JP2018153290A - Manufacturing method and manufacturing device of balloon catheter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a manufacturing method and a manufacturing device of a balloon catheter capable of forming an agent crystal uniformly on an outer surface of a balloon and making control of morphological forms of an agent easy.SOLUTION: There is provided a manufacturing method of a balloon catheter 10 in which a coat layer 40 containing a water-insoluble agent crystal 42 is formed on an outer surface of a balloon 30, having a step for applying a coating liquid 45 containing an agent and a solvent to the outer surface of the balloon 30, a step for rotating the balloon 30 around a shaft center of the balloon 30 and adhering a crystal fine particle 120 of the agent to the coating liquid at a state that the solvent of the coating liquid 45 is left after completion of coating of the coating liquid 45 to whole range forming the coat layer 40 of the balloon 30, and a step for vaporizing the solvent of the coating liquid 45.SELECTED DRAWING: Figure 6

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.

  Moreover, it is preferable that the amount of the medicine on the outer surface of the balloon is uniformly dispersed so that the effect on the living body is not biased depending on the position. For example, Patent Document 1 describes a method in which a suspension obtained by pulverizing paclitaxel particles in water is attached to a balloon using a pipette, and the balloon is rotated until it is dried to uniformly disperse droplets in the balloon.

JP-A-2006-198543

  When manufacturing a balloon catheter having a drug, it is preferable that drug crystals can be uniformly formed on the outer surface of the balloon and the morphological type of the drug can be easily controlled in order to enhance the effect of treatment.

  The present invention has been made to solve the above-described problems, and a balloon catheter manufacturing method and apparatus capable of uniformly forming drug crystals on the outer surface of the balloon and facilitating control of the drug morphological type. 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 crystal of a water-insoluble drug is formed on the outer surface of the balloon, and the drug and the solvent are included on the outer surface of the balloon. After the step of applying the coating liquid and the application of the coating liquid to the entire area where the coating layer of the balloon is formed are completed, the balloon is attached to the balloon in a state where the solvent of the coating liquid remains. The method includes the steps of adhering crystal fine particles of a drug to the coating liquid while rotating about an axis, and volatilizing a solvent of the coating liquid.

  In the method of manufacturing a balloon catheter configured as described above, the fine particles adhere to the coating liquid while rotating the balloon while the solvent of the coating liquid remains, so that the coating liquid is kept uniform by rotation. The crystal particles can be uniformly attached to the coating liquid. Furthermore, crystallization of the drug can be promoted simultaneously under substantially the same conditions in the entire range where the coating liquid is applied using the crystal fine particles as nuclei. 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.

  In the step of attaching the crystal particles, the crystal particles may be attached to the coating liquid by spraying the crystal particles together with a gas. Thereby, the quantity of the crystal fine particles adhering to the coating liquid supplied to the balloon can be adjusted with high accuracy.

  In the step of attaching the crystal particles, a drug-containing liquid containing a drug and a solvent may be sprayed to volatilize the solvent to form the crystal particles, and the crystal particles may be attached to the coating solution. Thereby, the quantity of the crystal fine particles adhering to the coating liquid supplied to the balloon can be adjusted with high accuracy. Further, it is possible to uniformly adhere to the coating liquid while forming crystal particles having a uniform size.

  In the step of attaching the crystal particles, the balloon may be housed inside a housing portion that rotatably accommodates the crystal particles, and the crystal particles may be adhered to the coating liquid inside the housing portion. Thereby, scattering of crystal particles can be suppressed and the amount of crystal particles adhering to the coating liquid can be adjusted with high accuracy. Further, by suppressing the scattering of the crystal particles, the cost can be reduced and the safety of the operator can be ensured.

  The solvent is water, acetic acid, benzene, chlorohexane, glycerin, ethanol, hexane, ethyl acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane, i-butyl alcohol, s-butyl. It may contain at least one selected from the group consisting of alcohol, t-butyl alcohol, propanol, butanol, toluene, and ethylene glycol. Thereby, the volatility of the solvent is lowered, and the solvent is less likely to volatilize from the coating liquid applied to the balloon. For this reason, it becomes easy to make it the state which remains in the whole range which the solvent of the coating liquid apply | coated until the coating liquid is apply | coated to the whole application | coating range of a balloon. Therefore, the crystallization of the drug can be simultaneously promoted under substantially the same conditions in the entire range where the coating liquid is applied at the timing when the crystal particles are adhered.

