Patent Publication Number: US-2020282188-A1

Title: Drug layer applying device and method for forming drug layer

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
     This application is a continuation of International Application No. PCT/JP2018/043180 filed on Nov. 22, 2018, which claims priority to Japanese Application No. 2017-224338 filed on Nov. 22, 2017, the entire content of both of which is incorporated herein by reference. 
    
    
     FIELD OF THE DISCLOSURE 
     The present disclosure generally relates to a drug layer applying device that places or applies a drug on a surface of a medical instrument such as a balloon, and a method for forming a drug layer. 
     BACKGROUND DISCUSSION 
     In recent years, a balloon catheter has been used to improve a lesion (stenotic part) generated in a body lumen. The balloon catheter typically includes an elongated shaft portion and a radially inflatable balloon provided on a distal side of the shaft portion. When the deflated balloon is inflated after reaching a target location in a body via a relatively thin body lumen, a lesion can be pushed to be widened. 
     However, when the lesion is forcibly pushed to be widened, smooth muscle cells may excessively proliferate to cause new stenosis (restenosis) at the lesion. Therefore, recently, a drug eluting balloon (DEB) in which a surface of the balloon is coated with a drug for suppressing stenosis has been used. The drug eluting balloon inflates to instantaneously release the drug with which the surface has been coated to the lesion, thereby suppressing restenosis. 
     As a method for forming a drug layer on a surface of a balloon, for example, U.S. Pat. No. 8,597,720 B2 describes a method of spraying a solution containing a drug on a balloon, a dipping method, a coating method using a brush, a coating method using a rotating body, and a method of supplying a solution using a pipette. 
     Japanese Patent Application Publication No. 2010-154919 A describes a device in which a portion between a balloon for dilatation and a balloon for drug supply located outside the balloon for dilatation is filled with a drug. Japanese Patent Application Publication No. 2010-154919 A further describes that a large number of micropores for releasing the drug are formed in the drug supply balloon, and a drug can be additionally supplied from the outside to the portion between the balloon for dilatation and the balloon for drug supply. 
     With the methods described in U.S. Pat. No. 8,597,720 B2, it can be difficult to quickly apply an appropriate amount of a drug on a surface of a balloon. In addition, the device described in Japanese Patent Application Publication No. 2010-154919 A is capable of supplying the drug to the balloon from the outside, but is incapable of rather easily providing the drug on the balloon due to its complicated structure. 
     SUMMARY 
     A drug layer applying device and a method for forming a drug layer are disclosed, which can relatively quickly and rather easily provide an appropriate amount of a drug on a surface of a medical instrument. 
     A drug layer applying device is disclosed which is attachable to a medical instrument used by being inserted into a living body and includes: a flexible sheet; and a drug layer provided on one surface of the sheet. 
     A method is disclosed for forming a drug layer on a surface of a medical instrument insertable into a living body, and includes attaching a surface of a drug layer applying device, provided with a drug layer on one surface of a flexible sheet, to a surface of the medical instrument, the surface of the drug layer applying device opposite to a side where the drug layer of the drug layer applying device is provided. 
     Another method is disclosed for forming a drug layer which applies a drug on a surface of a balloon, the method comprising: injecting a predetermined amount of an inflation fluid into the balloon; inserting the balloon into a through-hole of a drug layer applying device, the drug layer applying device being a heat-shrinkable tube; and attaching a surface of the drug layer applying device to a surface of the balloon, the surface of the drug layer applying device being opposite to a side of the heat-shrinkable tube to where the drug layer of the drug layer applying device is provided. 
     The drug layer applying device configured as described above can relatively quickly and rather easily provide the appropriate amount of the drug layer on the surface of the medical instrument by being attached to the surface of the medical instrument. 
     The drug layer applying device may further include an adhesive layer provided on a surface of the sheet opposite to a side on which the drug layer is provided. As a result, the adhesive layer can adhere to the surface of the medical instrument, and the drug layer can be rather effectively placed on the surface of the medical instrument without being peeled off. 
     In accordance with an aspect, the sheet may have a cylindrical shape, and the drug layer may be provided on an outer circumferential surface of the sheet. As a result, an appropriate amount of the drug layer can be relatively quickly and rather easily placed on the outer circumferential surface of a cylindrical medical instrument such as a balloon. 
     The sheet may be a heat-shrinkable tube. As a result, the sheet can be reduced in diameter by heating the medical instrument with the drug layer applying device covered on the medical instrument, and can be placed in contact with the medical instrument. 
     The adhesive layer may exhibit an adhesive force when heated. As a result, the adhesive layer is also heated when the heat-shrinkable tube is heated, and the adhesive layer exhibits the adhesive force. Therefore, the adhesive layer can be prevented from adhering to an unintended position before the heating. Therefore, the heat-shrinkable tube can be attached to an appropriate position on the surface of the medical instrument after positioning the drug layer with respect to the medical instrument with high precision. 
     The medical instrument may be a balloon capable of inflating and deflating. As a result, the appropriate amount of the drug layer can be relatively quickly and rather easily placed on the surface of the balloon. 
     The drug in the drug layer may contain at least one selected from the group including rapamycin, paclitaxel, docetaxel, and everolimus. As a result, restenosis of a stenotic part in a blood vessel can be favorably suppressed by the drug layer. 
     The drug in the drug layer may contain at least one selected from the group including a water-insoluble drug, a water-soluble drug, and a hydrophilic polymer. As a result, it is possible to apply, to the drug layer, a drug that is appropriate for conditions and the like, alone or in combination, with various other drugs. 
