WO2022019733A1 - Graft copolymer of amphoteric compound and anionic compound and preparation method therefor - Google Patents

Abstract

The present invention relates to a graft copolymer of an amphoteric compound and an anionic compound and a preparation method therefor, and is characterized as a graft copolymer composition of an amino acid amphoteric compound and an anionic compound selected from the group consisting of a sulfonic group, a carboxyl group, and a phosphoric group.

Description

Graft copolymer of zwitterionic compound and anionic compound and manufacturing method thereof

The present invention relates to a graft copolymer of a zwitterionic compound and an anionic compound and a method for preparing the same.

In the case of existing medical devices in various fields, including the cardiovascular system, which come into contact with blood, a technology of coating a material having antibacterial and antithrombotic properties has been developed to inhibit infection and thrombus formation, but the surface coating has poor safety, Problems such as difficulties in the process and induction of toxicity in the body have been raised, and they have not been completely resolved to this day. Therefore, there is a very high need for the development of a high-molecular compound having antithrombotic properties and antibacterial properties with high versatility and a composition for chemical addition using the same.

In general, protein adsorption occurs spontaneously on the surface of medical materials in contact with blood. As a result, cells and various components in the blood are slowly dispersed and attached to the surface of the medical material already adsorbed with protein. Protein adsorption not only reduces the function of medical materials, but also causes side effects such as blood clot formation and inflammation.

In addition, protein adsorption reduces the sensitivity of the medical device sensor inserted to check the patient's health condition, thereby reducing diagnostic efficiency. In particular, in the case of a blood-contact type medical device that is inserted into the body, it is important to suppress protein adsorption, which is a primary phenomenon that occurs during insertion into the body.

In general, thrombus occurs due to the adsorption of proteins and platelets in the blood. When a thrombus is formed, blood circulation is not smooth, causing various diseases in the human body. In particular, Upper Deep Vein Thrombosis caused by medical devices is a very serious disease requiring immediate treatment. Blood clots can form as a result of blood clots. Among nosocomial infections, bloodstream infection is the second most frequent infection after urethral infection. This bloodstream infection usually occurs frequently in catheters during blood contact medical devices, and accounts for more than 30% of all hospital-acquired infections.

In order to prevent various diseases caused by protein adsorption, such as thrombogenesis and infection by thrombus, unnecessary social and patient costs are required. For this reason, there is a need for a functional medical device that inhibits protein adsorption, thrombus formation, and biofilm formation.

Among medical devices, blood contact medical devices generally have two problems. Thrombogenesis by protein adsorption and bloodstream infection by thrombogenesis. In order to solve these side effects, techniques for improving blood compatibility, inhibiting protein adsorption, and inhibiting thrombogenesis by modifying the surface of medical devices are being applied.

The coating method is the most widely known surface modification technique. It is quick and easy to apply and is widely used for general purpose. However, when applied to medical devices, both safety and effectiveness must be considered, so a coating method that weighs on effectiveness is not appropriate.

The coating method has a fatal weakness of peeling phenomenon. Blood compatibility is lowered where exfoliation occurs, and proteins are adsorbed, resulting in the formation of blood clots and infection by bacterial biofilm formation. There is a graft method as a method to solve this disadvantage, and the graft method can be divided into a graft from and a graft to, but the graft from method is suitable in terms of efficiency.

The graft from method reacting from the outer surface of the medical device is a method that can satisfy both the safety and effectiveness of the medical device. In particular, it can prevent peeling, which is a disadvantage of coating, so it is more suitable for application to medical devices. As such, the need for the development of materials for inhibiting adsorption of medical devices is gradually increasing.

The present invention aims to develop a method capable of improving blood compatibility of medical devices, inhibiting protein adsorption, and inhibiting thrombogenesis.

An object of the present invention is to provide a graft copolymer of an amino acid zwitterionic compound and an anionic compound and a method for preparing the same in order to solve the technical necessity.

Another object of the present invention is to provide an implantable medical device comprising a graft polymer layer having improved protein adsorption inhibitory function and thrombus adsorption inhibitory function, and a grafting method of the implantable medical device.

However, these problems are exemplary, and the scope of the present invention is not limited thereto.

The present invention has the effect of providing a graft copolymer of a zwitterionic compound and an anionic compound and a method for preparing the same.

In addition, there is an effect of providing a graft composition and a graft method that can be used without a separate solute and solvent circulation device for a medical device inserted into the body.

In addition, by grafting the surface for medical devices inserted into the body, protein adsorption, platelet, and bacterial adsorption can be significantly reduced, thrombus formation is suppressed, and blood adsorption and blood cell adsorption suppression functions are improved.

In addition, since the adhesive strength is improved, the surface is not peeled off even after vigorous movement after insertion into the body, so that it can be usefully used in the manufacture of medical devices for insertion into the body with reduced side effects.

1 is a schematic diagram of a medical device for insertion into the body including a graft polymer layer according to an embodiment.

2 is a schematic diagram illustrating a grafting method of a medical device for insertion into the body according to an embodiment.

3 is a graph showing the results of infrared spectroscopy (FT-IR) of the substrate surface according to an embodiment and a comparative example.

4 is a measurement of the contact angle of the surface on which the graft polymerization layer of one embodiment and a comparative example is formed.

5 is an image observing the adsorption amount of fibrinogen in Examples and Comparative Examples.

6 is an image of observing the adsorption amount of bovine serum albumin (BSA) in Examples and Comparative Examples.

7 is an image of observing the amount of thrombus according to the canine blood flow loop test according to an embodiment and a comparative example.

In order to achieve the above technical problem, there is provided a graft copolymer composition of an amino acid zwitterionic compound and an anionic compound selected from the group consisting of a sulfone group, a carboxyl group and a phosphoric group.

According to one embodiment of the present invention, the amino acid zwitterionic compound is characterized in that it comprises at least one selected from the group consisting of a methacrylate group, an acrylate group and an acrylamide group.

According to one embodiment of the present invention, the anionic compound is characterized in that it includes at least one selected from the group consisting of a methacrylate group, an acrylate group, and an acrylamide group.

According to an embodiment of the present invention, the anionic compound is the sulfone group (-SO ₃ ^- , -OSO ₃ ^- ), a carboxyl group (-CO ₂ ^- ) and a phosphoric group (-PO ₃ ^- , -OPO ₃ ^- ) characterized in that it is charged with one selected from the group consisting of.

According to one embodiment of the present invention, the anionic compound charged with the sulfone group is poly sodium 4-styrenesulfonate (Poly(sodium 4-styrenesulfonate)), poly(2,3-dihydrothieno-1,4- Dioxin)-poly(styrenesulfonate) (Poly(2,3-dihydrothieno-1,4-dioxin)-poly(styrenesulfonate)), Poly(4-styrenesulfonic acid) sodium salt), 4-Vinylbenzenesulfonic acid sodium salt, sodium allylsulfonate, Vinylsulfonic acid sodium salt, sodium-4-vinylbenzenesulfonate ( Sodium 4-vinylbenzenesulfonate), 3-sulfopropyl methacrylate potassium salt (3-Sulfopropyl methacrylate potassium salt), and sodium-p- styrene sulfonate (Sodium p-Styrenesulfonate) characterized in that at least one selected from the group consisting of.

According to one embodiment of the present invention, the anionic compound charged with a carboxyl group is sodium methacrylate (Sodium methacrylate), zinc methacrylate (Zinc methacrylate), and methacrylic acid sodium salt (methacrylic acid sodium salt) It is characterized in that at least one selected from the group.

According to one embodiment of the present invention, the graft copolymer is characterized in that it comprises a polymer compound including at least one selected from the compound of Formula 1 and the compound of Formula 2 below.

[Formula 1]

In Formula 1, R ₁ is NH ₂ or a carboxyl group.

In Formula 1, R ₂ is a hydrogen atom (H), an alkyl group (C ₁ to C ₂₀ ), or a carboxyl group.

_{R 3} of Formula 1 is NH ₂ or an alkyl group (C ₁ to C ₂₀ ).

