Balloon catheter, method of manufacturing a balloon catheter, and treatment method

A balloon catheter by which a drug can be effectively delivered to living body tissue and a method of manufacturing the balloon catheter, and a treatment method. The balloon catheter is provided on an outer surface of a balloon with a plurality of elongate bodies which are independent crystals of a water-insoluble drug that extend in an elongate form. The elongate bodies have long axes extending in directions along the outer surface of the balloon when the balloon is in a deflated state. Deformation, when the balloon is inflated from the deflated state, of portions on an outer surface side of the balloon to which end portions of the elongate bodies are fixed causes a force to act on the elongate bodies such that the long axes of the elongate bodies approach perpendicularity to the outer surface of the balloon.

TECHNICAL FIELD

The present disclosure relates to a balloon catheter having a balloon coated on its surface with a crystalline drug, a method of manufacturing a balloon catheter, and a treatment method using the balloon catheter.

BACKGROUND ART

In recent years, for improving lesion affected areas (stenosed parts) in body lumens, balloon catheters have been used. A balloon catheter normally includes an elongate shaft section, and a balloon which is provided on the distal side of the shaft section and is inflatable in the radial direction. After the balloon in a deflated state is brought to a target site in the body by way of a thin body lumen, the balloon is inflated, whereby the lesion affected area can be pushed wide open (widened).

However, if a lesion affected area is forcibly pushed wide open, excessive proliferation of smooth muscle cells may occur, causing new stenosis (restenosis) at the lesion affected area. In view of this, recently, drug eluting balloons (DEBs) in which an outer surface of a balloon is coated with a drug for restraining stenosis have been used. The drug eluting balloon, by being inflated, is able to instantaneously release the drug contained in the coating on the outer surface of the balloon to the lesion affected area, thereby restraining restenosis.

In recent years, it has been becoming clear that the morphological form of the drug in the coating on the surface of the balloon influences the releasing property of the drug from the balloon surface and/or the tissue transferability of the drug at the lesion affected area. For instance, U.S. Patent Application Publication No. 2014/0271775 describes a balloon catheter in which crystals of a drug are formed in elongate form on a surface of a balloon.

SUMMARY

For enhancing a therapeutic effect, a drug eluting balloon catheter is desirably configured in such a manner that the deliverability of the drug on the surface of the balloon to living body tissue is relatively high.

A balloon catheter is disclosed by which a drug can be effectively delivered to living body tissue and a method of manufacturing a balloon catheter, and a treatment method.

A balloon catheter according to the present disclosure for achieving the aforesaid objects is a balloon catheter provided on an outer surface of a balloon with a plurality of elongate bodies which are crystals of a water-insoluble drug that extend while having independent long axes. The elongate bodies have the long axes (i.e., longitudinal axis) extending in directions along the outer surface of the balloon when the balloon is in a deflated state, and deformation, when the balloon is inflated from the deflated state, of portions on an outer surface side of the balloon to which end portions of the elongate bodies are fixed (held or attached) causes a force to act on the elongate bodies such that the long axes of the elongate bodies approach perpendicularity to the outer surface of the balloon.

In the balloon catheter configured as aforesaid, inflation of the balloon causes the long axes of the elongate bodies approach perpendicularity to the outer surface of the balloon, so that the elongate bodies become liable (i.e., likely) to pierce the living body tissue. As a result, releasing property (i.e., ability of the drug to be released) of the drug from the outer surface of the balloon and transferability of the drug (i.e., the transferability of the drug onto the tissue) to the living body tissue can be enhanced, and the drug can be effectively delivered to the living body tissue. Note that the portions on the outer surface side of the balloon are not limited to the portions constituted of the balloon itself, and may be portions (for example, a layer of an excipient) formed on the outer surface of the balloon.

The balloon may have an overlapping portion where portions of the outer surface of the balloon overlap with each other when the balloon is folded in the deflated state, and the elongate bodies may be provided on the portions of the outer surface of the balloon that overlap with each other at the overlapping portion, which helps ensure that the elongate bodies are not exposed to the outside when the balloon is in the deflated state, so that the elongate bodies can be protected until the balloon reaches the target position. Therefore, the drug can be restrained (or prevented) from falling off (i.e., be removed from) the outer surface of the balloon or flowing out into blood stream or the like during delivery, and the drug can be effectively delivered to the living body tissue.

The water-insoluble drug may be rapamycin, paclitaxel, docetaxel, or everolimus. As a result of this, restenosis at a stenosed part in a blood vessel can be favorably restrained by the elongate bodies.

In addition, a method of manufacturing a balloon catheter according to the present disclosure is a method of manufacturing a balloon catheter provided on an outer surface of a balloon with a plurality of elongate bodies which are crystals of a water-insoluble drug that extend while having independent long axes, the method including a step of forming the elongate bodies on the outer surface of the balloon, a step of forming the balloon with a wing portion projecting in a radial direction, and a step of folding the wing portion, formed in the balloon, along a circumferential direction. In at least one of the step of forming the wing portion and the step of folding the wing portion, portions on an outer surface side of the balloon to which end portions of the elongate bodies are fixed are deformed by a force exerted for deforming the balloon, whereby the long axes of the elongate bodies are inclined into directions along the outer surface of the balloon. According to the method of manufacturing a balloon catheter configured as aforesaid, the elongate bodies fixed to the portions on the outer surface side of the balloon can be efficiently inclined, through utilization of the force exerted on the balloon in the step of forming the balloon with the wing portion or the step of folding the wing portion.

An overlapping portion where portions of the outer surface of the balloon overlap with each other may be formed, in the step of folding the wing portion, and the long axes of the elongate bodies provided on the portions of the outer surface that face each other at the overlapping portion may be inclined into directions along the outer surface of the balloon, which helps ensure that the force exerted on the balloon for folding the wing portion acts on the surfaces located inside the overlapping portion indirectly, so that the force acting on the elongate bodies can be controlled, and a desirable force for inclining the elongate bodies can be easily exerted.

In addition, a treatment method according to the present disclosure is a treatment method of delivering a drug to a lesion affected area in a body lumen by use of the aforementioned balloon catheter, the treatment method including a step of inserting the balloon into the body lumen to deliver the balloon to the lesion affected area, a step of inflating the balloon to cause the elongate bodies to be erected at such an angle as to approach perpendicularity to the outer surface of the balloon, a step of pressing the erected elongate bodies against living body tissue, and a step of deflating the balloon and withdrawing the balloon out of the body lumen. In the treatment method configured as aforesaid, inflation of the balloon causes the long axes of the elongate bodies which are crystals of a water-insoluble drug to approach perpendicularity to the outer surface of the balloon, so that the elongate bodies become liable (i.e., likely) to pierce the living body tissue. As a result, releasing property of the drug from the outer surface of the balloon and transferability of the drug to the living body tissue can be relatively enhanced, and the drug can be effectively delivered to the living body tissue.

DETAILED DESCRIPTION

An embodiment of the present disclosure will be described below referring to the drawings. Note that the dimensional ratios in the drawings may be exaggerated and different from the actual ratios, for convenience of explanation.

As depicted inFIGS. 1 and 2, a balloon catheter10according to an embodiment of the present disclosure is a drug eluting type catheter provided with crystals of a drug on an outer surface of a balloon30. Note that, in the present specification, the side on which the balloon catheter10is inserted into a body lumen will be referred to as “distal end” or “distal side,” while the operator's hand side on which the balloon catheter10is operated will be referred to as “proximal end” or “proximal side.”

First, the structure of the balloon catheter10will be described. The balloon catheter10includes an elongate catheter main body20, the balloon30provided at a distal portion of the catheter main body20, a coating layer40that contains a drug and that is provided on the outer surface of the balloon30, and a hub26firmly attached to a proximal end of the catheter main body20. The balloon30provided with the coating layer40is protected by being covered with a protective sheath15until put to use.

The catheter main body20includes an outer tube21that is a tube body opening at a distal end and a proximal end, and an inner tube22that is a tube body disposed inside the outer tube21. The inner tube22is accommodated in the hollow (i.e., an annular space or lumen) inside of the outer tube21, and the catheter main body20has a double-tube structure at a distal portion of the catheter main body20. The hollow inside of the inner tube22is a guide wire lumen24for passing a guide wire therethrough (i.e., a guide wire is positionable in or insertable through the guide wire lumen24). In addition, in the hollow inside of the outer tube21and on the outside of the inner tube22, there is formed an inflation lumen23. An inflation fluid for inflating the balloon30may pass through the inflation lumen23. The inner tube22is opening to the exterior (i.e., surrounding environment) at an opening portion25. The inner tube22protrudes to the distal side beyond a distal end of the outer tube21.

Of the balloon30, a proximal-side end portion is fixed to a distal portion of the outer tube21, and a distal-side end portion is fixed to a distal portion of the inner tube22. This results in that the inside of the balloon30communicates with the inflation lumen23. With the inflation fluid injected through the inflation lumen23into the balloon30, the balloon30can be inflated. The inflation fluid may be a gas or a liquid; for example, gases such as helium gas, CO2gas, O2gas, N2gas, Ar gas, air, or mixed gas, and liquids such as physiological saline solution or a contrast agent, can be used as the inflation fluid.

At a central portion in regard of the axial direction of the balloon30, there is formed a hollow cylindrical straight portion31(inflatable portion) having an equal outside diameter when inflated, and tapered portions33where the outside diameter gradually varies are formed on both sides of the straight portion31in regard of the axial direction. In addition, a coating layer40which contains a drug is formed on the whole part of the outer surface of the straight portion31. Note that the range of the balloon30in which the coating layer40is formed is not limited only to the straight portion31; the range may include at least part of the tapered portions33in addition to the straight portion31, or may be only part of the straight portion31.

