WO2018169053A1

WO2018169053A1 - Balloon catheter, production method therefor, production device, and treatment method

Info

Publication number: WO2018169053A1
Application number: PCT/JP2018/010472
Authority: WO
Inventors: 村田悠; 黒崎靖夫; 後藤博
Original assignee: テルモ株式会社
Priority date: 2017-03-16
Filing date: 2018-03-16
Publication date: 2018-09-20
Also published as: JPWO2018169053A1; JP7073338B2

Abstract

Provided are: a balloon catheter capable of uniformly forming a drug crystal on the outer surface of a balloon and capable of readily controlling the morphological form of the drug; a production method therefor; a production device; and a treatment method. This production method for a balloon catheter (10) having a coat layer (40) including crystals of a water insoluble drug, formed on the outer surface of a balloon (30), has: a step in which a conductive metal is deposited and a metal layer (37) is formed on the outer surface of the balloon (30); a step in which a coating fluid (45) including the drug and a solvent is coated on the outer surface of the metal layer (37); and a step in which, after the coating of the coating fluid (45) on to the entire area forming the coat layer (40) of the balloon (30) has been completed, current is supplied to the metal layer (37), heat is generated, and the solvent is volatized, in a state in which the coating fluid (45) solvent remains.

Description

Balloon catheter, manufacturing method and manufacturing apparatus thereof, and treatment method

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

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

In recent years, it has become clear that the morphological form of the drug coated on the outer surface of the balloon affects the drug release 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.

By the way, various conditions such as coating parameters and the environment such as the fluctuation of the technique 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.

Patent Document 1 describes a method of drying a coating composition applied to a balloon while applying a fluid for adjusting the temperature condition of the coating composition inside the balloon. Patent Document 2 describes a method in which conductive ink is applied to a balloon by a method such as pad printing, ink jet printing, spraying, marker striping, painting, or electrostatic coating. Thereby, it becomes possible to flow an electric current through the stent mounted on the balloon, and it is possible to apply a coating to the stent by an electrostatic coating method.

JP 2014-200269 A International Publication No. 2005/060870

The method described in Patent Document 1 is complicated because it requires a fluid whose temperature is controlled to flow into a rotating balloon. The method described in Patent Document 2 is a technique for applying a coating of a drug or the like to a stent by electrostatic coating, and does not increase the uniformity of the drug provided on the balloon.

The present invention has been made to solve the above-described problem, and a balloon catheter capable of uniformly forming a drug crystal on the outer surface of the balloon and easily controlling the morphological type of the drug, and a manufacturing method and a manufacturing apparatus thereof. An object of the present invention is to provide a treatment method.

A method for manufacturing a balloon catheter that achieves the above object is a method for manufacturing a balloon catheter in which a coating layer containing a water-insoluble drug crystal is formed on the outer surface of the balloon, and a conductive metal is applied to the outer surface of the balloon. Forming a metal layer by vapor deposition, applying a coating liquid containing a drug and a solvent to the outer surface of the metal layer, and applying the coating liquid to the entire area of the balloon forming the coating layer. After completion, in a state where the solvent of the coating solution remains, a current is passed through the metal layer to generate heat to volatilize the solvent.

The balloon catheter manufacturing method configured as described above was applied because the coating solution solvent can be volatilized by heating with a metal layer in a state where the coating solution solvent remains in the entire range applied. Crystallization of the entire range of drugs can be promoted simultaneously under substantially the same conditions. 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 manufacturing method, in the step of volatilizing the solvent, a current is supplied to the metal layer by a terminal that is slidably in contact with the metal layer while rotating the balloon around the axis of the balloon. Good. Thereby, an electric current can be sent through a metal layer and a solvent can be volatilized, without stopping rotation of the balloon which plays the role which makes a coating liquid uniform. For this reason, drug crystals can be formed uniformly, and the morphological type of the drug can be easily controlled.

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 be 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 current is supplied to the metal layer.

The water-insoluble drug may be rapamycin, paclitaxel, docetaxel, or everolimus. Thereby, restenosis of the stenosis part in a blood vessel can be suppressed favorably.

An apparatus for manufacturing a balloon catheter that achieves the above object applies a rotating mechanism that applies a rotational force to the balloon, and a coating solution containing a drug and a solvent on the outer surface of a metal layer deposited on the rotating balloon. A supply unit; and a terminal that slidably contacts the metal layer and supplies current to the metal layer.

The balloon catheter manufacturing apparatus configured as described above has a current flowing in the metal layer by means of a terminal that slidably contacts the metal layer of the rotating balloon with the solvent of the coating solution remaining in the entire range. To heat the metal layer and volatilize the solvent of the coating solution. For this reason, crystallization of the whole range of the applied drug can be promoted simultaneously under substantially the same conditions. Therefore, drug crystals can be uniformly formed on the outer surface of the balloon, and the morphological type of the drug can be easily controlled, regardless of various conditions and fluctuations in the procedure.

