KR101734489B1

KR101734489B1 - Medical catheter comprising oxidized polysaccharide and hydrophilic polymer-containing coating layer and manufacturing method thereof

Info

Publication number: KR101734489B1
Application number: KR1020150113245A
Authority: KR
Inventors: 이영우; 임소연
Original assignee: (주)헵틸와이
Priority date: 2015-08-11
Filing date: 2015-08-11
Publication date: 2017-05-11
Also published as: KR20170019183A

Abstract

The present invention relates to a method for improving the hydrophilicity of a medical catheter by coating oxidized polysaccharides and hydrophilic polymers oxidized with an oxidizing agent on the surface of a medical catheter, thereby greatly increasing the lubricity on the surface portion of the medical catheter, .
The medical catheter comprising the oxidized polysaccharide and the hydrophilic polymer-containing coating layer produced according to the present invention has excellent biocompatibility and maintains the self-lubricating property of the surface of the catheter, so that it is not necessary to process the lubricant before insertion into the human body conduit, Perforation, separation, and tissue damage, so that it can be applied as a variety of medical conduits to be inserted into a catheter, including a catheter, in addition to a blood vessel.

Description

TECHNICAL FIELD The present invention relates to a medical catheter comprising an oxidized polysaccharide and a hydrophilic polymer-containing coating layer,

TECHNICAL FIELD The present invention relates to a medical catheter comprising a polysaccharide and a hydrophilic polymer-containing coating layer, and a method for producing the same, and more particularly, to a medical catheter comprising a medical catheter coated with oxidized polysaccharide and hydrophilic polymer oxidized using an oxidizing agent, The present invention relates to a technique for greatly increasing the lubricity on the surface of a medical catheter in which friction with tissues occurs during insertion into the human body by improving hydrophilicity.

In general, a catheter is a thin tube formed by extrusion molding using a medical material, and is generally referred to as a catheter inserted into a human body for the purpose of treating a disease or performing surgery. That is, since the catheter is applied to a variety of clinical fields such as cardiovascular, urinary and digestive machines, it is inserted into a human body such as steel, a tube, and a blood vessel. Particularly, in order to diagnose or treat ischemic cardiovascular diseases such as arteriosclerosis and angina pectoris, a guiding catheter and a balloon catheter are inserted through the femoral or wrist aorta into the narrowed blood vessel region, and then the balloon is inflated to expand the coronary artery Percutaneous transluminal coronary angioplasty.

However, the success rate of percutaneous coronary angioplasty was 84 ~ 92%, which is higher than the initial success rate of 50 ~ 60%, but there is still a problem of 20 ~ 65% restenosis depending on the site of vascular stenosis. In addition, since most of the catheters used in intracorporeal catheter insertion including percutaneous coronary angioplasty are hydrophobic polymers such as polyethylene, polytetrafluoroethylene, polyamide, polyurethane, silicone, and the like, A certain pressure is required to insert into the body conduit. In addition, since the human body conduit is not distributed in a certain shape or angle in the human body, sufficient lubricity should be given to the surface of the catheter for smooth insertion into the human body conduit. In addition, if such lubrication is not sufficient, there is a risk that the catheter will rub against the inner wall of the body conduit during insertion of the catheter into the body conduit, resulting in side effects such as puncturing or separation of the conduit, Reported.

Therefore, prior to inserting the catheter into the body conduit in order to alleviate the above-mentioned side effects, a water-soluble lubricant may be applied to the surface of the catheter to impart lubrication to the catheter. However, in the process of inserting the catheter into the body conduit, And the frictional force between the catheter and the inner wall of the body conduit may be recovered again, which makes it difficult to easily operate the catheter when the catheter is inserted (Patent Documents 1 to 3).

Therefore, the present inventors have solved the problem caused by the use of the conventional medical catheter, and have not yet found an example in which a coating layer based on a mixture of an oxidizing polysaccharide and a hydrophilic polymer is formed on the catheter. It has been found that coating with a mixture of oxidized polysaccharide and hydrophilic polymer improves hydrophilicity and greatly increases lubricity upon insertion into a human body conduit, thereby completing the present invention.

