Medical devices

Abstract

The present invention provides a coated medical device that includes an expandable tubular body configured to be implantable in a lumen, which can prevent or reduce the formation of blood clots around the device. [Solution] A medical device having an outer surface to which a polymer is bonded, which is obtained by free radical polymerization of an alkoxyalkyl acrylate and a monomer containing an amine, carboxylic acid, or hydroxyl group.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 505,726, filed May 17, 2017, and incorporates by reference the entire disclosure thereof herein.

[0002] (Technical Field) This specification describes a medical device that includes a stent and a shunt having a covalently - bonded polymer coating capable of reducing thrombosis. Methods of making and using the medical device are also described.

Summary of the Invention

Problems to be Solved by the Invention

[0003] The coatings of medical devices are described herein. The coatings can be used for any medical device that may come into contact with tissue and / or blood. In some embodiments, the coating can prevent or reduce thrombus formation around the device when compared to an uncoated device.

[0004] Expandable tubular bodies, including stents and shunts, are widely used in the medical field to treat various vascular conditions, including stenosis and dilation, or arterial wall weakness (i.e., aneurysms). For the treatment of stenosis, a stent is inserted and positioned within the occlusion of a blood vessel. The stent reinforces the occlusion from within the lumen of the blood vessel and restores blood flow. For the treatment of intracranial aneurysms, a stent can be deployed across the neck of the aneurysm to support subsequent coiling of the aneurysm. Alternatively, a shunt can be positioned across the neck of the aneurysm to reduce or eliminate exposure of the aneurysm wall to blood flow.

[0005] Stents and diverters are widely used to successfully treat a variety of vascular conditions, but they are not without limitations. One such limitation is the need for antiplatelet therapy to prevent stent thrombus formation. Currently, dual antiplatelet therapy is the standard treatment. Low-dose aspirin is recommended indefinitely. P2Y12 inhibitors (i.e., clopidogrel (Plavix), prasugrel (Efient), ticagrelor (Brilinta), and cangrelol (Kengreal)) are recommended up to 12 months post-procedure. While dual antiplatelet therapy is effective in maintaining the lumen of the stented vessel, complications such as bleeding (i.e., gastrointestinal or intracranial) can occur. Although infrequent, such complications are associated with morbidity and mortality. As a result, efforts are being made to reduce or eliminate dual antiplatelet therapy.

[0006] One such coating for reducing stent thrombus formation is phosphorylcholine. In such embodiments, cobalt-chromium braided stream dividers are covalently coated with phosphorylcholine to reduce thrombus formation. In thrombogram tests, coated stream dividers may show reduced thrombus formation compared to uncoated stream dividers.

[0007] Another coating that may reduce thrombus formation on stents is heparin. In such embodiments, the heparin coating is formed on the stent by dip coating or spray coating to reduce thrombus formation. However, the effect of heparin coating on reducing thrombus formation is not well known.

[0008] Antithrombotic coatings can be applied to a wide range of blood-contact medical devices, including tubes, catheters, cardiopulmonary bypass machines, and blood gas machines, as well as to tubular and expandable devices. For example, polymer coatings containing poly(methoxyethyl acrylate) were developed for coating blood gas machines. This polymer is coated on all surfaces of the perfusion circuit, reducing thrombus formation. However, because this polymer is simply adsorbed onto the surface, it is only suitable for devices used for short periods.

[0009] Many other molecules have been evaluated for coatings on stents, dispersers, and other medical devices that come into contact with blood. However, a satisfactory and durable coating has not yet been found. [Means for solving the problem]

[0010] This specification describes tubular expandable devices. These devices can be configured to be implanted in blood vessels or other lumens. The surface of the medical device is tubular and bonded with a polymer that can reduce thrombus formation of the expandable device. In some embodiments, the bonding is covalent.

[0011] In one embodiment, a tubular expandable device includes a plurality of braided filaments woven into a configuration such that it is implanted in a blood vessel. The braided filaments may be metallic. The metallic composition may include gold, silver, copper, steel, aluminum, titanium, cobalt, chromium, platinum, nickel, combinations thereof, alloys thereof such as nitinol (nickel-titanium), cobalt-nickel, cobalt-chromium, platinum-tungsten, and combinations thereof, but is not limited to the following.

[0012] In another embodiment, the tubular expandable device may include a metal tube laser-cut into a configuration suitable for implantation in a blood vessel. The metal tube may include gold, silver, copper, steel, aluminum, titanium, cobalt, chromium, platinum, nickel, combinations thereof, alloys thereof such as nitinol (nickel-titanium), cobalt-nickel, cobalt-chromium, platinum-tungsten, and combinations thereof.

