WO2007148714A1 - Implant utilisant un dérivé de rifamycine - Google Patents

Implant utilisant un dérivé de rifamycine Download PDF

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Publication number
WO2007148714A1
WO2007148714A1 PCT/JP2007/062385 JP2007062385W WO2007148714A1 WO 2007148714 A1 WO2007148714 A1 WO 2007148714A1 JP 2007062385 W JP2007062385 W JP 2007062385W WO 2007148714 A1 WO2007148714 A1 WO 2007148714A1
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Prior art keywords
group
formula
implant
rifamycin derivative
chemical
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PCT/JP2007/062385
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English (en)
Japanese (ja)
Inventor
Takaoki Saneyasu
Masaki Ichimura
Shinji Hayashi
Masaji Kawatsu
Kazunori Hosoe
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Kaneka Corporation
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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A61L33/0017—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate using a surface active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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

Definitions

  • the present invention relates to an implant that has excellent antithrombogenicity and tissue compatibility and suppresses stenosis.
  • These medical devices are required to be compatible with body fluids such as blood, tissue fluid, and lymph fluid, as well as organs to be implanted and biological tissues of the site, while placed in the implanted site.
  • body fluids such as blood, tissue fluid, and lymph fluid
  • organs to be implanted and biological tissues of the site while placed in the implanted site.
  • a medical device that is implanted in a site that is in contact with blood flow such as a stent, an artificial blood vessel, or a catheter that is placed for a long time
  • blood adheres to the surface or blood clots and does not inhibit the blood flow.
  • It is required to have excellent antithrombogenicity and tissue compatibility so that it does not become incompatible with living tissue and does not cause stenosis due to the formation of neointimal or phenotypic changes of fibroblasts.
  • Similar characteristics are also required for medical devices embedded in ureters, urethra, lymphatic vessels, and the like.
  • a drug-coated stent holds a drug that limits vascular restenosis and exerts its effect by the sustained release of the drug over time.
  • various drug coated stents have been developed, and attempts to reduce the restenosis rate have been reported (see Patent Document 1 and Non-Patent Document 1). Restenosis involves factors such as thrombus formation, inflammation, endothelial injury, and vascular smooth muscle cell migration and proliferation starting from vascular disorders, and many drugs (anticoagulants, antiplatelet substances) that target each factor.
  • Antispasmodic agents, antibacterial agents, antitumor agents, antimicrobial agents, anti-inflammatory agents, antimetabolite agents, immunosuppressive agents, etc. are being studied.
  • Patent Document 1 Japanese Patent Publication No. 5-502179
  • Non-Patent Document 1 Toru Yamaro et al. Drug-Eluting Stent Medical School January 1, 2004 Disclosure of Invention
  • the above-mentioned problems related to antithrombogenicity, tissue compatibility and stenosis are not limited to stents, but are common to various medical devices implanted in the body.
  • medical devices such as stents that are implanted in the body for a long period of time after being implanted in the body are required to continuously and stably exhibit their antithrombogenicity, tissue compatibility, and restenosis suppressing action. Therefore, there is a need for a drug-coated stent that maintains superior antithrombogenicity and tissue compatibility and suppresses vascular restenosis compared to conventional drug-coated stents.
  • rifamycin derivatives are known to be antibiotics that are extremely strong against pneumonia chlamydia and have antibacterial activity (JP-A-9-216824, Patricia M. Robhn, et al. al. Antimicrobial Agents and Chemotherapy, 2003, 47 (3), 1135- 11-6).
  • a rifamycin derivative inhibits the proliferation of vascular smooth muscle cells without strongly inhibiting the proliferation of vascular endothelial cells, and by coating the rifamycin derivative, We have developed an implant that has excellent antithrombogenicity and tissue compatibility and can suppress stenosis.
  • the present invention relates to an implant including a rifamycin derivative.
  • Another aspect of the present invention is an implant comprising a vascular disease treatment agent containing a rifamycin derivative as an active ingredient.
  • Another aspect of the present invention provides a cell growth regulator comprising a rifamycin derivative as an active ingredient. It is an implant characterized by including.
  • the rifamycin derivative is an implant that exhibits a strong growth inhibitory action on vascular smooth muscle cells compared to vascular endothelial cells.
