Side-chain crystallizable polymers for medical applications

• US 20060024266A1
• Filed: 07/07/2005
• Published: 02/02/2006
• Est. Priority Date: 07/08/2004
• Status: Active Grant

• Current Assignee: REVA Medical LLC
• Original Assignee: REVA Medical Inc.
• Inventors: Schmid, Eric V., Zeltinger, Joan, Mallon, Joseph J., Brandom, Donald K.
• Granted Patent: US 7,939,611 B2
• Time in Patent Office: Days
• US Class Current: 424/78.170
• CPC Class Codes: A61B 17/12022 Occluding by internal devices, e.g. balloons or releasable wires plugging an opening in the wall of an organ A61B17/0057; occluders for the cervical canal A61F6/146; vas deferens occluders A61F6/20
• CPC Class Codes: A61B 17/12036 partial occlusion
• CPC Class Codes: A61B 17/12145 having a pre-set deployed three-dimensional shape methods of manufacturing A61B2017/00526
• CPC Class Codes: A61B 17/12186 liquid materials adapted to be injected
• 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 31/74 Synthetic polymeric materials
• CPC Class Codes: A61K 33/18 Iodine; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0442 Polymeric X-ray contrast-enhancing agent comprising a halogenated group
• CPC Class Codes: A61K 49/0476 Particles, beads, capsules, spheres
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/18 Materials at least partially X-ray or laser opaque
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C08F 220/1818 C13or longer chain (meth)acrylate, e.g. stearyl (meth)acrylate
• CPC Class Codes: C08G 2261/126 block
• CPC Class Codes: C08G 63/68 Polyesters containing atoms other than carbon, hydrogen and oxygen C08G63/64 takes precedence
• CPC Class Codes: C08G 63/6826 Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 63/6856 : Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 63/6886 : Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 63/916 : Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 64/10 : containing halogens
• CPC Class Codes: C08G 64/12 : containing nitrogen
• CPC Class Codes: C08G 64/42 : Chemical after-treatment
• CPC Class Codes: C08G 65/40 : from phenols (I) and other compounds (II), e.g. OH-Ar-OH + X-Ar-X, where X is halogen atom, i.e. leaving group
• CPC Class Codes: C08G 77/24 : halogen-containing groups

Abstract

Inherently radiopaque side-chain crystallizable polymers (IRSCCP'"'"'s) are useful in various medical applications. An example of a IRSCCP is a polymer that comprises a main chain, a plurality of crystallizable side chains, and a plurality of heavy atoms attached to the polymer, the heavy atoms being present in an amount that is effective to render the polymer radiopaque. A polymeric material that includes a IRSCCP may be fabricated into a medical device useful for at least partially occluding a body cavity. For example, such a medical device may be an embolotherapy product.

Claims

1. A polymer comprising:

a main chain;

a plurality of crystallizable side chains; and

a plurality of heavy atoms attached to the polymer, the heavy atoms being present in an amount that is effective to render the polymer radiopaque.

2. The polymer of claim 1 having a melting point in the range of about 30°

C. to about 80°

C.

3. The polymer of claim 1 that is biocompatible.

4. The polymer of claim 1 that is bioresorbable.

5. The polymer of claim 1 in which the plurality of heavy atoms comprise an atom having an atomic number of at least 17.

6. The polymer of claim 5 in which the plurality of heavy atoms comprise an atom having an atomic number of at least 35.

7. The polymer of claim 1 in which the plurality of heavy atoms comprise an atom selected from the group consisting of bromine, iodine, bismuth, gold, platinum tantalum, tungsten, and barium.

8. The polymer of claim 1 in which the plurality of heavy atoms are covalently attached to the polymer.

9. The polymer of claim 1 in which the plurality of heavy atoms are ionically attached to the polymer.

10. The polymer of claim 1 that is a copolymer comprising at least two different recurring units.

11. The polymer of claim 10 that is a random copolymer.

12. The polymer of claim 10 that is a block copolymer.

13. The polymer of claim 1 in which the heavy atoms are attached to the polymer in a manner that minimizes disruption of side chain crystallinity.

