Bioabsorbable, biobeneficial polyester polymers for use in drug eluting stent coatings

• US 7,186,789 B2
• Filed: 06/11/2003
• Issued: 03/06/2007
• Est. Priority Date: 06/11/2003
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Pacetti, Stephen D., Hossainy, Syed F. A.
• Primary Examiner(s): BOYKIN, TERRESSA M
• Application Number:
  US10/460,016
• Publication Number:
  US 20040253203A1
• Time in Patent Office: 1,364 Days
• Field of Search: 424/78.08, 528/271, 528/272, 623/1.42, 623/1.46
• US Class Current: 528/272
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: C08G 63/20 Polyesters having been prepared in the presence of compounds having one reactive group or more than two reactive groups
• CPC Class Codes: C08G 63/668 derived from polycarboxylic acids and polyhydroxy compounds
• CPC Class Codes: C08G 63/6854 derived from polycarboxylic acids and polyhydroxy compounds
• CPC Class Codes: C08G 63/6886 Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08L 2666/18 Polyesters or polycarbonates according to C08L67/00 - C08L69/00; Derivatives thereof
• CPC Class Codes: C08L 2666/20 Macromolecular compounds having nitrogen in the main chain according to C08L75/00 - C08L79/00; Derivatives thereof
• CPC Class Codes: C08L 67/02 Polyesters derived from dicarboxylic acids and dihydroxy compounds C08L67/06 takes precedence
• CPC Class Codes: C08L 67/025 containing polyether sequences
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C08L 69/00 Compositions of polycarbonates; Compositions of derivatives of polycarbonates
• CPC Class Codes: C08L 73/02 Polyanhydrides

Abstract

This disclosure covers polymers, some of which are useful in medical device applications. Some of these medical devices are implantable within a mammalian body, such as in a body lumen. The copolymers comprise at least one alcoholic moiety derived from a diol, triol, or polyol. Additionally, the copolymers comprise an acidic moiety, derived from a polycarboxylic acid, and a biobeneficial moiety. Some of these copolymers are biodegradable or bioerodable. Medical devices comprising these polymers and methods of making these polymers are within the scope of this disclosure.

Claims

1. A polymer with the following formula:

14. The polymer of claim 1 wherein the formula is

15. The polymer of claim 1 wherein the formula is

16. The polymer of claim 1 wherein the formula is

28. A method for preparing the polymer of claim 1 comprising:

a) preparing a polymerizable biobeneficial moiety based on BB;

b) polymerizing a polycarboxylic acid based on Q with the polymerizable biobeneficial moiety;

c) then polymerizing a mixture of a polycarboxylic acid based on Q′

, a di-, tri-, or polyol based on T, and the product of b).

29. The method of claim 28 wherein preparing a polymerizable biobeneficial moiety based on BB comprises connecting a biobeneficial moiety, BB, to a di-, tri-, or poly-ol based on W.

30. A method for preparing the polymer of claim 1 comprising:

a) polymerizing a polycarboxylic acid based on Q with the biobeneficial moiety, BB; and

b) then copolymerizing a polycarboxylic acid based on Q′

, a di- , tri-, or polyol based on W, and the product of a).

31. A composition comprising a first polymer blended with the polymer of claim 1.

32. The composition of claim 31 wherein the first polymer modulates biological outcome.

33. The composition of claim 31 wherein the first polymer comprises polycaprolactone, poly(D,L-lactide), poly(L-lactide), poly(D,L-lactide-co-L-lactide), poly(glycolide), poly(D,L-lactide-co-glycolide), poly(dioxanone), poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(3 -hydroxy valerate), poly(hydroxybutyrate-co-hydroxyvalerate), poly(tyrosine derive carbonates), poly(tyrosine arylates), poly(imino carbonates), poly(trimethylene carbonate), poly(anhydrides), poly(orthoesters), or poly(ester amides).

