Medical devices and methods for manufacturing the same

Abstract

To provide a medical appliance that can exhibit antibacterial properties for a relatively long period of time.SOLUTION: A medical appliance (10) includes a substrate (1), an intermediate layer (2) formed on the surface of the substrate, and a surface layer (3) disposed on the surface of the intermediate layer that is remote from the substrate. The intermediate layer includes antibacterial metal fine particles, and silane coupling agent-derived compounds. The surface layer includes hydrophilic polymers. Preferably, the intermediate layer should be formed solely from the antibacterial metal fine particles and the silane coupling agent-derived compounds.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a medical instrument having a coating with hydrophilic and antibacterial properties and a method for manufacturing the same.

Background Art

[0002] Conventionally, a coating has been applied to the surface of a catheter inserted into a blood vessel, digestive organ, urinary organ, etc. to impart hydrophilicity and antibacterial properties. For example, on the surface of a urethral catheter inserted into the urethra, a surface layer that swells with water and becomes slippery is formed, making it easier to insert into the urethra. However, since some damage may occur to the urethra when inserting the urethral catheter, it is important to impart not only hydrophilicity but also antibacterial properties.

[0003] Patent Document 1 discloses a method of forming an antibacterial layer by pretreating the surface of a catheter substrate with chromic acid, immersing it in an aqueous solution containing a tin ion-containing salt, then immersing it in an aqueous solution containing a silver-containing salt, and further immersing it in a stabilizing solution containing salts of platinum and gold in dilute acid, and drying. In the same document, a method of subsequently forming a hydrophilic surface layer composed of PVP and a polyurea network on the surface of the antibacterial layer to form a coating having a two-layer structure is also disclosed.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] In the medical device described in Patent Document 1, trace amounts of active metal ions, such as silver, contained in the antibacterial layer permeate the hydrophilic surface layer and leach out, thereby exhibiting antibacterial properties. Since the amount of trace active metal contained in the antibacterial layer is limited, if the leaching rate is fast, the antibacterial effect will be transient and cannot be maintained over a long period. In the experiment described in Patent Document 1, the amount of silver leached out after a maximum of 300 seconds was measured, but since urethral catheters can be left in the urethra for several days to several weeks, a transient antibacterial effect is insufficient.

[0006] This invention provides a medical device capable of exhibiting antibacterial properties for a relatively long period of time, and a method for manufacturing the same. [Means for solving the problem]

[0007] [1] A medical device comprising a substrate, an intermediate layer formed on the surface of the substrate, and a surface layer laminated on the surface of the intermediate layer opposite to the substrate, wherein the intermediate layer contains antimicrobial metal nanoparticles and a compound derived from a silane coupling agent, and the surface layer contains a hydrophilic polymer. [2] The medical device according to [1], wherein the intermediate layer is formed solely of the antimicrobial metal nanoparticles and the compound derived from the silane coupling agent. [3] The medical device according to [1] or [2], wherein the compound derived from the silane coupling agent forms a chemical bond with the functional group of the surface layer. [4] A medical device according to any one of [1] to [3], wherein the compound derived from the silane coupling agent forms a chemical bond with the functional group on the surface of the substrate. [5] The medical device according to any one of [1] to [4], wherein the antibacterial metal microparticles include at least silver particles. [6] A medical device according to any one of items [1] to [5], wherein the substrate is made of silicone rubber. [7] The medical device is a urethral catheter, or any one of the medical devices described in [1] to [6]. [8] A method for manufacturing a medical device, comprising the steps of: applying a solution containing antimicrobial metal nanoparticles and a silane coupling agent to the surface of a substrate, causing a chemical bond to be formed between a first functional group of the silane coupling agent and a functional group on the surface of the substrate, thereby bonding a compound derived from the silane coupling agent to the surface of the substrate and forming an intermediate layer containing the antimicrobial metal nanoparticles; and applying a solution containing an isocyanate compound, a polyol, and a hydrophilic polymer to the surface of the intermediate layer, causing a bond to be formed between the isocyanate compound or the polyol and a second functional group of a compound derived from the silane coupling agent constituting the intermediate layer, thereby forming a surface layer having a three-dimensional crosslinked network containing the hydrophilic polymer. [9] The method for manufacturing a medical device according to [8], wherein the first functional group of the silane coupling agent is an alkoxy group or a hydroxyl group obtained by hydrolysis of an alkoxy group, and the second functional group is an isocyanate group. [Effects of the Invention]

[0008] The antibacterial layer of the medical device of the present invention can continue to exhibit antibacterial properties by leaching ions of antibacterial metal nanoparticles for at least several days. Furthermore, the surface layer of the medical device of the present invention exhibits high adhesion to the antibacterial layer and can demonstrate strength that prevents it from easily peeling off even when rubbed in water. [Brief explanation of the drawing]

