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EP1523345A1 - Dispositifs medicaux comprenant un inhibiteur de proteine-tyrosine kinase utilises pour inhiber la restenose - Google Patents

Dispositifs medicaux comprenant un inhibiteur de proteine-tyrosine kinase utilises pour inhiber la restenose

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Publication number
EP1523345A1
EP1523345A1 EP03765751A EP03765751A EP1523345A1 EP 1523345 A1 EP1523345 A1 EP 1523345A1 EP 03765751 A EP03765751 A EP 03765751A EP 03765751 A EP03765751 A EP 03765751A EP 1523345 A1 EP1523345 A1 EP 1523345A1
Authority
EP
European Patent Office
Prior art keywords
protein
tyrosine kinase
kinase inhibitor
stent
medical device
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03765751A
Other languages
German (de)
English (en)
Inventor
Patrice Tremble
Wenda Carlyle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medtronic Vascular Inc
Original Assignee
Medtronic AVE Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medtronic AVE Inc filed Critical Medtronic AVE Inc
Publication of EP1523345A1 publication Critical patent/EP1523345A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes

Definitions

  • the present invention relates to medical devices and methods of using medical devices to treat or inhibit restenosis. Specifically, the present invention relates to stents that provide in situ controlled release delivery of anti-restenotic compounds. More specifically, the present invention provides vascular stents that provide anti-restenotic effective amounts of imatinib mesylate directly to tissues at risk for restenosis.
  • Athersclerosis is a multifactorial disease that results in a narrowing, or stenosis, of a vessel lumen.
  • pathologic inflammatory responses resulting from vascular endothelium injury causes monocytes and vascular smooth muscle cells (VSMCs) to migrate from the sub endothelium and into the arterial wall's intimal layer. There the VSMC proliferate and lay down an extracellular matrix causing vascular wall thickening and reduced vessel patency.
  • VSMCs vascular smooth muscle cells
  • Cardiovascular disease caused by stenotic coronary arteries is commonly treated using either coronary artery by-pass graft (CABG) surgery or angioplasty.
  • Angioplasty is a percutaneous procedure wherein a balloon catheter is inserted into the coronary artery and advanced until the vascular stenosis is reached. The balloon is then inflated restoring arterial patency.
  • One angioplasty variation includes arterial stent deployment. Briefly, after arterial patency has been restored, the balloon is deflated and a vascular stent is inserted into the vessel lumen at the stenosis site. The catheter is then removed from the coronary artery and the deployed stent remains implanted to prevent the newly opened artery from constricting spontaneously.
  • restenosis This biological process whereby a previously opened artery becomes re-occluded is referred to as restenosis.
  • Treating restenosis requires additional, generally more invasive, procedures including CABG in severe cases. Consequently, methods for preventing restenosis, or treating incipient forms, are being aggressively pursued.
  • One possible method for preventing restenosis is the administration of anti-inflammatory compounds that block local invasion/activation of monocytes thus preventing the secretion of growth factors that may trigger VSMC proliferation and migration.
  • chemotherapeutics including rapamycin and paclitaxel.
  • Rapamycin is generally considered an immunosuppressant best known as a organ transplant rejection inhibitor.
  • rapamycin is also used to treat severe yeast infections and certain forms of cancer.
  • Paclitaxel known by its trade name Taxol ® , is used to treat a variety of cancers, most notably breast cancer.
  • anti-inflammatory and anti-proliferative compounds can be toxic when administer systemically in anti-restenotic-effective amounts. Furthermore, the exact cellular functions that must be inhibited and the duration of inhibition needed to achieve prolonged vascular patency (greater than six months) is not presently known. Moreover, it is believed that each drug may require its own treatment duration and delivery rate. Therefore, in situ, or site-specific drug delivery using anti- restenotic coated stents has become the focus of intense clinical investigation. [0006] Recent human clinical studies on stent-based anti-restenotic delivery have centered on rapamycin and paclitaxel. In both cases excellent short-term anti- restenotic effectiveness has been demonstrated. However, side effects including vascular erosion have also been seen.
  • vascular erosion can lead to stent instability and further vascular injury. Furthermore, the extent of cellular inhibition may be so extensive that normal re-endothelialization will not occur.
  • the endothelial lining is essential for maintaining vascular elasticity and as an endogenous source of nitric oxide. Therefore, compounds that exert localized anti-restenotic effects while minimizing vascular and cellular damage are essential for the long-term success of drug delivery stents.
  • the present invention provides an in situ drug delivery platform that can be used to administer anti-restenotic tissue levels of protein-tyrosine kinase inhibitors without systemic side effects.
  • the drug delivery platform is a medical device including, without limitations, stents, catheters, micro-particles, probes and vascular grafts.
  • a vascular stent is coated with imatinib mesylate.
