JP6697917B2 - Balloon catheter, manufacturing method thereof, and treatment method - Google Patents

Description

  TECHNICAL FIELD The present invention relates to a balloon catheter having a balloon whose surface is coated with a drug, a manufacturing method thereof, and a treatment method.

  BACKGROUND ART A balloon catheter is widely used to improve a lesion (stenosis) generated in a living body lumen. A balloon catheter usually includes a long catheter shaft and a balloon provided on the distal end side of the catheter shaft and expandable in the radial direction. A deflated balloon can be expanded by reaching a target location in the body through a thin living body lumen and then expanding the balloon.

  On the other hand, if the lesion is forcibly expanded by a balloon, the endothelial cells may excessively proliferate and new stenosis (restenosis) may occur in the lesion. Therefore, in recent years, a drug eluting balloon (DEB) in which the surface of the balloon is coated with a drug for suppressing stenosis has been used. By expanding the drug-eluting balloon, the drug coated on the surface can be released to the lesion site and the drug can be transferred to the living tissue, whereby restenosis can be suppressed.

  In recent years, it has become clear that the morphological form of the drug coated on the surface of the balloon affects the release property of the drug from the balloon surface at the lesion site and the tissue migration property. For example, Patent Document 1 describes a balloon catheter in which a crystal of a drug is formed long on the surface of a balloon.

U.S. Patent Application Publication No. 2014/0271775

  A balloon catheter for eluting a drug is desired to have a high delivery property of the drug on the balloon surface to a living tissue in order to enhance the therapeutic effect.

  The present invention has been made to solve the above-mentioned problems, and an object of the present invention is to provide a balloon catheter capable of effectively delivering a drug to a living tissue, a manufacturing method thereof, and a treatment method.

The balloon catheter according to the present invention to achieve the above object has a balloon at the distal end of the catheter shaft, and a plurality of elongated bodies that are crystals of a water-insoluble drug extending with an independent long axis are the balloons. A balloon catheter provided on the surface of,
The balloon in the deflated state has a plurality of vanes in the circumferential direction and a circumferential surface portion along the circumferential direction of the catheter shaft, and the vanes are folded along the circumferential direction of the balloon,
The balloon is between the peripheral surface portion and the blade portion of the folded state, it has a layer structure in which the length and elongated body has overlap of the elongated body and the tilting state of upstanding,
The elongate body in the standing state and the elongate body in the tilted state of the layer structure portion are attached to each other and integrated .

Further, in the method for manufacturing a balloon catheter according to the present invention which achieves the above object, a plurality of elongated bodies, which are crystals of a water-insoluble drug and have independent long axes, are provided on the surface of the balloon. In the method of manufacturing a balloon catheter,
Forming the elongated body in a standing state on the surface of the balloon,
By pressing the surface of the balloon with the blade of the pleating portion, a blade portion that radially projects is formed on the balloon, and the elongated body in the region that becomes the blade portion is tilted, and the blade portion is formed. A step of maintaining the standing state of the elongated body in a region to be a peripheral surface portion facing to,
By pressing the surface of the balloon with the blade of the folding portion, the blade portion formed on the balloon is laid along the circumferential direction to overlap the peripheral surface portion, and the elongated body in a tilted state of the blade portion and A step of forming a layered structure portion in which the elongated body in the standing state of the peripheral surface portion overlaps with each other;
Have a,
When the vane portion of the balloon is superposed on the peripheral surface portion, by heating the surface of the balloon, the elongated body in the tilted state of the vane portion and the length in the standing state of the peripheral surface portion overlap each other. The scale is attached and integrated .

  In the balloon catheter configured as described above, the elongate body in the standing state is maintained as it is during the folding process of the balloon and the insertion process into the living body lumen due to the layered structure portion between the blade portion and the peripheral surface portion. In addition, it is possible to suppress the change or breakage of the shape of the drug crystal due to an external force. Therefore, it is possible to effectively deliver the elongate body in a standing state up to the lesioned part of the living body lumen and effectively transfer the drug in the lesioned part.

  The elongated body in the tilted state in the layer structure portion has an angle of 30 degrees or less with respect to the surface of the balloon. Therefore, it is possible to prevent the thickness of the layer structure portion from becoming too large.

  If the elongated body in the standing state and the elongated body in the tilted state of the layer structure part are adhered to each other and integrated, the layer structure part becomes stronger and the shape of the drug crystal is improved. The change and destruction of can be suppressed more.

  The layered structure portion has the elongated body in which the surface of the balloon forming the vane portion is tilted, and the surface of the balloon forming the peripheral surface portion is in the standing state. As a result, in the process of pleating to form the blade portion, the long body is tilted, and in the folding process of folding the blade portion, the tilted long body and the standing long body are overlapped with each other. As a result, a layer structure part can be formed.

  When the water-insoluble drug is rapamycin, paclitaxel, docetaxel, or everolimus, restenosis of the stenotic part in the blood vessel can be suppressed well.

  The method for manufacturing a balloon catheter configured as described above uses the force acting on the balloon in the step of forming the vane portion on the balloon and the step of folding the vane portion to form a layered structure between the vane portion and the peripheral surface portion. Parts can be formed.

It is a front view showing the balloon catheter concerning this embodiment. It is sectional drawing of the front-end|tip part of a balloon catheter. It is a schematic perspective view which shows the elongate body which consists of a drug crystal|crystallization on the surface of a balloon. It is a schematic diagram showing a long body and a base layer which consist of a drug crystal on the surface of a balloon. FIG. 3 is a schematic enlarged cross-sectional view of a balloon having a layered structure in which a long body in a standing state and a long body in a tilted state overlap with each other. FIG. 7 is a cross-sectional view showing a state before folding the balloon (FIG. 6A), a state in which the wings are formed on the balloon (FIG. 6B), and a state in which the balloon is folded (FIG. 6C). It is a schematic diagram showing a balloon coating device. FIG. 6 is a cross-sectional view showing the dispensing tube in contact with the balloon. It is a perspective view showing a balloon folding device. It is a front view which shows arrangement|positioning of the blade of a pleating part, and a film supply part. It is a front view which shows the blade of the pleating part. It is a front view which shows arrangement|positioning of the blade of a folding part, and a film supply part. It is a front view which shows the blade of a folding part. It is sectional drawing which shows the balloon catheter arrange|positioned at the pleating part. It is a front view which shows the blade of the state which formed the blade|wing part in the balloon by rotating the blade of the pleating part. A schematic cross-sectional view of the surface of the balloon having the elongated body in a tilted state during pleating (FIG. 16A) and a schematic cross-sectional view of the surface of the balloon having the elongated body that maintains the standing state during pleating. (Fig. 16(b)). It is sectional drawing which shows the balloon catheter arrange|positioned at the folding part. It is a front view which shows the blade of the state which folded the blade of the balloon by rotating the blade of the folding part. FIG. 6 is a schematic cross-sectional view showing a process in which a blade portion and a peripheral surface portion are close to each other at the time of folding, and a layer structure portion is formed by an elongated body on the surface. It is sectional drawing which shows the state which expanded the narrowing part of the blood vessel with the balloon catheter which concerns on this embodiment. It is a schematic diagram showing a long body and a base layer when a base layer is a film-like amorphous. FIG. 6 is a cross-sectional view of a balloon in a folded state having differently shaped vane portions.

  Embodiments of the present invention will be described below with reference to the drawings. The dimensional ratios in the drawings may be exaggerated and different from the actual ratios for convenience of description. In the present specification, the side of the balloon catheter 10 that is inserted into the body lumen is referred to as the “tip” or the “tip side”, and the operating side is referred to as the “base end” or the “base end side”.

  First, the balloon catheter of this embodiment will be described. As shown in FIG. 1, the balloon catheter 10 includes a long and hollow catheter shaft 11, a balloon 12 provided at the distal end of the catheter shaft 11, and a coating layer containing a drug provided on the surface of the balloon 12. It has a hub 30 fixed to the proximal end of the catheter shaft 11. The balloon 12 provided with the coat layer 30 is covered and protected by the protective sheath 15 until it is used.

  The length of the balloon 12 in the axial direction is not particularly limited, but is preferably 5 to 500 mm, more preferably 10 to 300 mm, and further preferably 20 to 200 mm.

  The outer diameter of the balloon 12 when expanded is not particularly limited, but is preferably 1 to 10 mm, more preferably 2 to 8 mm.