In Formula 1, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

In Formula 1, n is an integer of 1 to 100.

In Formula 1, m is an integer of 1 to 1000.

[Formula 2]

In Formula 2, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

In Formula 2, R ₅ is a hydrogen atom or an alkyl group (C ₁ to C ₂₀ ).

In Formula 2, R ₆ is a sulfone group, a carboxyl group, or a phosphoric group.

The range of l in Formula 2 is an integer from 1 to 1000.

According to one embodiment of the present invention, the compound of Formula 1 is an amino acid zwitterionic compound, and the compound of Formula 2 is an anionic compound.

According to one embodiment of the present invention, the graft copolymer is characterized in that it comprises a polymer compound including the compound of Formula 1 and the compound of Formula 2 as at least one repeating unit.

According to another aspect of the present invention, it comprises a substrate for insertion into the body and a graft polymer layer formed on at least one of a surface and an inner surface of the substrate for insertion into the body, wherein the graft polymer layer is amino acid zwitterionic It provides a medical device for insertion into the body in which a graft copolymer of a compound and an anionic compound is formed.

According to one embodiment of the present invention, the substrate for insertion into the body is characterized in that it is selected from the group consisting of metal, ceramic, synthetic polymer, glass, biological tissue, woven fiber, non-woven fiber, semi-metal, and combinations thereof. .

According to one embodiment of the present invention, the graft polymer layer reacts with the amino acid zwitterionic compound and the anionic compound to form the aforementioned graft copolymer, and any one surface and the inner surface of the substrate for insertion into the body It is characterized in that a polymer brush is formed on the above.

According to one embodiment of the present invention, the substrate for insertion into the body further comprises a -C=C group formed on at least one of a surface and an inner surface of the substrate for insertion into the body.

According to one embodiment of the present invention, the graft polymer layer is characterized in that the water contact angle is less than 80 °.

According to another aspect of the present invention, a compound having an isocyanate group, an initiator, and a substrate for insertion into the body are mixed with a reaction solvent and reacted to modify at least one of the surface and the inner surface of the substrate for insertion into the body. , and a second surface modification step of forming a graft polymer layer by adding the surface-modified substrate for insertion into the body, an amino acid zwitterionic compound, an anionic compound, and a reducing agent to a reaction solvent and polymerization A grafting method for medical devices is provided.

According to one embodiment of the present invention, the first surface modification step is characterized in that -NCO group or -C=C group is formed on at least one of the surface and the inner surface of the substrate for insertion into the body.

According to an embodiment of the present invention, the compound having an isocyanate group is 2-isocyanatoethyl acrylate, 2-isocyanatoethyl methacrylate, isophorone diisocyanate It is characterized in that it is selected from the group consisting of (isophorone diisocyanate) and hexamethylene diisocyanate.

According to one embodiment of the present invention, the reaction solvent is benzene, toluene, n-hexane, chloroform, diethyl ether, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), isopropyl alcohol, propanol, butanol , ethyl acetate (EA), dimethylformamide (DMF), dichloromethane (methylene dichloride), acetone, ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), 1,2-dichloro Ethane (ethylene dichloride), 1,2-dichloroethylene (acetylene dichloride), carbon tetrachloride, carbon disulfide, 1,1,2,2-tetrachloroethane (acetylene tetrachloride), trichloroethylene, methylcyclohexanone, methyl Cyclohexanol, methyl butyl ketone, methyl ethyl ketone, 1-butanol, 2-butanol, cyclohexanone, cyclohexanol, styrene, ethylene glycol monomethyl ether (methyl cellosolve), ethylene glycol monoethyl ether ( Cellosolve), ethylene glycol monoethyl ether acetate (cellosolve acetate), ethylene glycol monobutyl ether (butyl cellosolve), ethyl ether, N,N-dimethylformamide, ortho-dichlorobenzene, isobutyl alcohol, Isopentyl alcohol (isoamyl alcohol), isopropyl alcohol, methyl acetate, butyl acetate, ethyl acetate, isobutyl acetate, isopentyl acetate (isoamyl acetate), isopropyl acetate, pentyl acetate (amyl acetate), propyl acetate, It is characterized in that it is selected from the group consisting of cresol, chlorobenzene, xylene, tetrachloroethylene (par-chloroethylene), 1,1,1-trichloroethane, and water.

According to one embodiment of the present invention, in the second surface modification step, the -C = C group formed on at least one surface and the inner surface of the substrate for insertion into the body polymerizes the zwitterionic compound and the anionic compound to form a graph It is characterized in that the polymer layer is formed.

According to one embodiment of the present invention, in the second surface modification step, radicals formed on at least one of the surface and the inner surface of the substrate for insertion into the body through the first surface modification step, the zwitterionic compound and the anionic It is characterized in that the compound polymerizes to form a physical bond between the formed graft polymer.

Hereinafter, the present invention will be described in detail with reference to embodiments and drawings of the present invention. It will be apparent to those of ordinary skill in the art that these examples are only illustratively disclosed to explain the present invention in more detail, and that the scope of the present invention is not limited by these examples. .

In addition, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and in case of conflict, this specification, including definitions description will take precedence.

The terms used in the present invention are only used to describe specific embodiments, and are not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly dictates otherwise. In the present invention, the terms include or have is intended to designate that a feature, number, step, operation, component, part, or combination thereof described in the specification exists, but one or more other features, number, step , it should be understood that it does not preclude in advance the possibility of the presence or addition of an operation, component, part, or combination thereof.

As used herein, the term "medical device for insertion into the body" is also briefly referred to as "medical device", and is a medical device in which infection by bacterial biofilm frequently occurs in medical devices with high risk of thrombosis and high infection that occur in blood-contact medical devices. Instruments, medical or dental devices, instruments, implants, scaffolds, valves, pacemakers, stents, catheters, rods, implants, fracture fixators, pumps, tubing, wiring, electrodes, endoscopes, especially those that come into contact with living tissue. Other devices include, but are not limited to.

The coating method, which is one of the methods for modifying the surface of the substrate, is not suitable because it does not ensure stability as a method for surface modification of the human circulatory system because peeling occurs easily from the substrate. Therefore, there is a need for a surface modification method that does not cause exfoliation to external as well as internal stimuli. In addition, in a blood-contacting medical device having a small lumen, occlusion occurs due to stagnation in the inner diameter of the solute and solvent, making it difficult to perform a smooth function as a medical device.

In order to solve this problem, an object of the present invention is to satisfy both safety and effectiveness by graft composition of an amino acid zwitterionic compound and anionic compound and applying it to a medical device for insertion into the body.

On the other hand, in the present invention, the polymer layer is formed using a graft method. The graft method can be divided into graft from and graft to, but the graft from method is effective in terms of efficiency. proper. However, the present invention is not limited thereto.

The graft from method reacts from the outer surface of the substrate, and compared to the "grafting to" method, which is a chemisorption method through reaction between the terminal functionalized polymer and the surface to which a complementary functional group is attached. A higher surface density non-fouling material can be produced. A high concentration of polymerization initiator can be introduced into the substrate, for example, by swelling the substrate in the presence of the initiator. At this time, radicals are formed by the initiator introduced into the substrate, and the radicals and the compound are polymerized to form a graft, thereby forming a polymer brush.

Accordingly, the graft copolymer according to the present invention, a medical device for insertion into the body including the same, and a manufacturing method thereof will be described in detail below.

In one aspect, the present invention provides a graft copolymer of an amino acid zwitterionic compound and an anionic compound.

The amino acid zwitterionic compound includes at least one selected from the group consisting of a methacrylate group, an acrylate group, and an acrylamide group.

Zwitterion means a neutral molecule with both positive and negative ions. Since amino acids have both an acidic carboxyl group and a basic amine, the amine in the molecule _{becomes the cation of NH 3} ⁺ and the carboxylic acid is the anion ^{of COO -} Therefore, it has the property of a zwitterion.

The amino acid zwitterionic compound may be, in detail, L-cysteine methacrylate (CysMA) as an amino acid zwitterionic compound having a methacrylate group, but is not limited thereto.

