WO2011059123A1 - Heparin compound bound to adhesive material, preparation method thereof, solid surface coating agent containing same as active ingredient, and coating method of solid surface using same - Google Patents

Abstract

The present invention relates to a heparin compound bound to an adhesive material, a preparation method thereof, a solid surface coating agent containing the same as an active ingredient, and a coating method of a solid surface using the same. To this end, the present invention prepares a heparin compound bound to an adhesive material by activating a carboxyl group of heparin under a weak acidic condition and reacting the activated one with an adhesive material, and a coating agent containing the prepared compound as an active ingredient can be easily coated on a solid surface under a weak basic condition. According to the present invention, various kinds of solid surfaces can be coated with heparin by easily providing adhesion to heparin, and thus the heparin-coated solid surface can be very useful in the medical field, particularly in the field of blood compatible material development.

Description

Heparin compound combined with an adhesive material, preparation method thereof, solid surface coating agent containing the same as an active ingredient, and solid surface coating method using the same

The present invention provides a heparin compound combined with an adhesive material, a method for preparing the same, a solid surface coating agent containing the same as an active ingredient, and a method for coating a solid surface using the same.

Heparin is a type of acidic polysaccharide with sulfate groups, a substance that has a strong anticoagulant effect, and is present in organs and blood where there are many capillaries such as liver and lung of higher animals. Heparin can be obtained by extracting alkalis from animal tissues to remove proteins. The molecular weight of heparin ranges from 1,200 to 50,000 Da, depending on the number of chain units, with an average molecular weight of approximately 10,000 to 20,000. Heparin inhibits the coagulation action of thrombin and factor Xa. In addition, thrombin activates the action of platelets, the presence of heparin inhibits platelet activation.

In many fields, such as medicine, biology, and artificial organs, experiments have been conducted to introduce heparin's anticoagulant properties to solid surfaces by immobilizing the heparin on a solid surface. Heyman et al. (1985) reported that heparin activated by EDC (1-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide) was transferred to a polyetherurethane catheter through a diaminoalkane spacer. Fixed. The immobilized heparin binds to thrombin and factor Xa in the blood to inactivate it. Larm et al. (1983) decomposed heparin into small units containing aldeed groups and reacted with primary amino groups of polyethyleneimine (PEI) to fix them on the surfaces of plastics, glass and steel. Park et al. (1988) also coated heparin on polyurethane using polyethylene oxide (PEO) as a spacer. In addition, many methods of immobilizing heparin have been studied, but the limitations of these studies are that the surface fixing process is complicated and the types of surfaces that can be fixed are limited. In other words, in order to immobilize heparin on a surface, a special spacer that can bind to heparin first needs a specific functional group that can bind to the surface to be fixed. Therefore, the spacer has a problem in that the fixing process is complicated because it must satisfy both the binding with heparin and the bonding with the surface. In addition, there is a problem that the surface that can be fixed at the same time heparin is also limited.

Accordingly, the inventors of the present invention have completed the present invention by studying a method for preparing a heparin compound combined with an adhesive material by an easy method, a solid surface coating agent containing the same as an active ingredient, and a method for coating a solid surface using the same.

SUMMARY OF THE INVENTION An object of the present invention is to provide a heparin compound bonded to an adhesive material, a method for preparing the same, a solid surface coating agent containing the same as an active ingredient, and a method for coating a solid surface using the same.

In order to achieve the above object, the present invention is a heparin compound bonded to an adhesive material, a method for producing a heparin compound bonded to the adhesive material by reacting the adhesive material and heparin under weakly acidic conditions, containing it as an active ingredient It provides a solid surface coating agent, and a method for coating a solid surface under weak base conditions using the same.

According to the present invention, not only can heparin easily be attached to heparin, but also heparin can be fixed to various solid surfaces. In particular, according to the present invention there is an advantage to overcome the complexity of the fixing step and the limitation of the surface type that the conventional heparin surface fixing method has. In connection with the development of blood compatible materials, such as dark-on artificial blood vessels or bioactive ethic acid biomers, which have been used for medical purposes, many existing blood compatible materials have coated anti-thrombotic substances on polymeric materials such as polyurethane. In the present invention, the dopamine bound to heparin is well coated on the polyurethane surface, and thus the present invention can be usefully used for blood compatible material development.

