Patent Publication Number: US-2020276421-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 Patent Application No. PCT/JP2018/043181 filed on Nov. 22, 2018, which claims priority to Japanese patent Application No. 2017-224340 filed on Nov. 22, 2017, the entire content of both of which is incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention generally relates to a drug layer applying device that applies or provides a drug layer 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) present in a body lumen. The balloon catheter typically includes an elongated shaft portion and a radially inflatable balloon provided on a distal side or distal portion of the shaft portion. When the deflated balloon is inflated after reaching a target location in a body via a living 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 in some cases. Therefore, recently, a drug eluting balloon (DEB) in which a surface of a balloon is coated with a drug for suppressing stenosis has been used. The drug eluting balloon inflates to instantaneously release, to the lesion, the drug which has been applied to the surface of the balloon, thereby suppressing restenosis. 
     Japanese Patent Application Publication No. 2015-119804 discloses an example of a method for forming a drug layer on a surface of the balloon that involves applying a coating liquid containing a drug to a rotating balloon using a porous body such as a sponge and performing drying to form a drug layer. 
     SUMMARY 
     In the method described in Japanese Patent Application Publication No. 2015-119804, the coating liquid is applied to the balloon by bringing the porous body such as the sponge containing the coating liquid into contact with the balloon that rotates about an axis. Therefore, a device for rotating the balloon is required, and it is difficult to easily apply the drug on the balloon. 
     Disclosed here is a drug layer applying device and a method for forming a drug layer which can quickly and easily provide or apply an appropriate amount of a drug on a surface of a medical instrument. 
     A drug layer applying device to apply a drug layer on a surface of a medical instrument to be inserted into a living body includes: a deformable porous body configured to hold a coating solution containing a drug and a solvent; a removal unit that is flexibly deformable and arranged alongside the porous body; and a holding base that holds the porous body and the removal unit. 
     A method for forming a drug layer on a surface of a medical instrument to be inserted into a living body so that a drug exists on the surface of the medical instrument includes: bringing the medical instrument, after having been removed from the living body after use in the living body, into contact with a deformable porous body that holds a coating solution containing a drug and a solvent, and applying the coating solution to the surface of the medical instrument; and drying the solvent in the coating solution applied to the surface of the medical instrument. 
     The drug layer applying device configured as described above can remove blood or the like from the used medical instrument using the removal unit, and can apply the coating solution to the medical instrument using the porous body. Therefore, an appropriate amount of the drug layer can be quickly and easily formed on the surface of the medical instrument. 
     The drug layer applying device may further include a powdered drug held by the porous body. As a result, the powdered drug can be dissolved in the solvent by supplying the solvent to the porous body, so that the coating solution held by the porous body can be obtained. 
     The porous body may have a concave portion configured to receive the medical instrument. As a result, the medical instrument hardly deviates from the concave portion by arranging the medical instrument in the concave portion, and a contact area between the porous body and the medical instrument increases. Therefore, the coating solution can be effectively applied to the surface of the medical instrument. 
     The drug layer applying device may include a heating unit that heats the porous body, and a pressurizing unit that pressurizes the porous body. As a result, an adhesive force between the medical instrument and the drug can be enhanced, and the drop of the drug from the medical instrument can be suppressed. 
     The removal unit may have a removal concave portion configured to receive the medical instrument to be arranged. As a result, blood or the like on the surface of the medical instrument can be effectively removed by arranging the medical instrument in the removal concave portion. 
     The holding base may have a recessed portion, and the porous body may be positioned in the recessed portion. As a result, it is difficult for the coating solution to leak out of the porous body, and the porous body is easily brought into contact with the medical instrument. Therefore, the coating solution can be effectively applied to the surface of the medical instrument. 
     The holding base may be deformable so as to close an entrance of the recessed portion. As a result, the porous body can be pressed against the surface of the medical instrument by deforming the holding base, and the coating solution can be effectively applied. 
     The medical instrument may be a balloon configured to inflate and deflate. As a result, the appropriate amount of the drug layer can be quickly and easily applied 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, from various drugs. 
