WO2018059207A1 - 氨来呫诺的新用途 - Google Patents

氨来呫诺的新用途 Download PDF

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Publication number
WO2018059207A1
WO2018059207A1 PCT/CN2017/100885 CN2017100885W WO2018059207A1 WO 2018059207 A1 WO2018059207 A1 WO 2018059207A1 CN 2017100885 W CN2017100885 W CN 2017100885W WO 2018059207 A1 WO2018059207 A1 WO 2018059207A1
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Prior art keywords
drug
stent
medical device
ammonia
rapamycin
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PCT/CN2017/100885
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English (en)
French (fr)
Inventor
陈陆
李俊菲
陈飞
成晓
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上海微创医疗器械（集团）有限公司
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Priority to EP17854657.8A priority Critical patent/EP3520789B1/en
Priority to US16/337,357 priority patent/US11547702B2/en
Priority to JP2019538301A priority patent/JP6761547B2/ja
Publication of WO2018059207A1 publication Critical patent/WO2018059207A1/zh

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—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
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • 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 the use of amlexanox or a salt thereof or a solvate thereof for the preparation of a medicament having a smooth muscle cell inhibitory effect, particularly for the prevention and treatment of vascular restenosis.
  • the invention also relates to the field of medical device technology.
  • Amlexanox generic name 2-amino-7-isopropyl-5-oxo-5H[1]phenylpyranyl-[2,3,-b]-pyridin-3-carbolic acid Toluic acid, also known as CHX3673.
  • English chemical name 2-amimo-7-isopropyl-5-oxo-5H-[1]benzopyrano-[2,3,-b]pyridine-3-carboxylic acid.
  • Ammonium is an allergic reaction medium blocker, which inhibits the degranulation by stabilizing the cell membrane of mast cells, thereby preventing the release of allergic reaction media and exerting an anti-allergy effect.
  • FDA US Food and Drug Administration
  • Amaconone is the only prescription drug approved for FDA approval for the treatment of Aphthous ulcers. Its pharmacological action is mainly to accelerate the healing of aphthous ulcers by anti-allergy and anti-inflammatory.
  • ammonia is mainly used to treat allergies and oral ulcers.
  • Cardiovascular disease is currently the most serious threat to human health. According to WHO statistics, the number of deaths due to cardiovascular disease each year is as high as 30% of global deaths. Cardiovascular interventional surgery for cardiovascular disease is a trend in clinical development. However, for traditional interventional devices, such as stents, balloons, occlusion devices, and interventional valves, the formation of thrombosis and neoplasms may occur after interventional procedures, and stenosis (RS) may occur, which reduces the expected effect of surgery.
  • RS stenosis
  • vascular smooth muscle cells are important factors in the occurrence of RS.
  • a large number of studies have confirmed that the proliferation/migration of VSMCs into the intima of the arterial membrane is a key link in the development and ultimately formation of RS.
  • the phenotype of the VSMCs in the arterial membrane changes (from a resting/contracted state to a proliferative/synthetic phenotype), and the VSMCs proliferate and migrate to the intima, while over-synthesizing and secreting a large amount.
  • the extracellular matrix causes neovascularization of the angiogenesis and causes restenosis.
  • the implanted stent should be coordinated with the "inner environment" of the coronary artery to maintain normal Endothelialization and endothelial function are intact, the stent is implanted with normal systolic and diastolic function of the coronary arteries, and the structural integrity and normal remodeling of the blood vessels.
  • DES loaded with vascular smooth muscle cell proliferation inhibitors is the most commonly used treatment for clinical prevention of restenosis.
  • vascular smooth muscle cell proliferation inhibitors rapamycin and its analogs, paclitaxel
  • DES inhibits the proliferation of vascular smooth muscle cells. Delayed endothelium repair, resulting in incomplete endometrialization, thrombosis and other cardiovascular adverse events, and ultimately weakened the long-term effect of anti-restenosis.
  • amlexanox has a biological activity of inhibiting proliferation of vascular smooth muscle cells, but at the same time does not inhibit endothelial cell growth, that is, has a selective inhibitory effect, thereby preventing vascular restenosis after PCI. problem.
  • the present invention relates to the use of amlexanox or a salt thereof or a solvate thereof for the preparation of a medicament having a smooth muscle cell inhibitory effect.
  • the ampicillin salt in the present invention means that the ampicillin forms a pharmaceutically acceptable acid or base addition salt with a wide variety of acids or bases, and includes physiologically acceptable salts which are commonly used in the pharmaceutical industry.
  • the acid and base are organic acids or bases, and may also be inorganic acids or bases.
  • the medicament is a medicament for preventing and treating vascular restenosis. Since ammonia decanoxin inhibits the proliferation of smooth muscle cells without inhibiting the growth of endothelial cells, it is beneficial to damage the healing of blood vessels and prevent the formation of blood clots, thereby shortening the time for patients to take antithrombotic and platelet drugs after surgery.
  • the vascular restenosis refers to a condition in which a patient has recurrence of symptoms at a target lesion or a re-stenosis of a blood vessel diameter after undergoing an interventional procedure.
  • the medicament is an oral administration dosage form, an injection administration dosage form, a respiratory administration dosage form, a mucosal administration dosage form, a transdermal administration dosage form or a channel administration dosage form.
  • the medicament is a tablet, a powder, a capsule, a granule, a solution, an emulsion, a spray, a patch or a gel.
  • compositions can be prepared by methods known in the art.
  • the solution and emulsion may be formulated as an oral liquid for oral administration, as an injection suitable for administration by the muscle, subcutaneous or intravenous route, as an external coating suitable for external application, configured to be suitable for application.
  • the coating applied to the surface of the medical device is administered topically.
  • the powder may be administered orally or by a medical device into the body for topical administration.
  • the present invention also provides a medical device comprising a substrate and an active substance or a pharmaceutical composition distributed on a surface of the substrate, the active substance being amlexanox or a salt thereof, the pharmaceutical composition comprising amlexinopro or Its salt.
  • the pharmaceutical composition further comprises one of an immunosuppressive drug, an anti-inflammatory drug, an anti-proliferative drug, a re-endothelializing drug, an anti-cell migration drug, an intercellular matrix regulator drug, and other extracellular matrix proteins. the above.
  • the pharmaceutical composition consists of ammonia or a salt thereof and an anti-proliferative drug.
  • the mass ratio of the drug to the anti-proliferative drug is (1:10)-(10:1); preferably (1:3)-(3:1); most preferably (1:2.5) )-(1.5:1).
