JP2017169737A - Balloon catheter, and production method and treatment method therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a balloon catheter capable of effectively delivering a medicament to a biological tissue, and a production method and a treatment method therefor.SOLUTION: A balloon catheter 11 comprises a balloon 12 on a tip end part of a catheter shaft 11, in which plural long bodies 33 which have an independent long axis and extend, and which are crystals of a water-insoluble medicament, are provided on the surface of the balloon 12. The balloon 12 in a shrunk state comprises plural wing parts 40 in a peripheral direction, and a peripheral face part 41 along a peripheral direction of the catheter shaft 11. The wing parts 40 are folded along a peripheral direction of the balloon 12, and the balloon 12 has, between the wing parts 40 in a folded state and the peripheral face part 41, a layer structure part in which long bodies 33 in an erecting state and long bodies 33 in a tilted state are overlapped in the balloon catheter 10.SELECTED DRAWING: Figure 5

Description

  The present invention relates to a balloon catheter having a balloon whose surface is coated with a drug, a method for manufacturing the same, and a treatment method.

  A balloon catheter is widely used to improve a lesion (stenosis) occurring in a living body lumen. The balloon catheter usually includes a long catheter shaft and a balloon that is provided on the distal end side of the catheter shaft and is expandable in the radial direction. By expanding the deflated balloon after reaching a target location in the body via a thin living body lumen, the lesioned part can be expanded.

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

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

US Patent Application Publication No. 2014/0271775

  A balloon catheter that elutes a drug is desired to have high drug deliverability to the living tissue of the balloon surface in order to enhance the effect in the treatment.

  The present invention has been made to solve the above-described problems, and an object thereof 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 that achieves the above object has a balloon at the distal end portion of the catheter shaft, and a plurality of elongated bodies that are crystals of a water-insoluble drug extending with an independent long axis. A balloon catheter provided on the surface of
The deflated balloon has a plurality of blade portions in the circumferential direction and a circumferential surface portion along the circumferential direction of the catheter shaft, and the blade portions are folded along the circumferential direction of the balloon,
The balloon has a layered structure portion in which the elongated body in an upright state and the elongated body in an inclined state overlap each other between the wing portion in a folded state and the peripheral surface portion.

In the balloon catheter manufacturing method according to the present invention that achieves the above object, a plurality of elongated bodies that are crystals of a water-insoluble drug extending with independent long axes are provided on the surface of the balloon. In the method of manufacturing a balloon catheter,
Forming the elongated body standing on the surface of the balloon;
By pressing the surface of the balloon with a blade of a pleating part, a wing part protruding in the radial direction is formed on the balloon, and the elongated body in the region to be the wing part is tilted, and the wing part Maintaining the standing state of the elongate body in the region that becomes the peripheral surface portion facing with,
By pressing the surface of the balloon with the blade of the folding part, the blades formed on the balloon are laid down along the circumferential direction and overlapped with the peripheral surface part, and the elongated body in the tilted state of the blade part and Forming a layered structure portion that overlaps the elongated body in the standing state of the peripheral surface portion;
Have

The treatment method according to the present invention for achieving the above object is a treatment method for delivering a drug to a lesion in a living body lumen using a balloon catheter,
Inserting the balloon into the body lumen to reach the lesion;
Expanding the balloon and pressing the elongated body against the living tissue;
Deflating the balloon and removing it from the body lumen.

  In the balloon catheter configured as described above, the long body in the standing state is maintained as it is in the balloon folding process and the insertion process into the living body lumen by the layer structure part between the blade part and the peripheral surface part. In addition, it is possible to suppress changes in the shape and destruction of the drug crystal due to external force. For this reason, the elongate body in the standing state can be effectively delivered to the lesioned part of the living body lumen, and the drug can be effectively transferred to 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. For this reason, it can prevent that the thickness of a layer structure part becomes large too much.

  If the elongated body in the standing state of the layer structure portion and the elongated body in the tilted state are attached to each other and integrated, the layer structure portion becomes stronger and the shape of the drug crystal Change and destruction can be further suppressed.

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

  If the water-insoluble drug is rapamycin, paclitaxel, docetaxel, or everolimus, restenosis of the stenosis in the blood vessel can be satisfactorily suppressed.

  The method for manufacturing a balloon catheter configured as described above has a layer structure between the blade portion and the peripheral surface portion by using the force acting on the balloon in the step of forming the blade portion on the balloon and the step of folding the blade portion. Part can be formed.

  In the treatment method configured as described above, when the balloon is expanded at the lesioned part, the crystal of the standing drug possessed by the layer structure part easily migrates to the inner wall surface of the living body lumen, and the drug is applied to the living tissue. It can be transferred effectively.

It is a front view which shows the balloon catheter which concerns on this embodiment. It is sectional drawing of the front-end | tip part of a balloon catheter. It is a schematic perspective view which shows the elongate body which consists of a drug crystal | crystallization of the surface of a balloon. It is the schematic which shows the elongate body and base layer which consist of a drug crystal | crystallization of the surface of a balloon. It is a general | schematic expanded sectional view of the balloon which has a layer structure part with which the elongate elongated body and the tilted elongated body overlapped. FIG. 7 is a cross-sectional view of a state before the balloon is folded (FIG. 6A), a state in which blades are formed on the balloon (FIG. 6B), and a state in which the balloon is folded (FIG. 6C). It is the schematic which shows a balloon coating apparatus. It is sectional drawing which shows the dispensing tube which contacted the balloon. It is a perspective view which shows a balloon folding apparatus. It is a front view which shows arrangement | positioning of the braid | blade of a pleating part, and a film supply part. It is a front view which shows the braid | blade of a pleating part. It is a front view which shows arrangement | positioning of the braid | blade of a folding part, and a film supply part. It is a front view which shows the braid | blade of a folding part. It is sectional drawing which shows the balloon catheter arrange | positioned at a pleating part. It is a front view which shows the braid | blade of the state which rotated the braid | blade of the pleating part and formed the blade | wing part in the balloon. Schematic cross-sectional view of the surface of a balloon having a long body that has been tilted during pleating (FIG. 16A), and schematic cross-sectional view of the surface of a balloon having a long body that maintains a standing state during pleating (FIG. 16B). It is sectional drawing which shows the balloon catheter arrange | positioned at the folding part. It is a front view which shows the braid | blade of the state which rotated the braid | blade of the folding part and folded the blade | wing part of the balloon. It is a schematic sectional drawing showing the process in which a blade | wing part and a surrounding surface part adjoin each other at the time of folding, and form a layer structure part by the long body of a surface. It is sectional drawing which shows the state which expanded the stenosis part of the blood vessel with the balloon catheter which concerns on this embodiment. It is the schematic which shows a elongate body and base layer in case a base layer is film-form amorphous. It is sectional drawing of the balloon of the folded state which has a blade | wing part of a different form.