34. The composition of claim 32 wherein the first polymer comprises polycaprolactone, poly(D,L-lactide), poly(L-lactide), poly(D,L-lactide-co-L-lactide), poly(glycolide), poly(D,L-lactide-co-glycol ide), poly(dioxanone), poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(3 -hydroxy valerate), poly(hydroxybutyrate-co-hydroxyvalerate), poly(tyrosine derive carbonates), poly(tyrosine arylates), poly(imino carbonates), poly(trimethylene carbonate), poly(anhydrides), poly(orthoesters), or poly(ester amides).

2. A medical device comprising a polymer comprising:

a) an alcoholic moiety derived from an aliphatic diol, triol, or polyol;

b) an acidic moiety derived from a polycarboxylic acid; and

c) a biobeneficial moiety derived from polypropylene glycol, PLURONIC™

surfactants, block copolymers comprising polyethylene glycol and polypropylene glycol, hydroxy functional poly(vinyl pyrrolidone), dextrin, sodium hyaluronate, hyaluronic acid, elastin, water-soluble heparin, water-soluble elastin, tropoelastin, poly(2-hydroxyethyl methylmethacrylate), heparin, hirudin, sulfonated polystyrene, superoxide dismutase mimetics, anti-oxidants, or free radical scavengers,

wherein the polycarboxylic acid is selected from the acidic moiety derived from at least one diacid selected from the group consisting of straight chain aliphatic diacids having 2 to 20 carbon atoms, terephthalic acid, fumaric acid, citric acid, citramalic acid, tricarballylic acid, tartaric acid, isophthalic acid, 1,6-bis(p-carboxy phenoxy)hexane, 1,3-bis(p-phenoxy carboxy)propane, 1,4-bis(p-phenoxy carboxy)butane, and oligomeric diacids with anhydride bonds in the backbone.

3. The medical device of claim 2 wherein the alcoholic moiety is derived from a diol having from 1 to 25 carbon atoms or a saccharide.

4. The medical device of claim 3 wherein the alcoholic moiety is derived from a diol having 1 to 16 carbon atoms.

5. The medical device of claim 2 wherein the alcoholic moiety is derived from at least one of ethylene glycol, 1,2-propane diol, 1,3-propane diol, 1,4-butanediol, 1,5-butanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, higher diols up to C16, glycerol, trimethylol propane, pentaerythritol, cyclohexanedimethanol, serinol, diethanolamine, or saccharides.

6. The medical device of claim 5 wherein saccharides are selected from erythrose, threose, ribose, arabinose, xylose, lyxose, dihydroxyacetone, erythrulose, xylulose, aldoses, or ketoses.

7. The medical device of claim 6 comprising at least three alcoholic moieties derived from an aliphatic diol, triol, or polyol.

8. The medical device of claim 2 wherein the acidic moiety is derived from at least one of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azaleic acid, sebacic acid, terephthalic acid, or malic acid.

9. The medical device of claim 2 wherein oligomeric diacids with anhydride bonds in the backbone are selected from poly(sebacic anhydride), poly(suberic anhydride), poly(adipic anhydride), poly(succinic anhydride), poly(maleic anhydride), poly( 1,6-bis(p-phenoxy carboxy)hexane), poly( 1,4-bis(p-phenoxy carboxy)butane), poly( 1,3-bis(p-phenoxy carboxy)propane), and poly( 1,4-dicarboxybenzene).

10. The medical device of claim 8 comprising at least two acidic moieties each derived from a different polycarboxylic acid.

11. The medical device of claim 2 wherein the biobeneficial moiety, the non-fouling moiety, or the bioactive moiety are selected such that they give rise to a released molecule that can pass through a mammalian kidney.

12. The medical device of claim 11 wherein the biobeneficial moiety, the non-fouling moiety, or the bioactive moiety are selected such that the released molecule has a molecular weight of less than or equal to 40,000 daltons.

