Drug loaded polymeric material and method of manufacture

• US 5,605,696 A
• Filed: 03/30/1995
• Issued: 02/25/1997
• Est. Priority Date: 03/30/1995
• Status: Expired due to Term

• Current Assignee: Advanced Cardiovascular Systems Incorporated (Abbott Laboratories)
• Original Assignee: Advanced Cardiovascular Systems Incorporated (Abbott Laboratories)
• Inventors: Garguilo, Darlene, Villareal, Plaridel, Eury, Robert P.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US08/413,475
• Time in Patent Office: 698 Days
• Field of Search: 424/486, 424/423, 424/501, 264/4.3, 623/1
• US Class Current: 424/423
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2300/622 Microcapsules
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/146 Porous materials, e.g. foams or sponges
• 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: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C08L 31/04 Homopolymers or copolymers of vinyl acetate
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C08L 83/04 Polysiloxanes

Abstract

The drug loaded polymeric material containing a therapeutic drug can be applied to a structure of an intravascular stent. A therapeutically effective amount of a therapeutic drug is incorporated into such a layer of polymeric material, without significantly increasing the thickness of the stent, to avoid interfering with the function of the stent. The drug loaded polymer coating of the stent can formed to include pores, can be multi-layered to permit the combination of a plurality of different drug containing materials in a single stent, and can include a rate controlling membrane to allow for controlled retention and delivery of selected drugs within the affected blood vessel upon implantation. The layer of polymeric material is manufactured by combining the selected polymeric material with a relatively high loading of the therapeutic drug in a thermal process, such as coextrusion of the therapeutic drug with the polymeric material. The therapeutic drug is dispersed and incorporated into the polymer as small particles, preferably having a maximum cross-sectional dimension of 10 microns.

Claims

1. A method of incorporating a therapeutically effective amount of a therapeutic drug into a polymeric material for application to an intravascular stent, the method comprising the steps of:

forming solid particles of a therapeutic drug to have a maximum cross-sectional dimension of about 10 microns;

uniformly dispersing said solid particles of said therapeutic drug in said polymeric material such that said particles of said therapeutic drug form up to 70% by weight of the total weight of the therapeutic drug and the polymeric material; and

uniformly dispersing a porosigen in said polymeric material together with said therapeutic drug, said porosigen being selected from the group consisting of sodium chloride, lactose, sodium heparin, polyethylene glycol, copolymers of polyethylene oxide and polypropylene oxide, and mixtures thereof.

2. The method of claim 1, wherein said step of forming solid particles of said therapeutic drug comprises air milling crystals of said therapeutic drug.

3. The method of claim 1, wherein said step of forming solid particles of said therapeutic drug comprises recrystallizing crystals of said therapeutic drug.

4. The method of claim 1, wherein said step of forming solid particles of said therapeutic drug comprises ball milling crystals of said therapeutic drug.

5. The method of claim 1, wherein said step of forming solid particles of said therapeutic drug comprises grinding crystals of said therapeutic drug.

6. The method of claim 1, wherein said therapeutic drug is selected from the group consisting of heparin, D-phe-pro-arg-chloromethylketone, dipyridamole, hirudin, recombinant hirudin, thrombin inhibitor, angiopeptin, angiotensin converting enzyme inhibitors, calcium channel blockers, colchicine, fibroblast growth factor antagonists, fish oil, omega 3-fatty acid, low molecular weight heparin, histamine antagonists, inhibitors of HMG-CoA reductase, methotrexate, monoclonal antibodies, nitroprusside, phosphodiesterase inhibitors, prostacyclin and prostacyclin analogues, prostaglandin inhibitor, PDGF antagonists, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine, alpha-interferon, and genetically engineered epithelial cells, and mixtures thereof.

7. The method of claim 1, wherein said polymeric material has a relatively low thermal processing temperature.

8. The method of claim 1, wherein said polymeric material has a thermal processing temperature of not more than approximately 100°

C.