The hub26is formed with a proximal opening portion27that communicates with the inflation lumen23of the outer tube21and that functions as a port for permitting the inflation fluid to flow in and out therethrough.

The length in an axial direction of the balloon30is not particularly limited, and is, for example, preferably 5 mm to 500 mm, more preferably 10 mm to 300 mm, and still more preferably 20 mm to 200 mm.

The outside diameter of the balloon30when inflated is not specifically restricted, and is, for example, preferably 1 mm to 10 mm, and more preferably 2 mm to 8 mm.

The outer surface of the balloon30before the formation of the coating layer40is smooth and non-porous. The outer surface of the balloon30before the formation of the coating layer40may have minute holes that do not pierce through the film. Alternatively, the outer surface of the balloon30before the formation of the coating layer40may have both a region of being smooth and non-porous and a region of having minute (i.e., extremely small) holes that do not pierce through the film. The minute holes may be sized to have, for example, a diameter of 0.1 μm to 5 μm and a depth of 0.1 μm to 10 μm, and one or a plurality of holes may be provided per drug crystal. In addition, the minute (i.e., extremely small) holes may be sized to have, for example, a diameter of 5 μm to 500 μm and a depth of 0.1 μm to 50 μm, and one or a plurality of drug crystals may be provided per one hole.

Preferably, the balloon30has a certain degree of flexibility and a certain degree of hardness such that the drug can be released from the coating layer40provided on the surface of the balloon30when the balloon30is inflated upon arrival at a blood vessel or tissue. Specifically, the balloon30is formed from metal or resin. It is preferable that at least the outer surface of the balloon30on which to provide the coating layer40is formed of resin. Examples of the material which can be used for forming at least the outer surface of the balloon30include thermoplastic resins such as polyolefins (e.g., polyethylene, polypropylene, polybutene, ethylene-propylene copolymers, ethylene-vinyl acetate copolymers, ionomers, or mixtures of two or more of them), flexible polyvinyl chloride resin, polyamides, polyamide elastomers, nylon elastomers, polyester, polyester elastomers, polyurethane, fluororesins, etc., silicone rubbers, and latex rubbers. Among the thermoplastic resins, preferred are the polyamides. Specifically, at least part of the outer surface of the inflatable portion of the balloon30to be coated with the drug is made of a polyamide. The polyamide is not particularly limited so long as it is a polymer which has an amide linkage. Examples of the polyamide include homopolymers such as polytetramethylene adipamide (nylon 46), polycaprolactam (nylon 6), polyhexamethylene adipamide (nylon 66), polyhexamethylene sebacamide (nylon 610), polyhexamethylene dodecamide (nylon 612), polyundecanolactam (nylon 11), polydodecanolactam (nylon 12), etc., copolymers such as caprolactam/lauryllactam copolymer (nylon 6/12), caprolactam/aminoundecanoic acid copolymer (nylon 6/11), caprolactam/ω-aminononanoic acid copolymer (nylon 6/9), caprolactam/hexamethylenediammonium adipate copolymer (nylon 6/66), etc., and aromatic polyamides such as copolymers of adipic acid with metaxylenediamine, or copolymers of hexamethylenediamine with m,p-phthalic acid. Further, polyamide elastomers as block copolymers in which nylon 6, nylon 66, nylon 11, nylon 12 or the like constitutes hard segments and a polyalkylene glycol, a polyether, an aliphatic polyester or the like constitutes soft segments can also be used as the base material of the medical device according to the present disclosure. One of the aforesaid polyamides may be used singly, or two or more of the aforesaid polyamides may be used in combination. Particularly, the balloon30preferably has a smooth surface of a polyamide.

The balloon30is formed on an outer surface of the balloon30with the coating layer40, either directly or through a pre-treatment layer such as a primer layer between the balloon30and the coating layer40, by a method which will be described later. As depicted inFIGS. 3 to 5, the coating layer40includes a base material41(excipient) which is an additive layer containing a water-soluble low-molecular compound disposed in a layer form on the outer surface of the balloon30, and a plurality of elongate bodies42which are crystals of a water-insoluble drug that extend while having independent long axes.

The elongate bodies42include first elongate bodies42athat extend from the outer surface of the base material41toward the outside of the surface, second elongate bodies42bthat extend from the outer surface of the balloon30to the outside of the base material41by penetrating the base material41, and third elongate bodies42cthat extend from the inside of the base material41to the outside of the base material41. In other words, base portions45of the elongate bodies42may be in direct contact with the outer surface of the balloon30, or may not make direct contact with the outer surface of the balloon30but the base material41(excipient) may be present between the base portions45and the outer surface of the balloon30. Since the elongate bodies42a,42band42care different in deliverability of the drug to the living body, it is possible, by regulating the positions of the base portions45of the crystals of the drug, to control the deliverability of the drug. Preparation may be made in which almost only the elongate bodies42aare present on the surface of the balloon30. Preparation may be made in which almost only the elongate bodies42bare present on the surface of the balloon30. Preparation may be made in which almost only the elongate bodies42care present on the surface of the balloon30. In addition, preparation may be made in which a combination of the plurality of kinds of elongate bodies are present on the surface of the balloon30. Examples of such a combination include a combination of the elongate bodies42awith the elongate bodies42b, a combination of the elongate bodies42bwith the elongate bodies42c, and a combination of the elongate bodies42cwith the elongate bodies42a. Preparation may be made in which all the elongate bodies42a,42band42care present on the surface of the balloon30.

In addition, a long axis of each of the elongate bodies42is inclined relative to the outer surface of the balloon30, in a state in which the balloon30is deflated (a state before use). Therefore, the long axes of the elongate bodies42extend into directions along the outer surface of the balloon30. When the first elongate bodies42aand the third elongate bodies42c, of which the base portions45are in contact not with the balloon30but with the base material41, are inclined relative to the outer surface of the balloon30in the manufacturing process which will be described later, the base material41is deformed, whereby base material deformed portions46are formed. Attendant on the deformation of the base material41, the outer surface of the balloon30may also be deformed. In the inside of the base material deformed portions46, stress due to deformation may be left. The base material deformed portions46appear, for example, as projected portions or recessed portions in the outer surface of the base material41. When the second elongate bodies42b, of which the base portions45are in contact with the balloon30, are inclined relative to the outer surface of the balloon30in the manufacturing process which will be described later, the balloon30is deformed, whereby balloon deformed portions36are formed. In the inside of the balloon deformed portions36, stress due to deformation may be left. Further, the second elongate bodies42bare penetrating the base material41, and, therefore, the base material deformed portions46are also formed. The balloon deformed portions36appear, for example, as projected portions or recessed portions in the outer surface of the balloon30.

The inclination angle α of the elongate bodies42relative to the outer surface of the balloon30or the base material41when the balloon30is in the deflated state is not particularly limited; as depicted inFIG. 5, the inclination angle α is, for example, preferably 0 degrees to 89 degrees, more preferably 3 degrees to 80 degrees, and still more preferably 30 degrees to 45 degrees.

When an inflation fluid is made to flow into the inside of the balloon30to inflate the balloon30, the materials of the balloon30and the base material41are stretched in the circumferential direction, as depicted inFIG. 6(see alternate long and two short dashes line in the figure). As a result, the balloon deformed portions36and the base material deformed portions46are stretched to return into original smooth shapes, and the long axes of the elongate bodies42approach perpendicularity to the outer surface of the balloon30. The angle θ of the long axis of the elongate body42relative to the outer surface of the balloon30after inflation of the balloon30is greater than the angle α, preferably close to 90 degrees. The angle θ is, for example, 1 degree to 90 degrees, preferably 30 degrees to 90 degrees, more preferably 45 degrees to 90 degrees, and still more preferably 60 degrees to 90 degrees. Note that with the balloon30folded and with its portions made to overlap with each other, the elongate bodies42may be inclined relative to the outer surface of the balloon30, under pressing forces. In this case, when the balloon30is inflated, the overlapping is released, and the pressing forces which would incline the elongate bodies42disappear. As a result, residual stress in the balloon deformed portions36and the base material deformed portions46is relieved, and the long axes of the elongate bodies42can approach perpendicularity to the outer surface of the balloon30.

When the long axis of the elongate body42approaches perpendicularity to the outer surface of the balloon30, the elongate body42becomes liable to pierce the living body tissue. As a result, releasing property of the drug from the outer surface of the balloon30and transferability of the drug to the living body tissue can be enhanced, and the drug can be delivered to the living body tissue more effectively.

The plurality of elongate bodies42may be disposed regularly on the outer surface of the balloon30. Alternatively, the plurality of elongate bodies42may be disposed irregularly on the outer surface of the balloon30. In addition, the elongate bodies42whose angles relative to the balloon30approaches perpendicularity when the balloon30is inflated may be provided throughout the coating layer40, or may be provided only in part of the coating layer40. All the elongate bodies42may not necessarily be in such a form that their angles relative to the balloon30approach perpendicularity when the balloon30is inflated, and the elongate bodies42in other forms may be simultaneously present.

The amount of the drug contained in the coating layer40is not particularly limited; the amount in density is 0.1 μg/mm2to 10 μg/mm2, preferably 0.5 μg/mm2to 5 μg/mm2, more preferably 0.5 μg/mm2to 3.5 μg/mm2, and still more preferably 1.0 μg/mm2to 3 μg/mm2. The amount of the crystals in the coating layer40is not particularly limited, and is 5 crystals/(10 μm2) to 500,000 crystals/(10 μm2) (the number of crystals per 10 μm2), preferably 50 crystals/(10 μm2) to 50,000 crystals/(10 μm2), and more preferably 500 crystals/(10 μm2) to 5,000 crystals/(10 μm2).