  • the anti-proliferative drug is selected from the group consisting of everolimus, tacrolimus, dexamethasone, temsirolimus, zotarolimus, iramoxie, immunosuppressant ABT-578, and sedative Rice pine, imidazolidine, rapamycin, paclitaxel and its derivatives, actinomycin, vincristine and its derivatives, statins, 2-chlorodeoxyadenosine, ribozyme, bamastat, One or more of clopidogrel and probucol, preferably rapamycin and its derivatives, ie everolimus, tacrolimus, diphosphomos, temsirolimus, zodia One or more of Moss and Rapamycin.
  • the medical device is a combination of one or more of a heart valve, a cardiac occluder, a blood vessel stent, an artificial blood vessel, a catheter, a pacemaker, a pacemaker derivation, and a defibrillator.
  • the base material may be a metal material or a polymer material commonly used in medical devices.
  • the metal material may be a degradable or non-degradable metal material
  • the non-degradable material may be titanium, cobalt, ruthenium, nickel-titanium alloy, nickel-titanium-niobium alloy, medical stainless steel material, etc., and degradable alloy materials such as aluminum-magnesium alloy, Complete degradation and absorption of the organism can be achieved.
  • Polymer materials also classified as degradable or non-degradable materials, wherein the degradable materials can be poly Lactone (PCL), polyglycolic acid (PGA), poly-L-lactic acid (PLLA), polycaprolactone monoacrylate (PCLA), polylactic acid-glycolic acid copolymer (PLGA), and the like.
  • PCL poly Lactone
  • PGA polyglycolic acid
  • PLLA poly-L-lactic acid
  • PCLA polycaprolactone monoacrylate
  • PLGA polylactic acid-glycolic acid copolymer
  • the drug or pharmaceutical composition may be distributed on the surface of the medical device by a drug carrier or may be distributed on the surface of the medical device without a carrier.
  • the drug or pharmaceutical composition is immobilized in the pharmaceutical carrier by physical dispersion, electrostatic adsorption or chemical bonding.
  • the material of the pharmaceutical carrier can be classified into organic or inorganic, biodegradable or non-biodegradable, as well as synthetic or natural substances.
  • the organic carrier material mainly refers to a polymer material
  • the inorganic carrier material mainly refers to a porous inorganic coating prepared on the surface of the stent, and the porous structure is used to adsorb the drug on the surface of the stent.
  • the non-degradable polymer material may be a polymethacrylic acid (PMMA) type or a polystyrene-isobutadiene-styrene copolymer (SIBS).
  • the degradable polymeric carrier material may be polylactic acid (PLA) and copolymers thereof with other materials, such as copolymer PLGA with glycolic acid, and copolymer PELA with ethylene glycol.
  • the surface of the substrate is distributed with grooves or micropores of 0.1 ⁇ m to 10 ⁇ m.
  • the invention also provides a method for preparing a medical device, comprising the steps of: preparing a micropowder containing ammonia or a solution containing ammonia, and loading the drug into the substrate by dripping, landfilling or coating methods; surface.
  • the coating method is selected from one or more of ultrasonic atomization spraying, chemical vapor deposition, physical vapor deposition, ion beam spraying, dip coating, micro-spraying or brush coating.
  • the spraying method is direct spraying, electrostatic spraying or anodic polarization spraying;
  • the dip coating method is direct dip coating or electrode polarization dip coating.
  • the present invention can select a method of loading a drug on the surface of the medical device substrate to distribute the ammonia to the surface of the medical device substrate.
  • the solvent used for the ammonia solution is selected from the group consisting of paraffins, olefins, alcohols, aldehydes, amines, Esters, ethers, ketones, aromatic hydrocarbons, hydrogenated hydrocarbons, terpene oxides, halogenated hydrocarbons, heterocyclic compounds, nitrogen-containing compounds, and sulfur-containing compounds
  • the solvent used in the solution containing ampicol is selected from one or more selected from the group consisting of ethyl acetate, n-propyl acetate, acetone, tetrahydrofuran, chloroform and dichloromethane.
  • the present invention also provides a drug scaffold comprising a scaffold body and an active substance or a pharmaceutical composition distributed on a surface of the scaffold body, the active substance being amlexanox or a salt thereof, the pharmaceutical composition comprising ammonia Connaught or its salt.
  • the pharmaceutical composition further comprises an anti-proliferative drug.
  • the drug loading amount of the ampicillin on the drug stent is 20 ⁇ g/cm 2 -140 ⁇ g/cm 2 .
  • the anti-proliferative drug is selected from the group consisting of rapamycin, everolimus, tacrolimus, dexamethasone, temsirolimus, zotarolimus, wortmannin, perifolin or Aide Laris.
  • the mass ratio of the drug to the anti-proliferative drug is (1:10)-(10:1); preferably (1:3)-(3:1); most preferably (1:2.5) - (1.5:1).
  • the invention inhibits the proliferation of smooth muscle cells of the blood vessel wall through the sustained release of ammonia to the surface of the stent, promotes the re-endothelialization of blood vessels, promotes the healing of the damaged blood vessel wall, prevents the occurrence of thrombus in the stent, and reduces the antithrombotic administration of the patient after surgery. And the time of platelet drugs.
  • the drug carrier is loaded with a drug-free drug carrier.
  • the carrierless drug scaffold can be any unsupported drug scaffold which has been developed at present, and is mainly divided into a nanoporous preloaded drug type, a surface crystallization preloaded drug type of the stent beam, and a roughened preloaded drug type of the stent beam surface.
  • the specific embodiment can refer to the prior art, such as the Janus stent produced by Sorin, Italy, the Yukon stent produced by Translumina, Germany, the BioFreedom stent produced by Biosensors of Singapore, and the Dalian Yiyi stent. And the music stand of the Lepu Medical and so on.
  • the material of the bracket body may be a metal material or a polymer material.
  • the metal material may be a degradable or non-degradable metal material
  • the non-degradable material may be titanium, cobalt, ruthenium, nickel-titanium alloy, nickel-titanium-niobium alloy, medical stainless steel material, etc., and degradable alloy materials such as aluminum-magnesium alloy, Complete degradation and absorption of the organism can be achieved.
  • degradable polymer materials can be polycaprolactone (PCL), polyglycolic acid (PGA), poly-L-lactic acid (PLLA), polycaprolactone single Acrylate (PCLA), polylactic acid-glycolic acid copolymer (PLGA), and the like.
  • the material of the stent body is a biodegradable metal material and/or a biodegradable polymer material.
  • the carrier-free drug scaffold can avoid the allergic and inflammatory reaction brought by the carrier, and becomes the stent body after the drug is released, which leads to lower possibility of late thrombosis and inflammation and high safety.
  • the stent mechanically supports the vessel for a period of time after intervention and prevents restenosis by means of the eluted drug. After that, the stent body slowly degrades and is completely absorbed by the tissue. The probability of occurrence of late stent thrombosis is reduced, and long-term antiplatelet drug therapy is not needed, and there is no worries.