Figure 1 (a) is a result of taking a solution obtained by dissolving the compound dopamine bonded to heparin in distilled water with a UV detector, (b) is a result of taking a solution in which only heparin dissolved in distilled water by a UV detector.

Figure 2 (a) is a result of dissolving only heparin in distilled water, poured on the surface of the gold and evaporated, followed by FT-IR, (b) is a surface of gold by dissolving a compound in which heparin is bonded to dopamine as an adhesive substance in distilled water After pour into and evaporated, the result was taken with FT-IR, and (c) is a result of coating with a dopamine-bonded compound on heparin on the surface of the gold wafer, washed with distilled water, and then taken with FT-IR.

Figure 3 (a) is a coating of a heparin compound in combination with a dopamine according to the present invention on gold (Au), silicon (Si), and titanium (Ti) wafer to measure the thickness of the coating, (b) is Adsorption of fibrinogen on the coated substrates was performed to measure the thickness, and (c) was measured by dropping blood on the coated substrates to coagulate, washing with water, and measuring the thickness.

4 is a dopamine-bound heparin compound according to the present invention coated on gold (Au), titanium (Ti), polycarbonate (PC), polyurethane (PU) and silicone rubber (a), coating The contact angle photograph is compared with the surface (b) which is not made.

Figure 5 (a) is a photograph of the platelet adhesion test on the bare polyurethane surface, (b) is a photograph of the same test on the surface of the polyurethane coated with the heparin compound according to the present invention. (The scale is 10 mm.)

FIG. 6 shows the thickness of the coated heparin compound remaining after 2 hours, 4 hours, and 6 hours after coating the heparin compound according to the present invention on an Au surface and immersing the surface in 50% ethanol solution. One graph.

Figure 7 is a narrow scan (Narrow scan) photographs with a photoelectron spectroscopy (XPS), (a) is a bare polyurethane surface, (b) is a polyurethane surface coated with a heparin compound according to the present invention (c) is a polyurethane surface dipped in 50% ethanol solution for two hours after coating the heparin compound according to the invention, (d) is a bare silicone rubber surface, and (e) is according to the invention A silicone rubber surface coated with a heparin compound, and (f) is a silicone rubber surface dipped in 50% ethanol solution for two hours after coating the heparin compound according to the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a heparin compound represented by the following Chemical Formula 1 in combination with an adhesive material:

<Formula 1>

.

Where

L is

Wherein K is an integer from 1 to 10;

X is H or OH;

M and N are each an integer from 1 to 50;

A and B are independently β-D-glucuronic acid (GlcA), α-L-iduronic acid (IdoA), 2-O-sulfo-α 2-O-sulfo-α-L-iduronic acid (IdoA (2S)), 2-deoxy-2-acetamino-α-D-glucopyranosyl (2-deoxy-2- acetamido-α-D-glucopyranosyl (GlcNAc)), 2-deoxy-2-sulfamido-α-D-glucopyranosyl (2-deoxy-2-sulfamido-α-D-glucopyranosyl (GlcNS)), and 2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate (2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate (GlcNS (6S)) ) Is any one selected from the group consisting of.

Wherein A and B represent hexagonal ring units constituting heparin, A represents an amide bond, and B represents an amide bond. In addition, the range of heparin molecular weight used for the present invention has a value between the molecular weight of 3 kDa and 50 kDa. Through this, heparin used in the present invention may include all kinds present in nature. The heparin compound according to Chemical Formula 1 is a composite in which A and B are optionally arranged, and M / (M + N), which is a ratio of A and B, is preferably 0.02 or more. That is, it is preferable that at least 2% of the heparin compounds bonded with the adhesive material according to the present invention form amide bonds in the number of -COOH groups inherent in heparin. If the amide bond is less than 2%, there is a problem that the adhesion efficiency of the heparin compound according to the present invention is lowered. The adhesive material bound to heparin according to the present invention includes dopamine (dopamine, 3-hydroxytyramine hydrochloride) as shown in the following formula (2), and the chemical structure of dopamine, whether or not one or a plurality of X OH in the formula (1) It is very similar to maintain the physical and chemical properties of dopamine.

<Formula 2>

Haeshin Lee et al. (2006, 2007) studied mussels that have adhesion in water and on water, as well as on organic and inorganic surfaces, and found that the basic unit of adhesion is dopamine. Has been successfully coated on various surfaces including polytetrafluoroethylene (PTFE). Since the heparin compound of Formula 1 according to the present invention has the physical and chemical properties of dopamine, it is possible to coat on various surfaces.

