JP2018153289A - Method and apparatus for manufacturing baloon catheter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method and apparatus for manufacturing a balloon catheter in which drug crystals can uniformly be formed on the outer surface of a balloon and the morphology of the drug crystals can easily be controlled.SOLUTION: Provided is a method for manufacturing a balloon catheter 10 in which a coating layer 40 containing a water insoluble medicament crystal 42 is formed on the outer surface of a balloon 30, including steps of: applying a coating liquid 45 containing a medicament and a solvent to the outer surface of the balloon 30; mixing a fine particle suspension 46 containing fine particles 49 and a solvent in the coating liquid 45; causing the fine particles 49 to move in a Brownian motion on the outer surface of the balloon 30 and crystallizing the medicament contained in the coating liquid 45 by the Brownian motion; and volatilizing the solvent contained in the coating liquid 45.SELECTED DRAWING: Figure 4

Description

  The present invention relates to a method and apparatus for manufacturing a balloon catheter in which a drug is provided on the outer surface of the 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. However, various conditions such as parameters in the coating, and the environment such as the technique fluctuation and the drying method greatly depend on the morphological type of the drug formed on the surface of the balloon. For this reason, it is difficult to control the crystals to be formed, and this difficulty causes variations in quality.

  For example, Patent Document 1 discloses a method of coating a balloon with a drug by partially immersing the balloon in a coating solution containing a water-insoluble drug and a volatile solvent and vibrating the balloon while rotating the balloon. As a result, the coating liquid can be uniformly attached to the balloon to form crystals or amorphous uniformly. Patent Document 1 also describes that the volatilization of the solvent is promoted by vibration.

Japanese Patent Laying-Open No. 2015-008844

  In the method described in Patent Document 1, since the rotating balloon repeats soaking and lifting with respect to the coating liquid, the drug gradually adheres to the balloon so as to be laminated. For this reason, the uniformity of the medicine provided on the balloon may be reduced.

  The present invention has been made to solve the above-described problems, and a balloon catheter manufacturing method and apparatus capable of uniformly forming a drug crystal on the outer surface of the balloon and easily controlling the shape of the drug crystal. The purpose is to provide.

  A method of manufacturing a balloon catheter that achieves the above object is a method of manufacturing a balloon catheter in which a coating layer containing a water-insoluble drug crystal is formed on the outer surface of the balloon, and the drug and the solvent are included on the outer surface of the balloon. A step of applying a coating liquid, a step of mixing a fine particle suspension containing fine particles and a solvent in the coating liquid, a Brownian motion of the fine particles on the outer surface of the balloon, and a crystallization of the drug by the Brownian motion And a step of volatilizing the solvent.

  The method for manufacturing a balloon catheter configured as described above can adjust the crystallization of a drug by Brownian motion of fine particles. For this reason, regardless of various conditions and fluctuations in the procedure, the drug crystals can be uniformly formed on the outer surface of the balloon, and the morphology of the drug crystals can be easily controlled.

  The manufacturing method may form crystal nuclei of the drug in the step of crystallizing the drug. Thus, it is possible to favorably promote crystal growth from the formed crystal nucleus.

  In the manufacturing method, in the step of applying the coating liquid, the balloon is rotated from the tubular dispensing tube for supplying the coating liquid to the outer surface of the balloon while rotating the balloon about the axis of the balloon. In the step of applying and mixing the coating liquid, the fine particle suspension may be mixed with the coating liquid after being discharged from the inside of the dispensing tube or the dispensing tube. As a result, the fine particle suspension is mixed with the coating liquid immediately before, during, or just after the coating liquid is applied from the dispensing tube to the balloon. For this reason, the crystallization of the drug can be promoted at an appropriate timing, and the control of the crystallization of the drug becomes easy. In addition, since the coating amount can be controlled with high accuracy by applying the coating liquid from the dispensing tube to the rotating balloon, the drug crystals can be uniformly formed on the outer surface of the balloon, and the crystallization of the drug is further controlled. It becomes easy.

  The solvent of the fine particle suspension may include an organic solvent, and the fine particles may be water-soluble. Thereby, it can suppress that a microparticle melt | dissolves in a solvent and can produce a Brownian motion effectively. Further, since the fine particles are water-soluble, they can be dissolved and absorbed in a living body.