  • the present invention has discovered a novel biological activity of amlexanox, which has a high activity of inhibiting the proliferation of smooth muscle cells, and has low endothelial cell growth inhibitory activity compared with the currently used smooth muscle cell proliferation inhibitors. It is especially suitable for medical devices to prevent the incidence of vascular restenosis without delaying endothelium repair. Therefore, it can shorten the time for patients taking antithrombotic and platelet drugs after surgery, and greatly improve the long-term efficacy.
  • carrier refers to a pharmaceutically acceptable carrier which does not cause the biological activity or property of the compound to disappear, and is relatively non-toxic, for example, giving a substance to an individual without causing unwanted Biologically interact or interact in a harmful manner with any of the components it contains.
  • subject or “patient” are used interchangeably herein to refer to an animal (including a human) that is treatable by the compounds and/or methods.
  • “Individual” or “patient” is used herein to encompass both male and female genders unless specifically stated otherwise.
  • individual or “patient” includes any mammal, including, but not limited to, human, non-human primates, such as mammals, dogs, cats, horses, sheep, pigs, cattle, etc., which may be utilized The compounds benefit from treatment. Animals suitable for treatment with the compounds and/or methods of the invention are preferably human. In general, the terms “patient” and “individual” are used interchangeably herein.
  • medical device means an appliance, device, or instrument for direct or indirect use in a patient.
  • the medical device according to the present invention may be an instrument or an extracorporeal device implanted in the body.
  • the device can be used temporarily for a short period of time or permanently implanted for a long time.
  • the medical device includes but is not limited to the following devices: stent, stent graft, synthetic patch, lead, electrode, needle, surgical instrument, angioplasty ball, wound drainage tube, shunt, tube, infusion Infusion sleeve, cannula, pellet, implant, blood oxygenation generator, pump, vascular graft, vascular access port, heart valve, annuloplasty ring , suture, surgical clip, surgical nail, pacemaker, nerve stimulator, integral surgical instrument, cerebrospinal fluid shunt, implantable drug pump, cage, artificial disc occluder, artificial blood vessel, drug balloon Wait.
  • the drug scaffold loaded with ampicillin was placed in a DMSO solution, completely dissolved, and further diluted to form a solution having a drug concentration of 10 -2 mmol/ml.
  • rapamycin-loaded drug scaffold was placed in a DMSO solution, completely dissolved, and further diluted to form a solution having a drug concentration of 10 -2 mmol/ml.
  • A10 cells with good growth and stable growth were selected. After the digestion, a cell suspension having a concentration of 1 ⁇ 10 4 /ml, 2 ⁇ 10 4 /ml, 4 ⁇ 10 4 /ml, 5 ⁇ 10 4 /ml, and 10 ⁇ 10 4 /ml was prepared. The cell suspension of the above concentration was inoculated into a 96-well cell culture plate and cultured by MTT colorimetry. Finally, the enzyme plate reader measured the absorbance at a wavelength of 570 nm of 0.6-1.5 as the concentration of the cell inoculum to be tested.
  • HASMC aortic smooth muscle cells
  • HAEC human aortic endothelial cells
  • Control group no drug added
  • Rapamycin group 1 ⁇ mol, 6 ⁇ mol and 10 ⁇ mol rapamycin in the medium;
  • Ammoniazone group 1 ⁇ mol, 6 ⁇ mol and 10 ⁇ mol of ammonia to the medium;
  • Rapamycin + Alemtene Group The medium contains 1 ⁇ mol, 6 ⁇ mol, and 10 ⁇ mol of rapamycin and ammonia to sino.
  • the ratio of ammonia to sirolimus was slightly higher than that of smooth muscle cells, while the inhibition rate to endothelial cells was greatly reduced, and the selectivity was particularly prominent.
  • a smooth muscle cell inhibition rate of more than 30% can be obtained at a lower drug content, and the inhibition rate of endothelial cells is reduced compared to the inhibition rate of a single rapamycin. a lot of.
  • the combination of ammonia and rapamycin, as the drug-containing increase the growth rate of inhibition of endothelial cells is not obvious.
  • the surface of the stainless steel stent body is formed into fine lines by rubbing treatment, and the micronized ammonia and the stent body are placed in a high-pressure sealing device to open the device, so that the drug particles are embedded in the fine lines of the stent body.
  • the drug loading amount reached 50 ⁇ g/cm 2 to obtain a drug-eluting stent.
  • a stent body is provided, and a groove is provided on the surface of the stent body to lay a condition for subsequent loading of the drug.
  • the ammonia and the solvent are mixed into a solution; wherein the solvent is a paraffin, an olefin, an alcohol, an aldehyde, an amine, an ester, an ether, a ketone, an aromatic hydrocarbon, a hydrogenated hydrocarbon, a decene, a halogenated hydrocarbon, a miscellaneous a cyclized compound, a nitrogen-containing compound, or a sulfur-containing compound.
  • the solvent is a paraffin, an olefin, an alcohol, an aldehyde, an amine, an ester, an ether, a ketone, an aromatic hydrocarbon, a hydrogenated hydrocarbon, a decene, a halogenated hydrocarbon, a miscellaneous a cyclized compound, a nitrogen-containing compound, or a sulfur-containing compound.
  • the solution is then loaded onto the stent body. Specifically, the solution is loaded in a groove on the surface of the stent body.
  • the solution is loaded by: dripping or coating, and the coating includes one of ultrasonic atomization spraying, chemical vapor deposition, physical vapor deposition, ion beam spraying, dip coating, micro-spraying or brush coating or A variety.
  • Pigs with hyperglycemia, hyperinsulinemia, and early diabetic nephropathy such as microalbuminuria, urine glucose, and nephritis were selected as subjects.
  • Rapamycin stent group Animals implanted with rapamycin-containing scaffolds (scaffold loading: rapamycin 140 ⁇ g/cm 2 )
  • ammonia to the stent group the animal implanted with a stent containing ammonia to the sino (the amount of drug loading: ammonia to the Connaught 140 ⁇ g / cm 2 )
  • rapamycin + ammonia to the stent group 1 animal implanted with rapamycin and ammonia to the stent (support drug loading: rapamycin 140 ⁇ g / cm 2 , ammonia to 20% /cm 2 )
  • rapamycin + ammonia to the stent group 2 animal implanted with rapamycin and ammonia to the stent (support drug loading: rapamycin 140 ⁇ g / cm 2 , ammonia to 70 °g /cm 2 )
  • rapamycin + ammonia to the stent group 3 animal implanted with rapamycin and ammonia to the stent (support drug loading: rapamycin 140 ⁇ g / cm 2 , ammonia to 140% /cm 2 )
  • Aspirin and clopidogrel were administered daily starting 3 days before surgery.