  The surface of the balloon 12 before the coat layer 30 is formed is smooth and non-porous, but may have fine pores that do not penetrate the membrane. The size of the minute pores is, for example, 0.1 to 5 μm in diameter and 0.1 to 10 μm in depth, and one crystal may have one or more pores. The size of the minute holes is, for example, 5 to 500 μm in diameter and 0.1 to 50 μm in depth, and one hole may have one or a plurality of crystals.

  In this balloon catheter 10, a long catheter shaft 11 is inserted into a living body organ, and a balloon 12 provided on the distal side thereof is expanded at a lesion site, so that the lesion site can be expanded and treatment can be performed. It is possible.

  Next, the structure of the distal end portion of the catheter shaft 11 and the balloon 12 will be described. As shown in FIG. 2, the catheter shaft 11 has a hollow outer tube 20 and a hollow inner support 21. The inner tube 21 is housed in the hollow inside of the outer tube 20, and the catheter shaft 11 has a double-tube structure at its distal end. The hollow inside of the inner tube 21 forms a guide wire lumen 23 through which the guide wire 14 is inserted. Further, inside the hollow of the outer tube 20 and outside the inner tube 21, an expansion lumen 22 for allowing the expansion fluid of the balloon 12 to flow is formed. The inner tube 21 is open to the outside at the opening 24. The inner pipe 21 projects further to the tip side than the tip of the outer pipe 20.

The proximal end of the balloon 12 is fixed to the distal end of the outer tube 20, and the distal end of the balloon 12 is fixed to the distal end of the inner tube 21. As a result, the inside of the balloon 12 communicates with the expansion lumen 22. The balloon 12 can be expanded by injecting an expansion fluid into the balloon 12 via the expansion lumen 22. The expanding fluid may be a gas or a liquid, and for example, a gas such as helium gas, CO ₂ gas, O ₂ gas, or a liquid such as physiological saline or a contrast medium can be used. In addition, in FIG. 2, the balloon 12 is in an expanded state.

  A cylindrical straight portion 12a (expansion portion) having the same outer diameter when expanded is formed in the central portion of the balloon 12 in the axial direction, and the outer diameter gradually increases on both sides of the straight portion 12a in the axial direction. The tapered portion 12b that changes to Then, the coat layer 30 containing the drug is formed on the entire surface of the straight portion 12a. The range in which the coat layer 30 is formed in the balloon 12 is not limited to the straight portion 12a, and may include at least a part of the tapered portion 12b in addition to the straight portion 12a, or one portion of the straight portion 12a. It may be only a part.

  The outer tube 20 and the inner tube 21 are preferably made of a material having a certain degree of flexibility. Examples of such a material include polyethylene, polypropylene, polybutene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, ionomer, polyolefin such as a mixture of two or more thereof, and soft polyvinyl chloride resin, Examples thereof include polyamide, polyamide elastomer, polyester, polyester elastomer, polyurethane, fluororesin such as polytetrafluoroethylene, silicone rubber, and latex rubber.

  It is preferable that the balloon 12 has a certain degree of flexibility and a certain degree of hardness so that it can be expanded when it reaches a blood vessel, a tissue or the like, and the drug can be released from the coat layer 30 on its surface. Specifically, although it is made of metal or resin, it is preferable that at least the surface of the balloon 12 on which the coat layer 30 is provided is made of resin. The constituent material of at least the surface of the balloon 12 is, for example, a polyolefin such as polyethylene, polypropylene, polybutene, an ethylene-propylene copolymer, an ethylene-vinyl acetate copolymer, an ionomer, or a mixture of two or more thereof, or a soft polychlorinated material. Thermoplastic resins such as vinyl resin, polyamide, polyamide elastomer, nylon elastomer, polyester, polyester elastomer, polyurethane, fluororesin, silicone rubber, latex rubber and the like can be used. Of these, polyamides are preferred. That is, at least a part of the surface of the expanded portion of the medical device that coats the drug is a polyamide. The polyamides are not particularly limited as long as they are polymers having an amide bond, and examples thereof include polytetramethylene adipamide (nylon 46), polycaprolactam (nylon 6), polyhexamethylene adipamide (nylon 66), Homopolymers such as polyhexamethylene sebacamide (nylon 610), polyhexamethylene dodecamide (nylon 612), polyundecanolactam (nylon 11), polydodecanolactam (nylon 12), caprolactam/lauryllactam copolymer Combined (nylon 6/12), caprolactam/aminoundecanoic acid copolymer (nylon 6/11), caprolactam/ω-aminononanoic acid copolymer (nylon 6/9), caprolactam/hexamethylene diammonium adipate copolymer ( Examples thereof include copolymers such as nylon 6/66), copolymers of adipic acid and metaxylenediamine, and aromatic polyamides such as a copolymer of hexamethylenediamine and m,p-phthalic acid. Further, a polyamide elastomer, which is a block copolymer having nylon 6, nylon 66, nylon 11, nylon 12, etc. as a hard segment and polyalkylene glycol, polyether, or an aliphatic polyester as a soft segment, also relates to the present invention. Used as a base layer for medical devices. The above polyamides may be used alone or in combination of two or more.

  The coating layer 30 is formed on the surface of the balloon 12 directly or through a pretreatment layer such as a primer layer on the surface of the balloon 12 by a method described later. As shown in FIGS. 3 and 4, the coat layer 30 has a base layer 32 (excipient) containing a water-soluble low-molecular compound arranged in layers on the surface 31 of the balloon 12 and has an independent long axis and extends. And a plurality of elongated bodies 33 which are crystals of the existing water-insoluble drug.

The amount of drug contained in the coat layer 30 is not particularly ^{limited, 0.1μg / mm 2 ~10μg / mm} 2, at a density of preferably ^{0.5μg / mm 2 ~5μg / mm 2} , more preferably 0.5 [mu] g / ^{mm 2} ~3.5μg / ^mm 2, more preferably included at a density of ^{1.0μg / mm 2 ~3μg / mm 2} . In addition, the amount of crystals of the coat layer 30 is not particularly limited, but is 5 to 500000 crystals/10 μm ² (the number of crystals per 10 μm ² ), preferably 50 to 50000 crystals/10 μm ² , and more preferably 500 to 5000 crystals/10 μm ^2. Is.

  The elongated body 33 may be hollow or solid. When the elongated body 33 is hollow, at least the vicinity of its tip is hollow. The cross section of the long body 33 in a plane perpendicular to the long axis of the long body 33 is vertical. In the elongated body 33 having the hollow, the cross section of the elongated body 33 in a plane perpendicular to the long axis (perpendicular) is polygonal. The polygon is, for example, a triangle, a quadrangle, a pentagon, a hexagon, or the like. Therefore, the elongated body 33 has a distal end (or a distal end surface) and a proximal end (or a proximal end face), and a side surface between the distal end (or the distal end face) and the proximal end (or the proximal end face) has a plurality of substantially flat surfaces. Is formed as a long polyhedron. This crystal morphology type (hollow elongated crystal morphology type) constitutes all or at least a part of a certain plane on the surface of the base layer.

  The length in the axial direction of the elongated body 33 having the major axis is preferably 5 μm to 20 μm, more preferably 9 μm to 11 μm, and even more preferably about 10 μm. The diameter of the elongated body 33 having the major axis is preferably 0.01 μm to 5 μm, more preferably 0.05 μm to 4 μm, and further preferably 0.1 μm to 3 μm. As an example of a combination of the axial length and the diameter of the elongated body 33 having the long axis, a combination in which the diameter is 0.01 to 5 μm when the length is 5 μm to 20 μm, and a length is 5 to 20 μm Examples include a combination having a diameter of 0.05 to 4 μm and a combination having a diameter of 0.1 to 3 μm when the length is 5 to 20 μm. The elongated body 33 having the major axis is substantially linear in the major axis direction, but may be curved in a curved shape.

  The elongated body 33 having a long axis after coating and before the balloon 12 is folded is formed so as to stand on the surface of the balloon 12 without lying. At this time, the elongated body 33 changes its angle with respect to the surface of the balloon 12 by changing the angle of the elongated body 33 by pleating the balloon 12 (step of forming the blade portion on the balloon) or folding (step of folding the blade portion). The angle of the long axis of the body 33 can be changed. Therefore, while the crystals formed on the surface of the balloon 12 from the beginning are fixed (fixed) to the surface of the balloon 12 and the adjacent elongated body 33, the standing elongated body 33 is It is not formed by being physically fixed to the surface of the balloon 12 or the adjacent elongated body 33. Therefore, the standing elongate body 33 is only positioned (disposed) so as to contact the surface of the balloon 12 or the adjacent elongate body 33, and the position is changed three-dimensionally. It is possible. Therefore, the coated long body 33 is formed so that the angle and the position can be changed before and after the pleating and folding of the balloon 12. A part of the elongated body 33 may be embedded in the surface of the balloon 12.