The anionic compound includes at least one selected from the group consisting of a methacrylate group, an acrylate group, and an acrylamide group, and specifically, may be an anionic compound having an acrylate group, but is not limited thereto.

Further, the anionic compound is negatively charged, with a sulfone group (-SO ₃ ^- , -OSO ₃ ^- ), a carboxyl group (-CO ₂ ^- ) and a phosphoric group (-PO ₃ ^- , -OPO ₃ ^- ). One selected from the group consisting of may be charged to form an anionic monomer.

For example, anionic compounds charged with sulfone groups include poly(sodium 4-styrenesulfonate), poly(2,3-dihydrothieno-1,4-dioxine)-poly(styrene). sulfonate) (Poly(2,3-dihydrothieno-1,4-dioxin)-poly(styrenesulfonate)), poly(4-styrenesulfonic acid) sodium salt, 4-vinyl Benzenesulfonic acid sodium salt (4-Vinylbenzenesulfonic acid sodium salt), sodium allylsulfonate (sodium allylsulfonate), vinylsulfonic acid sodium salt (Vinylsulfonic acid sodium salt), sodium-4-vinylbenzenesulfonate (Sodium 4-vinylbenzenesulfonate) It may be selected from the group consisting of 3-Sulfopropyl methacrylate potassium salt and sodium p-Styrenesulfonate, but is not limited thereto. These monomers may be used alone or in combination to maximize the antithrombotic effect.

As another example, the anionic compound charged with the carboxyl group may be selected from the group consisting of sodium methacrylate, zinc methacrylate, and methacrylic acid sodium salt. and is not limited thereto. These monomers may be used alone or in combination to maximize the antithrombotic effect.

Meanwhile, the present invention provides a graft copolymer of an amino acid zwitterionic compound and a cationic compound. In this case, the cationic compound may include an acryloyl group.

Furthermore, the cationic compound including the acryl group is positively charged, and may be charged with ammonium (nitrogen quaternized, N ⁺ ) to form a cationic monomer.

For example, cationic monomers having an ammonium-charged acryloyl group include Methacrylatoethyl trimethyl ammonium chloride (MAC), 2-acryloyloxyethyltrimethylammonium chloride [2-(Acryloyloxy)ethyl] trimethylammonium chloride], 3-acrylamidopropyl trimethylammonium chloride), vinylbenzyltrimethylammonium chloride [(Vinylbenzyl)trimethylammonium chloride], and 3-methacryloylaminopropyl trimethylammonium chloride ([3 -(Methacryloylamino)propyl]trimethylammonium chloride) may be selected from the group consisting of, but is not limited thereto. These monomers may be used alone or in combination to maximize the antithrombotic effect.

Furthermore, the graft copolymer may include a polymer compound including at least one selected from the compound of Formula 1 and the compound of Formula 2 below.

[Formula 1]

In Formula 1, R ₁ is NH ₂ or a carboxyl group.

In Formula 1, R ₂ is a hydrogen atom (H), an alkyl group (C ₁ to C ₂₀ ), or a carboxyl group.

_{R 3} of Formula 1 is NH ₂ or an alkyl group (C ₁ to C ₂₀ ).

In Formula 1, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

In Formula 1, n is an integer of 1 to 100.

In Formula 1, m is an integer of 1 to 1000.

[Formula 2]

In Formula 2, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

In Formula 2, R ₅ is a hydrogen atom or an alkyl group (C ₁ to C ₂₀ ).

In Formula 2, R ₆ is a sulfone group, a carboxyl group, or a phosphoric group.

The range of l in Formula 2 is an integer from 1 to 1000.

Specifically, R ₆ of Formula 2 is

or

or

or,

And, X may be an alkyl group (C ₁ to C ₂₀ ) or nothing (Null), but is not limited thereto.

For example, in Formula 2, R ₆ is

In the case of , it is represented by the formula (3).

[Formula 3]

In Formula 3, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

In Formula 3, R ₅ is a hydrogen atom or an alkyl group (C ₁ to C ₂₀ ).

The range of l in Formula 3 is an integer from 1 to 1000.

In addition, in Formula 2, R ₆ is

In the case of , it is represented by the formula (4).

[Formula 4]

In Formula 4, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

In Formula 4, R ₅ is a hydrogen atom or an alkyl group (C ₁ to C ₂₀ ).

X of Formula 4 is an alkyl group (C ₁ to C ₂₀ ), but is not limited thereto.

The range of l in Formula 4 is an integer from 1 to 1000.

In addition, the formula (2)

When it is included, it is represented by Formula 5.

[Formula 5]

In Formula 5, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

In Formula 5, R ₅ is a hydrogen atom or an alkyl group (C ₁ to C ₂₀ ).

X in Formula 5 is an alkyl group (C ₁ to C ₂₀ ), but is not limited thereto.

The range of l in Formula 5 is an integer from 1 to 1000.

In addition, the formula (2)

In the case of including, it is represented by Formula 6.

[Formula 6]

In Formula 6, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

In Formula 6, R ₅ is a hydrogen atom or an alkyl group (C ₁ to C ₂₀ ).

X in Formula 6 is an alkyl group (C ₁ to C ₂₀ ), but is not limited thereto.

The range of l in Formula 6 is an integer from 1 to 1000.

Furthermore, Chemical Formula 2 may further include ammonium (nitrogen quaternization, N ⁺ ). That is, it can become a zwitterionic compound by adding ammonium (nitrogen quaternization, N ⁺ ) to Formula 2, and a zwitterion formed by adding ammonium to the zwitterionic compound of Formula 1 and Formula 2 The sexual compound may form a graft polymer.

For example, Formula 2 including ammonium (nitrogen quaternization, N ⁺ ) may be represented by Formula 7 or Formula 8 below.

[Formula 7]

In Formula 7, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

In Formula 7, R ₅ is a hydrogen atom or an alkyl group (C ₁ to C ₂₀ ).

The range of l in Formula 7 is an integer from 1 to 1000.

The compound of Formula 7 may be specifically represented by Formula 8.

[Formula 8]

In Formula 8, R ₅ is a hydrogen atom or an alkyl group (C ₁ to C ₂₀ ).

The range of l in Formula 8 is an integer from 1 to 1000.

Specifically, the graft copolymer may include a polymer compound including the compound of Formula 1 or the compound of Formula 2 as one repeating unit. More specifically, the graft copolymer may include a polymer compound including the compound of Formula 1 and the compound of Formula 2 as at least one repeating unit.

In the present invention, the amino acid zwitterionic compound may be a compound represented by Formula 1, and the anionic compound may be a compound represented by Formula 2, specifically, a compound represented by Formulas 3 to 6.

That is, the compound of Formula 1 and the compound of Formula 2 may form a graft copolymer to form a polymer compound (polymer film).

In another aspect, the present invention provides a medical device for insertion into the body, comprising the graft polymer layer formed on at least one of the surface and the inner surface of the substrate for insertion into the body.

1 is a schematic diagram of a medical device 100 for insertion into the body including a graft polymer layer according to an embodiment.

Referring to FIG. 1 , the medical device 100 for insertion into the body includes a substrate 110 for insertion into the body and a graft polymer layer 120 , and the graft polymer layer 120 is an amino acid zwitterionic compound. and graft copolymers of anionic compounds may be formed.

The description of the “graft copolymer” of the “amino acid zwitterionic compound” and the “anionic compound” is the same as described above.

The substrate for insertion into the body may be selected from the group consisting of metal, ceramic, synthetic polymer, glass, biological tissue, woven fiber, non-woven fiber, semi-metal, silicone, and combinations thereof, but is not limited thereto.

Specifically, the metal may be selected from the group consisting of titanium or an alloy thereof, stainless steel, tantalum, palladium, zirconium, niobium, cobalt or an alloy thereof, molybdenum, nickel-chromium, and combinations thereof, but is not limited thereto.

