WO2018169052A1 - Balloon catheter production method - Google Patents

Balloon catheter production method Download PDF

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Publication number
WO2018169052A1
WO2018169052A1 PCT/JP2018/010471 JP2018010471W WO2018169052A1 WO 2018169052 A1 WO2018169052 A1 WO 2018169052A1 JP 2018010471 W JP2018010471 W JP 2018010471W WO 2018169052 A1 WO2018169052 A1 WO 2018169052A1
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WO
WIPO (PCT)
Prior art keywords
balloon
amphiphilic
layer
drug
coating liquid
Prior art date
Application number
PCT/JP2018/010471
Other languages
French (fr)
Japanese (ja)
Inventor
村田悠
黒崎靖夫
後藤博
Original Assignee
テルモ株式会社
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Filing date
Publication date
Application filed by テルモ株式会社 filed Critical テルモ株式会社
Priority to JP2019506298A priority Critical patent/JP7073337B2/en
Publication of WO2018169052A1 publication Critical patent/WO2018169052A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters

Definitions

  • the present invention relates to a method for manufacturing a balloon catheter in which a drug is provided on the outer surface of the balloon.
  • the balloon catheter has been used to improve a lesion (stenosis) occurring in a living body lumen.
  • the balloon catheter usually includes a long shaft portion and a balloon that is provided on the distal end side of the shaft portion and is expandable in the radial direction. By expanding the deflated balloon after reaching a target location in the body via a thin living body lumen, the lesioned part can be expanded.
  • a drug eluting balloon in which a drug for suppressing stenosis is coated on the outer surface of the balloon is used.
  • the drug coated on the outer surface is instantaneously released to the lesioned part, thereby preventing restenosis.
  • the outer surface of the balloon is subjected to a hydrophilic treatment in order to improve the slipping property in the living body.
  • a hydrophilic treatment since an organic solvent is required at the time of coating, it is difficult to coat the outer surface of the balloon with a hydrophobic drug while maintaining the function obtained by the hydrophilic treatment.
  • Patent Document 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 the balloon. Since the amphiphilic compound has both a hydrophilic group and a hydrophobic group, it plays a role of holding a hydrophobic drug on the hydrophilic layer.
  • the balloon can release the drug quickly by holding the drug well to the target position in the living body and expanding it at the target position.
  • the present invention has been made to solve the above-described problem, 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 quickly 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 coating layer containing a water-insoluble drug is formed on the outer surface of the balloon, and a hydrophilic polymer compound is formed on the outer surface of the balloon.
  • Forming a hydrophilic layer forming an amphiphilic layer composed of an amphiphilic low-molecular compound on the outer surface of the hydrophilic layer, and a coating solution containing a water-insoluble drug and a solvent. Applying to the adhesive layer and volatilizing the solvent of the coating solution.
  • an amphiphilic layer is formed on the outer surface of the hydrophilic layer, and then a coating solution containing a water-insoluble drug is applied to the outer surface of the amphiphilic layer.
  • the coating solution spreads smoothly on the outer surface of the amphiphilic layer, and the coating layer containing the water-insoluble drug is uniformly and stably held on the balloon.
  • an amphiphilic layer consists of a low molecular compound, it melt
  • the coating liquid may further contain an amphiphilic low molecular compound.
  • an amphiphilic low molecular compound contained in the coating liquid is stably held with respect to the amphiphilic low molecular weight compound in the amphiphilic layer, and a coating layer that holds the drug well can be formed.
  • the amphiphilic low-molecular compound dissolves rapidly in the living body, the drug can be quickly 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.
  • the amphiphilic low molecular weight compounds are 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, aspartic acid dimethyl ester.
  • a tubular dispensing tube for supplying the coating liquid while rotating the balloon around the axis of the balloon is provided.
  • the coating liquid may be applied to the outer surface of the balloon by moving it relative to the balloon in the axial direction of the balloon.
  • the dispensing tube can apply the required amount of coating liquid to the balloon, so that the amphiphilic low molecular weight compound in the amphiphilic layer dissolves more than necessary and moves or drops by the solvent contained in the coating liquid. Can be suppressed. For this reason, a uniform coat layer can be stably formed on the outer surface of the amphiphilic layer.
  • the balloon catheter manufacturing method is a method for manufacturing a drug-eluting balloon catheter 10 in which drug crystals are provided on the outer surface of the balloon 30, as shown in FIGS.
  • the side of the balloon catheter 10 to be inserted into the living body lumen is referred to as “tip” or “tip side”
  • the proximal side for operation is referred to as “base end” or “base end side”.
  • the balloon catheter 10 has a long catheter body 20, a balloon 30 provided at the distal end portion 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 coated with a hydrophilic layer 37 made of a hydrophilic polymer compound, an amphiphilic layer 38 made of an amphiphilic low-molecular compound, and a coat layer 40 containing a drug.
  • the catheter body 20 includes an outer tube 21 that is a tube having an open front end and a proximal end, 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 interior of the inner tube 22 is a guide wire lumen 24 through which the guide wire is inserted.
  • an expansion lumen 23 through which the expansion fluid of the balloon 30 flows is formed inside the hollow of the outer tube 21 and outside the inner tube 22.
  • the inner tube 22 opens 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 portion fixed to the distal end portion of the outer tube 21 and a distal end portion fixed to the distal end portion of the inner tube 22. Thereby, the inside of the balloon 30 communicates with the expansion lumen 23.
  • the balloon 30 can be expanded by injecting an expansion fluid into the balloon 30 through the expansion lumen 23.
  • the expansion fluid may be a gas or a liquid.
  • a gas such as helium c, CO 2 gas, O 2 gas, N 2 gas, Ar gas, air, mixed gas, or a liquid such as physiological saline or contrast medium is used. Can do.
  • a cylindrical straight portion 31 having the same outer diameter when expanded is formed in the central portion of the balloon 30 in the axial direction, and a taper whose outer diameter gradually changes on both sides of the straight portion 31 in the axial direction.
  • a portion 33 is formed.
  • medical agent is formed in the whole outer surface of the straight part 31.
  • FIG. The range in which the coating layer 40 is formed in the balloon 30 is not limited to the straight portion 31, and may include at least a part of the tapered portion 33 in addition to the straight portion 31, or one of the straight portions 31. It may be only part.
  • the hub 26 is formed with a base end opening portion 27 that functions as a port that communicates with the expansion lumen 23 of the outer tube 21 and allows the expansion fluid to flow in and out.
  • 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 at the time of expansion 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.
  • 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 where there are minute holes that do not penetrate the membrane.
  • the size of the minute holes is, for example, 0.1 to 5 ⁇ m in diameter and 0.1 to 10 ⁇ m in depth, and may have one or a plurality of holes for one crystal.
  • the size of the minute holes is, for example, a diameter of 5 to 500 ⁇ m and a depth of 0.1 to 50 ⁇ m, and one hole or a plurality of crystals may be included for one hole.
  • the balloon 30 has a certain degree of flexibility so that it can be expanded when it reaches a blood vessel, tissue, etc., and has a certain degree of hardness so that the drug can be released from the coat layer 40 on its outer surface.
  • the balloon 30 is made of metal or resin, but at least the outer surface of the balloon 30 on which the coat layer 40 is provided is preferably 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, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, ionomer, or a mixture of two or more of these, soft poly
  • a thermoplastic resin such as vinyl chloride resin, polyamide, polyamide elastomer, nylon elastomer, polyester, polyester elastomer, polyurethane, fluororesin, silicone rubber, latex rubber, or the like can be used.
  • polyamides are preferable. That is, at least a part of the outer surface of the balloon 30 that coats the drug is a polyamide.
  • the polyamide is not particularly limited as long as it is a polymer having an amide bond.
  • 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), caprolactam / lauryl lactam copolymer Polymer (nylon 6/12), caprolactam / aminoundecanoic acid copolymer (nylon 6/11), caprolactam / ⁇ -aminononanoic acid copolymer (nylon 6/9), caprolactam / hexamethylene diammonium adipate copolymer ( Nylon 6/66 Copolymers such as a copolymer of adipic acid and meta-x
  • a polyamide elastomer which is a block copolymer having nylon 6, nylon 66, nylon 11, nylon 12 or the like as a hard segment and polyalkylene glycol, polyether, aliphatic polyester or the like as a soft segment is also a material of the balloon 30.
  • the said polyamides may be used individually by 1 type, and may use 2 or more types together.
  • 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 high slipperiness (lubricity) in the living body.
  • the hydrophilic layer 37 is provided in order to improve the passability of the balloon 30 in the living body.
  • the hydrophilic polymer compound of the hydrophilic layer 37 include polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, collagen, chitosan, and a polymer polyglycidyl methacrylate-dimethylacrylamide (PGMA-DMAA) block copolymer. And their copolymers and derivatives.
  • a polymer polyglycidyl methacrylate-dimethylacrylamide (PGMA-DMAA) block copolymer is disposed as a hydrophilic layer 37 on a polyamide balloon 30, and an amino acid ester 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 can be disposed, and a coat layer 40 including paclitaxel can be disposed thereon.
  • the hydrophilic layer 37 and the amphiphilic layer 38 are in direct contact, and the amphiphilic layer 38 and the coat layer 40 are in direct contact.
  • the amphiphilic layer 38 is coated after the hydrophilic layer 37 is dried on the balloon 30.
  • the coat layer 40 is coated after the amphiphilic layer 38 is dried on the hydrophilic layer 37.
  • the hydrophilic layer 37 has an amphiphilic layer 38 made of an amphiphilic low-molecular compound formed on the outer surface thereof.
  • An amphiphilic low molecular weight compound is a low molecular weight compound having a hydrophilic group and a hydrophobic group.
  • the amphiphilic layer 38 plays a role of mediating between the hydrophilic hydrophilic layer 37 and the 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 (polymer or the like) is continuously formed, forms a network-like three-dimensional structure, and has a fine space therein.
  • the amphiphilic layer 38 may form a matrix.
  • the amphiphilic layer 38 is coated on the outer surface of the hydrophilic layer 37 while being dissolved in a solvent, and then dried to form a layer.
  • the amphiphilic layer 38 is amorphous.
  • the amphiphilic layer 38 may be crystal particles.
  • the amphiphilic layer 38 may exist as a mixture of amorphous and crystalline particles.
  • the amphiphilic layer 38 in FIG. 3 is in the 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 ⁇ m, preferably 0.1 to 10 ⁇ m, more preferably 0.1 to 3 ⁇ m.
  • the amphiphilic layer 38 has a coat layer 40 containing a drug formed on the outer surface thereof.
  • the coat layer 40 has an additive 41 (excipient) arranged in a layered manner 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 amphiphilic layer 38, but is not 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 portion of the drug crystal 42 may be positioned 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 the drug contained in the coat layer 40 is not particularly limited, but is 0.1 ⁇ g / mm 2 to 10 ⁇ g / mm 2 , preferably 0.5 ⁇ g / mm 2 to 5 ⁇ g / mm 2 , more preferably 0.5 ⁇ g. / Mm 2 to 3.5 ⁇ g / mm 2 , more preferably 1.0 ⁇ g / mm 2 to 3 ⁇ g / mm 2 .
  • the amount of crystals of the coat layer 40 is not particularly limited, but is preferably 5 to 500,000 [crystal / (10 ⁇ m 2 )] (number of crystals per 10 ⁇ m 2 ), more preferably 50 to 50,000 [crystal / (10 ⁇ m 2 )], more preferably 500 to 5,000 [crystal / (10 ⁇ m 2 )].
  • the drug crystal 42 may have a form having independent long axes. Further, the drug crystal 42 may be other morphological types.
  • the plurality of drug crystals 42 may be present in a state where they are combined, or may be present in contact with each other with a plurality of adjacent drug crystals 42 forming different angles.
  • the plurality of drug crystals 42 may be positioned on the balloon surface with a space (a space not including a crystal).
  • On the surface of the amphiphilic layer 38 there may be both a plurality of drug crystals 42 in a combined state and a plurality of drug crystals 42 that are separated from each other and independent.
  • the plurality of drug crystals 42 may be arranged in a brush shape around the circumference having different major axis directions.
  • Each of the drug crystals 42 exists independently and 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 almost linear.
  • the drug crystal 42 forms a predetermined angle with respect to the surface with which the base portion where the major axes intersect is in contact.
  • 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.
  • 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 to the major axis of the drug crystal 42 (perpendicular) has a hollow.
  • the drug crystal 42 having the hollow has a polygonal cross section of the drug crystal 42 in a plane perpendicular (perpendicular) to the long axis.
  • the polygon is, for example, a triangle, a tetragon, a pentagon, or a hexagon.
  • the drug crystal 42 has a distal end (or distal end surface) and a proximal end (or proximal end surface), and a side surface between the distal end (or distal end surface) and the proximal end (or proximal end surface) is a plurality of substantially flat surfaces. It is formed as a configured long polyhedron.
  • This crystal form type (hollow elongated body crystal form type) constitutes the whole or at least a part of a certain plane on the surface in contact with the base.
  • the length in the major axis direction of the drug crystal 42 having a major axis is preferably 5 ⁇ m to 20 ⁇ m, more preferably 9 ⁇ m to 11 ⁇ m, and even more preferably around 10 ⁇ m.
  • the diameter of the drug crystal 42 having a long axis is preferably 0.01 ⁇ m to 5 ⁇ m, more preferably 0.05 ⁇ m to 4 ⁇ m, and even more preferably 0.1 ⁇ m to 3 ⁇ m.
  • a combination having a diameter of 0.01 to 5 ⁇ m when the length is 5 ⁇ m to 20 ⁇ m, and a combination when the length is 5 to 20 ⁇ m examples include combinations having a diameter of 0.05 to 4 ⁇ m, and combinations having a diameter of 0.1 to 3 ⁇ m when the length is 5 to 20 ⁇ m.
  • the drug crystal 42 having the long axis is linear in the long axis direction, but may be curved. Both the linear drug crystal 42 and the curved drug crystal 42 may exist on the surface of the balloon 30.
  • the above-mentioned crystal morphology type having the drug crystal 42 having the long axis is 50% by volume or more, more preferably 70% by volume or more with respect to 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 on the outer surface of the balloon 30 or the additive 41.
  • the additive 41 is present in the region where the drug crystal 42 is present, and may not be present in the region where the drug crystal 42 is absent.
  • the amphiphilic low molecular compound constituting the additive 41 may be the same as the amphiphilic low molecular compound constituting 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 weight compound constituting the additive 41 may be different from the amphiphilic low molecular weight compound constituting the amphiphilic layer 38. Thereby, the amphiphilic low molecular weight compound of the additive 41 and 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 the space between the plurality of drug crystals 42 in the forest.
  • the proportion of the substance constituting the coat layer 40 is preferably such that the water-insoluble drug crystal 42 occupies a larger volume than the additive 41.
  • the additive 41 does not form a matrix.
  • the matrix is a layer in which a relatively high-molecular substance (polymer or the like) is continuously formed, forms a network-like three-dimensional structure, and has a fine space therein. Therefore, the water-insoluble drug constituting the crystal is not attached to the matrix material. The water-insoluble drug constituting the crystal is not embedded in the matrix material.
  • the additive 41 may form a matrix.
  • the additive 41 is coated on the outer surface of the amphiphilic layer 38 while being dissolved in a solvent, and then dried to form a layer.
  • the additive 41 is amorphous.
  • the additive 41 may be crystal particles.
  • Additive 41 may be present as a mixture of amorphous and crystalline particles.
  • the additive 41 in FIG. 3 is in the state of crystal grains 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 that does not contain a water-insoluble drug.
  • the thickness of the additive 41 is 0.1 to 5 ⁇ m, preferably 0.3 to 3 ⁇ m, more preferably 0.5 to 2 ⁇ m.
  • the layer containing the drug crystal 42 of a long crystal form type has low toxicity and high stenosis-inhibiting effect when delivered into the body.
  • a water-insoluble drug containing a hollow long crystalline form is effective because it has good permeability to the tissue and good solubility because one unit of the crystal becomes small when the drug moves into the tissue. It can act to suppress stenosis.
  • toxicity is low because the drug hardly remains in the tissue as a large mass.
  • the layer containing the drug crystal 42 having a long crystal form type has a small crystal size (length in the long axis direction) that moves to the tissue of about 10 ⁇ m. Therefore, it acts uniformly on the affected part of the lesion and increases tissue permeability. Furthermore, since the size of the transferred drug crystal 42 is small, an excessive amount of drug does not stay in the affected area for an excessive period of 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, crystals and amorphous materials may be arranged irregularly.