14. The polymer of claim 1 that comprises a recurring unit of the formula (I):

15. The polymer of claim 14 in which Q comprises from about 20 to about 30 carbon atoms.

16. The polymer of claim 14 in which R⁵ is —

CH═

CH—

or —

(CH₂)_a—

;

R⁶ is —

(CH₂)_a—

; and

Q is an ester group comprising from about 10 to about 30 carbon atoms.

17. The polymer of claim 1 that comprises a recurring unit of the formula (II):

18. The polymer of claim 17 in which A³ comprises a metal carboxylate or metal sulfonate.

19. The polymer of claim 18 in which A³ comprises barium.

20. The polymer of claim 17 in which A³ comprises an ester or amide linkage.

21. The polymer of claim 17 in which A³ comprises an aromatic group bearing at least one halogen atom selected from the group consisting of bromine and iodine.

22. The polymer of claim 17 in which A³ comprises a chemical group of the formula —

L₁—

(CH₂)_n2-L₂—

Ar¹, wherein L₁ and L₂ each independently represent a nullity, ester, ether or amide group;

n2 is zero or an integer in the range of about 1 to about 30; and

Ar¹ comprises a halogenated aromatic group containing from about 2 to about 20 carbon atoms.

23. The polymer of claim 17 that comprises a second recurring unit, the second recurring unit comprising at least one of the crystallizable side chains.

24. The polymer of claim 23 in which the second recurring unit is of the formula (III):

25. The polymer of claim 1 that comprises a recurring unit of the formula (IV):

26. The polymer of claim 25 in which A³ comprises an aromatic group bearing at least one halogen atom selected from the group consisting of bromine and iodine.

27. The polymer of claim 25 that comprises a second recurring unit, the second recurring unit comprising at least one of the crystallizable side chains.

28. The polymer of claim 27 in which the second recurring unit is of the formula (V):

29. A medical device that comprises the polymer of claim 1.

30. The medical device of claim 29 that further comprises an effective amount of at least one therapeutic agent.

31. A medical device that comprises a polymeric material, the polymeric material comprising a biocompatible inherently radiopaque side chain crystallizable polymer.

32. The medical device of claim 31 in which the polymeric material comprises a second polymer in admixture with the inherently radiopaque polymer.

33. The medical device of claim 31 in which the inherently radiopaque polymer is bioresorbable.

34. The medical device of claim 31 that is configured to be deliverable to a body cavity of a mammal.

35. The medical device of claim 34 that is configured to be deliverable by injection or by catheter.

36. The medical device of claim 34 that comprises an embolotherapy product, the embolotherapy product comprising at least a portion of the inherently radiopaque polymer.

37. The medical device of claim 36 in which at least a portion of the inherently radiopaque polymer in the embolotherapy product is formed into at least one configuration selected from the group consisting of a rod, a particle, or a sheet.

38. The medical device of claim 37 in which the rod is in the form of a coil.

39. The medical device of claim 38 in which the coil is a memory coil.

40. The medical device of claim 37 in which the particle is selected from the group consisting of a spherical particle, a geometrically non-uniform particle, a porous particle, a hollow particle, a solid particle, and a particle having an excluded diameter of from about 10 microns to about 5,000 microns.

41. The medical device of claim 40 in which the geometrically non-uniform particle is a flake or a chip.

42. The medical device of claim 34 in which the polymeric material has a melting point in the range of about 30°

C. to about 80°

C.

43. The medical device of claim 42 in which the polymeric material is configured to flow at a temperature above the melting point.

44. The medical device of claim 43 in which the polymeric material has a viscosity in the range of about 50 cP to about 500 cP at the temperature above the melting point.

45. The medical device of claim 43 in which the polymeric material has a viscosity in the range of about 500 cP to about 5,000 cP at the temperature above the melting point.

