A new degradable hydroxamate linkage for pH-controlled drug delivery.

A new drug delivery system based on a hydrodegradable hydroxamate linkage was evaluated. The carrier support system was poly(N-hydroxyacrylamide), which was synthesized via free radical polymerization of acryloyl chloride in 1,4-dioxane, initiated with 2,2'-azobisisobutyronitrile. The poly(acryloyl chloride) was modified in two steps. First, N-hydroxysuccinimide was added to give the imide ester of poly(acryloyl). In the second step, the imide ester of poly(acryloyl) was reacted with either hydroxylamine or N-methylhydroxylamine to give the corresponding hydroxamic acid. The hydroxamide functionality was then used to link the model drug ketoprofen. All products and intermediates were characterized by elemental analysis and FTIR and 1H NMR spectra. In vitro drug release was performed under specific conditions to elucidate the influence of the pH, polymer microstructure, and temperature on the hydrolysis rate of the amido-ester bond that linked the drug to the macromolecule. The drug release rate from N-methylhydroxamic acid polymers was faster than from hydroxamic acid polymers. All polymers showed higher rates of drug release at higher pH values (9.0 > 7.4 > 2.0) and at higher temperatures (37 degrees C > 20 degrees C).