[0009] [Figure 1] This is a cross-sectional view of a catheter, which is an example of a medical device according to the present invention. [Figure 2] This shows the test results for the antibacterial activity of the catheters prepared in the example against E. coli. [Figure 3] This shows the test results for the antibacterial activity of the catheters prepared in the example against Pseudomonas aeruginosa. [Figure 4] This shows the test results for the antibacterial activity of the catheters prepared in the example against enterococci. [Figure 5] This shows the measurement results of the amount of silver ions eluted from the catheters prepared in the example. [Modes for carrying out the invention]

[0010] Medical devices A first aspect of the present invention is a medical device comprising a substrate, an intermediate layer formed on the surface of the substrate, and a surface layer laminated on the surface of the intermediate layer opposite to the substrate, wherein the intermediate layer contains antimicrobial metal nanoparticles and a compound derived from a silane coupling agent, and the surface layer contains a hydrophilic polymer.

[0011] As an example of this embodiment, the case of a catheter will be described below. The catheter 10 illustrated in Figure 1 has a catheter base 1 which is a silicone rubber tube, an intermediate layer 2 formed on the outer surface 1a of the catheter base 1, and a surface layer 3 formed on the outer surface 2a of the intermediate layer 2.

[0012] Intermediate layer 2 contains antibacterial metal nanoparticles and a compound derived from a silane coupling agent. The silane coupling agent is the material used to form intermediate layer 2. Since the silane coupling agent has highly reactive functional groups, it usually reacts with the functional groups on at least one of the surfaces of the catheter substrate 1 and the surface layer 3 that are in contact with intermediate layer 2. In this embodiment, the substance after this reaction (reaction product) is referred to as the compound derived from the silane coupling agent.

[0013] Antimicrobial metal nanoparticles can be any nanoparticles that generate metal ions known to have antimicrobial properties, such as silver, silver salts, gold, zinc, copper, and cerium. These metals may be oxidized or form compounds with other elements (e.g., silver compounds, copper compounds) as long as they exhibit antimicrobial properties. The antimicrobial metal nanoparticles may consist of only one type of metal, or two or more types may be combined in any way.

[0014] The primary particle diameter of the antibacterial metal fine particles is preferably 1 to 100 nm, more preferably 1 to 50 nm, and even more preferably 1 to 30 nm. When within the above range, the leaching of metal ions from the intermediate layer does not end transiently, and can continue gently over several tens of days. The primary particle diameter of the antibacterial metal fine particles is taken as the average value obtained by measuring the major diameters of 10 or more antibacterial metal fine particles contained in the intermediate layer using an electron microscope (SEM or TEM).

[0015] Since the intermediate layer 2 contains a compound derived from a silane coupling agent, the leaching of metal ions from the antibacterial metal fine particles continues gently. As for this mechanism, it is considered that the compound derived from the silane coupling agent is bonded to the catheter substrate 1 or the surface layer 3 and is in an anchored state, so the diffusion and movement of metal ions from the antibacterial metal fine particles in the intermediate layer 2 are reduced within the intermediate layer 2.

[0016] Since the intermediate layer 2 can gently leach metal ions from the antibacterial metal fine particles, the intermediate layer 2 does not need to contain a large amount of antibacterial metal fine particles. Assuming that the leaching amount is constant per unit time, if the intermediate layer 2 contains a large amount of antibacterial metal fine particles, it is theoretically possible to extend the leachable period. However, the intermediate layer 2 containing a large amount of antibacterial metal fine particles is likely to peel off from the outer peripheral surface 1a of the catheter substrate 1, and since the light is blocked by the metal particles, it becomes difficult to visually recognize the liquid or the like flowing through the flow path 1b of the catheter substrate 1. Also, there is a problem of discoloration such as yellowing due to oxidation of the metal particles or the like.

[0017] The content of the antibacterial metal fine particles contained in the intermediate layer 2 is preferably 0.1 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, and even more preferably 1.0 to 10 parts by mass with respect to 100 parts by mass of the content of the compound derived from the silane coupling agent contained in the intermediate layer 2. Within the above range, metal ions can be continuously and gently leached from the antibacterial metal fine particles over a period of dozens of days, the flow path 1b of the catheter substrate 1 can be visually inspected through the intermediate layer 2, and the appearance defect due to the discoloration of the metal can be made inconspicuous.

