JP6831721B2 - Balloon catheter manufacturing method and manufacturing equipment - Google Patents

Description

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

In recent years, balloon catheters have been used to improve lesions (stenosis) that occur in the lumen of a living body. A balloon catheter usually includes a long shaft portion and a balloon provided on the distal end side of the shaft portion and expandable in the radial direction. The lesion can be expanded by expanding the contracted balloon after reaching the destination in the body via a narrow biological lumen.

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

In recent years, it has become clear that the morphological form of a drug coated on the outer surface of a balloon affects the release of the drug from the balloon surface and the tissue transferability at the lesion site. The form of the drug coated on the outer surface of the balloon can be adjusted by applying a coating solution containing the drug and the solvent to the outer surface of the balloon and then changing the conditions for volatilizing the solvent. For example, Patent Document 1 describes a method of volatilizing a solvent by applying a fluid for adjusting temperature conditions to the inside of a balloon in order to adjust the morphology of the drug. Further, in Patent Document 2, a coating liquid containing a drug and a solvent is applied to the outer surface of the balloon, frozen, and then the frozen solvent is sublimated by vacuum drying to form a porous layer containing the drug. How to do it is described. Porous chemicals are prone to cracking and therefore have high transferability to living tissues.

Japanese Unexamined Patent Publication No. 2014-200269 Japanese Unexamined Patent Publication No. 2014-008241

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. Therefore, before freezing, drying has already proceeded depending on the location of the balloon, and the amount of solvent after freezing tends to vary depending on the site. If the amount of the solvent differs depending on the site, the conditions for vacuum drying become non-uniform, and it becomes difficult to form a coat layer having a uniform shape and morphology.

The present invention has been made to solve the above-mentioned problems, and provides a method and an apparatus for manufacturing a balloon catheter capable of uniformly forming a porous structure of a drug in a coat layer containing a water-insoluble drug on the surface of a balloon. The purpose is to do.

A method for manufacturing a balloon catheter that achieves the above object is a method for manufacturing a balloon catheter in which a coat layer containing a water-insoluble agent is formed on the outer surface of the balloon, and the balloon is rotated about the axis of the balloon. A step of applying a coating liquid containing a drug and a solvent to the outer surface of the balloon, and a step of freezing the coating liquid while rotating the balloon while the solvent of the applied coating liquid remains. the solvent of the coating solution was frozen have a, a step of sublimating by vacuum, in step of the freeze, a plurality of particulate solids of various sizes formed by the solvent, in step of the sublimation, the The granular solid is sublimated to form a coat layer having a plurality of voids .

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. Therefore, the solvent is sublimated to obtain a dried coat layer. Has a porous structure. As a result, the coat layer has an increased surface area and is easily broken, so that the coat layer can be easily separated from the balloon. Therefore, the drug has high transferability to living tissues. Therefore, this production method can produce a balloon catheter selectively provided with drug crystals having high transferability to living tissues. Further, since the coating liquid is applied and frozen while maintaining the rotation of the balloon that plays a role of homogenizing the coating liquid, the coating liquid is uniformly applied to the outer surface of the balloon and frozen. As a result, the drug morphology and porous structure of the coated layer formed is uniform on the surface of the balloon in a desirable state .

In the production method, a plurality of granular solids of various sizes are formed by the solvent in the freezing step, and the granular solid is sublimated to form a coat layer having a plurality of voids in the sublimation step. It may be formed. As a result, this production method can form a coat layer having a plurality of voids of various sizes and having high transferability to living tissues.

In the manufacturing method, in the step of applying the coating liquid, the coating liquid is applied while moving the coating liquid supply unit for supplying the coating liquid relative to the balloon in the axial direction of the balloon. You may freeze sequentially from the application site. As a result, it is possible to prevent the solvent from volatilizing before freezing, so that the amount of the solvent contained in the frozen coating liquid becomes uniform on the surface of the balloon. Therefore, the morphological form and the porous structure of the drug of the formed coat layer become uniform on the surface of the balloon, and a uniform drug layer having high transferability to the 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 to obtain 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 freezing portion that moves following the dispensing tube. As a result, the amount of coating liquid applied to the balloon by the dispensing tube can be adjusted with high accuracy, and the coating liquid at almost all positions on the balloon freezes for a short 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 liquid becomes uniform on the surface of the balloon, and a uniform layer of the drug having high transferability to the living tissue can be formed.

In the manufacturing method, in the step of freezing the coating liquid, after the application of the coating liquid to the entire range forming the coat layer of the balloon is completed, all the coating liquids applied to the balloon are frozen. It may start at the same time. As a result, the coating liquid uniformly applied by rotating the balloon 30 freezes while remaining uniform. Therefore, the solvent of the uniform coating liquid can be sublimated at the same time under reduced pressure. Therefore, the morphological form and the porous structure of the drug of the formed coat layer become uniform on the surface of the balloon, and a uniform drug layer having high transferability to the living tissue can be formed.

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

The solvent consists of 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 and cyclohexane. It may contain at least one selected. As a result, the volatility of the solvent becomes low, and the solvent is less likely to volatilize from the coating liquid applied to the balloon. Therefore, the amount of the solvent contained in the frozen coating liquid becomes uniform on the surface of the balloon, and a uniform layer of the drug having high transferability to the living tissue can be formed.