  • the imatinib mesylate can be attached to the vascular stent's surface using any means that provide a drug-releasing platform. Coating methods include, but are not limited to precipitation, coacervation, and crystallization.
  • the imatinib mesylate of the present invention can be bound covalently, ionically, or through other intramolecular interactions including without limitation hydrogen bonding and van der Waals forces.
  • the imatinib mesylate is complexed with a suitable biocompatible polymer.
  • the polymer-drug complex is then used to either form a controlled-release medical device, integrated into a preformed medical device or used to coat a medical device.
  • the biocompatible polymer may be any non-thrombogenic material that does not cause a clinically relevant adverse response. Other methods of achieving controlled drug release are contemplated as being part of the present invention.
  • the imatinib mesylate of the present invention can be combined with other anti-restenotic compounds including cytotoxic, cytostatic, anti-metabolic and anti-inflammatory compounds.
  • an anti-restenotic compound coated stent can be combined with the systemic delivery of the same or another anti-restenotic compound to achieve a synergistic or additive effect at the medical device placement site. This is particularly beneficial in that non-toxic therapeutic levels of both imatinib mesylate and other anti-restenotic therapeutics can be combined to achieve dose specific synergism.
  • the imatinib mesylate is directly coated onto the surface of a metal stent.
  • the stent is coated with a bioerodable polymer having the imatinib mesylate dispersed therein.
  • the stent is coated with a non-bioerodable polymer having the imatinib mesylate dispersed therein.
  • a stent is coated with a first polymer layer having the imatinib mesylate dispersed therein and a second layer of polymer provided over the first polymer layer.
  • a stent is provided with an imatinib mesylate coating and at least one other antiplatelet, antimigratory, antifibrotic antiproliferatives and/or antiinflammatories agent combined therewith.
  • the stent is selected from the group consisting of vascular stents, biliary stents, esophageal stent, and urethral stents.
  • the stent is a polymer stent.
  • Figure 1 depicts a vascular stent used to deliver the antirestenotic compounds of the present invention.
  • Figure 2 depicts a balloon catheter assembly used for angioplasty and the site specific delivery of stents to anatomical lumens at risk for restenosis.
  • Figures 3 and 4 depict various coating configurations for a vascular stent coated in accordance with the teachings of the present invention.
  • the present invention relates to restoring patency to anatomical lumens that have been occluded, or stenosed, as a result of mechanical trauma, surgical injury, pathologies or normal biological processes including genetic anomalies.
  • the present invention can be used to restore and maintain patency in any anatomical lumen, including, but not limited to blood vessels, ducts such as the biliary duct, and wider lumens including the esophagus and urethra.
  • graft site associated stenoses can also be treated using the teachings of the present invention.
  • the stenosed lumen is an artery, specially a coronary artery.
  • Stenosed coronary arteries generally result from plaque that develops on the interior lining of a coronary artery.
  • Present models attribute this pathology to vascular injuries that are associated with life style and diet.
  • Two major categories of vascular plaque are thought to contribute to over 90% of coronary artery disease (CAD): vulnerable plaque and stable plaque. While both plaque types can contribute to stenosis requiring invention consistent with the teachings of the present invention, vulnerable plaque is more frequently associated with sudden coronary death resulting from plaque rupture and the associated thrombogenic processes.
  • Stable plague is not prone to rupture due to the presence of a thick fibrous cap and less amorphous, more stable, smaller lipid core than found in vulnerable plaque. Therefore, the majority of vascular stenoses requiring intervention are associated with stable plaque.
  • percutaneous transluminal coronary angioplasty (PTCA), or balloon angioplasty, is used to correct stenoses found in coronary, iliac or kidney arteries.
  • PTCA percutaneous transluminal coronary angioplasty
  • stent deployment are mesh-like structures or coils that are mounted to an angioplasty balloon or on self-expanding devices and are permanently placed in the artery or vein following balloon expansion of the stricture.
  • Stents are mesh-like structures or coils that are mounted to an angioplasty balloon or on self-expanding devices and are permanently placed in the artery or vein following balloon expansion of the stricture.
  • a sheath is inserted to provide access to the vascular system for a guidewire and coronary catheter.
  • the coronary catheter is advanced over the guidewire and gently brought near the orifice of the coronary arteries.
  • the guidewire is then removed and intravenous x-ray contrast dye is injected into the coronary arteries to facilitate visualizing the exact location of the stricture and the degree of narrowing.
  • the patient's blood pressure, heart rate, electrocardiogram, and oxygen saturation are monitored continuously.
  • an angioplasty balloon is inflated to dilate the stenosed region and a vascular stent is deployed to prevent immediate tissue elastic recoil and arterial re-occlusion.
  • Exact stent placement is confirmed using repeat x-rays and when appropriate, intra-coronary ultrasound.
