Quality by design approach for developing chitosan-Ca-alginate microspheres for colon delivery of celecoxib-hydroxypropyl-β-cyclodextrin-PVP complex

The aim of the present work was to develop a new multiparticulate system, designed for colon-specific delivery of celecoxib for both systemic (in chronotherapic treatment of arthritis) and local (in prophylaxis of colon carcinogenesis) therapy. The system simultaneously benefits from ternary complexation with hydroxypropyl-β-cyclodextrin and PVP (polyvinylpyrrolidone), to increase drug solubility, and vectorization in chitosan-Ca-alginate microspheres, to exploit the colon-specific carrier properties of these polymers. Statistical experimental design was employed to investigate the combined effect of four formulation variables, i.e., % of alginate, CaCl2, and chitosan and time of cross-linking on microsphere entrapment efficiency (EE%) and drug amount released after 4 h in colonic medium, considered as the responses to be optimized. Design of experiment was used in the context of Quality by Design, which requires a multivariate approach for understanding the multifactorial relationships among formulation parameters. Doehlert design allowed for defining a design space, which revealed that variations of the considered factors had in most cases an opposite influence on the responses. Desirability function was used to attain simultaneous optimization of both responses. The desired goals were achieved for both systemic and local use of celecoxib. Experimental values obtained from the optimized formulations were in both cases very close to the predicted values, thus confirming the validity of the generated mathematical model. These results demonstrated the effectiveness of the proposed jointed use of drug cyclodextrin complexation and chitosan-Ca-alginate microsphere vectorization, as well as the usefulness of the multivariate approach for the preparation of colon-targeted celecoxib microspheres with optimized properties.

Graphical abstractResponse surface plots showing the effect of variations of formulation parameters (% alginate, chitosan (CSL) and calcium chloride and time of cross-linking (TCl)) on entrapment efficiency (EE%) and % drug released at 4 h (DR%) of colon-targeted celecoxib microspheres.Figure optionsDownload full-size imageDownload as PowerPoint slide