  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 to the outer surface of the rotating balloon; and a crystal supply for attaching drug crystal particles to the coating liquid applied to the outer surface of the balloon. Part.

  The balloon catheter manufacturing apparatus configured as described above attaches crystal particles to the coating solution by the crystal supply unit while rotating the balloon by the rotation mechanism unit while the solvent of the coating solution applied to the balloon remains. Can be made. For this reason, the crystal particles can be uniformly attached to the coating liquid while maintaining the coating liquid uniform by rotation. Furthermore, crystallization of the drug can be promoted simultaneously under substantially the same conditions in the entire range where the coating liquid is applied using the crystal fine particles as nuclei. 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 crystal supply unit may have a discharge port for discharging the crystal fine particles together with a gas. Thereby, the quantity of the crystal fine particles adhering to the coating liquid supplied to the balloon can be adjusted with high accuracy.

  The crystal supply unit may have a spray port for spraying a drug-containing liquid containing a drug and a solvent. Thereby, the quantity of the crystal fine particles adhering to the coating liquid supplied to the balloon can be adjusted with high accuracy. Further, it is possible to uniformly adhere to the coating liquid while forming crystal particles having a uniform size.

  The manufacturing apparatus may further include a storage unit that rotatably stores the balloon. Thereby, scattering of crystal particles can be suppressed and the amount of crystal particles adhering to the coating liquid can be adjusted with high accuracy. Further, by suppressing the scattering of the crystal particles, the cost can be reduced and the safety of the operator can be ensured.

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 a perspective view which shows the accommodating part of a manufacturing apparatus. It is sectional drawing which shows the accommodating part and crystal supply part of a manufacturing apparatus. It is sectional drawing which shows the dispensing tube which contacted the balloon. It is sectional drawing which shows the balloon folded, (A) is the state before folding of a balloon, (B) is the state in which the blade | wing part was formed in the balloon, (C) shows the state by which the blade | wing part was folded. It is sectional drawing which shows the state which expanded the stenosis part of the blood vessel with the balloon catheter. It is sectional drawing which shows the modification of a crystal supply part. It is sectional drawing which shows the other modification of a crystal supply part.

  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 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 of the drug crystals 42 exists independently, has a certain length, and one end (base end) of the length portion is fixed to the additive 41 or the balloon 30. The drug crystal 42 does not form a complex structure with the adjacent drug crystal 42 and is not connected. The major axis of the crystal is almost linear. The drug crystal 42 forms a predetermined angle with respect to the surface with which the base portion where the major axes intersect is in contact.

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

  The additive 41 is distributed and present in the space between the plurality of drug crystals 42 in the forest. The proportion of the substance constituting the coat layer 40 is preferably such that the water-insoluble drug crystal 42 occupies a larger volume than the additive 41. The additive 41 does not form a matrix. The matrix is a layer in which a relatively high-molecular substance (polymer or the like) is continuously formed, forms a network-like three-dimensional structure, and has a fine space therein. Therefore, the water-insoluble drug constituting the crystal is not attached to the matrix material. The water-insoluble drug constituting the crystal is not embedded in the matrix material. The additive 41 may form a matrix.

  The additive 41 is coated on the outer surface of the 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.

  A layer containing a long crystalline 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, crystals and amorphous materials may be arranged irregularly.

  Next, the manufacturing apparatus 50 for the balloon catheter 10 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 manufacturing apparatus 50 includes a rotation mechanism 60 that rotates the balloon catheter 10 and a support base 70 that supports the balloon catheter 10. The manufacturing apparatus 50 further includes a coating liquid supply unit 90 provided with a dispensing tube 94 that applies the coating liquid 45 to the outer surface of the balloon 30, a moving mechanism unit 80 that moves the dispensing tube 94 relative to the balloon 30, and Have The manufacturing apparatus 50 further includes a crystal supply unit 110 for causing the drug crystal fine particles 120 to adhere to the coating liquid 45 applied to the balloon 30, and a control unit 100 that controls each part of the manufacturing apparatus 50.

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

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

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

  The coating liquid supply unit 90 is a part that applies the coating liquid 45 to the outer surface of the balloon 30. The coating liquid supply unit 90 includes a container 92 that stores the coating liquid 45, a liquid feeding pump 93 that feeds the coating liquid 45 in an arbitrary liquid feeding amount, and a dispensing tube 94 that applies the coating liquid 45 to the balloon 30. It has.