  • 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 a hydrophilic layer 37 on the outer surface of the balloon 30 by dipping. Inside the first tank 110, a hydrophilic solution 111 containing a hydrophilic polymer compound constituting the hydrophilic layer 37 and a solvent is accommodated.
  • a hydrophilic polymer compound for example, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, collagen, chitosan, and their copolymers and derivatives can be used.
  • the solvent examples include water, lower alcohols, dichloroethylene, dichloroethane, chloroform, acetonitrile, methylene chloride, acetone, and a mixed solvent thereof.
  • the hydrophilic layer 37 may be formed by a method other than dipping.
  • the coating apparatus 50 mentioned later can also be used.
  • the second tank 120 is a tank for forming an 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 constituting the amphiphilic layer 38 and a solvent 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, the coating apparatus 50 mentioned later can also be used.
  • the molecular weight of the amphiphilic low-molecular compound constituting the amphiphilic layer 38 is 50 to 2000, preferably 50 to 1000, more preferably 50 to 500, and further preferably 50 to 200.
  • the constituent materials of amphiphilic low molecular weight compounds are 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 of these can be used.
  • the amphiphilic low molecular weight compound has a hydrophilic group and a hydrophobic group and is characterized by being dissolved in water.
  • the amphiphilic low molecular weight compound is preferably non-swellable or hardly swellable.
  • the solvent of the amphiphilic solution 121 for example, water, ethanol, methanol, glycerin, or the like can be used.
  • the coating apparatus 50 can form a coating layer 40 on the outer surface of the amphiphilic layer 38 of the balloon 30 as shown in FIGS.
  • the coating apparatus 50 includes a rotation mechanism unit 60 that rotates the balloon catheter 10 and a support base 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 that applies the coating liquid 45 to the outer surface of the balloon 30, and a moving mechanism unit 80 that moves the dispensing tube 94 relative to the balloon 30.
  • Have The coating apparatus 50 further includes a control unit 100 that controls each part of the coating apparatus 50.
  • the rotation mechanism unit 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 built-in driving source such as a motor.
  • a built-in driving source such as a motor.
  • the 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.
  • a three-way cock that can open and close the flow path is connected to the proximal end opening 27 of the hub 26 in order to control the flow of fluid to the expansion lumen 23.
  • the support base 70 includes a tubular proximal end support portion 71 that accommodates the catheter main body 20 in a rotatable manner, and a distal end side support portion 72 that rotatably supports the core member 61. Note that the distal end side support portion 72 may rotatably support the distal end portion of the catheter body 20 instead of the core member 61 if possible.
  • 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 move linearly by a driving source such as a built-in motor. As the moving table 81 moves, the dispensing tube 94 linearly moves 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 linearly moves the coating liquid supply unit 90 in both directions along the axis.
  • the coating liquid supply unit 90 is a part where the coating liquid 45 is applied to the outer surface of the amphiphilic layer 38 of the balloon 30.
  • the coating liquid supply unit 90 includes a container 92 that stores the coating liquid 45, a liquid feeding pump 93 that feeds the coating liquid 45 in an arbitrary liquid feeding amount, and a dispensing that applies the coating liquid 45 to the amphiphilic layer 38.
  • a tube 94 A tube 94.
  • the liquid feed 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 through the suction tube 91 and to the dispensing tube 94 through the supply tube 96. Can be supplied at an arbitrary liquid feeding amount.
  • the liquid feed pump 93 is installed on the moving table 81 and can move linearly by the movement of the moving table 81.
  • the liquid feed pump 93 is not limited to a syringe pump as long as the coating liquid 45 can be fed, and may be a tube pump, for example.
  • the dispensing tube 94 communicates with the supply tube 96 and discharges the coating liquid 45 supplied from the liquid feed pump 93 through 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 that 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 against the amphiphilic layer 38 and is bent.
  • the dispensing tube 94 may not be a circular tube as long as the coating liquid 45 can be supplied.
  • the dispensing tube 94 may not 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 accompanying 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), PFA (tetra Fluororesin such as fluoroethylene / perfluoroalkyl vinyl ether copolymer) or FEP (tetrafluoroethylene / hexafluoropropylene copolymer) can be applied, but if it is flexible and deformable There is no particular limitation.
  • 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 within 5 times the balloon diameter, for example, 1.0 mm to 50 mm, preferably 3 mm to 40 mm, more preferably 5 mm to 35 mm. .
  • the control unit 100 is configured by a computer, for example, and comprehensively controls the rotation mechanism unit 60, the movement mechanism unit 80, and the coating liquid supply unit 90. Therefore, the control unit 100 can comprehensively control the rotation speed of the balloon 30, the moving speed of the dispensing tube 94 in the axial direction relative to the balloon 30, the medicine discharge speed 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 extending on the outer surface of the amphiphilic layer 38 with an independent long axis. 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.
  • Water-insoluble drug means a drug that is insoluble or sparingly soluble in water. Specifically, the solubility in water is less than 5 mg / mL at pH 5-8. 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 drugs include immunosuppressants, such as cyclosporines 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, antiparalytic agents, antagonists, neuron blocking agents, anticholinergics and cholinergic agents, antimuscarinic and muscarinic agents, antiadrenergic agents, Contains antiarrhythmic, antihypertensive, hormonal and nutritional agents.
  • immunosuppressants such as cyclosporines 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, antiparalytic agents, antagonist
  • 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, paclitaxel and rapamycin, especially docetaxel, and evelimel.
  • rapamycin, paclitaxel, docetaxel, and everolimus include analogs and / or derivatives thereof as long as they have similar medicinal effects.
  • paclitaxel and docetaxel are in an analog relationship.
  • Rapamycin and everolimus are in a derivative relationship. Of these, paclitaxel is more preferred.
  • an amphiphilic low-molecular compound applicable to the above-described amphiphilic layer 38 can be used.
  • 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 (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.
  • 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 adheres to the blood vessel. Has the effect of increasing the amount.
  • the additive 41 is preferably not a hydrogel. Since the additive 41 is a low molecular weight compound, it dissolves rapidly without swelling when in contact with an aqueous solution. Furthermore, 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. It has the effect of increasing the amount of adhesion.
  • the additive 41 is a matrix made of a contrast agent such as Ultravist (registered trademark)
  • crystal particles are embedded in the matrix, and crystals are not generated from the amphiphilic layer 38 toward the outside of the matrix.
  • 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, methanol Dichloromethane, hexane, ethyl acetate, i-butyl alcohol, s-butyl alcohol, propanol, butanol, toluene, ethylene glycol and the like.
  • some of these mixed solvents are preferable among tetrahydrofuran, ethanol, and acetone.
  • organic solvent and water mixture examples include, for example, tetrahydrofuran and water, tetrahydrofuran and ethanol and water, tetrahydrofuran and acetone and water, acetone and ethanol and water, and tetrahydrofuran, acetone, ethanol, and water.
  • an expansion fluid is supplied into the balloon 30 through a three-way cock connected to the proximal end opening 27 of the balloon catheter 10.
  • the three-way cock is operated in a state where the balloon 30 is expanded to seal the expansion lumen 23, and the state where the balloon 30 is expanded is maintained.
  • the balloon 30 is expanded at a pressure (for example, 4 atmospheres) lower than a pressure (for example, 8 atmospheres) at the time of use in the blood vessel.
  • the coating layer 40 can also be formed on the outer surface of the balloon 30 without expanding the balloon 30, and in this case, it is not necessary to supply the expansion fluid into the balloon 30.
  • 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. Note that the immersion and lifting of the balloon 30 in the hydrophilic solution 111 may be performed a plurality of times.
  • the balloon 30 is immersed in the amphiphilic solution 121 in the second tank 120 and then pulled up. Thereafter, the amphiphilic layer 38 is formed on the outer surface of the hydrophilic layer 37 by volatilizing the solvent. Note that the immersion and lifting of the balloon 30 in the amphiphilic solution 121 may be performed a plurality of times.
  • the balloon catheter 10 is rotatably installed on the support base 70, and the hub 26 is connected to the rotation mechanism 60. .
  • the position of the moving table 81 is adjusted, and the dispensing tube 94 is positioned with respect to the balloon 30.
  • the dispensing tube 94 is positioned at the most distal end position where the coating layer 40 is formed in the balloon 30.
  • the extending direction (discharge direction) of the dispensing tube 94 is opposite to the rotation direction of the balloon 30 as shown in FIG. Accordingly, 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 dispensing tube 94 is brought into contact. Thereby, physical stimulation can be given to the coating liquid 45 and formation of the crystal nucleus of a drug crystal can be promoted.
  • the extending direction (discharge direction) toward the opening 95 of the dispensing tube 94 is opposite to the rotation direction of the balloon 30, so that the water formed on the outer surface of the amphiphilic layer 38 of the balloon 30.
  • Insoluble drug crystals tend to be formed including morphological forms that include a plurality of drug crystals 42 each having an independent major axis.
  • the extending direction of the dispensing tube 94 does not have to be the reverse direction of the rotation direction of the balloon 30, and can therefore be the same direction or can be perpendicular.
  • the balloon catheter 10 is rotated by the rotation mechanism 60. Subsequently, while the amount of liquid fed is adjusted by the liquid feed pump 93 and the coating liquid 45 is supplied to the dispensing tube 94, the moving table 81 is moved to move the dispensing tube 94 along the axial direction of the balloon 30. Gradually move toward the proximal direction.
  • 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. While being applied.
  • 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 ⁇ L / sec, preferably 0.01 to 1.0 ⁇ L / sec, more preferably 0.03 to 0. .8 ⁇ L / 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, 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 volatilizes in a state where the water-insoluble drug, the amphiphilic low-molecular compound and water are left on the outer surface of the amphiphilic layer 38. As described above, when the organic solvent is volatilized with water remaining, a water-insoluble drug is precipitated inside the amphiphilic low-molecular compound containing water, and the crystal gradually grows from the crystal nucleus.
  • a morphological drug crystal 42 including a plurality of crystals each having an independent major axis is formed on the outer surface of the medicinal layer 38.
  • the base of the drug crystal 42 is located on the outer surface of the amphiphilic layer 38, the surface of the additive 41, or inside the additive 41 (see FIG. 3).
  • water is evaporated more slowly than the organic solvent, and an additive 41 containing an amphiphilic low molecular weight compound is formed.
  • the time for water to evaporate is appropriately set according to the type of drug, the type of amphiphilic low molecular weight compound, the type of organic solvent, the ratio of materials, the coating amount of the coating liquid 45, etc. About seconds.
  • the solvent can partially dissolve the amphiphilic low-molecular compound constituting the amphiphilic layer 38.
  • the amphiphilic low molecular weight compound of the amphiphilic layer 38 and the amphiphilic low molecular weight compound of the additive 41 may be partially mixed. Therefore, the amphiphilic layer 38 is strongly bonded to the coat layer 40 while reliably separating the hydrophilic layer 37 and the coat layer 40, and stably connects the hydrophilic layer 37 and the coat layer 40. .
  • the dispensing tube 94 is gradually moved in the axial direction of the balloon 30 while rotating the balloon 30. Thereby, a layer of the coating liquid 45 is gradually formed on the outer surface of the amphiphilic layer 38 in the axial direction. After the coating liquid 45 layer is formed over the entire area to be coated by the amphiphilic layer 38, the moving mechanism 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, manufacture of the balloon catheter 10 is completed.
  • the balloon 30 has a substantially circular cross section in a state where the expansion fluid is injected therein. From this state, the balloon 30 is formed with the protruding blade portion 32, so that the blade outer portion 34a constituting the outer surface of the blade portion 32 and the inner portion of the blade portion 32 are formed as shown in FIG. A blade inner portion 34b constituting the 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. 7C, the blade portion 32 protruding outward in the radial direction is folded in the circumferential direction.
  • a root-side space portion 36 is formed between the root portion of the blade portion 32 and the intermediate portion 34c.
  • a minute gap is formed between the blade part 32 and the intermediate part 34c.
  • the region on the tip side of the base side space portion 36 of the blade portion 32 is in close contact with the intermediate portion 34c.
  • the ratio of the circumferential length of the base side space portion 36 to the circumferential length of the blade portion 32 is in the range of 1 to 95%.
  • the blade outer portion 34a of the balloon 30 receives a pressing force that rubs in the circumferential direction from a blade for folding the balloon 30, and is further heated. As a result, the long drug crystal 42 provided on the blade outer portion 34 a falls down on the surface of the balloon 30 and is easy to sleep. It is not necessary for all of the drug crystal 42 to sleep.
  • the drug crystal 42 is difficult to sleep.
  • the region that does not face the root side space portion 36 that is, the region where the blade inner portion 34b and the intermediate portion 34c are in close contact with each other, Easy to receive pressure. Therefore, in this region, the drug crystal 42 falls down and tends to sleep.
  • the surgeon punctures a blood vessel from the skin by a known method such as the Seldinger method, and places an introducer (not shown).
  • the guide wire 200 (see FIG. 8) is inserted into the guide wire lumen 24.
  • the guide wire 200 and the balloon catheter 10 are inserted into the blood vessel from the inside of the introducer.
  • the balloon catheter 10 is advanced while the guide wire 200 is advanced, and the balloon 30 reaches the stenosis.
  • the balloon 30 can be smoothly reached to the target position.
  • a guiding catheter may be used to reach the balloon catheter 10 to the stenosis 300.
  • a predetermined amount of expansion fluid is injected from the proximal end opening 27 of the hub 26 using an inflator or a syringe, and the expansion fluid is sent into the balloon 30 through the expansion lumen 23.
  • the folded balloon 30 is expanded, and the narrowed portion 300 is pushed and expanded by the balloon 30.
  • the coat layer 40 provided on the outer surface of the balloon 30 contacts the narrowed portion 300.
  • the additive 41 and the amphiphilic layer 38 which are the amphiphilic low-molecular compounds contained in the coat layer 40, dissolve gradually or quickly, and the drug crystals 42 is delivered to the living body.
  • the drug crystals 42 of the coat layer 40 are uniformly formed by the manufacturing method described above. For this reason, a medicine can be made to act satisfactorily on a living body without variation.
  • the amphiphilic layer 38 stably and favorably 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 held in the balloon 30 uniformly and stably.
  • the drug crystal 42 is sandwiched between the amphiphilic low-molecule additives 41 and is separated from the hydrophilic layer 37 by the amphiphilic layer 38, so that the additive is an amphiphilic low-molecular compound. If 41 and the hydrophilic layer 37 melt
  • the expansion fluid is sucked and discharged from the proximal end opening 27 of the hub 26, and the balloon 30 is deflated and folded.
  • the guide wire 200 and the balloon catheter 10 are removed from the blood vessel via the introducer, and the procedure is completed.
  • the method for manufacturing the balloon catheter 10 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.
  • the amphiphilic layer 38 is formed on the outer surface of the hydrophilic layer 37, and then the coating liquid containing a water-insoluble drug on the outer surface of the amphiphilic layer 38. 45 is applied, the coating liquid 45 spreads smoothly on the outer surface of the amphiphilic layer 38, and the coat layer 40 including the water-insoluble drug crystals 42 is uniformly and stably held on the balloon 30.
  • the amphiphilic layer 38 consists of a low molecular compound, it melt
  • the coating liquid 45 may further include an additive 41 made of an amphiphilic low molecular compound.
  • an additive 41 made of an amphiphilic low molecular compound is stably held with respect to the amphiphilic low molecular weight compound of the amphiphilic layer 38, and the water-insoluble drug crystal 42 is stably held.
  • the coat layer 40 can be formed.
  • the amphiphilic low molecular weight compound contained in the amphiphilic layer 38 and the coat layer 40 dissolves rapidly in the living body, the water-insoluble drug crystal 42 can be quickly transferred to the living tissue.
  • the water-insoluble drug may be rapamycin, paclitaxel, docetaxel, or everolimus.
  • the amphiphilic low molecular weight compound may be an amino acid ester compound, and is an amino group at the ⁇ -position of glycine, serine, asparagine, aspartic acid, glutamine, glutamic acid, arginine, threonine, histidine, lysine, tyrosine, tryptophan, and these amino acids.
  • amphiphilic low molecular weight compounds include 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, and valine ethyl ester.
  • medical agent can be rapidly transferred to a biological tissue.
  • a tubular dispensing for supplying the coating liquid 45 while rotating the balloon 30 around the axis of the balloon 30.
  • 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.
