JP5555406B2 - Implantable medical device covering containing endothelial cell attractant - Google Patents

Description

Detailed Description of the Invention

[Cross-reference of related applications]
This application claims priority to US Provisional Application No. 60/654212, filed Feb. 17, 2005, the teachings of which are incorporated herein by reference.
[background]

[Field of the Invention]
The present invention relates generally to coatings for implantable medical devices such as drug delivery vascular stents.
[Description of related technology]

  Percutaneous coronary intervention (PCI) is a treatment to treat heart disease. A catheter assembly having a balloon portion is percutaneously introduced into the patient's cardiovascular system via the brachial artery or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once placed across the lesion, the balloon is inflated to a predetermined size to radially push the lesion's atherosclerotic plaque and remodel the lumen wall. The balloon is then deflated to a smaller profile so that the catheter can be withdrawn from the patient's vasculature.

  Problems associated with the procedure include the formation of intimal flaps or damaged arterial linings that can collapse after the balloon is deflated and occlude blood conduits. Moreover, arterial thrombosis and restenosis may develop for several months after this procedure, which may require another angioplasty procedure or surgical bypass surgery. To reduce partial or total occlusion of the artery due to collapse of the arterial lining and reduce the likelihood of thrombosis or restenosis, a stent is implanted in the artery and the artery is kept open.

  Drug delivery stents have reduced the incidence of post-PCI in-stent restenosis (ISR), which has been a challenge for cardiovascular intervention for over a decade (see, for example, Serruys, PW, et al., J. Am. Coll. Cardiol. 39: 393-399 (2002)). However, given the high volume of coronary intervention and its expanding use, ISR still poses a major problem. The pathophysiological mechanism of ISR involves interactions between cellular and acellular components of blood vessel walls and blood. Damage to the endothelium during PCI constitutes a major factor in the development of ISR (see, eg, Kipsidze, N., et al., J. Am. Coll. Cardiol. 44: 733-739 (2004)).

Embodiments of the present invention address these issues as well as other issues that will be apparent to those skilled in the art.
[Overview]

  In the present invention, a coating containing a chemoattractant for endothelial cells is provided. This coating can provide controlled release of the chemoattractant. In some embodiments, the coating can include one or more polymers that can control the release of the chemoattractant. The chemoattractant is in an amount sufficient to recruit endothelial cells or endothelial progenitor cells to the surface, through the polymer coating, through the layer of absorbed protein and cells (acute phase after implantation), and the neointimal (long term phase) Can diffuse through the lumen surface.

  In some embodiments, the release profile includes an initial burst release of chemoattractant followed by a sustained release. In some other embodiments, the release profile may be zero order sustained release.

  The chemoattractant and optionally other bioactive agents can be mixed into the coating in the form of a substrate. The chemoattractant can be formulated in a coating with one or more biocompatible polymers, which in some embodiments can be an amphiphilic block copolymer. In some embodiments, the chemoattractant can be bound to the coating via physical or chemical bonds. The physical bond may be, for example, a hydrogen bond or an interpenetrating network. Chemical bonding can occur through a linking agent.

  Any bioactive agent can be included in the coating along with the chemoattractants described herein. Some examples of bioactive agents include siRNA and / or other oligonucleotides that block endothelial cell migration. The bioactive agent may be lysophosphatidic acid (LPA) or sphingosine-1-phosphate (S1P). LPA is a “bioactive” phospholipid capable of producing growth factor-like activity in a wide variety of normal and malignant cell types. LPA plays an important role in normal physiological processes such as wound healing and in vascular tone, vascular integrity, or reproduction. Some other representative bioactive agents are paclitaxel, docetaxel, estradiol, 17β-estradiol, nitric oxide donor, superoxide dismutase, superoxide dismutase mimic, 4-amino-2,2,6,6 -Tetramethylpiperidine-1-oxyl (4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, rapamycin, rapamycin derivative, 40-O- (2-hydroxy) ethyl-rapamycin (everolimus), 40-O- (3- Hydroxy) propyl-rapamycin, 40-O- [2- (2-hydroxy) ethoxy] ethyl-rapamycin, and 40-O-tetrazole-rapamycin, 40-epi- (N1-tetrazolyl) rapamycin (ABT-578), gamma -Hydride Hiridoun, clobetasol, pimecrolimus, imatinib mesylate, midostaurine, its prodrug, its codrug, and combinations thereof.

