Lubricating inserts and methods of use for medical devices

Abstract

To provide insertion tools and articles that facilitate entry of a medical device, such as a balloon catheter, into the body, and that can provide advantages in terms of balloon insertion, safety and drug delivery.SOLUTION: An insertion tool includes (i) a tubular portion that accommodates a balloon portion of a balloon catheter, and (ii) one or more separation margins in the wall of the tubular portion or one or more splits in the tubular wall. In addition, the insertion tool includes (i) a proximal tab extending from a second lengthwise half and having a portion obliquely intersecting the lengthwise axis, or (ii) a proximal tab that is in the form of a solid article comprising a concave surface and is fastened to an outer surface of the second lengthwise half of the tubular portion. Alternatively, the insertion tool includes first and second tabs that extend respectively from first and second lengthwise halves of the tubular portion.SELECTED DRAWING: Figure 12

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This regular patent application claims the rights of U.S. Provisional Application No. 62 / 395,610 (filed on September 16, 2016, with the title "LUBRICIOUS INSERTION TOOLS FOR MEDICAL DEVICES AND METHODS FOR USING") and U.S. Provisional Application No. 62 / 464,520 (filed on February 28, 2017, with the title "LUBRICIOUS INSERTION TOOLS FOR MEDICAL DEVICES AND METHODS FOR USING"), which are shared with the applicant. The entire contents of the above - mentioned U.S. provisional applications are incorporated herein by reference.

[0002] [Technical Field] The present disclosure relates to insertion tools that facilitate the insertion of medical devices into the vasculature of the body.

Background Art

[0003] Atherosclerosis is a disease that affects the arteries of the body, often the coronary arteries. When this disease occurs in the arteries of the legs (arteries above or below the knee), it is usually referred to as peripheral artery disease (PAD). When atherosclerosis develops, changes in the arterial wall characterized by an increase in cholesterol content and an increase in scar tissue are seen. Subsequently, atherosclerotic plaques accumulate, thickening the arterial wall, and generally, lesions are formed that cause narrowing or stenosis of the artery. As a result, blood flow decreases. In these later stages, calcium may be present in the plaques.

[0004] Generally, it is desirable to treat patients with plaque findings. This is because the presence of plaque, regardless of whether it obstructs blood flow, carries a risk of rupture leading to coronary events. Ruptured plaque can activate the formation of local blood clots, which can block blood flow. If this occurs in the coronary arteries, it can cause a myocardial infarction. If it occurs in peripheral blood vessels, it can cause severe pain. Furthermore, if it occurs in multiple blood vessels, it can lead to severe limb ischemia. [Overview of the project]

[0005] This specification describes inserts for medical devices introduced into the vascular system, which can be used for the treatment of arterial diseases (such as atherosclerotic plaques). The inserts can be used to house and protect implantable or insertable medical devices when storing and positioning them. The inserts can also be used to protect and facilitate the insertion of medical devices (such as balloon catheters). The inserts may facilitate the insertion of a balloon catheter into the patient's catheter lumen through a hemostatic valve. The inserts can also protect the surface of the balloon component of the balloon while the balloon is loaded. The inserts can prevent contamination of the device and / or minimize (or prevent) damage to the coating of the balloon catheter during insertion into the body.

[0006] The insertion device of this disclosure can also be used to prevent contact between healthcare professionals and drug coatings applied to medical devices that are inserted into the human body. Furthermore, the insertion device can also protect moisture-sensitive drug coatings and prevent accidental contact between the drug coating and fluids before insertion into the body of a mammal.

[0007] The above-mentioned insert is part of a kit or system used in a medical procedure. Such a kit or system is also an embodiment of the present invention. For example, the above kit may include one or more of the following components: one or more delivery catheters, balloon treatment devices, inflatable catheters, guidewires, hemostatic valves, or a combination thereof.

[0008] In one embodiment, the present invention provides an inserter configured to facilitate the entry of the balloon portion of a balloon catheter into the patient's body via a hemostatic valve. The inserter comprises: a proximal end and a distal end along the longitudinal axis; a tubular portion extending proximal from the distal end and having a length equal to or greater than the length of the balloon portion; and a knob at the proximal end. The tubular portion comprises: a wall; an inner diameter capable of accommodating the balloon portion of the balloon catheter; and a separation margin in the wall of the first longitudinal half of the tubular portion, which (i) represents a structural weakness in the wall of the first half, or (ii) represents a division in the wall of the first half. The knob at the proximal end is (a) a knob extending from the second longitudinal half of the tubular portion and having a portion that is oblique to the longitudinal axis, or (b) a knob in the form of a solid object having a concave surface and fixed to the outer surface of the second longitudinal half of the tubular portion.

[0009] The present invention also provides a balloon catheter insertion system. This system comprises (i) a balloon catheter having a balloon portion having a certain length, (ii) a hemostatic valve, and (iii) an insertion device (as described herein) that facilitates the balloon portion of the balloon catheter entering the patient's body via the hemostatic valve.

[0010] The present invention also provides a method for inserting a balloon catheter into a patient's body. The method includes the steps of: (a) providing a balloon catheter comprising a balloon portion having a certain length and a catheter shaft adjacent to the balloon portion; and (ii) an insertion device (as described herein) for easily advancing the balloon catheter into the patient's body; (b) inserting the distal end of the insertion device into a hemostatic valve; (c) advancing the tubular portion of the insertion device and the balloon catheter contained therein into the patient's body through the hemostatic valve; (d) withdrawing the tubular portion of the insertion device from the hemostatic valve, positioning at least the proximal portion of the tubular portion around the catheter shaft; and (e) moving the insertion device relative to the balloon catheter, separating the separation margin, so that the insertion device can move away from the catheter shaft.

[0011] In another embodiment, the present invention provides an inserter configured to facilitate the entry of the balloon portion of a balloon catheter into the patient's body via a hemostatic valve. The inserter comprises: a proximal end and a distal end along the longitudinal axis; a tubular portion extending proximal from the distal end and having a length equal to or greater than the length of the balloon portion; a first knob extending from the first longitudinal half of the tubular portion; and a second knob extending from the second longitudinal half of the tubular portion. The tubular portion has a wall; an inner diameter capable of accommodating the balloon portion of a balloon catheter; and a first separation margin and a second separation margin in the wall of the tubular portion, which represent a structural weakness or division in the wall of the tubular portion and define the first and second longitudinal halves of the tubular portion. The present invention also provides a balloon catheter insertion system comprising the inserter described above. Furthermore, the present invention also provides a method for inserting a balloon catheter into a patient's body, using the aforementioned insertion device or a system equipped with said insertion device. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 is a diagram of an inserting device according to one embodiment of the present disclosure. [Figure 2] Figure 2 is a view of a part of an inserting device according to one embodiment of the present disclosure, as seen from the distal end. [Figure 3] Figure 3 is a cross-sectional view of an insert according to one embodiment of the present disclosure. [Figure 4] Figure 4 shows the distal end of an insertor according to one embodiment of the present disclosure. [Figure 5A] Figure 5A is a view of the distal end of an insertor according to one embodiment of the present disclosure. [Figure 5B] Figure 5B is a cross-sectional view of a portion of the distal end of an insertor according to one embodiment of the present disclosure. [Figure 6A] Figures 6A to 6D show the proximal end of an embodiment of the insert. [Figure 6B] Same as Figure 6A. [Figure 6C] Same as Figure 6A. [Figure 6D] Same as Figure 6A. [Figure 7] Figure 7 shows the proximal or distal end of an embodiment of the insert. [Figure 8] Figure 8 shows the proximal or distal end of an embodiment of the insert. [Figure 9] Figure 9 is a view of a part of an inserting device according to one embodiment of the present disclosure, as seen from the distal end. [Figure 10] Figure 10 is a view of a part of an insert according to one embodiment of the present disclosure, seen from the proximal end. [Figure 11] Figure 11 is a view of a part of an insert according to one embodiment of the present disclosure, seen from the proximal end. [Figure 12] Figure 12 is a perspective view of an inserter according to one embodiment of the present disclosure. [Figure 13] Figure 13 shows the distal end of an insertor according to one embodiment of the present disclosure. [Figure 14] Figure 14 is a partial diagram of a balloon catheter according to one embodiment of the present disclosure. [Figure 15] Figure 15 is a view of the distal end of the balloon catheter. It shows the balloon portion in a folded state. [Figure 16] Figure 16 is a view of the distal end of the balloon catheter. It shows the balloon portion in a folded state and the balloon portion loaded in various inserters. [Figure 17] Figure 17 is a view of a part of the balloon catheter inside the inserter. [Figure 18] Figure 18 is a view showing a part of the balloon catheter inside the inserter and a part of the inserter inside the hemostatic valve.

Embodiments for Carrying Out the Invention

[0013] The embodiments of the present invention described in this specification are not intended to be exhaustive, nor are they intended to limit the present invention to the exact forms disclosed in the following detailed description. Rather, the following embodiments are selected and described so that the principles and practice of the present invention can be recognized and understood by other persons skilled in the art.

[0014] All publications and patents mentioned in this specification are incorporated by reference. The publications and patents described in this specification are provided only for the purpose of their disclosure. None of the descriptions in this specification should be construed as an admission that the inventors have any right prior to any publication and / or patent (including any publication and / or patent cited in this specification).

[0015] In this specification, the terms “proximal” and “distal” are used to define the location of specific feature points of a balloon catheter insert or related system components (such as a balloon catheter or hemostatic valve). The proximal end (user end) refers to the location of the system's feature points on the user side (i.e., outside the body). The distal end (treatment end) refers to the location of the system's feature points away from the user end (i.e., on the treatment site side). The “proximal portion” refers to the portion closer to the proximal end than to the portion closer to the distal end (distal portion). The “internal surface” (inner surface of the lumen) refers to the surface of an object located inside the lumen of a hollow object. Conversely, the “external surface” refers to the outer surface of a hollow object (outer surface of the lumen). Similarly, the “internal diameter” can be defined by the internal surface of a hollow object, and the “external diameter” can be defined by the external surface. In this case, the “wall thickness” can be defined by the difference between the outer diameter and the internal diameter (such as the wall thickness of the insert). The arrangement of feature points of an insert can also be described in relation to the “longitudinal axis” of the insert. The longitudinal axis is a line that includes the points at the proximal and distal ends of the insert and extends parallel to the wall of the insert.

[0016] Refer to Figure 1. In one embodiment, the disclosure provides a balloon catheter inserter 100 comprising a tubular portion 112 having a proximal end 114 and a distal end 116. The tubular portion 112 has a longitudinal axis parallel to the walls of the tubular portion 112 (each part of the inserter may be described in relation to the longitudinal axis). The length of the tubular portion (i.e., the distance between the proximal end 114 and the distal end 116) may be long enough to accommodate the length of the balloon portion of the balloon catheter. The inserter can be used to accommodate balloon catheters of various shapes and dimensions and to facilitate insertion. For example, the length of the tubular portion may be about 10 mm or more (e.g., about 10 mm to about 300 mm; other examples include about 10 mm to about 100 mm, about 50 mm to about 150 mm, and about 150 mm to about 300 mm).

[0017] Figure 2 shows the tubular portion of the insert as viewed from the distal end 116. The tubular portion is drawn to appear circular when viewed from the end. However, this shape is suitable for accommodating the balloon portion of the balloon catheter and can be any shape that facilitates insertion through the hemostatic valve (e.g., oval or polygonal).

[0018] Figure 2 also shows the outer surface 130 and inner surface 132 of the tubular portion. The distance between two opposing points on the outer surface (passing through the center of the tubular portion) represents the outer diameter (OD). The distance between two opposing points on the inner surface (passing through the center of the tubular portion) represents the inner diameter (ID). In exemplary embodiments, the outer diameter of the tubular portion may be about 0.35 mm to about 10 mm, about 1.5 mm to about 5 mm, or about 1.6 mm to about 3 mm. In exemplary embodiments, the outer circumference of the tubular portion may be about 1.1 mm to about 32 mm, about 2.5 mm to about 15 mm, or about 3 mm to about 6 mm. In exemplary embodiments, the inner diameter of the tubular portion may be 0.25 mm to 5 mm, about 1 mm to about 4 mm, about 1.2 mm to about 3 mm, or about 1.25 mm to about 2.75 mm. The lumen of the tubular portion can also be defined by its cross-sectional area. The cross-sectional area is, for example, approximately 0.05 mm². 2 ~about 20mm 2 , or approximately 0.75 mm 2 ~approx. 12.5mm 2 That's fine.