Patent Document 1: Japanese Patent Application Laid-Open No. 10-2013-0122538 Patent Document 2: JP-A-10-1168676 Patent Document 3: Registered Patent Publication No. 10-1124599

SUMMARY OF THE INVENTION The present invention has been made in view of the above problems, and it is an object of the present invention to provide a catheter that has excellent biocompatibility and maintains self-lubricating property of a surface of a catheter, A porous layer containing oxidized polysaccharide and hydrophilic polymer which does not cause side effects such as piercing, separation, and tissue damage, and a method for producing the catheter.

To achieve these and other advantages and in accordance with the purpose of the present invention, there is provided a medical catheter comprising a polysaccharide and a hydrophilic polymer-containing coating layer.

The oxidized polysaccharide may be selected from the group consisting of oxidized carboxymethylcellulose, carboxyethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, dextrin, dextran, dextran sulfate, alginic acid, hyaluronic acid, chitin, chitosan, gellan gum, glucan, And at least one selected from the group consisting of chondroitin sulfate, glycogen, starch, cellulose, regenerated cellulose, maltodextrin, fructan, galactan and mannan.

The oxidized polysaccharide is characterized in that the molecular weight of the polysaccharide before oxidation is 1,000 to 100,000.

The oxidation polysaccharide has an oxidation degree of 5 to 70%.

The hydrophilic polymer may include polyethylene glycol or polypropylene glycol having a carbon-carbon double bond at the terminal, polyethylene glycol or polypropylene glycol having an amine group at the terminal, polyacrylamide, polyhydroxy methyl methacrylate, polyhydroxyethyl methacrylate Polyacrylic acid, polymethacrylic acid, and poly (N-isopropylacrylamide).

The present invention also relates to a method for preparing an oxidation reaction mixture, comprising the steps of: I) mixing an oxidant aqueous solution and a polysaccharide aqueous solution to obtain an oxidation reaction mixture; II) washing the oxidation reaction mixture with ethanol for several times, filtering and drying to obtain a powdery oxidized polysaccharide; III) mixing the oxidized polysaccharide solution in which the powdery oxidized polysaccharide is dissolved and the hydrophilic polymer solution to obtain a coating solution; And IV) coating the coating solution on the surface of the pretreated catheter.

The oxidizing agent is at least one selected from the group consisting of hydrogen peroxide, iron nitrate, ozone, peracetic acid, potassium permanganate, potassium peroxodisulfate, potassium peroxodisulfate, sodium periodate, sodium bromate, sodium perborate and sodium percarbonate .

The polysaccharide may be selected from the group consisting of carboxymethylcellulose, carboxyethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, dextrin, dextran, dextran sulfate, alginic acid, hyaluronic acid, chitin, chitosan, gellan gum, glucan, betaglucan, chondroitin sulfate, And at least one selected from the group consisting of glycogen, starch, cellulose, regenerated cellulose, maltodextrin, fructan, galactan and mannan.

The oxidant aqueous solution has a concentration of 0.1 to 40% by weight.

The polysaccharide aqueous solution has a concentration of 1 to 30% by weight.

The oxidation reaction is performed at 25 to 37 ° C for 1 to 96 hours in an atmosphere in which light is blocked.

The oxidized polysaccharide solution has a concentration of 5 to 40% by weight.

The hydrophilic polymer solution has a concentration of 0.1 to 20% by weight.

The pretreatment is characterized in that the surface of the catheter is treated by plasma, gamma ray, electron beam, ultraviolet irradiation or radical initiator.

The coating is characterized in that it is carried out by a dip coating method or a spray coating method.

