Medical device and method for producing same

Abstract

Provided is a medical device having a coating layer having excellent leak resistance (blood leak resistance) by a means different from conventional techniques.　A medical device according to the present invention comprises a base material having a porous structure and a coating layer formed on at least a part of the surface of the base material. The coating layer contains a crosslinked hyaluronic acid in which a first hyaluronic acid having a viscosity-average molecular weight of 600,000 or more and a second hyaluronic acid having a viscosity-average molecular weight of 100,000 or less are crosslinked by a crosslinking agent.

Description

Medical devices and methods for manufacturing the same

[0001] This invention relates to a medical device and a method for manufacturing the same.

[0002] Technologies for sealing porous artificial blood vessel substrates are being developed. A commonly known such technology is pre-clotting, which involves exposing the surface (vascular wall) of the artificial blood vessel to the patient's blood for coagulation. However, in recent years, technologies have been proposed that involve coating the porous structure of the substrate with bio-derived materials such as gelatin and collagen for sealing (for example, Japanese Patent Publication No. 2005-124959).

[0003] However, the technology disclosed in Japanese Patent Publication No. 2005-124959 makes it difficult to obtain sufficient leak resistance (blood leakage resistance). Therefore, there is still a need for other means to obtain a medical device having a coating layer that exhibits good leak resistance (blood leakage resistance).

[0004] Therefore, the present invention has been made in view of the above circumstances, and aims to provide a medical device having a coating layer with excellent leak resistance (blood leakage resistance) by means different from the prior art. Another object of the present invention is to provide a method for manufacturing a medical device having a coating layer with excellent leak resistance (blood leakage resistance) by means different from the conventional method.

[0005] The inventors conducted diligent research. As a result, they discovered that by providing a coating layer formed using a first hyaluronic acid having a specific viscosity-average molecular weight, a second hyaluronic acid having a different specific viscosity-average molecular weight from the first hyaluronic acid, and a crosslinking agent on the surface of a substrate (a substrate having a porous structure), a medical device with a coating layer having excellent leak resistance (blood leakage resistance) can be obtained, leading to the completion of the present invention.

[0006] The above objective can be achieved by the present invention having the following configuration, and the present invention encompasses the following aspects and forms.

[0007] One aspect of the present invention is: 1. A medical device comprising a substrate having a porous structure and a coating layer formed on at least a part of the surface of the substrate, wherein the coating layer contains crosslinked hyaluronic acid formed by crosslinking a first hyaluronic acid having a viscosity-average molecular weight of 600,000 or more and a second hyaluronic acid having a viscosity-average molecular weight of 100,000 or less with a crosslinking agent; 2. In the medical device described in 1. above, the mass ratio of the first hyaluronic acid to the second hyaluronic acid is preferably 0.5 to 2; 3. In the medical device described in 1. or 2. above, the viscosity-average molecular weight of the first hyaluronic acid is preferably 800,000 to 1,600,000; 4. In the medical device described in any of 1. to 3. above, the viscosity-average molecular weight of the second hyaluronic acid is preferably 50,000 or less; 5. In the medical device described in any of the above, the ratio of the viscosity-average molecular weight of the first hyaluronic acid to the viscosity-average molecular weight of the second hyaluronic acid is preferably 6 to 400; 6. In the medical device described in any of the above 1 to 5, the crosslinking agent preferably contains an epoxy compound having three epoxy groups; 7. In the medical device described in any of the above 1 to 6, the crosslinking agent preferably contains one or more selected from the group consisting of diglycerol triglycidyl ether, glycerol triglycidyl ether, trimethylolethane triglycidyl ether, trimethylolpropane triglycidyl ether, and tris(4-hydroxyphenyl)methane triglycidyl ether; 8. In the medical device described in any of the above 1 to 7, the first hyaluronic acid and the second hyaluronic acid are preferably of non-animal origin; 9. The medical device described in any of the above 1 to 8 is preferably sterilized; 10. In the medical device described in any of items 1 to 9 above, the medical device is preferably an artificial blood vessel, a stent graft, or a covered stent.

[0008] Another aspect of the present invention is a method for manufacturing a medical device, comprising: 11. A coating step of applying a coating solution containing a first hyaluronic acid having a viscosity-average molecular weight of 600,000 or more, a second hyaluronic acid having a viscosity-average molecular weight of 100,000 or less, a crosslinking agent, and a solvent to at least a portion of a substrate having a porous structure; and a crosslinking step of reacting the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent to form crosslinked hyaluronic acid and forming a layer containing the crosslinked hyaluronic acid; 12. In the method for manufacturing a medical device according to 11., it is preferable that the crosslinking agent is a heat-reactive crosslinking agent, and the crosslinking step includes heating the first hyaluronic acid, the second hyaluronic acid, and the heat-reactive crosslinking agent; 13. In the method for manufacturing a medical device according to 11. or 12., it is preferable that the coating step and the crosslinking step are performed multiple times; 14. The methods described in 11. to 13. In the method for manufacturing a medical device as described in any of the above, it is preferable to further include a step of performing sterilization (sterilization step).

[0009] Figure 1 is a schematic partial cross-sectional view showing the structure of a typical embodiment of the medical device according to the present invention. Figure 2 is a schematic partial cross-sectional view showing a different configuration example as an application example of the embodiment of Figure 1. Figure 3 is a front view of the artificial blood vessel.

[0010] According to one aspect of the present invention, a medical device is provided comprising a base material (a base material having a porous structure) and a coating layer formed on at least a part of the surface of the base material. The coating layer contains cross-linked hyaluronic acid, which is formed by cross-linking a first hyaluronic acid having a viscosity-average molecular weight of 600,000 or more and a second hyaluronic acid having a viscosity-average molecular weight of 100,000 or less with a cross-linking agent.

[0011] The inventors have surprisingly discovered that medical devices having such a configuration possess excellent leak resistance (blood leakage resistance) (i.e., they can effectively suppress the leakage of blood from a porous substrate). The mechanism by which the above effects are exerted by the configuration of the present invention is presumed to be as follows.

[0012] The medical device according to the present invention contains the above-mentioned crosslinked hyaluronic acid in a coating layer formed on the surface of a substrate (a substrate having a porous structure). This crosslinked hyaluronic acid is formed by crosslinking a first hyaluronic acid having a viscosity-average molecular weight of 600,000 or more and a second hyaluronic acid having a viscosity-average molecular weight of 100,000 or less with a crosslinking agent. In this case, the first hyaluronic acid, which has a relatively large viscosity-average molecular weight, is presumed to have high viscosity and exist in a state where its molecular chains are not relatively densely packed together (i.e., in a state with gaps). On the other hand, the second hyaluronic acid, which has a relatively small viscosity-average molecular weight, has a small volume occupied by its molecular chains, and can therefore enter into the gaps (intervals) between the molecular chains of the first hyaluronic acid. As a result, crosslinking proceeds in a state where the density of the crosslinked hyaluronic acid as a whole (first hyaluronic acid and second hyaluronic acid) is high, improving the sealing performance of the coating layer and enhancing the effect of suppressing blood leakage. Therefore, the present invention provides a medical device having a coating layer with excellent leak resistance (blood leakage resistance).

[0013] It should be noted that the above mechanism is speculative and does not in any way limit the technical scope of the present invention.

[0014] In this specification, a medical device having the above configuration is also simply referred to as "medical device according to the present invention" or "medical device." Also in this specification, a "substrate having a porous structure" is also simply referred to as "substrate according to the present invention" or "substrate." In this specification, a "first hyaluronic acid having a viscosity-average molecular weight of 600,000 or more" is also simply referred to as "first hyaluronic acid according to the present invention" or "first hyaluronic acid." In this specification, a "second hyaluronic acid having a viscosity-average molecular weight of 100,000 or less" is also simply referred to as "second hyaluronic acid according to the present invention" or "second hyaluronic acid." In this specification, a crosslinking agent used for crosslinking crosslinked hyaluronic acid is also simply referred to as "crosslinking agent according to the present invention" or "crosslinking agent." In this specification, crosslinked hyaluronic acid obtained by crosslinking the first hyaluronic acid according to the present invention and the second hyaluronic acid according to the present invention with a crosslinking agent is also simply referred to as "crosslinked hyaluronic acid according to the present invention" or "crosslinked hyaluronic acid."

[0015] In this specification, the range "X to Y" includes X and Y, meaning "X or greater and Y or less." Furthermore, "A and / or B" means at least one of A and B, and includes A, B, and combinations of A and B. Unless otherwise specified, operations and measurements of physical properties are performed under room temperature (20-25°C) / relative humidity of 40-50% RH.

[0016] In this specification, when a constituent unit is described as "derived from" a monomer or component, it means that the constituent unit has the structure after the corresponding monomer or component has undergone the structural changes necessary for crosslinking (crosslinking reaction).

[0017] Embodiments of the present invention will be described below. However, the present invention is not limited to the embodiments described below, and can be modified in various ways within the scope of the claims. Furthermore, the embodiments described herein can be combined in any way to form other embodiments. The dimensional ratios in the drawings are exaggerated for illustrative purposes and may differ from actual ratios. Also, when describing embodiments of the present invention with reference to the drawings, the same elements are denoted by the same reference numerals in the description of the drawings, and redundant explanations are omitted.

[0018] Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0019] [Medical Device] The configuration of a medical device according to one embodiment of the present invention will be described below with reference to the attached drawings.

[0020] Figure 1 is a schematic partial cross-sectional view showing the structure of a typical embodiment of the medical device according to the present invention. Figure 2 is a schematic partial cross-sectional view showing a different configuration example as an application example of this embodiment.

[0021] As shown in Figures 1 and 2, a medical device 100 according to one embodiment of the present invention comprises a base material 10 having a porous structure and a coating layer 11 formed on at least a part of the surface of the base material 10. That is, a medical device 100 according to one embodiment of the present invention has the base material 10 and a coating layer 11 supported on at least a part of the surface of the base material 10. "Supported" means a state in which the coating layer 11 is fixed in a state in which it does not easily detach from the surface of the base material 10. Here, in this embodiment, the medical device 100 is formed by directly laminating the base material 10 and the coating layer 11 in this order. That is, the base material 10 and the coating layer 11 are laminated adjacent to each other in this order.

