JP2018153287A - Manufacturing method and manufacturing device of balloon catheter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a manufacturing method and a manufacturing device of a balloon catheter capable of forming a uniform layer of an agent high in transition property to biological tissues.SOLUTION: There is provided a manufacturing method of a balloon catheter 10 in which a coat layer 40 containing a water-insoluble agent is formed on an outer surface of a balloon 30, having a step for rotating the balloon 30 around the shaft center of the balloon 30 and applying a coating liquid 45 containing an agent and a solvent to the outer surface of the balloon 30, a step for freezing the coating liquid 45 while rotating the balloon 30 at a state that the solvent of the applied coating liquid 45 is left, and a step for sublimating the solvent of the frozen coating liquid 45 by pressure reduction.SELECTED DRAWING: Figure 4

Description

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

  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.

  However, if the lesion is forcibly expanded, smooth muscle cells may proliferate and new stenosis (restenosis) may develop in the lesion. For this reason, recently, a drug eluting balloon (DEB) in which a drug for suppressing stenosis is coated on the outer surface of the balloon has been used. By expanding the drug-eluting balloon, the drug coated on the outer surface is instantaneously released to the lesioned part, thereby preventing restenosis.

  In recent years, it has become clear that the morphological form of the drug coated on the outer surface of the balloon affects the release of the drug from the balloon surface and the tissue transferability at the lesion. The form of the drug coated on the outer surface of the balloon can be adjusted by changing the conditions for volatilizing the solvent after applying a coating liquid containing the drug and the solvent to the outer surface of the balloon. For example, Patent Document 1 describes a method of volatilizing a solvent by applying a fluid for adjusting a temperature condition inside a balloon in order to adjust a morphological type of a drug. Patent Document 2 discloses that a porous layer containing a drug is formed by applying a coating liquid containing a drug and a solvent to the outer surface of the balloon and freezing it, and then sublimating the frozen solvent by drying under reduced pressure. How to do is described. Since the porous drug is easily cracked, it has a high transferability to a living tissue.

JP 2014-200269 A JP 2014008241 A

  Since the solvent contained in the coating liquid applied to the balloon is usually easily volatilized, volatilization starts immediately after the coating liquid containing the solvent is applied to the balloon catheter. For this reason, before freezing, drying has already progressed depending on the location of the balloon, and the amount of the solvent after freezing is likely to vary depending on the site. When the amount of the solvent varies depending on the site, the conditions for drying under reduced pressure are not uniform, and it is difficult to form a coat layer having a uniform shape and shape.

  The present invention has been made in order to solve the above-described problems, and an object of the present invention is to provide a balloon catheter manufacturing method and manufacturing apparatus that can form a uniform drug layer having high transferability to living tissue. .

  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, wherein the balloon is rotated about the axis of the balloon. While applying a coating liquid containing a drug and a solvent to the outer surface of the balloon, and freezing the coating liquid while rotating the balloon while the solvent of the applied coating liquid remains. And sublimating the frozen solvent of the coating solution under reduced pressure.

  In the method for manufacturing a balloon catheter configured as described above, the coating liquid on the outer surface of the balloon in a state where the solvent remains is frozen and then depressurized. Becomes a porous structure. Thereby, the surface area of the coat layer increases, and the coat layer is easily broken and easily detached from the balloon. For this reason, the transferability of the drug to the living tissue is high. Therefore, this manufacturing method can manufacture a balloon catheter that is selectively provided with a drug crystal having a high transferability to a living tissue. In addition, since the coating liquid is applied and frozen while maintaining the rotation of the balloon that plays the role of homogenizing the coating liquid, the coating liquid is uniformly applied to the outer surface of the balloon and frozen. For this reason, the morphological type and the porous structure of the coating layer to be formed are uniform in a desired state on the surface of the balloon. Therefore, this manufacturing method can form a uniform drug layer having a high transferability to living tissue.

  In the manufacturing method, in the freezing step, a plurality of granular solids of various sizes are formed with the solvent, and in the sublimating step, the granular solid is sublimated to form a coating layer having a plurality of voids. It may be formed. Thereby, this manufacturing method can form a coat layer having a plurality of voids of various sizes and having high transferability to living tissue.

  In the manufacturing method, in the step of applying the coating liquid, the coating liquid supply unit for supplying the coating liquid is moved relative to the balloon in the axial direction of the balloon, and the coating liquid is supplied. You may freeze sequentially from the apply | coated site | part. Thereby, since it can suppress that a solvent volatilizes before freezing, the quantity of the solvent contained in the frozen coating liquid becomes uniform on the surface of a balloon. Therefore, the morphological type and the porous structure of the drug of the coat layer to be formed are uniform on the surface of the balloon, and a uniform drug layer having a high migration property to a living tissue can be formed.

  In the manufacturing method, in the step of applying the coating liquid, a tubular dispensing tube for supplying the coating liquid is moved relative to the balloon in the axial direction of the balloon, In the step of applying the coating liquid to the outer surface and freezing the coating liquid, the coating liquid applied to the balloon may be frozen by a refrigeration unit that moves following the dispensing tube. As a result, the amount of the coating liquid applied to the balloon can be adjusted with high accuracy by the dispensing tube, and the coating liquid at almost all positions on the balloon is frozen after a short period of time and approximately a certain time after being discharged from the dispensing tube. To do. Therefore, the amount of the solvent contained in the frozen coating solution is uniform on the surface of the balloon, and a uniform drug layer having high migration to a living tissue can be formed.

