Hyaluronic acid based copolymers

• US 20050244363A1
• Filed: 04/30/2004
• Published: 11/03/2005
• Est. Priority Date: 04/30/2004
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated (Abbott Laboratories)
• Original Assignee: Advanced Cardiovascular Systems Incorporated (Abbott Laboratories)
• Inventors: Kwok, Connie, Glauser, Thierry, Hossainy, Syed Faiyaz Ahmed, Pacetti, Stephen Dirk, Michal, Eugene
• Granted Patent: US 8,293,890 B2
• Time in Patent Office: Days
• US Class Current: 424/78.300
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08L 5/10 Heparin; Derivatives thereof

Abstract

Hyaluronic acid (HA) conjugates or crosslinked HAs compositions for coating an implantable device are provided. The implantable device can be used for treating a disorder such as atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

Claims

1. A hyaluronic acid (HA) conjugate comprising HA and at least a component selected from the group consisting of

heparin,

poly(ethylene glycol) (PEG),

hydrophobic side chains,

biocompatible hydrophobic polymers, and

combinations thereof.

2. The HA conjugate of claim 1 wherein the short hydrophobic side chains are selected from the group consisting of saturated and unsaturated fatty acids and fatty alcohols.

3. The HA conjugate of claim 1 wherein the biocompatible hydrophobic polymers are selected from the group consisting of poly(ester amide), poly(ester amide) that may contain alkyl groups, amino acid groups, or poly(ethylene glycol) (PEG) groups, polyethylene glycol (PEG), polylakanoates (PHA), polyesters, poly(D,L-lactide), poly(L-lactide), polyglycolide, poly(D,L-lactide-co-glycolide), polycaprolactone, poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine ester) and derivatives thereof, poly(imino carbonates), poly(phosphoesters), polyphosphazenes, poly(amino acids), polysaccharides, collagen, chitosan, alginate, polyethers, polyamides, polyurethanes, polyalkylenes, polyalkylene oxides, polyethylene oxide, polypropylene oxide, polyethylene glycol (PEG), PHA-PEG, polyvinylpyrrolidone (PVP), alkylene vinyl acetate copolymers such as ethylene vinyl acetate (EVA), alkylene vinyl alcohol copolymers such as ethylene vinyl alcohol (EVOH or EVAL), poly(n-butyl methacrylate) (PBMA), SOLEF™

(poly (vinylidene fluoride-co-hexafluoropropene) and combinations thereof.

4. The HA conjugate of claim 3 wherein the PHA is selected from the group consisting of poly(2-hydroxyalkanoates), poly(3-hydroxyalkanoates), poly(3-hydroxypropanoate), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate), poly(3-hydroxyoctanoate), poly(4-hydroxyalknaote), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymers comprising any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein or blends thereof, and combinations thereof.

5. The HA conjugate of claim 1 wherein the hydrophobic side chains are selected from the group consisting of castor oil, laurate, state, palmitate, oleate, hexanol, dodecanol, stanol, sterol, cholesterol, cetyl, and combination thereof.

6. The HA conjugate of claim 1 comprising a heparin and a crosslinker which comprises a moiety selected from the group consisting of difunctional carbodiimide, PEG-dialdehyde, and a bis-succinidyl moieties.

7. The HA conjugate of claim 1 comprising a poly(ester amide) which optionally comprises one or more groups selected from the group consisting of alkyl, amino acids, PEG, and combinations thereof.

8. The HA conjugate of claim 1 wherein the biocompatible polymer is biodegradable.

9. The HA conjugate of claim 1 which is a copolymer comprising a PEG-HA-(C12-C18 alkyl) conjugate.

18. An implantable device comprising the HA conjugate of claim 1.

19. An implantable device comprising the HA conjugate of claim 2.

20. An implantable device comprising the HA conjugate of claim 3.

21. An implantable device comprising the HA conjugate of claim 4.

22. An implantable device comprising the HA conjugate of claim 5.

23. An implantable device comprising the HA conjugate of claim 6.

24. An implantable device comprising the HA conjugate of claim 7.

25. An implantable device comprising the HA conjugate of claim 8.

26. An implantable device comprising the HA conjugate of claim 9.

35. The implantable device of claim 18 further comprising a bioactive agent.

36. The implantable device of claim 18 further comprising a bioactive agent selected from the group consisting of ABT-578™

, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugs thereof, co-drugs thereof, and combinations thereof.