  The base layer 32 is distributed and exists in the space between the plurality of long bodies 33 standing in a forest. Regarding the ratio of the substance forming the coat layer 30, it is preferable that the crystal of the water-insoluble drug occupies a larger volume than the base layer 32. The excipient forming the base layer 32 does not form a matrix. The matrix is a layer in which relatively high-molecular substances (polymers, etc.) are continuously formed, and forms a three-dimensional network structure, in which fine spaces are present. Therefore, the water-insoluble drug that constitutes the crystal is not attached to the matrix substance. The water-insoluble drug that constitutes the crystal is also not embedded in the matrix material.

  The base layer 32 is coated on the surface of the balloon 12 in the form of an aqueous solution and then dried to form a layer. The base layer 32 is present as amorphous, crystalline particles, or a mixture thereof. The base layer 32 of FIG. 4 is in a state of crystalline particles and/or amorphous particles. The base layer 32 may be formed as a layer containing a water-insoluble drug, or may be formed as a separate layer containing no water-insoluble drug. The base layer 32 has a thickness of 0.1 to 5 μm, preferably 0.3 to 3 μm, and more preferably 0.5 to 2 μm.

  The coat layer 30 having the hollow elongated body-shaped elongated body 33 has low toxicity when delivered to the body and has a high stenosis suppressing effect. A water-insoluble drug containing a hollow elongated crystal form has good penetrability into the tissue because one unit of the crystal becomes small when the drug migrates to the tissue, and has good solubility, so that it is effective. It can act and suppress stenosis. Further, it is considered that the drug is less likely to remain in the tissue as a large lump, so that the toxicity is reduced.

  Further, the layer containing the hollow elongated crystal morphology is a plurality of substantially uniform elongated bodies 33 having a long axis, and the morphology in which the base layer surface has regularity and is lined up substantially uniformly. Is. Therefore, the size (length in the major axis direction) of crystals that migrate to the structure is as small as about 10 μm. Therefore, it acts uniformly on the affected part of the lesion and the tissue permeability is enhanced. Furthermore, since the size of the crystal to be transferred is small, an excessive amount of the drug does not remain in the affected area for an excessive period of time, and it is considered that it is possible to exhibit a high stenosis-inhibiting effect without causing toxicity. ..

  The drug coated on the surface of the balloon 12 may include an amorphous type. Crystals and amorphouss may be arranged so as to have regularity in the coat layer 30, but may be arranged irregularly.

  The state of the elongated body 33 that is a drug crystal on the surface of the balloon 12 will be further described. As shown in FIG. 3, in the state in which the elongated body 33 is formed, each elongated body 33 is in a standing state with respect to the surface of the balloon 12. On the other hand, by folding the balloon 12 and applying heat and force from the outside to the surface of the balloon 12, the layer structure portion 37 can be formed between the surfaces of the balloon 12 that overlap each other.

  As shown in FIG. 5, the layer structure portion 37 is formed so as to form a layer between the surfaces of the balloons 12 facing each other. The layer structure part 37 has the elongated body 33 in an erected state (erected state) on one side (lower side in the figure) in the facing direction of the surface of the balloon 12 and a tilted state (tilted state) on the other side (upper side in the figure). The elongated body 33 of FIG. The tilted state of the long body 33 refers to a state in which θ, which is an angle formed with respect to the surface of the balloon 12, is 30 degrees or less, and a state in which the long body 33 is erected means that θ is larger than 30 degrees. To tell. In the layered structure portion 37, the distal end portion of the elongated body 33 in the upright state is attached to and integrated with the elongated body 33 in the tilted state at a longitudinal intermediate position. For this reason, the layer structure portion 37 has a layer 37a in which the elongated body 33 in an upright state is juxtaposed on one side between the surfaces of the balloon 12 and the elongated body 33 in a tilted state on the other side. Form a two-layer structure having layers 37b juxtaposed with each other. The long body 33 in the tilted state means a state in which the angle θ with respect to the surface of the balloon 12 is 30 degrees or less, and the long body 33 in the standing state means a state other than the tilted state. ..

  As shown in FIG. 6A, the balloon 12 has a substantially circular cross section in a state where the expansion fluid is injected therein. From this state, the balloon 12 is configured to have the blade portion 40 as shown in FIG. 6B by the pleating portion 120 described later. In this state, the surface of the balloon 12 is divided into a region of the peripheral surface portion 41 along the circumferential direction of the catheter shaft 11 and a region of the blade portion 40 protruding to the outer peripheral side. Further, the blade portion 40 has a blade inner portion 40a that is a surface that faces the peripheral surface portion 41 when folded, and a blade outer portion 40b that is a surface that faces the outer peripheral side when folded. In this state, the elongated body 33 is in a tilted state in the region of the blade inner side portion 40a and the blade outer side portion 40b, and the elongated body 33 is in an upright state in the region of the peripheral surface portion 41.

  From the state shown in FIG. 6B, the balloon 12 is folded into a folded state as shown in FIG. 6C by the folding unit 130 described later. In this state, the peripheral surface portion 41 is divided into a facing surface portion 41a facing the blade inner side portion 40a of the blade portion 40 and an outer peripheral constituent surface portion 41b toward the outer peripheral side. Further, when the balloon 12 is folded, a root-side space 42 is formed between the root of the blade 40 and the peripheral surface 41. In the region of the root side space portion 42, a minute gap is formed between the blade portion 40 and the peripheral surface portion 41. On the other hand, the region of the blade portion 40 on the tip side of the root-side space portion 42 is in close contact with the peripheral surface portion 41. The ratio of the circumferential length of the root side space portion 42 to the circumferential length of the blade portion 40 is in the range of 1 to 95%. In the folded balloon 12 shown in FIG. 6C, the layer structure portion 37 of the elongated body 33 is formed in a region facing the root side space portion 42 between the blade inner side portion 40a and the facing surface portion 41a. To be done. In the layer structure portion 37, the layer 37a in which the elongated body 33 is erected is on the facing surface portion 41a side, and the layer 37b in which the elongated body 33 is tilted is on the blade inner side portion 40a side.

  When the balloon 12 is folded from the state of FIG. 6(a) to the state of FIG. 6(b) and then to the state of FIG. 6(c), force is applied to the surface of the balloon 12. The scale 33 may be deformed or crushed by the force applied to the surface of the balloon 12. On the other hand, a layered structure portion 37 in which the elongated body 33 in the standing state and the elongated body 33 in the tilted state are integrated is formed between the blade inner side portion 40a and the facing surface portion 41a which are folded and overlap each other. As a result, the elongated body 33 in the upright state is maintained as it is between the blade inner side portion 40a and the facing surface portion 41a, and it is possible to suppress the change or breakage of the shape of the drug crystal due to the force applied during folding.

  The balloon 12 is inserted into a living body lumen such as a blood vessel in the folded state of FIG. 6C and is expanded at the lesioned portion to be in the state of FIG. 6A. Even in the process in which the balloon 12 is inserted into the living body lumen, the elongate body 33 in the standing state can maintain the shape as it is because the layered structure portion 37 is formed, and even the lesioned portion can be maintained. The elongated body 33 in an upright state can be delivered. In the balloon 12 expanded at the lesioned part, the layered structure part 37 is exposed to the outside, and the elongated body 33 in the standing state is also exposed to the outside and abuts on the inner wall surface of the living body lumen. Since the long body 33 in the standing state has a good migration property to the living tissue, by reliably delivering the long body 33 in the standing state to the lesion site, the drug is effectively applied to the living tissue. Can be transferred.

  Next, a balloon coating system for forming the coat layer 30 on the balloon 12 described above will be described. The present system includes a balloon coating device 50 (see FIG. 7) for forming the coat layer 30 on the balloon 12 and a balloon folding device 100 (see FIG. 9) for folding the balloon 12 having the coat layer 30 formed thereon. It has and. By using the balloon coating device 50, a plurality of elongated bodies, which are crystals of the water-insoluble drug and have independent long axes, are formed on the surface of the balloon 12. After that, the balloon 12 is folded by the balloon folding device 100, so that in a part of the surface of the balloon 12, the elongated body 33 is tilted in the axial direction from the standing state.