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

  The dispensing tube 94 communicates with the supply tube 96 and discharges the coating liquid 45 supplied from the liquid feed pump 93 through the supply tube 96 to the outer surface of the balloon 30. The dispensing tube 94 is a flexible tubular member. The dispensing tube 94 has an upper end fixed to the tube fixing portion 83, extends vertically downward from the tube fixing portion 83, and has an opening 95 at the discharge end 97 that is the lower end. The dispensing tube 94 can move linearly in both directions along the axial direction of the balloon catheter 10 together with the liquid feed pump 93 installed on the moving table 81 by moving the moving table 81. The dispensing tube 94 can supply the coating liquid 45 to the outer surface of the balloon 30 in a state where the dispensing tube 94 is bent by being pressed against the balloon 30.

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

  The dispensing tube 94 is preferably made of a flexible material so as to reduce the contact load on the balloon 30 and absorb the change in the contact position accompanying the rotation of the balloon 30 by bending. The constituent material of the dispensing tube 94 is, for example, polyolefin such as polyethylene and polypropylene, cyclic polyolefin, polyester, polyamide, polyurethane, PTFE (polytetrafluoroethylene), ETFE (tetrafluoroethylene / ethylene copolymer), PFA (tetra Fluororesin such as fluoroethylene / perfluoroalkyl vinyl ether copolymer) or FEP (tetrafluoroethylene / hexafluoropropylene copolymer) can be applied, but if it is flexible and deformable There is no particular limitation.

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

  The crystal supply unit 110 is a part that supplies the crystal fine particles 120 from the air in order to attach the crystal fine particles 120 to the coating liquid 45 applied to the balloon 30. The crystal particles 120 are crystal particles made of the same drug as the drug crystal 42. The crystal particles 120 serve as a nucleus for forming the drug crystal 42 on the outer surface of the balloon 30. Therefore, the size of the crystal particle 120 is smaller than the drug crystal 42. The size of the crystal fine particles 120 is, for example, 0.001 to 10 μm, preferably 0.01 to 5 μm, and more preferably 0.1 to 1 μm.

  The crystal supply unit 110 includes a storage unit 111 that can store the balloon 30, and a discharge unit 115 that discharges the crystal particles 120 inside the storage unit 111. The crystal supply unit 110 further includes a fine particle supply pipe 116 communicating with the discharge unit 115, and the crystal fine particles 120 are gasified (for example, air, nitrogen, carbon dioxide, argon (Ar)) through the fine particle supply pipe 116 to the discharge unit 115. And an inert gas such as helium (He).

  The lower part of the accommodating part 111 is released, and the balloon 30 that is supported by the support base 70 and rotates can be covered from above. The accommodating portion 111 has a distal slit 118 from which the catheter body 20 located on the distal side of the balloon 30 is led out rotatably, and the catheter body 20 located on the proximal side of the balloon 30 is led out rotatably. A proximal slit 119. The distal slit 118 and the proximal slit 119 are cuts extending upward from the lower end of the side wall of the housing portion 111. Therefore, by covering the balloon 30 with the accommodating portion 111 so that the catheter body 20 is positioned in the distal slit 118 and the proximal slit 119, the balloon 30 is placed in the accommodating portion 111 while maintaining the rotation of the balloon 30. Can be accommodated. In addition, since the accommodating portion 111 does not cover a portion other than the balloon 30 of the balloon catheter 10, it is possible to suppress the attachment of the crystal fine particles 120 to other than the balloon 30. Note that a portion where it is not desired to attach the crystal fine particles 120 may be masked or covered with another member. The discharge part 115 is disposed inside the accommodating part 111 substantially parallel to the balloon 30 accommodated in the accommodating part 111. The discharge unit 115 has a plurality of discharge ports 117 arranged along the balloon 30. The discharge port 117 can discharge the crystal fine particles 120 supplied together with the gas into the housing portion 111. By providing the plurality of discharge ports 117, the crystal fine particles 120 can be uniformly attached to the balloon 30 that is long in the axial direction. Further, it is preferable that the discharge port 117 is separated from the balloon 30 to some extent so that the crystal fine particles 120 can be discharged uniformly to the balloon 30. The discharge port 117 is located above the balloon 30, but may not be located above. Moreover, the discharge port 117 may be only one.

  The crystal delivery unit 112 includes a fine particle container 114 that stores the crystal fine particles 120, and a compressor 113 that mixes the gas with the crystal fine particles 120 in the fine particle container 114 and sends the mixed gas to the fine particle supply pipe 116. The crystal delivery unit 112 is controlled by the control unit 100.