A balloon catheter that achieves the above-mentioned object is a balloon catheter that can be inserted into a living body lumen, and is a long catheter body, a balloon that is provided on the distal side of the catheter body and is expandable in the radial direction, A metal layer deposited on the outer surface of the balloon; a water-insoluble drug crystal disposed on the outer surface of the metal layer; and a proximal side along the catheter body electrically connected to the metal layer And a conductive wire extending to the surface.

The balloon catheter configured as described above can supply an electric current to the metal layer disposed on the balloon inserted into the living body via a lead wire. For this reason, the drug crystal can be heated in the living body to improve the transferability of the drug to the living tissue.

A treatment method for achieving the above object is a treatment method for delivering a drug to a lesion in a living body lumen using a balloon catheter, the step of inserting the balloon into the living body lumen to reach the lesion Expanding the balloon and the metal layer to press against the living tissue, and bringing the drug crystal into contact with the living tissue; passing an electric current through the conductor to the metal layer to heat the metal layer; Heating the drug crystal; and deflating the balloon to remove it from the living body lumen.

Since the treatment method configured as described above generates heat in the metal layer and heats the drug crystal, it is possible to improve the transferability of the drug to a living tissue.

It is a front view which shows the balloon catheter which concerns on this embodiment. 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 and terminal which contacted the balloon. It is a front view which shows the state which has volatilized the solvent of the coating liquid apply | coated to the balloon. It is sectional drawing which shows the balloon folded, (A) is the state before folding of a balloon, (B) is the state in which the blade | wing part was formed in the balloon, (C) shows the state by which the blade | wing part was folded. It is sectional drawing which shows the state which expanded the stenosis part of the blood vessel with the balloon catheter. It is a front view which shows the modification of a balloon catheter. It is a front view which shows the other modification of a balloon catheter.

Hereinafter, an embodiment of the present invention will be described with reference to the drawings. In addition, the dimension ratio of drawing is exaggerated on account of description, and may differ from an actual ratio.

The balloon catheter 10 according to the present embodiment is a drug-eluting catheter 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 includes a long catheter body 20, a balloon 30 provided at the distal end of the catheter body 20, a metal layer 37 provided on the outer surface of the balloon 30, and a drug provided on the outer surface of the metal layer 37. The coating layer 40 includes a hub 26 fixed to the proximal end of the catheter body 20.

The catheter body 20 includes an outer tube 21 that is a tube having an open front end and a proximal end, and an inner tube 22 that is a tube disposed inside the outer tube 21. The inner tube 22 is housed in the hollow interior of the outer tube 21, and the catheter body 20 has a double tube structure at the distal end. The hollow interior of the inner tube 22 is a guide wire lumen 24 through which the guide wire is inserted. Further, an expansion lumen 23 through which the expansion fluid of the balloon 30 flows is formed inside the hollow of the outer tube 21 and outside the inner tube 22. The inner tube 22 opens to the outside at the opening 25. The inner tube 22 protrudes further to the distal end side than the distal end of the outer tube 21.

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 portion 27 that functions as a port that communicates with the expansion lumen 23 of the outer tube 21 and allows the expansion fluid to flow in and out.

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

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

The outer surface of the balloon 30 before the metal layer 37 and the coat layer 40 are formed is smooth and non-porous. The outer surface of the balloon 30 before the metal layer 37 and the coat layer 40 are 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 a plurality of holes for one crystal. The size of the minute holes is, for example, a diameter of 5 to 500 μm and a depth of 0.1 to 50 μm, and one hole or a plurality of crystals may be included for one hole.