[0019] The wall thickness of a tubular member can be defined by dividing the difference between the outer diameter and the inner diameter by 2. The wall thickness may be uniform or non-uniform along the perimeter of the wall. In exemplary embodiments, the wall thickness of the tubular portion may be approximately 0.025 mm or more, approximately 0.05 mm or more, approximately 0.075 mm or more, or approximately 0.10 mm or more (e.g., approximately 0.05 mm to approximately 2.5 mm, approximately 0.05 mm to approximately 0.5 mm, approximately 0.05 mm to approximately 0.25 mm, approximately 0.05 mm to approximately 0.20 mm, approximately 0.05 mm to approximately 0.15 mm, approximately 0.10 mm to approximately 0.25 mm, or approximately 0.15 mm to approximately 1.5 mm).

[0020] For the purpose of illustrating aspects of this disclosure, refer to Figure 2. The tubular portion may be described as having a first longitudinal half 141 (shown as an upper semicircle) and a second longitudinal half 143 (shown as a lower semicircle). The first and second longitudinal halves are understood to extend along the entire length of the tubular portion between the proximal and distal ends. At least the first longitudinal half 141 may have a separation margin that can be broken when force is applied to the insert (for example, when force is applied to the knob of the insert as described herein).

[0021] In one embodiment, the separation margin may be in the form of a groove 150 in the wall of the first longitudinal half 141 (e.g., a fissure, crevice, cut line, or indentation). The groove 150 may be any desired shape (e.g., V-shaped, U-shaped, rectangular, square). Figure 2 shows a V-shaped groove 150 in the outer wall of the first longitudinal half 141.

[0022] The groove can be described in relation to its depth in the wall of the tubular portion. For example, in some embodiments, the groove depth may be about 10% or more of the thickness of the wall in which the groove exists. In some embodiments, the groove depth may be about 10% to about 75% of the wall thickness, or about 20% to about 60% of the wall thickness. The groove depth is, for example, about 0.025 mm to about 1 mm, about 0.05 mm to about 0.25 mm, or about 0.05 mm to about 0.15 mm. For example, if the wall thickness is about 0.5 mm, the groove depth may be about 0.05 mm to about 0.375 mm. Or, if the wall thickness is about 0.075 mm, the groove depth may be about 0.025 mm to about 0.070 mm. The desired groove depth may be determined by the wall thickness, the material used in the manufacture of the tubular portion, the shape of the groove, or a combination thereof.

[0023] In another embodiment, the separation margin is a structural weak point in the wall of the tubular portion. This weak point may result from differences in the tubular portion material. Alternatively, it may result from differences in physical properties (e.g., molecular orientation) when comparing the material of the separation margin with the material of the rest of the tubular member. Such weak points can be introduced into the tubular member by manufacturing process (e.g., extrusion). In extrusion, a structural weak point can be formed along the separation margin by stretching the polymer composition used to manufacture the tubular member. Stretching may be performed before, during, or after extrusion, or a combination of these. Stretching can cause the polymer molecules to be aligned coaxially along the separation margin. This allows the separation margin to become a weak point in the tubular member when a force is applied perpendicular to the orientation of the polymer molecules.

[0024] The separation margin may be continuous along the first longitudinal half 141 (i.e., extending from the proximal end to the distal end of the tubular portion) or it may be discontinuous. If the separation margin is discontinuous along the first longitudinal half 141, it is preferable that the separation margin has few interruptions without grooves. In this way, the tubular member can be divided within the first longitudinal half 141. Furthermore, the separation margin may be distributed linearly along the first longitudinal half 141, or it may not be linear along its entire length (for example, the separation margin may have one or more curves, angles, etc.).

[0025] In addition to the separation margin along the first longitudinal half 141, the tubular portion may have one or more additional grooves in an optional configuration. These additional grooves may be located in the first longitudinal half 141, in the second longitudinal half 143, or in both. If the tubular member has one or more other grooves (e.g., a second groove, a third groove, etc.), these grooves may or may not function as separation margins. For example, the tubular portion may have a groove 152 in the second longitudinal half 143 (located opposite the groove 150 in the first longitudinal half 141, etc.).

[0026] When force is applied to the tubular member, the groove 150 may be destroyed, creating a split in the first longitudinal half 141 (for example, by a force between the balloon catheter shaft and the inner surface of the tubular member adjacent to the groove 150). However, this force does not necessarily destroy the tubular wall adjacent to the groove 152 (if such a groove exists). Therefore, the second longitudinal half 143 may remain intact when the insert is removed from the catheter shaft. The tubular member can be easily manufactured by forming a pair of grooves facing each other within the tubular member.

[0027] Refer to Figure 3. Embodiments of the insert include those in which the proximal and / or distal ends of the tubular portion are straight, and those in which the proximal and / or distal ends of the tubular portion are not straight. Insert 200, in which the distal end 216 of the tubular member 212 is straight (flat). The end 214 of the tubular member 212 is depicted as a tapered end (the taper of the tubular portion extends from the first longitudinal half 241 to the second longitudinal half 243). Examples of non-straight structures include tapered and flared structures. An embodiment in which the insert has a tapered end 316 is depicted in Figure 4. This structure can be formed by cutting the distal end of the tubular article at a certain angle. An example in which the end 416 is both tapered and flared is shown in Figure 5A. The figure is a top view of the end portion of the insert, showing the first longitudinal half 441 and the separation margin 452, with the end portion 416 flaring out. This flare widens the end of the tubular portion. This is reflected in the fact that the width between points 425a and 425b is wider than the width (outer diameter) of the tubular portion adjacent to the end portion 416.

[0028] An insertion device with a flared proximal opening allows for easy insertion of the balloon from the end. Furthermore, this configuration minimizes or prevents the removal of therapeutic agent from the balloon's surface (otherwise, it may be removed by friction). By flaring the distal opening, the insertion device can be advanced on the balloon without scraping off the medication.

[0029] Embodiments of this disclosure also include those in which the wall of the tubular portion is tapered. See, for example, Figure 5B, which shows a portion of the cross-section of the tubular portion 455, in which the wall 460 is tapered at the end.

[0030] Embodiments of the present disclosure also include inserts having a knob at the proximal end of a tubular member. The knob has a portion extending from a second longitudinal half of the tubular portion. The knob portion is also oblique to the longitudinal axis of the tubular portion at a certain angle. Examples of knobs having a portion extending from a second longitudinal half of the tubular portion and oblique to the longitudinal axis are shown in Figures 1(120), 3(220), 6A(320), 6B(420), 6C(520), 6D(620), and 7(720).

[0031] In embodiments, the knob may be curved (as shown in Figures 1, 3, 6A, and 6B, which are side views of the proximal end portion of the insert). Refer to Figure 6A. 321 represents the portion of the knob that is oblique to the longitudinal axis of the tubular member (dashed line LA) (dashed line SA represents the oblique axis). With respect to a curved knob, it will be understood that multiple portions of the knob may be oblique to the longitudinal axis of the tubular member.

[0032] A curved knob can be described in various ways (for example, by the length of the curved portion of the knob). This length can be represented, for example, from point 225 to point 227 in Figure 3, from point 325 to point 327 in Figure 6A, and from point 425 to point 427 in Figure 6B. The length of the knob is, for example, approximately 5 mm to 100 mm, or approximately 20 mm to 40 mm.

[0033] Curved knobs can also be described by the degree of curvature (expressed in degrees (°)). For example, the curvature of the knob in Figure 3 is approximately 360°. Also, the curvature of the knob in Figure 6A is approximately 270°. Furthermore, the curvature of the knob in Figure 6B is approximately 180°. The curvature is, for example, approximately 15° to approximately 540° or approximately 30° to approximately 360°, and preferably approximately 45° to approximately 270°.

[0034] Curved knobs can also be described by their radius. For example, in Figure 6A, the radius of the knob is represented by line 328. The radius of a curved knob may be the same over its entire length or it may vary. In some embodiments, the radius of the knob may decrease. This decrease may be, for example, less than 50% of the initial radius or less than 25% of the initial radius (where the initial radius is, for example, the radius at point 235 or the radius at a point adjacent to point 235). The radius of a curved knob may be, for example, about 1 mm to about 20 mm, or about 3 mm to about 10 mm.

[0035] In the embodiments of the present disclosure shown in Figures 6C and 6D, the knob may have one or more non-curved portions (e.g., straight portions) when viewed from a longitudinal cross-section of the insert. These are represented as knob portions 520 and 620.

[0036] Embodiments of the present disclosure also include a knob having a second portion extending from a second longitudinal half of a tubular portion, where the second knob portion is parallel to the longitudinal axis of the tubular portion. Figure 7 illustrates a knob having a first portion 720 and a second portion 730. The first portion 720 (i.e., the curved portion) is oblique to the longitudinal axis of the tubular portion at a certain angle. The second portion 730 (i.e., the flat portion) is parallel to the longitudinal axis of the tubular portion. Thus, the second portion 730 has a width axis perpendicular to the longitudinal axis of the tubular member (e.g., dashed line 714) and a longitudinal axis parallel to the longitudinal axis of the tubular member. On the other hand, the first portion 720 has a width axis perpendicular to the longitudinal axis of the tubular member and a longitudinal axis oblique to the longitudinal axis of the tubular member.

[0037] Furthermore, an embodiment of a knob directly adjacent to the proximal end of a tubular portion can be described. For example, the knob may have a curved distal portion 725 (this distal portion extends from the curved portion of the second longitudinal half of the proximal end of the tubular portion). As the knob extends proximal, the curved shape can be made flat (in the width direction). Also, as the knob extends proximal, the width of the knob can be made wider than the narrow width of the portion adjacent to the proximal end of the tubular member. Thus, the width of the knob can be increased from the distal side to the proximal side. In an exemplary embodiment, the width of the knob is about 0.5 mm to about 30 mm, or about 2 mm to about 3.5 mm. A notch 735 may be provided in the first longitudinal half at the proximal end of the tubular member.

[0038] Figure 8 shows another embodiment, pinched to indicate a first portion 750 and a second portion 760. The first portion 750 (i.e., the curved portion) may be oblique to the longitudinal axis of the tubular portion at some angle. The second portion 760 (i.e., the flat portion) may be parallel to the longitudinal axis of the tubular portion. Figure 8 also shows that a tapered transition portion 765 may be provided between the proximal end 764 of the tubular portion and the second portion 760 (i.e., the flat portion).

[0039] A knob that extends from the second longitudinal half of a tubular portion and has a portion that can intersect the longitudinal axis of the tubular portion at a certain angle can be formed by processing the straight end of the tubular member. For example, a knob can be formed by the following steps: (a) Prepare a tube with straight proximal and distal ends. (b) Make a partial cut through the longitudinal axis of the tube and perpendicular to it. The distance of the cut should be at least half the distance through the tube. (c) Make a second cut between the proximal end of the tube and the cut. This cut is made at an angle intersecting the bottom of the cut. This forms a wedge-shaped cut in the upper half of the tube. Flatten at least partially the proximal end of the cut (for example, by thermoforming).

[0040] In other embodiments, the inserter may have a split in the wall of the first half of the tubular portion. In this embodiment, the balloon catheter can be held within the inner diameter of the tubular member having the above configuration during the insertion process. After the inserter facilitates the insertion of the balloon catheter through the hemostatic valve, the tubular portion can be moved proximal so that it surrounds a portion of the balloon catheter shaft. Next, force can be applied to the knob to open the first half of the tubular portion to allow the catheter shaft to move out of the inner diameter of the tubular portion. Specifically, the force applied to the knob can separate the walls of the tubular portion on both sides of the split. This creates a longitudinal gap through which the catheter shaft can move.

[0041] Figure 9 shows an exemplary embodiment of an insert having a division in the wall of the first half 841 of the tubular portion. The figure shows a cross-section of the tubular portion as viewed from the distal end. The division in the first half of the wall may create a first edge 802 and a second edge 804. These edges extend along the entire length of the tubular portion. A point on the outer wall adjacent to the first edge 802 may be in contact with a point 805 on the inner wall of the first half of the tubular member. Thus, as viewed from the proximal end, the first half may have an inner wall overlap 806 and an outer wall overlap 808.