[0022] In this embodiment, the cross-linked hyaluronic acid constituting the coating layer may penetrate into the pores (between the mesh) of the porous substrate. With such a structure, the porous structure of the substrate 10 is sealed, and the leak resistance (blood leakage resistance) of the medical device 100 can be further improved.

[0023] Furthermore, in this specification, the reason why the coating layer is described as "formed on at least a part of the surface of the substrate" is that, in the case of medical devices such as artificial blood vessels, stent grafts, and covered stents, which are examples of medical device applications, it is not necessarily required to impart leak resistance (blood leakage resistance) to all surfaces (the entire surface) of these medical devices. It is sufficient for the coating layer to be formed only on the surface portion (which may be a part or the entire surface) where leak resistance (blood leakage resistance) is required. For this reason, it is preferable that the coating layer be formed on at least the portion of the substrate 10 that comes into contact with blood. For example, if the medical device is an artificial blood vessel, stent graft, or covered stent, it is preferable that the coating layer be formed on the entire surface of the substrate. Also, although Figures 1 and 2 illustrate a state in which the coating layer 11 is formed on only one surface of the substrate 10, the coating layer 11 may be formed on both surfaces of the substrate 10.

[0024] 《Substrate (Substrate Layer)》 The substrate 10 has a porous structure. The substrate 10 is sealed by covering part or all of its surface with a coating layer containing cross-linked hyaluronic acid, which will be described later. In addition to the coating layer, the substrate 10 may also be sealed by covering part or all of its surface with biological tissue such as endothelial cells or proteins.

[0025] In one embodiment of the present invention, the substrate 10 is preferably made of a porous material. According to a more preferred embodiment of the present invention, the substrate includes a plastic substrate, and the plastic substrate is a porous material. In this specification, "porous structure" means a structure having voids (pores) that allow the growth or invasion of bodily fluids and / or cells. Also in this specification, "porous material" means a structure having the above-mentioned porous structure. The average pore diameter of the above-mentioned voids (pores) is preferably 1 to 100 μm, and more preferably 1 to 20 μm. Here, the average pore diameter is measured by the following method. First, the surface of the substrate is observed using a scanning electron microscope (SEM), and the pore area of ​​each pore observed in several to tens of fields of view is measured. Then, the diameter of a perfect circle having the same area as the pore area of ​​each pore (equivalent circle diameter) is calculated, and the arithmetic mean of these is taken as the average pore diameter.

[0026] The shape of the base material 10 is not particularly limited and can be appropriately selected depending on the intended use, such as a sheet, film, tube, a shape with multiple branched tubes (e.g., Y-shaped), a linear shape (wire), or a fibrous (thread) shape.

[0027] The base material 10 constituting the medical device according to one embodiment of the present invention is not particularly limited, but preferably includes at least one of a plastic base material (polymer base material) and a metal base material. As the plastic base material, the optimal base material can be appropriately selected according to the properties required for medical devices such as artificial blood vessels, stent grafts, and covered stents (e.g., mechanical strength), and as an example, a base material having properties required for a base material such as mechanical strength, flexibility, and smoothness is preferred. As the metal base material, the optimal base material can be appropriately selected according to the properties required for medical devices such as stent grafts and covered stents (e.g., mechanical strength), and as an example, a base material having properties required for a base material such as mechanical strength, elasticity, and toughness is preferred.

[0028] Preferably, at least the surface of the base material 10 is made of a plastic or metal base material. For example, as shown in Figure 1, the entire base material may be made of a plastic or metal base material. Alternatively, as shown in Figure 2, the base material may have a structure in which a base material core portion 10a made of a material such as a ceramic material has a base material surface layer 10b made of a plastic or metal base material on its surface. Alternatively, the base material core portion 10a and the base material surface layer 10b may be composited (through an appropriate reaction treatment) to form the base material 10. Therefore, the base material core portion 10a may be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which members made of different materials are joined together for each part of the medical device. Furthermore, another middle layer (not shown) may be formed between the base material core portion 10a and the base material surface layer 10b. Furthermore, the substrate surface layer 10b may also be a multilayer structure formed by laminating different materials in multiple layers, or a composite structure in which components made of different materials are joined together, as long as its surface is composed of (formed) a plastic substrate or a metal substrate.

[0029] The plastic material (polymer material) that constitutes (forms) the base material 10 and the base material surface layer 10b is not particularly limited, and polymer materials commonly used in medical devices such as artificial blood vessels, stent grafts, and covered stents are used. Specifically, polyamide resins such as nylon 6, nylon 11, nylon 12, and nylon 66 (all registered trademarks), polyethylene such as linear low-density polyethylene (LLDPE), low-density polyethylene (LDPE), high-density polyethylene (HDPE), and modified polyethylene, polyolefin resins such as polypropylene, polyester resins such as polyethylene terephthalate (PET), polytrimethylene terephthalate (PTT), polybutylene terephthalate (PBT), and polyethylene naphthalate (PEN), styrene resins such as polystyrene, cyclic polyolefin resins, modified polyolefin resins, epoxy resins, urethane resins, diallyl phthalate resins (allyl resins), polycarbonate resins, polytetrafluoroethylene (PTFE), and ePTFE (expanded polyethylene tetrafluoroethylene) are used. Examples of polymer materials include fluororesins such as polytetrafluoroethylene, polyurethane resins, amino resins (urea resin, melamine resin, benzoguanamine resin), acrylic resins, polyacetal resins, vinyl acetate resins, phenolic resins, vinyl chloride resins, silicone resins (silicon resins), polyether resins such as polyetheretherketone (PEEK), and polyimide resins. These may be used individually or in combination of two or more. The above polymer materials can be appropriately selected depending on the application of the medical device. As an example of an application, the polymer material (plastic) that constitutes (forms) the base material of an artificial blood vessel, stent graft, covered stent, etc., preferably contains one or more selected from the group consisting of polyester resin, fluororesin, polyurethane resin, and silicone resin (silicon resin), and more preferably contains one or more selected from the group consisting of polyester resin, fluororesin, polyurethane resin, and silicone resin (silicon resin). Furthermore, from the viewpoint of mechanical strength, it is more preferable for the above polymer material (plastic) to contain polyester resin.

[0030] Furthermore, the metal materials constituting (forming) the base material 10 and the base material surface layer 10b are not particularly limited, and metal materials commonly used in medical devices such as stent grafts, covered stents, and stents can be used. Specifically, examples include gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, stainless steel (e.g., SUS304, SUS314, SUS316, SUS316L, SUS420J2, SUS630, SUS631), nickel-titanium alloys, nickel-cobalt alloys, cobalt-chromium alloys, zinc-tungsten alloys, etc. These may be used individually or in combination of two or more. The above metal materials can be appropriately selected according to the application of the medical device. As for the metal material that constitutes (forms) the base material of stent grafts, covered stents, etc., which are examples of applications, it is more preferable that it be one or more selected from the group consisting of stainless steel and nickel-titanium alloys, and even more preferable from the viewpoint of versatility that it be one or more selected from the group consisting of nickel-titanium alloys.

[0031] The material that can be used for the base material core 10a described above is not particularly limited, and any material that can fully exhibit the optimal function of the base material core 10a according to the application of the medical device should be appropriately selected. When the base material 10 and the base material surface layer 10b are made of plastic material, examples of materials for the base material core 10a include the various metal materials and various ceramic materials described above, as well as metal-ceramic composites, but are not limited to these. Furthermore, when the base material 10 and the base material surface layer 10b are made of metal material, examples of materials for the base material core 10a include the various plastic materials and various ceramic materials described above, as well as inorganic materials, but are not limited to these.

[0032] Alternatively, the base material core portion 10a may be composed of a plastic material or metal material other than the plastic material or metal material that forms (constitutes) the base material surface layer 10b. Examples of such plastic materials or metal materials are not particularly limited and include those similar to those described above. These may be used individually or in combination of two or more types.

[0033] Preferably, the base material 10 includes or is composed of a plastic material, or the base material surface layer 10b includes or is composed of a plastic material. More preferably, the base material 10 is composed of a plastic material, or the base material surface layer 10b is composed of a plastic material. That is, according to one embodiment of the present invention, the base material includes a plastic base material. According to a more preferred embodiment of the present invention, the base material consists of a plastic base material.

[0034] Hereinafter, a preferred embodiment of the present invention will be described in which the medical device is an artificial blood vessel. Figure 3 shows an artificial blood vessel 1 of a preferred embodiment of the present invention viewed from the front.

[0035] In the artificial blood vessel 1, the base material 10 is partially or entirely covered on its inner surface and / or outer surface by a coating layer containing cross-linked hyaluronic acid, as described later. With this configuration, the artificial blood vessel 1 has excellent leak resistance (blood leakage resistance).

[0036] The base material 10 constituting the artificial blood vessel 1 adopts a bellows structure so that its side surface will not be crushed even if it is bent during surgery. Note that, instead of this bellows structure, ring-shaped ribs may be formed on the outer peripheral surface of the base material 10, or if the base material 10 itself has a certain elastic force, it may be formed with a smooth surface. Also, the artificial blood vessel 1 may include a branch pipe branching from the base material 10 (main pipe). There are no particular restrictions on the number, position, inner diameter, outer diameter, etc. of the branch pipes. As an example, the artificial blood vessel 1 can be used as a substitute for partially replacing the aortic arch in the surgical treatment of the aortic arch (aortic arch replacement surgery). In this case, the base material 10 (tube) constituting the artificial blood vessel 1 can be set to have an outer diameter of about 12 mm to 30 mm, a wall thickness of about 0.1 mm to 1 mm, and a length of about 100 mm to 600 mm.