  • the coating liquid 45 can be applied to the balloon 30 by the dispensing tube 94 in a necessary amount, the amphiphilic low molecular weight compound in the amphiphilic layer 38 is dissolved and moved or dropped by the solvent contained in the coating liquid 45. Can be suppressed. For this reason, the uniform coat layer 40 can be stably formed on the outer surface of the amphiphilic layer 38.
  • the present invention is not limited to the above-described embodiment, and various modifications can be made by those skilled in the art within the technical idea of the present invention.
  • the above-described balloon catheter 10 is a rapid exchange type, but may be an over-the-wire type.
  • the balloon catheter 10 may move along the axis without moving the dispensing tube 94. Further, the coat layer 40 may not include the additive 41 as long as it includes a drug.

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Abstract

Provided is a production method for a balloon catheter having high slipperiness in vivo and being capable of satisfactorily holding a non-hydrophilic drug. This production method for a balloon catheter (10) having formed therein a coat layer (40) including a water insoluble drug on the outer surface of a balloon (30) has: a step in which a hydrophilic layer (37) comprising a hydrophilic polymer compound is formed on the outer surface of the balloon (30); a step in which an amphiphilic layer (38) comprising an amphiphilic low-molecular-weight compound is formed on the outer surface of the hydrophilic layer (37); a step in which a coating fluid (45) including a water insoluble drug and a solvent is coated on the amphiphilic layer (38); and a step in which the solvent in in the coating fluid (45) is volatized.

Description

バルーンカテーテルの製造方法Balloon catheter manufacturing method
　本発明は、バルーンの外表面に薬剤が設けられたバルーンカテーテルの製造方法に関する。 The present invention relates to a method for manufacturing a balloon catheter in which a drug is provided on the outer surface of the balloon.
　近年、生体管腔内に生じた病変部（狭窄部）の改善のために、バルーンカテーテルが用いられている。バルーンカテーテルは、通常、長尺なシャフト部と、シャフト部の先端側に設けられて径方向に拡張可能なバルーンとを備えている。収縮されているバルーンを、細い生体管腔を経由して体内の目的の場所まで到達させた後に拡張させることで、病変部を押し広げることができる。 In recent years, a balloon catheter has been used to improve a lesion (stenosis) occurring in a living body lumen. The balloon catheter usually includes a long shaft portion and a balloon that is provided on the distal end side of the shaft portion and is expandable in the radial direction. By expanding the deflated balloon after reaching a target location in the body via a thin living body lumen, the lesioned part can be expanded.
　しかしながら、病変部を強制的に押し広げると、平滑筋細胞が過剰に増殖して病変部に新たな狭窄（再狭窄）が発症する場合がある。このため、最近では、バルーンの外表面に狭窄を抑制するための薬剤をコーティングした薬剤溶出バルーン（Ｄｒｕｇ　Ｅｌｕｔｉｎｇ　Ｂａｌｌｏｏｎ：ＤＥＢ）が用いられている。薬剤溶出バルーンは、拡張することで外表面にコーティングされている薬剤を病変部へ瞬時に放出し、これにより、再狭窄を抑制することができる。 However, if the lesion is forcedly expanded, smooth muscle cells may proliferate and new stenosis (restenosis) may develop in the lesion. Therefore, recently, a drug eluting balloon (DEB) in which a drug for suppressing stenosis is coated on the outer surface of the balloon is used. By expanding the drug-eluting balloon, the drug coated on the outer surface is instantaneously released to the lesioned part, thereby preventing restenosis.
　ところで、バルーンの外表面は、生体内での滑り性を向上させるため、親水性処理が施される。しかしながら、コーティング時に有機溶媒を必要とすることから、親水性処理によって得られる機能を維持したまま、疎水性の薬物をバルーンの外表面に被覆することが難しい。 Incidentally, the outer surface of the balloon is subjected to a hydrophilic treatment in order to improve the slipping property in the living body. However, since an organic solvent is required at the time of coating, it is difficult to coat the outer surface of the balloon with a hydrophobic drug while maintaining the function obtained by the hydrophilic treatment.
　このため、例えば特許文献１には、バルーンの表面の親水性の層の上に、水不溶性の薬剤粒子および両親媒性化合物を配置したバルーンカテーテルが記載されている。両親媒性化合物は、親水基と疎水基の両方を有しているため、親水性の層の上で疎水性の薬剤を保持する役割を果たす。 For this reason, for example, Patent Document 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 the balloon. Since the amphiphilic compound has both a hydrophilic group and a hydrophobic group, it plays a role of holding a hydrophobic drug on the hydrophilic layer.
国際公開第２０１４／１８６７２９号International Publication No. 2014/186729
　バルーンは、生体内の目的の位置まで薬剤を良好に保持し、目的の位置で拡張することで、薬剤を速やかに放出できることが好ましい。 It is preferable that the balloon can release the drug quickly by holding the drug well to the target position in the living body and expanding it at the target position.
　本発明は、上述した課題を解決するためになされたものであり、水不溶性薬剤を含むコート層が均一かつ安定して保持され、目的の位置で薬剤が速やかに放出されるバルーンカテーテルの製造方法を提供することを目的とする。 The present invention has been made to solve the above-described problem, 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 quickly released at a target position. The purpose is to provide.
　上記目的を達成するバルーンカテーテルの製造方法は、バルーンの外表面に水不溶性の薬剤を含むコート層が形成されたバルーンカテーテルの製造方法であって、前記バルーンの外表面に親水性高分子化合物からなる親水性層を形成するステップと、前記親水性層の外表面に両親媒性低分子化合物からなる両親媒性層を形成するステップと、水不溶性の薬剤および溶媒を含むコーティング液を前記両親媒性層に塗布するステップと、前記コーティング液の溶媒を揮発させるステップと、を有する。 A method for manufacturing a balloon catheter that achieves the above object is a method for manufacturing a balloon catheter in which a coating layer containing a water-insoluble drug is formed on the outer surface of the balloon, and a hydrophilic polymer compound is formed on the outer surface of the balloon. Forming a hydrophilic layer, forming an amphiphilic layer composed of an amphiphilic low-molecular compound on the outer surface of the hydrophilic layer, and a coating solution containing a water-insoluble drug and a solvent. Applying to the adhesive layer and volatilizing the solvent of the coating solution.
　上記のように構成したバルーンカテーテルの製造方法は、親水性層の外表面に両親媒性層を形成した後、両親媒性層の外表面に、水不溶性の薬剤を含むコーティング液を塗布するため、コーティング液が両親媒性層の外表面で滑らかに広がり、水不溶性薬剤を含むコート層が均一かつ安定してバルーンに保持される。また、両親媒性層は、低分子化合物からなるため、生体内で迅速に溶ける。このため、両親媒性層の外表面に、目的の位置で速やかに放出されるコート層を形成できる。 In the method for manufacturing a balloon catheter configured as described above, an amphiphilic layer is formed on the outer surface of the hydrophilic layer, and then a coating solution containing a water-insoluble drug is applied to the outer surface of the amphiphilic layer. The coating solution spreads smoothly on the outer surface of the amphiphilic layer, and the coating layer containing the water-insoluble drug is uniformly and stably held on the balloon. Moreover, since an amphiphilic layer consists of a low molecular compound, it melt | dissolves rapidly in the living body. For this reason, the coat layer released rapidly at the target position can be formed on the outer surface of the amphiphilic layer.
　前記コーティング液は、両親媒性低分子化合物をさらに含んでもよい。これにより、コーティング液に含まれる両親媒性低分子化合物が、両親媒性層の両親媒性低分子化合物に対して安定して保持され、薬剤を良好に保持したコート層を形成できる。また、両親媒性低分子化合物は、生体内で迅速に溶けるため、薬剤を生体組織へ速やかに移行させることができる。 The coating liquid may further contain an amphiphilic low molecular compound. Thereby, the amphiphilic low molecular weight compound contained in the coating liquid is stably held with respect to the amphiphilic low molecular weight compound in the amphiphilic layer, and a coating layer that holds the drug well can be formed. In addition, since the amphiphilic low-molecular compound dissolves rapidly in the living body, the drug can be quickly transferred to the living tissue.
　前記水不溶性薬剤は、ラパマイシン、パクリタキセル、ドセタキセルおよびエベロリムスからなる群から選択される少なくとも１つを含有してもよい。これにより、血管内の狭窄部の再狭窄を良好に抑制できる。 The water-insoluble drug may contain at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus. Thereby, restenosis of the stenosis part in a blood vessel can be suppressed favorably.
　前記両親媒性低分子化合物は、ベンジルグリシンエチルエステル、ベンジルグリシンメチルエステル、アルギニンエチルエステル、アルギニンメチルエステル、ベンゾイルアルギニンエチルエステル、ベンゾイルアルギニンメチルエステル、アスパラギン酸ジエチルエステル、アスパラギン酸メチルエステル、アスパラギン酸ジメチルエステル、グリシンエチルエステル、グリシンメチルエステル、セリンエチルエステルおよびセリンメチルエステル、およびバリンエチルエステルからなる群から選択される少なくとも１つを含有してもよい。これにより、両親媒性低分子化合物がバルーン拡張時に迅速に溶けるため、薬剤を生体組織へ速やかに移行させることができる。 The amphiphilic low molecular weight compounds are 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, aspartic acid dimethyl ester. You may contain at least 1 selected from the group which consists of ester, glycine ethyl ester, glycine methyl ester, serine ethyl ester and serine methyl ester, and valine ethyl ester. Thereby, since an amphiphilic low molecular weight compound melt | dissolves rapidly at the time of balloon expansion, a chemical | medical agent can be rapidly transferred to a biological tissue.
　前記製造方法は、前記コーティング液ｐを前記両親媒性層に塗布するステップにおいて、前記バルーンを当該バルーンの軸心を中心として回転させつつ、前記コーティング液を供給するための管状のディスペンシングチューブを前記バルーンの軸心方向へ当該バルーンに対して相対的に移動させて、前記バルーンの外表面に前記コーティング液を塗布してもよい。これにより、ディスペンシングチューブから回転するバルーンへコーティング液を塗布することで、塗布量を高精度に制御できるため、バルーンの外表面に薬剤結晶を均一に形成でき、かつ薬剤の結晶化の制御が容易となる。また、ディスペンシングチューブによってコーティング液を必要な分量だけバルーンに塗布できることで、コーティング液に含まれる溶媒によって、両親媒性層の両親媒性低分子化合物が必要以上に溶けて移動したり脱落することを抑制できる。このため、両親媒性層の外表面に、均一なコート層を安定して形成できる。 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 while rotating the balloon around the axis of the balloon is provided. The coating liquid may be applied to the outer surface of the balloon by moving it relative to the balloon in the axial direction of the balloon. As a result, since the coating amount can be controlled with high accuracy by applying the coating liquid from the dispensing tube to the rotating balloon, the drug crystals can be uniformly formed on the outer surface of the balloon, and the crystallization of the drug can be controlled. It becomes easy. In addition, the dispensing tube can apply the required amount of coating liquid to the balloon, so that the amphiphilic low molecular weight compound in the amphiphilic layer dissolves more than necessary and moves or drops by the solvent contained in the coating liquid. Can be suppressed. For this reason, a uniform coat layer can be stably formed on the outer surface of the amphiphilic layer.
バルーンカテーテルを示す正面図である。It is a front view which shows a balloon catheter. バルーンカテーテルの先端部の断面図である。It is sectional drawing of the front-end | tip part of a balloon catheter. バルーンの外表面の概略断面図である。It is a schematic sectional drawing of the outer surface of a balloon. バルーンに親水性層および両親媒性層を形成するための槽を示す斜視図である。It is a perspective view which shows the tank for forming a hydrophilic layer and an amphiphilic layer in a balloon. コーティング装置を示す正面図である。It is a front view which shows a coating apparatus. バルーンに接触したディスペンシングチューブを示す断面図である。It is sectional drawing which shows the dispensing tube which contacted the balloon. 折り畳まれるバルーンを示す断面図であり、（Ａ）はバルーンの折り畳み前の状態、（Ｂ）はバルーンに羽根部が形成された状態、（Ｃ）は羽根部が折り畳まれた状態を示す。It is sectional drawing which shows the balloon folded, (A) is the state before folding of a balloon, (B) is the state in which the blade | wing part was formed in the balloon, (C) shows the state by which the blade | wing part was folded. バルーンカテーテルにより血管の狭窄部を押し広げた状態を示す断面図である。It is sectional drawing which shows the state which expanded the stenosis part of the blood vessel with the balloon catheter.
　以下、図面を参照して、本発明の実施の形態を説明する。なお、図面の寸法比率は、説明の都合上、誇張されて実際の比率とは異なる場合がある。 Hereinafter, an embodiment of the present invention will be described with reference to the drawings. In addition, the dimension ratio of drawing is exaggerated on account of description, and may differ from an actual ratio.
　本実施形態に係るバルーンカテーテルの製造方法は、図１、２に示すように、バルーン３０の外表面に薬剤の結晶が設けられた薬剤溶出型のバルーンカテーテル１０を製造するための方法である。なお、本明細書では、バルーンカテーテル１０の生体管腔に挿入する側を「先端」若しくは「先端側」、操作する手元側を「基端」若しくは「基端側」と称することとする。 The balloon catheter manufacturing method 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 the 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 “tip” or “tip side”, and the proximal side for operation is referred to as “base end” or “base end side”.
　まず、バルーンカテーテル１０の構造を説明する。バルーンカテーテル１０は、長尺なカテーテル本体２０と、カテーテル本体２０の先端部に設けられるバルーン３０と、カテーテル本体２０の基端に固着されたハブ２６とを有している。バルーン３０の外表面には、親水性高分子化合物からなる親水性層３７と、両親媒性低分子化合物からなる両親媒性層３８と、薬剤を含むコート層４０とが被覆されている。 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 portion 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 coated with a hydrophilic layer 37 made of a hydrophilic polymer compound, an amphiphilic layer 38 made of an amphiphilic low-molecular compound, and a coat layer 40 containing a drug.
　カテーテル本体２０は、先端および基端が開口した管体である外管２１と、外管２１の内部に配置される管体である内管２２とを備えている。内管２２は、外管２１の中空内部に納められており、カテーテル本体２０は、先端部において二重管構造となっている。内管２２の中空内部は、ガイドワイヤを挿通させるガイドワイヤルーメン２４である。また、外管２１の中空内部であって、内管２２の外側には、バルーン３０の拡張用流体を流通させる拡張ルーメン２３が形成される。内管２２は、開口部２５において外部に開口している。内管２２は、外管２１の先端よりもさらに先端側まで突出している。 The catheter body 20 includes an outer tube 21 that is a tube having an open front end and a proximal end, 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 interior of the inner tube 22 is a guide wire lumen 24 through which the guide wire is inserted. Further, an expansion lumen 23 through which the expansion fluid of the balloon 30 flows is formed inside the hollow of the outer tube 21 and outside the inner tube 22. The inner tube 22 opens 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.
　バルーン３０は、基端側端部が外管２１の先端部に固定され、先端側端部が内管２２の先端部に固定されている。これにより、バルーン３０の内部が拡張ルーメン２３と連通している。拡張ルーメン２３を介してバルーン３０に拡張用流体を注入することで、バルーン３０を拡張させることができる。拡張用流体は気体でも液体でもよく、例えばヘリウムｃ、ＣＯ２ガス、Ｏ２ガス、Ｎ２ガス、Ａｒガス、空気、混合ガス等の気体や、生理食塩水、造影剤等の液体を用いることができる。 The balloon 30 has a proximal end portion fixed to the distal end portion of the outer tube 21 and a distal end portion fixed to the distal end portion of the inner tube 22. Thereby, the inside of the balloon 30 communicates with the expansion lumen 23. The balloon 30 can be expanded by injecting an expansion fluid into the balloon 30 through the expansion lumen 23. 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, mixed gas, or a liquid such as physiological saline or contrast medium is used. Can do.
　バルーン３０の軸心方向における中央部には、拡張させた際に外径が等しい円筒状のストレート部３１が形成され、ストレート部３１の軸心方向の両側に、外径が徐々に変化するテーパ部３３が形成される。そして、ストレート部３１の外表面の全体に、薬剤を含むコート層４０が形成される。なお、バルーン３０においてコート層４０を形成する範囲は、ストレート部３１のみに限定されず、ストレート部３１に加えてテーパ部３３の少なくとも一部が含まれてもよく、または、ストレート部３１の一部のみであってもよい。 A cylindrical straight portion 31 having the same outer diameter when expanded is formed in the central portion of the balloon 30 in the axial direction, and a taper whose outer diameter gradually changes on both sides of the straight portion 31 in the axial direction. A portion 33 is formed. And the coat layer 40 containing a chemical | medical agent is formed in the whole outer surface of the straight part 31. FIG. The range in which the coating layer 40 is formed in the balloon 30 is not limited to the straight portion 31, and may include at least a part of the tapered portion 33 in addition to the straight portion 31, or one of the straight portions 31. It may be only part.