[0018] Examples of one or more silane coupling agents that form the intermediate layer 2 include vinyltrimethoxysilane, vinyltriethoxysilane, 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane, 3-glycidoxypropylmethyldimethoxysilane, 3-glycidoxypropyltrimethoxysilane, 3-glycidoxypropylmethyldiethoxysilane, 3-glycidoxypropyltriethoxysilane, p-styryltrimethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxypropyltrimethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, 3-acryloxypropyltrimethoxy Examples include sisilane, N-2-(aminoethyl)-3-aminopropylmethyldimethoxysilane, N-2-(aminoethyl)-3-aminopropyltrimethoxysilane, 3-aminopropyltrimethoxysilane, 3-aminopropyltriethoxysilane, 3-triethoxysilyl-N-(1,3-dimethylbutylidene)propylamine, N-phenyl-3-aminopropyltrimethoxysilane, hydrochloride of N-(vinylbenzyl)-2-aminoethyl-3-aminopropyltrimethoxysilane, 3-ureidopropyltrialkoxysilane, 3-mercaptopropylmethyldimethoxysilane, 3-mercaptopropyltrimethoxysilane, and 3-isocyanatetopropyltriethoxysilane. Among these, N-2-(aminoethyl)-3-aminopropylmethyldimethoxysilane, N-2-(aminoethyl)-3-aminopropyltrimethoxysilane, 3-aminopropyltrimethoxysilane, 3-aminopropyltriethoxysilane, 3-triethoxysilyl-N-(1,3-dimethylbutylidene)propylamine, N-phenyl-3-aminopropyltrimethoxysilane, hydrochloride salt of N-(vinylbenzyl)-2-aminoethyl-3-aminopropyltrimethoxysilane, and 3-isocyanatetopropyltriethoxysilane are particularly preferred. Among these, silane coupling agents having alkoxy groups and isocyanate groups that form active hydrogen groups are preferred. Active hydrogen groups such as hydroxyl groups formed by hydrolysis of the alkoxy groups of the silane coupling agent can form chemical bonds by dehydration condensation with hydroxyl groups present on the outer surface 1a of the catheter substrate 1, for example. In addition, isocyanate groups and amino groups of the silane coupling agent can form chemical bonds by reacting with functional groups of isocyanate compounds, polyols, or hydrophilic polymers constituting the surface layer 3, for example. In other words, the silane coupling agent constituting the intermediate layer 2 can chemically crosslink the catheter substrate 1 and the surface layer 3. By forming the above chemical bonds, the adhesion between the intermediate layer 2 and the catheter base 1, as well as the adhesion between the intermediate layer 2 and the surface layer 3, can be significantly improved.

[0019] The dry thickness of the intermediate layer 2 is preferably 0.05 to 5.0 μm, more preferably 0.05 to 1.0 μm, and even more preferably 0.05 to 0.5 μm. If the value is above the lower limit of the above range, it can contain a sufficient amount of antibacterial metal nanoparticles, which can continue to leach out and exhibit antibacterial properties over a relatively long period of time. If the value is below the upper limit of the above range, the strength of the intermediate layer 2 is improved, and the adhesion between the catheter base 1 and the surface layer 3 with the intermediate layer 2 in between can be further enhanced. In addition, the transparency of the intermediate layer 2 is increased, making it easier to visualize the inside of the channel 1b of the catheter 1. The thickness of the intermediate layer 2 is determined by observing the cross-section in the thickness direction using a magnifying observation method such as an electron microscope, and taking the average value measured at five representative arbitrary locations.

[0020] From the viewpoint of facilitating the control of the degree of metal ion leaching from antimicrobial metal nanoparticles in the intermediate layer 2, it is preferable that the intermediate layer 2 is formed solely from the antimicrobial metal nanoparticles and compounds derived from the silane coupling agent.

[0021] Examples of hydrophilic polymers included in the surface layer 3 include polyvinyl compounds, poly(vinyl alcohol), polyvinylpyrrolidone (PVP), heparin, dextran, xanthan gum, polysaccharides, derivatized polysaccharides, cellulose, hydroxypropylcellulose, methylcellulose, polyurethane, polyacrylate, polyhydroxyacrylate, polymethacrylate, polyacrylamide, polyalkylene oxide, polyethylene oxide, polyvinyl alcohol, polyamide, polyacrylic acid, copolymers of the above polymers, copolymers of vinyl compounds and acrylates or anhydrides, and vinylpyrrolidone and hydroxy Examples include copolymers with ethyl methyl acrylate, cationic copolymers of polyvinylpyrrolidone, copolymers of polymethyl vinyl ether and maleic anhydride, polyethylene oxide (PEO), polyethylene glycol (PEG), hyaluronic acid and its salts and derivatives, sodium alginate, chondroitin sulfate, chitin, chitosan, agarose, xanthan gum, dermatan sulfate, keratin sulfate, emilzan, gellan, curdlan, amylose, carrageenan, amylopectin, dextran, glycogen, starch, heparin sulfate, and limit dextrin and their fragments, as well as synthetic hydrophilic polymers. The most preferred hydrophilic polymer is polyvinylpyrrolidone (PVP).