  • an implant characterized by exhibiting a non-cell growth inhibitory effect on vascular endothelial cells and a cell growth inhibitory effect on vascular smooth muscle cells by using the rifamycin derivative as an active ingredient is more preferable. .
  • the rifamycin derivative may be rifalazil ⁇ Rifalazil, 3'-Hydro xy-o— (4—isobutyl— 1— piperazmyl) benzoxazinorifamycin, KRMl648 ⁇ , KRMl 5 /, KRM1671, KRM1689
  • the power of KRM1690 or their physiologically acceptable salts is preferred.
  • the chemical formulas of KRM1648, KRM1657, KRM1671, KRM1689, and KR M1690 will be described in the later-described embodiment items.
  • the rifamycin derivative is preferably an implant present in a biocompatible polymer or biodegradable polymer.
  • the biodegradable polymer is preferably a lactic acid-glycolic acid copolymer!
  • the rifamycin derivative may be filled in a vesicle.
  • the vesicles are preferably in the form of microparticles, nanoparticles or ribosomes.
  • Another embodiment of the present invention includes one in which the implant is a stent.
  • Another aspect of the present invention includes a step of preparing a solution containing a biocompatible polymer or biodegradable polymer and a rifamycin derivative, and a step of applying or holding the solution to an implant.
  • the manufacturing method of the characteristic implant is mentioned.
  • Another embodiment of the present invention includes a method for treating a vascular disease using the implant.
  • the rifamycin derivative used in the implant or the like of the present invention strongly suppresses the proliferation of vascular smooth muscle cells as compared with vascular endothelial cells. Therefore, the rifamycin induction of the present invention
  • An implant including a conductor is excellent in antithrombogenicity and tissue compatibility, and can effectively suppress stenosis or restenosis of blood vessels.
  • FIG. 1 is a development view of a stent according to an embodiment.
  • FIG. 2 is a schematic view of a stent as an embodiment.
  • FIG. 3 is a graph showing the relationship between each concentration of rifalazil and the growth inhibitory effect of CASMC.
  • FIG. 4 is a graph showing the relationship between each concentration of rifalazil and the growth inhibitory action of CAEC.
  • FIG. 5 is a graph showing the relationship between each concentration of ravamycin and the growth inhibitory effect of CASMC.
  • FIG. 6 is a graph showing the relationship between each concentration of rabamycin and the growth inhibitory action of CAEC.
  • FIG. 7 is an SEM image of a stent surface coated with rifalazil.
  • FIG. 8 is a graph showing the relationship between each concentration of KRM1657 and the growth inhibitory action of CASMC and CAEC.
  • FIG. 9 is a graph showing the relationship between each concentration of KRM1671 and the growth inhibitory action of CASMC and CAEC.
  • FIG. 10 is a graph showing the relationship between each concentration of KRM1689 and the growth inhibitory action of CASMC and CAEC.
  • FIG. 11 is a graph showing the relationship between each concentration of KRM1690 and the growth inhibitory action of CASMC and CAEC.
  • X 1 represents an oxygen atom or a sulfur atom
  • R 1 represents a acetyl group or a hydrogen atom
  • R 2 represents a methyl group or a hydroxymethyl group
  • R 4 is the same or different and represents a hydroxyl group, a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a group represented by the formula (II), or a group represented by the following formula (IV). Or a physiologically acceptable salt thereof.
  • R 5 and R 6 are the same or different and represent an alkyl group having 1 to 3 carbon atoms or a group represented by formula (III).
  • R 7 and R 8 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • X 2 represents an oxygen atom, a sulfur atom, a carbonyl group
  • a group represented by (V) or a group represented by the following formula (IV) is shown.
  • R 9 and R 1Q are the same or different, and are represented by the following formula by combining a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or R 9 and R 1Q. Indicates a group.
  • k represents an integer of 1 to 4.
  • m represents 0 or 1
  • R 11 represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, or a group represented by the following formula.
  • n represents an integer of 1 to 4
  • X 3 represents an alkoxy group having 1 to 3 carbon atoms, a vinyl group, an ethynyl group, or a group represented by the following formula (VII).
