Ionically covalently crosslinked and crosslinkable biocompatible encapsulation compositions and methods

• US 5,334,640 A
• Filed: 04/08/1992
• Issued: 08/02/1994
• Est. Priority Date: 04/08/1992
• Status: Expired due to Term

• Current Assignee: ReNeuron Limited (ReNeuron Group Plc)
• Original Assignee: Clover Consolidated, Ltd.
• Inventors: Soon-Shiong, Patrick, Desai, Neil P., Sandford, Paul A., Heintz, Roswitha E.
• Primary Examiner(s): Michl, Paul R.
• Assistant Examiner(s): DEWITT, LAVONDA R
• Application Number:
  US07/866,038
• Time in Patent Office: 846 Days
• Field of Search: 524/56, 524/54, 524/28, 424/488, 424/499, 435/177, 435/178
• US Class Current: 524/56
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: C08G 65/332 containing carboxyl groups, or halides, or esters thereof
• CPC Class Codes: C08L 2666/02 Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 2666/26 Natural polymers, natural resins or derivatives thereof according to C08L1/00 - C08L5/00, C08L89/00, C08L93/00, C08L97/00 or C08L99/00
• CPC Class Codes: C08L 5/04 Alginic acid; Derivatives thereof
• CPC Class Codes: C08L 71/00 Compositions of polyethers obtained by reactions forming an ether link in the main chain of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: C12N 11/04 entrapped within the carrier, e.g. gel or hollow fibres
• 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

Abstract

Crosslinked biocompatible compositions comprising an ionically crosslinked component and a covalently crosslinked component for encapsulating biologics are disclosed. In accordance with the present invention, also disclosed are crosslinkable biocompatible mixtures comprising an ionically crosslinkable component and a covalently crosslinkable component. Methods for encapsulating biologics with the crosslinked and crosslinkable biocompatible compositions are provided. Also, retrievable macrocapsules for encapsulating microcapsules or biologics are disclosed.

Claims

1. A crosslinked biocompatible material comprising:

at least one ionically crosslinked component; and

at least one covalently crosslinked component, wherein the ionically crosslinked component is selected from a polysaccharide, a polyanion, or a polycation.

2. The crosslinked biocompatible material of claim 1, wherein the ionically crosslinked component is alginate.

3. The crosslinked biocompatible material of claim 2, wherein the alginate is a high G block alginate having at least 60% α

-L-guluronic acid.

4. The crosslinked biocompatible material of claim 3, wherein the alginate comprises at least 70% α

-L-guluronic acid.

5. The crosslinked biocompatible material of claim 2, further comprising a biologic encapsulated by the material.

6. The crosslinked biocompatible material of claim 5, wherein the material is effective to provide immunoprotection for the biologic in a physiological environment.

7. The crosslinked biocompatible material of claim 6, wherein the material provides immunoprotection of the biologic when xenotransplanted.

8. The crosslinked biocompatible material of claim 5, wherein the biologic is a biologically active material or a diagnostic marker.

9. The crosslinked biocompatible material of claim 8, wherein the biologically active materials are living cells selected from islets of Langerhans, dopamine secreting cells, erythropoietin secreting cells, nerve growth factor secreting cells, hepatocytes, adrenaline/angiotensin secreting cells, parathyroid cells, or norepinephrine/metacephalin secreting cells.

10. The crosslinked biocompatible material of claim 8, wherein the biologically active material is a drug.

11. A crosslinked biocompatible material comprising:

at least one ionically crosslinked component; and

at least one covalently crosslinked component, wherein the covalently crosslinked component is derived from a polyalkylene oxide.

12. The crosslinked biocompatible material of claim 11, wherein the covalently crosslinked component is polyethylene glycol diacrylate.

13. The crosslinked biocompatible material of claim 11, further comprising a biologic encapsulated by the material.

14. The crosslinked biocompatible material of claim 13, wherein the material is effective to provide immunoprotection for the biologic in a physiological environment.