  The fine particles may have a diameter of 0.001 μm or more and 1 μm or less. Thereby, the fine particles can be subjected to Brownian motion by the thermal motion of the solvent, and the drug can be stimulated to promote crystallization.

  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.

  A 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 crystal is formed on an outer surface of a balloon, and the rotation that causes a rotational force to act on the balloon. A mechanism part; a coating liquid supply part for applying a coating liquid containing a drug and a solvent on the outer surface of the rotating balloon; and a fine particle suspension containing fine particles and a solvent on the outer surface of the rotating balloon or the coating liquid supply part. A fine particle supply unit for supplying a liquid.

  The balloon catheter manufacturing apparatus configured as described above can mix the fine particle suspension supplied from the fine particle supply unit with the coating liquid on the outer surface of the balloon or the inside of the coating liquid supply unit. Crystallization can be controlled. For this reason, drug crystals can be uniformly formed on the outer surface of the balloon, and the morphological form of the drug can be easily controlled regardless of various conditions and fluctuations in the procedure.

  The coating liquid supply unit includes a tubular dispensing tube that supplies the coating liquid, and the fine particle supply unit includes a fine particle tube that supplies the fine particle suspension to the inside or the opening of the dispensing tube. You may have. As a result, the fine particle suspension is mixed with the coating liquid immediately before, during, or just after the coating liquid is applied from the dispensing tube to the balloon. For this reason, the crystallization of the drug can be promoted at an appropriate timing, and the control of the crystallization of the drug becomes easy. In addition, the coating liquid can be applied to the rotating balloon from the dispensing tube, so that the application amount can be controlled with high accuracy, so that drug crystals can be uniformly formed on the outer surface of the balloon and control of drug crystallization is easier. It becomes.

It is a front view which shows a balloon catheter. It is sectional drawing of the front-end | tip part of a balloon catheter. It is a schematic sectional drawing of the outer surface of a balloon. It is a front 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 perspective view which shows the lower end part of the dispensing tube and the tube for particles. 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 a front view 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 a front view which shows the further another 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 having the same outer diameter when expanded is formed in the central portion of the balloon 30 in the axial direction, and a taper whose outer diameter gradually changes on both sides of the straight portion 31 in the axial direction. A portion 33 is formed. And the coat layer 40 containing a chemical | medical agent is formed in the whole outer surface of the straight part 31. FIG. The range in which the coating layer 40 is formed in the balloon 30 is not limited to the straight portion 31, and may include at least a part of the tapered portion 33 in addition to the straight portion 31, or one of the straight portions 31. It may be only part.

  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 extends with an additive 41 (excipient) containing a water-soluble low-molecular compound disposed in layers on the outer surface of the balloon 30 and an independent long axis. And water-insoluble drug crystals 42. The coat layer 40 has a porous structure and includes a large number of voids 43. 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 drug crystals 42 may have a form having independent long axes. Further, the drug crystal 42 may be other morphological types. The plurality of drug crystals 42 may be present in a state where they are combined, or may be present in contact with each other with a plurality of adjacent drug crystals 42 forming different angles. The plurality of drug crystals 42 may be positioned on the balloon surface with a space (a space not including a crystal). There may be both a plurality of drug crystals 42 in a combined state and a plurality of drug crystals 42 independent from each other on the surface of the balloon 30. The plurality of drug crystals 42 may be arranged in a brush shape around the circumference having different major axis directions. Each drug crystal 42 exists independently, has a certain length, and one end (base end) of the length portion is fixed to the additive 41 or the balloon 30. The drug crystal 42 does not form a complex structure with the adjacent drug crystal 42 and is not connected. The long axis of the drug crystal is substantially linear. The drug crystal 42 forms a predetermined angle with respect to the surface with which the base portion where the major axes intersect is in contact.

  The drug crystals 42 preferably stand independently without contacting each other. The base of the drug crystal 42 may be in contact with another base on the base material of the balloon 30. Alternatively, the base part of the drug crystal 42 may be independent on the base material of the balloon 30 without coming into contact with other base parts.

