5-氟尿嘧啶pH依赖—时滞型结肠定位微丸的研究
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摘要
5-氟尿嘧啶(5-fluorouracil，5-FU)是结肠癌首选的化疗药物，普通制剂口服给药吸收不完全，生物利用度低，胃肠道毒副作用大。将5-FU制成口服结肠定位给药系统用于结肠癌的化疗，使药物在结肠局部定位释药，可提高局部治疗浓度，降低全身吸收和毒副作用。
首先，本研究建立了微丸的含量和体外释放试验的测定方法，并进行了方法学考察：采用挤出-滚圆法将5-FU制成载药丸芯，以微丸的圆整度、粒径分布和体外释放度为考察指标，对筛网规格、挤出速度、滚圆速度、滚圆时间等工艺单因素和微丸的载药量，填充剂、粘合剂、崩解剂的种类和用量等处方因素进行了单因素考察，采用正交设计优化载药丸芯的处方组成和制备工艺，对最佳处方和工艺进行了重现性试验。结果表明，采用紫外分光光度法测定微丸中5-FU的含量与体外释放度方法简便、灵敏、专属性强；单因素考察结果表明，CMS-Na和乳糖的用量、CMS-Na和乳糖的比例、滚圆速度和滚圆时间对微丸的圆整度、粒径分布和体外释放度影响较大，通过正交试验筛选，我们确定了工艺参数为：筛网直径(L/R=0.477)为1.0mm，挤出速度20Hz，滚圆速度21.5Hz，滚圆时间3min。最优处方组成为：含药量为20％，MCC为主要填充剂，以适量的水为粘合剂，CMS-Na和乳糖(比例为1:3)的用量为25％。所制备的载药丸芯粉体学性质良好，释放度符合要求。
其次，本研究以Eudragit FS 30D水分散体为pH敏感包衣材料，渗透型的丙烯酸树脂为控释层包衣材料，利用流化床包衣法制备pH依赖-时滞型结肠定位微丸，考察了控释层中增塑剂的用量、Eudragit RS/RL的比例、包衣厚度以及塑化温度和时间，肠溶层中增塑剂的用量和包衣厚度对时滞及体外释放度的影响，采用全因子设计-效应曲面法优化内层包衣和外层包衣的厚度，筛选出最佳处方；以“时滞”和“释放百分率”为评价指标，结合微丸体外模拟释放的扫描电镜照片，探讨5-FU结肠定位给药系统的体外释药机理。结果表明，增塑剂的用量、塑化温度和时间对药物的释放均有一定的影响，控释层中Eudragit RS的比例增加，控释层和肠溶层包衣厚度增加时滞均增大，药物释放速率变慢，控释层和肠溶层之间存在交互作用，控释层包衣增重对微丸释药性的影响较肠溶层显著；包衣微丸最佳处方为：控释层材料Eudragit RS/RL比例为1:0，增塑剂TEC用量为20％，在40℃条件下塑化12h，pH敏感材料Eudragit FS 30D的增塑剂TEC用量为5％；控释层包衣增重为5-5.6％，肠溶层包衣增重为19-20％；最佳处方制备的微丸在pH1.2的HCI和pH6.8PBS中几乎不释药，当进入pH7.2的环境后，外层肠溶衣溶解，药物在Eudragit RS层的控制下缓慢释放。
最后，建立了大鼠结肠内容物和血浆中5-FU浓度的测定方法，并进行了方法学考察；考察了口服给药后微丸在大鼠消化道分布、消化道中微丸药物含量以及大鼠结肠内容物药物浓度；测定载药微丸和pH依赖-时滞型包衣微丸经大鼠口服后血药浓度。结果表明：采用高效液相色谱法测定结肠内容物和血浆中5-FU的浓度，简便、灵敏，专属性强；大鼠口服5-FU载药微丸后，未在结肠检测到药物，口服pH依赖-时滞型包衣微丸后，在进入盲肠之前，药物在消化道中的含量均大于95％，5-16h内，在结肠内容物中可检测到5-FU，且药物含量最高可达到84.26％。大鼠口服载药微丸后在第15min即测到药物，0.5h达到最大血药浓度1204.6ng／ml，口服包衣微丸后，仅在5-6h范围内可以测到血药浓度，且最高血药浓度为166.3ng/ml。
结论通过电镜照片观察，包衣微丸外观形态圆整，粒度分布窄，包衣层均匀致密；通过动物实验的验证，pH依赖-时滞型包衣微丸在胃和小肠中几乎不释药，在回盲部包衣膜逐渐溶解，缓慢释放药物。由此可见pH依赖-时滞型包衣微丸实现了5-FU口服结肠定位的效果，提高了结肠部位局部治疗的药物浓度，减少药物的全身吸收，达到了预期设计的目的。
5-Fluorouracil (5 -FU) is a metabolic antagonist, which is used clinically as an effective chemotherapeutic drug for the treatment of colorectal cancer. However, 5-FU shows low biological availability, great toxicity and side-effects in addition to its incomplete absorption after oral administration. Therefore, we designed the oral colon-specific drug delivery system containing 5-FU which had the initiate release in the proximal colon property in order to elevate the local concentration in colon, avoid the systemic absorption and reduce the side effects.