It is preferable that the balloon 30 has a certain degree of flexibility so that it can be expanded when it reaches a blood vessel, tissue, etc., and has a certain degree of hardness so that the drug can be released from the coat layer 40 on its outer surface. Specifically, the balloon 30 is made of metal or resin, but at least the outer surface of the balloon 30 on which the coat layer 40 is provided is preferably made of resin. The constituent material of at least the outer surface of the balloon 30 is, for example, a polyolefin such as polyethylene, polypropylene, polybutene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, ionomer, or a mixture of two or more of these, soft poly A thermoplastic resin such as vinyl chloride resin, polyamide, polyamide elastomer, nylon elastomer, polyester, polyester elastomer, polyurethane, fluororesin, silicone rubber, latex rubber, or the like can be used. Among these, polyamides are preferable. That is, at least a part of the outer surface of the balloon 30 that coats the drug is a polyamide. The polyamide is not particularly limited as long as it is a polymer having an amide bond. For example, polytetramethylene adipamide (nylon 46), polycaprolactam (nylon 6), polyhexamethylene adipamide (nylon 66), Homopolymers such as polyhexamethylene sebacamide (nylon 610), polyhexamethylene dodecamide (nylon 612), polyundecanolactam (nylon 11), polydodecanolactam (nylon 12), caprolactam / lauryl lactam copolymer Polymer (nylon 6/12), caprolactam / aminoundecanoic acid copolymer (nylon 6/11), caprolactam / ω-aminononanoic acid copolymer (nylon 6/9), caprolactam / hexamethylene diammonium adipate copolymer ( Nylon 6/66 Copolymers such as a copolymer of adipic acid and meta-xylylenediamine, or hexamethylene diamine and m, and aromatic polyamides such as a copolymer of p- phthalic acid. Further, a polyamide elastomer which is a block copolymer having nylon 6, nylon 66, nylon 11, nylon 12 or the like as a hard segment and polyalkylene glycol, polyether, aliphatic polyester or the like as a soft segment is also a material of the balloon 30. Used as The said polyamides may be used individually by 1 type, and may use 2 or more types together. In particular, the balloon 30 preferably has a smooth surface of polyamide.

As shown in FIG. 3, a conductive metal material is deposited on the outer surface of the balloon 30 to form a metal layer 37, and a coat layer 40 is formed on the outer surface.

The constituent material of the metal layer 37 is a conductive metal, for example, gold (Au), platinum (Pt), chromium (Cr), zinc (Zn), nickel (Ni), silver (Ag), copper (Cu ) And alloys thereof. The thickness of the metal layer 37 is not particularly limited as long as it can be formed to have conductivity by vapor deposition and does not hinder the flexibility of the balloon 30, but is, for example, 0.1 to 500 nm, preferably 0.1 It is ˜100 nm, more preferably 0.1 to 50 nm.

The coat layer 40 includes an additive 41 (excipient) containing a water-soluble low-molecular compound disposed in a layered manner on the outer surface of the metal layer 37 of the balloon 30, and a water-insoluble extending with an independent long axis. The drug crystal 42 is included. The end of the drug crystal 42 may be in direct contact with the outer surface of the metal layer 37, but the additive 41 is not directly contacted between the end of the drug crystal 42 and the outer surface of the metal layer 37. May be present. The end portion of the drug crystal 42 may be positioned on the surface of the layer of the additive 41, and the drug crystal 42 may protrude from the additive 41. The plurality of drug crystals 42 may be regularly arranged on the outer surface of the metal layer 37. Alternatively, the plurality of drug crystals 42 may be irregularly arranged on the outer surface of the metal layer 37.

The amount of the drug contained in the coat layer 40 is not particularly limited, but is 0.1 μg / mm ² to 10 μg / mm ² , preferably 0.5 μg / mm ² to 5 μg / mm ² , more preferably 0.5 μg. / Mm ² to 3.5 μg / mm ² , more preferably 1.0 μg / mm ² to 3 μg / mm ² . The amount of crystals of the coat layer 40 is not particularly limited, but is preferably 5 to 500,000 [crystal / (10 μm ² )] (number of crystals per 10 μm ² ), more preferably 50 to 50,000 [crystal / (10 μm ² )], more preferably 500 to 5,000 [crystal / (10 μm ² )].

The drug crystal 42 may have a form having independent long axes. Further, the drug crystal 42 may be other morphological types. The plurality of drug crystals 42 may be present in a state where they are combined, or may be present in contact with each other with a plurality of adjacent drug crystals 42 forming different angles. The plurality of drug crystals 42 may be positioned on the surface of the metal layer 37 with a space (a space not including a crystal). On the surface of the metal layer 37, there may be both a plurality of drug crystals 42 in a combined state and a plurality of drug crystals 42 that are separated from each other and independent. The plurality of drug crystals 42 may be arranged in a brush shape around the circumference having different major axis directions. Each of the drug crystals 42 exists independently, has a certain length, and one end (base end) of the length portion is fixed to the additive 41 or the metal layer 37. 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.

It is preferable that the drug crystals 42 stand independently without contacting each other. The base of the drug crystal 42 may be in contact with another base on the metal layer 37. Alternatively, the base of the drug crystal 42 may be independent on the metal layer 37 without being in contact with other bases.

The drug crystal 42 may be hollow or solid. Both the hollow drug crystal 42 and the solid drug crystal 42 may exist on the surface of the metal layer 37. 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 even more preferably 0.1 μm to 3 μm. As an example of the combination of the length and the diameter in the long axis direction of the drug crystal 42 having a long axis, a combination having a diameter of 0.01 to 5 μm when the length is 5 μm to 20 μm, and a combination when the length is 5 to 20 μm Examples include combinations having a diameter of 0.05 to 4 μm, and combinations having a diameter of 0.1 to 3 μm when the length is 5 to 20 μm. The drug crystal 42 having the long axis is linear in the long axis direction, but may be curved. Both the linear drug crystal 42 and the curved drug crystal 42 may exist on the surface of the metal layer 37.