  In the manufacturing method, in the step of freezing the coating solution, all the coating solution applied to the balloon is frozen after the coating solution is completely applied to the entire area where the balloon coat layer is formed. You may start at the same time. Thereby, the coating liquid uniformly applied by rotating the balloon 30 is frozen while being uniform. For this reason, the solvent of the uniform coating liquid can be sublimated simultaneously under reduced pressure. Therefore, the morphological type and the porous structure of the drug of the coat layer to be formed are uniform on the surface of the balloon, and a uniform drug layer having a high migration property to a living tissue can be formed.

  In the manufacturing method, the coating liquid may be frozen with liquid nitrogen in the step of freezing the coating liquid. Thereby, the solvent can be instantly frozen in a desired state, and a uniform coat layer can be formed.

  The solvent is selected from the group consisting of water, acetic acid, t-butyl alcohol, benzene, chlorohexane, glycerin, ethanol, hexane, ethyl acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane. It may contain at least one selected. Thereby, the volatility of the solvent is lowered, and the solvent is less likely to volatilize from the coating liquid applied to the balloon. For this reason, the amount of the solvent contained in the frozen coating liquid becomes uniform on the surface of the balloon, and a uniform drug layer having high transferability to a living tissue can be formed.

  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.

  The balloon catheter manufacturing apparatus that achieves the above object is a balloon catheter manufacturing apparatus in which a coating layer containing a water-insoluble drug is formed on the outer surface of the balloon, and a rotating mechanism that applies a rotational force to the balloon. A coating solution supply unit that applies a coating solution containing a drug and a solvent to the outer surface of the rotating balloon, and a freezing unit that freezes the coating solution applied to the balloon while the balloon is rotating And having.

  The balloon catheter manufacturing apparatus configured as described above can freeze the coating liquid on the outer surface of the balloon in a state where the solvent remains in the freezing unit. Thereby, the frozen coating liquid can be dried under reduced pressure by a vacuum dryer. For this reason, the coating layer after freeze-drying has a porous structure, increases the surface area, and is easily broken and easily detached from the balloon. For this reason, the transferability of the drug to the living tissue is enhanced. Therefore, this manufacturing apparatus can manufacture a balloon catheter that is selectively provided with a drug crystal having a high transferability to a living tissue. Further, since the coating liquid is applied and frozen while rotating the balloon, the coating liquid is uniformly applied to the outer surface of the balloon and frozen. For this reason, after drying under reduced pressure, the morphological type and the porous structure of the drug in the coat layer become uniform in a desired state on the surface of the balloon, and a uniform drug layer having a high transferability to living tissue can be formed.

  The manufacturing apparatus may further include a vacuum dryer for drying the coating liquid applied to the balloon and frozen. Thereby, the coating liquid frozen on the balloon can be dried under reduced pressure to form a porous coating layer.

  The coating liquid supply unit is movable relative to the balloon in the axial direction of the balloon and has a tubular dispensing tube for supplying the coating liquid, and the freezing unit includes the dispensing unit. It may be movable following the sensing tube. Thereby, the coating liquid applied to the balloon can be sequentially frozen by the freezing unit. For this reason, since it can suppress that a solvent evaporates before freezing, the quantity of the solvent contained in the frozen coating liquid becomes uniform on the surface of a balloon. Therefore, after drying under reduced pressure, the drug morphological type and porous structure of the coat layer become uniform on the surface of the balloon, and a uniform drug layer having a high transferability to living tissue can be formed.

It is a front view which shows a balloon catheter. It is sectional drawing of the front-end | tip part of a balloon catheter. It is a schematic sectional drawing of the outer surface of a balloon, (A) shows the example from which a space | gap has a substantially uniform magnitude | size, (B) shows the example from which the magnitude | size of a space | gap differs. It is a side view which shows the manufacturing apparatus of a balloon catheter. It is sectional drawing which shows the dispensing tube which contacted the balloon. It is a schematic sectional drawing which shows the state from which a solvent volatilizes from the coating liquid apply | coated to the balloon. 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. It is sectional drawing which shows the state which expanded the stenosis part of the blood vessel with the balloon catheter. It is sectional drawing which shows the modification of the manufacturing apparatus of a balloon catheter. It is a front view which shows the other modification of the manufacturing apparatus of a balloon catheter. It is sectional drawing which shows the other modification of the manufacturing apparatus of a balloon catheter.

  Embodiments of the present invention will be described below 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.

  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”.

  First, the structure of the balloon catheter 10 will be described. The balloon catheter 10 is fixed to a long catheter body 20, a balloon 30 provided at the distal end portion of the catheter body 20, a coat layer 40 containing a drug provided on the outer surface of the balloon 30, and a proximal end of the catheter body 20. Hub 26.

  The catheter main 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.

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 gas, 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 (expanded portion) having the same outer diameter when expanded is formed in the central portion of the balloon 30 in the axial direction, and the outer diameter gradually increases on both sides of the straight portion 31 in the axial direction. A taper portion 33 that changes to 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.

