Method for restoring a damaged or degenerated intervertebral disc

• US 20040091540A1
• Filed: 12/15/2003
• Published: 05/13/2004
• Est. Priority Date: 11/15/2000
• Status: Abandoned Application

• Current Assignee: Piramal Healthcare Limited (Piramal Enterprises Limited)
• Original Assignee: Piramal Healthcare Limited (Piramal Enterprises Limited)
• Inventors: Berrada, Mohammed, Chaput, Cyril, Chenite, Abdellatif, Desrosiers, Eric Andre
• Application Number:
  US10/416,947
• Publication Number:
  US 20040091540A1
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61F 2002/30677 Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
• CPC Class Codes: A61F 2002/444 for replacing the nucleus pulposus
• CPC Class Codes: A61F 2002/4445 Means for culturing intervertebral disc tissue
• CPC Class Codes: A61F 2002/445 Intervertebral disc tissue harvest sites
• 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 31/722 Chitin, chitosan
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 31/737 Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate A61K31/727 takes precedence
• CPC Class Codes: A61K 31/765 Polymers containing oxygen
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 2300/64 Animal cells
• CPC Class Codes: A61L 2430/38 for reconstruction of the spine, vertebrae or intervertebral discs
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders

Abstract

The present invention relates to a minimally-invasive method for restoring a damaged or degenerated intervertebral disc at an early stage. The method comprises the step of administering an injectable in situ setting formulation in the nucleus pulposus of the damaged or degenerated disc of a patient. The formulation once injected combines with nucleus matters and host cells, and becomes viscous or gels in situ within the annulus fibrosus of the disc for increasing the thickness and volume of the damaged or degenerated disc. The formulation is retained within the disc for providing restoration of the damaged or degenerated disc.

Claims

1. A method for restoring a damaged or degenerated intervertebral disc, said method comprising the step of:

a) administering percutaneously an injectable in situ setting formulation in the nucleus pulposus of the damaged or degenerated disc of a patient for increasing the thickness of the damaged or degenerated disc, said solution becoming viscous pasty or turning into a gel or solid in situ within the disc, is retained within the annulus fibrosus of the disc for providing restoration of the damaged or degenerated disc.

2. The method of claim 1, wherein said injectable in situ setting formulation once administered mixes and combines in situ nucleus matters and host cells.

3. The method of claim 1, wherein said injectable in situ setting formulation turns into a gel in situ.

4. The method of claim 1, wherein said injectable in situ setting formulation is a thermogelling solution.

5. The method of claim 1, wherein said injectable in situ setting formulation comprises an in situ self-gelling cellulosic, polysaccharide or/and polypeptidic aqueous solution.

6. The method of claim 1, wherein said injectable in situ setting formulation comprises a thermogelling cellulosic, polysaccharide or/and polypeptidic aqueous solution.

7. The method of claim 1, wherein said injectable in situ setting formulation comprises a thermogelling aqueous solution containing at least chitosan.

8. The method of claim 1, wherein said injectable in situ setting formulation comprises a thermogelling aqueous solution containing-at least one phosphate salt.

9. The method of claim 1, wherein said injectable in situ setting formulation comprises a polymeric aqueous solution covalently crosslinkable into an aqueous gel in situ.

10. The method of claim 1, wherein said injectable in situ setting formulation contains chondroitin sulfate, or hyaluronic acid, or poly(ethylene glycol), or a derivative thereof.

11. The method of claim 1, wherein said injectable in situ setting formulation comprises:

a) 0.1 to 5.0% by weight of a water soluble cellulosic, polysaccharide or polypeptidic or a derivative thereof, or a mixture thereof; and

b) i) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group comprising mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar;

or ii) 1.0 to 20% by weight of a salt selected from the group comprising phosphate, carbonate, sulfate, sulfonate, and the like.

wherein said solution has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 20 to 70°

C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.