The above-mentioned crystal form type having a crystal having a long axis is 50% by volume or more, and more preferably 70% by volume or more with respect to the entire drug crystal on the outer surface of the metal layer 37. 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 metal layer 37 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 metal layer 37 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 of a long crystal form type has low toxicity and high stenosis-inhibiting effect when delivered into the body. A water-insoluble drug containing a hollow long crystalline form is effective because it has good permeability to the tissue and good solubility because one unit of the crystal becomes small when the drug moves into the tissue. It can act to suppress stenosis. In addition, it is considered that toxicity is low because the drug hardly remains in the tissue as a large mass.

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

The drug coated on the outer surface of the metal layer 37 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 manufacturing apparatus 50 can form the metal layer 37 and the coat layer 40 on the balloon 30. As shown in FIGS. 4 and 5, the balloon catheter manufacturing apparatus 50 includes a rotation mechanism 60 that rotates the balloon catheter 10 and a support base 70 that supports the balloon catheter 10. The manufacturing apparatus 50 further includes a coating liquid supply unit 90 provided with a dispensing tube 94 that applies the coating liquid 45 to the outer surface of the metal layer 37, and 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 current supply unit 110 that supplies current to the metal layer 37, a vapor deposition apparatus 120 that deposits metal on the outer surface of the balloon 30 to form the metal layer 37, and each part of the manufacturing apparatus 50. And a control unit 100 for controlling.

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

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

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

The coating liquid supply unit 90 is a part that applies the coating liquid 45 to the metal layer 37 on the 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 metal layer 37. And.

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 metal layer 37 on the 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 metal layer 37 in a state where the dispensing tube 94 is pressed against the metal layer 37 and is bent.

The dispensing tube 94 may not be a circular tube as long as the coating liquid 45 can be supplied. The dispensing tube 94 may not extend in the vertical direction as long as the coating liquid 45 can be discharged from the opening 95. The dispensing tube 94 may supply the coating liquid 45 to the metal layer 37 at a position away from the outer surface of the metal layer 37.

The dispensing tube 94 is preferably made of a flexible material so as to reduce the contact load on the metal layer 37 and absorb the change in the contact position accompanying the rotation of the balloon 30 by bending. The constituent material of the dispensing tube 94 is, for example, polyolefin such as polyethylene and polypropylene, cyclic polyolefin, polyester, polyamide, polyurethane, PTFE (polytetrafluoroethylene), ETFE (tetrafluoroethylene / ethylene copolymer), PFA (tetra Fluororesin such as fluoroethylene / perfluoroalkyl vinyl ether copolymer) or FEP (tetrafluoroethylene / hexafluoropropylene copolymer) can be applied, but if it is flexible and deformable There is no particular limitation.

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

The current supply unit 110 is a part that applies current to the metal layer 37 on the surface of the balloon 30. The metal layer 37 generates heat when an electric current flows, and volatilizes the solvent of the coating liquid 45 to be applied. The current supply unit 110 includes two terminals 111 that are slidably in contact with the distal end portion and the proximal end portion of the balloon 30, and a power source 112 that supplies current to the terminal 111. The terminal 111 can flow a current supplied from the power source 112 to the metal layer 37 in contact with the terminal 111. The power source 112 supplies a direct current or an alternating current to the terminal 111. The power source 112 can adjust the voltage, current and frequency of the current to be supplied. The two terminals 111 are in contact with a position different from a range where the coating layer 40 of the metal layer 37 is formed (a range where the coating liquid 45 is applied). The position where the terminal 111 contacts is, for example, the tapered portion 33 (see FIG. 2). Thereby, the formation of the coat layer 40 is not inhibited by the terminals 111. The terminal 111 is preferably flexible so that the balloon 30 and the metal layer 37 are not damaged. The terminal 111 has, for example, a bifurcated structure so as to contact the metal layer 37 reliably. In addition, the shape of the terminal 111 will not be specifically limited if it can contact the metal layer 37 so that sliding is possible, For example, one rod shape may be sufficient. Further, if the metal layer 37 is heated while the rotation of the balloon 30 is stopped to volatilize the solvent of the coating liquid 45, the terminal 111 can effectively pass a current through the metal layer 37. The structure which can be clamped like a clip may be sufficient.

The deposition apparatus 120 is an apparatus that forms a metal layer 37 by depositing metal on the outer surface of the balloon 30. The vapor deposition apparatus 120 can use a well-known thing. The vapor deposition apparatus 120 is a vacuum vapor deposition apparatus, for example.