  First, the balloon coating device 50 will be described. As shown in FIGS. 7 and 8, the balloon coating device 50 includes a rotation mechanism unit 60 that rotates the balloon catheter 10 and a support base 70 that supports the balloon catheter 10. The balloon coating device 50 further includes a coating mechanism section 90 provided with a dispensing tube 94 for coating the coating solution on the surface of the balloon 12, and a moving mechanism section 80 for moving the dispensing tube 94 with respect to the balloon 12. , And a control unit 99 for controlling the balloon coating device 50.

  The rotation mechanism unit 60 holds the hub 13 of the balloon catheter 10 and rotates the balloon catheter 10 about the axis of the balloon 12 by a drive source such as a built-in motor. In the balloon catheter 10, the core material 61 is inserted and held in the guide wire lumen 23, and the core material 61 prevents the coating solution from flowing into the guide wire lumen 23. Further, in the balloon catheter 10, in order to control the flow of the fluid to the dilation lumen 22, a three-way stopcock capable of controlling the opening and closing of the flow path is connected to the proximal end opening 13 a of the hub 13.

  The support base 70 includes a tubular base end side support portion 71 that accommodates the catheter shaft 11 therein and rotatably supports the catheter shaft 11, and a tip end side support portion 72 that rotatably supports the core material 61. If possible, the distal end side support portion 72 may rotatably support the distal end portion of the catheter shaft 11 instead of the core material 61.

  The moving mechanism unit 80 includes a moving base 81 that is linearly movable in a direction parallel to the axis of the balloon 12, and a tube fixing unit 83 to which the dispensing tube 94 is fixed. The moving table 81 can be moved linearly by a drive source such as a built-in motor. The tube fixing portion 83 fixes the upper end of the dispensing tube 94 to the moving table 81. Therefore, when the moving table 81 moves, the dispensing tube 94 moves linearly in a direction parallel to the axis of the balloon 12. Further, the coating mechanism unit 90 is placed on the moving table 81, and the coating mechanism unit 90 is linearly moved in both directions along the axis.

  The coating mechanism 90 is a portion that coats the surface of the balloon 12 with the coating solution. The coating mechanism 90 includes a container 92 for containing the coating solution, a liquid feed pump 93 for feeding the coating solution at an arbitrary liquid feed amount, and a dispensing tube 94 for coating the balloon 12 with the coating solution. ..

  The liquid feeding pump 93 is, for example, a syringe pump, and is controlled by the control unit 99 to suck the coating solution from the container 92 via the suction tube 91 and arbitrarily supply the coating solution to the dispensing tube 94 via the supply tube 96. Can be supplied at The liquid feeding pump 93 is installed on the movable table 81 and can be moved linearly by the movement of the movable table 81. The liquid feed pump 93 is not limited to the syringe pump as long as it can feed the coating solution, and may be, for example, a tube pump.

  The dispensing tube 94 communicates with the supply tube 96, and is a member that discharges the coating solution supplied from the liquid feed pump 93 via the supply tube 96 onto the surface of the balloon 12. The dispensing tube 94 is a flexible tubular member. The dispensing tube 94 has an upper end fixed to the tube fixing portion 83, extends vertically downward from the tube fixing portion 83, and has an opening 95 formed at a discharge end 97 which is the lower end. By moving the moving table 81, the dispensing tube 94 can move linearly in both directions along the axial direction of the balloon catheter 10 together with the liquid feeding pump 93 installed on the moving table 81. The dispensing tube 94 is capable of supplying the coating solution to the surface of the balloon 12 while being pressed by the balloon 12 and bent.

  The dispensing tube 94 need not be circular as long as it can supply the coating solution. Further, the dispensing tube 94 does not have to extend in the vertical direction as long as the coating solution can be discharged from the opening 95.

  The dispensing tube 94 is preferably made of a flexible material so as to reduce the contact load on the balloon 12 and absorb the change in the contact position due to the rotation of the balloon 12 by bending. The constituent material of the dispensing tube 94 is, for example, polyolefin such as polyethylene and polypropylene, cyclic polyolefin, polyester, polyamide, polyurethane, PTFE (polytetrafluoroethylene), ETFE (tetrafluoroethylene/ethylene copolymer), PFA (tetra. Fluorine-based resins such as fluoroethylene/perfluoroalkyl vinyl ether copolymer) and FEP (tetrafluoroethylene/hexafluoropropylene copolymer) can be applied as long as they are flexible and deformable. It is not particularly limited.

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

  The control unit 99 is composed of, for example, a computer, and controls the rotating mechanism unit 60, the moving mechanism unit 80, and the coating mechanism unit 90 as a whole. Therefore, the control unit 99 can comprehensively control the rotation speed of the balloon 12, the moving speed of the dispensing tube 94 in the axial direction with respect to the balloon 12, the drug discharge speed from the dispensing tube 94, and the like.

  The coating solution supplied to the balloon 12 by the dispensing tube 94 is a solution or suspension containing the constituent material of the coat layer 30, and contains a water-insoluble drug, an excipient, an organic solvent, and water. After the coating solution is supplied to the surface of the balloon 12, the organic solvent and water are volatilized to form a plurality of long crystals, which are crystals of a water-insoluble drug, which extend on the surface of the balloon 12 with independent long axes. The coat layer 30 having a scale is formed. The viscosity of the coating solution is 0.5-1500 cP, preferably 1.0-500 cP, more preferably 1.5-100 cP.

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

  Examples of some preferred water-insoluble drugs include immunosuppressive agents, for example, cyclosporins including cyclosporine, immunoactive agents such as rapamycin, anticancer agents such as paclitaxel, antiviral agents or antibacterial agents, antineoplastic agents, Analgesics and anti-inflammatory agents, antibiotics, antiepileptics, anxiolytics, antiparalytics, antagonists, neuron block agents, anticholinergic and cholinergic agents, antimuscarinic and muscarinic agents, antiadrenergic agents, Includes antiarrhythmic agents, antihypertensive agents, hormonal agents and nutritional agents.

  The water-insoluble drug is preferably at least one selected from the group consisting of rapamycin, paclitaxel, docetaxel and everolimus. In the present specification, rapamycin, paclitaxel, docetaxel and everolimus include their analogs and/or their derivatives as long as they have similar pharmacological effects. For example, paclitaxel and docetaxel are analogs. Rapamycin and everolimus are in a derivative relationship. Of these, paclitaxel is more preferable.

  The excipient constitutes the base layer 32 on the balloon 12. Excipients include water-soluble low molecular weight compounds. The water-soluble low molecular weight compound has a molecular weight of 50 to 2000, preferably 50 to 1000, more preferably 50 to 500, and further preferably 50 to 200. The water-soluble low molecular weight compound is preferably 5 to 10000 parts by mass, more preferably 5 to 200 parts by mass, and further preferably 8 to 150 parts by mass with respect to 100 parts by mass of the water-insoluble drug. Water-soluble low molecular weight compounds are composed of serine ethyl ester, citrate ester, polysorbate, water-soluble polymer, sugar, contrast agent, amino acid ester, glycerol ester of short-chain monogalvic acid, pharmaceutically acceptable salt and surfactant. Agents, etc., or a mixture of two or more of these can be used. The water-soluble low molecular weight compound has a hydrophilic group and a hydrophobic group and is characterized by being soluble in water. The water-soluble low molecular weight compound is preferably non-swelling or hardly swelling. The excipient is preferably amorphous on the balloon 12. The excipient containing the water-soluble low molecular weight compound has an effect of uniformly dispersing the water-insoluble drug on the surface of the balloon 12. Further, since the base layer 32 is easily dissolved when the balloon 12 is expanded in the blood vessel, the long body 33 of the water-insoluble drug on the surface of the balloon 12 is easily released, and the amount of the drug attached to the blood vessel is increased. Has the effect of

  The organic solvent is not particularly limited, but tetrahydrofuran, acetone, glycerin, ethanol, methanol, dichloromethane, hexane, ethyl acetate, water, among them, a mixed solvent of tetrahydrofuran, ethanol, acetone, and water is preferable. For example, a combination of tetrahydrofuran and water, tetrahydrofuran and ethanol and water, tetrahydrofuran and acetone and water, acetone and ethanol and water, tetrahydrofuran, acetone, ethanol and water, and the like can be given.