The coating can be formed on an implantable device such as a stent that can be implanted in a patient to treat, prevent, alleviate, or reduce vascular conditions or provide a healing-enhancing effect. Examples of such conditions include atherosclerosis, thrombosis, restenosis, bleeding, vascular dissection or vascular perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, lameness (for veins and artificial grafts ) Anastomotic growth, bile duct obstruction, ureteral obstruction, neoplastic obstruction, or combinations thereof.
[Detailed description]

  In the present invention, a coating comprising a chemoattractant for endothelial cells is provided. This coating can provide controlled release of the chemoattractant. In some embodiments, the coating can include one or more polymers that can control the release of the chemoattractant. The chemoattractant is in an amount sufficient to recruit endothelial cells or endothelial progenitor cells to the surface, through the polymer coating, through the layer of absorbed protein and cells (acute phase after implantation), and the neointimal (long term phase) Can diffuse through the lumen surface.

  In some embodiments, the release profile includes an initial burst release of chemoattractant followed by a sustained release. In some other embodiments, the release profile may be zero order sustained release.

  A chemoattractant and optionally other bioactive agents can be mixed into the coating. In some embodiments, a blend or mixture of chemoattractant and coating material can form a substrate. The chemoattractant can be formulated in a coating with one or more biocompatible polymers, which in some embodiments can be an amphiphilic block copolymer. In some embodiments, the chemoattractant can be bound to the coating via physical or chemical bonds. The physical bond may be, for example, a hydrogen bond or an interpenetrating network. Chemical bonding can occur through a linking agent.

  In these or other embodiments, the chemoattractant can be bound to the surface of the medical device. In some of these embodiments, if the medical device is formed of a polymer or a metal coated with a polymer, the surface is a modified metal surface (eg, modified with siloxane) Alternatively, it may be a polymer surface. The chemoattractant can be bound to the coating using physical or chemical bonds.

  The physical bond may be, for example, a hydrogen bond, an interpenetrating molecule, or an interpenetrating network. For chemical bonding, a linking agent or a direct bond between the surface and the coating material can be used.

  Any bioactive agent can be included in the coating along with the chemoattractants described herein. Some examples of bioactive agents include siRNA and / or other oligonucleotides that block endothelial cell migration. The bioactive agent may be lysophosphatidic acid (LPA) or sphingosine-1-phosphate (S1P). LPA is a “bioactive” phospholipid capable of producing growth factor-like activity in a wide variety of normal and malignant cell types. LPA plays an important role in normal physiological processes such as wound healing and in vascular tone, vascular integrity, or reproduction. Some other representative bioactive agents are paclitaxel, docetaxel, estradiol, 17β-estradiol, nitric oxide donor, superoxide dismutase, superoxide dismutase mimic, 4-amino-2,2,6,6 Tetramethylpiperidine-1-oxyl (4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, rapamycin, rapamycin derivative, 40-O- (2-hydroxy) ethyl-rapamycin (everolimus), 40-O- (3- Hydroxy) propyl-rapamycin, 40-O- [2- (2-hydroxy) ethoxy] ethyl-rapamycin, and 40-O-tetrazole-rapamycin, 40-epi- (N1-tetrazolyl) rapamycin (ABT-578), gamma -Hydride Ung, clobetasol, pimecrolimus, imatinib mesylate, midostaurine, its prodrug, its codrug and combinations thereof.

  The coating can be formed on an implantable device such as a stent that can be implanted in a patient to treat, prevent, alleviate, or reduce vascular conditions or provide a healing-enhancing effect. Examples of such conditions include atherosclerosis, thrombosis, restenosis, bleeding, vascular dissection or vascular perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, lameness, anastomotic growth (in veins and artificial grafts) In contrast, biliary obstruction, ureteral obstruction, neoplastic obstruction, or combinations thereof.

