Implantation of encapsulated biological materials for treating diseases

• US 20040136971A1
• Filed: 10/14/2003
• Published: 07/15/2004
• Est. Priority Date: 10/11/2002
• Status: Active Grant

• Current Assignee: Novocell, Inc. (Vertex Pharmaceuticals Incorporated)
• Original Assignee: Novocell, Inc. (Vertex Pharmaceuticals Incorporated)
• Inventors: Yu, Xiaojie, Hubbell, Jeffrey Alan, Latta, Paul, Yue, Chengyun, Scharp, David
• Granted Patent: US 7,427,415 B2
• Time in Patent Office: Days
• US Class Current: 424/93.7
• CPC Class Codes: A61K 2035/126 Immunoprotecting barriers, e.g. jackets, diffusion chambers
• 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: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5036 Polysaccharides, e.g. gums, alginate; Cyclodextrin
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C12N 11/04 entrapped within the carrier, e.g. gel or hollow fibres
• CPC Class Codes: C12N 11/089 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: C12N 2533/30 Synthetic polymers
• CPC Class Codes: C12N 2533/74 Alginate
• CPC Class Codes: C12N 5/0012 Cell encapsulation
• CPC Class Codes: C12N 5/0677 Three-dimensional culture, tissue culture or organ culture; Encapsulated cells

Abstract

The present invention relates to compositions and methods of treating a disease, such as diabetes, by implanting encapsulated biological material into a patient in need of treatment. This invention provides for the placement of biocompatible coating materials around biological materials using photopolymerization while maintaining the pre-encapsulation status of the biological materials. Several methods are presented to accomplish coating several different types of biological materials. The coatings can be placed directly onto the surface of the biological materials or onto the surface of other coating materials that hold the biological materials. The components of the polymerization reactions that produce the coatings can include natural and synthetic polymers, macromers, accelerants, cocatalysts, photoinitiators, and radiation. This invention also provides methods of utilizing these encapsulated biological materials to treat different human and animal diseases or disorders by implanting them into several areas in the body including the subcutaneous site. The coating materials can be manipulated to provide different degrees of biocompatibility, protein diffusivity characteristics, strength, and biodegradability to optimize the delivery of biological materials from the encapsulated implant to the host recipient while protecting the encapsulated biological materials from destruction by the host inflammatory and immune protective mechanisms without requiring long-term anti-inflammatory or anti-immune treatment of the host.

Claims

1. A composition for cellular therapy, comprising:

a plurality of encapsulating devices comprising a polyethylene glycol (PEG) coating, said PEG having a molecular weight between about 900 and about 3,000 Daltons; and

a plurality of cells encapsulated in the encapsulating devices, wherein said composition has a cell density of at least about 100,000 cells/ml.

2. The composition of claim 1, wherein the encapsulating devices are microcapsules.

3. The composition of claim 2, wherein the microcapsules are conformally coated cell aggregates.

4. The composition of claim 3, wherein the cell aggregates are pancreatic islets.

5. The composition of claim 4, wherein the cell density is at least about 6,000,000 cells/ml.

6. The composition of claim 1, where the cell is selected from the group consisting of neurologic, cardiovascular, hepatic, endocrine, skin, hematopoietic, immune, neurosecretory, metabolic, systemic, and genetic.

7. The composition of claim 6, where the cell is selected from the group consisting of autologous, allogeneic, xenogeneic and genetically-modified.

8. The composition of claim 7, where the endocrine cell is an insulin producing cell.

17. A method of using the therapeutic composition of claim 1, comprising implanting said composition into an implantation site in an animal in need of treatment for a disease or disorder.

18. The method of claim 17, where the disease or disorder is selected from the group consisting of neurologic, cardiovascular, hepatic, endocrine, skin, hematopoietic, immune, neurosecretory, metabolic, systemic, and genetic.