  • One of the major complications associated with vascular stenting is restenosis. Restenosis results from injury to the vascular endothelium associated PTCA and stenting procedures. Briefly, the process of inflating the balloon catheter can tear the vessels' initmal layer of endothelial cells. The damaged endothelial cells secrete growth factors and other mitogenic agents causing monocytes and vascular smooth muscle cells (VSMCs) to migrate from the sub endothelium and into the arterial wall's intimal layer.
  • VSMCs vascular smooth muscle cells
  • stenting procedures for peripheral vascular disease such as, but not limited to, iliac artery stenosis, renal hypertension due to severe renal artery stenosis, and carotid artery stenosis.
  • neurovascular applications of the present invention are also considered within the scope of the present invention.
  • the compounds used to prevent restenosis may be referred to herein or elsewhere as imatinib mesylate, GleevecTM, GlivecTM, Glivac, CGP 57148B, CGP 53716STI-571 , protein-tyrosine kinase inhibitors, anti-restenotics, anti-restenotic compounds, drugs, therapeutics, anti-proliferatives, cytostatic agents, cytotoxic agents, or anti-metabolic agents.
  • GleevecTM and GlivecTM are trademarks of Novartis AG Corporation Switzerland Ch- 4002 Basel Switzerland and referred to the chemical composition 4-[(4-Methyl-1- piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]- phenyljbenzamide methanesulfonate (also known as imatinib mesylate).
  • imatinib mesylate in pharmaceutically acceptable forms, has been approved for treating chronic myeloid leukemia (CML).
  • CML chronic myeloid leukemia
  • Neo-intima formation resulting from VSMC proliferation at the site of vascular injury accounts for the majoring of non-elastic recoil restenosis. Physical stress applied to the stenosed artery's intimal lining during angioplasty often results in rupture of the endothelial layer and damage to the underlying VSMC layer. The associated cell injury triggers a cascade of events that result in platelet aggregation and the paracrine and autocrine release of growth factors such as PDGF.
  • the released growth factors then bind to receptors on VSMC causing the VSMCs to de- differentiate and proliferate through the damaged intima re-occluding the artery (See Myllamiemi, M. et al. 1999. Selective Tyrosine Kinase Inhibitor for the Platelet- Derived Growth Factor Receptor In Vitro Inhibits Smooth Muscle Cell Proliferation After Re-Injury of Arterial Intima In Vivo. Cardiovascular Drugs and Therapy; 13:159- 168.)
  • Growth factor such as PDGF bind to specific receptors on cell surfaces and activate a family of intracellular phosphotransferase enzymes known as kinases.
  • Kinases participate in the transfer of phosphate groups, usually from ATP, to specific molecular targets within a cell (phosphorylation).
  • the molecular target is a protein-tyrosine.
  • Protein-tyrosine kinases phosphorylate proteins on their tyrosine residues using ATP as the phosphate donor. The phosphorylation of protein-tyrosine initiates a series of down-stream processes involved in the signaling process associated with cell growth.
  • the proteintyrosine kinase receptor is a switch that must be turned on in order for a cell to proliferate.
  • the key that turns the switch on is PDGF.
  • PDGF binds to the protein-tyrosine kinase membrane receptor, phosporylation of protein-tyrosine results which in turn initiates biochemical pathways leading to cell proliferation.
  • Imatinib mesylate mimics PDGF sufficiently to effectively block the protein-tyrosine membrane receptor keeping PDGF from switching on the cell proliferation pathway.
  • the present invention includes novel compositions and methods for delivering protein-tyrosine kinase inhibitors directly to tissues susceptible to restenosis. Specifically, the present invention is directed at implantable medical devices that provide for the in situ, site-specific controlled release of ligands that bind to and prevent activation of platelet-derived growth factor (PDGF) receptors inhibiting vascular smooth muscle cell (VSMC) proliferation.
  • PDGF platelet-derived growth factor
  • medical devices are provided with a protein-tyrosine kinase inhibitor such as, but not limited to 4-[(4-Methyl-1 - piperazinyl)methyl]-N-[4-methyI-3-[[4-(3-pyridinyl)-2-pyrimidinyI]amino]- phenyljbenzamide methanesulfonate (imatinib mesylate) as depicted in Formula 1 :
  • a protein-tyrosine kinase inhibitor such as, but not limited to 4-[(4-Methyl-1 - piperazinyl)methyl]-N-[4-methyI-3-[[4-(3-pyridinyl)-2-pyrimidinyI]amino]- phenyljbenzamide methanesulfonate (imatinib mesylate) as depicted in Formula 1 :
  • Formula 1 is but one of many pharmaceutically acceptable salts of the protein-tyrosine kinase inhibitor of the present invention. Many other salts and other pharmaceutically acceptable forms can be synthesized and are still considered to within the scope of the present invention. Moreover, many derivatives are also possible that do not affect the efficacy or mechanism of action of the protein-tyrosine kinase inhibitor of the present invention.
