JPWO2018169052A1 - Manufacturing method of balloon catheter - Google Patents

Abstract

Provided is a method for manufacturing a balloon catheter having high slipperiness in a living body and capable of favorably holding a non-hydrophilic drug. A method for producing a balloon catheter (10) in which a coat layer (40) containing a water-insoluble drug is formed on the outer surface of a balloon (30), wherein the outer surface of the balloon (30) is made of a hydrophilic polymer compound. Forming a hydrophilic layer (37), forming an amphiphilic layer (38) comprising an amphiphilic low molecular compound on the outer surface of the hydrophilic layer (37), and removing a water-insoluble drug and a solvent. The method includes a step of applying the coating liquid (45) containing the solvent to the amphiphilic layer (38) and a step of volatilizing the solvent of the coating liquid (45).

Description

  The present invention relates to a method for manufacturing a balloon catheter in which a drug is provided on the outer surface of a balloon.

  2. Description of the Related Art In recent years, balloon catheters have been used to improve a lesion (stenosis) generated in a body lumen. The balloon catheter usually includes a long shaft portion and a balloon provided on the distal end side of the shaft portion and expandable in a radial direction. By inflating the deflated balloon after reaching a target location in the body via a thin living body lumen, the lesion can be spread.

  However, when the lesion is forcibly expanded, the smooth muscle cells may excessively proliferate and a new stenosis (restenosis) may occur in the lesion. For this reason, a drug eluting balloon (DEB) in which a drug for suppressing stenosis is coated on the outer surface of the balloon has recently been used. The drug-eluting balloon, when expanded, releases the drug coated on the outer surface to the affected part instantaneously, thereby suppressing restenosis.

  By the way, the outer surface of the balloon is subjected to a hydrophilic treatment in order to improve the sliding property in a living body. However, since an organic solvent is required at the time of coating, it is difficult to coat a hydrophobic drug on the outer surface of the balloon while maintaining the function obtained by the hydrophilic treatment.

  For this reason, for example, Patent Literature 1 describes a balloon catheter in which water-insoluble drug particles and an amphiphilic compound are arranged on a hydrophilic layer on the surface of a balloon. Since the amphiphilic compound has both a hydrophilic group and a hydrophobic group, it plays a role of retaining a hydrophobic drug on the hydrophilic layer.

International Publication No. WO 2014/186729

  It is preferable that the balloon can hold the drug satisfactorily up to the target position in the living body and can release the drug quickly by expanding at the target position.

  The present invention has been made to solve the above-described problems, and a method for manufacturing a balloon catheter in which a coat layer containing a water-insoluble drug is uniformly and stably held, and the drug is promptly released at a target position. The purpose is to provide.

  A method for manufacturing a balloon catheter that achieves the above object is a method for manufacturing a balloon catheter in which a coat layer containing a water-insoluble drug is formed on the outer surface of the balloon, wherein the outer surface of the balloon is formed from a hydrophilic polymer compound. Forming a hydrophilic layer comprising: a step of forming an amphiphilic layer comprising an amphiphilic low molecular compound on the outer surface of the hydrophilic layer; and coating the coating liquid containing a water-insoluble drug and a solvent with the amphiphile. Applying to the conductive layer, and volatilizing the solvent of the coating liquid.

  The method for manufacturing a balloon catheter configured as described above, after forming an amphiphilic layer on the outer surface of the hydrophilic layer, to apply a coating solution containing a water-insoluble drug to the outer surface of the amphiphilic layer. The coating liquid spreads smoothly on the outer surface of the amphiphilic layer, and the coat layer containing the water-insoluble drug is uniformly and stably held on the balloon. Further, since the amphiphilic layer is made of a low molecular compound, it is rapidly dissolved in a living body. For this reason, a coat layer which is quickly released at a target position can be formed on the outer surface of the amphiphilic layer.

  The coating liquid may further include an amphiphilic low molecular compound. Thereby, the amphiphilic low molecular weight compound contained in the coating liquid is stably retained with respect to the amphiphilic low molecular weight compound of the amphiphilic layer, and a coat layer which favorably holds the drug can be formed. In addition, since the amphiphilic low molecular weight compound is rapidly dissolved in the living body, the drug can be rapidly transferred to the living tissue.

  The water-insoluble drug may contain at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus. Thereby, restenosis of a stenosis part in a blood vessel can be favorably suppressed.

  The amphiphilic low molecular weight compound is benzyl glycine ethyl ester, benzyl glycine methyl ester, arginine ethyl ester, arginine methyl ester, benzoyl arginine ethyl ester, benzoyl arginine methyl ester, aspartic acid diethyl ester, aspartic acid methyl ester, dimethyl aspartate It may contain at least one selected from the group consisting of esters, glycine ethyl ester, glycine methyl ester, serine ethyl ester and serine methyl ester, and valine ethyl ester. Thereby, the amphiphilic low-molecular compound is rapidly dissolved when the balloon is expanded, so that the drug can be quickly transferred to the living tissue.

  In the manufacturing method, in the step of applying the coating liquid p to the amphiphilic layer, a tubular dispensing tube for supplying the coating liquid is supplied while rotating the balloon around an axis of the balloon. The coating liquid may be applied to the outer surface of the balloon by moving the balloon relative to the balloon in the axial direction of the balloon. By applying the coating liquid from the dispensing tube to the rotating balloon, the amount of application can be controlled with high precision, so that drug crystals can be uniformly formed on the outer surface of the balloon and control of the crystallization of the drug can be achieved. It will be easier. In addition, the dispensing tube can apply the necessary amount of the coating solution to the balloon, so that the solvent contained in the coating solution dissolves the amphiphilic low-molecular compound in the amphiphilic layer more than necessary and moves or drops off. Can be suppressed. Therefore, a uniform coat layer can be stably formed on the outer surface of the amphiphilic layer.

It is a front view which shows a balloon catheter. It is sectional drawing of the front-end | tip part of a balloon catheter. It is a schematic sectional drawing of the outer surface of a balloon. It is a perspective view which shows the tank for forming a hydrophilic layer and an amphiphilic layer in a balloon. It is a front view showing a coating device. It is sectional drawing which shows the dispensing tube which contacted the balloon. It is sectional drawing which shows the balloon to be folded, (A) shows the state before folding of a balloon, (B) shows the state in which the wing part was formed in the balloon, and (C) shows the state in which the wing part was folded. It is sectional drawing which shows the state which expanded the stenosis part of the blood vessel with the balloon catheter.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings. The dimensional ratios in the drawings may be exaggerated and different from the actual ratios for convenience of explanation.

  The method for manufacturing a balloon catheter according to the present embodiment is a method for manufacturing a drug-eluting balloon catheter 10 in which drug crystals are provided on the outer surface of a balloon 30, as shown in FIGS. In this specification, the side of the balloon catheter 10 to be inserted into the living body lumen is referred to as “distal end” or “distal end side”, and the operation side is referred to as “proximal end” or “proximal end side”.