The ceramic may be selected from the group consisting of an oxide of a transition metal element, a carbide of a transition metal element, a nitride of a transition metal element, an oxide of a metalloid element, a carbide of a metalloid element, and a nitride of a metalloid element, but is not limited thereto. does not

The synthetic polymer polymer is polyurethane, polyguanidine, polymethacrylate, polystyrene, substituted polystyrene, polysulfone, polysiloxane, polyamine, polyamide, polyacrylate, polymethacrylamide, polyacrylamide, polyazine, polyacrylic Ronitrile, polyanhydride, polyalkene, polyester, poly(orthoester), polyether, polyetheretherketone (PEEK), polyolefin, polyurethane, polyurea, polyimide, poly(carbonate), Polyketal, poly(ketone), polyphosphazine, polyfluorocarbon, poly(hydroxyalkanoate), Teflon, polytetrafluoroethylene (PTFE), natural elastomer, synthetic elastomer, polysaccharide, halogenated polymers, silicones, aldehyde crosslinking resins, epoxy resins, phenolic resins, latex, Kevlar, Nomex, Dacron, nylon, or copolymers or combinations thereof.

The graft polymer layer 120 is characterized in that it is formed on at least one of the surface and the inner surface of the substrate 110 for insertion into the body.

For example, as shown in FIG. 1(a), the graft polymer layer 120 may be formed on the surface of the substrate 110 for insertion into the body, and as shown in FIG. 1(b), the It may be formed on the inner surface of the substrate for insertion into the body 110 , and may be formed on both the surface and the inner surface of the substrate for insertion into the body 110 as shown in FIG. 1( c ).

That is, as the graft polymer layer 120 is formed on at least one of the surface and the inner surface of the medical device 100 for insertion into the body, the polymer brush is formed on at least one of the surface and the inner surface of the insert for insertion into the body. is formed, and at least one of the surface and the inner surface of the medical device 100 for insertion into the body is modified to have hydrophilicity.

Accordingly, the water contact angle of the medical device 100 for insertion into the body according to the present invention may be less than 80°, specifically, 10 to 60°. As the water contact angle is less than 80°, the adsorption of proteins, platelets, and bacteria to both the surface and the inner surface of the medical device 100 for insertion into the body may be significantly reduced.

In addition, as the compound having an isocyanate group reacts with at least one of the surface and inner surfaces of the substrate 110 for insertion into the body, -NCO groups or -C=C group.

The isocyanate group may be used to improve bonding properties between the substrate for insertion into the body 110 and the graft polymer layer 120 .

In addition, the C = C group formed on the surface of the substrate 110 for insertion into the body is polymerized with the zwitterionic compound and the anionic compound to form a graft polymer, in this case, the C = C group and the graft polymer A chemical bond is formed between them.

Accordingly, the medical device for insertion into the body is a medical device in which infection by bacterial biofilm frequently occurs in medical devices with high risk of thrombosis and high infection that occur in blood-contact medical devices. devices, instruments, implants, scaffolds, valves, pacemakers, stents, catheters, rods, fracture fixators, pumps, tubing, wiring, electrodes, contraceptives, endoscopes, and other devices that come into contact with living tissue, especially , but not limited to these.

For example, endovascular tube catheters such as peripheral venous catheters (PICC), central venous catheters (CVC), or hemodialysis catheters, venous valves, punctal plugs, intra-ocular devices and implants, etc. By forming the graft polymer layer 120 according to the present invention, the adsorption of plasma proteins, platelets, etc. is remarkably reduced, thereby reducing the formation of blood clots and infection by bacteria. In addition, when applied to a multi-lumen catheter having a small inner diameter, occlusion due to stagnant solutes and solvents can be prevented, and unlike the coating method, there is no concern about peeling.

In another aspect, the present invention provides a grafting method of a medical device for insertion into the body.

The method of forming the medical device 100 for insertion into the body including the graft polymer layer 120 includes a first surface modification step of modifying the surface of the substrate 110 for insertion into the body and the first surface modification step. and a second surface modification step of forming the graft polymer layer 120 on the surface-modified substrate 100 for insertion into the body.

The first surface modification step is to modify at least one of the surface and the inner surface of the substrate 110 for insertion into the body, and the compound having the isocyanate group, the initiator, and the substrate for insertion into the body are mixed in the reaction solvent, and -20 It is a step of reacting at a temperature of ℃ to 250 ℃.

Specifically, in the first surface modification step, a compound having an isocyanate group, an initiator, and a substrate for insertion into the body are added to the reaction solvent and reacted to form -NCO on at least one of the surface and the inner surface of the substrate for insertion into the body 110 . forming a group or a -C=C group.

First, as the substrate for insertion into the body 110, the compound having an isocyanate group, and an initiator are added to the reaction solvent and reacted, the substrate for insertion into the body 110 swells, and the swollen substrate for insertion into the body 110 The initiator penetrates into the inside of the

In this case, a catalyst may be further included in order to promote the reaction and improve the binding reaction.

For example, as the catalyst, a titanium, tin, or bismuth-based catalyst may be used, and more specifically, a bismuth-based catalyst (Bi catalyst) may be used, but is not limited thereto. The addition of the catalyst is to further activate the reaction between the polyurethane base and the compound having an isocyanate group, thereby shortening the reaction time and increasing the reactivity.

In addition, the initiator is to start free radical polymerization, and when the initiator is initiated as the initiator penetrates into the interior of the substrate for insertion into the body, free radicals can be formed from the interior of the substrate.

That is, the initiator may permeate (introduce) into the substrate 110 for insertion into the body by swelling the substrate 110 for insertion into the body in the presence of the initiator, and as the initiator penetrates (introduced), the initiator When initiated by a reducing agent to be described later, the free radical polymerization can be initiated.

For example, the initiator may be a swollen polyurethane, polyguanidine, polymethacrylate, polystyrene, substituted polystyrene, polysulfone, polysiloxane, polyamine, polyamide, polyacrylate, polymethacrylamide, polyacrylamide, polyazine , polyacrylonitrile, polyanhydride, polyalkene, polyester, poly(orthoester), polyether, polyetheretherketone (PEEK), polyolefin, polyurethane, polyurea, polyimide, poly( carbonate), polyketal, poly(ketone), polyphosphazine, polyfluorocarbon, poly(hydroxyalkanoate), Teflon, polytetrafluoroethylene (PTFE), natural and synthetic elastomers, polysaccharides , halogenated polymers, silicones, aldehyde crosslinking resins, epoxy resins, phenolic resins, latex, Kevlar, Nomex, Dakron, nylon, or copolymers or combinations thereof. radicals can be formed.

The initiator may include one selected from the group consisting of a thermal initiator, a thermal decomposition initiator, a redox initiator, a photoinitiator, a radiation initiator, and an ultraviolet initiator, but is not limited thereto.

Specifically, in the present invention, one selected from the group consisting of hydroperoxide, dialkyl peroxide, peroxyester, diacyl peroxide, peroxycarbonate, peroxyketal and ketone peroxide may be used. can, but is not limited thereto.

More specifically, peroxydicarbonate may be used, di(2-ethoxyethyl)peroxydicarbonate, di-n-propylperoxydicarbonate, diisopropylperoxydicarbonate, t-butylperoxyisopropyl Carbonate, 1,6-bis(t-butylperoxycarbonyloxy)hexane, di(3-methoxybutyl)peroxydicarbonate, di-sec-butylperoxydicarbonate, t-butylperoxy2-ethylhexyl carbonate , di(2-ethylhexyl)peroxydicarbonate, di-1-methylheptylperoxydicarbonate, di(4-t-butylcyclohexyl)peroxydicarbonate, polyether poly-t-butylperoxy carbonate and t- At least one selected from the group consisting of butyl peroxy-3,5,5-trimethylhexanoate may be used. Specifically, polyether poly-t-butylperoxy carbonate (JWEB50) may be used, but is not limited thereto, and an initiator capable of initiating free radical polymerization may be used without limitation.

Furthermore, the initiator may be used in an amount of 0.01 wt% to 20 wt%, and when the content of the initiator is less than 0.01 wt%, the amount of polymer generated inside or on the surface of the substrate is significantly reduced, so that the desired properties may not be exhibited on the surface. And, when the content of the initiator exceeds 20% by weight, there may be a problem in that the properties of the polyurethane change.

