JP2018153286A - Balloon coating method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a balloon coating method for forming a uniform crystal on a surface of a balloon without being affected by external factors.SOLUTION: There is provided a balloon coating method for forming a coat layer 30 on a surface of a balloon 11 in a catheter 1 having the balloon 11 on a tip of a shaft 10, having a step for supplying a coating liquid containing an agent from a supply part 92 and applying the same while rotating the supply part 92 around a shaft center of the shaft 10 to a surface of the balloon 11, a step for coating at least an apply part of the balloon 11 with an evacuation dryer 100 at a state that the coating liquid is not dried after applying the coating liquid over whole apply part of the balloon 11, and a step for volatilizing a solvent of the coating liquid by reducing pressure in the evacuation dryer 100.SELECTED DRAWING: Figure 3

Description

  The present invention relates to a method of coating a drug on the balloon surface of a balloon catheter.

  A balloon catheter is widely used to improve a lesion (stenosis) occurring in a living body lumen. The balloon catheter usually includes a long catheter shaft and a balloon that is provided on the distal end side of the catheter shaft 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.

  On the other hand, if the lesioned part is forcibly expanded by a balloon, the endothelial cells may proliferate excessively and may cause new stenosis (restenosis) in the lesioned part. For this reason, recently, a drug eluting balloon (DEB) in which a balloon surface is coated with a drug for suppressing stenosis has been used. By expanding the drug-eluting balloon, the drug coated on the surface can be released to the lesioned part, and the drug can be transferred to the living tissue, thereby suppressing restenosis.

  Examples of methods for forming a coating layer containing a drug on a balloon include a spray method, a drop method, and a stringing method. The spray method is a method in which a coating liquid containing a drug is sprayed in a mist form from a nozzle that does not contact the balloon, and then the coating liquid is dried to form a coating layer on the surface of the balloon. The drop method is a method of forming a coating layer on the surface of the balloon by dropping the coating liquid from a nozzle that does not contact the balloon and then drying the coating liquid. The thread drawing method is a method in which a coating liquid is supplied onto the surface of the balloon via a thread or the like that contacts the balloon, and then the coating liquid is dried to form a coating layer on the surface of the balloon.

  When applying the coating liquid to the balloon by the various methods described above, the entire surface of the balloon is moved by moving the nozzle, thread, and other devices for supplying the coating liquid in the axial direction of the balloon while rotating the balloon. A coating solution can be applied to the substrate (for example, see Patent Document 1).

Japanese Patent No. 4906926

  In the drug coating on the balloon, in order to make the drug crystals in the desired type, size, and shape, the formulation of solvent type, ratio, amount, etc. of the coating solution, coating method, coating parameters such as temperature and flow rate, etc. It is necessary to control precisely.

  In the actual coating, there are fluctuation factors in the environment such as the temperature of the manufacturing room and the airflow. In addition, there are factors such as variations in operator's technique and individual differences in the coating liquid and balloon, resulting in variations in the crystal formation process, and the target crystals may not be formed uniformly.

  The present invention has been made to solve the above-described problems, and an object of the present invention is to provide a balloon coating method for forming uniform crystals on the surface of a balloon without being affected by external factors.

The balloon coating method according to the present invention for achieving the above object is a balloon coating method for forming a coating layer on the surface of the balloon in a catheter having a balloon at the tip of a shaft,
Supplying and applying a coating liquid containing a drug from a supply unit while rotating about the axis of the shaft with respect to the surface of the balloon;
When the coating liquid is applied to the entire balloon application site, the coating liquid is in an undried state, and at least the balloon application site is covered with a vacuum dryer;
Reducing the pressure in the vacuum dryer to volatilize the solvent of the coating solution;
Have

  In the balloon coating method configured as described above, the coating liquid on the surface of the balloon dries as the pressure is reduced, so that the crystallization of the drug can be controlled by adjusting the pressure in the vacuum dryer. Thereby, the same crystal can always be formed on the surface of the balloon, and the variation can be reduced.

  When the pressure in the vacuum dryer is reduced to volatilize the solvent of the coating solution, the balloon is rotated about the shaft center. Thereby, the coating layer can be uniformly formed on the surface of the balloon without being biased in the circumferential direction of the balloon when the coating liquid dries.

  The vacuum dryer can control the crystallization rate of the drug by increasing the degree of vacuum over time.

  If the inside of the vacuum dryer is heated during decompression, the solvent of the coating solution can be volatilized faster and the time required for crystallization can be shortened.

  In order to air-tighten the inside of the vacuum dryer, the vacuum dryer covers the tip of the balloon and the long shaft provided on the proximal end side of the balloon so as to cover the tip near the balloon. What is necessary is just to seal the outer peripheral surface of a shaft, and the area | region to seal can be made into the minimum and airtightness can be made high.

  The balloon is connected to a pressure adjusting unit that adjusts an internal pressure, and the internal pressure of the balloon is adjusted by the pressure adjusting unit so as to maintain a constant volume of the balloon when the inside of the vacuum dryer is depressurized. Is done. Thereby, when the inside of the vacuum dryer is depressurized, the shape of the balloon can be prevented from changing, and the state in which the coating liquid is uniformly applied to the surface of the balloon can be maintained. For this reason, a coat layer can be uniformly formed on the surface of the balloon.

  If the drug contained in the coating solution is rapamycin, paclitaxel, docetaxel, or everolimus, restenosis of the stenosis in the blood vessel can be satisfactorily suppressed.