  The control unit 100 is configured by a computer, for example, and comprehensively controls the rotation mechanism unit 60, the movement mechanism unit 80, the coating liquid supply unit 90, and the crystal supply unit 110. Therefore, the control unit 100 rotates the balloon 30, moves the dispensing tube 94 in the axial direction relative to the balloon 30, discharges the drug from the dispensing tube 94, and supplies the crystal fine particles 120 from the crystal supply unit 110. Quantity etc. can be controlled comprehensively.

  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 water-insoluble drug crystal particles on the outer surface of the balloon 30 are easily released, and the crystal particles of the drug adhere to the blood vessel. Has the effect of increasing the amount. The additive 41 is preferably not a hydrogel. Since the additive 41 is a low molecular weight compound, it dissolves rapidly without swelling when in contact with an aqueous solution. Furthermore, since the additive 41 is easily dissolved when the balloon 30 is expanded in the blood vessel, the particles of the water-insoluble drug crystal 42 on the outer surface of the balloon 30 are easily released. It has the effect of increasing the amount of adhesion. When the additive 41 is a matrix made of a contrast agent such as Ultravist (registered trademark), crystal particles are embedded in the matrix, and crystals are not generated from the 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.

  It is preferable that the solvent has low volatility so that the solvent remains in the coating liquid 45 in the entire applied area until the application of the coating liquid 45 to the entire area forming the coating layer 40 of the balloon 30 is completed. The solvent contains at least one of an organic solvent and water.

  The organic solvent is not particularly limited, and tetrahydrofuran, acetone, glycerin, acetic acid, benzene, chlorohexane, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane, ethanol, methanol, dichloromethane, hexane, Examples thereof include ethyl acetate, i-butyl alcohol, s-butyl alcohol, t-butyl alcohol, propanol, butanol, toluene, and ethylene glycol. 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.

  Low volatile solvents are, for example, water, acetic acid, benzene, chlorohexane, glycerin, ethanol, hexane, ethyl acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane, i-butyl alcohol , S-butyl alcohol, t-butyl alcohol, propanol, butanol, toluene, ethylene glycol and the like. The volatility of the solvent can be adjusted by, for example, the viscosity of the solution, the concentration of the solution (solvent content ratio), and the like.

  Next, a method for manufacturing 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 is positioned with respect to the balloon 30. At this time, the dispensing tube 94 is positioned at the most distal end position where the coating layer 40 is formed in the balloon 30. As an example, the extending direction (discharge direction) of the dispensing tube 94 is opposite to the rotation direction of the balloon 30 as shown in FIG. Accordingly, the balloon 30 rotates in the direction opposite to the direction in which the coating liquid 45 is discharged from the dispensing tube 94 at the position where the dispensing tube 94 is brought into contact. Thereby, physical stimulation can be given to the coating liquid 45 and formation of the crystal nucleus of a drug crystal can be promoted. 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 drug crystals 42 each having an independent major axis. The extending direction of the dispensing tube 94 does not have to be the reverse direction of the rotation direction of the balloon 30, and can therefore be the same direction or can be perpendicular. The 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.

  Next, the balloon catheter 10 is rotated by the rotation mechanism unit 60. Subsequently, while the amount of liquid fed is adjusted by the liquid feed pump 93 and the coating liquid 45 is supplied to the dispensing tube 94, the moving table 81 is moved to move the dispensing tube 94 along the axial direction of the balloon 30. Gradually move toward the proximal direction. Note that when the coating liquid 45 is applied to the balloon 30, the accommodating portion 111 does not cover the balloon 30. The coating liquid 45 discharged from the opening 95 of the dispensing tube 94 is applied while drawing a spiral on the outer peripheral surface of the balloon 30 as the dispensing tube 94 moves relative to the balloon 30. Since the balloon 30 is rotating, the coating liquid 45 applied to the outer peripheral surface of the balloon 30 tends to be uniform in the circumferential direction.

  Although the moving speed of the dispensing tube 94 is not specifically limited, For example, it is 0.01-2 mm / sec, Preferably it is 0.03-1.5 mm / sec, More preferably, it is 0.05-1.0 mm / sec. The discharge speed of the coating liquid 45 from the dispensing tube 94 is not particularly limited, but is, for example, 0.01 to 1.5 μL / sec, preferably 0.01 to 1.0 μL / sec, more preferably 0.03 to 0. .8 μL / sec. Although the rotational speed of the balloon 30 is not specifically limited, For example, it is 10-300 rpm, Preferably it is 30-250 rpm, More preferably, it is 50-200 rpm. Although the diameter of the balloon 30 at the time of apply | coating the coating liquid 45 is not specifically limited, For example, it is 1-10 mm, Preferably it is 2-7 mm.