     In the method for forming a drug layer as described above, the coating solution can be applied to the used medical instrument using the porous body. Therefore, the appropriate amount of the drug layer can be quickly and easily applied on the surface of the medical instrument. 
     The method for forming a drug layer may involve removing blood from the surface of the medical instrument using a flexibly deformable removal unit, provided alongside the porous body, prior to the applying of the coating solution to the surface of the medical instrument. As a result, the removal unit can remove blood or the like from the used medical instrument, and the coating solution can be favorably applied to the used medical instrument to form the drug layer. 
     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 quickly and easily apply or 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 quickly and easily apply 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 apply 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 an embodiment. 
         FIGS. 2A and 2B  are front views illustrating the drug layer applying device, in which  FIG. 2A  illustrates a state before a holding base is closed, and  FIG. 2B  illustrates a state where the holding base is closed. 
         FIG. 3  is a cross-sectional view taken along the section line III-III of  FIG. 2B ; 
         FIG. 4  is a front view illustrating a balloon catheter. 
         FIGS. 5A and 5B  are front views illustrating a distal portion of the balloon catheter, in which  FIG. 5A  illustrates a state where the balloon is deflated, and  FIG. 5B  illustrates a state where the balloon is inflated. 
         FIG. 6  is a cross-sectional view taken along line VI-VI of  FIG. 5A . 
         FIGS. 7A and 7B  are cross-sectional views illustrating a state at the time of applying a coating solution to the balloon by the drug layer applying device, in which  FIG. 7A  is a state before the coating solution is applied to the balloon, and  FIG. 7B  is a state where the coating solution is applied to the balloon. 
         FIG. 8  is a cross-sectional view illustrating the balloon on which a drug layer is formed. 
         FIGS. 9A and 9B  are perspective views illustrating a first modification of the drug layer applying device, in which  FIG. 9A  illustrates a state where an entrance of the holding base is open, and  FIG. 9B  illustrates a state where the entrance of the holding base is narrowed. 
         FIG. 10  is a perspective view illustrating a second modification of the drug layer applying device. 
         FIG. 11  is a cross-sectional view illustrating a third modification of the drug layer applying device. 
         FIG. 12  is a perspective view illustrating a fourth modification of the drug layer applying device. 
     
    
    
     DETAILED DESCRIPTION 
     Set forth below with reference to the accompanying drawings is a detailed description of embodiments of a drug layer applying device and method of forming or applying a drug layer on a surface of a medical instrument to be inserted into a living body, representing examples of the inventive drug layer applying device and method disclosed here. Dimensional ratios of the drawings are exaggerated for the convenience of description and may differ from actual ratios in some cases. 
     A drug layer applying device  10  according to the embodiment is a device configured to apply a drug layer on a surface of a balloon  70  (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 to 4 . A medical instrument on which the drug layer applying device  10  applies the drug layer is not limited to the balloon  70 , and may be, for example, a guide wire, a guiding sheath, a guiding catheter, a stent, or the like. The description below will describe an example in which the drug layer is applied on the balloon  70  by the drug layer applying device  10 . 
     The drug layer applying device  10  includes a porous body  20 , a removal unit  30 , and a holding base  40 . 
     The holding base  40  holds the porous body  20  and the removal unit  30 . The holding base  40  is a substantially C-shaped member that is deformable. The holding base  40  includes a first holding portion  41  and a second holding portion  42  that can approach and separate from each other (are movable toward and away from one another), and a connecting portion  43  that connects the first holding portion  41  and the second holding portion  42  to each other. 
     Opposing surfaces of the first holding portion  41  and the second holding portion  42  have recessed portions  44  that house or hold the porous body  20  and the removal unit  30 , respectively. The recessed portions  44  may be concave-shaped as illustrated in  FIGS. 1, 2A and 2B . 
     A claw portion  45 , which protrudes in a direction Y orthogonal to a direction X in which the first holding portion  41  is movable with respect to the second holding portion  42 , is formed at an end of the first holding portion  41 . The claw portion  45  has a first inclined surface  45 A that is inclined with respect to the moving direction X of the first holding portion  41  on the side of the claw portion closer to the second holding portion  42 . The claw portion  45  has a first orthogonal surface  45 B, substantially orthogonal to the moving direction X of the first holding portion  41 , on the side of the claw portion facing away from the second holding portion  42 . 