  Embodiments of the present invention will be described below with reference to the drawings. The dimensional ratios in the drawings are exaggerated for convenience of explanation and may differ from the actual ratios. Further, in this specification, the side of the balloon catheter 10 that is inserted into the living body lumen is referred to as “tip” or “tip side”, and the proximal side for operation is referred to as “base end” or “base end side”.

  First, the balloon catheter of this embodiment is demonstrated. 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. 30 and a hub 13 fixed to the proximal end portion 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 still more preferably 20 to 200 mm.

  Although the outer diameter at the time of expansion | swelling of the balloon 12 is not specifically limited, Preferably it is 1-10 mm, More preferably, it is 2-8 mm.

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

  This balloon catheter 10 allows a long catheter shaft 11 to be inserted into a living organ and a balloon 12 provided on the distal side of the balloon catheter 10 is expanded at the lesioned part to expand and spread the lesioned part. It can be done.

  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 an inner tube 21 that is a hollow inner support. The inner tube 21 is housed in the hollow interior of the outer tube 20, and the catheter shaft 11 has a double tube structure at the tip. The hollow interior of the inner tube 21 forms a guide wire lumen 23 through which the guide wire 14 is inserted. Further, an expansion lumen 22 through which the expansion fluid of the balloon 12 is circulated is formed inside the hollow of the outer tube 20 and outside the inner tube 21. The inner tube 21 opens to the outside at the opening 24. The inner tube 21 protrudes further to the distal end side than the distal end of the outer tube 20.

The balloon 12 has a proximal end portion fixed to the distal end portion of the outer tube 20 and a distal end portion fixed to the distal end portion of the inner tube 21. Thereby, the inside of the balloon 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 expansion fluid may be a gas or a liquid. For example, a gas such as helium gas, CO ₂ gas, or O ₂ gas, or a liquid such as physiological saline or contrast medium can be used. In FIG. 2, the balloon 12 is in an expanded state.

  A cylindrical straight portion 12a (expanded portion) having the same outer diameter when expanded is formed at the central portion in the axial direction of the balloon 12, and the outer diameter gradually increases on both sides of the straight portion 12a in the axial direction. A taper portion 12b that changes to is formed. And the coat layer 30 containing a chemical | medical agent is formed in the whole surface of the straight part 12a. In addition, the range in which the coating 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 of the straight portions 12a. It may be only part.

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

  The balloon 12 preferably has a certain degree of flexibility and a certain degree of hardness so that it can be expanded when it reaches a blood vessel, tissue, etc., and the drug can be released from the coat layer 30 on its surface. Specifically, it is made of metal or resin, but at least the surface of the balloon 12 on which the coat layer 30 is provided is preferably 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, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, ionomer, or a mixture of two or more thereof, or soft polychlorinated Vinyl resins, polyamides, polyamide elastomers, nylon elastomers, polyesters, polyester elastomers, polyurethanes, thermoplastic resins such as fluorine resins, silicone rubbers, latex rubbers and the like can be used. Among these, polyamides are preferable. That is, at least a part of the surface of the extended portion of the medical device that coats the drug is a polyamide. The polyamide is not particularly limited as long as it is a polymer having an amide bond. For example, polytetramethylene adipamide (nylon 46), polycaprolactam (nylon 6), polyhexamethylene adipamide (nylon 66), Homopolymers such as polyhexamethylene sebacamide (nylon 610), polyhexamethylene dodecamide (nylon 612), polyundecanolactam (nylon 11), polydodecanolactam (nylon 12), caprolactam / lauryl lactam copolymer Polymer (nylon 6/12), caprolactam / aminoundecanoic acid copolymer (nylon 6/11), caprolactam / ω-aminononanoic acid copolymer (nylon 6/9), caprolactam / hexamethylene diammonium adipate copolymer ( Nylon 6/66 And aromatic polyamides such as a copolymer of adipic acid and metaxylenediamine, or 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 or the like as a hard segment and polyalkylene glycol, polyether or aliphatic polyester as a soft segment also relates to the present invention. Used as a base layer for medical devices. The said polyamides may be used individually by 1 type, and may use 2 or more types together.

  A coating layer 30 is formed on the surface of the balloon 12 directly or via a pretreatment layer such as a primer layer on the surface thereof 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 disposed in a layer on the surface 31 of the balloon 12 and an independent long axis. And a plurality of elongated bodies 33 that are crystals of existing water-insoluble drugs.

The amount of drug contained in the coat layer 30 is not particularly ^{limited, 0.1μg / mm 2 ~10μg / mm} 2, at a density of preferably ^{0.5μg / mm 2 ~5μg / mm 2} , more preferably 0.5 [mu] g / ^{mm 2} ~3.5μg / ^mm 2, more preferably included at a density of ^{1.0μg / mm 2 ~3μg / mm 2} . The amount of crystals in the coat layer 30 is not particularly limited, but is 5 to 500,000 crystal / 10 μm ² (number of crystals per 10 μm ² ), preferably 50 to 50000 crystal / 10 μm ² , more preferably 500 to 5000 crystal / 10 μm ^2. It is.

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

  The length of the long body 33 having the long axis is preferably 5 μm to 20 μm, more preferably 9 μm to 11 μm, and still more preferably around 10 μm. The diameter of the long body 33 having a long axis is preferably 0.01 μm to 5 μm, more preferably 0.05 μm to 4 μm, and still more preferably 0.1 μm to 3 μm. As an example of the combination of the length and diameter in the axial direction of the long body 33 having a long axis, when the length is 5 μm to 20 μm, the diameter is 0.01 to 5 μm, and when the length is 5 to 20 μm Combinations having a diameter of 0.05 to 4 μm and combinations having a diameter of 0.1 to 3 μm when the length is 5 to 20 μm can be mentioned. The long body 33 having the long axis is substantially linear in the long axis direction, but may be curved in a curved shape.