19. The method of claim 18, wherein the endocrine disease is diabetes.

20. The method of claim 17, wherein the animal is from an Order of Subclass Theria selected from the group consisting of Artiodactyla, Camivora, Cetacea, Perissodactyla, Primate, Proboscides, and Lagomorpha.

21. The method of claim 20, where the primate is a Human.

22. The method of claim 17, where the implanting is an injection.

23. The method of claim 20, where the implantation site is selected from the group consisting of subcutaneous, intramuscular, intraorgan, arterial/venous vascularity of an organ, cerebro-spinal fluid, and lymphatic fluid.

24. The method of claim 23, where the implantation site is subcutaneous.

25. The method of claim 24, further comprising implanting encapsulated islets in a subcutaneous implantation site.

26. The method of claim 17, further comprising administering an immunosuppressant or anti-inflammatory agent.

27. The method of claim 26, where the immunosuppressant or anti-inflammatory agent is administered for less than 6 months.

28. The method of claim 27, where the immunosuppressant or anti-inflammatory agent is administered for less than 1 month.

9. A therapeutically effective composition comprising a plurality of encapsulating devices having an average diameter of less than 400 μ

m, said encapsulating devices comprising encapsulated cells in an encapsulation material, wherein the composition comprises at least about 500,000 cells/ml.

10. The therapeutically effective composition of claim 9, wherein the average diameter of the encapsulating device is less than 300 micron.

11. The therapeutically effective composition of claim 9, wherein the average diameter of the encapsulating device is less than 200 micron.

12. The therapeutically effective composition of claim 9, wherein the average diameter of the encapsulating device is less than 100 micron.

13. The therapeutically effective composition of claim 9, wherein the average diameter of the encapsulating device is less than 50 micron.

29. A method of using the therapeutic composition of claim 9, comprising implanting said composition into an implantation site in an animal in need of treatment for a disease or disorder.

30. The method of claim 29, where the disease or disorder is selected from the group consisting of neurologic, cardiovascular, hepatic, endocrine, skin, hematopoietic, immune, neurosecretory, metabolic, systemic, and genetic.

31. The method of claim 30, wherein the endocrine disease is diabetes.

32. The method of claim 29, wherein the animal is from an Order of Subclass Theria selected from the group consisting of Artiodactyla, Carnivora, Cetacea, Perissodactyla, Primate, Proboscides, and Lagomorpha.

33. The method of claim 32, where the primate is a Human.

34. The method of claim 29, where the implantation is an injection.

35. The method of claim 29, where the implantation site is selected from the group consisting of subcutaneous, intramuscular, intraorgan, arterial/venous vascularity of an organ, cerebro-spinal fluid, and lymphatic fluid.

36. The method of claim 35, where the implantation site is subcutaneous.

37. The method of claim 36, further comprising implanting encapsulated islets in a subcutaneous implantation site.

38. The method of claim 29, further comprising administering an immunosuppressant or anti-inflammatory agent.

39. The method of claim 38, where the immunosuppressant or anti-inflammatory agent is administered for less than 6 months.

40. The method of claim 39, where the immunosuppressant or anti-inflammatory agent is administered for less than 1 month.

14. A therapeutically effective composition comprising a plurality of encapsulating devices having an average diameter of less than 400 μ

m, said encapsulating devices comprising encapsulated cells in an encapsulation material, wherein the composition comprises a ratio of volume of encapsulating device to volume of cells of less than about 20;

1.

15. The therapeutically effective composition of claim 14, wherein the composition comprises a ratio of volume of encapsulating device to volume of cells of less than about 10:

1.

16. The therapeutically effective composition of claim 14, wherein the composition comprises a ratio of volume of encapsulating device to volume of cells of less than about 2:

1.