The plurality of elongate bodies42in which crystals have mutually independent long axes may be present in their combined state (i.e., the plurality of elongate bodies42are in contact with one another). In addition, the plurality of adjacent elongate bodies42may be present in contact with one another while forming different angles. The plurality of elongate bodies42may be located on the balloon surface with a space (a space where the crystal is not contained) between the plurality of elongate bodies42. Both the plurality of elongate bodies42in the combined state and the plurality of mutually spaced independent elongate bodies42may be present on the surface of the balloon30. The plurality of elongate bodies42may be disposed circumferentially and in brush-shaped form while having different long axis directions. Each of the elongate bodies42exists independently, and has a certain length, and one end (base end) of the length portion is fixed to the base material41or the balloon30. The elongate body42does not form a composite structure with, and is not joined to, adjacent elongate bodies42. The long axes of the crystals are substantially rectilinear. The elongate body42forms a predetermined angle relative to the surface which its long axis intersects and with which its base portion45makes contact.

In accordance with an exemplary embodiment, it can be preferable that the elongate bodies42are standing independently, without making contact with one another. The base portions45of the elongate bodies42may be in contact with other base portions45on the substrate of the balloon30. Alternatively, the base portions45of the elongate bodies42may be independent, without making contact with other base portions45, on the substrate of the balloon30.

The elongate bodies42may be hollow or may be solid. Both hollow elongate bodies42and solid elongate bodies42may exist on the surface of the balloon30. Where the elongate body42is hollow, at least a portion of the elongate body42near a top end44of the elongate body42is preferably hollow. A section of the elongate body42in a plane perpendicular (orthogonal) to the long axis of the elongate body42has a void (hollow portion). In the elongate body42thus having a void, the section of the elongate body42in a plane perpendicular (orthogonal) to the long axis is polygonal in shape. The polygon here is, for example, a triangle, a tetragon, a pentagon, or a hexagon. Therefore, the elongate bodies42are each formed as an elongate polyhedron which has a distal end (or a distal surface) and a proximal end (or a proximal surface) and in which a side surface between the distal end (or the distal surface) and the proximal end (or the proximal surface) is composed of a plurality of substantially plain surfaces. In addition, the elongate bodies42may be needle-like in shape. This crystalline morphological form (hollow elongate body crystalline morphological form) constitutes the whole part or at least part of a plane, at the surface of the base material41or the balloon30in contact therewith.

The length in the long axis direction of the elongate bodies42having the long axes is, for example, preferably 5 μm to 20 μm, more preferably 9 μm to 11 μm, and still more preferably around 10 μm. Note that the length in the long axis direction of the elongate bodies42can be defined as the length before spreading of cracks. The diameter of the elongate bodies42having the long axes is, for example, 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. Examples of the combination of length in the long axis direction and diameter of the elongate bodies42having the long axes include a combination of a diameter of 0.01 μm to 5 μm when the length is 5 μm to 20 μm, a combination of a diameter of 0.05 μm to 4 μm when the length is 5 μm to 20 μm, and a combination of a diameter of 0.1 μm to 3 μm when the length is 5 μm to 20 μm. The elongate bodies42having the long axes are rectilinear in the long axis direction of the elongate bodies42, and may also be curved in curved line forms. Both rectilinear elongate bodies42and curved elongate bodies42may exist on the surface of the balloon30.

The crystalline morphological form having the crystals having long axes as aforementioned accounts for not less than 50% by volume, preferably not less than 70% by volume, based on the whole of the drug crystals on the outer surface of the balloon30.

The crystal particles having the long axes after the coating of the coating layer40and before the folding of the balloon30are formed not to lie flat but to stand in relation to the outer surface of the balloon30. The base material41may exist in a region where the elongate bodies42are present and may not exist in a region where the elongate bodies42are absent. In the crystal particles in this instance, the angle of the crystal particles is changed by the pleating (the step of forming the balloon30with the wing portions32) or the folding (the step of folding the wing portions32), whereby the angles of the long axes of the crystal particles relative to the outer surface of the balloon30can be changed. Therefore, while the crystals which are formed in the manner of lying flat on the outer surface of the balloon30from the beginning are firmly attached (fixed) to the outer surface of the balloon30and/or the adjacent crystal particles, the crystal particles which are standing are not formed in the state of being physically fixed to the outer surface of the balloon30or the adjacent crystal particles. For this reason, the standing crystal particles are only positioned (arranged) in such a manner as to make contact with, for example, the outer surface of the balloon30or the adjacent crystal particles, and their positions can be changed on a three-dimensional basis. Accordingly, the crystal particles after the coating are formed such that the angles and positions of the crystal particles can be changed through the pleating or folding of the balloon30. Part of the crystal particles may be embedded in the surface of the balloon30.

The base material41is present in the state of being distributed into spaces between the plurality of elongate bodies42standing together. In regard of the proportions of the materials constituting the coating layer40, the crystals of the water-insoluble drug preferably occupy a larger volume than that occupied by the base material41. The excipient constituting the base material41does not form a matrix. The matrix is a layer which is configured by continuation of a comparatively high-molecular material (polymer or the like), which forms a network-like three-dimensional structure, and in which minute spaces are present. Therefore, the water-insoluble drug constituting the crystals is not adhered to the inside of a matrix material. Moreover, the water-insoluble drug constituting the crystals is not embedded in the matrix material.

The base material41is formed as a dried layer, after being applied in an aqueous solution state to the outer surface of the balloon30. The base material41is amorphous. The base material41may be crystal particles. The base material41may exist as a mixture of an amorphous state with crystal particles. The base material41inFIG. 4is in a state including crystal particles and/or particulate amorphous portions. The base material41is formed as a layer including the water-insoluble drug. Alternatively, the base material41may be formed as an independent layer that does not include the water-insoluble drug. The thickness of the base material41is 0.1 μm to 5 μm, preferably 0.3 μm to 3 μm, and more preferably 0.5 μm to 2 μm.

The layer including the elongate body crystalline morphological form is low in toxicity and high in stenosis inhibitory effect at the time of delivery into a body. The water-insoluble drug including the hollow elongate body crystalline morphological form has good property of penetration into tissue because of a small crystal unit size upon transfer of the drug to the tissue, and, since it has good solubility, it acts effectively and can inhibit stenosis. In addition, it is considered that the drug is less liable to remain in the tissue as large lumps (i.e., in a relatively large lump form) and, therefore, exhibits low toxicity.

In addition, the layer including the elongate body crystalline morphological form has a plurality of substantially uniform elongate bodies42having the long axes, and the elongate bodies42are substantially uniformly standing together on the surface with which their base portions45make contact. Therefore, the size (the length in the long axis direction) of the crystals transferred to the tissue is as small as approximately 10 μm. For this reason, the drug uniformly acts on the lesion affected area, with an enhanced property for penetration into the tissue. Furthermore, since the size of the crystals transferred is small, there is no possibility that an excess amount of the drug might remain at the affected area for an excess of time; for this reason, it is considered, the drug can exhibit a high stenosis inhibitory effect, without exhibiting toxicity.

The drug in the coating on the outer surface of the balloon30may include an amorphous phase. The crystals and the amorphous phase may be disposed regularly in the coating layer40. Alternatively, the crystals and the amorphous phase may be disposed irregularly.

The protective sheath15is a member for restraining the drug from falling off the balloon30, and is removed before the balloon catheter10is put to use. The protective sheath15is formed from a flexible material. Examples of the material which can be used here include thermoplastic resins such as polyolefins (e.g., polyethylene, polypropylene, polybutene, ethylene-propylene copolymers, ethylene-vinyl acetate copolymers, ionomers, or mixtures of two or more of them), flexible polyvinyl chloride resin, polyamides, polyamide elastomers, polyesters, polyester elastomers, polyurethane, fluororesins, etc., silicone rubbers, and latex rubbers.

Now, a balloon coating system for forming the coating layer40on the aforementioned balloon30will be described below. The present system includes a balloon coating apparatus50(seeFIG. 7) for forming the coating layer40on the balloon30, and a balloon folding apparatus100(seeFIG. 9) for folding the balloon30formed with the coating layer40. By use of the balloon coating apparatus50, crystals of a water-insoluble drug that extend while having independent long axes are formed on the outer surface of the balloon30. Thereafter, the balloon30is folded by the balloon folding apparatus100, whereby the long axes of the elongate bodies42are inclined such as to extend along the outer surface of the balloon30.

In the first place, the balloon coating apparatus50will be described. As depicted inFIGS. 7 and 8, the balloon coating apparatus50includes a rotation mechanism section60for rotating the balloon catheter10, and a support base70for supporting the balloon catheter10. The balloon coating apparatus50further includes an application mechanism section90provided with a dispensing tube94for applying a coating solution to an outer surface of the balloon30, a movement mechanism section80for moving the dispensing tube94relative to the balloon30, and a control unit99for controlling the balloon coating apparatus50.

The rotation mechanism section60holds the hub26of the balloon catheter10, and rotates the balloon catheter10around an axis of the balloon30by a drive source, such as a motor, incorporated in the rotation mechanism60. The balloon catheter10is held, with a core member61inserted in the guide wire lumen24, and the core member61prevents the coating solution from flowing into the guide wire lumen24. In addition, in the balloon catheter10, for operating the flow of a fluid into the inflation lumen23, a three-way cock capable of operating the opening/closing of a passage or passages is connected to a proximal opening portion27of the hub26.

