钩吻素子膜控缓释微丸的制备及其体内外评价

发布时间：2018-07-28 14:03

【摘要】：钩吻素子(koumine)为钩吻中含量最高的一种生物碱单体，属单萜吲哚类生物碱。本课题组先期系列研究表明钩吻素子具有高效低毒的抗慢性疼痛和抗类风湿性关节炎作用，提示钩吻素子具有创制新型药物的重大潜能。若将钩吻素子制成普通口服制剂，则存在血药浓度波动大，服药次数多的缺陷。为方便今后钩吻素子的临床应用，可通过缓释剂型减少给药次数，降低服药后血药浓度的波动，提高患者顺应性。本文拟通过调节Surelease包衣增重等因素以及包衣工艺的优化以获得体外释药12h的钩吻素子膜控缓释微丸的最佳制备工艺；采用影响因素试验和加速试验初步考察钩吻素子缓释微丸胶囊的稳定性；以自制钩吻素子普通片为参比制剂，测定钩吻素子缓释微丸胶囊比格犬单次口服给药后血药浓度-时间曲线，对其体内释药特性进行评价。主要研究内容如下：1.钩吻素子膜控缓释微丸的制备采用液相层积法制备钩吻素子载药微丸、底喷流化床法制备钩吻素子膜控缓释微丸。以微丸的收率、圆整度为指标，采用正交试验优化流化床上药和包衣的工艺参数。上药工艺参数优化结果为喷液流速为35r/min、鼓风频率为21HZ、雾化压力为0.03Mpa；包衣工艺参数优化结果为喷液流速为45r/min、鼓风频率为19HZ、雾化压力为0.05Mpa时，缓释微丸制备效果良好。以微丸的收率、圆整度和钩吻素子体外释放速率为评价指标，采用单因素考察试验优化筛选钩吻素子膜控缓释微丸处方。结果表明，羟丙甲基纤维素（HPMC）（5cps）作为黏合剂且浓度为15g/L时缓释微丸收率提高，圆整度好；缓释微丸的释放速率随着处方中包衣材料苏丽丝（Surelease）的增加而减慢，包衣增重30%时，12h内钩吻素子释放良好；缓释微丸的释放速率随着隔离层HPMC（5cps）的增加而减慢，HPMC（5cps）用量为1%时，钩吻素子12h内释放平稳。综上，单因素考察结果筛选优化的处方如下：缓释微丸处方质量（mg）空白蔗糖丸芯10000 钩吻素子100 HPMC300 Surelease300钩吻素子膜控缓释微丸含药量为0.67%，处方工艺重现性和钩吻素子释放均一性均良好。综上提示，，制备的钩吻素子膜控缓释微丸，工艺重现性和释放均一性良好，其在12h内体外释药稳定、缓慢、完全。2.钩吻素子缓释微丸胶囊的初步稳定性考察取300mg上述缓释微丸填装3号胶囊，得钩吻素子缓释微丸胶囊，规格为2mg/粒，初步考察钩吻素子缓释微丸胶囊的稳定性。影响因素试验结果表明，钩吻素子缓释微丸胶囊在60℃条件下放置10天，或在相对湿度为90%中室温放置10天，或在光照条件4000LX下放置10天，体外释放度发生明显变化，提示该制剂稳定性受高温、高湿及光照等剧烈因素影响较大。在钩吻素子缓释微丸胶囊稳定性影响因素试验的基础上进行加速试验，结果显示，缓释微丸在温度为40℃，相对湿度为75%下放置6个月，制剂的外观色泽、体外释放度均无显著变化。这为钩吻素子缓释微丸胶囊贮存条件设立提供实验依据。3.钩吻素子缓释微丸胶囊在比格犬体内的释药特性评价本部分建立了比格犬钩吻素子血药浓度LC-MS/MS测定方法。以自制钩吻素子普通片为参比制剂，LC-MS/MS测定钩吻素子缓释微丸胶囊比格犬单次口服给药后血药浓度-时间曲线，评价其在比格犬体内的释药特性。结果表明，钩吻素子缓释微丸胶囊与其普通片生物等效，但未有显著的缓释效果，提示本膜控缓释微丸制备及其体内释放特性评价有待于优化。本研究为后续的钩吻素子膜控缓释微丸优化制备提供参考。
[Abstract]:Koumine is the highest content of the alkaloid, which belongs to the monoterpene indole alkaloid. The first series of studies in this group show that the hychoidin has the effect of high efficiency and low toxicity against chronic pain and anti rheumatoid arthritis. It suggests that the hychoidin has the great potential to create new drugs. In order to facilitate the clinical application of the hychornus hychornus, it can reduce the number of drug delivery, reduce the fluctuation of blood drug concentration after taking the medicine, and improve the compliance of the patients. This paper aims to adjust the weight gain of Surelease coating, as well as the optimization of coating technology. The optimum preparation process of the in vitro release of 12h was obtained. The stability of the capsule of the sustained release pellet of the hychornin was preliminarily investigated by the influence factor test and the accelerated test. The concentration of the blood drug concentration after the single oral administration of the slow-release pellet capsule Beagle was measured by the self-made common tablet of the hychornin as the reference preparation. The time curve was used to evaluate the drug release characteristics in the body.
The main research contents are as follows: 1. preparation of the film controlled release pellets
The liquid phase stratification method was used to prepare the pellets of the hychornus hychorchus, and the bottom jet fluidized bed method was used to prepare the membrane controlled release pellets of the hychornus hychornus. With the yield of the pellets and the roundness as the index, the orthogonal test was used to optimize the process parameters of the fluidized-bed coating and coating. The optimum result of the process parameters of the injection was 35r/min, the air blast frequency was 21HZ, and the atomization pressure For 0.03Mpa, the coating parameters optimization result is that the spraying liquid velocity is 45r/min, the blowing frequency is 19HZ, and the atomization pressure is 0.05Mpa. The sustained-release pellets have good preparation effect.
