Medical device

Abstract

Provided is a medical device having an excellent sliding property. The medical device is at least temporarily inserted into a living body, or is inserted therein over the long term, and comprises a base material and a coating film formed on the base material. Additionally, the coating film comprises: a first layer that is formed on the base material and that is composed of a first polymer, which is a polymer of a monomer comprising a vinyl group; and a second layer that is formed on the first layer and that is composed of a hydrophilic second polymer. The second polymer is a polymer provided with higher hydrophilicity than the first polymer, and the coating film has an elastic modulus based on a nanoindentation test of 0.1824-0.2369 N / mm2.

Description

medical devices

[0001] The present disclosure relates to a medical device that is inserted into the living body of an animal. This application claims priority to Japanese Patent Application No. 2024-092851, filed on June 7, 2024, the entire contents of which are incorporated herein by reference.

[0002] In the medical field, it is generally preferred to reduce the burden on patients by making incisions as small as possible, from the viewpoints of reducing the amount of bleeding during surgery, reducing postoperative pain for patients and enabling them to recover in a short period of time, and making scars less noticeable.

[0003] When inserting a medical device into a microincision in tissue or a thin blood vessel, the device is inserted while in contact with the tissue, raising concerns about damage to surrounding tissue and breakage of the medical device. Therefore, medical devices inserted into the human or animal body (e.g., syringes, catheters, intraocular lenses, and intraocular lens inserters) require slipperiness so that they can be inserted smoothly and safely into body cavities without damaging the tissue inside the body. Coating the surface of such medical devices is one way to improve the slipperiness of the devices.

[0004] For example, Japanese Patent Publication No. 2023-551015 discloses an intraocular implant having a lubricious coating formed thereon. ２ -CH ２ Based on such polymers, it is said that they have the specificity of being slippery and completely waterproof.

[0005] JP 2023-551015 A JP 2023-128728 A

[0006] The present inventors have a desire to provide a medical device with excellent lubricity. The present disclosure has been made in view of such circumstances, and a primary object thereof is to provide a medical device with excellent lubricity.

[0007] The medical device disclosed herein is inserted into a living body at least temporarily or for a long period of time. The medical device comprises a substrate and a coating film formed on the substrate. The coating film has a first layer formed on the substrate and made of a first polymer, which is a polymer of a monomer having a vinyl group, and a second layer formed on the first layer and made of a hydrophilic second polymer. Here, the second polymer is a polymer with higher hydrophilicity than the first polymer, and the coating film has an elastic modulus of 0.1824 N / mm based on a nanoindentation test. ２ 0.2369N / mm or more ２ The following is the result.

[0008] The inventors of the present invention have conducted various studies to achieve excellent slipperiness in medical devices. Through these studies, it has been found that the medical device having the above-described configuration has extremely excellent slipperiness. Specifically, this medical device has a coating film made of two different types of polymers. The second layer of this coating film is made of a polymer that has higher hydrophilicity than the first layer. In addition, the modulus of elasticity (0.1824 N / mm ２ 0.2369N / mm or more ２ With this configuration, a suitable coefficient of dynamic friction (0.02 or less) can be obtained. That is, with a medical device having the above configuration, excellent slipperiness can be achieved. This effect allows the medical device to be inserted into the living body smoothly and safely.

[0009] In the medical device disclosed herein, the second polymer is a zwitterionic polymer, which can suppress nonspecific adsorption of proteins to the coating film and improve biocompatibility.

[0010] The medical device disclosed herein has an elastic modulus of 0.2068 N / mm ２ More than 0.2220N / mm ２ With such a modulus of elasticity, a dynamic friction coefficient of 0.01 or less can be achieved. This allows the medical device to achieve particularly excellent slipperiness. This effect allows the medical device to be inserted into the body more smoothly and safely.

[0011] In the medical device disclosed herein, the substrate is made of a polyolefin resin or an acrylic resin, which improves the biocompatibility of the medical device and further reduces the burden on the body.

[0012] The medical devices disclosed herein are intraocular lenses, intraocular contact lenses, and instruments for inserting medical devices into the body. By providing the coating film of the present disclosure, these medical devices can be inserted smoothly into the eye, and the ICL or IOL will not get caught on the tip of the nozzle, thereby reducing damage to the device.

[0013] FIG. 1 is a longitudinal cross-sectional view schematically illustrating the surface of a medical device according to one embodiment disclosed herein. FIG. 2 is an explanatory diagram illustrating the configuration of a medical device according to one embodiment disclosed herein. FIG. 3 is a graph showing the correlation between the coefficient of dynamic friction of the medical device according to the present invention when the modulus of elasticity is between 0.01 and 0.02. FIG. 4 is a graph showing the correlation between the coefficient of dynamic friction of the medical device according to the present invention when the modulus of elasticity is 0.01 or less. FIG. 5 is a graph confirming the presence or absence of speed dependency for a medical device according to one embodiment disclosed herein. FIG. 6 is a graph comparing the coefficient of static friction of a polypropylene plate and an acrylic plate for the substrate of a medical device according to the present invention. FIG. 7 is a graph comparing the coefficient of dynamic friction of a polypropylene plate and an acrylic plate for the substrate of a medical device according to the present invention.

[0014] Exemplary embodiments of the present disclosure are described in detail below. Matters necessary for implementation other than those specifically mentioned in this specification can be understood as design matters for a person skilled in the art based on the prior art in the relevant field. The present disclosure can be implemented based on the contents disclosed in this specification and the technical common sense in the relevant field. Furthermore, in the following drawings, components and parts that perform the same function may be denoted by the same reference numerals, and redundant explanations may be omitted or simplified. Furthermore, the dimensional relationships (length, width, thickness, etc.) in each figure are schematic to clearly explain the present disclosure and do not necessarily accurately reflect the actual dimensional relationships.