41. A method of encapsulating a biological material comprising:

a) adding a solution comprising a first buffer to the biological material;

b) centrifuging the biological material to form a pelleted biological material;

c) removing supernatant;

d) adding a solution comprising a photoinitiator dye conjugated to a cell adsorbing material to the pelleted biological material;

e) resuspending and incubating the pelleted biological material with the solution comprising the photoinitiator dye conjugated to the cell adsorbing material for an effective amount of time;

f) centrifugating mixture;

g) removing the solution comprising the photoinitiator dye conjugated to the cell adsorbing material;

h) resuspending the pelleted biological material with a second solution comprising a second buffer;

i) centrifugating and removing the second buffer;

j) resuspending and mixing the biological material with a photoactive polymer solution; and

k) irradiating the resuspended biological material with a photoactive polymer solution with an energy source to form an encapsulated biological material.

42. The method of claim 41, where the cell adsorbing material is a polycationic polymer.

43. The method of claim 42, where the polycationic polymer is a PAMAM Dendrimer.

44. The method of claim 42, where the polycationic polymer is poly(ethyleneimine).

45. The method of claim 41, wherein the biological material is an organ, tissue or cell.

46. The method of claim 45, wherein the tissue is a cluster of insulin producing cells.

47. The method of claim 46, wherein the cell is an insulin producing cell.

48. The method of claim 41, wherein the encapsulated biological material is a PEG conformal coated islet allograft.

49. The method of claim 41, wherein the first and second buffer is 1 to 200 mM.

50. The method of claim 49, wherein the first and second buffer is 10 to 50 mM.

51. The method of claim 50, wherein the first and second buffer is 20 mM.

52. The method of claim 41, wherein the photoinitiator is selected from the group consisting of carboxyeosin, ethyl eosin, eosin Y, fluorescein, 2,2-dimethoxy, 2-phenylacetophenone, 2-methoxy, 2-phenylacetophenono, camphorquinone, rose bengal, methylene blue, erythrosin, phloxine, thionine, riboflavin and methylene green.

53. The method of claim 52, wherein the photoinitiator is carboxyeosin.

54. The method of claim 41, where the photoactive polymer solution comprises a polymerizable high density ethylenically unsaturated PEG and a sulfonated comonomer.

55. The method of claim 54, where the polymerizable high density ethylenically unsaturated PEG is a polymerizable high density acrylated PEG.

56. The method of claim 55, where the polymerizable high density acrylated PEG has a molecular weight of 1.1 kD.

57. The method of claim 54, where the sulfonated comonomer is selected from the group consisting of 2-acrylamido-2-methyl-1-propanesulfonic acid, vinylsulfonic acid, 4-styrenesulfonic acid, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylate, and n-vinyl maleimide sulfonate.

58. The method of claim 57, where the sulfonated comonomer is 2-acrylamido-2-methyl-1-propanesulfonic acid.

59. The method of claim 54, wherein the photoactive polymer solution further comprises a cocatalyst selected from the group consisting of triethanolamine, triethylamine, ethanolamine, N-methyl diethanolamine, N,N-dimethyl benzylamine, dibenzyl amino, N-benzyl ethanolamine, N-isopropyl benzylamine, tetramethyl ethylenediamine, potassium persulfate, tetramethyl ethylenediamine, lysine, ornithine, histidine and arginine.

60. The method of claim 59, where the cocatalyst is triethanolamine.

61. The method of claim 54, wherein the photoactive polymer solution further comprises an accelerator selected from the group consisting of N-vinyl pyrrolidinone, 2-vinyl pyridine, 1-vinyl imidazole, 9-vinyl carbazone, 9-vinyl carbozol, acrylic acid, n-vinylcarpolactam, 2-allyl-2-methyl-1,3-cyclopentane dione, and 2-hydroxyethyl acrylate.

62. The method of claim 61, where the accelerator is N-vinyl pyrrolidinone.

63. The method of claim 54, wherein the photoactive polymer solution further comprises a viscosity enhancer selected from the group consisting of natural and synthetic polymers.

64. The method of claim 63, where the viscosity enhancer is selected from the group consisting of 3.5 kD PEG-triol and 4 kD PEG-diol.