The isocyanate group may be used to improve bonding properties between the substrate for insertion into the body 110 and the graft polymer layer 120 .

In detail, a -NCO group or -C=C group may be formed as the isocyanate group reacts with at least one of the surface and the inner surface of the substrate 110 for insertion into the body.

In more detail, -NH and -NCO groups formed on one or more surfaces of the surface and the inner surface of the substrate 110 for insertion into the body by reacting the surface of the substrate 110 for insertion into the body and the isocyanate group form a chemical bond will do

In addition, the C = C group formed on the surface of the substrate 110 for insertion into the body is polymerized with the zwitterionic compound and the anionic compound to form a graft polymer, in this case, the C = C group and the graft polymer A chemical bond is formed between them.

That is, the initiator penetrates into the inside of the substrate 110 for insertion into the body to start free radical polymerization, and the compound having an isocyanate group reacts with at least one of the surface and the inner surface of the substrate 110 for insertion into the body. Thus, a -NCO group or a -C=C group is formed.

For example, the compound having an isocyanate group is 2-isocyanatoethyl acrylate, 2-isocyanatoethyl methacrylate, isophorone diisocyanate ( It may be selected from the group consisting of isophorone diisocyanate) and hexamethylene diisocyanate, but is not limited thereto.

On the other hand, in order to improve the bondability of the substrate for insertion into the body 110 and the graft polymer layer 120, a compound containing an acrylate group, a methacrylate group, a methacrylamide group and an allyl group in addition to the isocyanate group can be added

The reaction solvent is benzene, toluene, n-hexane, chloroform, diethyl ether, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), isopropyl alcohol, propanol, butanol, ethyl acetate (EA), dimethylform Amide (DMF), dichloromethane (methylene dichloride), acetone, ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), 1,2-dichloroethane (ethylene dichloride), 1, 2-dichloroethylene (acetylene dichloride), carbon tetrachloride, carbon disulfide, 1,1,2,2-tetrachloroethane (acetylene tetrachloride), trichloroethylene, methylcyclohexanone, methylcyclohexanol, methylbutylketone, methyl Ethyl ketone, 1-butanol, 2-butanol, cyclohexanone, cyclohexanol, styrene, ethylene glycol monomethyl ether (methyl cellosolve), ethylene glycol monoethyl ether (cellosolve), ethylene glycol monoethyl ether Acetate (Cellosolve Acetate), ethylene glycol monobutyl ether (butyl Cellosolve), ethyl ether, N,N-dimethylformamide, ortho-dichlorobenzene, isobutyl alcohol, isopentyl alcohol (isoamyl alcohol), Isopropyl alcohol, methyl acetate, butyl acetate, ethyl acetate, isobutyl acetate, isopentyl acetate (isoamyl acetate), isopropyl acetate, pentyl acetate (amyl acetate), propyl acetate, cresol, chlorobenzene, xylene, tetrachloro It is selected from the group consisting of ethylene (par-chloroethylene), 1,1,1-trichloroethane, and water, and is not limited thereto as long as it is a solvent that can swell the substrate 110 for insertion into the body.

The second surface modification step is performed by adding a substrate for insertion into the body, an amino acid zwitterionic compound, an anionic compound, and a reducing agent whose surface has been modified through the first surface modification step, to the reaction solvent and polymerizing the graft polymer layer. (120) is a step of forming.

Specifically, in the second surface modification step, a chemical bond and a physical bond may be formed on at least one of the surface and the inner surface of the substrate 110 for insertion into the body.

The chemical bond may be formed by polymerization of a -C=C group formed on at least one surface and an inner surface of the substrate for insertion into the body and a zwitterionic compound and an anionic compound.

In other words, a chemical bond is formed between the -C=C group formed by chemical bonding on at least one of the surface and the inner surface of the polyurethane through the first surface modification step and the graft polymer layer 120. can

On the other hand, the graft polymer layer may form a physical bond with at least one of the surface and the inner surface of the substrate for insertion into the body.

In detail, the initiator penetrating into the body for insertion into the body and the reducing agent react, the initiator is initiated by the reducing agent, and the radical formed as the initiator is initiated and the zwitterionic compound and the anionic compound are polymerized As a result, a physical bond is formed.

More specifically, the radical is formed from the inside of the substrate for insertion into the body, and as the radical, the zwitterionic compound, and the anionic compound undergo a polymerization reaction, the graft polymer layer is formed, and the graft polymer layer is formed. The polymer layer is immobilized inside the substrate for insertion into the body to form a strong physical bond. In this case, the physical bond may be formed from the inside of 1 nm to 1000 nm from the surface of the substrate for insertion into the body, but is not limited thereto.

That is, as the graft polymer layer 120 having physical and chemical bonds formed on the substrate 110 for insertion into the body is formed, the graft polymer layer 120 does not peel from the substrate for insertion into the body 110 . can be stably fixed.

Furthermore, a crosslinking agent (crosslinking agent) may be further included to form the graft polymer layer 120, and the graft polymer formed as the zwitterionic compound and the anionic compound react with the addition of the crosslinking agent. Cross-links can be formed between them.

In detail, as the crosslinking agent (crosslinking agent) is added, the graft polymer layer 120 is physically bonded to the substrate 110 for insertion into the body, and the graft polymer is chemically bonded to the substrate 110 for insertion into the body. By cross-linking between the layers 120, the bond can be more firmly fixed like a mesh.

That is, when the crosslinking agent is used, a stronger bond can be formed. Accordingly, the polyvalent crosslinking agent may be contained in an amount of 0.01 wt% to 30 wt% in the graft polymer layer.

For example, the crosslinking agent is butanediol diacrylate, 1,6 hexanediol diacrylate, neopentyl glycol diacrylate, ethylene glycol dimethyl acrylate, diethylene glycol diacrylate, trimethylolpropane triacrylate, penta It may be selected from the group consisting of erythritol triacrylate, and glyceryl propoxylated triacrylate, but is not limited thereto.

In addition, the reducing agent is a metal salt such as a salt of Fe(II), Cu(II), Cr(II), V(II), Ti(III) or Ag(I), an oxyacid of sulfur, an alcohol, a hydroxy acid , thiols, ketones, amine aldehydes, or amides. For example, in some embodiments, the reducing agent is an iron(II) salt such as iron(II) L-ascorbate, ferrous sulfate, iron(II) acetate, iron(II) ethylenediammonium sulfate, iron(II) gluconate, iron(II) acetylacetonate, iron(II) lactate, iron(II) oxalate, iron(II) sulfate, etc. may be used, and specifically, iron(II) gluconate (Glue) iron conate) may be used, but is not limited thereto.

In addition, the second surface modification step is polymerization using a synthesis means, and the synthesis means is free radical polymerization, ionic polymerization, atomic transfer radical polymerization, nitroxide mediated polymerization, reversible-addition fragmentation polymerization, ring-opening metathesis. polymerization, telluride mediated polymerization, acyclic diene metathesis polymerization and UV, thermal, redox free radical initiated polymerization.

The graft polymer layer 120 formed by the second surface modification step reacts with an amino acid zwitterionic compound and anionic compound to form a graft copolymer, and among the surface and inner surfaces of the medical device for insertion into the body A graft copolymer formed on one or more surfaces may form a polymer brush.

As the polymer brush is formed in the medical device for insertion into the body, a hydration phenomenon occurs in which water molecules are attached to the surface of the substrate 110 for insertion into the body, thereby forming a hydration layer on the surface of the substrate.

Accordingly, plasma proteins, serum, blood cells, platelets, etc. inhibit adsorption and inhibit the formation of a bacterial biofilm, and the adhesion of proteins and/or cells is reduced, resulting in thrombus formation due to protein adsorption, infection due to thrombus formation may lower the risk of

2 is a view showing a grafting method of a medical device for insertion into the body according to an embodiment.

In detail, Figure 2 shows a grafting method using polyurethane.