  First, the structure of the balloon catheter 10 will be described. The balloon catheter 10 has a long catheter body 20, a balloon 30 provided at the distal end of the catheter body 20, and a hub 26 fixed to the proximal end of the catheter body 20. The outer surface of the balloon 30 is covered with a hydrophilic layer 37 made of a hydrophilic polymer compound, an amphiphilic layer 38 made of an amphiphilic low molecular compound, and a coating layer 40 containing a drug.

  The catheter main body 20 includes an outer tube 21 that is a tube having open distal and proximal ends, and an inner tube 22 that is a tube disposed inside the outer tube 21. The inner tube 22 is housed in the hollow interior of the outer tube 21, and the catheter body 20 has a double tube structure at the distal end. The hollow inside of the inner tube 22 is a guide wire lumen 24 through which a guide wire is inserted. An expansion lumen 23 for flowing the expansion fluid of the balloon 30 is formed inside the outer tube 21 and outside the inner tube 22. The inner tube 22 is open to the outside at the opening 25. The inner tube 22 protrudes further to the distal end side than the distal end of the outer tube 21.

The balloon 30 has a proximal end fixed to the distal end of the outer tube 21 and a distal end fixed to the distal end of the inner tube 22. Thus, the inside of the balloon 30 communicates with the expansion lumen 23. By injecting an expansion fluid into the balloon 30 via the expansion lumen 23, the balloon 30 can be expanded. The expansion fluid may be a gas or a liquid. For example, a gas such as helium c, CO ₂ gas, O ₂ gas, N ₂ gas, Ar gas, air, a mixed gas, or a liquid such as physiological saline or a contrast agent is used. Can be.

  A cylindrical straight portion 31 having the same outer diameter when expanded is formed at the center of the balloon 30 in the axial direction, and tapered on both sides in the axial direction of the straight portion 31 with the outer diameter gradually changing. A part 33 is formed. Then, a coating layer 40 containing a drug is formed on the entire outer surface of the straight portion 31. The range in which the coat layer 40 is formed in the balloon 30 is not limited to only the straight portion 31, and may include at least a part of the tapered portion 33 in addition to the straight portion 31. Only a part may be used.

  The hub 26 is provided with a proximal opening 27 that functions as a port that communicates with the expansion lumen 23 of the outer tube 21 and flows in and out of the expansion fluid.

  The length of the balloon 30 in the axial direction is not particularly limited, but is preferably 5 to 500 mm, more preferably 10 to 300 mm, and still more preferably 20 to 200 mm.

  The outer diameter of the balloon 30 when expanded is not particularly limited, but is preferably 1 to 10 mm, more preferably 2 to 8 mm.

  The outer surface of the balloon 30 before the hydrophilic layer 37 is formed is smooth and non-porous. The outer surface of the balloon 30 before the hydrophilic layer 37 is formed may have minute holes that do not penetrate the membrane. Alternatively, the outer surface of the balloon 30 before the hydrophilic layer 37 is formed may have both a smooth and non-porous range and a range with minute holes that do not penetrate the membrane. The size of the fine holes is, for example, 0.1 to 5 μm in diameter and 0.1 to 10 μm in depth, and one crystal may have one or more holes. The size of the minute holes is, for example, 5 to 500 μm in diameter and 0.1 to 50 μm in depth, and one hole may have one or more crystals.

  The balloon 30 preferably has a certain degree of flexibility and a certain degree of hardness so that the balloon 30 is expanded when it reaches a blood vessel, a tissue, or the like, so that the drug can be released from the coat layer 40 provided on the outer surface thereof. Specifically, the balloon 30 is made of metal or resin, but it is preferable that at least the outer surface of the balloon 30 on which the coat layer 40 is provided is made of resin. The constituent material of at least the outer surface of the balloon 30 is, for example, a polyolefin such as polyethylene, polypropylene, polybutene, an ethylene-propylene copolymer, an ethylene-vinyl acetate copolymer, an ionomer, or a mixture of two or more thereof, or a soft polyolefin. Thermoplastic resins such as vinyl chloride resin, polyamide, polyamide elastomer, nylon elastomer, polyester, polyester elastomer, polyurethane, and fluororesin, silicone rubber, latex rubber, and the like can be used. Among them, polyamides are preferred. That is, at least a part of the outer surface of the balloon 30 coated with the drug is a polyamide. The polyamide is not particularly limited as long as it is a polymer having an amide bond, and examples thereof include polytetramethylene adipamide (nylon 46), polycaprolactam (nylon 6), polyhexamethylene adipamide (nylon 66), Homopolymers such as polyhexamethylene sebacamide (nylon 610), polyhexamethylene dodecamide (nylon 612), polyundecanolactam (nylon 11), polydodecanolactam (nylon 12), and caprolactam / lauryl lactam Copolymer (nylon 6/12), caprolactam / aminoundecanoic acid copolymer (nylon 6/11), caprolactam / ω-aminononanoic acid copolymer (nylon 6/9), caprolactam / hexamethylene diammonium adipate copolymer ( Nylon 6/66 Copolymers such as a copolymer of adipic acid and meta-xylylenediamine, or hexamethylene diamine and m, and aromatic polyamides such as a copolymer of p- phthalic acid. Further, a polyamide elastomer which is a block copolymer having a hard segment of nylon 6, nylon 66, nylon 11, nylon 12, or the like and a soft segment of polyalkylene glycol, polyether, or aliphatic polyester is also used as a material of the balloon 30. Used as The above polyamides may be used alone or in combination of two or more. In particular, the balloon 30 preferably has a smooth surface of polyamide.

  The balloon 30 has a hydrophilic layer 37 made of a hydrophilic polymer compound formed on the outer surface thereof. The hydrophilic layer 37 has a high sliding property (lubricity) in a living body. The hydrophilic layer 37 is provided to enhance the passage of the balloon 30 in a living body. The hydrophilic polymer compound of the hydrophilic layer 37 is, for example, a block copolymer of polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, collagen, chitosan, polymer polyglycidyl methacrylate-dimethylacrylamide (PGMA-DMAA). And their copolymers and derivatives. As a specific combination, a block copolymer of polymer polyglycidyl methacrylate-dimethylacrylamide (PGMA-DMAA) is arranged as a hydrophilic layer 37 on a balloon 30 made of polyamide, and an amino acid ester 38 is formed as an amphiphilic layer 38 thereon. , A layer containing at least one of serine ethyl ester, valine ethyl ester, and aspartic acid methyl ester, and a coat layer 40 containing paclitaxel thereon. The hydrophilic layer 37 and the amphiphilic layer 38 are in direct contact, and the amphiphilic layer 38 and the coating layer 40 are in direct contact. The amphiphilic layer 38 is coated on the balloon 30 after the hydrophilic layer 37 has dried. The coat layer 40 is coated on the hydrophilic layer 37 after the amphiphilic layer 38 is dried.

