Method of preparation of an oxidized derivative of hyaluronic acid and a method of modification thereof

摘要

The invention relates to a new method of preparation of a hyaluronan derivative with an aldehydic group in the position (6) of the polysaccharide glucosamine part. The hyaluronic acid oxidation can be performed by means of TEMPO/NaCIO or TEMPO/TCC systems in a protic environment with or without the presence of anorganic salts. Thus prepared aldehyde can be used for binding amines, diamines, amino acids, peptides and other compounds containing an amino group, e.g. by means of the reductive amination with NaBH3CN in water or in a water-organic solvent system. When a diamine or compounds containing three or more amino groups are used, cross-linked hyaluronan derivatives can be prepared. Cross-linked derivatives can be also prepared by a reaction of the aldehyde with a hyaluronan substituted by an amino-alkyl group HA-alkyl-NH2.

主权项

1. A method of modification of a hyaluronic acid derivative comprising:
reacting hyaluronic acid with 4-R-TEMPO and a co-oxidant in a protic solvent, where R is a linear or branched alkyl chain, optionally containing aromatic or heteroaromatic groups, wherein the oxidized derivative of hyaluronic acid is selectively oxidized to an aldehyde at position 6 of the glucosamine portion of the derivative and 4-R-TEMPO is present in an amount within the range from 0.005 to 0.5 molar equivalent with respect to the hyaluronic acid; and reacting the oxidized hyaluronic acid derivative with either a compound of a general formula H2N-R, where the general formula H2N-R defines an amino acid, peptide, or polysaccharide containing a free amino group or where R is a linear or branched C1—C30 alkyl chain, optionally containing aromatic or heteroaromatic groups, thereby defining an amine, or with a hyaluronan, substituted by an -R-NH2 group, where R is a linear or branched C1—C30 alkyl chain, optionally containing aromatic or heteroaromatic groups, to form an imino form of HA of a general formula I