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

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

  The above-mentioned crystal form type having a crystal having a long axis is 50% by volume or more, more preferably 70% by volume or more with respect to the entire drug crystal on the outer surface of the balloon 30. The drug crystal 42, which is a crystal particle having a long axis, is formed so as to stand on the outer surface of the balloon 30 or the additive 41. The additive 41 is present in the region where the drug crystal 42 is present, and may not be present in the region where the drug crystal 42 is absent.

  The additive 41 is distributed and present in the space between the plurality of drug crystals 42 in the forest. The proportion of the substance constituting the 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 in FIG. 3 is in the state of crystal grains and / or particulate amorphous. Alternatively, the additive 41 may be in a film-like amorphous state. The additive 41 is formed as a layer containing a water-insoluble drug. Alternatively, the additive 41 may be formed as an independent layer that does not contain a water-insoluble drug. The thickness of the additive 41 is 0.1 to 5 μm, preferably 0.3 to 3 μm, more preferably 0.5 to 2 μm.

  The layer containing the drug crystal 42 having a long crystal form has low toxicity and high stenosis-inhibiting effect when delivered into the body. A water-insoluble drug containing a hollow long crystalline form is effective because it has good permeability to the tissue and good solubility because one unit of the crystal becomes small when the drug moves into the tissue. It can act to suppress stenosis. In addition, it is considered that toxicity is low because the drug hardly remains in the tissue as a large mass.

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

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

  Next, the balloon catheter manufacturing apparatus 50 will be described. The balloon catheter manufacturing apparatus 50 can form the coat layer 40 on the balloon 30. As shown in FIGS. 4 to 6, 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 application unit 9 provided with a dispensing tube 94 that applies the coating liquid 45 to the outer surface of the balloon 30, and a moving mechanism unit 80 that moves the dispensing tube 94 relative to the balloon 30. Have The production apparatus 50 further includes a fine particle supply unit 110 including a fine particle tube 114 that supplies the fine particle suspension 46 containing the fine particles 49 to the dispensing tube 94, and a control unit 100 that controls each part of the production apparatus 50. Have.

  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 particle 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 fine particle tube 114 linearly move in a direction parallel to the axis of the balloon 30. The moving table 81 has a coating liquid application unit 90 mounted thereon, and linearly moves the coating liquid application unit 90 in both directions along the axis.

  The coating liquid application unit 90 is a part that applies the coating liquid 45 to the outer surface of the balloon 30. The coating liquid application unit 90 includes a container 92 that stores the coating liquid 45, a liquid feeding pump 93 that feeds the coating liquid 45 at an arbitrary liquid feeding amount, 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 tubular member having flexibility. 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 discharge end 97 is connected to the fine particle tube 114. The discharge end 97 and the fine particle tube 114 are connected so that the outer peripheral surface has a single cylindrical shape. Accordingly, the opening 95 of the dispensing tube 94 has a half moon shape. In addition, the opening 115 of the fine particle tube 114 has a half-moon shape that is paired with the opening 95 of the dispensing tube 94. 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 shape of the dispensing tube 94 is not particularly limited as long as the coating liquid 45 can be supplied. Therefore, the dispensing tube 94 may not have a half-moon shape as long as two liquids can be supplied together with the fine particle tube 114. 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 fine particle supply unit 110 is a part that supplies the fine particle suspension 46 containing the fine particles 49 and the solvent to the outer surface of the balloon 30. The fine particle supply unit 110 includes a fine particle container 112 that stores the fine particle suspension 46, a fine particle pump 113 that supplies the fine particle suspension 46 in an arbitrary amount, and the fine particle suspension 46 to the balloon 30. And a fine particle tube 114 that discharges toward the surface.

  The fine particle pump 113 is a syringe pump, for example, and is controlled by the control unit 100 to suck the fine particle suspension 46 from the fine particle container 112 through the fine particle suction tube 111 and through the fine particle transport tube 116. The fine particle suspension 46 can be supplied to the tube 114 at an arbitrary amount. The fine particle pump 113 is installed on the moving table 81 and can move linearly by the movement of the moving table 81. The fine particle pump 113 is not limited to a syringe pump as long as the fine particle suspension 46 can be fed, and may be a tube pump, for example.