49. A method of treating a disorder selected from the group consisting of atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof, comprising:

implanting in the human being the implantable device of claim 18.

10. A crosslinked HA composition produced by a process comprising

crosslinking a HA having crosslinking groups by a crosslinking means selected from the group consisting of photo radiation, heating, chemical reaction, physical crosslinking, and combinations thereof.

11. The crosslinked HA composition of claim 10 wherein the crosslinking groups are olefinic groups, and

wherein the crosslinking means is photo radiation.

12. The crosslinked HA composition of claim 11 wherein the olefinic groups are selected from the group consisting of acryloyl groups, methacryloyl groups, and combinations thereof.

27. An implantable device comprising the crosslinked HA composition of claim 10.

28. An implantable device comprising the crosslinked HA composition of claim 11.

29. An implantable device comprising the crosslinked HA composition of claim 12.

37. The implantable device of claim 27 further comprising a bioactive agent.

38. The implantable device of claim 27 further comprising a bioactive agent selected from the group consisting of ABT-578™

, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugs thereof, co-drugs thereof, and combinations thereof.

50. A method of treating a disorder selected from the group consisting of atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof, comprising:

implanting in the human being the implantable device of claim 27.

13. A crosslinked HA composition produced by a process comprising

crosslinking HA with a crosslinker by chemical reaction.

14. The crosslinked HA composition of claim 13 wherein the crosslinker comprises a hydrophobic moiety or PEG and two or more crosslinking moieties.

15. The crosslinked HA composition of claim 14 wherein the hydrophobic moiety is selected from the group consisting of saturated and unsaturated fatty acids, fatty alcohols, hydrophobic polymers, and combinations thereof;

and

wherein the two or more crosslinking moieties are selected from the group consisting of hydazides, azeridines, aldehydes, amines, diacrylate, bisacrylamide, and combinations thereof.

16. The crosslinked HA composition of claim 14 wherein the hydrophobic moiety is selected from the group consisting of castor oil, laurate, state, palmitate, oleate, hexanol, dodecanol, stanol, sterol, cholesterol, cetyl, poly (ester amides), poly(caprolactone), polylactide, polyglycolide, poly(lactide-co-glycolide), poly(DL-lactide-co-glycolide), polyhydroxyalkanoate (PHA), poly(3-hydroxybutyrate) (PHB), poly(3-hydroxybutyrate-co-valerate) (PHBV), poly(3-hydroxyproprionate) (PHP), poly(3-hydroxyhexanoate) (PHH), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate);

poly(4-hydroxyhexanoate), poly(dioxanone), and PHA-PEG, and a combination thereof.

17. The crosslinked HA composition of claim 15 wherein the crosslinker is cyclic dimmer of 3-hydroxypropionatealdehyde.

30. An implantable device comprising the crosslinked HA composition of claim 13.

31. An implantable device comprising the crosslinked HA composition of claim 14.

32. An implantable device comprising the crosslinked HA composition of claim 15.

33. An implantable device comprising the crosslinked HA composition of claim 16.

34. An implantable device comprising the crosslinked HA composition of claim 17.

51. A hyaluronic acid (HA) conjugate comprising a moiety derived from HA and at least one moiety derived from a material selected from the group consisting of

heparin,

poly(ethylene glycol) (PEG),

hydrophobic side chains,

biocompatible hydrophobic polymers, and

combinations thereof.

52. An implantable device comprising the HA conjugate of claim 51.

53. The implantable device of claim 52 further comprising a bioactive agent.

54. A method of treating a disorder selected from the group consisting of atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof, comprising:

implanting in the human being the implantable device of claim 53.