The water-insoluble agent may contain at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus. As a result, restenosis of the stenotic portion in the blood vessel can be satisfactorily suppressed.

Further, the balloon catheter manufacturing device that achieves the above object is a balloon catheter manufacturing device in which a coat layer containing a water-insoluble drug is formed on the outer surface of the balloon, and a rotation mechanism unit that applies a rotational force to the balloon. A coating liquid supply unit that applies a coating liquid containing a drug and a solvent to the outer surface of the rotating balloon, and a freezing unit that freezes the coating liquid applied to the balloon while the balloon is rotating. When the coating liquid that has been frozen is applied to the balloon have a, a vacuum dryer for drying under reduced pressure, the freezing unit forms a plurality of particulate solids of various sizes by the solvent, The vacuum dryer sublimates the granular solid to form a coat layer having a plurality of voids .

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 portion. As a result, the frozen coating liquid can be dried under reduced pressure with a vacuum dryer. Therefore, the coat layer after freeze-drying has a porous structure, the surface area is increased, and the coat layer is easily broken and easily separated from the balloon. Therefore, the transferability of the drug to the living tissue is increased. Therefore, this manufacturing apparatus can manufacture a balloon catheter selectively provided with a drug crystal having 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. Therefore, after vacuum drying, the drug morphotypes and porous structure of the coating layer is made uniform in the desired state on the surface of the balloon, it can form a layer of uniform one drug.

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

The coating liquid supply unit has a tubular dispensing tube that can move relative to the balloon in the axial direction of the balloon and supplies the coating liquid, and the freezing unit has the dispensing unit. It may be movable following the ballooning tube. As a result, the coating liquid applied to the balloon can be sequentially frozen by the freezing unit. Therefore, it is possible to suppress the evaporation of the solvent before freezing, so that the amount of the solvent contained in the frozen coating liquid becomes uniform on the surface of the balloon. Therefore, after drying under reduced pressure, the morphological form and porous structure of the drug in the coat layer become uniform on the surface of the balloon, and a uniform layer of the drug having high transferability to the living tissue can be formed.

It is a front view which shows the balloon catheter. It is sectional drawing of the tip part of a balloon catheter. It is a schematic cross-sectional view of the outer surface of a balloon, (A) shows an example of a substantially uniform size of a void, and (B) shows an example of a different size of a void. It is a side view which shows the manufacturing apparatus of a balloon catheter. It is sectional drawing which shows the dispensing tube which came in contact with a balloon. It is a schematic cross-sectional view which shows the state which the solvent volatilizes from the coating liquid applied to a balloon. It is sectional drawing which shows the balloon to be folded, (A) shows the state before folding of a balloon, (B) shows the state which the wing part was formed in the balloon, (C) shows the state where the wing part was folded. It is sectional drawing which shows the state which expanded the stenotic part of a blood vessel by a 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 balloon catheter manufacturing apparatus. It is sectional drawing which shows the other modification of the manufacturing apparatus of a balloon catheter.

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

As shown in FIGS. 1 and 2, the method for manufacturing a balloon catheter according to the present embodiment is a method for manufacturing a drug-eluting type balloon catheter 10 in which drug crystals are provided on the outer surface of the balloon 30. In the present specification, the side of the balloon catheter 10 to be inserted into the biological lumen is referred to as "tip" or "tip side", and the hand side to be operated 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 the long catheter body 20, the balloon 30 provided at the tip of the catheter body 20, the coat layer 40 containing the drug provided on the outer surface of the balloon 30, and the proximal end of the catheter body 20. It has a hub 26 that has been catheterized.

The catheter body 20 includes an outer tube 21 which is a tubular body having an open tip and a proximal end, and an inner tube 22 which is a tubular body arranged inside the outer tube 21. The inner tube 22 is housed inside the hollow of the outer tube 21, and the catheter body 20 has a double tube structure at the tip. The hollow inside of the inner pipe 22 is a guide wire lumen 24 through which a guide wire is inserted. Further, an expansion lumen 23 for circulating the expansion fluid of the balloon 30 is formed inside the hollow inside of the outer pipe 21 and outside the inner pipe 22. The inner pipe 22 is open to the outside at the opening 25. The inner pipe 22 projects further to the tip side than the tip of the outer pipe 21.

The base end side end of the balloon 30 is fixed to the tip end of the outer tube 21, and the tip end side end is fixed to the tip end of the inner tube 22. As a result, 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 via the expansion lumen 23. The expansion fluid may be a gas or a liquid, and for example, a gas such as helium gas, CO ₂ gas, O ₂ gas, N ₂ gas, Ar gas, air, or mixed gas, or a liquid such as physiological saline or a contrast agent should be used. Can be done.

Cylindrical straight portions 31 (expansion portions) having the same outer diameter when expanded are formed in the central portion of the balloon 30 in the axial direction, and the outer diameters gradually increase on both sides of the straight portion 31 in the axial direction. A tapered portion 33 that changes to is formed. Then, a coat layer 40 containing a drug is formed on the entire outer surface of the straight portion 31. The range in which the coat layer 40 is formed in the balloon 30 is not limited to 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 a part.

