Nucleation of Drug Delivery Balloons to Provide Improved Crystal Size and Density

• US 20110015664A1
• Filed: 06/14/2010
• Published: 01/20/2011
• Est. Priority Date: 07/17/2009
• Status: Active Grant

• Current Assignee: Boston Scientific Scimed, Inc. (Boston Scientific Corporation)
• Original Assignee: Boston Scientific Scimed, Inc. (Boston Scientific Corporation)
• Inventors: Kangas, Steve, Ekberg, Dave, Patterson, Jon, Haun, Erik, Henderson, Eric, Chen, Yen-Lane, Owens, Michael Sean, Foss, Aaron
• Granted Patent: US 10,080,821 B2
• Time in Patent Office: Days
• US Class Current: 606/192
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2300/622 Microcapsules
• CPC Class Codes: A61L 2300/63 Crystals
• CPC Class Codes: A61L 29/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C08L 77/00 Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain of polyhydrazides C08L79/06; of polyamideimides or polyamide acids C08L79/08; Compositions of derivatives of such polymers

Abstract

Drug delivery balloons have densely packed crystals of small particle size of the drug thereon. An amorphous drug coating is applied to a balloon surface and annealed to provide the crystals. The balloon surface is nucleated to induce formation of drug crystals in the annealing step to provide the crystals in high density with small size.

Claims

1. A method of making a drug delivery balloon having a coating thereon comprising a drug, wherein the drug has characteristic amorphous and crystalline forms comprising:

a) applying a coating of the drug in amorphous form, and

b) annealing the coated balloon to produce a crystalline form of the drug on the balloon,

wherein in the applying step a) the drug coating is applied to a balloon surface that has been nucleated to induce formation of drug crystals in the annealing step.

2. A method as in claim 1 wherein the coated balloon is annealed in step b) with a solvent vapor.

3. A method as in claim 2 wherein the solvent vapor comprises an alcohol and water.

4. A method as in claim 1 wherein the balloon surface is nucleated by treatment with a nucleating agent for said drug.

5. A method as in claim 1 wherein the balloon surface is nucleated by blooming of a component in the balloon material to the surface thereof prior to applying the drug coating.

6. A method as in claim 5 wherein said blooming is facilitated by a pretreatment of the balloon surface prior to applying the drug coating.

7. A method as in claim 6 wherein said pretreatment comprises a solvent vapor annealing of the balloon.

8. A method as in claim 1 wherein the balloon material comprises a polyamide block copolymer.

9. A method as in claim 1 wherein the drug is applied to the device as a formulation with an excipient.

10. A method as in claim 9 wherein said excipient is a member of the group consisting of water soluble polymers, sugars, contrast agents, citrate esters, glycerol esters of short chain monocarboxylic acids and pharmaceutically acceptable salts.

11. A method as in claim 2 wherein in the annealing step the balloon is placed in an annealing chamber in which the solvent vapor, at the time the balloon is put into the chamber, is at a vapor pressure that is less than saturation at the temperature and pressure of the chamber.

14. A method as in claim 2 wherein the in the annealing step the solvent vapor is provided in an annealing chamber having a chamber volume to solvent surface ratio in the range of from about 35-75 ml/cm².

15. A method as in claim 1 wherein the balloon surface is nucleated with particulate nucleating agent on the surface of the balloon, said particulate nucleating agent having a major dimension in the size range of from about 10 nm to about 20 μ

m.

16. A method as in claim 15 wherein the particulate nucleating agent has a density on the balloon of from about 10 particle/mm² to about 5000 particles/mm²

17. A method as in claim 15 wherein the particulate nucleating agent has a density on the balloon of from about 100 particles/mm² to about 2000 particles/mm².

18. A method as in claim 1 wherein the drug is selected from the group consisting of paclitaxel, paclitaxel analogous and derivatives, rapamycin rapamycin analogous and derivatives, everolimus, everolimus analogous and derivatives, and mixtures thereof.

19. A method as in claim 1 wherein the drug is paclitaxel.

20. A drug delivery balloon produced by a method as in claim 18.

31. A method as in any one of claims 1-8 wherein the drug is applied to the device as a formulation without an excipient.

32. A method as in claim 1

wherein in the applying step a) the nucleation of the balloon surface provides a controlled distribution of drug crystals in the annealing step.

12-13. -13. (canceled)

21. A drug delivery balloon comprising a layer of crystalline drug particles of average length less than 100 μ

m length substantially uniformly distributed over the balloon.

22. A drug delivery balloon as in claim 21 wherein the crystalline drug particles have an average length in the range of 1 μ

m to 50 μ

m.

26. A drug delivery balloon as in claim 21 wherein the drug is paclitaxel.

23. A drug delivery balloon comprising a layer of crystalline drug particles of less than 100 μ

m average length on at least a portion of the surface of the balloon, said drug particles densely stacked substantially parallel to the surface of said portion.

24. A drug delivery balloon as in claim 23 wherein the layer of crystalline drug particles is less than 10 μ

m thick.

25. A drug delivery balloon as in claim 23 wherein the layer of crystalline drug particles is less than 2 μ

m thick.

27. A drug delivery balloon carrying crystalline paclitaxel on the surface thereof the balloon being characterized as delivering a particle count as counted with a laser particle counter in a closed loop recirculating artery model system in a 50-125 μ

m size range bin that are less than 50% of that of a commercial prior art control balloon having paclitaxel and iopromide excipient, over a total 4 minute interval during which the balloon is tracked to a deployment site, held at the site, deployed, removed and monitored for 2 minutes post-deployment.

28. A balloon as in claim 27 wherein said particle count is about 33% or less relative to said control balloon.

29. A drug delivery balloon carrying crystalline paclitaxel on the surface thereof the balloon being characterized as delivering in a recirculating ex-vivo porcine artery tissue model a tissue concentration of drug in tissue 4 hrs post-delivery of at least 300 ng/mg.

30. A drug delivery balloon as in claim 29 wherein said concentration is at least 400 ng/mg.

33-51. -51. (canceled)