Preparation of highly water soluble tacrolimus derivatives: poly(Ethylene glycol) esters as potential prodrugs

Tacrolimus (FK506), which is isolated from Streptomyces tsukubaensis, is a new potent immunosuppressant. Because of poor solubility in water, the conventional intravenous dosage forms of tacrolimus contain surfactants such as cremophor EL (BASF Wyandotte Co.) or hydrogenated polyoxy 60 castor oil (HCO-60) which may cause adverse effects. This study relates to a polymer-tacrolimus conjugate, which can be dissolved in water, formed by chemically binding the sparingly soluble drug, tacrolimus, with the water soluble polymer, methoxypoly(ethylene glycol) (mPEG). Water soluble tacrolimus-mPEG conjugates have been synthesized and shown to be functionin vitro as prodrugs. These conjugates are in the form of an ester wherein the 24-, 32- or 24,32-positions are esterified. The desired 24-, 32- or 24,32-esterified compounds were obtained by initially acylating of tacrolimus with iodoacetic acid at the 24-, 32-, or 24,32-positions and then reacting the resulting acylated tacrolimus with a mPEG in the presence of a base such as sodium bicarbonate. These conjugates were converted again into tacrolimus by the action of enzymes in human liver homogenate, and the half-lives of the conjugates are approximately 10 min in the homogenate, indicating that the esterified tacrolimus derivatives may be practically applicable as a prodrug for the immunosuppressant.