Drug coated balloon manufacturing method and drug coated balloon

Abstract

The present invention provides a method for manufacturing a drug-coated balloon and a drug-coated balloon obtained by the method. The method for manufacturing a drug-coated balloon is used to apply a drug coating on the surface of a balloon body prepared in advance and in a filled and expanded state, and the anti-proliferative drug component in the drug coating is one or more of nimustine, carmustine, 5-fluorouracil, fluguanosine, gemcitabine, daunorubicin, doxorubicin, paclitaxel, vinblastine, topotecan, aminoglutethimide, sirolimus, everolimus, and zotarolimus. The drug-coated balloon prepared by the method can effectively ensure that when the balloon enters the human body, the thickness of the drug coating on the balloon surface is more uniform and consistent, thereby improving the clinical use effect.

Description

Technical Field

[0001] The present invention generally relates to a method for manufacturing a medical device, and more particularly to a method for manufacturing a drug-coated balloon, and more particularly to a method for manufacturing a novel drug-coated balloon for use in the field of coronary and peripheral intervention and various embodiments of the novel drug-coated balloon manufactured by the manufacturing method. Background Art

[0002] As is known to all, drug-coated balloons are a new treatment method for intracavitary treatment that has emerged in recent years. It is known that drug-coated balloon intervention technology can significantly reduce the probability of restenosis and can be used in any part of the human blood vessels, especially in the field of coronary and peripheral intervention. In addition, even if restenosis unfortunately occurs, drug-coated balloon intervention technology will not increase the difficulty of reoperation, showing the good prospects for the use of drug-coated balloons.

[0003] However, although drug-coated balloons can alleviate the side effects of balloon angioplasty and stent implantation to a certain extent, drug loss is inevitable during the delivery process of drug-coated balloons, which more or less affects the final efficacy.

[0004] It is well known that in order to reduce drug loss during drug balloon delivery (for example, due to improper operation during the delivery process, the attached drug coating touches the inner wall of the blood vessel and causes complete or partial detachment, etc.), technical means can be adopted, such as optimizing the structure of the balloon catheter, reducing the outer diameter of the balloon after folding, reducing the contact area between the balloon and the hemostatic valve, and improving the formulation of the drug coating on the balloon surface. For example, see Patent Document 1 and Patent Document 2 given below.

[0005] For example, Patent Document 2 mentions that a balloon is pre-folded into three wings, and then the folded balloon is inflated and expanded. Thereafter, the inflated balloon (at this time, the three wings of the balloon are in a popped-out state) is placed in a vacuum environment, and a coating machine is used to disperse the drug on the balloon surface to form a uniform surface coating. Finally, negative pressure is applied to the drug-coated balloon prepared as above to deform it into a three-wing coated shape, and a protective sleeve is placed therein to protect the drug coating from loss.

[0006] Although the solution provided in Patent Document 2 can achieve uniform coating and consistent thickness on the surface of a specific object (inflated balloon) by the coating machine to a certain extent, the inventor of the present invention has found after a large number of experiments and in vivo tests that the above-mentioned uniform coating and consistent thickness are only achieved temporarily in the intermediate state (transition state) of the drug balloon preparation process, rather than on the final product (i.e., the balloon product available on the market). In particular, as mentioned above, in the subsequent step after the coating step of the coating machine, i.e., the step of pumping negative pressure on the balloon with the drug coating on the surface, when the inflated balloon is deformed into a balloon in a compact state of a three-wing coated shape by negative pressure, part of the drug coating will be unfavorably caused to fall off or be damaged near the fold position of the three wings due to bending stress. Accordingly, the final product (drug-coated balloon) obtained after placing the drug-coated balloon in the protective cover and the balloon in the three-wing pop-up state after the final product is delivered to the human blood vessels and inflated and opened during use, cannot satisfactorily achieve uniformity and consistent thickness of the drug coating on the balloon surface.

[0007] Citations

[0008] Patent document 1, CN209108383U.

[0009] Patent document 2, CN115105727A. Summary of the invention

[0010] The purpose of the embodiment of the present invention is to provide a drug-coated balloon manufacturing device and a manufacturing method thereof, as well as a drug-coated balloon obtained by the drug-coated balloon manufacturing device and the manufacturing method thereof, to solve the technical problem that although the thickness of the balloon surface can be ensured to be uniform in the intermediate state (the inflated and expanded balloon), it cannot be ensured that the thickness of the balloon surface is basically uniform in the final state (the compact state of the balloon flaps covering the balloon body). In order to solve the above technical problems, the embodiment of the present invention is implemented as follows:

[0011] In the first aspect, an embodiment of the present invention provides a method for manufacturing a drug-coated balloon, which is used to coat a drug coating on the surface of a balloon body that has been prepared in advance and is inflated and expanded, and a plurality of marking lines are pre-arranged on a connecting portion that is connected to the balloon body and rotates coaxially with the balloon body, and two adjacent marking lines on the connecting portion correspond to the crease positions corresponding to the fold wings of the balloon formed on the balloon body. The drug coating balloon manufacturing method includes: providing a drug in a liquid or solid particle suspension state, and coating the drug on the surface of the balloon body in a filled and expanded state through a coating device to form a drug coating; driving the coating device to move in one or more directions among the three directions of the X axis, the Y axis, and the Z axis; driving the balloon body and the connecting part to coaxially rotate at a predetermined speed in a clockwise or counterclockwise direction; when driving the balloon body and the connecting part to coaxially rotate at a predetermined speed, sequentially detecting each of the multiple marking lines pre-set on the connecting part; and, during the period of detecting two adjacent marking lines twice, sending a control instruction to change the movement of the coating device in one or more axes of the X axis, the Y axis, and the Z axis, and / or the speed of the balloon body. The drug coating thickness formed at the corresponding fold position on the surface of the balloon body in the filled and expanded state obtained by the drug coating balloon manufacturing method is substantially greater than the drug coating thickness at other positions except the corresponding fold position.

[0012] The technical solution (drug-coated balloon manufacturing method) given above in the present invention proposes a compromise strategy, that is, it proposes to pre-compensate at multiple preset crease positions for the loss of thickness value caused by stress peeling or falling off of the drug coating already applied at these crease positions due to the negative pressure operation in subsequent steps, thereby effectively ensuring that the thickness of the drug coating on the balloon surface is basically consistent in the final state (the compact state of the balloon folds covering the balloon body).

[0013] According to some optional embodiments of the present invention, the thickness of the drug coating formed on the surface of the balloon body in the inflated and expanded state at the corresponding crease position is approximately 1.5 to 2 times the thickness of the drug coating at other positions except the corresponding crease position.

[0014] According to the technical solution given above in the present invention, after a large number of simulation experiments and applications under real conditions, it can be determined based on a priori knowledge and a posteriori knowledge that, considering that the drug coatings applied at these fold positions are subjected to stress peeling or shedding due to the negative pressure pumping operation in the subsequent steps, the thickness value of the drug coating formed at the corresponding fold positions on the surface of the balloon body in the inflated state is intentionally set to be larger in the previous coating step, for example, preferably set to be about 1.5 to 2 times the thickness value of the drug coating at other positions except the corresponding fold positions. In this way, it can be effectively ensured that the thickness of the drug coating on the balloon surface is basically consistent in the final state (the compact state of the balloon folds covering the balloon body).

[0015] According to some optional embodiments of the present invention, there are three, five or six crease positions in total, and the three, five or six crease positions are used to form three balloon flaps, five balloon flaps or six balloon flaps, respectively.

[0016] According to the technical solution given above, by cleverly selecting a marking line formed by, for example, a metal wire (for example, an extremely thin copper wire, with a diameter of 0.001 to 0.005 mm), a position corresponding to the fold position of the balloon body is outlined on the connection portion connected to the balloon body. In particular, the extremely thin metal wire can not only be set inside the connection portion but also be exposed to the outside, which can not only facilitate, for example, ultrasonic detection to detect the marking line, but also will not affect the appearance of the connection portion that drives the balloon body to coaxially rotate. In addition, practice has proved that drug-coated balloons with three wings, five wings, and six wings are particularly conducive to the full contact between the therapeutic drug coated on the balloon and the vascular lesion site to achieve targeted drug administration, and also facilitate the removal of the drug-coated balloon from the peripheral blood vessels or coronary blood vessels.

[0017] According to some optional embodiments of the present invention, when the marking line detection device detects the marking line for the first time during a period in which the marking line detection device detects the marking line twice in succession, a first control instruction is sent to reduce the driving speed of the coating device in the X-axis direction in which the balloon body extends axially.

[0018] According to the technical solution given above in the present invention, the corresponding fold position on the balloon body is outlined by cleverly selecting a marking line formed by, for example, a metal wire on the connecting portion, and the fold position area of ​​the balloon that needs special treatment (i.e., increasing the coating in the coating process) is determined by detecting the marking line twice in succession within a very short period of time. In the first specific operation process, the driving speed of the coating device in the X-axis direction in which the balloon body is axially extended is reduced to achieve coating and deposition of a larger amount of drug at the corresponding fold position per unit time.

[0019] According to some optional embodiments of the present invention, when the marking line detection device detects the marking line for the first time during a period in which the marking line detection device detects the marking line twice in succession, a second control instruction is sent to drive the coating device in the Z-axis direction perpendicular to the plane in which the balloon is set to be closer to the balloon in the inflated and expanded state.

[0020] According to the technical solution given above of the present invention, the corresponding fold position on the balloon body is outlined by cleverly selecting a marking line formed by, for example, a metal wire on the connecting part, and the fold position area that needs to be specially treated (i.e., increasing the coating in the coating process) is determined by detecting the marking line twice in a very short period of time. In the second specific operation process, the coating device is driven on the Z-axis perpendicular to the plane in which the balloon body is set to be closer to the balloon body in the filled and expanded state (i.e., the distance between the coating device and the balloon body in the Z-axis direction is shortened), so as to achieve coating and deposition of a larger amount of drug at the corresponding fold position per unit time.

[0021] According to some optional embodiments of the present invention, when the marking line is detected for the first time between two consecutive detections, a third control instruction is sent to reduce the rotation speed of the balloon in the filled and expanded state driven in a clockwise or counterclockwise direction around the rotation axis.