  • the animals were anesthetized before surgery, and they were placed on the operating table to establish a venous access, tracheal intubation and ventilator assisted breathing.
  • the right femoral artery was punctured, and the guide wire was delivered through the puncture needle.
  • the 6F femoral artery sheath was delivered along the guide wire, and 150 Ukg of heparin was administered through the sheath.
  • the 6F right coronary guiding catheter was delivered through the sheath to perform left and right coronary angiography.
  • Target vessel choose to avoid large blood vessel branches as much as possible.
  • the balloon is filled with a pressure pump to release the stent in vitro, and the balloon is withdrawn after the stent is completely attached and causes damage.
  • the angiography was reviewed after surgery. The catheter was withdrawn, the femoral artery sheath was withdrawn, and the site was locally pressurized to stop bleeding. After the pig is awake, return it to Longzhong and continue feeding.
  • Ammonia, paclitaxel and poly(styrene-b-isobutylene-b-styrene) triblock copolymer (SIBS) were weighed in a weight ratio of 1:1:10, and then mixed with tetrahydrofuran to a solid. The percentage of content is 1%.
  • a stent body having a channel structure is prepared, and the solution obtained is then injected into the channel structure by micro-spraying.
  • the drug-loaded stent prepared after removing the tetrahydrofuran was dried under vacuum for 6 hours.
  • a drug balloon for treating vascular stenosis is prepared using a nylon balloon.
  • step (2) Dissolving polylysine in ethanol to obtain a 60 mg/ml solution, and winding the balloon flap obtained in step (1) with a Hamilton MOD710SYR 100 ⁇ l NR syringe (Dongle Natural Gene Life Science Co., Ltd., China) The above solution is dripped on the balloon and naturally dried to obtain a modified balloon;
  • the surface of the modified balloon obtained in the step (2) is brushed with the drug crystal obtained in the step (3), weighed and repeatedly brushed 5 times, heated to 60 ° C under vacuum at 1000 Pa, wrapped in a flap, packaged. Sterilize to obtain a drug balloon.
  • the technical solution provided by the invention can inhibit the biological activity of smooth muscle cell proliferation of blood vessel wall, but At the same time, it does not inhibit endothelial cell growth, that is, it has a selective inhibitory effect.
  • the technical solution provided by the invention prevents the incidence of vascular restenosis and does not delay the endothelium repair, thereby shortening the time for taking antithrombotic and platelet drugs after surgery, and greatly improving the long-term therapeutic effect.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