     With the method for forming a drug layer configured as described above, the appropriate amount of the drug layer can be relatively quickly and rather easily placed on the surface of the medical instrument by attaching the drug layer applying device to the medical instrument. 
     In the attaching of the surface of the drug layer applying device, providing an adhesive layer provided on a surface of the sheet opposite to the side on which the drug layer may be attached to a surface of the medical instrument. As a result, the adhesive layer can be attached to the surface of the medical instrument, and the drug layer can be rather effectively placed on the surface of the medical instrument without being peeled off. 
     In the attaching of the surface of the drug layer applying device, the drug layer applying device may be attached to the medical instrument removed from a living body. As a result, the medical instrument that has been used in the living body can be removed from the living body, and then, the drug layer can be placed on the same medical instrument for reuse. 
     The medical instrument may be a balloon capable of inflating and deflating, guidewire, guiding sheath, guiding catheter, or stent. As a result, it is possible to relatively quickly and rather easily provide an appropriate amount of the drug layer on a surface of the balloon, the guidewire, the guiding sheath, the guiding catheter, or the stent. If the medical instrument is the balloon, the appropriate amount of the drug layer can be relatively quickly and rather easily placed on the surface of the balloon. In addition, the balloon used for pre-dilation of a target site in the living body can be removed, and then, the drug layer can be placed on the same balloon to reuse the balloon for post-dilation of the target site. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a perspective view illustrating a drug layer applying device according to a first embodiment disclosed here. 
         FIG. 2  is a cross-sectional view of the drug layer applying device. 
         FIG. 3  is a front view illustrating a balloon catheter. 
         FIG. 4  is a front view illustrating a distal portion of the balloon catheter. 
         FIG. 5  is a cross-sectional view taken along line V-V of  FIG. 4 . 
         FIG. 6  is a perspective view illustrating a state where the drug layer applying device is attached to a balloon. 
         FIG. 7  is a cross-sectional view illustrating the balloon to which the drug layer applying device is attached. 
         FIG. 8  is a perspective view illustrating a drug layer applying device according to a second embodiment disclosed here. 
         FIG. 9  is a cross-sectional view taken along line IX-IX of  FIG. 8 . 
         FIG. 10  is a front view illustrating a state where a balloon is covered with the drug layer applying device. 
         FIG. 11  is a cross-sectional view taken along line XI-XI of  FIG. 10 . 
         FIG. 12  is a front view illustrating the balloon to which the drug layer applying device is attached. 
         FIG. 13  is a cross-sectional view taken along line XIII-XIII of  FIG. 12 . 
         FIG. 14  is a front view illustrating a balloon to which a drug layer applying device according to a third embodiment is attached. 
         FIG. 15  is a cross-sectional view illustrating a first modification of the drug layer applying device. 
         FIGS. 16A and 16B  are front views illustrating modifications of the drug layer applying device, in which  FIG. 16A  illustrates a second modification and  FIG. 16B  illustrates a third modification. 
     
    
    
     DETAILED DESCRIPTION 
     Set forth below with reference to the accompanying drawings is a detailed description of embodiments of a drug layer applying device that applies a drug on a surface of a medical instrument such as a balloon, and a method for forming a drug layer representing examples of the inventive drug layer applying device that applies a drug on a surface of a medical instrument such as a balloon, and method for forming a drug layer disclosed here. Note that dimensional ratios of the drawings are exaggerated for the convenience of description and may differ from actual ratios in some cases. 
     First Embodiment 
     A drug layer applying device (i.e., drug loading instrument)  10  according to a first embodiment of the present disclosure is a device configured to apply a drug layer on a surface of a balloon  30  (see  FIG. 3 ), which is inserted into a stenotic part of a living body lumen, such as a blood vessel, to push and widen the stenotic part, thereby forming a drug-eluting balloon as illustrated in  FIGS. 1 and 2 . Note that a medical instrument (or medical devices) on which the drug layer applying device  10  applies the drug layer is not limited to the balloon  30 , and may be, for example, a guide wire, a guiding sheath, a guiding catheter, a stent, or the like. Hereinafter, a case where the drug layer can be applied to the balloon  30  by the drug layer applying device  10  will be described. 
     The drug layer applying device  10  can include a flexible sheet  11 , a drug layer  12  containing a drug, and an adhesive layer  13  having an adhesive force. 
     In accordance with an exemplary embodiment, the sheet  11  is a film-shaped member that is flexible and thin. The sheet  11  is preferably relatively thin so as to be foldable together with the balloon  30 . A thickness of the sheet  11  can be, for example, 1 μm to 250 μm, preferably 5 μm to 100 μm, and more preferably 10 μm to 50 μm. The sheet  11  may have a concave and/or convex portion shaped to fold the balloon  30 . Such shaping can be performed by heating the sheet  11  in the state of being deformed into a predetermined shape by applying a force. The concave and/or convex portion has a function of assisting the drug layer applying device  10  after being attached to the balloon  30  inflated from the folded state (see  FIG. 5 ) to return (rewrap) the balloon  30  to the folded state. 
     The material of the sheet  11  can include, for example, polyolefin, polyvinyl chloride, polystyrene, polyethylene, polypropylene, polyethylene terephthalate, a fluoropolymer, a thermoplastic elastomer, a nonwoven fabric, and the like. 