The solid surface coated by the coating agent containing the heparin compound of Formula 1 as an active ingredient is, for example, polytetrafluoroethylene (PTFE), polycarbonate (polycarnonate), polyurethane (polyurethane), nitrocellulose (nitrocellulose), Polymeric materials including polystyrene (PS), polyethylene (PE), polyethylene terephthalate (PET), polydimethylsiloxane (PDMS), and polyether ether ketone (PEEK), gold (Au), silver (Ag), platinum Precious metal materials including (Pt), palladium (Pd), and copper (Cu), metal materials including steel, nitinol alloy (NiTi), gallium arsenide (GaAs), and titanium (Ti), silicon oxide Metal oxide materials including (SiO ₂ ), titanium oxide (TiO ₂ ), aluminum oxide (Al ₂ O ₃ ), and niobium oxide (Nb ₂ O ₅ ), and nonmetals including silicon, silicone rubber, and glass It may be a material of, but is not limited thereto.

The present invention also provides a method for preparing a heparin compound in combination with an adhesive material.

In the method for preparing a heparin compound according to the present invention, a step of activating the -COOH group of heparin by reacting heparin with N-hydroxysuccinimide (NHS), as shown in Scheme 1 below, in a weakly acidic buffer solution. (Step 1); And

Reacting the -COOH group-activated heparin with the adhesive material to prepare a heparin compound in which the adhesive material is bound (step 2):

<Scheme 1>

.

In Scheme 1,

L is

Wherein K is an integer from 1 to 10;

X is H or OH;

M and N are each an integer from 2 to 50;

A and B are independently β-D-glucuronic acid (GlcA), α-L-iduronic acid (IdoA), 2-O-sulfo-α 2-O-sulfo-α-L-iduronic acid (IdoA (2S)), 2-deoxy-2-acetamino-α-D-glucopyranosyl (2-deoxy-2- acetamido-α-D-glucopyranosyl (GlcNAc)), 2-deoxy-2-sulfamido-α-D-glucopyranosyl (2-deoxy-2-sulfamido-α-D-glucopyranosyl (GlcNS)), and 2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate (2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate (GlcNS (6S)) ) Is any one selected from the group consisting of.

Step 1 is a step of reacting heparin with NHS in order to activate the -COOH group of heparin, through the reaction, for example, the -COOH group of heparin, such as the following formula (3) is activated as shown in formula (4).

<Formula 3>

<Formula 4>

Step 2 is a step of bonding the adhesive material to heparin -COOH group activated, the adhesive material is preferably dopamine. Through step 2, a heparin compound in which a substance of Formula 4 is reacted with an adhesive substance of Formula 5 is prepared by reacting with an amine group of dopamine.

<Formula 5>

Step 1 and step 2 is preferably carried out under weakly acidic conditions. This is because weakly acidic conditions inhibit dopamine self-polymerization.

The method for preparing a heparin compound combined with an adhesive material according to the present invention may further include performing dialysis and lyophilization. In order to prevent the self-polymerization of dopamine during dialysis, it is desirable to maintain weakly acidic conditions.

Furthermore, the present invention provides a solid surface coating agent containing a heparin compound in which the adhesive material represented by Formula 1 is bound as an active ingredient.

In addition, the present invention provides a method for coating a solid surface using the coating agent.

Coating of the solid surface with the solid surface coating agent containing the heparin compound according to the present invention as an active ingredient is preferably carried out under weak base conditions of pH 7.5 ~ 0.5. This is because weak base conditions induce polydopamine polymerization between dopamines bound to heparin.

Solid surfaces on which the solid surface coatings according to the invention can be coated are, for example, polytetrafluoroethylene (PTFE), polycarbonate (polycarnonate), polyurethane, nitrocellulose, polystyrene (PS), Polymeric materials, including polyethylene (PE), polyethylene terephthalate (PET), polydimethylsiloxane (PDMS), and polyether ether ketone (PEEK), gold (Au), silver (Ag), platinum (Pt), palladium (Pd), and precious metal materials including copper (Cu), steel, nitinol alloys (NiTi), gallium arsenide (GaAs), and metal materials including titanium (Ti), silicon oxide (SiO ₂ ), Metal oxide materials including titanium oxide (TiO ₂ ), aluminum oxide (Al ₂ O ₃ ), and niobium oxide (Nb ₂ O ₅ ), and nonmetallic materials including silicon, silicone rubber, and glass, It is not limited to this.