[0015] In this specification, when a numerical range is described as "A to B (where A and B are any numerical values)," it means "A or more and B or less," and also includes the meanings of "greater than A and less than B," "greater than A and B or less," and "greater than A and less than B."

[0016] As used herein, the term "biocompatibility" is defined as it is commonly used in the art, i.e., it means that the material has affinity with biological tissues and organs and can be brought into contact with biological tissues and organs without causing adverse effects such as rejection or foreign body reactions.

[0017] <Medical Device> The medical device disclosed herein comprises a substrate and a coating film formed on the substrate. A part or all of the medical device disclosed herein is used in direct contact with tissues or organs in a living body. That is, the medical device disclosed herein can be inserted into a living body at least temporarily or for a long period of time. As used herein, "in vivo" refers to the inside of the body of a human or a non-human animal (e.g., mammals such as mice, rats, rabbits, monkeys, dogs, and cats, birds, amphibians, reptiles, fish, etc.). As used herein, "inserting" a medical device into a living body refers to introducing a part or all of the medical device into the body, such as a body cavity, duct, subcutaneous, intramuscular, intraosseous, intracerebral, intraocular, or intraorgan, invasively, for example, percutaneously (i.e., through the skin) through the skin (more specifically, the epithelium) or an orifice of the body, or noninvasively, for example, orally, intranasally, intraauricularly, intravaginally, intraanally, or via a tube.

[0018] Examples of medical devices that are at least temporarily inserted into a living body include catheters, cannulas, syringes, and instruments for inserting medical devices into a living body. Examples of instruments for inserting medical devices into a living body include intraocular lens inserters, intraocular contact lens inserters, glaucoma implant inserters, intracapsular expandable ring inserters, artificial iris inserters, artificial vitreous inserters, and artificial retina inserters. In this specification, "temporarily inserting" a medical device into a living body refers to its use in the diagnosis, treatment, or prevention of a disease or disorder in a human or non-human animal, its use during a procedure that affects the structure or function of the body, and its removal upon completion of the procedure. Such medical devices typically come into contact with the living body for a total of 24 hours or less. These medical devices may be used either once (disposable) or multiple times.

[0019] Examples of medical devices that are inserted into a living body for a long period of time include catheters, cannulas, artificial blood vessels, artificial valves, hemodialysis membranes, intraocular lenses (IOLs), intraocular contact lenses (ICLs), microchips, stents, implants, sheaths, defibrillators, pacemakers, artificial bones, artificial hearts, artificial teeth, glaucoma implants, intracapsular expander rings, artificial irises, artificial vitreous bodies, and artificial retinas. As used herein, "long-term insertion" of a medical device into a living body refers to its use in the diagnosis, treatment, or prevention of diseases or disorders in humans or non-human animals, and its placement for the length of time required to affect the structure or function of the body. The duration of placement can be determined appropriately depending on the medical device used and its purpose, and may include semi-permanent or permanent placement of the medical device. For example, such a medical device may be in contact with the living body for a cumulative total of more than 24 hours. It may also include cases where a medical device placed in a living body is partially or completely replaced as needed (e.g., due to deterioration over time). In addition, the term "placement" as used herein refers to fixing a device while it is inserted into a living body, and can be used interchangeably with the terms "implantation," "implantation," and "embedding."

[0020] A medical device 1 according to one embodiment disclosed herein will be described below. FIG. 1 is a longitudinal cross-sectional view schematically illustrating the surface of the medical device 1. The medical device 1 is inserted into a living body at least temporarily, or for a long period of time. As shown in FIG. 1 , the medical device 1 includes a substrate 10 and a coating film 20 formed on the substrate 10. The coating film 20 includes a first layer 30 formed on the substrate 10 and made of a first polymer, which is a polymer of a monomer having a vinyl group, and a second layer 40 formed on the first layer 30 and made of a hydrophilic second polymer. Here, the second polymer is a polymer with higher hydrophilicity than the first polymer, and the coating film 20 has an elastic modulus of 0.1824 N / mm based on a nanoindentation test. ２ 0.2369N / mm or more ２ The following is a summary of the results. This allows for excellent slipperiness. This effect allows medical devices to be inserted smoothly and safely into the body. Note that, unless otherwise specified, the "elastic modulus" in this specification refers to a value measured by the nanoindentation test described below.

[0021] <Substrate> The substrate 10 is a base component of the medical device 1. The substrate 10 has a surface on which a coating film 20 containing a polymer can be formed. The substrate 10 may have a multi-layer structure, in which case the coating film 20 is formed on the outermost layer. The surface of the substrate 10 on which the coating layer 20 is formed may be smooth or rough. From the viewpoint of the thickness of the coating film described below, the surface roughness Ra (surface roughness) of the substrate 10 is preferably 100 nm or less, more preferably 50 nm or less, and even more preferably 30 nm or less. Even if the surface of the substrate 10 is rough, the surface roughness can be adjusted and made smooth by performing processing such as polishing.

[0022] The shape, size, and thickness of the substrate 10 are not particularly limited. The substrate 10 may be plate-shaped or tubular. For example, in the case of a plate-shaped substrate, the coating film 20 is formed on the front and / or back surface. In the case of a tubular substrate, the coating film 20 is formed on the inner and / or outer surface.