Referring to FIG. 2 , first, polyurethane, an initiator, 2-isocyanatoethyl acrylate, and a bismuth catalyst are added to a reaction solvent and reacted to perform a first surface modification step.

As the first surface modification step is performed, the polyurethane is swollen by the reaction solvent, and the initiator penetrates into the swollen polyurethane.

In addition, the -NH group of the polyurethane and the 2-isocyanate ethyl acrylate group react to form a -C=C group and a -NCO group on the surface of the polyurethane. In this case, the -NCO group of the 2-isocyanate ethyl acrylate (2-Isocyanatoethyl acrylate) is bonded to -NH on the surface of the polyurethane, and the -NCO group forms a chemical bond with the polyurethane.

As a next step, a second surface modification step is performed to form a graft polymer layer by adding iron (II) gluconate (iron gluconate) and a zwitterionic compound and an anionic compound.

Specifically, as the second surface modification step proceeds, the initiator penetrating into the polyurethane is initiated by the reducing agent to form radicals, and the formed radicals, zwitterionic compounds and anionic compounds polymerize A graft polymer layer is formed.

That is, as the graft polymer layer polymerizes with radicals formed from the inside of the polyurethane, a strong physical bond with the polyurethane is formed.

On the other hand, the C = C group formed on the surface of the polyurethane through the first surface modification step to form a graft polymer by polymerization reaction with the zwitterionic compound and the anionic compound, in this case, the C = C group and the graft chemical bonds are formed between the polymers.

That is, the graft polymer layer forms a strong physical bond from the inside of the polyurethane and forms a chemical bond with the surface of the polyurethane, so that the graft polymer layer 120 in the form of a polymer brush is formed.

Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, the following Examples and Experimental Examples only illustrate the present invention, and the present invention is not limited by the following Examples and Experimental Examples.

Examples and Experimental Examples.

Example 1. 3-Sulfopropyl methacrylate potassium salt (SMPS) and Cysteine methacrylate (CysMA) grafting

After stirring 0.05 wt% Bi catalyst, 5 wt% 2-Isocyanatoethyl acrylate (ICEA) and 1 wt% multi-functional initiator (trade name: JWEB 50) in toluene for 2 hours in a polyurethane tube, the polyurethane tube was dried.

Thereafter, the dried (pre-treated) polyurethane tube was grafted with 5 mM iron gluconate, 0.2 mol of Cysteine methacrylate (CysMA) and 0.3 mol of 3-Sulfopropyl methacrylate potassium salt in distilled water at 40° C. for 5 hours. Then, it was washed in distilled water for 2 hours and dried in an oven at 40° C. to finally obtain a surface-modified polyurethane tube.

Example 2. 3-Sulfopropyl methacrylate potassium salt (SMPS) and Cysteine methacrylate (CysMA) grafting

After stirring 0.05 wt% Bi catalyst, 5 wt% 2-Isocyanatoethyl acrylate (ICEA) and 1 wt% multi-functional initiator (trade name: JWEB 50) in toluene for 2 hours in a polyurethane tube, the polyurethane tube was dried. Thereafter, the dried (pre-treated) polyurethane tube was grafted with 5 mM iron gluconate, 0.2 mol of Cysteine methacrylate (CysMA) and 0.2 mol of 3-Sulfopropyl methacrylate potassium salt in distilled water at 40° C. for 5 hours. Then, it was washed in distilled water for 2 hours and dried in an oven at 40° C. to finally obtain a surface-modified polyurethane tube.

Example 3. Sodium p-Styrenesulfonate (SPSS) and Cysteine methacrylate (CysMA) grafting

After stirring 0.05 wt% Bi catalyst, 5 wt% 2-Isocyanatoethyl acrylate (ICEA) and 1 wt% multi-functional initiator (trade name: JWEB 50) in toluene for 2 hours in a polyurethane tube, the polyurethane tube was dried.

Thereafter, the dried (pre-treated) polyurethane tube was grafted with 5 mM iron gluconate, 0.2 mol of Cysteine methacrylate (CysMA) and 0.3 mol of sodium p-Styrenesulfonate (SPSS) in distilled water at 40° C. for 5 hours. Then, it was washed in distilled water for 2 hours and dried in an oven at 40° C. to finally obtain a surface-modified polyurethane tube.

Example 4. Sodium p-Styrenesulfonate (SPSS) and Cysteine methacrylate (CysMA) grafting

After stirring 0.05 wt% Bi catalyst, 5 wt% 2-Isocyanatoethyl acrylate (ICEA) and 1 wt% multi-functional initiator (trade name: JWEB 50) in toluene for 2 hours in a polyurethane tube, the polyurethane tube was dried. Thereafter, the dried (pre-treated) polyurethane tube was grafted with 5 mM iron gluconate, 0.2 mol of Cysteine methacrylate (CysMA) and 0.2 mol of sodium p-Styrenesulfonate (SPSS) in distilled water at 40° C. for 5 hours. Then, it was washed in distilled water for 2 hours and dried in an oven at 40° C. to finally obtain a surface-modified polyurethane tube.

Example 5 Sodium methacrylate (SM) and Cysteine methacrylate (CysMA) grafting

After stirring 0.05 wt% Bi catalyst, 5 wt% 2-Isocyanatoethyl acrylate (ICEA) and 1 wt% multi-functional initiator (trade name: JWEB 50) in toluene for 2 hours in a polyurethane tube, the polyurethane tube was dried. Thereafter, the dried (pre-treated) polyurethane tube was grafted with 5 mM iron gluconate, 0.2 mol of Cysteine methacrylate (CysMA) and 0.3 mol of sodium methacrylate (SM) in distilled water at 40° C. for 5 hours. Then, it was washed in distilled water for 2 hours and dried in an oven at 40° C. to finally obtain a surface-modified polyurethane tube.

Example 6. Sodium methacrylate (SM) and Cysteine methacrylate (CysMA) grafting

After stirring 0.05 wt% Bi catalyst, 5 wt% 2-Isocyanatoethyl acrylate (ICEA) and 1 wt% multi-functional initiator (trade name: JWEB 50) in toluene for 2 hours in a polyurethane tube, the polyurethane tube was dried. Then, the dried (pre-treated) polyurethane tube was grafted with 5 mM iron gluconate, 0.2 mol of Cysteine methacrylate (CysMA) and 0.2 mol of sodium methacrylate (SM) in distilled water at 40°C for 5 hours. Then, it was washed in distilled water for 2 hours and dried in an oven at 40° C. to finally obtain a surface-modified polyurethane tube.

Comparative Example 1. Polyurethane without surface modification treatment

An untreated polyurethane tube was used as a control.

Comparative Example 2. Cysteine methacrylate (CysMA) grafting

After stirring 0.05 wt% Bi catalyst, 5 wt% 2-Isocyanatoethyl acrylate (ICEA) and 1 wt% multi-functional initiator (trade name: JWEB 50) in toluene for 2 hours in a polyurethane tube, the polyurethane tube was dried. A dry (pretreated) polyurethane tube was grafted with 5 mM iron gluconate and 0.2 mol of Cysteine methacrylate (CysMA) in distilled water for 5 hours at 40°C. Then, it was washed in distilled water for 2 hours and dried in an oven at 40° C. to finally obtain a surface-modified polyurethane tube.

Comparative Example 3. Coating of 3-Sulfopropyl methacrylate potassium salt (SMPS) and Cysteine methacrylate (CysMA).

In a polyurethane tube, 1 wt% multi-functional initiator (trade name: JWEB 50), 5 mM iron gluconate, 0.2 moles of Cysteine methacrylate (CysMA) and 0.3 moles of 3-Sulfopropyl methacrylate potassium salt were added in distilled water and reacted to react the polyurethane coated on the surface tube was obtained.

Unlike Examples 1 to 6, when the polyurethane base, the initiator, the reducing agent, the zwitterionic compound, and the anionic compound are added to the reaction solvent at one time and the reaction proceeds, the physical bond between the graft polymers inside or on the surface of the polyurethane is was not observed.