13. The medical device of claim 2 wherein the biobeneficial moiety is at least one of the polypropylene glycol, block polymer surfactants of polyethylene glycol and polypropylene glycol, hydroxy functional poly(vinyl pyrrolidone), dextrin, sodium hyaluronate, heparin, elastin, chitosan, water-soluble derivatives of heparin, water-soluble derivatives of elastin, water-soluble derivatives of chitosan, tropoelastin, poly(2-hydroxyethyl methacrylate), hirudin, or sulfonated polystyrene.

17. A medical device comprising a block copolymer comprising at least two blocks wherein:

a) the first block comprises a block copolymer comprising;

i) a first-block alcoholic moiety derived from a di-, tri-, or poly-ol; and

ii) a first-block acidic moiety derived from a di-, tri-, or poly-acidic carboxylic acid; and

b) the second block comprises a block copolymer comprising;

i) a second-block alcoholic moiety derived from a di-, tri-, or poly-ol; and

ii) a second-block acidic moiety derived from a di-, tri-, or poly-acidic carboxylic acid

wherein at least one of the first- or second-block alcoholic moieties or first- or second-block acidic moieties is attached to a biobeneficial moiety derived from polypropylene glycol, PLURONIC™

surfactants, block copolymers comprising polyethylene glycol and polypropylene glycol, hydroxy functional poly(vinyl pyrrolidone), dextrin, sodium hyaluronate, hyaluronic acid, elastin, water-soluble heparin, water-soluble elastin, tropoelastin, poly(2-hydroxyethyl methylmethacrylate), heparin, hirudin, sulfonared polystyrene, superoxide dismutase mimetics, anti-oxidants, or free radical scavengers.

18. The medical device of claim 17 further comprising a third block comprising a block copolymer comprising:

a) a third-block alcoholic moiety derived from a di-, tri-, or poly-ol; and

b) a third-block acidic moiety derived from a di-, tri-, or poly-acidic carboxylic acid.

19. The medical device of claim 17 wherein the first- and the second-block alcoholic constituents are independently derived from 1-to-50-carbon-atom molecules.

20. The medical device of claim 19 wherein the first- and the second-block alcoholic moieties are independently derived from 1-to-10-carbon-atom molecules.

21. The medical device of claim 17 wherein first- and second-block alcoholic moieties are independently derived from at least one of ethylene glycol, 1,2-propane diol, 1,3-propane dial, 1,4-butanediol, 1,5-butanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, higher diols up to C_16, glycerol, trimethylol propane, pentaerythritol, cyclohexanedimethanol, serinol, diethanolamine, or saccharides.

22. The medical device of claim 21 wherein saccharides are selected from erythrose, threose, ribose, arabinose, xylose, lyxose, dihydroxyacetone, erythrulose, xylulose, aldoses, or ketoses.

23. The medical device of claim 17 wherein the first- and second-block acidic moieties are independently derived from 1-to-50-carbon-atom molecules.

24. The medical device of claim 23 wherein the first- and the second-block acidic moieties are independently derived from 1-to-10-carbon-atom molecules.

25. The medical device of claim 17 wherein the first- and the second-block acidic moieties are independently derived from at least one of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azaleic acid, sebacic acid, terephthalic acid, malic acid, fumaric acid, citric acid, citramalic acid, tricarballylic acid, tartaric acid, isophthalic acid, phthalic acid, 1,6-bis(p-carboxy phenoxy)hexane, 1,3-bis(p-phenoxy carboxy)propane, 1,4-bis(p-phenoxy carboxy)butane, dodecanedioic acid, tetradecanedioic acid, hexadecanedioic acid, or oligomeric diacids with anhydride bonds in the backbone.

26. The medical device of claim 25 wherein oligomeric diacids with anhydride bonds in the backbone are selected from poly(sebacic anhydride), poly(suberic anhydride), poly(adipic anhydride), poly(succinic anhydride), poly(maleic anhydride), poly( 1,6-bis(p-phenoxy carboxy)hexane), poly(1,4-bis(p-phenoxy carboxy)butane), poly(1,3-bis(p-phenoxy carboxy)propane), and poly(1 ,4-dicarboxybenzene).

