JP5669035B2 - Medical device having a lubricious surface - Google Patents

Description

Detailed Description of the Invention

The present invention provides a medical device having excellent durability and wet lubricity and biocompatibility and a method for producing the same, and a medical device such as a guide wire, a catheter, a blood filter, a blood extracorporeal circulation system, and an artificial lung. It is an invention useful for the functionalization of the surface.

In the medical field, a medical device such as a trachea, digestive tract, ureter, blood vessel, other body cavity, or a catheter inserted into a tissue, an introducer, and a guide wire inserted therein accesses a target site at the time of insertion. In order to improve operability and minimize tissue damage to the blood vessel inner wall and mucous membrane, a surface having lubricity is required. For this purpose, a hydrophilic polymer is coated on the surface of the substrate to improve the lubricity when wet.

Japanese Patent Application Laid-Open No. 59-081341 (Patent Document 1) describes a method in which an isocyanate group is formed on a material surface by pretreatment, and then a hydrophilic polymer is immobilized by covalent bonding to make the surface hydrophilic. Has been. In JP-A-58-193766 (Patent Document 2) and JP-A-58-193767 (Patent Document 3), polyethylene oxide or polyvinylpyrrolidone is used as a hydrophilic polymer, and surface hydrophilization by the above method is performed. Have been described.

On the other hand, Japanese Patent Application Laid-Open No. 60-259269 (Patent Document 4) describes a method of hydrophilizing the surface of a medical device by the same method as described above using a maleic anhydride copolymer. Further, JP 05-115541 A (Patent Document 5) and JP 07-047120 A (Patent Document 6) coat a blend solution of an anhydrous maleic copolymer and a silyl group-containing fluoropolymer. And a method for hydrophilization is described. In this method, the anhydrous maleic copolymer is firmly immobilized on the surface of the medical device by accelerating the condensation reaction due to the formation of a siloxane bond by hydrolysis of the silyl group. Therefore, when there is no reactive functional group such as isocyanate group or silyl group, the anhydrous maleic copolymer cannot be firmly fixed on the surface of the medical device. Yes.

Further, as a base material such as a guide wire, a metal material such as stainless steel or nickel / titanium alloy is preferably used. However, when a hydrophilic compound is directly coated on these metal substrates, there is a great problem that the hydrophilic compound easily peels off and falls off, and it has no practical value. Recently, in order to solve these problems, an adhesive organic compound having a functional group capable of chemisorbing to at least one metal in the molecule and at least one reactive functional group as a primer is used as a guide. Although a method of coating a hydrophilic polymer on the metal surface of the wire has been disclosed (Patent Document 7), even in these methods, the hydrophilic polymer is easily removed from the metal surface when stress is applied, such as lightly rubbing by hand. Actually, practical performance is not obtained at all because of peeling and desorption.

JP 59-081341 A JP 58-193766 JP 58-193767 A JP-A-60-259269 JP 05-115541 A Japanese Patent Laid-Open No. 07-047120 JP 2007-267757 A

An object of the present invention is to thinly coat a specific high-molecular primer resin with high safety without using a highly toxic compound such as an isocyanate monomer when immobilizing a hydrophilic polymer on a substrate surface of a medical device. It is an object of the present invention to provide a wet lubrication method having excellent durability from a simple and economical production method. In particular, when applied to a PTCA guide wire, it is extremely useful because it can provide excellent lubrication durability while ensuring the flexibility of the metal coil.

As a result of intensive studies, the present inventor has found that the above object can be achieved by the present invention described below, and has completed the present invention.

Surface when wet is a medical device having a lubricious, directly against the substrate surface made of a metallic material constituting the medical device, the primer resin satisfying the following conditions (1) to (4) is coated Further, the medical device characterized in that a hydrophilic polymer is coated on the primer resin (1) The primer resin comprises a polymer diol (a), a diisocyanate (b) and a low molecular compound (c ) , And the primer resin has one or more functional groups selected from an amino group and a hydroxyl group as a functional group having reactivity with the hydrophilic polymer in the molecule. to have (2) polymeric diol (a) is a polycarbonate diol having a molecular weight of at least 600 and / or polytetramethylene glycol
(3) The low molecular compound (c) is an alkoxysilane compound having two amino groups and an alkoxysilane compound having one amino group or an isocyanate group-containing alkoxysilane compound (d) and two reactive with isocyanate. It is a chain extender (e) having a molecular weight of 300 or less other than (d) having active hydrogen.
(4) The copolymerization ratio of the alkoxysilane compound (d) and the chain extender (e) is a molar ratio of d / e = 0.1 / 0.9 to 0.8 / 0.2.