Chemoattractant As used herein, a chemoattractant includes any synthetic or natural molecule that can attract endothelial cells. In some embodiments, the chemoattractant comprises any synthetic or natural molecule that can attract an effective number of endothelial cells. Attractors generally have some degree of selectivity for these cells. Chemoattractants also include any synthetic or natural molecule that can bind to an adhesion receptor that is differentially expressed on endothelial cells. One such adhesion receptor can be an integrin. Some representative chemoattractants include, but are not limited to, integrin-binding small molecules, RGD peptides or cyclic RGD peptides (cRGD), synthetic cyclic RGD (cRGD) mimetics, and differential expression on endothelial cells Small molecules that bind to other adhesion receptors.

  In some embodiments, the chemoattractant can specifically exclude certain RGD peptides or cyclic RGD peptides (cRGD).

  In some embodiments, the chemoattractant can be a molecule that can bind to an ICAM (intercellular adhesion molecule) molecule or a VCAM (vascular cell adhesion molecule) molecule present in endothelial cells. Such chemoattractants can include, for example, receptors bound to ICAM or VCAM in endothelial cells, including but not limited to decoy receptor 3 (DcR3), Tumor necrosis factor (TNF), which binds preferentially to ICAM and VCAM, β_2 integrin LFA (expressed in lymphocytes) with higher conformational changes in the extracellular region and increased binding affinity for the ligand ICAM-1 -1 (LFA-1Af), or a combination thereof.

  In some embodiments, the chemoattractant can be used as a capsule shape, eg, an encapsulate in other materials such as liposomes or biodegradable polymers. The encapsulated chemoattractant can be used with a catheter and, in some embodiments, can subsequently be released from the catheter.

cRGD Mimics or RGD Mimetics The cRGD mimics or RGD mimics described herein include any peptide or peptidomimetic that results from modification of a cyclic Arg-Gly-Asp peptide. This modification can be made to the pendant group and / or the backbone of the peptide. Peptide synthesis, including the synthesis of peptidomimetics, is well documented and can be easily achieved using, for example, combinatorial chemistry.

Some examples of cRGD mimics or RGD mimics include α _v β ₃ antagonists such as IIb / IIIb antagonists (Coller, BS, Thromb. Haemost. 86 (1): 427-43 (2001) (review)) ( One example is Abciximax (Blindt, R., J. Mol. Cell. Cardiol. 32: 2195-2206 (2000))), XJ 735 (Srivatsa, SS, et al., Cardiovasc. Res. 36: 408 -428 (1997)), anti-β ₃ integrin antibody Fl1, cRGD (Sajid, M., et al, Am J. Physiol Cell Physiol, 285:.... C1330-1338 (2003)), as well as laminin-derived SIKVAV ( Fittkau, MH, et al, Biomaterials, 26: 167-174 (2005)), YIGSR derived from laminin (Kouvroukoglou, S., et al, Biomaterials, 21: 1725-1733 (2000)), KQAGDV, and VAPG (Mann, BK, J. Biomed. Mater. Res. 60 (1): 86-93 (2002)).

  The basic procedure for peptide synthesis including peptidomimetics is described below.

  Prior to initiating peptide synthesis, the amine terminus of the amino acid (starting material) is protected with FMOC (9-fluoromethylcarbamate) or other protecting group and a solid support such as Merrifield resin (free amine) is used as the initiator . Next, the reaction from step (1) to step (3) is performed and repeated until the desired peptide is obtained. (1) react the free amine with the carboxyl terminus using carbodiimide chemistry, (2) purify the amino acid sequence, (3) remove protecting groups such as FMOC protecting groups under mildly acidic conditions to obtain the free amine . The peptide can then be cleaved from the resin to yield the free intact peptide or peptidomimetic.

  In some embodiments, the coating can exclude and exclude any of the chemoattractants described above. For example, the coating can exclude and exclude RGD peptides or cyclic RGD peptides (cRGD).

In some embodiments, the chemoattractant can be attached to the polymer substrate by a labile linker or by physical interaction such as an interpenetrating network. The labile linker can be a linker that is sensitive to stimuli. For example, the linker may be a hydrolyzable linker or an enzyme-degradable linker.

