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

• US 5,410,016 A
• Filed: 03/01/1993
• Issued: 04/25/1995
• Est. Priority Date: 10/15/1990
• Status: Expired due to Fees

• 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, Jennifer L.
• Primary Examiner(s): Foelak, Morton
• Assistant Examiner(s): Dodson, Shelley A.
• Application Number:
  US08/022,687
• Time in Patent Office: 785 Days
• Field of Search: 424/426, 424/489, 514/772.1, 514/772.3, 514/773, 514/777, 525/54.1, 525/54.2, 525/408, 525/413, 525/415, 528/354, 528/361, 128/898
• US Class Current: 528/354
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61K 47/6927 the form being a solid microparticle having no hollow or gas-filled cores
• 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: 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 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• 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 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 29/085 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: 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: 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: 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

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 biodegradable, polymerizable macromer having a solubility of at least about 1 g/100 ml in an aqueous solution comprising at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and free radical polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer interlinking, wherein the polymerizable end groups are separated from each other by at least one degradable region.

2. The macromer of claim 1 wherein the water soluble region is attached to a degradable region, at least one polymerizable end group is attached to the water soluble region, and at least one polymerizable end group is attached to the degradable region.

3. The macromer of claim 1 wherein the water soluble region forms a central core, at least two degradable regions are attached to the core, and the polymerizable end groups are attached to the degradable regions.

4. The macromer of claim 2 wherein the degradable region is a central core, at least two water soluble regions are attached to the core, and a polymerizable end group is attached to each water soluble region.

5. The macromer of claim 1 wherein the water soluble region is a macromer backbone, the degradable region is a branch or graft attached to the macromer backbone, and polymerizable end groups are attached to the degradable regions.

6. The macromer of claim 1 wherein the degradable region is a macromer backbone, the water soluble region is a branch or graft attached to the degradable backbone, and polymerizable end groups are attached to the water soluble branches or grafts.

7. The macromer of claim 1 wherein the water soluble region is a star backbone, the degradable region is a branch or graft attached to the water soluble star backbone, and at least two polymerizable end groups are attached to a degradable branch or graft.

8. The macromer of claim 1 wherein the degradable region is a star backbone, the water soluble region is a branch or graft attached to the degradable star backbone, and two or more polymerizable end groups are attached to the water soluble branch or graft.

9. The macromer of claim 1 wherein the water soluble region is also the degradable region.

10. The macromer of claim 1 wherein the water soluble region is also the degradable region, one or more additional degradable regions are grafts or branches upon the water soluble region.

11. The macromer of claim 1 comprising 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.

12. The macromer of claim 11 wherein

each extension comprises biodegradable poly(hydroxy acid);

and

each end cap comprises an acrylate oligomer or monomer.

13. The macromer of claim 12 wherein the poly(ethylene glycol) has a molecular weight between about 400 and 30,000 Da;

the poly(hydroxy acid) oligomers have a molecular weight between about 200 and 1200 Da; and

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

14. The macromer of claim 1 wherein the polymerizable end groups contain a carbon-carbon double bond capable of cross-linking and polymerizing macromers.

15. The macromer of claim 1 wherein crosslinking and polymerization of the macromer can be initiated by a light-sensitive free-radical polymerization initiator with or without a cocatalyst, further comprising a free radical polymerization initiator.

16. The macromer of claim 15 wherein the initiator is selected from the group consisting of xanthine dyes, acridine dyes, thiazine dyes, phenazine dyes, camphorquinone dyes, and acetophenone dyes.

17. The macromer of claim 16 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.

18. The macromer of claim 1 wherein crosslinking or polymerizations can be initiated in situ by light having a wavelength of 320 nm or longer.

19. The macromer of claim 1 wherein the degradable region is selected from the group consisting of poly (hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(phosphazines), and poly(phosphoesters).

20. The macromer of claim 19 wherein the degradable region is a poly(α

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

21. The macromer of claim 19 wherein the poly(lactone) is selected from the group consisting of poly(ε

-caprolactone), poly (δ

-valerolactone) or poly(λ

-butyrolactone).

22. The macromer of claim 1 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)-copoly(propyleneoxide) block copolymers, polysaccharides, carbohydrates, proteins, and combinations thereof.

23. The macromer of claim 1 further comprising biologically active molecules selected from the group consisting of proteins, carbohydrates, nucleic acids, organic molecules, inorganic biologically active molecules, cells, tissues, and tissue aggregates.