Firstly, the ultraviolet spectrophotometry method was applied to determine the content of the 5-FU and the release behavior of the pellets in vitro. The drug-loaded pellets were prepared using the extrusion- spheronization method. The behaviors of the pellets were evaluated by the characteristics of drug release, roundness degree of the pellets (aspect ratio), product yield and size distributions, etc. The effects of the sizes of the sieve, the extrusion speed, spheronization speed and spheronization time on the aspect of the pellets were invested; the influences of the category and amount of the disintegrating agent, bulking agent, and adhesive material on the drug loading were discussed, the optimum formulation and technology of the fluorouracil pellets were achieved by orthogonal design and the stability of the formulation and the technique were validated by the reproducibility test. The results showed that the UV method is convenient, sensitive, and of high specificity. The ratio and amount of the CMS-Na and lactose, spheronization speed and spheronization time have important effects on the characteristics of drug release, roundness degree of the pellets; the optimum technology parameters were as follows: the grit diameter (L/R=0.477) was 1 .0mm, the extrusion speed was 20Hz, while the spheronization speed and time were 21.5Hz and 3 minutes, respectively. The optimum formulation was as follows: 5-FU concentration in the pellets was 20%, sufficient quantum H_2O was used as the adhesive material, MCC was the mainly bulking agent, CMS-Na was the disintegrating agent, and the contents of CMS-Na and lactose (1:3) were 25%. The drug-loaded pellets showed a good powder-technology characteristic and the release behavior met the requirement as designed. Secondly, the pH-and time-based pellets of 5-FU for the colonic delivery system was developed using pH-independent polymers as the control release layer and Eudragit FS 30D as the outer coating enteric layer in a fluidized-bed apparatus. The effects of formulation factors on the drug release and the lag time of the pellets were investigated. The inner coating effect factors included the amount of the triethyl citrate which is used as plasticizer, the ratio and coating levels of the Eudragit~(?) RL and RS, the temperature and time during the heat-treatment process; the outer coating effect factors included the amount of the triethyl citrate and the coating levels of the Eudragit FS 30D. The full factor design-response surface methodology was used to optimize the coating levels of the inner layer and the outer layer, as well as the optimum formulation. To evaluate the release characteristics mechanism in vitro of 5-FU colon-specific drug delivery system, the lag time and the cumulative released percentage of the coated pellets in vitro were combined with the Scanning electron micrograph (SEM) pictures of the coated pellets, which were taken from the medium at different time intervals during the release experiment. The result showed that the amount of the TEC, the temperature and time during the heat-treatment process had some effects on the release behavior of the coated pellets, the release rate was slower with higher coating levels of inner coating or outer coating, also with the higher ratio of the Eudragit RS in the inner coating, and the two coaters have some reciprocate effects. The coating level of Eudragit RS had more significant effect than the Eudragit FS on the release behavior in vitro. The optimal formulation were as follows: the inner coater material was Eudragit RS/RL with the best ratio of 1:0, including 20% triethyl citrate (counted as the dry polymer percent); the pellets were cured in an oven for 12h at 40°C; the amount of the triethyl citrate in the Eudragit FS was 5 % (counted as the dry polymer percent); and the coating level of Eudragit RS and Eudragit FS were 5-5.6%, 19-20%, respectively. In the in vitro study, the results showed that the system could forbid drug release in 0.1M HCI and in PBS (pH6.8). The Eudragit FS could dissolve in PBS (pH7.2), then the coated pellets showed sustained-release of 5-FU, controlled by the inner coater of Eudragit RS 30D.