Hydrolyzable linkers can degrade in the presence of water under physiological conditions. In other words, the stimulus for the hydrolyzable linker is the presence of water. The hydrolyzable linker can bond the chemoattractant and the polymer by the reactive group of the linker. For example, in some embodiments, the linker can be an amino acid group that includes an amino group, a thiol group, and / or a carboxylic acid group. Some representative strategies for forming hydrolyzable linkers include:
(1) The ε-amino group of lysine (which can be incorporated into the polymer) and the α-amino group of the protein. The amine can be on the polymer backbone (with or without spacers such as PEG or alkyl chains). Thereby, an amide bond, a thiourea bond, an alkylamine bond, or a urethane bond is obtained.
(2) A thiol group or a free cysteine that forms a thioether bond.
(3) A thiol group on cysteine capable of binding to vinyl sulfone (R—SO ₂ —CH═CH ₂ ).
(4) Carboxylic acid groups on aspartic acid and glutamic acid.
Is included.

  As some examples of hydrolyzable linkages, an amide bond, disulfide (R-L1-SS), which can be generated by reacting an amine group with a succinate such as N-hydroxysuccinimide (NHS). -L2-R ') where the length of linkers L1 and L2 controls hydrolysis, or the carboxy terminus of the peptide has a polymer backbone (spacer, eg PEG or alkyl chain, or Ester bonds formed by coupling with hydroxyls on (not). Esterification can be performed using methods established in the art (eg, carbodiimide chemistry in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC)).

  Enzymatic degradable linkers / linkages can be degraded by enzymes and often target specific regions of the body or organ. In other words, the stimulus for the enzyme-degradable linker is the presence of the enzyme. For example, a particular dipeptide sequence can be incorporated into a linker that can be cleaved by an enzyme. Some examples of enzymatically degradable linkers or linkages include, but are not limited to, dipeptides such as self-sacrificing p-aminobenzyloxycarbonyl (PABC) spacers between dipeptides and polymers, phenylaniline-lysine, valine-cysteine PEG / dipeptide bonds such as alanyl-valine, alanyl-proline, glycyl-proline.

  Some other linkers / linkages are described in “Biodegradable Polymers for Protein and Peptide Drug Delivery” Bioconjugate Chem. 1995, 6: 332-351; MP Lutolf and JA Hubbell, Biomacromolecules 2003, 4.313-722; and US Patent Application No. 10/871658. Can be found in the issue description. Some additional representative coupling chemistries are described in US patent application Ser. No. 10 / 871,658, the entire disclosure of which is incorporated herein by reference.

Biocompatible Polymers Any biocompatible polymer can form a film with the chemoattractants described herein. The biocompatible polymer may be biodegradable (both bioerodible or bioabsorbable) or non-degradable, and may be hydrophilic or hydrophobic.