[0023] The material of the substrate 10 is not particularly limited as long as it does not significantly impair the effects of the technology of the present disclosure. Typically, the material of the substrate 10 may be the same as that used in conventional medical devices of this type. Examples of materials for the substrate 10 include resins such as acrylic resin, polyolefin resin, polyester resin, polyether resin, fluororesin, silicone resin, vinyl chloride resin, polysulfone resin, aromatic polyetherketone resin, polystyrene, polyimide resin, polyamide, and polyphenylene sulfide, as well as metal and glass. Examples of polyolefin resins include polyethylene (PE), polypropylene (PP), and ethylene-propylene copolymer. Examples of acrylic resins include polyacrylic acid (PAC), polymethacrylic acid (PMA), and polymethyl methacrylate (PMMA). Examples of polyester resins include polyethylene terephthalate (PET). Examples of polyether resins include polyethylene glycol (PEG). Examples of fluororesins include polytetrafluoroethylene (PTFE) and perfluoroalkoxyalkane (PFA). Examples of silicone resins include polydimethylsiloxane (PDMS). Examples of polysulfone resins include polysulfone (PSU), polyphenylsulfone (PPSU), and polyethersulfone (PES). Examples of aromatic polyetherketone resins include polyetheretherketone (PEEK), polyetherketone (PEK), and polyetherketoneketone (PEKK). Examples of polyimide resins include polyetherimide (PEI) and polyamideimide (PAI). The substrate 10 may be made of one of these resins, or a combination of two or more. Among these, polyolefin resins and acrylic resins are preferred for the substrate 10 from the viewpoint of biocompatibility. In this specification, "polyolefin resin" refers to a resin containing polyolefin as a primary component. In other words, a substrate made of polyolefin resin is a substrate containing polyolefin as a material. In this specification, "acrylic resin" refers to a resin containing acrylic as a primary component.In this specification, the term "major" used to describe the amount of a component in a composition or article means that the amount exceeds 50%. Furthermore, PP or PMMA is more preferably used as the material for the substrate 10 due to its durability (e.g., high resilience, particularly against external forces) and high transparency. Furthermore, PES or PEI is also preferably used as the material for the substrate 10.

[0024] <Coating film 20> The medical device 1 disclosed herein comprises a coating film 20 formed on a substrate 10. The coating film 20 may be provided on a portion where the medical device 1 comes into direct contact with the inside of a living body and / or a portion where the medical device 1 comes into direct contact with an instrument for inserting the medical device into a living body. Furthermore, in the portion where the medical device 1 comes into direct contact with an instrument for inserting the medical device into a living body, the coating film 20 may be provided on both the medical device 1 side and the insertion instrument side, or on either one of them.

[0025] The coating film 20 is formed partially or entirely on the surface of the substrate 10. The coating film 20 may also be formed intermittently on the surface of the substrate 10. From the viewpoint of ensuring a certain level of slipperiness, the coating film 20 is preferably formed entirely on the surface of the substrate 10. The coating film 20 may be physically or chemically bonded to the surface of the substrate 10.

[0026] The coating film 20 has a first layer 30 made of a first polymer, which is a polymer of a monomer having a vinyl group, and a second layer 40 made of a second hydrophilic polymer. The first hydrophilic polymer is formed on the substrate 10. The second hydrophilic polymer is formed on the first layer 30.

[0027] The thickness of the coating film 20 is not particularly limited as long as it does not significantly impair the effects of the technology of the present disclosure. However, if the thickness of the coating film 20 is less than the surface roughness of the substrate 10, a portion of the surface of the substrate 10 may be exposed through the coating film 20, which may affect the slipperiness. Therefore, the thickness of the coating film 20 need only be equal to or greater than the surface roughness of the substrate 10. This allows the coating film 20 to sufficiently cover the surface of the substrate 10. Furthermore, from the viewpoint of eliminating speed dependency, the lower limit of the thickness of the coating film 20 may be 140 nm or more, preferably 145 nm or more, more preferably 150 nm or more, and even more preferably 155 nm or more. The upper limit of the thickness of the coating film 20 may be 220 nm or less, 200 nm or less, or 160 nm or less. The thickness (film thickness) of the coating film 20 and the thickness of each layer can be measured using a scanning electron microscope (SEM) as described in the Examples below.

[0028] <First Layer and First Polymer> The coating film 20 disclosed herein has a first layer 30 made of a first polymer formed on a substrate 10. The first polymer may be a polymer of a monomer having a vinyl group (vinyl monomer). The vinyl monomer generates radicals in the presence of a polymerization initiator or the like, and the carbon-carbon double bonds (C=C) of the vinyl group undergo a chain reaction to generate a polymer. In other words, the first polymer is a vinyl polymer obtained by polymerizing the vinyl monomer.

[0029] The first polymer is a polymer of a vinyl monomer. Examples of monomers constituting the first polymer include methyl methacrylate (MMA), 2-hydroxyethyl methacrylate (HEMA), N-vinyl-2-pyrrolidone (NVP), vinyl acetate (VA), and 2-hydroxyethyl acrylate (HEA). These monomers may be used alone or in combination of two or more. Of these, from the viewpoint of biocompatibility, MMA or HEMA is preferred as the monomer constituting the first polymer. Furthermore, HEMA is more preferred from the viewpoint of hydrophilicity. In this specification, a "hydrophilic" monomer refers to a monomer having an octanol / water partition coefficient (LogPow) of less than 1 at 20°C. The above partition coefficient can be measured in accordance with JIS Z 7260-117:2006.

[0030] Specific examples of the first polymer include polymethyl methacrylate, poly2-hydroxyethyl methacrylate, poly(N-vinyl-2-pyrrolidone), polyvinyl acetate, poly2-hydroxyethyl acrylate, polymethacrylic acid, polyacrylic acid, and ethylene-methyl methacrylate copolymer. Of these, from the viewpoint of biocompatibility, the first polymer is preferably polymethyl methacrylate or poly2-hydroxyethyl methacrylate. The first polymer may be linear or branched.

[0031] The thickness of the first layer 30 is not particularly limited as long as it does not significantly impair the effects of the technology of the present disclosure. The lower limit of the thickness of the first layer 30 is preferably 125.3 nm or more, and more preferably 127.1 nm or more. The upper limit of the thickness of the first layer 30 is preferably 133.8 nm or less, and more preferably 132.6 nm or less.