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 current supply unit 110. Therefore, the control unit 100 determines the rotational speed of the balloon 30, the moving speed of the dispensing tube 94 in the axial direction relative to the balloon 30, the drug discharge speed from the dispensing tube 94, the voltage, current, and frequency of the current supply unit 110. Can be comprehensively controlled.

The coating liquid 45 supplied to the metal layer 37 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 metal layer 37 on the outer surface of the balloon 30, the solvent is volatilized, so that the water-insoluble drug crystal extending on the outer surface of the metal layer 37 with an independent long axis extends. A coat layer 40 having 42 is formed.

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

Water-insoluble drug means a drug that is insoluble or sparingly soluble in water. Specifically, the solubility in water is less than 5 mg / mL at pH 5-8. Its solubility may be less than 1 mg / mL and even less than 0.1 mg / mL. Water-insoluble drugs include fat-soluble drugs.

Examples of some preferred water-insoluble drugs include immunosuppressants, such as cyclosporines including cyclosporine, immunoactive agents such as rapamycin, anticancer agents such as paclitaxel, antiviral or antibacterial agents, anti-neoplastic agents, Analgesics and anti-inflammatory agents, antibiotics, antiepileptics, anxiolytics, antiparalytic agents, antagonists, neuron blocking agents, anticholinergics and cholinergic agents, antimuscarinic and muscarinic agents, antiadrenergic agents, Contains antiarrhythmic, antihypertensive, hormonal and nutritional agents.

Water-insoluble drugs are preferably paclitaxel and paclitaxel derivatives, taxanes, docetaxel and rapamycin and rapamycin derivatives, such as biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, fasudil and epothilone, paclitaxel and rapamycin, especially docetaxel, and evelimel. In the present specification, rapamycin, paclitaxel, docetaxel, and everolimus include analogs and / or derivatives thereof as long as they have similar medicinal effects. For example, paclitaxel and docetaxel are in an analog relationship. Rapamycin and everolimus are in a derivative relationship. Of these, paclitaxel is more preferred.

Additive 41 includes a water-soluble low molecular weight compound. The molecular weight of the water-soluble low molecular weight compound is 50 to 2000, preferably 50 to 1000, more preferably 50 to 500, and further preferably 50 to 200. The water-soluble low molecular weight compound is preferably 5 to 10,000 parts by weight, more preferably 5 to 200 parts by weight, and still more preferably 8 to 150 parts by weight with respect to 100 parts by weight 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 metal layer 37. 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 metal layer 37. 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 metal layer 37 can be easily released, and the drug crystal particles in the blood vessel are released. It has the effect of increasing the amount of adhesion. 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 metal layer 37 are easily released, and the drug crystal 42 into the blood vessel. It has the effect of increasing the amount of adhesion. When the additive 41 is a matrix made of a contrast agent such as Ultravist (registered trademark), crystal particles are embedded in the matrix, and crystals are not generated from the metal layer 37 toward the outside of the matrix. On the other hand, the drug crystal 42 of the present embodiment can extend from the surface of the metal layer 37 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 range until the application of the coating liquid 45 to the entire range in which the coating layer 40 of the metal layer 37 is formed 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, for example, tetrahydrofuran and water, tetrahydrofuran and ethanol and water, tetrahydrofuran and acetone and water, acetone and ethanol and water, and tetrahydrofuran, acetone, ethanol, and water.

Low volatile solvents include, 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 of forming the water-insoluble drug crystal 42 on the metal layer 37 on the outer surface of the balloon 30 using the manufacturing apparatus 50 for the balloon catheter 10 described above will be described.

First, a metal layer 37 is formed on the outer surface of the balloon 30 by a known vapor deposition device 120. Note that the metal layer 37 can be formed only on the surface of the balloon 30 by performing masking or the like on the portion of the balloon catheter 10 where the metal layer 37 is not formed.

Next, an expansion fluid is supplied into the balloon 30 through a three-way cock connected to the proximal end opening 27 of the balloon catheter 10. Next, the three-way cock is operated in a state where the balloon 30 is expanded to seal the expansion lumen 23, and the state where the balloon 30 is expanded is maintained. The balloon 30 is expanded at a pressure (for example, 4 atmospheres) lower than a pressure (for example, 8 atmospheres) at the time of use in the blood vessel. Note that the coating layer 40 can also be formed on the outer surface of the balloon 30 without expanding the balloon 30, and in this case, it is not necessary to supply the expansion fluid into the balloon 30.

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 60.