  • R 3 , R 4 , R 5 , R 6 examples of the alkyl group having 1 to 3 carbon atoms of R 9 and R 1Q include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cycloalkyl group, and an alkyl group having 1 to 6 carbon atoms in R 11
  • methyl group Group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, sec butyl group, tert butyl group, cyclobutyl group, cyclopropylmethyl group, pentyl group, isopentyl group, sec pentyl group, tert pentyl group, cyclopentyl group
  • a chain or cyclic alkyl group such as a group, a cyclobutylmethyl group, a hexyl group, a 4-methylpentyl
  • Examples of the alkoxy group having 1 to 3 carbon atoms of X 3 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a cyclopropoxy group.
  • X 1 in the above formula (I) is an oxygen atom
  • R 1 represents a acetyl group or a hydrogen atom
  • R 2 represents a methyl group or a hydroxymethyl group
  • R 4 is the same or different and is a hydroxyl group, a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or formula (VIII):
  • R 12 represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms) or a physiologically acceptable salt thereof.
  • alkyl group having 1 to 7 carbon atoms of R 12 examples include methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, sec butyl group, tert butyl group, cyclobutyl Group, cyclopropylmethyl group, pentyl group, isopentyl group, sec pentyl group, tert pentyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, cyclopentyl group, cyclobutylmethyl group, hexyl group, 4-methylpentyl group, cyclo Examples thereof include a linear or cyclic alkyl group such as a hexyl group, a 3-methylcyclopentyl group, a heptyl group, and an isoheptyl group.
  • X 1 in the formula (I) is an oxygen atom
  • R 2 is a methyl group
  • R 3 is a hydroxyl group
  • R 4 is a compound represented by the formula (IX):
  • X 1 in the formula (I) is an oxygen atom
  • R 1 is a acetyl group
  • R 2 is a methyl group
  • R 3 is a hydroxyl group
  • R 4 is the formula (X):
  • KRM1657 represented by or a physiologically acceptable salt thereof.
  • X 1 in the formula (I) is an oxygen atom
  • R 1 is a hydroxyl group
  • R 2 cate group is a hydroxyl group
  • R 3 is a hydroxyl group
  • R 4 is formula (IX):
  • KRM1671 represented by or a physiologically acceptable salt thereof.
  • X 1 in the formula (I) is an oxygen atom
  • R is a acetyl group
  • R 2 force S methyl group
  • R 3 and R 4 is the formula (IX):
  • KRM1689 represented by or a physiologically acceptable salt thereof.
  • An exemplary rifamycin derivative has the formula (I) in which X 1 is an oxygen atom, R is a acetyl group, R 2 is a hydroxymethyl group, and R 3 is a hydroxyl group.
  • R 4 is the formula (IX) [0058] [Chemical 26] One NN CH.CH (CH,). (IX)
  • KRM1690 or a physiologically acceptable salt thereof are provided.
  • an implant containing a rifamycin derivative is used, and at this time, it has a strong antiproliferative action on vascular smooth muscle cells compared to vascular endothelial cells.
  • the rifamycin derivative has been used at a very low concentration in the past when it was known to be an antibiotic having an extremely strong antibacterial activity against pneumonia chlamydia.
  • the present invention was made when the present inventors found for the first time an unexpected effect unrelated to the antibacterial activity, that the “rifamycin derivative” has the above-described cell growth inhibitory action. Is.
  • an implant containing a rifamycin derivative can be expected to have an antibacterial effect that is conventionally known in addition to the above-mentioned cell growth inhibitory action. .
  • “Strongly suppresses proliferation of vascular smooth muscle cells compared to endothelial cells” means “does not exhibit cytostatic activity of vascular endothelial cells and proliferates to vascular smooth muscle cells. Including the case of “inhibiting action”. For example, rifamycin derivatives can be adjusted so as to show growth inhibitory activity against vascular smooth muscle cells but not against vascular endothelial cells by adjusting the concentration. . In addition, since the appropriate amount varies depending on the form of the vascular disease treatment agent or the cell growth inhibitor, it is necessary to appropriately adjust the amount depending on the form.
  • Show cell growth suppression refers to a case where the cell growth is statistically significantly suppressed.
  • does not exhibit a cell growth inhibitory effect means a case where it is not statistically significant.