  Next, a method of forming crystals of a water-insoluble drug on the surface of the balloon 12 using the above-mentioned balloon coating device 50 will be described.

  First, a dilating fluid is supplied into the balloon 12 via a three-way stopcock connected to the proximal end opening 13a of the balloon catheter 10. Next, with the balloon 12 expanded, the three-way stopcock is operated to seal the expansion lumen 22, and the expanded state of the balloon 12 is maintained. The balloon 12 is inflated at a pressure (for example, 4 atmospheres) lower than the pressure (for example, 8 atmospheres) during use in the blood vessel. The coating layer 30 may be formed on the surface of the balloon 12 without expanding the balloon 12, and in that case, it is not necessary to supply the expansion fluid into the balloon 12.

  Next, the balloon catheter 10 is rotatably installed on the support base 70 and the hub 13 is connected to the rotation mechanism unit 60 in a state where the dispensing tube 94 is not in contact with the surface of the balloon 12.

  Next, the position of the moving table 81 is adjusted to position the dispensing tube 94 with respect to the balloon 12. At this time, the dispensing tube 94 is positioned at the position of the balloon 12 that is closest to the tip side where the coat layer 30 is formed. As an example, the extending direction (discharging direction) of the dispensing tube 94 is opposite to the rotating direction of the balloon 12. Therefore, the balloon 12 rotates in the direction opposite to the discharging direction of the coating solution from the dispensing tube 94 at the position where the dispensing tube 94 is in contact. This can stimulate the coating solution and promote the formation of drug crystal nuclei. The extending direction (discharging direction) of the dispensing tube 94 toward the opening 95 is opposite to the rotation direction of the balloon 12, so that the crystal of the water-insoluble drug formed on the surface of the balloon 12 is crystallized. Is likely to be formed including a morphological form including a plurality of elongated bodies each having an independent long axis. It should be noted that the extending direction of the dispensing tube 94 does not have to be the reverse direction of the rotation direction of the balloon 12, and thus can be the same direction or can be vertical.

  Next, the coating solution is supplied to the dispensing tube 94 while adjusting the amount of solution to be delivered by the solution delivery pump 93, and the balloon catheter 10 is rotated by the rotation mechanism section 60, and the moving table 81 is moved to move the dispensing tube. 94 is gradually moved in the proximal direction along the axial direction of the balloon 12. The coating solution discharged from the opening 95 of the dispensing tube 94 is applied while drawing a spiral on the outer peripheral surface of the balloon 12 as the dispensing tube 94 moves relative to the balloon 12.

  The moving speed of the dispensing tube 94 is not particularly limited, but is, for example, 0.01 to 2 mm/sec, preferably 0.03 to 1.5 mm/sec, and more preferably 0.05 to 1.0 mm/sec. The discharge rate of the coating solution from the dispensing tube 94 is not particularly limited, but is, for example, 0.01 to 1.5 μL/sec, preferably 0.01 to 1.0 μL/sec, more preferably 0.03 to 0. 8 μL/sec. The rotation speed of the balloon 12 is not particularly limited, but is, for example, 10 to 300 rpm, preferably 30 to 250 rpm, and more preferably 50 to 200 rpm. The diameter of the balloon 12 when applying the coating solution is not particularly limited, but is, for example, 1 to 10 mm, preferably 2 to 7 mm.

  Then, the organic solvent contained in the coating solution applied to the surface of the balloon 12 volatilizes before water. Therefore, the organic solvent volatilizes with the water-insoluble drug, the water-soluble low-molecular compound and water left on the surface of the balloon 12. In this way, when the organic solvent volatilizes with water remaining, the water-insoluble drug precipitates inside the water-soluble low-molecular compound containing water, and the crystal gradually grows from the crystal nuclei to form the balloon 12 Morphologic form drug crystals including a plurality of elongated bodies 33 each having a long axis independent of each other are formed on the surface of the drug crystal. The elongated body 33 in this state is in a standing state with respect to the surface of the balloon 12. The proximal end of the elongated body 33 may be located on the surface of the balloon 12, the surface of the base layer 32, or the inside (see FIG. 4 ). After the organic solvent volatilizes and the drug crystals are deposited as a plurality of elongated bodies 33, water evaporates more slowly than the organic solvent, and the base layer 32 containing the water-soluble low molecular weight compound is formed. The time for evaporating water is appropriately set according to the type of drug, the type of water-soluble low molecular weight compound, the type of organic solvent, the ratio of materials, the coating amount of the coating solution, etc., but for example, about 1 to 600 seconds Is.

  Then, the coating tube 30 is gradually formed on the surface of the balloon 12 in the axial direction by gradually moving the dispensing tube 94 in the axial direction of the balloon 12 while rotating the balloon 12. After the coating layer 30 having the elongated body 33 is formed on the entire coating range of the balloon 12, the rotation mechanism unit 60, the moving mechanism unit 80, and the coating mechanism unit 90 are stopped.

  After this, the balloon catheter 10 is removed from the balloon coating device 50, and the coating of the balloon 12 is completed.

  Next, the balloon folding device 100 will be described. The balloon folding device 100 is a device capable of folding the balloon 12 so as to wind the balloon 12 around the inner tube 21.

  As shown in FIG. 9, the balloon folding device 100 has a pedestal-shaped base 110 on which a pleating part 120, a folding part 130, and a support base 140 are arranged. The pleating part 120 may form the blade part 40 protruding in the radial direction on the balloon 12. The folding part 130 can fold the vane part 40 formed on the balloon 12 in the circumferential direction. The support base 140 can hold the balloon catheter 10 mounted thereon. The vane portion 40 formed on the balloon 12 is formed by a fold line extending substantially in the axial direction of the balloon 12, and when viewed in a cross section perpendicular to the axial center of the balloon 12, the fold line extends from the long axis of the balloon 12. It is formed so as to project in the direction. The length of the blade portion 40 in the long axis direction does not exceed the length of the balloon 12. The length in the direction in which the blade portion 40 projects from the catheter shaft 11 in the circumferential direction is 1 to 8 mm. The number of blades 40 is not particularly limited, and can be selected from any of two, three, four, five, six, and seven, but is three in the present embodiment.

  A film supply unit 150 that supplies the first film 155 and the second film 156 to the pleating unit 120 is disposed on the base 110 adjacent to the pleating unit 120. In addition, a film supply unit 180 that supplies the first film 181 and the second film 182 to the folding unit 130 is disposed on the base 110 adjacent to the folding unit 130.

  The pleating part 120 has a front plate 121 that is perpendicular to the base 110, and the front plate 121 has an insertion hole 121 a into which the tip of the balloon catheter 10 can be inserted. Further, the folding part 130 has a front plate 131 which is perpendicular to the base 110, and the front plate 131 has an insertion hole 131 a into which the tip part of the balloon catheter 10 can be inserted. The front plate 131 of the folding part 130 faces in a direction different from the front plate 121 of the pleating part 120 by a predetermined angle.

  A support shaft 111, which projects upward from the base 110, is pivotally mounted on the side of the support base 140 away from the pleating part 120 and the folding part 130. The support 140 is positioned at a position facing the front plate 121 of the pleating part 120 and a position facing the front plate 131 of the folding part 130 by slidingly moving the upper surface of the base 110 about the support shaft 111. it can.

  The support base 140 has a base 141 mounted on the base 110, and a holding base 142 that is horizontally movable on the base 141. The base 141 is slidable on the upper surface of the base 110. The holding base 142 slides on the upper surface of the base 141 and can move forward or backward toward the pleating part 120 or the folding part 130.

  On the upper surface of the holding table portion 142, a groove-shaped mounting portion 142a on which the catheter shaft 11 of the balloon catheter 10 can be mounted is formed. Further, the holding base 142 is provided with a holding portion 143 that holds the catheter shaft 11 placed on the placing portion 142a. Note that the balloon catheter 10 may be fixed by another method as long as the balloon catheter 10 can be fixed.