  The long body 33 having a long axis after coating and before the balloon 12 is folded is formed so as to stand without sleeping on the surface of the balloon 12. At this time, the long body 33 changes the angle of the long body 33 by the pleating of the balloon 12 (step of forming a wing portion on the balloon) or folding (step of folding the wing portion), and the long body 33 is long with respect to the surface of the balloon 12. The angle of the long axis of the body 33 can be changed. Therefore, the crystal formed as if lying on the surface of the balloon 12 from the beginning is fixed (fixed) to the surface of the balloon 12 or the adjacent long body 33, whereas the standing long body 33 is The surface of the balloon 12 and the adjacent long body 33 are not physically fixed. For this reason, the standing long body 33 is only positioned (disposed) so as to contact the surface of the balloon 12 or the adjacent long body 33, for example, and its position is changed three-dimensionally. Is possible. Therefore, the elongated body 33 after coating is formed so that the angle and 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 present in a space between the plurality of long bodies 33 that stand. The ratio of the substance constituting the coat layer 30 is preferably such that the crystal of the water-insoluble drug occupies a larger volume than the base layer 32. The excipient constituting the base layer 32 does not form a matrix. The matrix is a layer in which a relatively high-molecular substance (polymer or the like) is continuously formed, forms a network-like three-dimensional structure, and has a fine space therein. Therefore, the water-insoluble drug constituting the crystal is not attached to the matrix material. The water-insoluble drug constituting the crystal is not embedded in the matrix material.

  The 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 exists as amorphous, crystal particles, or a mixture thereof. The base layer 32 in FIG. 4 is in the state of crystal grains and / or particulate amorphous. The base layer 32 may be formed as a layer containing a water-insoluble drug, or may be formed as an independent layer not containing a water-insoluble drug. The thickness of the base layer 32 is 0.1 to 5 μm, preferably 0.3 to 3 μm, more preferably 0.5 to 2 μm.

  The coat layer 30 having the elongated body 33 in the form of a hollow elongated body has low toxicity and high stenosis-inhibiting effect when delivered to the body. A water-insoluble drug containing a hollow long crystalline form is effective because it has good permeability to the tissue and good solubility because one unit of the crystal becomes small when the drug moves into the tissue. It can act to suppress stenosis. In addition, it is considered that toxicity is low because the drug hardly remains in the tissue as a large mass.

  The layer including the hollow long crystal form is a plurality of substantially uniform long bodies 33 having a long axis, and the base layer surface has regularity and is arranged almost uniformly. It is. Therefore, the size of the crystal that moves to the structure (length in the major axis direction) is as small as about 10 μm. Therefore, it acts uniformly on the affected part of the lesion and increases tissue permeability. Furthermore, since the size of the migrating crystals is small, an excessive amount of drug does not stay in the affected area for an excessive period of time, so that it is possible to exhibit a high stenosis-inhibiting effect without developing toxicity. .

  The drug coated on the surface of the balloon 12 may include an amorphous type. Crystals and amorphous materials 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, which is a drug crystal, on the surface of the balloon 12 will be further described. As shown in FIG. 3, in the state where the long body 33 is formed, each long body 33 is in a standing state with respect to the surface of the balloon 12. On the other hand, the layer structure part 37 can be formed between the surfaces of the balloons 12 that overlap each other by folding the balloon 12 and applying heat and force to the surface from the outside.

  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 portion 37 has an elongated state 33 in an erect state on one side (lower side in the figure) and a tilted state on the other side (upper side in the figure) in the opposing direction of the surface of the balloon 12. Each of the long bodies 33 is provided. The state in which the long body 33 is tilted 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 the state in which the long body 33 is standing is a state in which θ is greater than 30 degrees. say. In the layer structure portion 37, the end portion of the standing long body 33 is attached to and integrated with the middle position in the longitudinal direction of the long body 33 in a tilted state. For this reason, the layer structure portion 37 has a layer 37 a in which the standing long bodies 33 are juxtaposed between the surfaces of the balloon 12 on one side, and the tilted long body 33 on the other side. Forms a two-layer structure having layers 37b arranged side by side. The elongated body 33 in the tilted state refers to a state where θ, which is an angle made with respect to the surface of the balloon 12, is 30 degrees or less, and the elongated body 33 in the standing state refers to 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 a blade portion 40 as shown in FIG. 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. Moreover, the blade | wing part 40 has the blade | wing inner side part 40a used as the surface which goes to the surrounding surface part 41 by being folded, and the blade | wing outer side part 40b used as the surface which goes to the outer peripheral side by being folded. In this state, in the region of the blade inner portion 40a and the blade outer portion 40b, the long body 33 is in a tilted state, and in the region of the peripheral surface portion 41, the long body 33 is in a standing state.

  From the state shown in FIG. 6B, the balloon 12 is folded as shown in FIG. In this state, the peripheral surface portion 41 is divided into an opposing surface portion 41a that faces the blade inner portion 40a of the blade portion 40 and an outer peripheral configuration surface portion 41b that faces the outer peripheral side. Further, in a state where the balloon 12 is folded, a root-side space portion 42 is formed between the root portion of the blade portion 40 and the peripheral surface portion 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 tip side region of the blade portion 40 is closer to the peripheral surface portion 41 than the base side space portion 42. The ratio of the circumferential length of the base 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 portion 40a and the opposed surface portion 41a. Is done. In the layer structure portion 37, the layer 37a in which the long body 33 is erected is on the facing surface portion 41a side, and the layer 37b in which the long body 33 is tilted is on the blade inner portion 40a side.

  When the balloon 12 is folded from the state shown in FIG. 6 (a) to the state shown in FIG. 6 (c), a force is applied to the surface of the balloon 12, so that the length of the standing state is particularly long. 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 elongate long body 33 and the tilted long body 33 are integrated is formed between the folded blade overlapping inner portion 40a and the facing surface portion 41a. By doing so, the elongated body 33 in the standing state is maintained as it is between the blade inner portion 40a and the opposed surface portion 41a, and it is possible to suppress a change or breakage of the shape of the drug crystal due to a 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. 6 (c), and is expanded at the lesioned portion to be in the state of FIG. 6 (a). Even in the process in which the balloon 12 is inserted into the living body lumen, since the layered structure portion 37 is formed, the elongate body 33 can maintain the shape as it is, and the lesion portion can be maintained. The elongated body 33 in the standing state can be delivered. In the balloon 12 expanded at the lesioned part, the layer structure part 37 is exposed to the outside, and the elongate long body 33 is also exposed to the outside and comes into contact with the inner wall surface of the living body lumen. Since the standing body 33 has good migration to the living tissue, the medicine can be effectively delivered to the living tissue by reliably delivering the standing body 33 to the lesion. Can be migrated.