  Solvents contained in the coating solution are water, acetic acid, i-butyl alcohol, s-butyl alcohol, t-butyl alcohol, propanol, butanol, toluene, ethylene glycol, benzene, chlorohexane, glycerin, ethanol, hexane, and ethyl acetate. If at least one selected from the group consisting of o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, and cyclohexane is contained, the volatility of the solvent is reduced, and the balloon The solvent is less likely to evaporate from the applied coating solution. This ensures that the balloon surface is kept in a wet state until the pressure is reduced by the vacuum dryer after the coating solution is applied, and the drug is crystallized under certain conditions in the vacuum dryer. it can.

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 whole block diagram of a balloon coating apparatus. It is a whole block diagram of the balloon coating apparatus of the state which covered the balloon with the vacuum dryer. FIG. 7 is a cross-sectional view of a state before the balloon is folded (FIG. 6A), a state in which blades are formed on the balloon (FIG. 6B), and a state in which the balloon is folded (FIG. 6C). It is sectional drawing which shows the state which expanded the stenosis part of the blood vessel with the balloon catheter.

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

  First, the structure of the catheter 1 will be described. As shown in FIGS. 1 and 2, the catheter 1 includes a long shaft 10, a balloon 11 provided at the tip of the shaft 10, a coat layer 30 containing a drug provided on the outer surface of the balloon 11, and the shaft 10. And a hub 12 fixed to the base end of the head.

  The shaft 10 includes an outer tube 20 that is a tubular body having an open front end and a base end, and an inner tube 21 that is a tubular body disposed inside the outer tube 20. The inner tube 21 is housed in the hollow interior of the outer tube 20, and the shaft 10 has a double tube structure at the tip. The hollow interior of the inner tube 21 is a guide wire lumen 23 through which the guide wire is inserted. Further, an expansion lumen 22 through which the expansion fluid of the balloon 11 is circulated is formed inside the hollow of the outer tube 20 and outside the inner tube 21. The inner tube 21 opens to the outside at the opening 24. The inner tube 21 protrudes further to the distal end side than the distal end of the outer tube 20.

The balloon 11 has a proximal end portion fixed to the distal end portion of the outer tube 20, and a distal end portion fixed to the distal end portion of the inner tube 21. Thereby, the inside of the balloon 11 communicates with the expansion lumen 22. The balloon 11 can be expanded by injecting the expansion fluid into the balloon 11 via the expansion lumen 22. 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, a mixed gas thereof, or a liquid such as physiological saline or contrast medium may be used. Can be used.

  A cylindrical straight portion 11a (expanded portion) having the same outer diameter when expanded is formed in the central portion in the axial direction of the balloon 11, and the outer diameter gradually increases on both sides of the straight portion 11a in the axial direction. A taper portion 11b that changes to is formed. And the coat layer 30 containing a chemical | medical agent is formed in the whole outer surface of the straight part 11a. In addition, the range in which the coating layer 30 is formed in the balloon 11 is not limited to the straight portion 11a, but may include at least a part of the tapered portion 11b in addition to the straight portion 11a, or one of the straight portions 11a. It may be only part.

  The hub 12 is formed with a proximal end opening 40 that communicates with the expansion lumen 22 of the outer tube 20 and functions as a port through which expansion fluid flows in and out.

  The length of the balloon 11 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 | swelling of the balloon 11 is not specifically limited, Preferably it is 1-10 mm, More preferably, it is 2-8 mm.

  The outer surface before the coating layer 30 of the balloon 11 is formed is smooth and nonporous. The outer surface of the balloon 11 before the coating layer 30 is formed may have minute holes that do not penetrate the membrane. Alternatively, the outer surface of the balloon 11 before the coating layer 30 is formed may have both a smooth and non-porous range and a range with a minute hole that does 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.

  The balloon 11 preferably has a certain degree of flexibility and is expanded when the blood vessel or tissue is reached, and has a certain degree of hardness so that the drug can be released from the coat layer 30 provided on the outer surface thereof. Specifically, the balloon 11 is made of metal or resin, but at least the outer surface of the balloon 11 on which the coat layer 30 is provided is preferably made of resin. The constituent material of at least the outer surface of the balloon 11 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, 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 11 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, the 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 or aliphatic polyester as a soft segment is also a material of the balloon 11. Used as The said polyamides may be used individually by 1 type, and may use 2 or more types together. In particular, the balloon 11 preferably has a smooth surface of polyamide.

  The coating layer 30 is formed on the outer surface of the balloon 11 directly or via a pretreatment layer such as a primer layer by a method described later. As shown in FIG. 3, the coat layer 30 extends with an independent long axis and an additive 130 (excipient) containing a water-soluble low-molecular compound arranged in a layer on the outer surface of the balloon 11. And a water-insoluble drug crystal 131. The end of the drug crystal 131 may be in direct contact with the outer surface of the balloon 11, but the additive 130 exists between the end of the drug crystal 131 and the outer surface of the balloon 11 without being in direct contact. May be. The end portion of the drug crystal 131 may be positioned on the surface of the layer of the additive 130, and the drug crystal 131 may protrude from the additive 130. The plurality of drug crystals 131 may be regularly arranged on the outer surface of the balloon 11. Alternatively, the plurality of drug crystals 131 may be irregularly arranged on the outer surface of the balloon 11.