     The drug layer  12  is provided on one surface of the sheet  11 . The drug contained in the drug layer  12  may be a water-soluble drug or a water-insoluble drug. A water-insoluble drug means a drug that is insoluble or poorly soluble in water, and specifically solubility in water may be less than 1 mg/mL, and further, may be less than 0.1 mg/mL. Water-insoluble drugs can include fat-soluble drugs. An amount of the drug contained in the drug layer  12  is not particularly limited, but the drug is contained at a density, for example, of 0.1 μg/mm 2  to 10 μg/mm 2 , preferably at a density of 0.5 μg/mm 2  to 5 μg/mm 2 , and more preferably at a density of 0.5 μg/mm 2  to 3.5 μg/mm 2 . A thickness of the drug layer  12  is not particularly limited, but can be, for example, 0.1 μm to 100 μm, preferably 0.5 μm to 50 μm, and more preferably 0.5 μm to 10 μm or 10 μm to 30 μm. A form of the water-insoluble or water-soluble drug is not particularly limited, and may be, for example, a crystal or not. 
     The water-insoluble drug can include, for example, immunosuppressants, for example, cyclosporines containing cyclosporine, immunoadjuvants such as rapamycin, carcinostatics such as paclitaxel, antiviral agents or antibacterial agents, antineoplastic agents, analgesic agents and anti-inflammatory agents, antibiotics, antiepileptics, anxiolytic agents, antiparalytic agents, antagonists, neuron blocking agents, anticholinergic agents and cholinergic agents, muscarine antagonists agents and muscarine agents, antiadrenergic agents, antiarrhythmic agents, antihypertensive agents, hormone preparations, and nutritional supplements. 
     The water-insoluble drug is preferably, for example, at least one selected from the group including rapamycin, paclitaxel, docetaxel, and everolimus. The rapamycin, paclitaxel, docetaxel, and everolimus in the present specification can include their analogs and/or derivatives as long as the analogs and/or derivatives have equivalent drug effect. For example, paclitaxel and docetaxel are in an analog relation. Rapamycin and everolimus are in a derivative relation among these, paclitaxel is more preferable. 
     The water-soluble drug may be a drug having solubility in water of 1 mg/mL or more, preferably 5 mg/mL or more, more preferably 10 mg/mL or more, and still more preferably 33 mg/mL or more. Water-soluble antiplatelet drugs can include, for example, clopidogrel sulfate, ticlopidine hydrochloride, prasugrel hydrochloride, sarpogrelate hydrochloride, and the like (incidentally, water-insoluble antiplatelet drugs include aspirin, cilostazol, ticagrelor, and the like). Examples of the water-soluble anticoagulant can include warfarin, edoxaban tosilate hydrate, heparin, dabigatran etexilate methanesulfonate, and the like. The drug may also be a hydrophilic polymer, and a wet coating using the hydrophilic polymer (the coating that exhibits lubricity when wetted with water) is possible. The drug may be applied as the hydrophilic polymer. on a surface (inner and outer surfaces) of a medical instrument to be inserted into a blood vessel (for example, a guidewire, a guiding sheath, a guiding catheter, or the like) without being limited to the surface (inner and outer surfaces) of the balloon catheter. 
     The drug layer  12  may contain an additive (for example, an excipient). When the drug layer  12  contains the additive, examples of the additive can include, for example, a water-soluble low molecular weight compound and the like. A molecular weight of the water-soluble low molecular weight compound is 50 to 2,000, preferably 50 to 1,000, more preferably 50 to 500, and still more preferably 50 to 200. An amount of the water-soluble low molecular weight compound is preferably 10 parts by weight to 5,000 parts by weight, more preferably 50 parts by weight to 3000 parts by weight, and still more preferably 100 parts by weight to 1000 parts by weight, per 100 parts by weight of the water-insoluble drug. The water-soluble low molecular weight compound material can be, for example, a serine ethyl ester, sugars such as glucose, sugar alcohols such as sorbitol, citrate, polysorbate, polyethylene glycol, and urea. 
     In accordance with an embodiment, the water-soluble low molecular weight compound can be water-soluble polymers, a contrast agent, an amino acid ester, a glycerol ester of a short-chain monocarboxylic acid, a pharmaceutically acceptable salt, and a surfactant, or a mixture of two or more of the water-soluble low molecular weight compound materials can be used. The water-soluble low molecular weight compound has a hydrophilic group and a hydrophobic group, and can be characterized by being soluble in water. The water-soluble low molecular weight compound is preferably non-swellable or hardly swellable (i.e., only a small part of a compound is swellable). The additive containing the water-soluble low molecular weight compound has an effect of uniformly dispersing the water-insoluble drug on the surface of the sheet  11 . In accordance with an embodiment, it can be preferable that the additive is not a hydrogel. The additive contains the low molecular weight compound, and thus, dissolves relatively quickly without swelling when coming into contact with an aqueous solution. Further, the additive can rather easily dissolve when the balloon  30  is inflated in the blood vessel so that crystal particles of the water-insoluble drug on the surface of the balloon  30  are rather easily released, and thus, there is an effect of increasing the number of the crystal particles of the drug adhering to the blood vessel. 
     The water-soluble low molecular weight compound has a molecular weight of 50 to 2,000, and can be dissolved at an amount of 1 mg/mL or more in water, preferably dissolved at an amount of 5 mg/mL or more in water, more preferably dissolved at an amount of 10 mg/mL or more in water, still more preferably dissolved at an amount of 33 mg/mL or more in water, and preferably dissolved in water without inflating. In accordance with an exemplary embodiment, it can be preferable that the water-soluble low molecular weight compound is not a hydrogel. The water-soluble low molecular weight compound is preferably not a polymer, and more preferably not a water-insoluble polymer. In accordance with an exemplary embodiment, it can be preferable that the water-soluble low molecular weight compound is not polyethylene glycol (PEG) and a water-soluble PEG (for example, polyethylene glycol 200-600). 