The support base70includes a pipe-shaped proximal-side support section71that accommodates the catheter main body20in the support base70and rotatably supports the catheter main body20, and a distal-side support section72that rotatably supports the core member61. Note that the distal-side support section72may, if possible, rotatably support a distal portion of the catheter main body20, instead of the core member61.

The movement mechanism section80includes a movable base81which can be moved rectilinearly in a direction parallel to the axis of the balloon30, and a tube fixing section83to which the dispensing tube94is fixed. The movable base81can be moved rectilinearly by a drive source, such as a motor, incorporated in the movable base81. The tube fixing section83fixes an upper end of the dispensing tube94relative to the movable base81. With the movable base81moved, therefore, the dispensing tube94is moved rectilinearly in a direction parallel to the axis of the balloon30. In addition, the application mechanism section90is mounted on the movable base81, and the movable base81moves the application mechanism section90rectilinearly in both directions (both senses) along the axis.

The application mechanism section90is a section that applies the coating solution to the outer surface of the balloon30. The application mechanism section90includes a container92containing the coating solution, a feed pump93that feeds the coating solution at an arbitrary feed rate, and the dispensing tube94that applies the coating solution to the balloon30.

The feed pump93is, for example, a syringe pump. Controlled by the control unit99, the feed pump93can draw the coating solution from the container92through a suction tube91, and feed the coating solution into the dispensing tube94through a supply tube96at an arbitrary feed rate. The feed pump93is disposed on the movable base81, and can be moved rectilinearly by the movement of the movable base81. Note that the feed pump93is not limited to the syringe pump so long as it can feed the coating solution, and may be, for example, a tube pump.

The dispensing tube94is a member which communicates with the supply tube96and discharges to the outer surface of the balloon30the coating solution supplied from the feed pump93through the supply tube96. The dispensing tube94is a flexible circular pipe-shaped member. The dispensing tube94has its upper end fixed to the tube fixing section83, extends downward in the vertical direction from the tube fixing section83, and is formed with an opening portion95at a discharge end97which is its lower end. With the movable base81moved, the dispensing tube94can be moved rectilinearly in both directions (both senses) along the axial direction of the balloon catheter10, together with the feed pump93disposed on the movable base81. The dispensing tube94can supply the coating solution to the outer surface of the balloon30, in the state of being bent by being pressed against the balloon30.

Note that the dispensing tube94may not necessarily be circular pipe-shaped so long as it can supply the coating solution. In addition, the dispensing tube94may not necessarily extend in the vertical direction so long as it can discharge the coating solution through the opening portion95.

The dispensing tube94is preferably formed from a flexible material such that contact burden on the balloon30can be reduced and that variations in the contact position attendant on the rotation of the balloon30can be absorbed by flexure of the dispensing tube94. Examples of the applicable material for the dispensing tube94include polyolefins such as polyethylene, polypropylene, etc., cyclic polyolefins, polyesters, polyamides, polyurethane, and fluororesins such as PTFE (polytetrafluoroethylene), ETFE (tetrafluoroethylene-ethylene copolymer), PFA (tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer), FEP (tetrafluoroethylene-hexafluoropropylene copolymer), etc., but the material is not particularly limited so long as it is flexible and deformable.

The outside diameter of the dispensing tube94is not particularly limited, and 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 inside diameter of the dispensing tube94is not particularly limited, and 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 tube94is not particularly limited, and is preferably a length of not more than five times the balloon diameter, for example, 1.0 mm to 50 mm, preferably 3 mm to 40 mm, and more preferably 5 mm to 35 mm.

The control unit99is composed, for example, of a computer, which controls the rotation mechanism section60, the movement mechanism section80, and the application mechanism section90. Therefore, the control unit99can control the rotating speed of the balloon30, the moving speed of the dispensing tube94in the axial direction of the balloon30, the drug discharge rate from the dispensing tube94, and so on.

The coating solution supplied from the dispensing tube94to the balloon30is a solution or dispersion containing the constituent materials of the coating layer40, and contains a water-insoluble drug, an excipient, an organic solvent, and water. After the coating solution is supplied to the outer surface of the balloon30, the organic solvent and water volatilize, whereby a coating layer40including a plurality of elongate bodies which are crystals of the water-insoluble drug that extend while having independent long axes is formed on the outer surface of the balloon30.

The viscosity of the coating solution is 0.5 cP to 1,500 cP, preferably 1.0 cP to 500 cP, and more preferably 1.5 cP to 100 cP.

The water-insoluble drug means a drug which is insoluble or difficultly soluble in water; specifically, the water-insoluble drug is a drug of which the solubility in water is, for example, less than 5 mg/mL at pH 5 to 8. The solubility may be less than 1 mg/mL, or, further, may be less than 0.1 mg/mL. The water-insoluble drug includes fat-soluble drugs.

The water-insoluble drug is preferably at least one selected from a group composed of rapamycin, paclitaxel, docetaxel, and everolimus. The rapamycin, paclitaxel, docetaxel and everolimus herein include their analogs and/or derivatives so long as the analogs and/or derivatives have equivalent drug activity to the original. For example, paclitaxel and docetaxel are in an analog relation. Rapamycin and everolimus are in a derivative relation. Among these, more preferable is paclitaxel.

The excipient constitutes the base material41on the balloon30. The excipient includes a water-soluble low-molecular compound. The molecular weight of the water-soluble low-molecular compound is 50 to 2,000, preferably 50 to 1,000, more preferably 50 to 500, and still more preferably 50 to 200. The amount of the water-soluble low-molecular compound is preferably 5 parts by mass to 10,000 parts by mass, more preferably 5 parts by mass to 200 parts by mass, and still more preferably 8 parts by mass to 150 parts by mass, per 100 parts by mass of the water-insoluble drug. Examples of the applicable constituent material of the water-soluble low-molecular compound include serine ethyl ester, citric acid esters, polysorbates, water-soluble polymers, sugars, contrast agents, amino acid esters, glycerol esters of short-chain monocarboxylic acids, pharmaceutically acceptable salts and surfactants, and mixtures of two or more of these. The water-soluble low-molecular compound is characterized in that it has a hydrophilic group and a hydrophobic group and is soluble in water. Preferably, the water-soluble low-molecular compound is non-swellable or difficultly swellable. The excipient is preferably amorphous on the balloon30. The excipient including the water-soluble low-molecular compound has an effect of uniformly dispersing the water-insoluble drug on the outer surface of the balloon30. The excipient constituting the base material41is preferably not a hydrogel. Being the low-molecular compound, the base material41is rapidly dissolved without being swelled upon contact with an aqueous solution. Further, since the base material41becomes easily soluble upon inflation of the balloon30in a blood vessel, the crystal particles of the water-insoluble drug on the outer surface of the balloon30become easily releasable; thus, the base material41has an effect of increasing the amount of the crystal particles of the drug adhered to the blood vessel. In the case where the base material41is a matrix composed of a contrast agent such as Ultravist®, the crystal particles are embedded in the matrix, and crystals are not produced to extend from the substrate of the balloon30toward the outside of the matrix. On the other hand, the elongate bodies42according to the present embodiment extend from the surface of the substrate of the balloon30to the outside of the base material41. The length of that portion of the elongate body42which is located on the outside of the base material41is greater than the length of that portion of the elongate body42which is located inside the base material41. The base material41is formed in such a manner as to support the base portions45of the elongate bodies42which are crystals.

The organic solvent is not particularly limited, and examples of the organic solvent include tetrahydrofuran, acetone, glycerin, ethanol, methanol, dichloromethane, hexane, and ethyl acetate. Among these, preferred are mixed solvents of some of tetrahydrofuran, ethanol, and acetone.

Examples of mixture of organic solvent with water include a mixture of tetrahydrofuran with water, a mixture of tetrahydrofuran and ethanol with water, a mixture of tetrahydrofuran and acetone with water, a mixture of acetone and ethanol with water, and a mixture of tetrahydrofuran and acetone and ethanol with water.

A method of forming crystals of the water-insoluble drug on the outer surface of the balloon30by use of the aforementioned balloon coating apparatus50will be described below.

First, the inflation fluid is supplied into the balloon30through the three-way cock connected to the proximal opening portion27of the balloon catheter10. Next, in a state where the balloon30is inflated, the three-way cock is operated to seal up the inflation lumen23, thereby maintaining the balloon30in the inflated state. The balloon30is inflated with a pressure (e.g., 4 atm) lower than a pressure (e.g., 8 atm) at the time of use in a blood vessel. Note that the coating layer40can also be formed on the outer surface of the balloon30without inflating the balloon30, and, in that case, it is unnecessary to supply the inflation fluid into the balloon30.

Subsequently, in a state in which the dispensing tube94does not make contact with the outer surface of the balloon30, the balloon catheter10is rotatably disposed on the support base70, and the hub26is interlocked with the rotation mechanism section60.

Next, the position of the movable base81is adjusted to position the dispensing tube94in relation to the balloon30. In this instance, the dispensing tube94is positioned to a position on the most distal side on the balloon30where to form the coating layer40. As an example, the extending direction (discharge direction) of the dispensing tube94is opposite to the rotating direction of the balloon30. Therefore, at the position where the dispensing tube94is put in contact with the balloon30, the balloon30is rotated in the direction opposite to the discharge direction in which the coating solution is discharged from the dispensing tube94. By this, a physical stimulus can be given to the coating solution, whereby formation of crystal nuclei of the drug crystal can be promoted. Since the extending direction (discharge direction) of the dispensing tube94toward the opening portion95is opposite to the rotating direction of the balloon30, the crystals of the water-insoluble drug formed on the outer surface of the balloon30are liable to be formed including a morphological form in which the crystals include a plurality of elongate bodies having mutually independent long axes. Note that the extending direction of the dispensing tube94may not necessarily be opposite to the rotating direction of the balloon30, and, hence, may be the same as or perpendicular to the rotating direction.

