Patent EA-001550-B1 (EA)
Title: Drug complexes
Inventor: INOUE KAZUHIRO
IPC: A61K47/48
Filed: 1997-06-05
Abstract: 1. A drug complex characterized in that a carboxy(C1-4)alkyldextran polyalcohol and a residue of a drug compound are bound to each other by means of a spacer comprising an amino acid or a spacer comprising peptide-bonded 2 to 8 amino acids, wherein the residue of a drug compound represents a structure of a drug compound residuary from bonding between spacer and drug compound. 2. The drug complex according to claim 1, characterized in that the dextran polyalcohol that constitutes the carboxy(C1-4)alkyldextran polyalcohol is a dextran polyalcohol which is obtained by treating a dextran under a condition that enables substantially complete polyalcoholization. 3. The drug complex according to claim 1 or claim 2, wherein the carboxy(C1-4)alkyldextran polyalcohol is carboxymethyldextran polyalcohol. 4. The drug complex according to any one of claims 1 to 3, wherein the drug compound is an antineoplastic agent. 5. The drug complex according to claim 4, wherein the drug compound is an antineoplastic agent which concentration-dependently exhibits antineoplastic activity. 6. The drug complex according to claim 4, wherein the drug compound is an antineoplastic agent which time-dependently exhibits antineoplastic activity. 7. The drug complex according to claim 4, wherein the antineoplastic agent is doxorubicin or (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione. 8. The drug complex according to any one of claims 5 to 7, wherein the spacer is a dipeptide of the formula -X-Z- wherein "-X-Z-" represents a residue which consists of a dipeptide that is formed by peptide bonding of a hydrophobic amino acid (X) and a hydrophilic acid (Z) being at the N-terminal side and the C-terminal side, respectively, and whose one hydrogen atom and one hydroxyl group are removed from the amino-group at the N-terminus and from the carboxyl group at the C-terminus, respectively, or wherein the spacer contains the dipeptide as a partial peptide sequence. 9. The drug complex according to claim 8, wherein the hydrophobic amino acid is phenylalanine and the hydrophilic amino acid is glycine. 10. The drug complex according to claim 9, wherein the spacer is (N-terminus)-Gly-Gly-Phe-Gly-. 11. The drug complex according to any one of claims 5 to 10, wherein an introduced amount of the residue of the antineoplastic agent is in the range of from 1 to 15% by weight. 12. The drug complex according to any one of claims 5 to 10, wherein an introduced amount of the residue of the antineoplastic agent is in the range of from 3 to 15% by weight. 13. The drug complex according to any one of claims 5 to 10, wherein an introduced amount of the residue of the antineoplastic agent is in the range of from 5 to 6% by weight. 14. The drug complex according to claim 1, wherein the N-terminus of a peptide represented by formula H2N-Gly-Gly-Phe-Gly-COOH is bound to a carboxyl group of a carboxymethyldextran polyalcohol by means of an acid-amide bond and C-terminus of the peptide is bound to 1-amino group of (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo-[de]pyrano[3',4':6,7]indolizino-[1,2-b]quinoline-10,13(9H,15H)dione by means of an acid-amide bond. 15. The drug complex according to claim 14, wherein the introduced amount of (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino-[1,2-b]quinoline-10,13(9H,15H)dione residue is in the range of from 2 to 10% by weight. 16. The drug complex according to claim 14 or claim 15, wherein the carboxy-(C1-4)alkyldextran polyalcohol is a carboxymethyldextran polyalcohol having a molecular weight in the range of from 5,000 to 500,000 and the degree of carboxymethylation is in the range of from 0.01 to 2,0. 17. The drug complex according to claim 14 or claim 15, wherein the carboxy-(C1-4)alkyldextran polyalcohol is a carboxymethyldextran polyalcohol having a molecular weight in the range of from 50,000 to 450,000 and the degree of carboxymethylation is in the range of from 0.1 to 1,0. 18. The drug complex according to claim 14 or claim 15, wherein the carboxy-(C1-4)alkyldextran polyalcohol is a carboxymethyldextran polyalcohol having a molecular weight in the range of from 200,000 to 400,000 and the degree of carboxymethylation is in the range of from 0.3 to 0.5. 19. The drug complex according to claim 14, wherein the introduced amount of (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)dione residue is in the range of from 5 to 6% by weight, the molecular weight of carboxy-(C1-4)alkyldextran polyalcohol is about 228,000, and the degree of carboxymethylation is about 0.4. 20. A drug delivery carrier for binding a drug compound which comprises a carboxy-(C1-4) alkyldextran polyalcohol. 21. The drug delivery carrier according to claim 20, wherein the molecular weight of the carboxy-(C1-4)alkyldextran polyalcohol is in the range of from 5,000 to 500,000, and the degree of carboxymethylation is in the range of from 0.01 to 2.0. 22. The drug delivery carrier according to claim 20, wherein the molecular weight of the carboxy-(C1-4)alkyldextran polyalcohol is in the range of from 50,000 to 450,000, and the degree of carboxymethylation is in the range of from 0.1 to 1.0. 23. The drug delivery carrier according to claim 20, wherein the molecular weight of the carboxy-(C1-4)alkyldextran polyalcohol is in the range of from 200,000 to 400,000, and the degree of carboxymethylation is in the range of from 0.3 to 0.5. 24. The drug delivery carrier according to any one of claims 20 to 23, wherein the carboxy-(C1-4)alkyldextran polyalcohol is a carboxymethyldextran polyalcohol. 25. A use of a carboxy-(C1-4)alkyldextran polyalcohol for a manufacture of a drug complex in which a residue of a drug compound and the carboxy-(C1-4)alkyldextran polyalcohol are bound to each other by means of a spacer, wherein the residue of a drug compound represents a structure of a drug compound residuary from bonding between spacer and drug compound.