  • the present invention is intended to encompass 4-[(4-Methyl-1 - piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]- phenyljbenzamide methanesulfonate (imatinib mesylate or GleevecTM) and pharmaceutically acceptable derivatives and salts thereof.
  • pharmaceutically acceptable includes all derivatives and salts that are not substantially toxic at anti-restenotic effective levels in vivo.
  • “Not substantially toxic” as used herein shall mean systemic or localized toxicity wherein the benefit to the recipient is out-weighed by the physiologically harmful effects of the treatment as determined by physicians and pharmacologists having ordinary skill in the art of chemotherapy and toxicology.
  • the protein-tyrosine kinase inhibitors of the present invention may be delivered, alone or in combination with synergistic and/or additive therapeutic agents, directly to the affected area using medical devices.
  • synergistic and/or additive therapeutic agents may include drugs that impact a different aspect of the restenosis process such as antiplatelet, antimigratory or antifibrotic agents. Alternately they may include drugs that also act as antiproliferatives and/or anti- inflammatories.
  • synergistic combination considered to within the scope of the present invention include at least one protein-tyrosine kinase inhibitor and bioactive compound is an anti-proliferative including, but not limited to, macrolide antibiotics including FKBP 12 binding compounds, estrogens, chaperone inhibitors, protein-tyrosine kinase inhibitors, peroxisome proliferator-activated receptor gamma ligands (PPAR ⁇ ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, anti-sense nucleotides and transforming nucleic acids, at least one protein-tyrosine kinase inhibitor and rapamycin or analogues and derivatives thereof such a 40-0-(2-hydroxyethyl)-rapamycin or ABT-578 (Abbott Laboratories, see United States Patent Number 6,015,815) at least one proteintyrosine kinase inhibitor and ex
  • the medical devices used in accordance with the teachings of the present invention may be permanent medical implants, temporary implants, or removable devices.
  • the medical devices of the present invention may include, stents, catheters, micro-particles, probes and vascular grafts.
  • stents are used as the drug delivery platform.
  • the stents may be vascular stents, urethral stents, biliary stents, or stents intended for use in other ducts and organ lumens.
  • Vascular stents may be used in peripheral, neurological or coronary applications.
  • the stents may be rigid expandable stents or pliable self-expanding stents. Any biocompatible material may be used to fabricate or the stents of the present invention including, without limitation, metals or polymers.
  • the stents of the present invention may also be bioresorbable.
  • vascular stents are implanted into coronary arteries immediately following angioplasty.
  • metallic vascular stents are coated with one or more anti-restenotic compound, specifically protein-tyrosine kinase inhibitors, more specifically the protein-tyrosine kinase inhibitor is imatinib mescylate.
  • the protein-tyrosine kinase inhibitor may be dissolved or suspended in any carrier compound that provides a stable composition that does not react adversely with the device to be coated or inactivate the protein-tyrosine kinase inhibitor.
  • the metallic stent is provided with a biologically active protein-tyrosine kinase inhibitor coating using any technique known to those skilled in the art of medical device manufacturing. Suitable non-limiting examples include impregnation, spraying, brushing, dipping and rolling. After the protein-tyrosine kinase inhibitor- containing solution is applied to the stent it is dried leaving behind a stable proteintyrosine kinase inhibitor delivering medical device. Drying techniques include, but are not limited to heated forced air, cooled forced air, vacuum drying or static evaporation.
  • the medical device specifically a metallic vascular stent, can be fabricated having grooves or wells in its surface that serve as receptacles or reservoirs for the protein-tyrosine kinase inhibitor compositions of the present invention.
  • the preferred concentration of protein-tyrosine kinase inhibitor used in accordance with the teachings of the present invention can be determined using a titration process. Titration is accomplished by preparing a series of stent sets. Each stent set will be coated, or contain different dosages of the protein-tyrosine kinase inhibitor selected. The highest concentration used will be partially based on the known toxicology of the compound. The maximum amount of drug delivered by the stents made in accordance with the teaching of the present invention will fall below known toxic levels. Each stent set will be tested in vivo using the preferred animal model as described in Example 5 below. The dosage selected for further studies will be the minimum dose required to achieve the desired clinical outcome.
  • the desired clinical outcome is defined as the inhibition of vascular re-occiusion, or restenosis.
  • the protein-tyrosine kinase inhibitor is precipitated or crystallized on or within the stent.
  • the protein-tyrosine kinase inhibitor is mixed with a suitable biocompatible polymer (bioerodable, bioresorbable or non-erodable). The polymer-protein-tyrosine kinase inhibitor blend can then be used to produce a medical device such as, but not limited to stents, grafts, micro-particles, sutures and probes.