Hereinafter, the present invention will be described by way of examples. However, the following examples are merely to illustrate the invention, the present invention is not limited by the following examples.

<Example 1>

Preparation of Dopamine-bound Solid Heparin Compounds

400 mg of heparin, 230 mg of NHS, and 766 mg of EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochlorid) as shown in Chemical Formula 3, 40 mg of MES (2-morpholinoethanesulfonic acid) buffer at pH 5.5 and 0.05 M Completely dissolved and reacted for 2 hours 30 minutes to activate the -COOH group of heparin:

<Formula 3>

.

120 mg of dopamine was added to the -COOH group-activated heparin solution for 8 hours. The solution reacted for 10 hours and 30 minutes as described above was dialyzed by injection into a molecular porous membrane tube (MWCO: 12-14000). In dialysis, 1 ml of 5 M HCl was injected per liter to prevent the self-polymerization of dopamine bound to heparin. Dialysis with several exchanges of water for 12 hours, and the dialysis solution was lyophilized to give a solid heparin compound as shown in Formula 5 wherein dopamine was bound:

<Formula 5>

.

<Example 2>

Dopamine-bound Heparin Compound Coatings on Gold Wafers

50 mg of the dopamine-coupled heparin compound prepared in Example 1 was dissolved in 5 ml of TRIS buffer at 10 mM and pH 8.5, and then coated with gold wafer pieces for 12 hours with stirring.

<Example 3>

Dopamine-bound heparin compound coating on titanium wafers

Surface coating was performed in the same manner as in Example 2 except that the solid used for coating was a titanium wafer.

<Example 4>

Dopamine-bound heparin compound coated on polyurethane

Surface coating was carried out in the same manner as in Example 2, except that the solid used for coating was polyurethane.

Example 5

Dopamine-bound heparin compound coating on polycarbonate

Surface coating was performed in the same manner as in Example 2 except that the solid used for coating was polycarbonate.

<Example 6>

Dopamine-bound heparin compound coating on silicone rubber

Surface coating was performed in the same manner as in Example 2 except that the solid used for coating was silicone rubber.

Experimental Example 1

Confirmation of Heparin and Dopamine Binding by UV Detector

In order to confirm whether dopamine is bound to the heparin compound prepared in Example 1, the peak was confirmed through an ultraviolet detector. Figure 1 (b) is taken only by dissolving heparin in distilled water with an ultraviolet detector. It can be seen that no peak emerges at 280 nm, the absorbing wavelength of dopamine. On the other hand, Figure 1 (a) is taken with an ultraviolet detector dissolved in a distilled water the dopamine-bound heparin compound prepared in Example 1 of the present invention. In Figure 1 (a) it can be seen that the peak at 280 nm, the absorption wavelength of dopamine is clearly seen. Since unreacted dopamine was removed through dialysis in Example 1, it can be seen that the peak at 280 nm is the peak of dopamine bound to heparin.

Experimental Example 2

Confirmation of Heparin and Dopamine Binding Using FT-IR

If heparin and dopamine are combined, an amide bond is formed, so -CONH-amide bond was confirmed through FT-IR. FIG. 2 (a) shows the result taken by FT-IR after evaporation of only heparin in distilled water, poured onto a gold wafer surface. In Figure 2 (a) it can be seen that the peak can not be confirmed near the 1560 cm ^-1 frequency range of the amide bond. On the other hand, Figure 2 (b) is a result obtained by FT-IR after evaporation of the dopamine-bound heparin compound prepared in Example 1 of the present invention dissolved in distilled water and poured on the surface of the gold wafer. In Figure 2 (b) it can be confirmed that the -CONH- peak near 1560 cm ^-1 , through which the binding of heparin and dopamine was well established.

Experimental Example 3

Identification of surface coatings using FT-IR

In order to confirm whether the dopamine-bound heparin compound according to the present invention is well coated on the surface of the gold wafer, an experiment using FT-IR was performed on the gold wafer coated by the dopamine-bound heparin compound according to Example 2. Was performed. Figure 2 (c) is a result of taking a gold wafer coated with a dopamine-bound heparin compound according to Example 2 after sufficiently washed with distilled water and FT-IR. In Figure 2 (c) it can be seen the peak -CONH- near 1560 cm ^-1 . Through this, it can be seen that the dopamine-coupled heparin compound according to the present invention is well adhered to the gold wafer surface.