12. The method of claim 1, wherein said injectable in situ setting formulation comprises:

a) 0.1 to 5.0% by weight of chitosan or collagen or a derivative thereof, or a mixture thereof; and

b) i) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar;

ii) 1.0 to 20% by weight of a salt selected from the group comprising phosphate, carbonate, sulfate, sulfonate, and the like;

wherein said solution has a pH ranging from 6.5to 7.4, and turns into a gel within a temperature range from 20 to 70°

C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.

13. The method of claim 1, wherein said injectable in situ setting formulation comprises:

a) 0.1 to 5.0% by weight of chitosan or collagen or a derivative thereof, or a mixture thereof; and

b) i) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar;

or ii) 1.0 to 20% by weight of a salt selected from the group comprising phosphate, carbonate, sulfate, sulfonate, and the like; and

d) 0.01 to 10% by weight of a water-soluble chemically reactive organic compound;

wherein said formulation has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 4 to 70°

C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.

14. The method of claim 11, 12 or 13, wherein, said salt is a mono-phosphate dibasic salt of glycerol selected from the group consisting of glycerol-2-phosphate, sn-glycerol 3-phosphate and L-glycerol-3-phosphate salts.

15. The method of claim 11, 12 or 13, wherein said salt is a mono-phosphate dibasic salt and said polyol is selected from the group consisting of histidinol, acetol, diethylstilbestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, and glucitol or a mixture thereof.

16. The method of claim 11, 12 or 13, wherein said salt is a mono-phosphate dibasic salt and said sugar is selected from the group consisting of fructose, galactose, ribose, glucose, xylose, rhamnulose, sorbose, erythrulose, deoxy-ribose, ketose, mannose, arabinose, fuculose, fructopyranose, ketoglucose, sedoheptulose, trehalose, tagatose, sucrose, allose, threose, xylulose, hexose, methylthio-ribose, and methylthio-deoxy-ribulose, or a mixture thereof.

17. The method of claim 11, 12 or 13, wherein said salt is a mono-phosphate dibasic salt and said polyol is selected from the group consisting of palmitoyl-glycerol, linoleoyl-glycerol, oleoyl-glycerol, and arachidonoyl-glycerol, or a mixture thereof.

18. The method of claim 11, 12 or 13, wherein said formulation comprises an aqueous solution selected from the group consisting of chitosan-β

-glycerophosphate, chitosan-α

-glycerophosphate, chitosan-glucose-1-glycero-phosphate, and chitosan-fructose-6-glycerophosphate.

19. The method of claim 11, 12 or 13, wherein said formulation comprises methyl-cellulose, hydroxyethyl-cellulose, hydroxypropyl-methylcellulose, or the like, or a mixture thereof.

20. The method of claim 1, wherein said injectable formulation comprises a biocompatible physiologically safe polymer.

21. The method of claim 20, wherein said polymer is polymerized or covalently crosslinked after being injected in situ.

22. The method of claim 1, wherein said injectable formulation is a dispersion comprising a nonsoluble solid component.

23. The method of claim 22, wherein said nonsoluble solid component comprises microparticles, microbeads, microspheres or granules.

24. The method of claim 1, wherein said injectable in situ setting formulation is nonaqueous and comprises an organic solvent.

25. The method of any one of claims 1 to 24, wherein said injectable in situ setting formulation comprises at least one fatty acid, said fatty acid being selected from the group consisting of oleate, palmitate, myristate, stearate, palmitoleate, and vaccenate, or the like, or a derivative thereof.

26. The method of any one of claims 1 to 24, wherein the fatty acid is mixed with a metabolically absorbable solvent or liquid vehicle to reduce viscosity and allow injectability.

27. The method of claims 1, wherein said formulation contains at least one bioactive agent or drug.

28. The method of claim 27, wherein said bioactive agent or drug is a cell stimulant.

29. The method of claim 28, wherein the cell stimulant is selected from the group consisting of growth factors and cytokines.