     A plurality of spaced-apart locking portions  46  that can be brought into contact with the claw portion  45  and protrude to the opposite side of the protruding direction Y of the claw portion  45  (i.e., the locking portions  46  protrude in a direction opposite the direction of protrusion of the claw portion  45 ) are formed at an end of the second holding portion  42 . The plurality of locking portions  46  each have a second inclined surface  46 A that is inclined with respect to the moving direction X of the first holding portion  41  on the side of the locking portion  46  closer to the first holding portion  41 . The locking portion  46  has a second orthogonal surface  46 B, substantially orthogonal to the moving direction X of the first holding portion  41 , on the side of the locking portion  46  facing away from the first holding portion  41 . The plurality of locking portions  46  are arranged side by side in the moving direction X of the first holding portion  41 . 
     The connecting portion  43  is located between the first holding portion  41  and the second holding portion  42 , and is thinner than the first holding portion  41  and the second holding portion  42 . Therefore, the connecting portion  43  can be deformed and bent such that the first holding portion  41  and the second holding portion  42  approach and move away from each other. In a state where the connecting portion  43  is not deformed, that is, in a natural state where no external force acts on the connecting portion  43 , the first holding portion  41  is separated from the second holding portion  42 , and the claw portion  45  is not in contact with the locking portion  46  (see  FIGS. 1 and 2A ). 
     The recessed portion  44  is formed in a groove shape in the direction Z through which an internal space of the holding base  40  penetrates. The direction Z is substantially orthogonal to both the moving direction X of the first holding portion  41  and the protruding direction Y of the claw portion  45 . 
     A constituent material from which the holding base  40  may be fabricated preferably has flexibility. Examples of such materials from which the holding base  40  may be fabricated include polyurethane, ABS, polypropylene, polycarbonate, nylon, polyethylene, polyacetal, stainless steel, polyethylene terephthalate (PET), silicon, Teflon, and the like. 
     The porous body  20  is a sponge-like member that can be flexibly deformed and can hold a liquid containing a drug. The porous body  20  is arranged in the recessed portion  44  of the first holding portion  41  and the recessed portion  44  of the second holding portion  42 . In the illustrated embodiment, the porous body is comprised of two porous bodies  20 . Each of the porous bodies  20  has a groove-shaped concave portion  21  extending in the direction Z. The concave portions  21  of the respective porous bodies  20  can overlap each other (e.g., may be aligned with one another) when the first holding portion  41  and the second holding portion  42  approach each other. 
     Examples of a constituent material from which the porous body  20  may be fabricated include foamed polyurethane, polyethylene foam, polyurethane foam, polypropylene foam, EVA cross-linked foam, PET resin foam, phenol foam, silicone foam, cellulose, chloroprene rubber, fluorine rubber, nitrile rubber, and the like. 
     The removal unit  30  functions as a wiper to wipe-off or remove a liquid such as blood. The removal unit  30  is a plate-shaped member that is flexibly deformable. The removal unit  30  is arranged in the recessed portion  44  of the first holding portion  41  and the recessed portion  44  of the second holding portion  42 . It is preferable that the removal unit  30  not be porous. In the illustrated embodiment, the removal unit is comprised of two removal units  30 . Each of the removal units  30  is arranged on one end surface side (i.e., at one axial end) of one of the porous bodies  20  alongside the porous body  20 . Each of the removal units  30  includes a surface to be contacted by a groove-like removal concave portion  31  extending in the direction Z. The removal concave portions  31  of the respective removal units  30  are arranged side by side so as to communicate with the concave portions  21  of the adjacent porous bodies  20 . The removal concave portions  31  of the respective removal units  30  can overlap each other (e.g., may be aligned with one another) when the first holding portion  41  and the second holding portion  42  approach each other. 
     Examples of a constituent material from which the removal unit  30  may be fabricated include various rubber materials such as natural rubber, silicone rubber, butyl rubber, isoprene rubber, butadiene rubber, and styrene-butadiene rubber, various thermoplastic elastomers such as polyurethanes, polyesters, polyamides, olefins, and styrenes or a mixture thereof, nonwoven fabric, nylon, and the like. 