本发明公开氨来呫诺或其盐或其溶剂化物在制备具有平滑肌细胞抑制作用药物的用途，特别是用于防治血管再狭窄药物中的用途。本发明还公开了医疗器械，特别是药物支架，为表面分布氨来呫诺或其盐或其药物组合物。氨来呫诺具有抑制平滑肌细胞增殖的活性，有低的内皮细胞生长抑制性的特点，特别适合于医疗器械上，防止血管再狭窄发生率的同时，不会延缓内皮修复。

Description

氨来呫诺的新用途 技术领域
本发明涉及氨来呫诺或其盐或其溶剂化物在制备具有平滑肌细胞抑制作用药物的用途，特别是用于防治血管再狭窄药物中的用途。
本发明还涉及医疗器械技术领域。
背景技术
氨来呫诺(Amlexanox)通用名为：2-氨基-7-异丙基-5-氧代-5H[1]苯吡喃基-[2，3，-b]-吡啶-3-石炭酸二甲苯酸，也称做CHX3673。英文化学名为：2-amimo-7-isopropyl-5-oxo-5H-[1]benzopyrano-[2,3,-b]pyridine-3-carboxylic acid。氨来呫诺为过敏反应介质阻滞剂，通过稳定肥大细胞的细胞膜，抑制其脱颗粒，从而阻止过敏反应介质释放而起抗过敏效果。1987年首次在日本上市，用来治疗过敏性支气管哮喘。后来应用于过敏性鼻炎。1996氨来呫诺被美国食品药品局(FDA)批准用于治疗口腔溃疡。
氨来呫诺作为美国FDA批准上市的唯一个用于治疗Aphthous(阿弗他)溃疡的处方药，它的药理作用主要是通过抗过敏和抗炎加速阿弗他溃疡愈合。
体外研究证实，氨来呫诺能够强有力地抑制从肥大细胞、噬中性白细胞及单
核细胞中炎症介质(组织胺、白三烯)的形成和释放。动物试验证实，氨来呫诺具有抗过敏和抗炎作用。体外研究表明，5％氨来呫诺口腔糊剂对大鼠10％醋酸致实验性口腔溃疡和对90％石炭酸致家兔实验性口腔溃疡有明显的治疗作用，可使溃疡面平均愈合时间缩短，与模型组相比，愈合时间分别提前2.5天和1.75天。
从目前的临床使用来看，氨来呫诺主要应用于治疗过敏和口腔溃疡。
心血管疾病是目前威胁人类生命健康最为严重的因素，根据WHO统计，每年因心血管疾病死亡的人数高达全球死亡总述的30％。经心血管介入植入手术治疗心血管疾病是临床发展的趋势。但是对于传统的介入器械，如支架、球囊、封堵器、介入瓣膜等，介入手术后可能导致血栓和赘生物的形成，发生血管狭窄(restenosis,RS)，降低手术的预期效果。
血管内皮功能损伤和血管平滑肌细胞(Vascular smooth muscle cell，VSMCs)过度增殖/迁移是RS发生的重要因素。大量研究证实，动脉中膜VSMCs向内膜的增殖/迁移是RS发展并最终形成的关键环节。当血管壁受到球囊或支架损伤后，动脉中膜VSMCs表型发生改变(由静息/收缩状态转变为增殖/合成表型)，VSMCs不断增殖并向内膜迁移，同时过度合成和分泌大量细胞外基质，导致血管新生内膜形成并引起再狭窄。
临床上，药物洗脱支架(drug-eluting stent，DES)植入后仍有一定比例的再狭窄发生。经皮冠状动脉介入术(PCI)后内皮功能不全可使粥样斑块病变进展，导致支架内再狭窄发生。而如平滑肌细胞的衰老、延迟内皮化、内皮表型改变、支架贴壁不良等因素都可能引起内皮化延迟。重新审视再狭窄的发生机制，目前的药物抗再狭窄是以血管内皮损伤或修复延迟为代价的。维持血管内皮结构和功能的完整性，对于减少PCI后支架内血栓和再狭窄均具有重要作用。更为理想的冠状动脉支架系统，除了支架本身具有良好的生物相容性、径向支撑力和通过病变的能力外，植入的支架更应与冠状动脉“内环境”相协调，能够维持正常的内皮化及内皮功能完整，支架植入处冠状动脉的正常舒缩功能，血管的结构完整及正常重塑。
目前，装载血管平滑肌细胞增殖抑制剂(雷帕霉素及其类似物、紫杉醇)的DES是临床预防再狭窄最常用的治疗手段。尽管DES的应用有效降低了术后短期内的再狭窄发生率，但研究表明，DES在抑制血管平滑肌细胞增殖的同时也 延缓了内皮修复，从而引起支架内膜化不完全、血栓形成等心血管不良事件，最终削弱了抗再狭窄的远期疗效。
发明内容
本发明的发明人出人意料的发现氨来呫诺具有抑制血管壁平滑肌细胞增殖的生物活性，但同时不会抑制内皮细胞生长，也就是具有选择性抑制效果，从而可以防止PCI术后血管再狭窄的问题。
本发明涉及氨来呫诺或其盐或其溶剂化物在制备具有平滑肌细胞抑制作用药物的用途。
本发明中所述氨来呫诺盐指氨来呫诺与许多种酸或碱形成药学上可接受的酸或碱加成盐，并包括制药工业上常用的生理上可接受的盐。
所述酸和碱为有机酸或碱，也可以为无机酸或碱。
进一步的，所述药物为用于防治血管再狭窄药物。由于氨来呫诺在抑制平滑肌细胞增殖的同时而不会抑制内皮细胞的生长，从而有利于损伤血管的愈合，防止血栓的形成，可以缩短病人术后服用抗血栓和血小板药物的时间。
根据本发明，所述血管再狭窄指病人在接受介入手术后，在靶病变处出现的症状复发或血管内径再次狭窄的情况。
进一步的，所述药物为口服给药剂型、注射给药剂型、呼吸道给药剂型、粘膜给药剂型、经皮给药剂型或腔道给药剂型。
进一步的，所述药物为片剂、粉剂、胶囊剂、颗粒剂、溶液剂、乳液剂、喷雾剂、贴剂或凝胶剂。
可以通过本领域已知的方法制备药物制剂。
所述溶液剂和乳液剂可配置成便于口服的口服液，配置成适于肌肉、皮下或静脉内途径施用的注射液，配置成适于胸外施用的外用涂液，配置成适于涂 覆在医疗器械表面的涂层进行局部给药。
所述粉剂可以经口服或经医疗器械带入体内进行局部给药。
本发明还提供了一种医疗器械，包括基体和所述基体表面分布的活性物质或药物组合物，所述活性物质为氨来呫诺或其盐，所述药物组合物包括氨来呫诺或其盐。
进一步的，所述药物组合物还包括免疫抑制剂药物、抗炎药物、抗增殖药物、促再内皮化药物、抗细胞迁移药物、细胞间基质调节剂药物和其他细胞外基质蛋白中的一种以上。
进一步的，所述药物组合物由氨来呫诺或其盐与抗增殖药物组成。
进一步的，所述氨来呫诺与抗增殖药物的载药质量比为(1:10)-(10:1)；优选(1:3)-(3:1)；最优选(1:2.5)-(1.5:1)。
进一步的，所述抗增殖药物选自依维莫司、他克莫司、地磷莫司、替西罗莫司、佐他莫司、艾罗莫司、免疫抑制剂ABT-578、地塞米松、咪唑立宾、雷帕霉素、紫杉醇及其衍生物、放线菌素、长春新碱及其衍生物、他汀类药物、2-氯去氧腺苷、核酶、巴马司他、溴氯哌喹酮和普罗布可的一种或几种，优选雷帕霉素及其衍生物，即依维莫司、他克莫司、地磷莫司、替西罗莫司、佐他莫司和雷帕霉素中的一种或几种。
进一步的，所述医疗器械为心脏瓣膜、心脏封堵器、血管支架、人造血管、导管、起搏器、起搏器导子和除颤器中的一种或多种的组合。
所述基体材质可以是医疗器械通常使用的金属材料，聚合物材料。