  Representative biocompatible polymers include, but are not limited to, poly (ester amide), polyhydroxyalkanoate (PHA), poly (3-hydroxypropanoate), poly (3-hydroxybutyrate), poly ( Poly (3-hydroxyalkanoate) such as 3-hydroxyvalerate), poly (3-hydroxyhexanoate), poly (3-hydroxyheptanoate), poly (3-hydroxyoctanoate), poly (4 Poly (4-hydroxybutyrate), poly (4-hydroxyvalerate), poly (4-hydroxyhexanote), poly (4-hydroxyheptanoate), poly (4-hydroxyoctanoate), etc. Alkanoate), and a 3-hydroxyalkanoate monomer described herein or 4 Copolymers or blends thereof containing any of the hydroxyalkanoate monomers, poly (D, L-lactide), poly (L-lactide), polyglycolide, poly (D, L-lactide-co-glycolide), poly (L- Lactide-co-glycolide), polycaprolactone, poly (lactide-co-caprolactone), poly (glycolide-co-caprolactone), poly (dioxanone), poly (orthoester), poly (anhydride), poly (tyrosine carbonate) and Its derivatives, poly (tyrosine ester) and its derivatives, poly (iminocarbonate), poly (glycolic acid-co-trimethylene carbonate), polyphosphate ester, polyphosphate ester urethane, poly (amino acid), polycyanoacrylate, poly ( Trimethyle Carbonates), poly (iminocarbonates), polyurethanes, polyphosphazenes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alpha olefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride, polyvinyl methyl ether, etc. Polyvinyl ethers, polyvinylidene halides such as polyvinylidene chloride, polyacrylonitrile, polyvinyl ketone, polyvinyl aromatics such as polystyrene, polyvinyl esters such as polyvinyl acetate, ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, Copolymers of vinyl monomers such as ethylene-vinyl acetate copolymer and olefins Mer, nylon 66, polyamide such as polycaprolactam, alkyd resin, polycarbonate, polyoxymethylene, polyimide, polyether, poly (glyceryl sebacate), poly (propylene fumarate), poly (n-butyl methacrylate), poly (sec -Butyl methacrylate), poly (isobutyl methacrylate), poly (tert-butyl methacrylate), poly (n-propyl methacrylate), poly (isopropyl methacrylate), poly (ethyl methacrylate), poly (methyl methacrylate), epoxy resin, polyurethane , Rayon, rayon triacetate, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ester Ter, carboxymethyl cellulose, polyethers such as poly (ethylene glycol) (PEG), copoly (ether esters) (eg, poly (ethylene oxide / poly (lactic acid) (PEO / PLA)), poly (ethylene oxide), poly (propylene oxide) ) And other polyalkylene oxides, poly (ether esters), polyalkylene oxalates, polyphosphazenes, phosphorylcholines, cholines, poly (aspirins), 2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropyl methacrylamide Polymers and copolymers of hydroxyl-containing monomers such as PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethyl phosphoryl Choline (MPC), and carboxylic acid-containing monomers such as n-vinylpyrrolidone (VP), methacrylic acid (MA), acrylic acid (AA), alkoxy methacrylate, alkoxy acrylate, 3-trimethylsilylpropyl methacrylate (TMSPMA), poly (styrene) -Isoprene-styrene) -PEG (SIS-PEG), polystyrene-PEG, polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG, poly (methyl methacrylate) -PEG (PMMA-PEG), Polydimethylsiloxane-co-PEG (PDMS-PEG), poly (vinylidene fluoride) -PEG (PVDF-PEG), PLURONIC ™ surfactant (polypropylene oxide-co-polyethylene glycol), Li (tetramethylene glycol), hydroxy-functional poly (vinyl pyrrolidone), chitosan, alginate, fibrin, fibrinogen, cellulose, starch, dextran, dextrin, hyaluronic acid fragments and derivatives, heparin, heparin fragments and derivatives, glycosami Examples include biomolecules such as noglycan (GAG), GAG derivatives, polysaccharides, chitosan, alginate, or combinations thereof. In some embodiments, the copolymers described herein can exclude any one of the aforementioned polymers.

  As used herein, each of poly (D, L-lactide), poly (L-lactide), poly (D, L-lactide-co-glycolide), and poly (L-lactide-co-glycolide) The terms are poly (D, L-lactic acid), poly (L-lactic acid), poly (D, L-lactic acid-co-glycolic acid), or poly (L-lactic acid-co-glycolic acid), respectively. Can be used interchangeably.

Biobeneficial Material In some embodiments, a chemoattractant can be included in the coating along with the biobeneficial material. The formulations can be mixed, blended, or patterned or arranged in separate layers. Biobeneficial materials useful in the coatings described herein can be polymeric or non-polymeric. The biobeneficial material is preferably sufficiently non-toxic, non-antigenic and non-immunogenic so that it can be successfully introduced into a patient. Biobeneficial materials are non-contaminating, blood compatible, effective non-thrombogenic, or anti-inflammatory, all of which are independent of the release of pharmaceutically active agents, so It enhances compatibility.