  The hydrophilic layer 37 has an amphiphilic layer 38 formed of an amphiphilic low molecular compound on its outer surface. The amphiphilic low molecular weight compound is a low molecular weight compound having a hydrophilic group and a hydrophobic group. The amphiphilic layer 38 has a role of mediating the hydrophilic hydrophilic layer 37 and a hydrophobic (water-insoluble) drug. That is, the water-insoluble drug cannot directly adhere to the hydrophilic layer 37, but can cover the outer periphery of the hydrophilic layer 37 through the amphiphilic layer 38. The amphiphilic low molecular weight compound of the amphiphilic layer 38 does not form a matrix. The matrix is a layer in which a relatively high-molecular substance (such as a polymer) is continuously formed, forms a network-like three-dimensional structure, and a fine space exists therein. Note that the amphiphilic layer 38 may form a matrix.

  The amphiphilic layer 38 is formed by coating the outer surface of the hydrophilic layer 37 in a state of being dissolved in a solvent and then drying it. The amphiphilic layer 38 is amorphous. The amphiphilic layer 38 may be a crystal particle. The amphiphilic layer 38 may be present as a mixture of amorphous and crystalline particles. The amphiphilic layer 38 in FIG. 3 is in a state of crystalline particles and / or particulate amorphous. Alternatively, the amphiphilic layer 38 may be in a film-like amorphous state. The thickness of the amphiphilic layer 38 is 0.1 to 30 μm, preferably 0.1 to 10 μm, and more preferably 0.1 to 3 μm.

  On the outer surface of the amphiphilic layer 38, a coating layer 40 containing a drug is formed. The coat layer 40 has an additive 41 (excipient) arranged in a layer on the outer surface of the amphiphilic layer 38 and a water-insoluble drug crystal 42 extending with an independent long axis. ing. The additive 41 contains an amphiphilic low molecular weight compound. The end of the drug crystal 42 may be in direct contact with the outer surface of the amphipathic layer 38, but may not be in direct contact between the end of the drug crystal 42 and the outer surface of the amphiphilic layer 38. Additive 41 may be present. The end of the drug crystal 42 may be located on the surface of the layer of the additive 41, and the drug crystal 42 may protrude from the additive 41. The plurality of drug crystals 42 may be regularly arranged on the outer surface of the amphiphilic layer 38. Alternatively, the plurality of drug crystals 42 may be irregularly arranged on the outer surface of the amphiphilic layer 38.

The amount of drug contained in the coating layer 40 is not particularly ^{limited, 0.1μg / mm 2 ~10μg / mm} 2, at a density of preferably ^{0.5μg / mm 2 ~5μg / mm 2} , more preferably 0.5 [mu] g / ^{mm 2} ~3.5μg / ^mm 2, more preferably included at a density of ^{1.0μg / mm 2 ~3μg / mm 2} . The amount of crystals in the coat layer 40 is not particularly limited, but is preferably 5 to 500,000 [crystal / (10 μm ² )] (the number of crystals per 10 μm ² ), and more preferably 50 to 50,000 [crystal / (10 μm ² )], and more preferably 500 to 5,000 [crystal / (10 μm ² )].

  The drug crystal 42 may have a form having independent major axes. Further, the drug crystal 42 may be in another form. The plurality of drug crystals 42 may be present in a state in which they are combined, or may be present in contact with adjacent drug crystals 42 forming different angles. The plurality of drug crystals 42 may be located on the balloon surface with a space (space containing no crystals). On the surface of the amphiphilic layer 38, both a plurality of drug crystals 42 in a combined state and a plurality of drug crystals 42 separated and independent from each other may exist. The plurality of drug crystals 42 may be circumferentially arranged in a brush shape having different major axis directions. Each of the drug crystals 42 exists independently, has a certain length, and one end (base end) of the length portion is fixed to the additive 41 or the amphiphilic layer 38. The drug crystal 42 does not form a complex structure with the adjacent drug crystal 42 and is not connected. The major axis of the crystal is substantially linear. The drug crystal 42 forms a predetermined angle with respect to the surface where the long axis crosses the base.

  It is preferable that the drug crystals 42 stand independently without contacting each other. The base of the drug crystal 42 may be in contact with another base on the amphiphilic layer 38. Alternatively, the base of the drug crystal 42 may be independent on the amphiphilic layer 38 without contacting other bases.

  The drug crystal 42 may be hollow or solid. Both a hollow drug crystal 42 and a solid drug crystal 42 may be present on the surface of the balloon 30. When the drug crystal 42 is hollow, at least the vicinity of its tip is hollow. The cross section of the drug crystal 42 in a plane perpendicular (perpendicular to) the long axis of the drug crystal 42 has a hollow. The drug crystal 42 having the hollow has a polygonal cross section of the drug crystal 42 in a plane perpendicular to (or perpendicular to) the long axis. The polygon is, for example, a triangle, a quadrangle, a pentagon, a hexagon, or the like. Therefore, the drug crystal 42 has a distal end (or a distal end surface) and a proximal end (or a proximal end surface), and the side surface between the distal end (or the distal end surface) and the proximal end (or the proximal end surface) has a plurality of substantially flat surfaces. It is formed as an elongated polyhedron. This crystal form type (hollow elongated body crystal form type) forms a whole or at least a part of a certain plane on a surface with which the base contacts.

  The length of the drug crystal 42 having a major axis in the major axis direction is preferably 5 μm to 20 μm, more preferably 9 μm to 11 μm, and even more preferably about 10 μm. The diameter of the drug crystal 42 having a long axis is preferably 0.01 μm to 5 μm, more preferably 0.05 μm to 4 μm, and even more preferably 0.1 μm to 3 μm. As an example of a combination of the length and the diameter of the drug crystal 42 having the long axis in the major axis direction, a combination of the diameter of 0.01 to 5 μm when the length is 5 μm to 20 μm, and the combination of the length of 5 to 20 μm Combinations having a diameter of 0.05 to 4 μm, and combinations having a diameter of 0.1 to 3 μm when the length is 5 to 20 μm are exemplified. The drug crystal 42 having a long axis is linear in the long axis direction, but may be curved in a curved shape. Both a linear drug crystal 42 and a curved drug crystal 42 may be present on the surface of the balloon 30.

  The crystal form having the drug crystal 42 having the long axis described above accounts for 50% by volume or more, more preferably 70% by volume or more, of the entire drug crystal on the outer surface of the balloon 30. The drug crystal 42, which is a crystal particle having a long axis, is formed so as to stand without standing on the outer surface of the balloon 30 or the additive 41. The additive 41 may be present in a region where the drug crystal 42 exists, and may not be present in a region where the drug crystal 42 does not exist.