46. The medical device of claim 43 in which the polymeric material has a viscosity in the range of about 5,000 cP to about 250,000 cP at the temperature above the melting point.

47. The medical device of claim 43 in which the polymeric material has a viscosity in the range of about 250,000 cP to about 1,000,000 cP at the temperature above the melting point.

48. The medical device of claim 43 in which the polymeric material comprises a crystalline region and a non-crystalline region at a temperature below the body temperature of the mammal.

49. The medical device of claim 48 in which the non-crystalline region has a glass transition temperature that is higher than the body temperature.

50. The medical device of claim 48 in which the non-crystalline region has a glass transition temperature that is lower than the body temperature.

51. The medical device of claim 43 in which the polymeric material is configured to form a solid mass upon delivery to the body cavity, the solid mass at least partically conforming to an interior dimension of the body cavity.

52. The medical device of claim 51 in which the polymeric material comprises an excipient selected from the group consisting of a photopolymerizable material, a blood reactive substance and a nucleating agent.

53. The medical device of claim 51 in which the solid mass retains a preformed shape.

54. The medical device of claim 53 in which the preformed shape is a coil.

55. The medical device of claim 31 that further comprises an effective amount of at least one therapeutic agent.

56. The medical device of claim 55 in which the therapeutic agent is selected from the group consisting of a chemotherapeutic agent, a non-steroidal anti-inflammatory, a steroidal anti-inflammatory, and a wound healing agent.

57. The medical device of claim 55 in which the therapeutic agent is selected to promote at least one biological response.

58. The medical device of claim 57 in which the biological response is selected from the group consisting of thrombosis, cell attachment, cell proliferation, attraction of inflammatory cells, deposition of matrix proteins, inhibition of thrombosis, inhibition of cell attachment, inhibition of cell proliferation, inhibition of inflammatory cells, and inhibition of deposition of matrix proteins.

59. The medical device of claim 55 in which at least a portion of the therapeutic agent is contained within the polymeric material.

60. The medical device of claim 59 in which at least a portion of the therapeutic agent is releasable from the polymeric material upon heating.

61. The medical device of claim 31 that further comprises an effective amount of at least one magnetic resonance enhancing agent.

62. A method of treatment comprising introducing a medical device into a body cavity of a mammal in an amount that is effective to at least partially occlude the body cavity, wherein the medical device comprises a polymeric material, and wherein the polymeric material comprises a biocompatible inherently radiopaque side chain crystallizable polymer.

63. The method of claim 62 in which the body cavity is selected from the group consisting of a tube, a tubule, a duct, a channel, a foramen, a vessel, a void, and a canal.

64. The method of claim 62 in which the polymeric material has a melting point in the range of about 30°

C. to about 80°

C.

65. The method of claim 64 in which introducing the medical device into the body cavity comprises heating the polymeric material to a temperature that is higher than the melting point.

66. The method of claim 65 in which introducing the medical device into the body cavity comprises cooling the polymeric material to a temperature that is lower than the melting point.

67. The method of claim 66 in which the body cavity is a blood vessel.

68. The method of claim 67 in which the blood vessel is a varicose vein.

69. The method of claim 67 in which introducing the medical device into the blood vessel comprises flowing the polymeric material through a catheter, a syringe, a nozzle or combination thereof.

70. A method for making an inherently radiopaque side chain crystallizable polymer, comprising copolymerizing a first monomer and a second monomer, the first monomer comprising a heavy atom and the second monomer comprising a crystallizable group.

71. The method of claim 70 in which the heavy atom is selected from the group consisting of bromine and iodine.

72. The method of claim 70 in which the crystallizable group comprises from about 6 to about 30 carbon atoms.

73. A method for making an inherently radiopaque side chain crystallizable polymer, comprising reacting a side chain crystallizable polymer with a heavy metal reagent under conditions selected to attach a plurality of heavy atoms to the side chain crystallizable polymer.

74. The method of claim 73 in which the heavy metal reagent comprises bromine.

75. The method of claim 73 in which the heavy metal reagent comprises iodine.