　ハブ２６は、外管２１の拡張ルーメン２３と連通して拡張用流体を流入出させるポートとして機能する基端開口部２７が形成されている。 The hub 26 is formed with a base end opening portion 27 that functions as a port that communicates with the expansion lumen 23 of the outer tube 21 and allows the expansion fluid to flow in and out.
　バルーン３０の軸心方向の長さは特に限定されないが、好ましくは５～５００ｍｍ、より好ましくは１０～３００ｍｍ、さらに好ましくは２０～２００ｍｍである。 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.
　バルーン３０の拡張時の外径は、特に限定されないが、好ましくは１～１０ｍｍ、より好ましくは２～８ｍｍである。 The outer diameter of the balloon 30 at the time of expansion is not particularly limited, but is preferably 1 to 10 mm, more preferably 2 to 8 mm.
　バルーン３０の親水性層３７が形成される前の外表面は、平滑であり、非多孔質である。バルーン３０の親水性層３７が形成される前の外表面は、膜を貫通しない微小な孔があってもよい。または、バルーン３０の親水性層３７が形成される前の外表面は、平滑であって非多孔質である範囲と、膜を貫通しない微小な孔がある範囲の両方を備えてもよい。微小な孔の大きさは、例えば、直径が０．１～５μｍ、深さが０．１～１０μｍであり、１つの結晶に対して、１つまたは複数の孔を有してもよい。また、微小な孔の大きさは、例えば、直径が５～５００μｍ、深さが０．１～５０μｍであり、１つの孔に対して、１つまたは複数の結晶を有してもよい。 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 where there are minute holes that do not penetrate the membrane. The size of the minute holes is, for example, 0.1 to 5 μm in diameter and 0.1 to 10 μm in depth, and may have one or a plurality of holes for one crystal. The size of the minute holes is, for example, a diameter of 5 to 500 μm and a depth of 0.1 to 50 μm, and one hole or a plurality of crystals may be included for one hole.
　バルーン３０は、ある程度の柔軟性を有するとともに、血管や組織等に到達した際に拡張されて、その外表面に有するコート層４０から薬剤を放出できるようにある程度の硬度を有するものが好ましい。具体的には、バルーン３０は、金属や、樹脂で構成されるが、コート層４０が設けられるバルーン３０の少なくとも外表面は、樹脂で構成されていることが好ましい。バルーン３０の少なくとも外表面の構成材料は、例えば、ポリエチレン、ポリプロピレン、ポリブテン、エチレン－プロピレン共重合体、エチレン－酢酸ビニル共重合体、アイオノマー、あるいはこれら二種以上の混合物等のポリオレフィンや、軟質ポリ塩化ビニル樹脂、ポリアミド、ポリアミドエラストマー、ナイロンエラストマー、ポリエステル、ポリエステルエラストマー、ポリウレタン、フッ素樹脂等の熱可塑性樹脂、シリコーンゴム、ラテックスゴム等が使用できる。そのなかでも、好適にはポリアミド類が挙げられる。すなわち、薬剤をコートするバルーン３０の外表面の少なくとも一部がポリアミド類である。ポリアミド類としては、アミド結合を有する重合体であれば特に制限されないが、例えば、ポリテトラメチレンアジパミド（ナイロン４６）、ポリカプロラクタム（ナイロン６）、ポリヘキサメチレンアジパミド（ナイロン６６）、ポリヘキサメチレンセバカミド（ナイロン６１０）、ポリヘキサメチレンドデカミド（ナイロン６１２）、ポリウンデカノラクタム（ナイロン１１）、ポリドデカノラクタム（ナイロン１２）などの単独重合体、カプロラクタム／ラウリルラクタム共重合体（ナイロン６／１２）、カプロラクタム／アミノウンデカン酸共重合体（ナイロン６／１１）、カプロラクタム／ω－アミノノナン酸共重合体（ナイロン６／９）、カプロラクタム／ヘキサメチレンジアンモニウムアジペート共重合体（ナイロン６／６６）などの共重合体、アジピン酸とメタキシレンジアミンとの共重合体、またはヘキサメチレンジアミンとｍ，ｐ－フタル酸との共重合体などの芳香族ポリアミドなどが挙げられる。さらに、ナイロン６、ナイロン６６、ナイロン１１、ナイロン１２などをハードセグメントとし、ポリアルキレングリコール、ポリエーテル、または脂肪族ポリエステルなどをソフトセグメントとするブロック共重合体であるポリアミドエラストマーも、バルーン３０の材料として用いられる。上記ポリアミド類は、１種単独で使用してもよいし、２種以上を併用してもよい。特に、バルーン３０はポリアミドの滑らかな表面を有することが好ましい。 It is preferable that the balloon 30 has a certain degree of flexibility so that it can be expanded when it reaches a blood vessel, tissue, etc., and has a certain degree of hardness so that the drug can be released from the coat layer 40 on its outer surface. Specifically, the balloon 30 is made of metal or resin, but at least the outer surface of the balloon 30 on which the coat layer 40 is provided is preferably 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, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, ionomer, or a mixture of two or more of these, soft poly A thermoplastic resin such as vinyl chloride resin, polyamide, polyamide elastomer, nylon elastomer, polyester, polyester elastomer, polyurethane, fluororesin, silicone rubber, latex rubber, or the like can be used. Among these, polyamides are preferable. That is, at least a part of the outer surface of the balloon 30 that coats the drug is a polyamide. The polyamide is not particularly limited as long as it is a polymer having an amide bond. For example, 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), caprolactam / lauryl lactam copolymer Polymer (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 nylon 6, nylon 66, nylon 11, nylon 12 or the like as a hard segment and polyalkylene glycol, polyether, aliphatic polyester or the like as a soft segment is also a material of the balloon 30. Used as The said polyamides may be used individually by 1 type, and may use 2 or more types together. In particular, the balloon 30 preferably has a smooth surface of polyamide.
　バルーン３０は、その外表面上に、親水性高分子化合物からなる親水性層３７が形成されている。親水性層３７は、生体内で高い滑り性（潤滑性）を有する。親水性層３７は、バルーン３０の生体内での通過性を高めるために設けられる。親水性層３７の親水性高分子化合物は、例えば、ポリエチレングリコール、ポリエチレンオキサイド、ポリビニルアルコール、ポリビニルピロリドン、ポリアクリルアミド、コラーゲン、キトサン、ポリマーポリグリシジルメタクリレート－ジメチルアクリルアミド（ＰＧＭＡ－ＤＭＡＡ）のブロック共重合体等とそれらの共重合体、誘導体を使用できる。具体的な組合せとして、ポリアミドのバルーン３０上に、親水性層３７としてポリマーポリグリシジルメタクリレート－ジメチルアクリルアミド（ＰＧＭＡ－ＤＭＡＡ）のブロック共重合体を配置し、その上に両親媒性層３８としてアミノ酸エステル、セリンエチルエステル、バリンエチルエステル、アスパラギン酸メチルエステルのうち少なくとも一つを含む層を配置し、その上にパクリタキセルを含むコート層４０を配置できる。親水性層３７および両親媒性層３８は、直接的に接触し、両親媒性層３８およびコート層４０は、直接的に接触する。両親媒性層３８は、バルーン３０上で親水性層３７が乾燥した後にコーティングされる。コート層４０は、親水性層３７上で両親媒性層３８が乾燥した後にコーティングされる。 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 high slipperiness (lubricity) in the living body. The hydrophilic layer 37 is provided in order to improve the passability of the balloon 30 in the living body. Examples of the hydrophilic polymer compound of the hydrophilic layer 37 include polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, collagen, chitosan, and a polymer polyglycidyl methacrylate-dimethylacrylamide (PGMA-DMAA) block copolymer. And their copolymers and derivatives. As a specific combination, a polymer polyglycidyl methacrylate-dimethylacrylamide (PGMA-DMAA) block copolymer is disposed as a hydrophilic layer 37 on a polyamide balloon 30, and an amino acid ester 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 can be disposed, and a coat layer 40 including paclitaxel can be disposed thereon. The hydrophilic layer 37 and the amphiphilic layer 38 are in direct contact, and the amphiphilic layer 38 and the coat layer 40 are in direct contact. The amphiphilic layer 38 is coated after the hydrophilic layer 37 is dried on the balloon 30. The coat layer 40 is coated after the amphiphilic layer 38 is dried on the hydrophilic layer 37.
　親水性層３７は、その外表面上に、両親媒性低分子化合物からなる両親媒性層３８が形成されている。両親媒性低分子化合物は、親水基および疎水基を備える低分子の化合物である。両親媒性層３８は、親水性の親水性層３７と、疎水性（水不溶性）の薬剤を仲介する役割を果たしている。すなわち、水不溶性の薬剤は、親水性層３７に対して直接的に付着できないが、両親媒性層３８を介することで、親水性層３７の外周囲を覆うことができる。両親媒性層３８の両親媒性低分子化合物は、マトリックスを形成しない。マトリックスとは、比較的高分子の物質（ポリマーなど）が連続して構成された層であり、網目状の三次元構造を形成し、その中に微細な空間が存在する。なお、両親媒性層３８は、マトリックスを形成してもよい。 The hydrophilic layer 37 has an amphiphilic layer 38 made of an amphiphilic low-molecular compound formed on the outer surface thereof. An amphiphilic low molecular weight compound is a low molecular weight compound having a hydrophilic group and a hydrophobic group. The amphiphilic layer 38 plays a role of mediating between the hydrophilic hydrophilic layer 37 and the 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 (polymer or the like) is continuously formed, forms a network-like three-dimensional structure, and has a fine space therein. The amphiphilic layer 38 may form a matrix.
　両親媒性層３８は親水性層３７の外表面へ溶媒に溶けた状態でコートされた後、乾燥して層として形成される。両親媒性層３８はアモルファスである。両親媒性層３８は、結晶粒子であってもよい。両親媒性層３８は、アモルファスおよび結晶粒子の混合物として存在してもよい。図３の両親媒性層３８は、結晶粒子及び／または粒子状アモルファスの状態である。または、両親媒性層３８は、フィルム状アモルファスの状態であってもよい。両親媒性層３８の厚みは、０．１～３０μｍ、好ましくは０．１～１０μｍ、より好ましくは０．１～３μｍである。 The amphiphilic layer 38 is coated on the outer surface of the hydrophilic layer 37 while being dissolved in a solvent, and then dried to form a layer. The amphiphilic layer 38 is amorphous. The amphiphilic layer 38 may be crystal particles. The amphiphilic layer 38 may exist as a mixture of amorphous and crystalline particles. The amphiphilic layer 38 in FIG. 3 is in the 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, more preferably 0.1 to 3 μm.
　両親媒性層３８は、その外表面上に、薬剤を含むコート層４０が形成されている。コート層４０は、両親媒性層３８の外表面に層状に配置される添加剤４１（賦形剤）と、独立した長軸を有して延在する水不溶性の薬剤結晶４２とを有している。添加剤４１は、両親媒性低分子化合物を含んでいる。薬剤結晶４２の端部は、両親媒性層３８の外表面と直接接触してもよいが、直接接触せずに、薬剤結晶４２の端部と両親媒性層３８の外表面との間に添加剤４１が存在してもよい。薬剤結晶４２の端部が添加剤４１の層の表面に位置して、薬剤結晶４２が添加剤４１から突出してもよい。複数の薬剤結晶４２は、両親媒性層３８の外表面に規則的に配置されてもよい。または、複数の薬剤結晶４２は、両親媒性層３８の外表面に不規則に配置されてもよい。 The amphiphilic layer 38 has a coat layer 40 containing a drug formed on the outer surface thereof. The coat layer 40 has an additive 41 (excipient) arranged in a layered manner 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 amphiphilic layer 38, but is not 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 portion of the drug crystal 42 may be positioned 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.
　コート層４０に含まれる薬剤量は、特に限定されないが、０．１μｇ／ｍｍ２～１０μｇ／ｍｍ２、好ましくは０．５μｇ／ｍｍ２～５μｇ／ｍｍ２の密度で、より好ましくは０．５μｇ／ｍｍ２～３．５μｇ／ｍｍ２、さらに好ましくは１．０μｇ／ｍｍ２～３μｇ／ｍｍ２の密度で含まれる。コート層４０の結晶の量は、特に限定されないが、好ましくは５～５００、０００［ｃｒｙｓｔａｌ／（１０μｍ２）］（１０μｍ２当たりの結晶の数）、より好ましくは５０～５０、０００［ｃｒｙｓｔａｌ／（１０μｍ２）］、さらに好ましくは５００～５、０００［ｃｒｙｓｔａｌ／（１０μｍ２）］である。 The amount of the drug contained in the coat layer 40 is not particularly limited, but is 0.1 μg / mm 2 to 10 μg / mm 2 , preferably 0.5 μg / mm 2 to 5 μg / mm 2 , more preferably 0.5 μg. / Mm 2 to 3.5 μg / mm 2 , more preferably 1.0 μg / mm 2 to 3 μg / mm 2 . The amount of crystals of the coat layer 40 is not particularly limited, but is preferably 5 to 500,000 [crystal / (10 μm 2 )] (number of crystals per 10 μm 2 ), more preferably 50 to 50,000 [crystal / (10 μm 2 )], more preferably 500 to 5,000 [crystal / (10 μm 2 )].
　薬剤結晶４２は、各々独立した長軸を有する形態であってもよい。また、薬剤結晶４２は、他の形態型であってもよい。複数の薬剤結晶４２は、これらが組み合された状態で存在していてもよいし、隣接する複数の薬剤結晶４２同士が異なる角度を形成した状態で接触して存在してもよい。複数の薬剤結晶４２はバルーン表面上で空間（結晶を含まない空間）をおいて位置していてもよい。両親媒性層３８の表面に、組み合された状態の複数の薬剤結晶４２と、互いに離れて独立した複数の薬剤結晶４２の両方が存在してもよい。複数の薬剤結晶４２は、異なる長軸方向を有して円周状にブラシ状として配置されてもよい。各々の前記薬剤結晶４２は独立して存在しており、ある長さを有し、その長さ部分の一端（基端）が、添加剤４１または両親媒性層３８に固定されている。薬剤結晶４２は隣接する薬剤結晶４２と複合的な構造を形成せず、連結していない。前記結晶の長軸は、ほぼ直線状である。薬剤結晶４２はその長軸が交わる基部が接する表面に対して所定の角度を形成している。 The drug crystal 42 may have a form having independent long axes. Further, the drug crystal 42 may be other morphological types. The plurality of drug crystals 42 may be present in a state where they are combined, or may be present in contact with each other with a plurality of adjacent drug crystals 42 forming different angles. The plurality of drug crystals 42 may be positioned on the balloon surface with a space (a space not including a crystal). On the surface of the amphiphilic layer 38, there may be both a plurality of drug crystals 42 in a combined state and a plurality of drug crystals 42 that are separated from each other and independent. The plurality of drug crystals 42 may be arranged in a brush shape around the circumference having different major axis directions. Each of the drug crystals 42 exists independently and 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 almost linear. The drug crystal 42 forms a predetermined angle with respect to the surface with which the base portion where the major axes intersect is in contact.
　薬剤結晶４２は、互いに接触せずに独立して立っていることが好ましい。薬剤結晶４２の基部は、両親媒性層３８上で他の基部と接触していてもよい。または、薬剤結晶４２の基部は、両親媒性層３８上で他の基部と接触せずに独立していてもよい。 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.
