Segmented polymers and their conjugates

• US 7,053,150 B2
• Filed: 12/11/2003
• Issued: 05/30/2006
• Est. Priority Date: 12/18/2000
• Status: Expired due to Term

• Current Assignee: Nektar Therapeutics Incorporated
• Original Assignee: Nektar Therapeutics Al Corporation (Nektar Therapeutics)
• Inventors: Fang, Zhihao, Shen, Xiaoming, Bentley, Michael D., Kozlowski, Antoni, Sander, Tony L.
• Primary Examiner(s): Acquah, Samuel A.
• Application Number:
  US10/734,858
• Publication Number:
  US 20040236015A1
• Time in Patent Office: 901 Days
• Field of Search: 525/54.1, 525/54.2, 525/398, 525/399, 525/400, 525/437, 525/535, 525/539, 525/540, 514/2, 514/23, 514/44, 514/54, 514/103, 514/476, 514/506, 514/553, 514/580
• US Class Current: 525/54.2
• CPC Class Codes: A61K 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: Y10S 530/815 Carrier is a synthetic polymer

Abstract

Segmented water soluble polymers, containing a higher molecular weight segment linked to a lower molecular weight segment, are described. In one embodiment, the polymer segments are poly(ethylene glycol) segments. The segmented polymers are functionalized and are useful for conjugation to various moieties such as pharmacologically active substances. Also described are conjugates of such polymers and methods of their preparation.

Claims

1. A water soluble polymer comprising:

(i) a first water soluble polymer segment having at least 4 and at most about 2000 monomeric units (POLY_A);

(ii) a second water soluble segment comprising 1 to about 120 monomeric units (POLY_B), which has a lower molecular weight than that of POLY_A and is covalently attached to POLY_A through a linkage X; and

(iii) a functional group, Y, attached to POLY_A or POLY_B;

wherein each of POLY_A and POLY_B independently comprises one monomer or up to three different monomers selected from the group consisting of alkylene glycol, olefinic alcohol, vinylpyrrolidone, hydroxyalkylmethacrylamide, hydroxyalkylmethacrylate, saccharide, α

-hydroxy acid, phosphazene, oxazoline, and N-acryloylmorpholine.

2. The polymer of claim 1, wherein the molecular weight of POLY_A is at least twice that of POLY_B.

3. The polymer of claim 1, wherein POLY_A has at most about 200 monomeric units.

4. The polymer of claim 1, wherein POLY_A has at most about 125 monomeric units.

5. The polymer of claim 1, wherein POLY_A has at most about 25 monomeric units.

6. The polymer of claim 1, wherein said functional group is located on POLY_B.

7. The polymer of claim 1, wherein POLY_B comprises at least 2 monomeric units.

8. The polymer of claim 1, wherein POLY_A and POLY_B have the same monomeric composition.

9. The polymer of claim 1, wherein each of POLY_A and POLY_B is a poly(alkylene glycol).

10. The polymer of claim 9, wherein each of POLY_A and POLY_B is a poly(ethylene glycol).

11. The polymer of claim 1, wherein X comprises an amide linkage, a carbonate linkage, a urea linkage, or a carbamate linkage.

12. The polymer of claim 1, wherein said functional group Y comprises a nucleophilic group, selected from hydroxyl, amine, hydrazine, hydrazide, and thiol, or an electrophilic group, selected from carboxylic acid, carboxylic ester, imide ester, orthoester, carbonate, isocyanate, isothiocyanate, aldehyde, ketone, thione, alkenyl, acrylate, methacrylate, acrylamide, sulfone, maleimide, disulfide, iodo, epoxy, sulfonate, thiosulfonate, silane, alkoxysilane, halosilane, and phosphoramidate.

13. The polymer of claim 12, wherein said nucleophilic group is selected from amine, hydrazine, hydrazide, and thiol.

14. The polymer of claim 12, wherein said electrophilic group is selected from maleimide, succinimidyl ester or carbonate, benzotriazole ester or carbonate, imidazoyl ester or carbonate, glycidyl ether, vinyl sulfone, p-nitrophenyl carbonate, tresylate, acrylate, aldehyde, and orthopyridyl disulfide.

15. The polymer of claim 10, wherein the linkage X comprises a carbamate, an amide, a urea, or a carbonate, POLY_A is end-capped with a capping group selected from C₁–

C₂₀ alkoxy, C₁–

C₂₀ aryloxy, and a phospholipid, and the functional group Y is attached to POLY_B.

16. The polymer of claim 15, wherein the capping group is C₁–

C₅ alkoxy.

17. The polymer of claim 15, wherein the capping group is derived from distearoylphosphatidylethanolamine (DSPE).

18. The polymer of claim 15, wherein the functional group is an amine.

19. A polymer as provided in claim 18, having the structure:

CH₃O—

(CH₂CH₂O)_n—

(CO)NH—

CH₂CH₂OCH₂CH₂OCH₂CH₂NH₂.

20. The polymer of claim 19, having a molecular weight selected from about 1000, about 5000, about 10000, and about 20000.

21. The polymer of claim 15, wherein POLY_A has a molecular weight of about 1000.

22. A conjugate comprising a polymer of claim 1 and a pharmacologically active agent covalently attached to the polymer.

23. The polymer of claim 10, wherein the polymer has a structure selected from:

(PEG_A-X-PEG_B)_p-L-Y 

 

(IIa)

(PEG_A-X)_p-L-PEG_B-Y 

 

(IIb)

and

(PEG_A)_p-L-X-PEG_B-Y 

 

(IIc)

wherein;

PEG_A represents poly(ethylene glycol) comprising at least 4 and at most about 2000 —

CH₂CH₂O—

monomeric units,

X is a covalent linkage,

L is a branched spacer group;

PEG_B represents poly(ethylene glycol) comprising at least 1 and at most about 120 —

CH₂CH₂O—

monomeric units, with the proviso that PEG_B has a lower molecular weight than that of PEG_A;

Y is a functional group, and

p=1 to about 100.