[0042] The circumferential distance between the first edge 802 and point 805 may form an inner diameter large enough to accommodate the selected balloon catheter. In these embodiments, the outer diameter of the tubular portion may be, for example, about 0.45 mm to about 10 mm, or about 1.5 mm to about 5 mm. The inner diameter of the tubular portion may be 0.25 mm to 5 mm, or about 1 mm to about 4 mm. The dimensions / length of the outer overlap 808 of the wall (between the edge 804 and point 805) can be described, for example, in relation to other parts of the insert. For example, the length of 804-805 may be shorter than the circumference of 802-805. Alternatively, the above length may be about 5% to about half of the above circumference (about 5% to 50% of 802-805).

[0043] A gap 809 may be provided between the inner surface of the outer overlap 808 of the wall (i.e., the adjacent part of the edge 804) and the adjacent point 811 on the outer surface of the inner overlap 806 of the wall. The distance of the gap 809 can range from a fraction of the wall thickness to several times the wall thickness. This distance is, for example, approximately 0 mm (no gap) to approximately 0.5 mm.

[0044] Figure 10 is a perspective view of the proximal portion of an insert 900 having a segment in the wall of the first half of a tubular portion and a knob 920 at the proximal end. The knob 920 is in the form of a solid object having a concave surface and is attached (e.g., fixed or secured) to the outer surface of the second longitudinal half of the tubular portion. The inner overlap 906 and outer overlap 908 of the wall are visible in the first half of the tubular portion. The distance from the proximal end of the tubular portion to the distal end of the knob 925 (i.e., the mounting length 923) can be approximately 5 mm to approximately 25 mm. The knob 920 may have two or more proximal extensions (e.g., proximal extensions 927a, 927b). The proximal extensions may have a relatively flat shape. The extension may be narrower in width from near the center of the knob to the proximal end (i.e., in the longitudinal direction). Furthermore, the thickness of the extension (i.e., in the radial direction) may be greater near the center of the knob than at the proximal end.

[0045] Figure 11 is a cross-sectional view (viewed from the proximal end) showing an embodiment of a knob 970, which is a solid object having a concave surface and can be fixed to the outer surface of the second longitudinal half of a tubular portion. The concave surface 975 of the knob 970 is shown. The concave surface 975 may be semicircular. The inner diameter of this semicircle corresponds to the outer diameter of the second half of the proximal end of the tubular portion. The outer diameter of the second half of the proximal end of the tubular portion can be attached to the concave surface 975 of the knob 970 via a suitable mounting material or mounting member (such as adhesive).

[0046] Figure 11 also shows that the outer surface 980 of the knob 970 may be curved (for example, partially circular) when viewed from the proximal end. The outer surface can be extended by a desired distance defined in degrees (°). This distance is, for example, about 45° to about 300°, or about 180° to about 270°, when measured between surfaces 981 and 983. An opening O (or gap) between surfaces 981 and 983 can also be defined. The opening O may be about 60° to about 315°, or about 90° to about 180°. A knob that is a solid object (e.g., 920, 970) can also be defined by the thickness between the inner surface and the outer surface (e.g., between the concave surface 975 and the outer surface 980). This thickness is, for example, about 0.5 mm to about 5 mm, or about 1 mm to about 2 mm. In one embodiment of the manufacturing process, an adhesive is applied between the concave surface 975 and the outer surface of the second longitudinal half of the tubular portion (i.e., the opposite side of the first longitudinal half which has a division in the wall). This attaches the solid object, the knob 970, to the tubular portion.

[0047] Refer to Figure 12. Inserts according to other embodiments include two curved knobs at the proximal end of the insert. Insert 1000 is shown with the distal end 1016 of the tubular portion 1012 being straight (flat). However, the distal end may be tapered instead (e.g., a tapered structure in inserts of other embodiments of the present disclosure). The tubular portion 1012 may extend for a predetermined distance (L1) from the distal end 1016 to point 1041 (at point 1041, the knobs 1020 and 1030 begin). Point 1041 may be located at a division in the tubular member. At point 1041, half of the tubular member may form the first knob 1020, and the other half of the tubular member may form the second knob 1030. As shown in the figure, the knobs 1020 and 1030 may be curved. Knobs 1020 and 1030 may terminate at their proximal ends 1027 and 1037, respectively.

[0048] Knobs 1020 and 1030 can follow any curved path (circular path, elliptical path, etc.). Knobs 1020 and 1030 can also be described by the degree of curvature (expressed in degrees (°)). For example, in Figure 12, the curvature of knobs 1020 and 1030 is approximately 90°. Knobs can range from approximately 45° to approximately 270°, or from approximately 45° to approximately 180°. Curved knobs 1020 and 1030 can also be described by their radius. For example, the radius of knob 1020 is represented by line 1028. The radius of knob 1020 may be the same as or different from the radius of knob 1030. The radius of a curved knob may be the same over its entire length or may vary. In this embodiment, the radius of the curved knob is, for example, about 5 mm to about 35 mm, or about 10 mm to about 30 mm.

[0049] The insert 1000 can also be described in relation to the lengths of the tubular portion 1012 and one or both of the knobs 1020 and 1030. In embodiments, the length L1 of the tubular portion 1012 is longer than the length L2 of one or both of the knobs 1020 and 1030. Preferably, the length L1 of the tubular portion 1012 is more than twice or more than three times the length L2 of one or both of the knobs 1020 and 1030. The length L1 of the tubular portion 1012 is, for example, about 25 mm to about 150 mm, or about 75 mm to about 125 mm.

[0050] The insert 1000 shown in Figure 12 can be manufactured using a tubular portion having the structure shown in Figure 13. The tubular portion in Figure 13 is similar to or the same as that in Figure 2 (showing the tubular portion as viewed from the distal end). The tubular portion may have a first longitudinal half 1141 (left), which is half of a semicircle, and a second longitudinal half 1143 (right), which is half of a semicircle. It will be understood that the first and second longitudinal halves extend along the entire length of the tubular portion 1012 between the proximal and distal ends. The first and second longitudinal halves are defined by a first separation margin 1150 (e.g., a V-shaped groove) and a second separation margin 1152 (e.g., another V-shaped groove). The knobs 1020 and 1030 are formed as extensions of the first and second longitudinal halves 1141 and 1143. These extensions are divided at point 1041 and configured to form an angle away from the central axis of the tubular portion 1012 (for example, as a curved structure as shown). Figure 13 also shows the outer surface 1130 and the inner surface 1132 of the tubular portion.

[0051] In some embodiments of the insert, the first separation margin 1150 and the second separation margin 1152 may be structural weak points in the tubular portion 1012. These weak points may represent differences in the material of the tubular portion or differences in the material properties (e.g., molecular orientation) in the separation margin. In some embodiments, weak points can be introduced into the tubular member by the manufacturing process. As a non-limiting example, structural weak points in the tubular portion can be intentionally introduced by the extrusion process. In the extrusion process, structural weak points along the separation margin can be introduced by stretching the polymer composition used to manufacture the tubular member. Stretching may be performed before, during, or after extrusion, or a combination thereof. Stretching can cause the polymer molecules to be aligned coaxially along the separation margin. This allows the separation margin to become a weak point in the tubular member when a force is applied perpendicular to the orientation of the polymer molecules. Furthermore, this separation margin naturally divides at point 1041.

[0052] When force is applied to the insert 1000, the first longitudinal half 1141 and the second longitudinal half 1143 can be separated. For example, a user can pull the knobs 1020 and 1030 outward, away from the central axis of the tubular portion 1012. In this case, the tubular portion 1012 may be broken along the first separation margin 1150 and the second separation margin 1152.

[0053] The embodiment shown in Figure 12 may include any dimensions described herein with respect to overall length, outer diameter, inner diameter, or wall thickness. The embodiment may include any tubular structure described herein (such as the structure of the distal end). The embodiment may be formed from any material described herein and may be formed by any manufacturing method. The embodiment may be used in conjunction with any balloon catheter or hemostatic valve described herein (or known in the art).

[0054] The tubular portion and / or knob can be formed by techniques such as extrusion, 3D printing, injection molding, compression molding, particulate leaching, solvent casting, thermoforming, or cutting. A combination of manufacturing techniques may be used. The feature points of the insert (separation margin, knob, etc.) may be formed during or after extrusion or molding. Examples of materials that can be used when manufacturing part or all of the insert include polymer materials. Polymer materials include fluorinated ethylene propylene (FEP), high-density polyethylene and low-density polyethylene (HDPE and LDPE), polytetrafluoroethylene (PTFE; Teflon®), polyurethane, PEBAX, polyesteramide, polyimide, polyester and polyamide (nylon).

[0055] The material used to manufacture a part of the insert (such as a tubular portion) may itself be transparent and transmit ultraviolet light. Various aliphatic polymers (including halogenated aliphatic polymers) can transmit ultraviolet light well. In some embodiments, a coating composition may be applied to the inner surface (inner diameter) of the tubular member of the insert (such as the ultraviolet-activated crosslinking agent described herein). Then, ultraviolet light may be irradiated onto the tubular member to activate the crosslinking agent and form a durable coating (ultraviolet light penetrates the material of the tubular member).

[0056] The insert may be manufactured in part or in whole so that it can be visually or detectably distinguished from other parts of the balloon catheter insertion system (such as the balloon catheter and / or hemostatic valve). The components of the balloon catheter insertion system may be manufactured from similar materials. In this case, if one or more of the components of the system are not made of a distinguishing material when the components are used together, it may be difficult to distinguish between the components. The distinguishing material may be, for example, a colorant, a light-reflecting material (e.g., to increase the opacity of the insert), a radiopaque material, a paramagnetic material, a gaseous material, or a radioisotope material.

[0057] For example, a coloring agent or contrast agent may be applied to one or more portions of the entire length of the insertor and / or balloon catheter. The coloring agent or contrast agent allows for easy monitoring of the progress of balloon catheter insertion into the patient. The coloring agent or contrast agent can provide clinicians with visual cues that indicate the spatial relationship between portions of the insertor and portions of the balloon catheter. Visual identification of the device portions can improve the insertion process.

[0058] The coloring agent or contrast agent may be applied to the surface of the polymer material used in the manufacture of the insert and / or balloon catheter, or may be incorporated into the material. The coloring agent may also be incorporated into a lubricating coating material (such as a hydrogel polymer coating) that is applied in any configuration to the surface of the insert and / or balloon catheter.

[0059] Examples of colorants include, but are not limited to, FD&C lake and D&C lake, titanium dioxide, magnesium carbonate, talc, calcined silica, iron oxide, channel black, insoluble dyes, natural colorants (such as riboflavin, carmine 40, curcumin, and annatto), dyes permitted for use by the Federal Drug Administration, or any combination thereof. Colorants used in the preparation of coating dispersions used for coating tablets, foods, confectionery, agricultural seeds, etc., may also be used in connection with the articles of this disclosure.

[0060] A coloring agent or contrast agent may be present at one or more locations on the insert, balloon catheter, or any other component that can be used in combination with the insert and catheter. This allows the catheter to be easily inserted into the body. See, for example, Figure 17, in which the balloon portion 1523 is shown positioned inside the tubular portion 1512 of the insert. The first catheter mark 1536 and the second catheter mark 1533 are located at points along the longitudinal direction of the catheter body 1522 and can be seen by the user during the insertion process. Markings along the catheter body may correspond positionally to parts of the catheter that may not be visible to the user (e.g., points on the balloon portion 1523). For example, the distance between the second catheter mark 1533 and the proximal end 1514 of the insert may correspond to the distance between the distal tip of the balloon catheter 1525 and the distal end 1516 of the insert. By monitoring the position of the second catheter marker 1533 relative to the proximal end 1514 of the insertion device, the user can understand when the distal tip 1525 has emerged from the distal end 1516 during the insertion process. Similarly, the distance between the first catheter marker 1536 and the distal end 1516 (or the second catheter marker 1533) allows the user to understand the position of the distal end 1526 of the balloon portion during the insertion of the balloon catheter.