With the yield of pellets, the roundness and the release rate of hychornin in vitro as the evaluation index, the single factor investigation was used to optimize the formulation of the membrane controlled release pellets of the hychornus hychornus. The results showed that the yield of the sustained-release pellets was improved when the HPMC (5cps) was used as the adhesive and the concentration was 15g/L, and the release rate of the sustained release pellets was good. The rate was slowed down with the increase of the coating material, Surelease, and the release rate of 12h in the coating was 30%, and the release rate of the sustained-release pellets slowed down with the increase of HPMC (5cps) in the isolation layer. When the HPMC (5cps) dosage was 1%, the release of the 12h in the 12h was stable. As follows:
Prescription quality of sustained-release pellets (mg)
Blank sucrose pellet core 10000
Hycho 100
HPMC300
The drug content of Surelease300 was 0.67%, the reproducibility of the formulation and the uniformity of the release of the extract were good.
To sum up, the preparation of hychornin membrane controlled release pellets, the process reproducibility and release homogeneity are good. The release of the drug in 12h is stable and slow, and the preliminary stability of the complete.2. hychornin sustained-release pellet capsule
The 300mg capsule was filled with 3 capsule, and the sustained-release pellet capsule was obtained with the specification of 2mg/ particles. The stability of the capsule of the sustained release pellet of the hychioninus was preliminarily investigated. The experimental results showed that the capsules were placed for 10 days at 60, or at room temperature for 10 days in the relative humidity of 90%, or in the light strip. The release degree in vitro changed obviously for 10 days under 4000LX, suggesting that the stability of the preparation was greatly influenced by the intense factors such as high temperature, high humidity and light. The accelerated test was carried out on the basis of the influence factors of the stability of the sustained-release pellet capsule. The results showed that the sustained release pellets were at the temperature of 40, and the relative humidity was 75% under 6. There are no significant changes in the appearance and in vitro release of the preparation in vitro. This provides an experimental basis for the establishment of the storage conditions of the sustained release pellet capsule of the hychornus hychornus.3. in the evaluation of the drug release characteristics in the Beagle dog.
In this part, a method for the determination of the blood concentration of the hychornus hycho LC-MS/MS was established. With the homemade common tablet of the hychornin as the reference preparation, LC-MS/MS was used to determine the drug concentration time curve of the single oral administration of the slow-release pellet capsule, and the drug release characteristics were evaluated in the beagle dog. The results showed that the sustained release pellets of the hychornin were released. The capsule is bioequivalent with its common tablets, but there is no significant release effect. It suggests that the preparation of the membrane controlled release pellets and the evaluation of the release characteristics in the body need to be optimized. This study provides a reference for the subsequent optimization of the membrane controlled release pellets of the hychonnus.
【学位授予单位】：福建医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943;R96

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