The amount of drug contained in the coat layer 30 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 30 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 131 may have a form having independent long axes. In addition, the drug crystal 131 may have other morphological types. The plurality of drug crystals 131 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 131 forming different angles. The plurality of drug crystals 131 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 131 in a combined state and a plurality of drug crystals 131 independent from each other on the surface of the balloon 11. The plurality of drug crystals 131 may be arranged in a brush shape around the circumference having different major axis directions. Each of the drug crystals 131 exists independently, has a certain length, and one end (base end) of the length portion is fixed to the additive 130 or the balloon 11. The drug crystal 131 does not form a complex structure with the adjacent drug crystal 131 and is not connected. The major axis of the crystal is almost linear. The drug crystal 131 forms a predetermined angle with respect to the surface with which the base where the major axes intersect is in contact.

  The drug crystals 131 preferably stand independently without contacting each other. The base of the drug crystal 131 may be in contact with another base on the base material of the balloon 11. Alternatively, the base of the drug crystal 131 may be independent on the base material of the balloon 11 without coming into contact with other bases.

  The drug crystal 131 may be hollow or solid. Both the hollow drug crystal 131 and the solid drug crystal 131 may exist on the surface of the balloon 11. When the drug crystal 131 is hollow, at least the vicinity of the tip thereof is hollow. The cross section of the drug crystal 131 in a plane perpendicular to the major axis of the drug crystal 131 (perpendicular) has a hollow shape. The hollow drug crystal 131 has a polygonal cross section of the drug crystal 131 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 131 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 131 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 131 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 major axis direction of the drug crystal 131 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 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 131 having the long axis is linear in the long axis direction, but may be curved. Both the linear drug crystal 131 and the curved drug crystal 131 may exist on the surface of the balloon 11.

  The above-mentioned crystal form type having a crystal having a long axis is 50% by volume or more, more preferably 70% by volume or more with respect to the entire drug crystal on the outer surface of the balloon 11. The drug crystal 131 which is a crystal particle having a long axis is formed so as to stand on the outer surface of the balloon 11 or the additive 130 without lying. The additive 130 is present in the region where the drug crystal 131 is present, and may not be present in the region where the drug crystal 131 is absent.

  The additive 130 is distributed in the space between the plurality of drug crystals 131 that stand. The proportion of the substance constituting the coat layer 30 is preferably such that the water-insoluble drug crystal 131 occupies a larger volume than the additive 130. Additive 130 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 130 may form a matrix.

  The additive 130 is coated on the outer surface of the balloon 11 while being dissolved in a solvent, and then dried to form a layer. The additive 130 is amorphous. The additive 130 may be crystal particles. Additive 130 may be present as a mixture of amorphous and crystalline particles. The additive 130 of FIG. 3 is in the state of crystalline particles and / or particulate amorphous. Alternatively, the additive 130 may be in a film-like amorphous state. The additive 130 is formed as a layer containing a water-insoluble drug. Alternatively, the additive 130 may be formed as a separate layer that does not contain a water-insoluble drug. The thickness of the additive 130 is 0.1 to 5 μm, preferably 0.3 to 3 μm, more preferably 0.5 to 2 μm.

  The layer containing the long crystalline form type drug crystal 131 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 131 having a long crystal form type has a small crystal size (length in the long axis direction) of about 10 μm that moves to the tissue. Therefore, it acts uniformly on the affected part of the lesion and increases tissue permeability. Furthermore, since the size of the transferred drug crystal 131 is small, an excessive amount of drug does not stay in the affected part for an excessive period of time, so that it is possible to exhibit a high stenosis-inhibiting effect without developing toxicity. Think.

  The drug coated on the outer surface of the balloon 11 may include an amorphous type. The drug crystal 131 and the amorphous may be arranged so as to have regularity in the coat layer 30. Alternatively, crystals and amorphous materials may be arranged irregularly.

  Next, the balloon coating apparatus 2 for forming the coat layer 30 on the balloon 11 will be described. The balloon coating apparatus 2 can form the coat layer 30 on the balloon 11. As shown in FIG. 4, the balloon coating apparatus 2 includes a rotation mechanism 50 that rotates the catheter 1 and a support base 70 that supports the catheter 1. The balloon coating apparatus 2 further includes an application mechanism 80 provided with a tube-like supply unit 92 for applying a coating liquid to the surface of the balloon 11, a moving mechanism 60 for moving the supply unit 92 with respect to the balloon 11, A vacuum dryer 100 that covers the balloon 11 and can decompress the inside, and a control unit 120 that controls the balloon coating apparatus 2 are provided.

  The rotation mechanism 50 holds the hub 12 of the catheter 1 and rotates the catheter 1 about the axis of the shaft 10 by a drive source such as a built-in motor. In the catheter 1, the core material 51 is inserted and held in the guide wire lumen 23, and the core material 51 prevents the coating liquid from flowing into the guide wire lumen 23. Further, in the catheter 1, a three-way cock that can open and close the flow path is connected to the proximal end opening 40 of the hub 12 in order to operate the flow of fluid to the expansion lumen 22.

  The support base 70 includes a tubular proximal end support portion 71 that accommodates the shaft 10 in a rotatable manner and a distal end support portion 72 that rotatably supports the core member 51. Note that the tip side support portion 72 may rotatably support the tip portion of the shaft 10 instead of the core material 51 if possible.