[0061] Refer to Figure 18. A mark may be provided on the outer surface of the tubular member 1612 of the insert. This mark can help understand the positioning of the distal end (not shown) of the insert relative to the position of the hemostatic valve 1603 through which the insert 1612 is passing. For example, during use, the insert 1612 passing through the hemostatic valve 1603 reaches the mark 1624. This may indicate that the distal end of the insert has reached the distal end of the hemostatic valve. Subsequently, the body 1622 of the balloon catheter can be advanced to move the balloon catheter into the patient's body.

[0062] Instead of (or in addition to) marking the insert, the tubular member of the insert may be provided with a stopper member (not shown) extending radially outward from the surface of the tubular member. By the stopper member reaching the proximal end 1605 of the hemostatic valve, the insert is effectively prevented from moving further distally through the hemostatic valve. The stopper member may be in the form of a circumferential lip or protrusion rising from the outer surface of the tubular member, or it may be any other structure that can contact the proximal portion of the hemostatic valve. The stopper member may be formed as part of the extrusion process used to manufacture the insert. Alternatively, the stopper member may be added to the tubular member after it has been formed (for example, by bonding a plastic ring to a desired position on the outer surface of the tubular member).

[0063] In embodiments of this disclosure, any part of any insert / article (or any part of the catheter of this disclosure) may be coated (e.g., a hydrophilic lubricating coating). For example, a hydrophilic polymer-based coating can be applied to a part of the insert / article (or any part of the catheter). This provides lubrication and reduces the loss of desired substances (e.g., therapeutic agent from the balloon surface). In other embodiments, any part of any insert / article (or any part of the catheter of this disclosure) may be associated with a low-friction article (e.g., a Teflon® sleeve). In some embodiments, all or part of the inner diameter of the tubular member of the insert is covered with a hydrophilic coating or lined with a lubricating low-friction sleeve (e.g., PTFE and a PTFE liner). In some embodiments, all or part of the outer surface of the balloon catheter is covered with a hydrophilic coating or lined with a lubricating low-friction sleeve. Other materials that provide a lubricating low-friction coating include silicone oils, perfluorinated oils, and waxes (which optionally have covalent bonds, thereby further reducing friction).

[0064] Synthetic hydrophilic polymers are a group of hydrophilic polymers useful as polymer materials for forming hydrophilic base coatings. Biostable synthetic hydrophilic polymers (i.e., synthetic hydrophilic polymers that do not decompose to a detectable degree in vivo) can be prepared from any suitable monomer (such as acrylic monomers, vinyl monomers, ether monomers, or combinations of one or more of these monomers). Examples of acrylic monomers include methacrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, methacrylic acid, acrylic acid, glycerol acrylate, glycerol methacrylate, acrylamide, methacrylamide, dimethylacrylamide (DMA), and derivatives and / or mixtures thereof. Examples of vinyl monomers include vinyl acetate, vinylpyrrolidone, vinyl alcohol, and derivatives thereof. Examples of ether monomers include ethylene oxide, propylene oxide, butylene oxide, and derivatives thereof. Examples of polymers that can be formed from these monomers include poly(acrylamide), poly(methacrylamide), poly(vinylpyrrolidone), poly(acrylic acid), poly(ethylene glycol), poly(vinyl alcohol), and poly(HEMA). Methyl vinyl ether / maleic anhydride copolymers and vinylpyrrolidone / (meth)acrylamide copolymers are also examples. Mixtures of homopolymers and / or copolymers may be used.

[0065] Several examples of acrylamide polymers are described in Example 2 of U.S. Patent No. 7,807,750 (Taton et al.) (e.g., poly(N,N dimethylacrylamide-co-aminopropyl methacrylamide) and poly(acrylamide-co-N,N dimethylaminopropyl methacrylamide)). This disclosure is incorporated herein by reference.

[0066] Other hydrophilic polymers available in this disclosure include derivatives of acrylamide polymers having photoreactive groups. One representative example of such hydrophilic polymers is a copolymer of N-[3-(4-benzoylbenzamide)propyl]methacrylamide (Formula I) and N-(3-aminopropyl)methacrylamide (Formula II). This copolymerization synthesizes the poly(N-3-aminopropyl)methacrylamide-co-N-[3-(4-benzoylbenzamide)propyl]methacrylamide (Formula III) polymer. A method for preparing this polymer is disclosed in Example 1 of U.S. Patent Publication 2007 / 0032882 (Lodhi et al.), which is incorporated herein by reference in its entirety.

[0067] [ka]

[0068] In some embodiments, the hydrophilic polymer may be a vinylpyrrolidone polymer or a vinylpyrrolidone / (meth)acrylamide copolymer (e.g., poly(vinylpyrrolidone-co-methacrylamide)). When a PVP copolymer is used, the PVP copolymer may be a copolymer of (i) vinylpyrrolidone and (ii) a monomer selected from the group of acrylamide monomers. Examples of acrylamide monomers include (meth)acrylamide and (meth)acrylamide derivatives. Examples of (meth)acrylamide derivatives include alkyl(meth)acrylamides (e.g., dimethylacrylamide) and aminoalkyl(meth)acrylamides (e.g., aminopropylmethacrylamide, dimethylaminopropylmethacrylamide). For example, poly(vinylpyrrolidone-co-N,N-dimethylaminopropylmethacrylamide) is described in Example 2 of U.S. Patent No. 7,807,750 (Taton et al.).

[0069] In one embodiment, the polymers and copolymers described above are derivatized by one or more photoactivated groups. Examples of photoreactive groups that can be pendant groups for biostable hydrophilic polymers include aryl ketones (such as acetophenone, benzophenone, anthraquinone, anthrone, quinone, and anthrone-like heterocycles). Specifically, diaryl ketones are given herein as examples of aryl ketones. The polymers herein provide hydrophilic polymers having photoactivated photoreactive pendant groups. These photoreactive groups can be applied to expandable and foldable structures. That is, these photoreactive groups can be treated with chemical rays strong enough to activate them, thereby forming covalent bonds with a target (such as materials for expandable and foldable structures). By using photoreactive hydrophilic polymers, durable coatings of flexible hydrogel matrices can be provided. These matrices contain hydrophilic polymer material covalently bonded to materials for expandable and foldable structures.

[0070] Flexible hydrogel coatings can be prepared using hydrophilic polymers having photoreactive pendant groups. Methods for preparing hydrophilic polymers having photoreactive groups are known in the art. For example, a method for preparing photoreactive PVP is described in U.S. Patent No. 5,414,075 (Swan et al.) (this disclosure is incorporated herein by reference). Hydrophilic photoreactive polyacrylamide polymers (such as "photoreactive PA," i.e., poly(acrylamide-co-N-(3-(4-benzoylbenzamide)propyl)metacylamide) and its derivatives) can be used to form hydrophilic base coatings on articles in exemplary embodiments of this disclosure. A method for preparing photoreactive polyacrylamide is described in U.S. Patent No. 6,007,833 (Chudzik et al.) (this disclosure is incorporated herein by reference).

[0071] Other embodiments of hydrophilic base coatings include derivatives of photoreactive polyacrylamide polymers having further reactive moieties. Some examples of reactive moieties include N-oxysuccinimide and glycidyl methacrylate. Representative examples of photoreactive polyacrylamide derivatives having further reactive moieties include poly(acrylamide-co-maleic acid-6-aminocaproic acid-N-oxysuccinimide-co-N-(3-(4-benzoylbenzamide)propyl)methacrylamide) and poly(acrylamide-co-(3-(4-benzoylbenzamide)propyl)methacrylamide)-co-glycidylmethacrylic acid. Photoreactive polyacrylamide polymers having further reactive moieties are subject to U.S. Patent No. 6,465,178 (Chappa This is described in Patent No. 6,762,019 (Swan et al.) and No. 7,309,593 (Ofstead et al.). These disclosures are incorporated herein by reference.

[0072] Other exemplary embodiments of hydrophilic base coatings, such as derivatives of photoreactive polyacrylamide polymers having further reactive moieties, are disclosed in U.S. Patent No. 6,514,734 (Clapper et al.), which is incorporated herein by reference in its entirety.

[0073] In further embodiments, the hydrophilic base coating may include derivatives of photoreactive polyacrylamide polymers having charged moieties. These charged moieties include both positively charged and negatively charged species. Examples of charged species include, but are not limited to, sulfonates, phosphates, and quaternary amine derivatives. Some examples include the negatively charged species N-acetylated poly(acrylamide-co-sodium-2-acrylamide-2-methylpropanesulfonate-co-N-(3-(4-benzoylbenzamide)propyl)methacrylamide)-co-methoxypoly(ethylene glycol) monomethacrylate. Other negatively charged species that may be included in the hydrophilic base coating are described in U.S. Patent No. 4,973,493 (Guire et al.), the disclosure of which is incorporated herein by reference in its entirety. Examples of positively charged species include poly(acrylamide-co-N-(3-(4-benzoylbenzamide)propyl)methacrylamide)-co-(3-(methacryloylamino)propyl)trimethylammonium chloride. Other positively charged species that may be included in hydrophilic base coatings are described in U.S. Patent No. 5,858,653 (Duran et al.), the disclosure of which is incorporated herein by reference in its entirety.

[0074] In another embodiment, the polymers and copolymers described above are derivatized with one or more polymerizable groups. Polymers having polymerizable pendant groups are generally referred to as macromers. The polymerizable groups may be located at the terminal portions (terminuses) of the polymer chain or may be present throughout the entire length of the polymer. In one embodiment, the polymerizable groups are randomly located throughout the entire length of the polymer.

[0075] Exemplary hydrophilic polymer coatings can be prepared using polymer grafting techniques. Polymer grafting techniques include, for example, applying a non-polymerizable grafting agent and monomer to a substrate surface, and then polymerizing the monomer on the substrate surface by appropriately activating the grafting agent (e.g., UV irradiation). Grafting methods for producing hydrophilic polymer surfaces are exemplified in U.S. Patents 7,348,055, 7,736,689, and 8,039,524 (all by Chappa et al.). Their full disclosures are incorporated herein by reference.

[0076] Alternatively, the coating composition may include a heat-reactive polymer (e.g., a hydrophilic polymer having heat-reactive peroxide pendant groups) as described in U.S. Patent No. 7,807,750 (Taton et al.). In an exemplary embodiment, the coating composition containing the heat-reactive polymer is applied to the inner surface (inner diameter) of a tubular member and heated to chemically react the activated pendant groups with the material of the tubular member, thereby bonding the polymer.

[0077] In any configuration, the coatings of articles of this disclosure may include a crosslinking agent. The crosslinking agent can promote the association of polymers in the coating and the bonding of polymers to the coated surface. The specific choice of crosslinking agent may depend on the components of the coating composition.

[0078] A suitable crosslinking agent may have two or more activatable groups that can react with the polymer in the composition. Suitable activatable groups include photoreactive groups such as aryl ketones described herein (e.g., acetophenone, benzophenone, anthraquinone, anthrone, quinone, and anthrone-like heterocycles). Crosslinking agents containing photoreactive groups may be referred to as "photocrosslinking agents" or "photoactivatable crosslinking agents." Photoactivatable crosslinking agents may be ionic and exhibit good solubility in aqueous compositions. Therefore, in some embodiments, a coating can be formed using one or more ionic photoactivatable crosslinking agents. Examples of ionic crosslinking agents include acidic groups or salts thereof (e.g., selected from sulfonic acids, carboxylic acids, phosphonic acids, and their salts). Exemplary counterions include alkalis, alkaline earth metals, ammonium, and protonated amines.

[0079] Examples of ionic photoactivatable crosslinking agents include 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid or salt, 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid or salt, 2,5-bis(4-benzoylmethyleneoxy)benzene-1-sulfonic acid or salt, and N,N-bis[2-(4-benzoylbenzyloxy)ethyl-2-aminoethanesulfonic acid or salt. See U.S. Patents No. 6,077,698 (Swan et al.), No. 6,278,018 (Swan), No. 6,603,040 (Swan), and No. 7,138,541 (Swan). These disclosures are incorporated herein by reference.

[0080] Other examples of ionic photoactivatable crosslinking agents include ethylenebis(4-benzoylbenzyldimethylammonium)dibromide and hexamethylenebis(4-benzoylbenzyldimethylammonium)dibromide. See U.S. Patent No. 5,714,360 (Swan et al.). This disclosure is incorporated herein by reference.

