Objectives: Investigate the potential of coated minispheres (SmPill (R)) to enhance localized Ciclosporin A (CsA) delivery to the colon.Methods: CsA self-emulsifying drug delivery systems (SEDDS) were encapsulated into SmPill (R) minispheres. Varying degrees of coating thickness (low, medium and high) were applied using ethylcellulose and pectin (E:P) polymers. In vitro CsA release was evaluated in simulated gastric and intestinal media. Bioavailability of CsA in vivo following oral administration to pigs of SmPill (R) minispheres was compared to Neoral (R) po and Sandimmun (R) iv in a pig model. CsA concentrations in blood and intestinal tissue were determined by HPLC-UV.Results: In vitro CsA release from coated minispheres decreased with increasing coating thickness. A linear relationship was observed between in vitro CsA release and in vivo bioavailability (r(2)=0.98). CsA concentrations in the proximal, transverse and distal colon were significantly higher following administration of SmPill (R), compared to Neoral (R) po and Sandimmun (R) iv (p<0.05). Analysis of transverse colon tissue subsections also revealed significantly higher CsA concentrations in the mucosa and submucosa using SmPill (R) minispheres (p<0.05).Conclusions: Modulating E:P coating thickness controls release of CsA from SmPill (R) minispheres. Coated minispheres limited CsA release in the small intestine and enhanced delivery and uptake in the colon. These findings demonstrate clinical advantages of an oral coated minisphere-enabled CsA formulation in the treatment of inflammatory conditions of the large intestine.Objectives: Investigate the potential of coated minispheres (SmPill (R)) to enhance localized Ciclosporin A (CsA) delivery to the colon.Methods: CsA self-emulsifying drug delivery systems (SEDDS) were encapsulated into SmPill (R) minispheres. Varying degrees of coating thickness (low, medium and high) were applied using ethylcellulose and pectin (E:P) polymers. In vitro CsA release was evaluated in simulated gastric and intestinal media. Bioavailability of CsA in vivo following oral administration to pigs of SmPill (R) minispheres was compared to Neoral (R) po and Sandimmun (R) iv in a pig model. CsA concentrations in blood and intestinal tissue were determined by HPLC-UV.Results: In vitro CsA release from coated minispheres decreased with increasing coating thickness. A linear relationship was observed between in vitro CsA release and in vivo bioavailability (r(2)=0.98). CsA concentrations in the proximal, transverse and distal colon were significantly higher following administration of SmPill (R), compared to Neoral (R) po and Sandimmun (R) iv (p<0.05). Analysis of transverse colon tissue subsections also revealed significantly higher CsA concentrations in the mucosa and submucosa using SmPill (R) minispheres (p<0.05).Conclusions: Modulating E:P coating thickness controls release of CsA from SmPill (R) minispheres. Coated minispheres limited CsA release in the small intestine and enhanced delivery and uptake in the colon. These findings demonstrate clinical advantages of an oral coated minisphere-enabled CsA formulation in the treatment of inflammatory conditions of the large intestine.