Copolymers of I-vinyl-2-pyrrolidone with maleic anhydride which contain oligopeptide sidechains with L-phenylalanine p-nitroanilide (Phe-NAP) end groups were synthesized. The chymotrypsin catalyzed hydrolysis of these polymers was studied. The rate of p-nitroaniline release was found to depend on the structure of the oligopeptide sequences: -Gly-Gly-Val-Phe-NAp > --Gly-Val-Phe-NAp > -Gly-Gly-Phe-NAP. From a comparison with similar substrates based on poly[N-(2-hydroxypropyl)methacrylamide] the influence of the structure of the polymeric backbone on the rate of cleavage of bonds at the ends of oligopeptide side-chains was estimated. a) Part 8: ~f .~3 ) .
An alternating copolymer of 1-vinyl-2-pyrrolidone and maleic anhydrig, I4C-labelled at the chain end, was synthetized with a mass-average relative molecular mass M, = 8000. Elimination kinetics and whole-body distribution of the copolymer in its monosodium salt form were studied in mice. Elimination of the copolymer was found to be fairly rapid and practically complete, i. e. 86,7% of it was excreted after 24 h and 95% after 56 h. Specific accumulation of the copolymer was observed in bone tissue and lacrimal gland. No appreciable accumulation occurred in the nervous system, spleen, and bone marrow. The results of elimination kinetics and the autoradiographic whole-body distribution study were in fairly good correlation.
The dextran-bound antirheumatic agent, Naproxen [ ( + )-2-(6-methoxy-2-naphtyl)propionic acid] (3) was synthesized by linking the 2-aminoethyl ester of Naproxen to the oxydized dextran via an alkylamine bond. The hydrolytic stabilities of modified dextrans were examined viscometrically. The drug release from polymeric prodrug samples containing 68 -172 mg of Naproxen per g product was followed at 37 "C by automatic titration at pH 8,4. The first order kinetic constant of hydrolysis, k l , was determined to be 2,46( +0,4) . s -'. Acute toxicity tests showed no toxic effect on CFLP mice administered intraperitoneally 300 mg/kg of dextran-bound Naproxen.
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