[0022] According to the technical solution given above in the present invention, the corresponding fold position on the balloon body is outlined by cleverly selecting a marking line formed by, for example, a metal wire on the connecting part, and the fold position area that needs to be specially treated (i.e., increasing the coating in the coating process) is determined by detecting the marking line twice in succession within a very short period of time. In the third specific operation process, the rotation speed of the balloon body in the filled and expanded state is reduced in a clockwise or counterclockwise direction around the rotation axis (i.e., the rotational angular velocity of the balloon body becomes smaller), so as to achieve coating and deposition of a larger amount of drug at the corresponding fold position per unit time.

[0023] According to some optional embodiments of the present invention, when the marking line is detected for the second time within a period of two consecutive detections of the marking line, a fourth control instruction is sent to reset the coating device to a normal working state.

[0024] According to the technical solution given above of the present invention, by cleverly selecting a marking line formed by, for example, a metal wire on the connecting part to outline the corresponding fold position on the balloon body, the fold position area that needs to be specially treated (increased coating in the coating process) is determined by detecting the marking line twice in succession within a very short period of time. In the fourth specific operation process, when the marking line is detected for the second time within a very short period of time, it can be determined that the special treatment needs to be ended, and the predetermined normal treatment at other positions except the corresponding fold position can be restored, so that although the thickness of the drug coating on the balloon surface is uneven in the intermediate state (inflated balloon), it can effectively ensure that the thickness of the drug coating on the balloon surface is basically consistent in the final state (the compact state of the balloon fold wrapped around the balloon body).

[0025] According to some optional embodiments of the present invention, the drug coating can also include various types of anti-proliferative drugs, as well as excipients and stabilizers. For example, the anti-proliferative drug component is one or more of nimustine, carmustine, 5-fluorouracil, fluguanosine, gemcitabine, daunorubicin, doxorubicin, paclitaxel, vinblastine, topotecan, aminoglutethimide, sirolimus, everolimus, and zotarolimus. The excipient is one or more of lacamine salt, citric acid, resveratrol, polybutyl methacrylate, stearic acid, magnesium stearate, sodium stearate, zinc stearate, stearamide, isooctyl palmitate, linoleic acid, linolenic acid, monoolein, iohexol, iopromide, urea, sorbitol, polysorbate, trihexyl citrate, phospholipids, ropizine matrix, cholesterol, vitamin E, and vitamin E polyethylene glycol succinate. The stabilizer is one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tocopherol, ascorbic acid and its sodium salt, phytic acid, and disodium edetate.

[0026] According to the technical solution given above in the present invention, it can be effectively ensured that the thickness of the drug coating on the balloon surface is more uniform when the balloon enters the human body, and because the above-mentioned anti-proliferative drugs, excipients and stabilizers are used, the drug-coated balloon made by the drug-coated balloon manufacturing method is compared with ordinary drug coatings, so that the drug coating on the balloon surface that finally reaches the affected area is more sufficient and uniform, so that the drug utilization is higher, it is easier to be absorbed by the human body, and the retention time of the blood vessel wall is longer, thereby significantly improving the long-term patency.

[0027] According to some optional embodiments of the present invention, the interval between two adjacent marking lines provided on the connecting portion is 0.01 mm to 0.05 mm.

[0028] According to the technical solution given above in the present invention, the interval between two adjacent marking lines arranged on the connecting part is 0.01mm to 0.05mm, and in conjunction with the marking line detection device, it can effectively detect extremely thin copper wires with a diameter of 0.001 to 0.005mm. Moreover, the interval range of 0.01mm to 0.05mm can meet the requirements of forming balloon folds. Therefore, the marking line detection device can advantageously realize the rapid and accurate determination of the timing of changing the movement of one or more axes of the coating device in the X-axis, Y-axis, and Z-axis, and / or the rotation speed of the balloon body in the direction of the rotation axis.

[0029] According to some optional embodiments of the present invention, two or more pre-prepared balloons in a filled and expanded state are arranged in a substantially parallel manner in the Y-axis direction perpendicular to the X-axis direction in which the balloon extends axially in the balloon arrangement plane. Preferably, the intervals between two adjacent balloons in the two or more pre-prepared balloons in a filled and expanded state are substantially the same, i.e., they are arranged equidistantly.

[0030] According to the technical solution given above in the present invention, by arranging two or more pre-prepared balloons in a filled and expanded state in a basically parallel manner in the Y-axis direction perpendicular to the X-axis direction of the axial extension of the balloon body within the balloon setting plane, a set of drug-coated balloon manufacturing equipment can be used to simultaneously perform drug coating treatment on multiple balloons, thereby greatly improving the processing speed and processing efficiency.

[0031] According to some optional embodiments of the present invention, the precision micro-coating device is a precision micro-coating device, and the marking line detection device is an ultrasonic detection device for detecting marking lines.

[0032] According to the technical solution given above, compared with vacuum evaporation, CVD and other coating processes, the cost of the precision micro-coating device is lower than that of the vacuum coating equipment, and the drug coating can be prepared under normal temperature and pressure, making the large-scale production of micron-level or even nano-level drug coating possible. In addition, the ultrasonic detection device can determine the presence of the elongated marking line in the balloon body by analyzing the reflected ultrasonic signal.

[0033] According to some optional embodiments of the present invention, the method for manufacturing a drug-coated balloon also includes: deforming the balloon body in an inflated and expanded state into a compact state in which the balloon folds wrap the balloon body through a suction negative pressure device; and placing the balloon body in the compact state into a protective sleeve.

[0034] According to the technical solution given above, the final preparation of the drug-coated balloon can be completed through the above steps. That is, the balloon body in the inflated state for sufficient drug coating is deformed into a compact state in which the balloon flaps wrap the balloon body, and is placed in a slender protective sleeve for sale.

[0035] In a second aspect, an embodiment of the present invention further provides a drug-coated balloon, wherein the drug-coated balloon is manufactured by any one of the drug-coated balloon manufacturing methods described in the first aspect.

[0036] According to some optional embodiments of the present invention, the thickness of the drug coating formed at the corresponding crease position on the surface of the balloon body in the inflated and expanded state is approximately 1.5 to 2 times the thickness of the drug coating at other positions except the corresponding crease position; and, the thickness of the drug coating at various positions on the entire surface of the balloon in a compact state where the balloon fold wraps the balloon body is basically the same.

[0037] According to the technical solution given above in the present invention, after a large number of simulation experiments and applications under real conditions, it can be determined based on prior knowledge and a posteriori knowledge that, considering that the drug coatings applied at these fold positions are stress-peeled or detached due to the negative pressure pumping operation in the subsequent steps, the thickness value of the drug coating formed at the corresponding fold positions on the surface of the balloon body in the inflated state is intentionally set to be larger in the previous coating step, for example, preferably about 1.5 to 2 times the thickness value of the drug coating at other positions except the corresponding fold positions. In this way, it can be effectively ensured that the thickness of the drug coating on the balloon surface is basically consistent in the final state (the compact state of the balloon folds covering the balloon body).

[0038] According to some optional embodiments of the present invention, the drug-coated balloon constitutes a part of a balloon catheter with a rapid exchange structure or a balloon catheter with a double-lumen structure.

[0039] According to the technical solution given above in the present invention, the drug-coated balloon provided by the embodiment of the present invention can be applied to the coronary artery or peripheral vascular lesions of the human body by using a balloon catheter with a rapid exchange structure or a balloon catheter with a double-lumen structure commonly used in the artery, which greatly facilitates the use and expands the application scenarios accordingly.

[0040] According to some optional embodiments of the present invention, the drug-coated balloon has three balloon flaps, five balloon flaps, or six balloon flaps.

[0041] According to the technical solution given above in the present invention, practice has proved that drug-coated balloons with three wings, five wings, and six wings are particularly beneficial for the therapeutic drugs coated on the balloon to fully contact with the vascular lesion site to achieve targeted drug delivery, and also facilitate the removal of the drug-coated balloon from the peripheral blood vessels or coronary blood vessels.

[0042] In the third aspect, an embodiment of the present invention provides a drug-coated balloon manufacturing device, which is used to coat a drug coating on the surface of a balloon body that has been prepared in advance and is inflated and expanded, and a plurality of marking lines are pre-arranged on a connecting portion that is connected to the balloon body and rotates coaxially with the balloon body, and two adjacent marking lines on the connecting portion correspond to the crease positions corresponding to the balloon folds formed on the balloon body. The drug-coated balloon manufacturing equipment includes: a precision micro-coating device, which is used to provide drugs in a liquid or solid particle suspension state, and coat the drugs on the surface of the balloon body in a filled and expanded state to form a drug coating; an XYZ three-dimensional stepping device, which is connected to the precision micro-coating device and can drive the precision micro-coating device to move in one or more directions of the three directions of the X-axis, Y-axis, and Z-axis; a rotating shaft driving device, which includes the connecting part, and is connected to the balloon body in the filled and expanded state through the connecting part, so as to drive the balloon body and the connecting part to rotate coaxially at a predetermined speed in a clockwise or counterclockwise direction. Rotation; a marking line detection device, the marking line detection device is used to detect each of the multiple marking lines pre-set on the connecting part in sequence when the rotating shaft driving device drives the balloon body and the connecting part to rotate coaxially at a predetermined speed; and a control device, the control device is connected to the XYZ three-dimensional stepping device, the rotating shaft driving device, and the marking line detection device. During the period when the marking line detection device detects the marking line twice in succession, the control device sends a control instruction to the XYZ three-dimensional stepping device and / or the rotating shaft driving device to change the movement of the precision micro-coating device in one or more axes of the X-axis, Y-axis, and Z-axis, and / or the speed of the balloon body in the rotating shaft direction. Specifically, under the control of the control device, the thickness of the drug coating formed at the corresponding fold position on the surface of the balloon body in the filled and expanded state is substantially greater than the thickness of the drug coating at other positions except the corresponding fold position.