The hub 26 is formed with a base end opening 27 that communicates with the expansion lumen 23 of the outer pipe 21 and functions as a port for inflowing and discharging the expansion fluid.

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

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

The outer surface of the balloon 30 before the coat 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 coat layer 40 is formed may have both a smooth and non-porous range and a range with micropores that do not penetrate the membrane. The size of the minute pores is, for example, 0.1 to 5 μm in diameter and 0.1 to 10 μm in depth, and one crystal may have one or more pores. Further, the size of the minute pores is, for example, 5 to 500 μm in diameter and 0.1 to 50 μm in depth, and one pore may have one or more crystals.

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

A coat 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 a layer 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 has a large number of voids 43. The plurality of voids 43 may have a certain uniform size as shown in FIG. 3 (A), but may have various sizes of large and small as shown in FIG. 3 (B). Good. The gap 43 may be located inside the coat layer 40 or may be open on the surface of the coat layer 40. The end of the drug crystal 42 may be in direct contact with the outer surface of the balloon 30, but without direct contact, the additive 41 is present between the end of the drug crystal 42 and the outer surface of the balloon 30. You may. The end of the drug crystal 42 may be located on the surface of the layer of the additive 41 so that the drug crystal 42 protrudes 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 in 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 50,000 to 50,000 [crystal /]. (10 μm ² )], more preferably 500 to 5,000 [crystal / (10 μm ² )].

The additive 41 is distributed and exists in the space between the plurality of drug crystals 42. As for the ratio of the substances constituting the coat layer 40, it is preferable that the drug crystal 42 of the water-insoluble drug occupies a larger volume than the additive 41. Additive 41 does not form a matrix. A matrix is a layer in which relatively high molecular weight substances (polymers, etc.) are continuously formed, forms a mesh-like three-dimensional structure, and a fine space exists in the layer. Therefore, the water-insoluble chemicals constituting the crystals are not attached to the matrix substance. The water-insoluble agents that make up the crystals are also 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 in a solvent-dissolved state, and then dried to form a layer. Additive 41 is amorphous. The additive 41 may be crystalline particles. Additive 41 may be present as a mixture of amorphous and crystalline particles. Additive 41 is in the state of crystalline particles and / or particulate amorphous. Alternatively, the additive 41 may be in a film-like amorphous state.

The agent coated on the outer surface of the balloon 30 may include an amorphous type. Crystals and amorphous materials may be arranged so as to have regularity in the coat layer 40. Alternatively, the 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 broken. When the coat layer 40 comes into contact with the living tissue, it is destroyed to further increase the surface area, and the coat layer 40 is easily detached from the balloon 30. Therefore, the coat layer 40 having a porous structure has a high transferability of the drug crystal 42 to the biological tissue.

Next, the manufacturing apparatus 50 of the balloon catheter 10 will be described. The manufacturing device 50 of the balloon catheter 10 can form a coat layer 40 on the balloon 30. As shown in FIGS. 4 and 5, the balloon catheter manufacturing apparatus 50 has a rotation mechanism unit 60 for rotating the balloon catheter 10 and a support base 70 for supporting the balloon catheter 10. The manufacturing apparatus 50 further includes a coating liquid supply unit 90 provided with a dispensing tube 94 for applying the coating liquid 45 to the outer surface of the balloon 30, and a moving mechanism unit 80 for moving the dispensing tube 94 with respect to the balloon 30. Has. The manufacturing apparatus 50 further includes a freezing section 110 including a freezing tube 114 for supplying 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 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 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. Further, in the balloon catheter 10, in order to control the flow of fluid to the expansion lumen 23, a three-way stopcock capable of operating the opening and closing of the flow path is connected to the base end opening 27 of the hub 26.

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

The moving mechanism unit 80 includes a moving table 81 that can move linearly in a direction parallel to the axis of the balloon 30, and a tube fixing portion 83 to which the dispensing tube 94 and the freezing tube 114 are fixed. The moving table 81 can be linearly moved by a drive source such as a built-in motor. When the moving table 81 moves, the dispensing tube 94 and the freezing tube 114 move linearly in a direction parallel to the axis of the balloon 30. Further, on the moving table 81, the coating liquid supply unit 90 is placed, and the coating liquid supply unit 90 is linearly moved 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, bolts. The position of the tube fixing portion 83 to which 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 portion where the coating liquid 45 is applied to the outer surface of the balloon 30. The coating liquid supply unit 90 includes a container 92 for accommodating the coating liquid 45, a liquid feeding pump 93 for feeding the coating liquid 45 at an arbitrary liquid feeding amount, and a dispensing tube 94 for applying the coating liquid 45 to the balloon 30. Is equipped with.

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 via the supply tube 96. Can be supplied in any amount of liquid to be sent. The liquid feed pump 93 is installed on the moving table 81 and can move linearly by moving the moving table 81. The liquid feed pump 93 is not limited to the syringe pump as long as the coating liquid 45 can be fed, and may be, for example, a tube pump.