  The moving mechanism 60 includes a moving table 61 that can move linearly in a direction parallel to the axis of the shaft 10 and a tube fixing portion 62 to which the supply portion 92 is fixed. The moving table 61 can move linearly by a driving source such as a built-in motor. An application mechanism 80 is placed on the moving table 61, and the application mechanism 80 is linearly moved in both directions along the axis of the shaft 10. Further, the moving mechanism 60 can move horizontally as a whole while the coating mechanism 80 is placed. In FIG. 4, the moving table 61 is arranged so as to cover the upper side of the catheter 1, but when the moving mechanism 60 moves, the upper side of the catheter 1 is opened and the vacuum dryer 100 covers the balloon 11. Can be able to.

  The application mechanism 80 includes a supply container 90 that stores the coating liquid, a liquid supply pump 91 that supplies the coating liquid in an arbitrary amount, and a supply unit 92 that applies the coating liquid to the balloon 11. The liquid feed pump 91 is a syringe pump, for example, and is controlled by the control unit 120. The liquid feed pump 91 can suck the pretreatment liquid from the supply container 90 through the suction pipe 93 and supply the coating liquid to the supply section 92 through the supply pipe 94 in an arbitrary liquid feed amount. The liquid feed pump 90 is installed on the moving table 61. The liquid feed pump 90 is not limited to a syringe pump as long as the coating liquid can be fed, and may be, for example, a tube pump.

  The supply unit 92 communicates with the supply pipe 94 and discharges the coating liquid supplied from the liquid feed pump 91 through the supply pipe 94 to the surface of the balloon 11. The supply unit 92 is a tubular member. The supply unit 92 has an upper end fixed to the tube fixing unit 62. The supply unit 92 extends downward from the tube fixing unit 62 in the vertical direction, and is formed with a discharge port 92a that opens at the lower end.

  The supply unit 92 can move linearly in both directions along the axial direction of the catheter 1 together with the liquid feeding pump 91 installed on the moving table 61 by moving the moving table 61. The supply unit 92 does not have to be a circular tube as long as the coating liquid can be supplied. The supply unit 92 may not extend in the vertical direction as long as the coating liquid can be discharged from the discharge port 92a.

In this embodiment, the supply part 92 is arrange | positioned so that a front-end | tip part may contact the surface of the balloon 11. FIG. Thereby, crystallization on the surface of the balloon 11 can be promoted. Supply unit 9
The material 2 is preferably a flexible material so as to reduce the contact load on the balloon 11 and absorb the change in the contact position accompanying the rotation of the balloon 11 by bending. Constituent materials of the supply unit 92 are, for example, polyolefins such as polyethylene and polypropylene, cyclic polyolefins, polyesters, polyamides, polyurethanes, PTFE (polytetrafluoroethylene), ETFE (tetrafluoroethylene / ethylene copolymer), PFA (tetrafluoroethylene). Fluorine-based resins such as ethylene / perfluoroalkyl vinyl ether copolymer) and FEP (tetrafluoroethylene / hexafluoropropylene copolymer) can be applied, but if they are flexible and deformable, There is no particular limitation. The supply unit 92 can also be arranged so as not to contact the balloon 11. In this case, various materials such as a soft or hard resin material or a metal material can be used for the supply unit 92.

  Although the outer diameter of the supply part 92 is not specifically limited, For example, it is 0.1 mm-5.0 mm, Preferably it is 0.15 mm-3.0 mm, More preferably, it is 0.3 mm-2.5 mm. Although the internal diameter of the supply part 92 is not specifically limited, For example, it is 0.05 mm-3.0 mm, Preferably it is 0.1 mm-2.0 mm, More preferably, it is 0.15 mm-1.5 mm. Although the length of the supply part 92 is not specifically limited, It is good that it is the length within 5 times the balloon diameter, for example, 1.0 mm-50 mm, Preferably it is 3 mm-40 mm, More preferably, it is 5 mm-35 mm.

  The vacuum dryer 100 has a space inside thereof that can cover the balloon 11 supported by the support base 70 and its surroundings. The vacuum dryer 100 can depressurize the space in an airtight state. The vacuum dryer 100 is disposed at a position away from the balloon 11 as shown in FIG. 4 when the coating liquid is applied to the balloon 11. When the coating liquid is applied to the balloon 11, the moving mechanism 60 moves from above the balloon 11 to another place, and instead, the reduced-pressure dryer 100 moves to cover the balloon 11 as shown in FIG. .

  The vacuum dryer 100 needs to be airtight to the outside in order to reduce the pressure in the internal space. For this reason, the vacuum dryer 100 covers the entire balloon 11, the distal end support portion 72 that supports the balloon 11 on the distal end side, and the distal end portion of the shaft 10. If the bottom surface of the vacuum dryer 100 is airtight, the portion where the interior of the vacuum dryer 100 communicates with the outside is a portion of the surface of the shaft 10. A seal portion 100a is provided for hermetically sealing the outer periphery. The seal portion 100a allows the shaft 10 to rotate while hermetically sealing the outer peripheral surface of the shaft 10, and is formed by rubber packing or the like.

  In a state where the vacuum dryer 100 covers the balloon 11, the pressure adjusting unit 101 is connected to the proximal end opening 40 of the hub 12. The pressure adjustment unit 101 can control the internal pressure of the balloon 11 under the control of the control unit 120. The pressure adjustment unit 101 may be one that adjusts the pressure manually like a syringe in addition to the one that automatically adjusts the pressure under the control of the control unit 120 as described above.