[0037] Note that after transplantation of the artificial blood vessel 1, living tissue may penetrate into the porous structure inside the base material 10, and the inner peripheral surface (inner surface) and the outer peripheral surface (outer surface) may be covered by the living tissue.

[0038] 《Coat layer》 The coat layer according to the present invention contains crosslinked hyaluronic acid in which a first hyaluronic acid having a viscosity average molecular weight of 600,000 or more and a second hyaluronic acid having a viscosity average molecular weight of 100,000 or less are crosslinked by a crosslinking agent. In this specification, the value measured by the intrinsic viscosity method is used as the viscosity average molecular weight of hyaluronic acid. Specifically, the viscosity average molecular weight of hyaluronic acid is measured by the following method: Precisely weigh about 50 mg of the hyaluronic acid to be measured, dissolve it in an aqueous solution of 0.2 mol / L sodium chloride, and make it exactly 100 mL to prepare a solution. Next, accurately measure 10 mL, 15 mL, and 20 mL of the solution, and add an aqueous solution of 0.2 mol / L sodium chloride to each to make it exactly 25 mL to obtain a sample solution. For the sample solution and the aqueous solution of 0.2 mol / L sodium chloride, measure the specific viscosity at 30.0 ± 0.1 °C by the viscosity measurement method, and calculate the reduced viscosity at each concentration. Draw a graph with the reduced viscosity on the vertical axis and the concentration of hyaluronic acid (concentration converted to dry matter) (g / 100 mL) on the horizontal axis, and obtain the intrinsic viscosity from the intersection of the straight line connecting each point and the vertical axis. However, the specific viscosity and the reduced viscosity are obtained from the following equations respectively.

[0039]

[0040] The viscosity-average molecular weight is determined by the following formula. For viscosity-average molecular weights less than 1.5 million, conversion formula A is used, and for viscosity-average molecular weights of 1.5 million or more, conversion formula B is used. In the following conversion formulas A and B, [η] uses the intrinsic viscosity determined by the above method. In the following conversion formulas A and B, for example, α = 35 - 40, β = 0.5 - 0.8, γ = 20 - 25, and δ = 0.8 - 1.0.

[0041]

[0042] Also, the number-average molecular weight of each hyaluronic acid constituting the crosslinked hyaluronic acid can be measured by the above method after performing a treatment to cleave the crosslinking with respect to the crosslinked hyaluronic acid.

[0043] The coating layer may be in a single-layer form or a laminated form of two or more layers. Preferably, the coating layer is in a laminated form of two or more layers. Although the upper limit of the number of laminations is not particularly limited, considering the productivity of the medical device, for example, it is 10 layers or less.

[0044] When the coating layer is formed by impregnating the substrate, the thickness (dry film thickness) of the coating layer may have some unevenness in thickness, but as an average thickness, for example, it is 0.1 - 10 μm, preferably 0.5 - 8 μm, and more preferably 1 - 5 μm. When the thickness of the coating layer is within the above range, the leak resistance by the coating layer can be sufficiently achieved. When the coating layer has the above laminated form as described above, the thickness of the coating layer intends the total thickness thereof.

[0045] (First / Second Hyaluronic Acid) The first hyaluronic acid and the second hyaluronic acid constituting the coating layer according to the present invention will be described below. In this specification, when simply described as "hyaluronic acid", both the first hyaluronic acid and the second hyaluronic acid are intended.

[0046] In this specification, "hyaluronic acid" refers to a polysaccharide having one or more constituent units consisting of a disaccharide formed by the bonding of glucuronic acid and N-acetylglucosamine. Furthermore, in this specification, unless otherwise specified, the term "hyaluronic acid" may include not only hyaluronic acid but also its salts. Here, "hyaluronic acid salt" is not particularly limited, but it is preferably a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of hyaluronic acid include, but are not limited to, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid; salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, lactic acid, and oleic acid; quaternary ammonium salts with methyl bromide and methyl iodide; salts with halide ions such as bromide, chloride, and iodide; salts with alkali metals such as lithium, sodium, and potassium; salts with alkaline earth metals such as calcium and magnesium; metal salts with iron and zinc; salts with ammonia; and salts with organic amines such as triethylenediamine. As salts of hyaluronic acid, salts with alkali metals (alkali metal salts of hyaluronic acid) are preferred, and sodium hyaluronate is more preferred. Furthermore, the above salts of hyaluronic acid may be in the form of hydrates or solvates.

[0047] Hyaluronic acid is not particularly limited as long as it has a constituent unit consisting of the disaccharide described above, and may be chemically modified (modified hyaluronic acid) or not chemically modified (unmodified hyaluronic acid). Examples of modified hyaluronic acid include, but are not limited to, alkylated hyaluronic acid, urethane-modified hyaluronic acid, thiolated hyaluronic acid, esterified hyaluronic acid, and etherified hyaluronic acid.

[0048] In one embodiment, the hyaluronic acid used as a raw material in the present invention is preferably unmodified hyaluronic acid. That is, the first hyaluronic acid and / or the second hyaluronic acid are preferably unmodified hyaluronic acid, and it is more preferable that the first and second hyaluronic acid are unmodified hyaluronic acid. In this configuration, since there is no need to modify the hyaluronic acid, it is possible to further improve not only the productivity of the medical device but also the stability of its quality. Furthermore, in this configuration, there is no need to consider the effects of the modifying group (functional group) itself on the living body, and the safety of the resulting medical device is further improved.

[0049] In the present invention, examples of hyaluronic acid used as a raw material include (i) extracted from natural products such as animals (e.g., living tissues such as chicken combs, umbilical cords, skin, and synovial fluid) by known methods; (ii) obtained by microbial fermentation or cultivation of plant cells; and (iii) synthesized chemically or enzymatically. Among these, (ii) and (iii) above are preferred. That is, it is preferable that the hyaluronic acid used in the present invention (first hyaluronic acid and second hyaluronic acid) is of non-animal origin (non-animal derived hyaluronic acid). By adopting such a form, the stability of the quality of the resulting medical device is further improved. Furthermore, as the hyaluronic acid used as a raw material, (ii) above is more preferred, and hyaluronic acid obtained by microbial fermentation is particularly preferred.

[0050] The viscosity-average molecular weight (Mv) of the first hyaluronic acid is 600,000 or more. Preferably, the viscosity-average molecular weight (Mv) of the first hyaluronic acid is 800,000 or more, more preferably 850,000 or more, even more preferably 1,000,000 or more, and particularly preferably 1,200,000 or more. On the other hand, there is no particular upper limit, but for example, it may be 4,000,000 or less, 3,000,000 or less, 2,200,000 or less, or 1,600,000 or less. In one embodiment, the viscosity-average molecular weight (Mv) of the first hyaluronic acid is preferably 800,000 to 3,000,000, more preferably 800,000 to 2,200,000, and particularly preferably 800,000 to 1,600,000. In another embodiment, the viscosity-average molecular weight (Mv) of the first hyaluronic acid may be 800,000 to 4,000,000, 850,000 to 3,000,000, 1,000,000 to 3,000,000, 1,200,000 to 2,200,000, or 1,200,000 to 1,600,000.

[0051] The viscosity-average molecular weight (Mv) of the second hyaluronic acid is 100,000 or less. Preferably, the viscosity-average molecular weight (Mv) of the second hyaluronic acid is 50,000 or less, more preferably 30,000 or less, and particularly preferably 10,000 or less. On the other hand, the lower limit is not particularly limited, but for example, it is 3,000 or more. In one embodiment, the viscosity-average molecular weight (Mv) of the second hyaluronic acid is preferably 3,000 or more and 50,000 or less, more preferably 3,000 or more and 30,000 or less, and particularly preferably 3,000 or more and 10,000 or less.

[0052] The relationship between the viscosity-average molecular weight of the first hyaluronic acid and the viscosity-average molecular weight of the second hyaluronic acid is not particularly limited, as long as the viscosity-average molecular weight of each hyaluronic acid is within the above range. In one embodiment, it is preferable that the viscosity-average molecular weight (Mv) of the first hyaluronic acid is 1.2 million or more, and the viscosity-average molecular weight (Mv) of the second hyaluronic acid is 10,000 or less. In another embodiment, it is preferable that the viscosity-average molecular weight (Mv) of the first hyaluronic acid is 1.2 million or more, and the viscosity-average molecular weight (Mv) of the second hyaluronic acid is 50,000 or less. In another embodiment, it is preferable that the viscosity-average molecular weight (Mv) of the first hyaluronic acid is 800,000 or more, and the viscosity-average molecular weight (Mv) of the second hyaluronic acid is 10,000 or less. In another embodiment, it is preferable that the viscosity-average molecular weight (Mv) of the first hyaluronic acid is 800,000 or more, and the viscosity-average molecular weight (Mv) of the second hyaluronic acid is 50,000 or less.

[0053] Furthermore, from the viewpoint of further improving leak resistance (blood leakage resistance), the ratio of the viscosity-average molecular weight of the first hyaluronic acid to the viscosity-average molecular weight of the second hyaluronic acid (Mv of the first hyaluronic acid / Mv of the second hyaluronic acid) is preferably 6 to 400. Moreover, from the viewpoint of further improving leak resistance (blood leakage resistance), the above ratio (Mv of the first hyaluronic acid / Mv of the second hyaluronic acid) is more preferably 16 to 200, particularly preferably 24 to 160, and most preferably 120 to 160.

[0054] The mass ratio of the first hyaluronic acid to the second hyaluronic acid contained in the coating layer is not particularly limited. From the viewpoint of further improving leak resistance (blood leakage resistance), the mass ratio of the first hyaluronic acid to the second hyaluronic acid (more specifically, the mass of constituent units derived from the first hyaluronic acid / the mass of constituent units derived from the second hyaluronic acid) is preferably 0.1 to 3, more preferably 0.5 to 2, even more preferably 0.8 to 1.8, particularly preferably 1 to 1.5, and most preferably 1. In other words, the mass ratio of the first hyaluronic acid to the second hyaluronic acid (more specifically, the mass of constituent units derived from the first hyaluronic acid to the mass of constituent units derived from the second hyaluronic acid) is preferably 0.1:1 to 3:1, more preferably 0.5:1 to 2:1, even more preferably 0.8:1 to 1.8:1, particularly preferably 1:1 to 1.5:1, and most preferably 1:1.