Next, the position of the moving table 81 is adjusted, and the dispensing tube 94 is positioned with respect to the balloon 30. At this time, the dispensing tube 94 is positioned at the most distal end position where the coating layer 40 is formed in the balloon 30. As an example, the extending direction (discharge direction) of the dispensing tube 94 is opposite to the rotation direction of the balloon 30 as shown in FIG. Accordingly, the balloon 30 rotates in the direction opposite to the direction in which the coating liquid 45 is discharged from the dispensing tube 94 at the position where the dispensing tube 94 is brought into contact. Thereby, physical stimulation can be given to the coating liquid 45 and formation of the crystal nucleus of a drug crystal can be promoted. The extending direction (discharge direction) toward the opening 95 of the dispensing tube 94 is the direction opposite to the rotation direction of the balloon 30, so that the water-insoluble drug formed on the metal layer 37 on the surface of the balloon 30. The crystal is easily formed to include a morphological form 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.

Next, as shown in FIGS. 4 and 5, the balloon catheter 10 is rotated by the rotation mechanism 60. Subsequently, while the amount of liquid fed is adjusted by the liquid feed pump 93 and the coating liquid 45 is supplied to the dispensing tube 94, the moving table 81 is moved to move the dispensing tube 94 along the axial direction of the balloon 30. Gradually move toward the proximal direction. The coating liquid 45 discharged from the opening 95 of the dispensing tube 94 is applied while drawing a spiral on the outer peripheral surface of the metal layer 37 as the dispensing tube 94 moves relative to the balloon 30. By rotating the balloon 30, the coating liquid 45 applied to the outer peripheral surface of the metal layer 37 tends to be uniform in the circumferential direction.

The moving speed of the dispensing tube 94 is not particularly limited, but is, for example, 0.01 to 2 mm / sec, preferably 0.03 to 1.5 mm / sec, and more preferably 0.05 to 1.0 mm / sec. The discharge speed of the coating liquid 45 from the dispensing tube 94 is not particularly limited, but is, for example, 0.01 to 1.5 μL / sec, preferably 0.01 to 1.0 μL / sec, more preferably 0.03 to 0. .8 μL / sec. The rotation speed of the balloon 30 is not particularly limited, but is, for example, 10 to 300 rpm, preferably 30 to 250 rpm, and more preferably 50 to 200 rpm. The diameter of the balloon 30 when applying the coating liquid 45 is not particularly limited, but is, for example, 1 to 10 mm, preferably 2 to 7 mm.

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 metal layer 37 on the surface of the balloon 30 in the axial direction. After the layer of the coating liquid 45 is formed over the entire coating range of the metal layer 37, the moving mechanism unit 80 and the coating liquid supply unit 90 are stopped. Since the solvent contained in the coating liquid 45 is low in volatility, the coating liquid 45 on the metal layer 37 is applied even after the coating liquid 45 is completely applied to the entire area where the coating layer 40 of the metal layer 37 is formed. In the entire range, the solvent remains.

Thereafter, the dispensing tube 94 is separated from the metal layer 37. Next, as illustrated in FIG. 6, the control unit 100 causes the power supply 112 to supply current to the terminal 111 in a state where the terminal 111 is in contact with the distal end portion and the proximal end portion of the balloon 30. As a result, a current flows through the metal layer 37, the metal layer 37 generates heat, and the volatilization of the solvent of the coating liquid 45 applied to the balloon 30 is promoted. At this time, the balloon 30 is rotated and the coating liquid 45 is heated in a state where the solvent of the coating liquid 45 remains in the whole range applied, so that the coating liquid 45 is kept uniform while maintaining the uniformity of the coating liquid 45. It is possible to simultaneously promote crystallization of the drugs under the same conditions. 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. After the predetermined time has elapsed and the solvent is completely volatilized to form the coat layer 40, the control unit 100 stops the supply of current from the power source 112 and stops the rotation of the balloon 30. Note that the supply of current from the power source 112 and the rotation of the balloon 30 may be stopped before the volatilization of the solvent is completely completed.

The organic solvent contained in the coating solution applied to the metal layer 37 on the outer surface of the balloon 30 is volatilized 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 metal layer 37. 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 drug crystal 42 containing a plurality of crystals each having an independent long axis is formed on the outer surface of the film. The base of the drug crystal 42 is located on the outer surface of the metal layer 37, the surface of the additive 41, or inside the additive 41 (see FIG. 3). After the organic solvent is volatilized and the drug crystals 42 are deposited, water is evaporated more slowly than the organic solvent, and an additive 41 containing a water-soluble low-molecular compound is formed. The time for which water evaporates 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 solution applied, etc., for example, about 1 to 600 seconds It is.

