Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers

• US 5,986,043 A
• Filed: 08/20/1996
• Issued: 11/16/1999
• Est. Priority Date: 02/28/1992
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Pathak, Chandrashekhar P., Sawhney, Amarpreet S., Desai, Neil P., Hubbell, Jeffrey A., Hill-West, Jennifer L.
• Primary Examiner(s): HAMPTON HIGHTOWER, PATRICIA
• Application Number:
  US08/700,237
• Time in Patent Office: 1,183 Days
• Field of Search: 528/354, 528/361, 424/426, 424/489, 514/777, 514/772.3, 514/773, 525/408, 525/54.1, 525/54.2, 525/413, 525/415
• US Class Current: 528/354
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 38/49 Urokinase; Tissue plasminogen activator
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• 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 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 2300/424 Anti-adhesion agents
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 26/0019 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/36 containing ingredients of undetermined constitution or reaction products thereof , e.g. transplant tissue, natural bone, extracellular matrix isolated natural compounds, e.g. collagen A61L27/24
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/3839 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/145 : Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/148 : Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08F 290/00 : Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
• CPC Class Codes: C08F 290/06 : Polymers provided for in subclass C08G
• CPC Class Codes: C08F 291/00 : Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
• CPC Class Codes: C08L 71/02 : Polyalkylene oxides
• CPC Class Codes: C09D 153/00 : Coating compositions based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers
• CPC Class Codes: C09J 153/00 : Adhesives based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Adhesives based on derivatives of such polymers
• CPC Class Codes: C12N 11/04 : entrapped within the carrier, e.g. gel or hollow fibres
• CPC Class Codes: C12N 2533/30 : Synthetic polymers
• CPC Class Codes: C12N 2533/32 : Polylysine, polyornithine
• CPC Class Codes: C12N 2533/40 : Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable 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
• CPC Class Codes: C12Y 302/01017 : Lysozyme (3.2.1.17)
• CPC Class Codes: C12Y 304/21068 : Tissue plasminogen activator (3.4.21.68), i.e. tPA
• CPC Class Codes: Y10T 428/29 : Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
• CPC Class Codes: Y10T 428/2913 : Rod, strand, filament or fiber
• CPC Class Codes: Y10T 428/2967 : Synthetic resin or polymer
• CPC Class Codes: Y10T 428/31786 : Of polyester [e.g., alkyd, etc.]

Abstract

Hydrogels of polymerized and crosslinked macromers comprising hydrophilic oligomers having biodegradable monomeric or oligomeric extensions, which biodegradable extensions are terminated on free ends with end cap monomers or oligomers capable of polymerization and cross linking are described. The hydrophilic core itself may be degradable, thus combining the core and extension functions. Macromers are polymerized using free radical initiators under the influence of long wavelength ultraviolet light, visible light excitation or thermal energy. Biodegradation occurs at the linkages within the extension oligomers and results in fragments which are non-toxic and easily removed from the body. Preferred applications for the hydrogels include prevention of adhesion formation after surgical procedures, controlled release of drugs and other bioactive species, temporary protection or separation of tissue surfaces, adhering of sealing tissues together, and preventing the attachment of cells to tissue surfaces.

Claims

1. A method for the treatment of a medical condition, the method comprising:

applying to tissue or cells an aqueous solution comprising a covalently polymerizable biodegradable monomer; and

polymerizing monomers in the solution on the tissue or cells,

wherein the monomer is an at least substantially water soluble macromer comprising at least one water soluble region, at least one degradable region, and at least two free radical polymerizable regions, wherein the polymerizable regions are separated from each other by at least one degradable region.

2. The method of claim 1 wherein the treatment of a medical condition involves preventing surgical adhesions, controlled drug delivery, adhering tissue, coating tissue, and supporting tissue.

3. The method of claim 1 wherein the method comprises

applying to the tissue or cells a free radical initiator and a biodegradable, polymerizable macromer, the macromer having a solubility of at least about 1 g/100 ml in aqueous solution, wherein the macromer comprises at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and free radical polymerizable end groups, and wherein the polymerizable end groups are separated from each other by at least one degradable region, and

polymerizing the macromer in the presence of the initiator on the tissue or cell surface.

4. The method of claim 3 wherein the polymer forms a shape selected from the group consisting of microshperes, sheets, rods, and particles.

5. The method of claim 1 wherein the aqueous solution further comprises a biologically active substance.

6. The method of claim 5 wherein the biological substance is provided in the macromer solution prior to application of the solution to the tissue or cells, wherein the biological molecule is incorporated within the polymerized macromer after polymerization.

7. The method of claim 5 wherein the biologically active substance is selected from the group consisting of proteins, carbohydrates, nucleic acids, inorganic biologically active materials, cells, tissues, and tissue or cell aggregates.

8. The method of claim 5 wherein the biologically active substance is an organic molecule.

9. The method of claim 5 wherein the biologically active substance is selected from the group consisting of enzymes, antibiotics, antineoplastic agents, local anesthetics, hormones, antiangiogenic agents, antibodies, neurotransmitters, psychoactive drugs, drugs affecting reproductive organs, and oligonucleotides.