  • the rifamycin derivative is a vascular disease (for example, arteriosclerosis (atherosclerosis, medial calcification sclerosis, microarteriosclerosis), aneurysm, pseudoaneurysm, arterial dissection, Nature including inflammatory arterial disease, non-inflammatory arterial disease, or dialysis shunt It is used for the prevention or treatment of developmental vascular diseases, non-natural vascular diseases including vascular restenosis or reocclusion after percutaneous angioplasty. Examples of angioplasty include balloon dilation, stent placement, atherectomy, and laser angioplasty.
  • a vascular disease treatment agent comprising a rifamycin derivative as an active ingredient is a concept including a composition or preparation (medicine) for treating a vascular disease comprising a rifamycin derivative as an active ingredient.
  • the “cell growth regulator containing a rifamycin derivative as an active ingredient” is a concept including a cell growth regulating composition or preparation (medicine) containing a rifamycin derivative as an active ingredient.
  • therapeutic agent for vascular diseases or cell growth regulator based on rifamycin derivative as an active ingredient based on low cell growth inhibitory action on vascular endothelial cells and high cell growth inhibitory action on vascular smooth muscle cells” I like it.
  • Treatment of vascular disease is a concept of treating vascular disease or reducing its progression
  • anticoagulants In the preparation of preparations for the prevention or treatment of vascular diseases, other drugs (anticoagulants, antiplatelet substances, antispasmodics, antibacterial drugs, antitumor drugs, antimicrobial drugs, anti-inflammatory drugs, It may be combined with an anti-metabolite, an immunosuppressant, etc.
  • the rifamycin derivative is used to suppress proliferation more strongly against vascular smooth muscle cells than vascular endothelial cells. Thereby, smooth muscle hypertrophy is suppressed without inhibiting vascular endothelium regeneration, and vascular stenosis or restenosis is prevented.
  • the material, shape, dimensions, form, etc. of the main body of the “implant” as an embodiment are not particularly limited, and are appropriately determined according to the size, compliance, tissue, cell type, etc. of the site where the medical device is placed. .
  • the implant is hereinafter also referred to as “medical implant”, “implantable implant”, “medical device”, or “in-vivo device” as appropriate.
  • the material may have a required characteristic depending on a portion where the metal material or the polymer material is placed, that is, a blood vessel, a urinary tract, a lymphatic vessel, or a tissue such as a muscle. However, it is preferably a material having biocompatibility and biodegradability.
  • metal material examples include stainless steel, titanium or titanium alloy, tantalum or tantalum alloy, platinum or platinum alloy, gold or gold alloy, correlate base alloy, magnesium or magnesium alloy, and the like.
  • stainless steel SUS316L, which has the best corrosion resistance, is suitable.
  • biocompatible polymer used for implants, any biocompatible polymer can be used as long as it does not show any irritation to tissues to which platelets hardly adhere and can dissolve drugs.
  • synthetic polymers included in “biocompatible polymers” include polyether polyurethane and dimethyl silicone blends or block copolymers, polyurethanes such as segmented polyurethane, polyacrylamide, polyethylene oxide, polyethylene carbonate, polypropylene.
  • Polycarbonates such as carbonates can be used, and fibrin, gelatin, collagen and the like can be used as natural biocompatible polymers. These polymers can be used alone or in appropriate combination.
  • Biodegradable polymer refers to any biodegradable polymer as long as it is enzymatically and non-enzymatically degraded in vivo, the degradation product does not exhibit toxicity, and the drug can be released. Can also be used.
  • Implant examples examples of implants that can be placed in the body and exhibit desired medical effects include stents, stent grafts, artificial blood vessels, catheters (including balloon catheters), artificial heart valves, pacemaker leads, bone screws, artificial bones, artificial tracheas And sutures.
  • a stent used to secure a sufficient lumen by being placed in a blood vessel, ureter, urethra, lymphatic vessel, or the like that causes stenosis of a living body is a specific example of the implant of the present invention. It is suitable as a mode.
  • the rifamycin derivative as an embodiment is not limited to a stent but can be applied to implants well known to those skilled in the art.
  • methods known to those skilled in the art disclosed in JP-A-9-38195 and JP-A-2003-24452 can be employed.
  • FIG. 1 is a developed view of the stent
  • FIG. Fig. 2 is a schematic view.
  • a method for producing a stent and a method for fixing a drug to the stent which will be described later, for example, methods known to those skilled in the art disclosed in JP 2005-65981 A and JP 2004-222953 A may be employed. it can.