     A coating solution containing a drug and a solvent is supplied to the porous body  20  from a solution supply unit  100  such as a syringe (see  FIG. 1 ) and is held in the porous body  20 . The drug contained in the coating solution 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 include fat-soluble drugs. A form of the water-insoluble or water-soluble drug is not particularly limited, and may be, for example, a crystal or not. 
     Some preferred examples of the water-insoluble drug include 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 at least one selected from the group including rapamycin, paclitaxel, docetaxel, and everolimus. The rapamycin, paclitaxel, docetaxel, and everolimus in the present specification 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 include 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 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. 
     Preferably, the solvent is an organic solvent. The organic solvent preferably has a quick-drying property, and examples thereof include tetrahydrofuran, acetone, glycerin, ethanol, methanol, dichloromethane, hexane, ethyl acetate, and the like. The solvent may include water. 
     The coating solution may contain an additive (excipient). When the coating solution contains the additive, examples of the additive include 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 to 5,000 parts by weight, more preferably 50 to 3000 parts by weight, and still more preferably 100 to 1000 parts by weight, per 100 parts by weight of the water-insoluble drug. The constituent material of the water-soluble low molecular weight compound is serine ethyl ester, sugars such as glucose, sugar alcohols such as sorbitol, citrate, polysorbate, polyethylene glycol, urea, 
     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 these can be used. The water-soluble low molecular weight compound has a hydrophilic group and a hydrophobic group, and is characterized by being soluble in water. The water-soluble low molecular weight compound is preferably non-swellable or hardly 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 balloon  70 . It is preferable that the additive be not a hydrogel. The additive contains the low molecular weight compound, and thus, dissolves quickly without swelling when coming into contact with an aqueous solution. Further, the additive easily dissolves when the balloon  70  is inflated in the blood vessel so that crystal particles of the water-insoluble drug on the surface of the balloon  70  are 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 is 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. It is preferable that the water-soluble low molecular weight compound be not a hydrogel. The water-soluble low molecular weight compound is preferably not a polymer, and more preferably not a water-insoluble polymer. It is preferable that the water-soluble low molecular weight compound be 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 this case, the dissolved amount is more than 1000 mg/mL. Examples of such a substance 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 this case, the dissolved amount is more than 100 mg/mL and 1000 mg/mL or less. Examples of such a substance 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 this case, the dissolved amount is more than 33 mg/mL and 100 mg/mL or less. Examples of such a substance 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 this case, the dissolved amount is 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 this case, the dissolved amount is 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 this case, the dissolved amount is 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 this case, the dissolved amount is 0.1 mg/mL or less. Examples of such a substance 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”. 
     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. 4 to 6 . 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” or “distal end” and an operating hand side of the balloon catheter  50  is referred to as a “proximal side” or “proximal end”. 
     The balloon catheter  50  includes an elongated shaft portion  60 , the balloon  70  provided at a distal portion of the shaft portion  60 , and a hub  66  fixed to a proximal end of the shaft portion  60 . 
     The shaft portion  60  includes an outer tube  61  that is a tubular body of which distal end and proximal end are open, and an inner tube  62  that is a tubular body arranged inside the outer tube  61 . The inner tube  62  is housed in a hollow interior of the outer tube  61 , and the shaft portion  60  has a double-tube structure at the distal portion. The hollow interior of the inner tube  62  is a guide wire lumen  64  through which a guide wire is inserted. An inflation lumen  63  for circulating inflation fluid of the balloon  70  is formed in the hollow interior of the outer tube  61  outside the inner tube  62 . The inner tube  62  is open to the outside at a side opening  65 . The inner tube  62  protrudes further to the distal side from the distal end of the outer tube  61 . That is, the inner tube  62  protrudes distally beyond the distal-most end of outer tube  61 . A distal tip, which is a separate member, may be provided at a distal portion of the inner tube  62 . 