[0032] <Second Layer and Second Polymer> The coating film 20 disclosed herein has a second layer 40 made of a second polymer formed on the first layer 30. The second polymer may be made of a hydrophilic monomer. The second polymer has higher hydrophilicity than the first polymer. In this specification, "highly hydrophilic" refers to an octanol / water partition coefficient (LogPow) of less than -2 at 20°C and a lower octanol / water partition coefficient than the first polymer.

[0033] The bond between the second polymer and the first polymer is not particularly limited. The second polymer is physically or chemically bonded to the first polymer. The second polymer may be a polymer of a monomer having a vinyl group. Preferably, the second polymer and the first polymer are bonded via a living radical polymerization agent. Living radical polymerization can suppress the polydispersity index (PDI) to 1.3 or less, thereby making the length of the formed polymer uniform. This effect allows the formation of a coating film with a uniform thickness. Furthermore, the use of a living radical polymerization agent chemically bonds the second polymer and the first polymer, thereby suppressing peeling of the second layer 40. The second polymer may be linear or branched.

[0034] The second polymer may be a zwitterionic polymer. This improves hydrophilicity and inhibits nonspecific adsorption of proteins (in other words, reduces fouling). The zwitterionic monomer constituting the second polymer is preferably biocompatible, and examples thereof include betaine-type monomers such as phosphobetaine, carboxybetaine, and sulfobetaine. Among these, betaine-type monomers having a methacrylic group are preferred. More specifically, examples of phosphobetaine (PB) include 2-methacryloyloxyethyl phosphorylcholine (MPC). Examples of carboxybetaine (CB) include 2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetic acid. Examples of sulfobetaine (SB) include 4-[(3-methacrylamidopropyl)dimethylammonio]butane-1-sulfonic acid. These monomers may be used alone or in combination of two or more.

[0035] Specific examples of the second polymer include betaine-type polymers, such as poly{2-methacryloyloxyethylphosphorylcholine}, poly{2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetic acid}, and poly{4-[(3-methacrylamidopropyl)dimethylammonio]butane-1-sulfonic acid}.

[0036] The thickness of the second layer 40 is not particularly limited as long as it does not significantly impair the effects of the technology of the present disclosure. The lower limit of the thickness of the second layer 40 is preferably 19.0 nm or more, and more preferably 19.5 nm or more. The upper limit of the thickness of the second layer 40 is preferably 21.4 nm or less, and more preferably 20.7 nm or less.

[0037] <Elastic Modulus of Coating Film> In the medical device disclosed herein, a coating film 20 is formed on a substrate 10. The coating film 20 comprises a first layer 30 made of a vinyl polymer and a second layer 40 formed on the first layer 30. In this coating film 20, the first layer 30 has a certain degree of rigidity (here, elastic modulus) and can serve as a base supporting the second layer 40. Because the second layer 40 is softer than the first layer 30, forming it on the first layer 30 provides the rigidity of the layer so that the polymer does not collapse (or recovers even if collapsed). Furthermore, the second layer 40 has high hydrophilicity, thereby improving biocompatibility. The elastic modulus of the first or second layer can be measured by forming the first or second layer on the substrate 10 based on a nanoindentation test. The elastic modulus of the first layer is 0.2449 N / mm ２ 0.2945N / mm or more ２ or less (preferably, 0.2645 N / mm ２ 0.2745N / mm or more ２ The elastic modulus of the second layer is 0.1154 N / mm ２ 0.1845N / mm or more ２ or less (preferably, 0.1458 N / mm ２ 0.1652N / mm or more ２ (See below) is sufficient.

[0038] By having the above-described two-layer structure, the coating film 20 has an elastic modulus of 0.1824 N / mm based on a nanoindentation test. ２ 0.2369N / mm or more ２The coefficient of dynamic friction is as follows. This makes it possible to achieve a suitable coefficient of dynamic friction (specifically, 0.02 or less) when inserting a medical device into a living body. While not intending to limit the technology disclosed herein, it is presumed that such a significant improvement in slipperiness is achieved by forming a coating film with a composition that prevents the polymer from collapsing (or restores its shape even if it collapses), and then having a hydrophilic polymer that is compatible with biological tissue present on the surface of the coating film. The effect of such a coefficient of dynamic friction allows the medical device to be inserted smoothly into a living body. This reduces the burden on the human or non-human animal body. From this perspective, the lower limit of the elastic modulus of the coating film is preferably 0.1840 N / mm ２ More preferably, 0.1874 N / mm ２ More preferably, 0.2064 N / mm ２ The upper limit of the elastic modulus of the coating film is preferably 0.2330 N / mm ２ or less, more preferably 0.2281 N / mm ２ or less, more preferably 0.2220 N / mm ２ The elastic modulus of the coating film is 0.1824 N / mm ２ 0.2369N / mm or more ２ When the coating film has an elastic modulus of 0.2064 N / mm or less, the static friction coefficient can be kept to 0.02 or less. This reduces the strain on tissue or medical equipment when restarting during intermittent medical operations. Furthermore, the coating film has an elastic modulus of 0.2064 N / mm ２ More than 0.2220N / mm ２ When the coefficient of friction is 0.01 or less, it is possible to achieve ultra-low friction that is not speed-dependent (specifically, a dynamic friction coefficient of 0.01 or less and a static friction coefficient of 0.01 or less). This makes it possible to further reduce the load on surrounding tissues when the medical device is inserted into a living body.

[0039] The elastic modulus of the coating film can be measured by carrying out a nanoindentation test in accordance with ISO 14577. In the nanoindentation test, the coating film may be in a dry state or a wet state.

