TEMPERATURE AND PH-SENSITIVE POLYMERS FOR HUMAN CALCITONIN DELIVERY

Purpose. Stimuli-sensitive polymers are suitable candidates for oral p eptide drug delivery vehicles since they will prevent gastric degradat ion in the stomach while providing a controlled release of a peptide d rug such as calcitonin later. The purpose of this study was to fabrica te polymeric beads from pH/temperature sensitive linear terpolymers so propylacrylamide-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 calcito nin. This solution was added dropwise into an oil bath kept at a tempe rature above the LCST of a polymer, precipitating polymer and entrappi ng the peptide. The quantity and the physical state of the peptide wer e analyzed by reverse-phase HPLC, CD and FTIR and its biological activ ity after loading was determined in vivo. Results, The loading efficie ncy and stability of human calcitonin into the polymeric beads was stu died 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 relea se of human calcitonin were also studied as a function of acrylic acid content in the terpolymers. As the acrylic acid content increased fro m 0 to 10 mol %, the loading efficiency and stability of calcitonin im proved significantly. The same trend was observed for the quantity of released calcitonin. In vivo biological activity of the released hormo ne was preserved. Conclusions. The results showed that the beads made of the polymers with high content of acrylic acid (most hydrophilic) p rovided better loading, stability and release of human calcitonin. The designed beads represent a new potential system for oral delivery of calcitonin and other peptides.