[0013] In one embodiment, the polymer can be prepared by polymerizing an alkoxyalkyl (meth)acrylate or a derivative thereof with a second monomer containing an amine, carboxylic acid, or hydroxyl group. In one embodiment, the second monomer is aminoethyl methacrylate, N-(3-aminopropyl)methacrylamide, a combination thereof, or a derivative thereof. In another embodiment, the second monomer is acrylic acid, methacrylic acid, a combination thereof, or a derivative thereof. In yet another embodiment, the second monomer is hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, a combination thereof, or a derivative thereof.

[0014] In other embodiments, the polymer is prepared by polymerizing tetrahydrofurfuryl acrylate or a derivative thereof with a second monomer containing an amine, carboxylic acid, or hydroxyl group. In one embodiment, the second monomer is aminoethyl methacrylate, N-(3-aminopropyl)methacrylamide, a combination thereof, or a derivative thereof. In another embodiment, the second monomer is acrylic acid, methacrylic acid, a combination thereof, or a derivative thereof. In yet another embodiment, the second monomer is hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, a combination thereof, or a derivative thereof.

[0015] A method of coating an implantable medical device is also described. The method can include activating the surface of the implantable medical device by silanization and bonding a polymer formed from a first acrylate monomer and a second monomer containing an amine, carboxylic acid, or hydroxyl group to the activated surface.

[0016] In some embodiments, the method further includes hydroxylating the surface using an oxygen plasma.

[0017] In some embodiments,

Chem.

Chem.

Chem.

Chem.

[0018] In some embodiments, the method further includes argon plasma treatment after silanization.

[0019] In some embodiments, the first monomer is an alkoxyalkyl (meth)acrylate or tetrahydrofurfuryl acrylate. In other embodiments, the second monomer is acrylic acid, methacrylic acid, hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, aminoethyl methacrylate, N-(3-aminopropyl)methacrylamide, a combination thereof.

Best Mode for Carrying Out the Invention

[0020] The medical devices described herein may be any material or device that comes into contact with blood flow, including artificial lungs, artificial blood vessels, cardiopulmonary bypass machines, catheters, guide wires, stents, shunts, venous filters, vascular protection devices for obliteration, tubes, stent grafts, and the like. In some embodiments, the medical device is a stent or a shunt. In other embodiments, the medical device is a braided stent or a shunt.

[0021] At least a portion of the surface of the medical device can be coated. In some embodiments, a portion of the medical device may be masked using the coatings described herein. In some embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 95% of the surface of the medical device can be coated.

[0022] The surface of the medical device can be treated / coated to reduce thrombus formation. The medical device can include not only methods for applying coatings to the medical device but also surface treatments for reducing thrombus formation.

[0023] The substrate for the coating can be any suitable material including metals, glasses, polymers, ceramics, combinations thereof, and the like. In some embodiments, the substrate is a metal. Any metal surface can be used, and suitable metals can include gold, silver, copper, steel, aluminum, titanium, cobalt, chromium, platinum, nickel, alloys thereof, and combinations thereof. Suitable alloys can include nitinol (nickel-titanium), cobalt-nickel, cobalt-chromium, and platinum-tungsten. In one embodiment, the substrate is a combination of nitinol and platinum-tungsten.

[0024] Polymers for coatings that reduce thrombus formation can be prepared by polymerizing two or more monomers. The first monomer has the following chemical formula: [ka] It can be expressed as R 1 R is a hydrogen atom or a methyl group, 2 R is an alkylene group having 1 to 4 carbon atoms. 3 These are alkyl groups with 1 to 4 carbon atoms.

[0025] In some embodiments, the first monomer is methoxyethyl acrylate, R 1 is a hydrogen atom, R 2 is an ethyl group and R 3 This is a methyl group.

[0026] The second and subsequent monomers may include polymerizable acrylates or methacrylates, as well as amines, carboxylic acids, or hydroxyl groups. Monomers containing amines may include N-(3-aminopropyl)methacrylamide, 2-aminoethyl methacrylate, N-(3-methylpyridine)acrylamide, 2-(N,N-dimethylamino)ethyl methacrylate, 2-(N,N-dimethylamino)ethyl acrylate, 2-(tert-butylamino)ethyl methacrylate, methacryloyl-L-lysine, N-(2-(4-aminophenyl)ethyl)acrylamide, N-(4-aminophenyl)acrylamide, and N-(2-(4-imidazolyl)ethyl)acrylamide, their derivatives, and combinations thereof. Monomers containing carboxylic acids may include acrylic acid, methacrylic acid, their derivatives, and combinations thereof. Monomers containing hydroxyl groups may include 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, their derivatives, and combinations thereof.