27. The medical device of claim 17 wherein the biobeneficial molecule is at least one of the polypropylene glycol, block copolymer surfactants of polyethylene glycol and polypropylene glycol, hydroxy functional poly(vinyl pyrrolidone), dextrin, sodium hyaluronate, heparin, elastin, water-soluble derivatives of heparin, water-soluble derivatives of elastin, water-soluble derivatives of chitosan, tropoelastin, poly(2-hydroxyethyl methacrylate), hirudin, or sulfonated polystyrene.

35. A polymer with the following formula:

36. A polymer comprising:

an alcoholic moiety derived from an aliphatic diol having from 1 to 25 carbon atoms or a saccharide;

an acidic moiety derived from a polycarboxylic acid; and

a biobeneficial moiety is derived from polypropylene glycol, PLURONIC™

surfactants, block copolymers comprising polyethylene glycol and polypropylene glycol, hydroxy functional poly(vinyl pyrrolidone), dextrin, sodium hyaluronate, hyaluronic acid, elastin, water-soluble heparin, water-soluble elastin, tropoelastin, poly(2-hydroxyethyl methylmethacrylate), heparin, hirudin, sulfonated polystyrene, superoxide dismutase mimetics, anti-oxidants, or free radical scavengers, wherein the polycarboxylic acid is selected from the acidic moiety derived from at least one diacid selected from the group consisting of straight chain aliphatic diacids having 2 to 20 carbon atoms, terephthalic acid, fumaric acid, citric acid, citramalic acid, tricarballylic acid, tartaric acid, isophthalic acid, 1,6-bis(p-carboxy phenoxy)hexane, 1,3-bis(p-phenoxy carboxy)propane, 1,4-bis(p-phenoxy carboxy)butane, and oligomeric diacids with anhydride bonds in the backbone.

37. A polymer comprising:

an alcoholic moiety derived from an aliphatic diol, triol, or polyol;

an acidic moiety derived from a polycarboxylic acid; and

a biobeneficial moiety having biobeneficial characteristics, a non-fouling moiety having non-fouling characteristics, a bioactive moiety having bioactive characteristics, or a moiety that has any combination of biobeneficial, non-fouling, or bioactive characteristics, wherein the biobeneficial moiety is derived from polypropylene glycol, PLURONIC™

surfactants, block copolymers comprising polyethylene glycol and polypropylene glycol, hydroxy functional poly(vinyl pyrrolidone), dextrin, sodium hyaluronate, hyaluronic acid, elastin, water-soluble heparin, water-soluble elastin, tropoelastin, poly(2 -hydroxyethyl methylmethacrylate), heparin, hirudin, sulfonated polystyrene, superoxide dismutase mimetics, anti-oxidants, or free radical scavengers, and wherein the polycarboxylic acid is selected from the acidic moiety is derived from at least one diacid selected from the group consisting of straight chain aliphatic diacids having 2 to 20 carbon atoms, terephthalic acid, fumaric acid, citric acid, citramalic acid, tricarballylic acid, tartaric acid, isophthalic acid, 1,6-bis(p-carboxy phenoxy)hexane, 1,3-bis(p-phenoxy carboxy)propane, 1,4-bis(p-phenoxy carboxy)butane, and oligomeric diacids with anhydride bonds in the backbone.