The dispensing tube 94 communicates with the supply tube 96, and discharges the coating liquid 45 supplied from the liquid feed pump 93 via the supply tube 96 to the outer surface of the balloon 30. The dispensing tube 94 is a flexible circular tubular member. The upper end of the dispensing tube 94 is fixed to the tube fixing portion 83, extends downward in the vertical direction from the tube fixing portion 83, and an opening 95 is formed at the discharge end 97 which is the lower end. By moving the moving table 81, the dispensing tube 94 can be linearly moved in both directions along the axial direction of the balloon catheter 10 together with the liquid feeding pump 93 installed on 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 of being pressed against the balloon 30 and bent.

The dispensing tube 94 does not have to be circular as long as the coating liquid 45 can be supplied. Further, the dispensing tube 94 does not have to extend in the vertical direction as long as the coating liquid 45 can be discharged from the opening 95. Further, the dispensing tube 94 may supply the coating liquid 45 to the balloon 30 at a position away from the outer surface of the 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 to absorb the change in the contact position due to the rotation of the balloon 30 by bending. The constituent materials of the dispensing tube 94 include, for example, polyolefins such as polyethylene and polypropylene, cyclic polyolefins, polyesters, polyamides, polyurethanes, PTFE (polytetrafluoroethylene), ETFE (tetrafluoroethylene / ethylene copolymer), and PFA (tetra). Fluorine-based resins such as fluoroethylene / perfluoroalkyl vinyl ether copolymer) and FEP (fluorinated ethylene / propylene hexafluoride copolymer) can be applied, but if they are flexible and deformable. , Not particularly limited.

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

The freezing unit 110 is a portion that supplies liquid nitrogen to the outer surface of the balloon 30. The refrigerating section 110 includes a nitrogen container 112 for accommodating liquid nitrogen, a nitrogen pump 113 for delivering liquid nitrogen at an arbitrary liquid feeding amount, and a refrigerating tube 114 for discharging liquid nitrogen toward the balloon 30. ing.

The nitrogen pump 113 is, for example, a syringe pump, which is controlled by the control unit 100 to suck liquid nitrogen from the nitrogen container 112 through the nitrogen suction tube 111 and liquid to the refrigeration tube 114 via the nitrogen transport tube 116. Nitrogen can be supplied at any amount. The nitrogen pump 113 is installed on the moving table 81 and can move linearly by moving the moving table 81. The nitrogen pump 113 is not limited to the syringe pump as long as it can send liquid nitrogen.

The freezing tube 114 is a member that communicates with the nitrogen transport tube 116 and 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 upper end of the freezing tube 114 is fixed to the tube fixing portion 83, extends downward in the vertical direction from the tube fixing portion 83, and an opening 115 is formed at the lower end. The opening 115 is separated from the balloon 30. By moving the moving table 81, the refrigerating tube 114 can be linearly moved in both directions along the axial direction of the balloon catheter 10 together with the nitrogen pump 113 installed on the moving table 81. The freezing tube 114 can supply liquid nitrogen to the outer surface of the balloon 30 in a state of being separated from the balloon 30 by a predetermined length. The liquid nitrogen released from the freezing tube 114 removes heat from the coating liquid 45 in contact and vaporizes, and freezes the coating liquid 45. The freezing tube 114 is located on the opposite side of the dispensing tube 94 in the moving direction of the dispensing tube 94. As a result, 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 it can supply liquid nitrogen. Further, the freezing tube 114 does not have to 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 capable of transporting liquid nitrogen. As the constituent material of the freezing tube 114, for example, stainless steel, copper, aluminum, nickel, high-density polyethylene, borosilicate glass and the like can be applied.

The control unit 100 is composed of, for example, a computer, and collectively controls the rotation mechanism unit 60, the movement mechanism unit 80, the coating liquid supply unit 90, and the freezing unit 110. Therefore, the control unit 100 determines the rotation speed of the balloon 30, the moving speed of the dispensing tube 94 in the axial direction with respect to the balloon 30, the chemical discharge speed from the dispensing tube 94, and the discharge amount of liquid nitrogen from the refrigerating tube 114. Etc. can be controlled comprehensively.

As the vacuum dryer 120, a known one can be used. The vacuum dryer 120 can accommodate an object to be vacuum dried. Therefore, the vacuum dryer 120 can accommodate the balloon catheter 10 and 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 materials of the coat layer 40, and contains a water-insoluble agent, an additive, and a solvent. After the coating liquid 45 is supplied to the outer surface of the balloon 30, the solvent volatilizes to form a coat layer 40 having the water-insoluble drug crystals 42 and the additive 41 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 sparingly soluble in water, and specifically, the solubility in water is less than 5 mg / mL at pH 5 to 8. Its solubility may be less than 1 mg / mL and even less than 0.1 mg / mL. Water-insoluble agents include fat-soluble agents.

Examples of some preferred water-insoluble agents include immunosuppressive agents, such as cyclosporines containing cyclosporin, immunoactive agents such as rapamycin, anticancer agents such as paclitaxel, antiviral or antibacterial agents, antineoplastic agents, Analgesics and anti-inflammatory agents, antibiotics, antiepileptic agents, anxiety-relieving agents, antiparasitic agents, antagonists, neuroblocks, anticholinergic and cholinergic agents, antimuscarinic and muscarinic agents, antiadrenaline agonists, Includes anti-arrhythmic agents, anti-hypertensive agents, hormonal agents and nutritional agents.