The object of the present invention is to coat the primer resin of the present invention in the form of a thin film before coating the hydrophilic polymer on the surface of various substrates, particularly the surface of the metal material, and further to the hydrophilic polymer on the coating. It is an object of the present invention to provide a medical device that imparts excellent lubricity and water retention and also has high sliding durability and biocompatibility even in blood. The medical device according to the present invention has excellent water retention, low friction coefficient, excellent lubricity when wet, excellent operability in actual use, and product performance does not change over a long period of time. Therefore, it is possible to realize a medical device capable of maintaining lubricity and lubrication durability even under severe use conditions. Moreover, since a highly toxic compound such as an isocyanate monomer is not used, it is excellent in safety and reliability. In addition, the manufacturing process is simple and the economy is excellent. In particular, when applied to a PTCA guide wire, the thickness of the primer resin layer can be made very thin, so that excellent lubrication durability is imparted without impairing the flexibility of the metal coil. Can be extremely useful.

The present invention is characterized in that a specific primer resin is coated in the form of a thin film on the surface of various base materials constituting a medical device, and further, a hydrophilic polymer is chemically fixed and coated thereon. The present invention relates to a medical device having a lubricious surface. The primer resin in the present invention is a resin comprising a polymer diol, a diisocyanate, and a chain extender having an isocyanate-reactive active hydrogen, and the chain extender has a low molecular weight of 300 or less having at least two active hydrogens. A polyurethane urea resin or polyurethane resin obtained by copolymerizing a molecular compound and a silane compound having at least one active hydrogen, and in the molecule, any one or more selected from an amino group, a hydroxyl group, and an isocyanate group It has a functional group. Through these functional groups, the hydrophilic polymer is chemically bonded and immobilized with the primer resin, so that a medical device with very excellent lubrication durability can be obtained.

The polymer diol which is a constituent component of the primer resin includes polycarbonate diol having a molecular weight of 600 or more, polycarbonate ester diol, polycarbonate ether diol, polyether diol, polyester diol, polyester ether diol, polyolefin diol, or a mixture or copolymer thereof. The most preferred polymer diol from the viewpoint of lubrication durability, adhesion, and water resistance includes polycarbonate diol and polytetramethylene ether diol. Further, the number average molecular weight of the polymer diol is required to be 600 or more from the viewpoint of water resistance, flexibility, and lubrication durability, and more preferably 1000 to 5000. Above 5000, problems arise in quality stability, such as a decrease in solution stability.

The polycarbonate diol having a molecular weight of 600 or more used in the present invention can be produced from a diol component and a carbonate compound by a known method, that is, a transesterification reaction. As the diol, an aliphatic polycarbonate diol mainly composed of a diol having 5 or more carbon atoms is suitable. From the viewpoint of water resistance and lubrication durability, pentamethylenediol, neopentyl glycol, 3-methyl-1,5-pentanediol, hexamethylenediol, octamethylenediol, 2-ethylhexamethylenediol, nonamethylenediol, 2- More preferred is a polycarbonate diol mainly composed of a diol having 6 or more carbon atoms such as methyl octamethylene diol. When a polycarbonate diol comprising a diol having less than 5 carbon atoms is used, the water resistance, lubrication durability and flexibility are inferior. Here, as the carbonate compound used for the synthesis of the polycarbonate diol, diaryl carbonates such as dialkyl carbonate and diphenyl carbonate, alkylene carbonates and the like are preferably used.

Furthermore, polytetramethylene ether glycol is mentioned as polyether diol which can be used by this invention. Polyurethane urea resins using polytetramethylene ether glycol are excellent in hydrolysis resistance, but are inferior in lubrication durability and adhesion compared to polycarbonate diol-based polyurethane urea resins. Therefore, it is also possible to use a mixture of polyether diol, polycarbonate diol, polyester diol and the like.