Experimental Example 1. Infrared spectroscopy (FT-IR) of the surface of the graft tube

Infrared spectroscopy was performed on the surface of the polyurethane tube without surface treatment (control) and the polyurethane tube surface on which the graft polymer layers of Examples 1, 3 and 5 were formed.

3 is a graph showing the results of infrared spectroscopy (FT-IR) of the substrate surface according to an embodiment and a comparative example.

Referring to FIG. 3(a), in the case of Example 1, the characteristic peak of SMPS ^{was confirmed at 1038 cm -1} , and it was confirmed that the NH peak disappeared at ^{3300 cm -1 .} That is, it can be confirmed that the graft polymer layer is formed on the polyurethane through this.

In addition, referring to FIG. 3(b), in the case of Example 3, the characteristic peak of SPSS ^{was confirmed at 1000 cm -1} to 1040 cm ^-1 , and it was confirmed that the NH peak disappeared at ^{3300 cm -1 .} That is, it can be confirmed that the graft polymer layer is formed on the polyurethane through this.

In addition, referring to FIG. 3(c), in the case of Example 5, ^{it can be confirmed that the NH peak disappears at 3300 cm -1} , thereby confirming that a graft polymer layer is formed on the polyurethane. The characteristic peak of SM overlapped with the characteristic peak of urethane and was not observed separately. Unlike Example 5, SMPS of Example 1 and SPSS of Example 3 had a functional group (-SO _{3 )} that was not present in urethane, so a characteristic peak was observed.

Experimental Example 2. Analysis of surface characteristics of graft tube (water contact angle)

When hydration occurs, in which water molecules are attached to the surface of the polyurethane tube, a hydration layer is formed on the surface of the polyurethane tube to inhibit the adsorption of plasma proteins, serum, blood cells, platelets, etc., and inhibit the formation of a bacterial biofilm. Therefore, a water contact angle test was performed to primarily check the scale of hydration.

Specifically, about 0.2ml of DW was injected into a syringe with a needle and fixed to a contact angle measuring device. After fixing the surface-treated polyurethane rod to the equipment, the syringe was placed vertically. After holding the focus and setting the baseline, 0.75 μl, the required amount for one experiment, was input and the experiment was conducted. When the water droplet touched the sample, the needle was raised and the contact angle was measured.

4 is a measurement of the contact angle of the surface on which the graft polymerization layer of one embodiment and a comparative example is formed.

Referring to Figure 4, the contact angle of the polyurethane tube (control) of Comparative Example 1 is 108 °, the surface contact angle of Examples 1 to 6 in which the graft polymer layer is formed is 10 ° to less than 60 ° The contact angle is low can be seen.

In addition, the contact angle of the polyurethane butte of Comparative Example 2 is 62°, which is lower than the contact angle of the polyurethane butt of Comparative Example 1, which is not surface-treated, but it can be confirmed that it is larger than the contact angle of the polyurethane tubes of Examples 1 to 6. .

This means that as the graft polymer layer is formed on the surface of the polyurethane tube, the surface of the polyurethane tube is modified to be hydrophilic, and thus the contact angle is lowered.

Experimental Example 3. Effect of Graft Tube on Protein Adsorption Resistance - Fibrinogen Adsorption Test

For the graft tube, the sample of Example 1 was used and the polyurethane tube without surface treatment of Comparative Example 1 was used as a control. The two samples were subjected to a protein adsorption experiment in the same way.

The polyurethane tube was cut into 6 pieces with a size of 1 cm x 1 cm to prepare a sample. The prepared sample was added to each well of a 24-well plate. 1ml of PBS was added and hydrated for 2 hours.

After removing the PBS solution from each well through suction, 1 ml of fibrinogen solution (0.1 mg/ml fibrinogen (Fibrinogen, Sigma-Aldrich)) was added and maintained at room temperature for 10 minutes.

After that, the fibrinogen solution was removed and the sample was washed 4 to 5 times with PBS solution. 1 ml of a 2 wt% sodium dodecyl sulfate (SDS) solution was added to each well, and the mixture was stirred at room temperature at a speed of about 100 rpm for about 2 hours. The absorbance of the reactant was measured at a wavelength of 562 nm using a UV detector, and the protein was quantified from the measured absorbance.

As a result, the polyurethane rod on which the graft polymer layer was formed was 3.27 μg/cm ² , and the control (reference substrate) was 35.10 μg/cm ² . That is, it was confirmed that the adsorption amount of fibrinogen in the polyurethane rod of Example 1 was reduced by 91% compared to Comparative Example 1 (control group).

In addition, FIG. 5 is an image observing the amount of fibrinogen adsorption in Example and Comparative Example 1 (control group). Referring to FIG. 5 , in the case of the control group, it was confirmed that fibrinogen was adsorbed on the surface of the polyurethane. In contrast, in the case of the polyurethane of Example 1 in which the graft polymer layer was formed, it could be confirmed that the amount of fibrinogen observed was significantly reduced compared to the control.

Experimental Example 4. Effect of Graft Tube on Protein Adsorption Resistance - Bovine Serum Albumin (BSA) Adsorption Test

For the graft tube, the sample of Example 1 was used and the urethane tube without surface treatment of Comparative Example 1 was used as a control. The two samples were subjected to a protein adsorption experiment in the same way.

The polyurethane tube was cut into 6 pieces with a size of 1 cm x 1 cm to prepare a sample. The prepared sample was added to each well of a 24-well plate. 1ml of PBS was added and hydrated for 2 hours.

After suction of PBS solution in each well, 1 ml of Bovine Serum Albumin solution (2 mg/ml BSA (Sigma-Aldrich)) was added and maintained at room temperature for 10 minutes.

After that, the BSA solution was removed and the sample was washed 4 to 5 times with PBS solution. 1 ml of a 2 wt% sodium dodecyl sulfate (SDS) solution was added to each well, and the mixture was stirred at room temperature at a speed of about 100 rpm for about 2 hours. The absorbance of the reactant was measured at a wavelength of 562 nm using a UV detector, and the protein was quantified from the measured absorbance.

As a result, the polyurethane rod on which the graft polymer layer was formed was 2.22 μg/cm ² , and the control (reference substrate) was 20.6 μg/cm ² . That is, it was confirmed that the adsorption amount of BSA from the control was reduced by 90%.

In addition, FIG. 6 is an image observing the adsorption amount of bovine serum albumin (BSA) in Example and Comparative Example (control group). Referring to FIG. 6 , in the case of Comparative Example 1 (control group), polyurethane It can be confirmed that bovine serum albumin is adsorbed on the surface. In contrast, in the case of polyurethane with a graft polymer layer, it can be seen that the amount of observed bovine serum albumin was significantly reduced compared to the control.

Experimental Example 5. Canine blood flow loop test

For the graft tube, the sample of Example 1 was used, and as a control, a canine blood flow loop test was performed using the non-surface-treated polyurethane tube of Comparative Example 1. For the test method, each test/control tube was put in a silicone tube with an inner diameter of 6.4 mm, and the blood flow was circulated at 200 ml/min at 37°C for 120 minutes. After that, the sample was taken out of the silicone tube, washed in PBS solution, and the weight of the clot attached to the polyurethane tube was measured.

As a result, in Comparative Example 1 (control group), 823 mg of thrombus was formed, while Example 1 was 24 mg, confirming the thrombus reduction effect of 97% compared to Comparative Example 1 (control). In addition, Example 3 confirmed the thrombus reduction effect of 93% compared to Comparative Example 1 (control) at 54 mg. Also, Example 6 was 845 mg, which was 102% compared to Comparative Example 1 (control group), confirming that there was no difference from the control group.

In addition, FIG. 7 is an image of observing the amount of thrombus according to the canine blood flow loop test according to one embodiment and a comparative example. Referring to FIG. 7 , it was confirmed that the amount of thrombus formation was small in the tubes of Examples 1 and 3 can do. That is, it can be confirmed that the lower the contact angle, the smaller the amount of thrombus generated.