　薬剤結晶４２は、中空である場合と、中実である場合がある。バルーン３０の表面に、中空の薬剤結晶４２と、中実の薬剤結晶４２の両方が存在してもよい。薬剤結晶４２は、中空である場合、少なくともその先端付近が中空である。薬剤結晶４２の長軸に直角な（垂直な）面における薬剤結晶４２の断面は中空を有する。当該中空を有する薬剤結晶４２は長軸に直角な（垂直な）面における薬剤結晶４２の断面が多角形である。当該多角形は、例えば３角形、４角形、５角形、６角形などである。したがって、薬剤結晶４２は先端（または先端面）と基端（または基端面）とを有し、先端（または先端面）と基端（または基端面）との間の側面が複数のほぼ平面で構成された長尺多面体として形成される。この結晶形態型（中空長尺体結晶形態型）は基部が接する表面において、ある平面の全体または少なくとも一部を構成する。 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 to the major axis of the drug crystal 42 (perpendicular) has a hollow. The drug crystal 42 having the hollow has a polygonal cross section of the drug crystal 42 in a plane perpendicular (perpendicular) to the long axis. The polygon is, for example, a triangle, a tetragon, a pentagon, or a hexagon. Therefore, the drug crystal 42 has a distal end (or distal end surface) and a proximal end (or proximal end surface), and a side surface between the distal end (or distal end surface) and the proximal end (or proximal end surface) is a plurality of substantially flat surfaces. It is formed as a configured long polyhedron. This crystal form type (hollow elongated body crystal form type) constitutes the whole or at least a part of a certain plane on the surface in contact with the base.
　長軸を有する薬剤結晶４２の長軸方向の長さは５μｍ～２０μｍが好ましく、９μｍ～１１μｍがより好ましく、１０μｍ前後であるのがさらに好ましい。長軸を有する薬剤結晶４２の径は、０．０１μｍ～５μｍであるのが好ましく、０．０５μｍ～４μｍであるのがより好ましく、０．１μｍ～３μｍであるのがさらに好ましい。長軸を有する薬剤結晶４２の長軸方向の長さと径の組み合わせの例として、長さが５μｍ～２０μｍのときに径が０．０１～５μｍである組み合わせ、長さが５～２０μｍのときに径が０．０５～４μｍである組み合わせ、長さが５～２０μｍのときに径が０．１～３μｍである組み合わせが挙げられる。長軸を有する薬剤結晶４２は、長軸方向に直線状であるが、曲線状に湾曲してもよい。バルーン３０の表面に、直線状の薬剤結晶４２と、曲線状の薬剤結晶４２の両方が存在してもよい。 The length in the major axis direction of the drug crystal 42 having a major axis is preferably 5 μm to 20 μm, more preferably 9 μm to 11 μm, and even more preferably around 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 the combination of the length and the diameter in the long axis direction of the drug crystal 42 having a long axis, a combination having a diameter of 0.01 to 5 μm when the length is 5 μm to 20 μm, and a combination when the length is 5 to 20 μm Examples include 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. The drug crystal 42 having the long axis is linear in the long axis direction, but may be curved. Both the linear drug crystal 42 and the curved drug crystal 42 may exist on the surface of the balloon 30.
　上述した長軸を有する薬剤結晶４２を有する結晶形態型は、バルーン３０の外表面の薬剤結晶全体に対して５０体積％以上、より好ましくは７０体積％以上である。長軸を有する結晶粒子である薬剤結晶４２は、バルーン３０または添加剤４１の外表面に対して寝ておらず立っているように形成される。添加剤４１は、薬剤結晶４２がある領域に存在し、薬剤結晶４２がない領域にはなくてもよい。 The above-mentioned crystal morphology type having the drug crystal 42 having the long axis is 50% by volume or more, more preferably 70% by volume or more with respect to 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 on the outer surface of the balloon 30 or the additive 41. The additive 41 is present in the region where the drug crystal 42 is present, and may not be present in the region where the drug crystal 42 is absent.
　添加剤４１を構成する両親媒性低分子化合物は、両親媒性層３８を構成する両親媒性低分子化合物と同じであってよい。これにより、添加剤４１を含むコート層４０が、両親媒性層３８と安定して結合する。添加剤４１を構成する両親媒性低分子化合物は、両親媒性層３８を構成する両親媒性低分子化合物と異なってもよい。これにより、添加剤４１と両親媒性層３８の両親媒性低分子化合物を、任意に選択でき、バルーン３０における水不溶性薬剤の保持性および目的位置での放出性を、より自在に設定できる。添加剤４１は、林立する複数の薬剤結晶４２の間の空間に分配されて存在する。コート層４０を構成する物質の割合は、水不溶性の薬剤結晶４２の方が、添加剤４１よりも大きい体積を占めることが好ましい。添加剤４１は、マトリックスを形成しない。マトリックスとは、比較的高分子の物質（ポリマーなど）が連続して構成された層であり、網目状の三次元構造を形成し、その中に微細な空間が存在する。したがって、結晶を構成する水不溶性薬剤はマトリックス物質中に付着していない。結晶を構成する水不溶性薬剤は、マトリックス物質中に埋め込まれてもいない。なお、添加剤４１は、マトリックスを形成してもよい。 The amphiphilic low molecular compound constituting the additive 41 may be the same as the amphiphilic low molecular compound constituting 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 weight compound constituting the additive 41 may be different from the amphiphilic low molecular weight compound constituting the amphiphilic layer 38. Thereby, the amphiphilic low molecular weight compound of the additive 41 and 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 the space between the plurality of drug crystals 42 in the forest. The proportion of the substance constituting the coat layer 40 is preferably such that the water-insoluble drug crystal 42 occupies a larger volume than the additive 41. The additive 41 does not form a matrix. The matrix is a layer in which a relatively high-molecular substance (polymer or the like) is continuously formed, forms a network-like three-dimensional structure, and has a fine space therein. Therefore, the water-insoluble drug constituting the crystal is not attached to the matrix material. The water-insoluble drug constituting the crystal is not embedded in the matrix material. The additive 41 may form a matrix.
　添加剤４１は両親媒性層３８の外表面で溶媒に溶けた状態でコートされた後、乾燥して層として形成される。添加剤４１はアモルファスである。添加剤４１は、結晶粒子であってもよい。添加剤４１は、アモルファスおよび結晶粒子の混合物として存在してもよい。図３の添加剤４１は、結晶粒子及び／または粒子状アモルファスの状態である。または、添加剤４１は、フィルム状アモルファスの状態であってもよい。添加剤４１は、水不溶性薬剤を含んだ層として形成されている。または、添加剤４１は、水不溶性薬剤を含まない独立した層として形成されてもよい。添加剤４１の厚みは、０．１～５μｍ、好ましくは０．３～３μｍ、より好ましくは０．５～２μｍである。 The additive 41 is coated on the outer surface of the amphiphilic layer 38 while being dissolved in a solvent, and then dried to form a layer. The additive 41 is amorphous. The additive 41 may be crystal particles. Additive 41 may be present as a mixture of amorphous and crystalline particles. The additive 41 in FIG. 3 is in the state of crystal grains 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 that does not contain a water-insoluble drug. The thickness of the additive 41 is 0.1 to 5 μm, preferably 0.3 to 3 μm, more preferably 0.5 to 2 μm.
　長尺な結晶形態型の薬剤結晶４２を含む層は、体内に送達する際に、毒性が低く、狭窄抑制効果が高い。中空長尺体結晶形態を含む水不溶性薬剤は、薬剤が組織に移行した時に結晶の一つの単位が小さくなるために組織への浸透性が良く、かつ、良好な溶解性を有するため、有効に作用して狭窄を抑制できる。また、薬剤が大きな塊として組織に残留することが少ないために毒性が低くなると考えられる。 The layer containing the drug crystal 42 of a long crystal form type has low toxicity and high stenosis-inhibiting effect when delivered into the body. A water-insoluble drug containing a hollow long crystalline form is effective because it has good permeability to the tissue and good solubility because one unit of the crystal becomes small when the drug moves into the tissue. It can act to suppress stenosis. In addition, it is considered that toxicity is low because the drug hardly remains in the tissue as a large mass.
　また、長尺な結晶形態型の薬剤結晶４２を含む層は、組織に移行する結晶の大きさ（長軸方向の長さ）が約１０μｍと小さい。そのために病変患部に均一に作用し、組織浸透性が高まる。さらに、移行する薬剤結晶４２の寸法が小さいために過剰量の薬剤が、過剰時間、患部に留まることがなくなるために、毒性を発現することなく、高い狭窄抑制効果を示すことが可能であると考える。 In addition, the layer containing the drug crystal 42 having a long crystal form type has a small crystal size (length in the long axis direction) that moves to the tissue of about 10 μm. Therefore, it acts uniformly on the affected part of the lesion and increases tissue permeability. Furthermore, since the size of the transferred drug crystal 42 is small, an excessive amount of drug does not stay in the affected area for an excessive period of time, so that it is possible to exhibit a high stenosis suppressing effect without developing toxicity. Think.
　バルーン３０の外表面にコーティングされる薬剤は、非晶質（アモルファス）型を含んでもよい。薬剤結晶４２や非晶質は、コート層４０において規則性を有するように配置されてもよい。または、結晶や非晶質は、不規則に配置されてもよい。 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, crystals and amorphous materials may be arranged irregularly.
　次に、バルーンカテーテル１０の製造装置について説明する。製造装置は、図４に示す第１の槽１１０および第２の槽１２０と、図５に示すコーティング装置５０を有している。 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.
　第１の槽１１０は、図４に示すように、バルーン３０の外表面に、親水性層３７をディッピングにより形成するための槽である。第１の槽１１０の内部には、親水性層３７を構成する親水性高分子化合物および溶媒を含む親水性溶液１１１が収容されている。親水性高分子化合物は、例えば、ポリエチレングリコール、ポリエチレンオキサイド、ポリビニルアルコール、ポリビニルピロリドン、ポリアクリルアミド、コラーゲン、キトサン等とそれらの共重合体、誘導体を使用できる。溶媒は、例えば、水、低級アルコール類、ジクロロエチレン、ジクロロエタン、クロロホルム、アセトニトリル、塩化メチレン、アセトン等及びそれらの混合溶剤を使用できる。なお、親水性層３７は、ディッピング以外の方法により形成されてもよい。例えば、後述するコーティング装置５０を用いることもできる。 As shown in FIG. 4, the first tank 110 is a tank for forming a hydrophilic layer 37 on the outer surface of the balloon 30 by dipping. Inside the first tank 110, a hydrophilic solution 111 containing a hydrophilic polymer compound constituting the hydrophilic layer 37 and a solvent is accommodated. As the hydrophilic polymer compound, for example, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, collagen, chitosan, and their copolymers and derivatives can be used. Examples of the solvent that can be used include water, lower alcohols, dichloroethylene, dichloroethane, chloroform, acetonitrile, methylene chloride, acetone, and a mixed solvent thereof. The hydrophilic layer 37 may be formed by a method other than dipping. For example, the coating apparatus 50 mentioned later can also be used.
　第２の槽１２０は、バルーン３０の外表面に形成された親水性層３７の外表面に、両親媒性層３８をディッピングにより形成するための槽である。第２の槽１２０の内部には、両親媒性層３８を構成する両親媒性低分子化合物および溶媒を含む両親媒性溶液１２１が収容されている。両親媒性溶液１２１は、水不溶性薬剤を含んでいない。なお、両親媒性層３８は、ディッピング以外の方法により形成されてもよい。例えば、後述するコーティング装置５０を用いることもできる。 The second tank 120 is a tank for forming an 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 constituting the amphiphilic layer 38 and a solvent 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, the coating apparatus 50 mentioned later can also be used.
　両親媒性層３８を構成する両親媒性低分子化合物の分子量は、５０～２０００であり、好ましくは５０～１０００であり、より好ましくは５０～５００であり、さらに好ましくは５０～２００である。両親媒性低分子化合物の構成材料は、セリンエチルエステル、クエン酸エステル、ポリソルベート、水溶性ポリマー、糖、造影剤、アミノ酸エステル、短鎖モノカルボン酸のグリセロールエステル、医薬として許容される塩および界面活性剤等、あるいはこれら二種以上の混合物等が使用できる。両親媒性低分子化合物は、親水基と疎水基を有し、水に溶解することを特徴とする。両親媒性低分子化合物は、非膨潤性または難膨潤性であることが好ましい。両親媒性溶液１２１の溶媒は、例えば、水、エタノール、メタノール、グリセリン等を使用できる。 The molecular weight of the amphiphilic low-molecular compound constituting the amphiphilic layer 38 is 50 to 2000, preferably 50 to 1000, more preferably 50 to 500, and further preferably 50 to 200. The constituent materials of amphiphilic low molecular weight compounds are 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 of these can be used. The amphiphilic low molecular weight compound has a hydrophilic group and a hydrophobic group and is characterized by being dissolved in water. The amphiphilic low molecular weight compound is preferably non-swellable or hardly swellable. As the solvent of the amphiphilic solution 121, for example, water, ethanol, methanol, glycerin, or the like can be used.
　コーティング装置５０は、図５、６に示すように、バルーン３０の両親媒性層３８の外表面にコート層４０を形成することができる。コーティング装置５０は、バルーンカテーテル１０を回転させる回転機構部６０と、バルーンカテーテル１０を支持する支持台７０とを有する。コーティング装置５０は、さらに、バルーン３０の外表面にコーティング液４５を塗布するディスペンシングチューブ９４が設けられるコーティング液供給部９０と、ディスペンシングチューブ９４をバルーン３０に対して移動させる移動機構部８０とを有する。コーティング装置５０は、さらに、コーティング装置５０の各部位を制御する制御部１００を有する。 The coating apparatus 50 can form a coating layer 40 on the outer surface of the amphiphilic layer 38 of the balloon 30 as shown in FIGS. The coating apparatus 50 includes a rotation mechanism unit 60 that rotates the balloon catheter 10 and a support base 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 that applies the coating liquid 45 to the outer surface of the balloon 30, and a moving mechanism unit 80 that moves the dispensing tube 94 relative to the balloon 30. Have The coating apparatus 50 further includes a control unit 100 that controls each part of the coating apparatus 50.
　回転機構部６０は、バルーンカテーテル１０のハブ２６を保持し、内蔵されるモータ等の駆動源によってバルーンカテーテル１０を、バルーン３０の軸心を中心に回転させる。バルーンカテーテル１０は、ガイドワイヤルーメン２４内に芯材６１が挿通されて保持されるとともに、芯材６１によってコーティング液４５のガイドワイヤルーメン２４内への流入が防止されている。また、バルーンカテーテル１０は、拡張ルーメン２３への流体の流通を操作するために、ハブ２６の基端開口部２７に、流路の開閉を操作可能な三方活栓が接続される。 The rotation mechanism unit 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 built-in driving source such as a motor. In the balloon catheter 10, the 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 open and close the flow path is connected to the proximal end opening 27 of the hub 26 in order to control the flow of fluid to the expansion lumen 23.
　支持台７０は、カテーテル本体２０を内部に収容して回転可能に支持する管状の基端側支持部７１と、芯材６１を回転可能に支持する先端側支持部７２とを備えている。なお、先端側支持部７２は、可能であれば、芯材６１ではなしにカテーテル本体２０の先端部を回転可能に支持してもよい。 The support base 70 includes a tubular proximal end support portion 71 that accommodates the catheter main body 20 in a rotatable manner, and a distal end side support portion 72 that rotatably supports the core member 61. Note that the distal end side support portion 72 may rotatably support the distal end portion of the catheter body 20 instead of the core member 61 if possible.
　移動機構部８０は、バルーン３０の軸心と平行な方向へ直線的に移動可能な移動台８１と、ディスペンシングチューブ９４が固定されるチューブ固定部８３とを備えている。移動台８１は、内蔵されるモータ等の駆動源によって、直線的に移動可能である。移動台８１が移動することで、ディスペンシングチューブ９４がバルーン３０の軸心と平行な方向へ直線的に移動する。また、移動台８１は、コーティング液供給部９０が載置されており、コーティング液供給部９０を軸心に沿う両方向へ直線的に移動させる。 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 move linearly by a driving source such as a built-in motor. As the moving table 81 moves, the dispensing tube 94 linearly moves 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 linearly moves the coating liquid supply unit 90 in both directions along the axis.
　コーティング液供給部９０は、バルーン３０の両親媒性層３８の外表面にコーティング液４５を塗布する部位である。コーティング液供給部９０は、コーティング液４５を収容する容器９２と、任意の送液量でコーティング液４５を送液する送液ポンプ９３と、コーティング液４５を両親媒性層３８に塗布するディスペンシングチューブ９４とを備えている。 The coating liquid supply unit 90 is a part where the coating liquid 45 is applied to the outer surface of the amphiphilic layer 38 of the balloon 30. The coating liquid supply unit 90 includes a container 92 that stores the coating liquid 45, a liquid feeding pump 93 that feeds the coating liquid 45 in an arbitrary liquid feeding amount, and a dispensing that applies the coating liquid 45 to the amphiphilic layer 38. A tube 94.