  The hub 26 is formed with a base end opening 27 that communicates with the expansion lumen 23 of the outer tube 21 and functions as a port through which expansion fluid flows 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.

  Although the outer diameter at the time of expansion of the balloon 30 is not particularly limited, it is preferably 1 to 10 mm, more preferably 2 to 8 mm.

  The outer surface of the balloon 30 before the coating layer 40 is formed is smooth and non-porous. The outer surface of the balloon 30 before the coat layer 40 is formed may have minute holes that do not penetrate the membrane. Alternatively, the outer surface of the balloon 30 before the coating layer 40 is formed may have both a smooth and non-porous range and a range with minute holes that do not penetrate the membrane. The size of the 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 more 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.

  It is preferable that the balloon 30 has a certain degree of flexibility and expands when reaching a blood vessel, tissue, or the like, and has a certain degree of hardness so that the drug can be released from the coat layer 40 on the outer surface thereof. 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, polyolefin such as polyethylene, polypropylene, polybutene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, ionomer, or a mixture of two or more of these, and 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.

  The coating layer 40 is formed on the outer surface of the balloon 30 directly or via a pretreatment layer such as a primer layer by a method described later. As shown in FIG. 3, the coat layer 40 has an additive 41 (excipient) containing a water-soluble low molecular weight compound arranged in layers on the outer surface of the balloon 30 and a water-insoluble drug crystal 42. ing. The coat layer 40 has a porous structure and includes a large number of voids 43. The plurality of gaps 43 may have a uniform size to some extent as shown in FIG. 3A, but may have various sizes of large and small as shown in FIG. Good. The gap 43 may be located inside the coat layer 40 or may be opened on the surface of the coat layer 40. The end of drug crystal 42 may be in direct contact with the outer surface of balloon 30, but additive 41 is present between the end of drug crystal 42 and the outer surface of balloon 30 without direct contact. May be. 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 balloon 30. Alternatively, the plurality of drug crystals 42 may be irregularly arranged on the outer surface of the balloon 30.

The amount of drug contained in the coating layer 40 is not particularly ^{limited, 0.1μg / mm 2 ~10μg / mm} 2, at a density of preferably ^{0.5μg / mm 2 ~5μg / mm 2} , more preferably 0.5 [mu] g / ^{mm 2} ~3.5μg / ^mm 2, more preferably included at a density of ^{1.0μg / mm 2 ~3μg / mm 2} . The amount of crystals 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 )].

  The additive 41 is distributed and present in the space between the plurality of drug crystals 42. The proportion of the substance constituting the coating 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 balloon 30 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 is in the state of crystal particles and / or particulate amorphous. Alternatively, the additive 41 may be in a film-like amorphous state.

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

  Since the coat layer 40 has a porous structure, it has a large surface area and is easily destroyed. The coat layer 40 is destroyed by contact with the living tissue, and the surface area is further increased, and the coat layer 40 is easily detached from the balloon 30. For this reason, the coat layer 40 having a porous structure has a high transferability of the drug crystal 42 to the living tissue.

  Next, the manufacturing apparatus 50 for the balloon catheter 10 will be described. The manufacturing apparatus 50 of the balloon catheter 10 can form the coat layer 40 on the balloon 30. As shown in FIGS. 4 and 5, the balloon catheter manufacturing apparatus 50 includes a rotation mechanism 60 that rotates the balloon catheter 10 and a support base 70 that supports the balloon catheter 10. The manufacturing 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, a moving mechanism unit 80 that moves the dispensing tube 94 relative to the balloon 30, and Have The manufacturing apparatus 50 further includes a refrigeration unit 110 including a refrigeration tube 114 that supplies liquid nitrogen to the coating liquid 45 on the outer surface of the balloon 30, and a vacuum dryer 120. The manufacturing apparatus 50 further includes a control unit 100 that controls each part of the manufacturing apparatus 50.

  The rotation mechanism 60 holds the hub 26 of the balloon catheter 10 and rotates the balloon catheter 10 around the axis of the balloon 30 by a drive source such as a built-in 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.

  The support base 70 includes a tubular proximal end support portion 71 that accommodates and rotatably supports the catheter body 20, 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 and the freezing tube 114 are 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 and the freezing tube 114 linearly move 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 dispensing tube 94 and the freezing tube 114 can be fixed to the tube fixing portion 83 with, for example, a bolt or the like. The position of the tube fixing portion 83 where the dispensing tube 94 and the freezing tube 114 are fixed is adjustable. Therefore, the separation distance between the dispensing tube 94 and the freezing tube 114 can be appropriately adjusted according to the conditions.

  The coating liquid supply unit 90 is a part that applies the coating liquid 45 to the outer surface 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 tube 94 that applies the coating liquid 45 to the balloon 30. It has.

  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 balloon 30. 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 balloon 30 in a state where the dispensing tube 94 is bent by being pressed against the balloon 30.

  The dispensing tube 94 may not be circular 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 balloon 30.