  The amphiphilic low-molecular compound forming the additive 41 may be the same as the amphiphilic low-molecular compound forming the amphiphilic layer 38. Thereby, the coat layer 40 containing the additive 41 is stably bonded to the amphiphilic layer 38. The amphiphilic low-molecular compound forming the additive 41 may be different from the amphiphilic low-molecular compound forming the amphiphilic layer 38. Thus, the additive 41 and the amphiphilic low molecular compound of the amphiphilic layer 38 can be arbitrarily selected, and the retention of the water-insoluble drug in the balloon 30 and the release at the target position can be set more freely. The additive 41 is distributed and present in a space between the plurality of drug crystals 42 that stand. It is preferable that the water-insoluble drug crystal 42 occupies a larger volume than the additive 41 in the proportion of the substance constituting the coat layer 40. Additive 41 does not form a matrix. The matrix is a layer in which a relatively high-molecular substance (such as a polymer) is continuously formed, forms a network-like three-dimensional structure, and a fine space exists therein. Therefore, the water-insoluble drug constituting the crystals does not adhere to the matrix material. The water-insoluble drug constituting the crystals is not embedded in the matrix material. Note that the additive 41 may form a matrix.

  The additive 41 is coated on the outer surface of the amphiphilic layer 38 in a state of being dissolved in a solvent, and then dried to form a layer. Additive 41 is amorphous. The additive 41 may be a crystal particle. Additive 41 may be present as a mixture of amorphous and crystalline particles. The additive 41 of FIG. 3 is in a state of crystalline particles and / or particulate amorphous. Alternatively, the additive 41 may be in a film-like amorphous state. The additive 41 is formed as a layer containing a water-insoluble drug. Alternatively, the additive 41 may be formed as an independent layer containing no water-insoluble drug. The thickness of the additive 41 is 0.1 to 5 μm, preferably 0.3 to 3 μm, and more preferably 0.5 to 2 μm.

  The layer containing the long crystal form-type drug crystal 42 has low toxicity and high stenosis suppressing effect when delivered into the body. A water-insoluble drug containing a hollow elongated crystal form has good permeability to tissue because one unit of the crystal becomes small when the drug migrates to the tissue, and has good solubility, so it is effectively used. By acting, stenosis can be suppressed. Further, it is considered that the toxicity is reduced because the drug hardly remains in the tissue as a large mass.

  In the layer containing the long crystal form-type drug crystal 42, the size (length in the long axis direction) of the crystal that migrates to the tissue is as small as about 10 μm. As a result, it uniformly acts on the affected part of the lesion and increases the tissue permeability. Furthermore, since the size of the transferred drug crystal 42 is small, an excessive amount of the drug does not remain in the affected area for an excessive time, so that it is possible to exhibit a high stenosis suppressing effect without developing toxicity. Think.

  The drug coated on the outer surface of the balloon 30 may include an amorphous type. The drug crystal 42 and the amorphous may be arranged so as to have regularity in the coat layer 40. Alternatively, the crystals and the amorphous may be arranged irregularly.

  Next, an apparatus for manufacturing the balloon catheter 10 will be described. The manufacturing apparatus has a first tank 110 and a second tank 120 shown in FIG. 4, and a coating apparatus 50 shown in FIG.

  The first tank 110 is a tank for forming the hydrophilic layer 37 on the outer surface of the balloon 30 by dipping, as shown in FIG. Inside the first tank 110, a hydrophilic solution 111 containing a hydrophilic polymer compound and a solvent constituting the hydrophilic layer 37 is accommodated. As the hydrophilic polymer compound, for example, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, collagen, chitosan, etc., and their copolymers and derivatives can be used. As the solvent, for example, water, lower alcohols, dichloroethylene, dichloroethane, chloroform, acetonitrile, methylene chloride, acetone and the like and a mixed solvent thereof can be used. Note that the hydrophilic layer 37 may be formed by a method other than dipping. For example, a coating device 50 described later can be used.

  The second tank 120 is a tank for forming the amphiphilic layer 38 on the outer surface of the hydrophilic layer 37 formed on the outer surface of the balloon 30 by dipping. Inside the second tank 120, an amphiphilic solution 121 containing an amphiphilic low-molecular compound and a solvent constituting the amphiphilic layer 38 is accommodated. The amphiphilic solution 121 does not contain a water-insoluble drug. The amphiphilic layer 38 may be formed by a method other than dipping. For example, a coating device 50 described later can be used.

  The molecular weight of the amphiphilic low molecular compound constituting the amphiphilic layer 38 is from 50 to 2,000, preferably from 50 to 1,000, more preferably from 50 to 500, and still more preferably from 50 to 200. The constituent materials of the amphiphilic low molecular weight compound include serine ethyl ester, citrate ester, polysorbate, water-soluble polymer, sugar, contrast agent, amino acid ester, glycerol ester of short-chain monocarboxylic acid, pharmaceutically acceptable salt and interface An activator or the like, or a mixture of two or more thereof can be used. The amphiphilic low molecular weight compound has a hydrophilic group and a hydrophobic group, and is characterized by being soluble in water. The amphiphilic low molecular weight compound is preferably non-swellable or hardly swellable. As a solvent of the amphiphilic solution 121, for example, water, ethanol, methanol, glycerin and the like can be used.

  The coating apparatus 50 can form a coat layer 40 on the outer surface of the amphiphilic layer 38 of the balloon 30 as shown in FIGS. The coating device 50 has a rotation mechanism 60 that rotates the balloon catheter 10 and a support 70 that supports the balloon catheter 10. The coating apparatus 50 further includes a coating liquid supply unit 90 provided with a dispensing tube 94 for applying the coating liquid 45 to the outer surface of the balloon 30, and a moving mechanism unit 80 for moving the dispensing tube 94 with respect to the balloon 30. Having. The coating device 50 further includes a control unit 100 that controls each part of the coating device 50.

  The rotation mechanism 60 holds the hub 26 of the balloon catheter 10, and rotates the balloon catheter 10 about the axis of the balloon 30 by a drive source such as a built-in motor. In the balloon catheter 10, a core material 61 is inserted and held in the guide wire lumen 24, and the core material 61 prevents the coating liquid 45 from flowing into the guide wire lumen 24. In the balloon catheter 10, a three-way cock that can be operated to open and close the flow path is connected to the base end opening 27 of the hub 26 in order to control the flow of the fluid to the expansion lumen 23.

  The support base 70 includes a tubular base-side support portion 71 that accommodates the catheter body 20 therein and rotatably supports it, and a distal-side support portion 72 that rotatably supports the core material 61. Note that, if possible, the distal end side support portion 72 may rotatably support the distal end portion of the catheter body 20 instead of the core material 61.

  The moving mechanism unit 80 includes a moving table 81 that can move linearly in a direction parallel to the axis of the balloon 30, and a tube fixing unit 83 to which the dispensing tube 94 is fixed. The moving table 81 can be moved linearly by a driving source such as a built-in motor. As the moving table 81 moves, the dispensing tube 94 moves linearly in a direction parallel to the axis of the balloon 30. The moving table 81 has a coating liquid supply unit 90 mounted thereon, and moves the coating liquid supply unit 90 linearly in both directions along the axis.

