In-vitro release of fluoropyrimidines from PLGA film implants

The release of two low-molecular weight water-soluble fluoropyrimidines, 5-fluorouracil and 5-fluorouridine, from implants of PLGA films was modulated by varying the area (diameter) and number of layers of film per implant. The aim was to achieve continuous release without burst effect for at least a month. The film implants were prepared by the solvent evaporation technique. Except with 5-fluorouracil films, the in-vitro release profiles were in all cases triphasic, indicating that release proceeds by a combination of diffusion and polymer erosion. The experimental data fit the equation resulting from the sum of two exponentials, one direct and the other inverse. 5-fluorouridine release from simple films presented a relatively minor burst effect (24-28%). In contrast, the delivery of both compounds from sandwich-type implants occurred continuously without a burst effect, and lasted for 17-20 days. During the first phase, both 3- and 5-mm sandwiches released 55% of the dose of 5-fluorouridine, at rate constants of 0.037+/-0.021 h(-1) (n = 3) and 0.009+/-0.003 h(-1) (n=3), respectively. In the second phase, release was gradual from both simple films (k2 = 0.011-0.015 h(-1)) and sandwiches (k2 = 0.018-0.058 h(-1)). According to the analysis-of-variance results, neither the area nor type of implant influenced the rate constants significantly. The release profiles of 5-fluorouracil from simple films showed a severe burst effect (64-71%). Release of 5-fluorouracil was gradual only from sandwiches, 5 mm in diameter, showing a lag time unobserved in the 3-mm sandwiches. In the second phase, release was gradual (k2 = 0.014+/-0.003 h(-1)) from 3-mm implants. However, the high variability in results for 5-mm implants prevents conclusions being drawn about the model parameters. Therefore, the sandwich-type film implants showed their utility for releasing water-soluble drugs for a prolonged time, without burst effect.