  Representative biobeneficial materials include, but are not limited to, polyethers such as poly (ethylene glycol) and copoly (ether ester), polyalkylene oxides such as poly (ethylene oxide) and poly (propylene oxide), poly (ether) Esters), polyalkylene oxalates, polyphosphazenes, phosphorylcholines, cholines, poly (aspirins), hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), polymers and copolymers of hydroxyl-containing monomers such as hydroxypropyl methacrylamide, poly ( Ethylene glycol) acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethyl phosphorylcholine (MPC) and n-vinylpyrrolidone (V ), Methacrylic acid (MA), acrylic acid (AA), alkoxy methacrylate, alkoxy acrylate and carboxylic acid-containing monomers such as 3-trimethylsilylpropyl methacrylate (TMSPMA), poly (styrene-isoprene-styrene) -PEG (SIS-PEG) , Polystyrene-PEG, polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG, poly (methyl methacrylate) -PEG (PMMA-PEG), polydimethylsiloxane-co-PEG (PDMS-PEG), Poly (vinylidene fluoride) -PEG (PVDF-PEG), PLURONIC ™ surfactant (polypropylene oxide-co-polyethylene glycol), poly (tetramethylene glycol), hydroxy Active poly (vinyl pyrrolidone), fibrin, fibrinogen, cellulose, starch, dextran, dextrin, hyaluronic acid, fragments and derivatives of hyaluronic acid, heparin, fragments and derivatives of heparin, glycosaminoglycan (GAG), GAG derivatives, poly Saccharides, chitosan, alginate, silicone, PolyActive ™, and combinations thereof. In some embodiments, the coating can exclude any of the aforementioned polymers.

  The term PolyActive ™ refers to a block copolymer having flexible poly (ethylene glycol) and poly (butylene terephthalate) blocks (PEGT / PBT). PolyActive ™ is an AB, ABA, BAB copolymer (eg, poly (ethylene glycol) -block-poly (butylene terephthalate) -block poly (ethylene glycol) (PEG-PBT-PEG) having segments such as PEG and PBT. ) Is intended to be included.

  In a preferred embodiment, the biobeneficial material can be a polyether such as poly (ethylene glycol) (PEG) or polyalkylene oxide.

Bioactive Agents In some embodiments, the coating having one or more chemoattractants described herein can optionally include one or more bioactive agents. Such a bioactive agent can be any agent that is a therapeutic, prophylactic, or diagnostic agent. These agents can have anti-proliferative or anti-inflammatory properties, or anti-tumor, anti-platelet, anti-coagulant, anti-fibrin, anti-thrombotic, anti-mitotic, anti-microbial, anti-anti-tumor It can have other properties such as allergic or antioxidant properties.

  These agents are cell division inhibitors, agents that promote endothelial healing (independent of NO release or generation), or promote endothelial cell attachment, migration, and proliferation while inhibiting smooth muscle cell proliferation Can be a drug to do. Examples of suitable therapeutic and prophylactic agents include synthetic inorganic and synthetic organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activity Can be given. Nucleic acid sequences include genes, antisense molecules that bind to complementary DNA and inhibit transcription, and ribozymes. Other examples of bioactive agents include antibodies, receptor ligands, enzymes, adhesion peptides, blood clotting factors, streptokinase, tissue plasminogen activator and other inhibitors or thrombolytic agents, immunizing antigens, hormones and growth Factors, oligonucleotides such as antisense oligonucleotides, and ribozymes, and retroviral vectors for use in gene therapy. Examples of antiproliferative agents include rapamycin and its functional or structural derivatives, 40-O- (2-hydroxy) ethyl-rapamycin (everolimus), and its functional or structural derivatives, paclitaxel and its functional derivatives and Structural derivatives are mentioned. Examples of rapamycin derivatives include ABT-578, 40-O- (3-hydroxy) propyl-rapamycin, 40-O- [2- (2-hydroxy) ethoxy] ethyl-rapamycin and 40-O-tetrazole-rapamycin. It is done. An example of a paclitaxel derivative is docetaxel. Examples of anti-tumor and / or anti-mitotic agents include methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (eg, Adriamycin® from Pharmacia & Upjohn, Peapack NJ, and Mycin) For example, Bristol-Myers Squibb Co., Tamford, Conn. (Mutamycin®). Examples of such antiplatelet drugs, anticoagulants, antifibrin substances, and antithrombin substances include heparin sodium, low molecular weight heparin, heparinoid, hirudin, argatroban, forskolin, bapiprost, prostacyclin and prostacyclin analogs, dextran , D-phe-pro-arg-chloromethyl ketone (synthetic antithrombin substance), dipyridamole, glycoprotein IIb / IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, Angiomax (Biogen, Inc., Cambridge, Mass.), Etc. Thrombin inhibitors, calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGP) antagonist, fish oil (ω3-fatty acid), histamine Tagonist, lovastatin (inhibitor of HMG-CoA reductase, cholesterol-lowering drug, trade name Mevacor® from Merck & Co., Inc., Whitehouse Station, NJ), monoclonal antibody (platelet derived growth factor (PDGF) receptor) Specific, etc.), nitroprusside, phosphodiesterase inhibitor, prostaglandin inhibitor, suramin, serotonin blocker, steroid, thioprotease inhibitor, triazolopyrimidine (PDGF antagonist), superoxide dismutase, superoxide dismutase mimic 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol, Cancer agents, dietary supplements such various vitamins, and combinations thereof. Examples of anti-inflammatory drugs, including steroidal and non-steroidal anti-inflammatory drugs, include biolimus, tacrolimus, dexamethasone, clobetasol, corticosteroids or combinations thereof. Examples of such cell division inhibitors include angiopeptin and captopril (for example, Capoten® and Capozide® or Caprazide® from Bristol-Myers Squibb Co., Stamford, Conn.) Angiotensin converting enzyme inhibitors such as (eg, Privilil® and Prinzide® from Merck & Co., Inc., Whitehouse Station, NJ). An example of an antiallergic agent is permirolast potassium. Other therapeutic agents or drugs that may be suitable include alpha interferon, pimecrolimus, imatinib mesylate, midostaurin and genetically modified epithelial cells. The aforementioned substances can also be used in the form of their prodrugs or codrugs. The aforementioned substances can also include their metabolites and / or prodrugs of the metabolites. The foregoing materials are listed by way of example and are not intended to be limiting. Other active agents currently available or other active agents that may be developed in the future are equally applicable.

