Progenitor Endothelial Cell Capturing with a Drug Eluting Implantable Medical Device

• US 20070129789A1
• Filed: 11/20/2006
• Published: 06/07/2007
• Est. Priority Date: 03/15/2000
• Status: Abandoned Application

• Current Assignee: Orbusneich Medical Incorporated (Orbusneich Medical)
• Original Assignee: Orbusneich Medical Incorporated (Orbusneich Medical)
• Inventors: Rowland, Stephen, Cottone, Robert, Parker, Sherry
• Application Number:
  US11/561,730
• Publication Number:
  US 20070129789A1
• Time in Patent Office: Days
• US Class Current: 623/1.410
• CPC Class Codes: A61F 2/0077 Special surfaces of prostheses, e.g. for improving ingrowth A61F2/30767 takes precedence
• CPC Class Codes: A61F 2/91 made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• 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 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 2300/256 Antibodies, e.g. immunoglobulins, vaccines
• CPC Class Codes: A61L 2300/412 Tissue-regenerating or healing or proliferative agents
• 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 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2400/12 Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
• CPC Class Codes: A61L 2400/18 Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
• CPC Class Codes: A61L 2420/06 Coatings containing a mixture of two or more compounds
• CPC Class Codes: A61L 27/306 Other specific inorganic materials not covered by A61L27/303 - A61L27/32
• 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 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/106 : Inorganic materials other than carbon
• CPC Class Codes: A61L 29/146 : Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 29/16 : Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/047 : Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
• CPC Class Codes: A61L 31/088 : Other specific inorganic materials not covered by A61L31/084 or A61L31/086
• 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: C12N 2510/00 : Genetically modified cells
• CPC Class Codes: C12N 5/0692 : Stem cells; Progenitor cells; Precursor cells

Abstract

A medical device for implantation into vessels or luminal structures within the body is provided, which stimulates positive blood vessel remodeling. The medical device, such as a stent and a synthetic graft, is coated with a pharmaceutical composition consisting of a controlled-release matrix and one or more pharmaceutical substances for direct delivery of drugs to surrounding tissues. The coating on the medical device further comprises a ligand such as a peptide, an antibody or a small molecule for capturing progenitor endothelial cells in the blood contacting surface of the device for restoring an endothelium at the site of injury. In particular, the drug-coated stents are for use, for example, in balloon angioplasty procedures for preventing or inhibiting restenosis.

Claims

1. An implantable medical device having a luminal surface, an abluminal surface and a coating;

the coating comprising one or more layers of a matrix;

one or more pharmaceutical substances at least on the abluminal surface, and a ligand attached to said matrix and configured to capture circulating progenitor cells on at least the luminal surface of said device after implantation of said medical device into a patient.

2. The implantable medical device of claim 1, wherein the medical device is a stent, a vascular graft, a synthetic graft, a heart valve, a catheter, a vascular prosthetic filter, a pacemaker, a pacemaker lead, a defibrillator, a patent foramen ovale (PFO) septal closure device, a vascular clip, a vascular aneurysm occluder, a hemodialysis graft, a hemodialysis catheter, an atrioventricular shunt, an aortic aneurysm graft device or components, a venous valve, a sensor, a suture, a vascular anastomosis clip, an indwelling venous or arterial catheter, a vascular sheath and a drug delivery port.

3. The implantable medical device of claim 1, wherein the matrix comprises a polymer, or non-polymer material.

4. The implantable medical device of claim 3, wherein the non-polymer material is formed of a porous material comprising nanoparticles nanoparticles comprise a metal, or a metallic alloy.

5. The implantable medical device of claim 1, wherein the ligand is selected from the group consisting of an antibody, an antibody fragment or combinations thereof;

proteins;

peptides; and

small molecules.

6. The implantable medical device of claim 1, wherein the ligand has specificity to and binds an antigen or cell membrane molecule selected from the group consisting of CD133, CD45, CD34, CD31, CD14, CDw90, CD117, VEGFR-1, VEGFR-2, Muc-18 (CD146), CD130, stem cell antigen (Sca-1), stem cell factor 1 (SCF/c-Kit ligand), Tie-2, MHC H-2Kk and HLA-DR.

7. The implantable medical device of claim 3, wherein the non-polymer material comprises nanoparticles forming porous openings of from about 5 nm to about 5 μ

m in diameter and the ligand is an antibody, antibody fragments or combinations thereof.