[0043] The technical solution (drug-coated balloon manufacturing equipment) given above in the present invention proposes a compromise strategy, that is, it proposes to pre-compensate at multiple preset crease positions for the loss of thickness value caused by stress peeling or falling off of the drug coating already applied at these crease positions due to the negative pressure operation in subsequent steps, thereby effectively ensuring that the thickness of the drug coating on the balloon surface is basically consistent in the final state (the compact state of the balloon folds covering the balloon body).

[0044] According to some optional embodiments of the present invention, the thickness of the drug coating formed on the surface of the balloon body in the inflated and expanded state at the corresponding crease position is approximately 1.5 to 2 times the thickness of the drug coating at other positions except the corresponding crease position.

[0045] According to some optional embodiments of the present invention, there are three, five or six crease positions in total, and the three, five or six crease positions are used to form three balloon flaps, five balloon flaps or six balloon flaps, respectively.

[0046] According to some optional embodiments of the present invention, when the marking line detection device detects the marking line for the first time during the period in which the marking line detection device detects the marking line twice in succession, the control device sends a first control instruction to the XYZ three-dimensional stepping device to reduce the driving speed of the XYZ three-dimensional stepping device in driving the precision micro-coating device in the X-axis direction of the axial extension of the balloon body.

[0047] According to some optional embodiments of the present invention, when the marking line detection device detects the marking line for the first time during the period in which the marking line detection device detects the marking line twice in succession, the control device sends a second control instruction to the XYZ three-dimensional stepping device, so that the XYZ three-dimensional stepping device drives the precision micro-coating device to be closer to the balloon in the filled and expanded state in the Z-axis direction perpendicular to the plane in which the balloon is set.

[0048] According to some optional embodiments of the present invention, when the marking line detection device detects the marking line for the first time during a period in which the marking line detection device detects the marking line twice in succession, the control device sends a third control instruction to the rotating axis driving device so that the rotating axis driving device drives the balloon body in the filled and expanded state in a clockwise or counterclockwise direction centered on the rotating axis to reduce the rotation speed.

[0049] According to some optional embodiments of the present invention, when the marking line detection device detects the marking line for the second time during the period in which the marking line detection device detects the marking line twice in succession, the control device sends a fourth control instruction to the XYZ three-dimensional stepping device and / or the rotating axis driving device to reset the XYZ three-dimensional stepping device and / or the rotating axis driving device to a normal working state.

[0050] According to some optional embodiments of the present invention, the anti-proliferative drug component in the drug-coated balloon is one or more of nimustine, carmustine, 5-fluorouracil, fluguanidine, gemcitabine, daunorubicin, doxorubicin, paclitaxel, vinblastine, topotecan, aminoglutethimide, sirolimus, everolimus, and zotarolimus.

[0051] According to some optional embodiments of the present invention, the measurement accuracy of the marking line detection device is not less than 0.005 mm.

[0052] According to the technical solution given above, the marking line detection device can effectively detect extremely fine copper wires with a diameter of 0.001 to 0.005 mm, especially when such fine copper wires are arranged inside the connecting part instead of being exposed to the outside. Therefore, the marking line detection device can advantageously help the control device to quickly and accurately determine the timing of changing the movement of one or more axes of the precision micro-coating device in the X-axis, Y-axis, and Z-axis, and / or the speed of the balloon in the direction of the rotation axis.

[0053] According to some optional embodiments of the present invention, two or more pre-prepared balloons in a filled and expanded state are arranged in a substantially parallel manner in the Y-axis direction perpendicular to the X-axis direction in which the balloon extends axially in the balloon arrangement plane. Preferably, the intervals between two adjacent balloons in the two or more pre-prepared balloons in a filled and expanded state are substantially the same, i.e., they are arranged equidistantly.

[0054] According to some optional embodiments of the present invention, the precision micro-coating device is a precision micro-coating device, and the marking line detection device is an ultrasonic detection device for detecting marking lines.

[0055] The present invention is provided to introduce selected aspects and embodiments of the present invention in a simplified form, and is not intended to identify the key features or essential features of the claimed subject matter, nor is it intended to be used to help determine the scope of the claimed subject matter. The selected aspects and embodiments are presented only to provide the reader with a brief overview of some forms that the present invention may take, and are not intended to limit the scope of the present invention. Other aspects and embodiments of the present invention are described in the section of the detailed description.

[0056] These and various other aspects, embodiments, features and advantages of the present invention will be better understood when the following detailed description is read in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or related technologies, the drawings required for use in the embodiments or related technical descriptions are briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be easily obtained based on these drawings without paying creative labor.

[0058] Figure 1 is a schematic structural diagram of a balloon catheter exemplarily depicting a rapid exchange (Rx) structure.

[0059] Figure 2 is a schematic structural diagram exemplarily depicting a balloon catheter with a double-lumen structure.

[0060] Figure 3 It is a schematic diagram exemplarily depicting the overall architecture of a drug-coated balloon manufacturing device provided according to an embodiment of the present invention.

[0061] Figure 4 It is a schematic diagram which exemplarily depicts the connection portion 3031 provided according to an embodiment of the present invention after being cut along the plane formed by the X-axis and the Z-axis and the surface SF of the connection portion 3031 is unfolded, wherein multiple straight marking lines (multiple dot-dashed lines) arranged on the connection portion 3031 and positions AA corresponding to the positions of the folds arranged on the connection portion 3031 for forming the fold wings of the balloon and positions BB corresponding to other positions on the balloon are schematically shown.

[0062] Figure 5 It is a schematic diagram which exemplarily depicts the connection portion 3031 provided according to an embodiment of the present invention after being cut along the plane formed by the X-axis and the Z-axis and the surface SF of the connection portion 3031 is unfolded, wherein multiple parabolic marking lines (multiple dot-dashed lines) arranged on the connection portion 3031 and positions AA corresponding to the positions of the folds arranged on the connection portion 3031 for forming the fold wings of the balloon and positions BB corresponding to other positions on the balloon are schematically shown.

[0063] Figure 6 FIG. 4 is a flow chart exemplarily depicting a first specific operation process of the method for manufacturing a drug-coated balloon according to the first embodiment of the present invention.

[0064] Figure 7 FIG. 4 is a flow chart exemplarily depicting a second specific operation process of the method for manufacturing a drug-coated balloon according to the second embodiment of the present invention.

[0065] Figure 8 is a flow chart exemplarily depicting a third specific operation process of the method for manufacturing a drug-coated balloon according to the third embodiment of the present invention.

[0066] Fig. 9 The invention exemplarily depicts a novel drug-coated balloon obtained by the drug-coated balloon manufacturing method provided by various embodiments of the present invention. Figure 3 The cross-sectional schematic diagram of the YZ plane shown shows the main improvements of the new drug-coated balloon (the balloon is in a state of being inflated and expanded and has not yet been subjected to the balloon fold coating treatment on the balloon body) compared with the conventional drug-coated balloon. DETAILED DESCRIPTION

[0067] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0068] The terms "first", "second", etc. in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable where appropriate, so that the embodiments of the present application can be implemented in an order other than those illustrated or described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated before and after are in an "or" relationship; and the character "-" generally indicates that the objects associated before and after are in an "and" relationship.

[0069] In the description of the embodiments of the present invention, it should be understood that the terms "center", "length", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside", "axial", "radial", "circumferential" and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the embodiments of the present invention and simplifying the description, and do not indicate or imply that the referred device or element must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as a limitation on the embodiments of the present invention.

[0070] In the embodiments of the present invention, unless otherwise clearly specified and limited, the terms "installed", "connected", "connected", "fixed" and the like should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection, an electrical connection, or a communication; it can be a direct connection, or an indirect connection through an intermediate medium, and it can be the internal connection of two elements or the interaction relationship between two elements. For ordinary technicians in this field, the specific meanings of the above terms in the embodiments of the present invention can be understood according to specific circumstances.

[0071] In the embodiments of the present invention, unless otherwise clearly specified and limited, the first feature being "above" or "below" the second feature may mean that the first and second features are in direct contact, or the first and second features are in indirect contact through an intermediate medium. Moreover, the first feature being "above", "above" and "above" the second feature may mean that the first feature is directly above or obliquely above the second feature, or simply means that the first feature is higher in level than the second feature. The first feature being "below", "below" and "below" the second feature may mean that the first feature is directly below or obliquely below the second feature, or simply means that the first feature is lower in level than the second feature.

[0072] Important terms

[0073] First, for the convenience of description, definitions of some important terms involved in this application are given.

[0074] Interventional medical systems

[0075] An interventional medical system refers to a device that is inserted into the human body or natural cavity through surgical means for short-term treatment or examination and is removed after the treatment or examination is completed.

[0076] Generally speaking, interventional medical systems include, but are not limited to, interventional medical device diagnosis, interventional medical device operation, and interventional medical device implantation.

[0077] Intravascular system

[0078] In various embodiments of the present invention, the intravascular system refers to a medical device system that implements the implantation / deployment / placement of a balloon catheter at a specific position in a human blood vessel through the above-mentioned interventional medical system.

[0079] Balloon Catheter

[0080] A balloon catheter, sometimes also called a balloon dilatation catheter, is a medical interventional device. Generally speaking, a balloon catheter consists of a catheter, a balloon body, a connector, a guidewire insertion tube, and a balloon inflation tube.

[0081] Coronary arteries

[0082] The coronary artery, also known as the coronary artery, is shaped like an inverted, slightly flattened cone front and back. If it is regarded as a head, the coronary artery located on the top of the head and almost surrounding the heart is like a crown. This is the origin of its name.

[0083] peripheral blood vessels

[0084] Peripheral blood vessels are blood vessels other than cardiovascular and cerebrovascular vessels, including arteries and veins in the limbs, head, neck, and trunk.

[0085] Ultrasonic testing

[0086] The ultrasonic detection device can use the ultrasonic wave generated by the ultrasonic sound source to emit into the interior of the object to be tested. If there are defects (other materials) inside the object to be tested, an interface is formed between the other materials and the material of the object to be tested. The acoustic impedance between the interfaces is different. When the ultrasonic wave encounters the interface, it will be reflected. The reflected ultrasonic signal is received, and the internal situation of the object to be tested is judged by analyzing the received ultrasonic signal. This is the working principle of ultrasonic detection.