  Then, the dispensing tube 94 is gradually moved in the axial direction of the balloon 30 while rotating the balloon 30. Thereby, the layer of the coating liquid 45 is gradually formed on the outer surface of the balloon 30 in the axial direction. After the layer of the coating liquid 45 is formed over the entire area to be coated by the balloon 30, the moving mechanism unit 80 and the coating liquid supply unit 90 are stopped. Since the solvent contained in the coating liquid 45 has low volatility, even after the application of the coating liquid 45 to the entire area where the coating layer 40 of the balloon 30 is formed, the entire coating liquid 45 on the balloon 30 is applied. Solvent remains in the range.

  Next, the dispensing tube 94 is separated from the balloon 30. Subsequently, as shown in FIG. 6, the accommodating portion 111 is placed on the balloon 30 so that the catheter body 20 is positioned in the distal slit 118 and the proximal slit 119 while maintaining the rotation of the balloon 30. Next, the control unit 100 drives the crystal delivery unit 112 to send the crystal particles 120 in the particle container 114 to the particle supply pipe 116 together with the gas. The crystal particles 120 reach the discharge unit 115 through the particle supply pipe 116 and are discharged from the discharge port 117. After the control unit 100 ejects a predetermined amount of the crystal fine particles 120, the driving of the crystal delivery unit 112 is stopped. That is, the amount of the crystal fine particles 120 to be discharged is only an amount necessary as a crystal nucleus for forming the drug crystal 42. The discharged crystal particles 120 adhere to the coating liquid 45 on the outer surface of the rotating balloon 30. At this time, since the balloon 30 is rotating, the crystal particles 120 can be uniformly adhered to the coating liquid 45 while maintaining the coating liquid 45 on the outer surface of the balloon 30 uniform. When the crystalline fine particles 120 adhere to the coating liquid 45, the chemical contained in the coating liquid 45 is likely to precipitate with the crystalline fine particles 120 as nuclei, and crystallization is promoted. Furthermore, the crystallization of the drug can be promoted simultaneously under substantially the same conditions in the entire range where the coating liquid 45 is applied using the crystal fine particles 120 as a nucleus. For this reason, the drug crystals 42 can be uniformly formed on the outer surface of the balloon 30, and the control of the morphological type of the drug is facilitated. After the predetermined time has elapsed, the solvent is completely volatilized and the coat layer 40 is formed, and then the control unit 100 stops the rotation of the balloon 30. The rotation of the balloon 30 may be stopped before the solvent has completely evaporated.

  The organic solvent contained in the coating solution 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 compound, the type of organic solvent, the ratio of materials, the amount of coating solution applied, etc. It is.

  Next, the accommodating portion 111 that covers the balloon 30 is removed from the balloon 30, and the balloon catheter 10 is removed from the support base 70. Next, the expansion fluid is discharged from the balloon 30, and the balloon 30 is contracted and folded. Thereby, manufacture of the balloon catheter 10 is completed.

  As shown in FIG. 8A, the balloon 30 has a substantially circular cross section in a state where the expansion fluid is injected therein. From this state, the balloon 30 is formed with the protruding blade portion 32, so that the blade outer portion 34a constituting the outer surface of the blade portion 32 and the inner portion of the blade portion 32 are formed as shown in FIG. A blade inner portion 34b constituting the side surface and an intermediate portion 34c located between the blade outer portion 34a and the blade inner portion 34b are formed. From this state, as shown in FIG. 8C, 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 priming the balloon catheter 10, the guide wire 200 (see FIG. 9) 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. 9, 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.

  Thereafter, the expansion fluid is sucked and discharged from the proximal end opening 27 of the hub 26, and the balloon 30 is deflated and folded. Thereafter, the guide wire 200 and the balloon catheter 10 are removed from the blood vessel via the introducer, and the procedure is completed.