Subsequently, the coating solution is supplied to the dispensing tube94while adjusting the feed rate by the feed pump93, the balloon catheter10is rotated by the rotation mechanism section60, and the movable base81is moved so that the dispensing tube94is gradually moved proximally along the axial direction of the balloon30. The coating solution discharged from the opening portion95of the dispensing tube94is applied to the outer circumferential surface of the balloon30while drawing a spiral, since the dispensing tube94is moved relative to the balloon30.

The moving speed of the dispensing tube94is not particularly limited, and is, for example, 0.01 mm/second to 2 mm/second, preferably 0.03 mm/second to 1.5 mm/second, and more preferably 0.05 mm/second to 1.0 mm/second. The discharge rate of the coating solution from the dispensing tube94is not particularly limited, and is, for example, 0.01 μL/second to 1.5 μL/second, preferably 0.01 μL/second to 1.0 μL/second, and more preferably 0.03 μL/second to 0.8 μL/second. The rotating speed of the balloon30is not particularly limited, and is, for example, 10 rpm to 300 rpm, preferably 30 rpm to 250 rpm, and more preferably 50 rpm to 200 rpm. The diameter of the balloon30when coated with the coating solution is not particularly limited, and is, for example, 1 mm to 10 mm, preferably 2 mm to 7 mm.

Thereafter, the organic solvent contained in the coating solution applied to the outer surface of the balloon30volatilizes earlier than water. Therefore, the organic solvent volatilizes in a condition where the water-insoluble drug, the water-soluble low-molecular compound and water are left on the outer surface of the balloon30. When the organic solvent thus volatilizes with water left in the coating, the water-insoluble drug is precipitated inside the water-soluble low-molecular compound that contains water, and crystals gradually grow from crystal nuclei, so that drug crystals of a morphological form in which the crystals include a plurality of elongate bodies42having mutually independent long axes are formed on the outer surface of the balloon30. The base portions45of the elongate bodies42may be located on the outer surface of the balloon30, on the outer surface of the base material41, or in the inside of the base material41(seeFIG. 4). After the organic solvent has volatilized and the drug crystals are precipitated as the plurality of elongate bodies42, water evaporates more slowly than the organic solvent, and the base material41including the water-soluble low-molecular compound is formed. The time taken for evaporation of water is appropriately set in accordance with the kind of the drug, the kind of the water-soluble low-molecular compound, the kind of the organic solvent, the ratios of the amounts of the materials, the coating amount of the coating solution, and the like, and is, for example, approximately 1 seconds to 600 seconds.

Then, while rotating the balloon30, the dispensing tube94is gradually moved in the axial direction of the balloon30, whereby the coating layer40is gradually formed on the outer surface of the balloon30along the axial direction of the balloon30. After the coating layer40is formed over the whole range of coating for the balloon30, operations of the rotation mechanism section60, the movement mechanism section80and the application mechanism section90are stopped.

Thereafter, the balloon catheter10is removed from the balloon coating apparatus50, to complete the coating of the balloon30.

Now, the balloon folding apparatus100will be described below. The balloon folding apparatus100is an apparatus capable of folding the balloon30in the manner of winding around the inner tube22.

As depicted inFIG. 9, the balloon folding apparatus100has a pleating section120, a folding section130and a support base140which are disposed on a base110formed in a base shape. The pleating section120is capable of forming the balloon30with wing portions32projecting in radial directions. The folding section130is capable of folding the wing portions32formed in the balloon30, in the manner of lying flat in the circumferential direction. The support base140is capable of mounting and holding the balloon catheter10thereon. The wing portions32formed in the balloon30are formed by pleats extending substantially in an axial direction of the balloon30, such that the pleats project in the circumferential direction from a long axis of the balloon30when viewed in a section perpendicular to the axis of the balloon30. The length in the long axis direction of the wing portions32does not exceed the length of the balloon30. The length of the wing portions32in the direction of projecting in the circumferential direction of the catheter main body20is 1 to 8 mm. The number of the wing portions32is not particularly limited, it can be selected from among the numbers of two to seven, and it is three in the present embodiment.

On the base110, a film supply section150that supplies a first film155and a second film156to the pleating section120is disposed adjacently to the pleating section120. In addition, on the base110, a film supply section180that supplies a first film181and a second film182to the folding section130is disposed adjacently to the folding section130.

The pleating section120has a front surface plate121perpendicular to the base110, and the front surface plate121has an insertion hole121ainto which a distal portion of the balloon catheter10can be inserted. In addition, the folding section130has a front surface plate131perpendicular to the base110, and the front surface plate131has an insertion hole131ainto which the distal portion of the balloon catheter10can be inserted. The front surface plate131of the folding section130faces in a direction different by a predetermined angle from the direction in which the front surface plate121of the pleating section120faces.

On that side of the support base140which is remote from the pleating section120and the folding section130, a support shaft111projecting upward from the base110is pivotally mounted. The support base140, by sliding movement on an upper surface of the base110with the support shaft111as a center, can be positioned in a position for facing the front surface plate121of the pleating section120and a position for facing the front surface plate131of the folding section130.

The support base140has a base section141mounted on the base110, and a holding base section142horizontally movable on the base section141. The base section141is slidable on the upper surface of the base110. The holding base section142can be advanced or retracted in relation to (in regard of a direction toward) the pleating section120or the folding section130, by sliding movement on the upper surface of the base section141.

An upper surface of the holding base section142is formed with a groove-shaped mounting section142aon which the catheter main body20of the balloon catheter10can be mounted. In addition, the holding base section142is provided with a holding section143in such a manner as to cover a part of the mounting section142afrom above. The holding section143is capable of fixing by holding the catheter main body20of the balloon catheter10mounted on the mounting section142a. Note that the balloon catheter10may be fixed by other method so long as the balloon catheter10can be fixed.

In a state in which the support base140faces the front surface plate121of the pleating section120, the center of the insertion hole121aformed in the front surface plate121is located on an extension line of the mounting section142aof the holding base section142. Therefore, the balloon catheter10with the catheter main body20mounted on the mounting section142ais inserted into the inside of the pleating section120through the center position of the insertion hole121a. In a state in which the support base140faces the front surface plate131of the folding section130, the center of the insertion hole131aformed in the front surface plate131is located on an extension line of the mounting section142aof the holding base section142. Therefore, the balloon catheter10with the catheter main body20mounted on the mounting section142ais inserted into the inside of the folding section130through the center position of the insertion hole131a, by sliding movement of the holding base section142on the base section141.

Now, the structure of the pleating section120will be described below. As depicted inFIG. 10, the pleating section120has three blades122(wing-forming members) in the inside of the pleating section120. Each of the blades122is a plate-shaped member formed to have an equal sectional shape at positions along the axial direction of the balloon catheter10inserted. The blades122are disposed at mutual angles of 120 degrees, with the center position of insertion of the balloon30as a reference. In other words, the blades122are disposed at regular angular intervals along the circumferential direction. The blade122has a rotary movement center portion122anear its outer circumferential end, and can be moved rotationally around the rotary movement center portion122a. In addition, the blade122has a moving pin122dextending in the axial direction, on the inner circumference side relative to the rotary movement center portion122a. The moving pin122dis fitted in a fitting groove124aformed in a rotary member124which is rotatable inside the pleating section120. The rotary member124is interlocked with a beam section126extending substantially horizontally. The rotary member124can be moved rotationally by receiving a rotating force from the beam section126which is inclined by receiving a force from a drive source125such as a hydraulic cylinder or a motor. When the rotary member124is rotated, the moving pins122dfitted in the fitting grooves124aare moved in the circumferential direction, whereby each of the blades122is moved rotationally around the rotary movement center portion122aof the rotary member124. With the three blades122moved rotationally, a space region in a central area surrounded by the blades122can be narrowed. Note that the number of the blades122is not particularly limited so long as it is not less than two.

The blade122has a first shape forming portion122band a second shape forming portion122c, which are substantially arcuate in shape, at its inner circumferential end portions on the side opposite to the rotary movement center portion122a. As the blade122is moved rotationally, the first shape forming portion122bcomes into contact with a surface of the balloon30inserted in the pleating section120, whereby the balloon30can be formed with the wing portion32projecting in a radial direction. As the blade122is rotated, the second shape forming portion122ccomes into contact with the wing portion formed in the balloon30, whereby the wing portion32can be curved in a predetermined direction. In addition, the pleating section120has a heater (not depicted) for heating the blades122. The length of the blade122along the axial direction of the balloon catheter10is greater than the length of the balloon30. In addition, the lengths of the first shape forming portion122band the second shape forming portion122cof the blade122may range or may not range over the whole length of the blade122.

The blades122are supplied from the film supply section150with the first film155and the second film156which are made of resin. For guiding each of the films, a plurality of rotary shaft portions123are provided in the pleating section120. The first film155is passed from a first film holding section151and through the rotary shaft section123, to be engaged on a surface of the blade122disposed at an upper portion. In addition, the first film155is passed from the blade122and through the rotary shaft section123, to reach a film take-up section153which is rotationally driven by a drive source such as a motor not depicted. The second film156is passed from a second film holding section152and through the rotary shaft section123, to be engaged on the two blades122disposed at lower portions. In addition, the second film156is passed through the rotary shaft section123, to reach the film take-up section153. By these, a state is established in which the center position of the pleating section120in which the balloon30is inserted and passed is surrounded by the first film155and the second film156.