38. A polymer comprising:

an alcoholic moiety derived from an aliphatic diol, triol, or polyol;

an acidic moiety derived from a polycarboxylic acid; and

a biobeneficial moiety is derived from polypropylene glycol, PLURONIC™

surfactants, block copolymers comprising polyethylene glycol and polypropylene glycol, hydroxy functional poly(vinyl pyrrolidone), dextrin, sodium hyaluronate, hyaluronic acid, elastin, water-soluble heparin, water-soluble elastin, tropoelastin, poly(2-hydroxyethyl methylmethacrylate), heparin, hirudin, sulfonated polystyrene, superoxide dismutase mimetics, anti-oxidants, or free radical scavengers having a molecular weight of less than or equal to 40,000 daltons, wherein the polycarboxylic acid is selected from the acidic moiety is derived from at least one diacid selected from the group consisting of straight chain aliphatic diacids having 2 to 20 carbon atoms, terephthalic acid, fumaric acid, citric acid, citramalic acid, tricarballylic acid, tartaric acid, isophthalic acid, 1,6-bis(p-carboxy phenoxy)hexane, 1,3-bis(p-phenoxy carboxy)propane, 1,4-bis(p-phenoxy carboxy)butane, and oligomeric diacids with anhydride bonds in the backbone.

39. A block copolymer comprising at least two blocks wherein:

a) the first block comprises a block copolymer comprising;

i) a first-block alcoholic moiety independently derived from at least one of ethylene glycol, 1,2-propane diol, 1,3-propane diol, 1,4-butanediol, 1,5-butanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, higher diols up to C16, glycerol, trimethylol propane, pentaerythritol, cyclohexanedimethanol, serinol, diethanolamine, or saccharides; and

ii) a first-block acidic moiety derived from a di-, tri-, or poly-acidic carboxylic acid; and

b) the second block comprises a block copolymer comprising;

i) a second-block alcoholic moiety independently derived from at least one of ethylene glycol, 1,2-propane diol, 1,3-propane diol, 1,4-butanediol, 1,5-butanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, higher diols up to C16, glycerol, trimethylol propane, pentaerythritol, cyclohexanedimethanol, serinol, diethanolamine, or saccharides; and

ii) a second-block acidic moiety derived from a di-, tri-, or poly-acidic carboxylic acid;

wherein at least one of the first- or second-block alcoholic moieties or first- or second-block acidic moieties is attached to a biobeneficial moiety derived from polypropylene glycol, PLURONIC™

surfactants, block copolymers comprising polyethylene glycol and polypropylene glycol, hydroxy functional poly(vinyl pyrrolidone), dextrin, sodium hyaluronate, hyaluronic acid, elastin, water-soluble heparin, water-soluble elastin, tropoelastin, poly(2-hydroxyethyl methylmethacrylate), heparin, hirudin, sulfonated polystyrene, superoxide dismutase mimetics, anti-oxidants, or free radical scavengers.

40. The copolymer of claim 39 wherein saccharides are selected from erythrose, threose, ribose, arabinose, xylose, lyxose, dihydroxyacetone, erythrulose, xylulose, aldoses, or ketoses.

41. A composition comprising:

a first polymer, wherein the first polymer comprises polycaprolactone, poly(D,L-lactide), poly( L-lactide), poly(D,L-lactide-co-L-lactide), poly(glycolide), poly(D,L-lactide-co-glycolide), poly(dioxanone), poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(3-hydroxy valerate), poly(hydroxybutyrate-co-hydroxyvalerate), poly(tyrosine derive carbonates), poly(tyrosine arylates), poly(imino carbonates), poly(trirnethylene carbonate), poly(anhydrides), poly(orthoesters), or poly(ester amides), blended with

a second polymer, wherein the second polymer comprises

an alcoholic moiety derived from an aliphatic diol, triol, or polyol;

an acidic moiety derived from a polycarboxylic acid; and

a biobeneficial moiety derived from polypropylene glycol, PLURONIC™

surfactants, block copolymers comprising polyethylene glycol and polypropylene glycol, hydroxy functional poly(vinyl pyrrolidone), dextrin, sodium hyaluronate, hyaluronic acid, elastin, water-soluble heparin, water-soluble elastin, tropoelastin poly(2-hydroxyethyl methylmethacrylate), heparin, hirudin, sulfonated polystyrene, superoxide dismutase mimetics, anti-oxidants, or free radical scavengers.

42. The composition of claim 41 wherein the first polymer modulates biological outcome.