Inherently radiopaque polymeric products for embolotherapy

• US 20050106119A1
• Filed: 09/27/2004
• Published: 05/19/2005
• Est. Priority Date: 09/25/2003
• Status: Active Grant

• Current Assignee: Rutgers University
• Original Assignee: Rutgers University
• Inventors: Bolikal, Durgadas, Zeltinger, Joan, Kohn, Joachim B., Schmid, Eric, Brandom, Donald K.
• Granted Patent: US 8,685,367 B2
• Time in Patent Office: Days
• US Class Current: 424/78.80
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61K 49/0442 Polymeric X-ray contrast-enhancing agent comprising a halogenated group
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 9/10 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

Abstract

Preferred embodiments relate to compositions of inherently radiopaque, biocompatible, bioresorbable polymeric particles and methods of using them for embolizing a body lumen.

Claims

1. An embolotherapy product, comprising a particulate formulation comprising a biocompatible, bioresorbable polymer, and optionally including stereoisomers thereof, wherein the polymer comprises a sufficient number of halogen atoms to render the embolotherapy product inherently radiopaque.

2. The embolotherapy product of claim 1, wherein said polymer further comprises a homopolymer, a heteropolymer, or a blend thereof.

3. The embolotherapy product of claim 1, wherein said polymer comprises one or more units described by Formula I:

4. The embolotherapy product of claim 3, wherein R and R₂ are selected from the groups:

5. The embolotherapy product of claim 1, wherein said polymer comprises one or more units described by Formula II:

6. The embolotherapy product of claim 5, wherein all X groups are ortho-directed and Y is 1 or 2

7. The embolotherapy product of claim 5, wherein R₄ is an alkyl group.

8. The embolotherapy product of claim 7, wherein R₄ has the structure:

9. The embolotherapy product of claim 8, wherein R₉ for at least one unit comprises a pendant —

COOR₁ group, wherein, for each unit in which it is present, the subgroup R₁ is independently a hydrogen or an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N.

10. The embolotherapy product of claim 8, wherein each R₉ independently has the structure:

11. The embolotherapy product of claim 8, wherein each R₉ independently has the structure:

12. The embolotherapy product of claim 8, wherein each R₉ independently has the structure:

13. The embolotherapy product of claims 3-12, wherein said polymer is copolymerized with a poly(C₁-C₄ alkylene glycol).

14. The embolotherapy product of claim 13, wherein said poly(C₁-C₄ alkylene glycol) is present in a weight fraction of less than about 75 wt %.

15. The embolotherapy product of claim 14, wherein said poly(alkylene glycol) is poly(ethylene glycol).

16. The embolotherapy product of claim 13, wherein between about 0.01 and about 0.99 percent of said polymer units comprise a pendant —

COOH group.

17. The embolotherapy product of claim 5, wherein R₄ is an aryl or alkylaryl group.

18. The embolotherapy product of claim 17, wherein the R₄ aryl or alkylaryl group is selected so that the polymer units are diphenols.

19. The embolotherapy product of claim 1, wherein said polymer comprises one or more units described by Formula III:

20. The embolotherapy product of claim 19, wherein all X groups are ortho-directed.

21. The embolotherapy product of claim 19, wherein Y1 and Y2 are independently 2 or less, and Y1+Y2=1, 2, 3 or 4.

22. The embolotherapy product of claim 19, wherein R₂ for at least one unit comprises a pendant —

COOR₁ group, wherein, for each unit in which said —

COOR₁ group is present, the subgroup R₁ is independently a hydrogen or an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N.

23. The embolotherapy product of claim 19, wherein each R₂ independently has the structure:

24. The embolotherapy product of claim 19, wherein each R₂ independently has the structure:

25. The embolotherapy product of claim 19, wherein each R₂ independently has the structure:

26. The embolotherapy product of claim 19, wherein between about 0.01 and about 0.99 percent of said polymer units comprise a pendant —

COOH group.

27. The embolotherapy product of claim 19, wherein said polymer is copolymerized with up to 75 wt % of a poly(C₁-C₄ alkylene glycol).

28. The embolotherapy product of claim 27, wherein said poly(C₁-C₄ alkylene glycol) is poly(ethylene glycol).

29. The embolotherapy product of claim 1, wherein said polymer comprises one or more units described by Formula IV:

30. The embolotherapy product of claim 29, wherein P is a poly(ethylene glycol) that is present in a weight fraction of about 50% or less.

31. The embolotherapy product of claim 29, wherein P is a poly(ethylene glycol) that is present in a weight fraction of about 30% or less.

32. The embolotherapy product of claim 29, wherein both R and R₂ comprise a pendant COOR₁ group;

wherein for R, the subgroup R₁ is independently an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N; and

wherein for R₂, the subgroup R₁ is a hydrogen atom.

33. The embolotherapy product of claim 29, wherein each R and R₂ independently has the structure:

34. The embolotherapy product of claim 29, wherein each R₂ independently has the structure:

35. The embolotherapy product of claim 29, wherein each R₂ independently has the structure:

36. The embolotherapy product of claims 34 or 35, wherein each R₁ subgroup for R of said polymer is either ethyl or butyl.

37. The embolotherapy product of claim 29, wherein A of said polymer is a —

C(═

O)—

group.

38. The embolotherapy product of claim 29, wherein A of said polymer is:

39. The embolotherapy product of claim 38, wherein R₃ is selected so that A is a moiety of a dicarboxylic acid that is a naturally occurring metabolite.

40. The embolotherapy product of claim 38, wherein R₃ of said polymer is a moiety selected from the group consisting of —

CH₂—

C(═

O)—

, —

CH₂—

CH₂—

C(═

O)—

, —

CH═

CH— and

(—

CH₂—

)_z, wherein z is an integer from 1 to 8, inclusive.