  The coating liquid supply unit 90 is a part that applies the coating liquid 45 to the outer surface of the amphiphilic layer 38 of the balloon 30. The coating liquid supply unit 90 includes a container 92 containing the coating liquid 45, a liquid supply pump 93 that supplies the coating liquid 45 at an arbitrary liquid supply amount, and dispensing that applies the coating liquid 45 to the amphiphilic layer 38. And a tube 94.

  The liquid supply pump 93 is, for example, a syringe pump, and is controlled by the control unit 100 to suck the coating liquid 45 from the container 92 via the suction tube 91 and to supply the coating liquid 45 to the dispensing tube 94 via the supply tube 96. Can be supplied at an arbitrary liquid sending amount. The liquid feed pump 93 is installed on the movable table 81 and can be moved linearly by the movement of the movable table 81. Note that the liquid sending pump 93 is not limited to a syringe pump as long as the coating liquid 45 can be sent, and may be, for example, a tube pump.

  The dispensing tube 94 communicates with the supply tube 96, and discharges the coating liquid 45 supplied from the liquid supply pump 93 via the supply tube 96 to the outer surface of the amphiphilic layer 38. The dispensing tube 94 is a flexible tubular member. The dispensing tube 94 has an upper end fixed to the tube fixing portion 83, extends vertically downward from the tube fixing portion 83, and has an opening 95 at the discharge end 97, which is the lower end. The dispensing tube 94 can move linearly in both directions along the axial direction of the balloon catheter 10 together with the liquid feed pump 93 installed on the moving table 81 by moving the moving table 81. The dispensing tube 94 can supply the coating liquid 45 to the outer surface of the amphiphilic layer 38 in a state where the dispensing tube 94 is pressed and bent against the amphiphilic layer 38.

  Note that the dispensing tube 94 does not have to be a circular tube as long as the coating liquid 45 can be supplied. Further, the dispensing tube 94 does not have to extend in the vertical direction as long as the coating liquid 45 can be discharged from the opening 95. Further, the dispensing tube 94 may supply the coating liquid 45 to the balloon 30 at a position away from the outer surface of the amphiphilic layer 38.

  The dispensing tube 94 is preferably made of a flexible material so as to reduce the contact load on the amphiphilic layer 38 and absorb the change in the contact position due to the rotation of the balloon 30 by bending. The constituent material of the dispensing tube 94 is, for example, polyolefin such as polyethylene and polypropylene, cyclic polyolefin, polyester, polyamide, polyurethane, PTFE (polytetrafluoroethylene), ETFE (tetrafluoroethylene / ethylene copolymer), and PFA (tetrafluoroethylene). Fluorinated resins such as fluoroethylene / perfluoroalkylvinyl ether copolymer) and FEP (ethylene tetrafluoride / hexafluoropropylene copolymer) can be used, but if they are flexible and deformable Is not particularly limited.

  The outer diameter of the dispensing tube 94 is not particularly limited, but is, for example, 0.1 mm to 5.0 mm, preferably 0.15 mm to 3.0 mm, and more preferably 0.3 mm to 2.5 mm. The inner diameter of the dispensing tube 94 is not particularly limited, but is, for example, 0.05 mm to 3.0 mm, preferably 0.1 mm to 2.0 mm, and more preferably 0.15 mm to 1.5 mm. The length of the dispensing tube 94 is not particularly limited, but is preferably not more than five times the balloon diameter, for example, 1.0 mm to 50 mm, preferably 3 mm to 40 mm, and more preferably 5 mm to 35 mm. .

  The control unit 100 is configured by, for example, a computer, and controls the rotation mechanism unit 60, the movement mechanism unit 80, and the coating liquid supply unit 90 as a whole. Therefore, the control unit 100 can control the rotational speed of the balloon 30, the moving speed of the dispensing tube 94 in the axial direction with respect to the balloon 30, the speed of discharging the medicine from the dispensing tube 94, and the like.

  The coating liquid 45 supplied to the amphiphilic layer 38 by the dispensing tube 94 is a solution or suspension containing the constituent material of the coat layer 40, and contains a water-insoluble drug, an additive, and a solvent. After the coating liquid 45 is supplied to the outer surface of the amphiphilic layer 38, the solvent is volatilized, so that the water-insoluble drug having an independent long axis extends on the outer surface of the amphiphilic layer 38. A coat layer 40 having crystals 42 is formed.

  The viscosity of the coating liquid 45 is 0.2 to 500 cP, preferably 0.2 to 50 cP, more preferably 0.2 to 10 cP.

  The water-insoluble drug means a drug that is insoluble or hardly soluble in water, and specifically has a solubility in water of less than 5 mg / mL at pH 5 to 8. Its solubility may be less than 1 mg / mL and even less than 0.1 mg / mL. Water-insoluble drugs include fat-soluble drugs.

  Examples of some preferred water-insoluble agents include immunosuppressants, for example, cyclosporins, including cyclosporine, immunoactive agents such as rapamycin, anticancer agents such as paclitaxel, antiviral or antibacterial agents, anti-neoplastic agents, Analgesics and anti-inflammatory agents, antibiotics, antiepileptics, anxiolytics, antiparalytics, antagonists, neuron blocking agents, anticholinergic and cholinergic agents, antimuscarinic and muscarinic agents, antiadrenergic agents, Includes antiarrhythmic agents, antihypertensive agents, hormonal agents and nutritional supplements.

  Water-insoluble drugs are preferably paclitaxel and paclitaxel derivatives, taxanes, docetaxel and rapamycin and rapamycin derivatives, such as biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, fasudil and epothilone, with paclitaxel and rapamycin particularly preferred. As used herein, rapamycin, paclitaxel, docetaxel, and everolimus include their analogs and / or their derivatives as long as they have similar efficacy. For example, paclitaxel and docetaxel are in an analogous relationship. Rapamycin and everolimus are in a derivative relationship. Of these, paclitaxel is more preferred.

  As the additive 41, an amphiphilic low molecular compound applicable to the aforementioned amphiphilic layer 38 can be used. Note that, as described above, the amphiphilic low molecular weight compound used for the additive 41 and the amphiphilic low molecular weight compound used for the amphiphilic layer 38 may be the same or different. The additive 41 is preferably amorphous on the balloon 30. The additive 41 containing a water-soluble low-molecular compound has an effect of uniformly dispersing the water-insoluble drug on the outer surface of the balloon 30. Further, since the additive 41 is easily dissolved when the balloon 30 is expanded in the blood vessel, the drug crystal 42 of the water-insoluble drug on the outer surface of the balloon 30 is easily released, and the drug crystal 42 is attached to the blood vessel. Has the effect of increasing the amount. It is preferable that the additive 41 is not a hydrogel. Since the additive 41 is a low molecular compound, it dissolves quickly without swelling when in contact with an aqueous solution. Further, since the additive 41 is easily dissolved when the balloon 30 is expanded in the blood vessel, the particles of the water-insoluble drug crystal 42 on the outer surface of the balloon 30 are easily released, and the drug crystal 42 is dispersed into the blood vessel. It has the effect of increasing the amount of adhesion. When the additive 41 is a matrix made of a contrast agent such as Ultravist (registered trademark), crystal particles are embedded in the matrix, and no crystal is generated from the amphiphilic layer 38 toward the outside of the matrix. On the other hand, the drug crystal 42 of the present embodiment can extend from the surface of the amphiphilic layer 38 to the outside of the additive 41.