30. The method of claim 1, wherein the injectable formulation comprises living tissue cells prior to administration.

31. The method of any one of claims 1 to 30, wherein the injectable formulation comprises living tissue cells adhered onto a solid substrate.

32. The method of claim 1, wherein the injectable formulation is flowable, but has a viscosity above 10 mpa.s at the time of administration.

33. The method of claim 1, wherein the nucleus pulposus is excised prior to administering the formulation.

34. The method of claim 1, wherein the restoration of the, degenerated or damaged intervertebral disc provides a more biomechanically stable spine.

35. A nucleus pulposus formulation comprising at least one fatty acid, wherein said formulation forms a solid material in situ, said material allowing to increase the thickness of a damaged or degenerated disc, said solution being retained within the annulus fibrosus of the disc for providing restoration of the damaged or degenerated disc.

36. The nucleus pulposus formulation of claim 35, wherein the fatty acid is selected from the group consisting of oleate, palmitate, myristate, stearate, palmitoleate, and vaccenate, or the like, or a derivative thereof.

37. The nucleus pulposus formulation of claim 35, wherein said formulation comprises a metabolically absorbable solvent.

38. The nucleus pulposus formulation of claim 37, wherein said metabolically absorbable solvent is selected from the group consisting of water, triacetin, alcohol, glycerol, and lactate based solvent, or the like.

39. A nucleus pulposus formulation comprising:

a) 0.1 to 5.0% by weight of a water-soluble polymer selected from the group consisting of cellulosic, polysaccharide and polypeptidic, and

b) 1.0 to 20% by weight of a water-soluble salt selected from the group consisting of phosphate, glycerol-phosphate, glucose-phosphate, and fructose phosphate, or the like,

wherein said formulation has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 20 to 70°

C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.

43. The nucleus pulposus formulation of any one of claims 39 to 42;

wherein said formulation comprises 0.1 to 3.0% of a chitosan, and 1.0 to 10% of a water-soluble phosphate salt, wherein said formulation has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 20 to 40°

C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.

44. The nucleus pulposus formulation of any one of claims 39 to 41, wherein said formulation comprises 0.1 to 3.0% of a chitosan, and 1.0 to 10% of a water-soluble phosphate salt, and 0.01 to 5% of a water-soluble chemically reactive organic compounds, wherein said formulation has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 20 to 40°

C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.

45. The nucleus pulposus formulation of claims 39, wherein said polymer is a methyl-cellulose, a hydroxyethyl-cellulose, a hydroxypropyl-cellulose, a hydroxypropyl methylcellulose, a chitosan or a collagen, or a mixture thereof.

46. The nucleus pulposus formulation of claims 39, wherein said salt is a sodium or magnesium salt.

49. The nucleus pulposus formulation of claim 43 or 44, wherein said water-soluble phosphate salt is a dibasic phosphate salt.

50. The nucleus pulposus formulation of claim 49, wherein said phosphate salt is selected from the group consisting of sodium phosphate and magnesium phosphate or the like.

51. The nucleus pulposus formulation of claim 44, wherein said water-soluble chemically reactive organic compound is reactive toward free amine groups.

52. The nucleus pulposus formulation of claim 44, wherein said water-soluble chemically reactive organic compound is a functionalized poly(ethylene glycol).

53. The nucleus pulposus formulation of claim 44, wherein said water-soluble chemically reactive organic compound is a monofunctional methoxy-poly(ethylene glycol).

54. The nucleus pulposus formulation of claim 44, wherein said water-soluble chemically reactive organic compound is a multifunctional poly(ethylene glycol).

55. The nucleus pulposus formulation of claim 44, wherein said water-soluble chemically reactive organic compound is selected from the group consisting of aldehyde, anhydride acid, azide, azolide, carboimide, carboxylic acid, epoxide, esters, glycidyl ether, halide, imidazole, imidate, succinimide, succinimidyl ester, acrylate and methacrylate, or a mixture thereof.