     The balloon  70  includes: a straight portion or intermediate portion  71  formed in a main body in the axial direction; a proximal tapered portion  72  located on the proximal side of the straight portion  71 ; and a distal tapered portion  73  located on the distal side of the straight portion  71 . The straight portion  71  has a cylindrical shape that has substantially the same outer diameter along its entire length when inflated. An outer diameter of the proximal tapered portion  72  gradually decreases from the straight portion  71  toward the proximal side. An outer diameter of the distal tapered portion  73  gradually decreases from the straight portion  71  toward the distal side. 
     The straight portion  71  is a portion of the balloon  70  where the drug is applied by the drug layer applying device  10 . The range in which the drug is applied by the drug layer applying device  10  is not limited only to the straight portion  71 , but may include at least a part of the proximal tapered portion  72  and the distal tapered portion  73  in addition to the straight portion  71 . Alternatively, the range in which the drug is applied by the drug layer applying device  10  may be only a part of the straight portion  71 . 
     In the balloon  70 , a balloon fusing portion  74  located at the proximal end of the proximal tapered portion  72  is fused to the distal portion of the outer tube  61 . In addition, a balloon fusing portion  75  located at the distal end of the distal tapered portion  73  is fused to the distal portion of the inner tube  62  in the balloon  70 . A method for fixing the balloon  70  to the outer tube  61  and the inner tube  62  is not limited to fusion, but may be, for example, adhesion. As a result, the inside of the balloon  70  communicates with the inflation lumen  63 . The balloon  70  can be inflated by injecting the inflation fluid into the balloon  70  via the inflation lumen  63 . 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 physiological saline and a contrast agent can be used. 
     The balloon  70  has a plurality of pleats  77  shaped to protrude in the radial direction. The pleats  77  can be folded in the circumferential direction. The pleats  77  are each formed by a fold extending substantially in the axial direction of the balloon  70 . The length of each pleat  77  in the long-axis direction does not exceed the length of the balloon  70 . The number of the pleats  77  is not particularly limited, and is one to seven, for example, but is three in the present embodiment. The plurality of pleats  77  are preferably arranged to be uniform in the circumferential direction of the balloon  70 , but are not limited thereto. 
     The length of the balloon  70  in the axial direction is not particularly limited, but is preferably 5 to 500 mm, more preferably 10 to 300 mm, and still more preferably 20 to 200 mm. The outer diameter of the balloon  70  when inflated is not particularly limited, but is preferably 1 to 10 mm, and more preferably 2 to 8 mm. 
     It is preferable that the balloon  70  have a certain degree of flexibility and a certain degree of hardness such that the balloon  70  can be inflated when reaching a blood vessel, a tissue, or the like, and release the drug on the outer surface of the balloon  70 . Specifically, the balloon  70  is made of metal or resin, but it is preferable that at least the surface of the balloon  70  be made of resin. As a constituent material of at least the surface of the balloon  70 , 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 kinds thereof, 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. Among them, polyamides are preferably used. 
     In the hub  66 , a proximal opening  67 , which communicates with the inflation lumen  63  of the outer tube  61  and functions as a port for inflow and outflow of the inflation fluid, is formed. 
     Next, an operation of the drug layer applying device  10  according to the present embodiment will be described. 
     First, the balloon  70  that has been used for pre-dilation of a stenotic part such as a blood vessel is deflated and removed from the blood vessel. As a result, blood or the like adheres to the surface of the balloon  70 . 
     Next, the coating solution containing the drug and the solvent is supplied to the porous body  20  from the solution supply unit  100 , such as a syringe, as illustrated in  FIG. 1 . As a result, the porous body  20  is in the state of holding the coating solution. 
