Des-methyl-tocopherol therapy for restenosis prevention

• US 8,101,199 B2
• Filed: 10/21/2004
• Issued: 01/24/2012
• Est. Priority Date: 10/21/2003
• Status: Expired due to Fees

• Current Assignee: Medlogics Device Corporation
• Original Assignee: Celonova Biosciences, Inc. (Boston Scientific Corporation)
• Inventors: Larrick, James W., Peacock, James C. III
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US10/595,453
• Publication Number:
  US 20070014827A1
• Time in Patent Office: 2,651 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61L 2300/258 Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
• 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 2300/428 Vitamins, e.g. tocopherol, riboflavin
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

A stent is provided in combination with delivery of a tocopherol agent, and in particular a des-methyl tocopherol agent, and further beneficially a gamma-tocopherol agent, so as to reduce restenosis along the vessel or other lumenal wall where the stent is implanted. In particular applications, the stent is an endolumenal stent, and more specific beneficial applications is an endovascular stent, and the gamma-tocopherol elutes from a coating or carrier coupled with the stent. Certain combinations are provided with the des-methyl-tocopherol or phytyl substituted chromanol, e.g. gamma-tocopherol, combined with an additional agent such as an anti-restenosis agent, e.g. sirolimus, tacrolimus, everolimus, or paclitaxel, in order to provide synergistic benefit to tissues along the stented or recanalized regions. Other forms of tocopherol or tocotrienol, or other phytyl substituted chromanols, and other compounds such as palm oil, are also contemplated, for use to treat restenosis.

Claims

1. A method for treating a patient, comprising:

delivering an angioplasty balloon to a site along a lumen in the patient;

inflating the balloon to contact a wall of the lumen at the site; and

locally delivering to the lumen wall at the site a volume of des-methyl tocopherol, or a precursor, analog, or derivative thereof.

2. The method of claim 1, wherein the des-methyl tocopherol is a gamma-tocopherol agent.

3. The method of claim 1, wherein said volume comprises a precursor of the des-methyl tocopherol that comprises a DNA plasmid encoding the production of the des-methyl tocopherol.

4. The method of claim 1, wherein said volume comprises a precursor of the des-methyl tocopherol that comprises a viral or non-viral gene vector encoding the production of the des-methyl tocopherol.

5. The method of claim 1, further comprising:

delivering an endolumenal stent to the site;

deploying the stent to contact the wall at the site; and

delivering the volume into the wall at the site from the deployed stent.

6. The method of claim 5, further comprising:

coating or adsorbing the stent with a delivery carrier containing the volume; and

delivering the volume to the wall at the site via release from the delivery carrier.

7. The method of claim 1, further comprising:

coupling said volume to the angioplasty balloon; and

delivering said volume to the wall at the site by releasing the volume from the angioplasty balloon.

8. The method of claim 1, further comprising:

administering a therapeutic dose of the des-methyl tocopherol in said volume in a manner providing a higher bioactivity of the of des-methyl tocopherol at said site than elsewhere in the body.

9. The method of claim 1, further comprising:

in combination with said volume of des-methyl tocopherol, delivering into the wall at the site a therapeutic dose of a second bioactive agent that is different from the des-methyl tocopherol.

10. The method of claim 9, wherein said second bioactive agent comprises an anti-restenosis agent delivered in a manner that provides a higher bioactivity at said site than elsewhere in the body.

11. The method of claim 10, wherein said dose of antirestenosis agent is delivered in a manner sufficient to inhibit restenosis at said site following balloon angioplasty or stent implantation.

12. The method of claim 10, wherein said antirestenosis agent comprises at least one agent selected from the group consisting of sirolimus, tacrolimus, everolimus, ABT-578, paclitaxel, dexamethasone, 17-betaestradiol, steroid, des-aspartate angiotensin I (DAA-1), angiotensin converting enzyme inhibitor (ACE inhibitor), angiotensin II receptor blocker, tachykinin, sialokinin, apocynin, pleiotrophin, exochelin, an iron chelator, VEGF, heparin, coumadin, clopidogrel, Ilb/IIIa inhibitor, nitric oxide, a nitric oxide donor, an eNOS antagonist, a nitric oxide synthesis promoter, and a statin, or a precursor, analog, or derivative thereof, or a combination or blend thereof.

13. The method of claim 9, further comprising:

locally delivering the first bioactive agent and second bioactive agent into the wall at the site.

14. The method of claim 12, further comprising:

eluting at least one of the des-methyl tocopherol and said second bioactive agent from the angioplasty balloon or an implanted stent into the wall at the site.

15. The method of claim 12, further comprising:

systemically delivering the other of the des-methyl tocopherol and the second bioactive agent.

16. The method of claim 9, further comprising:

eluting both the des-methyl tocopherol and the second bioactive agent from the angioplasty balloon or an implanted stent.

17. The method of claim 9, further comprising:

coating an implantable endolumenal stent with a porous non-polymeric carrier matrix;

holding the volume of des-methyl tocopherol principally within the porous metal carrier matrix;

delivering and deploying the stent to contact the wall at the site; and

eluting the volume from the matrix into the wall at the site from the deployed stent.

18. A system for treating a patient, comprising:

an angioplasty balloon that is deliverable to a site along a lumen in a patient and is inflatable to contact a wall of the lumen at the site;

a volume of a pharmaceutically acceptable preparation of des-methyl tocopherol, or a precursor, analog, or derivative thereof; and

a local drug delivery system coupled to the volume and configured to deliver the volume to the lumen wall at the site.

19. The system of claim 18, wherein:

said local drug delivery system comprises a carrier coupling the volume to at least one of the angioplasty balloon and an implantable endolumenal stent;

said volume is held and deliverable to the wall at the site via release from the carrier.