[0055] The constituent components and their proportions in the coating layer, as well as the constituent components and their proportions in each constituent unit, can be determined, for example, by NMR measurement. １ H-NMR, １３ These can be identified by 13C-NMR and reaction pyrolysis GC / MS measurement. Furthermore, the proportion (mass ratio) of these components can be controlled by adjusting the mass ratio of each hyaluronic acid used during coating layer formation and / or the concentration in the coating solution.

[0056] (Crosslinking agent) The crosslinked hyaluronic acid according to the present invention is obtained by crosslinking the first hyaluronic acid and the second hyaluronic acid with a crosslinking agent. The crosslinking agent used in the present invention is not particularly limited as long as it is a compound that can crosslink hyaluronic acid, and examples include compounds having two or more crosslinkable groups. The crosslinkable groups are preferably heat-reactive groups that react upon heating. That is, the crosslinking agent is preferably a crosslinking agent having heat-reactive groups (also referred to as "heat-reactive crosslinking agent" in this specification). Here, "heat-reactive groups that react upon heating" means crosslinkable groups that produce a crosslinking reaction between hyaluronic acid and the crosslinking agent when heated to 40°C or higher. Specific examples of such heat-reactive groups include vinyl groups (CH ２=CH-), acryloyl group (CH ２ =CH-C(=O)-), methacryloyl group (CH ２ =C(CH ３ )-C(=O)-), etc. of ethylenically unsaturated groups; epoxy group (-C ２ H ３ O), oxetanyl group, etc. of cyclic ether groups; thiol group; halogen atom; isocyanate group, crosslinking groups such as onium salt structure, etc. Among these, the crosslinking agent (thermal reactive crosslinking agent) preferably has an ethylenically unsaturated group or a cyclic ether group, more preferably has a cyclic ether group, and particularly preferably has an epoxy group. The epoxy group may be contained in the form of a glycidyl group (-CH ２ (C ２ H ３ O)) in the molecule.

[0057] The number of the above crosslinkable groups (preferably, thermal reactive groups) contained in the crosslinking agent (the number in one molecule) is not particularly limited. In one embodiment, the number of the above crosslinkable groups (the number in one molecule) is preferably 2 to 5, more preferably 3 to 4, and particularly preferably 3. Particularly when the number of crosslinkable groups is 3, the crosslinking with hyaluronic acid proceeds easily, and the leak resistance (bleeding resistance) of the coating layer is improved. Also, since excessive crosslinking is suppressed, the flexibility of the coating layer is also good, and it is suitable for medical devices that require flexibility, such as artificial blood vessels.

[0058] Also, in another embodiment, the average number of the above crosslinkable groups (preferably, thermal reactive groups) contained in the crosslinking agent is preferably 2 to 5, more preferably 3 to 4, and particularly preferably 3. Particularly when the average number of crosslinkable groups is 3, the crosslinking with hyaluronic acid proceeds easily, and the leak resistance (bleeding resistance) of the coating layer is improved. Also, since excessive crosslinking is suppressed, the flexibility of the coating layer is also good, and it is suitable for medical devices that require flexibility, such as artificial blood vessels.

[0059] In one embodiment, the crosslinking agent preferably contains an epoxy compound having 2 to 5 epoxy groups, more preferably contains an epoxy compound having 3 to 4 epoxy groups, and particularly preferably contains an epoxy compound having 3 epoxy groups.

[0060] Specific examples of crosslinking agents having three epoxy groups include, but are not limited to, aliphatic glycidyl ethers such as diglycerol triglycidyl ether (diglycerin triglycidyl ether), glycerol triglycidyl ether (glycerin triglycidyl ether), trimethylolethane triglycidyl ether, and trimethylolpropane triglycidyl ether; and aromatic glycidyl ethers such as tris(4-hydroxyphenyl)methane triglycidyl ether. These may be used individually or in combination of two or more.

[0061] In one embodiment, the crosslinking agent preferably comprises one or more selected from the group consisting of diglycerol triglycidyl ether, glycerol triglycidyl ether, trimethylolethane triglycidyl ether, trimethylolpropane triglycidyl ether, and tris(4-hydroxyphenyl)methane triglycidyl ether.

[0062] In other embodiments, the crosslinking agent preferably contains an aliphatic glycidyl ether having three epoxy groups, more preferably contains one or more selected from the group consisting of diglycerol triglycidyl ether, glycerol triglycidyl ether, trimethylolethane triglycidyl ether, and trimethylolpropane triglycidyl ether, more preferably contains diglycerol triglycidyl ether and / or glycerol triglycidyl ether, and particularly preferably contains diglycerol triglycidyl ether.

[0063] The molecular weight of the crosslinking agent is not particularly limited, but from the viewpoint of further improving leak resistance (blood leakage resistance), it is preferably 200 to 500, more preferably 250 to 400, and particularly preferably 300 to 380. A crosslinking agent having the above molecular weight is thought to easily penetrate between the molecular chains of hyaluronic acid and efficiently promote crosslinking. The molecular weight of the crosslinking agent can be measured by known methods, such as gas chromatography-mass spectrometry (GC-MS), after dissolving the coating layer in a suitable solvent and performing a treatment to cleave the bond between the crosslinking agent and hyaluronic acid.

[0064] As the crosslinking agent, commercially available products or synthetic products may be used. Examples of commercially available products include, but are not limited to, Denacol® EX-313, EX-314, EX-321, EX-321L, and EX-421 (manufactured by Nagase ChemteX Corporation).

[0065] The mass ratio of the crosslinking agent to the hyaluronic acid contained in the coating layer is not particularly limited. From the viewpoint of further improving leak resistance (blood leakage resistance), the mass ratio of the crosslinking agent to the hyaluronic acid (more specifically, (mass of constituent units derived from the crosslinking agent) / (total mass of constituent units derived from the first hyaluronic acid and the second hyaluronic acid)) is preferably 0.001 to 1, more preferably 0.01 to 0.8, even more preferably 0.03 to 0.5, and particularly preferably 0.04 to 0.1. In other words, the ratio of the total mass of hyaluronic acid (the sum of the first and second hyaluronic acid) to the mass of the crosslinking agent (more specifically, the total mass of constituent units derived from hyaluronic acid : the mass of constituent units derived from the crosslinking agent) is preferably 1:0.001 to 1:1, more preferably 1:0.01 to 1:0.8, even more preferably 1:0.03 to 1:0.5, and particularly preferably 1:0.04 to 1:0.1. When two or more types of crosslinking agents are used, the mass of the crosslinking agents refers to their total mass. These proportions (mass ratios) can be controlled by adjusting the mass ratio of hyaluronic acid and crosslinking agents used during coating layer formation and / or the concentration in the coating solution. Even if the ratio falls outside the above range, it is still perfectly usable as long as it does not affect the effects of the present invention.

[0066] (Cross-linked hyaluronic acid) The cross-linked hyaluronic acid according to the present invention has a structure in which the first hyaluronic acid and the second hyaluronic acid described above are cross-linked by a cross-linking agent. Specifically, cross-linked hyaluronic acid refers to hyaluronic acid in which chemical bonds are formed between atoms contained in the hyaluronic acid molecule and atoms contained in the cross-linking agent, resulting in the formation of a three-dimensional network structure. The positions (cross-linking points) where cross-links are formed in cross-linked hyaluronic acid are not particularly limited, and cross-links may be formed not only between the molecular chains of the first hyaluronic acid and the molecular chains of the second hyaluronic acid, but also between and within the molecular chains of the first hyaluronic acid, and between and within the molecular chains of the second hyaluronic acid, or any one or more of these.

[0067] The cross-linking structure (chemical bond) in cross-linked hyaluronic acid is not particularly limited and depends on the structure of the cross-linking agent used, for example, ester bonds, ether bonds, etc. In one embodiment, the cross-linked hyaluronic acid may be a cross-linked hyaluronic acid in which ester bonds or ether bonds are formed between the carboxyl group or hydroxyl group of hyaluronic acid and the cross-linking agent.

[0068] As will be explained in detail below, in one preferred embodiment, the coating layer is formed by applying a coating solution containing a first hyaluronic acid, a second hyaluronic acid, and a crosslinking agent onto a substrate (substrate layer), and then crosslinking the first hyaluronic acid and the second hyaluronic acid. In this case, the crosslinked hyaluronic acid can be defined as being formed by crosslinking the first hyaluronic acid and the second hyaluronic acid contained in the coating solution applied to the substrate with a crosslinking agent. As described above, crosslinking of hyaluronic acid by the crosslinking agent can occur not only between the molecular chains of the first hyaluronic acid and the molecular chains of the second hyaluronic acid, but also between and within the molecular chains of the first hyaluronic acid, and between and within the molecular chains of the second hyaluronic acid. Since the crosslinking positions in this crosslinking reaction are random, the crosslinking positions of the crosslinked hyaluronic acid cannot be identified, or are very difficult to identify, and cannot be represented by a general formula (structure), or are very difficult to represent by a general formula (structure). Therefore, at the time of filing the application, it is impossible or impractical to directly identify the above-mentioned cross-linked hyaluronic acid by its structure or properties. Consequently, it may be appropriate to identify the cross-linked hyaluronic acid as a "substance" by the provision "cross-linked hyaluronic acid formed by cross-linking a first hyaluronic acid and a second hyaluronic acid with a cross-linking agent."