  The dose or concentration of bioactive agent required to produce a favorable therapeutic effect should be below the level at which the bioactive agent produces a toxic effect and above a level where no therapeutic results are obtained. The dose or concentration of the bioactive agent depends on the patient's specific circumstances, the nature of the injury, the nature of the desired treatment, the time that the administered component is present at the vascular site, and the substance or substance if other active agents are used. May depend on factors such as the nature or type of the combination. A therapeutically effective dose is, for example, injected into a blood vessel from a suitable animal model system and detecting the drug and its effects using immunohistochemistry, fluorescence or electron microscopy, or appropriate This can be determined experimentally by conducting in vitro studies. Standard pharmacological test methods for determining doses are understood by those skilled in the art.

Implantable Device Examples As used herein, an implantable device can be any suitable medical substrate that can be implanted in a human or animal patient. Examples of such implantable devices include self-expanding stents, balloon expandable stents, stent-grafts, grafts (eg, aortic grafts), heart valve prostheses (eg, prosthetic heart valves) or vascular grafts, Devices that promote anastomosis such as cerebrospinal fluid shunts, pacemaker electrodes, catheters, endocardial leads (eg, FINELINE and ENDOTAK available from Guidant Corporation, Santa Clara, Calif.), And the like. The underlying structure of the brace can be of virtually any design. The orthosis is not limited thereto, but includes cobalt chrome alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, such as BIODUR 108, cobalt chrome alloy L-605, "MP35N", "MP20N", ELASTIN1TE (Nitinol) , Tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or a combination thereof, or a metal material or alloy. “MP35N” and “MP20N” are registered in Standard Press Steel Co. , Jenkintown, Pa., Trade name for alloys of cobalt, nickel, chromium and molybdenum. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. A brace made from a bioabsorbable polymer or a biostable polymer could also be used in embodiments of the present invention. The appliance can be, for example, a bioabsorbable stent.

Methods of Use According to embodiments of the present invention, a chemoattractant can be included in an implantable brace or prosthesis, such as a stent. For appliances that include one or more active agents, during delivery and expansion of the appliance, the drug will remain on the appliance, such as a stent, and will be released at the implantation site at the desired rate for a predetermined duration. .

  The brace is preferably a stent. The stents described herein are useful in a variety of medical procedures including, for example, treatment of obstruction caused by a tumor in the bile duct, esophagus, trachea / bronchi and other in vivo passageways. Stents having the coating described above are particularly useful for treating occluded areas of blood vessels caused by abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis and restenosis. Stents can be placed in various blood vessels, both arteries and veins. Representative examples of sites include the iliac artery, renal artery, and coronary artery.

