Polymer compositions containing bioactive agents and methods for their use

• US 20030031699A1
• Filed: 09/30/2002
• Published: 02/13/2003
• Est. Priority Date: 09/30/2002
• Status: Active Grant

• Current Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Inventors: Van Antwerp, William P.
• Granted Patent: US 6,770,729 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• 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: C08L 75/04 Polyurethanes
• CPC Class Codes: Y10T 428/31551 Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]

Abstract

Embodiments of the invention provide polymer coated implantable medical devices having a bioactive material posited in or on at least a portion of the coating layer, wherein the coating layer provides for the controlled release of the bioactive material from the coating layer. Preferably, the medical device is an intravascular stent.

Claims

1. An implantable medical device having at least one polymer coating composition, the polymer coating prepared from a reaction mixture of:

(a) a diisocyanate, the diisocyanate comprising about 50 mol % of the reactants in the mixture;

(b) a hydrophilic polymer which is a member selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof;

(c) a bioactive agent; and

optionally;

(d) a chain extender.

2. The medical device of claim 1, wherein the reaction mixture further comprises a siloxane polymer having functional groups at the chain termini.

3. The medical device of claim 2, wherein the functional groups are members selected from the group consisting of amino, hydroxyl and carboxylic acid.

4. The medical device of claim 1, wherein the bioactive agent is capable of being released from the polymer coating into the environment in which the medical device is placed.

5. The medical device of claim 4, wherein the release of the bioactive agent from the polymer coating is modulated by the diffusion coefficient of the polymer coating.

6. The medical device of claim 4, wherein the device has a plurality of polymer coatings having a plurality of diffusion coefficients, and wherein the release of the bioactive agent from the polymer coating is modulated by the plurality of polymer coatings.

7. The medical device of claim 4, wherein the release of the bioactive agent from the polymer coating is modulated by the pH of the polymer coating composition.

8. The medical device of claim 4, wherein the release of the bioactive agent from the polymer coating is modulated by hydrogen peroxide.

9. The medical device of claim 1, wherein the bioactive agent is an anti-thrombocytic, anti-inflammatory or anti-proliferative agent.

10. The medical device of claim 9, wherein the bioactive agent is rapamycin, heparin or an antisense oligonucleotide.

11. The medical device of claim 1, wherein the device is an intravascular stent.

12. The medical device of claim 1, wherein the reaction mixture further comprises glucose oxidase.

13. The medical device of claim 12, wherein the polymer coating has a glucose diffusion coefficient of from about 1×

10<sup>−

9</sup> cm²/sec to about 200×

10<sup>−

9</sup> cm²/sec, and a ratio of D_oxygen/ D_glucose of from about 5 to about 2000.

14. The medical device of claim 1, wherein the polymer coating has a water pickup of from about 25% to about 400% by weight.

15. The medical device of claim 1, wherein the diisocyanate is a member selected from the group consisting of isophorone diisocyanate, 1,6-hexamethylene diisocyanate and 4,4′

-methylenebis(cyclohexyl isocyanate).

16. The medical device of claim 1, wherein the reaction mixture further comprises a chain extender.

17. The medical device of claim 1, wherein the chain extender is selected from the group consisting of an alkylene diol, an alkylene diamine, an aminoalkanol and combinations thereof.

18. The medical device of claim 1, wherein the diisocyanate is 1,6-hexamethylene diisocyanate, the hydrophilic polymer is selected from the group consisting of PEG 400 and PEG 600 and is present in an amount of about 17 to about 32 mol %, and the siloxane polymer is aminopropyl polysiloxane having a molecular weight of about 2000 to about 4000 and is present in an amount of about 17 to about 32 mol %.

19. A polymer composition, the polymer composition formed by admixing (a) a diisocyanate, the diisocyanate comprising about 50 mol % of the reactants in the admixture;

(b) a hydrophilic polymer selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof;

(c) a bioactive agent and, optionally, (d) a chain extender.

20. A method for making a polymer composition, the method comprising:

admixing (a) a diisocyanate, the diisocyanate comprising about 50 mol % of the reactants in the admixture;

(b) a hydrophilic polymer selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof;

(c) a bioactive agent and, optionally, (d) a chain extender, thereby forming the polymer composition.

21. An implantable medical device having at least one polymer coating composition, the polymer coating prepared from a reaction mixture of:

(a) a diisocyanate, the diisocyanate comprising about 50 mol % of the reactants in the mixture;

(b) a hydrophilic polymer which is a member selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof;

(d) glucose oxidase;

(c) a bioactive agent wherein the bioactive agent is capable of being released from the polymer coating into the environment in which the medical device is placed, and wherein the bioactive agent is an anti-thrombocytic, anti-inflammatory or anti-proliferative agent;

wherein the release of the bioactive agent is modulated by a product that is produced from a reaction between the glucose oxidase that is present in the polymer coating and glucose that is present environment in which the medical device is placed.