15. The crosslinked biocompatible material of claim 14, wherein the material provides immunoprotection of the biologic when xenotransplanted.

16. The crosslinked biocompatible material of claim 13, wherein the biologic is a biologically active material or a diagnostic marker.

17. The crosslinked biocompatible material of claim 16, wherein the biologically active materials are living cells selected from islets of Langerhans, dopamine secreting cells, erythropoietin secreting cells, nerve growth factor secreting cells, hepatocytes, adrenaline/angiotensin secreting cells, parathyroid cells, or norepinephrine/metacephalin secreting cells.

18. The crosslinked biocompatible material of claim 16, wherein the biologically active material is a drug.

19. A crosslinkable biocompatible mixture comprising:

at least one ionically crosslinkable component; and

at least one covalently crosslinkable component, wherein the ionically crosslinkable component is selected from a polysaccharide, a polyanion, or a polycation.

20. The crosslinkable biocompatible mixture of claim 19, wherein the ionically crosslinkable component is alginate.

21. The crosslinkable biocompatible mixture of claim 20, wherein the alginate is capable of ionically crosslinking by adding multivalent cations to the mixture.

22. The crosslinkable biocompatible mixture of claim 19, wherein the composition ratio between the ionically crosslinkable component and the covalently crosslinkable component is effective for the stable crosslinking of the mixture, whereby a gelled encapsulation material is formed.

23. The crosslinkable biocompatible mixture of claim 22, wherein the concentration and the molecular weight(s) of the covalently crosslinkable component are effective to provide immunoprotection to the encapsulated functional core once the mixture has been crosslinked.

24. The crosslinkable biocompatible mixture of claim 23, wherein the mixture has an osmolarity and pH compatible with living tissue or cells.

25. The crosslinkable biocompatible mixture of claim 24, wherein the osmolarity of the mixture is about 290 milliosmoles per kilogram and the pH is about 7.4.

26. The crosslinkable biocompatible mixture of claim 23, wherein the concentration and molecular weight(s) of the covalently crosslinkable component are effective for the controlled release of the biologic or components of the biologic once the mixture has been crosslinked.

27. A crosslinkable biocompatible mixture comprising:

at least one ionically crosslinkable component; and

at least one covalently crosslinkable component, wherein the covalently crosslinkable component is a polyalkylene oxide.

28. The crosslinkable biocompatible mixture of claim 27, wherein the polyalkylene oxide is capable of covalently crosslinking by free radical polymerization.

29. The crosslinkable biocompatible mixture of claim 27, wherein the polyalkylene oxide is polyethylene glycol diacrylate.

30. The crosslinkable biocompatible mixture of claim 27, wherein the composition ratio between the ionically crosslinkable component and the covalently crosslinkable component is effective for the stable crosslinking of the mixture, whereby a gelled encapsulation material is formed.

31. The crosslinkable biocompatible mixture of claim 30, wherein the concentration and the molecular weight(s) of the covalently crosslinkable component are effective to provide immunoprotection to the encapsulated functional core once the mixture has been crosslinked.

32. The crosslinkable biocompatible mixture of claim 31, wherein the mixture has an osmolarity and pH compatible with living tissue or cells.

33. The crosslinkable biocompatible mixture of claim 32, wherein the osmolarity of the mixture is about 290 milliosmoles per kilogram and the pH is about 7.4.

34. The crosslinkable biocompatible mixture of claim 31, wherein the concentration and molecular weight(s) of the covalently crosslinkable component are effective for the controlled release of the biologic or components of the biologic once the mixture has been crosslinked.

35. A retrievable implantation material, comprising:

a crosslinked biocompatible macrocapsule comprising at least one ionically crosslinked component, and at least one covalently crosslinked component, whereby said macrocapsule encapsulates a microcapsule(s) or a biologic.

36. The retrievable implantation material of claim 35, wherein the macrocapsule provides immunoprotection to the encapsulated microcapsule(s) or biologic when xenotransplanted.