That is, according to the present invention, the medical device for insertion into the body whose surface is modified by the grafting method according to the present invention has a water contact angle of less than 80°, specifically between 10 and 60°, and an adsorption amount of proteins (fibrinogen and bovine serum albumin) of 10 μg/cm 2 It has the advantage that it is low, and the thrombogenicity is reduced by 60 to 97% by the non-grafted sample. In addition, as the thrombogenicity is less than or equal to the Thrombosis score grade 3, there is an effect of improving the antithrombotic properties.

In this specification, only a few examples among the various embodiments performed by the present inventors will be described, but the technical spirit of the present invention is not limited or limited thereto, and it is of course that it may be modified and variously implemented by those skilled in the art.

Claims (19)

1. A graft copolymer of an amino acid zwitterionic compound and an anionic compound selected from the group consisting of a sulfone group, a carboxyl group and a phosphoric group.
2. According to claim 1,

   The amino acid zwitterionic compound includes at least one selected from the group consisting of a methacrylate group, an acrylate group, and an acrylamide group,

   The anionic compound will include at least one selected from the group consisting of a methacrylate group, an acrylate group and an acrylamide group,

   graft copolymer.
3. According to claim 1,

   The anionic compound is charged with one selected from the group consisting of the sulfone group (-SO ₃ ^- , -OSO ₃ ^- ), a carboxyl group (-CO ₂ ^- ) and a phosphoric group (-PO ₃ ^- , -OPO ₃ ^{- )} to be,

   graft copolymer.
4. 4. The method of claim 3,

   The anionic compound charged with the sulfone group is

   Poly(sodium 4-styrenesulfonate), poly(2,3-dihydrothieno-1,4-dioxine)-poly(styrenesulfonate)(Poly(2,3-dihydrothieno-) 1,4-dioxin)-poly(styrenesulfonate)), poly(4-styrenesulfonic acid) sodium salt, 4-Vinylbenzenesulfonic acid sodium salt ), sodium allylsulfonate, vinylsulfonic acid sodium salt, sodium 4-vinylbenzenesulfonate, 3-sulfopropyl methacrylate potassium salt (3- Sulfopropyl methacrylate potassium salt) and sodium-p-styrenesulfonate (Sodium p-Styrenesulfonate) at least one selected from the group consisting of,

   graft copolymer.
5. 4. The method of claim 3,

   The anionic compound charged with the carboxyl group is at least one selected from the group consisting of sodium methacrylate, zinc methacrylate, and methacrylic acid sodium salt,

   graft copolymer.
6. According to claim 1,

   The graft copolymer is

   Which includes a polymer compound comprising at least one selected from the compound of Formula 1 and the compound of Formula 2 below,

   graft copolymer.

   [Formula 1]

   

   In Formula 1, R ₁ is NH ₂ or a carboxyl group.

   In Formula 1, R ₂ is a hydrogen atom (H), an alkyl group (C ₁ to C ₂₀ ), or a carboxyl group.

   _{R 3} of Formula 1 is NH ₂ or an alkyl group (C ₁ to C ₂₀ ).

   In Formula 1, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

   In Formula 1, n is an integer of 1 to 100.

   In Formula 1, m is an integer of 1 to 1000.

   [Formula 2]

   

   In Formula 2, R ₄ is NH, an oxygen atom (O), or a C ₁ to C ₈ alkoxy group.

   In Formula 2, R ₅ is a hydrogen atom or an alkyl group (C ₁ to C ₂₀ ).

   In Formula 2, R ₆ is a sulfone group, a carboxyl group, or a phosphoric group.

   The range of l in Formula 2 is an integer from 1 to 1000.
7. 7. The method of claim 6,

   The compound of Formula 1 is an amino acid zwitterionic compound, and the compound of Formula 2 is an anionic compound,

   graft copolymer.
8. 8. The method of claim 7,

   The graft copolymer comprises a polymer compound comprising the compound of Formula 1 and the compound of Formula 2 as at least one repeating unit,

   graft copolymer.
9. a substrate for insertion into the body; and

   The graft polymer layer of any one of claims 1 to 8, which is formed on at least one of the surface and the inner surface of the substrate for insertion into the body;

   The graft polymer layer is that a graft copolymer of an amino acid zwitterionic compound and an anionic compound is formed,

   Medical devices for insertion into the body.
10. 10. The method of claim 9,

    The substrate for insertion into the body is

    which is selected from the group consisting of metal, ceramic, synthetic polymer polymer, glass, living tissue, woven fiber, non-woven fiber, semi-metal, silicone, and combinations thereof,

    Medical devices for insertion into the body.
11. 10. The method of claim 9,

    The graft polymer layer is to form a polymer brush on at least one of the surface and the inner surface of the substrate for insertion into the body,

    Medical devices for insertion into the body.
12. 10. The method of claim 9,

    The substrate for insertion into the body further comprises a -C=C group formed on at least one of a surface and an inner surface of the substrate for insertion into the body.

    Medical devices for insertion into the body.
13. 10. The method of claim 9,

    The graft polymer layer has a water contact angle of less than 80 °,

    Medical devices for insertion into the body.
14. a first surface modification step of mixing a compound having an isocyanate group, an initiator, and a substrate for insertion into a reaction solvent and reacting to modify at least one surface and an interior surface of the substrate for insertion into the body; and

    A second surface modification step of forming a graft polymer layer by adding the surface-modified substrate for insertion into the body, an amino acid zwitterionic compound, an anionic compound, and a reducing agent to a reaction solvent and polymerization;

    A grafting method for a medical device for insertion into the body.
15. 15. The method of claim 14,

    The first surface modification step is

    That a -NCO group or -C=C group is formed on at least one of the surface and the inner surface of the substrate for insertion into the body

    A grafting method for a medical device for insertion into the body.
16. 15. The method of claim 14,

    The compound having the isocyanate group is 2-isocyanatoethyl acrylate, 2-isocyanatoethyl methacrylate, isophorone diisocyanate, and hexamethylene diisocyanate. (hexamethylene diisocyanate) which is selected from the group consisting of,

    A grafting method for a medical device for insertion into the body.
17. 15. The method of claim 14,

    The reaction solvent is benzene, toluene, n-hexane, chloroform, diethyl ether, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), isopropyl alcohol, propanol, butanol, ethyl acetate (EA), dimethylform Amide (DMF), dichloromethane (methylene dichloride), acetone, ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), 1,2-dichloroethane (ethylene dichloride), 1, 2-dichloroethylene (acetylene dichloride), carbon tetrachloride, carbon disulfide, 1,1,2,2-tetrachloroethane (acetylene tetrachloride), trichloroethylene, methylcyclohexanone, methylcyclohexanol, methylbutylketone, methyl Ethyl ketone, 1-butanol, 2-butanol, cyclohexanone, cyclohexanol, styrene, ethylene glycol monomethyl ether (methyl cellosolve), ethylene glycol monoethyl ether (cellosolve), ethylene glycol monoethyl ether Acetate (Cellosolve Acetate), ethylene glycol monobutyl ether (butyl Cellosolve), ethyl ether, N,N-dimethylformamide, ortho-dichlorobenzene, isobutyl alcohol, isopentyl alcohol (isoamyl alcohol), Isopropyl alcohol, methyl acetate, butyl acetate, ethyl acetate, isobutyl acetate, isopentyl acetate (isoamyl acetate), isopropyl acetate, pentyl acetate (amyl acetate), propyl acetate, cresol, chlorobenzene, xylene, tetrachloro which is selected from the group consisting of ethylene (par-chloroethylene), 1,1,1-trichloroethane, and water,

    A grafting method for a medical device for insertion into the body.
18. 15. The method of claim 14,

    In the second surface modification step, the -C = C group formed on at least one of the surface and the inner surface of the substrate for insertion into the body polymerizes the zwitterionic compound and the anionic compound to form a graft polymer layer,

    A grafting method for a medical device for insertion into the body.
19. 15. The method of claim 14,

    The second surface modification step is a graft polymer formed by polymerization of radicals formed on at least one of the surface and the inner surface of the substrate for insertion into the body in which -C=C groups are not formed, and the zwitterionic compound and the anionic compound. to form a physical bond between

    A grafting method for a medical device for insertion into the body.

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