  Next, a balloon coating system for forming the coat layer 30 on the balloon 12 will be described. This system includes a balloon coating apparatus 50 (see FIG. 7) for forming the coat layer 30 on the balloon 12, and a balloon folding apparatus 100 (see FIG. 9) for folding the balloon 12 on which the coat layer 30 is formed. And. By using the balloon coating apparatus 50, a plurality of elongated bodies that are crystals of a water-insoluble drug extending with independent long axes are formed on the surface of the balloon 12. Thereafter, the balloon 12 is folded by the balloon folding device 100, and in a partial region on the surface of the balloon 12, the elongated body 33 is tilted in the axial direction from the standing state.

  First, the balloon coating apparatus 50 will be described. As shown in FIGS. 7 and 8, the balloon coating apparatus 50 includes a rotation mechanism 60 that rotates the balloon catheter 10 and a support base 70 that supports the balloon catheter 10. The balloon coating apparatus 50 further includes an application mechanism 90 provided with a dispensing tube 94 for applying a coating solution to the surface of the balloon 12, and a moving mechanism 80 for moving the dispensing tube 94 relative to the balloon 12. And a control unit 99 for controlling the balloon coating apparatus 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, a three-way cock that can open and close the flow path is connected to the proximal end opening 13 a of the hub 13 in order to operate the flow of fluid to the expansion lumen 22.

  The support base 70 includes a tubular proximal end support portion 71 that accommodates the catheter shaft 11 and rotatably supports it, and a distal end support portion 72 that rotatably supports the core member 61. Note that the distal end side support portion 72 may rotatably support the distal end portion of the catheter shaft 11 instead of the core member 61 if possible.

  The moving mechanism unit 80 includes a moving table 81 that can move linearly in a direction parallel to the axis of the balloon 12 and a tube fixing unit 83 to which the dispensing tube 94 is fixed. The moving table 81 can move linearly by a driving source such as a built-in motor. The tube fixing part 83 fixes the upper end of the dispensing tube 94 to the moving table 81. Therefore, as the moving table 81 moves, the dispensing tube 94 moves linearly in a direction parallel to the axis of the balloon 12. In addition, an application mechanism 90 is placed on the movable table 81, and the application mechanism 90 is linearly moved in both directions along the axis.

  The application mechanism unit 90 is a part that applies a coating solution to the surface of the balloon 12. The coating mechanism unit 90 includes a container 92 that stores the coating solution, a liquid feeding pump 93 that feeds the coating solution in an arbitrary amount, and a dispensing tube 94 that coats the balloon 12 with the coating solution. .

  The liquid feed 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 through the suction tube 91 and arbitrarily supply the coating solution to the dispensing tube 94 through the supply tube 96. It is possible to supply with the amount of liquid fed. The liquid feed pump 93 is installed on the moving table 81 and can move linearly by the movement of the moving table 81. The liquid feed pump 93 is not limited to a syringe pump as long as the coating solution can be fed, and may be a tube pump, for example.

  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 through the supply tube 96 to 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 at the discharge end 97 that is the lower end. The dispensing tube 94 can move linearly in both directions along the axial direction of the balloon catheter 10 together with the liquid feed pump 93 installed on the moving table 81 by moving the moving table 81. The dispensing tube 94 can supply the coating solution to the surface of the balloon 12 in a state where the dispensing tube 94 is bent by being pressed against the balloon 12.

  The dispensing tube 94 may not be circular as long as the coating solution can be supplied. The dispensing tube 94 may not 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 a contact load on the balloon 12 and absorb a change in the contact position accompanying 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 Fluororesin such as fluoroethylene / perfluoroalkyl vinyl ether copolymer) or FEP (tetrafluoroethylene / hexafluoropropylene copolymer) can be applied, but if it is flexible and deformable There is no particular limitation.

  The outer diameter of the dispensing tube 94 is not particularly limited, but is, for example, 0.1 mm to 5.0 mm, preferably 0.15 mm to 3.0 mm, and more preferably 0.3 mm to 2.5 mm. The inner diameter of the dispensing tube 94 is not particularly limited, but is, for example, 0.05 mm to 3.0 mm, preferably 0.1 mm to 2.0 mm, and more preferably 0.15 mm to 1.5 mm. The length of the dispensing tube 94 is not particularly limited, but may be a length 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 configured by a computer, for example, and comprehensively controls the rotation mechanism unit 60, the movement mechanism unit 80, and the coating mechanism unit 90. Therefore, the control unit 99 can comprehensively control the rotational speed of the balloon 12, the moving speed of the dispensing tube 94 in the axial direction relative 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 coating 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, whereby a plurality of long crystals that are crystals of a water-insoluble drug extending on the surface of the balloon 12 with independent long axes. A 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 hardly soluble in water. Specifically, the solubility in water is less than 5 mg / mL at pH 5-8. Its solubility may be less than 1 mg / mL and even less than 0.1 mg / mL. Water-insoluble drugs include fat-soluble drugs.

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

  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 analogs and / or derivatives thereof as long as they have the same medicinal effect. For example, paclitaxel and docetaxel are in an analog relationship. Rapamycin and everolimus are in a derivative relationship. Of these, paclitaxel is more preferred.

  The excipient constitutes the base layer 32 on the balloon 12. The excipient contains a water-soluble low molecular weight compound. The molecular weight of the water-soluble low molecular weight compound is 50 to 2000, preferably 50 to 1000, more preferably 50 to 500, and further preferably 50 to 200. The water-soluble low molecular weight compound is preferably 5 to 10,000 parts by mass, more preferably 5 to 200 parts by mass, and still more preferably 8 to 150 parts by mass with respect to 100 parts by mass of the water-insoluble drug. Constituent materials of water-soluble low molecular weight compounds are serine ethyl ester, citrate ester, polysorbate, water-soluble polymer, sugar, contrast agent, amino acid ester, glycerol ester of short-chain monogalbonic acid, pharmaceutically acceptable salt and surfactant An agent, etc., or a mixture of two or more of these can be used. The water-soluble low molecular weight compound has a hydrophilic group and a hydrophobic group and is characterized by being dissolved in water. The water-soluble low molecular weight compound is preferably non-swellable or hardly swellable. The excipient is preferably amorphous on the balloon 12. The excipient containing the water-soluble low-molecular compound has an effect of uniformly dispersing the water-insoluble drug on the surface of the balloon 12. Furthermore, since the base layer 32 is easily dissolved when the balloon 12 is expanded in the blood vessel, the water-insoluble drug elongate body 33 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 some of these solvents are preferable among tetrahydrofuran, acetone, glycerin, ethanol, methanol, dichloromethane, hexane, ethyl acetate, water, especially tetrahydrofuran, ethanol, acetone, and water. For example, a combination of tetrahydrofuran and water, tetrahydrofuran and ethanol and water, tetrahydrofuran and acetone and water, acetone and ethanol and water, tetrahydrofuran, acetone, ethanol, and water can be used.