[0087] The overall structure of the balloon catheter

[0088] Figure 1 An example of a balloon catheter 100 of a rapid exchange structure applied to a novel drug-coated balloon according to an embodiment of the present invention is shown. In a general overview, the balloon catheter 100 of the exemplary rapid exchange structure comprises at least a tip 11, a novel drug-coated balloon 12, an identification ring 13, a shaft 14, a marker band 15, and a catheter seat 16. The balloon catheter 100 of the exemplary rapid exchange structure can be operated by a professional to deliver and deploy the novel drug-coated balloon 12 at a target site in a patient's body, so as to achieve full contact between the customized drug and the vascular lesion site to achieve targeted drug administration, and also facilitate the removal of the novel drug-coated balloon 12 from the patient's peripheral blood vessels or coronary blood vessels.

[0089] Figure 2An example of a double-lumen structure balloon catheter 200 used for a novel drug-coated balloon according to an embodiment of the present invention is shown. In a general overview, the exemplary double-lumen structure balloon catheter 200 includes at least a catheter seat 21, a shaft 22, a novel drug-coated balloon 23, a tip 24, and a marker ring 25. Similarly, similar to the balloon catheter 100 of the rapid exchange structure, the exemplary double-lumen structure balloon catheter 200 can be operated by a professional to deliver and deploy the novel drug-coated balloon 23 at a target site in the patient's body, so as to achieve full contact between the customized drug and the vascular lesion site to achieve targeted drug administration, and also facilitate the removal of the novel drug-coated balloon 23 from the patient's peripheral blood vessels or coronary blood vessels. Moreover, compared with the balloon catheter 100 of the rapid exchange structure, the structure is simpler and easier to operate and use.

[0090] Drug coated balloon manufacturing equipment and manufacturing method thereof

[0091] Here, the novel drug-coated balloon (balloon body) 12, 23, which is the core component of the balloon catheter 100 of the rapid exchange structure and the balloon catheter 200 of the double-lumen structure, is manufactured by the drug-coated balloon manufacturing method provided by the embodiment of the present invention. As a non-limiting example, for example, Figure 3 The drug-coated balloon manufacturing device 300 is used to apply a drug coating on the surface of a balloon body 12, 23 that is prepared in advance and in a state of inflation, and a connecting portion 3031 (see FIG. 1 ) that is connected to the balloon body 12, 23 and rotates coaxially with the balloon body 12, 23 is provided. Figure 3 ) is pre-set with a plurality of marking lines 401 (see Figure 4 , Figure 5 ), and the two adjacent marking lines 401 on the connecting portion correspond to the corresponding fold positions of the balloon fold wings formed on the balloon body 12, 23.

[0092] Here, it should be noted that the above-mentioned fold position does not constitute any component of the balloon body 12, 23 and the balloon catheter 100, 200, but is only a virtual position mark used to mark the approximate position corresponding to the formation of the balloon flap in the subsequent steps. And it can be understood that the above-mentioned fold position does not exist in the final product of the balloon body 12, 23 and the balloon catheter 100, 200.

[0093] Specifically, Figure 3As shown, the drug-coated balloon manufacturing device 300 includes, for example: a precision micro-coating device 301, an XYZ three-dimensional stepping device 302, a rotating shaft driving device 303, a marking line detection device 304, and a control device 305. The rotating shaft driving device 303 includes a connecting portion 3031, which is connected to the balloon body 12, 23 and can rotate coaxially with the balloon body 12, 23. Figure 3 The connecting lines between the various components shown in the figure schematically indicate that the related components are connected.

[0094] The precision micro-coating device 301 is used to provide a drug in a liquid or solid particle suspension state, and coat the drug on the surface of the balloon body 12, 23 in an inflated state to form a drug coating with a certain thickness.

[0095] In practice, the precision micro-coating device 301 needs to select a coating process suitable for a small-area thin film coating such as a drug balloon coating. For example, the precision micro-coating device 301 can be, for example, a pipette, a pipette pen, a pipette chamber, a pipette dropper, etc. Correspondingly, the coating particle size range of the precision micro-coating device 301 can be, for example, set to 15-40 μm, the coating width can be, for example, set to 2-10 mm, the coating flow rate can be, for example, set to 0.1 ml / min, and the coating height can be, for example, set to 10-30 mm. However, the data given above are merely exemplary and do not constitute any limitation to the embodiments of the present invention.

[0096] In addition, the XYZ three-dimensional stepping device 302 is connected to the precision micro-coating device 301, and can drive the precision micro-coating device 301 to move in the three directions of the X axis, the Y axis, and the Z axis. Figure 3 As shown, the X-axis corresponds to the axial extension direction of the balloon bodies 12 and 23, the Y-axis corresponds to the direction perpendicular to the X-axis direction of the axial extension of the balloon bodies 12 and 23 in the plane where the balloon bodies 12 and 23 are set, and the Z-axis corresponds to the direction perpendicular to the plane where the balloon bodies 12 and 23 are set. The XYZ three-dimensional stepping device 302 can be a micro-stepping motor of the model 8618HB1401 manufactured by BALE of Germany or an improved version thereof, which can achieve a driving accuracy of 0.01 to 0.05 mm, but such a selection is only an example and does not constitute any limitation to the embodiments of the present invention.

[0097] In addition, the rotating shaft driving device 303 is connected to the balloon bodies 12 and 23 in the inflated state through the connecting portion 3031, so as to drive the balloon bodies 12 and 23 and the connecting portion 3031 to rotate coaxially at a predetermined speed in a clockwise or counterclockwise direction. Figure 3It is only shown that each balloon body 12, 23 rotates in a clockwise direction as an example, but each balloon body 12, 23 can also rotate in a counterclockwise direction, for example. Even, if necessary, some of the multiple balloon bodies 12, 23 rotate in a clockwise direction, while other balloon bodies 12, 23 rotate in a counterclockwise direction. Therefore, the rotation direction of the balloon bodies 12, 23 is not limited. Here, the predetermined rotation speed can be set according to actual needs. Generally speaking, the rotation speed of the driving balloon bodies 12, 23 can be set to 30-120 radians / second (rad / s), for example.

[0098] In addition, the marking line detection device 304 is used to sequentially detect each marking line 401 (see FIG. 1 ) of the plurality of marking lines arranged on the surface or inside of the connecting portion 3031 when the rotating shaft driving device 303 drives the balloon bodies 12, 23 and the connecting portion 3031 to coaxially rotate at a predetermined speed. Figure 4 ).

[0099] Here, the marking line detection device 304 can determine the presence of the elongated marking line on the surface or inside the connecting portion 3031 by analyzing the reflected ultrasonic signal. The marking line detection device 304 can effectively detect extremely fine copper wires with a diameter of 0.001 to 0.005 mm, especially such fine copper wires are arranged inside the connecting portion 3031 instead of being exposed to the outside. Thus, the marking line detection device 304 can advantageously help the control device 305 to quickly and accurately determine the timing of changing the movement of one or more axes of the above-mentioned precision micro-coating device 301 in the X-axis, Y-axis, and Z-axis, and / or the speed of the balloon body 12, 23 in the direction of the rotation axis. For example, the marking line detection device 304 can select the FW-H02 model or a special version of the ultrasonic sensor probe manufactured by KEYENCE of Japan, and the special version of the ultrasonic probe can achieve a response speed of 1ms to 10ms, but such a selection is only an example and does not constitute any limitation to the embodiments of the present invention.

[0100] In addition, the control device 305 is connected to the XYZ three-dimensional stepping device 302, the rotation axis driving device 303, and the marking line detection device 304. When the marking line detection device 304 detects the marking line 401 twice (see Figure 4), the control device 305 sends a control instruction to the XYZ three-dimensional stepping device 302 and / or the rotating axis driving device 303 to change the movement of the precision micro-coating device 301 in one or more axes of the X-axis, Y-axis, and Z-axis, and / or the speed of the balloon body 12, 23 in the direction of the rotating axis. Here, the control device 305 can adopt the new microcontroller (MCU) model RH850 / U2B manufactured by the Japanese Renesas Electronics Group, which has vector extension and supports the fast execution of complex mathematical algorithms, but such a choice is only an example and does not constitute any limitation to the embodiments of the present invention.

[0101] Accordingly, under the control of the control device 305, the surfaces of the balloon bodies 12, 23 in the inflated and expanded state are creased at corresponding fold positions (corresponding to Figure 4 AA shown in the figure, and the size of the crease position is Figure 4 The drug coating thickness formed at the positions other than the corresponding fold positions (corresponding to Figure 4 The BB shown in the figure, and the sizes of other positions are Figure 4 Preferably, the thickness of the drug coating formed at the corresponding fold position on the surface of the balloon body in the inflated state is about 1.5 to 2 times the thickness of the drug coating at other positions except the corresponding fold position.

[0102] After a large number of simulation experiments and applications under real conditions conducted by the inventors, it can be determined based on prior knowledge and a posteriori knowledge that, considering that the drug coatings applied at these crease positions are stress-peeled or detached due to the negative pressure pumping operation in the subsequent steps, the loss of thickness is usually about 0.5 to 1 times the thickness of the drug coatings at other positions (the specific loss of thickness usually depends on the specific process operation in the subsequent crease folding step, which can be understood by those skilled in the art based on the prior art), the thickness of the drug coating formed at the corresponding crease positions on the surface of the balloon body in the inflated state is deliberately set larger in the previous coating step, for example, preferably about 1.5 to 2 times the thickness of the drug coating at other positions except the corresponding crease positions. In this way, it can be effectively ensured that the thickness of the drug coating on the balloon surface is basically consistent in the final state (the compact state of the balloon flaps covering the balloon body).