  • the polymer-protein tyrosine kinase inhibitor blend can be used to form a controlled release coating for the medical device surfaces.
  • the medical device can be immersed in the polymer-protein tyrosine kinase inhibitor blend, or the polymer-protein-tyrosine kinase inhibitor blend can be sprayed, or brushed onto the medical device.
  • the polymer-protein- tyrosine kinase inhibitor blend can be used to fabricate fibers or strands that are embedded into the medical device or used to wrap the medical device.
  • Polymers used in accordance with the teachings of the present invention include both bio-absorbable and non-absorbable materials.
  • Suitable non-limiting exemplary monomers include hydroxy alkyl methacrylate, N-vinyl pyrrolidine, alkyl methacrylate, vinyl alcohols, acrylic acids, acrylamides, ethylene, vinyl acetate, ethylene glycol, methacrylic acid, phosphorylcholine, caprolactone, lactic acid and co-polymers thereof.
  • a vascular stent 300 having the structure 302 is made from a material selected from the non-limiting group materials including stainless steel, nitinol, aluminum, chromium, titanium, ceramics, and a wide range of plastics and natural materials including collagen, fibrin and plant fibers.
  • the structure 302 is provided with a coating composition made in accordance with the teachings of the present invention.
  • FIG. 4 a-d are cross-sections of stent 300 showing various coating configurations.
  • a stent 300 has a first polymer coating 402 comprising a medical grade primer, such as but not limited to parylene or a parylene derivative; a second controlled release coating 404; and a third barrier, or cap, coat 406. in FIG.
  • 4 b stent 300 has a first polymer coating 402 comprising a medical grade primer, such as but not limited to parylene or a parylene derivative and a second controlled release coating 404.
  • a medical grade primer such as but not limited to parylene or a parylene derivative
  • a second controlled release coating 404 In FIG. 4 c stent 300 has a first controlled release coating 404 and a second barrier, or cap, coat 406. In FIG. 4 d stent 300 has only a controlled release coating 404.
  • EXAMPLES Providing a Metallic Surface with a Protein-tyrosine Kinase-eluting Coating The following Examples are intended to illustrate a non-limiting process for coating metallic stents with a protein-tyrosine kinase inhibitor and testing their anti- restenotic properties.
  • a metallic stent suitable for use in accordance with the teachings of the present invention is the Medtronic/AVE S670TM 316L stainless steel coronary stent.
  • Stainless steel stents were placed a glass beaker and covered with reagent grade or better hexane.
  • the beaker containing the hexane immersed stents was then placed into an ultrasonic water bath and treated for 15 minutes at a frequency of between approximately 25 to 50 KHz.
  • Next the stents were removed from the hexane and the hexane was discarded.
  • the stents were then immersed in reagent grade or better 2-propanol and vessel containing the stents and the 2-propanol was treated in an ultrasonic water bath as before.
  • the stents Following cleaning the stents with organic solvents, they were thoroughly washed with distilled water and thereafter immersed in 1.0 N sodium hydroxide solution and treated at in an ultrasonic water bath as before. Finally, the stents were removed from the sodium hydroxide, thoroughly rinsed in distilled water and then dried in a vacuum oven over night at 40°C. [0046] After cooling the dried stents to room temperature in a desiccated environment they were weighed their weights were recorded.
  • methanol is chosen as the solvent of choice.
  • Both the polymer and imatinib mesylate are freely soluble ion methanol.
  • Imatinib mesylate is also known to be freely soluble in water, slightly acidic buffered aqueous solutions, dimethyl sulfoxide, methanol, and ethanol.
  • Imatinib mesylate is insoluble in neutral and alkaline aqueous solutions, n-octanol, acetone and acetonitrile.
  • Persons having ordinary skill in the art of polymer chemistry can easily pair the appropriate solvent system to the polymer-drug combination and achieve optimum results with no more than routine experimentation.
  • the cleaned, dried stents are coated using either spraying techniques or dipped into the drug/polymer solution.
  • the stents are coated as necessary to achieve a final coating weight of between approximately 10 ⁇ g to 1 mg.
  • the coated stents are dried in a vacuum oven at 50°C over night. The dried, coated stents are weighed and the weights recorded.
  • the concentration of drug loaded onto (into) the stents is determined based on the final coating weight.
  • Final coating weight is calculated by subtracting the stent's pre-coating weight from the weight of the dried, coated stent.
  • a cleaned, dry stent is first coated with polyvinyl pyrrolidone (PVP) or another suitable polymer followed by a coating of imatinib mesylate. Finally, a second coating of PVP is provided to seal the stent thus creating a PVP-imatinib mesylate-PVP sandwich coated stent.
