Once-a-day oral dosing regimen of cyclosporin A: Combined therapy of cyclosporin A premicroemulsion concentrates and enteric coated solid-state premicroemulsion concentrates

Purpose. To develop once-a-day oral dosing regimen that provides the blood levels of cyclosporin A (CsA) in the therapeutic ranges over 24 hours. Methods. CsA. premicroemulsion concentrates (preME) were formulated from phase diagrams. Enteric-coated solid-state premicroemulsion concentrates (sME) were prepared by coating preME with enteric-coating matrials and solidifying them. CsA was measured using high-performance liquid chromatography or radioimmunoassay. Results. PreME consisted of CsA, oil, and mixture of surfactants and a cosurfactant. PreME spontaneously formed microemulsions in aqueous medium and showed oral absorption profiles similar to Sandimmune: Neoral (R) in dogs. Dispersion of sME in aqueous medium also formed microemulsions. Release rates of CsA from sME depended on pH and the type of enteric-coating materials and highly correlated with the extent of oral absorption. The co-administration of preME and sME (200 Ing CsA) showed the maximum blood level of CsA. not significantly different from that of preME (100 mg CsA) and the concentration of CsA close to the minimum therapeutic level at 24 hours. Conclusions. The combined treatment of preME and sME provided controlled oral absorption of CsA over a 24-hour period. Such once-a-day dosing regimens will lead to increased patient compliance and reduced episodes of organ rejection after transplantation.