[0081] In further embodiments, reagents having a limited number of functional groups, which include photoactivatable crosslinking groups, can be used. Some examples of reagents having these limited number of functional groups include tetrakis(4-benzoylbenzyl ether) of pentaerythritol and tetrakis(4-benzoylbenzoate ester) of pentaerythritol. See U.S. Patent No. 5,414,075 (Swan et al.) and No. 5,637,460 (Swan et al.). These disclosures are incorporated herein by reference.

[0082] Further crosslinking agents include those having the formula "Photo1-LG-Photo2". In the above formula, Photo1 and Photo2 independently represent one or more photoreactive groups. LG represents a linker group having one or more silicon atoms or one or more phosphorus atoms. In this case, the degradable linker agent has one or more covalent bonds between the photoreactive group and the linker group. One or more heteroatoms are interposed in the one or more covalent bonds between the photoreactive group and the linker group. See U.S. Patent No. 8,889,760 (Kurdyumov et al.). This disclosure is incorporated herein by reference. Further crosslinking agents include those having a core molecule. In this crosslinking agent, one or more charged groups and one or more photoreactive groups are covalently bonded to the core molecule via one or more degradable linkers. See U.S. Published Patent No. 2011 / 0144373 (Swan et al.). This disclosure is incorporated herein by reference.

[0083] In some embodiments, the molecular weight of the first crosslinking agent and / or the second crosslinking agent may be less than about 1500 kDa. In some embodiments, the molecular weight of the crosslinking agent may be less than about 1200, less than about 1100, less than about 1000, less than about 900, less than about 800, less than about 700, less than about 600, less than about 500, or less than about 400.

[0084] In some embodiments, one or more of the first and second crosslinking agents include a linker agent having the formula "Photo1-LG-Photo2". In the above formula, Photo1 and Photo2 independently represent one or more photoreactive groups. LG represents a linker group having one or more silicon atoms or one or more phosphorus atoms. A covalent bond exists between one or more photoreactive groups and linker groups. One or more heteroatoms are interposed in the covalent bond between the photoreactive group and one or more linker groups.

[0085] In some embodiments, at least one of the first crosslinking agent and the second crosslinking agent includes a linker agent represented by a formula selected from the following formulas (a) to (d).

[0086] [ka]

[0087] In the formula, R1, R2, R8, and R9 are arbitrary substituents. R3, R4, R6, and R7 are alkyl, aryl, or a combination thereof. R5 is any substituent, Each X is independently O, N, Se, S, or alkyl, or a combination thereof;

[0088] [ka]

[0089] In the formula, R1 and R5 are arbitrary substituents. R2 and R4 may be any substituent other than OH. R3 may be alkyl, aryl, or a combination thereof. X is independently O, N, Se, S, or alkylene, or a combination thereof;

[0090] [ka]

[0091] In the formula, R1, R2, R4, and R5 are arbitrary substituents. R3 is any substituent, R6 and R7 are alkyl, aryl, or a combination thereof. Each X can independently be O, N, Se, S, alkylene, or a combination thereof; and,

[0092] [ka]

[0093] In certain embodiments, the crosslinking agent may be bis(4-benzoylphenyl) phosphate.

[0094] In some embodiments, the photoactivatable crosslinking agent is ionic and may exhibit good solubility in aqueous compositions (such as the first and / or second coating compositions). Therefore, in some embodiments, one or more ionic photoactivatable crosslinking agents are used to form the coating. In some cases, the ionic photoactivatable crosslinking agent can crosslink polymers within the second coating layer, which can also improve the durability of the coating.

[0095] Any suitable ionic photoactivatable crosslinking agent can be used. In some embodiments, the ionic photoactivatable crosslinking agent is a compound represented by formula I "X1-Y-X2", where Y is a radical having one or more acidic groups, basic groups, or salts of acidic or basic groups. X1 and X2 are each independently radicals having a potential photoreactive group. This photoreactive group may be the same as the photoreactive groups described herein. The spacer may be part of X1 or X2 together with the potential photoreactive group. In some embodiments, the potential photoreactive group has an aryl ketone or a quinone.

[0096] The radical Y in formula I provides the desired water solubility to the ionic photoactivatable crosslinking agent. At room temperature and optimal pH, the water solubility is approximately 0.05 mg / mL or higher. In some embodiments, the solubility is approximately 0.1 to approximately 10 mg / mL or approximately 1 to approximately 5 mg / mL.

[0097] In some embodiments of formula I, Y is a radical having one or more acidic groups or salts thereof. Such photoactivatable crosslinking agents may be anionic depending on the pH of the coating composition. Examples of suitable acidic groups include sulfonic acids, carboxylic acids, and phosphonic acids. Examples of suitable salts of these groups include sulfonates, carboxylates, and phosphates. In some embodiments, the ionic crosslinking agent has a sulfonic acid or a sulfonic acid base. Suitable counterions include alkalis, alkaline earth metals, ammonium, and protonated amines.

[0098] For example, the compound of formula I may contain a radical Y having a sulfonic acid or a sulfonic acid base. X1 and X2 may have photoreactive groups (such as aryl ketones). Examples of such compounds include 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid or salt, 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid or salt, 2,5-bis(4-benzoylmethyleneoxy)benzene-1-sulfonic acid or salt, and N,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethanesulfonic acid or salt. See U.S. Patent No. 6,278,018 (Swan). The counterion of the salt may be, for example, ammonium or an alkali metal (such as sodium, potassium, or lithium).

[0099] In other embodiments of formula I, Y may be a radical having a basic group or a salt thereof. Examples of such radical Y include an ammonium group, a phosphonium group, or a sulfonium group. This group may be neutral or positively charged depending on the pH of the coating composition. In some embodiments, radical Y has an ammonium group. Suitable counterions include, for example, carboxylates, halides, sulfates, and phosphates. For example, the compound of formula I may contain radical Y having an ammonium group. X1 and X2 may have photoreactive groups having aryl ketones. Examples of such photoactivatable crosslinking agents include ethylenebis(4-benzoylbenzylmethylammonium) salt, hexamethylenebis(4-benzoylbenzylmethylammonium) salt, 1,4-bis(4-benzoylbenzyl)-1,4-dimethylpiperazinium salt, bis(4-benzoylbenzyl)hexamethylenetetramineium salt, bis[2-(4-benzoylbenzyldimethylammonio)ethyl]-4-benzoylbenzylmethylammonium salt, 4,4-bis(4-benzoylbenzyl)morpholinium salt, ethylenebis[(2-(4-benzoylbenzyldimethylammonio)ethyl)-4-benzoylbenzylmethylammonium] salt, and 1,1,4,4-tetrakis(4-benzoylbenzyl)piperazinium salt. See U.S. Patent No. 5,714,360 (Swan et al.). The counterion is usually a carboxylate ion or a halide. In one embodiment, the halide is a bromide.

[0100] In other embodiments, the ionic photoactivatable crosslinking agent may be a compound represented by the following formula.

[0101] [ka]

[0102] In the above formula, X1 has a first photoreactive group, X2 has a second photoreactive group, Y contains a core molecule, Z has one or more charged groups, D1 has a first decomposable linker, D2 has a second decomposable linker.

[0103] Examples of further degradable, photoactivatable ionic crosslinkers are described in U.S. Patent Application Publication No. 2011 / 0144373 (Swan et al., "Water Soluble Degradable Crosslinker"). This disclosure is incorporated herein by reference.

[0104] In some embodiments, nonionic photoactivatable crosslinking agents can be used. In one embodiment, a nonionic photoactivatable crosslinking agent is represented by the formula "XR1R2R3R4", where X is a chemical skeleton and R1, R2, R3, and R4 are radicals having potential photoreactive groups. Exemplary nonionic crosslinking agents are described, for example, in U.S. Patents 5,414,075 and 5,637,460 (Swan et al., "Restrained Multifunctional Reagent for Surface Modification"). The first photoreactive group, the second photoreactive group, and their respective spacers may be chemically the same or different.

[0105] In other embodiments, a nonionic photoactivatable crosslinking agent can be represented by the formula "PG2-LE2-X-LE1-PG1".

[0106] In the above formula, PG1 and PG2 independently have one or more photoreactive groups. The above photoreactive group is, for example, an arylketone photoreactive group (such as arylketones such as acetophenone, benzophenone, anthraquinone, anthrone, anthrone-like heterocycles, their substituted derivatives, or combinations thereof), LE1 and LE2 are independently linker elements (for example, parts having urea, carbamate, or a combination thereof), X represents a core molecule that can be either polymerizable or nonpolymerizable. Examples of the core molecules mentioned above include hydrocarbons (but are not limited to these), Examples of hydrocarbons include linear, branched, cyclic, or combination thereof; aromatic, non-aromatic, or combination thereof; monocyclic, polycyclic, carbocyclic, heterocyclic, or combination thereof; benzene or its derivatives; or combination thereof.

[0107] Other nonionic crosslinking agents are described, for example, in U.S. Patent Publication No. 2012 / 0149934 (Kurdyumov, "Photocrosslinker"). This disclosure is incorporated herein by reference.

[0108] Further embodiments of nonionic photoactivatable crosslinking agents are described, for example, in U.S. Patent Publication No. 2013 / 0143056 (Swan et al., "Photo-Vinyl Linking Agents"). This disclosure is incorporated herein by reference. Exemplary crosslinking agents include nonionic photoactivatable crosslinking agents represented by the general formula "R1-X-R2", where R1 is a radical having a vinyl group; X is a radical having about 1 to about 20 carbon atoms; and R2 is a radical having a photoreactive group.

[0109] One or any combination of photoactivatable crosslinking agents can be used to form the coating. In some embodiments, one or more nonionic crosslinking agents (such as tetrakis(4-benzoylbenzyl ether) of pentaerythritol) can be used in combination with one or more ionic crosslinking agents. For example, one or more nonionic photoactivatable crosslinking agents can be used in combination with one or more cationic photoactivatable crosslinking agents (such as ethylenebis(4-benzoylbenzyldimethylammonium) salt). Alternatively, one or more nonionic photoactivatable crosslinking agents can be used in combination with one or more anionic photoactivatable crosslinking agents (e.g., 4,5-bis(4-benzoyl-phenylmethyleneoxy)benzene-1,3-disulfonic acid or salt). In other examples, one or more nonionic crosslinking agents can be used in combination with one or more cationic crosslinking agents and one or more anionic crosslinking agents. Furthermore, in other embodiments, one or more cationic crosslinking agents may be used in combination with one or more anionic crosslinking agents, and nonionic crosslinking agents may not be used.

[0110] An example of a crosslinking agent is disodium 4,5-bis[(4-benzoylbenzyl)oxy]-1,3-benzene disulfonate (DBDS). This reagent can be prepared as follows: First, 4,5-dihydroxylbenzyl-1,3-disulfonate (CHBDS) and 4-bromomethylbenzophenone (BMBP) are combined in THF and sodium hydroxide. Next, the mixture is refluxed and cooled, then purified and recrystallized (this is also described in U.S. Patent No. 5,714,360, which is incorporated herein by reference).

[0111] Further crosslinking agents include those described in U.S. Patent No. 8,487,137 (Guire et al.) and U.S. Patent No. 7,772,393 (Guire et al.). The entire contents of these are incorporated herein by reference.

[0112] In some embodiments, the crosslinking agent may include a boron-containing linker agent. Examples of boron-containing linkers include, but are not limited to, those disclosed in U.S. Patent No. 9,410,044 (Kurdyumov) (this is incorporated herein by reference). For example, the linker agent may have a borate group, a borazine group, or a boronate group, and may include coatings and devices and related methods containing the above linker agent. In one embodiment, the linker agent includes a compound having structure (I).

[0113] [ka]

[0114] In the above formula, R1 is a radical having a photoreactive group. R2 is selected from OH and radicals, and the radical has a photoreactive group, an alkyl group and an aryl group. R3 is selected from OH and radicals, and the radical has a photoreactive group.

[0115] In some embodiments, bonds B-R1, B-R2, and B-R3 are independently selected and may be interposed by heteroatoms (such as O, N, S, or mixtures thereof).