     The solubility of a substance can be defined as a degree of dissolution within 30 minutes at 20° C. For example, the solubility of a substance can be defined by an amount of solvent (for example, an amount of water) required to dissolve 1 g (or 1 mL) of solute. When the amount of solvent required to dissolve 1 g of solute is less than 1 mL, the solute is extremely soluble in the solvent. In cases, of extremely soluble, the amount of dissolved solute is more than 1000 mg/mL. Examples of extremely soluble substances can include sorbitol, urea, and glycerol. When the amount of solvent required to dissolve 1 g of solute is 1 mL or more and less than 10 mL, the solute is freely soluble in the solvent. In cases of freely soluble, the amount of dissolved solute may be more than 100 mg/mL and 1000 mg/mL or less. Examples of freely soluble substances can include polysorbate, an amino acid ester, polyethylene glycol 200-600, a serine ethyl ester, a contrast agent (iopromide), and a water-soluble polymer. When the amount of solvent required to dissolve 1 g of solute is 10 mL or more and less than 30 mL, the solute is soluble in the solvent. In cases of soluble, the amount of dissolved solute may be more than 33 mg/mL and 100 mg/mL or less. Examples of soluble substances can include polyethylene glycol. When the amount of solvent required to dissolve 1 g of solute is 30 mL or more and less than 100 mL, the solute is slightly soluble in the solvent. In case of slightly soluble, the amount of dissolved solute may be more than 10 mg/mL and 33 mg/mL or less. When the amount of solvent required to dissolve 1 g of solute is 100 mL or more and less than 1000 mL, the solute is sparingly soluble in the solvent. In cases of sparingly soluble, the amount of dissolved solute may be more than 1 mg/mL and 10 mg/mL or less. When the amount of solvent required to dissolve 1 g of solute is 1000 mL or more and less than 10,000 mL, the solute is extremely insoluble in the solvent. In cases of extremely insoluble, the amount of dissolved solute may be more than 0.1 mg/mL and 1 mg/mL or less. When the amount of solvent required to dissolve 1 g of solute is 10,000 mL or more, the solute is hardly soluble in the solvent. In cases of hardly soluble, the amount of dissolved solute may be 0.1 mg/mL or less. Examples of hardly soluble substances can include a fatty acid ester of glycerin. The water-soluble substance refers to a substance other than a substance that is “extremely insoluble” and a substance that is “hardly soluble”. Specifically, the water-soluble substance indicates a substance that is “extremely soluble”, a substance that is “freely soluble”, a substance that is “slightly soluble”, and a substance that is “sparingly soluble”. The water-soluble substance preferably indicates a substance that is “extremely soluble”, a substance that is “freely soluble” and a substance that is “slightly soluble”. 
     In accordance with an exemplary embodiment, the adhesive layer  13  is provided on a surface of the sheet  11  opposite to the side on which the drug layer  12  is provided. The adhesive layer  13  is a layer adhering to the surface of the balloon  30 . A thickness of the adhesive layer  13  is not particularly limited, for example, the thickness of the adhesive layer  13  can be 0.01 μm to 50 μm, preferably 0.1 μm to 30 μm, and more preferably 0.1 μm to 5 μm. 
     The material of the adhesive layer  13  may be water-soluble or water-insoluble. Examples of the water-soluble adhesive can include a vinyl chloride resin adhesive, a vinyl acetate copolymer resin adhesive, an EVA resin adhesive, an acrylic resin adhesive, an acrylic ester adhesives, a styrene/butadiene copolymer latex, an aqueous urethane adhesive, and the like. The adhesive layer  13  can be, for example, a pressure-sensitive adhesive that adheres by pressing. Examples of the pressure-sensitive adhesive can include a natural rubber latex adhesive, a silicone pressure-sensitive adhesive, an MG latex adhesive, an acrylic adhesive, a silica adhesive, and the like. 
     The drug layer applying device  10  preferably has a size that can cover a range where a drug of the balloon  30  is applied (or placed). For example, when the drug is placed on a straight portion  31  of the balloon  30 , the drug layer applying device  10  preferably has a size that can cover the straight portion  31 . 
     Next, a balloon catheter  50  on which a drug is applied using the drug layer applying device  10  will be described with reference to  FIGS. 3 to 5 . In the present specification, a side of the balloon catheter  50  to be inserted into a living body lumen is referred to as a “distal side” and an operating hand side is referred to as a “proximal side”. 
     The balloon catheter  50  can include an elongated shaft portion  20 , the balloon  30  provided at a distal portion of the shaft portion  20 , and a hub  26  fixed to a proximal end of the shaft portion  20 . 
     The shaft portion  20  can include an outer tube  21  that is a tubular body of which distal end and proximal end are open and an inner tube  22  which is a tubular body provided inside the outer tube  21 . The inner tube  22  is housed in a hollow interior of the outer tube  21 , and the shaft portion  20  has a double-tube structure at the distal portion. The hollow interior of the inner tube  22  is a guide wire lumen  24  through which a guide wire is inserted. An inflation lumen  23  for circulating inflation fluid of the balloon  30  is formed in the hollow interior of the outer tube  21  outside the inner tube  22 . The inner tube  22  is open to the outside at a side opening  25 . The inner tube  22  protrudes further to the distal side from the distal end of the outer tube  21 . A distal tip, which is a separate member, may be provided at a distal portion of the inner tube  22 . 