[0040] A medical device provided with the coating film 20 as described above has suitable slip properties. When a medical device is inserted into a living body, frictional resistance occurs between the medical device and the surrounding tissue in contact with the medical device, which may result in tissue damage, deformation, or breakage of the medical device. The medical device of the present disclosure has a specific elastic modulus (0.1824 N / mm ２ 0.2369N / mm or more ２ It has been confirmed that the provision of a coating film (see below) provides favorable slip properties, thereby reducing the risk of tissue damage due to friction with biological tissue, as well as deformation and breakage of the medical device.

[0041] Specifically, the medical device disclosed herein has an elastic modulus of 0.1824 N / mm based on a nanoindentation test. ２ 0.2369N / mm or more ２ This allows for a reduction in friction (particularly dynamic friction) between the medical device and the surrounding tissues and / or the medical device when the medical device is inserted into a living body. ２ 0.2369N / mm or more ２ According to the following test (see below), a dynamic friction coefficient of 0.02 or less can be achieved. Furthermore, the static friction coefficient of the medical device of the present disclosure is not speed-dependent. Therefore, it also has a certain degree of slipperiness that is not dependent on usability.

[0042] <Molecular Weight Ratio of First Layer and Second Layer> As will be described in detail later, the present inventors have determined that the molecular weight ratio of the first layer to the second layer is 0.1824 N / mm ２ 0.2369N / mm or more ２ or less (preferably 0.2068 N / mm ２ More than 0.2220N / mm ２It has been confirmed that when a coating film having a first polymer composed of a vinyl group-containing monomer and a hydrophilic second polymer is used, excellent slip properties (i.e., dynamic friction coefficient) are significantly improved. One way to achieve the above elastic modulus is to change the molecular weight ratio of the first layer to the second layer in the coating film. Here, the "molecular weight ratio of the first layer to the second layer" in this specification refers to the value obtained by dividing the molecular weight ratio of the second polymer constituting the second layer by the molecular weight ratio of the first polymer constituting the first layer. The molecular weight ratio of the polymers constituting each layer can be determined by dividing the number average molecular weight of the polymers constituting each layer by the number average molecular weight of the whole (i.e., the first polymer and the second polymer). The number average molecular weight (and weight average molecular weight) can be measured by gel permeation chromatography (GPC), as described in the Examples below. The molecular weight ratio of the first layer to the second layer of the coating film required to achieve the above elastic modulus varies depending on the type of polymer constituting each layer. Such a molecular weight ratio can be appropriately determined by those skilled in the art through preliminary tests, etc.

[0043] For example, in a coating film having a first layer made of a HEMA polymer and a second layer made of a polymer of 4-[(3-methacrylamidopropyl)dimethylammonio]butane-1-sulfonic acid, the above-mentioned elastic modulus can be obtained by forming the coating film so that the molecular weight ratio between the first layer and the second layer is 0.28 to 0.59 (preferably 0.33 to 0.41). Also, in a coating film having a first layer made of an MMA polymer and a second layer made of a polymer of 4-[(3-methacrylamidopropyl)dimethylammonio]butane-1-sulfonic acid, the above-mentioned elastic modulus can be obtained by forming the coating film so that the molecular weight ratio between the first layer and the second layer is 0.46 to 0.78 (preferably 0.63 to 0.78). This allows for a suitable dynamic friction coefficient to be obtained.

[0044] For example, in a coating film having a first layer made of a HEMA polymer and a second layer made of a 2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetic acid polymer, the above-mentioned elastic modulus can be obtained by forming the coating film so that the molecular weight ratio between the first layer and the second layer is 0.29 or more and 0.62 or less (preferably 0.33 or more and 0.43 or less). Also, in a coating film having a first layer made of a HEMA polymer and a second layer made of an MPC polymer, the above-mentioned elastic modulus can be obtained by forming the coating film so that the molecular weight ratio between the first layer and the second layer is 0.31 or more and 0.61 or less (preferably 0.34 or more and 0.42 or less).

[0045] <Surface Modification of Substrate> The substrate may be surface-modified. Examples of surface modification include chemical modification such as introduction of functional groups and metal modification. Preferably, the substrate is surface-modified to provide hydrophilic groups (e.g., amino groups, carbonyl groups, hydroxyl groups, etc.). Surface modification is useful for bonding a polymer to a substrate surface with poor reactivity. By providing hydrophilic groups to the substrate surface, the substrate and the first polymer are bonded (typically by hydrogen bonding). Conventional surface modification methods such as heat treatment, plasma treatment, chemical treatment, corona discharge treatment, ultraviolet treatment, acid treatment, and alkali treatment can be used as appropriate. FIG. 2 is an explanatory diagram illustrating the configuration of a medical device according to one embodiment disclosed herein. In the embodiment of FIG. 2, the surface of the substrate 10a is modified (to provide hydrophilic groups 11) by plasma treatment. Such surface modification is particularly effective for polymer substrates with poor surface reactivity. The presence or absence of surface modification can be confirmed, for example, by measuring the infrared spectrum of the substrate surface using a Fourier transform infrared spectrophotometer (FT-IR) or by obtaining an XPS spectrum by X-ray photoelectron spectroscopy. －１ COO appears nearby － The presence or absence of a peak specific to radicals can be used to determine whether or not the surface has been modified.