  The control unit 120 is configured by, for example, a computer, and comprehensively controls the rotation mechanism 50, the movement mechanism 60, the coating mechanism 80, the vacuum dryer 100, and the pressure adjustment unit 101. Therefore, the control unit 120 controls the rotation speed of the balloon 11, the moving speed of the supply unit 92 in the axial direction relative to the balloon 11, the discharge speed of the coating liquid from the supply unit 92, the reduced pressure inside the vacuum dryer 100, and the pressure adjustment. The internal pressure or the like of the balloon 11 by the unit 101 can be comprehensively controlled.

  The coating liquid supplied to the surface of the balloon 11 by the supply unit 92 is a solution or suspension containing the constituent material of the coat layer 30 and includes a water-insoluble drug, an excipient, an organic solvent, and water. After the coating liquid is supplied to the surface of the balloon 11, the organic solvent and water are volatilized, so that a large number of water-insoluble drug crystals extending on the surface of the balloon 11 with independent long axes are formed. A coat layer 30 having a scale is formed. The viscosity of the coating liquid 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 the same medicinal effect. 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 excipient forms a base layer on which a long body that is a crystal of a water-insoluble drug is erected on the balloon 11. The excipient contains a water-soluble low molecular weight compound. The molecular weight of the water-soluble low molecular weight compound is 50 to 2000, preferably 50 to 1000, more preferably 50 to 500, and 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. 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 monogalbonic acid, pharmaceutically acceptable salt and surfactant An agent, etc., 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 excipient is preferably amorphous on the balloon 11. The excipient containing the water-soluble low-molecular compound has an effect of uniformly dispersing the water-insoluble drug on the surface of the balloon 11. Furthermore, since the base layer is easily dissolved when the balloon 11 is expanded in the blood vessel, it is easy to release the long body of the water-insoluble drug on the surface of the balloon 11, and the effect of increasing the adhesion amount of the drug to the blood vessel. Have

  A solvent in which the drug is dissolved is selected to have a low volatility. The solvent is preferably a non-freezing solvent. A non-freezing solvent is a solvent that does not freeze even under reduced pressure. The coating liquid containing the solvent is required not to be dried until it is applied to the surface of the balloon 11 from the front end to the base end by the application mechanism 80 and then covered with the vacuum dryer 100 and the inside is decompressed. The volatility can be lowered by adjusting the viscosity of the coating liquid and the concentration of the organic solvent. The substance of the organic solvent is not particularly limited, but tetrahydrofuran, acetone, glycerin, acetic acid, i-butyl alcohol, s-butyl alcohol, t-butyl alcohol, propanol, butanol, toluene, ethylene glycol, glycerin, o-dichlorobenzene, Of o-xylene, p-xylene, cyclohexanol, styrene, cyclohexane, ethanol, methanol, dichloromethane, hexane, ethyl acetate, water, among these tetrahydrofuran, ethanol, acetone, and water, some of these are preferred. For example, a combination of tetrahydrofuran and water, tetrahydrofuran and ethanol and water, tetrahydrofuran and acetone and water, acetone and ethanol and water, tetrahydrofuran, acetone, ethanol, and water can be used. Particularly, the low-volatile solvents include water, acetic acid, i-butyl alcohol, s-butyl alcohol, t-butyl alcohol, propanol, butanol, toluene, ethylene glycol, benzene, chlorohexane, glycerin, ethanol, hexane, and ethyl. It is preferable to contain at least one selected from the group consisting of acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, and cyclohexane.

  Next, a method for forming water-insoluble drug crystals on the surface of the balloon 11 using the above-described balloon coating apparatus 2 will be described. The coating process includes a first step of applying a coating solution to the surface of the balloon 11, a second step of covering the balloon 11 with a vacuum dryer 100, depressurizing the inside, and drying the coating solution to crystallize the drug. have. The first step is performed with the balloon coating apparatus 2 in the state of FIG. The second step is performed with the balloon coating apparatus 2 in the state shown in FIG.

  First, the first step will be described. First, an expansion fluid is supplied into the balloon 11 through a three-way cock connected to the proximal end opening 40 of the hub 12. Next, in a state where the balloon 11 is expanded, the three-way cock is operated to seal the expansion lumen 22, and the state where the balloon 11 is expanded is maintained. The balloon 11 is expanded at a pressure (for example, 4 atmospheres) lower than the pressure (for example, 8 atmospheres) at the time of use in the blood vessel.

  Next, the catheter 1 is rotatably installed on the support base 70, and the hub 12 is connected to the rotation mechanism 50. Next, the supply unit 92 is positioned with respect to the balloon 11 by adjusting the position of the moving table 61. At this time, the discharge port 92 a of the supply unit 92 is positioned so as to be close to the position on the most distal end side where the coating layer 30 is formed in the balloon 11.

  Next, the catheter 1 is rotated in the axial direction by the rotation mechanism 50 and the coating liquid is discharged from the supply unit 92 toward the balloon 11 while moving the moving table 61. The discharge amount of the coating liquid is adjusted by a liquid feed pump 91. By the moving table 61, the supply unit 92 moves from the distal end side of the balloon 11 toward the proximal end side. As the balloon 11 rotates and moves linearly, the coating liquid is applied to the surface of the balloon 11 while drawing a spiral.