Water-insoluble agents are paclitaxel and paclitaxel derivatives, taxanes, docetaxel and rapamycin and rapamycin derivatives, such as biolimus A9, pimechlorimus, everolimus, zotalolimus, tacrolimus, faszil and epotylon, with paclitaxel, lapamycin, docetaxel and docetaxel being particularly preferred. As used herein, rapamycin, paclitaxel, docetaxel, and everolimus include analogs thereof and / or derivatives thereof as long as they have similar efficacy. For example, paclitaxel and docetaxel are analogs. Rapamycin and everolimus are derivatives. Of these, paclitaxel is even more preferred.

Additive 41 contains a water-soluble low molecular weight 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 even more preferably 50 to 200. The water-soluble low molecular weight compound is preferably 5 to 10000 parts by mass, more preferably 5 to 200 parts by mass, and further 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, citric acid ester, polysorbate, water-soluble polymer, sugar, contrasting 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 soluble in water. The water-soluble low molecular weight compound is preferably non-swellable or non-swellable. The additive 41 is preferably amorphous on the balloon 30. The additive 41 containing a water-soluble low molecular weight compound has an effect of uniformly dispersing the water-insoluble agent on the outer surface of the balloon 30. Further, since the additive 41 is easily dissolved when the balloon 30 is expanded in the blood vessel, the drug crystal 42 of the water-insoluble drug on the outer surface of the balloon 30 is easily released, and the drug crystal 42 is attached to the blood vessel. It 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 it comes into contact with an aqueous solution. Further, the additive 41 is easily dissolved when the balloon 30 is expanded in the blood vessel, so that the particles of the water-insoluble drug crystal 42 on the outer surface of the balloon 30 are easily released, and the drug crystal 42 is easily released into the blood vessel. Has the effect of increasing the amount of adhesion. When the additive 41 is a matrix composed of a contrast agent such as Ultravist (registered trademark), crystal particles are embedded in the matrix and no crystals are formed from the base material of the balloon 30 toward the outside of the matrix. .. On the other hand, the drug crystal 42 of the present embodiment can extend from the surface of the base material of the balloon 30 to the outside of the additive 41.

The solvent contained in the coating liquid 45 is a freezing solvent that can be frozen, and it is preferable that the solvent has low volatility so that the coating liquid 45 does not completely volatilize until it is frozen after being applied to the balloon 30. When the solvent is frozen by following the dispensing tube 94 while applying the solvent through 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, etc. Ethanol, methanol, dichloromethane, hexane, ethyl acetate. Of these, tetrahydrofuran, ethanol, and acetone, some of which are mixed solvents are preferable.

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

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

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

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

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

Next, the position of the moving table 81 is adjusted to position the dispensing tube 94 with respect to the balloon 30. At this time, the dispensing tube 94 is positioned at the position closest to the tip of the balloon 30 that forms the coat layer 40. As an example, the extending direction (discharge direction) of the dispensing tube 94 is opposite to the rotation direction of the balloon 30. Therefore, the balloon 30 rotates in the direction opposite to the discharge direction of the coating liquid 45 from the dispensing tube 94 at the position where the dispensing tube 94 is brought into contact with the balloon 30. As a result, the coating liquid 45 can be physically stimulated to promote the formation of crystal nuclei of the drug crystal 42. The extending direction of the dispensing tube 94 does not have to be the direction opposite to the rotation direction of the balloon 30, and therefore can be the same direction or vertical.

Next, the balloon catheter 10 is rotated by the rotation mechanism unit 60. Subsequently, the liquid feed pump 93 adjusts the liquid feed amount to supply the coating liquid 45 to the dispensing tube 94, while moving the moving table 81 to move the dispensing tube 94 along the axial direction of the balloon 30. Gradually move toward the base end. 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 by moving the dispensing tube 94 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.

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 rate of the coating liquid 45 from the dispensing tube 94 is not particularly limited, but is, for example, 0.01 to 1.5 μL / sec, preferably 0.01 to 1.0 μL / sec, and more preferably 0.03 to 0. It is .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 the coating liquid 45 is applied is not particularly limited, but is, for example, 1 to 10 mm, preferably 2 to 7 mm.

Next, at the timing when the opening 115 of the freezing tube 114 following the dispensing tube 94 reaches the vicinity of the coating liquid 45 applied to the balloon 30, the liquid feed amount is adjusted by the nitrogen pump 113 to adjust the liquid. Nitrogen is supplied to the freezing tube 114. The liquid nitrogen released from the freezing tube 114 removes heat from the coating liquid 45 and vaporizes, 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 the solvent that volatilizes from the time it is applied to the balloon 30 to the time it freezes 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. Therefore, the coating liquid 45 at any position on the balloon 30 is frozen for a short time and substantially a certain time after being discharged from the dispensing tube 94. Therefore, the amount of the solvent contained in the frozen coating liquid 45 becomes uniform on the surface of the balloon 30.

Then, while rotating the balloon 30, the dispensing tube 94 and the freezing tube 114 are gradually moved in the axial direction of the balloon 30. As a result, a layer of the frozen coating liquid 45 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 over the entire range of the balloon 30 forming the coat layer 40, the rotation mechanism unit 60, the moving mechanism unit 80, the coating liquid supply unit 90, and the freezing unit 110 are stopped. The layer of the frozen coating solution 45 contains a plurality of granular solids 46 (see FIG. 6) of various (or uniform) sizes due to the freezing of the solvent.