[0046] <Method for Forming a Coating Film> The method for forming the coating film disclosed herein is not particularly limited as long as it does not significantly impair the effects of the technology of the present disclosure. Living radical polymerization can typically be used to form the coating film of the present disclosure. This allows the length of the polymer to be adjusted. Furthermore, it is not limited to the shape of the substrate (e.g., plate-like, tubular, etc.), and a uniform coating film can be easily formed. Examples of living radical polymerization include nitroxide-mediated polymerization (NMP method), atom transfer polymerization (ATRP method), reversible addition-fragmentation chain transfer polymerization (RAFT polymerization method), organotellurium-mediated polymerization (TERP method), organoantimony-mediated polymerization (SBRP method), organobismuth-mediated polymerization (BIRP method), iodine transfer polymerization (ITP method), organometallic-mediated radical polymerization (OMRP method), and reversible chain transfer catalyst polymerization (RTCP method). Among these, RAFT polymerization using a RAFT agent is preferred from the viewpoint of ease of controlling the molecular weight of the polymer. The RAFT agent used in the RAFT polymerization method is selected based on its compatibility with the monomers used. It is preferable to use a trithiocarbonate that reacts at both ends as the RAFT agent. By using a RAFT agent that reacts at both ends, the hydrophilic groups on the outermost surface of the coating film are not blocked, thereby maintaining favorable hydrophilicity. Examples of trithiocarbonates include 2-cyano-2-propyldodecyltrithiocarbonate, 4-cyano-4-[[(dodecylthio)carbonothioyl]thio]pentanoic acid, bis[4-(2-hydroxyethoxycarbonyl)benzyl], and bis{4-[ethyl-(2-acetyloxyethyl)carbamoyl]benzyl}.

[0047] The medical device 1a shown in FIG. 2 includes a substrate 10a and a coating film 20a formed on the substrate 10a. The coating film 20a primarily includes a first layer 30a and a second layer 40a. In this embodiment, the surface of the substrate 10a is modified to include hydrophilic groups 11. A first polymer 31 is provided in a linear chain on the substrate 10a. A second polymer is provided in a linear chain on the first polymer 31 via a living radical polymerization agent 50. In this embodiment, the brush-shaped coating film 20a is provided as shown in FIG. 2. As shown in FIG. 2, the chemical bonding via the living radical polymerization agent prevents the second layer 40a from peeling from the first layer 30a, thereby improving biocompatibility. For example, with respect to ophthalmic medical devices, this can reduce the risk of ocular hypertension, which can result from blockage of the intraocular aqueous humor pathway due to the polymer layer leaking into the eye.

[0048] As described above, the technology disclosed herein can be used for medical devices that are inserted into a living body at least temporarily or for a long period of time. Furthermore, in view of these effects, the technology disclosed herein can be particularly preferably used for IOLs, ICLs, and instruments for inserting these medical devices into a living body (hereinafter simply referred to as "IOL inserters"). An IOL inserter includes a main body that houses an IOL or ICL, a nozzle extending from the main body, and a plunger that pushes the IOL or ICL out of the main body. The nozzle at the tip of the IOL inserter is inserted into a microincision in the eye (typically a wound diameter of 2.5 mm or less in the cornea) to introduce the IOL or ICL into the eye. At this time, the IOL or ICL is in a folded state and is further compressed through the nozzle before being introduced into the eye. For IOL inserters, it is preferable to impart excellent slipperiness to the nozzle surface due to the effects of the technology disclosed herein. This allows for smooth insertion into the eye, prevents the ICL or IOL from getting caught on the tip of the nozzle, and reduces damage to the device. The same effect can also be achieved by adding excellent slipperiness to the surface of the ICL or IOL using the technology disclosed herein. For an example of an intraocular lens inserter, see Japanese Patent Application Laid-Open No. 2023-128728.

[0049] Examples and comparative examples are provided below to specifically explain the medical device of the present disclosure. Here, the medical device of the present disclosure uses polypropylene, which is commonly used for catheters, syringes, intraocular lenses, or intraocular contact lens inserters, or acrylic resin, which is commonly used for intraocular lenses and intraocular contact lenses, as its base material. However, the medical device of the present disclosure is not limited to the following examples.

[0050] <Preparation of Examples 1 to 13 and Comparative Examples 1 to 13> A polypropylene plate was prepared as a substrate, and the surface of the substrate was modified by irradiating it with plasma under atmospheric pressure conditions. The plasma was irradiated using a Touch Plasma FFPB20-N2 (manufactured by FUJI Corporation), with two line scans at an irradiation height of 18 mm. After plasma irradiation, the polypropylene plate was immersed in a sodium hydroxide solution and stirred. The polypropylene plate was removed from the sodium hydroxide solution and immersed in ultrapure water and stirred. The polypropylene plate was then removed from the ultrapure water and dried at room temperature.

[0051] <RAFT Substitution> Next, to form a coating film on the substrate, treatment with a living radical polymerization agent was carried out. A living radical polymerization solution was prepared by mixing PAFR-II (FUJIFILM Wako Pure Chemical Industries, Ltd.) and a RAFT agent (FUJIFILM Wako Pure Chemical Industries, Ltd.) in dioxane. After this solution was heated to 60°C, a polypropylene plate was added and stirred. The polypropylene plate was transferred to a new dioxane solution and stirred at room temperature. The polypropylene plate was removed, air-blown, and dried at room temperature.

[0052] <Formation of First Polymer Layer> HEMA and a polymerization initiator (4,4'-azobis-4-cyanovaleric acid (ACVA)) were dissolved in ultrapure water, and N ２ A first polymer solution was prepared. The polypropylene plate after the RAFT replacement was placed in this solution. N ２The mixture was then blown in and vacuumed three times, and the HEMA was allowed to polymerize sufficiently while stirring at 60°C. The polypropylene plate was then placed in ultrapure water and stirred at room temperature. The polypropylene plate was then removed from the ultrapure water, air-blowed, and then dried in a vacuum oven.

[0053] <Formation of second polymer layer> 4-[(3-methacrylamidopropyl)dimethylammonio]butane-1-sulfonic acid was added to ultrapure water and stirred at room temperature. Next, a polymerization initiator (ACVA) was added and stirred, and then N ２ The polypropylene plate on which the first polymer layer had been formed was placed in this solution. ２ The mixture was stirred at 60° C. and the 4-[(3-methacrylamidopropyl)dimethylammonio]butane-1-sulfonic acid was fully polymerized.