[0022] The surface layer 3 preferably has a three-dimensional crosslinked network capable of holding a hydrophilic polymer. A three-dimensional crosslinked network refers to a structure that maintains the thickness of the surface layer and has a crosslinked structure throughout the entire surface layer. It is preferable that at least a part of the three-dimensional crosslinked network has a polyurethane or polyurea network. The polyurethane or polyurea network can be formed, for example, by reacting a polyfunctional isocyanate compound with a polyfunctional compound having hydroxyl or amino groups. Some of the isocyanate groups of the isocyanate compound forming the polyurethane or polyurea network can react with the functional groups of the silane coupling agent constituting the intermediate layer 2 to form chemical bonds.

[0023] The content of the hydrophilic polymer relative to the total mass of the surface layer 3 when dry is preferably 50 to 95% by mass, more preferably 70 to 95% by mass, and even more preferably 85 to 95% by mass. Here, the remainder is preferably a polyurethane or polyurea network. If the value is above the lower limit of the above range, good hydrophilicity is obtained, and the smoothness when swollen with water is further improved. If the value is below the upper limit of the above range, the content of the polyurethane or polyurea network increases relatively, and as a result, metal ions from antimicrobial metal microparticles contained in the intermediate layer 2 can more easily permeate the surface layer 3.

[0024] The thickness of the surface layer 3 when dry is preferably 5 μm or less, and more preferably 2 μm or less. The lower limit of the thickness is not particularly limited, for example, 0.5 μm. When the value is above the lower limit of the above range, sufficient hydrophilicity can be obtained, and the leaching of metal ions from antibacterial metal nanoparticles can be moderated, allowing the leaching to continue for a relatively long period of time and exhibiting antibacterial properties. If the value is below the upper limit of the above range, it is possible to prevent a drastic decrease in the leaching of metal ions from antibacterial metal nanoparticles, and sufficient antibacterial activity can be achieved. The thickness of the surface layer 3 is determined by observing the cross-section in the thickness direction using a magnifying observation method such as an electron microscope, and taking the average value measured at five representative arbitrary locations.

[0025] The constituent material of the catheter base 1 is not particularly limited, and known materials can be used, such as silicone rubber, latex rubber, thermoplastic elastomer, other rubbers, polyurethane, polyvinyl chloride, polyacrylate, polyolefin, other vinyl polymers, polyester, polyamide, styrene block copolymer (SBS), polyether block amide (PEBA), etc.

[0026] The outer surface 1a of the catheter base 1 that is in contact with the intermediate layer 2 may be subjected to known surface treatments such as corona treatment, low-pressure mercury UV irradiation, excimer UV irradiation, or plasma treatment, for the purpose of forming active hydrogen groups such as hydroxyl groups.

[0027] The above describes the case in which the catheter surface is provided with an intermediate layer and a surface layer, but the present invention can be applied to medical devices in general other than catheters. Other medical devices include endoscopes and laryngoscopes, tubes for nutritional support or drainage or intratracheal use, contraceptives, wound dressings, contact lenses, implantates, extracorporeal blood conduits, membranes (e.g., translucency membranes), blood filters, circulatory support devices, and the like. The constituent material of the substrate in this embodiment is not limited to resin molded products, but may be a metal such as SUS.

[0028] ≪Methods for manufacturing medical devices≫ A second aspect of the present invention is a method for manufacturing a medical device, comprising at least one of the following steps. This aspect allows for the easy manufacture of the medical device according to the first aspect. One example of this embodiment includes a surface treatment step, an intermediate layer formation step, and a surface layer formation step.

[0029] The surface treatment step involves performing a surface treatment to form hydroxyl groups on the surface of the substrate. The surface treatment method can be any known method depending on the substrate material. For example, if the substrate material is silicone rubber, excimer UV irradiation is preferred. Forming hydroxyl groups on the substrate surface increases the wettability of the intermediate layer formation solution in the next step, facilitating the formation of the intermediate layer. Furthermore, the hydroxyl groups on the substrate surface can react with the silane coupling agent contained in the intermediate layer formation solution.

[0030] The intermediate layer formation step involves applying a solution containing antibacterial metal nanoparticles and a silane coupling agent (hereinafter sometimes referred to as solution A) to the surface of the substrate, and chemically bonding the first functional group of the silane coupling agent (for example, a hydroxyl group formed from an alkoxy group) with the functional group on the surface of the substrate, thereby bonding the compound derived from the silane coupling agent to the surface of the substrate and forming an intermediate layer containing the antibacterial metal nanoparticles. The descriptions of the antibacterial metal nanoparticles and silane coupling agent are the same as in the first embodiment, so redundant explanations are omitted here.

[0031] Solution A preferably contains a dispersion medium capable of dispersing antibacterial metal nanoparticles and a silane coupling agent. The dispersion medium can be appropriately selected based on its good wettability to the substrate surface to be coated; for example, a non-polar solvent such as toluene is suitable.