所述金属材料可以为可降解或不可降解金属材料，不可降解材料可以为钛、钴、钽、镍钛合金、镍钛锘合金、医用不锈钢材料等，而可降解合金材料如铝镁合金，则可以实现生物完全降解和吸收。
聚合物材料，也分为可降解或不可降解材料，其中可降解材料可以为聚己 内酯(PCL)、聚乙醇酸(PGA)、聚-L-乳酸(PLLA)、聚己内酯单丙烯酸酯(PCLA)、聚乳酸-羟基乙酸共聚物(PLGA)等。
所述药物或药物组合物可以为通过药物载体分布在医疗器械表面，也可以无载体方式分布在医疗器械表面。
所述药物或药物组合物通过物理分散、静电吸附或化学键合的方式固定在所述药物载体中。
所述药物载体的材料可以分为有机的或无机的、可生物降解或不可生物降解的、以及人工合成的或自然物质。有机载体材料主要是指高分子材料，无机载体材料主要是指支架表面制备的多孔的无机涂层，通过这些多孔的结构使药物吸附在支架表面。不可降解的高分子材料可以为聚甲基丙烯酸(PMMA)类、聚苯乙烯-异丁二烯-苯乙烯共聚物(SIBS)类。可降解的高分子载体材料可以为聚乳酸(PLA)以及其与其它物质的共聚物，如与与乙醇酸的共聚物PLGA，与乙二醇的共聚物PELA。
进一步的，所述基体表面分布有凹槽或0.1μm-10μm的微孔。
本发明还提供了一种医疗器械的制备方法，包括如下步骤：制备含有氨来呫诺的微粉或含有氨来呫诺溶液，通过滴注、填埋或涂覆方法将药物装载到所述基体表面。
进一步的，所述涂覆方法选自超声雾化喷涂、化学气相沉积、物理气相沉积、离子束喷涂、浸涂、微喷或刷涂中的一种或多种。
进一步的，所述喷涂方法为直接喷涂、静电喷涂或阳极极化喷涂；所述浸涂方法为直接浸涂或电极极化浸涂。
也就是说，本发明可以选择所述医疗器械基体表面装载药物的方法使氨来呫诺分布到医疗器械基体表面。
进一步的，所述氨来呫诺溶液所用溶剂选自链烷烃、烯烃、醇、醛、胺、 酯、醚、酮、芳香烃、氢化烃、萜烯烃、卤代烃、杂环化物、含氮化合物及含硫化合物
进一步的，所述含有氨来呫诺的溶液中所用溶剂选自乙酸乙酯、乙酸正丙酯、丙酮、四氢呋喃、三氯甲烷和二氯甲烷中的一种以上。
本发明还提供了一种药物支架，包括支架本体和所述支架本体表面分布的活性物质或药物组合物，所述活性物质为氨来呫诺或其盐，所述药物组合物包含氨来呫诺或其盐。
进一步的，所述药物组合物还包括抗增殖药物。
进一步的，所述药物支架上氨来呫诺的载药量20μg/cm2-140μg/cm2。
进一步的，所述抗增殖药物选自雷帕霉素、依维莫司、他克莫司、地磷莫司、替西罗莫司、佐他莫司、渥曼青霉素、哌立福辛或艾代拉里斯。
进一步的，所述氨来呫诺与抗增殖药物的载药质量比(1:10)-(10:1)；优选(1:3)-(3:1)；最优选(1:2.5)-(1.5:1)。
本发明通过支架表面分布的氨来呫诺的持续释放来抑制血管壁平滑肌细胞增殖，并促进血管再内皮化，促进损伤血管壁的愈合，防止支架内血栓的发生，减少病人术后服用抗血栓和血小板药物的时间。
进一步的，所述药物支架的载药方式为无载体药物支架。
所述无载体药物支架可以目前已开发出的任意一种无载体药物支架，主要分为纳米微孔预载药型、支架梁表面结晶化预载药型、支架梁表面粗糙化预载药型或微槽/微盲孔预载药型，具体实施方式可参考现有技术，比如意大利Sorin公司生产的Janus支架、德国Translumina公司生产的Yukon支架、新加坡Biosensors公司生产的BioFreedom支架、大连垠艺支架和乐普医疗的Nano支架等等。
所述支架本体材质可以为金属材料或聚合物材料。
所述金属材料可以为可降解或不可降解金属材料，不可降解材料可以为钛、钴、钽、镍钛合金、镍钛锘合金、医用不锈钢材料等，而可降解合金材料如铝镁合金，则可以实现生物完全降解和吸收。
聚合物材料，也分为可降解或不可降解材料，可降解聚合物材料可以为聚己内酯(PCL)、聚乙醇酸(PGA)、聚-L-乳酸(PLLA)、聚己内酯单丙烯酸酯(PCLA)、聚乳酸-羟基乙酸共聚物(PLGA)等。
进一步的，所述支架本体的材质为可生物降解金属材料和/或可生物降解聚合物材料。
无载体药物支架可以避免载体带来的过敏和炎症反应，药物释放后成为支架本体，导致晚期血栓和炎症发生的可能性更低，安全性高。若是采用完全可降解支架，在介入术后的一段时间内，支架使血管得到机械性支撑，并借助洗脱出的药物，防止再狭窄。之后支架本体即缓慢降解，并完全被组织完全吸收，晚期支架血栓的发生概率降低，无需长期的抗血小板药物治疗，没有后顾之忧。
本发明发现了氨来呫诺的一种全新的生物活性，其具有高的抑制平滑肌细胞增殖的活性，与目前常用的平滑肌细胞增殖抑制剂相比，其还拥有低的内皮细胞生长抑制性的特点，特别适合于医疗器械上，防止血管再狭窄发生率的同时，不会延缓内皮修复，因此可以缩短病人术后服用抗血栓和血小板药物的时间，极大的改善了远期疗效。
具体实施方式
下面结合具体实施例，进一步阐述本发明的技术方案。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，下列实施例中未注明来源的试剂均为市购商品。
本发明所指的“载体”如无特殊说明,均指药学上可接受的载体,不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
本文中交替使用“个体(subject)”或“患者(patient)”等词，其是指可接受所述化合物和/或方法治疗的动物(包括人类)。“个体”或“患者”在此涵盖了雄性与雌性两种性别，除非另有具体说明。因此“个体”或“患者”包含任何哺乳类动物，包括，但不限于，人类、非人类的灵长类，如哺乳动物、狗、猫、马、羊、猪、牛等，其可因利用所述化合物进行治疗而获益。适合接受本发明化合物和/或方法治疗的动物较佳为人类。一般来说，“患者”一词及“个体”一词在本文中可彼此交替使用。
本文中所使用的“医疗器械”是指用于直接或间接用于患者的器具、设备、仪器。本发明所涉及的医疗器械可以是植入体内的器械或体外器械。该器械可以短期暂时使用，或者长期永久性植入。本发明所涉及的医疗器械包括但不限于以下设备：支架、支架移植物、合成贴片、引线、电极、针、手术仪器、血管成形球、创口引流管、分流管(shunt)、管子、输液套简(infusion sleeve)、插管、小球、植入物、血液充氧发生器、泵、脉管移植物、埋入式介入药盒(vascular access port)、心瓣膜、瓣环成形术环、缝合线、手术夹、手术钉、起博器、神经刺激器、整型外科器械、脑脊髓液分流管、可植入药泵、椎笼、人造椎间盘封堵器、人造血管、药物球囊等。
实验例1：细胞实验
A药物的配制：
(一)氨来呫诺的配置：