[0116] Further reagents for use in the embodiments described herein include stilbene-based reactive compounds. Such compounds include, but are not limited to, those disclosed in U.S. Patent No. 8,487,137 (Kurdyumov et al., "Stilbene-Based Reactive Compounds, Polymeric Matrices Formed Therefrom, and Articles Visualizable by Fluorescence"), the contents of which are incorporated herein by reference.

[0117] Further photoreactives, crosslinking agents, hydrophilic coatings, and related reagents are disclosed in U.S. Patent No. 8,513,320 (Rooijmans et al.), No. 8,809,411 (Rooijmans), and No. 2010 / 0198168 (Rooijmans). The entire contents of these are incorporated herein by reference.

[0118] Natural polymers may be used to form a hydrophilic base coating. Examples of natural polymers include polysaccharides (e.g., polydextran, carboxymethylcellulose, and hydroxymethylcellulose), glycosaminoglycans (e.g., hyaluronic acid), polypeptides (e.g., soluble proteins such as collagen, albumin, and avidin), and combinations of these natural polymers. Combinations of natural polymers and synthetic polymers can also be used.

[0119] In some examples, a binding layer may be used to form a hydrophilic base layer. In yet another example, a binding layer may be added to the hydrophilic base layer. The binding layer may act to increase the adhesion between the hydrophilic base layer and the substrate. In another embodiment, the binding layer may act to increase the adhesion between the hydrophilic base layer and the hydrophobic surfactant. Examples of binding layers include, but are not limited to, silane, butadiene, polyurethane, and parylene. A silane binding layer is described in U.S. Patent Publication 2012 / 0148852 (Jelle et al.), which is incorporated herein by reference.

[0120] In exemplary embodiments, the hydrophilic base layer may contain tannic acid, polydopamine, or other catechol-containing substances.

[0121] In systems equipped with balloon catheters, insertors can be used. Balloon catheters are commonly used in angioplasty to treat arterial diseases. Balloon angioplasty generally involves dilating or reopening blocked intraluminal pathways. The structure of balloon catheters is well known in the art and described in various publications (e.g., U.S. Patents 4,195,637, 5,041,089, 5,087,246, 5,318,587, 5,382,234, 5,571,089, 5,776,101, 5,807,331, 5,882,336, 6,394,995, 6,517,515, 6,623,504, 6,896,842, 7,163,523, and 8,951,545). See Figure 14. A balloon catheter (parts are not drawn to scale) generally consists of four parts. Specifically, the components are a balloon 1212, a catheter shaft 1210, a guidewire (not shown), and a manifold 1214. The inflatable balloon 1212 is typically attached to the distal end of a flexible catheter shaft 2010. The catheter shaft 2010 may have one or more openings 1213. The presence of the openings 1213 allows for the inflation of the balloon (by fluid, etc.). The catheter shaft can be extended distally by a short length toward the distal tip 1211. A manifold 1214 is typically located at the proximal end of the catheter shaft. The manifold 1214 is configured to remain outside the patient and includes a guidewire port 1217 and an inflation fluid port 1216. At the end of the manifold, catheter placement using a guidewire may be facilitated. The guidewire is small and maneuverable and can facilitate the movement of the balloon catheter into the body through the insertion device and hemostatic valve. In some configurations, the balloon and catheter are fixed to the guidewire and can move together with the guidewire. In other configurations, the balloon and catheter are not fixed to the guidewire and can move independently.

[0122] The catheter body is usually flexible and can be moved through the arterial system once introduced into the subject. The catheter may have a more rigid portion 1215 immediately distal to the inflation port 2014. When it is straight (i.e., the catheter body is straight along a straight path), the catheter may have an axis, the "catheter axis (CA)". The length (L1) of the balloon catheter may vary. A standard balloon catheter length is approximately 50 cm to 150 cm.

[0123] The balloon portion of a balloon catheter may be of various lengths (L2). A specific length can be used based on the patient's diagnosis and the dimensions of the arterial region being treated. Balloon lengths include, for example, approximately 20mm to 300mm, 25mm to 250mm, or 30mm to 160mm. "Shorter" lengths include approximately 20mm to 60mm, or 30mm to 50mm. "Longer" lengths include approximately 80mm to 300mm, or 100mm to 250mm.

[0124] The balloon of a balloon catheter may have a variety of diameters. A specific diameter can be used based on the relative diameter of the artery at the patient's diagnostic and treatment site. The balloon diameter is measured in the inflated state. Diameters are, for example, approximately 0.5 mm to 12 mm, or approximately 1 mm to 8 mm, or approximately 2 mm to 7 mm. Balloon diameters are, for example, approximately 0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm, 3.0 mm, 3.5 mm, 4.0 mm, 4.5 mm, 5.0 mm, 5.5 mm, 6.0 mm, 6.5 mm, 7.0 mm, 7.5 mm, 8.0 mm, 8.5 mm, 9.0 mm, 9.5 mm, 10.0 mm, 10.5 mm, 11.0 mm, 11.5 mm, and 12.0 mm.

[0125] Refer to Figure 15, which shows a cross-sectional view of the balloon portion from the distal end. Before inflation, the balloon can be folded and compressed to deliver it to the target site. The balloon can be folded around the catheter body 1301. This reduces the radial profile of the balloon catheter, facilitating its movement into the body through the insertor. The balloon folding process may include (i) creating "arms" 1302 of the balloon material, and (ii) folding these arms inward (towards the catheter axis) to compress the balloon material. Depending on the balloon and the folding process, the deflated and folded balloon may have two or more arms (e.g., three, four, five, six, seven, eight, nine, ten, eleven, or twelve folding arms).

[0126] In its folded state, the balloon portion may have a "maximum cross-sectional profile." The "maximum cross-sectional profile" is the maximum diameter between the distal end 1215 of the manifold (Figure 14) and the distal end (tip) 1211 (Figure 14) of the catheter. The maximum cross-sectional profile may occur, for example, at one or more points, in a continuous section, over most of the folded balloon portion, or along its entire length. The maximum cross-sectional profile may also occur at points where the balloon is in contact with (e.g., joined to or bonded to) the catheter shaft (see points 1524 and 1526 in Figure 17).

[0127] In one embodiment, as shown in Figure 15, the maximum cross-sectional profile of the folded balloon is length L3. For example, length L3 may be the diameter of the folded balloon. This diameter is between the outer surface of the distal end 1305 of the folded balloon arm and the outer surface of the radially opposing distal end 1307 of the folded balloon arm. In some embodiments, the maximum cross-sectional profile is about 2.20 mm or less, about 2.15 mm or less, about 2.10 mm or less, about 2.05 mm or less, about 2.00 mm or less, about 1.95 mm or less, about 1.90 mm or less, or about 1.85 mm. In some embodiments, the maximum cross-sectional profile is about 1.60 mm to about 2.20 mm, about 1.65 mm to about 2.10 mm, or about 1.70 mm to about 2.00 mm, or about 1.75 mm to about 1.90 mm. In some embodiments, the maximum cross-sectional profile is approximately 1.70 mm to 2.00 mm, or approximately 1.75 mm to 1.90 mm, and the balloon length is approximately 100 mm or less (e.g., approximately 20 mm to 100 mm), or approximately 60 mm or less (e.g., approximately 20 mm to 100 mm).

[0128] Figures 16a to 16g illustrate various embodiments of loading a folded balloon catheter into an insert. These figures reflect cross-sectional views of the balloon portion and the insert from the distal end. Figure 16a shows a folded balloon portion with a maximum cross-sectional profile of "L4". L4 is, for example, about 1.70 mm to 2.00 mm, or about 1.75 mm to 1.90 mm. Figure 16b is a cross-sectional view of an insert where the inner diameter L5 is less than or equal to the maximum cross-sectional profile L4 of the folded balloon. In some cases, L5 is less than L4. For example, L5 is about 90% to 99% of the length L4, or about 95% to 99%. In these embodiments, the outer surface of the folded balloon exerts force on the inner wall of the insert. This can cause the insert to expand radially (e.g., the wall deforms), the folded balloon to compress further, or both. For example, Figure 16e shows an insert (as in Figure 16b) loaded with a folded balloon. This balloon expands the diameter of the insert radially. If L5 is less than or equal to L4, the wall 1401 of the insert may be relatively thin. The wall thickness is, for example, less than approximately 0.075 mm, less than 0.06 mm, or less than 0.05 mm (approximately 0.025 mm to approximately 0.06 mm, or approximately 0.025 mm to approximately 0.05 mm).

[0129] Figure 16c is a cross-sectional view of an insert where the inner diameter L6 is at least equal to or slightly greater than the maximum cross-sectional profile L4 of the folded balloon. In these embodiments, the folded balloon is contained within the inner diameter of the insert. The space between the inner wall of the insert and the outer surface of the folded balloon is minimal or nonexistent. This can be beneficial during balloon catheter insertion because it minimizes (or prevents) blood reflux. Minimizing blood reflux also improves the safety of the procedure and allows for the maintenance of desirable balloon properties (e.g., minimizing drug loss and / or preventing hydration of the balloon coating when using a drug-coated balloon). When L6 is greater than or equal to L4, the wall 1403 of the insert may be thicker. The wall thickness is, for example, greater than about 0.025 mm or greater than about 0.05 mm (e.g., about 0.05 mm to about 0.20 mm).

[0130] Figure 16d is a cross-sectional view of an insert in which the inner diameter L7 is greater than the maximum cross-sectional profile L4 of the folded balloon. In these embodiments, the folded balloon is housed within the inner diameter of the insert. A certain gap 1405 exists between the inner wall of the insert and the outer surface of the folded balloon. This configuration facilitates the movement of the balloon portion of the balloon catheter within the insert. However, preferably, the gap is limited to minimize blood backflow. In some preferred embodiments, the maximum cross-sectional profile of the folded balloon is about 80% or more, about 82% or more, about 84% or more, about 86% or more, about 88% or more, about 90% or more, about 92% or more, about 94% or more, about 96% or more, or about 98% or more of the inner diameter of the insert (for example, about 80% to about 99%, about 82% to about 99%, about 84% to about 99%, about 86% to about 99%, about 88% to about 99%, about 90% to about 99%, about 92% to about 99%, about 94% to about 99%, about 96% to about 99%, or about 98% to about 99%) of the inner diameter of the insert.

[0131] The method of the present disclosure allows for the insertion of a balloon catheter into a patient's body by a method comprising the following steps: First, (i) a balloon catheter comprising a catheter shaft and a balloon portion having a certain length, and (ii) an insertion device for inserting the balloon catheter into the patient's body. The insertion device is one of the present disclosures and comprises: a proximal end and a distal end along the longitudinal axis; a tubular portion having a length greater than or equal to the length of the balloon portion and extending proximal from the distal end; and a knob at the proximal end. The tubular portion comprises: a wall; an inner diameter capable of accommodating the balloon portion of the balloon catheter; and a separation margin in the wall of the first longitudinal half of the tubular portion, representing a structural weak point or a division in the wall of the first half. The knob is either (1) a knob extending from the second longitudinal half of the tubular portion and having a portion oblique to the longitudinal axis, or (2) a knob in the form of a solid object having a concave surface and fixed to the outer surface of the second longitudinal half of the tubular portion.

[0132] Next, the distal end of the insertion device, which contains a balloon, is inserted into the hemostatic valve. Then, the tubular portion of the insertion device and the balloon catheter inside it are advanced into the patient's body through the hemostatic valve.

[0133] A portion of the proximal end of the insert may remain proximal to the hemostatic valve during insertion. By partially advancing the insert through the hemostatic valve, the inflatable portion of the balloon catheter can be fully advanced into the body through the insert.

[0134] Next, withdraw the tubular portion of the insert from the hemostatic valve, positioning at least the proximal portion of the tubular portion around the catheter shaft proximal to the balloon portion. Then, move the insert relative to the balloon catheter, separating the separation margin so that the insert can move away from the catheter shaft.

[0135] Alternatively, the insertion device is positioned proximal to the inflatable portion of the balloon catheter. In this case, the inflatable portion remains protected by the separation protective sheath. After removing the sheath, the insertion device can be advanced over the folded inflatable portion. The balloon can then be inserted into the catheter through the hemostatic valve.