     The balloon  30  (medical instrument) can include a straight portion  31  formed at the center in the axial direction, a proximal tapered portion  32  located on the proximal side of the straight portion  31 , and a distal tapered portion  33  located on the distal side of the straight portion  31 . The straight portion  31  can have a cylindrical shape that has substantially the same outer diameter when inflated. An outer diameter of the proximal tapered portion  32  gradually decreases from the straight portion  31  toward the proximal side. An outer diameter of the distal tapered portion  33  gradually decreases from the straight portion  31  toward the distal side. 
     In accordance with an exemplary embodiment, the straight portion  31  is a portion where the drug is applied by the drug layer applying device  10 . Note that the range in which the drug is applied by the drug layer applying device  10  is not limited only to the straight portion  31 , but may include at least a part of the proximal tapered portion  32  and the distal tapered portion  33  in addition to the straight portion  31 . Alternatively, the range in which the drug is applied by the drug layer applying device  10  may be only a part (or portion) of the straight portion  31 . 
     In the balloon  30 , a balloon fusing portion  34  located at the proximal end of the proximal tapered portion  32  can be fused at the distal portion of the outer tube  21 . In addition, a balloon fusing portion  35  located at the distal end of the distal tapered portion  33  can be fused to the distal portion of the inner tube  22  in the balloon  30 . Note that a method for fixing the balloon  30  to the outer tube  21  and the inner tube  22  is not limited to the fusion, but may be, for example, adhesion. As a result, the interior of the balloon  30  communicates with the inflation lumen  23 . The balloon  30  can be inflated by injecting the inflation fluid into the balloon  30  via the inflation lumen  23 . In accordance with an embodiment, the inflation fluid may be a gas or a liquid, and, for example, a gas such as a helium gas, a CO 2  gas, an O 2  gas, an N 2  gas, an Ar gas, air, and a mixed gas, or a liquid such as a saline solution and a contrast agent can be used. 
     In accordance with an embodiment, the balloon  30  can have a plurality of blade portions  37  shaped to protrude in the radial direction. The blade portions  37  can be folded in the circumferential direction. The blade portion  37  is formed by a fold extending substantially in the axial direction of the balloon  30 . In accordance with an embodiment, a length of the blade portion  37  in the long-axis direction (i.e., axial direction) does not exceed a length of the balloon  30 . The number of the blade portions  37  is not particularly limited, and can be one to seven, for example, however, as shown in the present embodiment, the number of blades portions  37  is three. The plurality of blade portions  37  are preferably arranged to be uniform in the circumferential direction of the balloon  30 , but are not limited to being arranged to be uniform in the circumferential direction of the balloon  30 . 
     The length of the balloon  30  in the axial direction is not particularly limited, but is preferably, for example, 5 mm to 500 mm, more preferably 10 mm to 300 mm, and still more preferably 20 mm to 200 mm. The outer diameter of the balloon  30  when inflated is not particularly limited, but can be, for example, 1 mm to 10 mm, and more preferably 2 mm to 8 mm. 
     It is preferable that the balloon  30  have a certain degree of flexibility and a certain degree of hardness such that the balloon  30  can be inflated when reaching a blood vessel, a tissue, or the like, and release the drug on the surface of the balloon  30 . Specifically, the balloon  30  can be made of metal or resin. At least the surface of the balloon  30  is preferably made of resin. The material of at least the surface of the balloon  30 , can be, for example, polyolefins such as polyethylene, polypropylene, polybutene, an ethylene-propylene copolymer, an ethylene-vinyl acetate copolymer, and an ionomer, or a mixture of two or more of the polyolefins, thermoplastic resins such as soft polyvinyl chloride resin, polyamide, a polyamide elastomer, a nylon elastomer, polyester, a polyester elastomer, polyurethane, and a fluororesin, a silicone rubber, a latex rubber, and the like can be used. In accordance with an exemplary embodiment, the material of the at least the surface of the balloon  30 , polyamides are preferably used. 
     In the hub  26 , a proximal opening  27  is formed, which communicates with the inflation lumen  23  of the outer tube  21  and functions as a port for inflow and outflow of the inflation fluid. 
     Next, an operation of the drug layer applying device  10  according to the present embodiment will be described. 
     When applying the drug on the balloon  30  by the drug layer applying device  10 , a predetermined amount of the inflation fluid is injected from the proximal opening  27  of the hub  26  using an indeflator, a syringe, or the like to send the inflation fluid inside the balloon  30  through the inflation lumen  23 . As a result, the folded balloon  30  inflates. Next, the adhesive layer  13  of the drug layer applying device  10  is pressed against the straight portion  31  of the inflated balloon  30  as illustrated in  FIGS. 6 and 7 . As a result, the adhesive layer  13  is attached to the straight portion  31 . When the drug layer applying device  10  is larger than the straight portion  31 , the drug layer applying device  10  may be cut into an appropriate size. 
     Next, the inflation fluid is suctioned (i.e., sucked or removed) and discharged from the interior of the balloon  30  through the proximal opening  27  of the hub  26 . As a result, the balloon  30  is deflated and folded. As a result, the balloon  30  can be used for expansion of a stenotic part in a living body lumen, such as a blood vessel, as a drug eluting balloon. 
     As described above, the drug layer applying device  10  according to the present embodiment is the drug layer applying device  10  that is attachable to the balloon  30  (medical instrument) used by being inserted into the living body, and can include the flexible sheet  11  and the drug layer  12  provided on one surface of the sheet  11 . 