The medical catheter comprising the oxidized polysaccharide and the hydrophilic polymer-containing coating layer produced according to the present invention has excellent biocompatibility and maintains the self-lubricating property of the surface of the catheter, so that it is not necessary to process the lubricant before insertion into the human body conduit, Perforation, separation, and tissue damage, so that it can be applied as a variety of medical conduits to be inserted into a catheter, including a catheter, in addition to a blood vessel.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the lubricity of a medical catheter comprising a coating of oxidized polysaccharide and a hydrophilic polymer mixture prepared from Examples 2, 5 and 8 of the present invention and a commercialized medical catheter as a control.
2 is a graph showing the effect of the molecular weight of the polysaccharide on lubricity in a medical catheter comprising a coating layer of a mixture of oxidized polysaccharides and a hydrophilic polymer prepared by varying the molecular weight of the polysaccharide according to Example 4 of the present invention.
FIG. 3 is a graph showing the effect of oxidation degree of polysaccharide on lubricity in a medical catheter comprising a coating layer of oxidized polysaccharide and a hydrophilic polymer mixture prepared from Examples 1, 4 and 7 of the present invention.
4 is a graph showing the influence of the concentration of the hydrophilic polymer solution on the lubricity in the medical catheter comprising the coating layer of the oxidized polysaccharide and the hydrophilic polymer mixture prepared in Examples 7 to 9 of the present invention.

Hereinafter, the medical catheter including the oxidized polysaccharide and the hydrophilic polymer-containing coating layer according to the present invention will be described in detail.

First, the present invention provides a medical catheter comprising a coating layer containing an oxidized polysaccharide and a hydrophilic polymer.

Generally, since the main material of a catheter generally used is hydrophobic, its nature is different from that of a body fluid composed of more than 90% water which is filled in a human body conduit. Therefore, in the related art, hydrophilic material is coated on the surface of the hydrophobic catheter, and various side effects such as perforation of the catheter, tissue damage and the like which may be caused in the process of inserting the catheter into the human body can be partially solved. However, coating of a hydrophilic material alone makes it difficult to achieve complete lubrication when inserting the catheter into the body conduit. Particularly, among such hydrophilic substances, the reactive functional groups of the hydrophilic polymer are mainly polar and are likely to be easily separated from the surface of the catheter by dissolving or swelling when they come in contact with a hydrophilic (polar) body fluid.

Therefore, the present invention is characterized in that a coating layer is formed on the surface of the catheter so that a mixture of the hydrophilic polymer and the oxidizing polysaccharide forms a coating layer on the catheter surface in order to maintain a specific lubricity despite considerable friction and abrasion force when the catheter is inserted. This is because when the hydroxyl group of the polysaccharide is oxidized by the oxidizing agent, the aliphatic ring structure is opened and changed to the aldehyde group. Since the hydrophilic polymer is mixed with the oxidized polysaccharide to form a chemical bond, It is possible to form a coating layer on the catheter surface. Since oxidized polysaccharides are basically hydrophilic, they are mixed with hydrophilic polymers to maximize hydrophilicity on the surface of the catheter, thereby reducing the friction between the catheter surface and the inner wall of the catheter. Thus, Insertion and movement of the catheter can be performed to alleviate the pain of the patient, and it is possible to facilitate a series of catheter insertion operations in which the operator inserts the catheter into the body conduit and then moves to the lesion. , And tissue damage. Furthermore, even if a part of the hydrophilic polymer and the oxidized polysaccharide are separated by friction with the body fluid or the inner wall of the conduit, they can be decomposed and discharged in vivo by the water in the body fluids or blood, and the risk of the blood clotting It is safe to use.

The oxidized polysaccharide may be selected from the group consisting of carboxymethylcellulose, carboxyethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, dextrin, dextran, dextran sulfate, alginic acid, hyaluronic acid, chitin, chitosan, gellan gum, glucan, betaglucan, chondroitin sulfate Means one in which at least one polysaccharide selected from the group consisting of glycogen, starch, cellulose, regenerated cellulose, maltodextrin, fructan, galactan and mannan is oxidized by oxidation reaction.

The molecular weight of the oxidized polysaccharide before oxidation is preferably 1,000 to 100,000. If the molecular weight is less than 1,000, the hydrophilic effect of the surface of the catheter is low and the lubricity may deteriorate. If the molecular weight exceeds 100,000, It is difficult to bond to the surface or decomposition in the living body is slowed, so that it is difficult to discharge and when the body fluid is decomposed, the viscosity of the body fluid may increase.