  The fine particle tube 114 communicates with the fine particle conveyance tube 116 and is a member that discharges the fine particle suspension 46 supplied from the fine particle pump 113 via the fine particle conveyance tube 116 to the outer surface of the balloon 30. The fine particle tube 114 is a tubular member having flexibility. The fine particle tube 114 has an upper end fixed to the tube fixing portion 83 and an opening 115 formed at the lower end. The lower end of the fine particle tube 114 is connected to the discharge end 97 of the dispensing tube 94 as described above. The opening 115 of the fine particle tube 114 has a half-moon shape that is paired with the half-moon-shaped opening 95 of the dispensing tube 94. The discharge end 97 and the fine particle tube 114 are connected so that the outer peripheral surface has a single cylindrical shape. Therefore, the connected discharge end 97 and the fine particle tube 114 can smoothly contact the balloon 30. The fine particle tube 114 can move linearly in both directions along the axial direction of the balloon catheter 10 together with the fine particle pump 113 installed on the movable table 81 by moving the movable table 81. The fine particle suspension 114 can be supplied to the outer surface of the balloon 30 in a state in which the fine particle tube 114 is pressed against the balloon 30 and is bent. The fine particle suspension 46 discharged from the fine particle tube 114 is mixed with the coating liquid 4 discharged from the dispensing tube 94 on the outer surface of the balloon 30. The dispensing tube 94 and the fine particle tube 114 may be separated from the outer surface of the balloon 30 when supplying the coating liquid 45 and the fine particle suspension 46 to the balloon 30. The shape of the fine particle tube 114 is not limited as long as the fine particle suspension 46 can be supplied. Therefore, the dispensing tube 94 may not have a half-moon shape as long as two liquids can be supplied together with the dispensing tube 94.

  The dispensing tube 94 and the fine particle tube 114 are 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 materials of the dispensing tube 94 and the fine particle tube 114 are, for example, polyolefins such as polyethylene and polypropylene, cyclic polyolefins, polyesters, polyamides, polyurethanes, PTFE (polytetrafluoroethylene), ETFE (tetrafluoroethylene / ethylene copolymer). ), Fluororesins such as PFA (tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer), FEP (tetrafluoroethylene / hexafluoropropylene copolymer), etc. can be applied. There is no particular limitation as long as it can be deformed.

  The outer diameters of the dispensing tube 94 and the fine particle tube 114 are not particularly limited, but are, 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 diameters of the dispensing tube 94 and the fine particle tube 114 are not particularly limited, but are, 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 lengths of the dispensing tube 94 and the fine particle tube 114 are not particularly limited, but are preferably within 5 times the balloon diameter, for example, 1.0 mm to 50 mm, preferably 3 mm to 40 mm, more preferably 5 mm to 35 mm.

  The control unit 100 is configured by a computer, for example, and comprehensively controls the rotation mechanism unit 60, the movement mechanism unit 80, the coating liquid application unit 90, and the fine particle supply unit 110. Therefore, the control unit 100 controls the rotational speed of the balloon 30, the moving speed of the dispensing tube 94 and the fine particle tube 114 in the axial direction with respect to the balloon 30, the drug discharge speed from the dispensing tube 94, and the fine particle tube 114. The discharge speed of the fine particle suspension 46 can be comprehensively controlled.

  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, so that the coating layer having the water-insoluble drug crystals 42 extending on the outer surface of the balloon 30 with independent long axes. 40 is formed.

  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 and rapamycin, particularly docetaxel, 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 particles of the water-insoluble drug drug crystal 42 on the outer surface of the balloon 30 can be easily released, and the drug crystal 42 into the blood vessel. This has the effect of increasing the amount of particles attached. The additive 41 is preferably not a hydrogel. Since the additive 41 is a low molecular weight compound, it dissolves rapidly without swelling when in contact with an aqueous solution. Furthermore, since the additive 41 is easily dissolved when the balloon 30 is expanded in the blood vessel, the particles of the water-insoluble drug crystal 42 on the outer surface of the balloon 30 are easily released. It has the effect of increasing the amount of adhesion. When the additive 41 is a matrix made of a contrast agent such as Ultravist (registered trademark), crystal particles are embedded in the matrix, and crystals are not generated from the 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 and the solvent contained in the fine particle suspension 46 include at least one of an organic solvent and water. The solvent contained in the coating liquid 45 and the solvent contained in the fine particle suspension 46 may be the same or different.