Further studies were carried out in rats to observe the in vivo behavior of 5-FU pellets. A simple, rapid and sensitive high-performance liquid chromatographic method for the determination of 5-FU in rat plasma and colon content was established. The rats were oral administered drug-loaded pellets and pH-and time-based pellets, respectively, then, the distribution of pellets in the gastrointestinal tract (GIT), the amounts of pellets in the upper GIT, and the drug concentrations in the colon content and plasma were investigated. The results showed that no 5-FU was found in the colon after oral administration of the drug-loaded pellets, but more than 95% of the 5-FU was determined in the GIT above caecum after oral administration of the coated pellets, and the highest drug levels in the colon content was 84.26% during 5-16h after oral administration the pH-and time-based pellets. The maximum plasma concentration was 1204.6ng/ml at 0.5h after oral administration of drug-loaded pellets, and 5-FU could be determined in the plasma at 15min after oral administration. The maximum plasma concentration of 5-FU was 166.3ng/ml at 5-6h after oral administration of pH-and time-based pellets.
Finally, the Scanning electron micrograph (SEM) results of the coated pellets demonstrated that the pellets with a uniformity and homogeneity layer showed good roundness and narrow size distribution properties. The results of the in vivo experiments verified that the pH-and time-based pellet of 5-FU for colonic delivery was capable of protecting the drug from releasing in the upper GIT. 5-FU started to release in ileum and cecum, and most of 5-FU was delivered to colon, avoided the systemic absorption and reduced the side-effects, which indicated that the potential application of the pH-and time-based pellets as a drug delivery system targeting to colon.