     Next, the outer tube  61  of the balloon catheter  50  is housed inside the holding base  40  from a gap between the claw portion  45  and the locking portion  46  in the separated state. At this time, the removal unit  30  is located on the side close to the balloon  70 , and the porous body  20  is located on the side close to the hub  66 . Then, the outer tube  61  is housed in the removal concave portion  31  and the concave portion  21 , and outer surfaces of the first holding portion  41  and the second holding portion  42  are gripped and pressed, as illustrated in  FIG. 7A . As a result, the connecting portion  43  deflects, the first holding portion  41  and the second holding portion  42  approach each other, and the first inclined surface  45 A of the claw portion  45  is brought into contact with the second inclined surface  46 A of the locking portion  46 , as illustrated in  FIG. 2B . When the outer surfaces of the first holding portion  41  and the second holding portion  42  are further pressed, the first inclined surface  45 A advances over the second inclined surface  46 A. As a result, the first orthogonal surface  45 B of the claw portion  45  can come into contact with the second orthogonal surface  46 B. Since the first orthogonal surface  45 B and the second orthogonal surface  46 B are substantially orthogonal to the moving direction X of the first holding portion  41 , the claw portion  45  that has advanced over the locking portion  46  in the moving direction X is suppressed or prevented from returning to the opposite side in the moving direction X. Therefore, the claw portion  45  is locked by the locking portion  46 , and a distance between the first holding portion  41  and the second holding portion  42  is fixed. The claw portion  45  can be locked to or engaged with any of the locking portions  46 . Therefore, the claw portion  45  can be locked to or engaged with the desired locking portion  46  by moving the claw portion  45  in the moving direction X to the desired locking portion  46 . As a result, the distance between the first holding portion  41  and the second holding portion  42  can be appropriately adjusted in accordance with a size of the balloon  70  (and a size of the outer tube  61 ). The porous body  20  and the removal unit  30  can be appropriately deformed depending on positions of the first holding portion  41  and the second holding portion  42 . After the claw portion  45  is locked by the locking portion  46 , the claw portion  45  can be separated from the locking portion  46  by deforming the second holding portion  42  in the protruding direction Y of the claw portion  45  such that the locking portion  46  is separated from the claw portion  45 . 
     Next, the balloon  70  is moved to the relatively proximal side with respect to the drug layer applying device  10  as illustrated in  FIG. 7B . That is, the balloon  70  and the drug layer applying device  10  are relatively moved so that the balloon  70  moves in the proximal direction and enters the drug layer applying device  10 . As a result, the removal unit  30  (surface of the wiper) comes into contact with the surface of the balloon  70 . Therefore, the blood or the like adhering to the outer surface of the balloon  70  is removed by the removal unit  30 . The balloon  70  from which the blood or the like has been removed then comes into contact with the exposed surface of the porous body  20  that is arranged alongside the removal unit  30 . As a result, the coating solution containing the drug is applied to the surface of the balloon  70 . The coating solution is a liquid, and thus, can also enter a gap between the folded pleats  77  of the balloon  70 . The solvent of the coating solution is evaporated after completely withdrawing the balloon  70  from the drug layer applying device  10 . As a result, a drug layer  80  containing a drug is formed or exists on the surface of the balloon  70  as illustrated in  FIG. 8 . If the coating solution includes an additive, the drug layer  80  includes the additive. Thereafter, the balloon  70  having the drug layer  80  is inserted again into a blood vessel and is inflated, whereby a stenotic part can be expanded while causing the drug to act on a living tissue. 
     As described above, the drug layer applying device  10  according to the present embodiment is the drug layer applying device  10  configured to form or apply the drug layer  80  on the surface of the balloon  70  (medical instrument) to be inserted into the living body, and includes: the deformable porous body  20  capable of holding the coating solution containing the drug and the solvent; the removal unit  30  that is flexibly deformable and is arranged alongside the porous body  20 ; and the holding base  40  that holds the porous body  20  and the removal unit  30 . 
     The drug layer applying device  10  configured as described above can remove the blood or the like from the used balloon  70  using the removal unit  30  and can apply the coating solution to the balloon  70  using the porous body  20 . Therefore, the appropriate amount of the drug layer  80  can be quickly and easily formed on the surface of the balloon  70 . 
     The porous body  20  has the concave portion  21  which allows the balloon  70  to be arranged or properly positioned relative to the porous body. As a result, the balloon  70  hardly deviates from the concave portion  21  by arranging the balloon  70  in the concave portion  21 , and the contact area between the porous body  20  and the balloon  70  increases. Therefore, the coating solution can be effectively applied to the surface of the balloon  70 . 