  The organic solvent is not particularly limited, and tetrahydrofuran, acetone, glycerin, acetic acid, t-butyl alcohol, benzene, chlorohexane, hexane, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane, ethanol Methanol, dichloromethane, hexane, ethyl acetate, i-butyl alcohol, s-butyl alcohol, propanol, butanol, toluene, ethylene glycol and the like. Among these, some of these mixed solvents are preferable among tetrahydrofuran, ethanol, and acetone.

  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.

  The fine particles 49 contained in the fine particle suspension 46 can perform Brownian motion. The Brownian motion of the fine particles 49 is an irregular motion caused by an irregular collision of thermally moving solvent molecules. The size of the fine particles 49 is not particularly limited as long as Brownian motion is possible, but is, for example, 0.001 to 1 μm, preferably 0.005 to 0.5 μm, and more preferably 0.01 to 0.1 μm. If the fine particles 49 are too large, the Brownian motion becomes small and it becomes difficult to contribute to the crystallization of the drug. If the fine particles 49 are too small, the stimulation to the drug becomes small and it becomes difficult to contribute to the crystallization of the drug. The crystallization of the drug means the formation of crystal nuclei and the growth of crystals. The fine particles 49 may be colloidal particles. The colloidal particles are dispersed particles having a diameter of about 1 nm to 1 μm.

  The fine particles 49 contained in the fine particle suspension 46 may be insoluble or hardly soluble in water, but are preferably water-soluble. Being water-soluble, it dissolves in vivo and is safely absorbed. Since the fine particles 49 are water-soluble, the fine particles 49 can maintain the shape without being dissolved in a solvent including an organic solvent, and thus can perform a Brownian motion satisfactorily. As a constituent material of the water-soluble fine particles 49, for example, saccharides such as lactose, glucose, sorbitol, maltose, and cellulose can be used. As the constituent material of the fine particles 49 that are not water-soluble, for example, biodegradable polymers such as polylactic acid, metals such as Au and Ag, and the like can be used.

  As the solvent contained in the fine particle suspension 46, a solvent applicable to the coating liquid 45 described above can be used. The solvent of the fine particle suspension 46 may be the same as or different from the solvent of the coating liquid 45. When the fine particles 49 are water-soluble, the solvent of the fine particle suspension 46 preferably includes an organic solvent.

  Next, a method for manufacturing a balloon catheter 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 and the fine particle tube 114 are positioned with respect to the balloon 30. At this time, the dispensing tube 94 and the fine particle tube 114 are positioned at the most distal 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 and the fine particle tube 114 is opposite to the rotation direction of the balloon 30. Accordingly, the balloon 30 rotates in a direction opposite to the discharge direction of the coating liquid 45 and the fine particle suspension 46 from the dispensing tube 94 and the fine particle tube 114 at a position where the dispensing tube 94 and the fine particle tube 114 are in contact with each other. To do. Thereby, physical stimulation can be given to the coating liquid 45 and formation of the crystal nucleus of a drug crystal can be promoted. And since the extending direction (discharge direction) toward the opening 95 of the dispensing tube 94 is the direction opposite to the rotation direction of the balloon 30, the crystal of the water-insoluble drug formed on the outer surface of the balloon 30 is A crystal is easily formed including a morphological type including a plurality of crystals 42 each having an independent major axis. The extending direction of the dispensing tube 94 does not have to be the reverse direction of the rotation direction of the balloon 30, and can therefore be the same direction or can be perpendicular.