The first film155and the second film156have a function of protecting the balloon30by preventing the balloon30from making direct contact with the surfaces of the blades122when the balloon30is inserted into the pleating section120and the blades122are moved rotationally to form the balloon30with the wing portions32. After the wing portions32of the balloon30are formed, the first film155and the second film156are taken up onto the film take-up section153by a predetermined length. In other words, those portions of the first film155and the second film156which have once made contact with the balloon30do not make contact with the balloon30again, and, each time the balloon30is inserted, new portions of the films are supplied to the center position of the pleating section120.

As depicted inFIG. 11, in a state before the insertion of the balloon30, the first shape forming portions122band the second shape forming portions122cof the three blades122are spaced from one another. A central region among the blades122is surrounded by the first shape forming portions122bwhich are substantially arcuate in shape, and the balloon30before folded can be inserted in a central region among the blades122.

Now, the structure of the folding section130will be described below. As depicted inFIG. 12, the folding section130has ten blades132(wing-folding members) in the inside of the folding section130. Each of the blades132is a plate-shaped member formed to have an equal sectional shape at positions along the axial direction of the balloon catheter10inserted. The blades132are disposed at mutual angles of 36 degrees, with the center position of insertion of the balloon30as a reference. In other words, the blades132are disposed at regular angular intervals along the circumferential direction. The blade132has a rotary movement center portion132anear its center, and can be moved rotationally around the rotary movement center portion132a. In addition, each blade132has a moving pin132cextending in the axial direction, near its outer circumferential end. The moving pin132cis fitted in a fitting groove133aformed in a rotary member133which is rotatable inside the folding section130. The rotary member133is interlocked with a beam135extending substantially horizontally. The rotary member133can be moved rotationally by receiving a rotating force from the beam135which is inclined by receiving a force from a drive source134such as a hydraulic cylinder or a motor. When the rotary member133is rotated, the moving pins132cfitted in the fitting grooves133aare moved in the circumferential direction, whereby each of the blades132is moved rotationally around the rotary movement center portion132aof the rotary member133. With the ten blades132moved rotationally, a space region in a central area surrounded by the blades132can be narrowed. Note that the number of the blades132is not limited to ten.

The blade132is bent on a tip side, and its tip portion132bis sharp in shape. As the blades132are moved rotationally, the tip portions132bcome into contact with the surface of the balloon30inserted into the folding section130, whereby the wing portions32formed in the balloon30can be folded in the manner of lying flat in the circumferential direction. In addition, the folding section130has a heater (not depicted) for heating the blades132.

The blades132are supplied from the film supply section180with the first film181and the second film182which are made of resin. A supplying structure for each film is the same as that in the case of the pleating section120. The first film181and the second film182are disposed to face each other such that a central space region surrounded by the blades132is interposed between the first film181and the second film182. By the first film181and the second film182, the balloon30inserted in the folding section130can be prevented from making direct contact with the surfaces of the blades132. The first film181and the second film182are passed through the blades132, to reach a film take-up section183which is rotationally driven by a drive source such as a motor not depicted.

As depicted inFIG. 13, in a state before insertion of the balloon30, the tip portions132bof the blades132are in the state of being spaced from one another in the circumferential direction. In a central region which is surrounded by the blades132and is located between the first film181and the second film182, the balloon30formed with the wing portions32can be inserted.

Now, a method of folding the balloon30formed on its outer surface with crystals of a drug by the balloon coating apparatus50, by use of the balloon folding apparatus100, will be described below.

First, for forming the balloon30with the wing portions32, the catheter main body20is mounted on the mounting section142aof the support base140and is held by the holding section143. An inflation fluid is injected into the balloon30through the three-way cock (i.e., three-way value) attached to the hub26, the hub26and the inner tube22, whereby the balloon30is put into a state of being inflated to a certain extent. In addition, the blades122in the pleating section120are heated. The core member61is inserted in the guide wire lumen24. By the core member61, the catheter main body20is restrained from flexure due to the weight of the catheter main body20.

Next, as depicted inFIG. 14, the holding base section142is moved sliding on the base section141, to insert the balloon catheter10into the pleating section120through the insertion hole121a.

Subsequently, the drive source125is operated to rotate the rotary member124(seeFIG. 12), whereon as depicted inFIG. 15, the blades122are moved rotationally, and the first shape forming portions122bof the blades122approach one another, so that the central region among the blades122is narrowed. Attendant on this, the balloon30inserted in the central region among the blades122is pressed against the inner tube22by the first shape forming portions122b. That portion of the balloon30which is not pressed by the first shape forming portion122bis pushed out into a gap between a tip portion of one blade122and the second shape forming portion122cof the blade122adjacent to the one blade122, whereby the wing portion32curved to one side is formed. Since the balloon30is heated to approximately 50 degrees to 60 degrees by the blades122, the wing portions32thus formed can maintain their shapes. In this way, the balloon30is formed with three wing portions32along the circumferential direction.

In this instance, those surfaces of each blade122which make contact with the balloon30are covered by the first film155and the second film156, so that the balloon30does not make direct contact with the surfaces of the blades122. After the balloon30is formed with the wing portions32, the blades122are moved rotationally in the manner of returning into their original positions, and the balloon30is withdrawn out of the pleating section120. Note that since the internal volume of the balloon30is reduced in the process of pleating, it is preferable to regulate the three-way cock according to the volume reduction, to discharge the inflation fluid to the outside, thereby deflating the balloon30. By this, an excessive force can be restrained (or prevented) from acting on the balloon30.

As depicted inFIG. 18A, the balloon30has a substantially circular sectional shape in a state in which the inflation fluid has been injected into the balloon30. By being formed with the projecting wing portions32, starting from this state, the balloon30is formed with: wing outer portions34athat have been pressed by the second shape forming portions122cand constitute outside surfaces of the wing portions32; wing inner portions34bthat are pressed by tip portions of the blades122and constitute inside surfaces of the wing portions32; and intermediate portions34cthat have been pressed by the first shape forming portions122band are located between the coating layer wing outer portions34aand the wing inner portions34b, as depicted inFIGS. 15 and 18B. Note that in the process of pleating, the balloon30is pressed by the blades122while deflating the balloon30for forming the wing portions32, and, therefore, there is no need for strong pressing forces by the blades122. Accordingly, even when the balloon30is pressed by the blades122, the structure of the crystals formed on the surface of the balloon30is changed relatively little.

Next, the holding base section142is moved on the upper surface of the base section141to be spaced from the pleating section120, and the balloon catheter10is withdrawn out of the pleating section120. Subsequently, the support base140is moved sliding on the upper surface of the base110, whereby the support base140is positioned at a position for facing the front surface plate131of the folding section130. Thereafter, the holding base section142is moved on the upper surface of the base section141, whereby the balloon catheter10is inserted into the folding section130through the insertion hole131a, as depicted inFIG. 16. The blades132in the folding section130have already been heated to approximately 50 to 60 degrees.

After the balloon30formed with the wing portions32is inserted into the folding section130, the drive source134is operated to rotate the rotary member133, as depicted inFIG. 17, whereon the blades132are moved rotationally, and the tip portions132bof the blades132approach one another, so that a central region among the blades132is narrowed. Attendant on this, the balloon30inserted in the central region among the blades132is put into a state in which the wing portions32are laid flat in the circumferential direction by the tip portions132bof the blades132. Since the blades132have been preliminarily heated before insertion of the balloon30and the balloon30is heated by the blades132, the wing portions32laid flat in the circumferential direction by the blades132can maintain their shapes. In this instance, those surfaces of each blade132which make contact with the balloon30are covered by the first film181and the second film182, so that the balloon30does not make direct contact with the surfaces of the blades132.

When the wing portions32of the balloon30are folded, the wing inner portions34band the intermediate portions34care laid on each other and make contact with each other, to form overlapping portions35in which portions of the outer surface of the balloon30face each other and overlap with each other, as depicted inFIGS. 17 and 18C. In addition, part of the intermediate portion34cand the wing outer portion34aare not covered by the wing inner portion34b, but are exposed to the outside. In addition, in the state in which the balloon30is folded, a root-side space portion36is formed between a root portion of the wing portion32and the intermediate portion34c. In the region of the root-side space portion36, a minute gap is formed between the wing portion32and the intermediate portion34c. On the other hand, that region of the wing portion32which is located on the tip side relative to the root-side space portion36is in the state of being in close contact with the intermediate portion34c. The proportion of the circumferential length of the root-side space portion36to the circumferential length of the wing portion32is in the range from 1% to 95%. The wing outer portions34aof the balloon30receive pressing forces in the manner of rubbing in the circumferential direction from the first film181and the second film182both pressed by the blades132, thereby being heated further. As a result of this, the elongate bodies42provided on the wing outer portions34ahave their long axes inclined relative to the outer surface of the balloon30. Consequently, the base material41is formed with the base material deformed portions46, and the balloon30is formed with the balloon deformed portions36(seeFIGS. 3 to 5). Part of the elongate bodies42may be broken and thereby separated.