After that, the balloon catheter 10 is removed from the support base 70. Next, the three-way stopcock connected to the proximal opening 27 of the balloon catheter 10 is opened, and the fluid for expansion is discharged from the balloon 30. After that, the base end opening 27 is maintained in an open state. This prevents a pressure difference between the inside and outside of the balloon 30 from occurring during vacuum drying, and prevents the balloon 30 from bursting. After that, the balloon catheter 10 is housed in the vacuum dryer 120, and the coating liquid 45 coated and frozen on the outer surface of the balloon 30 is dried under reduced pressure. As a result, as shown in FIG. 6, the solvent is sublimated (volatilized) from the solid 46 of the solvent of the frozen coating liquid 45, and the coat layer 40 is formed. The coat layer 40 has a sponge-like structure in which a large number of small voids 43 in which the particles of the solid solvent 46 were present remain, that is, a porous structure, by sublimation of the particles of the solid solvent 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. Further, the void 43 may be formed between the additive 41 and the drug crystal 42. Further, the void 43 may 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, which has low solvent volatility and is applied to the balloon 30, is sequentially frozen by a freezing tube 114 that follows 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. Therefore, the voids 43 and the drug crystals 42 of the coat layer 40 are uniformly formed.

Next, the balloon catheter 10 is taken out from the vacuum dryer 120. Next, the balloon 30 is contracted and folded. This completes the production of the balloon catheter 10.

As shown in FIG. 7A, the balloon 30 has a substantially circular cross section with the expanding fluid injected therein. From this state, the balloon 30 has the blade outer portion 34a forming the outer surface of the blade portion 32 and the inner portion of the blade portion 32, as shown in FIG. 7B, by forming the protruding blade portion 32. An inner side portion 34b of the blade forming a side surface and an intermediate portion 34c located between the outer side portion 34a of the blade and the inner side portion 34b of the blade 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 forming the outer surface of the blade portion 32, the blade inner portion 34b forming the inner side 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 to form an overlapping portion 35 in which the outer surfaces of the balloon 30 face each other and overlap. Then, a part of the intermediate portion 34c and the blade outer portion 34a are not covered by the blade inner portion 34b and are exposed to the outside. Further, when the balloon 30 is folded, a root side space portion 36 is formed between the root portion and the intermediate portion 34c of the blade portion 32. In the region of the root side space portion 36, a minute gap is formed between the blade portion 32 and the intermediate portion 34c. On the other hand, the region on the tip side of the blade portion 32 with respect to the root side space portion 36 is in close contact with the intermediate portion 34c. The ratio of the circumferential length of the root side space 36 to the circumferential length of the blade 32 is in the range of 1 to 95%. The blade outer side portion 34a of the balloon 30 receives a pressing force such as rubbing in the circumferential direction from the blade for folding the balloon 30, and is further heated. As a result, the porous coat layer 40 provided on the outer side portion 34a of the blade is easily deformed on the surface of the balloon 30 to reduce the void 43. It is not necessary for all of the drug crystals 42 to sleep.

Further, since the outer surface overlapping in the overlapping portion 35 of the balloon 30 is not exposed to the outside, a pressing force acts indirectly from the blade when folding. Therefore, it is easy to adjust the force acting on the porous coat layer 40 provided on the overlapping outer surfaces of the overlapping portion 35 of the balloon 30 so as not to be too strong. Therefore, a desirable force can be applied to the porous coat layer 40 provided on the overlapping outer surfaces of the overlapping portion 35 of the balloon 30. Further, in the region of the blade inner portion 34b and the intermediate portion 34c facing each other, the region facing the root side space portion 36, that is, the region where the blade inner portion 34b and the intermediate portion 34c are not in close contact with each other, the porous coat layer 40 Is hard to receive pressing pressure. Therefore, in this region, the porous coat layer 40 is likely to be maintained without being deformed. Further, among the regions of the blade inner portion 34b and the intermediate portion 34c facing 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 is coated with a porous material. The layer 40 is susceptible to pressing force. Therefore, in this region, the porous coat layer 40 is easily deformed to reduce the voids 43.

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

First, the surgeon punctures a blood vessel through the skin by a known method such as the Seldinger method, and indwells 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 preceded, and the balloon 30 is brought to the constricted portion. A guiding catheter may be used to bring the balloon catheter 10 to the stenosis portion 300.

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

When the balloon 30 is expanded and the coat layer 40 is pressed against the living tissue, the additive 41, which is a water-soluble low molecular weight compound contained in the coat layer 40, is gradually or rapidly dissolved, and the drug crystals 42 of the drug are transferred to the living body. Will be delivered. Since the coat layer 40 has a large number of voids 43, it has a large surface area and is easily broken to separate from the balloon 30. Therefore, the transferability of the drug crystal 42 to the living tissue is improved. Further, since the solvent of the coating liquid 45 during production has low volatility and the coating liquid 45 applied to the balloon 30 is sequentially frozen by the freezing tube 114 following the dispensing tube 94, the coating layer 40 is used. The voids 43 and the drug crystals 42 are uniformly formed. Therefore, the drug can act satisfactorily on the living body without variation.