  • PVP polyvinyl pyrrolidone
  • a clean, dried stent is then sprayed with PVP until a smooth confluent polymer layer was achieved.
  • the stent was then dried in a vacuum oven at 50°C for 30 minutes.
  • imatinib mesylate 1.00 g is carefully weighed and added to a small neck glass bottle containing 12 ml of methanol. The imatinib mesylate-methanol suspension is then heated at 50°C for 15 minutes and then mixed until the imatinib mesylate is completely dissolved.
  • a clean, dried stent is mounted over the balloon portion of angioplasty balloon catheter assembly.
  • the stent is then sprayed with, or in an alternative embodiment, dipped into, the imatinib mesylate-methanol solution.
  • the coated stent is dried in a vacuum oven at 50°C over night. The dried, coated stent was weighed and its weight recorded.
  • the concentration of drug loaded onto (into) the stents is determined based on the final coating weight.
  • Final coating weight is calculated by subtracting the stent's pre-coating weight from the weight of the dried, coated stent.
  • the first control group tests the anti-restenotic effects of the clean, dried stent having neither polymer nor drug coatings.
  • the second control group tests the anti- restenotic effects of polymer alone. Clean, dried stents having PCL coatings without drug are used in the second control group.
  • Group 1 stents are designated the fast release group and are comprised of 50 ⁇ g imatinib mesylate coated onto a bare stent without polymer in accordance with the teachings of the present invention.
  • Group 2 designated the slow-release group, uses stents coated with 50 ⁇ g of imatinib mesylate impregnated within a polymer at an imatinib mesylate to polymer ratio of 1 :9 in accordance with the teachings of the present invention.
  • Group 3 designated the medium-release group, uses stents coated with 250 ⁇ g of imatinib mesylate impregnated within a polymer at an imatinib mesylate to polymer ratio of 1 :1 in accordance with the teachings of the present invention.
  • the swine has emerged as the most appropriate model for the study of the endovascular devices. The anatomy and size of the coronary vessels are comparable to that of humans.
  • Non-atherosclerotic acutely injured RCA, LAD, and/or LCX arteries of the Farm Swine (or miniswine) are utilized in this study. Placement of coated and control stents is random by animal and by artery. The animals are handled and maintained in accordance with the requirements of the Laboratory Animal Welfare Act (P.L.89-544) and its 1970 (P.L. 91-579), 1976 (P.L.
  • A. Pre-Operative Procedures [0066] The animals are monitored and observed 3 to 5 days prior to experimental use. The animals have their weight estimated at least 3 days prior to the procedure in order to provide appropriate drug dose adjustments for body weight. At least one day before stent placement, 650mg of aspirin is administered. Animals are fasted twelve hours prior to the procedure.
  • Anesthesia is induced in the animal using intramuscular Telazol and Xylazine.
  • Atropine is administered (20 ⁇ g/kg I.M.) to control respiratory and salivary secretions.
  • the subject animal is intubated.
  • Isoflurane 0.1 to 5.0% to effect by inhalation
  • oxygen is administered to maintain a surgical plane of anesthesia.
  • Continuous electrocardiographic monitoring is performed.
  • An IN. catheter is placed in the ear vein in case it is necessary to replace lost blood volume. The level of anesthesia is monitored continuously by ECG and the animal's response to stimuli.
  • the surgical access site is shaved and scrubbed with chlorohexidine soap.
  • An incision is made in the region of the right or left femoral (or carotid) artery and betadine solution is applied to the surgical site.
  • An arterial sheath is introduced via an arterial stick or cutdown and the sheath is advanced into the artery.
  • a guiding-catheter is placed into the sheath and advanced via a 0.035" guide wire as needed under fluoroscopic guidance into the ostium of the coronary arteries.
  • An arterial blood sample is obtained for baseline blood gas, ACT and HCT. Heparin (200 units/kg) is administered as needed to achieve and maintain ACT > 300 seconds.
  • angiographic images of the vessels are obtained in at least two orthagonal views to identify the proper location for the deployment site.
  • Quantitative coronary angiography QCA
  • Nitroglycerin 200 ⁇ g I.C.
  • the delivery system is prepped by aspirating the balloon with negative pressure for five seconds and by flushing the guidewire lumen with heparinized saline solution.
  • Deployment, patency and positioning of stent are assessed by angiography and a TIM I score is recorded.
  • Results are recorded on video and cine. Final lumen dimensions are measured with QCA and/or IVUS. These procedures are repeated until a device is implanted in each of the three major coronary arteries of the pig. After final implant, the animal is allowed to recover from anesthesia. Aspirin is administered at 325 mg p.o. qd until sacrifice.
  • the animals are anesthetized and a 6F arterial sheath is introduced and advanced.