In addition, since the portions of the outer surface of the balloon30that overlap with each other at the overlapping portions35are not exposed to the outside, the pressing forces from the blades132act on the portions of the outer surface of the balloon30that overlap with each other at the overlapping portions35indirectly. Therefore, the forces acting on the elongate bodies42provided on the portions of the outer surface of the balloon30that overlap with each other at the overlapping portions35can be easily controlled such as not to become excessively strong. Accordingly, desirable forces for inclining the elongate bodies42relative to the outer surface of the balloon30can be made to act on the elongate bodies42provided on the portions of the outer surface of the balloon30that overlap with each other at the overlapping portions35. For this reason, the portions of the outer surface of the balloon30that overlap with each other at the overlapping portions35can be formed with desirable base material deformed portions46and desirable balloon deformed portions36, in such a manner that the angles of the long axes of the elongate bodies42relative to the balloon30approach perpendicularity when the balloon30is inflated. There is the possibility that the base material deformed portions46and the balloon deformed portions36may have residual stress left in the inside of the base material deformed portions46and the balloon deformed portions36. In addition, in those regions of the wing inner portions34band the intermediate portions34cfacing each other which face the root-side space portion36, namely, in the regions where the wing inner portion34band the intermediate portion34care not in close contact with each other, the elongate bodies42hardly receive pressing forces. In the regions where the wing inner portion34band the intermediate portion34care not in close contact with each other, therefore, the elongate bodies42are hardly inclined, and desirable base material deformed portions46and desirable balloon deformed portions36are hardly formed. In addition, in those regions of the wing inner portions34band the intermediate portions34cfacing each other which do not face the root-side space portion36, namely, in the regions where the wing inner portion34band the intermediate portion34care in close contact with each other, the elongate bodies42are liable to receive pressing forces. In the regions where the wing inner portion34band the intermediate portion34care in close contact with each other, therefore, the elongate bodies42are liable to be inclined, and desirable base material deformed portions46and desirable balloon deformed portions36are liable to be formed. Note that part of the elongate bodies42may be broken, and thereby separated, at the overlapping portions35. The elongate bodies42in a state of having their long axes along the outer surface of the balloon30are sandwiched between portions of the outer surface of the balloon30at the overlapping portions35, and, therefore, this state is maintained favorably.

After the wing portions32of the balloon30are folded, the blades132are moved rotationally in the manner of returning into their original positions. Next, the balloon30is withdrawn out of the folding section130. Subsequently, the holding of the catheter main body20by the holding section143is released, the balloon30is covered by the tubular protective sheath15(seeFIG. 1), and the folding of the balloon30of the balloon catheter10is completed. The protective sheath15is a member for restraining the drug from falling off the balloon30, and it is removed before the balloon catheter10is put to use.

A method of using the balloon catheter10according to the present embodiment will be described below, taking as an example a case of treating a stenosed part in a blood vessel.

First, by a known method such as a Seldinger method, the operator percutaneously punctures a blood vessel and places an introducer (not depicted) indwelling. Next, the protective sheath15of the balloon catheter10is removed, priming is performed, and thereafter a guide wire200(seeFIG. 19) is inserted into the guide wire lumen24. In this state, the guide wire200and the balloon catheter10are inserted into the blood vessel through the inside of the introducer. Subsequently, the balloon catheter10is moved forward, with the guide wire200preceding, and the balloon30is delivered to a stenosed part. Note that a guiding catheter may be used for delivering the balloon catheter10to the stenosed part300.

When the balloon30is moved within a blood vessel, the overlapping portions35where portions of the outer surface of the balloon30overlap with each other are not liable (i.e., not likely) to make contact with the blood. Further, the elongate bodies42having their long axes inclined relative to the outer surface of the balloon30are not liable (i.e., not likely) to flow even when exposed to the blood, as compared to the case where their long axes are perpendicular to the outer surface. For this reason, the elongate bodies42which are drug crystals located at the overlapping portions35are not exposed to the blood, or are restrained from flowing out into the blood even if exposed to the blood, so that they are effectively delivered to the target position.

After the balloon30is disposed at the stenosed part300, a predetermined quantity of the inflation fluid is injected into the inside of the balloon30from the proximal opening portion27of the hub26through the inflation lumen23by use of an indeflator or a syringe. By this, as depicted inFIG. 19, the folded balloon30is inflated, and the balloon30and the base material41are stretched in the circumferential direction (seeFIG. 6). As a result, the balloon deformed portions36and the base material deformed portions46are stretched to return into original smooth shapes, and the long axes of the elongate bodies42approach perpendicularity to the outer surface of the balloon30. In addition, the elongate bodies42located at the portions of the outer surface of the balloon30that overlap with each other at the overlapping portions35are relieved from the pressing forces exerted from the overlapping balloon30; therefore, restoring forces of the balloon deformed portions36and the base material deformed portions46also act on the elongate bodies42, so that the long axes of the elongate bodies42approach perpendicularity to the outer surface of the balloon30. Note that part of the elongate bodies42may be broken and thereby separated, due to the inflation of the balloon30. The elongate bodies42thus broken become easily movable, so that deliverability of the drug is relatively enhanced. In addition, the inflation of the balloon30results in that the stenosed part300is pushed wide open (i.e., widened) by the balloon30. In this instance, the coating layer40provided on the outer surface of the balloon30and including the drug crystals makes contact with the stenosed part300. The elongate bodies42which are drug crystals included in the coating layer40have long axes nearly perpendicular to the outer surface of the balloon30, and, therefore, they are liable (i.e., likely) to pierce the living body tissue. For this reason, the drug is effectively delivered from the outer surface of the balloon30to the stenosed part300. Consequently, restenosis at the stenosed part300is restrained effectively.

When the balloon30is inflated to press the coating layer40against the living body tissue, the base material41which is the water-soluble low-molecular compound included in the coating layer40is dissolved gradually or rapidly, and during when the dissolution proceeds, the drug is delivered to the living body. The elongate bodies42a,42band42cwhich are crystals of the drug are different in the position of their base portions45relative to the base material41, and, therefore, they differ in deliverability to the living body tissue, as the base material41is dissolved gradually or rapidly. In addition, the inflation of the balloon30causes the base material41to be cracked and become easily soluble, so that the elongate bodies42which are the drug crystals become easily releasable from the base material41. For this reason, by controlling the positions of the base portions45of the elongate bodies42so as to provide the elongate bodies42a,42band42cthat are different in dissolution property, it is possible to set the deliverability of the drug.

Thereafter, the inflation fluid is sucked and discharged through the proximal opening portion27of the hub26, whereby the balloon30is deflated and put into the folded state. Thereafter, the guide wire200and the balloon catheter10are withdrawn from the blood vessel through the introducer, to finish the procedure.

As has been described above, the balloon catheter10according to the present embodiment is a balloon catheter10provided on an outer surface of a balloon30with a plurality of elongate bodies42which are independent crystals of a water-insoluble drug that extend in an elongate form. The elongate bodies42have long axes extending in a direction along the outer surface of the balloon30when the balloon30is in a deflated state, and deformation, when the balloon30is inflated from the deflated state, of portions (the balloon30or a base material41) on an outer surface side of the balloon30to which end portions of the elongate bodies42are fixed causes a force to act on the elongate bodies42such that the long axes of the elongate bodies42approach perpendicularity to the outer surface of the balloon30. In the balloon catheter10configured in this way, inflation of the balloon30causes the long axes of the elongate bodies42to approach perpendicularity to the outer surface of the balloon30, so that the elongate bodies42become liable (or likely) to pierce living body tissue, which results in that releasing property of the drug from the outer surface of the balloon30and transferability of the drug to the living body tissue can be enhanced, and the drug can be effectively delivered to the living body tissue.

In addition, until the balloon30is inflated, the elongate bodies42are maintained in the state of extending along the outer surface of the balloon30, so that the drug crystals can be restrained from peeling off the outer surface of the balloon30due to frictional force or flowing out due to blood stream during when the balloon30is carried within a blood vessel. In addition, crystals formed in the manner of lying flat on the outer surface of the balloon30from the beginning are firmly attached (fixed) to the outer surface of the balloon30and/or the adjacent crystal particles. In the present embodiment, on the other hand, the crystal particles standing on the outer surface of the balloon30are utilized and are laid flat along the outer surface of the balloon30. Therefore, the elongate bodies42are not formed to be physically fixed to the outer surface of the balloon30or the adjacent crystal particles, notwithstanding they extend along the outer surface of the balloon30. For this reason, while the elongate bodies42being small in crystal unit size and high in transferability to the living body tissue can be maintained in the state of lying flat on the outer surface of the balloon30until the balloon30is inflated, inflation of the balloon30can cause the elongate bodies42to stand such as to approach perpendicularity to the outer surface of the balloon30.

In addition, the balloon30has the overlapping portions35where portions of the outer surface of the balloon30overlap with each other when the balloon30is folded in the deflated state, and the elongate bodies42are provided on the portions of the outer surface of the balloon30that overlap with each other at the overlapping portions35. As a result, the elongate bodies42are not exposed to the outside in the deflated state of the balloon30, so that the elongate bodies42can be protected until the balloon30is delivered to the target position. Therefore, the drug can be restrained from peeling off the outer surface of the balloon30or flowing out into blood stream during delivery, and the drug can be effectively delivered to the living body tissue.

In addition, the water-insoluble drug may be rapamycin, paclitaxel, docetaxel, or everolimus, which helps ensure that restenosis at a stenosed part in a blood vessel can be favorably restrained (or prevented) by the elongate bodies42.