The degree of oxidation indicating degree of oxidation of the polysaccharide can be defined as a ratio (%) of the conversion of the hydroxyl group of the polysaccharide to the aldehyde by the oxidation reaction with the oxidizing agent and the like. The oxidizing polysaccharide has an oxidation degree of 5 to 70% . If the degree of oxidation is less than 5%, there are few reaction sites chemically bondable to the surface of the catheter, so that it is difficult to bind to the surface or only a small amount may be combined to exhibit a desired lubricating effect. When the degree of oxidation exceeds 70% It is easily decomposed by moisture, and when stored or contacted with body fluids, the molecular weight may be excessively reduced or eluted and decomposed to lower the lubricity.

Examples of the hydrophilic polymer include polyethylene glycol or polypropylene glycol having a carbon-carbon double bond at the terminal, polyethylene glycol or polypropylene glycol having an amine at the terminal, polyacrylamide, polyhydroxymethyl methacrylate, polyhydroxyethyl Methacrylate, polyacrylic acid, polymethacrylic acid, and poly (N-isopropylacrylamide) can be preferably used. The hydrophilic polymer may have a molecular weight of 500 to 500,000, more preferably 5000 to 100,000. If the molecular weight is less than 500, the lubricating effect is not sufficient. On the contrary, if the molecular weight is more than 500,000, it is difficult to dissolve and it may be difficult to separate and discharge in the body.

Examples of the oxidizing agent in the above step I) include 1) selected from the group consisting of hydrogen peroxide, iron nitrate, ozone, peracetic acid, potassium permanganate, potassium peroxodisulfate, potassium peroxodisulfate, sodium periodate, sodium bromate, sodium perborate, More than one species may be used, but the present invention is not limited thereto.

Examples of the polysaccharide in step I) include carboxymethyl cellulose, carboxyethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, dextrin, dextran, dextran sulfate, alginic acid, hyaluronic acid, chitin, chitosan, gellan gum, But is not limited to, at least one selected from the group consisting of beta-glucan, chondroitin sulfate, glycogen, starch, cellulose, regenerated cellulose, maltodextrin, fructan, galactan and mannan.

In the step I), the oxidizing agent is mixed with the polysaccharide in an aqueous solution to perform the oxidation reaction. It is preferable that the oxidizing agent solution has a concentration of 0.1 to 40% by weight and the polysaccharide aqueous solution has a concentration of 1 to 30% by weight. At this time, in order to suppress the peroxidation by light or temperature in the process of inducing the oxidation reaction from the oxidation reaction mixture, it is preferable to carry out the oxidation reaction at 25 to 37 ° C for 1 to 96 hours in a light-blocked atmosphere.

Then, the oxidation reaction mixture is washed several times with ethanol, filtered and dried through step II) to obtain a powdery oxidized polysaccharide.

Next, in step III), a coating solution is obtained by mixing a solution of oxidized polysaccharide in which powdery oxidized polysaccharide is dissolved and a hydrophilic polymer solution. As the solvent for dissolving the oxidized polysaccharide and the hydrophilic polymer in the powder, acetone, N, Organic solvents such as N, N-dimethylformamide (DMF), chloroform, dioxane, tetrahydrofuran (THF), methanol, ethanol, propanol or isopropanol can be preferably used.

If the concentration of the oxidized polysaccharide solution is less than 5% by weight, the effect of the hydrophilic coating is insignificant. If the concentration of the oxidized polysaccharide solution is more than 40% by weight, It is difficult to coat.

The concentration of the hydrophilic polymer solution is preferably 0.1 to 20% by weight, more preferably 1 to 10% by weight. If the concentration of the hydrophilic polymer solution is less than 0.1 wt%, the concentration is too low to impart a desired degree of lubricity to the surface of the catheter. If the concentration exceeds 20 wt%, the viscosity of the hydrophilic polymer solution becomes too high, A uniform coating can not be expected when coating the surface of the catheter, and when the catheter is inserted into the human body, too much body fluid is absorbed and swollen, which may cause tissue damage due to swelling of the human body conduit.

The pretreatment of the surface of the catheter may be performed by plasma, gamma ray, or the like before the coating process is performed through step IV). In order to induce more strong binding of the coating solution to the surface of the catheter, , An electron beam, ultraviolet radiation, or a radical initiator to form reactive functional groups or radicals on the catheter surface. After such pretreatment, the reactive functional groups or radicals formed on the surface of the catheter are chemically bonded to the aldehyde groups of the oxidized polysaccharide contained in the coating solution, thereby enhancing the binding force between the catheter surface and the coating solution.