[0069] (Optional Components) The coating layer must contain the above-mentioned cross-linked hyaluronic acid, but may also contain other components (optional components) such as pharmaceuticals. When the coating layer contains other components, there are no particular restrictions on the other components, and they are appropriately selected depending on the intended use of the medical device. Furthermore, there are no particular restrictions on the amount of other components added, and the amount normally used is applied in the same manner. Ultimately, the amount of other components added is appropriately selected by the attending physician, taking into consideration the severity of the disease to which it is applied, the patient's weight, etc. Preferably, the coating layer is substantially free of other components (i.e., the coating layer is substantially composed of cross-linked hyaluronic acid). Specifically, the content of other components (in terms of solid content) relative to the total mass of the coating layer is preferably less than 10% by mass, more preferably less than 5% by mass, and even more preferably less than 1% by mass (lower limit 0% by mass).

[0070] [Method for Manufacturing a Medical Device] Another aspect of the present invention also provides a method for manufacturing the medical device described above. That is, one embodiment of the present invention is a method for manufacturing a medical device (hereinafter also referred to simply as "method for manufacturing a medical device according to the present invention" or "manufacturing method") comprising: a coating step of applying a coating solution containing a first hyaluronic acid having a viscosity-average molecular weight of 600,000 or more, a second hyaluronic acid having a viscosity-average molecular weight of 100,000 or less, a crosslinking agent, and a solvent to at least a part of a substrate having a porous structure; and a crosslinking step of reacting the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent to form crosslinked hyaluronic acid and forming a layer containing the crosslinked hyaluronic acid.

[0071] The following describes preferred embodiments of each step in the manufacturing method of the medical device according to the present invention. However, the manufacturing method of the medical device according to the present invention is not limited to the embodiments described below.

[0072] The method for manufacturing a medical device according to the present invention includes the steps of: applying a coating solution containing the first hyaluronic acid, the second hyaluronic acid, a crosslinking agent, and a solvent to at least a part of the substrate (coating step); and reacting the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent to form crosslinked hyaluronic acid and forming a layer (coating layer) containing the crosslinked hyaluronic acid (crosslinking step). In this way, by applying a solution containing the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent as a coating solution to the surface of the substrate and forming a layer containing crosslinked hyaluronic acid, a medical device with excellent leak resistance (blood leakage resistance) can be obtained.

[0073] In the method for manufacturing medical devices according to the present invention, terms such as the first hyaluronic acid, the second hyaluronic acid, the crosslinking agent, and the crosslinked hyaluronic acid, as well as preferred forms thereof, are the same as those described in the [Medical Devices] section above, so their explanation is omitted here.

[0074] In the method for manufacturing a medical device according to the present invention, if necessary, steps such as preparing a coating solution (coating solution preparation step) may be performed before the above coating step. Furthermore, in the method for manufacturing a medical device according to the present invention, if necessary, steps such as washing the obtained medical device (washing step), drying the medical device (drying step), and sterilizing the medical device (sterilization step) may be performed after the above crosslinking step.

[0075] The following describes each of the above steps.

[0076] 《Coating Solution Preparation Step》 The method for manufacturing a medical device according to the present invention may further include a coating solution preparation step before the coating step described below. In this step, a coating solution containing a first hyaluronic acid, a second hyaluronic acid, a crosslinking agent, a solvent, and other components used as needed is prepared. Here, in this step, the coating solution may be prepared by mixing the first hyaluronic acid, the second hyaluronic acid, a crosslinking agent, a solvent, and other components used as needed to prepare the coating solution. Alternatively, a coating solution containing the first hyaluronic acid, the second hyaluronic acid, a crosslinking agent, a solvent, and other components used as needed may be purchased and used.

[0077] In the following, a preferred form of preparing the coating solution will be described in detail, which involves mixing the first hyaluronic acid, the second hyaluronic acid, a crosslinking agent, and a solvent to prepare the coating solution.

[0078] A coating solution is prepared using the first hyaluronic acid, the second hyaluronic acid, a crosslinking agent, and a solvent. The order and method of adding the first hyaluronic acid, the second hyaluronic acid, the crosslinking agent, and the solvent are not particularly limited. Each of the above components may be added together or separately, in stages or sequentially.

[0079] Furthermore, there are no particular restrictions on the method of mixing each component, and known methods can be used. Methods for preparing the coating solution include sequentially adding the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent to the solvent; adding the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent to the solvent all at once; and preparing the first hyaluronic acid solution, the second hyaluronic acid solution, and the crosslinking agent solution separately, and then mixing these solutions.

[0080] From the viewpoint of easily preparing a homogeneous solution (coating solution), it is preferable to prepare the coating solution by first preparing a first hyaluronic acid solution, a second hyaluronic acid solution, and a crosslinking agent solution, and then mixing these solutions. The order in which these solutions are mixed is not particularly limited, but from the viewpoint of easily controlling crosslinking by the crosslinking agent (suppressing the progress of the crosslinking reaction in the coating solution), it is preferable to pre-mix the first hyaluronic acid solution and the second hyaluronic acid solution before adding the crosslinking agent solution. This addition may be carried out while stirring if necessary. More specifically, it is preferable to mix the solvent with the first hyaluronic acid or the second hyaluronic acid to obtain the first hyaluronic acid solution and the second hyaluronic acid solution, respectively, then mix these solutions to prepare a hyaluronic acid solution, and then mix the hyaluronic acid solution with a crosslinking agent solution obtained by pre-mixing the solvent and the crosslinking agent. When using other components, the other components may be added directly at any of the above stages, or a solution of the other components may be prepared in advance and then added.

[0081] The solvent used in the preparation of the coating solution (first hyaluronic acid solution, second hyaluronic acid solution, and crosslinking agent solution) is not particularly limited as long as it can dissolve the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent (and other components if other components are used). Specific examples of solvents for the coating solution include, for example, water (reverse osmosis water (RO water), pure water, deionized water, distilled water, etc.); alcoholic solvents such as methanol, ethanol, isopropyl alcohol, butanol, ethylene glycol, and glycerin; ketone solvents such as acetone, methyl ethyl ketone, and cyclohexanone; ester solvents such as ethyl acetate and butyl acetate; ether solvents such as tetrahydrofuran (THF), butyl ether, and dioxane; aliphatic hydrocarbon solvents such as hexane and heptane; aromatic hydrocarbon solvents such as benzene and toluene; dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), etc. These may be used individually or mixed together in a mixed solvent form. In particular, the solvent preferably contains water, and more preferably contains RO water. Furthermore, when glycerin is used, as a secondary effect, it can be expected to improve the adsorption of hyaluronic acid to the substrate (e.g., fibers), thereby improving coating efficiency. Therefore, in one embodiment of the present invention, the coating liquid preferably contains a first hyaluronic acid, a second hyaluronic acid, a crosslinking agent, water, and glycerin.

[0082] The concentrations of each solution used in preparing the above coating solution (a first hyaluronic acid solution, a second hyaluronic acid solution, and a crosslinking agent solution, all prepared in advance) are not particularly limited. In one embodiment, the concentration of the first hyaluronic acid in the first hyaluronic acid solution is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, and particularly preferably 0.8 to 3% by mass. In one embodiment, the concentration of the second hyaluronic acid in the second hyaluronic acid solution is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, and particularly preferably 0.8 to 3% by mass. In one embodiment, the concentration of the crosslinking agent in the crosslinking agent solution is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, and particularly preferably 0.7 to 3% by mass. If the concentrations of each solution are within the above ranges, the leak resistance of the resulting coating layer can be sufficiently exhibited. Furthermore, the viscosity of the coating solution is within an appropriate range, which is preferable in terms of workability (e.g., ease of coating) and production efficiency. However, even if it falls outside the above range, it is still perfectly usable as long as it does not affect the effects of the present invention.

[0083] By mixing the first hyaluronic acid solution, the second hyaluronic acid solution, and the crosslinking agent solution described above, a coating solution with good applicability can be prepared.

[0084] In this case, the mixing ratio of the first hyaluronic acid solution and the second hyaluronic acid solution can be adjusted to match the mass ratio (content ratio) of constituent units derived from the first hyaluronic acid and constituent units derived from the second hyaluronic acid present in the coating layer described above. Preferably, the solutions are mixed such that the preferred mass ratio (mixing ratio) of the first hyaluronic acid and the second hyaluronic acid in the coating solution is the same as the preferred content ratio (mass ratio) of each constituent unit derived from the first hyaluronic acid and the second hyaluronic acid present in the coating layer. However, even if the ratio falls outside the above range, it is still perfectly usable as long as it does not affect the effects of the present invention.

[0085] Furthermore, the mixing ratio of the hyaluronic acid solution and the crosslinking agent solution can be adjusted to match the mass ratio (content ratio) of constituent units derived from hyaluronic acid (first hyaluronic acid and second hyaluronic acid) present in the coating layer described above to the constituent units derived from the crosslinking agent. Preferably, the solutions are mixed such that the preferred mass ratio (mixing ratio) of the first hyaluronic acid, second hyaluronic acid, and crosslinking agent in the coating solution is the same as the preferred content ratio (mass ratio) of each constituent unit derived from the first hyaluronic acid, second hyaluronic acid, and crosslinking agent present in the coating layer. However, even if the ratio falls outside the above range, it is still perfectly usable as long as it does not affect the effects of the present invention.

[0086] In one embodiment, the concentration of the first hyaluronic acid in the coating solution is preferably 0.05 to 5% by mass, more preferably 0.25 to 2.5% by mass, and particularly preferably 0.3 to 1.5% by mass. In one embodiment, the concentration of the second hyaluronic acid in the coating solution is preferably 0.05 to 5% by mass, more preferably 0.25 to 2.5% by mass, and particularly preferably 0.3 to 1.5% by mass. In one embodiment, the concentration of the crosslinking agent in the coating solution is preferably 0.005 to 0.5% by mass, more preferably 0.025 to 0.25% by mass, and particularly preferably 0.035 to 0.15% by mass. If the concentrations of each component in the coating solution are within the above ranges, the leak resistance of the resulting coating layer can be sufficiently exhibited. Furthermore, the viscosity of the coating solution is within an appropriate range, which is preferable in terms of workability (e.g., ease of coating) and production efficiency. However, even if the range falls outside the above range, it is still perfectly usable as long as it does not affect the effects and benefits of the present invention.