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

  First, a fluid for expansion is supplied into the balloon 12 through a three-way cock connected to the proximal end opening 13 a of the balloon catheter 10. Next, in a state where the balloon 12 is expanded, the three-way cock is operated to seal the expansion lumen 22, and the state where the balloon 12 is expanded is maintained. The balloon 12 is expanded at a pressure (for example, 4 atmospheres) lower than the pressure (for example, 8 atmospheres) when used in the blood vessel. Note that the coating layer 30 can also be formed on the surface of the balloon 12 without expanding the balloon 12, and in this case, it is not necessary to supply the expansion fluid into the balloon 12.

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

  Next, by adjusting the position of the moving table 81, the dispensing tube 94 is positioned with respect to the balloon 12. At this time, the dispensing tube 94 is positioned at the most distal end position where the coating layer 30 is formed in the balloon 12. As an example, the extending direction (discharge direction) of the dispensing tube 94 is opposite to the rotation direction of the balloon 12. Accordingly, the balloon 12 rotates in the direction opposite to the direction in which the coating solution is discharged from the dispensing tube 94 at the position where the dispensing tube 94 is brought into contact. Thereby, the coating solution can be stimulated to promote the formation of drug crystal nuclei. The extending direction (discharge direction) toward the opening 95 of the dispensing tube 94 is opposite to the rotation direction of the balloon 12, so that the water-insoluble drug crystals formed on the surface of the balloon 12 are crystals. Is easy to be formed including a morphological form including a plurality of long bodies each having an independent long axis. 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 can therefore be the same direction or can be perpendicular.

  Next, the coating solution is supplied to the dispensing tube 94 while adjusting the amount of liquid fed by the liquid feeding pump 93, the balloon catheter 10 is rotated by the rotating mechanism 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.

  Although the moving speed of the dispensing tube 94 is not specifically limited, For example, it is 0.01-2 mm / sec, Preferably it is 0.03-1.5 mm / sec, More preferably, it is 0.05-1.0 mm / sec. Although the discharge speed of the coating solution from the dispensing tube 94 is not particularly limited, for example, 0.01 to 1.5 μL / sec, preferably 0.01 to 1.0 μL / sec, more preferably 0.03 to 0.00. 8 μL / sec. Although the rotational speed of the balloon 12 is not specifically limited, For example, it is 10-300 rpm, Preferably it is 30-250 rpm, More preferably, it is 50-200 rpm. Although the diameter of the balloon 12 at the time of apply | coating a coating solution is not specifically limited, For example, it is 1-10 mm, Preferably it is 2-7 mm.

  Thereafter, the organic solvent contained in the coating solution applied to the surface of the balloon 12 volatilizes before water. Accordingly, the organic solvent is volatilized while the water-insoluble drug, the water-soluble low-molecular compound and water remain on the surface of the balloon 12. As described above, when the organic solvent is volatilized with water remaining, a water-insoluble drug is precipitated inside the water-soluble low-molecular compound containing water, and crystals gradually grow from the crystal nucleus. A morphological form of a drug crystal including a plurality of elongated bodies 33 each having an independent major axis is formed on the surface. Note that the elongated body 33 in this state is standing 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 inside (see FIG. 4). After the organic solvent is volatilized and the drug crystals are deposited as a plurality of long bodies 33, the water is evaporated more slowly than the organic solvent, and the base layer 32 containing the water-soluble low-molecular compound is formed. The time for water to evaporate is appropriately set according to the type of drug, the type of water-soluble low molecular weight compound, the type of organic solvent, the ratio of materials, the amount of coating solution applied, etc., for example, about 1 to 600 seconds It is.

  Then, the dispensing tube 94 is gradually moved in the axial direction of the balloon 12 while rotating the balloon 12, whereby the coat layer 30 is gradually formed on the surface of the balloon 12 in the axial direction. After the coating layer 30 having the elongated body 33 is formed over the entire area to be coated by the balloon 12, the rotation mechanism unit 60, the movement mechanism unit 80, and the coating mechanism unit 90 are stopped.

  Thereafter, the balloon catheter 10 is removed from the balloon coating apparatus 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 that can fold the balloon 12 so as to be wound around the inner tube 21.

  In the balloon folding device 100, as shown in FIG. 9, a pleating unit 120, a folding unit 130, and a support table 140 are arranged on a base 110 formed in a trapezoidal shape. The pleating portion 120 can form a blade portion 40 protruding in the radial direction on the balloon 12. The folding unit 130 can fold the wings 40 formed on the balloon 12 in the circumferential direction. The support stand 140 can place and hold the balloon catheter 10. The vane portion 40 formed on the balloon 12 is formed by a fold 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 is circumferential from the long axis of the balloon 12. It is formed so as to protrude in the direction. The length of the blade 40 in the major axis direction does not exceed the length of the balloon 12. The length in the direction in which the blade portion 40 protrudes from the catheter shaft 11 in the circumferential direction is 1 to 8 mm. The number of blade portions 40 is not particularly limited, and can be selected from 2, 3, 4, 5, 6, and 7, but in this embodiment, it is three.

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

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

  A support shaft 111 protruding upward from the base 110 is pivotally attached to the side of the support base 140 away from the pleating part 120 and the folding part 130. The support table 140 is positioned at a position facing the front plate 121 of the pleating unit 120 and a position facing the front plate 131 of the folding unit 130 by sliding and moving the upper surface of the base 110 around the support shaft 111. it can.

  The support stand 140 includes a base portion 141 placed on the base stand 110 and a holding stand portion 142 that can move horizontally on the base portion 141. The base 141 can slide on the upper surface of the base 110. The holding base part 142 slides on the upper surface of the base part 141 and can move forward or backward toward the pleating part 120 or the folding part 130.