[0054] The polypropylene plate on which the second polymer layer was formed was recovered, placed in methanol, and stirred. The polypropylene plate was then transferred to a sodium chloride solution and stirred. The polypropylene plate was then removed from the sodium chloride solution, air-blowed, and dried in a vacuum oven to obtain a polypropylene plate on which the coating film of Example 1 was formed. The lengths (here, molecular weights) of the first polymer and the second polymer can be adjusted by varying the polymerization reaction time of each polymer. In Examples 2 to 7 and Comparative Examples 1 to 7, the polymer lengths were adjusted by varying the polymerization reaction time of Example 1. In Examples 8 to 13 and Comparative Examples 8 to 13, the monomer constituting the first polymer was changed from HEMA to MMA.

[0055] <Measurement of molecular weight and polydispersity> The molecular weight of the coating layer (here, the number average molecular weight and weight average molecular weight of HEMA or MMA and SB) was measured by gel permeation chromatography (GPC). A 30 mm x 20 mm polypropylene plate on which a coating layer was formed was immersed in a citric acid solution to extract the polymer. The extracted solution was filtered through a hydrophobic filter. The filtered solution was diluted with ultrapure water and measured under the following conditions: Column: Shodex Ohpak SB-806M HQ (2 columns) Column flow rate: 1 mm / sec Column temperature: 40°C

[0056] The polydispersity index (PDI) was calculated from the number average molecular weight Mn and weight average molecular weight Mw obtained by GPC measurement. Furthermore, the molecular weight ratio and molecular weight ratio of each component (in this case, HEMA or MMA and SB) were calculated from the obtained number average molecular weight (i.e., the molecular weight per polymer chain). For example, the molecular weight ratio of HEMA was calculated by dividing the number average molecular weight of HEMA by the total number average molecular weight. The molecular weight ratio was calculated by dividing the molecular weight ratio of SB by the molecular weight ratio of HEMA.

[0057] <Measurement of Elastic Modulus> The polypropylene plate on which the coating film was formed was wetted by immersing it in ultrapure water. The polypropylene plate was then removed from the ultrapure water, and the surface was lightly wiped. The elastic modulus of the outermost surface of the polypropylene plate was then measured using a nanoindenter. The specific conditions for the nanoindentation method are as follows: Unit: Low load unit (0.0005 mN to 10 mN) Maximum load: 0.060 mN Terminal: Diamond terminal Indenter shape: Berkovich

[0058] <Coating Film Thickness (Film Thickness) Measurement> The polypropylene plate on which the coating film was formed was sliced ​​perpendicular to the coating surface using a microtome (manufactured by Leica Biosystems). This slice was then gold-osmium coated. The slice was placed on a carbon sheet, and the cross section was observed using an SEM. From the obtained image, the film thickness was measured using imageJ (image processing software) with reference to the scale bar. The specific conditions for observing the slice using an SEM are shown below. Acceleration voltage: 5.0 keV Stb PC: 20.0 Backscattered electron detector mode: SED

[0059] <Friction Coefficient Measurement> The opposing surfaces of the polypropylene plates on which the prepared coating film was formed were fixed with double-sided tape. Next, 0.2 mL of water was dropped onto the polypropylene plate, and a 3 mm x 3 mm acrylic resin plate was placed on top. The dynamic friction coefficient and static friction coefficient were measured using a surface measurement device. The specific measurement conditions are shown below. The friction coefficient was measured in accordance with JIS K7125 (ISO 8295). Load: 50 g, Travel speed: 20 mm / min, Travel distance: 20 mm, Number of plots: 30,000

[0060] Tables 1 and 2 were prepared based on the above test results. Table 1 below shows the test results for a coating film having a first layer made of HEMA polymer and a second layer made of SB polymer on a polypropylene substrate. Table 2 below shows the test results for a coating film having a first layer made of MMA polymer and a second layer made of SB polymer on a polypropylene substrate. In the tables, σ indicates standard deviation.

[0061]

[0062] As shown in Table 1, Examples 1 to 7 were shown to have excellent slip properties with a dynamic friction coefficient of 0.02 or less. Of these, Examples 2 to 5 were shown to have particularly excellent slip properties with a dynamic friction coefficient of 0.01 or less.

[0063]

[0064] As shown in Table 2, Examples 8 to 12 were shown to have excellent slip properties with a dynamic friction coefficient of 0.02 or less. Of these, Examples 11 and 12 were shown to have particularly excellent slip properties with a dynamic friction coefficient of 0.01 or less.

[0065] <Correlation with Dynamic Friction Coefficient> From the test results above, the correlation with the elastic modulus of the coating film was investigated for Examples 1 and 6 to 10, where the dynamic friction coefficient was in the range of 0.01 to 0.02. The results are shown in Table 4. Furthermore, the correlation with the elastic modulus of the coating film was investigated for Examples 2 to 5, 11, and 12, where the dynamic friction coefficient was 0.01 or less. The results are shown in Table 4.

[0066]

[0067] Figure 3 was created from the results in Table 3. As shown in Figure 3, when the dynamic friction coefficient was in the range of 0.01 to 0.02, the correlation with the elastic modulus of the coating film was a correlation coefficient R = 0.83, indicating a strong correlation. Therefore, from Table 3, it can be seen that the elastic modulus of the coating film required to achieve excellent slipperiness when the dynamic friction coefficient was 0.01 to 0.02 was 0.1824 N / mm ２ 0.2369N / mm or more ２ is.