  The dispensing tube 94 is preferably made of a flexible material so as to reduce the contact load on the balloon 30 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 may be a length 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 freezing unit 110 is a part that supplies liquid nitrogen to the outer surface of the balloon 30. The refrigeration unit 110 includes a nitrogen container 112 that stores liquid nitrogen, a nitrogen pump 113 that supplies liquid nitrogen in an arbitrary amount, and a refrigeration tube 114 that discharges liquid nitrogen toward the balloon 30. ing.

  The nitrogen pump 113 is a syringe pump, for example, and is controlled by the control unit 100 to suck liquid nitrogen from the nitrogen container 112 through the nitrogen suction tube 111 and liquid into the freezing tube 114 through the nitrogen transport tube 116. Nitrogen can be supplied in an arbitrary amount. The nitrogen pump 113 is installed on the moving table 81 and can move linearly by the movement of the moving table 81. The nitrogen pump 113 is not limited to a syringe pump as long as liquid nitrogen can be fed.

  The freezing tube 114 communicates with the nitrogen transport tube 116 and is a member that discharges liquid nitrogen supplied from the nitrogen pump 113 via the nitrogen transport tube 116 to the outer surface of the balloon 30. The freezing tube 114 is a circular tubular member. The freezing tube 114 has an upper end fixed to the tube fixing portion 83, extends vertically downward from the tube fixing portion 83, and has an opening 115 at the lower end. The opening 115 is separated from the balloon 30. The freezing tube 114 can move linearly in both directions along the axial direction of the balloon catheter 10 together with the nitrogen pump 113 installed on the moving table 81 by moving the moving table 81. The freezing tube 114 can supply liquid nitrogen to the outer surface of the balloon 30 while being separated from the balloon 30 by a predetermined length. The liquid nitrogen released from the freezing tube 114 takes the heat from the coating liquid 45 that comes into contact with the liquid nitrogen and vaporizes, thereby freezing the coating liquid 45. The freezing tube 114 is located on the opposite side to the dispensing tube 94 in the moving direction of the dispensing tube 94. Thereby, liquid nitrogen can be supplied to the coating liquid 45 supplied from the dispensing tube 94.

  The shape of the freezing tube 114 is not limited as long as liquid nitrogen can be supplied. The freezing tube 114 may not extend in the vertical direction as long as liquid nitrogen can be discharged from the opening 115.

  The freezing tube 114 is preferably made of a material that can transport liquid nitrogen. As a constituent material of the freezing tube 114, for example, stainless steel, copper, aluminum, nickel, high density polyethylene, borosilicate glass, or the like can be applied.

  The control unit 100 is configured by a computer, for example, and comprehensively controls the rotation mechanism unit 60, the movement mechanism unit 80, the coating liquid supply unit 90, and the freezing unit 110. Therefore, the controller 100 rotates the balloon 30, moves the dispensing tube 94 in the axial direction with respect to the balloon 30, discharges the drug from the dispensing tube 94, and discharges the liquid nitrogen from the freezing tube 114. Etc. can be comprehensively controlled.

  As the vacuum dryer 120, a known one can be used. The vacuum dryer 120 can accommodate an object to be dried under reduced pressure. Therefore, the vacuum dryer 120 accommodates the balloon catheter 10 and can dry the coating liquid 45 frozen on the outer surface of the balloon 30 under reduced pressure.

  The coating liquid 45 supplied to the balloon 30 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 balloon 30, the solvent is volatilized, whereby the coat layer 40 having the water-insoluble drug crystals 42 and the additive 41 is formed on the outer surface of the balloon 30.

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

  The water-insoluble drug means a drug that is insoluble or hardly 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.

  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, rapamycin, docetaxel and especially everolimus. 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.

  The additive 41 includes a water-soluble low molecular compound. The molecular weight of the water-soluble low molecular weight compound is 50 to 2000, preferably 50 to 1000, more preferably 50 to 500, and further preferably 50 to 200. The water-soluble low molecular weight compound is preferably 5 to 10,000 parts by mass, more preferably 5 to 200 parts by mass, and still more preferably 8 to 150 parts by mass with respect to 100 parts by mass of the water-insoluble drug. The constituent materials of water-soluble 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 water-soluble low molecular weight compound has a hydrophilic group and a hydrophobic group and is characterized by being dissolved in water. The water-soluble low molecular weight compound is preferably non-swellable or hardly swellable. 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 can be easily released, and the drug crystal 42 into the blood vessel. It has the effect of increasing the amount of adhesion. When the additive 41 is a matrix made of a contrast agent such as Ultravist (registered trademark), crystal particles are embedded in the matrix, and crystals are not generated from the base material of the balloon 30 toward the outside of the matrix. . In contrast, the drug crystal 42 of the present embodiment can extend from the surface of the base material of the balloon 30 to the outside of the additive 41.

  The solvent contained in the coating liquid 45 is a freezing freezing solvent, and preferably has low volatility so that the coating liquid 45 is not completely volatilized after being applied to the balloon 30 until it is frozen. In the case where the solvent is frozen by following the dispensing tube 94 while the solvent is applied by the dispensing tube 94, the solvent is not limited to one having low volatility. The solvent contains at least one of an organic solvent and water.

  The freezing 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, and ethyl acetate. Among these, some of these mixed solvents are preferable among tetrahydrofuran, ethanol, and acetone.