     The removal unit  30  has the removal concave portion  31  which allows the balloon  70  to be arranged or properly positioned relative to the removal unit. As a result, the balloon  70  is arranged in the removal concave portion  31 , and the blood or the like on the surface of the balloon  70  can be effectively removed. 
     The holding base  40  has the recessed portion  44 , and the porous body  20  is arranged inside the recessed portion  44 . As a result, it is difficult for the coating solution to leak out of the porous body  20 , and the porous body  20  is easily brought into contact with the balloon  70 . Therefore, the coating solution can be effectively applied to the surface of the balloon  70 . 
     The medical instrument to which the coating solution is applied is the balloon  70  that is capable of inflating and deflating. As a result, the appropriate amount of the drug layer  80  can be quickly and easily applied on the surface of the balloon  70 . 
     The drug in the drug layer  80  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  80 . 
     The drug in the drug layer  80  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  80 , a drug that is appropriate for conditions and the like, alone or in combination, from various drugs. 
     The present invention also includes a method for forming a drug layer to apply a drug on a surface of the balloon  70  (medical instrument) to be inserted into a living body. The method for forming a drug layer includes: applying a coating solution to the surface of the balloon  70  by bringing the balloon  70  having been removed out of the living body after use in the living body into contact with the deformable porous body  20  that holds the coating solution containing the drug and a solvent; and a step of drying the solvent. 
     In the method for forming a drug layer configured as described above, the coating solution can be applied to the used balloon  70  using the porous body  20 . Therefore, the appropriate amount of the drug layer  80  can be quickly and easily formed on the surface of the balloon  70 . 
     The method for forming a drug layer may include removing blood from the surface of the balloon  70  using the flexibly deformable removal unit  30 , provided alongside the porous body  20 , prior to applying the coating solution to the surface of the balloon  70 . As a result, the removal unit  30  can remove the blood or the like from the used balloon  70 , and the coating solution can be favorably applied to the used balloon  70  to form the drug layer  80 . 
     The medical instrument is the balloon  70  that is capable of inflating and deflating. As a result, the appropriate amount of the drug layer  80  can be quickly and easily applied on the surface of the balloon  70 . In addition, the balloon  70  used for pre-dilation of a target site in the living body can be removed, and then, the drug layer  80  can be applied on the same balloon  70  to reuse the balloon  70  for post-dilation of the target site. The drug layer applying device  10  may be used to form the drug layer  80  on the balloon  70  before being inserted into the living body. 
     The present invention 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 invention. For example, the balloon catheter  50  is a rapid exchange type, but may be an over-the-wire type. 
     In addition, the drug layer applying device  10  may be configured such that the recessed portion  44  is formed inside the substantially C-shaped holding base  40 , and the substantially C-shaped porous body  20  and removal unit  30  are arranged in the recessed portion  44  as in a first modification illustrated in  FIG. 9A . When an outer surface of the substantially C-shaped holding base  40  is pressed to reduce the internal space, the concave portion  21  of the porous body  20  and the removal concave portion  31  of the removal unit  30  can be narrowed as illustrated in  FIG. 9B . As a result, the shapes of the porous body  20  and the removal unit  30  can be appropriately adjusted in accordance with a size of the balloon  70 . 
     In addition, the drug layer applying device  10  may be configured such that the concave portion  21  of the porous body  20  and the removal concave portion  31  of the removal unit  30  arranged in the recessed portion  44  of the holding base  40  have shapes that surround only a range of about 180 degrees of the balloon  70  as in a second modification illustrated in  FIG. 10 . The holding base  40  is not deformed. Even with such a configuration, when the balloon  70  is moved to the proximal side or in the proximal direction with respect to the drug layer applying device  10  while rotating the balloon  70 , blood or the like can be removed from the surface of the balloon  70  using the removal unit  30 , and the coating solution can be applied to the balloon  70  using the porous body  20 . 