  As described above, the method for manufacturing the balloon catheter 10 according to the present embodiment is a method for manufacturing the balloon catheter 10 in which the coat layer 40 including the water-insoluble drug crystal 42 is formed on the outer surface of the balloon 30. The coating liquid 45 containing the drug and the solvent is applied to the outer surface of the coating 30 and after the coating liquid 45 is applied to the entire area where the coating layer 40 of the balloon 30 is formed, the coating liquid 45 is applied to the entire area where the coating liquid 45 is applied. In the state where the solvent remains, rotating the balloon 30 around the axis of the balloon 30 while attaching the crystal fine particles 120 of the drug to the coating liquid 45, and volatilizing the solvent of the coating liquid 45 And having.

  In the method for manufacturing the balloon catheter 10 configured as described above, the crystal fine particles 120 are allowed to adhere to the coating liquid 45 while rotating the balloon 30 in a state where the solvent of the coating liquid 45 remains in the entire range applied. Therefore, the crystal particles 120 can be uniformly attached to the coating liquid 45 while maintaining the coating liquid 45 uniform by rotation. Furthermore, the crystallization of the drug can be promoted simultaneously under substantially the same conditions in the entire range where the coating liquid 45 is applied using the crystal fine particles 120 as a nucleus. 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.

  Further, in the manufacturing method, in the step of attaching the crystal fine particles 120, the crystal fine particles 120 are attached to the coating liquid 45 by spraying with the gas. Thereby, the amount of the crystal fine particles 120 attached to the coating liquid 45 supplied to the balloon 30 can be adjusted with high accuracy.

  Further, in the step of attaching the crystalline fine particles 120, the balloon 30 is accommodated inside the accommodating portion 111 that rotatably accommodates, and the crystalline fine particles 120 are adhered to the coating liquid 45 inside the accommodating portion 111. Thereby, scattering of the crystal fine particles 120 can be suppressed, and the amount of the crystal fine particles 120 adhering to the coating liquid 45 can be adjusted with high accuracy. Further, by suppressing the scattering of the crystal fine particles 120, the cost can be reduced and the safety of the operator can be secured.

  The solvent is water, acetic acid, benzene, chlorohexane, glycerin, ethanol, hexane, ethyl acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane, i-butyl alcohol, s- It may contain at least one selected from the group consisting of butyl alcohol, t-butyl alcohol, propanol, butanol, toluene, and ethylene glycol. Thereby, the volatility of the solvent is lowered, and the solvent is less likely to volatilize from the coating liquid 45 applied to the balloon 30. For this reason, the state in which the solvent of the coating liquid 45 remains in the entire applied area can be maintained until the application of the coating liquid 45 to the entire area forming the coating layer 40 of the balloon 30 is completed. Accordingly, the crystallization of the drug can be simultaneously promoted under substantially the same conditions in the entire range where the coating liquid of the balloon 30 is applied at the timing when the crystalline fine particles 120 are attached.

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

  The balloon catheter 10 manufacturing apparatus 50 is a balloon catheter 10 manufacturing apparatus 50 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. A rotating mechanism 60 to be applied; a coating liquid supply unit 90 for applying a coating liquid 45 containing a drug and a solvent to the outer surface of the rotating balloon 30; and a crystal particle of drug in the coating liquid 45 applied to the outer surface of the balloon 30. And a crystal supply unit 110 to which 120 is attached.

  The manufacturing apparatus 50 for the balloon catheter 10 configured as described above allows the crystal supply unit 110 to rotate the balloon 30 with the rotation mechanism unit 60 while the solvent of the coating liquid 45 applied to the balloon 30 remains. Crystal fine particles 120 can be adhered to the coating liquid 45. For this reason, the crystal particles 120 can be uniformly adhered to the coating liquid 45 while maintaining the coating liquid 45 uniform by rotation. Furthermore, the crystallization of the drug can be promoted simultaneously under substantially the same conditions in the entire range where the coating liquid 45 is applied using the crystal fine particles 120 as a nucleus. 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.

  In addition, the crystal supply unit 110 has a discharge port 117 for discharging the crystal fine particles 120 together with the gas. Thereby, the amount of the crystal fine particles 120 attached to the coating liquid 45 supplied to the balloon 30 can be adjusted with high accuracy.

  In addition, the manufacturing apparatus 50 further includes an accommodating portion 111 that accommodates the balloon 30 in a rotatable manner. Thereby, scattering of the crystal fine particles 120 can be suppressed, and the amount of the crystal fine particles 120 adhering to the coating liquid 45 can be adjusted with high accuracy. Further, by suppressing the scattering of the crystal fine particles 120, the cost can be reduced and the safety of the operator can be ensured.

  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. Moreover, the accommodating part 111 which accommodates the balloon 30 rotatably does not need to be provided.

