| 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 H2O 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. |
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