  • stents are used to expand the stenosis or occlusion site and reduce the lumen size. It is a medical device that is placed there for maintenance.
  • a stent is typically inserted into a blood vessel by a catheter and expanded to contact an unhealthy part of the arterial wall to provide mechanical support for the blood vessel lumen.
  • stent expansion is performed by either self-expansion due to its own physical characteristics (shape memory property, superelasticity, etc.) or forced expansion due to the expansion force of the balloon catheter.
  • the stent used as the base for coating the drug layer can be made of metallic forces such as stainless steel, Ni-Ti alloy, Cu-Al-Mn alloy, Co-Cr alloy, magnesium alloy, iridium, iridium oxide, and niobium. is there.
  • the stent can be manufactured by cutting a cylindrical metal material tube into a stent design by laser cutting and performing electropolishing in the same manner as a method normally manufactured by those skilled in the art.
  • the manufacturing method is It is not limited to the above methods, but it is also possible to use a processing method by etching, a method in which a flat metal is laser cut and then rolled and welded, or a method in which a metal wire is knitted.
  • the polymer is not limited to a metal material, but is a high molecule such as polyolefin, polyolefin elastomer, polyamide, polyamide elastomer, polyurethane, polyurethane elastomer, polyester, polyester elastomer, polyimide, polyamideimide, polyetheretherketone.
  • Inorganic materials such as materials, ceramics, hydroxyapatite can also be used.
  • a polymer layer may be provided on the stent surface for the purpose of fixing a drug or the like. Because it is used in living organisms, it is preferable to use biocompatible polymers or biodegradable polymers as the polymer.
  • a method for providing a polymer layer on the stent surface a method such as a method of dying a stent into a polymer solution or a method of spraying a polymer solution onto a stent by spraying can be used.
  • the above-described methods are all coating methods, but a separately prepared polymer sheet may be attached to the stent surface.
  • an arbitrary solvent having a polymer solubility can be selected as the solvent used in preparing the polymer solution.
  • a mixed solvent using two or more solvents may be used.
  • the concentration of the polymer solution is not particularly limited, and can be set to any concentration in consideration of the surface properties of the polymer layer, the required amount of drug retained, the release behavior of the retained drug, and the like.
  • the polymer solution prepared using such a solvent is applied to the stent and dried, or the operation of immersing the stent in the solution and drying it is repeated at least once, thereby forming the polymer layer on the stent.
  • the distance between the spray nozzle and the stent is preferably 50 cm or less in order to make the surface of the polymer layer uniform, more preferably 10 cm or more and 30 cm or less. Also, 50rpm or more is preferred to make the surface of the polymer layer even when the stent is rotated when spray coating or dating.
  • Extra polymer solution may be removed during and after z or after application.
  • Examples of the removing means include vibration, rotation, and decompression, and a plurality of these may be combined.
  • a drug (rifamycin derivative) layer is provided on the stent surface.
  • the drug can be attached to the stent by removing the solvent after adding the drug to the stent in a solution state. It is also possible to attach the drug to the stent using the aforementioned biocompatible polymer or biodegradable polymer.
  • a biocompatible polymer and Z or biodegradable polymer together with a drug can be used in a liquid or suitable solvent, such as water, buffer, acetic acid, hydrochloric acid, methanol, ethanol, acetone, acetonitrile,
  • a stent using a biocompatible polymer or a biodegradable polymer can be prepared by contacting the stent as a solution of methylene chloride, chloroform, tetrahydrofuran, etc. and then removing the solvent.
  • a stent is coated with a solution obtained by dissolving or suspending a drug in a solution prepared by dissolving a biocompatible polymer and Z or a biodegradable polymer in a low boiling point solvent.
  • a coating method a method of dating a stent into a solution or a method of spraying with a spray can be used.
  • the thickness of the coating layer when the coating layer is thickened, there is a possibility that the formation of a thrombus may be promoted due to unevenness in the blood vessel, and the restenosis rate may be increased. However, a certain amount of thickness is required to coat the sufficient dose required for treatment. From this viewpoint, the thickness of the coating layer is preferably 1 m or more and 10 ⁇ m or less, more preferably 3 ⁇ m or more and 5 ⁇ m or less.
