Temperature and pH-sensitive polymers for human calcitonin delivery.

PURPOSE

Stimuli-sensitive polymers are suitable candidates for oral peptide drug delivery vehicles since they will prevent gastric degradation in the stomach while providing a controlled release of a peptide drug such as calcitonin later. The purpose of this study was to fabricate polymeric beads from pH/temperature sensitive linear terpolymers (poly(N-isopropylacrylamide-co-butylmethacrylate-co-acrylic acid) and load them with a peptide drug, human calcitonin, which was dissolved in aqueous phase.

METHODS

The polymeric beads were formed by solubilizing a cold, aqueous solution of temperature sensitive polymer with human calcitonin. This solution was added dropwise into an oil bath kept at a temperature above the LCST of a polymer, precipitating polymer and entrapping the peptide. The quantity and the physical state of the peptide were analyzed by reverse-phase HPLC, CD and FTIR and its biological activity after loading was determined in vivo.

RESULTS

The loading efficiency and stability of human calcitonin into the polymeric beads was studied as a function of pH and ionic strength of the loading buffer and temperature of the oil bath. Final optimal loading conditions were 20 mM glycine/HCl buffer, pH 3.0 containing 0.15 M NaCl as a dissolution medium and 23 degrees C as the oil bath temperature. Loading and release of human calcitonin were also studied as a function of acrylic acid content in the terpolymers. As the acrylic acid content increased from 0 to 10 mol %, the loading efficiency and stability of calcitonin improved significantly. The same trend was observed for the quantity of released calcitonin. In vivo biological activity of the released hormone was preserved.

CONCLUSIONS

The results showed that the beads made of the polymers with high content of acrylic acid (most hydrophilic) provided better loading, stability and release of human calcitonin. The designed beads represent a new potential system for oral delivery of calcitonin and other peptides.