Immobilization of an active agent on a substrate

• US 9,895,468 B2
• Filed: 03/03/2017
• Issued: 02/20/2018
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc., Northwestern University
• Original Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc., Northwestern University
• Inventors: Hai, Ton That, Green, John-Bruce Devault, Fulghum, Timothy Michael, Messersmith, Phillip Byron, Sileika, Tadas Stanislovas
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): AL-AWADI, DANAH J
• Application Number:
  US15/449,752
• Publication Number:
  US 20170173226A1
• Time in Patent Office: 354 Days
• Field of Search: None
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2400/18 Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
• CPC Class Codes: A61L 2420/02 Methods for coating medical devices
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• 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 31/048 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61L 33/0011 Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
• CPC Class Codes: A61L 33/0017 using a surface active agent
• CPC Class Codes: A61L 33/0094 Physical treatment, e.g. plasma treatment
• CPC Class Codes: A61L 33/04 Use of organic materials, e.g. acetylsalicylic acid
• CPC Class Codes: A61L 33/068 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L33/062 takes precedence
• CPC Class Codes: A61L 33/08 Polysaccharides

Abstract

The invention provides methods of immobilizing an active agent to a substrate surface, including the steps of, depositing a primer compound on a substrate, thereby forming a primed substrate, contacting the primed substrate with a solution of a compound including a trihydroxyphenyl group, thereby forming a trihydroxyphenyl-treated primed substrate, and contacting the trihydroxyphenyl-treated primed substrate with a solution of an active agent, thereby immobilizing the active agent on the substrate. Further provided are methods of immobilizing an active agent on a substrate, including the steps of providing a substrate, combining a solution of a compound including a trihydroxyphenyl group with a solution of an active agent, thereby forming a solution of an active agent-trihydroxyphenyl conjugate, and contacting the primed substrate with the solution of the active agent-trihydroxyphenyl conjugate, thereby immobilizing the active agent on the substrate. The invention further provides substrates and medical device or device components with active agents immobilized on the surface thereof.

Claims

1. A method of immobilizing an active agent on a substrate surface, comprising the steps of:

depositing a primer compound on a substrate, thereby forming a primed substrate;

contacting the primed substrate with a solution of a compound including a trihydroxyphenyl group, thereby forming a trihydroxyphenyl-treated primed substrate; and

contacting the trihydroxyphenyl-treated primed substrate with a solution of an active agent, thereby forming a substrate with an active agent immobilized on the surface thereof, wherein the compound including a trihydroxyphenyl group is selected from the group consisting of gallic acid, phloroglucinol carboxylic acid, gallamide, 5-methyl-benzene-1,2,3-triol, 3,4,5-trihydroxybenzaldehyde, 2,3,4-trihydroxybenzaldehyde, gallacetophenone, 3,4,5-trihydroxybenzamide, 2,3,4-trihydroxybenzoic acid, 5-hydroxydopamine hydrochloride, methyl gallate, pyrogallol, salts of the foregoing, and combinations thereof.

2. The method of claim 1, further comprising the step of contacting the trihydroxyphenyl-treated primed substrate with a solution of a linker compound thereby coupling the linker compound to the trihydroxyphenyl group and/or the primer compound of the trihydroxyphenyl-treated primed substrate, prior to contacting the trihydroxyphenyl-treated substrate with the solution of active agent.

3. The method of claim 1, wherein the substrate is selected from the group consisting of metal substrates, inorganic oxide substrates, ceramic substrates, polymer substrates, semiconductor substrates and combinations thereof.

4. The method of claim 1, further comprising the step of modifying the surface of the substrate prior to contacting the substrate with the solution of the primer compound.

5. The method of claim 1, wherein the substrate comprises a surface of a medical device or medical device component.

6. The method of claim 5, wherein the medical device comprises an extracorporeal blood circuit or components of an extracorporeal blood circuit.

7. The method of claim 1, wherein the primer compound is selected from the group consisting of oligosaccharides, polyamines, amino functionalized silanes, mercaptosilanes, and combinations thereof.

8. The method of claim 1, wherein the active agent is selected from the group consisting of antimicrobial agents, antifouling agents, anti-inflammatory agents, antithrombogenic agents, and combinations thereof.

9. The method of claim 1, wherein the active agent is selected from the group consisting of chitosan, linear polyethylene glycol, looped polyethylene glycol, polyethylene glycol derivatives, fractionated heparin, unfractionated heparin, heparin derivatives, quaternary ammonium polymers, albumin, polyethylenimine, 4-hydroxycoumarin derivatives, and combinations of the foregoing.

10. A method of immobilizing an active agent on a substrate surface, comprising the steps of:

depositing a primer compound on the substrate thereby forming a primed substrate;

combining in solution a compound including a trihydroxyphenyl group and an active agent, thereby forming a solution of an active agent-trihydroxyphenyl conjugate; and

contacting the primed substrate with the solution of the active agent-trihydroxyphenyl conjugate, thereby coupling the trihydroxyphenyl group of the active agent-trihydroxyphenyl conjugate to the primed substrate and forming a substrate with an active agent immobilized on the surface thereof, wherein the compound including a trihydroxyphenyl group is selected from the group consisting of gallic acid, phloroglucinol carboxylic acid, gallamide, 5-methyl-benzene-1,2,3-triol, 3,4,5-trihydroxybenzaldehyde, 2,3,4-trihydroxybenzaldehyde, gallacetophenone, 3,4,5-trihydroxybenzamide, 2,3,4-trihydroxybenzoic acid, 5-hydroxydopamine hydrochloride, methyl gallate, pyrogallol, salts of the foregoing, and combinations thereof.

11. The method of claim 10, further comprising the step of contacting the trihydroxyphenyl-treated primed substrate with a solution of a linker compound thereby coupling the linker compound to the trihydroxyphenyl group and/or the primer compound of the trihydroxyphenyl-treated primed substrate, prior to contacting the trihydroxyphenyl-treated substrate with the solution of active agent.

12. The method of claim 10, wherein the substrate is selected from the group consisting of metal substrates, inorganic oxide substrates, ceramic substrates, polymer substrates, semiconductor substrates and combinations thereof.

13. The method of claim 10, further comprising the step of modifying the surface of the substrate prior to contacting the substrate with the solution of the primer compound.

14. The method of claim 10, wherein the substrate comprises a surface of a medical device or medical device component.

15. The method of claim 14, wherein the medical device comprises an extracorporeal blood circuit or components of an extracorporeal blood circuit.

16. The method of claim 10, wherein the primer compound is selected from the group consisting of oligosaccharides, polyamines, amino functionalized silanes, mercaptosilanes, and combinations thereof.

17. The method of claim 10, wherein the active agent is selected from the group consisting of antimicrobial agents, antifouling agents, anti-inflammatory agents, antithrombogenic agents, and combinations thereof.

18. The method of claim 10, wherein the active agent is selected from the group consisting of chitosan, linear polyethylene glycol, looped polyethylene glycol, polyethylene glycol derivatives, fractionated heparin, unfractionated heparin, heparin derivatives, quaternary ammonium polymers, albumin, polyethylenimine, 4-hydroxycoumarin derivatives, and combinations of the foregoing.

19. The method of claim 10, wherein the solution of the primer compound is at a pH in a range of about 7.5 to about 9.5.