  The solvent of the coating liquid 45 contains at least one of an organic solvent and water. The organic solvent is not particularly limited, and tetrahydrofuran, acetone, glycerin, acetic acid, t-butyl alcohol, benzene, chlorohexane, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane, ethanol, and methanol , Dichloromethane, hexane, ethyl acetate, i-butyl alcohol, s-butyl alcohol, propanol, butanol, toluene, ethylene glycol and the like. Among them, some mixed solvents of tetrahydrofuran, ethanol and acetone are preferable.

  Examples of the mixture of the organic solvent and water include tetrahydrofuran and water, tetrahydrofuran and ethanol and water, tetrahydrofuran and acetone and water, acetone, ethanol and water, tetrahydrofuran, acetone, ethanol and water.

  Next, a method for manufacturing the balloon catheter 10 according to the present embodiment will be described. In the present manufacturing method, a method of forming the water-insoluble drug crystals 42 on the outer surface of the balloon 30 using the above-described first and second tanks for dipping and the coating apparatus 50 will be described.

  First, a fluid for expansion is supplied into the balloon 30 via a three-way cock connected to the proximal opening 27 of the balloon catheter 10. Next, the three-way cock is operated while the balloon 30 is expanded to seal the expansion lumen 23, and the balloon 30 is maintained in the expanded state. The balloon 30 is inflated at a pressure (for example, 4 atm) lower than the pressure at the time of use in a blood vessel (for example, 8 atm). The coating layer 40 can be formed on the outer surface of the balloon 30 without expanding the balloon 30. In this case, it is not necessary to supply a fluid for expansion into the balloon 30.

  Next, in order to form the hydrophilic layer 37 on the balloon 30, as shown in FIG. 4, the balloon 30 is immersed in the hydrophilic solution 111 of the first tank 110 and then pulled up. Thereafter, the hydrophilic layer 37 is formed on the outer surface of the balloon 30 by volatilizing the solvent. The immersion and lifting of the balloon 30 in the hydrophilic solution 111 may be performed a plurality of times.

  Next, in order to form the amphiphilic layer 38 on the outer surface of the hydrophilic layer 37, the balloon 30 is immersed in the amphiphilic solution 121 of the second tank 120 and then pulled up. Thereafter, by evaporating the solvent, an amphiphilic layer 38 is formed on the outer surface of the hydrophilic layer 37. The immersion and lifting of the balloon 30 in the amphiphilic solution 121 may be performed a plurality of times.

  Next, with the dispensing tube 94 not in contact with the outer surface of the balloon 30, the balloon catheter 10 is rotatably installed on the support base 70, and the hub 26 is connected to the rotation mechanism 60, as shown in FIG. .

  Next, the position of the moving table 81 is adjusted to position the dispensing tube 94 with respect to the balloon 30. At this time, the dispensing tube 94 is positioned at the most distal position where the coat layer 40 is formed in the balloon 30. As an example, the extending direction (discharge direction) of the dispensing tube 94 is opposite to the rotation direction of the balloon 30, as shown in FIG. Therefore, the balloon 30 rotates in the direction opposite to the direction in which the coating liquid 45 is discharged from the dispensing tube 94 at the position where the balloon 30 is in contact with the dispensing tube 94. Thereby, a physical stimulus can be given to the coating liquid 45 to promote the formation of crystal nuclei of drug crystals. Since the direction in which the dispensing tube 94 extends toward the opening 95 (discharge direction) is opposite to the rotational direction of the balloon 30, water formed on the outer surface of the amphiphilic layer 38 of the balloon 30 is formed. The crystals of the insoluble drug are likely to be formed including a morphotype including a plurality of drug crystals 42 each having an independent long axis. Note that the direction in which the dispensing tube 94 extends does not need to be opposite to the direction of rotation of the balloon 30, and therefore can be the same direction or can be vertical.

  Next, the balloon catheter 10 is rotated by the rotation mechanism 60. Subsequently, the moving table 81 is moved while the coating liquid 45 is supplied to the dispensing tube 94 by adjusting the liquid sending amount by the liquid sending pump 93, and the dispensing tube 94 is moved along the axial direction of the balloon 30. Move gradually toward the proximal end. The coating liquid 45 discharged from the opening 95 of the dispensing tube 94 draws a spiral on the outer peripheral surface of the amphiphilic layer 38 of the balloon 30 as the dispensing tube 94 moves relative to the balloon 30. It is applied while. Due to the rotation of the balloon 30, the coating liquid 45 applied to the outer peripheral surface of the amphiphilic layer 38 tends to be uniform in the circumferential direction.

  The moving speed of the dispensing tube 94 is not particularly limited, but is, for example, 0.01 to 2 mm / sec, preferably 0.03 to 1.5 mm / sec, and more preferably 0.05 to 1.0 mm / sec. The discharge speed of the coating liquid 45 from the dispensing tube 94 is not particularly limited, but is, for example, 0.01 to 1.5 μL / sec, preferably 0.01 to 1.0 μL / sec, and more preferably 0.03 to 0 μL / sec. 0.8 μL / sec. The rotation speed of the balloon 30 is not particularly limited, but is, for example, 10 to 300 rpm, preferably 30 to 250 rpm, and more preferably 50 to 200 rpm. The diameter of the balloon 30 when applying the coating liquid 45 is not particularly limited, but is, for example, 1 to 10 mm, and preferably 2 to 7 mm.

  The organic solvent contained in the coating liquid 45 applied to the outer surface of the amphiphilic layer 38 volatilizes before water. Therefore, the organic solvent is volatilized in a state where the water-insoluble drug, the amphiphilic low-molecular compound and the water are left on the outer surface of the amphiphilic layer 38. As described above, when the organic solvent is volatilized in a state where water is left, a water-insoluble drug precipitates inside the amphiphilic low-molecular compound containing water, and crystals gradually grow from crystal nuclei, and the On the outer surface of the medium layer 38, a drug crystal 42 of a morphological form including a plurality of crystals each having an independent long axis is formed. The base of the drug crystal 42 is located on the outer surface of the amphiphilic layer 38, on the surface of the additive 41, or inside the additive 41 (see FIG. 3). After the organic solvent is volatilized and the drug crystals 42 precipitate, the water evaporates more slowly than the organic solvent, and the additive 41 containing the amphiphilic low molecular weight compound is formed. The time for water to evaporate is appropriately set according to the type of the drug, the type of the amphiphilic low-molecular compound, the type of the organic solvent, the ratio of the materials, the amount of the coating liquid 45 applied, and the like. On the order of seconds.

