Injectable Carrier for Zero-Order Release of Salmon Calcitonin.

Salmon calcitonin (sCT) was developed as an antiresorptive for the management of osteoporosis, a major public health threat worldwide. However, its clinical application was severely limited by its short half-life. Herein, an injectable drug carrier, that is, polylactic acid (PLA) microspheres coated with TA/PEG-sCT (TA: tannic acid. PEG-sCT: PEGylated sCT) layer-by-layer (LBL) films, was designed. An in vitro test demonstrated that, unlike previously developed drug carriers, the new carrier released PEG-sCT at a constant rate. The unique zero-order release kinetics originates from its unique drug release mechanism, that is, drug release via gradual disintegration of the dynamic TA/PEG-sCT LBL film. The small size of the PLA microspheres allows the carrier to be administrated via subcutaneous injection. An in vivo test demonstrated that a single injection of the carrier could maintain the plasma level of PEG-sCT stable for an extended period and thus induced a stable reduction in the plasma calcium level in rats. Using a rat model of osteoporosis induced by ovariectomy, it was further demonstrated that a single injection of the new carrier gave better therapeutic outcomes than daily injection of sCT of the same dose, thanks to the improved pharmacokinetic profile. Given the advantages of the new carrier, including facile subcutaneous administration, less frequent dosing, no initial burst release, no peak plasma drug level, and improved therapeutic outcomes, it is expected to have potential in long-term management of osteoporosis and other metabolic bone diseases.