  On the upper surface of the holding base part 142, a groove-like placement part 142a on which the catheter shaft 11 of the balloon catheter 10 can be placed is formed. The holding table 142 is provided with a holding part 143 that holds the catheter shaft 11 placed on the placing part 142a. As long as the balloon catheter 10 can be fixed, the balloon catheter 10 may be fixed by other methods.

  In a state where the support base 140 faces the front plate 121 of the pleating unit 120, the center of the insertion hole 121 a formed in the front plate 121 is positioned on the extension line of the mounting portion 142 a of the holding base unit 142. For this reason, the balloon catheter 10 on which the catheter shaft 11 is placed on the placement portion 142a is inserted into the pleating portion 120 from the center position of the insertion hole 121a. In a state where the support base 140 faces the front plate 131 of the folding unit 130, the center of the insertion hole 131 a formed in the front plate 131 is positioned on the extension line of the mounting unit 142 a of the holding table 142. For this reason, the balloon catheter 10 having the catheter shaft 11 placed on the placement portion 142a is moved from the center position of the insertion hole 131a to the inside of the folding portion 130 by sliding the holding base portion 142 on the base portion 141. Inserted.

  Next, the structure of the pleating unit 120 will be described. As shown in FIG. 10, the pleating section 120 has three blade forming blades 122 inside. Each blade 122 is a plate-like member formed with the same cross-sectional shape at each position along the axial direction of the balloon catheter 10 to be inserted. The blades 122 are arranged so as to form an angle of 120 degrees with reference to the center position through which 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 in the vicinity of the outer peripheral end portion, and can rotate around the rotation center portion 122a. The blade 122 has a moving pin 122d extending in the axial direction on the inner peripheral side from the rotation center portion 122a. The moving pin 122d is fitted in a fitting groove 124a formed in a rotating member 124 that is rotatable in the pleating portion 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 rotating 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 central space area 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 122 b and a second shape forming portion 122 c at the inner peripheral end on the side opposite to the rotation center portion 122 a. As the blade 122 rotates, the first shape forming portion 122b abuts on the surface of the balloon 12 inserted into the pleating portion 120, and forms the blade portion 40 protruding radially in the balloon 12. be able to. As the blade 122 rotates, the second shape forming portion 122c can come into contact with the blade portion 40 formed on the balloon 12 and bend the blade portion 40 in a predetermined direction. The pleating unit 120 includes 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. Further, the lengths of the first shape forming part 122b and the second shape forming part 122c of the blade 122 may or may not extend over the entire length of the blade 122.

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

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

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

  Next, the structure of the folding unit 130 will be described. As shown in FIG. 12, the folding unit 130 has ten blade folding blades 132 therein. Each blade 132 is a plate-like member formed with the same cross-sectional shape at each position along the axial direction of the balloon catheter 10 to be inserted. The blades 132 are arranged so as to form an angle of 36 degrees with respect to the center position through which 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, and can rotate around the rotation center portion 132a. Each blade 132 has a moving pin 132c extending in the axial direction in the vicinity of the substantially outer peripheral end. The moving pin 132 c is fitted in a fitting groove 133 a formed in a rotating member 133 that can rotate in the folding portion 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 rotating 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, the space area of the central portion surrounded by the blades 132 can be narrowed. The number of blades 132 is not limited to ten.

  The blade 132 is bent at the distal end side, and the distal end portion 132b has a pointed shape. As the blade 132 rotates, the distal end portion 132b abuts on the surface of the balloon 12 inserted into the folding portion 130 and folds so that the blade portion 40 formed on the balloon 12 lies in the circumferential direction. Can do. The folding unit 130 includes a heater (not shown) for heating the blade 132.

  The blade 132 is supplied with the first film 181 and the second film 182 made of resin from the film supply unit 180. The supply structure of each film is the same as 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 region surrounded by the blade 132. With the first film 181 and the second film 182, the balloon 12 inserted into the folding unit 130 can be prevented from directly contacting the surface of the blade 132. The first film 181 and the second film 182 pass through the blade 132 and reach the film winding unit 183 that is rotationally driven by a driving source such as a motor (not shown).

  As shown in FIG. 13, in the state before insertion of the balloon 12, the front-end | tip part 132b of each braid | blade 132 is the state spaced apart in the circumferential direction, respectively. The balloon 12 formed with the blades 40 can be inserted between the first film 181 and the second film 182 in the central region surrounded by the blade 132.

  Next, a method of folding the balloon 12 on which the drug crystals are formed by the balloon coating apparatus 50 using the balloon folding apparatus 100 will be described.

  First, in order to form the blade portion 40 in the balloon 12, the catheter shaft 11 is placed on the placement 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 cock 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. A core material 61 is inserted into the guide wire lumen 23. The core member 61 suppresses the bending due to the weight of the catheter shaft 11.

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

  Next, when the drive source 125 is operated to rotate the rotating member 124 (see FIG. 10), the blades 122 are rotated as shown in FIG. 16, and the first shape forming portions 122b of the blades 122 are mutually connected. Approaching, the central area between the blades 122 narrows. Accordingly, 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. A portion of the balloon 12 that is not pressed by the first shape forming portion 122 b is pushed into a gap between the tip portion of the blade 122 and the second shape forming portion 122 c of the blade 122 adjacent to the blade 122, and is curved to one side. The blade part 40 is formed. Since the balloon 12 is heated to about 50 to 60 degrees by the blade 122, the formed blade part 40 can maintain the shape as it is. In this way, three blade portions 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.

  The balloon 12 is formed with a protruding blade portion 40, and forms a surface that 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. Of the inner tube 21, pressed by the blade outer portion 40 b, the blade inner portion 40 a that is pressed by the tip of the blade 122 and forms the surface facing the peripheral surface portion 41 of the blade 40, and the first shape forming portion 122 b. A peripheral surface portion 41 is formed along the peripheral surface.

  When the blade portion 40 is formed on the balloon 12 by the blade 122 of the pleating portion 120, the pressing force, the pressing time, and the heating temperature of the balloon 122 by the blade 122 are appropriately set, so that the blade on the surface of the balloon 12 About the area | region of the blade | wing inner side part 40a pressed by the front-end | tip part of 122, the elongate body 33 can be made into the state inclined as shown to Fig.16 (a). In addition, the elongated body 33 is also tilted in the region of the blade outer portion 40b 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 long body 33 maintains the standing state as shown in FIG.