65. The method of claim 54, wherein the photoactive polymer solution further comprises a density adjusting agent.

66. The method of claim 65, where the density adjusting agent is selected from the group consisting of Nycodenz and Ficoll.

67. The method of claim 54, wherein the photoactive polymer solution further comprises a “

Good”

buffer.

68. The method of claim 67, where the “

Good”

buffer is selected from the group consisting of HEPES and MOPS.

69. The method of claim 68, where the “

Good”

buffer is MOPS.

70. The method of claim 54, where the energy source is an Argon laser.

71. The method of claim 41, where the biological material is selected from the group consisting of neurologic, cardiovascular, hepatic, endocrine, skin, hematopoietic, immune, neurosecretory, metabolic, systemic, and genetic.

72. The method of claim 41, where the biological material is from an animal of Subclass Theria of Class Mammalia.

73. The method of claim 72, where the animal is from an Order of Subclass Theria selected from the group consisting of Artiodactyla, Camivora, Cetacea, Perissodactyla, Primate, Proboscides, and Lagomorpha.

74. The method of claim 73, where the primate is a Human.

75. A composition for encapsulating biological material comprising a polymerizable high density ethylenically unsaturated PEG having a molecular weight between 900 and 3,000 Daltons, and a sulfonated comonomer.

76. The composition of claim 75, where the polymerizable high density ethylenically unsaturated PEG is a high density acrylated PEG.

77. The composition of claim 76, where the polymerizable high density acrylated PEG has a molecular weight of 1.1 kD.

78. The composition of claim 75, where the sulfonated comonomer is selected from the group consisting of 2-acrylamido-2-methyl-1-propanesulfonic acid, vinylsulfonic acid, 4-styrenesulfonic acid, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylate, and n-vinyl maleimide sulfonate.

79. The composition of claim 78, where the sulfonated comonomer is 2-acrylamido-2-methyl-1-propanesulfonic acid.

80. The composition of claim 75, further comprising a cocatalyst selected from the group consisting of triethanolamine, triethylamine, ethanolamine, N-methyl diethanolamine, N,N-dimethyl benzylamine, dibenzyl amino, N-benzyl ethanolamine, N-isopropyl benzylamine, tetramethyl ethylenediamine, potassium persulfate, tetramethyl ethylenediamine, lysine, omithine, histidine and arginine.

81. The composition of claim 80, where the cocatalyst is triethanolamine.

82. The composition of claim 75, further comprising an accelerator selected from the group consisting of N-vinyl pyrrolidinone, 2-vinyl pyridine, 1-vinyl imidazole, 9-vinyl carbazone, 9-vinyl carbozol, acrylic acid, n-vinylcarpolactam, 2-allyl-2-methyl-1,3-cyclopentane dione, and 2-hydroxyethyl acrylate.

83. The composition of claim 82, where the accelerator is N-vinyl pyrrolidinone.

84. The composition of claim 75, wherein the composition is biocompatible with a score of at least about a “

2”

.

85. The composition of claim 84, wherein the composition is biocompatible in a mammal.

86. The composition of claim 85, wherein the composition is biocompatible in a sub-human primate.

87. The composition of claim 86, wherein the composition is biocompatible in a human.

88. The composition of claim 75, wherein the composition has the quality of permselectivity.

89. The composition of claim 88, wherein the permselectivity can be engineered by manipulating the composition.

90. The composition of claim 75, wherein the composition has an allowance of cell functionality with a score of at least about a “

2”

.

91. The composition of claim 90, wherein the composition has the allowance of cell functionality in a mammal.

92. The composition of claim 91, wherein the composition has the allowance of cell functionality in a sub-human primate.

93. The composition of claim 92, wherein the composition has the allowance of cell functionality in a human.

94. The composition of claim 75, which is biodegradable.

95. The composition of claim 94, which is biodegradable in a mammal.

96. The composition of claim 95, which is biodegradable in a sub-human primate.

97. The composition of claim 96, which is biodegradable in a human.