  In a state where the support base 140 faces the front plate 121 of the pleating part 120, the center of the insertion hole 121a formed in the front plate 121 is located on the extension line of the mounting part 142a of the holding base part 142. Therefore, the balloon catheter 10 having the catheter shaft 11 mounted on the mounting portion 142a is inserted into the pleating portion 120 from the center position of the insertion hole 121a. When the support base 140 faces the front plate 131 of the folding part 130, the center of the insertion hole 131a formed in the front plate 131 is located on the extension line of the mounting part 142a of the holding base part 142. Therefore, in the balloon catheter 10 in which the catheter shaft 11 is mounted on the mounting portion 142a, the holding base portion 142 is slid on the base portion 141 to move the holding portion 142 from the center position of the insertion hole 131a to the inside. Is inserted.

  Next, the structure of the pleating unit 120 will be described. As shown in FIG. 10, the pleating part 120 has three blades 122 for blade formation inside. Each blade 122 is a plate-shaped member having the same cross-sectional shape at each position along the axial direction of the inserted balloon catheter 10. The blades 122 are arranged so that each of them makes an angle of 120 degrees with reference to the center position where the balloon 12 is inserted. That is, the blades 122 are arranged at equal angles in the circumferential direction. The blade 122 has a rotation center portion 122a near the outer peripheral end portion, and can rotate about this rotation center portion 122a. Further, the blade 122 has a moving pin 122d extending in the axial direction on the inner peripheral side of the rotation center portion 122a. The moving pin 122d is fitted in a fitting groove 124a formed in the rotating member 124 rotatable in the pleating part 120. The rotating member 124 is connected to a beam portion 126 extending in a substantially horizontal direction. The rotating member 124 is rotatable by receiving a rotational force from a beam portion 126 that is inclined by receiving a force from a driving source 125 such as a hydraulic cylinder or a motor. When the rotating member 124 rotates, the moving pin 122d fitted in the fitting groove 124a moves in the circumferential direction, whereby each blade 122 rotates about the rotation center portion 122a. By rotating the three blades 122, the space area of the central portion surrounded by the blades 122 can be narrowed. The number of blades 122 is not particularly limited as long as it is two or more.

  As shown in FIG. 11, the blade 122 has a substantially arc-shaped first shape forming portion 122b and a second shape forming portion 122c at the inner peripheral end portion on the side opposite to the rotation center portion 122a. The first shape forming portion 122b contacts the surface of the balloon 12 inserted in the pleating portion 120 as the blade 122 rotates, and forms the blade portion 40 protruding in the radial direction on the balloon 12. be able to. The second shape forming portion 122c can abut the blade portion 40 formed on the balloon 12 as the blade 122 rotates, and can bend the blade portion 40 in a predetermined direction. The pleating section 120 also has a heater (not shown) for heating the blade 122. The length of the blade 122 along the axial direction of the balloon catheter 10 is longer than the length of the balloon 12. The lengths of the first shape forming portion 122b and the second shape forming portion 122c of the blade 122 may or may not extend over the entire length of the blade 122.

  The first film 155 and the second film 156 made of resin are supplied to the blade 122 from the film supply unit 150. A plurality of rotating shafts 123 are provided in the pleating unit 120 to guide each film. The first film 155 is engaged with the surface of the blade 122 arranged on the upper side of the first film holding portion 151 via the rotary shaft portion 123. Further, the first film 155 reaches from the blade 122 through the rotary shaft portion 123 to a film winding portion 153 which is rotationally driven by a drive source such as a motor (not shown). The second film 156 is engaged with the two blades 122 arranged in the lower portion from the second film holding portion 152 via the rotating shaft portion 123. Further, the second film 156 reaches the film winding section 153 via the rotary shaft section 123. As a result, the central position of the pleating part 120, through which the balloon 12 is inserted, is surrounded by the first film 155 and the second film 156.

  The first film 155 and the second film 156 are directly attached to the surface of the blade 122 when the balloon 12 is inserted into the pleating part 120 and the blade 122 rotates to form the blade part 40 on the balloon 12. It has the function of protecting against contact. After forming the blade portion 40 of the balloon 12, the first film 155 and the second film 156 are wound by the film winding portion 153 to a predetermined length. That is, the portions of the first film 155 and the second film 156 that have once come into contact with the balloon 12 do not come into contact with the balloon 12 again, and a new portion is supplied to the central position of the pleating part 120 each time the balloon 12 is inserted. It

  As shown in FIG. 11, in the state before the insertion of the balloon 12, the first shape forming portion 122b and the second shape forming portion 122c of the three blades 122 are in a separated state. The central region between the blades 122 is surrounded by the substantially arc-shaped first shape forming portions 122b, and the balloon 12 before folding can be inserted therein.

  Next, the structure of the folding unit 130 will be described. As shown in FIG. 12, the folding part 130 has ten blades 132 for folding the blades therein. Each blade 132 is a plate-shaped member having the same cross-sectional shape at each position along the axial direction of the inserted balloon catheter 10. The blades 132 are arranged so that each of them makes an angle of 36 degrees with reference to the center position where the balloon is inserted. That is, the blades 132 are arranged at equal angles in the circumferential direction. The blade 132 has a rotation center portion 132a near the center thereof and can rotate around this rotation center portion 132a. Further, each blade 132 has a moving pin 132c that extends in the axial direction near the outer peripheral end portion. The moving pin 132c is fitted in a fitting groove 133a formed in the rotating member 133 rotatable in the folding part 130. The rotating member 133 is connected to a beam 135 extending in a substantially horizontal direction. The rotating member 133 is rotatable by receiving a rotational force from a beam 135 that is inclined by receiving a force from a driving source 134 such as a hydraulic cylinder or a motor. When the rotating member 133 rotates, the moving pin 132c fitted in the fitting groove 133a moves in the circumferential direction, whereby each blade 132 rotates about the rotation center portion 132a. By rotating the ten blades 132, it is possible to narrow the space area of the central portion surrounded by the blades 132. The number of blades 132 is not limited to ten.

  The blade 132 is bent at the tip side, and the tip portion 132b has a sharp shape. As the blade 132 rotates, the tip portion 132b comes into contact with the surface of the balloon 12 inserted into the folding portion 130 and folds the blade portion 40 formed on the balloon 12 so as to lie down in the circumferential direction. You can The folding unit 130 also has a heater (not shown) for heating the blade 132.

  A first film 181 and a second film 182 made of resin are supplied to the blade 132 from the film supply unit 180. The supply structure of each film is similar to that of the pleating unit 120. The first film 181 and the second film 182 are arranged to face each other so as to sandwich a central space area surrounded by the blade 132. The first film 181 and the second film 182 prevent the balloon 12 inserted into the folding part 130 from directly contacting the surface of the blade 132. The first film 181 and the second film 182 reach the film winding unit 183, which is rotated by a drive source such as a motor (not shown) via the blade 132.

  As shown in FIG. 13, in a state before the balloon 12 is inserted, the tip ends 132b of the blades 132 are in a state of being separated from each other in the circumferential direction. The balloon 12 having the blade portion 40 may be inserted between the first film 181 and the second film 182 in the central region surrounded by the blade 132.

  Next, a method for folding the balloon 12 on the surface of which the drug crystal is formed by the balloon coating device 50 by using the balloon folding device 100 will be described.

  First, in order to form the blade portion 40 on the balloon 12, the catheter shaft 11 is placed on the placing portion 142 a of the support base 140 and held by the holding portion 143. An expansion fluid is injected into the balloon 12 through the three-way stopcock attached to the hub 13, the hub 13 and the inner tube 21, so that the balloon 12 is expanded to some extent. Further, the blade 122 of the pleating unit 120 is heated. The core material 61 is inserted into the guide wire lumen 23. The core material 61 suppresses the bending of the catheter shaft 11 due to its own weight.

  Next, as shown in FIG. 14, the holding base 142 is slid on the base 141 to insert the balloon catheter 10 into the pleating part 120 through the insertion hole 121a.

  Next, when the driving source 125 is operated to rotate the rotating member 124 (see FIG. 10 ), the blades 122 rotate and the first shape forming portions 122 b of the blades 122 are mutually rotated as shown in FIG. 16. Approaching, the central area between the blades 122 narrows. Along with this, the balloon 12 inserted in the central region between the blades 122 is pressed against the inner tube 22 by the first shape forming portion 122b. The portion of the balloon 12 that is not pressed by the first shape forming portion 122b is extruded into the gap between the tip end portion of the blade 122 and the second shape forming portion 122c of the blade 122 that is adjacent to the blade 122, and bends to one side. The blade portion 40 is formed. Since the balloon 122 heats the balloon 12 to about 50 to 60 degrees, the formed blade portion 40 can maintain its shape. In this way, the three blades 40 in the circumferential direction are formed on the balloon 12.