     The drug layer applying device  10  configured as described above can relatively quickly and rather easily place the appropriate amount of the drug layer  12  on the surface of the balloon  30  by being attached to the surface of the balloon  30 . The drug layer applying device  10  can relatively quickly and rather easily place the drug layer  12  on the balloon  30 , and thus, can be also used in the state of covering the balloon  30  after use, for example, in a clinical field regardless of a place of use. Therefore, for example, the drug layer applying device  10  can be applied to the balloon  30  removed from the living body after being used for pre-dilation of the stenotic part to obtain the balloon  30  for post-dilation having the drug layer  12 . Therefore, when a balloon for pre-dilation and a balloon for post-dilation are required, the single balloon  30  can fulfill the two roles. In addition, it is also possible to appropriately select and use an appropriate drug layer applying device  10 , for example, from among a plurality of drug layer applying devices  10  having different sizes, types of drugs, amounts of drugs, and the like. In addition, the drug layer applying device  10  can be provided in the form of the sheet, and thus, a large drug layer applying device  10  can be cut out to an appropriate size in accordance with a diameter and a length of the balloon  30  and used, for example, in a clinical field. 
     The drug layer applying device  10  further includes the adhesive layer  13  provided on the surface of the sheet  11  opposite to the side on which the drug layer  12  is provided. As a result, the adhesive layer  13  can adhere to the surface of the balloon  30 , and the appropriate amount of the drug layer  12  can be effectively applied to the surface of the balloon  30  without being peeled off. 
     In addition, the adhesive layer  13  may be water-soluble. As a result, the adhesive layer  13  can exhibit a favorable adhesiveness since the balloon  30  contains moisture. Therefore, the surface of the balloon  30  may be wetted before the balloon  30  is covered with the drug layer applying device  10 . In addition, the balloon  30  removed from the living body after the pre-dilation is highly likely to contain moisture, and the adhesiveness can be improved. 
     In accordance with an aspect, the water-insoluble drug in the drug layer  12  contains at least one selected from the group including rapamycin, paclitaxel, docetaxel, and everolimus. As a result, restenosis of the stenotic part in the blood vessel can be favorably suppressed by the drug layer  12 . 
     In accordance with another aspect, the drug in the drug layer  12  may contain at least one selected from the group including a water-insoluble drug, a water-soluble drug, and a hydrophilic polymer. As a result, it is possible to apply, to the drug layer  12 , a drug that is appropriate for conditions and the like, alone or in combination with various other drugs. 
     The medical instrument to which the drug layer applying device  10  is attached is the balloon  30  that is capable of inflating and deflating. Therefore, the drug layer  12  can be relatively quickly and rather easily placed on the surface of the balloon  30 . 
     In addition, the present disclosure also includes a method for forming a drug layer configured to apply a drug on the surface of the balloon  30 . The method for forming the drug layer which applies the drug on the surface of the balloon  30  (medical instrument) used by being inserted into the living body, and includes: attaching the surface of the drug layer applying device  10 , provided with the drug layer  12  on one surface of the flexible sheet  11 , to the surface of the balloon  30 , the surface of the drug layer applying device  10  opposite to the side where the drug layer  12  of the drug layer applying device  10  is provided. 
     According to the method for forming a drug layer configured as described above, an appropriate amount of the drug can be relatively quickly and rather easily placed on the surface of the balloon  30  by attaching the drug layer applying device  10  to the balloon  30 . 
     In the attaching of the surface of the drug layer applying device  10  to the surface of the balloon  30 , the adhesive layer  13  provided on the surface of the sheet  11  opposite to the side where the drug layer  12  is provided may be attached to the surface of the balloon  30 . As a result, the adhesive layer  13  can adhere to the surface of the balloon  30 , and the drug layer  12  can be effectively applied to the surface of the balloon  30  without being peeled off. 
     In the attaching of the surface of the drug layer applying device  10  to the surface of the balloon  30 , the drug layer applying device  10  may be attached to the balloon  30  removed from the inside of the living body. As a result, the balloon  30  that has been used in the living body can be removed from the living body, and then, the drug layer  12  can be placed on the same balloon  30  for reuse. 
     The medical instrument to which the drug layer applying device  10  is attached is the balloon  30  that is capable of inflating and deflating. As a result, the appropriate amount of the drug layer  12  can be relatively quickly and rather easily placed on the surface of the balloon  30 . In addition, the balloon  30  that has been used for pre-dilation of a target site of the living body can be removed, and then, the drug layer  12  can be placed on the same balloon  30  to reuse the balloon  30  for post-dilation of the target site. 
     Second Embodiment 
     A drug layer applying device  60  according to a second embodiment of the present disclosure is different from the first embodiment in terms of being cylindrical as illustrated in  FIGS. 8 and 9 . Note that parts having the same functions as those in the first embodiment are denoted by the same reference signs, and the description of those parts having the same functions as those in the first embodiment will be omitted. 
     In accordance with an embodiment, the drug layer applying device  60  can include: a heat-shrinkable tube  61  (sheet) that shrinks when heated; the drug layer  12  containing a drug; and the adhesive layer  13  having an adhesive force. The drug layer  12  is provided on an outer circumferential surface of the heat-shrinkable tube  61 . The adhesive layer  13  is provided on an inner circumferential surface of the heat-shrinkable tube  61 . 