[0087] 《Coating Process》 In this process, the coating liquid prepared in the coating liquid preparation process described above is applied to at least a portion of the substrate (substrate layer, hereinafter the same) to form a coating film (precursor layer) on the substrate.

[0088] The substrate may be composed of any material, but examples include metal materials, polymer materials, and ceramics. Specific examples of these materials are the same as those described in the section on "Substrate (Substrate Layer)" above, so a detailed explanation is omitted here.

[0089] The method for applying the coating liquid to the surface of the substrate (substrate layer) is not particularly limited, and conventionally known methods such as coating / printing, immersion (dipping method, dip coating method), spraying method, spin coating method, mixed solution impregnation sponge coating method, bar coating method, die coating method, reverse coating method, comma coating method, gravure coating method, and doctor knife method can be applied. Of these, the immersion method (dipping method, dip coating method) is preferred.

[0090] Furthermore, in order to form a coating layer on a substrate having a porous structure on its surface and to impart excellent leak resistance, it is preferable to use a method in which the substrate is immersed in a coating solution and the system is degassed under reduced pressure (vacuum impregnation). By degassing under reduced pressure, the coating solution can be quickly penetrated into the pores on the surface of the substrate, thereby promoting the formation of the coating layer.

[0091] The conditions for vacuum impregnation are not particularly limited. The reduced pressure may be, for example, -0.8 to -1 MPa relative to atmospheric pressure, and preferably -0.9 to -1 MPa. The temperature is not particularly limited, but is, for example, 20 to 40°C. The time for vacuum impregnation of the substrate may be, for example, 1 minute to 1 hour, and preferably 5 minutes to 30 minutes. It is preferable to perform vacuum impregnation multiple times, for example, 2 to 10 times, and preferably 3 to 8 times. This allows the coating liquid to penetrate the substrate sufficiently.

[0092] Furthermore, when forming a coating layer on only a portion of the substrate, the coating layer can be formed on the desired surface area of ​​the substrate by immersing only a portion of the substrate in the coating solution and coating that portion with the solution.

[0093] If it is difficult to immerse only a portion of the substrate (substrate layer) in the coating solution, the surface portion of the substrate that does not need to be coated can be protected (covered, etc.) beforehand with a suitable removable member or material, then the substrate can be immersed in the coating solution to coat the substrate, and after coating the substrate with the coating solution, the protective member (material) on the surface portion of the substrate that does not need to be coated can be removed to form a coating layer on the desired surface portion of the substrate. However, the present invention is not limited in any way to these formation methods, and the coating layer can be formed by using conventionally known methods as appropriate. For example, if it is difficult to immerse only a portion of the substrate in the coating solution, other coating methods may be applied instead of the immersion method (for example, a method of applying the coating solution to a predetermined surface portion of a medical device using an application device such as a spray device, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, or doctor's knife). Furthermore, in cases where the structure of a medical device requires both the outer and inner surfaces of a cylindrical device to have a coating layer, the dipping method is preferred because it allows both the outer and inner surfaces to be coated at once.

[0094] The amount of coating liquid applied is preferably such that the thickness (dry film thickness) of the resulting coating film (coating layer) falls within the range described in the "Coating Layer" section of the above-mentioned [Medical Devices].

[0095] After forming a coating film (precursor layer) on the substrate as described above, the substrate with the coating film may be suspended using a clip or other holding means and left to stand in order to remove excess coating liquid. The standing time is not particularly limited, but for example, it can be from 1 minute to 10 hours. The temperature is also not particularly limited, but for example, it can be from 10 to 40°C.

[0096] Furthermore, the coating step may be performed again after the crosslinking step described below. That is, in the method for manufacturing a medical device according to the present invention, the coating step and the crosslinking step may be performed multiple times (for example, 2 to 10 times, preferably 3 to 8 times). By adopting such a configuration, a coating layer of sufficient thickness can be formed, and a medical device with even better leak resistance can be obtained.

[0097] 《Crosslinking Process》 In this process, after applying a coating liquid to the substrate (substrate layer) in the above coating process to form a coating film (precursor layer), the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent contained in the coating film (precursor layer) are reacted (crosslinked) to form crosslinked hyaluronic acid. This forms a layer (coat layer) containing crosslinked hyaluronic acid.

[0098] The conditions for this process are not particularly limited as long as they are conditions under which the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent react (crosslink reaction) to form crosslinked hyaluronic acid, but heat treatment is preferred. That is, in one embodiment, the crosslinking step includes heating the coating film (precursor layer) formed in the coating step. In another embodiment, the crosslinking agent contained in the coating film (precursor layer) is a heat-reactive crosslinking agent, and the crosslinking step includes heating the first hyaluronic acid, the second hyaluronic acid, and the heat-reactive crosslinking agent contained in the coating film (precursor layer). By performing heat treatment, the above crosslinking reaction can be promoted, and a coating layer with better leak resistance can be formed. In addition, the removal of the solvent from the coating film (precursor layer) formed in the above coating step becomes easier. Note that the term "heat-reactive crosslinking agent" and its preferred form are the same as those described in the [Medical Devices] section above, so the explanation is omitted here.

[0099] The temperature of the heat treatment is not particularly limited, but is preferably 40 to 100°C, and more preferably 50 to 80°C. Maintaining (heating) at such a temperature allows the crosslinking reaction to proceed sufficiently, making it easy to form a coating layer with excellent leak resistance. Furthermore, maintaining at the above temperature results in the formation of a strong coating layer. Note that the above temperature may be changed during the heat treatment.

[0100] Furthermore, while there are no particular restrictions on the heating time, it is preferably 10 minutes to 10 hours, more preferably 30 minutes to 5 hours. By heating for such a time, the crosslinking reaction can proceed sufficiently, making it easy to form a coating layer with excellent leak resistance. In addition, by heating for the above time, a strong coating layer is formed.

[0101] Drying may be performed before the above heat treatment. Drying removes some of the solvent, allowing the subsequent heat treatment to proceed more efficiently. The drying temperature is not particularly limited, but it is preferably 10°C or higher and less than 40°C, and more preferably 20 to 30°C. The drying time is also not particularly limited, but it is preferably 1 minute to 10 hours, more preferably 3 minutes to 5 hours. Furthermore, there are no restrictions on the pressure conditions during drying; it can be carried out under normal pressure (atmospheric pressure), or under pressurized or reduced pressure.

[0102] For the above-mentioned heat treatment (crosslinking process) and drying, for example, an oven or a vacuum dryer can be used as the means (apparatus), but in the case of natural drying, no special drying means (apparatus) is required.

[0103] 《Cleaning Step》 The method for manufacturing a medical device according to the present invention may further include a cleaning step for cleaning the medical device obtained through the crosslinking step described above, if necessary. In this step, the coating layer formed on the medical device is cleaned. The cleaning method is not particularly limited, but may include ultrasonic cleaning, immersion of the coating layer in a cleaning solvent, pouring the cleaning solvent over the coating layer, or a combination thereof. The cleaning solvent used at this time is not particularly limited as long as it does not dissolve the coating layer, but water (e.g., deionized water, distilled water, RO water, filtered water, sterile water, purified water, etc.), hot water, and alcohol-based solvents (e.g., methanol, ethanol, isopropyl alcohol, butanol, ethylene glycol, glycerin, etc.) are preferably used. These may be used individually or in combination of two or more (in the form of a mixed solvent). In particular, the cleaning solvent preferably contains water and / or an alcohol-based solvent, more preferably contains at least one selected from the group consisting of water, isopropyl alcohol, and glycerin, and particularly preferably contains isopropyl alcohol and / or glycerin. On the other hand, as a secondary effect, the washing solvent containing ethylene glycol and glycerin can improve the flexibility (flexibility) of the coating layer.

[0104] In one embodiment, the washing step is preferably performed with a washing solvent containing ethylene glycol and / or glycerin, and more preferably with a washing solvent containing glycerin. This configuration facilitates the elution and removal of excess (unreacted) crosslinking agent, as well as the maintenance of the flexibility of the coating layer. Therefore, in one embodiment of the present invention, the washing solvent used in the washing step preferably contains water and at least one selected from ethylene glycol and glycerin, and more preferably contains water and glycerin. In another embodiment, the washing step may involve washing with a washing solvent containing glycerin, followed by further washing with a washing solvent containing an alcohol-based solvent other than glycerin (preferably isopropyl alcohol).

[0105] The temperature of the cleaning solvent is not particularly limited, but is preferably 20°C to 60°C. The cleaning time (the time the cleaning solvent is in contact with the coating layer) is also not particularly limited, but is preferably 0.1 to 60 minutes.

[0106] Furthermore, if necessary, the above cleaning process (cleaning step) may be repeated multiple times (for example, 2 to 5 times).

[0107] Drying Process After the washing process described above, a drying process may be carried out. The drying method and drying conditions (temperature, time, etc.) are not particularly limited, and conventionally known methods can be used. The drying temperature is not particularly limited, but it is preferably 10 to 80°C, and more preferably 20 to 30°C. The drying time is also not particularly limited, but it is preferably 1 to 30 hours, and more preferably 3 to 20 hours. Furthermore, the pressure conditions during drying are not limited in any way, and it can be carried out under normal pressure (atmospheric pressure), or it may be carried out under pressurized or reduced pressure. As for the means (apparatus) for carrying out the drying process, refer to the description in the Crosslinking Process described above.

[0108] <Sterilization Step> The method for manufacturing a medical device according to the present invention may further include a step (sterilization step) of sterilizing the medical device obtained through the crosslinking step (preferably a medical device obtained by further washing and drying steps after the crosslinking step), if necessary. In this step, the medical device is sterilized. That is, in one embodiment, it is preferable that the medical device is sterilized.

[0109] The sterilization method is not particularly limited, but known methods can be used, such as radiation sterilization including gamma ray sterilization and electron beam sterilization, EOG (ethylene oxide gas) sterilization, and high-pressure steam sterilization (autoclave sterilization).

