Formulation and in vivo pharmacokinetic evaluation of ethyl cellulose-coated sustained release multiple-unit system of tacrolimus.

A novel once-a-day sustained-release (SR) system of tacrolimus (FK506), a poorly water-soluble immunosuppressive agent, was designed employing ethyl cellulose (EC) polymer as release retardant. Drug (5 mg) was layered onto sugar spheres (518.3 mg) with hypromellose (5 mg), to transform the drug from a crystalline to an amorphous form. Subsequently, the drug-layered pellets were recoated with EC polymer (0.5-1.5 mg) using a fluid bed granulator. Drug release from the reservoir-type pellets was markedly impeded by the outer EC-based coating layer (EC 1 mg), displaying about 60% of drug release after 8 h, regardless of the acidity of the media. In an in vivo pharmacokinetic study in fasted Cynomolgus monkeys, the drug level in blood was gradually increased over 4.7 h and high drug concentration was maintained until 24 h, with an elimination half-life of 16.6 h. There were no statistical differences between the novel SR pellets and the recently marketed SR capsule (Advagraf, Astellas Pharma, Japan) in terms of maximum blood concentration, area under the curve, and half-life values, in both fasted and fed states. Therefore, the novel EC-coated pellets are expected to be bioequivalent to the commercial SR capsule, providing a once-daily dosing regimen in patients with allogenic rejection.