  Although the moving speed of the supply part 92 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 amount of the coating liquid supply unit 92 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 11 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 11 at the time of apply | coating a coating liquid is not specifically limited, For example, it is 1-10 mm, Preferably it is 2-7 mm.

  When the coating liquid is applied to the surface of the balloon 11, the second step is subsequently performed. As described above, before the coating liquid applied to the balloon 11 is dried, the balloon 11 is covered with the vacuum dryer 100 as shown in FIG. The balloon 11 covered with the vacuum dryer 100 is kept rotated in the axial direction by the rotation mechanism 50. In this state, the inside of the vacuum dryer 100 is depressurized. The depressurization is gradually performed over a predetermined time so that the degree of depressurization increases with time. The time for depressurization is, for example, 1 to 900 seconds. The pressure may be reduced stepwise by setting the degree of vacuum to 500 to 250 Torr and reducing pressure for 10 to 180 seconds, and then setting the degree of vacuum to 100 to 10 Torr and reducing pressure for 10 to 600 seconds. . Moreover, you may dry under reduced pressure, carrying out bumping by making it reduce pressure rapidly. When the outside of the balloon 11 is depressurized, the balloon 11 is further expanded if the internal pressure remains the same, so that the internal pressure of the balloon 11 is lowered by the pressure adjusting unit 101 so that the shape of the balloon 11 is not changed from before the depressurization.

  By reducing the pressure around the balloon 11, the coating liquid applied to the surface of the balloon 11 is volatilized. At this time, the organic solvent contained in the coating liquid volatilizes before water. Therefore, the organic solvent volatilizes in a state where the water-insoluble drug, the water-soluble low molecular weight compound, and water remain on the surface of the balloon 11. As described above, when the organic solvent is volatilized with water remaining, the water-insoluble drug is precipitated inside the water-soluble low-molecular compound containing water, and the crystal gradually grows from the crystal nucleus. As shown in FIG. 4, a morphological form of drug crystal including a plurality of drug crystals 131 each having a long axis independent of each other is formed on the surface of the balloon 11. The crystallization rate of the drug crystal 131 can be controlled by the reduced pressure rate in the reduced pressure dryer 100 and the reduced pressure arrival point. The drug crystal 131 in this state stands on the surface of the balloon 11. The proximal end of the drug crystal 131 may be located on the surface of the balloon 11, the surface of the additive 130, or the inside thereof. After the organic solvent is volatilized and the drug crystals are precipitated as a plurality of drug crystals 131, the water is evaporated more slowly than the organic solvent, and the additive 130 containing the water-soluble low-molecular compound is formed. The time until the water evaporates is adjusted by the pressure inside the vacuum dryer 100, and is, for example, about 1 to 600 seconds. Further, the temperature in the vacuum dryer 100 may be increased during pressure reduction. As temperature at the time of temperature rise, it can be 10-60 degreeC, for example. By increasing the temperature in the vacuum dryer 100, the solvent can be volatilized faster.

  As described above, the balloon coating method of the present embodiment employs a method that does not easily volatilize in the coating liquid, prevents the coating liquid from drying while the coating liquid is applied to the balloon 11, and a vacuum dryer after applying the coating liquid. The balloon 11 is covered with 100, and the coating liquid is dried by reducing the pressure. For this reason, since the coating liquid is dried along with the reduced pressure, the crystallization of the drug can be controlled by adjusting the pressure. When the coating solution is naturally dried at atmospheric pressure, the same crystal is always obtained in crystallization of the drug because the crystal size and shape can change depending on parameters such as temperature and flow rate during coating and fluctuations in the procedure. However, in this embodiment, since the crystallization of the drug can be controlled by adjusting the pressure of the vacuum dryer 100, the same crystal can always be formed on the surface of the balloon 11, and the variation can be reduced.

  Further, when the periphery of the balloon 11 is depressurized, the rotation state along the axial direction of the balloon 11 is maintained, so that the coating liquid is not biased in the circumferential direction of the balloon 11 and is uniformly applied to the surface of the balloon 11. The coat layer 30 can be formed.

  After the coat layer 30 having the drug crystals 131 is formed, the rotation mechanism 50 is stopped, and the inside of the vacuum dryer 100 is returned to the atmospheric pressure and moved to expose the balloon 11. Thereafter, the catheter 1 is removed from the balloon coating apparatus 2, and the coating of the balloon 11 is completed.

  As shown in FIG. 6A, the balloon 11 has a substantially circular cross section in a state where the expansion fluid is injected therein. From this state, the balloon 11 is formed with the protruding blade portion 140, and as shown in FIG. 6B, the blade outer portion 140 b constituting the outer surface of the blade portion 140 and the inner portion of the blade portion 140 are formed. A blade inner portion 140a constituting the side surface, and an intermediate portion 140c positioned between the blade outer portion 140b and the blade inner portion 140a are formed. From this state, as shown in FIG.6 (c), the blade | wing part 140 which protrudes to a radial direction outer side is folded by the circumferential direction. When the wing part 140 of the balloon 11 is folded, the wing inner part 140a and the intermediate part 140c are overlapped and contacted to form an overlapping part 141 where the outer surfaces of the balloon 11 are opposed to each other. And a part of intermediate part 140c and the blade | wing outer side part 140b are not covered with the blade | wing inner side part 140a, but are exposed outside. Further, in a state where the balloon 11 is folded, a root-side space portion 142 is formed between the root portion of the blade portion 140 and the intermediate portion 140c. In the area of the root side space part 142, a minute gap is formed between the blade part 140 and the intermediate part 140c. On the other hand, the region on the tip side of the base portion space portion 142 of the blade portion 140 is in close contact with the intermediate portion 140c. The ratio of the circumferential length of the base side space 142 to the circumferential length of the blade 140 is in the range of 1 to 95%. The blade outer portion 140b of the balloon 11 receives a pressing force that rubs in the circumferential direction from a blade for folding the balloon 11, and is further heated. As a result, the long drug crystal 131 provided on the outer blade portion 140 b falls on the surface of the balloon 11 and is likely to sleep. It is not necessary for all of the drug crystal 131 to sleep.

