Optimization of cross-linked high amylose starch microspheres containing 5-fluorouracil

Abstract

The objective of the present investigation was the preparation of microspheres consisting of high amylose starch cross-linked in situ by means of sodium trimetaphosphate. 5-fluorouracil was chosen as a model drug. Since this preparation entailed several process and formulation variables, a preliminary screening design was applied to identify the most important factors and thereby simplify the system under study. This was performed with regard to the spherical shape and the capacity of drug encapsulation of the obtainable microparticles. An eight-factor 12-run Plackett-Burman design enabled the factor number to be reduced so that a three-factor face-centered central composite design could subsequently be applied in order to optimize the formulation by response surface methodology. The factors involved in the optimization process were the concentrations of the following components: 5-fluorouracil, starch and cross-linker. The responses evaluated were the morphology of the microspheres (a qualitative response) and the drug encapsulation efficiency. An optimal formulation yielded microparticles that were spherical in shape, with a volume diameter of 25.5±0.6pm and a narrow particle size distribution. Particle yield ranged from 85 to 98%, the encapsulation efficiency reached about 30% and the drug loading was in the range of 0.8-1.5%. Due to polymer swelling properties, 5-fluorouracil was released in vitro in a sustained manner by an anomalous release mechanism. Microparticles also showed good mucoadhesion properties that would make them suitable for peroral drug administration.