[0027] In one embodiment, two or more monomers and initiators are dissolved in a solvent to prepare a polymer. Generally, any solvent that dissolves two or more monomers and initiators can be used. Careful selection of the solvent may be necessary because the solubility of alkoxyalkyl (meth)acrylates and monomers containing amine salts differs. Suitable solvents may include methanol / water, ethanol / water, isopropanol / water, dioxane / water, tetrahydrofuran / water, dimethylformamide / water, dimethyl sulfoxide and / or water, and combinations thereof. For monomers containing carboxylic acids and hydroxyls, a broader range of solvents can be used, including toluene, xylene, dimethyl sulfoxide, dioxane, THF, methanol, ethanol and dimethylformamide.

[0028] Polymerization initiators can be used to initiate the polymerization of monomers in solution. Polymerization can be initiated by oxidation-reduction, radiation, heat, or any other method known in the art. Radiation crosslinking of monomer solutions can be achieved by ultraviolet or visible light with a suitable initiator, or by ionizing radiation (e.g., electron beams or gamma rays) without an initiator. Polymerization can also be achieved by applying heat, either by heating the solution in a conventional manner using a heat source such as a heating well, or by irradiating the monomer solution with infrared radiation.

[0029] In some embodiments, an initiator may not be used.

[0030] In one embodiment, the polymerization initiator is azobisisobutyronitrile (AIBN), or a water-soluble AIBN derivative (2,2'-azobis(2-methylpropionamidine) dihydrochloride), or 4,4'-azobis(4-cyanopentanoic acid). Other suitable initiators include N,N,N',N'-tetramethylethylenediamine, ammonium persulfate, benzoyl peroxide, and combinations thereof, and azobisisobutyronitrile. The initiator concentration can be in the range of about 0.25% to about 2% w / w of the mass of monomer in solution. The polymerization reaction can be carried out at high temperatures, such as in the range of about 65 to about 85°C. After polymerization is complete, the polymer can be recovered by precipitation in a non-solvent and dried under vacuum.

[0031] In some embodiments, the polymers described herein are greater than about 10,000 g / mol, between about 10,000 g / mol and about 200,000 g / mol, between about 8,000 g / mol and about 200,000 g / mol, between about 100,000 g / mol and about 200,000 g / mol, between about 50,000 g / mol and about 200,000 g / mol, between about 25,000 g / mol and about 200,000 g / mol, and between about 8,000 g / mol and about 100 It may have molecular weights between 1,000 g / mol, between approximately 10,000 g / mol and approximately 100,000 g / mol, between approximately 50,000 g / mol and approximately 100,000 g / mol, between approximately 75,000 g / mol and approximately 100,000 g / mol, between approximately 75,000 g / mol and approximately 200,000 g / mol, approximately 10,000 g / mol, approximately 50,000 g / mol, approximately 100,000 g / mol, approximately 150,000 g / mol, or approximately 200,000 g / mol.

[0032] In one embodiment, the polymer is applied to the substrate in multiple steps, each step being optional. In some embodiments, the polymer is applied to the substrate in four steps. The necessity of each step depends on the choice of substrate.

[0033] Step 1 includes a washing step. To clean the substrate, it may be incubated under sonication in acetone, methanol, ethanol, isopropyl alcohol, water, or a combination thereof. The duration of each washing step ranges from about 1 minute to about 20 minutes. The temperature of the sonication can range from about 18 to 55°C. Following the completion of Step 1, the substrate is moved to Step 2. In some embodiments, Step 2 follows immediately after Step 1.

[0034] In some embodiments, the cleaning step may optionally include washing with soap / detergent and water.

[0035] Step 2 involves hydroxylation, which is a process that increases the number of hydroxyl groups on the surface of the substrate. The surface to be treated may be hydroxylated using many different oxidizing agents, including acids, bases, peroxides, plasma treatments, and combinations thereof.

[0036] Acids for treatment include hydrochloric acid, nitric acid, sulfuric acid, hydrofluoric acid, perchloric acid, and combinations thereof. Bases for treatment include sodium hydroxide, ammonium hydroxide, and combinations thereof. Peroxides for treatment include hydrogen peroxide, t-butyl peroxide, and combinations thereof. In one embodiment, the oxidizing agent is hydrogen peroxide. The oxidizing agent used for hydroxylation may be at a concentration of about 1% to about 100%. The duration of hydroxylation can be in the range of about 0.25 hours to about 4 hours at a temperature in the range of about 18°C ​​to about 100°C. After hydroxylation, the substrate may be washed with or without ultrasound in acetone, methanol, ethanol, isopropyl alcohol, water, or combinations thereof. The duration of each wash can be in the range of about 1 minute to about 15 minutes. Following washing, drying may optionally be performed under vacuum. In one embodiment, hydroxylation is performed using about 10% hydrogen peroxide at about 100°C for about 45 minutes, followed by washing with water, ethanol and acetone for about 5 minutes, and then drying under vacuum.