After that, the expansion fluid is sucked and discharged from the base end opening 27 of the hub 26, and the balloon 30 is contracted to be in a folded state. After that, 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 the method for manufacturing the balloon catheter 10 in which the coat layer 40 containing the water-insoluble agent is formed on the outer surface of the balloon 30, and the balloon 30 is used. While rotating around the axis of the balloon 30, the balloon 30 is subjected to the step of applying the coating liquid 45 containing the drug and the solvent to the outer surface of the balloon 30 and the state in which the solvent of the applied coating liquid 45 remains. It has a step of freezing the coating liquid 45 while rotating it, and a step of sublimating the solvent of the frozen coating liquid 45 under reduced pressure.

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, so that the solvent is sublimated and dried. The coat layer 40 of the above has a porous structure. As a result, the surface area of the coat layer 40 is increased, and the coat layer 40 is easily broken and easily separated from the balloon 30. Therefore, the transferability of the drug to the living tissue is increased. Therefore, this production method can produce a balloon catheter 10 selectively provided with a drug crystal 42 having high transferability to a living tissue. Further, in order to apply the coating liquid 45 to the balloon 30 and freeze it while maintaining the rotation of the balloon 30 that plays a role of homogenizing the coating liquid 45, the coating liquid 45 is uniformly applied to the outer surface of the balloon 30. to freeze. Therefore, the morphological form and the porous structure of the drug of the coated layer 40 formed become uniform on the surface of the balloon 30 in a desirable state. Therefore, this production method can form a uniform layer of the drug with high transferability to living tissues.

The manufactured balloon catheter 10 has a coating layer 40 having a porous structure containing drug crystals 42 on the outer surface of the balloon 30. The coating layer 40 having a porous structure 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, which has a large surface area and is easily destroyed and easily detached from the balloon 30, can be rapidly transferred to the living tissue.

Further, in the present production 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, the granular solids 46 are sublimated to form a plurality of voids 43. The coat layer 40 having the above may be formed. As a result, the present production method can form a coat layer 40 having a plurality of voids 43 having various sizes and having high transferability to living tissues.

Further, in the present 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 frozen sequentially from the portion to which the coating liquid 45 is applied. Let me. As a result, it is possible to prevent the solvent from volatilizing before freezing, so that the amount of the solvent contained in the frozen coating liquid 45 becomes uniform on the surface of the balloon 30. Therefore, the morphological form and the porous structure of the drug of the coated layer 40 to be formed become uniform on the surface of the balloon 30, and a uniform layer of the drug having high transferability to the living tissue can be formed.

Further, in the present manufacturing method, in the step of applying the coating liquid 45, the 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. As a result, the amount of the coating liquid 45 applied to the balloon 30 by the dispensing tube 94 can be adjusted with high accuracy, and the coating liquid at substantially all positions on the balloon 30 can be discharged from the dispensing tube 94 in a short time. Freezes after approximately a certain amount of time. Therefore, the amount of the solvent contained in the frozen coating liquid 45 becomes uniform on the surface of the balloon 30, and a uniform layer of the drug having high transferability to the living tissue can be formed.

Further, in this production method, in the step of freezing the coating liquid 45, it is frozen in liquid nitrogen. As a result, the solvent can be instantly frozen in a desired state, and a 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, and cyclohexane. It may contain at least one selected from. As a result, the volatility of the solvent becomes low, and the solvent is less likely to volatilize from the coating liquid 45 applied to the balloon 30. Therefore, the amount of the solvent contained in the frozen coating liquid 45 becomes uniform on the surface of the balloon 30, and a uniform layer of the drug having high transferability to the living tissue can be formed.

The water-insoluble agent may also contain at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus. As a result, the drug crystal 42 can satisfactorily suppress restenosis of the narrowed portion in the blood vessel.

Further, the manufacturing device 50 in the present embodiment is a manufacturing device 50 for a 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 is a rotation mechanism for applying a rotational force to the balloon 30. The part 60, the coating liquid supply part 90 for applying the coating liquid 45 containing a drug and a solvent to the outer surface of the rotating balloon 30, and the coating liquid 45 applied to the balloon 30 in a state where the balloon 30 is rotating. It has 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 in a state where the solvent remains in the freezing unit 110. As a result, the frozen coating liquid 45 can be dried under reduced pressure by the vacuum dryer 120. Therefore, the coat layer 40 after freeze-drying has a porous structure, the surface area is increased, and the coat layer 40 is easily broken and easily separated from the balloon 30. Therefore, the transferability of the drug to the living tissue is increased. Therefore, this manufacturing apparatus can manufacture a balloon catheter 10 selectively provided with crystals having high transferability to living tissues. 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. Therefore, after drying under reduced pressure, the morphological form and porous structure of the drug in the coat layer 40 become uniform on the surface of the balloon 30 in a desirable state, and a uniform layer of the drug having high transferability to the living tissue can be formed.