  For stent implantation, an angiogram is first performed to determine the appropriate location for stent treatment. Angiography is usually realized by injecting an X-ray contrast medium through a catheter inserted into an artery or vein when imaging with x-rays. The guide wire is then advanced through the lesion or proposed treatment site. A delivery catheter is passed over the guide wire that allows the stent to be inserted into the passage in a collapsed configuration. The delivery catheter is inserted percutaneously or surgically into the femoral artery, brachial artery, femoral vein or brachial vein and advanced through the vasculature into the appropriate blood vessel by manipulating the catheter under fluoroscopic guidance . The stent with the coating described above is then expanded at the desired treatment area. An appropriate position can be confirmed using angiography after insertion.

While particular embodiments of the present invention have been shown and described, it will be apparent to those skilled in the art that changes and modifications can be made in a broader manner without departing from the invention. Accordingly, the appended claims are to encompass within their scope all such changes and modifications as fall within the spirit and scope of this invention.

Claims (21)

A medical device comprising a chemoattractant for endothelial cells,
The chemoattractant, decoy receptor 3 (DcR3) or β_2 integrin LFA-1 (LFA-1Af) Ru der, medical device.   The medical device of claim 1 having a coating comprising a polymer and the chemoattractant.   The medical device of claim 2, wherein a linker attaches the chemoattractant to the polymer.   The medical device according to claim 3, wherein the linker is a hydrolyzable linker or a proteolytic linker.   The medical device according to claim 3, wherein the linker is an enzyme-degradable linker.   The medical device according to claim 3, wherein the linker comprises poly (ethylene glycol) (PEG) or an alkyl chain.   The medical device according to claim 4, wherein the hydrolyzable linker is selected from the group consisting of an amide bond, a thiol bond, an ester bond, a thiourea bond, an alkylamine bond, a urethane bond, a thioether bond, and combinations thereof.   The medical device according to claim 4, wherein the hydrolyzable linker includes a cysteine unit, an aspartic acid unit, a glutamic acid unit, or a combination thereof.   The medical device according to claim 3, wherein the linker is a biodegradable polymer.   The medical device of claim 5, wherein the enzyme-degradable linker comprises a dipeptide sequence.   The medical device according to claim 5, wherein the enzyme-degradable linker includes a spacer.   The spacer is selected from the group consisting of p-aminobenzyloxycarbonyl (PABC), dipeptide, PEG and combinations thereof, wherein the dipeptide is phenylaniline-lysine, valine-cysteine, alanyl-valine, alanyl-proline, glycyl. 12. The medical device of claim 11 selected from the group consisting of proline and combinations thereof.   The medical device of claim 1, wherein the chemoattractant can be released from a catheter.   The medical device according to claim 2, further comprising a bioactive agent.   Paclitaxel, docetaxel, estradiol, 17-β-estradiol, nitric oxide donor, superoxide dismutase, superoxide dismutase mimic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4- Amino-TEMPO), biolimus, tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O- (2-hydroxy) ethyl-rapamycin (everolimus), 40-O- (3-hydroxy) propyl-rapamycin, 40-O- [ 2- (2-Hydroxy) ethoxy] ethyl-rapamycin and 40-O-tetrazole-rapamycin, 40-epi- (N1-tetrazolyl) -rapamycin (ABT-578), gamma-hiridun, clobeta The medical device according to claim 2, further comprising a bioactive agent selected from the group consisting of sol, pimecrolimus, imatinib mesylate, midostaurin, a prodrug thereof, a codrug thereof, and combinations thereof.   A bioactive agent selected from the group consisting of siRNA, oligonucleotides that inhibit endothelial cell migration, lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P), prodrugs, codrugs, and combinations thereof The medical device according to claim 2, further comprising:   The medical device according to claim 1, which is a stent.   The medical device according to claim 2, which is a stent.   The medical device according to claim 15, which is a stent.   The medical device according to claim 1, which is a bioabsorbable stent. The medical device according to claim 15, which is a bioabsorbable stent.