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

As shown in FIG. 7A, the balloon 30 has a substantially circular cross section in a state where the expansion fluid is injected therein. From this state, the balloon 30 is formed with the protruding blade portion 32, so that the blade outer portion 34a constituting the outer surface of the blade portion 32 and the inner portion of the blade portion 32 are formed as shown in FIG. A blade inner portion 34b constituting the side surface and an intermediate portion 34c located between the blade outer portion 34a and the blade inner portion 34b are formed. From this state, as shown in FIG. 7C, the blade portion 32 protruding outward in the radial direction is folded in the circumferential direction. When the blade portion 32 of the balloon 30 is folded, the blade outer portion 34a that forms the outer surface of the blade portion 32, the blade inner portion 34b that forms the inner surface of the blade portion 32, the blade outer portion 34a, and the blade inner portion 34b. An intermediate portion 34c located between the two is formed. When the blade portion 32 of the balloon 30 is folded, the blade inner portion 34b and the intermediate portion 34c overlap and come into contact with each other, and an overlapping portion 35 is formed in which the outer surfaces of the balloon 30 face each other and overlap. And a part of intermediate part 34c and the blade | wing outer side part 34a are not covered with the blade | wing inner side part 34b, but are exposed outside. Further, in a state where the balloon 30 is folded, a root-side space portion 36 is formed between the root portion of the blade portion 32 and the intermediate portion 34c. In the area of the root side space part 36, a minute gap is formed between the blade part 32 and the intermediate part 34c. On the other hand, the region on the tip side of the base side space portion 36 of the blade portion 32 is in close contact with the intermediate portion 34c. The ratio of the circumferential length of the base side space portion 36 to the circumferential length of the blade portion 32 is in the range of 1 to 95%. The blade outer portion 34a of the balloon 30 receives a pressing force that rubs in the circumferential direction from a blade for folding the balloon 30, and is further heated. As a result, the long drug crystal 42 provided on the blade outer portion 34 a falls down on the surface of the balloon 30 and is easy to sleep. It is not necessary for all of the drug crystal 42 to sleep.

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

Next, a method of using the balloon catheter 10 according to this embodiment 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 removing the protective sheath 15 of the balloon catheter 10 and performing priming, 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 sent into the balloon 30 through the expansion lumen 23. Thereby, as shown in FIG. 8, the folded balloon 30 is expanded, and the narrowed portion 300 is pushed and expanded by the balloon 30. At this time, the coat layer 40 provided on the reinforcing layer 35 on the surface of the balloon 30 comes into contact with the narrowed portion 300.

When the balloon 30 is expanded and the coat layer 40 is pressed against the living tissue, the 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 containing water-insoluble drug crystals is formed on the outer surface of the balloon 30. Forming a metal layer 37 by depositing a conductive metal on the outer surface of the substrate, applying a coating liquid 45 containing a drug and a solvent to the outer surface of the metal layer 37, and forming a coat layer 40 of the balloon 30 And after the application of the coating liquid 45 to the entire range is completed, in a state where the solvent of the coating liquid 45 remains, a current is passed through the metal layer 37 to generate heat and volatilize the solvent.

In the method of manufacturing the balloon catheter 10 configured as described above, the solvent of the coating liquid 45 is volatilized by heating with the metal layer 37 in a state where the solvent of the coating liquid 45 remains in the entire range applied. The crystallization of the entire range of drugs can be promoted simultaneously under substantially the same conditions. 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 step of volatilizing the solvent, an electric current is supplied to the metal layer 37 by the terminal 111 that slidably contacts the metal layer 37 while rotating the balloon 30 around the axis of the balloon 30. Thereby, an electric current can be sent through the metal layer 37 to volatilize the solvent without stopping the rotation of the balloon 30 that plays the role of making the coating liquid 45 uniform. For this reason, the drug crystal 42 can be formed uniformly, and the control of the morphological type of the drug is facilitated.

Solvents are 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 be 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, it becomes easy to make it the state which the solvent of the coating liquid 45 remains in the whole range which apply | coated until the coating liquid 45 is apply | coated to the whole application | coating range of the balloon 30. FIG. Therefore, the crystallization of the drug can be simultaneously promoted under substantially the same conditions in the entire range where the coating liquid 45 of the balloon 30 is applied at the timing when the current is supplied to the metal layer 37.

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 a blood vessel can be suppressed favorably.

In addition, the manufacturing apparatus 50 for the balloon catheter 10 according to the present embodiment applies a drug and a solvent to the outer surface of the rotation mechanism 60 that applies a rotational force to the balloon 30 and the metal layer 37 deposited on the rotating balloon 30. The coating liquid supply part 90 which apply | coats the coating liquid 45 to be included, and the terminal 111 which slidably contacts the metal layer 37 and supplies an electric current to the metal layer 37 are provided.

The manufacturing apparatus 50 configured as described above supplies a current to the metal layer 37 by the terminal 111 slidably contacting the metal layer 37 of the rotating balloon 30 in a state where the solvent of the coating liquid 45 remains. Thus, the metal layer 37 can generate heat, and the solvent of the coating liquid 45 can be volatilized. For this reason, crystallization of the whole range of the applied drug can be promoted simultaneously under substantially the same conditions. Therefore, the drug crystal 42 can be uniformly formed on the outer surface of the balloon 30 regardless of various conditions and the fluctuation of the technique, and the morphological type of the drug can be easily controlled.