[0136] To remove the insert, an outward or proximal force may be applied to the insert's knob. This separates the separation margin, allowing the insert to move away from the catheter shaft. Alternatively, the tubular portion of the insert can be pulled out along the entire catheter shaft to the proximal hub. The proximal hub acts as a wedge, separating the separation margin. As a result, the insert can move away from the catheter shaft. Alternatively, the user can move the insert to the proximal end of the balloon catheter (the OD of the proximal end of the balloon catheter is greater than the ID of the tubular portion). Up to the proximal end of the catheter, it acts as a wedge, allowing the insert to cleave along the split.

[0137] The treatment of plaque areas will be explained in more detail. The balloon portion of the balloon catheter is inserted into the insert and can be advanced through the hemostatic valve in its undinverted state. The flared opening of the insert can prevent loss of the coating on the balloon portion. After moving the guidewire to the position for plaque treatment, the balloon portion is moved through the hemostatic valve. Next, the catheter with the balloon portion is advanced along the guidewire until the balloon reaches the site for plaque treatment. Then, the balloon can be inflated at the plaque site to perform the treatment. A manifold can also be used to control the introduction of fluid into the shaft and inflate the balloon.

[0138] Balloons are typically inflated using a fluid, which is injected through an inflation port. The mechanism for transferring and introducing the fluid into the balloon varies depending on the specific design of the catheter. Such mechanisms are well known in the art.

[0139] In some embodiments, a bioactive substance is associated with the surface of the balloon portion of a balloon catheter. The bioactive substance may be associated in a way that allows it to be released from the balloon portion. Alternatively, the bioactive substance may be associated in a way that prevents it from being released from the balloon portion, in a manner that allows it to be delivered to body tissue. In some embodiments, the balloon portion has a coating (such as a hydrophilic coating or hydrogel coating as described herein). This coating can regulate the release of the bioactive substance. For example, the bioactive substance may be present in a polymer material coated on the surface of the balloon and be releaseable from the material. Alternatively, a polymerizable coating may be applied over a drug or drug-containing layer to function as a topcoat that regulates the release of the bioactive substance.

[0140] Examples of bioactive substances include, but are not limited to, antibiotics, anti-inflammatory agents, growth inhibitors, immunomodulators, mitotic inhibitors, and anesthetics.

[0141] Examples of physiologically active substances that may be released from or present in the balloon portion include the following:: Sirolimus (rapamycin), rapamycin analog (rapalog), tacrolimus, everolimus, zotarolimus, temsirolimus, pimecrolimus, ridaflorimus, paclitaxel, taxane, dexamethasone, betamethasone, paclitaxel, vinblastine, vincristine, vinorelbine, poside, teniposide, dactinomycin (actinomycin D), daunorubicin, doxorubicin, idarubicin, anthracycline, mitoxantrone, bleomycin, plicamycin (mitramycin), mitomycin, Mechloretamine, cyclophosphamide and its analogues, melphalan, chlorambucil, ethyleneimine and methylmelamine, alkylsulfonate-busulfan, nitrosourea, carmustine (BCNU) and its analogues, streptozocin, trazene-dacarbazine, methotrexate, fluorouracil, floxuridine, cytarabine, mercaptopurine, thioguanine, pentostatin, 2-chlorodeoxyadenosine, cisplatin, carboplatin, procarbazine, hydroxyurea, mitotane, aminoglutethyme Estrogen, heparin, synthetic heparin salts, tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, clopidogrel, absiximab, breferdin, cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6U-methylprednisolone, triamcinolone, aspirin, acetaminophen, indomethacin, sulindac, etodolac, tolmetin, diclofenac, ketrolac, ibuprofen and derivatives, mefenamic acid, meclo Fenamic acid, piroxicam, tenoxicam, phenylbutazone, oxyfentatrazone, nabumetone, auranofin, gold thioglucose, sodium gold thiomalate, cyclosporine, tacrolimus (FK-506), azathioprine, mycophenolate mofetil, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiotensin receptor blockers, nitric oxide donors, antisense oligonucleotides and combinations thereof, cell cycle inhibitors, mTOR inhibitors, and growth factor signaling kinase inhibitors.

[0142] Other exemplary embodiments of bioactive substances include plaque-penetrating peptides (such as those reported in She et al., J. Contr. Rel. 238:212-220), therapeutic antibodies, and siRNA or microRNAs (miRNAs; e.g., Feinberg et al.) that target atherosclerosis. Examples include, but are not limited to, Circ Res. 118:703-20 (2016).

[0143] Other exemplary embodiments of bioactive substances include, but are not limited to, bioactive substances for the treatment of hypertension (HTN) (such as guanethidine).

[0144] In certain embodiments, the bioactive substance is selected from the group consisting of paclitaxel, sirolimus (rapamycin), and mixtures thereof.

[0145] In some embodiments, the bioactive substance is associated with the balloon portion and is present within or in the form of microparticles. These microparticles are associated with the balloon portion. When the second tube expands, the microparticles may be released or dissociated from the balloon surface. Examples of coatings include coatings containing hydrophilic polymers and coatings containing biodegradable polymers. After release from the balloon portion, the microparticles become associated with tissue and are able to release the bioactive substance.

[0146] In one embodiment, the plaque treatment portion comprises a flexible hydrogel coating and microparticles associated with the balloon coating. The microparticles may be associated with the coating in a non-homogeneous manner. For example, the microparticles may be associated (a) near the surface of the flexible hydrogel coating, (b) mainly near the flexible hydrogel coating / surface, or (c) homogeneously distributed and associated within the flexible hydrogel coating. When visualized, microparticles slightly embedded in the flexible hydrogel coating may appear to be adhering to the coating surface. Examples of balloon coatings containing microparticles with a bioactive substance (e.g., paclitaxel) are described in U.S. Patents 8,951,545 and 9,669,192.

[0147] In one embodiment, the balloon comprises a flexible hydrogel coating, on which a coating containing a bioactive substance and an additive is provided. The additive may function as a release agent (or an agent that facilitates the delivery of a drug to the treatment tissue). The additive may be a polycation.

[0148] The microparticles may be particulate components containing bioactive substances. Furthermore, the microparticles can be released from the surface of the balloon portion. The microparticles can be any three-dimensional particles (e.g., approximately 100 nm to 10 μm; spherical or substantially spherical, non-spherical, or irregularly shaped (e.g., rod-shaped, fibrous, fragment-shaped, or needle-shaped)) that are sufficiently large and shaped to be attached to the surface via the coating material and then dissociate during balloon inflation.

[0149] The microparticles may contain biocompatible materials that incorporate and / or coat with bioactive substances. These biocompatible materials may include biodegradable polymers (such as PLA and PLGA), (semi)solid lipids, and biosilica.

[0150] Microparticles formed from only one or more bioactive substances can also be associated with the balloon surface and released in vivo to target tissue. In other words, microparticles may be formed from substantially one or more bioactive substances, or entirely from one or more bioactive substances. In this case, no additives are required to control the release of bioactive substances from the microparticles. Microparticles that consist entirely of (or almost entirely of) bioactive substances are sometimes referred to herein as “pure” microparticles (for example, they may contain trace amounts of one or more other components).

[0151] Bioactive substances can be in amorphous, crystalline, or any mixture thereof.

[0152] For example, the preparation of paclitaxel microparticles is described in U.S. Patent No. 6,610,317. U.S. Patent Applications 14 / 280,054 (2014 / 0343491; Slager) and 14 / 303,309 (2015 / 0017219; Slager et al.) by the same applicant describe methods for preparing macrolide particles of desired shape and size using various solvents and / or processing techniques.