  In a state where the solvent remains in the coating liquid 45 applied to the amphiphilic layer 38, the solvent can partially dissolve the amphiphilic low-molecular compound forming the amphiphilic layer 38. Therefore, the amphiphilic low molecular compound of the amphiphilic layer 38 and the amphiphilic low molecular compound of the additive 41 may be partially mixed. Therefore, while the amphiphilic layer 38 reliably separates the hydrophilic layer 37 and the coat layer 40, the amphiphilic layer 38 is strongly bonded to the coat layer 40 to stably and satisfactorily connect the hydrophilic layer 37 and the coat layer 40. .

  Then, the dispensing tube 94 is gradually moved in the axial direction of the balloon 30 while rotating the balloon 30. Thus, a layer of the coating liquid 45 is gradually formed on the outer surface of the amphiphilic layer 38 toward the axial direction. After the layer of the coating liquid 45 is formed on the entire area to be coated with the amphiphilic layer 38, the moving mechanism section 80 and the coating liquid supply section 90 are stopped. Next, the balloon catheter 10 is removed from the support base 70. Next, the expansion fluid is discharged from the balloon 30, and the balloon 30 is contracted and folded. Thereby, the manufacture of the balloon catheter 10 is completed.

  As shown in FIG. 7A, the balloon 30 has a substantially circular cross section in a state in which the expansion fluid is injected therein. In this state, the balloon 30 is formed with the protruding wing portions 32, and as shown in FIG. 7B, the wing outer portion 34 a constituting the outer surface of the wing portion 32 and the inner portion of the wing portion 32. A blade inner portion 34b constituting a side surface and an intermediate portion 34c located between the blade outer portion 34a and the blade inner portion 34b are formed. From this state, as shown in FIG. 7 (C), the blade portion 32 projecting outward in the radial direction is folded in the circumferential direction. When the blade 32 of the balloon 30 is folded, the blade outer portion 34a forming the outer surface of the blade 32, the blade inner portion 34b forming the inner surface of the blade 32, the blade outer portion 34a and the blade inner portion 34b. And an intermediate portion 34c located between the two. When the wing portion 32 of the balloon 30 is folded, the wing inner portion 34b and the intermediate portion 34c overlap and come into contact with each other, and an overlapping portion 35 is formed in which the outer surfaces of the balloon 30 face each other and overlap. Then, a part of the intermediate portion 34c and the blade outer portion 34a are not covered by the blade inner portion 34b and are exposed to the outside. When the balloon 30 is folded, a root-side space 36 is formed between the root of the blade 32 and the intermediate portion 34c. In the region of the root side space portion 36, a minute gap is formed between the blade portion 32 and the intermediate portion 34c. On the other hand, the region of the blade portion 32 on the tip side of the root side space portion 36 is in a state of being in close contact with the intermediate portion 34c. The ratio of the circumferential length of the root side space portion 36 to the circumferential length of the blade portion 32 is in the range of 1 to 95%. The outer blade portion 34a of the balloon 30 receives a pressing force that rubs in a circumferential direction from a blade for folding the balloon 30, and is further heated. Thereby, the long drug crystal 42 provided on the outer blade portion 34 a falls down on the surface of the balloon 30 and is easy to sleep. Note that it is not necessary for all of the drug crystals 42 to sleep.

  In addition, since the outer surfaces of the overlapping portions 35 of the balloon 30 that are overlapped with each other are not exposed to the outside, a pressing force acts indirectly from the blade when the balloon 30 is folded. For this reason, it is easy to adjust the force acting on the drug crystal 42 provided on the outer surface overlapping at the overlapping portion 35 of the balloon 30 so as not to become too strong. Therefore, a desired force can be applied to lay down the drug crystal 42 provided on the outer surface overlapping at the overlapping portion 35 of the balloon 30. In the region of the blade inner portion 34b and the intermediate portion 34c facing each other, in the region facing the root side space portion 36, that is, in the region where the blade inner portion 34b and the intermediate portion 34c are not in close contact with each other, the drug crystal 42 exerts a pressing force. Hard to receive. Therefore, in this region, the drug crystal 42 is difficult to sleep. In the region of the blade inner portion 34b and the intermediate portion 34c facing each other, in the region not facing the root side space portion 36, that is, in the region where the blade inner portion 34b and the intermediate portion 34c are in close contact, the drug crystal 42 Easy to receive pressing force. Therefore, in this region, the drug crystal 42 falls down and is easy to sleep.

  Next, a method of using the balloon catheter 10 will be described by taking as an example a case of treating a stenosis in a blood vessel.

  First, an operator punctures a blood vessel from the skin by a known method such as the Seldinger method, and places an introducer (not shown). Next, after priming of the balloon catheter 10, the guide wire 200 (see FIG. 8) is inserted into the guide wire lumen 24. In this state, the guide wire 200 and the balloon catheter 10 are inserted into the blood vessel from inside the introducer. Subsequently, the balloon catheter 10 is advanced while the guide wire 200 is advanced, and the balloon 30 reaches the stenosis. At this time, since the hydrophilic layer 37 having high lubricity is provided on the outer surface of the balloon 30, the balloon 30 can reach the target position smoothly. In addition, a guiding catheter may be used to reach the stenosis part 300 from the balloon catheter 10.

  Next, a predetermined amount of inflation fluid is injected from the proximal end opening 27 of the hub 26 using an indeflator or a syringe or the like, and the inflation fluid is sent into the balloon 30 through the inflation lumen 23. Thereby, as shown in FIG. 8, the folded balloon 30 is expanded, and the stenosis portion 300 is expanded by the balloon 30. At this time, the coat layer 40 provided on the outer surface of the balloon 30 comes into contact with the stenotic portion 300.

  When the balloon 30 is expanded and the coat layer 40 is pressed against the living tissue, the additive 41, which is an amphiphilic low molecular compound, and the amphiphilic layer 38 contained in the coat layer 40 are gradually or rapidly dissolved, and the drug crystal is dissolved. 42 is delivered to the living body. The drug crystals 42 of the coat layer 40 are formed uniformly by the above-described manufacturing method. For this reason, the medicine can act satisfactorily on the living body without variation. The amphiphilic layer 38 stably and satisfactorily connects the hydrophilic layer 37 and the coat layer 40 while separating the hydrophilic layer 37 and the coat layer 40. For this reason, the drug crystal 42 is uniformly and stably held by the balloon 30. Since the drug crystal 42 is separated from the hydrophilic layer 37 by the amphiphilic layer 38 while being sandwiched by the additive 41 made of an amphiphilic low molecule, the additive which is an amphiphilic low molecular compound is added. When the 41 and the hydrophilic layer 37 are rapidly dissolved in the living body, the balloon 30 can be quickly and reliably transferred from the balloon 30 to the living tissue.

  Thereafter, the expanding fluid is sucked and discharged from the proximal end opening 27 of the hub 26, and the balloon 30 is contracted to be in a folded state. Thereafter, the guide wire 200 and the balloon catheter 10 are removed from the blood vessel via the introducer, and the procedure ends.