9. The method of claim 1, wherein said polymeric material is selected from the group consisting of polycaprolactone, poly(ethylene-co-vinyl acetate), poly(vinyl acetate), silicone gum rubber, poly-DL-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, polyphosphazenes, and mixtures thereof.

10. The method of claim 1, wherein said particles of said therapeutic drug comprise up to 70% by weight of the total weight of the therapeutic drug and the polymeric material.

11. The method of claim 1, wherein said step of uniformly dispersing said solid particles of said therapeutic drug in said polymeric material comprises coextruding said particles of said therapeutic drug and said polymeric material.

12. The method of claim 1, wherein said step of uniformly dispersing said solid particles of said therapeutic drug in said polymeric material comprises calendaring said particles of said therapeutic drug and said polymeric material together.

13. The method of claim 1, wherein said step of uniformly dispersing said solid particles of said therapeutic drug in said polymeric material comprises solvent casting said particles of said therapeutic drug together with said polymeric material.

14. The method of claim 1, wherein said step of uniformly dispersing a porosigen in said polymeric material together with said therapeutic drug comprises coextruding said porosigen together with said therapeutic drug and said polymeric material.

15. The method of claim 1, further including the step of dissolving said porosigen in said polymeric material to leave pores in said polymeric material.

16. The method of claim 15, wherein said pores have a maximum cross-sectional dimension of about 10 microns.

17. The method of claim 15, wherein said pores have a maximum cross-sectional dimension of about one micron.

18. The method of claim 1, further including the step of applying a rate-controlling membrane over said polymeric material to control the release rate of said therapeutic drug from said polymeric material.

19. The method of claim 18, wherein said step of applying a rate-controlling membrane over said polymeric material comprises forming said rate-controlling membrane to include a uniform dispersion of a porosigen in said rate-controlling membrane.

20. The method of claim 19, further including the step of dissolving said porosigen in said rate-controlling membrane to leave pores in said rate-controlling membrane.

21. The method of claim 19, wherein said porosigen in said rate-controlling membrane is selected from the group consisting of sodium chloride, lactose, sodium heparin, polyethylene glycol, polyethylene oxide/polypropylene oxide copolymers, and mixtures thereof.

22. The method of claim 1, further including the step of forming said polymeric material containing said therapeutic drug as a sheet at least about 25 microns thick.

23. The method of claim 22, further including the step of laminating said sheet of polymeric material containing said therapeutic drug to an intravascular stent structure.

24. The method of claim 23, further including the step of removing excess polymeric material laminated to said intravascular stent structure.

25. A polymeric material containing a therapeutic drug for application to an intravascular stent for carrying and delivering said therapeutic drug within a blood vessel in which said intravascular stent is placed, comprising:

a polymeric material having a thermal processing temperature no greater than about 100°

C;

particles of a therapeutic drug incorporated in said polymeric material; and

a porosigen uniformly dispersed in said polymeric material, said porosigen being selected from the group consisting of sodium chloride, lactose, sodium heparin, polyethylene glycol, copolymers of polyethylene oxide and polypropylene oxide, and mixtures thereof.

26. The polymeric material of claim 25, wherein said polymeric material is selected from the group consisting of polycaprolactone, poly(ethylene-co-vinyl acetate), poly(vinyl acetate), silicone gum rubber, poly-DL-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, polyphosphazenes, and mixtures thereof.

27. The polymeric material of claim 25, wherein said particles of said therapeutic drug can have a maximum cross-sectional dimension of up to 50 microns.

28. The polymeric material of claim 25, wherein said therapeutic drug is a drug selected from the group consisting of heparin, D-phe-pro-arg-chloromethylketone, dipyridamole, hirudin, recombinant hirudin, thrombin inhibitor, angiopeptin, angiotensin converting enzyme inhibitors, calcium channel blockers, colchicine, fibroblast growth factor antagonists, fish oil, omega 3- fatty acid, low molecular weight heparin, histamine antagonists, inhibitors of HMG-CoA reductase, methotrexate, monoclonal antibodies, nitroprusside, phosphodiesterase inhibitors, prostacyclin and prostacyclin analogues, prostaglandin inhibitor, PDGF antagonists, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine, alpha-interferon, and genetically engineered epithelial cells, and mixtures thereof.

