Central composite rotatable design for optimization of budesonide-loaded cross-linked chitosan-dextran sulfate nanodispersion: characterization, diffusion and aerodynamic study.

Budesonide is a BCS class II drug with low water solubility (0.045 mg/mL) and low oral bioavailability (6-8%) due to high first pass effect. The aim is to prepare cross-linked chitosan-dextran sulfate nanoparticles and/or nanodispersion. Nebulizable cross-linked nanodispersion was prepared by the solvent evaporation technique and characterized through XRPD, FTIR, mean particle size (MPS), polydispersity index (PDI), zeta potential (ZP), drug loading, entrapment efficiency, SEM, % production yield, diffusion, aerodynamic and stability study. The optimization of formulation was done by using central composite rotatable design to study the effect of independent variables, concentration of chitosan (X1) and concentration dextran sulfate (X2) on the dependent variables, MPS (Y1), drug loading (Y2) and % CDR (% cumulative drug release) (Y3). The MPS, PDI, and ZP of budesonide-loaded nanoparticles were 160.8 ± 0.27 nm, 0.36 ± 0.04, and 13 ± 0.894 mV, respectively. The percent drug loading of all the batches was found in range of 10-16%. The emitted drug in target region (alveoli) was measured by using HPLC and it was found to be 18.26%. It was found that, nanodispersion had the optimum aerodynamic behavior. Stability study results showed no significant change in MPS, PDI, ZP, and % CDR after three month storage. In conclusion, cross-linked chitosan-dextran sulfate nanoparticles had properties suitable for nebulizable dispersion of increased drug loading, drug release and avoiding the first pass effect.