     The heat-shrinkable tube  61  as the sheet is a tube (i.e., tubular member) of which diameter is reduced when heated. The heat-shrinkable tube  61  has strength enough to maintain a through-hole  62 . Note that the heat-shrinkable tube  61  may be a cylindrical film. The cylindrical film can be flexible and thin, and thus, does not always have such strength as to be capable of maintaining the through-hole  62  and can be deformed into a flat plate shape such that the through-hole  62  is closed. 
     The material of the heat-shrinkable tube  61  is not limited as long as the material of the heat-shrinkable tube  61  can be reduced in diameter by heating, and is preferably a material capable of coating the inner circumferential surface with a drug. In accordance with an embodiment, the heat-shrinkable tube  61  preferably shrinks at a relatively low heating temperature. The temperature at which the heat-shrinkable tube  61  shrinks can be, for example, 40° C. to 150° C., preferably 40° C. to 100° C. Since the heat-shrinkable tube  61  shrinks at a relatively low temperature, deterioration of the drug, deformation of the balloon  30 , and the like can be suppressed. A shrinkage ratio of an inner diameter of the heat-shrinkable tube  61  (inner diameter after shrinkage/inner diameter before shrinkage) is not particularly limited, but is preferably 40% to 80%. The heat-shrinkable tube  61  may have a concave and/or convex portion shaped to fold the balloon  30 . Such shaping of the concave and/or convex portion can be performed by heating the sheet  11  in the state of being deformed into a predetermined shape by applying a force. The concave and/or convex portion has a function of assisting the drug layer applying device  60  after being attached to the inflated balloon  30  to return (rewrap) the balloon  30  to the folded state. 
     The material of the tubular heat-shrinkable tube  61  can include, for example, polyolefin, a fluorine-based polymer, polyvinyl chloride, thermoplastic elastomer, and the like. 
     The material of the heat-shrinkable tube  61  in the case of a tubular film can be, for example, polyolefin, polyvinyl chloride, polystyrene, polyethylene, polypropylene, polyethylene terephthalate, or the like. 
     The adhesive layer  13  may be a material that exhibits an adhesive force by raising its temperature to a temperature at which the heat-shrinkable tube  61  is heated. Examples of the material of the adhesive layer  13  that exhibits the adhesive force when heated can include a styrene-butadiene rubber-based adhesive, a poly (lactide-co-glycotide) copolymer, a polymer such as polycaprolactone, a surfactant such as polyethylene glycol, a polyoxyethylene fatty acid diester, a polyoxyethylene fatty acid monoester, and a polyoxyethylene polyoxypropylene block polymer, an α-cyanoacrylate adhesive, and a fibrin adhesive used as medical adhesives, and the like. 
     The drug layer applying device  60  is used by housing the balloon  30  in an inflated state in the drug layer applying device  60 . Therefore, an inner diameter of the drug layer applying device  60  is preferably equal to or larger than an outer diameter of the inflated balloon  30 . 
     It is preferable that an axial length of the drug layer applying device  60  be equal to or longer than an axial length of a range in which the drug of the balloon  30  is applied when the drug layer applying device  60  is heated to shrink. In the present embodiment, the axial length of the drug layer applying device  60  exceeds a length of the straight portion  31 . 
     Next, an operation of the drug layer applying device  60  according to the second embodiment will be described. 
     When applying the drug on the balloon  30  by the drug layer applying device  60 , a predetermined amount of the inflation fluid is injected from the proximal opening  27  of the hub  26  using an indeflator (i.e., an inflation/deflation device), a syringe, or the like to send the inflation fluid inside the balloon  30  through the inflation lumen  23 . As a result, the folded balloon  30  inflates as illustrated in  FIGS. 10 and 11 . Next, the balloon  30  is inserted into the through-hole  62  of the drug layer applying device  60 . Note that the balloon  30  may be inflated after inserting the balloon  30  into the through-hole  62 . 
     Next, the drug layer applying device  60  is heated to a temperature at which the heat-shrinkable tube  61  shrinks by a dryer, an oven, or the like that supplies hot air when a current flows. As a result, the heat-shrinkable tube  61  can be reduced in diameter, and the adhesive layer  13  is in contact with the balloon  30  as illustrated in  FIGS. 12 and 13 . As a result, the adhesive layer  13  adheres to the surface of the balloon  30 . When the adhesive layer  13  is an adhesive that exhibits an adhesive force by heating, the adhesive layer  13  is also heated when the heat-shrinkable tube  61  is heated, and the adhesive layer  13  adheres to the surface of the balloon  30 . If an axial length of the drug layer applying device  60  with the heat shrunken heat-shrinkable tube  61  applied to the drug layer applying device  60  exceeds the length of the straight portion  31 , the drug layer applying device  60  with the heat shrunken heat-shrinkable tube  61  applied to the drug layer applying device  60  can cover the entire straight portion  31 . Further, a distal end of the shrunk drug layer applying device  60  covers a proximal portion of the distal tapered portion  33 , and a proximal end of the shrunk drug layer applying device  60  can cover a distal portion of the proximal tapered portion  32 . As a result, both the ends of the drug layer applying device  60  are smaller in diameter than the portion that covers the straight portion  31  and thermally shrink. As a result, the drug layer applying device  60  is firmly fixed to the balloon  30  and is not detachable. Note that the distal end of the shrunk drug layer applying device  60  does not necessarily cover the proximal portion of the distal tapered portion  33 . In addition, the proximal end of the shrunk drug layer applying device  60  do not necessarily cover the distal portion of the proximal tapered portion  32 . 
     Next, the inflation fluid is suctioned (i.e., sucked) and discharged from the interior of the balloon  30  through the proximal opening  27  of the hub  26 . As a result, the balloon  30  is deflated and folded. As a result, the balloon  30  can be used for expansion of a stenotic part in a living body lumen, such as a blood vessel, as a drug eluting balloon. 