[0103] like Figure 4As shown, the connecting portion 3031 connected to the drug-coated balloons 12 and 23 provided in the embodiment of the present invention in the inflated state is exemplarily described along the X-axis and the Z-axis (see Figure 3 ) is cut open and the surface SF is unfolded, wherein multiple marking lines 401 (multiple dot-dashed lines) and positions AA corresponding to the fold positions (fold areas) for forming the flaps of the balloon are schematically shown. Figure 4 In the figure, the reference numeral AA identifies a position on the connecting portion 3031, but corresponds to a fold position on the surface of the balloon body in an inflated and expanded state, while the reference numeral BB identifies a position on the connecting portion 3031, but corresponds to other positions on the surface of the drug-coated balloon 12, 23 except for multiple fold positions.

[0104] In addition, although Figure 4 Twelve marking lines 401 are shown, and six crease positions (crease areas) are formed correspondingly, so as to form six balloon flaps accordingly. However, it can be understood by those skilled in the art that the number of marking lines and corresponding crease positions (crease areas) can also be set according to actual needs. For example, ten marking lines 401 and five crease positions (crease areas) can also be set, so as to form five balloon flaps accordingly. Alternatively, six marking lines 401 and three crease positions (crease areas) can also be set, so as to form three balloon flaps accordingly.

[0105] In addition, as those skilled in the art will appreciate, the shape of the marking line 401 is not necessarily a straight line, and can also be set to other suitable shapes, such as a hyperbolic parabola, according to actual needs, especially the formation method of the balloon flap. Figure 5 shown.

[0106] Next, we will refer to Figures 3 to 5 , Figures 6 to 9 Various embodiments and variations of the present invention are described in detail to better understand the drug-coated balloon manufacturing method and how to use, for example, the drug-coated balloon manufacturing device 300 to implement the specific operation process of the drug-coated balloon manufacturing method, so as to pre-compensate for the loss of thickness value of the drug coating applied at these crease positions due to stress peeling or falling off caused by the negative pressure operation in subsequent steps at a plurality of pre-set crease positions, thereby effectively ensuring that the thickness of the drug coating on the balloon surface is basically consistent in the final state (the compact state of the balloon folds covering the balloon body).

[0107] It should be noted that the various embodiments and variations of the present invention described below are all for a balloon body 12, 23 in a filled and expanded state as the processing object. At this time, the XYZ three-dimensional stepping device 302 remains basically unchanged in the Y-axis direction, and is driven in the X-axis and Z-axis directions. It is clear that if a plurality of balloon bodies 12, 23 (such as Figure 3 As shown), the XYZ three-dimensional stepping device 302 is required to drive in the three directions of X-axis, Y-axis and Z-axis.

[0108] First embodiment

[0109] Figure 6 1 is a flowchart of a first specific operation process of the method for manufacturing a drug-coated balloon according to the first embodiment of the present invention. The method for manufacturing a drug-coated balloon according to the first embodiment of the present invention can be used, for example, as follows Figure 3 The drug-coated balloon manufacturing device 300 is shown. Of course, this does not constitute a limitation, and the drug-coated balloon manufacturing method can also be implemented by other similar drug-coated balloon manufacturing devices. Specifically, for the specific structure of the drug-coated balloon manufacturing device 300, please refer to Figure 3 In addition, regarding the arrangement of the positions corresponding to the marking lines and folding positions on the connecting portion 3031, please refer to Figure 4 and Figure 5 shown.

[0110] Here, at the beginning Figure 6 Before each step shown, the preparatory work of forming the balloon bodies 12, 23 prepared in advance and in the inflated state has been completed. These preparatory work include: preparing, filling and providing the specific drug coating solution to the precision micro-coating device 301, filling the balloon bodies 12, 23 under the condition of a filling pressure of, for example, about 1 atm, and placing one or more balloon bodies 12, 23 in the inflated state on the rotating shaft driving device 303.

[0111] like Figure 3 and Figure 6 As shown, the first specific operation process of the method for manufacturing a drug-coated balloon according to the first embodiment of the present invention includes, for example, the following steps:

[0112] Step S601, providing a drug in a liquid or solid particle suspension state, and continuously coating the drug on the surface of the balloon body 12, 23 in a filled and expanded state by a precision micro-coating device 301;

[0113] Step S602, driving the precision micro-coating device 301 to move in the X-axis direction, that is, in the axial direction of the balloon body 12, 23, by means of the XYZ three-dimensional stepping device 302 connected to the precision micro-coating device 301;

[0114] Step S603, the rotating shaft driving device 303 connected to the balloon bodies 12 and 23 in the inflated and expanded state through the connecting part 3031 drives the balloon bodies 12 and 23 and the connecting part 3031 to coaxially rotate at a predetermined speed in a clockwise or counterclockwise direction;

[0115] Step S604, when the rotating shaft driving device 303 drives the balloon bodies 12, 23 and the connecting portion 3031 to coaxially rotate at a predetermined speed, each of the multiple marking lines 401 disposed on the surface or inside of the connecting portion 3031 is detected in sequence by the marking line detecting device 304;

[0116] Step S605, through the control device 305 connected to the XYZ three-dimensional stepping device 302, the rotating shaft driving device 303, and the marking line detection device 304, when the marking line 401 is detected for the first time during the period in which the marking line detection device 304 detects the marking line 401 twice in succession, the control device 305 sends a first control instruction to the XYZ three-dimensional stepping device 302, so that the driving speed of the XYZ three-dimensional stepping device 302 to drive the precision micro-coating device 301 in the X-axis direction of the axial extension of the balloon body 12, 23 is reduced; and

[0117] Step S606, when the marking line detection device 304 detects the marking line 401 for the second time during the period in which the marking line detection device 304 detects the marking line 401 twice, the control device 305 sends a fourth control instruction to the XYZ three-dimensional stepping device 302, so that the XYZ three-dimensional stepping device 302 is reset to a normal working state, that is, restored to the state except for the state corresponding to Figure 4 and Figure 5 The working state at position BB (corresponding to other positions on the balloon body 12 , 23 ) other than position AA (corresponding to the fold position on the balloon body 12 , 23 ) is shown.

[0118] It is worth noting that steps S602 and S603 are usually performed in parallel. Of course, if necessary, these two steps can also be set to be performed in sequence, and the embodiments of the present invention are not limited thereto.

[0119] In addition, steps S605 and S606 will be repeatedly executed until the thickness of the drug coating on the surface of the balloon body 12, 23 reaches a predetermined value. In practical applications, the marking line detection device 304 is, for example, an ultrasonic detection device for detecting the marking line. The ultrasonic detection device may also have the function of detecting the thickness of the drug coating on the surface of the balloon body 12, 23 using ultrasonic echoes, which will not be described in detail here.

[0120] Next, a specific description will be given of the control device 305 sending a first control instruction to the XYZ three-dimensional stepping device 302 so that the XYZ three-dimensional stepping device 302 reduces the driving speed of the precision micro-coating device 301 in the X-axis direction where the balloon bodies 12 and 23 extend axially.

[0121] First, as those skilled in the art understand, the first and fourth control instructions in various embodiments of the present invention are, for example, programmable logic control (PLC) programs or program segments. Of course, with the different types of control devices selected, the first and fourth control instructions in various embodiments of the present invention may also be programs or program segments of other types of digital logic controllers, as long as they can achieve fast and accurate control of the stepping (servo) drive of the XYZ three-dimensional stepping device 302, and will not be repeated here.

[0122] Here, if Figure 3 As shown, the parameters considered by the control device 305 to achieve control include but are not limited to: (i) the real-time dynamic three-dimensional (X, Y, Z) coordinate values ​​of the precision micro-coating device 301 obtained by feedback from the XYZ three-dimensional stepping device 302, (ii) the rotational angular velocity θ of the balloon 12, 23 obtained by feedback from the rotating shaft driving device 303, (iii) the marking line detection result (true / false (TRUE / FALSE)) and (iv) the count value obtained by feedback from the marking line detection device 304, (v) the dynamic coating thickness on the surface of the balloon 12, 23 obtained by feedback from the marking line detection device 304, (vi) the amount of drug applied by the precision micro-coating device 301 per unit time and the conversion rate (i.e., the approximate ratio of the drug that can be retained on the surface of the balloon 12, 23), etc.

[0123] Therefore, in the first embodiment, the inventors, after sophisticated design and a large number of experiments, determined that parameters (iii) and (iv) are used as judgment factors for starting and ending special processing (in the first embodiment, slowing down the movement speed SP of the XYZ three-dimensional stepping device 302 in the X-axis direction of the axial extension of the balloon body 12, 23), and parameter (i) is used to determine the movement speed of the XYZ three-dimensional stepping device 302 in the X-axis direction of the axial extension of the balloon body 12, 23 and the degree to which it needs to be slowed down.

[0124] In particular, the inventors have found that, under the condition that other parameters are substantially constant, the change in the motion speed SP as a variable and the change in the thickness of the drug coating formed on the surface of the balloon body 12, 23 in the inflated and expanded state are in a certain form of linear relationship. Therefore, such a linear relationship can be obtained based on a large number of experiments, and such a linear relationship can be pre-stored using a PLC program for the control device 305 to call and implement corresponding control, so as to achieve the expected control effect.

[0125] Finally, after the above steps are repeatedly performed, the surfaces of the balloon bodies 12 and 23 in the inflated state are creased at the corresponding fold positions (corresponding to Figure 4 , Figure 5 The thickness of the drug coating formed at the position AA) is different from that at other positions (corresponding to Figure 4 , Figure 5 Preferably, the drug coating thickness at the corresponding fold position (corresponding to the position BB) on the surface of the balloon body in the inflated state is substantially greater. Figure 4 , Figure 5 The thickness of the drug coating formed at the position AA) shown in FIG. 1 is the thickness of the drug coating formed at the position other than the corresponding fold position (corresponding to Figure 4 , Figure 5 The thickness of the drug coating at the position BB) shown in FIG. 1 is about 1.5 to 2 times the thickness of the drug coating at the position BB shown in FIG. 1. However, the above thickness ratio is only an example, and the thickness ratio of the two thicknesses can also be set to other values ​​according to actual needs, and the various embodiments of the present invention are not limited thereto.