a)实验前，将载有氨来呫诺的药物支架从置于DMSO溶液中，完全 溶解后并进一步稀释形成药物浓度为10-2mmol/ml的溶液。
b)再将10-2mmol/ml的药物溶液用二甲基亚砜(DMSO)稀释成浓度为10-3,10-4,10-5，10-6,10-7,10-8,10-9mmol/ml的药物溶液。
c)将上述配制的系列浓度药物溶液分装后，置于-20摄氏度暂存备用。
d)使用时，将保存的DMSO稀释后的10-2～10-9的药液取出恢复常温后，用相应完全细胞培养基将每个浓度的药物溶液稀释1000倍进行细胞试验，即最终的使用浓度分别为10-5,10-6,10-7,10-8,10-9,10-10,10-11,10-12mmol/mL。
(二)雷帕霉素的配置：
a)实验前，将载有雷帕霉素的药物支架从置于DMSO溶液中，完全溶解后并进一步稀释形成药物浓度为10-2mmol/ml的溶液。
b)再将10-2mmol/ml的药物溶液用二甲基亚砜(DMSO)稀释成浓度为10-3,10-4,10-5，10-6,10-7,10-8,10-9mmol/ml的药物溶液。
c)将上述配制的系列浓度药物溶液分装后，置于-20摄氏度暂存备用。
d)使用时，将保存的DMSO稀释后的10-2～10-9的药液取出恢复常温后，用相应完全细胞培养基将每个浓度的药物溶液稀释1000倍进行细胞试验，即最终的使用浓度分别为10-5,10-6,10-7,10-8,10-9,10-10,10-11,10-12mmol/mL。
(三)组合药物的配制：
a)实验前，将载有雷帕霉素和氨来呫诺(摩尔比1：1)的药物支架从置于DMSO溶液中，完全溶解后并进一步稀释形成氨来呫诺或雷帕霉素药物浓度为10-2mmol/ml的溶液。
b)再将10-2mmol/ml的药物溶液用二甲基亚砜(DMSO)稀释成浓度为10-3,10-4,10-5，10-6,10-7,10-8,10-9mmol/ml的药物溶液。
c)将上述配制的系列浓度药物溶液分装后，置于-20摄氏度暂存备用。
d)使用时，将保存的DMSO稀释后的10-2～10-9的药液取出恢复常温后，用相应完全细胞培养基将每个浓度的药物溶液稀释1000倍进行细胞试验，即最终的使用浓度分别为10-5,10-6,10-7,10-8,10-9,10-10,10-11,10-12mmol/mL。
B体外细胞增殖及测定
a)细胞接种浓度的选择：选择生长状态良好，生长稳定的A10细胞。消化后配制成浓度分别为1×104/ml、2×104/ml、4×104/ml、5×104/ml、10×104/ml的细胞悬液。将上述浓度的细胞悬液接种于96孔细胞培养板，按MTT比色法进行培养。最后酶标仪测得570nm波长下吸光值为0.6-1.5的为要进行试验的细胞接种液浓度。
b)配制既定的细胞浓度悬液接种于96孔细胞培养板上。
c)吸去细胞培养液添加最终浓度的含药细胞培养液，并以无药细胞培养液作为空白对照组，含1/1000浓度的DMSO细胞培养液作为背景对照组。细胞培养箱培养72小时。
d)添加MTT培养4小时，弃去培养板上的细胞培养液添加DMSO溶解测试吸光度
C实验分组
实验分别选用主动脉平滑肌细胞(HASMC)和人主动脉内皮细胞(HAEC)；根据药物的不同进行分组，每组n＝6，具体如下：
1.对照组：无药物添加；
2.雷帕霉素组：培养基中含1μmol、6μmol和10μmol雷帕霉素；
3.氨来呫诺组：培养基中含1μmol、6μmol和10μmol氨来呫诺；
4.雷帕霉素+氨来呫诺组：培养基中含1μmol、6μmol和10μmol雷帕霉素和氨来呫诺。
D实验结果
各组实验对于平滑肌细胞和内皮细胞的抑制率见下表1。
表1
Figure PCTCN2017100885-appb-000001
表1中组实验对于平滑肌细胞和内皮细胞的抑制率均是以对照组数据为基准数据。
如表1所示，氨来呫诺与雷帕霉素相比，可以发现对平滑肌细胞抑制率略高，而对内皮细胞抑制率则大幅降低，抑制选择性特别突出。另外，氨来呫诺和雷帕霉素组合使用时，在较低含药量时就可以获得30％以上的平滑肌细胞抑制率，同时内皮细胞抑制率则比单一雷帕霉素的抑制率减少很多。并且，氨来呫诺和雷帕霉素组合使用，随着含药的增加，对内皮细胞抑制率的增长并不明显。
实施例2 药物洗脱支架
将300mg氨来呫诺(药物)和300mgPLGA(药物载体)混合置于20ml氯仿中，待溶质完全溶解后，用超声雾化的方式将溶液均匀喷涂在L605钴铬合金金属支架表面，至载药量达到50μg/cm2。室温下待溶剂完全挥发后即制得药物洗脱支架。
实施例3 纳米微孔预载药型
通过摩擦处理使不锈钢支架本体表面形成细微纹痕，将经过微粉化处理后的氨来呫诺与支架本体置于高压密闭设备内，开启设备，使药物微粒镶嵌于支架本体的细微纹痕之中，待载药量达到50μg/cm2，得到药物洗脱支架。
实施例4 含槽药物支架制备方法
首先，提供支架本体，并将所述支架本体表面设置凹槽，以为后续装载药物奠定条件。
接着，将氨来呫诺和溶剂混合成溶液；其中，所述溶剂为链烷烃、烯烃、醇、醛、胺、酯、醚、酮、芳香烃、氢化烃、萜烯烃、卤代烃、杂环化物、含氮化合物或含硫化合物。
然后，将所述溶液装载于所述支架本体上。具体的，所述溶液装载在所述支架本体表面的凹槽内。所述溶液装载的方式为：滴注或涂覆，所述涂覆包括超声雾化喷涂、化学气相沉积、物理气相淀积、离子束喷涂、浸涂、微喷或刷涂中的一种或多种。
最后，待所述溶剂挥发后，获得所述载药支架。
实验例5 动物实验
A研究对象：
选择小型猪，雄性，月龄1-2月，以诱导饲料配方喂养。选择出现高血糖症、高胰岛素血症，并观察到微蛋白尿、尿糖和肾炎等早期糖尿肾病表现的猪作为实验对象。
B实验分组
1、雷帕霉素支架组：动物植入含有雷帕霉素的支架(支架载药量：雷帕霉素140μg/cm2)
2、氨来呫诺支架组：动物植入含有氨来呫诺的支架(支架载药量：氨来呫诺140μg/cm2)
3、雷帕霉素+氨来呫诺支架组1：动物植入含有雷帕霉素和氨来呫诺的支架(支架载药量：雷帕霉素140μg/cm2，氨来呫诺20μg/cm2)
4、雷帕霉素+氨来呫诺支架组2：动物植入含有雷帕霉素和氨来呫诺的支架(支架载药量：雷帕霉素140μg/cm2，氨来呫诺70μg/cm2)
5、雷帕霉素+氨来呫诺支架组3：动物植入含有雷帕霉素和氨来呫诺的支架(支架载药量：雷帕霉素140μg/cm2，氨来呫诺140μg/cm2)
上述支架组的制备方法请参考实施例4
C支架植入术