  Next, the balloon catheter 10 is rotated by the rotation mechanism unit 60. Subsequently, the coating liquid 45 is supplied to the dispensing tube 94 by adjusting the liquid feeding amount by the liquid feeding pump 93. The fine particle suspension 46 is supplied to the fine particle tube 114 by adjusting the amount of liquid fed by the fine particle pump 113. Then, the moving table 81 is moved to gradually move the dispensing tube 94 and the fine particle tube 114 in the proximal direction along the axial direction of the balloon 30. The coating liquid 45 discharged from the opening 95 of the dispensing tube 94 is mixed with the fine particle suspension 46 discharged from the opening 115 of the fine particle tube 114 on the outer surface of the balloon 30. The mixed liquid 47 is applied while drawing a spiral on the outer peripheral surface of the balloon 30 as the dispensing tube 94 and the fine particle tube 114 move relative to the balloon 30. As the balloon 30 rotates, the liquid mixture 47 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 and the fine particle tube 114 is not particularly limited, but is, for example, 0.01 to 2 mm / sec, preferably 0.03 to 1.5 mm / sec, more preferably 0.05 to 1.0 mm. / Sec. The total discharge speed of the coating liquid 45 and the fine particle suspension 46 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. ~ 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.

  A mixed liquid 47 composed of the coating liquid 45 and the fine particle suspension 46 mixed on the outer surface of the balloon 30 includes fine particles 49. For this reason, the fine particles 49 perform a Brownian motion, and the Brownian motion promotes the formation and crystallization of a drug crystal nucleus. For this reason, the drug crystal 42 can be uniformly formed on the outer surface of the balloon 30. In addition, control of the morphological type of the drug crystal 42 on the outer surface of the balloon 30 is facilitated.

  The organic solvent contained in the coating liquid 45 applied to the outer surface of the balloon 30 volatilizes before water. Therefore, the organic solvent is volatilized in a state where the water-insoluble drug, the water-soluble low-molecular compound and water are left on the outer surface of the balloon 30. As described above, when the organic solvent is volatilized with water remaining, a water-insoluble drug is precipitated inside the water-soluble low-molecular compound containing water, and the crystal gradually grows from the crystal nucleus. A morphological form of drug crystal 42 including a plurality of crystals each having an independent major axis is formed on the outer surface of the substrate. The base of the drug crystal 42 is located on the outer surface of the balloon 30, the surface of the additive 41, or the inside of the additive 41 (see FIG. 3). After the organic solvent is volatilized and the drug crystals 42 are deposited, water is evaporated more slowly than the organic solvent, and an additive 41 containing a water-soluble low-molecular compound is formed. The time for water to evaporate is appropriately set according to the type of drug, the type of water-soluble low molecular weight compound, the type of organic solvent, the ratio of materials, the amount of coating liquid 45 applied, etc., for example, 1 to 600 seconds Degree. The fine particles 49 are embedded in the coat layer 40.

  Then, the dispensing tube 94 is gradually moved in the axial direction of the balloon 30 while rotating the balloon 30, whereby the coat layer 40 is gradually formed on the outer surface of the balloon 30 in the axial direction. After the coating layer 40 having the drug crystals 42 is formed over the entire area to be coated with the balloon 30, the rotation mechanism 60, the movement mechanism 80, the coating liquid application unit 90, and the fine particle supply unit 110 are stopped.

  Thereafter, the balloon catheter 10 is removed from the support base 70, and the coating of the balloon 30 is completed. Thereafter, the expansion fluid is discharged from the balloon 30, and the balloon 30 is contracted and folded. Thereby, manufacture of the balloon catheter 10 is completed.

  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 long drug crystal 42 provided on the blade outer portion 34 a falls down on the surface of the balloon 30 and is easy to sleep. It is not necessary for all of the drug crystal 42 to sleep.

  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 drug crystal 42 provided on the outer surface overlapping in the overlapping portion 35 of the balloon 30 so as not to become too strong. Therefore, a desirable force can be applied to lay down the drug crystal 42 provided on the outer surface overlapping in the overlapping portion 35 of the balloon 30. Moreover, in the area | region of the blade | wing inner side part 34b and the intermediate part 34c which mutually oppose, the area | region which faces the root side space part 36, ie, the area | region where the blade | wing inner side part 34b and the intermediate part 34c are not closely_contact | adhered, It is difficult to receive. Therefore, in this region, the drug crystal 42 is difficult to sleep. Further, in the regions of the blade inner portion 34b and the intermediate portion 34c that face each other, the region that does not face the root side space portion 36, that is, the region where the blade inner portion 34b and the intermediate portion 34c are in close contact with each other, Easy to receive pressure. Therefore, in this region, the drug crystal 42 falls down and tends to sleep.