Experimental Example 4

Measurement of Coating Thickness

The coating thicknesses were measured for the coated gold wafers, titanium wafers, and silicon wafers prepared in Examples 2, 3, and 6. An ellipsometer was used for the coating thickness measurement. According to (a) of FIG. 3, gold wafers were coated with an average of 21.026 mmW, silicon wafers with an average of 11.7 mmW, and titanium wafers with an average of 19.758 mmW.

Experimental Example 5

Protein adsorption experiments confirm the non-fouling effect of surface heparin

1 cm × 1 cm heparin-coated gold wafers, titanium wafers, and silicon wafers prepared in Examples 2, 3, and 6 of the present invention were prepared, and each wafer was phosphoric acid having a fibrinogen concentration of 1 mg / ml. Immerse in buffered saline (PBS). After soaking at 37 ° C. for 2 hours under static conditions, the thickness was measured using an ellipsometer after washing. Bare gold wafers, bare silicon wafers, bare titanium wafers were used as a control, and the results are shown in FIG. According to (b) of FIG. 3, it can be seen that the amount of fibrinogen adsorbed on the heparin-coated surface is significantly reduced compared to the amount of fibrinogen adsorbed on the bare surface of the heparin-coated bare surface. Since heparin is an anti-fouling material, it is indirectly known that heparin is well coated on the surface by reducing the amount of adsorbed fibrinogen.

Experimental Example 6

Coagulation experiments confirm the anti-fouling effect of surface-immobilized heparin

Through the surface coating of the dopamine-bound heparin compound according to the present invention, in order to determine whether the heparin immobilized on the surface performs the solution solution in the solution solution, under the condition of water vapor saturation, uncoated gold, silicon, and After dropping blood on the surface of gold, titanium, and silicon coated with titanium and the dopamine-conjugated heparin compound according to Examples 2, 3, and 6 of the present invention, the mixture was left for 2 hours. Thereafter, the surfaces were sufficiently washed with distilled water, and then the thickness of the blood component adsorbed on the surface was measured using an ellipsometer, which is shown in FIG. According to (c) of Figure 3 it can be seen that the amount of components adsorbed on the heparin-coated surface is significantly reduced compared to the amount of components adsorbed on the uncoated bare surface. Since heparin is an anti-fouling material, it can be indirectly known that heparin is well coated on the surface by reducing the amount of adsorbed blood components.

Experimental Example 7

Measurement of contact angle

The contact angle was measured to confirm that the coating of the dopamine-bound heparin compound according to the present invention on the solid surface was well performed. A drop of distilled water was added dropwise to the gold wafer, the titanium wafer, the polycarbonate, the polyurethane, and the silicone rubber and the coated solid surface prepared in Examples 2 to 6 according to the present invention, and then the contact angle was checked through a contact angle meter. The results are shown in FIG. 4 is a photograph for confirming a contact angle in each case. According to FIG. 4, in the case of gold wafer, titanium wafer, polycarbonate, polyurethane, and silicone rubber, the contact angles of the case where the dopamine-bound heparin compound according to the present invention is not coated and when coating the dopamine are significantly different You can see the others. Through this, it can be seen that the coating according to the present invention was well made.

Experimental Example 8

Identification of non-fouling effects of surface heparin through platelet adhesion

The 1 cm × 1 cm heparin coated polyurethane surface prepared by Example 4 of the present invention was immersed in PBS (pH 7.4) for 24 hours. This surface was then immersed in 5 ml of platelet concentrate and maintained at 37 ° C. for 2 hours. Washed with PBS to remove weakly attached platelets. Thereafter, the surface was immediately immersed in formaldehyde for 24 hours, platelets were fixed, and the remaining formaldehyde was removed with PBS. This surface was then immersed in 50, 60, 70, 80, 90% ethanol solution for 15 minutes in order to replace water with ethanol. Finally, the surface was analyzed by SEM, which is shown in FIG. 5. The same analysis was carried out on the untreated polyurethane surface in order to contrast with the polyurethane surface according to the invention. According to FIG. 5, it can be seen that the amount of platelets adhered to the surface of heparin-coated polyurethane is significantly reduced compared to the amount of platelets adhered to the surface of bare polyurethane without heparin-coated. Through these results, it can be seen that the heparin compound according to the present invention is well coated on the surface of polyurethane to show the anti-fouling effect of heparin.