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

Further, the coating liquid supply unit 90 has a tubular dispensing tube 94 that can move relative to the balloon 30 in the axial direction of the balloon 30 and supplies the coating liquid 45, and the freezing unit 110. Is movable following the dispensing tube 94. As a result, the coating liquid 45 applied to the balloon 30 can be sequentially frozen by the freezing unit 110. Therefore, since it is possible to suppress the evaporation of the solvent before freezing, the amount 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 form and porous structure of the drug in the coat layer 40 become uniform on the surface of the balloon 30, and a uniform layer of the drug having high transferability to the living tissue can be formed.

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-mentioned balloon catheter 10 is a rapid exchange type (Rapid exchange type), but may be an over-the-wire type (Over-the-wire type).

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

Further, the method of 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.

Further, as shown in FIG. 9, the freezing unit 130 for supplying liquid nitrogen may have a hollow ring 131 surrounding the balloon 30 instead of being tubular. The ring 131 has a plurality of openings 132 in which liquid nitrogen can flow through the inside and are 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 a 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 for supplying the coating liquid 45 may be a sprayer capable of atomizing a wide range on the outer surface of the rotating balloon 30. As a result, the coating liquid 45 can be quickly applied to the outer surface of the balloon 30. The freezing unit 150 that supplies liquid nitrogen may have a hollow tubular body 151 that surrounds the balloon 30 instead of being tubular. Liquid nitrogen can flow through the cylinder 151, and the cylinder 151 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 tubular body 151 is preferably, but is not limited to, the axial length of the range in which the coat layer 40 of the balloon 30 is formed. When the coating liquid 45 is applied to the balloon 30 by the coating liquid supply unit 140 which is a sprayer, the tubular body 151 is located on the tip side or the base 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. After that, while rotating the balloon 30, liquid nitrogen is released from the opening 152 of the tubular body 151. Since the tubular body 151 can release liquid nitrogen from a plurality of openings 152 arranged in the circumferential direction and the axial direction, all the coating liquids 45 applied to the balloon 30 are efficiently frozen without moving the tubular body 151. be able to.

As described above, in the method for manufacturing the balloon catheter 10, in the step of freezing the coating liquid 45, the coating liquid 45 is applied to the balloon 30 after the coating liquid 45 is completely applied to the entire range of the balloon 30 forming the coat layer 40. Freezing of all the coated liquids 4 can be started. As a result, the coating liquid 45 uniformly applied by rotating the balloon 30 freezes in a uniform state. Therefore, the solvent of the uniform coating liquid 45 can be sublimated at the same time under reduced pressure. Therefore, the morphological form and porous structure of the drug of the coat layer 40 become uniform on the surface of the balloon 30, and a uniform drug layer having high transferability to the living tissue can be formed.

10 Balloon catheter 30 Balloon 40 Coat layer 41 Additive 42 Drug crystal 43 Void 45 Coating liquid 46 Granular solid 50 Catheter manufacturing equipment 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 Refrigeration unit 114 Refrigeration tube 120 Vacuum dryer

Claims (9)

A method for manufacturing a balloon catheter in which a coat layer containing a water-insoluble drug is formed on the outer surface of the balloon.
A step of applying a coating liquid containing a drug and a solvent to the outer surface of the balloon while rotating the balloon around the axis of the balloon.
A step of freezing the coating liquid while rotating the balloon while the solvent of the applied coating liquid remains.
The solvent of the frozen the coating liquid have a, a step of sublimating by vacuum,
In the freezing step, a plurality of granular solids of various sizes are formed with the solvent.
A method for producing a balloon catheter in which the granular solid is sublimated to form a coat layer having a plurality of voids in the sublimation step . 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 sequentially applied from the portion to which the coating liquid is applied. The method for manufacturing a balloon catheter according to claim 1, 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, and the outer surface of the balloon is coated with the coating. Apply the liquid and
The method for manufacturing a balloon catheter according to claim 2 , wherein in the step of freezing the coating liquid, the coating liquid applied to the balloon is frozen by a freezing portion that moves following the dispensing tube. In the step of freezing the coating liquid, after application of the coating solution to the entire range of forming the coating layer of the balloon is completed, according to claim 1 for starting the freezing of all of the coating liquid applied to said balloon The method for manufacturing a balloon catheter according to. The method for manufacturing a catheter according to any one of claims 1 to 4 , wherein the coating liquid is frozen in liquid nitrogen in the step of freezing the coating liquid. The solvent comprises 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 and cyclohexane. The method for producing a balloon catheter according to any one of claims 1 to 5 , which contains at least one selected. The method for producing a balloon catheter according to any one of claims 1 to 6 , wherein the water-insoluble agent contains at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus. A device for manufacturing a balloon catheter in which a coat layer containing a water-insoluble drug is formed on the outer surface of the balloon.
A rotation mechanism that applies a rotational force to the balloon,
A coating liquid supply unit that applies a coating liquid containing a drug and a solvent to the outer surface of the rotating balloon, and
A freezing section that freezes the coating liquid applied to the balloon while the balloon is rotating.
The coating liquid that has been frozen is applied to the balloon have a, a vacuum dryer for drying under reduced pressure,
In the freezing part, a plurality of granular solids of various sizes are formed by the solvent.
The vacuum dryer is a device for manufacturing a balloon catheter that sublimates the granular solid to form a coat layer having a plurality of voids . 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 supplies the coating liquid.
The balloon catheter manufacturing apparatus according to claim 8 , wherein the freezing unit can move following the dispensing tube.

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