     As described above, the sheet according to the second embodiment is cylindrical, and the drug layer  12  is provided on the outer circumferential surface of the sheet. As a result, the appropriate amount of the drug layer  12  can be relatively quickly and rather easily placed on the outer circumferential surface of the cylindrical medical instrument such as the balloon  30 . 
     In addition, the sheet of the drug layer applying device  60  is the heat-shrinkable tube  61 . As a result, when the balloon  30  covered with the drug layer applying device  60  is heated, the heat-shrinkable tube  61  as the sheet can be reduced in diameter, and the balloon  30  can be brought into contact with the balloon. 
     The adhesive layer  13  may exert an adhesive force when heated. As a result, the adhesive layer  13  is also heated when the heat-shrinkable tube  61  is heated, and the adhesive layer  13  exhibits the adhesive force. Therefore, it is possible to prevent the adhesive layer  13  from adhering to an unintended position before the heating. Therefore, the heat-shrinkable tube  61  can be attached to an appropriate position on the surface of the balloon  30  after positioning the drug layer  12  with respect to the balloon  30  with high precision. 
     Third Embodiment 
     A drug layer applying device  70  according to a third embodiment of the present disclosure is different from the first embodiment in terms of being a strip-shaped long tape as illustrated in  FIG. 14 . Note that parts having the same functions as those in the first embodiment are denoted by the same reference signs, and the description of those parts having the same function as those in the first embodiment will be omitted. A structure (the sheet  11 , the drug layer  12 , and the adhesive layer  13 ) of the drug layer applying device  70  other than the shape is the same as that of the first embodiment. 
     When using the drug layer applying device  70 , the drug layer applying device  70  is cut into a length in accordance with a size of the balloon  30 , and the resultant is spirally wound around the inflated balloon  30  to attach the adhesive layer  13  to the balloon  30 . As a result, the drug layer  12  having an appropriate size can be rather easily placed or applied on the balloon  30  having desired size. 
     Note that the present disclosure is not limited to only the above-described embodiment, and various modifications can be made by those skilled in the art within a technical idea of the present disclosure. For example, the balloon catheter  50  can be a rapid exchange type, but may be an over-the-wire type. 
     In addition, a target to which the drug layer  12  is applied by the drug layer applying device  10 ,  60 , or  70  is not limited to the balloon  30  as long as the target is a medical instrument that is used by being inserted into a living body, and may be, for example, a stent, a covered stent, an implant, or the like. 
     In addition, the drug layer applying device is not necessarily provided with the adhesive layer as long as the drug layer applying device is attached to the surface of the balloon  30 . In this case, an adhesive is applied to an adhering surface of the drug layer applying device or the surface of the balloon  30  at the time of attaching the drug layer applying device to the balloon  30 . The adhesive is not particularly limited, but is preferably a liquid adhesive, and examples of the liquid adhesive can include a cyanoacrylate-based instant adhesive, a fibrin adhesive, a starch-based adhesive, a natural rubber-based adhesive, a cellulose-based adhesive, a polyimide-based adhesive, and the like. As a result, the drug layer applying device can be attached to the surface of the balloon  30  even if the drug layer applying device is not provided with an adhesive layer in advance. 
     In addition, a protective film  17  that can be peeled off from the adhesive layer  13  may be attached to the adhesive layer  13  as in a first modification illustrated in  FIG. 15 . As a result, it is possible, for example, to suppress dust and the like from adhering to the adhesive layer  13  before use. The protective film  17  can be rather easily peeled off before attaching the adhesive layer  13  to the balloon  30 . In addition, a drug protective film  18  covering the drug layer  12  may be attached to the drug layer  12 . The drug protective film  18  is attached to the drug layer  12  in a peelable manner. Alternatively, the drug protective film  18  may be a water-soluble film. In this case, the balloon  30  can be inserted into a blood vessel without removing the drug protective film  18  from the drug layer  12  after attaching the adhesive layer  13  to the balloon  30 . The balloon catheter  50  to which the drug layer applying device equipped with the drug protective film  18  is attached can suppress detachment of the drug when inserted into the blood vessel. The material of the drug protective film  18  can include, for example, a gelatin film, a collagen film, a starch film, and the like. The drug protective film  18  may be attached to the drug layer  12  via a biocompatible adhesive. Examples of the biocompatible adhesive can include a cyanoacrylate-based adhesive, a gelatin-based adhesive, a fibrin-based adhesive, and the like. 
     In addition, the drug layer  12  may be partially placed on the surface of the sheet  11  (or the heat-shrinkable tube  61 ) as in a second modification illustrated in  FIG. 16A . Note that a shape of the range where the drug layer  12  is provided is not particularly limited. Therefore, the range in which the drug layer  12  is provided can be set to a desired range in the drug layer applying device  10 ,  60 , or  70 . 
     In addition, the drug layer applying device  10 ,  60 , or  70  may have a plurality of holes  16  as in a third modification illustrated in  FIG. 16B . The number and shapes of the holes  16  are not particularly limited. 
     The detailed description above describes embodiments of a drug layer applying device that applies a drug on a surface of a medical instrument such as a balloon, and a method for forming a drug layer. The invention is not limited, however, to the precise embodiments and variations described. Various changes, modifications and equivalents may occur to one skilled in the art without departing from the spirit and scope of the invention as defined in the accompanying claims. It is expressly intended that all such changes, modifications