Drug incorporating and releasing polymeric coating for bioprosthesis

• US 5,900,246 A
• Filed: 06/05/1995
• Issued: 05/04/1999
• Est. Priority Date: 03/18/1993
• Status: Expired due to Fees

• Current Assignee: Cedars-Sinai Medical Center (Cedars Sinai Health System)
• Original Assignee: Cedars-Sinai Medical Center (Cedars Sinai Health System)
• Inventors: Lambert, Thomas L.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/464,381
• Time in Patent Office: 1,429 Days
• Field of Search: 424/486, 424/423, 424/427, 424/429, 604/264, 604/266, 604/915, 623/2, 623/3, 427/2.1, 427/2.24, 427/2.28, 428/423.1
• US Class Current: 424/429
• CPC Class Codes: A61L 2300/606 Coatings
• 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: A61M 2025/0057 Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings
• CPC Class Codes: A61M 25/104 used for angioplasty
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: C08L 75/04 Polyurethanes

Abstract

In accordance with the present invention, there are provided prosthetic articles having polyurethane coatings with biologically active compounds incorporated within the interstices of the polymer. Methods for the preparation of such articles are also provided. Thus, a polyurethane coating is applied to a prosthetic article, the coating then swelled (without significantly dissolving the polymer) so that substantial quantities of biologically active compounds can be incorporated within the interstices of the polymer. Upon long term exposure of a prosthetic article of the invention to physiological conditions, the biologically active compound is slowly released by the treated polymer. The biologically active compound is, therefore, released only at the site where it is desired, i.e., where the prosthetic article is positioned.

Claims

1. A drug delivery system for localized delivery of a biologically active compound to a subject, comprising:

a substrate having coated thereon a medical grade, linear, aliphatic polyurethane elastomer and at least one biologically active compound absorbed into the interstices of said coating,

wherein said substrate is selected from the group consisting of a stent, a prostheses, a heart valve, a pacemaker, a catheter, a balloon, an ocular implant, and a contact lens,

wherein said linear aliphatic polyurethane elastomer coating has a thickness of at least 20 microns,

wherein said linear, aliphatic polyurethane elastomer coating is the reaction product of a) polytetramethylene ether glycol, b) an aliphatic diisocyanate, and c) a chain extender, and wherein said chain extender is an aliphatic diol.

2. The drug delivery system of claim 1 wherein the biological agent is absorbed substantially throughout the entire thickness of the polyurethane elastomer coating.

3. The drug delivery system of claim 2 wherein the polyurethane polymer coating has a thickness in the range of about 25 up to 500 microns.

4. The drug delivery system of claim 3, wherein the polytetramethylene ether glycol has a molecular weight in the range of about 500 to about 5000.

5. The drug delivery system of claim 4, wherein the ratio of chain extender to polytetramethylene ether glycol is in the range of about 1:

1 to 5;

1.

6. The drug delivery system of claim 5, wherein the chain extender is 1,4 butane diol.

7. The drug delivery system of claim 6, wherein said aliphatic diisocyanate is selected from the group consisting of hexamethylene diisocyanate, isophorone diisocyanate, trimethyl hexamethylene diisocyanate, and dicyclohexylmethane diisocyanate.

8. The drug delivery system of claim 7, wherein the aliphatic diisocyanate is dicyclohexylmethane diisocyanate.

9. The drug delivery system of claim 8, wherein said biologically active compound is a lipophilic compound.

10. The drug delivery system of claim 3, wherein the ratio of chain extender to polytetramethylene ether glycol is in the range of about 1:

1 to 5;

1.

11. The drug delivery system of claim 3, wherein the chain extender is 1,4 butane diol.

12. The drug delivery system of claim 3, wherein said aliphatic diisocyanate is selected from the group consisting of hexamethylene diisocyanate, isophorone diisocyanate, trimethyl hexamethylene diisocyanate, and dicyclohexylmethane diisocyanate.

13. The drug delivery system of claim 12, wherein the aliphatic diisocyanate is dicyclohexylmethane diisocyanate.

14. The drug delivery system of claim 3, wherein said biologically active compound is a lipophilic compound.

15. The drug delivery system of claim 3, wherein said prostheses is a prosthetic joint.

16. A drug delivery system for localized delivery of a biologically active compound to a subject, comprising:

a substrate having coated thereon a medical grade, linear, aliphatic polyurethane elastomer and at least one biologically active compound absorbed into the interstices substantially throughout the entire thickness of said coating,

wherein said substrate is selected from the group consisting of a stent, a prostheses, a heart valve, a pacemaker, a catheter, a balloon, an ocular implant, and a contact lens,

wherein said linear, aliphatic polyurethane elastomer coating has a thickness in the range of about 25 up to 500 microns,

wherein said linear, aliphatic polyurethane elastomer coating is the reaction product of a) polytetramethylene ether glycol, b) an aliphatic diisocyanate, and c) a chain extender, and wherein said chain extender is an aliphatic diol, and

wherein said drug delivery system is prepared by treating the medical-grade, polyurethane polymer coating with a coating expansion solution at a temperature, under a pressure and for a time sufficient to cause the biologically active compound to penetrate into the interstices of the polymer coating,

said coating expansion solution comprising the biologically active compound and an organic solvent system,

wherein the organic solvent system comprises at least one solvent for the polymer coating and at least one non-solvent for the polymer coating, wherein the solvent and the non-solvent are present in the organic solvent system at a ratio of solvent to non-solvent in the range of about 1;

1 to about 1;

20 by volume, and

wherein the biologically active compound is present in the coating expansion solution in a concentration of at least 0.1 parts per 100 parts of the organic solvent system; and

then drying the thus treated polymer coating to substantially eliminate the organic solvent system.

17. The drug delivery system of claim 16, wherein said biologically active compound is a lipophilic compound.

18. A drug delivery system for localized delivery of a biologically active compound to a subject, comprising:

a substrate having coated thereon a medical grade, linear, aliphatic polyurethane elastomer and at least one biologically active compound absorbed into the interstices substantially throughout the entire thickness of said coating,

wherein said substrate is selected from the group consisting of a stent, a prostheses, a heart valve, a pacemaker, a catheter, a balloon, an ocular implant, and a contact lens,

wherein said linear, aliphatic polyurethane elastomer coating has a thickness in the range of about 25 up to 500 microns,

wherein said linear, aliphatic polyurethane elastomer coating is the reaction product of a) polytetramethylene ether glycol, b) an aliphatic diisocyanate, and c) a chain extender, and wherein said chain extender is an aliphatic diol, and

wherein said drug delivery system is prepared by treating the medical-grade, polyurethane polymer coating with a coating expansion solution at a temperature, under a pressure and for a time sufficient to cause the biologically active compound to penetrate into the interstices of the polymer coating,

said coating expansion solution comprising the biologically active compound and an organic solvent system,

wherein the organic solvent system comprises at least one solvent for the polymer coating and at least one non-solvent for the polymer coating, wherein the solvent and the non-solvent are present in the organic solvent system at a ratio of solvent to non-solvent in the range of about 1;

1 to about 1;

20 by volume, then drying the thus treated aliphatic polyurethane elastomer coating to substantially eliminate the organic solvent system.

19. The drug delivery system of claim 18, wherein said biologically active compound is a lipophilic compound.

20. The drug delivery system of claim 18, wherein the ratio of chain extender to polytetramethylene ether glycol is in the range of about 1:

1 to 5;

1.

21. The drug delivery system of claim 18, wherein the chain extender is 1,4 butane diol.