　送液ポンプ９３は、例えばシリンジポンプであり、制御部１００によって制御されて、容器９２から吸引チューブ９１を介してコーティング液４５を吸引し、供給チューブ９６を介してディスペンシングチューブ９４へコーティング液４５を任意の送液量で供給できる。送液ポンプ９３は、移動台８１に設置され、移動台８１の移動により直線的に移動可能である。なお、送液ポンプ９３は、コーティング液４５を送液可能であればシリンジポンプに限定されず、例えばチューブポンプであってもよい。 The liquid feed 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 through the suction tube 91 and to the dispensing tube 94 through the supply tube 96. Can be supplied at an arbitrary liquid feeding amount. The liquid feed pump 93 is installed on the moving table 81 and can move linearly by the movement of the moving table 81. The liquid feed pump 93 is not limited to a syringe pump as long as the coating liquid 45 can be fed, and may be a tube pump, for example.
　ディスペンシングチューブ９４は、供給チューブ９６と連通しており、送液ポンプ９３から供給チューブ９６を介して供給されるコーティング液４５を、両親媒性層３８の外表面へ吐出する。ディスペンシングチューブ９４は、可撓性を備えた円管状の部材である。ディスペンシングチューブ９４は、チューブ固定部８３に上端が固定されており、チューブ固定部８３から鉛直方向下方へ延在し、下端である吐出端９７に開口部９５が形成されている。ディスペンシングチューブ９４は、移動台８１を移動させることで、移動台８１に設置される送液ポンプ９３とともに、バルーンカテーテル１０の軸心方向に沿う両方向へ直線的に移動可能である。ディスペンシングチューブ９４は両親媒性層３８に押し付けられて撓んだ状態で、コーティング液４５を両親媒性層３８の外表面に供給可能である。 The dispensing tube 94 communicates with the supply tube 96 and discharges the coating liquid 45 supplied from the liquid feed pump 93 through 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 that 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 against the amphiphilic layer 38 and is bent.
　なお、ディスペンシングチューブ９４は、コーティング液４５を供給可能であれば、円管状でなくてもよい。また、ディスペンシングチューブ９４は、開口部９５からコーティング液４５を吐出可能であれば、鉛直方向に延在していなくてもよい。また、ディスペンシングチューブ９４は、両親媒性層３８の外表面から離れた位置でバルーン３０へコーティング液４５を供給してもよい。 The dispensing tube 94 may not be a circular tube as long as the coating liquid 45 can be supplied. The dispensing tube 94 may not 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.
　ディスペンシングチューブ９４は、両親媒性層３８への接触負担を低減し、かつバルーン３０の回転に伴う接触位置の変化を撓みにより吸収できるように、柔軟な材料であることが好ましい。ディスペンシングチューブ９４の構成材料は、例えば、ポリエチレン、ポリプロピレン等のポリオレフィン、環状ポリオレフィン、ポリエステル、ポリアミド、ポリウレタン、ＰＴＦＥ（ポリテトラフルオロエチレン）、ＥＴＦＥ（テトラフルオロエチレン・エチレン共重合体）、ＰＦＡ（テトラフルオロエチレン・パーフルオロアルキルビニルエーテル共重合体）、ＦＥＰ（四フッ化エチレン・六フッ化プロピレン共重合体）等のフッ素系樹脂等を適用できるが、可撓性を有して変形可能であれば、特に限定されない。 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 accompanying 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), PFA (tetra Fluororesin such as fluoroethylene / perfluoroalkyl vinyl ether copolymer) or FEP (tetrafluoroethylene / hexafluoropropylene copolymer) can be applied, but if it is flexible and deformable There is no particular limitation.
　ディスペンシングチューブ９４の外径は、特に限定されないが、例えば０．１ｍｍ～５．０ｍｍ、好ましくは０．１５ｍｍ～３．０ｍｍ、より好ましくは０．３ｍｍ～２．５ｍｍである。ディスペンシングチューブ９４の内径は、特に限定されないが、例えば０．０５ｍｍ～３．０ｍｍ、好ましくは０．１ｍｍ～２．０ｍｍ、より好ましくは０．１５ｍｍ～１．５ｍｍである。ディスペンシングチューブ９４の長さは、特に限定されないが、バルーン直径の５倍以内の長さであることがよく、例えば１．０ｍｍ～５０ｍｍ、好ましくは３ｍｍ～４０ｍｍ、より好ましくは５ｍｍ～３５ｍｍである。 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 within 5 times the balloon diameter, for example, 1.0 mm to 50 mm, preferably 3 mm to 40 mm, more preferably 5 mm to 35 mm. .
　制御部１００は、例えばコンピュータにより構成され、回転機構部６０、移動機構部８０およびコーティング液供給部９０を統括的に制御する。したがって、制御部１００は、バルーン３０の回転速度、ディスペンシングチューブ９４のバルーン３０に対する軸心方向への移動速度、ディスペンシングチューブ９４からの薬剤吐出速度等を、統括的に制御できる。 The control unit 100 is configured by a computer, for example, and comprehensively controls the rotation mechanism unit 60, the movement mechanism unit 80, and the coating liquid supply unit 90. Therefore, the control unit 100 can comprehensively control the rotation speed of the balloon 30, the moving speed of the dispensing tube 94 in the axial direction relative to the balloon 30, the medicine discharge speed from the dispensing tube 94, and the like.
　ディスペンシングチューブ９４により両親媒性層３８に供給されるコーティング液４５は、コート層４０の構成材料を含む溶液または懸濁液であり、水不溶性薬剤、添加剤、溶媒を含んでいる。コーティング液４５が両親媒性層３８の外表面に供給された後、溶媒が揮発することで、両親媒性層３８の外表面に、独立した長軸を有して延在する水不溶性の薬剤結晶４２を有するコート層４０が形成される。 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 extending on the outer surface of the amphiphilic layer 38 with an independent long axis. A coat layer 40 having crystals 42 is formed.
　コーティング液４５の粘度は、０．２～５００ｃＰ、好ましくは０．２～５０ｃＰ、より好ましくは０．２～１０ｃＰである。 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.
　水不溶性薬剤とは、水に不溶または難溶性である薬剤を意味し、具体的には、水に対する溶解度が、ｐＨ５～８で５ｍｇ／ｍＬ未満である。その溶解度は、１ｍｇ／ｍＬ未満、さらに、０．１ｍｇ／ｍＬ未満でもよい。水不溶性薬剤は脂溶性薬剤を含む。 Water-insoluble drug means a drug that is insoluble or sparingly soluble in water. Specifically, the solubility in water is less than 5 mg / mL at pH 5-8. Its solubility may be less than 1 mg / mL and even less than 0.1 mg / mL. Water-insoluble drugs include fat-soluble drugs.
　いくつかの好ましい水不溶性薬剤の例は、免疫抑制剤、例えば、シクロスポリンを含むシクロスポリン類、ラパマイシン等の免疫活性剤、パクリタキセル等の抗がん剤、抗ウイルス剤または抗菌剤、抗新生組織剤、鎮痛剤および抗炎症剤、抗生物質、抗てんかん剤、不安緩解剤、抗麻痺剤、拮抗剤、ニューロンブロック剤、抗コリン作動剤およびコリン作動剤、抗ムスカリン剤およびムスカリン剤、抗アドレナリン作用剤、抗不整脈剤、抗高血圧剤、ホルモン剤ならびに栄養剤を含む。 Examples of some preferred water-insoluble drugs include immunosuppressants, such as cyclosporines 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, antiparalytic agents, antagonists, neuron blocking agents, anticholinergics and cholinergic agents, antimuscarinic and muscarinic agents, antiadrenergic agents, Contains antiarrhythmic, antihypertensive, hormonal and nutritional agents.
　水不溶性薬剤は、パクリタキセルおよびパクリタキセル誘導体、タキサン、ドセタキセルならびにラパマイシンおよびラパマイシン誘導体、例えば、バイオリムスＡ９、ピメクロリムス、エベロリムス、ゾタロリムス、タクロリムス、ファスジルおよびエポチロンが好ましく、パクリタキセルおよびラパマイシン、ドセタキセル、エベロリムスが特に好ましい。本明細書においてラパマイシン、パクリタキセル、ドセタキセル、エベロリムスとは、同様の薬効を有する限りそれらの類似体および／またはそれらの誘導体を含む。例えば、パクリタキセルとドセタキセルは類似体の関係にある。ラパマイシンとエベロリムスは誘導体の関係にある。これらのうちでは、パクリタキセルがさらに好ましい。 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, paclitaxel and rapamycin, especially docetaxel, and evelimel. In the present specification, rapamycin, paclitaxel, docetaxel, and everolimus include analogs and / or derivatives thereof as long as they have similar medicinal effects. For example, paclitaxel and docetaxel are in an analog relationship. Rapamycin and everolimus are in a derivative relationship. Of these, paclitaxel is more preferred.
　添加剤４１は、前述した両親媒性層３８に適用可能な両親媒性低分子化合物を使用できる。なお、前述したように、添加剤４１に使用する両親媒性低分子化合物と、両親媒性層３８に使用する両親媒性低分子化合物は、同じであってもよいが、異なってもよい。添加剤４１は、バルーン３０上でアモルファス（非晶質）であることが好ましい。水溶性の低分子化合物を含む添加剤４１は、バルーン３０の外表面上で水不溶性薬剤を均一に分散させる効果を有する。さらに、血管内でのバルーン３０の拡張時に添加剤４１が溶解しやすくなることで、バルーン３０の外表面上の水不溶性薬剤の薬剤結晶４２を放出しやすくなり、血管への薬剤結晶４２の付着量を増加させる効果を有する。添加剤４１は、ハイドロゲルでないことが好ましい。添加剤４１は低分子化合物であることで、水溶液に接すると膨潤することなく速やかに溶解する。さらに、血管内でのバルーン３０の拡張時に添加剤４１が溶解しやすくなることで、バルーン３０の外表面上の水不溶性の薬剤結晶４２の粒子を放出しやすくなり、血管への薬剤結晶４２の付着量を増加させる効果を有する。添加剤４１がウルトラビスト（Ｕｌｔｒａｖｉｓｔ）（登録商標）のような造影剤からなるマトリクスである場合、結晶粒子がマトリクスに埋め込まれ、両親媒性層３８からマトリクスの外側に向かって結晶が生成しない。これに対し、本実施形態の薬剤結晶４２は、両親媒性層３８の表面から添加剤４１の外側まで延在することができる。 As the additive 41, an amphiphilic low-molecular compound applicable to the above-described amphiphilic layer 38 can be used. 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 (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. Furthermore, 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 adheres to the blood vessel. Has the effect of increasing the amount. The additive 41 is preferably not a hydrogel. Since the additive 41 is a low molecular weight compound, it dissolves rapidly without swelling when in contact with an aqueous solution. Furthermore, 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. 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 crystals are not generated from the amphiphilic layer 38 toward the outside of the matrix. In contrast, 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.
　コーティング液４５の溶媒は、有機溶媒および水の少なくとも一方を含んでいる。有機溶媒は、特に限定されず、テトラヒドロフラン、アセトン、グリセリン、酢酸、ｔ－ブチルアルコール、ベンゼン、クロロヘキサン、ｏ－ジクロロベンゼン、ｏ－キシレン、ｐ－キシレン、シクロヘキサノール、スチレン、シクロヘキサン、エタノール、メタノール、ジクロロメタン、ヘキサン、エチルアセテート、ｉ－ブチルアルコール、ｓ－ブチルアルコール、プロパノール、ブタノール、トルエン、エチレングリコール等である。中でも、テトラヒドロフラン、エタノール、アセトンのうち、これらのいくつかの混合溶媒が好ましい。 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, methanol Dichloromethane, hexane, ethyl acetate, i-butyl alcohol, s-butyl alcohol, propanol, butanol, toluene, ethylene glycol and the like. Among these, some of these mixed solvents are preferable among tetrahydrofuran, ethanol, and acetone.
　有機溶媒と水の混合例として、例えば、テトラヒドロフランと水、テトラヒドロフランとエタノールと水、テトラヒドロフランとアセトンと水、アセトンとエタノールと水、テトラヒドロフランとアセトンとエタノールと水が挙げられる。 Examples of the organic solvent and water mixture include, for example, tetrahydrofuran and water, tetrahydrofuran and ethanol and water, tetrahydrofuran and acetone and water, acetone and ethanol and water, and tetrahydrofuran, acetone, ethanol, and water.
　次に、本実施形態に係るバルーンカテーテル１０の製造方法を説明する。本製造方法では、上述したディッピング用の第１の槽および第２の槽、およびコーティング装置５０を用いてバルーン３０の外表面に水不溶性の薬剤結晶４２を形成する方法を説明する。 Next, a method for manufacturing the balloon catheter 10 according to this embodiment will be described. In the present manufacturing method, a method of forming the water-insoluble drug crystal 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.
　初めに、バルーンカテーテル１０の基端開口部２７に接続した三方活栓を介して拡張用の流体をバルーン３０内に供給する。次に、バルーン３０を拡張させた状態で三方活栓を操作して拡張ルーメン２３を密封し、バルーン３０を拡張させた状態を維持する。バルーン３０は、血管内での使用時の圧力（例えば８気圧）よりも低い圧力（例えば４気圧）で拡張される。なお、バルーン３０を拡張させずに、バルーン３０の外表面にコート層４０を形成することもでき、その場合には、拡張用の流体をバルーン３０内に供給する必要はない。 First, an expansion fluid is supplied into the balloon 30 through a three-way cock connected to the proximal end opening 27 of the balloon catheter 10. Next, the three-way cock is operated in a state where the balloon 30 is expanded to seal the expansion lumen 23, and the state where the balloon 30 is expanded is maintained. The balloon 30 is expanded at a pressure (for example, 4 atmospheres) lower than a pressure (for example, 8 atmospheres) at the time of use in the blood vessel. Note that the coating layer 40 can also be formed on the outer surface of the balloon 30 without expanding the balloon 30, and in this case, it is not necessary to supply the expansion fluid into the balloon 30.
　次に、バルーン３０に親水性層３７を形成するために、図４に示すように、バルーン３０を第１の槽１１０の親水性溶液１１１に浸漬した後、引き上げる。この後、溶媒を揮発させることで、バルーン３０の外表面に、親水性層３７が形成される。なお、親水性溶液１１１へのバルーン３０の浸漬および引き上げは、複数回行ってもよい。 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. Note that the immersion and lifting of the balloon 30 in the hydrophilic solution 111 may be performed a plurality of times.
　次に、親水性層３７の外表面に両親媒性層３８を形成するために、バルーン３０を第２の槽１２０の両親媒性溶液１２１に浸漬した後、引き上げる。この後、溶媒を揮発させることで、親水性層３７の外表面に、両親媒性層３８が形成される。なお、両親媒性溶液１２１へのバルーン３０の浸漬および引き上げは、複数回行ってもよい。 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 in the second tank 120 and then pulled up. Thereafter, the amphiphilic layer 38 is formed on the outer surface of the hydrophilic layer 37 by volatilizing the solvent. Note that the immersion and lifting of the balloon 30 in the amphiphilic solution 121 may be performed a plurality of times.
　次に、ディスペンシングチューブ９４がバルーン３０の外表面と接触しない状態で、図５に示すように、バルーンカテーテル１０を支持台７０に回転可能に設置し、ハブ２６を回転機構部６０に連結する。 Next, in a state where the dispensing tube 94 is not in contact with the outer surface of the balloon 30, as shown in FIG. 5, the balloon catheter 10 is rotatably installed on the support base 70, and the hub 26 is connected to the rotation mechanism 60. .