  At this time, the surface of each blade 122 that contacts the balloon 12 is covered with the first film 155 and the second film 156, and the balloon 12 does not directly contact the surface of the blade 122.

  By forming the protruding blade portion 40, the balloon 12 constitutes a surface which is pressed by the second shape forming portion 122c toward the outer peripheral side of the blade portion 40, as shown in FIGS. 15 and 6B. The outer side portion 40b of the blade, the inner side portion 40a of the blade 122 which is pressed by the tip end portion of the blade 122 and constitutes a surface facing the peripheral surface portion 41 of the blade portion 40, and the inner shape of the inner pipe 21 which is pressed by the first shape forming portion 122b. A peripheral surface portion 41 is formed along the peripheral surface.

  When the blade 122 of the pleating part 120 is used to form the blade portion 40 on the balloon 12, by appropriately setting the pressing force, the pressing time, and the heating temperature for the balloon 12 by the blade 122, the blade of the surface of the balloon 12 The elongated body 33 can be tilted as shown in FIG. 16A in the region of the blade inner portion 40a that is pressed by the tip of the blade 122. The elongated body 33 is also tilted in the region of the blade outer side portion 40b that is pressed by the second shape forming portion 122c of the blade 122. On the other hand, in the region of the peripheral surface portion 41 pressed by the first shape forming portion 122b of the blade 122, the elongated body 33 maintains the standing state as shown in FIG. 16(b).

  After forming the blade portion 40 on the balloon 12, the blade 122 is rotated so as to return to the original position, and the balloon 12 is pulled out from the pleating portion 120. In the process of pleating, the volume of the inside of the balloon 12 decreases, and accordingly, it is preferable to adjust the three-way stopcock to discharge the expansion fluid to the outside and deflate the balloon 12 accordingly. Thereby, it is possible to suppress the excessive force from acting on the balloon 12. In the process of pleating, there is a step of slightly deflating after the balloon 12 is over-expanded, or a step of slightly deflating after the balloon 12 is expanded to an extent not over-expanding. Good.

  Next, the holding base 142 is moved on the upper surface of the base 141 to be separated from the pleating part 120, and the balloon catheter 10 is pulled out from the pleating part 120. Next, the orientation of the support base 140 is changed, and the support base 140 is positioned at a position facing the front plate 131 of the folding part 130. After that, the holding base 142 is moved on the upper surface of the base 141, and the balloon catheter 10 is inserted into the folding part 130 through the insertion hole 131a as shown in FIG. The blade 132 of the folding part 130 is preheated to about 50 to 60 degrees.

  After inserting the balloon 12 having the blade portion 40 into the folding portion 130, as shown in FIG. 18, when the driving source 134 is operated to rotate the rotating member 133, the blade 132 is rotated, and each blade 132 is rotated. Of the blades 132 approach each other, and the central region between the blades 132 narrows. Accordingly, in the balloon 12 inserted in the central region between the blades 132, the blade portions 40 are laid down in the circumferential direction by the tip end portions 132b of the blades 132. The blade 132 is preheated before the insertion of the balloon 12, and since the balloon 132 is heated by the blade 132, the blade portion 40 laid down in the circumferential direction by the blade 132 can maintain its shape as it is. it can. At this time, the surface of each blade 132 that contacts the balloon 12 is covered with the first film 181 and the second film 182, and the balloon 12 does not directly contact the surface of the blade 132.

  When the blade portion 40 of the balloon 12 is folded, the blade inner portion 40a of the blade portion 40 and the facing surface portion 41a of the peripheral surface portion 41 are in contact with each other as shown in FIGS. 18 and 6C, The surfaces of the balloon 12 face each other and overlap each other. Further, the blade outer side portion 40b of the blade portion 40 and the outer peripheral constituent surface portion 41b of the peripheral surface portion 41 are exposed on the outer peripheral side.

  When the surface of the balloon 12 is pressed by the blade 132 of the folding part 130, the blade inner part 40a having the elongated body 33 in the tilted state and the facing surface part 41a having the elongated body 33 in the upright state are shown in FIG. ), they are close to each other while facing each other. When the surface of the balloon 12 is further pressed, as shown in FIG. 19B, the elongated body 33 in the tilted state and the elongated body 33 in the upright state are in contact with each other. As the blades 132 are heated as they are, the portions of the elongated body 33 that are in contact with each other are fused, and the elongated body 33 in the tilted state and the elongated body 33 in the upright state are integrated. Thereby, as shown in FIG. 19C, the layer structure portion 37 is formed between the blade inner portion 40a and the facing surface portion 41a.

  As described above, in order to form the layer structure portion 37 between the blade inner side portion 40a and the facing surface portion 41a as the blade portion 40 of the balloon 12 is folded by the blade 132, the blade 132 is pressed against the balloon 12 in order to be formed. It is necessary to properly set the pressure, the pressing time and the heating temperature.

  After folding the blade portion 40 of the balloon 12, the blade 132 is rotated so as to return to the original position. Next, the balloon catheter 10 is removed from the grip 110 and the balloon 12 is pulled out from the folding part 130. Next, the holding of the catheter shaft 11 by the holding portion 143 is released, the balloon 12 is covered with the tubular protective sheath 15 (see FIG. 1), and the folding of the balloon 12 in the balloon catheter 10 is completed. The protective sheath 15 is a member that prevents the drug from falling off the balloon 12, and is removed before the balloon catheter 10 is used.

  By these steps, the balloon 12 is folded, and the elongate body 33 of the blade portion 40 is tilted from the standing state by the pressing force at the time of pleating, and further the tilting state is made by the pressing force at the time of folding. The elongate body 33 of the blade portion 40 and the elongate body 33 of the peripheral surface portion 41 in the erected state can be overlapped to form a layer structure portion 37 of the elongated body 33 between the blade portion 40 and the peripheral surface portion 41. ..

  Next, a method of using the balloon catheter 10 according to the present embodiment will be described by taking a case of treating a stenosis in a blood vessel as an example.

  First, the operator punctures a blood vessel from the skin by a known method such as the Seldinger method and places an introducer (not shown). Next, after removing the protective sheath 15 of the balloon catheter 10 and performing priming, the guide wire 200 (see FIG. 20) is inserted into the guide wire lumen 23. In this state, the guide wire 200 and the balloon catheter 10 are inserted into the blood vessel from the inside of the introducer. Subsequently, the balloon catheter 10 is advanced while the guide wire 200 is advanced, and the balloon 12 reaches the stenosis portion 300. A guiding catheter may be used to reach the stenosis portion 300 with the balloon catheter 10. When the balloon catheter 10 is inserted, the folded balloon 12 is in sliding contact with the inner wall surface of the blood vessel, but the drug crystal elongated body 33 formed on the blade portion 40 is in a tilted state during pleating. Therefore, it is suppressed that the blood vessel is caught on the inner wall surface of the blood vessel, and the drug is prevented from falling off.

  After the balloon 12 is placed in the stenosis 300, a predetermined amount of expansion fluid is injected from the proximal end opening 13a of the hub 13 using an indeflator or syringe, and the expansion fluid is injected into the balloon 12 through the expansion lumen 22. Inject fluid. As a result, as shown in FIG. 20, the folded balloon 12 is expanded, and the narrowed portion 300 is expanded by the balloon 12. At this time, the coating layer 30 containing the drug crystal provided on the surface of the balloon 12 contacts the narrowed portion 300. When the balloon 12 is expanded and the coat layer 30 is pressed against the biological tissue, the drug is delivered to the living body while the base layer 32, which is a low-molecular compound contained in the coat layer 30, is gradually or promptly dissolved. When the balloon 12 is expanded, a region that is not exposed on the outer peripheral side in the folded state is also exposed on the outer peripheral side. As a result, the layered structure portion 37 formed between the blade portion 40 and the peripheral surface portion 41 is also exposed to the outer peripheral side, and the elongated body 33 in the standing state forming the layered structure portion 37 is also the inner wall surface of the blood vessel. Pressed against. The elongated body 33 in the upright state has good transferability to living tissue, and can effectively transfer the drug to the stenosis portion 300. Therefore, restenosis of the narrowed portion 300 is effectively suppressed.

  After that, the expansion fluid is sucked and discharged from the base end opening 13a of the hub 13, and the balloon 12 is deflated and brought into a folded state. After this, the guide wire 200 and the balloon catheter 10 are removed from the blood vessel via the introducer, and the procedure is completed.