[0037] In another embodiment, oxygen plasma is used for processing. In a plasma processing machine, the substrate can be exposed to oxygen plasma. Parameters of the plasma processing may include oxygen flow rate, wattage, pressure, and time. The oxygen flow rate can be about 1 to 500 sccm, about 1 to 250 sccm, about 1 to 120 sccm, about 100 to 500 sccm, about 100 to 200 sccm, about 100 to 140 sccm, at least about 100 sccm, at least about 50 sccm, or less than about 500 sccm. The power can be about 1 to 600 watts, about 1 to 500 watts, about 1 to 400 watts, about 100 to 600 watts, about 200 to 600 watts, about 400 to 600 watts, at least about 400 watts, at least about 500 watts, or less than about 600 watts. The pressure can be approximately 120-2000 mTorr, approximately 200-2000 mTorr, approximately 200-1000 mTorr, approximately 300-500 mTorr, approximately 300-2000 mTorr, at least approximately 200 mTorr, at least approximately 300 mTorr, or less than approximately 2000 mTorr. The time can be approximately 1-15 minutes, approximately 5-15 minutes, approximately 5-10 minutes, at least approximately 5 minutes, at least approximately 4 minutes, at least approximately 3 minutes, at least approximately 2 minutes, or at least approximately 1 minute. In one embodiment, the oxygen flow rate is approximately 120 sccm, the power is approximately 500 watts, the pressure is approximately 400 mTorr, and the time is approximately 5 minutes.

[0038] Step 3 includes silanization, a process for bonding and introducing reactive groups to the substrate. Silane reactive groups may include acrylates, methacrylates, aldehydes, amines, epoxys, esters, halogens, combinations thereof, and derivatives thereof. The silane reactive group reacts with the amine, carboxylic acid, or hydroxyl group of the polymer's second monomer. In the case of a polymer containing an amine or hydroxyl group, the silane reacts with the amine, carboxylic acid, or hydroxyl group. [ka] [ka] This may include chlorophenyltriethoxysilane, chloromethyltriethoxysilane, chloromethyltrimethoxysilane, or a combination thereof.

[0039] In the case of polymers containing carboxylic acids, silanes are, [ka] [ka] Alternatively, combinations thereof may be included. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In one embodiment, n is 8 to 12.

[0040] To carry out silanization, the selected silane is dissolved in a solvent. Suitable solvents include ethanol, methanol, isopropanol, acetic acid, water, isopropanol, butanol, dimethylformamide, dimethyl sulfoxide, ethyl acetate, toluene, chloroform, dichloromethane, and combinations thereof. In general, any solvent or mixture of solvents that dissolves silane can be used. The solvent may be present in an amount of about 0.1% to about 99.9% by weight. The proportion of the solvent is in the range of about 90% to about 99%, or about 97%. The silane may be present in an amount of about 0.1% to about 99.9% by weight. The proportion of silane is in the range of about 1% to about 10%, or about 3%. In one embodiment, the silane:solvent system is 94% ethanol, 2% water, 1% acetic acid, and 3% silane.

[0041] Following hydroxylation, the substrate may be optionally plasma-treated using argon plasma to clean the surface.

[0042] The parameters for plasma treatment can include argon flow rate, wattage, pressure, and time. The argon flow rate can be approximately 1–500 sccm, approximately 1–250 sccm, approximately 1–120 sccm, approximately 100–500 sccm, approximately 100–200 sccm, approximately 100–140 sccm, at least approximately 100 sccm, at least approximately 50 sccm, or less than approximately 500 sccm. The power can be approximately 1–500 watts, approximately 1–400 watts, approximately 1–300 watts, approximately 100–500 watts, approximately 200–500 watts, approximately 200–400 watts, at least approximately 100 watts, at least approximately 200 watts, or less than approximately 500 watts. The pressure can be approximately 120-2000 mTorr, approximately 200-2000 mTorr, approximately 200-1000 mTorr, approximately 300-500 mTorr, approximately 300-2000 mTorr, at least approximately 200 mTorr, at least approximately 300 mTorr, or less than approximately 2000 mTorr. The time can be approximately 1-15 minutes, approximately 5-15 minutes, approximately 5-10 minutes, at least approximately 5 minutes, at least approximately 4 minutes, at least approximately 3 minutes, at least approximately 2 minutes, or at least approximately 1 minute. In one embodiment, the argon flow rate is approximately 365 sccm, the power is approximately 300 watts, the pressure is approximately 500 mTorr, and the time is approximately 10 minutes.

[0043] Following plasma treatment, the substrate can be placed in a silane:solvent system. The incubation period is approximately 6 to 24 hours at a temperature in the range of approximately 18°C ​​to 55°C. Silanation can be optionally performed by shaking at a speed of approximately 100 rpm to 250 rpm. In one embodiment, the silanation conditions are incubation at room temperature for approximately 18 hours with shaking at approximately 150 rpm.