Experimental Example 9

Stability Test of Heparin Compound Coatings According to the Present Invention

Heparin compound-coated gold wafers, polyurethanes, and silicone rubbers prepared according to Examples 2, 4, and 6 according to the present invention were immersed in 50% ethanol solution. Among them, the gold wafer coated with the heparin compound was immersed in the ethanol solution for 2 hours, 4 hours, and 6 hours under static conditions, respectively, and the thickness thereof was measured with an ellipsometer. Indicated. In addition, the polyurethane and silicone rubber coated with heparin compound were immersed in a 50% ethanol solution in a static state for 2 hours and then taken out and analyzed by XPS. At this time, as a control, the bare polyurethane and bare silicone rubber were analyzed by XPS, and the results are shown in FIG. 7. According to Figure 6 heparin-coated gold surface according to the present invention can be seen that the thickness does not change significantly after 2 hours, 4 hours, 6 hours in 50% ethanol solution. This shows that heparin coated on gold is stably coated on the surface. In (a) of FIG. 7, no S2p peak appeared on the bare polyurethane surface. However, in Figure 7 (b) it can be seen that the S2p peak in the case of the heparin-coated polyurethane surface according to the present invention. In addition, in Figure 7 (c) it can be seen that the S2p peak comes out from the surface of heparin-coated polyurethane dipped in 50% ethanol for 2 hours. Therefore, it can be seen that the heparin compound according to the present invention was stably coated on the polyurethane surface. Similarly, the peak of N1s did not come out from the surface of the bare silicone rubber in FIG. However, in the case of (e) of FIG. 7, the heparin-coated silicone rubber surface showed a N1s peak. In addition, it was confirmed that the N1s peak also appeared on the surface of heparin-coated silicone rubber dipped in 50% ethanol for 2 hours in Figure 7 (f). Through this, it can be seen that the heparin compound according to the present invention is stably coated on the silicone rubber surface.

Claims (10)

1. Heparin compound represented by the following Chemical Formula 1 combined with an adhesive substance:

   <Formula 1>

   

    (Wherein

   L is

   

   Wherein K is an integer from 1 to 10;

   X is H or OH;

   M and N are each an integer from 2 to 50;

   A and B are independently β-D-glucuronic acid (GlcA), α-L-iduronic acid (IdoA), 2-O-sulfo-α 2-O-sulfo-α-L-iduronic acid (IdoA (2S)), 2-deoxy-2-acetamino-α-D-glucopyranosyl (2-deoxy-2- acetamido-α-D-glucopyranosyl (GlcNAc)), 2-deoxy-2-sulfamido-α-D-glucopyranosyl (2-deoxy-2-sulfamido-α-D-glucopyranosyl (GlcNS)), and 2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate (2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate (GlcNS (6S)) It is any one selected from the group consisting of).
2. The heparin compound according to claim 1, wherein the heparin compound according to Chemical Formula 1 is a material in which A and B not bonded are arbitrarily arranged, and M / (M + N), which is a ratio of A and B, is 0.02. Heparin compound combined with an adhesive substance, characterized in that above.
3. The heparin compound of claim 1, wherein the heparin of Chemical Formula 1 has a molecular weight in the range of 3 kDa to 50 kDa.
4. In the weakly acidic buffer solution, reacting heparin with N-hydroxysuccinimide (NHS) as in Scheme 1 to activate the -COOH group of heparin (step 1); And

   Preparing a heparin compound in which an adhesive material is bonded by reacting the -COOH group-activated heparin with an adhesive material (step 2)

   Method for producing a heparin compound combined with an adhesive material comprising a:

   <Scheme 1>

   

    (In Scheme 1,

   L is

   

   Wherein K is an integer from 1 to 10;

   X is H or OH;

   M and N are each an integer from 2 to 50;

   A and B are materials in which an adhesive and an unbonded B are arbitrarily arranged, and M / (M + N), which is a ratio of A and B, is not less than 0.02, independently β-D-glucu Β-D-glucuronic acid (GlcA), α-L-iduronic acid (IdoA), 2-O-sulfo-α-L-iduronic acid (2-O-sulfo- α-L-iduronic acid (IdoA (2S))), 2-deoxy-2-acetamino-α-D-glucopyranosyl (2-deoxy-2-acetamido-α-D-glucopyranosyl (GlcNAc)), 2-deoxy-2-sulfamido-α-D-glucopyranosyl (GlcNS), and 2-deoxy-2-sulfamido-α -D-glucopyranosyl-6-O-sulfate (2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate (GlcNS (6S))).
5. The method of claim 4, wherein the method further comprises dialysis and lyophilization of the product of step 2.
6. The method of claim 4, wherein the adhesive material of step 2 is dopamine represented by Formula 2 below (dopamine, 3-Hydroxytyramine hydrochloride).