[0068]

[0069] Figure 4 was created from the results in Table 4. As shown in Figure 4, in the range of dynamic friction coefficient of 0.01 or less, the correlation with the elastic modulus of the coating film was a correlation coefficient R = 0.90, indicating a strong correlation. Therefore, from Table 4, it can be seen that the elastic modulus of the coating film that provides particularly excellent slipperiness when the dynamic friction coefficient is 0.01 or less is 0.2068 N / mm ２ More than 0.2220N / mm ２ The following is the result.

[0070] <Changing the Second Polymer> A study was also conducted in which the type of second polymer was changed. Here, the substrate was a polypropylene plate, the first polymer was a HEMA polymer, and the second polymer was either 2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetic acid or MPC. Tests were conducted in the same manner as in Example 1, except for changing the type of second polymer. Table 5 shows the coefficient of friction and the elastic modulus of the coating film when 2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetic acid was used as carboxybetaine (CB) to form the second polymer. Table 5 shows the results of Examples 13 to 16. Table 6 shows the coefficient of friction and the elastic modulus of the coating film when MPC was used as phosphobetaine (PB) to form the second polymer. Table 6 shows the results of Examples 17 to 20.

[0071]

[0072]

[0073] As shown in Tables 5 and 6, even when the type of the second polymer was changed, the elastic modulus of the coating film was 0.1824 N / mm ２ 0.2369N / mm or more ２ It was also shown that if the coefficient of dynamic friction is within the range of 0.02 or less, the elastic modulus of the coating film is 0.2068 N / mm ２ More than 0.2220N / mm ２ It was shown that when the coefficient of dynamic friction is within the following range, the coefficient of dynamic friction is 0.01 or less.

[0074] <Confirmation of Speed ​​Dependence> Next, in measuring the static friction coefficient, the moving speed was changed to 20 mm / min, 60 mm / min, 120 mm / min, 180 mm / min, and 240 mm / min to confirm the presence or absence of speed dependency. Example 21 used here was prepared using the same procedure as Example 1. The molecular weight ratio (SB / HEMA) of Example 21 was 0.358. Figure 5 is a graph confirming the presence or absence of speed dependency for a medical device of one embodiment disclosed herein. As shown in Figure 5, it was found that there was no change in the static friction coefficient even when the moving speed was changed. In other words, there was no speed dependency.

[0075] <Study on Different Substrate Materials> Next, a substrate made of a material different from a polypropylene plate was studied. Here, an acrylic resin measuring 30 mm in length, 20 mm in width, and 3.0 mm in thickness was prepared as the substrate material. Then, a coating film was formed on the acrylic plate while varying the amounts of HEMA and MPC added, as in Examples 1 to 7 and Comparative Examples 1 to 7 above. That is, except that the substrate material was changed from a polypropylene plate to an acrylic plate, a coating film was formed in the same manner as the polypropylene plate, and the friction coefficient was measured.

[0076] Figure 6 is a graph comparing the static friction coefficients of polypropylene and acrylic plates for the substrates of the medical device disclosed herein. Figure 7 is a graph comparing the dynamic friction coefficients of polypropylene and acrylic plates for the substrates of the medical device disclosed herein. As shown in Figures 6 and 7, no differences were observed in the static and dynamic friction coefficients depending on the substrate material.

[0077] The present disclosure has been described above with reference to excellent examples, but these descriptions are not limiting, and various modifications such as the type of polymer and the amount of addition are possible.

[0078] In the technology disclosed herein, the components and processes described herein may be omitted or combined as appropriate, unless a particular problem arises. This specification also includes the disclosures described in the following sections.

[0079] Item 1: A medical device that is inserted into a living body at least temporarily or for a long period of time, comprising: a substrate; and a coating film formed on the substrate, wherein the coating film has: a first layer formed on the substrate and made of a first polymer having a vinyl group; and a second layer formed on the first layer and made of a second hydrophilic polymer, wherein the second polymer is a polymer that is more hydrophilic than the first polymer; and the coating film has an elastic modulus of 0.1824 N / mm based on a nanoindentation test. ２ 0.2369N / mm or more ２ The following are medical devices.

[0080] Item 2: The medical device described in Item 1, wherein the second polymer is a zwitterionic polymer.

[0081] Item 3: The elastic modulus is 0.2068 N / mm ２ More than 0.2220N / mm ２ Item 3. The medical device according to item 1 or 2, which is:

[0082] Item 4: The medical device according to any one of Items 2 to 3, wherein the substrate is made of a polyolefin resin or an acrylic resin.

[0083] Item 5: The medical device according to any one of Items 1 to 4, wherein the medical device is an intraocular lens, an intraocular contact lens, or an instrument for inserting a medical device into a living body.

[0084] REFERENCE SIGNS LIST 1, 1a Medical device 10, 10a Substrate 11 Hydrophilic group 20, 20a Coating film 30, 30a First layer 31 First polymer 40, 40a Second layer 41 Second polymer 50 Living radical polymerization agent

Claims

1. A medical device to be inserted into a living body at least temporarily or for a long period of time, comprising: a substrate; and a coating film formed on the substrate, wherein the coating film has: a first layer formed on the substrate and made of a first polymer which is a polymer of a monomer having a vinyl group; and a second layer formed on the first layer and made of a hydrophilic second polymer, wherein the second polymer is a polymer having higher hydrophilicity than the first polymer; and the coating film has an elastic modulus of 0.1824 N / mm based on a nanoindentation test. ２ 0.2369N / mm or more ２ The following are medical devices.

2. The medical device of claim 1, wherein the second polymer comprises a zwitterionic polymer.

3. The elastic modulus is 0.2068 N / mm ２ More than 0.2220N / mm ２ 2. The medical device of claim 1, wherein:

4. The medical device according to claim 1, wherein the substrate is made of a polyolefin resin or an acrylic resin.

5. The medical device according to any one of claims 1 to 4, wherein the medical device is an intraocular lens, an intraocular contact lens, or an instrument for inserting a medical device into a living body.

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