  Moreover, since the outer surface which overlaps in the duplication part 141 of the balloon 11 is not exposed outside, pressing force acts indirectly from a braid | blade when folding. For this reason, it is easy to adjust the force acting on the drug crystal 131 provided on the overlapping outer surface of the overlapping portion 141 of the balloon 11 so as not to become too strong. Therefore, a desired force can be applied to lay down the drug crystal 131 provided on the outer surface overlapping in the overlapping portion 141 of the balloon 11. In the region of the blade inner portion 140a and the intermediate portion 140c facing each other, in the region facing the base side space portion 142, that is, the region where the blade inner portion 140a and the intermediate portion 140c are not in close contact, the drug crystal 131 is pressed. It is difficult to receive. Therefore, in this region, the drug crystal 131 is difficult to sleep. In the region of the blade inner portion 140a and the intermediate portion 140c that face each other, the region that does not face the root side space portion 142, that is, the region where the blade inner portion 140a and the intermediate portion 140c are in close contact with each other, Easy to receive pressure. Therefore, in this region, the drug crystal 131 falls down and tends to sleep.

  Next, a method of using the catheter 1 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 catheter 1, the guide wire 200 (see FIG. 7) is inserted into the guide wire lumen 23. In this state, the guide wire 200 and the catheter 1 are inserted into the blood vessel from the inside of the introducer. Subsequently, the catheter 1 is advanced while the guide wire 200 is advanced, and the balloon 11 reaches the stenosis. A guiding catheter may be used to reach the catheter 1 to the stenosis 300.

  Next, a predetermined amount of expansion fluid is injected from the proximal end opening 40 of the hub 12 using an indeflator or a syringe, and the expansion fluid is sent into the balloon 11 through the expansion lumen 22. Thereby, as shown in FIG. 7, the folded balloon 11 is expanded, and the narrowed portion 300 is pushed and expanded by the balloon 11. At this time, the coat layer 30 provided on the outer surface of the balloon 11 contacts the narrowed portion 300.

  When the balloon 11 is expanded and the coat layer 30 is pressed against the living tissue, the drug crystal 131 is delivered to the living body while the additive 130 that is a water-soluble low-molecular compound contained in the coat layer 30 is gradually or quickly dissolved. The The drug crystals 131 of the coat layer 30 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 40 of the hub 12, and the balloon 11 is deflated and folded. Thereafter, the guide wire 200 and the catheter 1 are removed from the blood vessel via the introducer, and the procedure is completed.

  As described above, the balloon coating method according to the present embodiment is a balloon coating method in which the coat layer 30 is formed on the surface of the balloon 11 in the catheter 1 having the balloon 11 at the distal end portion of the shaft 10. A large number of tube bodies 101 having properties are arranged along the axial direction of the balloon 11, the tip of the tube body 101 is brought into contact with the surface of the balloon 11 that rotates about the axis of the shaft 10, and each tube body 101 is in contact with the balloon. 11 has a coating process in which the coating liquid is discharged from the tip of the tube body 101 and applied to the surface of the balloon 11 while being deformed so as to follow the surface of the balloon 11. In the balloon coating method configured in this way, a large number of tube bodies 101 arranged along the axial direction of the balloon 11 discharge the coating liquid while deforming in accordance with the surface shape of the balloon 11, so that the axial direction of the balloon 11 The coating liquid can be applied uniformly along the line. In addition, since the coating liquid can be applied to the entire balloon 11 in the axial direction, the time required for coating can be shortened, the production efficiency can be improved, and the influence of fluctuations in external factors can be reduced.

  As described above, the balloon coating method according to the present embodiment is a balloon coating method in which the coat layer 30 is formed on the surface of the balloon 11 in the catheter 1 having the balloon 11 at the distal end portion of the shaft 10. On the other hand, while rotating around the axis of the shaft 10, supplying and applying the coating liquid containing the drug from the supply unit 92, and applying the coating liquid to the entire application site of the balloon 11, the coating liquid is not yet applied. In a dry state, there are a step of covering at least the application site of the balloon 11 with a vacuum dryer 100 and a step of reducing the pressure in the vacuum dryer 100 to volatilize the solvent of the coating solution. In the balloon coating method configured as described above, the coating liquid on the surface of the balloon 11 is dried along with the reduced pressure, so that the crystallization of the drug can be controlled by adjusting the pressure in the reduced pressure dryer 100. Specifically, the pressure reduction rate in the vacuum dryer 100 and the control of the pressure attainment point can be mentioned, and thereby the crystallization rate of the drug can be controlled. Thereby, the same crystal can always be formed on the surface of the balloon 11, and the variation can be reduced.

