Reversible lipidization for the oral delivery of salmon calcitonin

Salmon calcitonin (sCT), a 32-amino-acid polypeptide, was lipidized by using a reversible aqueous lipidization (REAL) technology. When injected subcutaneously into mice, the AUC of REAL-sCT was four times greater than that of sCT and a similar pattern of reduction in plasma calcium level was observed. The therapeutic effect of REAL-sCT was evaluated in ovariectomized (OVX) rats. The development of osteoporosis in OVX rats was determined by measuring the urinary level of deoxypyridinoline (DPD), a biochemical marker of bone resorption. It was found that the DPD levels were significantly reduced in rats that were orally administered a dose of 50 microg/kg/day of REAL-sCT. No reduction in urinary DPD levels could be detected in OVX rats treated similarly with unmodified sCT. In addition, significant levels of sCT were detected in rat plasma up to 12 h after oral administration of REAL-sCT at 500 microg/kg, while the plasma concentration of sCT was undetectable at 1 h after oral administration with the same dose of sCT. The AUC of oral REAL-sCT was at least 19 times higher than that of sCT. Our results indicate that reversibly lipidized polypeptides exhibit not only improved pharmacokinetic and pharmacodynamic behaviors, but also an enhanced oral bioavailability.