Examples of the diisocyanate that is a constituent component of the primer resin include aliphatic diisocyanates, alicyclic diisocyanates, and aromatic diisocyanates. From the viewpoint of solubility in general-purpose solvents, aliphatic diisocyanates and alicyclic diisocyanates are used. More preferred. For example, hexamethylene diisocyanate, nonamethylene diisocyanate, isophorone diisocyanate, dicyclohexylmethane diisocyanate, hydrogenated xylylene diisocyanate, and the like are preferably used. As the aromatic diisocyanate, diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI) or the like is preferably used.

As the chain extender having a molecular weight of 300 or less and having two active hydrogens of the present invention, diamine, diol and the like are preferably used. As the diamine, aliphatic diamine and alicyclic diamine are preferable from the viewpoint of solvent solubility of the primer resin. Examples of the aliphatic diamine and alicyclic diamine used in the present invention include ethylene diamine, propylene diamine, hexamethylene diamine, nonamethylene diamine, isophorone diamine, dicyclohexyl methane diamine, hydrogenated xylylene diamine, and the like. A diamine having a number of 6 or more is preferable from the viewpoint of water resistance and lubrication durability. For these aliphatic diamines and alicyclic diamines, aromatic diamines can be used in combination as long as solvent solubility is not impaired. Examples of the diol include ethylene glycol, butanediol, hexanediol, nonamethylene glycol and the like, but are not limited thereto.

As the silane compound having an amino group (d), 3-aminopropyltrimethoxysilane, 3-aminopropyltriethoxysilane, and 3-phenyl-aminopropyltrimethoxysilane. As the silane compound having two amino groups, silane compounds having an amino group such as 3- (2-aminoethyl) aminopropyltrimethoxysilane, 3- (2-aminoethyl) aminopropylmethyldimethoxysilane, etc. Is mentioned.

In order to achieve the object of the present invention, a copolymerization ratio of the silane compound (d) having at least one amino group and a chain extender (e) having a molecular weight of 300 or less not containing these silane compounds (d). Is in a molar ratio of d / e = 0.1 / 0.8 to 0.8 / 0.2. When the d / e ratio is 0.1 or less, the effects of the present invention such as adhesion to metal, lubrication durability and lubricity are inferior, and conversely when it is 0.8 or more, the viscosity stability of the primer solution. In addition, the adhesiveness between the guide wires immediately after the coating process is large, and the coating process passability decreases.

In addition, as a method for making the terminal of the primer resin of the present invention an amino group or a hydroxyl group , it can be achieved by controlling the charged molar ratio of isocyanate resin, polymer diol, diamine, diol, etc., which are the components of the primer resin is there.

As the solvent used in the primer resin of the present invention, for example, solvents such as methyl ethyl ketone, acetone, isopropanol, methanol, ethanol, diacetone alcohol, ethyl acetate, toluene, xylene, water and the like are preferably used. In particular, it is preferable to use a mixture of these solvents from the viewpoint of solution viscosity stability.

As the hydrophilic polymer, a maleic anhydride copolymer compound, hyaluronic acid, polyethylene glycol, polyvinylpyrrolidone and the like can be used. In the present invention, a maleic anhydride copolymer compound is particularly preferably used. In particular, the maleic anhydride copolymer compound has high reactivity with the primer resin of the present invention and is chemically fixed, and thus has excellent overall performance such as lubrication durability and lubricity.

Moreover, in this invention, when the base-material surface which comprises medical devices, such as a guide wire, is a metal material, the improvement effect using the primer resin of this invention becomes more remarkable. In particular, when the technique of the present invention is applied to a PTCA guide wire having a metal coil spring portion, excellent lubricity and lubrication durability can be imparted without impairing the flexibility of the coil portion. Moreover, even when the guide wire of the present invention is bent at the tip portion or the like, the coating resin layer is not peeled off or broken, and is excellent in formability. Examples of the metal material used for the guide wire include Ni / Ti alloys, stainless steel, Cu / Zn / Al alloys, Cu / Al / Ni alloys, platinum, platinum alloys, gold, and tungsten. It is not limited to.