[0032] The amount of antibacterial metal particles contained in solution A is preferably 50 to 5000 ppm, more preferably 100 to 3000 ppm, and even more preferably 500 to 3000 ppm, relative to the total mass of solution A. Within the above preferred range, it is easy to form an intermediate layer of the aforementioned preferred thickness, and it is easy to form an intermediate layer that can leach antibacterial metal nanoparticles over a relatively long period of time.

[0033] The amount of silane coupling agent contained in solution A is preferably 0.5 to 10% by mass, more preferably 1.0 to 7.0% by mass, and even more preferably 2.0 to 4.0% by mass, relative to the total mass of solution A. Within the above preferred range, it is easy to form an intermediate layer of the aforementioned preferred thickness, and it is easy to form an intermediate layer that can leach metal ions from antibacterial metal nanoparticles over a relatively long period of time.

[0034] In the intermediate layer formation process, the method of applying solution A to the substrate is not particularly limited, and known methods can be applied. The substrate may be immersed in solution A, applied with a coater, or sprayed with an air spray.

[0035] After coating the substrate with solution A, a reaction time may be allowed for the functional groups on the substrate surface to react with the silane coupling agent.

[0036] By applying solution A to a substrate, allowing sufficient reaction time as needed, removing the solvent from solution A from the surface of substrate A, and drying it, an intermediate layer containing antibacterial metal nanoparticles and compounds derived from a silane coupling agent can be formed on the substrate surface. There are no particular restrictions on the drying method; it can be air-dried, air-dried with warm air, or placed in a high-temperature drying room.

[0037] The surface layer formation step involves applying a solution (hereinafter sometimes referred to as Solution B) containing an isocyanate compound, a polyol, and a hydrophilic polymer to the surface of the intermediate layer formed in the preceding step. This solution reacts and bonds these components with the second functional groups (e.g., isocyanate groups, amino groups, etc.) of the compounds derived from the silane coupling agent constituting the intermediate layer, thereby forming a surface layer having a three-dimensional crosslinked network containing the hydrophilic polymer. Specifically, for example, it can be formed by applying solution B containing a polyol, polyisocyanate, hydrophilic polymer, and organic solvent, followed by crosslinking and drying. The resulting surface layer will contain a hydrophilic polymer and a three-dimensional crosslinked network (e.g., a crosslinked polyurethane mesh). With such a structure, the surface of the surface layer can maintain lubricity over a long period of time.

[0038] The explanation of hydrophilic polymers is the same as in the first embodiment, so redundant explanations are omitted here.

[0039] The one or more isocyanate compounds contained in solution B are preferably polyisocyanates containing at least two unreacted isocyanate groups per molecule, such as polyisocyanate monomers and polyisocyanate derivatives. Examples of polyisocyanate monomers include aromatic polyisocyanates, aromatic aliphatic polyisocyanates, aliphatic polyisocyanates, and alicyclic polyisocyanates. Examples of aromatic polyisocyanates include aromatic diisocyanates such as tolylene diisocyanate (2,4- or 2,6-tolylene diisocyanate or a mixture thereof) (TDI), phenylene diisocyanate (m-, p-phenylene diisocyanate or a mixture thereof), 4,4'-diphenyl diisocyanate, 1,5-naphthalene diisocyanate (NDI), diphenylmethane diisocyanate (4,4'-, 2,4'- or 2,2'-diphenylmethane diisocyanate or a mixture thereof) (MDI), 4,4'-toluidine diisocyanate (TODI), and 4,4'-diphenyl ether diisocyanate. Examples of aromatic aliphatic polyisocyanates include xylylene diisocyanate (1,3- or 1,4-xylylene diisocyanate or a mixture thereof) (XDI), tetramethylxylylene diisocyanate (1,3- or 1,4-tetramethylxylylene diisocyanate or a mixture thereof) (TMXDI), and aromatic aliphatic diisocyanates such as ω,ω'-diisocyanate-1,4-diethylbenzene. Examples of aliphatic isocyanate compounds include hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), lysine diisocyanate, norbornene diisocyanate methyl (NBDI), xylylene diisocyanate (XDI), and tetramethyl xylylene diisocyanate (TMXDI). Furthermore, examples of alicyclic isocyanates include transcyclohexane-1,4-diisocyanate, isophorone diisocyanate (IPDI), H6XDI (hydrogenated XDI), H12MDI (hydrogenated MDI), and 4,4'-dicyclohexylmethane diisocyanate. Examples of alicyclic polyisocyanates include 1,3-cyclopentane diisocyanate, 1,3-cyclopentene diisocyanate, cyclohexane diisocyanate (1,4-cyclohexane diisocyanate, 1,3-cyclohexane diisocyanate), 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (isophorone diisocyanate) (IPDI), methylenebis(cyclohexyl isocyanate) (4,4'-, 2,4'- or 2,2'-methylenebis(cyclohexyl isocyanate, their trans,trans-, trans,Cis-, Cis,Cis-, or mixtures thereof)) (H 12 Examples of alicyclic diisocyanates include MDI, methylcyclohexane diisocyanate (methyl-2,4-cyclohexane diisocyanate, methyl-2,6-cyclohexane diisocyanate), norbornane diisocyanate (various isomers or mixtures thereof) (NBDI), and bis(isocyanatomethyl)cyclohexane (1,3- or 1,4-bis(isocyanatomethyl)cyclohexane or mixtures thereof) (H6XDI). These polyisocyanate monomers can be used individually or in combination of two or more types. Examples of polyisocyanate derivatives include polymers of the polyisocyanate monomers mentioned above (e.g., dimers, trimers (e.g., isocyanurate modified, iminooxadiazinedione modified), pentamers, heptamers, etc.), allophanate modified forms (e.g., allophanate modified forms produced by the reaction of the polyisocyanate monomers mentioned above with low molecular weight polyols described later), polyol modified forms (e.g., polyol modified forms (alcohol adducts) produced by the reaction of polyisocyanate monomers with low molecular weight polyols described later), biuret modified forms (e.g., Examples include biuret-modified compounds (e.g., those produced by the reaction of the above-mentioned polyisocyanate monomer with water or amines), urea-modified compounds (e.g., urea-modified compounds produced by the reaction of the above-mentioned polyisocyanate monomer with diamines), oxadiazinetrione-modified compounds (e.g., oxadiazinetriones produced by the reaction of the above-mentioned polyisocyanate monomer with carbon dioxide), carbodiimide-modified compounds (e.g., carbodiimide-modified compounds produced by the decarboxylation condensation reaction of the above-mentioned polyisocyanate monomer), uretdione-modified compounds, and uretonimine-modified compounds. Furthermore, polyisocyanate derivatives such as polymethylene polyphenyl polyisocyanate (crude MDI, polymeric MDI) can also be mentioned. These polyisocyanate derivatives can be used individually or in combination of two or more. Furthermore, the polyisocyanate compounds can be used individually or in combination of two or more. In addition, the polyisocyanates used in this invention may be blocked polyisocyanates.