In addition, the method of manufacturing the balloon catheter10according to the present embodiment is a method of manufacturing a balloon catheter10provided on an outer surface of a balloon30with a plurality of elongate bodies42which are crystals of a water-insoluble drug that extend while having independent long axes, the method including: a step of forming the elongate bodies42on the outer surface of the balloon30; a step of forming the balloon30with a wing portion32projecting in a radial direction; and a step of folding the wing portion32, formed in the balloon30, along a circumferential direction. In at least one of the step of forming the wing portion32and the step of folding the wing portion32, portions on an outer surface side of the balloon30to which end portions of the elongate bodies42are fixed are deformed by a force exerted for deforming the balloon30, whereby the long axes of the elongate bodies42are inclined into a direction along the outer surface of the balloon30. According to the method of manufacturing the balloon catheter10, the elongate bodies42fixed to the portions on the outer surface side of the balloon30can be efficiently inclined by utilizing the force exerted on the balloon30in the step of forming the balloon30with the wing portion32or the step of folding the wing portion32.

In addition, in the step of folding the wing portion32, the overlapping portions35where portions of the outer surface of the balloon30face each other and overlap with each other may be formed, and the long axes of the elongate bodies42provided on the portions of the outer surface that face each other at the overlapping portions35may be inclined into a direction along the outer surface of the balloon30, which results in that the force exerted on the balloon30for folding the wing portion32acts on the overlapping portions35indirectly, so that the force acting on the elongate bodies42can be controlled, and a desirable force for inclining the elongate bodies42can be easily exerted. In other words, the outer surface of the balloon30where the overlapping portions35are located can take not only a state in which an external force acts but also a state in which an external force hardly acts. For this reason, the elongate bodies42standing such as to approach perpendicularity to the outer surface of the balloon30can be efficiently formed by inflation of the balloon30.

In addition, the present disclosure also includes a treatment (therapeutic) method of delivering a drug to a lesion affected area in a body lumen by use of the aforementioned balloon catheter10. The treatment method includes: a step of inserting the balloon30into the body lumen to deliver the balloon30to the lesion affected area; a step of inflating the balloon30to cause the elongate bodies42to be erected at such an angle as to approach perpendicularity to the outer surface of the balloon30; a step of pressing the erected elongate bodies42against living body tissue; and a step of deflating the balloon30and withdrawing the balloon30out of the body lumen. According to the treatment method configured in this way, the inflation of the balloon30causes the long axes of the elongate bodies42which are crystals of a water-insoluble drug to approach perpendicularity to the outer surface of the balloon30, so that the elongate bodies42become liable to pierce the living body tissue. As a result, releasing property of the drug from the outer surface of the balloon30and transferability of the drug to the living body tissue can be enhanced, and the drug can be effectively delivered to the living body tissue.

Note that the present disclosure is not limited only to the aforementioned embodiment, and various modifications can be made by those skilled in the art within the technical thought of the disclosure. For example, while the balloon catheter10according to the above embodiment is of the rapid exchange type, the balloon catheter may be of the over-the-wire type.

In addition, while the long axes of the elongate bodies42formed on the outer surface of the balloon30are inclined in the process of folding of the balloon30in the present embodiment, the elongate bodies42may be inclined relative to the outer surface of the balloon30by pressing by the blades122in the process of pleating (seeFIG. 15).

As aforementioned, the base material41is present as an amorphous phase, crystal particles, or a mixture of the amorphous phase and the crystal particles. While the base material41inFIG. 4is in a state of crystal particles and/or a particulate amorphous phase, the base material41may be in a film-shaped amorphous state, as depicted inFIG. 20. As depicted inFIG. 22, first elongate bodies42aextend from the outer surface of the base material41toward the outside of the surface. As depicted inFIG. 23, second elongate bodies42bextend from the outer surface of the balloon30to the outside of the base material41by penetrating the base material41. As depicted inFIG. 24, third elongate bodies42cextend from the inside of the base material41to the outside of the base material41.

In addition, while a tip end of the wing portion32of the folded balloon30does not reach the adjacent wing portion32in the present embodiment, the tip end of the wing portion32may reach the adjacent wing portion32, as in two examples depicted inFIG. 21. In the example ofFIG. 21A, a root-side space portion36is formed between the root side of the wing portion32and the intermediate portion34c, and a tip-side space portion37is formed between the tip side of the wing portion32and the intermediate portion34c. In this case, in those regions of the wing inner portions34band the intermediate portions34cwhich face the root-side space portion36and the tip-side space portion37, namely, in the regions where the wing inner portion34band the intermediate portion34cdo not make close contact with each other, the elongate bodies42hardly receive pressing forces. In the regions where the wing inner portion34band the intermediate portion34cdo not make close contact with each other, therefore, the elongate bodies42are hardly inclined, and desirable base material deformed portions46and desirable balloon deformed portions36are hardly formed. In addition, in those regions of the wing inner portions34band the intermediate portions34cwhich do not face the root-side space portion36or the tip-side space portion37, namely, in the regions where the wing inner portion34band the intermediate portion34care in close contact with each other, the elongate bodies42are liable to receive pressing forces. In these regions, therefore, the elongate bodies42are liable to be inclined, and desirable base material deformed portions46and desirable balloon deformed portions36are liable to be formed.

In the example ofFIG. 21B, a space portion38is formed between wing portion32and the intermediate portion34c, throughout the region ranging from the root side of the wing portion32to the adjacent wing portion32. In this case, the elongate bodies42hardly receive pressing forces, in the whole of the regions of the wing inner portion34band the intermediate portion34cwhich face each other. In the regions where the wing inner portion34band the intermediate portion34cwhich face each other, therefore, the elongate bodies42are hardly inclined, and desirable base material deformed portions46and desirable balloon deformed portions36are hardly formed.

In addition, the balloon folding apparatus100also may not be used for folding the balloon30.

In addition, the base material which is the excipient may not be provided in the coating layer on the outer surface of the balloon30.

In addition, as depicted inFIG. 25, the base material41which is an additive layer may have projections and recesses (ruggedness). The height of the projections is 0.1 μm to 5 μm. The elongate bodies42which are crystals are projecting from projecting portions43that constitute the projections of the base material41. In other words, the elongate bodies42which are crystals are supported by the projecting portions43of the base material41. Note that the base material41may have the projecting portions43from which the elongate bodies42are not projecting. The elongate bodies42which are crystals may project from recessed portions47that constitute the recesses of the base material41. The base material41may have both the projecting portions43which support the elongate bodies42and the projecting portions43which do not support the elongate bodies42. The base material41may have both the recessed portions47which support the elongate bodies42and the recessed portions47which do not support the elongate bodies42. In addition, the base material41may have both the projecting portions43which support the elongate bodies42and the recessed portions47which support the elongate bodies42. The base material41may have both the elongate bodies42which are substantially perpendicular to the outer surface of the balloon30and the elongate bodies42which are inclined relative to the outer surface of the balloon30. The base portions45of the elongate bodies42may be in direct contact with the outer surface of the balloon30. Alternatively, the base portions45of the elongate bodies42may be located in the inside of the base material41, without making contact with the outer surface of the balloon30. The base material41may have both the elongate bodies42which are in direct contact with the outer surface of the balloon30and the elongate bodies42which are not in contact with the outer surface of the balloon30.

In addition, as depicted inFIG. 26, the crystals may include fixed-side elongate bodies48(balloon base material contact crystal particles) originally projecting from the base material41, and separate-side elongate bodies49(balloon base material non-contact crystal particles) separated from the fixed-side elongate bodies48. The amount of the fixed-side elongate bodies48is larger than that of the separate-side elongate bodies49. The separate-side elongate bodies49are formed by breaking of elongate crystals and separation from the fixed-side elongate bodies48when the balloon30is folded in the manner of winding around the inner tube22. At least part of a distal portion, a proximal portion, and a portion between the distal portion and the proximal portion, of the separate-side elongate body49, is in contact with the base material41. Part of the separate-side elongate body49may be embedded in the base material41. The presence of the base material41helps ensure that the fixed-side elongate bodies48and the separate-side elongate bodies49are not liable to fall off (i.e., be removed from) the balloon30during carrying, because of their interactions with the base material41. The fixed-side elongate bodies48and the separate-side elongate bodies49become liable to be released through dissolution of the base material41upon contact with water (blood) when the balloon30is inflated. The fixed-side elongate bodies48and the separate-side elongate bodies49differing in morphological form are different in releasing property, which is preferable from the viewpoint of their action on the living body. The fixed-side elongate bodies48may be formed through breaking of crystals, or may be formed without breaking of crystals. The base material41may include both the fixed-side elongate bodies48formed through breaking of crystals, and the fixed-side elongate bodies48formed without breaking of crystals. The fixed-side elongate bodies48may be standing from the base material41, or may be lying flat along the base material41. The base material41may have both the fixed-side elongate bodies48standing from the base material41, and the fixed-side elongate bodies48lying flat along the base material41.

The length of the crystals fixed to the base material41, before breaking of the crystals fixed to the base material41, is 5 μm to 20 μm, for example. The length of the broken crystals is, for example, 3 μm to 20 μm. The length of the fixed-side elongate bodies48formed through breaking is, for example, 5 μm to 20 μm. The length of the separate-side elongate bodies49is, for example, 3 μm to 10 μm.

The detailed description above describes a balloon catheter having a balloon coated on its surface with a drug, a method of manufacturing the balloon catheter, and a treatment method. The invention is not limited, however, to the precise embodiments and variations described. Various changes, modifications and equivalents can be effected by one skilled in the art without departing from the spirit and scope of the invention as defined in the accompanying claims. It is expressly intended that all such changes, modifications and equivalents which fall within the scope of the claims are embraced by the claims.