Temperature- and pH-sensitive terpolymers for modulated delivery of streptokinase.

Controlled release devices were designed which respond to changes in pH and temperature by reversibly swelling and deswelling to control release of streptokinase. Copolymer hydrogels composed of N-isopropylacrylamide (NIPAAm) and methacrylic acid (MAA) as well as terpolymer hydrogels containing NIPAAm, acrylic acid (AA), and 2-hydroxyethyl methacrylate (HEMA) were synthesized. Hydrogels containing NIPAAm display a change in swelling behavior across the lower critical solubility temperature of PNIPAAm, whereas hydrogels with MAA and AA swelled only at high pH values due to the ionization of carboxylic pendant groups. HEMA was chosen as a third component to add mechanical strength and integrity to the hydrogel. Pulsatile pH- and temperature-dependent swelling studies were performed to determine the extent and rate at which the hydrogels swell in response to changing conditions. Results showed that increasing the NIPAAm concentration in the copolymers or terpolymers resulted in a higher degree of temperature-sensitive swelling. Synthesis of a terpolymer in which segments rich in NIPAAm were distributed within P(AA-co-HEMA) chains led to hydrogels displaying increased temperature sensitivity. Streptokinase was incorporated into the hydrogels, and its release was observed under the combined effects of temperature and pH. The streptokinase release pattern followed the swelling state of the hydrogel, with drug release occurring at a significantly higher rate from the most swollen hydrogels.