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

  Examples of low-volatile freezing solvents include water, acetic acid, t-butyl alcohol, benzene, chlorohexane, glycerin, ethanol, hexane, ethyl acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, and styrene. , Cyclohexane and the like. The volatility of the solvent can be adjusted by, for example, the viscosity of the solution, the concentration of the solution (solvent content ratio), and the like.

  Next, a method for manufacturing the balloon catheter 10 according to this embodiment will be described. In this manufacturing method, the water-insoluble drug crystal 42 is formed on the outer surface of the balloon 30 using the manufacturing apparatus 50 described above.

  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, in a state where the balloon 30 is expanded, the three-way cock is operated 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.

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

  Next, by adjusting the position of the moving table 81, 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. 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 the drug crystal 42 can be promoted. 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.

  Next, the balloon catheter 10 is rotated by the rotation mechanism unit 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 is applied while drawing a spiral on the outer peripheral surface of the balloon 30 as the dispensing tube 94 moves relative to the balloon 30. Since the balloon 30 is rotating, the coating liquid 45 applied to the outer peripheral surface of the balloon 30 tends to be uniform in the circumferential direction.

  Although the moving speed of the dispensing tube 94 is not specifically limited, For example, it is 0.01-2 mm / sec, Preferably it is 0.03-1.5 mm / sec, More preferably, it is 0.05-1.0 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. Although the rotational speed of the balloon 30 is not specifically limited, For example, it is 10-300 rpm, Preferably it is 30-250 rpm, More preferably, it is 50-200 rpm. Although the diameter of the balloon 30 at the time of apply | coating the coating liquid 45 is not specifically limited, For example, it is 1-10 mm, Preferably it is 2-7 mm.

  Next, at the timing when the opening 115 of the freezing tube 114 that follows the dispensing tube 94 reaches the vicinity of the coating liquid 45 applied to the balloon 30, the amount of liquid fed is adjusted by the nitrogen pump 113. Nitrogen is supplied to the freezing tube 114. The liquid nitrogen released from the freezing tube 114 takes the heat from the coating liquid 45 and vaporizes, thereby freezing the coating liquid 45. As a result, the solvent of the coating liquid 45 is instantly frozen. Since the solvent contained in the coating liquid 45 has low volatility, the amount of volatilization after being applied to the balloon 30 and before freezing is small. Further, the freezing tube 114 moves following the dispensing tube 94 to sequentially freeze the coating liquid 45 applied to the balloon 30. For this reason, the coating liquid 45 at any position on the balloon 30 is frozen after a short time and approximately a fixed time after being discharged from the dispensing tube 94. Therefore, the amount of the solvent contained in the frozen coating liquid 45 is uniform on the surface of the balloon 30.

  Then, the dispensing tube 94 and the freezing tube 114 are gradually moved in the axial direction of the balloon 30 while rotating the balloon 30. As a result, a frozen coating liquid 45 layer is gradually formed on the outer surface of the balloon 30 in the axial direction. After the layer of the frozen coating liquid 45 is formed in the entire range where the coating layer 40 of the balloon 30 is formed, the rotation mechanism section 60, the movement mechanism section 80, the coating liquid supply section 90, and the freezing section 110 are stopped. The layer of the frozen coating liquid 45 contains a plurality of granular solids 46 (see FIG. 6) of various (or uniform) sizes by freezing the solvent.

  Thereafter, the balloon catheter 10 is removed from the support base 70. Next, the three-way stopcock connected to the proximal end opening 27 of the balloon catheter 10 is opened, and the expansion fluid is discharged from the balloon 30. Thereafter, the proximal end opening 27 is kept open. This prevents a pressure difference between the inside and outside of the balloon 30 from being generated during drying under reduced pressure, and prevents the balloon 30 from bursting. Thereafter, the balloon catheter 10 is housed in a vacuum dryer 120, and the coating liquid 45 applied to the outer surface of the balloon 30 and frozen is dried under reduced pressure. As a result, as shown in FIG. 6, the solvent sublimates (volatilizes) from the solvent solid 46 of the frozen coating liquid 45, and the coating layer 40 is formed. The coat layer 40 has a sponge-like structure in which a large number of small voids 43 in which particles of the solvent solid 46 existed, that is, a porous structure, are obtained by sublimating the particles of the solvent solid 46. That is, the coat layer 40 has an additive 41 and a drug crystal 42 and has a porous structure in which a plurality of voids 43 are formed. The void 43 can be formed between the additive 41 and the additive 41. In addition, the gap 43 can be formed between the additive 41 and the drug crystal 42. In addition, the gap 43 can be formed between the drug crystal 42 and the drug crystal 42. When the coat layer 40 does not have the additive 41, the void 43 is formed between the drug crystal 42 and the drug crystal 42, that is, inside the drug crystal 42.

  In the present embodiment, the coating liquid 45 having low solvent volatility and applied to the balloon 30 is sequentially frozen by the freezing tube 114 that follows the dispensing tube 94. For this reason, the amount of the solvent contained in the frozen coating liquid 45 is uniform on the surface of the balloon 30. Accordingly, the voids 43 and the drug crystals 42 of the coat layer 40 are formed uniformly.

  Next, the balloon catheter 10 is taken out from the vacuum dryer 120. Next, the balloon 30 is deflated and folded. Thereby, manufacture of the balloon catheter 10 is completed.