  Further, as in the modification shown in FIG. 10, the crystal supply unit 130 that supplies the crystal fine particles 120 may have a spray port 137 that sprays the drug-containing liquid 140 containing the drug and the solvent. The drug-containing liquid 140 is a solution or suspension containing a drug. The crystal supply unit 130 includes a storage unit 111 that can store the balloon 30 and a spray unit 135 that sprays the drug-containing liquid 140 in a mist form inside the storage unit 111. The crystal supply unit 130 further includes a fine particle supply tube 136 that communicates with the spray unit 135 and a crystal delivery unit 132 that sends the drug-containing liquid 140 to the spray unit 135 via the fine particle supply tube 136. In addition, the same code | symbol is attached | subjected to the site | part which has the same function as the above-mentioned embodiment, and description is abbreviate | omitted. The drug contained in the drug-containing liquid 140 is the same drug as the drug crystal 42. The solvent is preferably highly volatile so that it can be volatilized in the air after being sprayed. For example, acetone, ethanol, methanol, diethyl ether, acetonitrile, water, and the like can be used.

  The spray unit 135 is disposed inside the storage unit 111 substantially parallel to the balloon 30 stored in the storage unit 111. The spray unit 135 has a plurality of spray ports 137 arranged along the balloon 30. The spray port 137 can spray the crystal fine particles 120 supplied together with the gas into the interior of the housing portion 111 in a mist form. By providing the plurality of spray ports 137, the crystal particles 120 can be uniformly attached to the balloon 30 that is long in the axial direction. In addition, the spray port 137 is preferably separated from the balloon 30 to some extent so that the crystal particles 120 can be uniformly discharged to the balloon 30. The spray port 137 is located above the balloon 30, but may not be located above. Further, there may be only one spray port 137.

  The crystal delivery unit 132 includes a drug-containing liquid container 134 that contains the drug-containing liquid 140, and a pump 133 that sends the drug-containing liquid 140 in the drug-containing liquid container 134 to the fine particle supply pipe 116. The crystal delivery unit 132 is controlled by the control unit 100.

  When the crystal particles 120 are supplied from the crystal supply unit 130, the dispensing tube 94 is separated from the balloon 30 after the coating liquid 45 is applied to the balloon 30 as in the above-described embodiment. Subsequently, the containing portion 111 is placed on the balloon 30 while maintaining the rotation of the balloon 30. Next, the control unit 100 drives the crystal delivery unit 132 to send out a predetermined amount of the drug-containing liquid 140 in the drug-containing liquid container 134 to the fine particle supply pipe 116. The drug-containing liquid 140 reaches the spray unit 135 through the fine particle supply pipe 116 and is sprayed from the spray port 137. The solvent of each sprayed droplet volatilizes in the air, and the drug contained in the droplet floats as crystalline fine particles 120. After the predetermined amount of crystal particles 120 is formed, the control unit 100 stops driving the crystal delivery unit 132. The suspended fine crystal particles 120 adhere to the coating liquid 45 on the outer surface of the rotating balloon 30. At this time, since the balloon 30 is rotating, the crystal particles 120 can be uniformly adhered to the coating liquid 45 while maintaining the coating liquid 45 on the outer surface of the balloon 30 uniform. When the crystalline fine particles 120 adhere to the coating liquid 45, the chemical contained in the coating liquid 45 is likely to precipitate with the crystalline fine particles 120 as nuclei, and crystallization is promoted as in the above-described embodiment. After the predetermined time has elapsed, the solvent is completely volatilized and the coat layer 40 is formed, and then the control unit 100 stops the rotation of the balloon 30. The rotation of the balloon 30 may be stopped before the solvent has completely evaporated.

  As described above, the crystal supply unit 130 according to the modification has the spray port 137 for spraying the drug-containing liquid 140 including the drug and the solvent. For this reason, when the drug-containing liquid 140 is sprayed from the spraying port 137, the solvent volatilizes in a state of floating in a mist state to form crystal fine particles 120, and the crystal fine particles 120 adhere to the coating liquid 45. Thereby, the crystal particles 120 can be uniformly attached to the coating liquid 45 while the crystal particles 120 having a uniform size are formed. Further, the amount of the crystal fine particles 120 to be created can be easily and accurately controlled by the amount of the drug-containing liquid 140.