  After the blade portion 40 is formed 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 pleating process, the volume inside 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. Thereby, it can suppress that excessive force acts on the balloon 12. FIG. In the process of pleating, there is a step of slightly deflating after the balloon 12 is overexpanded, or a step of slightly deflating after the balloon 12 is expanded to such an extent that the balloon 12 is not overexpanded. Also good.

  Next, the holding base part 142 is moved on the upper surface of the base part 141 to be separated from the pleating part 120, and the balloon catheter 10 is pulled out from the pleating part 120. Next, the direction 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 unit 130. Thereafter, the holding base part 142 is moved on the upper surface of the base part 141, and the balloon catheter 10 is inserted into the folding part 130 from the insertion hole 131a as shown in FIG. The blade 132 of the folding unit 130 is heated to about 50 to 60 degrees in advance.

  After inserting the balloon 12 in which the blade part 40 is formed into the folding part 130, as shown in FIG. 18, when the drive source 134 is operated to rotate the rotating member 133, the blade 132 rotates and each blade 132 is rotated. The leading end portions 132b approach each other, and the central region between the blades 132 is narrowed. Accordingly, the balloon 12 inserted in the central region between the blades 132 is in a state in which the blade portion 40 is laid down in the circumferential direction by the tip portion 132b of each blade 132. The blade 132 is preheated before the insertion of the balloon 12, and the balloon 12 is heated by the blade 132. Therefore, the blade portion 40 laid in the circumferential direction by the blade 132 can maintain the 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, as shown in FIGS. 18 and 6C, the blade inner portion 40 a of the blade portion 40 and the opposing surface portion 41 a of the peripheral surface portion 41 are in contact with each other. The surfaces of the balloon 12 overlap each other. In addition, the blade outer portion 40b of the blade portion 40 and the outer peripheral component surface portion 41b of the peripheral surface portion 41 are exposed to the outer peripheral side.

  When pressing the surface of the balloon 12 with the blade 132 of the folding part 130, the blade inner part 40a having the elongated body 33 in the tilted state and the opposing surface part 41a having the elongated body 33 in the standing state are shown in FIG. As shown in FIG. When the surface of the balloon 12 is further pressed, as shown in FIG. 19 (b), the tilted elongated body 33 and the standing elongated body 33 are in contact with each other. When the blades 132 are heated as they are, the portions of the long bodies 33 in contact with each other are fused, and the elongated long bodies 33 and the standing long bodies 33 are integrated. Thereby, as shown in FIG.19 (c), the layer structure part 37 is formed between the blade | wing inner side part 40a and the opposing surface part 41a.

  As described above, in order to form the layer structure portion 37 between the blade inner portion 40a and the opposed surface portion 41a as the blade 132 of the balloon 12 is folded by the blade 132, the blade 132 is pushed against the balloon 12. It is necessary to appropriately set the pressure, pressing time, and 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 grasping part 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, and the balloon 12 is covered with a cylindrical 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.

  Through 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 is further tilted by the pressing force at the time of folding. The long body 33 of the blade portion 40 and the long body 33 of the peripheral surface portion 41 in an upright state are overlapped to form a layer structure portion 37 of the long 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 as an example the case of treating a stenosis in a blood vessel.

  First, the surgeon punctures a blood vessel from the skin by a known method such as the Seldinger method and places an introducer (not shown). Next, after removing the protective sheath 15 of the balloon catheter 10 and performing priming, the guide wire 200 (see FIG. 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 narrowed portion 300. A guiding catheter may be used to reach the balloon catheter 10 to the stenosis 300. 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 long drug crystal 33 formed on the blade 40 is tilted during pleating. Therefore, it is suppressed that it is caught on the inner wall surface of the blood vessel, and the dropping of the drug is suppressed.

  After the balloon 12 is disposed in the narrowed portion 300, a predetermined amount of expansion fluid is injected from the proximal end opening 13 a of the hub 13 using an inflator or a syringe, and the expansion fluid 22 is expanded into the balloon 12 through the expansion lumen 22. Feed the fluid. Thereby, as shown in FIG. 20, the folded balloon 12 is expanded, and the narrowed portion 300 is pushed and expanded by the balloon 12. At this time, the coat layer 30 containing drug crystals 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 living tissue, the base layer 32 that is a low molecular compound contained in the coat layer 30 dissolves gradually or quickly, and the drug is delivered to the living body. When the balloon 12 is expanded, a region that is not exposed to the outer peripheral side in the folded state is also exposed to the outer peripheral side. Thereby, the layer structure part 37 formed between the blade part 40 and the peripheral surface part 41 is also exposed to the outer peripheral side, and the elongate body 33 that forms the layer structure part 37 is also the inner wall surface of the blood vessel. Pressed against. The elongated body 33 in the standing state has good transferability to the living tissue, and can effectively transfer the drug to the stenosis portion 300. Therefore, restenosis of the constricted portion 300 is effectively suppressed.

  Thereafter, the expansion fluid is sucked and discharged from the proximal end opening 13a of the hub 13, and the balloon 12 is contracted and folded. Thereafter, the guide wire 200 and the balloon catheter 10 are removed from the blood vessel via the introducer, and the procedure is completed.

  As described above, the balloon catheter 10 according to this embodiment has the balloon 12 at the distal end portion of the catheter shaft 11 and a plurality of long lengths that are crystals of a water-insoluble drug extending with an independent long axis. A balloon catheter 11 in which a body 33 is provided on the surface of the balloon 12, and the deflated balloon 12 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 in a tilted state with the elongate body 33 between the folded blade portion 40 and the peripheral surface portion 41. It has a layered structure where the elongated body 33 overlaps. Thereby, the elongate long body 33 is maintained as it is in the folding process of the balloon 12 and the insertion process into the living body lumen by the layer structure part 37 between the blade part 40 and the peripheral surface part 41, and the external structure It is possible to suppress changes in the shape and destruction of the drug crystal due to the force from the. For this reason, the elongate body 33 in the standing state can be effectively delivered to the lesion part of the living body lumen, and the drug can be effectively transferred to the lesion part.

  The elongated body 33 in the tilted state in the layer structure portion 37 has an angle of 30 degrees or less with respect to the surface of the balloon 12. For this reason, it is possible to prevent the thickness of the layer structure portion 37 from becoming too large.