  As shown in FIG. 7A, the balloon 30 has a substantially circular cross section in a state in which the expansion fluid is injected therein. 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 porous coat layer 40 provided on the blade outer side portion 34a is deformed on the surface of the balloon 30 and the gaps 43 are easily reduced. It is not necessary for all of the drug crystal 42 to sleep.

  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 folded. For this reason, it is easy to adjust the force acting on the porous coat layer 40 provided on the outer surface overlapping the overlapping portion 35 of the balloon 30 so as not to become too strong. Therefore, a desired force can be applied to the porous coat layer 40 provided on the outer surface overlapping the overlapping portion 35 of the balloon 30. Of the regions of the blade inner portion 34b and the intermediate portion 34c facing each other, the porous coat layer 40 is formed in a region facing the root side space portion 36, that is, in a region where the blade inner portion 34b and the intermediate portion 34c are not in close contact. Is less susceptible to pressure. Therefore, in this region, the porous coat layer 40 is easily maintained without being deformed. Further, in the regions of the blade inner portion 34b and the intermediate portion 34c facing each other, in a region not facing the root side space portion 36, that is, in a region where the blade inner portion 34b and the intermediate portion 34c are in close contact with each other, a porous coat Layer 40 is susceptible to pressing forces. Therefore, in this region, the porous coat layer 40 is deformed and the voids 43 are likely to be reduced.

  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.

  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. A guiding catheter may be used to reach the balloon catheter 10 to the stenosis 300.

  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 fed 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.

  When the balloon 30 is expanded and the coat layer 40 is pressed against the living tissue, the additive 41 that is a water-soluble low-molecular compound contained in the coat layer 40 dissolves gradually or quickly, and the drug crystal 42 of the drug enters the living body. Delivered. Since the coat layer 40 has a large number of voids 43, the coat layer 40 has a large surface area and is easily broken and easily detached from the balloon 30. For this reason, the transferability of the drug crystal 42 to the living tissue is improved. Further, since the solvent of the coating liquid 45 at the time of manufacturing is low in volatility and the coating liquid 45 applied to the balloon 30 is sequentially frozen by the freezing tube 114 that follows the dispensing tube 94, the coating layer 40 The voids 43 and the drug crystals 42 are uniformly formed. For this reason, a medicine can be made to act satisfactorily on a living body without variation.

  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.

  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. While rotating about the axis of the balloon 30, the step of applying the coating liquid 45 containing the drug and the solvent to the outer surface of the balloon 30, and the balloon 30 in the state where the solvent of the applied coating liquid 45 remains. A step of freezing the coating liquid 45 while rotating, and a step of sublimating the solvent of the frozen coating liquid 45 by decompression.

  In the method for manufacturing the balloon catheter 10 configured as described above, the coating liquid 45 on the outer surface of the balloon 30 in a state where the solvent remains is frozen and then depressurized. This coat layer 40 has a porous structure. As a result, the coat layer 40 has an increased surface area, is easily broken, and is easily detached from the balloon 30. For this reason, the transferability of the drug to the living tissue is enhanced. Therefore, this manufacturing method can manufacture the balloon catheter 10 that is selectively provided with the drug crystal 42 having a high transferability to a living tissue. Further, the coating liquid 45 is applied to the balloon 30 and frozen while maintaining the rotation of the balloon 30 that plays the role of making the coating liquid 45 uniform, so that the coating liquid 45 is uniformly applied to the outer surface of the balloon 30. to freeze. For this reason, the morphological type and the porous structure of the coating layer 40 to be formed are uniform in a desired state on the surface of the balloon 30. Therefore, this manufacturing method can form a uniform drug layer having a high transferability to living tissue.

  The manufactured balloon catheter 10 has a coat layer 40 having a porous structure including drug crystals 42 on the outer surface of the balloon 30. The porous coat layer 40 has a large number of voids 43. Therefore, when the balloon 30 is expanded and pressed against the living tissue, the drug crystal 42 of the coat layer 40 that has a large surface area and is easily broken and easily detached from the balloon 30 can quickly migrate to the living tissue.

  Further, in the manufacturing method, in the step of freezing the coating liquid 45, a plurality of granular solids 46 of various sizes are formed with a solvent, and in the step of sublimating, the granular solids 46 are sublimated to form a plurality of voids 43. A coat layer 40 having the following may be formed. Thereby, this manufacturing method has the several space | gap 43 of various magnitude | sizes, and can form the coat layer 40 with high transferability to a biological tissue.

  Further, in this manufacturing method, in the step of applying the coating liquid 45, the dispensing tube 94 for supplying the coating liquid 45 is moved in the axial direction of the balloon 30, and sequentially frozen from the portion where the coating liquid 45 is applied. Let Thereby, since it can suppress that a solvent volatilizes before freezing, the quantity of the solvent contained in the frozen coating liquid 45 becomes uniform on the surface of the balloon 30. Therefore, the morphological type and porous structure of the drug of the coat layer 40 to be formed are uniform on the surface of the balloon 30, and a uniform drug layer having a high transferability to a living tissue can be formed.