In the present invention, when a maleic anhydride copolymer compound is used, lubrication durability and water retention are further improved by blending an appropriate amount of a crosslinking agent. The blending ratio of the crosslinking agent is a weight ratio in the range of 0.01 to 1.0 part of the crosslinking agent with respect to 100 parts of the maleic anhydride copolymer compound, and a preferable range is 0.02 to 0.3 part. Outside this range, the lubricity and lubrication durability are rather inferior.

Conventionally adopted methods such as a method in which a maleic anhydride copolymer compound and a cross-linking agent are mixed in the above-mentioned composition, and a method of immersing in this solution, a method of applying a solution, a method of spraying a solution, etc. Can be used. As the solvent used in the coating solution, a general-purpose organic solvent such as a ketone solvent such as acetone or methyl ethyl ketone, an alcohol solvent such as methanol, ethanol or isopropanol, tetrahydrofuran or a mixed solvent thereof can be used. A coating solution is prepared by dissolving in these solvents at a concentration of 0.3 to 8% by weight, preferably 0.5 to 5% by weight.

After being immersed in the above coating solution, it is dried and subsequently subjected to heat treatment at a temperature of 60 to 120 ° C. for 10 to 300 minutes. By this treatment, the maleic anhydride copolymer compound chemically reacts with the polyurethane urea resin and is firmly fixed, and a crosslinked structure is introduced to further improve the lubrication durability.

Furthermore, by dipping in an alkaline solution and converting the carboxyl group of the maleic anhydride copolymer compound to an alkali salt, it is possible to produce a medical device having excellent lubricity and lubrication durability. As the alkali used for the alkali treatment, any alkali that can achieve the purpose of converting the carboxyl group into an alkali salt can be used. From the viewpoint of lubrication durability, sodium hydroxide, potassium hydroxide, carbonate An aqueous solution of sodium is preferred. Moreover, it is preferable to thoroughly remove the alkali by thoroughly washing with water, physiological saline or the like after the alkali treatment.

Specific examples and comparative examples according to the present invention will be described in more detail below, but the present invention is not limited to the following examples.
(Synthesis of amino group-terminated silane-modified polyurethane urea resin solution A)

A 500 cc three-necked flask was charged with 0.02 mol (40 g) of polycarbonate diol (Nippola 980R) having a molecular weight of 2000 and 0.08 mol (17.76 g) of isophorone diisocyanate, and reacted at 110 ° C. for 3 hours with stirring. Thereafter, the mixture was cooled to 50 ° C., and 176 g of dehydrated methyl ethyl ketone was added to obtain a uniform solution (prepolymer solution). On the other hand, 0.01 mol (2.064 g) of 3- (2-aminoethyl) aminopropylmethyldimethoxysilane and 0.01 mol (1.79 g) of 3-aminopropyltrimethoxysilane were dissolved in 43 g of dehydrated isoflopanol. The resulting solution was added to the above prepolymer solution with stirring. After stirring for 3 minutes, a solution in which 0.049 mol (8.33 g) of isophoronediamine was dissolved in 36 g of dehydrated isopropanol was further added, and the reaction was continued for 20 minutes. A polyurethane urea resin solution A having an amino group at the molecular end thus obtained was obtained.
(Synthesis of hydroxyl-terminated silane-modified polyurethane urea resin B)

A 500 cc three-necked flask was charged with 0.02 mol (40 g) of polycarbonate diol (Nipola 982R) having a molecular weight of 2000 and 0.08 mol (17.76 g) of isophorone diisocyanate and allowed to react at 110 ° C. for 3 hours with stirring. Thereafter, the mixture was cooled to 50 ° C. and 150 g of methyl ethyl ketone was added to obtain a uniform solution (prepolymer solution). On the other hand, 0.023 mol (5.16 g) of isophoronediamine, 0.025 mol (2.064 g) of 3- (2-aminoethyl) aminopropylmethyldimethoxysilane, 0.016 mol (1.666 g) of aminoethylaminoethanol Was dissolved in 70 g of isopropanol to obtain a homogeneous solution, and this solution was added to the prepolymer solution with stirring to perform polymerization, to obtain a polyurethane urea resin solution B having a terminal hydroxyl group.