[0044] After silanization, the substrate may be rinsed with ethanol, methanol, isopropanol, toluene, water, butanol, dimethylformamide, dimethyl sulfoxide, ethyl acetate, chloroform, dichloromethane, or combinations thereof. In one embodiment, the rinse is ethanol. The silane layer is then cured at a temperature in the range of about 30 to about 150°C for a duration of about 5 to 60 minutes. The curing conditions can be about 110°C for about 30 minutes.

[0045] Step 4 includes a polymer bonding step, which is a process for covalently bonding the polymer to the substrate. During this step, functional groups affixed to the polymer from a second or more monomers can react with functional groups affixed to the substrate via silane. In this step, the polymer can be dissolved in water, buffer solution, methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethyl sulfoxide, ethyl acetate, toluene, chloroform, dichloromethane, or a combination thereof. The solvent for this step can be 50% v / v ethanol:50% v / v citrate buffer solution (aqueous solution, pH 7). The concentration of the polymer in the solvent can range from about 0.5% to about 95% of the solvent. In one embodiment, the concentration of the polymer in the solvent is about 1%.

[0046] The polymer solution can be applied to the substrate by dip coating, spraying, brushing, or a combination thereof. In one embodiment, the substrate may be immersed in the polymer solution for about 1 hour to about 48 hours, or in another embodiment, for a duration of 18 hours. Incubation may be carried out at a temperature in the range of about 18 to about 100°C. In one embodiment, the temperature is room temperature. The bonding reaction may optionally be carried out with shaking at a speed of about 100 rpm to about 250 rpm. In one embodiment, the shaking condition is about 150 rpm.

[0047] After incubation, the substrate may optionally be rinsed with ethanol, methanol, isopropanol, toluene, water, butanol, dimethylformamide, dimethyl sulfoxide, ethyl acetate, chloroform, dichloromethane, or combinations thereof. In one embodiment, it is rinsed in 50% v / v ethanol:50% v / v water. After rinsing, the substrate may be dried using heat or vacuum. The substrate may be heated under vacuum or non-vacuum at a temperature in the range of about 40°C to about 100°C. In some embodiments, the drying conditions are 40°C under vacuum. After drying, the substrate can be sterilized and packaged.

[0048] The coated equipment can be sterilized without substantially degrading the coating. After sterilization, at least about 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% of the coating can remain in its original state. In one embodiment, the sterilization method may be autoclaving, gamma irradiation, pressure sterilization, and / or steam sterilization.

[0049] The coatings described herein can prevent thrombin growth. In some embodiments, the coatings can reduce the amount of wet thrombin formation by about 50% to about 90%, about 70% to about 90%, about 70% to about 100%, at least about 60%, or at least about 70%. In some embodiments, the coatings can reduce the amount of thrombin formation by about 60% to about 95%, about 70% to about 95%, about 70% to about 100%, at least about 70%, at least about 80%, or at least about 90% when measured in a dry state.

[0050] (Example 1) Preparation of braided medical devices for silane treatment First, the braided medical devices are pre-cleaned using continuous incubation with acetone, ethanol, and water for 5 minutes each while ultrasonically treating them. The cleaned braided medical devices are incubated in a 10% hydrogen peroxide solution at 100°C for approximately 45 minutes, and then rinsed three times with water. The braided medical devices are then cleaned again using continuous incubation with water, ethanol, and acetone for 5 minutes each while ultrasonically treating them. Finally, the braided medical devices are dried under vacuum for 18 hours.

[0051] (Example 2) Preparation of braided medical devices for silane formation via oxygen plasma First, the braided medical devices are pre-cleaned using continuous incubation with acetone, ethanol, and water for 5 minutes each while ultrasonically treating them. Then, the braided medical devices are transferred to a vacuum oven and dried under reduced pressure at 40°C for 30 minutes. The dried braided medical devices are then activated using an IoN40 plasma treatment system with the following parameters. [Table 1]

[0052] The activated braided medical device is then stored in a vial.

[0053] (Example 3) Silaneization of braided medical devices A silane solution consisting of 94% ethanol, 3% 7-bromoheptyltrimethoxysilane, 2% water, and 1% acetic acid is prepared and allowed to pre-react for 60 minutes. During the pre-reaction, the braided medical device of Example 1 or Example 2 is plasma-treated with argon plasma (365 sccm argon, 300 watts, 500 mTorr) for 10 minutes. Subsequently, the braided medical device is immersed in the silane solution and incubated at room temperature for 18 hours with swirling vibrations at 150 revolutions per minute, while being protected from light. At the end of incubation, the braided medical device is rinsed with ethanol and cured at 110°C for 30 minutes.