24. The polymer of claim 23, wherein PEG_A comprises at most 200 —

CH₂CH₂O—

monomeric units.

25. The polymer of claim 23, wherein X comprises a carbamate, an amide, or a carbonate.

26. The polymer of claim 23, where p is 2 to about 10.

27. The polymer of claim 26, wherein p=2.

28. The polymer of claim 10, wherein the polymer has a structure selected from:

PEG_A-L-(X-PEG_B-Y)_q 

 

(IIIa)

PEG_A-X-L-(PEG_B-Y)_q 

 

(IIIb)

and

PEG_A-X-PEG_B-L-(Y)_q 

 

(IIIc)

wherein;

PEG_A represents poly(ethylene glycol) comprising at least 4 and at most about 2000 —

CH₂CH₂O—

monomeric units,

X is a covalent linkage,

L is a branched spacer group;

PEG_B represents poly(ethylene glycol) comprising at least 1 and at most about 120 —

CH₂CH₂O—

monomeric units, with the proviso that PEG_B has a lower molecular weight than that of PEG_A;

Y is a functional group, and

q=1 to about 100.

29. The polymer of claim 28, wherein PEG_A comprises at most 200 —

CH₂CH₂O—

monomeric units.

30. The polymer of claim 28, wherein X comprises a carbamate, an amide, or a carbonate.

31. The polymer of claim 28, where l is 2 to about 10.

32. The polymer of claim 31, where 1=2.

33. The polymer of claim 10, wherein the polymer is a multi-arm polymer having the structure

M-{PEG_A-X-(PEG_B-Y)_q}_x

wherein:

M represents a multivalent core structure;

PEG represents poly(ethylene glycol) comprising at least 4 and at most about 2000 —

CH₂CH₂O—

monomeric units;

X is a covalent linkage;

PEG_B represents poly(ethylene glycol) comprising at least 1 and at most about 120 —

CH₂CH₂O—

monomeric units, with the proviso that PEG_B has a lower molecular weight than that of PEG_A;

Y is a functional group;

q=1 to about 10; and

x=3 to about 100.

34. The polymer of claim 33, wherein PEG represents poly(ethylene glycol) comprising at most 200 —

CH₂CH₂O—

monomeric units.

35. The polymer of claim 33, wherein q=1 or 2.

36. The polymer of claim 33, wherein M is selected from a polyol and a polyamine.

37. A hydrogel comprising a polymer of claim 1.

38. The hydrogel of claim 37, wherein said hydrogel is crosslinked.

39. A method of forming a water soluble polymer comprising two or more segments, said method comprising the steps of:

reacting a first water soluble polymer segment, having at least 4 and at most about 2000 monomeric units and having at least one first functional group Z, with a second water soluble segment, having from 1 to about 120 monomeric units and having at least one second functional group Y′

, thereby forming a covalent linkage between said first and second segments by reaction of said first and second functional groups;

wherein;

said second segment has a lower molecular weight than said first segment;

either said first or said second segment further comprises an additional functional group Y that is not readily reactive with either said first or said second functional group, and

each of said first and second segments independently comprises one monomer or up to three different monomers which are selected from the group consisting of alkylene glycol, olefinic alcohol, vinylpyrrolidone, hydroxyalkylmethacrylamide, hydroxyalkylmethacrylate, saccharides, α

-hydroxy acid, vinyl alcohol, polyphosphazene, polyoxazoline, and N-acryloylmorpholine.

40. The method of claim 39, wherein each of said first and second functional groups independently comprises a group selected from amine, hydrazide, hydroxyl, succinimidyl ester or carbonate, benzotriazole ester or carbonate, glycidyl ether, imidazolyl ester or carbonate, p-nitrophenyl carbonate, aldehyde, maleimide, ortho-pyridyl disulfide, acrylate, tresylate, isocyanate, and vinyl sulfone.

41. The method of claim 39, wherein said covalent linkage comprises an amide, an ester, an carbamate, or a urea.

42. The method of claim 39, wherein said additional functional group comprises a group selected from hydroxyl, amine, hydrazine, hydrazide, thiol, carboxylic acid, carboxylic ester, imide ester, orthoester, carbonate, isocyanate, isothiocyanate, aldehyde, ketone, thione, alkenyl, acrylate, methacrylate, acrylamide, sulfone, maleimide, disulfide, iodo, epoxy, sulfonate, thiosulfonate, tresylate, silane, alkoxysilane, halosilane, and phosphoramidate.

43. The method of claim 39, wherein said second segment comprises said additional functional group.

44. The method of claim 39, wherein each of said first and said second segments is a polyethylene glycol.

45. The method of claim 39, further comprising the step of conjugating a pharmacologically active agent to said water soluble polymer via reaction of said additional functional group Y.

46. The polymer of claim 10, wherein each of POLY_A and POLY_B is linear, POLY_A has a molecular weight range selected from about 200–

5000, POLY_B has at least two monomeric units, linkage X comprises an amide linkage, and each of POLY_A and POLY_B has an attached functional group Y, said functional groups comprising an amine or protected amine.

47. The polymer of claim 46, wherein POLY_A has at least 100 monomeric units.

48. The polymer of claim 47, wherein POLY_B has 2 monomeric units.