Finally, the medical catheter comprising the oxidized polysaccharide and the hydrophilic polymer-containing coating layer according to the present invention is prepared by coating the coating solution on the surface of the pretreated catheter. However, it is preferable that the coating is performed by a dip coating method or a spray coating method considering the ease of the coating process and the uniformity of the coating.

The hydrophilic surface treatment process of the medical catheter made through steps I) through IV) may be applied not only to general catheters for blood vessels but also to various catheters inserted into the body such as catheters, percutaneous catheters, Catheters, catheters for intracranial pressure measurement, dura mater, subarachnoid and extensor plexus catheters, tube for trachea, drug delivery catheter, and intrauterine catheter.

Hereinafter, embodiments according to the present invention will be described in detail with reference to the accompanying drawings.

[Production Examples 1 to 3] Preparation of oxidized polysaccharide powders

An oxidizing reaction mixture was obtained by mixing an aqueous solution of an oxidizing agent and a polysaccharide (molecular weight 100,000) as shown in Table 1 below at 25 DEG C for 24 hours (weight ratio 2: 8) using a light shaking incubator. The oxidation reaction mixture was washed three times with ethanol, filtered and dried to prepare oxidized polysaccharide powders.

Manufacturing example Oxidant aqueous solution Polysaccharide aqueous solution Oxidation degree Production Example 1 5% by weight sodium periodate 20% by weight of alginic acid 20% Production Example 2 10% by weight sodium periodate 20% by weight of alginic acid 40% Production Example 3 20 wt% Sodium iodate 20% by weight of alginic acid 60%

[Production Examples 4 to 12] Preparation of hydrophilic coating solution

Alginic acid powders of 20%, 40% and 60% in oxidation degree obtained from Production Examples 1 to 3 were dissolved in acetone to obtain a 10% by weight oxidized polysaccharide solution. On the other hand, polyethylene glycol (PEG, molecular weight: 10,000) having an acrylate group at the terminal was dissolved in acetone to obtain a 5% by weight, 10% by weight and 15% by weight hydrophilic polymer solution. As shown in Table 2 below, a hydrophilic coating solution was prepared by mixing the obtained oxidized polysaccharide solution and a hydrophilic polymer solution (weight ratio 5: 5).

Manufacturing example Oxidized polysaccharide solution (oxidation degree) The hydrophilic polymer solution Production Example 4 10% by weight alginic acid solution (20%) A PEG solution having an acrylate at 5% by weight end Production Example 5 10% by weight alginic acid solution (20%) A PEG solution having an acrylate at the end of 10% by weight Production Example 6 10% by weight alginic acid solution (20%) A PEG solution having an acrylate at the end of 15% by weight Production Example 7 10% by weight alginic acid solution (40%) A PEG solution having an acrylate at 5% by weight end Production Example 8 10% by weight alginic acid solution (40%) A PEG solution having an acrylate at the end of 10% by weight Production Example 9 10% by weight alginic acid solution (40%) A PEG solution having an acrylate at the end of 15% by weight Production Example 10 10% by weight alginic acid solution (60%) A PEG solution having an acrylate at 5% by weight end Production Example 11 10% by weight alginic acid solution (60%) A PEG solution having an acrylate at the end of 10% by weight Production Example 12 10% by weight alginic acid solution (60%) A PEG solution having an acrylate at the end of 15% by weight

[ Example 1 to 9] Preparation of Medical Catheters Containing Oxidized Polysaccharide and Hydrophilic Polymer Containing Coating Layer

The coating solutions obtained in Preparation Examples 4 to 12 were dip-coated on the surface of a catheter pretreated with plasma to prepare a catheter comprising a coating layer composed of a mixture of oxidized polysaccharide and hydrophilic polymer.

FIG. 1 is a graph showing the lubricity of commercialized medical catheters prepared from Examples 2, 5 and 8 as comparison examples among the medical catheters including the coating layer of oxidized polysaccharide and hydrophilic polymer mixture prepared from Examples 1 to 9 of the present invention The results of measuring the trackability force of the catheter after drying the coated catheter according to Examples 2, 5 and 8 of the present invention at 25 ° C for 1 hour and inserting the catheter into the catheter, .