  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 the balloon catheter 10 is primed, the guide wire 200 (see FIG. 7) 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 drug crystal 42 is delivered to the living body while the additive 41, which is a water-soluble low-molecular compound contained in the coat layer 40, gradually or rapidly dissolves. The The drug crystals 42 of the coat layer 40 are uniformly formed by the manufacturing method described above. For this reason, a medicine can be made to act satisfactorily on a living body without variation.

  Next, 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 including the water-insoluble drug crystal 42 is formed on the outer surface of the balloon 30. A step of applying a coating liquid 45 containing a drug and a solvent to the outer surface of 30; a step of mixing a fine particle suspension 46 containing fine particles 49 and a solvent in the coating liquid 45; And a step of crystallizing the chemical contained in the coating liquid 45 by the Brownian motion, and a step of volatilizing the solvent contained in the coating liquid 45.

  In the method of manufacturing the balloon catheter 10 configured as described above, the crystallization of the drug can be adjusted by the Brownian motion of the fine particles 49. For this reason, drug crystals can be uniformly formed on the outer surface of the balloon 30 and the morphology of the drug crystals can be easily controlled regardless of various conditions and fluctuations in the procedure.

  In the step of crystallizing the drug, crystal nuclei of the drug may be formed. Thus, it is possible to favorably promote crystal growth from the formed crystal nucleus.

  In the step of applying the coating liquid 45, the coating liquid 45 is applied to the outer surface of the balloon 30 from the tubular dispensing tube 94 for supplying the coating liquid 45 while rotating the balloon 30 around the axis of the balloon 30. In the step of applying and mixing 45, the fine particle suspension 46 is mixed with the coating liquid 45 discharged from the dispensing tube 94. As a result, the fine particle suspension 46 is mixed with the coating liquid 45 when the coating liquid 45 is applied from the dispensing tube 94 to the balloon 30 or immediately after the application. For this reason, the crystallization of the drug can be promoted at an appropriate timing, and the control of the crystallization of the drug becomes easy. In addition, since the coating amount 45 can be controlled with high accuracy by applying the coating liquid 45 from the dispensing tube 94 to the rotating balloon 30, the drug crystal 42 can be uniformly formed on the outer surface of the balloon 30, and the drug crystal It becomes easier to control the conversion.

  The solvent of the fine particle suspension 46 includes an organic solvent, and the fine particles 49 are water-soluble. Thereby, it can suppress that the fine particle 49 melt | dissolves in a solvent, and can produce a Brownian motion effectively. Further, since the fine particles 49 are water-soluble, they can be dissolved and absorbed safely in the living body.

  The fine particles 49 have a diameter of 0.001 μm or more and 1 μm or less. Thereby, the fine particles 49 can be subjected to Brownian motion by the thermal motion of the solvent, and the drug can be stimulated to promote crystallization.

  Moreover, 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 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 including a water-insoluble drug crystal 42 is formed on the outer surface of the balloon 30, and a rotational force is applied to the balloon 30. The rotating mechanism 60 to be applied, the coating liquid supply unit 90 for applying the coating liquid 45 containing the drug and the solvent to the outer surface of the rotating balloon 30, and the fine particles 49 and the outer surface of the rotating balloon 30 or the coating liquid supply unit 90. A fine particle supply unit 110 for supplying a fine particle suspension 46 containing a solvent.

  The manufacturing apparatus 50 configured as described above can mix the fine particle suspension 46 supplied from the fine particle supply unit 110 with the coating liquid 45 by the outer surface of the balloon 30 or the coating liquid supply unit 90, so that the Brownian motion of the fine particles 49 occurs. Can control the crystallization of the drug. For this reason, the drug crystal 42 can be uniformly formed on the outer surface of the balloon 30 and the morphological form of the drug can be easily controlled regardless of various conditions and fluctuations in the procedure.