  Further, in the manufacturing method, in the step of applying the coating liquid 45, a tubular dispensing tube 94 for supplying the coating liquid 45 is moved relative to the balloon 30 in the axial direction of the balloon 30. In the step of applying the coating liquid 45 to the outer surface of the balloon 30 and freezing the coating liquid 45, the coating liquid 45 applied to the balloon 30 is frozen by the freezing unit 110 that moves following the dispensing tube 94. Thereby, the amount of the coating liquid 45 applied to the balloon 30 can be adjusted with high accuracy by the dispensing tube 94, and the coating liquid at almost all positions on the balloon 30 can be released in a short time after being discharged from the dispensing tube 94. Freezes after a certain period of time. Therefore, the amount of the solvent contained in the frozen coating liquid 45 is uniform on the surface of the balloon 30, and a uniform drug layer having a high migration property to a living tissue can be formed.

  In the manufacturing method, the coating liquid 45 is frozen with liquid nitrogen in the step of freezing. Thereby, the solvent can be instantly frozen in a desired state, and the uniform coat layer 40 can be formed.

  The solvent is a group consisting of water, acetic acid, t-butyl alcohol, benzene, chlorohexane, glycerin, ethanol, hexane, ethyl acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane. You may contain at least 1 selected from these. Thereby, the volatility of the solvent is lowered, and the solvent is less likely to volatilize from the coating liquid 45 applied to the balloon 30. For this reason, the amount of the solvent contained in the frozen coating liquid 45 is uniform on the surface of the balloon 30, and a uniform drug layer having a high migration property to a living tissue can be formed.

  The water-insoluble drug may also contain at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus. Thereby, restenosis of the stenosis part in the blood vessel can be favorably suppressed by the drug crystal 42.

  The manufacturing apparatus 50 according to the present embodiment is a manufacturing apparatus 50 for the balloon catheter 10 in which a coat layer 40 containing a water-insoluble drug is formed on the outer surface of the balloon 30, and a rotation mechanism that applies a rotational force to the balloon 30. Part 60, coating liquid supply part 90 for applying coating liquid 45 containing a drug and a solvent to the outer surface of rotating balloon 30, and coating liquid 45 applied to balloon 30 in a state where balloon 30 is rotating. And a freezing unit 110 for freezing.

  The manufacturing apparatus 50 configured as described above can freeze the coating liquid 45 on the outer surface of the balloon 30 with the solvent remaining in the freezing unit 110. Thereby, the frozen coating liquid 45 can be dried under reduced pressure by the reduced pressure dryer 120. For this reason, the coating layer 40 after freeze-drying has a porous structure, increases the surface area, and is easily broken and easily detached from the balloon 30. For this reason, the transferability of the drug to the living tissue is enhanced. Therefore, this manufacturing apparatus can manufacture the balloon catheter 10 that is selectively provided with a crystal having a high transferability to a living tissue. Further, since the coating liquid 45 is applied and frozen while rotating the balloon 30, the coating liquid 45 is uniformly applied to the outer surface of the balloon 30 and frozen. For this reason, after drying under reduced pressure, the morphological type and the porous structure of the drug in the coat layer 40 become uniform in a desired state on the surface of the balloon 30, and a uniform drug layer having a high transferability to living tissue can be formed.

  The manufacturing apparatus 50 further includes a vacuum dryer 120 for drying the coating liquid 45 applied to the balloon 30 and frozen. Thereby, the coating liquid 45 applied to the balloon 30 and frozen can be dried under reduced pressure to form the porous coating layer 40.

  The coating liquid supply unit 90 includes a tubular dispensing tube 94 that is movable relative to the balloon 30 in the axial direction of the balloon 30 and supplies the coating liquid 45. Is movable following the dispensing tube 94. Thereby, the coating liquid 45 applied to the balloon 30 can be sequentially frozen by the freezing unit 110. For this reason, since it can suppress that a solvent evaporates before freezing, the quantity of the solvent contained in the frozen coating liquid 45 becomes uniform on the surface of the balloon 30. Therefore, after drying under reduced pressure, the morphological type and the porous structure of the drug in the coat layer 40 become uniform on the surface of the balloon 30, and a uniform drug layer having a high migration property to a living tissue can be formed.

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

  Further, the balloon catheter 10 may move along the axial center without moving the dispensing tube 94 and the freezing tube 114.

  The method for freezing the coating liquid 45 is not limited to the method using liquid nitrogen. Therefore, for example, a gas such as air having a temperature lower than the freezing point of the solvent may be blown.

  In addition, as shown in FIG. 9, the refrigeration unit 130 that supplies liquid nitrogen may have a hollow ring 131 that surrounds the balloon 30 instead of a tube shape. The ring 131 is capable of circulating liquid nitrogen therein and has a plurality of openings 132 arranged along the circumferential direction of the balloon 30 so as to face the balloon 30. Since such a ring 131 can release liquid nitrogen from the plurality of openings 132, the coating liquid 45 applied to the balloon 30 can be efficiently frozen.