[0040] The polyol contained in solution B is a compound different from the hydrophilic polymer and is a compound having at least two hydroxyl groups in its molecule. Specifically, various polyols commonly used in the preparation of polyurethanes can be used, and it is preferable that it be at least one polyol selected from, for example, polyether polyols, polyester polyols, polyacrylate polyols, and polycarbonate polyols. Examples of polyether polyols include polyethylene glycol, polypropylene glycol, polyalkylene glycols such as polypropylene glycol-ethylene glycol, polytetramethylene ether glycol, copolymer polyols of tetrahydrofuran and alkylene oxide, various modified forms thereof, and mixtures thereof. Polyester polyols have two or more ester bonds and two or more hydroxyl groups within their molecule. Examples of polyester polyols include condensation reaction products of dicarboxylic acids and other polyols exemplified herein. Examples of dicarboxylic acids include aromatic dicarboxylic acids such as phthalic acid, terephthalic acid, and isophthalic acid, and aliphatic dicarboxylic acids such as adipic acid and sebacic acid. Examples of polyacrylate polyols include copolymers of hydroxyl group-containing monomers with other olefin-based unsaturated monomers, such as (meth)acrylic acid esters, styrene, α-methylstyrene, vinyltoluene, vinyl esters, monoalkyl maleate and dialkyl maleate, monoalkyl fumarate and dialkyl fumarate, α-olefins, and other unsaturated oligomers and unsaturated polymers. Polycarbonate polyols have two or more carbonate bonds and two or more hydroxyl groups within their molecule. Examples of polycarbonate polyols include condensation reaction products of polyols and carbonate compounds, as described later. Examples of carbonate compounds include dialkyl carbonates, diaryl carbonates, and alkylene carbonates. Examples of polyols used as raw materials for polycarbonate polyols include diols such as hexanediol and butanediol, and triols such as 2,4-butanetriol. The number-average molecular weight of the polyol is preferably 1000 to 8000, and more preferably 1000 to 5000, due to its excellent compatibility with isocyanates. Here, the number-average molecular weight is the molecular weight converted to standard polystyrene by gel permeation chromatography (GPC).

[0041] Solution B may contain additives and catalysts commonly used in the reaction between polyols and polyisocyanates. Examples of additives include chain extenders and crosslinking agents. Examples of chain extenders and crosslinking agents include glycols, hexanetriol, trimethylolpropane, and amines. Examples of catalysts include tertiary amines such as N,N-dimethylaminoethanol, N,N-dimethylcyclohexamine-bis(2-dimethylaminoethyl) ether, N-ethylmorpholine, N,N,N',N'-pentamethyldiethylenetriamine, and 1-2(hydroxypropyl)imidazole, as well as metal catalysts such as tin, tin octanoate, dibutyltin dilaurate, dioctyltin dilaurate, dibutyltin mercaptide, ferric acetylacetone, lead octanoate, dibutyltin disicinolate, calcium carbonate, and iron(III) acetylacetonate.

