Polymer for use in conduits, medical devices and biomedical surface modification

• US 7,820,769 B2
• Filed: 01/20/2005
• Issued: 10/26/2010
• Est. Priority Date: 01/20/2004
• Status: Expired due to Fees

• Current Assignee: Ucl Biomedica Plc
• Original Assignee: Ucl Biomedica Plc
• Inventors: Seifalian, Alexander, Hancock, Steve, Ramesh, Bala, Darbyshire, Arnold, Salacinski, Henryk, Srai, Kaila
• Primary Examiner(s): PENG, KUO LIANG
• Application Number:
  US10/586,649
• Publication Number:
  US 20080233164A1
• Time in Patent Office: 2,105 Days
• Field of Search: 528 44- 45, 528/67, 528/28, 525/474
• US Class Current: 525/474
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: C08G 18/3893 containing silicon
• CPC Class Codes: C08G 18/44 Polycarbonates
• CPC Class Codes: C08L 75/04 Polyurethanes

Abstract

A copolymer comprising (a) one or more pendant group segments and (b) one or more polyol segments, each of said segments being linked to one or more further segments which may be the same or different,

wherein said one or more pendant group segments are the same or different and are selected from:

• (i) siloxane segments;
• (ii) segments containing phosphoryl choline or a derivative or analogue thereof;
• (iii) segments containing a di- or trifluoromethyl group;
• (iv) heparin-like segments containing a group of formula (XII)
  D-N═N—Ar—SO₃⁻  (XII)
  wherein D is an aliphatic or aromatic group and Ar—SO₃⁻ comprises one or more linked aryl and/or heteroaryl groups, at least one of the aryl and/or heteroaryl groups having an SO₃⁻ substituent; and
• (v) segments containing a group of formula (I)
  [P]_n′-[Lys]_n-Lys-[Spacer]-Lys-[Al]_x  (I)
  wherein:
  • [Al] is an inert amino acid;
  • x is 0, 1, 2 or 3;
  • [Spacer] is a fatty acid, amino acid, peptide or PEG;
  • [P]_n′-[Lys]_n is a dendritic structure formed from n lysine groups and terminating in n′ groups P;
  • n is an integer of from 1 to 15;
  • n′ is zero or an integer of up to 16; and
  • each P is the same or different and is an amino acid or a peptide having up to 25 amino acids,
    and wherein at least a part of each of said pendant group segment(s) is on a side chain of the copolymer.

The copolymer is useful in the production of implantable devices such as vascular grafts.

Claims

1. A copolymer comprising (a) one or more pendant group segments and (b) one or more polyol segments, each of said segments being linked to one or more further segments which may be the same or different,

wherein said one or more pendant group segments are the same or different and are siloxane segments, wherein each of said siloxane segments comprises a siloxane moiety which is either a linear siloxane with a molecular weight of up to 2000 Daltons, a silsesquioxane cage or a partial silsesquioxane cage, said moiety being attached to the copolymer backbone either directly or via a pendant arm that does not contain any ether groups, and wherein when said moiety is a silsesquioxane cage or partial silsesquioxane cage, then the molar ratio of pendant group segments to polyol segments is 1:

X wherein X is 10 or more, and wherein when said moiety is a linear siloxane, then the component (b) comprises one or more polycarbonate segments.

2. A copolymer according to claim 1, wherein the segments are linked via urea or urethane linkages.

3. A process for producing a copolymer according to claim 2, wherein said process comprises polymerising, in any order,

(i) one or more pendant group siloxane segments, wherein each of said siloxane segments comprises a siloxane moiety which is either a linear siloxane with a molecular weight of up to 2000 Daltons, a silsesquioxane cage or a partial silsesquioxane cage, said moiety being attached to the copolymer backbone either directly or via a pendant arm that does not contain any ether groups, and wherein when said moiety is a silsesquioxane cage or partial silsesquioxane cage, then the molar ratio of pendant group segments to polyol segments is 1:

X wherein X is 10 or more, and wherein each of said one or more segments is bonded to at least one group selected from primary or secondary amine, hydroxyl and carboxylic acid groups;

(ii) a polyol;

(iii) an aromatic compound having two or more isocyanate groups; and

optionally

(iv) one or more chain extenders selected from amino acids, peptides, polypeptides and C₁-C₆ aliphatic groups, each of which has at least one substituent selected from primary or secondary amine, hydroxyl and carboxylic acid groups,

wherein if the siloxane moiety in (i) is a linear siloxane, then the polyol (ii) comprises one or more polycarbonate segments.

4. A copolymer obtained by the process of claim 3.

5. A process for producing a copolymer according to claim 2, said copolymer comprising a linear siloxane attached directly to the backbone of the copolymer,

wherein said process comprises (i) reacting a polyol polyurethane with a strong base, and (ii) reacting the product of (i) with a siloxane.