   <Formula 2>

   

   .
7. Solid surface coating agent containing a heparin compound bonded to the adhesive material represented by the formula (1) as an active ingredient:

   <Formula 1>

   

    (Wherein

   L is

   

   Wherein K is an integer from 1 to 10;

   X is H or OH;

   M and N are each an integer from 2 to 50;

   A and B are materials in which an adhesive and an unbonded B are arbitrarily arranged, and M / (M + N), which is a ratio of A and B, is not less than 0.02, independently β-D-glucu Β-D-glucuronic acid (GlcA), α-L-iduronic acid (IdoA), 2-O-sulfo-α-L-iduronic acid (2-O-sulfo- α-L-iduronic acid (IdoA (2S))), 2-deoxy-2-acetamino-α-D-glucopyranosyl (2-deoxy-2-acetamido-α-D-glucopyranosyl (GlcNAc)), 2-deoxy-2-sulfamido-α-D-glucopyranosyl (GlcNS), and 2-deoxy-2-sulfamido-α -D-glucopyranosyl-6-O-sulfate (2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate (GlcNS (6S))).
8. The method of claim 7, wherein the solid to be coated is polytetrafluoroethylene, polycarbonate, polyurethane, nitrocellulose, polystyrene, polyethylene, polyethylene terephthalate Polymeric materials including (PET), polydimethylsiloxane (PDMS), and polyether ether ketone (PEEK), gold (Au), silver (Ag), platinum (Pt), palladium (Pd), and copper (Cu) Noble metal materials, including steel, steel, Nitinol alloy (NiTi), gallium arsenide (GaAs), and metal materials including titanium (Ti), silicon oxide (SiO ₂ ), titanium oxide (TiO ₂ ), oxidation Any one selected from the group consisting of metal oxide materials including aluminum (Al ₂ O ₃ ), and niobium oxide (Nb ₂ O ₅ ), and nonmetal materials including silicon, silicon rubber, and glass. Solid surface coating agent.
9. A method of coating a solid surface with a compound of Formula 1 under weakly basic conditions of pH 7.5 to 9.5:

   <Formula 1>

   

    (Wherein

   L is

   

   Wherein K is an integer from 1 to 10;

   X is H or OH;

   M and N are each an integer from 2 to 50;

   A and B are materials in which an adhesive and an unbonded B are arbitrarily arranged, and M / (M + N), which is a ratio of A and B, is not less than 0.02, independently β-D-glucu Β-D-glucuronic acid (GlcA), α-L-iduronic acid (IdoA), 2-O-sulfo-α-L-iduronic acid (2-O-sulfo- α-L-iduronic acid (IdoA (2S))), 2-deoxy-2-acetamino-α-D-glucopyranosyl (2-deoxy-2-acetamido-α-D-glucopyranosyl (GlcNAc)), 2-deoxy-2-sulfamido-α-D-glucopyranosyl (GlcNS), and 2-deoxy-2-sulfamido-α -D-glucopyranosyl-6-O-sulfate (2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate (GlcNS (6S))).
10. The method of claim 9, wherein the solid to be coated is polytetrafluoroethylene, polycarbonate, polyurethane, nitrocellulose, polystyrene, polyethylene, polyethylene terephthalate Polymeric materials including (PET), polydimethylsiloxane (PDMS), and polyether ether ketone (PEEK), gold (Au), silver (Ag), platinum (Pt), palladium (Pd), and copper (Cu) Noble metal materials, including steel, steel, nitinol alloy (NiTi), gallium arsenide (GaAs), and metal materials including titanium (Ti), silicon oxide (SiO ₂ ), titanium oxide (TiO ₂ ), oxidation Any one selected from the group consisting of metal oxide materials including aluminum (Al ₂ O ₃ ), and niobium oxide (Nb ₂ O ₅ ), and nonmetal materials including silicon, silicon rubber, and glass. Coating room of solid surface characterized by method.

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