Biphasic drug release: permeability and swelling of pectin/ethylcellulose films, and in vitro and in vivo correlation of film-coated pellets in dogs.

The major objectives of this study were i) to evaluate the permeability and swelling characteristics of isolated films prepared by mixing of pectin with ethylcellulose; and ii) to assess the absorption and in vitro/in vivo correlation (IVIVC) of 5-FU film-coated colon-targeted pellets in dogs. Free films were prepared by casting and solvent evaporation method. These free films were evaluated by swelling experiment and permeability to 5-FU in different media. Pectin/ethylcellulose films had suitable characteristics for colonic delivery; and when the addition of pectin was up to the ratio of 30%, the swelling and permeability of the mixed films was significantly increased in the simulated colonic fluid (SCF). Pharmacokinetic study in dogs gave Tmax/Cmax of 14 h/1.6 microg/ml and 16 h/1.7 microg/ml for total weight gain (TWG)-22% and 18% coated pellets, respectively. The plasma 5-FU levels of the TWG-22% and 18% coated pellets were maintained at a much lower level with a mean residence time (MRT) of 18-20 h, longer than 2.1 h for 5-FU uncoated pellets, confirming delayed absorption. There was no statistically significant difference in the area under the plasma concentration vs. times curve (AUC) values between the uncoated pellets and the coated pellets. Moreover, a good linear regression relationship was observed between the percent in vitro dissolution in SCF and the percent absorption or percent AUC. It was concluded that i) pectin within the mixed films were susceptible to colonic enzymes, and the film-coated pellets are potentially useful for colonic drug delivery; and ii) in vitro dissolution testing in SCF could be used to establish certain IVIVC for the colon-specific drug delivery systems activated by microflora.

Study on colon-specific pectin/ethylcellulose film-coated 5-fluorouracil pellets in rats.

The purpose of the present study is to assess the biodistribution and pharmacokinetics of pectin/ethylcellulose film-coated and uncoated pellets containing 5-fluorouracil (5-FU) in rats. Both coated and uncoated pellets were orally administered to the rats at a dosage equivalent to 15mg/kg. 5-FU concentrations in different parts of the gastrointestinal (GI) tract and plasma were quantitatively analyzed using a high-performance liquid chromatography (HPLC) assay. 5-FU released from uncoated pellets mainly distributes in the upper GI tract, however, 5-FU released from coated pellets mainly distributes in the cecum and colon. In plasma, the observed mean C(max) from the coated pellets group (3.65+/-2.3microg/mL) was lower than that of the uncoated pellets group (23.54+/-2.9microg/mL). The AUC values obtained from the uncoated pellets and the coated pellets were 49.08+/-3.1 and 9.06+/-1.2microgh/mL, respectively. The relatively high local drug concentration with prolonged exposure time provides a potential to enhance anti-tumor efficacy with low systemic toxicity for the treatment of colon cancer.

Selective drug delivery to the colon using pectin-coated pellets.

A combination of ethylcellulose and pectin, when applied as a film coat, has a potential value as a colon-specific delivery system. Dispersions of pectin in ethylcellulose were used as the film former for coating of 5-aminosalicylic acid (5-ASA) pellet cores. Drug release behavior was assessed, in vitro, under simulating conditions in term of pH and time in vivo during transit to the colon. Negligible drug release occurred during first 5 h, when the coated pellets were in the simulated gastric and small intestinal conditions. After that, rat cecal contents were added into the pH 6.8 medium to simulate the in vivo condition where there is the digestion of bacteria in the colon. Drug release depended on the composition of the mixed film, as well as the ratio of ethylcellulose to pectin. Drug release profiles seemed to conform to the mechanism involving the osmotically driven release and formation of channels in the film caused by dissolution of pectin. Channel formation was, in most cases, activated by the presence of rat cecal contents, showing that the pectin in the mixed film was subjected to enzymic breakdown. In conclusion, pectin could be used as an additive in ethylcellulose films to control the release of colonic delivery system. In addition, the mechanism of the hydrophilic drug release from pellets coated with ethylcellulose aqueous dispersions containing an aqueous gel-forming polymer (pectin) is also discussed.