Novel multiparticulate pH triggered delayed release chronotherapeutic drug delivery of celecoxib-β-cyclodextrin inclusion complexes by using Box-Behnken design

Abstract

This study aimed to prepare novel colon targeted celecoxib-β-cyclodextrin (CXB-β-CD) inclusion complex loaded eudragit S 100 (ES100) microparticles for chronotherapy of rheumatoid arthritis (RA) which is an innovative approach, never reported before, for the fabrication of CXB-β-CD complex in the form of microparticles and its colon targeting. CXB was complexed with β-cyclodextrin by kneading technique and we evaluated the effect of β-CD on saturation solubility of CXB. Microparticles were developed by oil-in-oil emulsion solvent evaporation technique and formulation variables (polymer conc, surfactant conc and stirring speed) were optimized by using three-factor three-level Box-Behnken design (BBD). SEM imaging revealed smooth, uniform and spherical shape microparticles. There was 7.3 fold increases in saturation solubility of CXB-β-CD inclusion complex in distilled water as compared to pure CXB. Particle size was in the range of 50.42 µm to 238.38 µm with entrapment efficiency of 68.47% to 91.65%. Biphasic drug release pattern was found i.e initially delayed release in stomach and small intestine followed by fast release at colonic pH. Response variable results achieved from optimized formulation were very close to the response values suggested by BBD signifying the actual reliability and robustness of BBD in the fabrication of colon targeted CXB-β-CD microparticles. The comparison of CXB-β-CD optimized formulation with optimized formulation containing pure CXB showed increase in drug release due to enhancement of water solubility of CXB-β-CD inclusion complex. So, it can be concluded that CXB-β-CD loaded ES100 microparticles can be successfully fabricated with enhanced solubility for the chronotherapy of rheumatoid arthritis.

Keywords: Celecoxib-β-cyclodextrin; Chronotherapy; Delayed-release; Microparticles.