[0126] Second embodiment

[0127] Figure 7 1 is a flowchart of a second specific operation process of the method for manufacturing a drug-coated balloon according to the second embodiment of the present invention. Figure 3 The drug-coated balloon manufacturing device 300 is shown. Of course, this does not constitute a limitation, and the drug-coated balloon manufacturing method can also be implemented by other similar drug-coated balloon manufacturing devices. Specifically, for the specific structure of the drug-coated balloon manufacturing device 300, please refer to Figure 3 In addition, regarding the arrangement of the positions corresponding to the marking lines and folding positions on the connecting portion 3031, please refer to Figure 4 and Figure 5 shown.

[0128] Here, at the beginning Figure 7Before each step shown, the preparatory work of forming the balloon bodies 12, 23 prepared in advance and in the inflated state has been completed. These preparatory work include: preparing, filling and providing the specific drug coating solution to the precision micro-coating device 301, filling the balloon bodies 12, 23 under the condition of a filling pressure of, for example, about 1 atm, and placing one or more balloon bodies 12, 23 in the inflated state on the rotating shaft driving device 303.

[0129] like Figure 3 and Figure 7 As shown, the second specific operation process of the method for manufacturing a drug-coated balloon according to the second embodiment of the present invention includes, for example, the following steps:

[0130] Step S701, providing a drug in a liquid or solid particle suspension state, and continuously coating the drug on the surface of the balloon body 12, 23 in a filled and expanded state by a precision micro-coating device 301;

[0131] Step S702, driving the precision micro-coating device 301 to move in the X-axis direction, that is, in the axial direction of the balloon body 12, 23, by means of the XYZ three-dimensional stepping device 302 connected to the precision micro-coating device 301;

[0132] Step S703, the rotating shaft driving device 303 connected to the balloon bodies 12 and 23 in the inflated and expanded state through the connecting part 3031 drives the balloon bodies 12 and 23 and the connecting part 3031 to rotate coaxially at a predetermined speed in a clockwise or counterclockwise direction;

[0133] Step S704, when the rotating shaft driving device 303 drives the balloon bodies 12, 23 and the connecting portion 3031 to coaxially rotate at a predetermined rotation speed θ1, each of the multiple marking lines 401 set on the surface or inside of the connecting portion 3031 is detected in sequence by the marking line detection device 304;

[0134] Step S705, through the control device 305 connected to the XYZ three-dimensional stepping device 302, the rotation axis driving device 303, and the marking line detection device 304, when the marking line detection device 304 detects the marking line 401 for the first time during the period in which the marking line detection device 304 detects the marking line 401 twice in succession, the control device 305 sends a second control instruction to the XYZ three-dimensional stepping device 302, so that the XYZ three-dimensional stepping device 302 moves in the plane with the balloon bodies 12 and 23 (i.e. Figure 3 The precision micro-coating device 301 is driven in the Z-axis direction perpendicular to the XY plane shown in FIG. 3 to be closer to the balloon bodies 12 and 23 in the filled and expanded state, that is, Figure 3Lowering the height of the XYZ three-dimensional stepping device 302 in the Z-axis direction as shown; and

[0135] Step S706: When the marking line 401 is detected for the second time during the period in which the marking line detection device 304 detects the marking line 401 twice, the control device 305 sends a fourth control instruction to the XYZ three-dimensional stepping device 302, so that the XYZ three-dimensional stepping device 302 is reset to a normal working state, that is, restored to the state except for the state corresponding to Figure 4 and Figure 5 The working state at position BB (corresponding to other positions on the balloon body 12 , 23 ) other than position AA (corresponding to the fold position on the balloon body 12 , 23 ) is shown.

[0136] It is worth noting that steps S702 and S703 are usually performed in parallel. Of course, if necessary, these two steps can also be set to be performed in sequence, and the embodiments of the present invention are not limited thereto.

[0137] In addition, steps S705 and S706 will be repeatedly executed until the thickness of the drug coating on the surface of the balloon body 12, 23 is detected to be satisfactory. In practical applications, the above-mentioned marking line detection device 304 is, for example, an ultrasonic detection device for detecting the marking line. The ultrasonic detection device can also have the function of detecting the thickness of the drug coating on the surface of the balloon body 12, 23 using ultrasonic echoes, which will not be repeated here.

[0138] Next, a specific description will be given of the control device 305 sending a second control instruction to the XYZ three-dimensional stepping device 302 so that the XYZ three-dimensional stepping device 302 drives the precision micro-coating device 301 in the Z-axis direction perpendicular to the plane in which the balloon bodies 12 and 23 are set to be closer to the balloon bodies 12 and 23 in the filled and expanded state.

[0139] First, as those skilled in the art understand, the second and fourth control instructions in various embodiments of the present invention are, for example, programmable logic control (PLC) programs or program segments. Of course, with the different types of control devices selected, the second and fourth control instructions in various embodiments of the present invention may also be programs or program segments of other types of digital logic controllers, as long as they can achieve fast and accurate control of the stepping (servo) drive of the XYZ three-dimensional stepping device 302, and will not be repeated here.

[0140] Here, if Figure 3As shown, the parameters considered by the control device 305 to achieve control include but are not limited to: (i) the real-time dynamic three-dimensional (X, Y, Z) coordinate values ​​of the precision micro-coating device 301 obtained by feedback from the XYZ three-dimensional stepping device 302, (ii) the rotation angular velocity θ of the balloon 12, 23 obtained by feedback from the rotating shaft driving device 303, (iii) the marking line detection result (true / false (TRUE / FALSE)) and (iv) the count value obtained by feedback from the marking line detection device 304, (v) the dynamic coating thickness on the surface of the balloon 12, 23 obtained by feedback from the marking line detection device 304, (vi) the amount of drug applied by the precision micro-coating device 301 per unit time and the conversion rate (i.e., the approximate ratio of the drug that can be retained on the surface of the balloon 12, 23), etc.

[0141] Therefore, in the second embodiment, the inventors, after sophisticated design and a large number of experiments, determined that parameters (iii) and (iv) are used as judgment factors for starting and ending special processing (in the second embodiment, reducing the height H of the XYZ three-dimensional stepping device 302 in the Z-axis direction), and parameter (i) is used as a factor for determining the height H of the XYZ three-dimensional stepping device 302 in the Z-axis direction and the degree to which the height H needs to be reduced.

[0142] Specifically, the inventors have found that, under the condition that other parameters are substantially constant, the change in the height H in the Z-axis direction as a variable and the change in the thickness of the drug coating formed on the surface of the balloon body 12, 23 in the inflated and expanded state present a certain form of nonlinear relationship. Therefore, such a nonlinear relationship (such as an exponential relationship) can be obtained based on a large number of experiments, and such a nonlinear relationship can be pre-stored using a PLC program for the control device 305 to call and implement corresponding control, so as to achieve the expected control effect.

[0143] Finally, after the above steps are repeatedly performed, the surfaces of the balloon bodies 12 and 23 in the inflated state are creased at the corresponding fold positions (corresponding to Figure 4 , Figure 5 The thickness of the drug coating formed at the position AA) is different from that at other positions (corresponding to Figure 4 , Figure 5 Preferably, the drug coating thickness at the corresponding fold position (corresponding to the position BB) on the surface of the balloon body in the inflated state is substantially greater. Figure 4 , Figure 5 The thickness of the drug coating formed at the position AA) shown in FIG. 1 is the thickness of the drug coating formed at the position other than the corresponding fold position (corresponding to Figure 4 , Figure 5The thickness of the drug coating at the position BB) shown in FIG. 1 is about 1.5 to 2 times the thickness of the drug coating at the position BB shown in FIG. 1. However, the above thickness ratio is only an example, and the thickness ratio of the two thicknesses can also be set to other values ​​according to actual needs, and the various embodiments of the present invention are not limited thereto.

[0144] Third embodiment

[0145] Figure 8 1 is a flowchart of a third specific operation process of the method for manufacturing a drug-coated balloon according to the third embodiment of the present invention. Figure 3 The drug-coated balloon manufacturing device 300 is shown. Of course, this does not constitute a limitation, and the drug-coated balloon manufacturing method can also be implemented by other similar drug-coated balloon manufacturing devices. Specifically, for the specific structure of the drug-coated balloon manufacturing device 300, please refer to Figure 3 In addition, regarding the arrangement of the positions corresponding to the marking lines and folding positions on the connecting portion 3031, please refer to Figure 4 and Figure 5 shown.

[0146] Here, at the beginning Figure 8 Before each step shown, the preparatory work of forming the balloon bodies 12, 23 prepared in advance and in the inflated state has been completed. These preparatory work include: preparing, filling and providing the specific drug coating solution to the precision micro-coating device 301, filling the balloon bodies 12, 23 under the condition of a filling pressure of, for example, about 1 atm, and placing one or more balloon bodies 12, 23 in the inflated state on the rotating shaft driving device 303.

[0147] like Figure 3 and Figure 8 As shown, the third specific operation process of the method for manufacturing a drug-coated balloon according to the third embodiment of the present invention includes, for example, the following steps:

[0148] Step S801, providing a drug in a liquid or solid particle suspension state, and continuously coating the drug on the surface of the balloon body 12, 23 in a filled and expanded state by a precision micro-coating device 301;

[0149] Step S802, driving the precision micro-coating device 301 to move in the X-axis direction, that is, in the axial direction of the balloon body 12, 23, by means of the XYZ three-dimensional stepping device 302 connected to the precision micro-coating device 301;

[0150] Step S803, the rotating shaft driving device 303 connected to the balloon bodies 12 and 23 in the inflated and expanded state through the connecting part 3031 drives the balloon bodies 12 and 23 and the connecting part 3031 to rotate coaxially at a predetermined speed in a clockwise or counterclockwise direction;

[0151] Step S804, when the rotating shaft driving device 303 drives the balloon bodies 12, 23 and the connecting portion 3031 to coaxially rotate at a predetermined speed, the marking line detection device 304 detects each of the multiple marking lines 401 disposed on the surface or inside of the connecting portion 3031 in sequence;

[0152] Step S805, through the control device 305 connected to the XYZ three-dimensional stepping device 302, the rotation axis driving device 303, and the marking line detection device 304, when the marking line 401 is detected for the first time during the period in which the marking line detection device 304 detects the marking line 401 twice in succession, the control device 305 sends a third control instruction to the rotation axis driving device 303, so that the rotation axis driving device 303 drives the balloon bodies 12, 23 and the connecting portion 3031 in the direction of the rotation axis of the balloon bodies 12, 23 to slow down the rotation angular velocity θ; and

[0153] Step S806, when the marking line detection device 304 detects the marking line 401 for the second time during the period in which the marking line detection device 304 detects the marking line 401 twice, the control device 305 sends a fourth control instruction to the rotating shaft driving device 303, so that the rotating shaft driving device 303 is reset to a normal working state, that is, restored to the state except for the state corresponding to Figure 4 and Figure 5 The working state at position BB (corresponding to other positions on the balloon body 12 , 23 ) other than position AA (corresponding to the fold position on the balloon body 12 , 23 ) is shown.