29. The polymeric material of claim 25, wherein said particles of said therapeutic drug comprise up to 70% by weight of the total weight of the therapeutic drug and the polymeric material.

30. The polymeric material of claim 25, wherein said particles of said therapeutic drug comprise up to 40% by weight of the total weight of the therapeutic drug and the polymeric material.

31. The polymeric material of claim 25, wherein said polymeric material comprises a surface defining pores with a maximum cross-sectional dimension of less than about 10 microns.

32. The polymeric material of claim 25, further including a rate-controlling membrane.

33. The polymeric material of claim 32, wherein said rate-controlling membrane is formed to include a uniform distribution of a porosigen, said porosigen being selected from the group consisting of sodium chloride, lactose, sodium heparin, polyethylene glycol, polyethylene oxide/polypropylene oxide copolymers, and mixtures thereof.

34. The polymeric material of claim 32, wherein said rate-controlling membrane comprises a surface defining pores with a maximum cross-sectional dimension of about ten microns.

35. The polymeric material of claim 32, wherein said rate-controlling membrane comprises a surface defining pores with a maximum cross-sectional dimension of about one micron.

36. The polymeric material of claim 25, wherein said polymeric material containing said therapeutic drug is formed as a sheet at least about 25 microns thick.

37. The polymeric material of claim 36, wherein said sheet of polymeric material containing said therapeutic drug is further laminated to an intravascular stent structure.

38. A method of incorporating a therapeutically effective amount of a therapeutic drug into a polymeric material for application to an intravascular stent, the method comprising the steps of:

forming solid particles of a therapeutic drug to have a maximum cross-sectional dimension of about 10 microns;

uniformly dispersing said solid particles of said therapeutic drug in said polymeric material such that said particles of said therapeutic drug form up to about 70% by weight of the total weight of the therapeutic drug and the polymeric material;

uniformly dispersing a porosigen in said polymeric material together with said therapeutic drug, said porosigen being selected from the group consisting of sodium chloride, lactose, sodium heparin, polyethylene glycol, copolymers of polyethylene oxide and polypropylene oxide, and mixtures thereof; and

applying a rate-controlling membrane over said polymeric material to control the release rate of said therapeutic drug from said polymeric material, said rate controlling membrane being formed of a polymeric material selected from the group consisting of polycaprolactone, poly(ethylene-co-vinyl acetate), poly(vinylacetate), silicone gum rubber, poly-DL-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates, aliphatic polycarbonat polyphosphazenes, and mixtures thereof, said rate controlling membrane polymeric material containing a uniform dispersion of said porosigen.

39. An apparatus containing a therapeutic drug for application to an intravascular stent for carrying and delivering said therapeutic drug within a blood vessel in which said intravascular stent is placed, comprising:

a polymeric material having a thermal processing temperature no greater than about 100°

C;

particles of a therapeutic drug incorporated in said polymeric material;

a porosigen uniformly dispersed in said polymeric material, said porosigen being selected from the group consisting of sodium chloride, lactose, sodium heparin, polyethylene glycol, copolymers of polyethylene oxide and polypropylene oxide, and mixtures thereof; and

a rate-controlling membrane disposed over said polymeric material to control a rate of release of said therapeutic drug from said polymeric material, said rate controlling membrane being formed of a polymeric material selected from the group consisting of polycaprolactone, poly(ethylene-co-vinyl acetate), poly(vinyl acetate), silicone gum rubber, poly-DL-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, polyphosphazenes, and mixtures thereof, said rate controlling membrane polymeric material containing a uniform dispersion of said porosigen.