  As described above, the balloon catheter 10 according to the present embodiment has the balloon 12 at the distal end portion of the catheter shaft 11, and has a plurality of long lengths that are crystals of a water-insoluble drug that extends with an independent long axis. The body 33 is the balloon catheter 11 provided on the surface of the balloon 12, and the balloon 12 in a deflated state has a plurality of blade portions 40 in the circumferential direction and a circumferential surface portion 41 along the circumferential direction of the catheter shaft 11. At the same time, the blade portion 40 is folded along the circumferential direction of the balloon 12, and the balloon 12 is placed between the blade portion 40 and the peripheral surface portion 41 in the folded state and the elongated body 33 in the standing state and in the tilted state. It has a layer structure portion in which the elongated body 33 overlaps. As a result, the elongated structure 33 in the upright state is maintained as it is during the folding process of the balloon 12 and the insertion process into the living body lumen by the layered structure portion 37 between the blade portion 40 and the peripheral surface portion 41. It is possible to suppress the change and breakage of the shape of the drug crystal due to the force from the. Therefore, the elongated body 33 in the standing state can be effectively delivered to the lesioned part of the body lumen, and the drug can be effectively transferred to the lesioned part.

  The long body 33 in the tilted state in the layer structure portion 37 forms an angle of 30 degrees or less with the surface of the balloon 12. Therefore, the thickness of the layer structure portion 37 can be prevented from becoming too large.

  If the elongated body 33 in the standing state and the elongated body 33 in the tilted state of the layer structure portion 37 are adhered to each other and integrated with each other, the layer structure portion 37 becomes stronger and the drug crystal It is possible to further suppress changes in shape and breakage.

  The layered structure portion 37 includes the elongated body 33 in which the surface of the balloon 12 forming the blade portion 40 is in a tilted state, and the elongated body 33 in which the surface of the balloon 12 forming the peripheral surface portion 41 is in an upright state. As a result, in the process of pleating to form the blade portion 40, while the elongated body 33 is tilted, in the process of folding the blade portion 40, the elongated body 33 in the tilted state and the elongated body 33 in the standing state. The layer structure portion 37 can be formed by superimposing 33 and 33.

  When the water-insoluble drug is rapamycin, paclitaxel, docetaxel, or everolimus, restenosis of the stricture in the body lumen can be suppressed well.

  In addition, the method for manufacturing the balloon catheter 10 according to the present embodiment is a balloon in which a plurality of elongated bodies 33, which are crystals of a water-insoluble drug and have independent long axes, are provided on the surface of the balloon 12. In the method for manufacturing the catheter 10, a step of forming the elongated body 33 in an upright state on the surface of the balloon 12 and pressing the surface of the balloon 12 with the blade 122 of the pleating part 120 causes the balloon 12 to move in the radial direction. The protruding blade portion 40 is formed, and the elongated body 33 in the area serving as the blade portion 40 is tilted to maintain the standing state of the elongated body 33 in the area serving as the peripheral surface portion 41 facing the blade portion 40. By pressing the surface of the balloon 12 with the step and the blade 132 of the folding part 130, the vane part 40 formed on the balloon 12 is laid down along the circumferential direction to overlap the peripheral surface part 41, and the vane part 40 is tilted. Forming a layered structure portion 37 in which the elongated body 33 and the elongated body 33 in the standing state of the peripheral surface portion 41 are overlapped with each other. Thereby, the layer structure portion 37 is formed between the blade portion 40 and the peripheral surface portion 41 by using the force acting on the balloon 12 in the step of forming the blade portion 40 on the balloon 12 and the step of folding the blade portion 40. it can.

  The treatment method according to the present embodiment is a treatment method in which a drug is delivered to a lesion in a living body lumen using a balloon catheter 10, and a balloon 12 is inserted into the living body lumen to reach the lesion. It has a step of arriving, a step of expanding the balloon 12 to press the elongated body 33 against the living tissue, and a step of contracting the balloon 12 to remove it from the living body lumen. Thereby, when the balloon 12 is expanded at the lesion, the drug crystal in the standing state of the layered structure portion 37 easily moves to the inner wall surface of the living body lumen, and the drug is effectively transferred to the living tissue. be able to.

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

  Further, in the balloon catheter 10 of the present embodiment, the elongated bodies 33 of the layered structure portion 37 that overlap each other are adhered and integrated, but the elongated bodies 33 only contact each other and are not integrated. May be.

  As mentioned above, the base layer 32 is present as amorphous, crystalline particles, or a mixture thereof. The base layer 32 in FIG. 4 is in a crystalline particle and/or particulate amorphous state, but as shown in FIG. 21, the base layer 32 may be in a film amorphous state.

  Further, in the present embodiment, the blade portions 40 of the folded balloon 12 do not reach the adjacent blade portions 40 at the tips, but reach the adjacent blade portions 40 at the tips as in the two examples shown in FIG. May be. In the example of FIG. 22A, a root-side space 42 is formed between the root side of the blade 40 and the peripheral surface 41, and a space between the tip side and the peripheral surface 41 of the blade 40 is located at the tip-side space. 43 is formed. Further, in the example of FIG. 22B, a space portion 44 is formed between the blade portion 40 and the peripheral surface portion 41 in the entire region from the root side of the blade portion 40 to the adjacent blade portion 40. In each of these cases, the layer structure portion 37 is formed in a region facing the root side space portion 42 or the space portion 44 in the region between the blade portion 40 and the peripheral surface portion 41.

10 catheter 11 catheter shaft 12 balloon 13 hub 20 outer tube 21 inner tube 22 expansion lumen 23 guide wire lumen 24 opening 30 coat layer 31 balloon surface 32 base layer 33 elongated body 40 blade portion 40a blade inner portion 40b blade outer portion 40c root Reference numeral 41 Peripheral surface portion 41a Opposing surface portion 41b Peripheral surface constituting surface portion 50 Balloon coating device 60 Rotation mechanism portion 70 Support base 80 Moving mechanism portion 90 Coating mechanism portion 94 Dispensing tube 100 Balloon folding device

Claims (5)

A balloon catheter having a balloon at the distal end of the catheter shaft, wherein a plurality of elongated bodies that are crystals of a water-insoluble drug extending with an independent long axis are provided on the surface of the balloon,
The balloon in the deflated state has a plurality of vanes in the circumferential direction and a circumferential surface portion along the circumferential direction of the catheter shaft, and the vanes are folded along the circumferential direction of the balloon,
The balloon is between the peripheral surface portion and the blade portion of the folded state, it has a layer structure in which the length and elongated body has overlap of the elongated body and the tilting state of upstanding,
The balloon catheter in which the elongated body in the standing state and the elongated body in the tilted state of the layered structure portion are attached and integrated with each other .   The balloon catheter according to claim 1, wherein the elongated body in the tilted state in the layer structure portion forms an angle of 30 degrees or less with respect to the surface of the balloon. The layered structure portion has the elongated body in which a surface of a balloon forming the vane portion is in a tilted state, and the surface of a balloon in which the peripheral surface portion is formed is in an upright state. Alternatively, the balloon catheter according to 2 . The water-insoluble drug, the balloon catheter according to any one of claims 1 to 3 which is a rapamycin, paclitaxel, docetaxel, or everolimus. In a method for producing a balloon catheter, wherein a plurality of elongated bodies, which are crystals of a water-insoluble drug extending with an independent long axis, are provided on the surface of the balloon,
Forming the elongated body in a standing state on the surface of the balloon,
By pressing the surface of the balloon with the blade of the pleating portion, a blade portion that radially projects is formed on the balloon, and the elongated body in the region that becomes the blade portion is tilted, and the blade portion is formed. A step of maintaining the standing state of the elongated body in a region to be a peripheral surface portion facing to,
By pressing the surface of the balloon with the blade of the folding portion, the blade portion formed on the balloon is laid along the circumferential direction to overlap the peripheral surface portion, and the elongated body in a tilted state of the blade portion and A step of forming a layered structure portion in which the elongated body in the standing state of the peripheral surface portion overlaps with each other;
Have a,
When the vane portion of the balloon is superposed on the peripheral surface portion, by heating the surface of the balloon, the elongated body in the tilted state of the vane portion and the length in the standing state of the peripheral surface portion overlap each other. A method for manufacturing a catheter, in which a scale is attached to and integrated with the scale .

Images