10. The method of claim 3 wherein the water soluble region is bonded to a degradable region, at least one polymerizable end group is bonded to the water soluble region, and at least one polymerizable end group is bonded to the degradable region.

11. The method of claim 3 wherein the water soluble region forms a central core, at least two degradable regions are bonded to the core, and at least two polymerizable end groups are bonded to the degradable regions.

12. The method of claim 3 wherein the degradable region is a central core, at least two water soluble regions are bonded to the core, and at least one polymerizable end group is bonded to each water soluble region.

13. The method of claim 3, wherein the water soluble region is a macromer backbone, the degradable region is a branch or graft bonded to the macromer backbone, and at least two polymerizable end groups are bonded to the degradable regions.

14. The method of claim 3, wherein the degradable region is a macromer backbone, the water soluble region is a branch or graft bonded to the degradable backbone, and at least two polymerizable end groups are bonded to the water soluble branches or grafts.

15. The method of claim 3 wherein the water soluble region is a star backbone, the degradable region is a branch or graft bonded to the water soluble star backbone, and at least two polymerizable end groups are bonded to a degradable branch or graft.

16. The method of claim 3 wherein the degradable region is a star backbone, the water soluble region is a branch or graft bonded to the degradable star backbone, and at least two polymerizable end groups are bonded to the water soluble branch or graft.

17. The method of claim 3 wherein the water soluble region is also the degradable region.

18. The method of claim 3 wherein the water soluble region is also the degradable region, and at least one additional degradable region is a graft or branch upon the water soluble region.

19. The method of claim 3 wherein the free radical initiator is a a light-sensitive free-radical polymerization initiator.

20. The method of claim 19 wherein the initiator is selected from the group consisting of xanthine dyes, acridine dyes, thiazine dyes, phenazine dyes, camphorquinone dyes, and acetophenone dyes.

21. The method of claim 19 wherein the initiator is selected from the group consisting of an eosin dye with triethanolamine, 2,2-dimethyl-2-phenyl acetophenone, and 2-methoxy-2-phenyl acetophenone.

22. The method of claim 19 wherein crosslinking or polymerization are initiated in situ by light having a wavelength between 320 nm and 700 nm.

23. The method of claim 3 wherein the initiator is a thermal initiator.

24. The method of claim 3 wherein the initiator is a peroxygen compound.

25. The method of claim 3 wherein the macromer comprises a water soluble core region, at least two degradable extensions on the core, and an end cap on at least two of the degradable extensions, wherein

the core comprises poly(ethylene glycol);

each extension comprises biodegradable poly(α

-hydroxy acid); and

each end cap comprises an acrylate oligomer or monomer.

26. The method of claim 25 wherein the poly(ethylene glycol) has a molecular weight between about 400 and 30,000 Da;

the poly(α

-hydroxy acid) oligomer has a molecular weight between about 200 and 1200 Da; and

the acrylate oligomer or monomer has a molecular weight between about 50 and 200 Da.

27. The method of claim 3 wherein the degradable region is selected from the group consisting of poly(α

-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(orthocarbonates) and poly(phosphoesters).

28. The method of claim 27 wherein the poly(α

-hydroxy acid) is selected from the group consisting of poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid).

29. The method of claim 27 wherein the poly(lactone) is selected from the group consisting of poly(ε

-caprolactone), poly(δ

-valerolactone), and poly(gamma-butyrolactone).

30. The method of claim 3 wherein the water soluble region is selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propyleneoxide) block copolymers, polysaccharides, carbohydrates, proteins, and combinations thereof.

31. The method of claim 3 wherein the polymerizable end groups contain a carbon-carbon double bond.

32. The method of claim 5 wherein the polymeric composition is capable of degrading under in vivo conditions at a rate which releases the biologically active substance in a controlled manner.

33. The method of claim 32 wherein at least one of the degradable region or the water soluble region of the macromer is selected to produce a preselected rate of release of the biologically active substance.

34. The method of claim 1 or 5 wherein the macromer is applied to tissue and polymerized thereon to inhibit restenosis or adhesions.

35. The method of claim 1 or 5 wherein the macromer is applied and polymerized to form a sealant.

36. The method of claim 35 wherein the macromer is applied and polymer to form a sealant for bleeding organs or bone defects.

37. The method of claim 1 or 5 wherein the macromer is applied and polymerized to form a tissue support within the body.

38. The method of claim 37 wherein the polymerized macromer forms a support to hold organs, vessels or tubes in a fixed position for a controlled period of time.

39. The method of claim 1 or 5 wherein the macromer is applied and polymerized to form a space filler for an aneurism.

40. The method of claim 39 wherein the macromer is applied and polymerized to form a space filler for a vascular aneurism.

41. The method of claim 1 or 5 wherein the macromer is applied and polymerized to form an adhesive.

42. The method of claim 41 wherein the macromer is applied to plural tissue surfaces and polymerized to form a sealant which adheres the tissue surfaces.