As shown in FIG. 1, the medical catheter comprising the coating layer of the oxidized polysaccharide and the hydrophilic polymer mixture prepared in Examples 2, 5 and 8 of the present invention has a higher effect on the insertion of the catheter into the tube than the commercialized medical catheter It is confirmed that the lubricity is significantly improved as compared with the conventional medical catheter.

In order to evaluate the effect of the molecular weight of the polysaccharide on the lubricity according to the present invention, a medical catheter comprising a coating layer of a mixture of oxidized polysaccharide and hydrophilic polymer prepared by varying the molecular weight of the polysaccharide according to Example 4 of the present invention The results of measurement of the trackability force when the catheter is inserted into the tube are shown in FIG.

As shown in FIG. 2, the higher the molecular weight of the polysaccharide, the higher the force applied when the catheter is inserted into the tube, and the lubricity is lowered.

In order to evaluate the effect of the degree of oxidation of the polysaccharide on the lubrication according to the present invention, the force exerted when inserting the catheter into the tube of the catheter manufactured in Examples 1, 4 and 7, The results of measurement of the trackability force are shown in FIG.

As shown in FIG. 3, the lower the degree of oxidation of the polysaccharide, the higher the force applied when the catheter was inserted into the tube, and the lower the lubricity, while the higher the degree of oxidation of the polysaccharide, the higher the lubricity.

In order to evaluate the influence of the concentration of the hydrophilic polymer solution on the lubrication according to the present invention, the force exerted when inserting the catheter into the tube of the catheter prepared in Examples 7 to 9, in which the concentration of the hydrophilic polymer solution was different The results of measurement of the trackability force are shown in FIG.

As shown in FIG. 4, the lower the concentration of the hydrophilic polymer solution, the higher the force applied when the catheter is inserted into the tube, and the lower the lubricity, while the higher the concentration of the hydrophilic polymer solution, the higher the lubricity.

Therefore, the medical catheter comprising the oxidized polysaccharide and the hydrophilic polymer-containing coating layer produced according to the present invention is excellent in biocompatibility and maintains the self-lubricating property of the surface of the catheter, so that the process of treating the pre-insertion lubricant in the human body conduit is not required, It is possible to apply the present invention to various medical ducts for insertion into a catheter including a catheter as well as a blood vessel.

Claims

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I) at least one oxidant aqueous solution selected from the group consisting of hydrogen peroxide, iron nitrate, ozone, peracetic acid, potassium permanganate, potassium peroxodisulfate, potassium peroxodisulfate, sodium periodate, sodium bromate, sodium perborate and sodium percarbonate Obtaining an oxidation reaction mixture by mixing an aqueous solution of polysaccharide and performing an oxidation reaction at 25 to 37 ° C for 1 to 96 hours in a light-blocked atmosphere;
II) washing the oxidation reaction mixture with ethanol for several times, filtering and drying to obtain a powdery oxidized polysaccharide;
III) mixing the oxidized polysaccharide solution in which the powdery oxidized polysaccharide is dissolved and the hydrophilic polymer solution to obtain a coating solution; And
IV) coating the coating solution on the surface of a catheter pretreated with plasma

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The composition of claim 6, wherein the polysaccharide is selected from the group consisting of carboxymethylcellulose, carboxyethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, dextrin, dextran, dextran sulfate, alginic acid, hyaluronic acid, chitin, chitosan, gellan gum, Wherein the at least one drug is at least one selected from the group consisting of beta-glucan, chondroitin sulfate, glycogen, starch, cellulose, regenerated cellulose, maltodextrin, fructan, galactan and mannan.

The method of manufacturing a medical catheter according to claim 6, wherein the oxidant aqueous solution has a concentration of 0.1 to 40% by weight.

7. The method of claim 6, wherein the polysaccharide aqueous solution has a concentration of 1 to 30% by weight.

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7. The method according to claim 6, wherein the oxidized polysaccharide solution has a concentration of 5 to 40% by weight.

[7] The method according to claim 6, wherein the hydrophilic polymer solution has a concentration of 0.1 to 20% by weight.

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7. The method of claim 6, wherein the coating is performed by a dip coating method or a spray coating method.