In order to hydrophobize heparin, dodecanal, cholic acid and stearic acid were conjugated, respectively, to partially N-desulfated heparin with the formation of imine bonds in the case of dodecanal and amide bonds in the case of the two latter compounds. It was found that the three conjugates were aggregated in aqueous solution with the formation of-300 nm aggregates. The conjugates retained the anticoagulant activity of the parent heparin according to in vitro tests. In vivo, slightly prolonged activity was observed after s.c. injection. The activity lasted for at least 2 hours after i.v. injection suggesting that aggregates of hydrophobized heparin were not captured by the reticuloendothelial system. These new water dispersed aggregates are of potential interest for the transport and slow release of hydrophobic drugs in blood either as macromolecular prodrugs or after molecular microencapsulation, and for oral administration.

Purified glutaraldehyde was allowed to react with the primary amino groups generated by mild acidolysis of glucosamine N -sulfamino residues present in heparinic acid. The reaction yielded high molecular mass heparinoids (HMMHEP) or hydrogels, depending on experimental conditions. It was shown that a selected HMMHEP exhibited a higher anticoagulant activity than the starting heparin or the parent partially N -desulfated heparin. This HMMHEP degraded slowly in vitro in an aqueous medium buffered at pH = 7.4. Moreover, HMMHEP was biologically active after i.v. injection but not after s.c. and i.m. injections. Hydrogels also degraded slowly to yield biologically active higher molecular mass heparinoid. These findings suggested that neither N -desulfation nor coupling of glutaraldehyde adducts affected in a large extend the activity of the parent heparin.