Polymer compositions comprising antifibrotic agents, and methods of treatment, pharmaceutical compositions, and methods of preparation therefor

A copolymer conjugate antifibrotic agent composition prepared by the process comprising:

• (1) covalently binding proline analog or derivative antifibrotic agent selected from the group of cis-4-hydroxy-L-proline (CHOP), 3,4-dehydro-DL-proline (DHP), (R)-(−)-2-thiazolidine-4-carboxylic acid (THP), and (S)-(−)-2-azetidinecarboxylic acid (ACA), and pharmaceutically acceptable salts thereof;
• to
• (2) L-lysine to form at least one dipeptide;
• and
• (3) covalently binding each dipeptide to PEG to form the copolymer conjugate.

A method for treating a pulmonary hypertension or defect in the metabolism of collagen condition in a patient in need of such treatment, comprising administering to the patient an antifibrotically effective amount of a copolymer conjugate antifibrotic composition, comprising:

• (a) a dipeptide consisting of a proline analog or derivative antifibrotic agent selected from the group of cis-4-hydroxy-L-proline (CHOP), 3,4-dehydro-DL-proline (DHP), (R)-(−)-2-thiazolidine-4-carboxylic acid (THP), and (S)-(−)-2-azetidinecarboxylic acid (ACA), covalently bound to L-lysine;
• (b) polyethylene glycol (PEG) to which the dipeptide is covalently bound to form a copolymer conjugate;
• wherein the proline analog or derivative antifibrotic agent is covalently attached to, in excess of 90% of the available sites thereof, and
• (c) a pharmaceutically acceptable carrier therefor.