　次に、移動台８１の位置を調節して、ディスペンシングチューブ９４を、バルーン３０に対して位置決めする。このとき、バルーン３０においてコート層４０を形成する最も先端側の位置に、ディスペンシングチューブ９４を位置決めする。一例として、ディスペンシングチューブ９４の延在方向（吐出方向）は、図６に示すように、バルーン３０の回転方向と逆方向である。したがって、バルーン３０は、ディスペンシングチューブ９４を接触させた位置において、ディスペンシングチューブ９４からのコーティング液４５の吐出方向と逆方向に回転する。これにより、コーティング液４５に物理的な刺激を与え、薬剤結晶の結晶核の形成を促すことができる。そして、ディスペンシングチューブ９４の開口部９５へ向かう延在方向（吐出方向）が、バルーン３０の回転方向と逆方向であることで、バルーン３０の両親媒性層３８の外表面に形成される水不溶性薬剤の結晶は、結晶が各々独立した長軸を有する複数の薬剤結晶４２を含む形態型を含んで形成されやすい。なお、ディスペンシングチューブ９４の延在方向は、バルーン３０の回転方向と逆方向でなくてもよく、したがって同方向とすることができ、または垂直とすることもできる。 Next, the position of the moving table 81 is adjusted, and the dispensing tube 94 is positioned with respect to the balloon 30. At this time, the dispensing tube 94 is positioned at the most distal end position where the coating 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. Accordingly, 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 dispensing tube 94 is brought into contact. Thereby, physical stimulation can be given to the coating liquid 45 and formation of the crystal nucleus of a drug crystal can be promoted. The extending direction (discharge direction) toward the opening 95 of the dispensing tube 94 is opposite to the rotation direction of the balloon 30, so that the water formed on the outer surface of the amphiphilic layer 38 of the balloon 30. Insoluble drug crystals tend to be formed including morphological forms that include a plurality of drug crystals 42 each having an independent major axis. The extending direction of the dispensing tube 94 does not have to be the reverse direction of the rotation direction of the balloon 30, and can therefore be the same direction or can be perpendicular.
　次に、回転機構部６０によりバルーンカテーテル１０を回転させる。続いて、送液ポンプ９３により送液量を調節してコーティング液４５をディスペンシングチューブ９４へ供給しつつ、移動台８１を移動させて、ディスペンシングチューブ９４をバルーン３０の軸心方向に沿って徐々に基端方向へ移動させる。ディスペンシングチューブ９４の開口部９５から吐出されるコーティング液４５は、ディスペンシングチューブ９４がバルーン３０に対して相対的に移動することで、バルーン３０の両親媒性層３８の外周面に螺旋を描きつつ塗布される。バルーン３０が回転していることで、両親媒性層３８の外周面に塗布されたコーティング液４５が周方向に均一となりやすい。 Next, the balloon catheter 10 is rotated by the rotation mechanism 60. Subsequently, while the amount of liquid fed is adjusted by the liquid feed pump 93 and the coating liquid 45 is supplied to the dispensing tube 94, the moving table 81 is moved to move the dispensing tube 94 along the axial direction of the balloon 30. Gradually move toward the proximal direction. 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. While being applied. By rotating 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.
　ディスペンシングチューブ９４の移動速度は、特に限定されないが、例えば０．０１～２ｍｍ／ｓｅｃ、好ましくは０．０３～１．５ｍｍ／ｓｅｃ、より好ましくは０．０５～１．０ｍｍ／ｓｅｃである。コーティング液４５のディスペンシングチューブ９４からの吐出速度は、特に限定されないが、例えば０．０１～１．５μＬ／ｓｅｃ、好ましくは０．０１～１．０μＬ／ｓｅｃ、より好ましくは０．０３～０．８μＬ／ｓｅｃである。バルーン３０の回転速度は、特に限定されないが、例えば１０～３００ｒｐｍ、好ましくは３０～２５０ｒｐｍ、より好ましくは５０～２００ｒｐｍである。コーティング液４５を塗布する際のバルーン３０の直径は、特に限定されないが、例えば１～１０ｍｍ、好ましくは２～７ｍｍである。 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, more preferably 0.03 to 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, preferably 2 to 7 mm.
　両親媒性層３８の外表面に塗布されたコーティング液４５に含まれる有機溶媒は、水よりも先に揮発する。したがって、両親媒性層３８の外表面に、水不溶性薬剤、両親媒性低分子化合物および水が残された状態で、有機溶媒が揮発する。このように、水が残された状態で有機溶媒が揮発すると、水不溶性の薬剤が、水を含む両親媒性低分子化合物の内部で析出し、結晶核から結晶が徐々に成長して、両親媒性層３８の外表面に、結晶が各々独立した長軸を有する複数の結晶を含む形態型（ｍｏｒｐｈｏｌｏｇｉｃａｌ　ｆｏｒｍ）の薬剤結晶４２が形成される。薬剤結晶４２の基部は、両親媒性層３８の外表面、添加剤４１の表面または添加剤４１内部に位置する（図３を参照）。有機溶媒が揮発して薬剤結晶４２が析出した後、水が有機溶媒よりもゆっくり蒸発し、両親媒性低分子化合物を含む添加剤４１が形成される。水が蒸発する時間は、薬剤の種類、両親媒性低分子化合物の種類、有機溶媒の種類、材料の比率、コーティング液４５の塗布量等に応じて適宜設定されるが、例えば、１～６００秒程度である。 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 volatilizes in a state where the water-insoluble drug, the amphiphilic low-molecular compound and water are left on the outer surface of the amphiphilic layer 38. As described above, when the organic solvent is volatilized with water remaining, a water-insoluble drug is precipitated inside the amphiphilic low-molecular compound containing water, and the crystal gradually grows from the crystal nucleus. A morphological drug crystal 42 including a plurality of crystals each having an independent major axis is formed on the outer surface of the medicinal layer 38. The base of the drug crystal 42 is located on the outer surface of the amphiphilic layer 38, 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 are deposited, water is evaporated more slowly than the organic solvent, and an additive 41 containing an amphiphilic low molecular weight compound is formed. The time for water to evaporate is appropriately set according to the type of drug, the type of amphiphilic low molecular weight compound, the type of organic solvent, the ratio of materials, the coating amount of the coating liquid 45, etc. About seconds.
　両親媒性層３８に塗布されたコーティング液４５に溶媒が残っている状態において、溶媒は、両親媒性層３８を構成する両親媒性低分子化合物を部分的に溶かし得る。このため、両親媒性層３８の両親媒性低分子化合物と、添加剤４１の両親媒性低分子化合物が部分的に混ざり合うことがあり得る。したがって、両親媒性層３８は、親水性層３７とコート層４０を確実に分離しつつも、コート層４０と強く結合して、親水性層３７とコート層４０を安定して良好に接続する。 In the 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 constituting the amphiphilic layer 38. For this reason, the amphiphilic low molecular weight compound of the amphiphilic layer 38 and the amphiphilic low molecular weight compound of the additive 41 may be partially mixed. Therefore, the amphiphilic layer 38 is strongly bonded to the coat layer 40 while reliably separating the hydrophilic layer 37 and the coat layer 40, and stably connects the hydrophilic layer 37 and the coat layer 40. .
　そして、バルーン３０を回転させつつディスペンシングチューブ９４を徐々にバルーン３０の軸心方向へ移動させる。これにより、両親媒性層３８の外表面に、軸心方向へ向かって、コーティング液４５の層を徐々に形成する。両親媒性層３８のコーティングする範囲の全体に、コーティング液４５の層が形成された後、移動機構部８０およびコーティング液供給部９０を停止させる。次に、バルーンカテーテル１０を支持台７０から取り外す。次に、バルーン３０から拡張用流体を排出し、バルーン３０を収縮させて折り畳む。これにより、バルーンカテーテル１０の製造が完了する。 Then, the dispensing tube 94 is gradually moved in the axial direction of the balloon 30 while rotating the balloon 30. Thereby, a layer of the coating liquid 45 is gradually formed on the outer surface of the amphiphilic layer 38 in the axial direction. After the coating liquid 45 layer is formed over the entire area to be coated by the amphiphilic layer 38, the moving mechanism 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, manufacture of the balloon catheter 10 is completed.
　バルーン３０は、図７（Ａ）に示すように、内部に拡張用流体が注入された状態で断面略円形状を有する。この状態から、バルーン３０は、突出する羽根部３２が形成されることで、図７（Ｂ）に示すように、羽根部３２の外側面を構成する羽根外側部３４ａと、羽根部３２の内側面を構成する羽根内側部３４ｂと、羽根外側部３４ａと羽根内側部３４ｂの間に位置する中間部３４ｃとが形成される。この状態から、図７（Ｃ）に示すように、径方向外側へ突出する羽根部３２が、周方向へ折り畳まれる。バルーン３０の羽根部３２が折り畳まれると、羽根部３２の外側面を構成する羽根外側部３４ａと、羽根部３２の内側面を構成する羽根内側部３４ｂと、羽根外側部３４ａと羽根内側部３４ｂの間に位置する中間部３４ｃとが形成される。バルーン３０の羽根部３２が折り畳まれると、羽根内側部３４ｂと中間部３４ｃが重なって接触し、バルーン３０の外表面同士が対向して重なる重複部３５が形成される。そして、中間部３４ｃの一部および羽根外側部３４ａは、羽根内側部３４ｂに覆われず、外側に露出する。また、バルーン３０が折り畳まれた状態では、羽根部３２の根元部と中間部３４ｃとの間に、根元側空間部３６が形成される。根元側空間部３６の領域では、羽根部３２と中間部３４ｃとの間に、微小な隙間が形成される。一方、羽根部３２の根元側空間部３６よりも先端側の領域は、中間部３４ｃに対して密接した状態となっている。羽根部３２の周方向長さに対する根元側空間部３６の周方向長さの割合は、１～９５％の範囲である。バルーン３０の羽根外側部３４ａは、バルーン３０を折り畳むためのブレードから周方向に擦れるような押圧力を受け、さらに加熱される。これにより、羽根外側部３４ａに設けられる長尺な薬剤結晶４２がバルーン３０の表面に倒れて寝やすい。なお、薬剤結晶４２の全てが寝る必要はない。 As shown in FIG. 7A, the balloon 30 has a substantially circular cross section in a state where the expansion fluid is injected therein. From this state, the balloon 30 is formed with the protruding blade portion 32, so that the blade outer portion 34a constituting the outer surface of the blade portion 32 and the inner portion of the blade portion 32 are formed as shown in FIG. A blade inner portion 34b constituting the 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. 7C, the blade portion 32 protruding outward in the radial direction is folded in the circumferential direction. When the blade portion 32 of the balloon 30 is folded, the blade outer portion 34a that forms the outer surface of the blade portion 32, the blade inner portion 34b that forms the inner surface of the blade portion 32, the blade outer portion 34a, and the blade inner portion 34b. An intermediate portion 34c located between the two is formed. When the blade portion 32 of the balloon 30 is folded, the blade 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. And a part of intermediate part 34c and the blade | wing outer side part 34a are not covered with the blade | wing inner side part 34b, but are exposed outside. Further, in a state where the balloon 30 is folded, a root-side space portion 36 is formed between the root portion of the blade portion 32 and the intermediate portion 34c. In the area of the root side space part 36, a minute gap is formed between the blade part 32 and the intermediate part 34c. On the other hand, the region on the tip side of the base side space portion 36 of the blade portion 32 is in close contact with the intermediate portion 34c. The ratio of the circumferential length of the base side space portion 36 to the circumferential length of the blade portion 32 is in the range of 1 to 95%. The blade outer portion 34a of the balloon 30 receives a pressing force that rubs in the circumferential direction from a blade for folding the balloon 30, and is further heated. As a result, the long drug crystal 42 provided on the blade outer portion 34 a falls down on the surface of the balloon 30 and is easy to sleep. It is not necessary for all of the drug crystal 42 to sleep.
　また、バルーン３０の重複部３５において重なる外表面は、外部に露出しないため、折り畳む際に、ブレードから押圧力が間接的に作用する。このため、バルーン３０の重複部３５において重なる外表面に設けられる薬剤結晶４２に作用する力を、強くなり過ぎないように調節することが容易である。したがって、バルーン３０の重複部３５において重なる外表面に設けられる薬剤結晶４２を寝かせるために望ましい力を作用させることができる。また、互いに対向する羽根内側部３４ｂと中間部３４ｃの領域のうち、根元側空間部３６に面する領域、すなわち羽根内側部３４ｂと中間部３４ｃとが密接しない領域では、薬剤結晶４２は押圧力を受け難い。したがって、この領域では、薬剤結晶４２が寝にくい。また、互いに対向する羽根内側部３４ｂと中間部３４ｃの領域のうち、根元側空間部３６に面しない領域、すなわち羽根内側部３４ｂと中間部３４ｃとが密接している領域では、薬剤結晶４２は押圧力を受けやすい。したがって、この領域では、薬剤結晶４２が倒れて寝やすい。 Further, since the outer surface overlapping the overlapping portion 35 of the balloon 30 is not exposed to the outside, a pressing force is indirectly applied from the blade when it is folded. For this reason, it is easy to adjust the force acting on the drug crystal 42 provided on the outer surface overlapping in the overlapping portion 35 of the balloon 30 so as not to become too strong. Therefore, a desirable force can be applied to lay down the drug crystal 42 provided on the outer surface overlapping in the overlapping portion 35 of the balloon 30. Moreover, in the area | region of the blade | wing inner side part 34b and the intermediate part 34c which mutually oppose, the area | region which faces the root side space part 36, ie, the area | region where the blade | wing inner side part 34b and the intermediate part 34c are not closely_contact | adhered, It is difficult to receive. Therefore, in this region, the drug crystal 42 is difficult to sleep. Further, in the regions of the blade inner portion 34b and the intermediate portion 34c that face each other, the region that does not face the root side space portion 36, that is, the region where the blade inner portion 34b and the intermediate portion 34c are in close contact with each other, Easy to receive pressure. Therefore, in this region, the drug crystal 42 falls down and tends to sleep.
　次に、バルーンカテーテル１０の使用方法を、血管内の狭窄部を治療する場合を例として説明する。 Next, a method of using the balloon catheter 10 will be described by taking as an example the case of treating a stenosis in a blood vessel.
　まず、術者は、セルジンガー法等の公知の方法により、皮膚から血管を穿刺し、イントロデューサ（図示せず）を留置する。次に、バルーンカテーテル１０のプライミングを行った後、ガイドワイヤルーメン２４内にガイドワイヤ２００（図８を参照）を挿入する。この状態で、ガイドワイヤ２００およびバルーンカテーテル１０をイントロデューサの内部より血管内へ挿入する。続いて、ガイドワイヤ２００を先行させつつバルーンカテーテル１０を進行させ、バルーン３０を狭窄部へ到達させる。このとき、バルーン３０の外表面に潤滑性の高い親水性層３７が設けられるため、バルーン３０を目的の位置まで円滑に到達させることができる。なお、バルーンカテーテル１０を狭窄部３００まで到達させるために、ガイディングカテーテルを用いてもよい。 First, the surgeon 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 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 the inside of 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 be smoothly reached to the target position. A guiding catheter may be used to reach the balloon catheter 10 to the stenosis 300.
　次に、ハブ２６の基端開口部２７より、インデフレーターまたはシリンジ等を用いて拡張用流体を所定量注入し、拡張ルーメン２３を通じてバルーン３０の内部に拡張用流体を送り込む。これにより、図８に示すように、折り畳まれたバルーン３０が拡張し、狭窄部３００が、バルーン３０によって押し広げられる。このとき、バルーン３０の外表面に設けられるコート層４０が、狭窄部３００に接触する。 Next, a predetermined amount of expansion fluid is injected from the proximal end opening 27 of the hub 26 using an inflator or a syringe, and the expansion fluid is sent into the balloon 30 through the expansion lumen 23. Thereby, as shown in FIG. 8, the folded balloon 30 is expanded, and the narrowed portion 300 is pushed and expanded by the balloon 30. At this time, the coat layer 40 provided on the outer surface of the balloon 30 contacts the narrowed portion 300.
　バルーン３０を拡張させてコート層４０を生体組織に押し付けると、コート層４０に含まれる両親媒性低分子化合物である添加剤４１および両親媒性層３８が徐々にまたは速やかに溶けつつ、薬剤結晶４２が生体へ送達される。コート層４０の薬剤結晶４２は、上述した製造方法によって、均一に形成されている。このため、薬剤を生体へばらつきなく良好に作用させることができる。両親媒性層３８は、親水性層３７とコート層４０を分離しつつ、親水性層３７とコート層４０を安定して良好に接続している。このため、薬剤結晶４２は、均一かつ安定してバルーン３０に保持されている。そして、薬剤結晶４２は、両親媒性低分子からなる添加剤４１に挟まれつつ、両親媒性層３８によって、親水性層３７から離間されているため、両親媒性低分子化合物である添加剤４１および親水性層３７が生体内で速やかに溶けると、バルーン３０から生体組織へ迅速かつ確実に移行できる。 When the balloon 30 is expanded and the coat layer 40 is pressed against the living tissue, the additive 41 and the amphiphilic layer 38, which are the amphiphilic low-molecular compounds contained in the coat layer 40, dissolve gradually or quickly, and the drug crystals 42 is delivered to the living body. The drug crystals 42 of the coat layer 40 are uniformly formed by the manufacturing method described above. For this reason, a medicine can be made to act satisfactorily on a living body without variation. The amphiphilic layer 38 stably and favorably 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 held in the balloon 30 uniformly and stably. The drug crystal 42 is sandwiched between the amphiphilic low-molecule additives 41 and is separated from the hydrophilic layer 37 by the amphiphilic layer 38, so that the additive is an amphiphilic low-molecular compound. If 41 and the hydrophilic layer 37 melt | dissolve rapidly in the living body, it can transfer to the biological tissue from the balloon 30 quickly and reliably.