[0153] [Aspects of the present invention] The present invention includes the following embodiments. <1> An insertion device configured to facilitate the entry of the balloon portion of a balloon catheter into the patient's body via a hemostatic valve, wherein the insertion device is The proximal and distal ends along the longitudinal axis, A tubular portion extending proximal from the distal end, having a length greater than or equal to the length of the balloon portion, wherein the tubular portion is wall; An inner diameter capable of accommodating the balloon portion of a balloon catheter; and, A separation margin in the wall of the first longitudinal half of the tubular portion, which represents (i) a structural weakness in the wall of the first half, or (ii) a split in the wall of the first half; It has a tubular portion and The knob located at the proximal end, (a) A knob having a portion that extends from the second longitudinal half of the tubular portion and is at an angle to the longitudinal axis; or, (b) A knob in the form of a solid object having a concave surface, attached to the outer surface of the second longitudinal half of the tubular portion; The knob is one of the following: An insertion device equipped with these features. <2> The above (a) and / or (b) are met, <1> Insertion device as described: (a) The distal end is tapered, inclined, flared, or a combination thereof; (b) The proximal end of the tubular portion is tapered, inclined, flared, or a combination thereof. <3> The proximal end of the tubular portion is tapered, and the second half is also tapered. <1> or <2> The insertion device described above. <4> The knob mentioned above extends from the tapered portion of the second half. <3> The insertion device described above. <5> The knob described above has multiple angles that intersect obliquely with respect to the longitudinal axis. <1> ~ <4> An insertion device as described in any of the following. <6> The knob described above has a curved structure relative to its longitudinal axis. <1> ~ <5> An insertion device as described in any of the following. <7> The knob described above has a width and length along its axis, The longitudinal axis of the tubular member is perpendicular to the axis of the width of the knob. <1> ~ <6> An insertion device as described in any of the following. <8> The tubular portion described above has an outer circumference, The width of the above knob is (i) 10% or more of the above circumference, or (ii) 10% to 100% of the above circumference. <7> The insertion device described above. <9> The length of the above knob is greater than the width of the knob. <7> The insertion device described above. <10> The above separation margin has a fissure in the wall of the tubular member. The depth of the crack is 10% or more of the thickness of the wall. <1> ~ <9> An insertion device as described in any of the following. <11> The above crack is V-shaped. <10> The insertion device described above. <12> The above separation margin has a dividing portion in the above wall, In the first half of the tubular member described above, the first longitudinal portion and the second longitudinal portion overlap. <1> ~ <9> An insertion device as described in any of the following. <13> Meets one or more of the following dimensions: <1> ~ <12> Insertion device as described in any of the following: (i) The length of the tubular portion is approximately 10 mm to 300 mm, approximately 10 mm to 100 mm, approximately 50 mm to 150 mm, or approximately 150 mm to 300 mm; (ii) The outer circumference of the tubular portion is approximately 1.1 mm to 32 mm, approximately 2.5 mm to 15 mm, or approximately 3 mm to 6 mm; (iii) The outer diameter of the tubular portion is approximately 0.35 mm to 10 mm, approximately 1.5 mm to 5 mm, or approximately 1.6 mm to 3 mm; (iv) The inner diameter of the tubular portion is approximately 0.25 mm to 5 mm, approximately 1 mm to 4 mm, approximately 1.2 mm to 3 mm, or approximately 1.25 mm to 2.75 mm; (v) The wall thickness of the above tubular portion is approximately 0.05 mm to approximately 2.5 mm, approximately 0.05 mm to approximately 0.5 mm, approximately 0.05 mm to approximately 0.25 mm, approximately 0.05 mm to approximately 0.20 mm, approximately 0.05 mm to approximately 0.15 mm, approximately 0.10 mm to approximately 0.25 mm, or approximately 0.15 mm to approximately 1.5 mm; and / or (vi) The depth of the crack is approximately 0.025 mm to 1 mm, approximately 0.05 mm to 0.25 mm, or approximately 0.05 mm to 0.15 mm. <14> The material comprises a material selected from the group consisting of fluorinated ethylene propylene (FEP), high-density polyethylene and low-density polyethylene (HDPE and LDPE), polytetrafluoroethylene (PTFE; Teflon), PEBAX, polyurethane, polyamide (nylon), polyimide, and polyester. <1> ~ <13> An insertion device as described in any of the following. <15> The above tubular member has an outer surface and an inner surface. The above-mentioned outer and inner surfaces can be associated with low-friction materials, independently of (or both of) each other. <1> ~ <14> An insertion device as described in any of the following. <16> The low-friction material mentioned above is a hydrophilic coating or a fluoropolymer sleeve. <15> The insertion device described above. <17> <1> ~ <16> An inserting device as described in any of the following, Balloon catheter and A balloon catheter insertion system equipped with, The balloon portion of the balloon catheter described above is of arbitrary configuration and is loaded into a part of the tubular portion of the balloon catheter described above. system. <18> The balloon portion described above includes a folded balloon and has the diameter of the folded balloon. The diameter of the folded balloon described above is either greater than, equal to, or less than the inner diameter of the tubular member described above. <17> The system described above. <19> The diameter of the folded balloon is greater than the inner diameter of the tubular member. The wall thickness of the above tubular member is less than 0.075 mm, less than 0.06 mm, or less than 0.05 mm, or approximately 0.025 mm to approximately 0.06 mm, or approximately 0.025 mm to approximately 0.05 mm. When introduced into the tubular member, the tubular member deforms to accommodate the folded balloon. <18> The system described above. <20> The diameter of the folded balloon is less than the inner diameter of the tubular member. The above diameters are approximately 80% to 99%, 86% to 99%, 90% to 99%, 94% to 99%, or 96% to 99% of the inner diameter of the above tubular member. <18> The system described above. <21> The outer surface of the above-mentioned insertion device, the outer surface of the catheter shaft of the above-mentioned balloon catheter, or both, are marked with one or more coloring agents or contrast agents. The above markings facilitate the positioning of the balloon catheter or the insertion device. <18> The system described above. <22> (i) A balloon catheter having a balloon portion of a certain length, (ii) Hemostatic valve and, (iii) Insertion device and A balloon catheter insertion system equipped with, The above-mentioned insertion device is an insertion device that facilitates the entry of the balloon portion of the balloon catheter into the patient's body via the hemostatic valve, The proximal and distal ends along the longitudinal axis, A tubular portion extending proximal from the distal end, having a length greater than or equal to the length of the balloon portion, wherein the tubular portion is wall; An inner diameter capable of accommodating the balloon portion of a balloon catheter; and, A separation margin in the wall of the first longitudinal half of the tubular portion, which represents (i) a structural weakness in the wall of the first half, or (ii) a split in the wall of the first half; It has a tubular portion and The knob located at the proximal end, (a) A knob having a portion that extends from the second longitudinal half of the tubular portion and is at an angle to the longitudinal axis; or, (b) A knob in the form of a solid object having a concave surface, fixed to the outer surface of the second longitudinal half of the tubular portion; The knob is one of the following: A balloon catheter insertion system equipped with the following features. <23> <1> ~ <16> An insert described in any of the following, <18> ~ <21> The system is equipped with one of the systems described in any of the following: <22> The system described above. <24> The balloon catheter described above has a therapeutic agent on the surface of the balloon, <22> or <23> The system described above. <25> The balloon catheter described above has a polymerizable coating on the surface of the balloon. <22> ~ <24> A system described in any of the following. <26> The following conditions (i) and / or (ii) are met: <24> or <25> The system described above: (i) The above therapeutic agent contains rapamycin; (ii) The polymerizable coating described above contains a hydrogel. <27> The above tubular member is equipped with a stopping member, The above-mentioned stopping member extends radially outward from the outer surface of the tubular member. The stopping member can contact a portion of the proximal end of the hemostatic valve, thereby preventing the insertion device from moving further distally through the hemostatic valve. <22> ~ <26> A system described in any of the following. <28> A method for inserting a balloon catheter into a patient's body, the above method is (a)(i) a balloon catheter comprising a balloon portion having a certain length and a catheter shaft adjacent to the balloon portion, and (ii) an insertion device for inserting the balloon catheter into the body of a patient, (b) The step of inserting the distal end of the above-mentioned insertion device into the hemostatic valve, (c) The step of advancing the tubular portion of the insertion device and the balloon catheter contained therein into the patient's body through the hemostatic valve, (d) The step of withdrawing the tubular portion of the insertion device from the hemostatic valve and positioning at least the proximal portion of the tubular portion around the catheter shaft, (e) The step of moving the insertion device relative to the balloon catheter, separating the separation margin, and enabling the insertion device to move away from the catheter shaft, Includes, The above-mentioned insert is The proximal and distal ends along the longitudinal axis, A tubular portion extending proximal from the distal end, having a length greater than or equal to the length of the balloon portion, wherein the tubular portion is wall; An inner diameter capable of accommodating the balloon portion of a balloon catheter; and, A separation margin in the wall of the first longitudinal half of the tubular portion, which represents (i) a structural weakness in the wall of the first half, or (ii) a split in the wall of the first half; It has a tubular portion and The knob located at the proximal end, (1) A knob having a portion that extends from the second longitudinal half of the tubular portion and is at an angle to the longitudinal axis; or, (2) A knob in the form of a solid object having a concave surface, fixed to the outer surface of the second longitudinal half of the tubular portion; The knob is one of the following: A method that includes [the following features]. <29> <1> ~ <16> An insert described in any of the following, <18> ~ <27> The step includes using the system described in any of the following: <28> Methods used. <30> The movement in step (e) includes a step of applying an outward force to the knob mentioned above. As a result, a force is generated from the outer surface of the catheter shaft toward the first half of the inner diameter of the tubular member. <28> or <29> Methods used. <31> The outward force in step (e) causes the wall of the tubular member to break along the separation margin, which is a structural weak point of the wall. <30> Methods used. <32> Due to the outward force in step (e), the divided portion on the wall expands outward. The first longitudinal portion in the first half of the tubular member separates from the second longitudinal portion in the first half of the tubular member. <30> Methods used. <33> In step (e), the user grasps the knob with two fingers and pulls the knob away from the catheter shaft. <28> ~ <32> One of the methods described above. <34> Used in conjunction with angioplasty procedures, <28> ~ <33> One of the methods described above. <35> An insertion device configured to facilitate the entry of the balloon portion of a balloon catheter into the patient's body via a hemostatic valve, wherein the insertion device is The proximal and distal ends along the longitudinal axis, A tubular portion extending proximal from the distal end, having a length greater than or equal to the length of the balloon portion, wherein the tubular portion is wall; The inner diameter that can accommodate the balloon portion of a balloon catheter; A first separation margin and a second separation margin on the wall of the tubular portion, which represent a structural weakness or a division in the wall of the tubular portion, and define the first longitudinal half and the second longitudinal half of the tubular portion; It has a tubular portion and A first knob extending from the first longitudinal half of the tubular portion, and a second knob extending from the second longitudinal half of the tubular portion, An insertion device equipped with these features. <36> The first knob and the second knob described above have a curved structure with respect to the longitudinal axis. <35> The insertion device described above. <37> The first separation margin and the second separation margin have a crack in the wall of the tubular member. The depth of the crack is 10% or more of the thickness of the wall. <35> or <36> The insertion device described above. <38> The above crack is V-shaped. <37> The insertion device described above. <39> Meets one or more of the following dimensions: <35> ~ <38> Insertion device as described in any of the following: (i) The length of the tubular portion is approximately 10 mm to 300 mm, approximately 10 mm to 100 mm, approximately 50 mm to 150 mm, or approximately 150 mm to 300 mm; (ii) The outer circumference of the tubular portion is approximately 1.1 mm to 32 mm, approximately 2.5 mm to 15 mm, or approximately 3 mm to 6 mm; (iii) The outer diameter of the tubular portion is approximately 0.35 mm to 10 mm, approximately 1.5 mm to 5 mm, or approximately 1.6 mm to 3 mm; (iv) The inner diameter of the tubular portion is approximately 0.25 mm to 5 mm, approximately 1 mm to 4 mm, approximately 1.2 mm to 3 mm, or approximately 1.25 mm to 2.75 mm; (v) The wall thickness of the above tubular portion is approximately 0.05 mm to approximately 2.5 mm, approximately 0.05 mm to approximately 0.5 mm, approximately 0.05 mm to approximately 0.25 mm, approximately 0.05 mm to approximately 0.20 mm, approximately 0.05 mm to approximately 0.15 mm, approximately 0.10 mm to approximately 0.25 mm, or approximately 0.15 mm to approximately 1.5 mm; and / or (vi) The depth of the crack is approximately 0.025 mm to 1 mm, approximately 0.05 mm to 0.25 mm, or approximately 0.05 mm to 0.15 mm. <40> The material comprises a material selected from the group consisting of fluorinated ethylene propylene (FEP), high-density polyethylene and low-density polyethylene (HDPE and LDPE), polytetrafluoroethylene (PTFE; Teflon), PEBAX, polyurethane, polyamide (nylon), polyimide, and polyester. <35> ~ <39> An insertion device as described in any of the following. <41> The above tubular member has an outer surface and an inner surface. The above-mentioned outer and inner surfaces can be associated with low-friction materials, independently of (or both of) each other. <35> ~ <40> An insertion device as described in any of the following. <42> The low-friction material mentioned above is a hydrophilic coating or a fluoropolymer sleeve. <41> The insertion device described above. <43> <35> ~ <42> An inserting device as described in any of the following, Balloon catheter and A balloon catheter insertion system equipped with, The balloon portion of the balloon catheter described above is of arbitrary configuration and is loaded into a part of the tubular portion of the balloon catheter described above. system. <44> The balloon portion described above includes a folded balloon and has the diameter of the folded balloon. The diameter of the folded balloon described above is either greater than, equal to, or less than the inner diameter of the tubular member described above. <43> The system described above. <45> The diameter of the folded balloon is greater than the inner diameter of the tubular member. The wall thickness of the above tubular member is less than 0.075 mm, less than 0.06 mm, or less than 0.05 mm, or approximately 0.025 mm to approximately 0.06 mm, or approximately 0.025 mm to approximately 0.05 mm. When introduced into the tubular member, the tubular member deforms to accommodate the folded balloon. <44> The system described above. <46> The diameter of the folded balloon is less than the inner diameter of the tubular member. The above diameters are approximately 80% to 99%, 86% to 99%, 90% to 99%, 94% to 99%, or 96% to 99% of the inner diameter of the above tubular member. <18> The system described above. <47> The outer surface of the above-mentioned insertion device, the outer surface of the catheter shaft of the above-mentioned balloon catheter, or both, are marked with one or more coloring agents or contrast agents. The above markings facilitate the positioning of the balloon catheter or the insertion device. <43> The system described above. <48> (i) <35> ~ <42> A balloon catheter insertion system comprising (ii) an insertion device as described in any of the above, and (ii) a hemostatic valve; or, (i) the above-mentioned insert and (ii) <35> ~ <42> A balloon catheter insertion system comprising (iii) a balloon catheter as described in any of the above, and (iii) a hemostatic valve. <49> A method of inserting a balloon catheter into a patient's body, <35> ~ <42> Steps using the insert described in any of the following: <43> ~ <48> Steps using one of the systems described above; Methods that include...

Claims

1. An insertion device configured to facilitate the entry of the balloon portion of a balloon catheter into the patient's body via a hemostatic valve, wherein the insertion device is The proximal and distal ends are aligned along the longitudinal axis, and each end has a tapered and flared opening. A tubular portion extending proximal from the distal end, having a length greater than or equal to the length of the balloon portion, wherein the tubular portion is wall; An inner diameter capable of accommodating the balloon portion of a balloon catheter; and, A separation margin in the wall of the first longitudinal half of the tubular portion, which represents (i) a structural weakness in the wall of the first longitudinal half, or (ii) a split in the wall of the first longitudinal half; It has a tubular portion and The above tubular portion has a tapered proximal end that tapers from the first longitudinal half to the second longitudinal half, A knob located at the proximal end, which extends from the second longitudinal half of the tubular portion and has a portion that is oblique to the longitudinal axis, An insertion device equipped with these features.

2. The tubular portion described above is composed of the first longitudinal half and the second longitudinal half, The first longitudinal half and the second longitudinal half are opposite each other. The tapered proximal end has a tapered shape in the second longitudinal half. The inserting device according to claim 1.

3. The inserting device according to claim 2, wherein the knob extends from the tapered shape of the second longitudinal half.

4. The inserting device according to any one of claims 1 to 3, wherein the knob has multiple angles that intersect obliquely with respect to the longitudinal axis.

5. The inserting device according to any one of claims 1 to 4, wherein the knob has a curved structure with respect to the longitudinal axis.

6. An inserting device according to any one of claims 1 to 5, Balloon catheter and A kit that includes these features.

7. The balloon portion of the balloon catheter described above is not loaded into the tubular portion of the insertion device described above. The kit according to claim 6.

8. An inserting device according to any one of claims 1 to 5, Balloon catheter and Hemostatic valve and, A balloon catheter insertion system equipped with the following features.

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