A SUS304 wire having a diameter of 0.4 mm and a length of 20 cm was ultrasonically cleaned in acetone and dried. The wire was immersed in a solution obtained by diluting the polyurethane urea solution B to 12%, pulled up at a rate of 3 cm / sec, left at room temperature for 10 minutes, and then dried at 110 ° C. for 60 minutes. Further, the wire treated with this polyurethane urea resin was immersed in a 2.0% solution of methyl vinyl ether maleic anhydride copolymer compound <GANTREZ-AN-169 manufactured by IPS>, pulled up at a rate of 3 cm / second, and air-dried. Then, drying was performed at 110 ° C. for 60 minutes to fix the lubricant to the surface. Then, it was immersed in an aqueous solution of 1 / 10N sodium hydroxide and treated at room temperature for 30 minutes. Further, it was thoroughly washed with water and dried at 60 ° C. for 30 minutes. The wire obtained by the above method showed excellent lubricity in water. In addition, the number of times that the wire was handled by hand in the water was measured until the lubricity disappeared, but the lubricity was maintained up to 5000 times and the lubrication durability was very excellent. confirmed. As described above, the film thickness of the primer resin layer was as thin as 7 microns, but the lubrication durability was very good. Further, the primer resin of the present invention was very strongly adhered to the SUS wire, and even when the primer resin was rubbed strongly with a nail, the primer resin was not peeled off.

A 10 cm SUS304 coil spring (coil wire 0.07 mm, inner diameter 0.2 mm, outer diameter 0.34 mm) was ultrasonically washed in acetone and dried. The coil spring was immersed in a 6% solution of the above polyurethane urea solution A, then pulled up at a speed of 3 cm / sec, left at room temperature for 10 minutes, and then dried at 120 ° C. for 60 minutes. Further, the wire treated with this polyurethane urea resin was immersed in a 2.0% solution of methyl vinyl ether maleic anhydride copolymer compound <GANTREZ-AN-169 manufactured by IPS>, pulled up at a rate of 3 cm / second, and air-dried. Then, drying was performed at 120 ° C. for 60 minutes to fix the lubricant on the surface. Then, it was immersed in an aqueous solution of 1 / 10N sodium hydroxide and treated at room temperature for 30 minutes. Further, it was thoroughly washed with water and dried at 60 ° C. for 30 minutes. The wire obtained by the above method showed excellent lubricity in water. In addition, the number of times that the wire was handled by hand in water was measured, but the lubricity was maintained up to 1000 times, and the lubrication durability was very excellent. confirmed. Thus, the film thickness of the primer resin layer is about 3 microns, which is very thin as compared with the conventional guide wire, but the lubrication durability was very good. Moreover, the coil spring was flexible and had good bending properties.

The medical device according to the present invention has excellent water retention, low coefficient of friction, excellent lubricity when wet, excellent operability during actual use, and product performance does not change over a long period of time. A medical device capable of maintaining lubricity and lubrication durability even under various use conditions can be realized. Moreover, since a highly toxic compound such as an isocyanate monomer is not used, it is excellent in safety and reliability. In addition, the manufacturing process is simple and the economy is excellent. Furthermore, when applied to a guide wire for PTCA, it is extremely useful because it can provide excellent lubrication durability without impairing the flexibility of the metal coil. As described above, the coating technique according to the present invention can be expected to have a wide range of applications including development to medical devices having new functions.

Claims (1)

Surface when wet is a medical device having a lubricious, directly against the substrate surface made of a metallic material constituting the medical device, the primer resin satisfying the following conditions (1) to (4) is coated Further, the medical device characterized in that a hydrophilic polymer is coated on the primer resin (1) The primer resin comprises a polymer diol (a), a diisocyanate (b) and a low molecular compound (c ) , And the primer resin has one or more functional groups selected from an amino group and a hydroxyl group as a functional group having reactivity with the hydrophilic polymer in the molecule. to have (2) polymeric diol (a) is a polycarbonate diol having a molecular weight of at least 600 and / or polytetramethylene glycol (3) low molecular The compound (c) has two active hydrogens reactive with an isocyanate and an alkoxysilane compound having two amino groups and an alkoxysilane compound having one amino group or an isocyanate group-containing alkoxysilane compound (d) ( a chain extender (e) having a molecular weight of 300 or less other than d)
(4) The copolymerization ratio of the alkoxysilane compound (d) and the chain extender (e) is a molar ratio of d / e = 0.1 / 0.9 to 0.8 / 0.2.