[0154] It is worth noting that steps S802 and S803 are usually performed in parallel. Of course, if necessary, these two steps can also be set to be performed in sequence, and the embodiments of the present invention are not limited thereto.

[0155] In addition, steps S805 and S806 will be repeatedly executed until the thickness of the drug coating on the surface of the balloon body 12, 23 reaches a predetermined value. In practical applications, the marking line detection device 304 is, for example, an ultrasonic detection device for detecting the marking line. The ultrasonic detection device may also have the function of detecting the thickness of the drug coating on the surface of the balloon body 12, 23 using ultrasonic echoes, which will not be described in detail here.

[0156] Next, a specific description will be given of the control device 305 sending a third control instruction to the rotating shaft driving device 303 so that the rotating shaft driving device 303 drives the balloon bodies 12, 23 and the connecting portion 3031 in the filled and expanded state in a clockwise or counterclockwise direction around the rotating shaft to reduce the rotation speed.

[0157] First, as those skilled in the art understand, the third and fourth control instructions in various embodiments of the present invention are, for example, programmable logic control (PLC) programs or program segments. Of course, with the different types of control devices selected, the third and fourth control instructions in various embodiments of the present invention may also be programs or program segments of other types of digital logic controllers, as long as they can achieve fast and accurate control of the stepping (servo) drive of the rotating shaft drive device 303, and will not be repeated here.

[0158] Then, if Figure 3 As shown, the parameters considered by the control device 305 to achieve control include but are not limited to: (i) the real-time dynamic three-dimensional (X, Y, Z) coordinate values ​​of the precision micro-coating device 301 obtained by feedback from the XYZ three-dimensional stepping device 302, (ii) the rotational angular velocity θ of the balloon 12, 23 obtained by feedback from the rotating shaft driving device 303, (iii) the marking line detection result (true / false (TRUE / FALSE)) and (iv) the count value obtained by feedback from the marking line detection device 304, (v) the dynamic coating thickness on the surface of the balloon 12, 23 obtained by feedback from the marking line detection device 304, (vi) the amount of drug applied by the precision micro-coating device 301 per unit time and the conversion rate (i.e., the approximate ratio of the drug that can be retained on the surface of the balloon 12, 23), etc.

[0159] Therefore, in the third embodiment, the inventors, after sophisticated design and a large number of experiments, determined that parameters (iii) and (iv) are used as judgment factors for starting and ending special processing (in the third embodiment, slowing down the angular velocity θ1 of the rotating shaft drive device 303 in the rotation direction of the balloon bodies 12, 23), and parameter (ii) is used as the judgment factor for determining the rotational angular velocity θ1 of the balloon bodies 12, 23 and the degree to which it needs to be slowed down (i.e., from a faster angular velocity θ1 to a slower angular velocity θ2, i.e., θ1>θ2).

[0160] In particular, the inventors have found that, under the condition that other parameters are substantially constant, the change in the motion speed SP as a variable and the change in the thickness of the drug coating formed on the surface of the balloon body 12, 23 in the filled and expanded state present a certain form of nonlinear relationship (for example, a power function relationship). Therefore, such a nonlinear relationship can be obtained based on a large number of experiments, and such a nonlinear relationship can be pre-stored using a PLC program for the control device 305 to call and implement corresponding control, so as to achieve the expected control effect.

[0161] Finally, after the above steps are repeatedly performed, the surfaces of the balloon bodies 12 and 23 in the inflated state are creased at the corresponding fold positions (corresponding to Figure 4 , Figure 5 The thickness of the drug coating formed at the position AA) is different from that at other positions (corresponding to Figure 4 , Figure 5 Preferably, the drug coating thickness at the corresponding fold position (corresponding to the position BB) on the surface of the balloon body in the inflated state is substantially greater. Figure 4 , Figure 5 The thickness of the drug coating formed at the position AA) shown in FIG. 1 is the thickness of the drug coating formed at the position other than the corresponding fold position (corresponding to Figure 4 , Figure 5 The thickness of the drug coating at the position BB) shown in FIG. 1 is about 1.5 to 2 times the thickness of the drug coating at the position BB shown in FIG. 1. However, the above thickness ratio is only an example, and the thickness ratio of the two thicknesses can also be set to other values ​​according to actual needs, and the various embodiments of the present invention are not limited thereto.

[0162] Finally, the steps of how to process the inflated and expanded drug-coated balloon into a balloon body coated with balloon wing are clear to those skilled in the art, and can be achieved by various conventional technical means known in the art, which will not be described in detail here.

[0163] Other embodiments and modifications

[0164] The first to third embodiments given above can be reasonably combined and modified according to the general understanding of those skilled in the art, so as to simultaneously change two or more of the parameters (i) to (vi) described above in two or more dimensions, as long as it is possible to achieve, under the control of the control device 305, that the thickness of the drug coating formed at the corresponding fold position on the surface of the balloon body 12, 23 in the inflated and expanded state is substantially larger (preferably, about 1.5 to 2 times) compared with the thickness of the drug coating at other positions except the corresponding fold position.

[0165] Drug coated balloon

[0166] The novel drug-coated balloon obtained by the drug-coated balloon manufacturing method provided by each embodiment of the present invention has the main improvement over the conventional drug-coated balloon in that the thickness of the drug coating formed at the corresponding fold position on the surface of the balloon body in the inflated state is about 1.5 to 2 times the thickness of the drug coating at other positions except the corresponding fold position. Fig. 9 (the balloon is in a state of being inflated and expanded and the balloon flaps have not yet been coated with the balloon body, and the ratio of the position AA on the connecting portion 3031 to the fold position on the balloon body 12, 23 is 1:1), taking the drug-coated balloon with three balloon flaps as an example, the fold position (corresponding to Figure 4 , Figure 5 The drug coating height / thickness H1 at the position AA) shown is approximately the same as that at other positions except the fold position (corresponding to Figure 4 , Figure 5 The height / thickness H2 of the drug coating at the position BB shown in the figure is about 1.5 to 2 times. In addition, the thickness values ​​of the drug coating at various positions on the entire surface of the balloon in the compact state where the balloon flaps are wrapped around the balloon body are substantially the same.

[0167] Specifically, the novel drug-coated balloon obtained by the drug-coated balloon manufacturing method provided by each embodiment of the present invention, the anti-proliferative drug component in the drug-coated balloon is one or more of nimustine, carmustine, 5-fluorouracil, fluguanidine, gemcitabine, daunorubicin, doxorubicin, paclitaxel, vinblastine, topotecan, aminoglutethimide, sirolimus, everolimus, and zotarolimus.

[0168] Specifically, the novel drug-coated balloon obtained by the drug-coated balloon manufacturing method provided in each embodiment of the present invention can, for example, constitute a part of a balloon catheter with a rapid exchange structure or a balloon catheter with a double-lumen structure.

[0169] Specifically, the novel drug-coated balloon obtained by the drug-coated balloon manufacturing method provided by each embodiment of the present invention may have, for example, three balloon flaps, five balloon flaps, or six balloon flaps.

[0170] Industrial Applicability

[0171] The various inventions described in this specification can be applied, for example, to the field of medical devices, especially to the field of drug-coated balloon manufacturing methods.

[0172] Beneficial technical effects of various embodiments of the present invention

[0173] Compared with the prior art, the beneficial effects obtained by various embodiments of the present invention include but are not limited to:

[0174] First, according to the technical solution given above in the present invention, it can effectively ensure that the thickness of the drug coating on the balloon surface is more uniform when the balloon enters the human body, and because the above-mentioned anti-proliferative drugs, excipients and stabilizers are used, the drug-coated balloon made by the drug-coated balloon manufacturing method is compared with ordinary drug coatings, so that the drug coating on the balloon surface that finally reaches the affected area is more sufficient and uniform, so that the drug utilization is higher, it is easier to be absorbed by the human body, and the retention time of the blood vessel wall is longer, thereby significantly improving the long-term patency.

[0175] Second, according to the present invention, the drug coating can also include various types of anti-proliferative drugs, as well as excipients and stabilizers. For example, the anti-proliferative drug component is one or more of nimustine, carmustine, 5-fluorouracil, fluguanosine, gemcitabine, daunorubicin, doxorubicin, paclitaxel, vinblastine, topotecan, aminoglutethimide, sirolimus, everolimus, and zotarolimus. The excipient is one or more of lacamine salt, citric acid, resveratrol, polybutyl methacrylate, stearic acid, magnesium stearate, sodium stearate, zinc stearate, stearamide, isooctyl palmitate, linoleic acid, linolenic acid, monoolein, iohexol, iopromide, urea, sorbitol, polysorbate, trihexyl citrate, phospholipids, ropizine matrix, cholesterol, vitamin E, and vitamin E polyethylene glycol succinate. The stabilizer is one or more of butylated hydroxyanisole, dibutyl hydroxytoluene, propyl gallate, tocopherol, ascorbic acid and its sodium salt, phytic acid, and disodium edetate. Compared with other balloon products, the therapeutic effect is better.