  The balloon 11 is rotated around the axis of the shaft 10 when the inside of the vacuum dryer 100 is depressurized to volatilize the solvent of the coating solution. Thereby, when the coating liquid dries, the coating layer can be uniformly formed on the surface of the balloon 11 without being biased in the circumferential direction of the balloon 11.

  The vacuum dryer 100 can control the crystallization rate of the drug by increasing the degree of vacuum over time.

  Moreover, if the inside of the vacuum dryer 100 is heated at the time of decompression, the volatilization of the solvent of the coating solution can be accelerated and the time required for crystallization can be shortened.

  Further, the vacuum dryer 100 is airtight when the balloon 11 and the long shaft 10 provided on the proximal end side of the balloon 11 are covered with the distal end portion close to the balloon 11. In order to achieve this, the outer peripheral surface of the shaft 10 may be sealed, and the sealing area can be minimized and the airtightness can be increased.

  The balloon 11 is connected to a pressure adjustment unit 101 that adjusts the internal pressure. When the pressure in the vacuum dryer 100 is reduced, the pressure adjustment unit 101 maintains the volume of the balloon 11 so that the volume of the balloon 11 is maintained constant. The internal pressure is adjusted. Thereby, when the inside of the vacuum dryer 100 is depressurized, the shape of the balloon 11 can be prevented from changing, and the state in which the coating liquid is uniformly applied to the surface of the balloon 11 can be maintained. For this reason, the coat layer 30 can be uniformly formed on the surface of the balloon 11.

  In addition, if the drug contained in the coating solution is rapamycin, paclitaxel, docetaxel, or everolimus, restenosis of the stenosis in the blood vessel can be satisfactorily suppressed.

  The solvent contained in the coating solution is water, acetic acid, i-butyl alcohol, s-butyl alcohol, t-butyl alcohol, propanol, butanol, toluene, ethylene glycol, benzene, chlorohexane, glycerin, ethanol, hexane, If at least one selected from the group consisting of ethyl acetate, o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, and cyclohexane is contained, the volatility of the solvent is reduced. The solvent is less likely to evaporate from the coating solution applied to the balloon. Thus, the surface of the balloon 11 is surely kept wet until the pressure is reduced by the vacuum dryer after the coating liquid is applied, and the drug is crystallized in the vacuum dryer 100 under certain conditions. be able to.

  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.

  In the above-described embodiment, the decompression dryer 100 covers the balloon 11, the distal end side support 72, and the distal end of the shaft 10, but it is sufficient that the decompression can be performed by covering at least the region of the balloon 11 to which the coating liquid is applied.

  Moreover, the coating method of coating liquid is not restricted to the above-mentioned embodiment, Other methods, such as a spray method and a thread drawing method, can be used.

DESCRIPTION OF SYMBOLS 1 Catheter 2 Balloon coating apparatus 10 Shaft 11 Balloon 12 Hub 15 Balloon 30 Coat layer 50 Rotation mechanism 60 Movement mechanism 61 Movement stand 62 Tube fixing | fixed part 70 Support stand 71 Base end side support part 72 Front end side support part 73 Supply part support part 80 Application mechanism 90 Supply container 91 Liquid feed pump 92 Supply part 92a Discharge port 93 Suction pipe 94 Supply pipe 100 Vacuum dryer 100a Sealing part 101 Pressure adjustment part 120 Control part

Claims (8)

A balloon coating method for forming a coating layer on a surface of a balloon in a catheter having a balloon at a tip portion of a shaft,
Supplying and applying a coating liquid containing a drug from a supply unit while rotating about the axis of the shaft with respect to the surface of the balloon;
When the coating liquid is applied to the entire balloon application site, the coating liquid is in an undried state, and at least the balloon application site is covered with a vacuum dryer;
Reducing the pressure in the vacuum dryer to volatilize the solvent of the coating solution;
A balloon coating method comprising:   The balloon coating method according to claim 1, wherein the balloon is rotated around the axis of the shaft when the inside of the vacuum dryer is decompressed to volatilize the solvent of the coating solution.   The balloon coating method according to claim 1, wherein the vacuum dryer increases the degree of vacuum over time.   The balloon coating method according to any one of claims 1 to 3, wherein the vacuum dryer raises the temperature of the interior during decompression.   The balloon coating method according to any one of claims 1 to 3, wherein the vacuum dryer covers a distal end portion close to the balloon of the balloon and a long shaft provided on a proximal end side of the balloon. . The balloon is connected to a pressure adjusting unit that adjusts an internal pressure,
The balloon coating according to any one of claims 1 to 5, wherein when the inside of the vacuum dryer is decompressed, the internal pressure of the balloon is adjusted by the pressure adjusting unit so as to maintain a constant volume of the balloon. Method.   The balloon coating method according to any one of claims 1 to 6, wherein the drug contained in the coating solution is rapamycin, paclitaxel, docetaxel, or everolimus.   Solvents contained in the coating solution are water, acetic acid, i-butyl alcohol, s-butyl alcohol, t-butyl alcohol, propanol, butanol, toluene, ethylene glycol, benzene, chlorohexane, glycerin, ethanol, hexane, and ethyl acetate. The balloon coating according to claim 1, comprising at least one selected from the group consisting of o-dichlorobenzene, o-xylene, p-xylene, cyclohexanol, styrene, and cyclohexane. Method.

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