[0042] The solvent constituting solution B is preferably one that does not react with the isocyanate group, and examples include methylene chloride, methylene bromide, dibromomethane, dibromoethane, dichloroethane, dichloroethylene, n-propyl bromide, ethyl acetate, acetone, chloroform, methyl ethyl ketone, acetonitrile, methyl benzolate, benzyl acetate, cyclohexanone, 1,3-dioxolane, and N-methylpyrrolidone.

[0043] In solution B, the mixing ratio of polyol and polyisocyanate is preferably such that the molar ratio [NCO / OH] of hydroxyl groups (OH) in the polyol to isocyanate groups (NCO) in the polyisocyanate is between 0.7 and 1.15. More preferably, this molar ratio is between 0.85 and 1.10, as this can prevent hydrolysis of the polyurethane.

[0044] The isocyanate compound content in solution B is preferably 0.01 to 0.80% by mass, more preferably 0.05 to 0.40% by mass, and even more preferably 0.10 to 0.20% by mass, relative to the total mass of solution B. Within the above preferred range, it is easy to retain hydrophilic polymers and to form a surface layer that can leach metal ions from antibacterial metal nanoparticles over a relatively long period of time.

[0045] The hydrophilic polymer content in solution B is preferably 0.1 to 5.0% by mass, more preferably 0.5 to 3.0% by mass, and even more preferably 1.0 to 2.0% by mass, relative to the total mass of the solution. Within the above preferred range, it is easy to form a surface layer of the aforementioned preferred thickness, and it is easy to form a surface layer that can leach metal ions from antibacterial metal nanoparticles over a relatively long period of time.

[0046] In the surface formation process, the method of applying solution B to the surface of the intermediate layer is not particularly limited, and known methods can be applied. The substrate may be immersed in solution B, applied with a coater, or sprayed with an air spray.

[0047] After applying solution B, time may be allowed for the hydrophilic polymer to react or adsorb on the surface of the intermediate layer or within the three-dimensional crosslinked network. Typically, the reaction or adsorption can be completed within a few minutes to a few hours.

[0048] By applying solution B, allowing sufficient reaction time as needed, removing the solvent from solution B from the surface of the intermediate layer, and drying it, a surface layer containing a three-dimensional crosslinked network including a hydrophilic polymer can be formed. There are no particular restrictions on the drying method; it can be air-dried, air-dried with warm air, or placed in a high-temperature drying room. [Examples]

[0049] [Example 1] As an example of a medical device of the present invention, the catheter described in the first embodiment was manufactured by the following method. <Formation of the middle layer> A catheter shaft (base) made of silicone rubber with an outer diameter of 14 Fr and a length of 400 mm was prepared, and hydroxyl groups were formed on its outer surface by irradiating it with excimer UV light. As a solution for forming the intermediate layer (Solution A), a solution was prepared in which 1000 ppm of silver particles (average particle size: 10 nm) and 6% by mass of a silane coupling agent (compound name: 3-isocyanatetopropyltriethoxysilane) were dispersed in a solvent (toluene). After immersing the catheter shaft in Solution A, it was removed and air-dried to form the intermediate layer.

[0050] <Surface layer: Formation of a cross-linked polyurethane network> The following raw materials were mixed to prepare a surface layer forming composition (crosslinked polyurethane network forming composition: Solution B). (1) Polyethylene glycol (molecular weight 1000): 100 parts by mass (2) Polyisocyanate (product name "Millionate MR-200", manufactured by Tosoh Corporation): 30 parts by mass (3) Polyvinylpyrrolidone (product name "K-90", manufactured by Nippon Shokubai Co., Ltd.): 300 parts by mass (4) Catalyst: Dibutylsullaureate: 0.6 parts by mass (5) Solvent: Dibromomethane: 20,000 parts by mass Here, the molar ratio [NCO / OH] of isocyanate groups (NCO) in polyisocyanate to hydroxyl groups (OH) in polyethylene glycol was 1.1 / 1. A surface-forming composition was applied to the surface of a catheter tube using a dipping method, and the surface was crosslinked and dried to form a surface made of a crosslinked polyurethane network containing polyvinylpyrrolidone.

[0051] The intermediate and surface layers of the catheter fabricated in Example 1 were 0.5 μm and 2 μm thick, respectively. Both the intermediate and surface layers were transparent, allowing visualization of the liquid passing through the internal channel of the catheter. Even after swelling the surface of the catheter prepared in Example 1 with water, the surface did not easily peel off when rubbed with a finger, maintaining a smooth surface condition.