  • the base stent was manufactured by cutting a stainless steel cylindrical tube into a stent design by laser cutting and performing electropolishing, in the same manner as a method usually produced by those skilled in the art.
  • the developed view of the stent used is shown in Fig. 1, and the schematic diagram is shown in Fig. 2.
  • the structure of this stent was a balloon etaspan double type, which is a type in which the stent is expanded and indwelled using a none catheter equipped with a balloon near the tip of the catheter.
  • the stent is set in a deflated state on the balloon portion of the balloon catheter. After delivery to the target site using the balloon catheter, the stent is expanded and placed by expanding the balloon.
  • a stent obtained by coating rifalazil on the above-described stent as a base using the polyether-type polyurethane resin is referred to as Production Example 1.
  • the coating procedure is as follows. First, the urethane solution is sprayed onto the base stent using an airbrush, followed by drying at 60 ° C for 10 minutes. The spraying and drying are repeated 5 times, and finally 100 g of the urethane per stent is coated on the stent. Next, the urethane-coated stent is immersed in a rifalazil solution for 1 hour and dried.
  • a stainless steel (SUS316L) cylindrical tube with an inner diameter of 1.50 mm and an outer diameter of 1.80 mm is cut into a stent design by laser cutting and electropolished in the same manner as those usually produced by those skilled in the art.
  • the design is such that the length of the stent is 13 mm, the thickness is 120 mm, and the nominal diameter after expansion is 3.5 mm.
  • Inner surface, an outer surface of the stent base material, the total surface area of the combined side surface is 88. 5 mm 2.
  • lactic acid Z glycolic acid 85 mol% Zl5 mol%
  • drug concentration Z biodegradable polymer concentration 0.
  • a stainless steel (SUS316L) cylindrical tube with an inner diameter of 1.50 mm and an outer diameter of 1.80 mm is cut into a stent design by laser cutting and electropolished in the same manner as those usually produced by those skilled in the art. It was produced by.
  • the stent was designed to have a length of 18 mm, a thickness of 120 mm, and a nominal diameter of 3.5 mm after expansion.
  • coating solutions with weight ratios of 40Z60, 30/70, 20/80, and 10Z90 were prepared.
  • the coating solution prepared using an airbrush was sprayed onto the stent to attach the coating solution to the stent.
  • the air pressure at the time of spraying was 2 kgZcm2, and the weight of biodegradable polymer and drug per stent was adjusted by adjusting the spray time.
  • FIG. 7 is an SEM image of the surface of a stent coated with a coating solution having a rifalazil Z lactic acid-glycolic acid copolymer weight ratio of 20Z80. As shown in Fig. 7, the coating surface was smooth both before and after the stent expansion, and no cracks, delamination or cracks were found. In addition, the same surface properties were exhibited even when the coating weight was increased to 810 g / stent with the same solution composition.
  • rifamycin induction as an embodiment of the present invention is performed using a cytostatic test of human coronary artery smooth muscle cells (CASMC) and human coronary artery endothelial cells (CAEC).
  • CASMC human coronary artery smooth muscle cells
  • CAEC human coronary artery endothelial cells
  • CAEC manufactured by Takara Bio Inc.
  • EMM-2 MV BulletKit
  • CASMC and CAEC that reached 70 80% confluence were collected from a 100 mm dish using a subculture reagent set (manufactured by Takara Bio Inc.). The obtained cells were seeded in a 96-well plate and cultured for 24 hours at 37 ° C in 5% CO. Next, 24 hours
  • BrdU uptake ability represents DNA synthesis ability, which is a parameter of cell proliferation.
  • FIG. 3 and FIG. 46 which will be described later, are graphs showing the relationship between each concentration of the drug and the growth inhibitory action of both cells.
  • the vertical axis represents the absorbance representing the BrdU uptake ability, and the value at each concentration relative to the absorbance in the non-drug-added group (control) was graphed. Also, in the graph
  • rifalazil showed statistically significant inhibition of CASMC growth at 100 and 1, OOOnM, compared to the group without rifalazil.
  • Example 4 CASMC and CAEC growth inhibition tests were performed in the same manner as in Example 3 above, except that KRM1657, KRM1671, KRM1 689, and KRM1690 were used instead of rifalazil and the incubation time after addition of the test substance was 72 hours. I went.