首先，本研究建立了微丸的含量和体外释放试验的测定方法，并进行了方法学考察：采用挤出-滚圆法将5-FU制成载药丸芯，以微丸的圆整度、粒径分布和体外释放度为考察指标，对筛网规格、挤出速度、滚圆速度、滚圆时间等工艺单因素和微丸的载药量，填充剂、粘合剂、崩解剂的种类和用量等处方因素进行了单因素考察，采用正交设计优化载药丸芯的处方组成和制备工艺，对最佳处方和工艺进行了重现性试验。结果表明，采用紫外分光光度法测定微丸中5-FU的含量与体外释放度方法简便、灵敏、专属性强；单因素考察结果表明，CMS-Na和乳糖的用量、CMS-Na和乳糖的比例、滚圆速度和滚圆时间对微丸的圆整度、粒径分布和体外释放度影响较大，通过正交试验筛选，我们确定了工艺参数为：筛网直径(L/R=0.477)为1.0mm，挤出速度20Hz，滚圆速度21.5Hz，滚圆时间3min。最优处方组成为：含药量为20％，MCC为主要填充剂，以适量的水为粘合剂，CMS-Na和乳糖(比例为1:3)的用量为25％。所制备的载药丸芯粉体学性质良好，释放度符合要求。
其次，本研究以Eudragit FS 30D水分散体为pH敏感包衣材料，渗透型的丙烯酸树脂为控释层包衣材料，利用流化床包衣法制备pH依赖-时滞型结肠定位微丸，考察了控释层中增塑剂的用量、Eudragit RS/RL的比例、包衣厚度以及塑化温度和时间，肠溶层中增塑剂的用量和包衣厚度对时滞及体外释放度的影响，采用全因子设计-效应曲面法优化内层包衣和外层包衣的厚度，筛选出最佳处方；以“时滞”和“释放百分率”为评价指标，结合微丸体外模拟释放的扫描电镜照片，探讨5-FU结肠定位给药系统的体外释药机理。结果表明，增塑剂的用量、塑化温度和时间对药物的释放均有一定的影响，控释层中Eudragit RS的比例增加，控释层和肠溶层包衣厚度增加时滞均增大，药物释放速率变慢，控释层和肠溶层之间存在交互作用，控释层包衣增重对微丸释药性的影响较肠溶层显著；包衣微丸最佳处方为：控释层材料Eudragit RS/RL比例为1:0，增塑剂TEC用量为20％，在40℃条件下塑化12h，pH敏感材料Eudragit FS 30D的增塑剂TEC用量为5％；控释层包衣增重为5-5.6％，肠溶层包衣增重为19-20％；最佳处方制备的微丸在pH1.2的HCI和pH6.8PBS中几乎不释药，当进入pH7.2的环境后，外层肠溶衣溶解，药物在Eudragit RS层的控制下缓慢释放。
最后，建立了大鼠结肠内容物和血浆中5-FU浓度的测定方法，并进行了方法学考察；考察了口服给药后微丸在大鼠消化道分布、消化道中微丸药物含量以及大鼠结肠内容物药物浓度；测定载药微丸和pH依赖-时滞型包衣微丸经大鼠口服后血药浓度。结果表明：采用高效液相色谱法测定结肠内容物和血浆中5-FU的浓度，简便、灵敏，专属性强；大鼠口服5-FU载药微丸后，未在结肠检测到药物，口服pH依赖-时滞型包衣微丸后，在进入盲肠之前，药物在消化道中的含量均大于95％，5-16h内，在结肠内容物中可检测到5-FU，且药物含量最高可达到84.26％。大鼠口服载药微丸后在第15min即测到药物，0.5h达到最大血药浓度1204.6ng／ml，口服包衣微丸后，仅在5-6h范围内可以测到血药浓度，且最高血药浓度为166.3ng/ml。
结论通过电镜照片观察，包衣微丸外观形态圆整，粒度分布窄，包衣层均匀致密；通过动物实验的验证，pH依赖-时滞型包衣微丸在胃和小肠中几乎不释药，在回盲部包衣膜逐渐溶解，缓慢释放药物。由此可见pH依赖-时滞型包衣微丸实现了5-FU口服结肠定位的效果，提高了结肠部位局部治疗的药物浓度，减少药物的全身吸收，达到了预期设计的目的。
5-Fluorouracil (5 -FU) is a metabolic antagonist, which is used clinically as an effective chemotherapeutic drug for the treatment of colorectal cancer. However, 5-FU shows low biological availability, great toxicity and side-effects in addition to its incomplete absorption after oral administration. Therefore, we designed the oral colon-specific drug delivery system containing 5-FU which had the initiate release in the proximal colon property in order to elevate the local concentration in colon, avoid the systemic absorption and reduce the side effects.
