Negatively charged amphiphilic block copolymer as drug carrier
The present invention provides an anionic group-containing amphiphilic block copolymer that is biocompatible and biodegradable and, when used as a drug carrier for a cationic drug, provides several advantages such as increased blood concentration and improved stability of the drug.
1. A block copolymer having the formula:
A-B-L-X-M + (1)
Wherein X represents an anionic group, M + represents H + or a metal cation, A is a biocompatible hydrophilic polymer, B is a biodegradable hydrophobic polymer, and L represents a linker selected from the group consisting of —O—, —NH—, —S— and —COO—.
2. The block copolymer of claim 1 wherein the number average molecular weights of A and B each is within the range of 100 to 100,000 Daltons.
3. The block copolymer of claim 1 wherein X is —SO 3 − , —PO 3 − , ═PO 2 − or —CO—(CH 2 ) z —COO − , wherein z denotes an integer of 0 to 4, and if X is ═PO 2 − , the anionic group is combined with two carbon atoms.
4. The block copolymer of claim 1 wherein M is a mono- or divalent metal ion.
5. The block copolymer of claim 4 wherein M is Li + , Na + , K + , Ca 2+ , Mg 2+ , Zn 2+ Cu 2+ .
6. A block copolymer having the formula:
A-B-L-X-M + (1)
Wherein X represents an anionic group, M + represents H + or a metal cation, L represents a linker selected from the group consisting of —O—, —NH—, —S— and —COO—, A is a member selected from the group consisting of polyalkyleneglycol, poly-alkyleneoxide, polyvinylpyrrolidone, polysaccharide, polyacrylamide, polymetacrylamide, polyvinylalcohol, and derivatives thereof and B is a biodegradable polyester.
7. The block copolymer of claim 6 wherein the number average molecular weights of A and B each is within the range of 100 to 100,000 Daltons.
8. The block copolymer of claim 6 wherein X is —SO 3 − , —PO 3 2− , ═PO 2 − or —CO—(CH 2 ) z —COO − , wherein z denotes an interger of 0 to 4, and if X is ═PO 2 − , the anionic group is combined with two carbon atoms.
9. The block copolymer of claim 6 wherein M is a mono- or divalent metal ion.
10. The block copolymer of claim 9 wherein M is Li + , Na + , K + , Ca 2+ , Mg 2+ , Zn 2+ or Cu 2+ .
11. A block copolymer having the formula:
A-B-L-X-M + (1)
Wherein X represents an anionic group, M + represents H + or a metal cation, A is a biocompatible hydrophilic polymer, B is a biodegradable hydrophobic polymer, L represents a linker selected from the group consisting of —O—, —NH—, —S— and —COO—, wherein A is a member selected from the group consisting of polyalkyleneglycol, poly-alkyleneoxide, polyvinylpyrrolidone, a polysaccharide, polyacrylamide, polymetacrylamide, polyvinylalcohol, and derivatives thereof and B is a biodegradable polyester synthesized from monomers selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone, ε-hydroxy hexonoic acid, and copolymers thereof.
12. The block copolymer of claim 11 wherein the number average molecular weights of A and B each is within the range of 100 to 100,000 Daltons.
13. The block copolymer of claim 11 wherein X is —SO 3 − , —PO 3 2− , ═PO 2 − or —CO—(CH 2 ) z —COO − , wherein z denotes an integer of 0 to 4, and if X is ═PO 2 − , the anionic group is combined with two carbon atoms.
14. The block copolymer of claim 11 wherein M is a mono- or divalent metal ion.
15. The block copolymer of claim 14 wherein M is Li + , Na + , K + , Ca 2+ , Mg 2+ , Zn 2+ or Cu 2+ .
16. A block copolymer having the formula:
A-B-L-X-M + (1)
Wherein X represents an anionic group, M + represents H + or a metal cation, A is a biocompatible hydrophilic polymer, B is a biodegradable hydrophobic polymer, L represents a linker selected from the group consisting of —O—, —NH—, —S— and —COO—; and wherein A is a degradable derivative prepared according to the following reaction scheme:
n Z+( n− 1)Y→Z—(Y—Z) n−2 —Y—Z
wherein Z represents a water-soluble polymer having a molecular weight of up to 5,000 Daltons, Y represents HOOC—(CH 2 ) m —COOH or O═C═N—(CH 2 ) m —N═C═O wherein m is an integer of 0 to 10, and n is an integer of 2 to 100.
17. The block copolymer of claim 16 wherein the number average molecular weights of A and B each is within the range of 100 to 100,000 Daltons.
18. The block copolymer of claim 16 wherein X is —SO 3 − , —PO 3 2− , PO 2 − or —CO—(CH 2 ) z —COO − , wherein z denotes an interger of 0 to 4, and if X is ═PO 2 − the anionic group is combined with two carbon atoms.
19. The block copolymer of claim 16 wherein M is a mono- or divalent metal ion.
20. The block copolymer of claim 19 wherein M is Li + , Na + , K + , Ca 2+ , Mg 2+ , Zn 2+ or Cu 2+ .
21. A composition comprising the block copolymer of claim 1 and a positively charged drug wherein the positively charged drugs combines with one or more of the block copolymers via electrostatic forces and forms a drug-block copolymer complex.
22. A composition comprising the block copolymer of claim 6 and a positively charged drug wherein the block copolymer combines with one or more of the positively charged drugs via electrostatic forces and forms a drug-block copolymer complex.
23. A composition comprising the block copolymer of claim 11 and a positively charged drug wherein the block copolymer combines with one or more of the positively charged drugs via electrostatic forces and forms a drug-block copolymer complex.
24. A composition comprising the block copolymer of claim 16 and a positively charged drug wherein the block copolymer combines with one or more of the positively charged drugs via electrostatic forces and forms a drug-block copolymer complex.