Implantation of encapsulated biological materials for treating diseases

• US 7,427,415 B2
• Filed: 10/14/2003
• Issued: 09/23/2008
• Est. Priority Date: 10/11/2002
• Status: Expired due to Fees

• 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
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US10/684,859
• Publication Number:
  US 20040136971A1
• Time in Patent Office: 1,806 Days
• Field of Search: None
• US Class Current: 424/497
• 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 thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• 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 comprising:

encapsulating devices comprising a conformal coating, and

cell aggregates,

wherein said composition has a cell density of at least about 100,000 cells/ml, wherein the conformal coating for the encapsulating devices comprises a polymerizable high density ethylenically unsaturated PEG having a molecular weight between 900 and 3,000 Daltons, and a sulfonated comonomer, and wherein the coating conforms to the size and shape of the cell aggregates.

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. The composition of any one of claims 1, 9, or 14, where the polymerizable high density ethylenically unsaturated PEG is a high density acrylated PEG.

18. The composition of claim 17, where the polymerizable high density acrylated PEG has a molecular weight of 1.1 kD.

19. The composition of any one of claims 1, 9, or 14, 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.

20. The composition of claim 19, where the sulfonated comonomer is 2-acrylamido-2-methyl-1-propanesulfonic acid.

21. The composition of any one of claims 1, 9, or 14, 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.

22. The composition of claim 21, where the cocatalyst is triethanolamine.

23. The composition of any one of claims 1, 9, or 14, 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.

24. The composition of claim 23, where the accelerator is N-vinyl pyrrolidinone.

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

m, said encapsulating devices comprising encapsulated cells aggregates conformally coated in an encapsulation material, wherein the composition comprises at least about 500,000 cells/ml and wherein the encapsulation material comprises a polymerizable high density ethylenically unsaturated PEG having a molecular weight of between 900 and 3,000 Daltons, and a sulfonated comonomer, wherein the coating conforms to the size and shape of the cell aggregates.

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

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

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

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

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

m, said encapsulating devices comprising encapsulated cells aggregates conformally coated 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 and wherein the encapsulation material comprises a polymerizable high density ethylenically unsaturated PEG having a molecular weight between 900 and 3,000 Daltons, and a sulfonated comonomer, and wherein the encapsulation material conforms to the size and shape of the cell aggregates.

15. The 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 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.

25. A composition comprising encapsulating devices comprising encapsulating cells in an encapsulation material with a polyethylene glycol (PEG) coating having a molecular weight between 900 and 3,000 Daltons, wherein said composition has a cell density of at least about 6,000,000 cells/ml.

26. The composition of claim 25, wherein the encapsulating devices are microcapsules.

27. The composition of claim 26, wherein the microcapsules are conformally coated cell aggregates.

28. The composition of claim 27, wherein the cell aggregates are pancreatic islets.

29. The composition of claim 25, where the cell is selected from the group consisting of neurologic, cardiovascular, hepatic, endocrine, skin, hematopoietic, immune, neurosecretory, metabolic, systemic, and genetic.

30. The composition of claim 29, where the cell is selected from the group consisting of autologous, allogeneic, xenogeneic and genetically-modified.

31. The composition of claim 30, where the endocrine cell is an insulin producing cell.

32. A 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 a cell density is at least about 6,000,000 cells/ml.

33. The composition of claim 32, wherein the average diameter of the encapsulating device is less than 300 micron.

34. The composition of claim 32, wherein the average diameter of the encapsulating device is less than 200 micron.

35. The composition of claim 32, wherein the average diameter of the encapsulating device is less than 100 micron.

36. The composition of claim 32, wherein the average diameter of the encapsulating device is less than 50 micron.