Firstly, the ultraviolet spectrophotometry method was applied to determine the content of the 5-FU and the release behavior of the pellets in vitro. The drug-loaded pellets were prepared using the extrusion- spheronization method. The behaviors of the pellets were evaluated by the characteristics of drug release, roundness degree of the pellets (aspect ratio), product yield and size distributions, etc. The effects of the sizes of the sieve, the extrusion speed, spheronization speed and spheronization time on the aspect of the pellets were invested; the influences of the category and amount of the disintegrating agent, bulking agent, and adhesive material on the drug loading were discussed, the optimum formulation and technology of the fluorouracil pellets were achieved by orthogonal design and the stability of the formulation and the technique were validated by the reproducibility test. The results showed that the UV method is convenient, sensitive, and of high specificity. The ratio and amount of the CMS-Na and lactose, spheronization speed and spheronization time have important effects on the characteristics of drug release, roundness degree of the pellets; the optimum technology parameters were as follows: the grit diameter (L/R=0.477) was 1 .0mm, the extrusion speed was 20Hz, while the spheronization speed and time were 21.5Hz and 3 minutes, respectively. The optimum formulation was as follows: 5-FU concentration in the pellets was 20%, sufficient quantum H_2O was used as the adhesive material, MCC was the mainly bulking agent, CMS-Na was the disintegrating agent, and the contents of CMS-Na and lactose (1:3) were 25%. The drug-loaded pellets showed a good powder-technology characteristic and the release behavior met the requirement as designed. Secondly, the pH-and time-based pellets of 5-FU for the colonic delivery system was developed using pH-independent polymers as the control release layer and Eudragit FS 30D as the outer coating enteric layer in a fluidized-bed apparatus. The effects of formulation factors on the drug release and the lag time of the pellets were investigated. The inner coating effect factors included the amount of the triethyl citrate which is used as plasticizer, the ratio and coating levels of the Eudragit~(?) RL and RS, the temperature and time during the heat-treatment process; the outer coating effect factors included the amount of the triethyl citrate and the coating levels of the Eudragit FS 30D. The full factor design-response surface methodology was used to optimize the coating levels of the inner layer and the outer layer, as well as the optimum formulation. To evaluate the release characteristics mechanism in vitro of 5-FU colon-specific drug delivery system, the lag time and the cumulative released percentage of the coated pellets in vitro were combined with the Scanning electron micrograph (SEM) pictures of the coated pellets, which were taken from the medium at different time intervals during the release experiment. The result showed that the amount of the TEC, the temperature and time during the heat-treatment process had some effects on the release behavior of the coated pellets, the release rate was slower with higher coating levels of inner coating or outer coating, also with the higher ratio of the Eudragit RS in the inner coating, and the two coaters have some reciprocate effects. The coating level of Eudragit RS had more significant effect than the Eudragit FS on the release behavior in vitro. The optimal formulation were as follows: the inner coater material was Eudragit RS/RL with the best ratio of 1:0, including 20% triethyl citrate (counted as the dry polymer percent); the pellets were cured in an oven for 12h at 40°C; the amount of the triethyl citrate in the Eudragit FS was 5 % (counted as the dry polymer percent); and the coating level of Eudragit RS and Eudragit FS were 5-5.6%, 19-20%, respectively. In the in vitro study, the results showed that the system could forbid drug release in 0.1M HCI and in PBS (pH6.8). The Eudragit FS could dissolve in PBS (pH7.2), then the coated pellets showed sustained-release of 5-FU, controlled by the inner coater of Eudragit RS 30D.
Further studies were carried out in rats to observe the in vivo behavior of 5-FU pellets. A simple, rapid and sensitive high-performance liquid chromatographic method for the determination of 5-FU in rat plasma and colon content was established. The rats were oral administered drug-loaded pellets and pH-and time-based pellets, respectively, then, the distribution of pellets in the gastrointestinal tract (GIT), the amounts of pellets in the upper GIT, and the drug concentrations in the colon content and plasma were investigated. The results showed that no 5-FU was found in the colon after oral administration of the drug-loaded pellets, but more than 95% of the 5-FU was determined in the GIT above caecum after oral administration of the coated pellets, and the highest drug levels in the colon content was 84.26% during 5-16h after oral administration the pH-and time-based pellets. The maximum plasma concentration was 1204.6ng/ml at 0.5h after oral administration of drug-loaded pellets, and 5-FU could be determined in the plasma at 15min after oral administration. The maximum plasma concentration of 5-FU was 166.3ng/ml at 5-6h after oral administration of pH-and time-based pellets.
Finally, the Scanning electron micrograph (SEM) results of the coated pellets demonstrated that the pellets with a uniformity and homogeneity layer showed good roundness and narrow size distribution properties. The results of the in vivo experiments verified that the pH-and time-based pellet of 5-FU for colonic delivery was capable of protecting the drug from releasing in the upper GIT. 5-FU started to release in ileum and cecum, and most of 5-FU was delivered to colon, avoided the systemic absorption and reduced the side-effects, which indicated that the potential application of the pH-and time-based pellets as a drug delivery system targeting to colon.
引文
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