[0176] Third, according to various embodiments of the present invention, a compromise strategy is proposed, that is, it is proposed to pre-compensate the thickness loss value of the drug coating that has been applied at these fold positions due to stress peeling or falling off caused by the negative pressure operation in the subsequent steps at a plurality of pre-set fold positions, so as to effectively ensure that the thickness of the drug coating on the balloon surface is basically consistent in the final state (the compact state of the balloon flaps covering the balloon body). In particular, it can be determined based on prior knowledge and a posteriori knowledge that, considering that the thickness loss value of the drug coating that has been applied at these fold positions due to stress peeling or falling off caused by the negative pressure operation in the subsequent steps is generally about 0.5 to 1 times the thickness value of the drug coating at other positions, the thickness value of the drug coating formed at the corresponding fold positions on the surface of the balloon body in the inflated and expanded state is deliberately set larger in the previous coating step, for example, preferably about 1.5 to 2 times the thickness value of the drug coating at other positions except the corresponding fold positions. In this way, it can be effectively ensured that the thickness of the drug coating on the balloon surface is basically consistent in the final state (the compact state in which the balloon flaps cover the balloon body).

[0177] Fourth, according to various embodiments of the present invention, by cleverly selecting a marking line formed by, for example, a metal wire (for example, an extremely thin copper wire, with a diameter of 0.001 to 0.005 mm), a position corresponding to the fold position of the balloon body is outlined on the connection portion connected to the balloon body. In particular, the extremely thin metal wire can not only be set inside the connection portion but also be exposed to the outside, which can not only facilitate, for example, ultrasonic detection to detect the marking line, but also will not affect the appearance of the connection portion that drives the coaxial rotation of the balloon body. In addition, practice has shown that drug-coated balloons with three wings, five wings, and six wings are particularly conducive to the full contact between the therapeutic drug coated on the balloon and the vascular lesion site to achieve targeted drug administration, and also facilitate the removal of the drug-coated balloon from the peripheral blood vessels or coronary blood vessels.

[0178] Fifth, according to various embodiments of the present invention, by cleverly selecting a marking line formed by, for example, a metal wire on the connecting portion to outline the corresponding fold position on the balloon body, and by detecting the marking line twice in succession within a very short period of time, the fold position area of ​​the balloon that needs special treatment (i.e., increasing the coating in the coating process) is determined. In a first specific operation process, the driving speed of the coating device in the X-axis direction of the axial extension of the balloon body is reduced, so as to achieve the coating and deposition of a larger amount of drug at the corresponding fold position per unit time.

[0179] Sixth, according to various embodiments of the present invention, by cleverly selecting a marking line formed by, for example, a metal wire on the connecting portion to outline the corresponding fold position on the balloon body, and by detecting the marking line twice in a very short period of time, the fold position area that needs to be specially treated (i.e., increasing the coating in the coating process) is determined. In a second specific operation process, the coating device is driven on the Z-axis perpendicular to the plane in which the balloon body is set to be closer to the balloon body in the filled and expanded state (i.e., the distance between the coating device and the balloon body in the Z-axis direction is shortened), so as to achieve coating and deposition of a larger amount of drug at the corresponding fold position per unit time.

[0180] Seventh, according to various embodiments of the present invention, by cleverly selecting a marking line formed by, for example, a metal wire on the connecting portion to outline the corresponding fold position on the balloon body, and by detecting the marking line twice in a very short period of time, the fold position area that needs to be specially treated (i.e., increasing the coating in the coating process) is determined. In the third specific operation process, the rotation speed of the balloon body in the filled and expanded state is reduced in a clockwise or counterclockwise direction around the rotation axis (i.e., the rotational angular velocity of the balloon body becomes smaller), so as to achieve the coating and deposition of a larger amount of drug at the corresponding fold position per unit time.

[0181] Eighth, according to various embodiments of the present invention, by cleverly selecting a marking line formed by, for example, a metal wire on the connecting portion to outline the corresponding fold position on the balloon body, the marking line is detected twice in succession within a very short period of time to determine the fold position area that needs to be specially treated (increased coating in the coating process), in the fourth specific operation process, when the marking line is detected for the second time within a very short period of time, it can be determined that the special treatment needs to be ended, and the predetermined normal treatment at other positions except the corresponding fold position can be restored, so that although the drug coating thickness on the balloon surface is uneven in the intermediate state (inflated balloon), it can effectively ensure that the drug coating thickness on the balloon surface is basically consistent in the final state (the compact state of the balloon fold wrapped around the balloon body).

[0182] It should be noted that, in this article, the terms "comprise", "include" or any other variant thereof are intended to cover non-exclusive inclusion, so that the process, method, article or device including a series of elements includes not only those elements, but also includes other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise one..." do not exclude the presence of other identical elements in the process, method, article or device including the element. In addition, it should be pointed out that the scope of the methods and devices in the embodiments of the present application is not limited to performing functions in the order shown or discussed, and may also include performing functions in a substantially simultaneous manner or in reverse order according to the functions involved, for example, the described method may be performed in an order different from that described, and various steps may also be added, omitted, or combined. In addition, the features described with reference to certain examples may be combined in other examples.

[0183] The embodiments of the present application are described above in conjunction with the accompanying drawings, but the present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A method for manufacturing a drug-coated balloon, the method for manufacturing a drug-coated balloon is used to coat a drug coating on the surface of a balloon body that is prepared in advance and in a filled and expanded state, a plurality of marking lines are pre-arranged on a connecting portion that is connected to the balloon body and rotates coaxially with the balloon body, and two adjacent marking lines on the connecting portion correspond to fold positions corresponding to the balloon flaps formed on the balloon body, the method for manufacturing a drug-coated balloon comprises: Providing a drug in a liquid or solid particle suspension state, and coating the drug on the surface of the balloon body in an inflated and expanded state through a coating device to form a drug coating; Driving the coating device to move in one or more directions among the three directions of X-axis, Y-axis and Z-axis; Driving the balloon body and the connecting portion to rotate coaxially at a predetermined speed in a clockwise or counterclockwise direction; When the balloon body and the connecting part are driven to coaxially rotate at a predetermined speed, each of the multiple marking lines pre-set on the connecting part is detected in sequence; as well as During the period when two adjacent marking lines are detected twice in succession, a control instruction is sent to change the movement of the coating device in one or more directions of the X-axis, Y-axis, and Z-axis, and / or the rotation speed of the balloon body, The thickness of the drug coating formed at the corresponding crease position on the surface of the balloon body in the inflated and expanded state obtained by the drug-coated balloon manufacturing method is 1.5 to 2 times the thickness of the drug coating at other positions except the corresponding crease position.

2. The method for manufacturing a drug-coated balloon according to claim 1, wherein: There are three, five or six crease positions in total, and three, five or six crease positions are used to form three balloon flaps, five balloon flaps or six balloon flaps respectively.

3. The method for manufacturing a drug-coated balloon according to claim 1, wherein: When the marking line is detected for the first time during two consecutive detections of the marking line, a first control instruction is sent to reduce the driving speed of the coating device in the X-axis direction in which the balloon body extends axially.

4. The method for manufacturing a drug-coated balloon according to claim 1, wherein: When the marking line is detected for the first time between two consecutive detections, a second control instruction is sent to drive the coating device in the Z-axis direction perpendicular to the balloon setting plane to be closer to the balloon in the filled and expanded state.

5. The method for manufacturing a drug-coated balloon according to claim 1, wherein: When the marking line is detected for the first time during the period of two consecutive detections of the marking line, a third control instruction is sent to reduce the rotation speed of the balloon body in the filled and expanded state in the clockwise or counterclockwise direction around the rotation axis.

6. The method for manufacturing a drug-coated balloon according to any one of claims 3 to 5, wherein: When the marking line is detected for the second time during the period of detecting the marking line twice in succession, a fourth control instruction is sent to reset the coating device to a normal working state.

7. The method for manufacturing a drug-coated balloon according to claim 1 or 2, wherein: The anti-proliferative drug component in the drug coating is one or more of nimustine, carmustine, 5-fluorouracil, fluguanidine, gemcitabine, daunorubicin, doxorubicin, paclitaxel, vinblastine, topotecan, aminoglutethimide, sirolimus, everolimus, and zotarolimus.

8. The method for manufacturing a drug-coated balloon according to claim 1 or 2, wherein: The interval between two adjacent marking lines arranged on the connecting portion is 0.01 mm to 0.05 mm.

9. The method for manufacturing a drug-coated balloon according to claim 1 or 2, wherein: Two or more balloons prepared in advance and in a filled and expanded state are arranged in a substantially parallel manner in the Y-axis direction perpendicular to the X-axis direction in which the balloon extends axially within the balloon arrangement plane.

10. The method for manufacturing a drug-coated balloon according to claim 9, wherein: The intervals between two adjacent balloon bodies among the two or more balloon bodies that are pre-prepared and inflated are substantially the same.

11. The method for manufacturing a drug-coated balloon according to claim 1 or 2, wherein: The coating device is a precision micro-coating device.

12. The method for manufacturing a drug-coated balloon according to claim 1 or 2, wherein: The marking line is detected by an ultrasonic detection device.

13. The method for manufacturing a drug-coated balloon according to claim 1 or 2, further comprising: By sucking the negative pressure device, the balloon body in the inflated and expanded state is deformed into a compact state in which the balloon folds wrap the balloon body; as well as The balloon body in a compact state is placed into a protective sleeve.

14. A drug-coated balloon, wherein the drug-coated balloon is manufactured by the method for manufacturing a drug-coated balloon according to any one of claims 1 to 13.

15. The drug-coated balloon according to claim 14, wherein: The thickness of the drug coating formed on the surface of the balloon body in the inflated state at the corresponding fold position is 1.5 to 2 times the thickness of the drug coating at other positions except the corresponding fold position; and The thickness values ​​of the drug coating at various positions on the entire surface of the balloon in a compact state where the balloon flaps wrap the balloon body are substantially the same.

16. The drug-coated balloon according to claim 14 or 15, wherein: The drug-coated balloon is a paclitaxel-coated balloon or a sirolimus-coated balloon.

17. The drug-coated balloon according to claim 14 or 15, wherein: The drug-coated balloon constitutes a part of a balloon catheter with a rapid exchange structure or a balloon catheter with a double-lumen structure.

18. The drug-coated balloon according to claim 14 or 15, wherein: The drug-coated balloon has three balloon flaps, five balloon flaps, or six balloon flaps.

Images