8. The implantable medical device of claim 7, wherein the antibody or antibody fragment is anti-CD34 or anti-CD133.

9. The implantable medical device of claim 1, wherein the one or more pharmaceutical substance(s) is/are selected from the group consisting of vasodilators, antibiotics/antimicrobials, antiproliferative agents, antineoplastic agents, antioxidants, endothelial cell growth factors, smooth muscle cell growth and/or migration inhibitors, thrombin inhibitors, immunosuppressive agents, anti-platelet aggregation agents, collagen synthesis inhibitors, therapeutic antibodies, nitric oxide donors, antisense oligonucleotides, wound healing agents, therapeutic gene transfer constructs, peptides, proteins, extracellular matrix components, thrombolytics, anti-metabolites, growth factor agonists, antimitotics, steroids, steroidal antiinflammatory agents, chemokines, proliferator-activated receptor-alpha agonists, proliferator-activated receptor-delta agonists;

proliferator-activated receptor-gamma agonists, nonsterodial antiinflammatory agents, angiotensin converting enzyme(ACE) inhibitors, free radical scavangers, inhibitors of the CX3CR1 receptor and anti-cancer chemotherapeutic agents.

10. The implantable medical device of claim 1, wherein said one or more pharmaceutical substance(s) is/are selected from the group consisting of peroxisome proliferator-activated receptor-alpha agonists, peroxisome proliferator-activated receptor-delta agonists, peroxisome proliferator-activated receptor-gamma agonists, calcitonin gene related peptide (α

-CGRP), monocyte chemoattractant protein-1, adenosine, prostacyclins₁ tachykinins, sialokinins, neurokinins, aromatase inhibitors, plasminogen activator, erythropoietin, darbepotin, serine proteinase-1 (SERP-1), cyclosporin A, mycophenolic acid, mycophenolate mofetil acid, rapamycin, rapamycin derivatives, everolimus, sirolimus, pimecrolimus, tacrolimus, temsirolimus, zotarolimus, Biolimus A9₁ AP23573, ABT-578, tranilast, dexamethasone, azathioprene, corticosteroid, retinoic acid, vitamin E, rosglitazone, simvastatins, fluvastatin, estrogen, 17β

-estradiol, dihydroepiandrosterone, testosterone, puerarin, platelet factor 4, basic fibroblast growth factor, fibronectin, butyric acid, butyric acid derivatives, paclitaxel, paclitaxel derivatives and probucol and metalloproteinases.

11. The implantable medical device of claim 7, wherein said vasodilators comprise from about 1 to about 99% (w/w) of the composition.

12. The implantable medical device of claim 7, wherein said coating on said medical device comprises multiple layers comprising one or more vasodilators.

13. The implantable medical device of claim 1, wherein the one or more layers of matrix comprises at least one layer of dextran, collagen, fibrin, tropoelastin, elastin, cross-linked tropoelastin or extracellular matrix component.

17. A method for treating vascular disease, comprising implanting into a patient in need of treatment the implantable medical device of claim 1.

18. The method of claim 17, wherein said disease is artherosclerosis, restenosis, or blood vessel occlusion.

19. The method of claim 17, wherein said one or more pharmaceutical substance(s) induces the formation of endothelium on the luminal surface of the device at the site of blood vessel injury.

20. The method of claim 17, wherein said one or more pharmaceutical substance(s) inhibits smooth muscle cell migration and/or proliferation.

14. An implantable medical device having a luminal surface and a coating;

said coating comprising one or more layers of a dextran matrix;

one or more pharmaceutical substances for inhibiting smooth muscle cell migration and proliferation and an antibody with affinity and specificity for binding an endothelial cell surface antigen in vivo.

15. The implantable medical device of claim 14, wherein the one or more pharmaceutical substances is selected from the group consisting of rapamycin, rapamycin derivatives, everolimus, sirolimus, pimecrolimus, tacrolimus, temsirolimus, zotarolimus, Biolimus A9, AP23573, ABT-578, tranilast, dexamethasone, azathioprene, corticosteroid, retinoic acid, vitamin E, rosglitazone, simvastatins, fluvastatin, estrogen, 17β

-estradiol, dihydroepiandrosterone and paclitaxel.

16. The implantable medical device of claim 14, wherein the antibody is selected from the group consisting of CD133, CD45, CD34, CD31, CD14, CDw90, CD117, VEGFR-1, VEGFR-2, Muc-18 (CD146), CD130, stem cell antigen (Sca-1), stem cell factor 1 (SCF/c-Kit ligand), Tie-2, MHC H-2Kk and HLA-DR.