　この後、拡張用流体をハブ２６の基端開口部２７より吸引して排出し、バルーン３０を収縮させて折り畳まれた状態とする。この後、イントロデューサを介して血管よりガイドワイヤ２００およびバルーンカテーテル１０を抜去し、手技が終了する。 Thereafter, the expansion fluid is sucked and discharged from the proximal end opening 27 of the hub 26, and the balloon 30 is deflated and folded. Thereafter, the guide wire 200 and the balloon catheter 10 are removed from the blood vessel via the introducer, and the procedure is completed.
　以上のように、本実施形態に係るバルーンカテーテル１０の製造方法は、バルーン３０の外表面に水不溶性の薬剤を含むコート層４０が形成されたバルーンカテーテル１０の製造方法であって、バルーン３０の外表面に親水性高分子化合物からなる親水性層３７を形成するステップと、親水性層３７の外表面に両親媒性低分子化合物からなる両親媒性層３８を形成するステップと、水不溶性の薬剤および溶媒を含むコーティング液４５を両親媒性層３８に塗布するステップと、コーティング液４５の溶媒を揮発させるステップと、を有する。 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; 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.
　上記のように構成したバルーンカテーテル１０の製造方法は、親水性層３７の外表面に両親媒性層３８を形成した後、両親媒性層３８の外表面に、水不溶性の薬剤を含むコーティング液４５を塗布するため、コーティング液４５が両親媒性層３８の外表面で滑らかに広がり、水不溶性の薬剤結晶４２を含むコート層４０が均一かつ安定してバルーン３０に保持される。また、両親媒性層３８は、低分子化合物からなるため、生体内で迅速に溶ける。このため、両親媒性層３８の外表面に、目的の位置で速やかに放出されるコート層４０を形成できる。 In the method of manufacturing the balloon catheter 10 configured as described above, the amphiphilic layer 38 is formed on the outer surface of the hydrophilic layer 37, and then the coating liquid containing a water-insoluble drug on the outer surface of the amphiphilic layer 38. 45 is applied, the coating liquid 45 spreads smoothly on the outer surface of the amphiphilic layer 38, and the coat layer 40 including the water-insoluble drug crystals 42 is uniformly and stably held on the balloon 30. Moreover, since the amphiphilic layer 38 consists of a low molecular compound, it melt | dissolves rapidly in the living body. For this reason, the coat layer 40 that is promptly released at the target position can be formed on the outer surface of the amphiphilic layer 38.
　また、コーティング液４５は、両親媒性低分子化合物からなる添加剤４１をさらに含んでもよい。これにより、コーティング液４５に含まれる両親媒性低分子化合物が、両親媒性層３８の両親媒性低分子化合物に対して安定して保持され、水不溶性の薬剤結晶４２を安定して保持したコート層４０を形成できる。また、両親媒性層３８およびコート層４０に含まれる両親媒性低分子化合物は、生体内で迅速に溶けるため、水不溶性の薬剤結晶４２を生体組織へ速やかに移行させることができる。 The coating liquid 45 may further include an additive 41 made of an amphiphilic low molecular compound. Thereby, the amphiphilic low molecular weight compound contained in the coating liquid 45 is stably held with respect to the amphiphilic low molecular weight compound of the amphiphilic layer 38, and the water-insoluble drug crystal 42 is stably held. The coat layer 40 can be formed. In addition, since the amphiphilic low molecular weight compound contained in the amphiphilic layer 38 and the coat layer 40 dissolves rapidly in the living body, the water-insoluble drug crystal 42 can be quickly transferred to the living tissue.
　また、水不溶性薬剤は、ラパマイシン、パクリタキセル、ドセタキセル、またはエベロリムスであってもよい。これにより、薬剤結晶４２により、血管内の狭窄部の再狭窄を良好に抑制できる。 The water-insoluble drug may be rapamycin, paclitaxel, docetaxel, or everolimus. Thereby, restenosis of the stenosis part in the blood vessel can be satisfactorily suppressed by the drug crystal 42.
　また、両親媒性低分子化合物は、アミノ酸エステル化合物でよく、グリシン、セリン、アスパラギン、アスパラギン酸、グルタミン、グルタミン酸、アルギニン、トレオニン、ヒスチジン、リシン、チロシン、トリプトファンおよびこれらのアミノ酸のα位のアミノ基の水素原子の少なくとも１つが炭素数５以下のアルキル基、ベンジル基またはベンゾイル基で置換されたアミノ酸、ならびにプロリンおよびプロリンのイミノ基の水素原子が炭素数５以下のアルキル基、ベンジル基またはベンゾイル基で置換されたアミノ酸からなる群から選択される少なくとも１つのアミノ酸と、炭素数５以下の一価アルコールとのエステル化合物からなる群から選択される少なくとも１つを含有してもよい。両親媒性低分子化合物は、具体的には、ベンジルグリシンエチルエステル、ベンジルグリシンメチルエステル、アルギニンエチルエステル、アルギニンメチルエステル、ベンゾイルアルギニンエチルエステル、ベンゾイルアルギニンメチルエステル、アスパラギン酸ジエチルエステル、アスパラギン酸メチルエステル、アスパラギン酸ジメチルエステル、グリシンエチルエステル、グリシンメチルエステル、セリンエチルエステルおよびセリンメチルエステル、バリンエチルエステルが挙げられる。これにより、両親媒性低分子化合物がバルーン３０の拡張時に迅速に溶けるため、薬剤を生体組織へ速やかに移行させることができる。 The amphiphilic low molecular weight compound may be an amino acid ester compound, and is an amino group at the α-position of glycine, serine, asparagine, aspartic acid, glutamine, glutamic acid, arginine, threonine, histidine, lysine, tyrosine, tryptophan, and these amino acids. An amino acid in which at least one of the hydrogen atoms is substituted with an alkyl group having 5 or less carbon atoms, a benzyl group or a benzoyl group, and an alkyl group, benzyl group or benzoyl group in which the hydrogen atoms of the imino group of proline and proline are 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. Specific examples of amphiphilic low molecular weight compounds include 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, and valine ethyl ester. Thereby, since an amphiphilic low molecular weight compound melt | dissolves rapidly at the time of expansion of the balloon 30, a chemical | medical agent can be rapidly transferred to a biological tissue.
　また、本製造方法は、コーティング液４５を両親媒性層３８に塗布するステップにおいて、バルーン３０を当該バルーン３０の軸心を中心として回転させつつ、コーティング液４５を供給するための管状のディスペンシングチューブ９４をバルーン３０の軸心方向へ当該バルーン３０に対して相対的に移動させて、バルーン３０の外表面にコーティング液４５を塗布してもよい。これにより、ディスペンシングチューブ９４から回転するバルーン３０へコーティング液４５を塗布することで、塗布量を高精度に制御できるため、バルーン３０の外表面に薬剤結晶４２を均一に形成でき、かつ薬剤の結晶化の制御が容易となる。また、ディスペンシングチューブ９４によってコーティング液４５を必要な分量だけバルーン３０に塗布できることで、コーティング液４５に含まれる溶媒によって、両親媒性層３８の両親媒性低分子化合物が溶けて移動したり脱落することを抑制できる。このため、両親媒性層３８の外表面に、均一なコート層４０を安定して形成できる。 Further, in the present manufacturing method, in the step of applying the coating liquid 45 to the amphiphilic layer 38, a tubular dispensing for supplying the coating liquid 45 while rotating the balloon 30 around the axis of the balloon 30. 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. Thereby, since the coating amount 45 can be controlled with high accuracy by applying the coating liquid 45 to the rotating balloon 30 from the dispensing tube 94, the drug crystal 42 can be uniformly formed on the outer surface of the balloon 30, and the drug Control of crystallization becomes easy. In addition, since the coating liquid 45 can be applied to the balloon 30 by the dispensing tube 94 in a necessary amount, the amphiphilic low molecular weight compound in the amphiphilic layer 38 is dissolved and moved or dropped by the solvent contained in the coating liquid 45. Can be suppressed. For this reason, the uniform coat layer 40 can be stably formed on the outer surface of the amphiphilic layer 38.
　なお、本発明は、上述した実施形態のみに限定されるものではなく、本発明の技術的思想内において当業者により種々変更が可能である。例えば、上述のバルーンカテーテル１０は、ラピッドエクスチェンジ型（Ｒａｐｉｄ　ｅｘｃｈａｎｇｅ　ｔｙｐｅ）であるが、オーバーザワイヤ型（Ｏｖｅｒ－ｔｈｅ－ｗｉｒｅ　ｔｙｐｅ）であってもよい。 Note that the present invention is not limited to 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 a rapid exchange type, but may be an over-the-wire type.
　また、ディスペンシングチューブ９４が移動せずに、バルーンカテーテル１０が軸心に沿って移動してもよい。また、コート層４０は、薬剤を含んでいれば、添加剤４１を含まなくてもよい。 Further, the balloon catheter 10 may move along the axis without moving the dispensing tube 94. Further, the coat layer 40 may not include the additive 41 as long as it includes a drug.
　さらに、本出願は、２０１７年３月１６日に出願された日本特許出願番号２０１７－０５０８３９号に基づいており、それらの開示内容は、参照され、全体として、組み入れられている。 Furthermore, this application is based on Japanese Patent Application No. 2017-050839 filed on Mar. 16, 2017, the disclosures of which are referred to and incorporated in their entirety.
　　１０　　バルーンカテーテル
　　３０　　バルーン
　　３７　　親水性層
　　３８　　両親媒性層
　　４０　　コート層
　　４１　　添加剤
　　４２　　薬剤結晶
　　４５　　コーティング液
　　５０　　コーティング装置
　　６０　　回転機構部
　　８０　　移動機構部
　　９０　　コーティング液供給部
　　９４　　ディスペンシングチューブ
　　１１０　　第１の槽
　　１２０　　第２の槽 DESCRIPTION OF SYMBOLS 10 Balloon catheter 30 Balloon 37 Hydrophilic layer 38 Amphiphilic layer 40 Coat layer 41 Additive 42 Drug crystal 45 Coating liquid 50 Coating apparatus 60 Rotation mechanism part 80 Movement mechanism part 90 Coating liquid supply part 94 Dispensing tube 110 1st Tank 120 Second tank

Claims (5)

  1. 　バルーンの外表面に水不溶性の薬剤を含むコート層が形成されたバルーンカテーテルの製造方法であって、
    　前記バルーンの外表面に親水性高分子化合物からなる親水性層を形成するステップと、
    　前記親水性層の外表面に両親媒性低分子化合物からなる両親媒性層を形成するステップと、
    　水不溶性の薬剤および溶媒を含むコーティング液を前記両親媒性層に塗布するステップと、
    　前記コーティング液の溶媒を揮発させるステップと、を有するバルーンカテーテルの製造方法。     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 composed of an amphiphilic low-molecular compound on the outer surface of the hydrophilic layer;
    Applying a coating solution comprising a water-insoluble drug and solvent to the amphiphilic layer;
    Volatilizing the solvent of the coating solution.
  2. 　前記コーティング液は、両親媒性低分子化合物をさらに含む請求項１に記載のバルーンカテーテルの製造方法。 The method for producing a balloon catheter according to claim 1, wherein the coating liquid further contains an amphiphilic low molecular weight compound.
  3. 　前記水不溶性薬剤は、ラパマイシン、パクリタキセル、ドセタキセルおよびエベロリムスからなる群から選択される少なくとも１つを含有している請求項１または２に記載のバルーンカテーテルの製造方法。 The method for producing a balloon catheter according to claim 1 or 2, wherein the water-insoluble drug contains at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus.
  4. 　前記両親媒性低分子化合物は、ベンジルグリシンエチルエステル、ベンジルグリシンメチルエステル、アルギニンエチルエステル、アルギニンメチルエステル、ベンゾイルアルギニンエチルエステル、ベンゾイルアルギニンメチルエステル、アスパラギン酸ジエチルエステル、アスパラギン酸メチルエステル、アスパラギン酸ジメチルエステル、グリシンエチルエステル、グリシンメチルエステル、セリンエチルエステルおよびセリンメチルエステル、およびバリンエチルエステルからなる群から選択される少なくとも１つを含有している請求項１～３のいずれか１項に記載のバルーンカテーテルの製造方法。 The amphiphilic low molecular weight compounds are 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, aspartic acid dimethyl ester. The at least one selected from the group consisting of ester, glycine ethyl ester, glycine methyl ester, serine ethyl ester and serine methyl ester, and valine ethyl ester according to any one of claims 1 to 3. A method for manufacturing a balloon catheter.
  5. 　前記コーティング液を前記両親媒性層に塗布するステップにおいて、前記バルーンを当該バルーンの軸心を中心として回転させつつ、前記コーティング液を供給するための管状のディスペンシングチューブを前記バルーンの軸心方向へ当該バルーンに対して相対的に移動させて、前記バルーンの外表面に前記コーティング液を塗布する請求項１～４のいずれか１項に記載のバルーンカテーテルの製造方法。 In the step of applying the coating liquid to the amphiphilic layer, a tubular dispensing tube for supplying the coating liquid is rotated in the axial direction of the balloon while rotating the balloon about the axial center of the balloon. The method for manufacturing a balloon catheter according to any one of claims 1 to 4, wherein the coating liquid is applied to an outer surface of the balloon by being moved relative to the balloon.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112402702A (en) * 2020-12-04 2021-02-26 上海康德莱医疗器械股份有限公司 Drug coating composition and drug coating balloon
WO2022105849A1 (en) * 2020-11-19 2022-05-27 上海申淇医疗科技股份有限公司 Drug-coated balloon and preparation method therefor

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07328124A (en) * 1994-06-03 1995-12-19 Terumo Corp Medicine dosing catheter
JP2010509991A (en) * 2006-11-20 2010-04-02 ルトニックス・インコーポレ−テッド Drug release coating for medical devices
JP2010540159A (en) * 2007-10-19 2010-12-24 ルトニックス・インコーポレ−テッド Drug release coating for medical devices
JP2012502690A (en) * 2008-09-15 2012-02-02 シーヴィー インジェニュイティ コーポレイション Local delivery of water-soluble or water-insoluble therapeutic agents to the body lumen surface
WO2013146377A1 (en) * 2012-03-27 2013-10-03 テルモ株式会社 Coating composition and medical device
WO2015151877A1 (en) * 2014-04-01 2015-10-08 テルモ株式会社 Balloon coating method, coat layer control method and balloon coating device
JP2016523593A (en) * 2013-05-16 2016-08-12 サーモディクス，インコーポレイテッド Compositions and methods for delivering hydrophobic bioactive agents

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07328124A (en) * 1994-06-03 1995-12-19 Terumo Corp Medicine dosing catheter
JP2010509991A (en) * 2006-11-20 2010-04-02 ルトニックス・インコーポレ−テッド Drug release coating for medical devices
JP2010540159A (en) * 2007-10-19 2010-12-24 ルトニックス・インコーポレ−テッド Drug release coating for medical devices
JP2012502690A (en) * 2008-09-15 2012-02-02 シーヴィー インジェニュイティ コーポレイション Local delivery of water-soluble or water-insoluble therapeutic agents to the body lumen surface
WO2013146377A1 (en) * 2012-03-27 2013-10-03 テルモ株式会社 Coating composition and medical device
JP2016523593A (en) * 2013-05-16 2016-08-12 サーモディクス，インコーポレイテッド Compositions and methods for delivering hydrophobic bioactive agents
WO2015151877A1 (en) * 2014-04-01 2015-10-08 テルモ株式会社 Balloon coating method, coat layer control method and balloon coating device

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022105849A1 (en) * 2020-11-19 2022-05-27 上海申淇医疗科技股份有限公司 Drug-coated balloon and preparation method therefor
CN112402702A (en) * 2020-12-04 2021-02-26 上海康德莱医疗器械股份有限公司 Drug coating composition and drug coating balloon

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