  Further, as shown in FIGS. 10 and 11, the coating liquid supply unit 140 that supplies the coating liquid 45 may be a sprayer capable of spraying in a wide area on the outer surface of the rotating balloon 30. Thereby, the coating liquid 45 can be rapidly applied to the outer surface of the balloon 30. And the freezing part 150 which supplies liquid nitrogen may have the hollow cylinder 151 surrounding the balloon 30 instead of a tube shape. The cylindrical body 151 is capable of circulating liquid nitrogen therein, and has a plurality of openings 152 arranged in the circumferential direction and the axial direction of the balloon 30 on the surface facing the balloon 30. The axial length of the cylinder 151 is preferably equal to or longer than the axial length of the range where the coating layer 40 of the balloon 30 is formed, but is not limited thereto. When the coating liquid 45 is applied to the balloon 30 by the coating liquid supply unit 140 that is a sprayer, the cylindrical body 151 is positioned on the distal end side or the proximal end side of the balloon 30 so as not to cover the balloon 30. . Then, after the coating liquid 45 is applied to the balloon 30 by the coating liquid supply unit 140, the cylinder 151 is moved to cover the balloon 30. Thereafter, liquid nitrogen is released from the opening 152 of the cylindrical body 151 while rotating the balloon 30. Since the cylinder 151 can release liquid nitrogen from the plurality of openings 152 arranged in the circumferential direction and the axial direction, all the coating liquid 45 applied to the balloon 30 can be efficiently frozen without moving the cylinder 151. be able to.

  As described above, in the method of manufacturing the balloon catheter 10, in the step of freezing the coating liquid 45, the coating liquid 45 is applied to the entire area where the coating layer 40 of the balloon 30 is formed and then applied to the balloon 30. Freezing of all the coating liquids 4 can be started. Thereby, the coating liquid 45 applied uniformly by rotating the balloon 30 is frozen in a uniform state. For this reason, the solvent of the uniform coating liquid 45 can be sublimated simultaneously under reduced pressure. Therefore, the morphological type and the porous structure of the drug in the coat layer 40 are uniform on the surface of the balloon 30, and a uniform drug layer having a high migration property to a living tissue can be formed.

DESCRIPTION OF SYMBOLS 10 Balloon catheter 30 Balloon 40 Coat layer 41 Additive 42 Drug crystal 43 Void 45 Coating liquid 46 Granular solid 50 Catheter manufacturing apparatus 60 Rotating mechanism part 80 Moving mechanism part 83 Tube fixing part 90, 140 Coating liquid supply part 94 Dispensing Tube 100 Control unit 110, 130, 150 Freezing unit 114 Freezing tube 120 Vacuum dryer

Claims (11)

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,
Applying a coating liquid containing a drug and a solvent to the outer surface of the balloon while rotating the balloon about the axis of the balloon;
Freezing the coating solution while rotating the balloon while the solvent of the applied coating solution remains;
And sublimating the frozen solvent of the coating solution under reduced pressure. In the freezing step, a plurality of granular solids of various sizes are formed with the solvent,
The method for manufacturing a balloon catheter according to claim 1, wherein in the sublimating step, the granular solid is sublimated to form a coat layer having a plurality of voids.   In the step of applying the coating liquid, the coating liquid supply unit for supplying the coating liquid is moved relative to the balloon in the axial direction of the balloon, and sequentially from the portion where the coating liquid is applied. The method for producing a balloon catheter according to claim 1 or 2, wherein the balloon catheter is frozen. In the step of applying the coating liquid, a tubular dispensing tube for supplying the coating liquid is moved relative to the balloon in the axial direction of the balloon, so that the outer surface of the balloon is coated with the coating liquid. Apply the liquid,
The method for manufacturing a balloon catheter according to claim 3, wherein in the step of freezing the coating liquid, the coating liquid applied to the balloon is frozen by a freezing unit that moves following the dispensing tube.   2. In the step of freezing the coating liquid, freezing of all the coating liquid applied to the balloon is started after the application of the coating liquid to the entire area where the coating layer of the balloon is formed is completed. Or the manufacturing method of the balloon catheter of 2.   The method for producing a catheter according to any one of claims 1 to 5, wherein in the step of freezing the coating liquid, the coating liquid is frozen with liquid nitrogen.   The solvent is selected from the group consisting of water, acetic acid, t-butyl alcohol, benzene, chlorohexane, glycerin, ethanol, hexane, ethyl acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane. The method for producing a balloon catheter according to any one of claims 1 to 6, comprising at least one selected.   The method for producing a balloon catheter according to any one of claims 1 to 7, wherein the water-insoluble drug contains at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel, and everolimus. A balloon catheter manufacturing apparatus in which a coating layer containing a water-insoluble drug is formed on the outer surface of a balloon,
A rotation mechanism for applying a rotational force to the balloon;
A coating solution supply unit for applying a coating solution containing a drug and a solvent to the outer surface of the rotating balloon;
A balloon catheter manufacturing apparatus, comprising: a freezing unit that freezes the coating liquid applied to the balloon while the balloon is rotating.   The balloon catheter manufacturing apparatus according to claim 9, further comprising a vacuum dryer for vacuum drying the coating liquid applied to the balloon and frozen. The coating liquid supply unit has a tubular dispensing tube that is movable relative to the balloon in the axial direction of the balloon and that supplies the coating liquid.
The balloon catheter manufacturing apparatus according to claim 9 or 10, wherein the refrigeration unit is movable following the dispensing tube.

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