泼尼松脉冲控释微丸的设计与评价

发布时间：2018-03-28 22:29

本文选题：脉冲给药系统　切入点：释药时滞　出处：《河南大学》2016年硕士论文

【摘要】：脉冲给药系统(Pulsatile delivery system)又名择时释药系统,可依据人体时辰节律特征以及疾病发作的时间规律,实现定时或定位释放药物。脉冲制剂不同于常见的缓控释制剂,并不能维持恒定的血药浓度,而是经服用后首先经历一个预定的释药时滞(Lag Time,TLag),而后于疾病发作的特定时间或者于特定部位即刻释放药物以达到所需血药浓度及组织中的药物浓度,因此可大大减轻药物不良反应、机体耐受性,提高患者的用药依从性。多微粒给药系统相比于单一单元型制剂,具有优良的释放调节性,能够显著改善胃肠道药物吸收一致性与重现性,所以已成为脉冲给药系统的研究热点。目前,口服多微粒脉冲释药系统的特定的释药曲线特征大多是通过制备功能性包衣薄膜的途径实现。泼尼松(Prednisone,PNS)是用于治疗类风湿性关节炎常用的肾上腺皮质激素类药物;2013年7月31日,FDA批准英国Napp制药公司的泼尼松脉冲择时控释片上市,其商品名为Lodotra,是用于类风湿性关节炎时辰药物疗法的一线制剂,其体内血浆药时曲线下面积(AUC)与市售普通制剂大致等同,但是Cmax往后推迟4~4.5h,可达到有效的迟释效应;由于只需临睡前服用,在很大程度上提高了患者的用药依从性,并获得了极为显著的临床疗效,大大减轻了类风湿性关节炎患者的临床症状。本研究是以泼尼松为模型药物,以丙烯酸树脂类包衣辅料为包衣材料,运用Glatt底喷流化床包衣技术制备包衣膜,成功制得了具有pH依赖性的、释药时滞为4~4.5h的脉冲微丸制剂;建立了专属性强、精密度高、准确性强的HPLC法,用于泼尼松脉冲控释微丸含药量、释放度及有关物质的测定。本实验运用底喷流化床包衣技术,采用混悬液上药法制备泼尼松载药微丸;并对载药微丸粒径、圆整度、脆碎度等指标进行考察,均符合后续的功能性包衣的要求。功能性包衣膜的制备仍采用底喷流化床包衣技术,参照丙烯酸树脂类包衣辅料使用指南,选用柠檬酸三乙酯(TEC)作为增塑剂、滑石粉(Talc)作为抗粘剂,筛选出了合适的包衣辅料为Eudragit?RS-100和Eudragit?L-100,并通过包衣增重、包衣辅料比例等单因素考察,确定了包衣增重、Eudragit?RS-100与Eudragit?L-100的比例是泼尼松脉冲控释微丸体外释放行为的主要影响因素,并采用星点设计-效应面优化法优化包衣处方,最终得到了较优的包衣处方范围。通过对自制泼尼松脉冲控释微丸的体外释放曲线与各释药模型进行拟合,结果表明,与Hixson-Crowell模型和一级模型的拟合度较高,证明药物的释放属于扩散与溶蚀相协同作用的机制。制剂初步稳定性考察实验表明,产品质量基本不受光、热、湿等因素的影响。
[Abstract]:Pulsatile delivery system, also known as time-selective drug delivery system, can release drugs periodically or locally according to the characteristics of human body hour rhythm and the time law of disease onset. Pulse preparation is different from common slow and controlled release preparations. Can't maintain a constant blood concentration, Instead, after taking the drug, they first experience a predetermined release time lag and then immediately release the drug at a specific time during the onset of the disease, or at a specific site, to reach the required blood and tissue drug concentrations. Therefore, it can greatly reduce adverse drug reactions, body tolerance, and improve patients' compliance with medication. Compared with single unit preparation, the multi-particle drug delivery system has excellent release regulation. It can significantly improve the consistency and reproducibility of gastrointestinal drug absorption, so it has become a research hotspot in the pulse drug delivery system. The characteristic of specific release curve of oral multi-particle pulse drug delivery system is mostly achieved by the preparation of functional coating film. Prednisone PNSs are commonly used in the treatment of rheumatoid arthritis. On July 31, 2013, the FDA approved the listing of prednisone pulse timing controlled-release tablets from Napp Pharmaceuticals in the UK, Its trade name is Lodotra.It is a first-line preparation used in the treatment of rheumatoid arthritis. The area under the plasma drug time curve in vivo is approximately the same as that of the ordinary preparations sold on the market. However, the delay of Cmax is 4 ~ 4.5 hours later, which can achieve an effective delayed release effect. Because it only needs to be taken before bedtime, the compliance of patients is improved to a great extent, and the clinical curative effect is very remarkable, which greatly alleviates the clinical symptoms of patients with rheumatoid arthritis. In this study, prednisone was used as the model drug. Using acrylic resin coating excipients as coating materials and Glatt bottom spray fluidized bed coating technology to prepare coating film, a pH-dependent pulse pellet with a time delay of 4 ~ 4.5h was successfully prepared, which was characterized by strong specificity and high precision. The HPLC method with high accuracy was used for the determination of the content, release and related substances of prednisone pulse controlled release pellets. In this experiment, prednisone pellets were prepared by suspension method with the technology of bottom spray fluidized bed coating, and the particle size of the pellets loaded with prednisone was determined. The roundness, brittle degree and other indexes met the requirements of subsequent functional coating. The preparation of functional coating film was still made by bottom spray fluidized bed coating technology, with reference to the guidelines for the use of acrylic resin coating accessories, Using triethyl citrate (TEC) as plasticizer and talc (talc) as tackifier, Eudragit? RS-100 and Eudragit? L-100, and through the investigation of single factors, such as weight gain and proportion of coating excipient, the Eudragit? RS-100 and Eudragit? The proportion of L-100 was the main factor influencing the release behavior of prednisone pulse controlled release pellets in vitro, and the coating prescription was optimized by star design-effect surface optimization method. By fitting the in vitro release curve of prednisone pulse controlled release pellets with each release model, the results showed that the drug release curve fitted well with the Hixson-Crowell model and the first order model. It is proved that the drug release belongs to the synergistic mechanism of diffusion and dissolution, and the preliminary stability of the preparation shows that the product quality is not affected by the factors of light, heat, humidity and so on.
【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R943

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