[0110] In radiation sterilization, the type of radiation used can be gamma rays (γ rays), electron beams, neutron beams, or X-rays. Among these, gamma rays or electron beams are preferred, and electron beams are more preferred, because they are easy to produce industrially.

[0111] The dose of radiation irradiated varies depending on the medical device being manufactured and is not particularly limited, but is, for example, 5 to 100 kGy, preferably 10 to 50 kGy, and more preferably 15 to 25 kGy. The irradiation atmosphere is not particularly limited, but may be an inert gas atmosphere or under vacuum (reduced pressure). The medical device may also be irradiated after being sealed in packaging material, in which case the inside of the packaging material may be filled with air or inert gas, or may be under vacuum. The temperature during radiation irradiation may be any, but is typically carried out at room temperature (25°C).

[0112] The conditions for EOG (ethylene oxide gas) sterilization vary depending on the medical device being manufactured and are not particularly limited. The temperature during processing is preferably 35 to 60°C, more preferably 40 to 55°C. The processing time is preferably 1 to 20 hours, more preferably 3 to 15 hours. Furthermore, the concentration of ethylene oxide gas, humidity during processing, pressure, etc., can be appropriately selected considering the type of medical device being manufactured.

[0113] The conditions for autoclaving vary depending on the medical device being manufactured and are not particularly limited. The heating temperature is preferably 100 to 150°C, more preferably 110 to 130°C. The heating time is preferably 1 to 120 minutes, more preferably 10 to 60 minutes. Furthermore, the pressure can be appropriately selected considering the type of medical device being manufactured.

[0114] [Uses of Medical Devices] The medical devices according to the present invention have excellent leak resistance (blood leakage resistance). Examples of medical devices according to the present invention include implantable artificial organs and treatment devices, extracorporeal circulation type artificial organs, etc. In particular, the medical devices are preferably intravascular implantable devices, and specifically include artificial blood vessels, tent grafts, covered stents, artificial valves, etc. A medical device according to one embodiment of the present invention is an artificial blood vessel, a stent graft, or a covered stent. Other medical devices are also shown below.

[0115] [Medical Device Kit] The medical device according to the present invention may be stored in a sealed bag-like packaging (packaging material such as an individual packaging bag). That is, another aspect of the present invention also provides a medical device kit in which the above medical device is packaged by a packaging (packaging material). The structure and material of the above packaging (packaging material) are not particularly limited, and known ones can be used. As an example, a medical device kit has a configuration in which the medical device is sandwiched between packaging materials such as nonwoven fabric or film material, and the packaging materials are joined together so as to surround the medical device. The method of joining the packaging materials is not particularly limited as long as it is a method that can be joined with sufficient adhesive force so that the packaging materials can be peeled apart when a surgeon or the like takes out the medical device. Examples of joining methods include joining by fusion such as heat fusion or ultrasonic fusion, or joining by using an adhesive.

[0116] As described above, the medical device according to the present invention may be manufactured through a sterilization process. Here, the sterilization process may be carried out with the medical device housed inside the packaging material. That is, according to one embodiment of the present invention, a medical device kit is also provided in which the above-mentioned medical device is packaged in a packaging material and has been sterilized.

[0117] The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, the units "parts" or "%" may be used, but unless otherwise specified, they represent "parts by mass" or "mass%", respectively. Also, unless otherwise specified, each operation was carried out at room temperature (25°C).

[0118] <Sample Preparation> [Preparation] The following hyaluronic acid samples were prepared. The viscosity-average molecular weight (Mv) of each hyaluronic acid sample is based on the molecular weight measured by the known intrinsic viscosity method described above.

[0119] 《Hyaluronic Acid》 (First Hyaluronic Acid (First HA)) ・Hyaluronic Acid 1 (Viscosity-average molecular weight: 1.2 million, Product name: Hyaluronsan HA-LQ, Manufactured by Kewpie Corporation) ・Hyaluronic Acid 2 (Viscosity-average molecular weight: 800,000, Product name: Hyabest (registered trademark) (J), Manufactured by Kewpie Corporation) ・Hyaluronic Acid 3 (Viscosity-average molecular weight: 1.6 million, Product name: Hyaluronsan HA-LQH, Manufactured by Kewpie Corporation) (Second Hyaluronic Acid (Second HA)) ・Hyaluronic Acid 4 (Viscosity-average molecular weight: 10,000, Product name: Hyalooligo (registered trademark), Manufactured by Kewpie Corporation) ・Hyaluronic Acid 5 (Viscosity-average molecular weight: 50,000, Product name: Hyaluronsan HA-LF5-A, Manufactured by Kewpie Corporation) Note that all of the above hyaluronic acids are non-animal derived (hyaluronic acid produced by microbial fermentation) and are unmodified hyaluronic acid.

[0120] (1) Preparation of the first hyaluronic acid solution Hyaluronic acid 1 (viscosity-average molecular weight: 1.2 million) as the first hyaluronic acid was added to reverse osmosis membrane water (RO water) and mixed to prepare a hyaluronic acid aqueous solution (1-1) with a hyaluronic acid concentration of 1.0% by mass. Furthermore, a hyaluronic acid aqueous solution (1-2) was prepared in the same manner as above, except that the hyaluronic acid used was changed to hyaluronic acid 2 (viscosity-average molecular weight: 800,000).

[0121] Hyaluronic acid 3 (viscosity-average molecular weight: 1.6 million) as the first hyaluronic acid was added to RO water and mixed to prepare hyaluronic acid aqueous solution (1-3) with a hyaluronic acid concentration of 1.0% by mass. Hyaluronic acid aqueous solutions (1-4), (1-5), and (1-6) were prepared in the same manner as above, except that the amount of hyaluronic acid added was changed so that the concentrations of hyaluronic acid 3 were 1.5% by mass, 2.0% by mass, and 0.5% by mass, respectively.

[0122] (2) Preparation of the second hyaluronic acid solution Hyaluronic acid 4 (viscosity-average molecular weight: 10,000) as the second hyaluronic acid was added to RO water and mixed to prepare a hyaluronic acid aqueous solution (2-1) with a hyaluronic acid concentration of 1.0% by mass. Furthermore, a hyaluronic acid aqueous solution (2-2) was prepared in the same manner as above, except that the hyaluronic acid used was changed to hyaluronic acid 5 (viscosity-average molecular weight: 50,000).

[0123] (3) Preparation of Crosslinking Agent Solution Diglycerol polyglycidyl ether (average number of epoxy groups: 3, containing diglycerol triglycidyl ether, trade name: Denacol EX-421, manufactured by Nagase ChemteX Corporation) was added to RO water and mixed to prepare a crosslinking agent solution (3-1) with a crosslinking agent concentration of 1.0% by mass. Crosslinking agent aqueous solutions (3-2) and (3-3) were prepared in the same manner as above, except that the amount of crosslinking agent added was changed so that the crosslinking agent concentrations were 0.5% by mass and 0.7% by mass, respectively.

[0124] [Example 1] <Preparation of coating solution> Hyaluronic acid aqueous solution (1-1) and hyaluronic acid aqueous solution (2-1) were mixed in a mass ratio of 1:1 to obtain 19 g of mixed aqueous solution (1). 1 g of crosslinking agent solution (3-1) was added to the mixed aqueous solution (1) and stirred, and then 0.7 g of glycerin was added and stirred to obtain coating solution (1).

[0125] Formation of the coating layer: A polyethylene terephthalate (PET) graft (inner diameter φ8 mm) was cut to a length of 10 cm. The cut graft was placed in the coating solution (1) and vacuum impregnation (coating) was performed for 10 minutes at a temperature of 22°C and a pressure of -0.95 MPa (relative to atmospheric pressure). After that, the graft was removed from the coating solution (1), suspended with a clip, and left to stand for 5 minutes to remove excess coating solution. The removed graft was dried in an oven set to 60°C for 1.5 hours. It is believed that crosslinking by the crosslinking agent proceeds effectively during this drying process. The above vacuum impregnation (coating) and drying process was repeated a total of four times.

[0126] 《Washing》 The grafts obtained by the above procedure were immersed in a glycerin aqueous solution (glycerin concentration: 15% by mass) at room temperature (25°C) for 1 minute and stirred. Then, the grafts were removed from the glycerin aqueous solution and immersed in isopropyl alcohol (IPA) for 5 minutes and stirred.

[0127] 《Drying and Sterilization》 The grafts obtained by the above procedure were dried overnight (8 hours or more) at room temperature (25°C). Subsequently, sterilization was performed by treating with ethylene oxide gas (EOG) at 45°C for 720 minutes (12 hours) to obtain Sample 1 with a coated layer. The thickness of the coated layer (dry film thickness) varied depending on the location, but on average it was about 5 μm (the same applies below).

[0128] [Example 2] Sample 2 was obtained in the same manner as in Example 1, except that the hyaluronic acid aqueous solution used in the "Preparation of Coating Solution" of Example 1 was changed, and hyaluronic acid aqueous solution (1-2) and hyaluronic acid aqueous solution (2-2) were mixed in a 1:1 mass ratio.

[0129] [Example 3] Sample 3 was obtained in the same manner as in Example 1, except that in the "Preparation of Coating Solution" of Example 1, hyaluronic acid aqueous solution (2-1) was changed to hyaluronic acid aqueous solution (2-2).

[0130] [Example 4] Sample 4 was obtained in the same manner as in Example 1, except that in the "Preparation of Coating Solution" of Example 1, hyaluronic acid aqueous solution (1-1) was changed to hyaluronic acid aqueous solution (1-2).

[0131] [Comparative Example 1] Comparative Sample 1 was obtained in the same manner as in Example 1, except that in the "Preparation of Coating Solution" of Example 1, only hyaluronic acid aqueous solution (1-2) was used as the hyaluronic acid solution, and the amount used was 19 g.

[0132] <Evaluation (Leak Resistance)> The leak resistance of each of the samples 1 to 4 and comparative sample 1 prepared as described above was evaluated using the following method.