[0054] (Example 4) Silaneization of braided medical devices A silane mixture is prepared using 7-bromoheptyltrimethoxysilane and 1,2-bis(trimethoxysilane)ethane in a ratio of 9:1 (v / v). The silane mixture is diluted to 5% by volume with toluene. The apparatus from Example 1 or Example 2 is treated with argon plasma under the same conditions as Example 3, while the silane is pre-reacted for approximately 60 minutes. Subsequently, the braided medical device is immersed in the silane solution and incubated at 70°C for 18 hours. At the end of incubation, the braided medical device is rinsed with toluene and cured at 110°C for 30 minutes.

[0055] (Example 5) Preparation of poly(2-methoxyethyl acrylate)-co-poly[(3-aminopropyl)methacrylamide hydrochloride] copolymer Dissolve 40 g of 2-methoxyethyl acrylate, 4 g of 3-aminopropyl methacrylate hydrochloride, and 440 mg of 4,4'-azobis(4-cyanovaleric acid) in a mixture of 40 mL of water and 40 mL of methanol. Polymerization occurs at 80°C for 4 hours. Precipitate and recover the copolymer in a mixture of isopropanol / hexane (500 mL:500 mL). Redissolve the copolymer in a mixture of 80 mL of tetrahydrofuran and 20 mL of ethanol, and reprecipitate in a mixture of isopropanol:hexane (400 mL:600 mL). Redissolve the copolymer in a mixture of 80 mL of tetrahydrofuran and 20 mL of ethanol, reprecipitate in a mixture of isopropanol:hexane (300 mL:700 mL), and dry under vacuum. The copolymer is a white, foamy solid.

[0056] (Example 6) Preparation of poly(tetrahydrofurylacrylate)-co-poly[(3-aminopropyl)methacrylamide hydrochloride] copolymer Dissolve 40 g of tetrahydrofurfuryl acrylate, 4 g of 3-aminopropyl methacrylate hydrochloride, and 440 mg of 4,4'-azobis(4-cyanovaleric acid) in a mixture of 40 mL of water and 40 mL of methanol. Polymerization occurs at 65°C for 20 hours. The copolymer is recovered by precipitation in a mixture of isopropanol:hexane (500 mL:500 mL). Redissolve the copolymer in 100 mL of tetrahydrofuran and reprecipitate in a mixture of isopropanol:hexane (400 mL:600 mL). Redissolve the copolymer in 100 mL of tetrahydrofuran and reprecipitate in a mixture of isopropanol:hexane (300 mL:700 mL). Redissolve the copolymer in 100 mL of tetrahydrofuran and reprecipitate in a mixture of isopropanol:hexane (200 mL:800 mL). Finally, the copolymer is stirred in 1 L of hexane for 1 hour and dried under vacuum. The copolymer is a slightly orange, foamy solid.

[0057] (Example 7) Preparation of coated braided medical devices using poly(2-methoxyethyl acrylate)-co-poly[(3-aminopropyl)methacrylamide hydrochloride] copolymer. The copolymer from Example 5 is dissolved in 50% / 50% ethanol / pH 7.0 citrate buffer (v / v) to a final concentration of 10 mg / mL. The braided medical device from Example 3 is placed in a vial containing the copolymer solution and incubated at room temperature for 18 hours in a 150 rpm orbital shaker. After incubation, the device is rinsed with 50% / 50% ethanol / water and cured under vacuum at 40°C for 30 minutes.

[0058] (Example 8) Evaluation of coated braided medical devices using the Chandler loop model A PVC tube (4mm inner diameter, 6mm outer diameter, 54.86cm length) is measured and cut to fit into the cradle of a Chandler Loop device (Industriedesign, Neufen, Germany). A single coated braided medical device (4.5mm x 2cm), weighed beforehand, is placed inside the tube. Fresh bovine blood is collected from a local slaughterhouse and heparinized at 1U / mL. The activated clotting time (ACT) is adjusted to between 150 and 250 seconds, using protamine as needed. The tube is filled with blood and sealed with a connector. The loop is fitted onto a polycarbonate stabilizing disc, which is then secured to the Chandler Loop device. The loop is heated at 37°C for 300 seconds. -1 Rotate it for 2 hours at this shear rate.

[0059] Next, the assembly is removed from the Chandler loop apparatus and the blood is drained into a PTFE beaker. The ACT of the drained blood is determined. The tubing is thoroughly rinsed three times with PBS to remove any remaining blood. The tubing is cut longitudinally with a razor blade, the braided medical device is recovered, and a photograph is taken. The weight (wet weight) of the stent is measured, and then it is dried at 37°C until the weight stabilizes (dry weight). The table below summarizes the results of the Chandler loop test. [Table 2]

[0060] The coating in Example 7 dramatically reduced both the wet and dry weight of the thrombus.