     The drug layer applying device  10  may include a heating unit  90  that can heat the porous body  20  as in a third modification illustrated in  FIG. 11 . The heating unit  90  is a heating wire embedded in the porous body  20  and has an outer surface covered so as not to come into direct contact with the porous body  20 . The heating unit  90  as the heating wire is supplied with a current from the outside. Alternatively, the heating unit  90  as the heating wire is supplied with a current from a battery (not illustrated) provided in the drug layer applying device  10 . The heating unit  90  can increase a bonding force between the balloon  70  and the drug by heating. A heating temperature using the heating unit  90  can be, for example, 30 to 80° C., but is preferably 30 to 60° C. A hydrophilic polymer (wet coating) applied to the surface of the medical instrument such as the balloon  70  can be fixed to the surface of the medical instrument by heating. 
     The configuration of the heating unit is not particularly limited. For example, the heating unit may be a pipe that circulates a heated fluid in the porous body  20  or to a side opposite to a side on which the drug is applied (for example, a position away from the porous body  20  and opposing the porous body  20  in  FIG. 10 ), or a heating plate which is arranged by being heated by a heating wire or a heated fluid. The drug layer applying device  10  can heat the porous body  20  to strengthen the bonding force between the drug and the balloon  70 , and can further cover and tighten the balloon  70  with the heated porous body  20 . That is, the porous body  20  can also function as a pressurizing unit that can tighten the balloon  70 . 
     In addition, the drug layer applying device may further include another device  100  including the heating unit  90  and pressurizing units  101  in addition to the above-described device including the porous body  20  (see  FIG. 1 ) as in a fourth modification illustrated in  FIG. 12 . This device  100  includes the pair of pressurizing units  101  in which concave portions  102  sandwiching the balloon  70 , coated with a drug by the porous body  20 , are formed. The pressurizing unit  101  can approach and separate (move towards and away) from each other. Although a structure of the device  100  other than the pressurizing unit  101  is substantially the same as the device illustrated in  FIG. 1 , the structure of the device  100  is not particularly limited. A constituent material for fabricating the pressurizing unit  101  is preferably a material such as Teflon that prevents peeling of the drug applied to the balloon  70 . Alternatively, a Teflon film may be arranged at a portion of the pressurizing unit  101  that is in contact with the balloon  70 . The heating unit  90  is embedded in the pressurizing unit  101 . 
     The device  100  heats and pressurizes the balloon  70 , coated with the drug through the porous body  20  of the device illustrated in  FIG. 1 , using the heated pressurizing unit  101 . As a result, an adhesive force between the balloon  70  and the drug can be strengthened, and the adhesive force between the balloon  70  and the drug can be further enhanced to reduce the crossing profile (outer diameter) of the balloon  70 . As a result, the detachment of the drug from the balloon  70  can be prevented. In addition, when the balloon catheter  50  is reused, it is possible to easily apply the drug to the balloon  70  and fold the balloon  70  by combining a part to be heated and a part to be pressurized. In addition, since the balloon  70  can be shaped by folding with the heating and pressurization, it is also possible to mitigate an insertion resistance to the blood vessel. 
     Although no gap is formed between the removal unit  30  and the porous body  20  in each of the above-described embodiments, such a gap may be provided. In addition, the removal unit  30  need not necessarily be arranged in the recessed portion  44  of the holding base  40 . In addition, the porous body  20  need not necessarily have the concave portion  21 , and the removal unit  30  need not necessarily have the removal concave portion  31 . 
     In addition, a powdered drug may be held in the porous body  20  before the coating solution is supplied. The powdered drug is crystalline or amorphous (non-crystalline). As a result, the powdered drug can be dissolved in the solvent by supplying the solvent containing no drug to the porous body  20 , so that the coating solution held by the porous body  20  can be obtained. 
     In addition, the balloon  70  is folded in the deflated state in the balloon catheter  50 , but the balloon  70  need not necessarily be folded. That is, the balloon  70  may be formed of a material having elasticity to be inflated while the thickness of the balloon  70  is reduced. 
     The detailed description above describes embodiments of a drug layer applying device and method of applying a drug layer on a surface of a medical instrument to be inserted into a living body, representing examples of the inventive a drug layer applying device and method disclosed here. The invention is not limited, however, to the precise embodiments and variations described. Various changes, modifications and equivalents can be effected by 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 and equivalents which fall within the scope of the claims are embraced by the claims.