[0133] First, a blood circulation circuit was created by connecting the grafts of each sample, a safer extension tube (manufactured by Terumo Corporation), a three-way stopcock (manufactured by Terumo Corporation), a syringe, and a handy manometer (model number: PG-100B-102R-W, manufactured by Nidek Components Co., Ltd.) using a connector. Next, the syringe was filled with heparin-anticoagulated fresh bovine blood (activated clotting time (ACT) > 1500 sec, hematocrit (HCT): 20%), and the pressurization condition was set to 120 mmHg (1.6 × 10⁻⁶). ４ The pressure was adjusted to Pa, and the presence or absence of blood leakage from the graft surface was evaluated based on the following evaluation criteria. The results are shown in Table 1 below. A score of A to C on the evaluation criteria indicates a practical range.

[0134] 《Evaluation Criteria》 A: No leaks at all B+: Almost no leaks B-: Very slight leaks C: Slight leaks D: Complete leaks (leaks even at low pressure).

[0135]

[0136] The results shown in Table 1 demonstrate that the leak resistance of the graft is improved by having a coating layer in which the first hyaluronic acid and the second hyaluronic acid are crosslinked in the present invention.

[0137] [Example 5] Sample 5 was obtained in the same manner as in Example 1, except that in the "Preparation of Coating Solution" of Example 1, hyaluronic acid aqueous solution (1-1) was changed to hyaluronic acid aqueous solution (1-3).

[0138] [Example 6] Sample 6 was obtained in the same manner as in Example 1, except that in the "Preparation of Coating Solution" of Example 1, hyaluronic acid aqueous solution (1-1) was changed to hyaluronic acid aqueous solution (1-4).

[0139] [Example 7] Sample 7 was obtained in the same manner as in Example 1, except that in the "Preparation of Coating Solution" of Example 1, hyaluronic acid aqueous solution (1-1) was changed to hyaluronic acid aqueous solution (1-5).

[0140] <Evaluation (Leak Resistance)> For each of the samples 5 to 7 prepared above, the leak resistance was evaluated using the same method as described in the <Evaluation (Leak Resistance)> section above. The results are shown in Table 2 below.

[0141]

[0142] The results in Table 2 show that the closer the ratio (mass ratio) of the first hyaluronic acid to the second hyaluronic acid in the present invention is to 1:1, the better the leak resistance of the graft.

[0143] [Reference Example 1] Hyaluronic acid aqueous solution (1-3), hyaluronic acid aqueous solution (2-1), and crosslinking agent solution (3-1) were mixed in a mass ratio of 1:1:1 (mass ratio of first hyaluronic acid to second hyaluronic acid = 1:1) to prepare reference coating solution (1). The reference coating solution (1) was placed in a mold, dried at 60°C for more than 1 hour, and EOG sterilization was performed under the same conditions as in Example 1 above to produce a gel film, which was designated as reference gel film 1.

[0144] [Reference Example 2] Hyaluronic acid aqueous solution (1-6), hyaluronic acid aqueous solution (2-1), and crosslinking agent solution (3-1) were mixed in a mass ratio of 1:1:1 (mass ratio of first hyaluronic acid to second hyaluronic acid = 0.5:1) to prepare reference coating solution (2). The reference coating solution (2) was placed in a mold, dried at 60°C for 12 hours or more, and EOG sterilization was performed under the same conditions as in Example 1 above to produce a gel film, which was designated as reference gel film 2.

[0145] <Evaluation (Swelling)> The above reference gel films 1 and 2 were each immersed in RO water and their swelling behavior was evaluated. As a result, the film of reference example 1 (reference gel film 1) showed better elasticity. Therefore, it can be said that the closer the amount ratio (mass ratio) of the first hyaluronic acid to the second hyaluronic acid in the present invention is to 1:1, the better the elasticity of the coating layer itself.

[0146] [Example 8] <Preparation of coating solution> Hyaluronic acid aqueous solution (1-5) and hyaluronic acid aqueous solution (2-1) were mixed in a mass ratio of 1:1 to obtain 19 g of mixed aqueous solution (8). 1 g of crosslinking agent solution (3-2) was added to the mixed aqueous solution (8) and stirred, and then 0.7 g of glycerin was added and stirred to obtain coating solution (8).

[0147] Formation of the coating layer: A polyethylene terephthalate (PET) graft (inner diameter φ8 mm) was cut to a length of 10 cm. The cut graft was placed in the coating solution (8) and vacuum impregnation (coating) was performed for 10 minutes at a temperature of 22°C and a pressure of -0.95 MPa (relative to atmospheric pressure). After that, the graft was removed from the coating solution (8), suspended with a clip, and left to stand for 5 minutes to remove excess coating solution. The removed graft was dried in an oven set to 60°C for 1.5 hours. It is thought that crosslinking by the crosslinking agent proceeds effectively during this drying process. The above vacuum impregnation (coating) and drying process was repeated a total of two times.

[0148] Washing, drying, and sterilization were performed in the same manner as in Example 1, to obtain Sample 8.

[0149] [Example 9] Sample 9 was obtained in the same manner as in Example 8, except that the crosslinking agent solution used in the "Preparation of Coating Solution" of Example 8 was changed to crosslinking agent solution (3-3).

[0150] [Example 10] Sample 10 was obtained in the same manner as in Example 8, except that the crosslinking agent solution used in the "Preparation of Coating Solution" of Example 8 was changed to crosslinking agent solution (3-1).

[0151] <Evaluation (Leak Resistance)> The leak resistance of each of the samples 8 to 10 prepared above was evaluated using the following method. The results are shown in Table 3 below.

[0152] [Pressure Resistance Evaluation] First, a blood circulation circuit was created by connecting the grafts of each sample, a safer extension tube (manufactured by Terumo Corporation), a three-way stopcock (manufactured by Terumo Corporation), a syringe, and a handy manometer (model number: PG-100B-102R-W, manufactured by Nidek Components Co., Ltd.) using a connector. Next, the syringe was filled with heparin-anticoagulated fresh bovine blood (activated clotting time (ACT) > 1500 sec, hematocrit (HCT): 20%), and the pressurization condition was set to 120 mmHg (1.6 × 10⁻⁶). ４ The pressure was adjusted to Pa, and the presence or absence of blood leakage from the graft surface was evaluated based on the following evaluation criteria. A score of A to C on the evaluation criteria indicates a practical range.

[0153] 《Evaluation Criteria》 A: No leaks at all B+: Almost no leaks B-: Very slight leaks C: Slight leaks D: Complete leaks (leaks even at low pressure).

[0154] [Needle Puncture Evaluation] A blood circulation circuit was prepared in the same manner as in the [Pressure Resistance Evaluation] above, and a needle (20G) was inserted into the graft. Subsequently, the presence or absence of blood leakage from the graft surface was evaluated based on the same evaluation criteria as above. If the evaluation criteria are A to C, it can be said that it is within a practical range.

[0155]

[0156] The results in Table 3 show that, when forming the coating layer, a higher concentration of the crosslinking agent in the coating solution improves the leak resistance of the graft.

[0157] This application is based on Japanese Patent Application No. 2024-169893, filed on 30 September 2024, the disclosures of which are referenced and incorporated as a whole.

[0158] 1 Artificial blood vessel, 10 Base material, 10a Base material core, 10b Base material surface layer, 11 Coating layer, 100 Medical device.

Claims

1. A medical device comprising a substrate having a porous structure and a coating layer formed on at least a part of the surface of the substrate, wherein the coating layer contains crosslinked hyaluronic acid, which is formed by crosslinking a first hyaluronic acid having a viscosity-average molecular weight of 600,000 or more and a second hyaluronic acid having a viscosity-average molecular weight of 100,000 or less with a crosslinking agent.

2. The medical device according to claim 1, wherein the mass ratio of the first hyaluronic acid to the second hyaluronic acid is 0.5 to 2.

3. The medical device according to claim 1, wherein the viscosity-average molecular weight of the first hyaluronic acid is 800,000 to 1,600,000.

4. The medical device according to claim 1, wherein the viscosity-average molecular weight of the second hyaluronic acid is 50,000 or less.

5. The medical device according to claim 1, wherein the ratio of the viscosity-average molecular weight of the first hyaluronic acid to the viscosity-average molecular weight of the second hyaluronic acid is 6 to 400.

6. The medical device according to claim 1, wherein the crosslinking agent comprises an epoxy compound having three epoxy groups.

7. The medical device according to claim 6, wherein the crosslinking agent comprises one or more selected from the group consisting of diglycerol triglycidyl ether, glycerol triglycidyl ether, trimethylolethane triglycidyl ether, trimethylolpropane triglycidyl ether, and tris(4-hydroxyphenyl)methane triglycidyl ether.

8. The medical device according to claim 1, wherein the first hyaluronic acid and the second hyaluronic acid are of non-animal origin.

9. The medical device according to claim 1, which has been sterilized.

10. The medical device according to claim 1, wherein the medical device is an artificial blood vessel, a stent graft, or a covered stent.

11. A method for manufacturing a medical device, comprising: a coating step of applying a coating solution containing a first hyaluronic acid having a viscosity-average molecular weight of 600,000 or more, a second hyaluronic acid having a viscosity-average molecular weight of 100,000 or less, a crosslinking agent, and a solvent to at least a portion of a substrate having a porous structure; and a crosslinking step of reacting the first hyaluronic acid, the second hyaluronic acid, and the crosslinking agent to form crosslinked hyaluronic acid and to form a layer containing the crosslinked hyaluronic acid.

12. The manufacturing method according to claim 11, wherein the crosslinking agent is a heat-reactive crosslinking agent, and the crosslinking step comprises heating the first hyaluronic acid, the second hyaluronic acid, and the heat-reactive crosslinking agent.

13. The manufacturing method according to claim 11, wherein the coating step and the crosslinking step are performed multiple times.

14. The manufacturing method according to claim 11, further comprising a step of performing a sterilization procedure.

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