56. Use of a formulation as defined in any one of claims 39 to 44, for restoring a damaged or degenerated intervertebral disk.

57. The use of claim 56, wherein said nucleus pulposus formulation further comprises a nonsoluble particulate material.

58. The use of claim 57, wherein said nucleus pulposus formulation further comprises a biodegradable organic particulate material.

59. The use of claim 58, wherein said biodegradable organic particulate material is made of an absorbable polymer.

60. The use of claim 59, wherein said absorbable polymer is selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic), poly(lactones), poly(orthoesters), poly(anhydrides), and poly(carbonates), or the like.

61. The use of claim 58, wherein said biodegradable organic particulate material is made of gelatin, collagen, or the like.

62. The use of claim 57, wherein said nucleus pulposus formulation further comprises an inorganic or mineral particulate material.

63. The use of claim 62, wherein said inorganic or mineral particulate material is selected from the group consisting of bioglass, calcium phosphate, and calcium carbonate, or the like.

64. The use of claim 56, wherein said nucleus pulposus formulation further comprises cells.

65. The use of claim 64, wherein said cells are autologous.

66. The use of claim 64, wherein said cells are modified.

67. The use of claim 64, wherein said cells are stem cells or chondrocytes.

68. The use of claim 56, wherein said nucleus pulposus formulation further comprises a bioactive or pharmaceutical agent.

69. The use of claim 68, wherein said bioactive or pharmaceutical agent is a cell stimulant, a cell preservative, or a cell differentiation factor.

70. The use of claim 68, wherein said bioactive or pharmaceutical agent is a cytokine or a growth factor.

71. The use of claim 68, wherein said bioactive or pharmaceutical agent is an anti-pain or anti-inflammation drug.

72. The use of claim 56, wherein said nucleus pulposus formulation mixes with biochemicals and living matters in situ.

73. The use of claim 56, wherein said nucleus pulposus formulation forms a viscous, gel, pasty or solid material in situ.

74. The use of claim 56, wherein said nucleus pulposus formulation has a viscosity above 10 mPa.s at the time of administration.

75. The use of claim 56, for decompressing the injected. intervertebral disc.

76. The use of claim 56, for stabilizing the spine of a patient.

40. A nucleus pulposus formulation comprising:

a) 0.1 to 5.0% by weight of a water soluble cellulosic, polysaccharide or polypeptidic or a derivative thereof, or a mixture thereof; and

b) i) 1.0 to 20% by weight of a salt of polyol or sugar selected from. the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar;

or ii) 1.0 to 20% by weight of a salt selected from the group consisting of phosphate, carbonate, sulfate, and sulfonate, or the like.

wherein said formulation has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 20 to 70°

C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.

47. The nucleus pulposus formulation of any one of claims 40 to 42, wherein said formulation comprises a mono-phosphate dibasic salt.

48. The nucleus pulposus formulation of any one of claims 40 to 42, wherein said formulation comprises a glycerophosphate salt.

41. A nucleus pulposus formulation comprising:

a) 0.1 to 5.0% by weight of chitosan or collagen or a derivative thereof, or a mixture thereof; and

b) i) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar;

or ii) 1.0 to 20% by weight of a salt selected from the group consisting of phosphate, carbonate, sulfate, and sulfonate, or the like;

wherein said formulation has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 20 to 70°

C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.

42. A nucleus pulposus formulation comprising:

a) 0.1 to 5.0% by weight of chitosan or collagen or a derivative thereof, or a mixture thereof; and

b) i) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar;

or ii) 1.0 to 20% by weight of a salt selected from the group consisting of phosphate, carbonate, sulfate, and sulfonate, or the like; and

c) 0.01 to 10% by weight of a water-soluble chemically reactive organic compound;

wherein said formulation has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 4 to 70°

C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.