  • FIGS. 8 to 11 are graphs showing the relationship between each concentration of the drug and the growth inhibitory action of both cells.
  • the solid line indicates CASMC and the broken line indicates CAEC.
  • the vertical axis represents the absorbance representing the BrdU uptake ability, and the value at each concentration relative to the absorbance in the rifalazil non-added group (control) was graphed.
  • Dunnett's test was performed as an example.
  • Fig. 8 ⁇ As shown in L 1, as with rifalazil, the four rifamycin derivatives tested tested strongly inhibited proliferation against CASMC compared to CAEC.
  • Comparative Example 1 CASMC and CAEC growth inhibition tests were conducted in the same manner as in Example 3 except that the test substance was changed to rifalazil and changed to rapamycin.
  • rapamycin was statistically significant at all concentrations (1, 10, 100, 1, OOOnM) in which the growth of CASMC was compared to the group without addition of rapamycin. Inhibited growth.
  • rapamycin is statistically significant at all concentrations (1, 10, 100, 1, OOOnM) at which CAEC growth was performed compared to the group without rapamycin. Intentionally, growth suppression was shown.
  • implants coated with rifalazil, KRM1657, KRM1671, KRM1689, and KRM1690 undergo endothelial regeneration. It is presumed to suppress the proliferation of vascular smooth muscle cells while not inhibiting the above.
  • the implant for example, the stent of Preparation Example 1, Preparation Example 2, or Preparation Example 3 is excellent in antithrombogenicity and tissue compatibility and is considered to be able to suppress stenosis.

Abstract

La présente invention concerne un implant présentant une excellente antithrombogénicité et compatibilité tissulaire et pouvant inhiber la sténose. L'invention concerne un implant contenant un dérivé de rifamycine en tant que principe actif. Selon un mode de réalisation préféré, cet implant contient un médicament pour traiter une maladie vasculaire ou un médicament pour contrôler la prolifération cellulaire comprenant en tant que principe actif le dérivé de rifamycine. Le dérivé de rifamycine assure une inhibition efficace de la prolifération de muscle lisse vasculaire comparée à des cellule endothéliales vasculaires. Ainsi, l'implant contenant le dérivé de rifamycine selon l'invention présente une excellente antithrombogénicité et compatibilité cellulaire et peut inhiber la sténose.
PCT/JP2007/062385 2006-06-21 2007-06-20 Implant utilisant un dérivé de rifamycine WO2007148714A1 (fr)

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WO2019103098A1 (fr) * 2017-11-22 2019-05-31 テルモ株式会社 Instrument de chargement de médicament et procédé de formation de couche de médicament
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US8641756B2 (en) 2007-09-04 2014-02-04 Japan Stent Technology Co., Ltd. Sustained drug-releasing stent
US8968392B2 (en) 2007-09-04 2015-03-03 Japan Stent Technology Co., Ltd. Method of inhibiting vascular intimal hyperplasia using stent
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WO2010101072A1 (fr) * 2009-03-02 2010-09-10 株式会社日本ステントテクノロジー Endoprothèse à élution médicamenteuse
US8591571B2 (en) 2009-03-02 2013-11-26 Japan Stent Technology Co., Ltd. Drug-eluting stent
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WO2019103098A1 (fr) * 2017-11-22 2019-05-31 テルモ株式会社 Instrument de chargement de médicament et procédé de formation de couche de médicament
WO2019103097A1 (fr) * 2017-11-22 2019-05-31 テルモ株式会社 Dispositif de transfert de médicament et procédé de formation de couche médicamenteuse
CN111372645A (zh) * 2017-11-22 2020-07-03 泰尔茂株式会社 药物施用器械及药物层的形成方法
JPWO2019103097A1 (ja) * 2017-11-22 2020-11-19 テルモ株式会社 薬剤転写デバイスおよび薬剤層の形成方法
JPWO2019103098A1 (ja) * 2017-11-22 2020-11-19 テルモ株式会社 薬剤付与器具および薬剤層の形成方法
JP7110229B2 (ja) 2017-11-22 2022-08-01 テルモ株式会社 薬剤転写デバイスおよび薬剤層の形成方法
JP7198218B2 (ja) 2017-11-22 2022-12-28 テルモ株式会社 薬剤付与器具および薬剤層の形成方法

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