术前3日开始每天喂服阿司匹林和氯吡格雷。术前麻醉动物，使其仰卧固定于手术台，建立静脉通路，气管插管及呼吸机辅助呼吸。冠脉造影局部消毒后，穿刺右股动脉，经穿刺针送入导引导丝，沿导丝送入6F股动脉鞘，经鞘管给以肝素150Ukg。经鞘管送入6F右冠指引导管分别行左右冠脉造影。靶血管 选择尽量避开大的血管分支。在体外用压力泵充盈球囊释放支架，待支架完全贴壁并造成损伤后撤出球囊。术后复查造影。撤出导管，拔出股动脉鞘，术区局部加压止血。猪清醒后送回隆中继续喂养。
D实验结果
支架植入后，持续饲养45天。45天后考察损伤部位血管内膜增生情况，测定支架植入出血管内膜(intima)和中膜厚度(media)计算其比值(I/M)ratio，结果见下表2。
表2
编号 实验组 I/M
1 雷帕霉素支架组 0.553±0.301
2 氨来呫诺支架组 0.349±0.160
3 雷帕霉素+氨来呫诺支架组1 0.190±0.104
4 雷帕霉素+氨来呫诺支架组2 0.225±0.133
5 雷帕霉素+氨来呫诺支架组3 0.207±0.089
从上述结果可以看出，雷帕霉素与氨来呫诺合用相比于单独使用雷帕霉素或者氨来呫诺的I/M更小，这表明二者合用，在动物体内对内膜的抑制作用比更小，更利用血管的快速内皮化。
实施例6 药物组合物洗脱支架
按1:1:10的重量比分别称取氨来呫诺、紫杉醇和聚(苯乙烯-b-异丁烯-b-苯乙烯)三嵌段共聚物(SIBS)，混合后加入四氢呋喃定容至固体含量百分比1％。制备含有槽结构的支架本体，然后将配得的溶液通过微喷的方法注入槽结构中。真空干燥6小时，除去四氢呋喃后制得的载药支架。
实施例7 载药药物球囊
用尼龙球囊制备用于治疗血管狭窄的药物球囊。
(1)对尼龙球囊表面进行预处理，采用低温等离子处理，选择氮气，温度-20℃，输出功率为2000W，频率为25Hz，处理时间为30分钟，气压为1Pa；
(2)将聚赖氨酸溶于乙醇中得到60mg/ml溶液，将步骤(1)得到的球囊折翼卷绕，用Hamilton MOD710SYR100μl NR型注射器(东乐自然基因生命科学公司，中国)将上述溶液滴涂于球囊上，自然晾干，得到改性球囊；
(3)将氨来呫诺溶于二甲基亚砜/水(体积比为70：30)的混合溶液中配制15mg/ml的氨来呫诺溶液，向10ml上述氨来呫诺溶液中加入400mg赖氨酸并以10转/分钟搅拌溶解，-5℃环境下放置24小时，过滤得固体，40℃加热60分钟至干燥，得到药物晶体；
(4)在步骤(2)得到的改性球囊表面刷涂步骤(3)得到的药物晶体，称重并重复刷涂5次，1000Pa真空下加热至60℃干燥，折翼卷绕，包装灭菌，得到药物球囊。
经测定，上述备的药物球囊氨来呫诺含量为345μg。
实施例8 载药药物球囊
准确称取500mg胶黏剂(如PVP)，溶解到10mL无水乙醇中，搅拌15min备用；将75mg氨来呫诺溶解到10ml 50％乙醇溶液中，搅拌15min备用。将胶黏剂溶液置于样品管中，将球囊以5mm/s的速度浸入到胶黏剂溶液中，停留15s后以2mm/s的速度提拉出来。然后将氨来呫诺溶液置于另外一个样品管中，将已涂好胶黏剂的球囊以同样的涂覆方式涂覆5次，得到载药球囊，可到达载药量200μg/cm2。
本发明所提供的技术方案,可以抑制血管壁平滑肌细胞增殖的生物活性，但 同时不会抑制内皮细胞生长，也就是具有选择性抑制效果。本发明所提供的技术方案，防止血管再狭窄发生率的同时，不会延缓内皮修复，因此可以缩短病人术后服用抗血栓和血小板药物的时间，极大的改善了远期疗效。

Claims (15)

  1. 氨来呫诺或其盐或其溶剂化物在制备具有平滑肌细胞抑制作用药物的用途。
  2. 根据权利要求1所述的用途，其特征在于，所述药物为用于防治血管再狭窄药物。
  3. 根据权利要求1所述的用途，其特征在于，所述药物为口服给药剂型、注射给药剂型、呼吸道给药剂型、粘膜给药剂型、经皮给药剂型或腔道给药剂型。
  4. 一种医疗器械，其特征在于，包括基体和分布于所述基体的活性物质或药物组合物，所述活性物质为氨来呫诺或其盐，所述药物组合物包括氨来呫诺或其盐。
  5. 根据权利要求4所述的医疗器械，其特征在于，所述药物组合物还包括免疫抑制剂药物、抗炎药物、抗增殖药物、促再内皮化药物、抗细胞迁移药物、细胞间基质调节剂药物和细胞外基质蛋白中的一种以上。
  6. 根据权利要求5所述的医疗器械，其特征在于，所述氨来呫诺与抗增殖药物的载药质量比为(1:10)-(10:1)；优选(1:3)-(3:1)；最优选(1:2.5)-(1.5:1)。
  7. 根据权利要求5所述的医疗器械，其特征在于，所述抗增殖药物选自依维莫司、他克莫司、地磷莫司、替西罗莫司、佐他莫司、艾罗莫司、免疫抑制剂ABT-578、地塞米松、咪唑立宾、雷帕霉素、紫杉醇及其衍生物、放线菌素、长春新碱及其衍生物、他汀类药物、2-氯去氧腺苷、核酶、巴马司他、溴氯哌喹酮和普罗布可中的一种或几种；优选：雷帕霉素及其衍生物，即依维莫司、他克莫司、地磷莫司、替西罗莫司、佐他莫司和雷帕霉素中的一种或几种。
  8. 根据权利要求5所述的医疗器械，其特征在于，所述医疗器械为心脏瓣膜、心脏封堵器、支架、人造血管、导管、起搏器、起搏器导子和除颤器中的一种或多种的组合。
  9. 一种医疗器械的制备方法，其特征在于，包括如下步骤：制备药物，所述药物为含有氨来呫诺的粉末或含有氨来呫诺的溶液；以及将所述药物装载到医疗器械表面。
  10. 根据权利要求9所述的制备方法，其特征在于，所述含有氨来呫诺的溶液中所用溶剂选自乙酸乙酯、乙酸正丙酯、丙酮、四氢呋喃、三氯甲烷和二氯甲烷中的一种以上。
  11. 一种药物支架，其特征在于，包括支架本体和所述支架本体表面分布的活性物质或药物组合物，所述活性物质为氨来呫诺或其盐，所述药物组合物包括氨来呫诺或其盐。
  12. 根据权利要求11所述的药物支架，其特征在于，所述药物组合物还包括抗增殖药物。
  13. 根据权利要求12所述的药物支架，其特征在于，所述抗增殖药物选自雷帕霉素、依维莫司、他克莫司、地磷莫司、替西罗莫司、佐他莫司、渥曼青霉素、哌立福辛或艾代拉里斯。
  14. 根据权利要求11所述的药物支架，其特征在于，所述药物支架上氨来呫诺的载药量20μg/cm2-140μg/cm2。
  15. 根据权利要求12-14任一所述的药物支架，其特征在于，所述氨来呫诺与抗增殖药物的载药摩尔量比(1:10)-(10:1)；优选(1:3)-(3:1)；最优选(1:2.5)-(1.5:1)。
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EP3520789A4 (en) 2019-09-11
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