Hyaluronic acid grafted with poly(ethylene glycol) as a novel peptide formulation

Hyaluronic acids (HA) grafted with poly(ethylene glycol) (PEG) (PEG-g-HA) w ere synthesized. The materials characterization, enzymatic degradability an d peptide (insulin) release from solutions of the copolymers were examined. Distribution of bioactive peptides within the polymer chain is well-known for combinations of PEG and polysaccharides as aqueous polymer two-phase sy stems. Insulin was preferentially partitioned into the PEG phase in a PEG/H A solution system. Enzymatic degradation of the copolymers was strongly dep endent on the PEG content. Thermal analysis revealed that PEG-g-HA exhibite d a variation in phase-separated structures depending on the PEG content. T he solution of PEG-g-HA enabled insulin to remain in the PEG moieties dispe rsed in the HA matrix. Leakage of insulin from the copolymers was dependent upon the PEG content. Leakage rate of insulin from copolymer containing be tween 7 and 39% by weight of PEG were similar. A dramatic increase in leaka ge rate occurred when the PEG content was increased to greater than 39% by weight. It is considered that the loaded insulin was partitioned into the P EG moieties and became entangled with the PEG chains. The conformational ch ange of insulin was effectively prevented in PEG-g-HA solutions, although i nsulin was denatured in storage of both phosphate buffered solution and HA solution. Such a heterogeneous-structured polymeric solution may be advanta geous as an injectable therapeutic formulation for ophthalmic or arthritis treatment. (C) 1999 Elsevier Science B.V. All rights reserved.