[0052] [Example 2] A catheter with an intermediate layer and a surface layer was prepared in the same manner as in Example 1, except that the concentration of silver particles in solution A was changed to 500 ppm.

[0053] [Example 3] A catheter with an intermediate layer and a surface layer was prepared in the same manner as in Example 1, except that the concentration of silver particles in solution A was changed to 2000 ppm.

[0054] <Evaluation of antibacterial properties> Catheters prepared in Examples 1-3 were immersed in a predetermined amount of artificial urine for 24 hours, allowing silver ions to leach from the catheter into the artificial urine during this immersion. After quantifying the silver ions contained in the artificial urine obtained in this way (after measuring the silver ion content per gram of artificial urine), Escherichia coli, Pseudomonas aeruginosa, or Enterococcus were inoculated, and a known shake-method antimicrobial test was performed. The antimicrobial activity of each artificial urine was calculated from the number of viable bacteria measured. The results for "artificial urine immersion days 0 days" are shown in Figures 2-5. In the figures, C1000 represents the result of Example 1, C500 represents the result of Example 2, and C2000 represents the result of Example 3. A higher antimicrobial activity value indicates higher antimicrobial activity. Similarly, each new catheter was immersed in a predetermined amount of artificial urine for 14 days, and then each catheter was immersed in another predetermined amount of fresh artificial urine for 24 hours. After quantifying the silver ions contained in the artificial urine obtained in this way, each bacterium was inoculated, and the antibacterial activity was calculated using the shake method. The results for "artificial urine immersion period of 14 days" are shown in Figures 2-5. Similarly, each new catheter was immersed in a predetermined amount of artificial urine for 31 days, and then each of these catheters was immersed in another predetermined amount of fresh artificial urine for 24 hours. After quantifying the silver ions contained in the artificial urine obtained in this way, each bacterium was inoculated, and the antibacterial activity was calculated using the shake method. The results for "artificial urine immersion period of 31 days" are shown in Figures 2-5. In this study, an antibacterial activity of approximately 2 or higher for "artificial urine immersion days of 31 days" was considered preferable, and a value greater than 2 was considered a more preferable result.

[0055] From the above results, it is clear that in the catheters of Examples 1 to 3 according to the present invention, since the intermediate layer contains a compound derived from a silane coupling agent, antibacterial silver ions leach out from the intermediate layer for more than 31 days, exhibiting antibacterial properties. Furthermore, it was confirmed that the liquid flowing inside the catheter could be visualized through the intermediate layer and the surface layer, and that the adhesion of the surface layer to the intermediate layer was excellent. [Explanation of symbols]

[0056] 1...Catheter base, 2...Intermediate layer, 3...Surface layer.

Claims

1. A medical device comprising a base, an intermediate layer formed on the surface of the base, and a surface layer laminated on the surface of the intermediate layer opposite to the base, The aforementioned intermediate layer comprises antibacterial metal nanoparticles having a primary particle size of 1 to 100 nm and a compound derived from a silane coupling agent. The aforementioned surface layer contains a hydrophilic polymer, and is a medical device.

2. The medical device according to claim 1, wherein the intermediate layer is formed solely from the antibacterial metal nanoparticles and the compound derived from the silane coupling agent.

3. The medical device according to claim 2, wherein the compound derived from the silane coupling agent forms a chemical bond with the functional group of the surface layer.

4. The medical device according to claim 3, wherein the compound derived from the silane coupling agent forms a chemical bond with the functional group on the surface of the substrate.

5. The medical device according to claim 4, wherein the antibacterial metal microparticles include at least silver particles.

6. The medical device according to claim 5, wherein the substrate is made of silicone rubber.

7. The medical device according to claim 6, wherein the medical device is a urethral catheter.

8. A step of applying a solution containing antibacterial metal nanoparticles with a primary particle size of 1 to 100 nm and a silane coupling agent to the surface of a substrate, a chemical bond being formed by the reaction of a first functional group of the silane coupling agent with a functional group on the surface of the substrate, a compound derived from the silane coupling agent being bonded to the surface of the substrate, and an intermediate layer containing the antibacterial metal nanoparticles being formed. A method for manufacturing a medical device, comprising the step of applying a solution containing an isocyanate compound, a polyol, and a hydrophilic polymer to the surface of the intermediate layer, thereby reacting and bonding the isocyanate compound or the polyol with a second functional group having a compound derived from the silane coupling agent constituting the intermediate layer, and forming a surface layer having a three-dimensional crosslinked network containing the hydrophilic polymer.

9. The method for producing a medical device according to claim 8, wherein the first functional group of the silane coupling agent is an alkoxy group or a hydroxyl group obtained by hydrolysis of an alkoxy group, and the second functional group is an isocyanate group.

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