  As described above, the method for manufacturing the balloon catheter 10 according to the present embodiment is a method for manufacturing the balloon catheter 10 in which the coat layer 40 containing the water-insoluble drug is formed on the outer surface of the balloon 30. Forming a hydrophilic layer 37 made of a hydrophilic polymer compound on the outer surface, forming an amphiphilic layer 38 made of an amphiphilic low molecular compound on the outer surface of the hydrophilic layer 37, The method includes a step of applying a coating liquid 45 containing a drug and a solvent to the amphiphilic layer 38, and a step of volatilizing the solvent of the coating liquid 45.

  In the method of manufacturing the balloon catheter 10 configured as described above, the coating liquid containing a water-insoluble drug is formed on the outer surface of the amphiphilic layer 38 after forming the amphiphilic layer 38 on the outer surface of the hydrophilic layer 37. Since the coating liquid 45 is applied, the coating liquid 45 spreads smoothly on the outer surface of the amphiphilic layer 38, and the coating layer 40 containing the water-insoluble drug crystals 42 is uniformly and stably held on the balloon 30. Further, since the amphiphilic layer 38 is made of a low molecular compound, it is rapidly dissolved in a living body. For this reason, the coat layer 40 which is quickly released at a target position can be formed on the outer surface of the amphiphilic layer 38.

  Further, the coating liquid 45 may further include an additive 41 composed of an amphiphilic low-molecular compound. As a result, the amphiphilic low-molecular compound contained in the coating liquid 45 is stably retained with respect to the amphiphilic low-molecular compound of the amphiphilic layer 38, and the water-insoluble drug crystal 42 is stably retained. The coat layer 40 can be formed. In addition, since the amphiphilic low-molecular compound contained in the amphiphilic layer 38 and the coat layer 40 is rapidly dissolved in the living body, the water-insoluble drug crystal 42 can be quickly transferred to the living tissue.

  Also, the water-insoluble drug may be rapamycin, paclitaxel, docetaxel, or everolimus. Thereby, the restenosis of the stenosis part in the blood vessel can be favorably suppressed by the drug crystal 42.

  In addition, the amphiphilic low molecular weight compound may be an amino acid ester compound, and glycine, serine, asparagine, aspartic acid, glutamine, glutamic acid, arginine, threonine, histidine, lysine, tyrosine, tryptophan and the amino group at the α-position of these amino acids An amino acid in which at least one of the hydrogen atoms of the above is substituted with an alkyl group, a benzyl group or a benzoyl group having 5 or less carbon atoms, and a proline and an alkyl group, a benzyl group or a benzoyl group having a hydrogen atom of the imino group of proline having 5 or less carbon atoms And at least one selected from the group consisting of ester compounds of at least one amino acid selected from the group consisting of amino acids substituted with a monohydric alcohol having 5 or less carbon atoms. Amphiphilic low molecular weight compounds include, specifically, benzyl glycine ethyl ester, benzyl glycine methyl ester, arginine ethyl ester, arginine methyl ester, benzoyl arginine ethyl ester, benzoyl arginine methyl ester, aspartic acid diethyl ester, aspartic acid methyl ester Dimethyl aspartate, glycine ethyl ester, glycine methyl ester, serine ethyl ester and serine methyl ester, valine ethyl ester. This allows the amphiphilic low-molecular-weight compound to be rapidly dissolved when the balloon 30 is expanded, so that the drug can be quickly transferred to the living tissue.

  Further, in the present manufacturing method, in the step of applying the coating liquid 45 to the amphiphilic layer 38, the tubular dispensing for supplying the coating liquid 45 while rotating the balloon 30 around the axis of the balloon 30 is performed. The coating liquid 45 may be applied to the outer surface of the balloon 30 by moving the tube 94 relative to the balloon 30 in the axial direction of the balloon 30. Thus, by applying the coating liquid 45 from the dispensing tube 94 to the rotating balloon 30, the amount of application can be controlled with high precision, so that the drug crystals 42 can be uniformly formed on the outer surface of the balloon 30, and Control of crystallization is facilitated. In addition, since the dispensing tube 94 can apply the necessary amount of the coating liquid 45 to the balloon 30, the solvent contained in the coating liquid 45 causes the amphiphilic low-molecular compound of the amphiphilic layer 38 to dissolve and move or drop off. Can be suppressed. Therefore, a uniform coat layer 40 can be stably formed on the outer surface of the amphiphilic layer 38.

  Note that the present invention is not limited to only the above-described embodiment, and various modifications can be made by those skilled in the art within the technical idea of the present invention. For example, the above-described balloon catheter 10 is of a rapid exchange type, but may be of an over-the-wire type.

  Further, the balloon catheter 10 may move along the axis without moving the dispensing tube 94. In addition, the coat layer 40 may not include the additive 41 as long as it includes a drug.

  Furthermore, the present application is based on Japanese Patent Application No. 2017-050839 filed on March 16, 2017, the disclosures of which are referenced and incorporated in its entirety.

DESCRIPTION OF SYMBOLS 10 Balloon catheter 30 Balloon 37 Hydrophilic layer 38 Amphiphilic layer 40 Coating layer 41 Additive 42 Drug crystal 45 Coating liquid 50 Coating device 60 Rotating mechanism part 80 Moving mechanism part 90 Coating liquid supply part 94 Dispensing tube 110 First Vessel 120 Second Vessel

Claims (5)

A method for producing a balloon catheter in which a coat layer containing a water-insoluble drug is formed on the outer surface of the balloon,
Forming a hydrophilic layer made of a hydrophilic polymer compound on the outer surface of the balloon,
Forming an amphiphilic layer comprising an amphiphilic low molecular compound on the outer surface of the hydrophilic layer,
Applying a coating solution containing a water-insoluble drug and a solvent to the amphiphilic layer,
Volatilizing the solvent of the coating solution.   The method of claim 1, wherein the coating liquid further includes an amphiphilic low molecular weight compound.   3. The method according to claim 1, wherein the water-insoluble drug contains at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel, and everolimus.   The amphiphilic low molecular weight compound is benzyl glycine ethyl ester, benzyl glycine methyl ester, arginine ethyl ester, arginine methyl ester, benzoyl arginine ethyl ester, benzoyl arginine methyl ester, aspartic acid diethyl ester, aspartic acid methyl ester, dimethyl aspartate The method according to any one of claims 1 to 3, further comprising at least one selected from the group consisting of an ester, glycine ethyl ester, glycine methyl ester, serine ethyl ester and serine methyl ester, and valine ethyl ester. Manufacturing method of balloon catheter.   In the step of applying the coating liquid to the amphipathic layer, while rotating the balloon around the axis of the balloon, a tubular dispensing tube for supplying the coating liquid is supplied in the axial direction of the balloon. The method for manufacturing a balloon catheter according to any one of claims 1 to 4, wherein the coating solution is applied to an outer surface of the balloon by moving the balloon catheter relative to the balloon.

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