  • a 6F large lumen guiding-catheter (diagnostic guide) is placed into the sheath and advanced over a guide wire under fluoroscopic guidance into the coronary arteries.
  • angiographic images of the vessel are taken to evaluate the stented sites.
  • the animal is euthanized with an overdose of Pentabarbitol IN. and KCL IN.
  • the heart, kidneys, and liver are harvested and visually examined for any external or internal trauma.
  • the organs are flushed with 1000 ml of lactated ringers at 100 mmHg and then flushed with 1000 ml of formalin at 100-120 mmHg. All organs are stored in labeled containers of formalin solution.
  • the stented vessels will be X-rayed prior to histology processing.
  • the stented segments are processed for routine histology, sectioned, and stained following standard histology lab protocols. Appropriate stains are applied in alternate fashion on serial sections through the length of the treated vessels.
  • Quantitative angiography is performed to measure the balloon size at peak inflation as well as vessel diameter pre- and post-stent placement and at the 28 day follow-up.
  • the following data are measured or calculated from angiographic data: Stent-to-artery-ratio Minimum lumen diameter (MLD) Distal and proximal reference lumen diameter
  • Percent Stenosis (Minimum lumen diameter -preference lumen diameter)x 100
  • Histologic measurements are made from sections from the native proximal and distal vessel and proximal, middle, and distal portions of the stent.
  • a vessel injury score is calculated using the method described by Schwartz et al. (Schwartz RS et al. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol 1992;19:267-74).
  • the mean injury score for each arterial segment is calculated. Investigators scoring arterial segment and performing histopathology are "blinded" to the device type. The following measurements are determined:
  • EEL External elastic lamina
  • neointimal area and % of in-stent restenosis are calculated as follows:
  • a given treatment arm will be deemed beneficial if treatment results in a significant reduction in neointimal area and/or in-stent restenosis compared to both the bone stent control and the polymer-on control.
  • G. Surgical Supplies and Equipment [0076] The following surgical supplies and equipment are required for the procedures described above:
  • HCASMC Human coronary smooth muscles cells
  • HCASMC basal media is supplied by Clonetics and is supplemented with fetal bovine serum, insulin, hFGF-B (human fibroblast growth factor) hEGF (human epidermal growth factor). 3. Imatinib Mesylate (GleevecTM: Novartis AG Corporation Switzerland Ch-4002 Basel Switzerland)
  • HCASMC Human coronary smooth muscles cells
  • Strategy 2 Cells are plated in cell culture media containing various concentrations of imatinib mesylate and incubated at 37° C for 48 hours. After the initial 48 hour incubation, the imatinib mesylate-containing plating media is changed and the cells are fed with imatinib mesylate-containing media and incubated for an additional 48 hours and then read.
  • FIG. 1a graphically depicts the percent inhibition at imatinib mesylate levels between 0.001 ⁇ g/mL to 50 ⁇ g/mL for both cell culture schemes. It can be seen from FIG 1a that significant HCASMC inhibition (>50% inhibition) begins at a dosage of 10 ⁇ g/mL and rises dramatically to nearly 100% at 50 ⁇ g/mL.
  • FIG. 1 b graphically depicts the same results in bar graph form based on cell counts.
  • Imatinib mesylate cytotoxicity against HCASMCs is evaluated by seeding 24 well cell culture plates with 5.0 X 10 5 HCASM cells/mL of cell culture media containing from 0.001 ⁇ g/mL to 10 ⁇ g/mL of imatinib mesylate. Samples are taken after 24 hours and tested for lactate dehydrogenase (LDL) concentration using methods known to those having ordinary skill in the art. Elevated LDL levels indicates cytotoxicity.
  • FIG. 1 c graphically depicts the cytotoxicity testing results. No cytotoxicity is detected at imatinib mesylate concentrations that demonstrated significant anti-proliferative effects.
  • HCAEC Human coronary artery endothelial cells
  • HCAEC basal media is supplied by Clonetics and is supplemented with fetal bovine serum, VEGF (vascular endothelial growth factor)hEGF heparin, ascorbic acid IGF (insulin growth factor) hydrocortisone
  • HCAEC Human coronary artery endothelial cells
  • HCAEC Human coronary artery endothelial cells
  • Two different feeding strategies and reading strategies are employed.
  • Strategy 1 Cells are plated in cell culture media containing various concentrations of imatinib mesylate and incubated at 37° C for 48 hours. After the initial 48 hour incubation, the imatinib mesylate containing plating media is changed and the cells are fed with drug free media and incubated for an additional 48 hours and then read.
  • Strategy 2 Cells are plated in cell culture media containing various concentrations of imatinib mesylate and incubated at 37° C for 48 hours. After the initial 48 hour incubation, the imatinib mesylate-containing plating media is changed and the cells are fed with imatinib mesylate-containing media and incubated for an additional 48 hours and then read.
