Treating medical conditions by polymerizing macromers to form polymeric materials

• US 6,465,001 B1
• Filed: 03/03/1998
• Issued: 10/15/2002
• Est. Priority Date: 04/20/1992
• Status: Expired due to Fees

• Current Assignee: ReNeuron Limited (ReNeuron Group Plc)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Hossainy, Syed, Desai, Neil, Sawhney, Amarpreet, Hill-West, Jennifer L., Pathak, Chandrashekhar P., Hubbell, Jeffrey A.
• Primary Examiner(s): Naff, David M.
• Application Number:
  US09/033,871
• Time in Patent Office: 1,687 Days
• Field of Search: 424/93.7, 424/422, 424/423, 424/426, 424/484, 424/486, 424/487, 424/488, 424/78.08, 424/78.31, 424/93.1, 424/94.1, 435/177, 435/178, 435/180, 435/182, 435/395, 435/396, 435/402, 435/382, 514/2, 530/812, 530/813, 530/815, 530/817
• US Class Current: 424/423
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• CPC Class Codes: A61K 38/42 Haemoglobins; Myoglobins
• CPC Class Codes: A61K 38/44 Oxidoreductases (1)
• 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 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• 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 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 27/3683 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• 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 31/10 : 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: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08B 37/003 : Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
• CPC Class Codes: C08B 37/0072 : Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• CPC Class Codes: C08B 37/0084 : Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
• 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 290/02 : on to polymers modified by introduction of unsaturated end groups
• CPC Class Codes: C08F 290/06 : Polymers provided for in subclass C08G
• CPC Class Codes: C08F 290/062 : Polyethers
• CPC Class Codes: C08F 290/08 : on to polymers modified by introduction of unsaturated side groups
• CPC Class Codes: C08F 290/10 : Polymers provided for in subclass C08B
• 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: 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 2533/32 : 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: Y10S 530/812 : Peptides or proteins is immobilized on, or in, an organic carrier
• CPC Class Codes: Y10S 530/813 : Carrier is a saccharide
• CPC Class Codes: Y10S 530/815 : Carrier is a synthetic polymer
• CPC Class Codes: Y10S 530/817 : Entrapped within the carrier, e.g. gel, hollow fibre
• CPC Class Codes: Y10T 428/2987 : Addition polymer from unsaturated monomers only
• CPC Class Codes: Y10T 428/2989 : Microcapsule with solid core [includes liposome]

Abstract

Water soluble macromers are modified by addition of free radical polymerizable groups, such as those containing a carbon-carbon double or triple bond, which can be polymerized under mild conditions to encapsulate tissues, cells, or biologically active materials. The polymeric materials are particularly useful as tissue adhesives, coatings for tissue lumens including blood vessels, coatings for cells such as islets of Langerhans, and coatings, plugs, supports or substrates for contact with biological materials such as the body, and as drug delivery devices for biologically active molecules. A medical condition at a localized site is treated by applying a polymerization initiator and then applying a substantially water-soluble, degradable macromer of at least 200 mw and having at least two crosslinkable substituents, and polymerizing the macromer to form a crosslinked polymeric material at the site. The crosslinked polymeric material may adhere two surfaces together, or be a barrier that provides immunoisolation or prevents adhesion of the site to another surface such as post-surgical adhesion. A biologically active material may be present when the macromer is polymerized to provide for delivery of the biologically active material, or to provide the polymeric material with a desired property such as resistance to bacterial growth or a decrease in inflammatory response.

Claims

1. A method for the treatment of a medical condition at a localized site, comprising the steps in the following order:

applying a polymerization initiator to the site;

applying a substantially water-soluble, degradable macromer of at least 200 mw to the site, wherein the macromer comprises at least two crosslinkable substituents, wherein at least one crosslinkable substituent can crosslink the macromer to other macromers under the influence of the initiator; and

polymerizing the macromer to form a crosslinked polymeric material at the site;

wherein the crosslinked material assists in treatment of the medical condition.

2. The method of claim 1 wherein the initiator is a free-radical initiator, and the substituent is a free-radical polymerizable substituent.

3. The method of claim 1 wherein the initiator absorbs to a material at the site.

4. The method of claim 1 wherein excess or unabsorbed initiator is removed prior to application of macromer or is substantially diluted by application of initiator.

5. The method of claim 1 wherein the treatment comprises creating a barrier around a site selected from the group consisting of a tissue, an organ, a cell, and a cluster of cells.

6. The method of claim 5 wherein the barrier provides immunoisolation of the site.

7. The method of claim 5 wherein the barrier prevents the adhesion of the site to another surface.

8. The method of claim 7 wherein the barrier prevents post-surgical adhesions.

9. The method of claim 6 wherein the barrier prevents the adhesion of nerves.

10. The method of claim 5 wherein the barrier is applied to a blood vessel.

11. The method of claim 1 where the macromer is in a solution that further comprises a biologically active molecule.

12. The method of claim 11 wherein the crosslinked polymeric meterial provides controlled release of the biologically active molecule.

13. The method of claim 1 wherein at least some of the macromer is polycationic.

14. The method of claim 1 wherein the crosslinked polymeric material is formed on a surface of an implanted material.

15. The method of claim 14 wherein the implanted surface is a synthetic material.

16. The method of claim 14 wherein the surface is the surface of a capsule surrounding a tissue, an organ, a cell or a cluster of cells.

17. The method of claim 1 wherein the crosslinked polymeric material adheres two surfaces together.