METHODS OF MANUFACTURING COPOLYMERS WITH ZWITTERIONIC MOIETIES AND DIHYDROXYPHENYL MOIETIES AND USE OF SAME

• US 20080153923A1
• Filed: 11/19/2007
• Published: 06/26/2008
• Est. Priority Date: 11/21/2006
• Status: Active Grant

• Current Assignee: Abbott Laboratories Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Pacetti, Stephen
• Granted Patent: US 8,101,156 B2
• Time in Patent Office: Days
• US Class Current: 514/772
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C08L 27/18 Homopolymers or copolymers or tetrafluoroethene

Abstract

Copolymers are manufactured to include a zwitterionic monomer (e.g., methacryloyloxyethyl phosphorylcholine monomer), a dihydroxyphenyl derivatized monomer, and optionally one or more additional monomers. The dihydroxyphenyl derivatized monomer gives the copolymers excellent adhesion properties. Optional monomers include a cationic amino monomer, a hydrocarbon monomer, and/or a hydrophilic monomer. The copolymers are biocompatible and can be used with medical devices.

Claims

1. A method for manufacturing a biocompatible polymer, comprising:

copolymerizing a zwitterion monomer with a dihydroxyphenyl monomer to yield a thermoplastic polymer having the following chemical formula,

2. A biocompatible polymer as in claim 1, wherein the 3,4-dihydroxyphenyl group is substituted with a 2,3-dihydroxyphenyl group.

6. A biocompatible polymer as in claims 1, wherein n+o+p+q+r=1.

7. A method as in claims 1, in which the zwitterion monomer comprises a zwitterionic group selected from the group consisting of phosphorylcholine, phosphoryl ethanolamine, phosphatidyl ethanolamine, phosphoethanolamine, phosphatidyl serine, sulfobetaine and combinations thereof.

8. A method as in claims 1, in which the ratio of monomers is selected to yield a thermoplastic polymer with a glass transition temperature in a range from about −

30°

C. to about 37°

C., when hydrated.

9. A method as in claims 1, in which the ratio of monomers is selected to yield a thermoplastic polymer with a glass transition temperature in a range from about −

30°

C. to about 100°

C., when dry.

10. A method as in claims 1, in which the copolymerization further comprises copolymerizing a cationic amino monomer to yield a thermoplastic polymer that includes cationic amino groups.

11. A method as in claim 10, in which the cationic amino monomer is selected from the group consisting of N,N′

-diethylaminoethyl methacrylate, 2-(dimethylamino)ethyl methacrylate, 2-aminoethyl methacrylate, N-(3-aminopropyl) methacrylamide, 2-(diethylamino)ethyl styrene, 2-(dimethylamino)ethyl acrylate, N-(2-(N,N′

-dimethylamino)ethyl) methacrylamide, N-(3-(N,N′

-dimethylamino)propyl) acrylamide, N-(3-N,N′

-dimethylamino)propyl methacrylamide, and combinations thereof.

12. A method as in claims 1, in which the copolymerization further comprises copolymerizing a hydrocarbon monomer to yield a copolymer that includes hydrocarbon groups.

13. A method as in claim 12, in which the hydrocarbon monomer is selected from the group consisting of ethyl methacrylate, n-butyl methacrylate, lauryl-methacrylate, methyl methacrylate, isopropyl methacrylate, n-propyl methacrylate, isobutyl methacrylate, sec-butyl methacrylate, tert-butyl methacrylate, n-hexyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, phenyl methacrylate, benzyl methacrylate, isobornyl methacrylate, trimethylcyclohexyl methacrylate, n-dodecyl methacrylate, methacrylates with pendant groups comprising up to 16 carbons, methyl acrylate, ethyl acrylate, propyl acrylate, n-butyl acrylate, isobutyl acrylate, sec-butyl acrylate, n-hexyl acrylate, cyclohexyl acrylate, phenyl acrylate, benzyl acrylate, styrene, alkyl substituted styrene, ethylene, propylene, 1-butene, isobutylene.

14. A method as in claims 1, in which the copolymerization further comprises copolymerizing a hydrophilic monomer to yield a copolymer that includes hydrophilic groups.

15. A method as in claim 14, wherein the hydrophilic monomer is selected from the group consisting of hydroxyethyl methacrylate, hydroxy propyl methacrylate, acrylamide, methacrylamide, hydroxyalkyl methacrylamides, 2-hydroxyethyl methacrylate, 3-hydroxypropyl methacrylate, 2-hydroxypropyl methacrylate, hydroxybutyl methacrylate, acrylic acid, methacrylic acid, 2-methoxyethyl acrylate, 2-methoxyethyl methacrylate, 2-ethoxyethyl methacrylate, PEG-methacrylate, PEG-acrylate, polypropylene glycol acrylate, polypropylene glycol methacrylate, vinyl pyrrolidone, allyl alcohol, vinyl sulfonic acid, 2-sulfoethyl methacrylate, 3-sulfopropyl methacrylate, styrene sulfonic acid, and combinations thereof.

16. A method as in claims 1, in which the thermoplastic polymer is substantially free of cross-linking.

17. A method as in claims 1, in which the thermoplastic polymer has a number average molecular weight in a range from about 20 kDa to about 800 kDa.

18. A method as in claims 1, in which the thermoplastic polymer has a number average molecular weight in a range from about 100 kDa to about 600 kDa.

19. A method as in claims 1, in which the thermoplastic polymer has a number average molecular weight in a range from about 2 kDa to about 200 kDa.

20. A method as in claims 1 further comprising forming the dihydroxyphenyl monomer by reacting a dihydroxyphenyl compound with a polymerizable group.

21. A method as in claims 1, in which the copolymerization reaction is carried out using free radical polymerization, atom transfer radical polymerization, cationic polymerization, anionic polymerization, or iniferter polymerization.

22. A method as in claims 1, in which the biocompatible polymer is mixed with at least one bioactive agent to form a drug coating.

23. A biocompatible polymer manufactured according to the method of claim 1.

3. A method for manufacturing a biocompatible polymer, comprising:

copolymerizing a zwitterion monomer with an acrylate co-monomer to yield an intermediate polymer product;

coupling a dihydroxyphenyl group to the acrylate co-monomer of the intermediate polymer product to yield a thermoplastic polymer.

4. A method as in claim 3, in which the molar concentration of the zwitterion monomer is in a range from about 1.0% to about 50% and the molar concentration of the acrylate co-monomer is in a range from about 1.0% to about 40%, based on the total molar concentration of monomer during the polymerization reaction.

5. A method for manufacturing a biocompatible polymer, comprising:

copolymerizing a dihydroxyphenyl monomer with an acrylate comonomer to yield an intermediate polymer product;

coupling a zwitterionic group to the acrylate comonomer of the intermediate polymer product to yield a thermoplastic polymer.

24. A method for using a biocompatible polymer on a medical device, comprising:

providing a copolymer comprising a first monomer having zwitterion moieties and second monomer having dihydroxyphenyl moieties; and

applying the copolymer to a supporting structure of a medical device.

25. A method as in claim 24, further comprising dissolving the copolymer in a solvent and applying the copolymer to the supporting structure as a copolymer solution.