41. The embolotherapy product of claim 29, wherein all X groups are ortho-directed.

42. The embolotherapy product of claim 29, wherein Y1 and Y2 are independently 2 or less, and Y1+Y2=1, 2, 3 or 4.

43. The embolotherapy product of claim 42, wherein all X groups are iodine.

44. The embolotherapy product of claim 29, wherein f is greater than 0.1 to about 0.3.

45. The embolotherapy product of claim 44, wherein f is greater than 0.2 to about 0.25.

46. The embolotherapy product of claim 29, wherein said poly(C₁-C₄ alkylene glycol) weight fraction is less than about 25 wt %.

47. The embolotherapy product of claim 29, wherein g is greater than about 0.1 to about 0.35.

48. The embolotherapy product of claim 47, wherein g is greater than about 0.2 to about 0.3.

49. The embolotherapy product of claim 1, wherein the polymer comprises one or more units of Formula V:

50. The embolotherapy product of claim 49, wherein P is a poly(ethylene glycol) unit.

51. The embolotherapy product of claim 49, wherein each R₄ and R₆ of said polymer contains a pendant —

COOR₁ group, wherein for each R₆, each subgroup R₁ is independently an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from the group consisting of O and N, and, for each R₄, each subgroup R₁ is a hydrogen atom.

52. The embolotherapy product of claim 49, wherein each R₄ and R₆ of said polymer are:

53. The embolotherapy product of claim 52, wherein each R₁ subgroup for R₄ of said polymer is either ethyl or butyl.

54. The embolotherapy product of claim 49, wherein A is a —

C(═

O)—

group.

55. The embolotherapy product of claim 49, wherein A is:

56. The embolotherapy product of claim 49, wherein R₃ is selected so that A is a moiety of a dicarboxylic acid that is a naturally occurring metabolite.

57. The embolotherapy product of claim 56, wherein R₃ of said polymer is a moiety selected from the group consisting of —

CH₂—

C(═

O)—

, —

CH₂—

CH₂—

C(═

O)—

, —

CH═

CH— and

(—

CH₂—

)_z, wherein z is an integer from 1 to 8, inclusive.

58. The embolotherapy product of claim 49, wherein all X groups are ortho-directed and y is 2 or 3.

59. The embolotherapy product of claim 58, wherein every X group is iodine.

60. The embolotherapy product of claim 49, wherein f is greater than about 0.1 to about 0.3.

61. The embolotherapy product of claim 49, wherein g is greater than about 0.1 to about 0.35.

62. The embolotherapy product of claim 1, wherein the particulate formulation is configured for administration via injection.

63. The embolotherapy product of claim 1, wherein said formulation comprises polymer particles selected from the group consisting of spherical particles, geometrically non-uniform particles, porous particles, hollow particles, solid particles, and particles having an excluded diameter of from about 10 microns to about 5,000 microns, and combinations thereof.

64. The embolotherapy product of claim 1, wherein the formulation comprises a polymer hydrogel composition.

65. The embolotherapy product of claim 1, wherein said polymer further comprises an effective amount of at least one therapeutic agent.

66. The embolotherapy product of claim 65, wherein said at least one therapeutic agent is selected from the group consisting of a chemotherapeutic agent, a non-steroidal anti-inflammatory, or a steroidal anti-inflammatory.

67. The embolotherapy product of claim 1, wherein the particulate formulation further comprises an effective amount of a magnetic resonance enhancing agent.

68. The embolotherapy product of claim 1, wherein the particulate formulation further comprises an effective amount of a radiopacifying agent, selected from the group consisting of iodine, bromine, barium, bismuth, gold, platinum, tantalum, tungsten, and mixtures thereof.

69. The embolotherapy product of claim 1, wherein the particulate formulation further comprises a biocompatible, bioresorbable polymeric coating adapted to promote a selected biological response.

70. The embolotherapy product of claim 69, wherein the biological response is selected from the group consisting of thrombosis, cell attachment, cell proliferation, attraction of inflammatory cells, and 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 or a combination thereof.

72. A method of embolizing a body lumen, comprising introducing into the body lumen an effective amount of the embolotherapy product of claim 1.

73. The method of claim 72, wherein said introducing is accomplished by injection via either a catheter or syringe.

74. A method of treating varicose and/or spider veins, comprising administering within said varicose and/or spider veins an effective amount of the embolotherapy product of claim 1.

75. The method of claim 74, wherein said administering is accomplished by injection via either a catheter or syringe.

76. A method for enhancing the local delivery of a therapeutic agent to a tissue, comprising the steps of:

administering to a blood vessel associated with said tissue an amount of the embolotherapy product of claim 1 sufficient to reduce the blood flow from said tissue;

administering the therapeutic agent to said blood vessel separately or in combination with the embolotherapy product, such that the local delivery of the therapeutic agent is enhanced; and

repeating said steps of administering said embolotherapy product and therapeutic agent after the embolotherapy product first administered has degraded sufficiently to allow for re-access to said blood vessel.

77. A method for re-treatment of a body lumen, comprising the steps of:

administering to a region of a blood vessel associated with said tissue an amount of the embolotherapy product of claim 1 sufficient to reduce the blood flow from said tissue for a period of time; and

administering at a later time any embolotherapy product, to the same approximate region of the blood vessel associated with said tissue such that the said tissue may be re-treated or allow for other forms of re-intervention.

78. The embolotherapy product of claim 1, wherein said polymer comprises a bioresorbable inherently radiopaque polymer that is not naturally occurring.

79. The embolotherapy product of claim 1, wherein said polymer comprises a bioresorbable inherently radiopaque polymer comprising at least one amino acid.

71. An embolotherapy product, comprising a particulate formulation comprising Formula I: