Formulation and Optimization of 5-Fluorouracil Loaded Chitosan Nanoparticles Employing Central Composite Design

Abstract

5-Fluorouracil (5-FU) is a hydrophilic drug with short plasma half-life. The objective of the current study was to prepare and optimize 5-FU loaded chitosan nanoparticles (CNPs) for controlled release. The nanoparticles were prepared by ionic gelation of chitosan with tripolyphosphate anions. A 23 central composite design (CCD) was employed to study the influence of formulation variables - concentration of Chitosan (X1), the concentration of sodium tripolyphosphate (NaTPP) (X2) and volume of NaTPP (X3) on the cumulative percentage of drug release. The relationship between the dependent and independent variables was further elucidated using multiple linear regression analysis (MLRA) and Pareto chart. The results show that cumulative percent of 5-FU release was highest and lowest at high levels of X1, X2, and low level of X3, and high level of X1, and low levels of X2 and X3, respectively. The optimized nanoparticles were studied morphologically by transmission electron microscopy (TEM) which showed separated and non-aggregated nanoparticles with spherical shapes and smooth surfaces. The mean particle size, entrapment efficiency and loading capacity of the optimal CNPs were found to be 109.6±2.28 nm, 83.84±1.46%, and 37.76±3.41%, respectively. Nanoparticles revealed a fast release during the first hour followed by a more gradual drug release during a 24-h period following a non-Fickian diffusion process. Analysis of variance (ANOVA) was applied on cumulative percent of drug release to study the fitting and significance of model. The estimated model may be further utilized as response surface for cumulative percent of drug release from nanoparticles. The 5-FU loaded CNPs optimized using CCD showed good entrapment efficiency and controlled release as well as can reduce dosing frequency, decrease side effects and improve patient compliance.