6. A copolymer according to claim 1, wherein the pendant siloxane segment(s) comprise a linear siloxane moiety, said linear siloxane moiety comprising repeating units of the formula (II)

7. A copolymer according to claim 6, wherein each R is the same or different and represents an alkyl, alkenyl, alkynyl, cycloalkyl or aryl group.

8. A copolymer according to claim 1 wherein the molar ratio of siloxane segment(s) to polyol segment(s) is 1:

10 or less.

9. A copolymer according to claim 8 wherein the ratio of pendant siloxane segment:

polyol segment is 1;

25 or less.

10. A copolymer according to claim 1, which comprises one or more pendant siloxane segments having a molecular weight of up to 5000.

11. A copolymer according to claim 1, which comprises two or more different pendant siloxane segments, each containing a silsesquioxane cage or partial cage.

12. A copolymer according to claim 1 which comprises two or more different pendant group segments.

13. A copolymer according to claim 1, further comprising (c) one or more chain extender segments, each of said chain extender segments being linked to one or more further segments, which may be the same or different.

14. A copolymer according to claim 13, wherein said chain extender segment(s) are selected from amino acids, peptides, polypeptides and C₁-C₆ aliphatic moieties.

15. A copolymer according to claim 14, wherein one or more of said chain extender segment(s) is an anticoagulant.

16. A copolymer according to claim 14, wherein one or more of said chain extender segment(s) is RGD (Arg-Gly-Asp).

17. A copolymer according to claim 1, which comprises as component (b) one or more polycarbonate segment(s).

18. A process for producing a lined copolymer, wherein said process comprises seeding cells onto the surface of a copolymer as claimed in claim 1.

19. A lined copolymer obtained by the process of claim 18.

20. A moulded article comprising a copolymer as claimed in claim 1 or a lined copolymer as claimed in claim 19.

21. A moulded article according to claim 20 which is an implantable device.

22. An implantable device according to claim 21 which is a vascular graft.

23. A method of treating a human or animal patient in need of the replacement of a body part, said method comprising replacing said body part with the implantable device of claim 21.

24. A copolymer according to claim 1 wherein the siloxane group is attached to the polymer via a pendant arm.

25. A copolymer according to claim 24, wherein the pendant siloxane segment(s) have the structure (III)

26. A copolymer according to claim 25, wherein S is a silsesquioxane cage.

27. A copolymer according to claim 26, wherein the silsesquioxane cage S consists of repeating units of formula (IV)

28. A copolymer according to claim 27, wherein each R′

is the same or different and represents an alkyl, alkenyl, alkynyl, cycloalkyl or aryl group.

29. A copolymer according to claim 24 wherein the pendant arm is attached at the end of the copolymer chain.

30. A copolymer according to claim 1, wherein each segment is linked to one or more further segments by a group of formula

31. A copolymer according to claim 1, which comprises one or more further pendant group segments which may be the same or different and are selected from:

(1) segments containing phosphoryl choline or a derivative thereof or segments(s) of formula (VII)

32. A copolymer according to claim 31, wherein the segment(s) containing phosphoryl choline or a derivative thereof have the formula (V)

33. A copolymer according to claim 31, wherein the segment(s) containing a di- or trifluoromethyl group are straight or branched, C_2-12 alkylene groups which are substituted with one or more di- or trifluoromethyl groups and optionally one or more fluorine atoms.

34. A copolymer according to claim 31, wherein the segments(s) containing a di- or trifluoromethyl group are siloxane segments, segments containing phosphoryl choline or a derivative or analogue thereof, heparin-like segments or segments of formula (I) which are substituted with a di- or trifluoromethyl group, wherein said segments containing an analogue of phosphoryl choline are segments of formula (VII)

35. A copolymer according to claim 31, wherein in the group of formula (XII) Ar comprises one or two linked aryl or heteroaryl groups selected from phenylene and pyrazolylene, Ar being substituted with one or two —

SO₃⁻

groups and one, two or three further substituents selected from methyl, ethyl, methoxy, methylthio, nitro and dimethylamino groups; and

D is a group D¹-D²-D³- wherein D¹ is an arylene or heteroarylene group which is unsubstituted or substituted with one, two or three substituents selected from methyl, ethyl and methoxy groups, D² is —

NR′

CO—

, —

CONR′

, —

OCO—

, —

COO—

, —

NR′

SO₂—

or —

SO₂NR′

—

wherein each R′

is the same or different and is hydrogen or a C_1-4 alkyl group and D³ is phenylene or a C_1-4 alkylene or C_2-4 alkenylene group which is unsubstituted or substituted with one, two or three substituents selected from methyl, ethyl and methoxy groups.

36. A copolymer according to claim 31, wherein the group of formula (XII) is a derivative of an Acid Yellow compound.

37. A copolymer according to claim 31, wherein in the group of formula (I), n is 7.

38. A copolymer according to claim 31, wherein in the group of formula (I), P is an amino acid or peptide in the D-form.