  • FIG. 1a graphically depicts the percent inhibition at imatinib mesylate levels between 0.001 ⁇ g/mL to 50 ⁇ g/mL for both cell culture schemes. It can be seen from FIG 2a that significant HCAEC inhibition (>50% inhibition) begins at a dosage of 5 ⁇ g/mL and rises dramatically to nearly 100% at 10 ⁇ g/mL.
  • FIG. 2b graphically depicts the same results in bar graph form based on cell counts.
  • Imatinib mesylate cytotoxicity against HCAECs is evaluated by seeding 24 well cell culture plates with 5.0 X 10 5 HCAE cells/mL of cell culture media containing from 0.001 ⁇ g/mL to 10 ⁇ g/mL of imatinib mesylate. Samples are taken after 24 hours and tested for lactate dehydrogenase (LDL) concentration using methods known to those having ordinary skill in the art. Elevated LDL levels indicate cytotoxicity.
  • FIG. 2c graphically depicts the cytotoxicity testing results. No cytotoxicity is detected at imatinib mesylate concentrations that demonstrated significant anti-proliferative effects.

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Abstract

La présente invention concerne des dispositifs médicaux implantables comportant des revêtements anti-resténose et plus spécifiquement des dispositifs médicaux implantables comportant des revêtements à base d'inhibiteurs de protéine-tyrosine kinase. L'inhibiteur de protéine-tyrosine kinase anti-resténose est le 4+4-Méthyl-1 -pipérazinyl)méthyl]-N-[4-méthyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phényl]benzamide méthanesulfonate ainsi que les dérivés pharmaceutiquement acceptables de ce dernier (imatinib mésylate). Les dispositifs médicaux anti-resténose comprennent des stents, des cathéters, des microparticules, des sondes et des greffes vasculaires. Les dispositifs médicaux peuvent être revêtus au moyen de n'importe quelle méthode connue dans l'art, y compris par mélange de l'inhibiteur de la protéine-tyrosine kinase avec un polymère biocompatible avant l'application du revêtement. Cette invention concerne également des dispositifs médicaux qui sont entièrement constitués de mélanges d'inhibiteur de protéine-tyrosine kinase et de polymère biocompatible; des dispositifs médicaux pourvus d'un revêtement comprenant au moins un inhibiteur de protéine-tyrosine kinase combiné à au moins un autre agent thérapeutique; et des méthodes d'utilisation et de préparation correspondantes des dispositifs implantables anti-resténose.
EP03765751A 2002-07-18 2003-07-17 Dispositifs medicaux comprenant un inhibiteur de proteine-tyrosine kinase utilises pour inhiber la restenose Withdrawn EP1523345A1 (fr)

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US20040073294A1 (en) 2002-09-20 2004-04-15 Conor Medsystems, Inc. Method and apparatus for loading a beneficial agent into an expandable medical device
US7763769B2 (en) 2001-02-16 2010-07-27 Kci Licensing, Inc. Biocompatible wound dressing
US7700819B2 (en) 2001-02-16 2010-04-20 Kci Licensing, Inc. Biocompatible wound dressing
US7758636B2 (en) * 2002-09-20 2010-07-20 Innovational Holdings Llc Expandable medical device with openings for delivery of multiple beneficial agents
WO2005049021A1 (fr) * 2003-11-03 2005-06-02 Oy Helsinki Transplantation R & D Ltd Substances et procedes pour inhiber l'hyperplasie neointime
KR100891148B1 (ko) * 2004-02-28 2009-04-06 헤모텍 아게 의료용 표면의 생체적합성 코팅, 방법 및 그 용도
US20050220835A1 (en) * 2004-03-30 2005-10-06 Jayaraman Ramesh B Agent eluting bioimplantable devices and polymer systems for their preparation
ES2663495T3 (es) * 2005-02-18 2018-04-13 Abraxis Bioscience, Llc Fármacos con hidrofobicidad mejorada para incorporación en dispositivos médicos
CA2913971C (fr) * 2013-05-31 2022-08-02 Universal Stabilization Technologies, Inc. Compositions polymeres contenant des produits biopharmaceutiques stables a temperature ambiante et leurs procedes de formulation

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US5788979A (en) * 1994-07-22 1998-08-04 Inflow Dynamics Inc. Biodegradable coating with inhibitory properties for application to biocompatible materials
CO4940418A1 (es) * 1997-07-18 2000-07-24 Novartis Ag Modificacion de cristal de un derivado de n-fenil-2- pirimidinamina, procesos para su fabricacion y su uso
US8029561B1 (en) * 2000-05-12 2011-10-04 Cordis Corporation Drug combination useful for prevention of restenosis
US20020103526A1 (en) * 2000-12-15 2002-08-01 Tom Steinke Protective coating for stent

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