Implantable polymer hydrogel for therapeutic uses

• US 5,863,551 A
• Filed: 10/16/1996
• Issued: 01/26/1999
• Est. Priority Date: 10/16/1996
• Status: Expired due to Term

• Current Assignee: Organogel Canada Ltee
• Original Assignee: Organogel Canada Ltee
• Inventors: Woerly, Stephane
• Primary Examiner(s): Kulkosky, Peter F.
• Application Number:
  US08/731,484
• Time in Patent Office: 832 Days
• Field of Search: 424/78.08, 424/423, 526/199, 526/200
• US Class Current: 424/423
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/3878 Nerve tissue, brain, spinal cord, nerves, dura mater
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/146 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: C08L 33/26 Homopolymers or copolymers of acrylamide or methacrylamide
• CPC Class Codes: C08L 5/00 Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00

Abstract

The hydrogel is a copolymer of an N-substituted methacrylamide or acrylamide, a cross-linking agent and a complex sugar or derivative, a tissue adhesion peptide or a polymer conjugate with antibodies, the polymer being heterogeneous, elastically deformable and having an equilibrium water content of at least about 80%. It can be used for tissue regeneration and for organ repair, for example, in the developing and adult nervous system.

Claims

1. A polymer hydrogel for therapeutic use, comprising:

a copolymer of (a) and N-substituted methacrylamide or acrylamide, (b) a cross-linking agent and (c) at least one type of copolymerizable, biologically active molecule, which is a complex sugar, a sugar derivative or a tissue adhesive peptide, said polymer hydrogel being heterogeneous, elastically deformable and having an equilibrium water content of at least about 80%, a fractional porosity of at least 80-90%, a mean pore diameter of about 15-35 μ

m and a porous volume of pores measuring at least 10 μ

m equal to substantially 100% of the total fractional porosity of the hydrogel.

2. The polymer hydrogel of claim 1, wherein (a) said N-substituted methacrylamide or acrylamide is selected from the group consisting of N-monoalkyl and N,N-dialkylmethacrylamides and acrylamides, (b) said cross-linking agent is acrylamide or precursors thereof, and (c) said copolymerizable, biologically active molecule, which is tissue adhesive, is glucosamine, N-acetylglucosamine or an N-acetyl derivative of neuraminic acid.

3. The ploymer hydrogel of claim 2, wherein said alkyl group contains 1-2 carbon atoms.

4. The polymer hydrogel of claim 3, wherein said alkyl is a hydroxyalkyl or an aminoalkyl.

5. The polymer hydrogel of claim 1, wherein said equilibrium water content is at least 96%.

6. The polymer hydrogel of claim 1, wherein said hydrogel is covalently cross-linked and substantially non-transparent.

7. The polymer hydrogel of claim 6, wherein said hydrogel shows a clear phase separated structure formed of polymer particles of about 1-10 μ

m, thereby providing an area of relatively coarse porosity where the hydrogel is intended to interface with a host tissue and of relatively fine porosity where it is intended to interface with ingrowing tissue.

8. The polymer hydrogel of claim 1, which has a specific surface area of at least 100 m² /gram and a hyperporous character in the range of 20 to 30 μ

m.

9. A method for preparing a heterogeneous, elastically deformable hydrogel for therapeutic use, which comprises:

(a) dissolving a cross-linking agent in a solvent with a free radical polymerization initiator selected from the group consisting of azobisisobutyronitrile, a peroxide, ascorbic acid, a peroxysulfate or a substituted azo compound, said initiator being present in an amount ranging from 0.01-2% by weight with respect to the polymer hydrogel which is formed, to form a solution;

(b) adding an N-substituted methacrylamide or acrylamide to the solution obtained in (a) to form a mixture,

(c) adding a solution of a copolymerizable, biologically active molecule, which is a complex sugar, a sugar derivative or a tissue adhesive peptide, to said solution; and

(d) polymerizing the components (a) to (c), thereby obtaining a polymer hydrogel which is heterogeneous, elastically deformable and has an equilibrium water content of at least about 80%, a fractional porosity of at least 80-90%, a mean pore diameter of about 15-25 μ

m and a porous volume of pores measuring at least 10 μ

m equal to substantially 100% of the total fractional porosity of the hydrogel.

10. The method of claim 9, which comprises:

dissolving azobisisobutyronitrile and methylene bisacrylamide in said solvent, thereby forming a solution;

mixing said solution with N-(2-hydroxypropyl)methacrylamide;

adding glucosamine or N-actylglucosamine or N-acetylneuraminic acid thereto;

polymerizing the monomer mixture; and

removing low molecular weight residual products and initiator traces therefrom.

11. The method of claim 9, wherein said cross-linking agent is acrylamide, precursors thereof or diving cross-linking agents.

12. The method of claim 9, wherein said complex sugar is glucosamine, N-acetylglucosamine, N-acetyl derivatives of neuraminic acid, polysialic acid or galactosamine derivatives.

13. The method of claim 9, wherein said solution of polymerizable material comprises at least one type of tissue adhesion peptide.

14. The method of claim 9 wherein the copolymerization reaction is conducted at a temperature ranging from 40°

-60°

C. for about 12 hours.