  In addition, as in another modification shown in FIG. 11, the crystal supply unit 150 that supplies the crystal fine particles 120 may include a fine particle container 151 that holds the crystal fine particles 120 in a releasable manner inside the storage unit 111. Good. The fine particle container 151 has a mesh-like bottom surface 152 having a large number of holes (discharge ports) and a vibrator 153 for exciting the fine particle container 151. The vibrator 153 is, for example, a piezoelectric element or a motor-driven weight. The vibrator 153 can be driven by the control unit 100.

  When the crystal particles 120 are supplied from the crystal supply unit 150, the dispensing tube 94 is separated from the balloon 30 after the coating liquid 45 is applied to the balloon 30 as in the above-described embodiment. Subsequently, the containing portion 111 is placed on the balloon 30 while maintaining the rotation of the balloon 30. Next, the control unit 100 drives the vibrator 153 to vibrate the particle container 151 and shakes the crystal particles 120 from the mesh-shaped bottom surface 152. After the vibrator 153 is driven for a predetermined time to shake off a predetermined amount of the crystal fine particles 120, the control unit 100 stops the vibrator 153. The crystal particles 120 dropped from the particle container 151 adhere to the coating liquid 45 on the outer surface of the rotating balloon 30. At this time, since the balloon 30 is rotating, the crystal particles 120 can be uniformly adhered to the coating liquid 45 while maintaining the coating liquid 45 on the outer surface of the balloon 30 uniform. When the crystalline fine particles 120 adhere to the coating liquid 45, the chemical contained in the coating liquid 45 is likely to precipitate with the crystalline fine particles 120 as nuclei, and crystallization is promoted as in the above-described embodiment. After the predetermined time has elapsed, the solvent is completely volatilized and the coat layer 40 is formed, and then the control unit 100 stops the rotation of the balloon 30. The rotation of the balloon 30 may be stopped before the solvent has completely evaporated.

DESCRIPTION OF SYMBOLS 10 Balloon catheter 30 Balloon 40 Coat layer 41 Additive 42 Drug crystal 45 Coating liquid 50 Catheter manufacturing apparatus 60 Rotation mechanism part 80 Movement mechanism part 90 Coating liquid supply part 94 Dispensing tube 100 Control part 110,130,150 Crystal supply part 111 Container 117 117 Discharge Port 120 Crystal Fine Particle 137 Spray Port 140 Drug-Containing Liquid

Claims (10)

A method for producing a balloon catheter in which a coat layer containing water-insoluble drug crystals 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;
After the application of the coating liquid to the entire area of the balloon forming the coating layer is completed, the balloon is rotated about the balloon axis while the solvent of the coating liquid remains. Adhering drug fine crystal particles to the coating solution;
Volatilizing the solvent of the coating solution.   The method for producing a balloon catheter according to claim 1, wherein, in the step of attaching the crystal particles, the crystal particles are attached to the coating solution by spraying the crystal particles together with a gas.   The balloon according to claim 1, wherein in the step of attaching the crystal fine particles, a drug-containing liquid containing a drug and a solvent is sprayed, the solvent is volatilized to form the crystal fine particles, and the crystal fine particles are attached to the coating liquid. A method for manufacturing a catheter.   The step of adhering the crystalline fine particles accommodates the balloon in a rotatable accommodating portion, and adheres the crystalline fine particles to the coating liquid inside the accommodating portion. 2. A method for producing a balloon catheter according to item 1.   The solvent is water, acetic acid, benzene, chlorohexane, glycerin, ethanol, hexane, ethyl acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane, i-butyl alcohol, s-butyl. The method for producing a balloon catheter according to any one of claims 1 to 4, comprising at least one selected from the group consisting of alcohol, t-butyl alcohol, propanol, butanol, toluene, and ethylene glycol.   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 water-insoluble drug crystals is formed on the outer surface of a balloon,
A rotation mechanism for applying a rotational force to the balloon;
A coating solution supply unit for applying a coating solution containing a drug and a solvent to the outer surface of the rotating balloon;
A balloon catheter manufacturing apparatus, comprising: a crystal supply unit that attaches crystal fine particles of a drug to the coating liquid applied to the outer surface of the balloon.   The balloon catheter manufacturing apparatus according to claim 7, wherein the crystal supply unit has a discharge port for discharging the crystal fine particles together with a gas.   The balloon crystal manufacturing apparatus according to claim 7, wherein the crystal supply unit has a spray port for spraying a drug-containing liquid containing a drug and a solvent.   The balloon catheter manufacturing apparatus according to any one of claims 7 to 9, further comprising a housing portion that rotatably accommodates the balloon.

Images