  If the long body 33 in the standing state and the long body 33 in the tilted state of the layer structure part 37 are attached to each other and integrated, the layer structure part 37 becomes stronger, and the drug crystal Shape change and destruction can be further suppressed.

  The layer structure portion 37 has a long body 33 in which the surface of the balloon 12 forming the blade portion 40 is tilted, and the long body 33 in which the surface of the balloon 12 forming the peripheral surface portion 41 is erected. Thereby, in the process of pleating to form the blade portion 40, the elongated body 33 is placed in a tilted state, while in the folding process of folding the blade portion 40, the tilted long body 33 and the standing body in a standing state. The layer structure portion 37 can be formed by superimposing 33.

  If the water-insoluble drug is rapamycin, paclitaxel, docetaxel, or everolimus, it is possible to satisfactorily suppress restenosis of a stenosis in a living body lumen.

  Further, in the method for manufacturing the balloon catheter 10 according to the present embodiment, a balloon in which a plurality of elongated bodies 33 that are crystals of a water-insoluble drug extending with independent long axes are provided on the surface of the balloon 12 is provided. In the method of manufacturing the catheter 10, the step of forming the elongated body 33 on the surface of the balloon 12 and pressing the surface of the balloon 12 with the blade 122 of the pleating unit 120 cause the balloon 12 to radially move. The protruding blade part 40 is formed, the long body 33 in the region that becomes the blade part 40 is tilted, and the standing state of the long body 33 in the region that becomes the peripheral surface part 41 facing the blade part 40 is maintained. By stepping and pressing the surface of the balloon 12 with the blade 132 of the folding part 130, the blade part 40 formed on the balloon 12 is moved along the circumferential direction. And a step of forming a layered structure portion 37 in which the elongated body 33 in the tilted state of the blade portion 40 and the elongated body 33 in the standing state of the peripheral surface portion 41 are overlapped with each other while being superposed on the laying circumferential surface portion 41. . Thus, 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 for delivering a drug to a lesion in a living body lumen using the balloon catheter 10, and the balloon 12 is inserted into the living body lumen to reach the lesion. And 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 and removing it from the living body lumen. As a result, when the balloon 12 is expanded at the lesioned part, the crystal of the standing drug possessed by the layer structure part 37 easily moves to the inner wall surface of the living body lumen, and effectively transfers the drug to the living tissue. be able to.

  Note that the present invention is not limited to the above-described embodiments, and various modifications can be made by those skilled in the art within the technical idea of the present invention. For example, the balloon catheter 10 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 long bodies 33 that overlap each other in the layer structure portion 37 are attached and integrated, but the long bodies 33 are not integrated only by contacting each other. May be.

  As described above, the base layer 32 exists as an amorphous material, a crystal particle, or a mixture thereof. The base layer 32 in FIG. 4 is in a crystalline particle and / or particulate amorphous state, but the base layer 32 may be in a film-like amorphous state as shown in FIG.

  Further, in the present embodiment, the wing portion 40 of the folded balloon 12 does not reach the adjacent wing portion 40, but as shown in FIG. 22, the wing portion 40 reaches the adjacent wing portion 40. It may be. In the example of FIG. 22A, a root side space portion 42 is formed between the root side of the blade portion 40 and the peripheral surface portion 41, and a tip side space portion is provided between the tip side of the blade portion 40 and the peripheral surface portion 41. 43 is formed. 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.

DESCRIPTION OF SYMBOLS 10 Catheter 11 Catheter shaft 12 Balloon 13 Hub 20 Outer tube 21 Inner tube 22 Expansion lumen 23 Guide wire lumen 24 Opening portion 30 Coat layer 31 Balloon surface 32 Base layer 33 Long body 40 Blade portion 40a Blade inner portion 40b Blade outer portion 40c Root Part 41 Peripheral surface part 41a Opposing surface part 41b Outer peripheral component surface part 50 Balloon coating device 60 Rotating mechanism part 70 Support base 80 Moving mechanism part 90 Application mechanism part 94 Dispensing tube 100 Balloon folding apparatus

Claims (8)

A balloon catheter having a balloon at the distal end portion of the catheter shaft, and a plurality of elongated bodies that are crystals of a water-insoluble drug extending with an independent long axis provided on the surface of the balloon,
The deflated balloon has a plurality of blade portions in the circumferential direction and a circumferential surface portion along the circumferential direction of the catheter shaft, and the blade portions are folded along the circumferential direction of the balloon,
The balloon has a layered structure portion in which the elongated body in an upright state and the elongated body in an inclined state overlap each other between the wing portion and the peripheral surface portion in a folded state.   The balloon catheter according to claim 1, wherein 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.   The balloon catheter according to claim 1 or 2, wherein the elongated body in the standing state of the layer structure and the elongated body in the tilted state are attached to each other and integrated.   The said layer structure part has the said elongate body in which the surface of the balloon which forms the said blade | wing part inclines, and the surface of the balloon which forms the said surrounding surface part has the said elongate body in the standing state. The balloon catheter of any one of -3.   The balloon catheter according to any one of claims 1 to 4, wherein the water-insoluble drug is rapamycin, paclitaxel, docetaxel, or everolimus. In the method of manufacturing a balloon catheter, 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.
Forming the elongated body standing on the surface of the balloon;
By pressing the surface of the balloon with a blade of a pleating part, a wing part protruding in the radial direction is formed on the balloon, and the elongated body in the region to be the wing part is tilted, and the wing part Maintaining the standing state of the elongate body in the region that becomes the peripheral surface portion facing with,
By pressing the surface of the balloon with the blade of the folding part, the blades formed on the balloon are laid down along the circumferential direction and overlapped with the peripheral surface part, and the elongated body in the tilted state of the blade part and Forming a layered structure portion that overlaps the elongated body in the standing state of the peripheral surface portion;
The manufacturing method of the catheter which has this.   When the balloon blade portion is overlaid on the peripheral surface portion, by heating the surface of the balloon, the long body in an inclined state of the blade portion and the length of the peripheral surface portion standing on each other overlap each other. The balloon catheter according to claim 6, wherein the scale body is attached and integrated. A treatment method for delivering a drug to a lesion in a living body lumen using the balloon catheter according to any one of claims 1 to 5,
Inserting the balloon into the body lumen to reach the lesion;
Expanding the balloon and pressing the elongated body against the living tissue;
Deflating the balloon and removing it from the living body lumen.

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