  The coating liquid supply unit 90 has a tubular dispensing tube 94 that supplies the coating liquid 45, and the fine particle supply unit 110 is for fine particles that supplies the fine particle suspension 46 to the opening 95 of the dispensing tube 94. It has a tube 114. Thereby, the fine particle suspension 46 is mixed with the coating liquid 45 when the coating liquid 45 is applied from the dispensing tube 94 to the balloon 30 or immediately after the application. For this reason, the crystallization of the drug can be promoted at an appropriate timing, and the control of the crystallization of the drug becomes easy. In addition, since the coating amount 45 can be controlled with high accuracy by applying the coating liquid 45 from the dispensing tube 94 to the rotating balloon 30, the drug crystal 42 can be uniformly formed on the outer surface of the balloon 30, and the drug crystal It becomes easier to control the conversion.

  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 fine particle tube 114.

  Further, as in the modification shown in FIG. 9, the fine particle supply unit 120 that supplies the fine particle suspension 46 is connected to the middle of the dispensing tube 94, and the fine particle suspension 46 is placed inside the dispensing tube 94. You may have the tube 121 for fine particles to supply. Thereby, the fine particle suspension 46 can be mixed with the coating liquid 45 immediately before the coating liquid 45 is applied to the balloon by the dispensing tube 94. For this reason, the crystallization of the drug can be promoted at an appropriate timing, and the control of the crystallization of the drug becomes easy. Further, since the coating liquid 45 and the fine particle suspension 46 can be mixed well inside the dispensing tube 94, the drug crystals 42 can be formed uniformly and the control of the crystallization of the drug is facilitated.

  In addition, as in another modification shown in FIG. 10, the fine particle tube 114 may be disposed inside the dispensing tube 94. In this case, the coating liquid 45 flows between the inner peripheral surface of the dispensing tube 94 and the outer peripheral surface of the fine particle tube 114. Alternatively, the arrangement of the dispensing tube 94 and the fine particle tube 114 may be the reverse of the example shown in FIG. That is, the dispensing tube 94 may be disposed inside the fine particle tube 114.

  Further, as in another modification shown in FIG. 11, the dispensing tube 94 and the fine particle tube 114 may be circular tubes arranged in parallel.

DESCRIPTION OF SYMBOLS 10 Balloon catheter 30 Balloon 40 Coat layer 41 Additive 42 Drug crystal 45 Coating liquid 46 Fine particle suspension 47 Mixed liquid 49 Fine particle 50 Catheter manufacturing apparatus 60 Rotating mechanism part 80 Moving mechanism part 90 Coating liquid application part 94 Dispensing tube 100 Control unit 110, 120 Particle supply unit 114, 121 Tube for particle

Claims (8)

A method for producing a balloon catheter in which a coating layer containing a water-insoluble drug crystal 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;
Mixing a fine particle suspension containing fine particles and a solvent in the coating liquid;
Browning the fine particles on the outer surface of the balloon, and crystallizing the drug contained in the coating liquid by the Brownian movement,
Volatilizing a solvent contained in the coating solution.   The method for producing a balloon catheter according to claim 1, wherein in the step of crystallizing the drug, crystal nuclei of the drug are formed. In the step of applying the coating liquid, the coating liquid is applied to the outer surface of the balloon from a tubular dispensing tube for supplying the coating liquid while rotating the balloon about the axis of the balloon. ,
The method for producing a balloon catheter according to claim 1 or 2, wherein, in the mixing step, the fine particle suspension is mixed with the coating liquid after being discharged from the inside of the dispensing tube or the dispensing tube.   The method for manufacturing a balloon catheter according to any one of claims 1 to 3, wherein the solvent of the fine particle suspension includes an organic solvent, and the fine particles are water-soluble.   The method for producing a balloon catheter according to claim 1, wherein the fine particles have a diameter of 0.001 μm or more and 1 μm or less.   The method for producing a balloon catheter according to any one of claims 1 to 5, 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 coat layer containing a water-insoluble drug crystal 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;
An apparatus for manufacturing a balloon catheter, comprising: a fine particle supply unit that supplies a fine particle suspension containing fine particles and a solvent to the outer surface of the rotating balloon or the coating liquid supply unit. The coating liquid supply unit has a tubular dispensing tube for supplying the coating liquid,
8. The balloon catheter manufacturing apparatus according to claim 7, wherein the fine particle supply unit includes a fine particle tube for supplying the fine particle suspension to the inside or the opening of the dispensing tube.

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