[0061] (Example 9) Evaluation of coated braided medical devices using X-ray photoelectron spectroscopy. The atomic composition of the support columns of braided medical devices was determined by analyzing them using X-ray photoelectron spectroscopy. The results are summarized in the table below. [Table 3]

[0062] XPS did not detect silicon or bromine on the surface of the uncoated braided medical device. The braided medical device of Example 3 had significant silicon and bromine, indicating successful silanation. The braided medical device of Example 7 no longer showed a Si-to-Br ratio close to 1:1, indicating that most of the bromine was substituted and the coupling reaction was successful.

[0063] (Example 10) Evaluation of coated medical devices using thrombograms Thrombograms are performed using a thrombinoscope (Thrombinoscope BV, Maastricht, Netherlands) according to the manual. Negative control, test sample, and thrombin calibrator are arranged in nine repeats for each group on a 96-well plate. Platelet-deficient plasma (PPP, 240 μL) is added to all wells, and PPP reagent (60 μL) is added to the negative control and test sample. After adding FluCa solution to the instrument, the start button is pressed, the 96-well plate is inserted into the instrument, and a 10-minute incubation is initiated. Results are processed and reported at the end of the incubation. The results are summarized below. [Table 4]

[0064] The thrombogram in Example 7 shows results comparable to the negative control, indicating that the coating withstood thrombin formation.

[0065] (Example 11) Evaluation of coated braided medical devices using Blood Loop The braided medical device of Example 7 is packaged in a delivery system and sterilized with an electron beam. A 140 cm length of PVC tubing (OD=5 / 16”, ID=3 / 16”, Terumo, Japan) with an X coating lined to the inside is cut. The tubing is filled with saline solution, and three identical devices are deployed inside the tubing. The saline solution is replaced with sheep's blood (heparinized at 1 U / mL), with the blood ACT being between 150 and 250 seconds. To begin the test, the tubing connector is used to close the tubing into a loop, and it is mounted on a peristaltic pump. The loop is incubated in a heating chamber for 273 seconds. -1 Blood is circulated for 2 hours ± 30 minutes. At the end of incubation, blood is drained from each loop and ACT is measured. The entire length of the tubing is rinsed with saline solution. The stent is cut out of the tubing, its weight is measured (wet weight), and then it is dried at 37°C until the weight stabilizes (dry weight). The following table summarizes the experimental results for the Chandler loop. [Table 5]

[0066] The coating in Example 7 dramatically reduced both the wet and dry weight of the thrombus.

[0067] Unless otherwise specified, all figures representing quantities of properties such as the amount of components, molecular weight, and reaction conditions used herein and in the claims should be understood to be modified in all examples by the term "approximately." Therefore, unless otherwise indicated, the numerical parameters described herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained by the invention. At the very least, and without the intention of limiting the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be interpreted by taking into account the number of significant figures reported and by applying the usual methods of approximation. Although the numerical ranges and parameters representing the broad scope of the invention are approximations, the numerical values ​​described in specific examples are reported as accurately as possible. However, the numerical values ​​inherently contain certain errors that inevitably arise from the standard deviation found in each test measurement.

[0068] The terms “a,” “an,” and “the,” and similar references used in the context describing the present invention (particularly in the context of the following claims), should be construed as encompassing both singular and plural unless otherwise shown herein or unless the context clearly contradicts them. The enumeration of numerical ranges herein is intended to function merely as a concise way of individually referring to each individual value that falls within that range. Unless otherwise shown herein, individual values ​​are incorporated herein as if they were individually cited herein. All methods described herein can be carried out in any suitable order unless otherwise shown herein or unless the context clearly contradicts them. Any and all examples or use of illustrative language (e.g., “like”) provided herein are intended merely to better illustrate the present invention and not to limit the scope of the invention as described in the claims. No language in the specification should be construed as indicating an element not described in the claims that is essential to carrying out the present invention.

[0069] The grouping of alternative elements or embodiments of the invention disclosed herein should not be construed as limitation. Each group's components may be referenced and claimed individually or in any combination with other components of the groups found herein. It is anticipated that one or more components may be included in or excluded from a group for convenience and / or patentability reasons. In any event of such inclusion or exclusion, the specification shall be deemed to include the modified group and satisfy the description requirements of all Markush groups used in the appended claims.

[0070] Specific embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Naturally, variations of the embodiments described will be obvious to those skilled in the art by reading the above description. The inventors expect that those skilled in the art will appropriately adopt such variations, and the inventors intend that the invention will be carried out in ways other than those specifically described herein. Accordingly, the invention includes all variations and all variations and equivalents of the subject matter described in the appended claims, to the extent permitted by applicable law. Furthermore, any combination of the elements described above in all possible variations is included in the invention unless otherwise shown herein or is clearly inconsistent with the context.

