APPLICATION OF CENTRAL COMPOSITE DESIGNS TO THE PREPARATION OF POLYCAPROLACTONE NANOPARTICLES BY SOLVENT DISPLACEMENT

Cyclosporin A (CyA) is a good candidate for incorporation in colloidal carriers such as nanoparticles (NP) that would diminish the adverse e ffects associated with its use under conventional pharmaceutical dosag e forms and improve bioavailability after oral administration. In this study a composite rotational experimental design was used to evaluate the joint influence of five formulation variables: temperature of the aqueous phase, needle gauge, volume of the organic phase, and the amo unts of polymer and surfactant on the micromeritic characteristics of the CyA-loaded NP obtained by the method of Fessi et al. The percentag e of drug encapsulated in the NP was also evaluated for each formulati on, and the yield, which was expressed as the ratio between the experi mentally measured quantity of drug in the formulation and the theoreti cal content, was determined because CyA undergoes surface adsorption. Potential variables such as stirring speed (500 rpm), final drug conce ntration (100 mu g/ml), or injection rates (GR(i) = 0.379 mL/s) were m aintained constant. The ANOVA corresponding to the experimental design showed that the amounts of polymer and surfactant, and the diameter o f the needle used in the preparation of NP, significantly affected the percentage of entrapped drug (r(2) = 0.8916). The mean particle size, was significantly affected by all the formulation variables tested ex cept for the amount of surfactant dissolved in the external aqueous ph ase (r(2) = 0.9518). Neither the yield (mean value of 99.61%) nor the size distribution parameters (polydispersity and coefficient of variat ion) presented good correlation coefficients for the equations obtaine d, although some variables showed statistical significance. A second s tudy was carried out to investigate the effects on the drug-loaded NP characteristics of varying the global injection rates (GR(i)) for the organic phase into the aqueous medium. The results showed a dramatic d ecrease in both particle size and drug incorporation in the carrier as the rate of mixing increased. From the results of both the experiment al design and the second study, a theoretical model for nanoparticle f ormation is proposed that considers the most significant variables, an d an empirical relationship to predict mean particle size is presented . Thus, particle size can be controlled by the injection rates (GR(i)) , the needle gauge, and the polymer concentration.