The balloon catheter 10 according to this embodiment is a balloon catheter 10 that can be inserted into a living body lumen, and is provided on the distal side of the long catheter body 20 and the catheter body 20 so as to expand in the radial direction. A possible balloon 30, a metal layer 37 deposited on the outer surface of the balloon 30, and a water-insoluble drug crystal 42 disposed on the outer surface of the metal layer 37.

In the balloon catheter 10 configured as described above, since the drug crystal 42 is disposed on the outer surface of the metal layer 37, the transfer property of the drug to the living body is adjusted by the metal layer 37 having a surface structure different from that of the balloon 30. it can.

The present invention also includes a treatment method (therapeutic method) for delivering a drug to a lesion in a living body lumen using the balloon catheter 10. The treatment method includes a step of inserting the balloon 30 into the body lumen to reach the lesioned part, a step of expanding the balloon 30 and the metal layer 37 and pressing the body 30 against the living tissue, and bringing the drug crystal 42 into contact with the living tissue. And deflating the balloon 30 to remove it from the living body lumen.

In the treatment method configured as described above, since the drug crystal 42 arranged on the outer surface of the metal layer 37 is pressed against the living tissue by the balloon 30, the metal layer 37 having a surface structure different from that of the balloon 30 is used. Transferability to living tissue can be adjusted.

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

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

Further, as in the modification shown in FIG. 9, the balloon catheter 10 further includes a conductive wire 39 that is electrically connected to the metal layer 37 and extends proximally along the catheter body 20. May be. The conducting wire 39 can be connected to an external power supply device (not shown) via 28 provided on the hub 26. Thereby, an electric current can be supplied to the metal layer 37 disposed on the balloon 30 inserted in the living body via the conductive wire 39. For this reason, the drug crystal 42 can be heated by the metal layer 37 in the living body to improve the transferability of the drug to the living tissue.

Further, as in another modification shown in FIG. 10, the metal layer 37 may be partially provided on the outer surface of the balloon 30. A part of the balloon 30 has an exposed portion 38 where the metal layer 37 is not provided. The exposed portion 38 can be formed by masking the surface of the balloon 38 when the metal layer 37 is deposited on the balloon 30. The coat layer 40 is directly disposed on the exposed portion 38 of the balloon 30. Thereby, the site | part from which the transferability to the biological tissue of a chemical | medical agent differs on the balloon 30 can be formed arbitrarily. The shape of the exposed portion 38 is not particularly limited.

Furthermore, this application is based on Japanese Patent Application No. 2017-050838 filed on Mar. 16, 2017, the disclosures of which are referenced and incorporated as a whole.

DESCRIPTION OF SYMBOLS 10 Balloon catheter 20 Catheter main body 30 Balloon 37 Metal layer 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 Current Supply section 111 Terminal 120 Vapor deposition equipment

Claims

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,
Depositing a conductive metal on the outer surface of the balloon to form a metal layer;
Applying a coating liquid containing a drug and a solvent to the outer surface of the metal layer;
After the application of the coating liquid to the entire area of the balloon forming the coating layer is completed, with the solvent of the coating liquid remaining, an electric current is passed through the metal layer to generate heat and the solvent is removed. And a step of volatilizing the balloon catheter.
2. The balloon according to claim 1, wherein in the step of volatilizing the solvent, a current is supplied to the metal layer by a terminal that slidably contacts the metal layer while rotating the balloon about the axis of the balloon. A method for manufacturing a catheter.
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 claim 1 or 2, 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 3, 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 supply unit for applying a coating liquid containing a drug and a solvent to the outer surface of the metal layer deposited on the rotating balloon;
And a terminal for supplying current to the metal layer in slidable contact with the metal layer.
A balloon catheter that can be inserted into a body lumen,
A long catheter body;
A balloon provided on the distal side of the catheter body and radially expandable;
A conductive metal layer deposited on the outer surface of the balloon;
A water-insoluble drug crystal disposed on the outer surface of the metal layer;
And a conductive wire electrically connected to the metal layer and extending proximally along the catheter body.
A treatment method for delivering a drug to a lesion in a living body lumen using the balloon catheter according to claim 6,
Inserting the balloon into the body lumen to reach the lesion;
Expanding the balloon and the metal layer to press against the living tissue and bringing the drug crystal into contact with the living tissue;
Heating the drug crystal by causing an electric current to flow to the metal layer through the conductive wire to generate heat in the metal layer;
Deflating the balloon and removing it from the living body lumen.