
本课题结合国内缓控制剂辅料研究使用情况,选用不同黏度的羟丙甲基纤维素(HPMC)以一定比例混合作为基本骨架材料,乳糖作为填充剂,制备了能够持续24小时释放的酮洛芬骨架片。课题通过前期处方筛选对骨架材料、填充剂、黏合剂、润滑剂和助流剂的种类和用量以及片剂制备方法进行初步确定,发现黏合剂的种类和制粒干燥温度对释放度均匀性有较大影响。在此基础上,以酮洛芬在pH7.2缓冲液中的释放度为指标,考察了处方中影响主药释放的各种因素,包括HPMC用量、乳糖用量、主药粒径、黏合剂浓度,从结果看出,不同黏度的HPMC能不同程度地阻滞酮洛芬缓释片中药物的释放,乳糖促进药物的释放。进一步考察了工艺中制片方法、片剂大小以及制片压力对酮洛芬释放的影响,其中制片方法对片剂缓释效果有较大影响。根据上述考察结果确定了最优的处方和制备工艺,并连续制作了三批片剂样品,结果表明,酮洛芬的释放与预先估计一致,三批样品重量差异小,释放速率稳定。本课题还对酮洛芬24小时缓释片的体外释放数据用Higuchi模型、零级释放模型、一级释放模型及Ritger-Peppas模型进行拟合,结果表明,酮洛芬缓释片的释药曲线符合一级方程,其释放机制为药物扩散和骨架溶蚀综合作用,属于不规则转运。
本课题探讨了24 h缓释制剂开发、研制的一般途径,为今后缓释制剂处方的设计和筛选,提供了思路和方法。
Ketoprofen is one of non-steroidal anti-inflammatory drugs, which contains phenylpropionic acid in structure. It has a clear anti-inflammatory, analgesic and antipyretic effect and frequently used for rheumatoid arthritis, rheumatic arthritis, osteoarthritis, ankylosing spondylitis, acute gout, but common oral dosage forms of ketoprofen has shortcomings of short biological half-life(1.6-1.9 h) and blood drug level decreased in short time so that patients need frequent administration(t.i.d or q.i.d).Ketoprofen stimulates gastrointestinal tract and patients suffer digestive ulcer or gastrointestinal hemorrhage if treated for a long time.At present, most of domestic preparations of ketoprofen are common tablets or enteric-coated capsules that need to be administered several times a day, which affects therapeutic effect and medication safety. Therefore it's necessary to study on ketoprofen sustained-release preparations.
Based on the domestic research of pharmaceutical materials used for sustained-release and controlled-release preparations, hydroxypropyl methylcellulose (HPMC) of different viscosities mixed in certain proportion were chosen as major matrix material and lactose as bulking agent, and ketoprofen matrix tablets which can continuously release drug for 24 hours were prepared. First of all, the matrix material, bulking agent, lubricant, glidant and procedure of preparation were screened, and in the next various factors in formulation including amount of HPMC and lactose, particle size of ketoprofen and concentration of adhesive which affect the release of drug were studied by determinate drug release in vitro in buffer(pH 7.2). The results indicated that HPMC decreased the drug release and lactose promoted it. The tableting method, the size of tablets and the tableting pressure were studied furthermore and the tableting method had significantly effects on the drug release. The formulation and procedure optimized according to the results were verified by prepared 3 batches of tablets consecutively. The drug release was good and stable as expected. Finally, the mechanism of release of ketoprofen in the sustained-release tablets was studied by fitting the drug release data to zero-order, first-order, Higuchi and Ritger-Peppas equation.The results showed that the drug release pattern from the matrix tablets was approach to first-order eqution, and was interaction of diffusion and corrosion which belonged to the irregular transport.
Common ways of developing 24-hour-sustained-release preparations were discussed in this topic, which provided ideas and methods for the design and screening of sustained-release preparations in the future.
本课题结合国内缓控制剂辅料研究使用情况,选用不同黏度的羟丙甲基纤维素(HPMC)以一定比例混合作为基本骨架材料,乳糖作为填充剂,制备了能够持续24小时释放的酮洛芬骨架片。课题通过前期处方筛选对骨架材料、填充剂、黏合剂、润滑剂和助流剂的种类和用量以及片剂制备方法进行初步确定,发现黏合剂的种类和制粒干燥温度对释放度均匀性有较大影响。在此基础上,以酮洛芬在pH7.2缓冲液中的释放度为指标,考察了处方中影响主药释放的各种因素,包括HPMC用量、乳糖用量、主药粒径、黏合剂浓度,从结果看出,不同黏度的HPMC能不同程度地阻滞酮洛芬缓释片中药物的释放,乳糖促进药物的释放。进一步考察了工艺中制片方法、片剂大小以及制片压力对酮洛芬释放的影响,其中制片方法对片剂缓释效果有较大影响。根据上述考察结果确定了最优的处方和制备工艺,并连续制作了三批片剂样品,结果表明,酮洛芬的释放与预先估计一致,三批样品重量差异小,释放速率稳定。本课题还对酮洛芬24小时缓释片的体外释放数据用Higuchi模型、零级释放模型、一级释放模型及Ritger-Peppas模型进行拟合,结果表明,酮洛芬缓释片的释药曲线符合一级方程,其释放机制为药物扩散和骨架溶蚀综合作用,属于不规则转运。
本课题探讨了24 h缓释制剂开发、研制的一般途径,为今后缓释制剂处方的设计和筛选,提供了思路和方法。
Ketoprofen is one of non-steroidal anti-inflammatory drugs, which contains phenylpropionic acid in structure. It has a clear anti-inflammatory, analgesic and antipyretic effect and frequently used for rheumatoid arthritis, rheumatic arthritis, osteoarthritis, ankylosing spondylitis, acute gout, but common oral dosage forms of ketoprofen has shortcomings of short biological half-life(1.6-1.9 h) and blood drug level decreased in short time so that patients need frequent administration(t.i.d or q.i.d).Ketoprofen stimulates gastrointestinal tract and patients suffer digestive ulcer or gastrointestinal hemorrhage if treated for a long time.At present, most of domestic preparations of ketoprofen are common tablets or enteric-coated capsules that need to be administered several times a day, which affects therapeutic effect and medication safety. Therefore it's necessary to study on ketoprofen sustained-release preparations.
Based on the domestic research of pharmaceutical materials used for sustained-release and controlled-release preparations, hydroxypropyl methylcellulose (HPMC) of different viscosities mixed in certain proportion were chosen as major matrix material and lactose as bulking agent, and ketoprofen matrix tablets which can continuously release drug for 24 hours were prepared. First of all, the matrix material, bulking agent, lubricant, glidant and procedure of preparation were screened, and in the next various factors in formulation including amount of HPMC and lactose, particle size of ketoprofen and concentration of adhesive which affect the release of drug were studied by determinate drug release in vitro in buffer(pH 7.2). The results indicated that HPMC decreased the drug release and lactose promoted it. The tableting method, the size of tablets and the tableting pressure were studied furthermore and the tableting method had significantly effects on the drug release. The formulation and procedure optimized according to the results were verified by prepared 3 batches of tablets consecutively. The drug release was good and stable as expected. Finally, the mechanism of release of ketoprofen in the sustained-release tablets was studied by fitting the drug release data to zero-order, first-order, Higuchi and Ritger-Peppas equation.The results showed that the drug release pattern from the matrix tablets was approach to first-order eqution, and was interaction of diffusion and corrosion which belonged to the irregular transport.
Common ways of developing 24-hour-sustained-release preparations were discussed in this topic, which provided ideas and methods for the design and screening of sustained-release preparations in the future.
引文
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