[0071] Furthermore, numerous references are made throughout this specification to patents and printed publications. Each of the aforementioned references and printed publications is incorporated herein by individual citation.

[0072] Finally, the embodiments of the invention disclosed herein should be understood as illustrating the principles of the invention. Other modifications that may be adopted are included within the scope of the invention. Accordingly, alternative configurations of the invention can be adopted in accordance with the teachings herein, not as limitations but as examples. Thus, the invention is not limited to those shown and described.

[0073] [Note] [Note 1] A medical device having an outer surface to which a polymer is bonded, which is obtained by free radical polymerization of an alkoxyalkyl acrylate and a monomer containing an amine, carboxylic acid, or hydroxyl group.

[0074] [Note 2] Includes an expandable tubular body configured to be embedded in a blood vessel, A medical device as described in Appendix 1, characterized by the features described herein.

[0075] [Note 3] The expandable tubular body includes metal, A medical device as described in Appendix 2, characterized by the features described herein.

[0076] [Note 4] The aforementioned metals include, but are not limited to, gold, silver, copper, steel, aluminum, titanium, cobalt, chromium, platinum, nickel, combinations thereof, alloys thereof such as nitinol (nickel-titanium), cobalt-nickel, cobalt-chromium, platinum-tungsten, or combinations thereof. A medical device as described in Appendix 2, characterized by the features described herein.

[0077] [Note 5] The aforementioned metal is a combination of nitinol and platinum-tungsten. A medical device as described in Appendix 4, characterized by the features described herein.

[0078] [Note 6] The polymer is covalently bonded to the outer surface. A medical device as described in Appendix 1, characterized by the features described herein.

[0079] [Note 7] It includes an expandable tubular body configured to be implantable in a blood vessel, A polymer is bonded to the outer surface of the expandable tubular body, which is obtained by free radical polymerization of tetrahydrofurfuryl acrylate and a monomer containing an amine, carboxylic acid, or hydroxyl group. A medical device characterized by the following features.

[0080] [Note 8] The expandable tubular body includes metal, A medical device as described in Appendix 7, characterized by the features described herein.

[0081] [Note 9] The aforementioned metals include nitinol, nickel, titanium, platinum, chromium, cobalt, alloys thereof, or combinations thereof. A medical device as described in Appendix 8, characterized by the features described herein.

[0082] [Note 10] The polymer is covalently bonded to the tubular body. A medical device as described in Appendix 7, characterized by the features described herein.

[0083] [Note 11] A process for activating the surface of an implantable medical device by silaneization, A step of bonding a polymer formed from a first acrylate monomer and a second monomer containing an amine, carboxylic acid, or hydroxyl group to the activated surface, Equipped with, A method for coating implantable medical devices.

[0084] [Note 12] The process further comprises a step of hydroxylating the surface using oxygen plasma. The method described in Appendix 11, characterized by the features described herein.

[0085] [Note 13] The oxygen plasma is applied by an oxygen flow rate of approximately 120 sccm, a power of approximately 500 watts, a pressure of approximately 400 mTorr, a time of approximately 5 minutes, or a combination thereof. The method described in Appendix 12, characterized by the features described herein.

[0086] [Note 14] Silane formation is, [ka] [ka] Compounds having the structure, chlorophenyltriethoxysilane, chloromethyltriethoxysilane, chloromethyltrimethoxysilane, [ka] [ka] This occurs through reactions with compounds having the structure, or combinations thereof. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. The method described in Appendix 11, characterized by the features described herein.

[0087] [Note 15] n is between 8 and 12. The method described in Appendix 14, characterized by the features described herein.

[0088] [Note 16] It further includes argon plasma treatment after silanization. The method described in Appendix 11, characterized by the features described herein.

[0089] [Note 17] The argon plasma is applied by an argon flow rate of approximately 365 sccm, a power of approximately 300 watts, a pressure of approximately 500 mTorr, a duration of approximately 10 minutes, or a combination thereof. The method described in Appendix 16, characterized by the features described herein.

[0090] [Note 18] The bonding process may involve dip coating, spraying, brushing, or a combination thereof. The method described in Appendix 11, characterized by the features described herein.

[0091] [Note 19] The first monomer is an alkoxyalkyl (meth)acrylate or a tetrahydrofurfuryl acrylate. The method described in Appendix 11, characterized by the features described herein.

[0092] [Note 20] The second monomers are acrylic acid, methacrylic acid, hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, aminoethyl methacrylate, aminopropyl methacrylamide, and combinations thereof. The method described in Appendix 11, characterized by the features described herein.

Claims

[Claim 1] A medical device having an outer surface to which a polymer is bonded, which is obtained by free radical polymerization of an alkoxyalkyl acrylate and a monomer containing an amine, carboxylic acid, or hydroxyl group.

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