Drug-loaded balloon catheter and method for producing the same, balloon catheter system, and method for producing an in-situ vascular stent

Abstract

A drug-loaded balloon catheter and its manufacturing method, balloon catheter system, and in situ vascular production method are provided, the drug-loaded balloon catheter including a tube body (100) having opposing distal and proximal ends (110 and 120), for transporting a fluid into the balloon body (200), and a hollow balloon body (200) fixed to the distal end (110) of the tube body (100) and communicating with the tube body (100), having a corresponding inflated state and a deflated state suitable for interventional delivery, the balloon body (200) being loaded with a drug, the drug being loaded in one of solid embedding, solid coating, and solution impregnation. This technical solution can improve the drug administration effect of the drug-loaded balloon catheter.

Description

[Technical Field]

[0001] The present application relates to the field of medical devices, and in particular to a drug-loaded balloon catheter and a method for making the same, a balloon catheter system, and a method for producing a vascular in-situ stent. [Background technology]

[0002] In the field of interventional therapy, balloon dilation catheters are common medical devices that are widely used for dilating upper gastrointestinal stenosis, dilating the cervix and inducing labor, and dilating airway stenosis. In recent years, the shortcomings of traditional balloon dilatation catheters have gradually become apparent, and balloons with special functions have attracted attention.

[0003] For example, microneedles in balloon dilatation catheters with microneedles are considered a new, minimally invasive and nearly painless biomedical device. They can penetrate the epidermis and form small channels while avoiding contact with capillaries and nerve endings. This allows for minimal invasiveness, painlessness, and the prevention of infection, while also enabling sustained drug release. The invention patent application with publication number CN114470341 discloses a composite microneedle balloon and a preparation method for achieving controllable drug release. However, the low burst pressure of conventional balloons makes it difficult to effectively dilate calcified lesions, especially those with severe calcifications. At the same time, the low pressure makes it difficult to effectively push microneedles through calcified blood vessel walls or narrow walls of the digestive tract, cervix, airway, etc.

[0004] In another example, a balloon dilatation catheter containing a photosensitive compound or drug differs from conventional drug balloons in that the balloon body of this type of balloon dilatation catheter scatters visible light, exciting the photosensitive compound, thereby rapidly binding to collagen and elastin in the vascular wall, forming a stent in situ, and achieving vascular healing and repair. However, in conventional technologies, the photosensitive compound is relatively dispersed, and its efficiency in inducing binding to collagen and elastin in the vascular wall is low.

[0005] Another example is an angioplasty balloon, which can form a microstent in situ within a blood vessel. Angioplasty balloons are used to widen calcified stenotic lesions in arterial walls, and there is a high possibility that the stenotic lesions will narrow again after simple balloon dilation. Currently, angioplasty balloons can be used to open calcified lesions in arterial walls and are one of the main methods of revascularization for arterial stenosis. However, during angioplasty, damage to the blood vessel wall can occur, leading to thrombosis and the release of growth factors, which can cause restenosis and subsequent reclosure of the dilated blood vessel.

[0006] Currently, these problems are primarily solved by implanting vascular stents into blood vessels. Existing vascular stents are divided into two main types: 1) biocompatible metal stents, which can cause thrombosis and immunogenicity. Furthermore, these permanently placed stents can interfere with subsequent treatment, leading to corrosion, perforation, and possible aneurysms. 2) Biodegradable stents solve the problem of the permanent presence of metal stents, but the acidic products produced by their degradation can trigger severe inflammatory reactions, leading to atrophy and degeneration of the muscular elastic elements in the arterial wall, and potentially to arterial dilation. Medicated stents are widely used to reduce the rate of restenosis in stented lesions. While medicated stents can reduce vascular smooth muscle cell proliferation and vascular restenosis, they also hinder the long-term recovery of the endothelial cell layer, potentially leading to thrombosis in the blood vessel wall. Summary of the Invention

[0007] Based on this, a drug-loaded balloon catheter and a method for manufacturing the same, a balloon catheter system, and a method for producing a vascular in-situ stent are provided.

[0008] A drug-loaded balloon catheter, a tube body having opposite distal and proximal ends for transporting a fluid into the body of the balloon; a balloon body secured to the distal end of the tube body and in communication with the tube body, the balloon body having a hollow structure and a corresponding inflated state and a deflated state suitable for interventional delivery; The balloon body is loaded with a drug, and the drug loading method is one of solid embedding, solid coating, and solution infiltration.

[0009] Some optional methods are also presented below, but these are not intended as additional restrictions on the overall technical solution above. As long as there is no technical or logical contradiction, each optional method can be combined individually or multiple optional methods can be combined with the overall technical solution above.

[0010] Optionally, the balloon body is loaded with a drug by a solid embedding method, and the drug-loaded balloon catheter comprises: The balloon is made of a polymer material and is wrapped around the balloon body. The balloon has a large number of cells, each of which has a width of X and a length of Y, and the ratio of X:Y=1:0.5 to 2 is satisfied. The area of ​​the cells is 1 to 50 mm. 2 a braided mesh, and drug-loaded microneedles disposed on the surface of the balloon body and positioned within the cells of the braided mesh and / or at the interlacing points of the cells.

[0011] Optionally, multiple microneedles are dispersed within each cell, the distance between any two adjacent microneedles within a cell is between 30 μm and 3 mm, and the height of said microneedles is between 25 and 2000 μm.

[0012] Optionally, the braided mesh comprises: a first braided thread wound spirally around the outer periphery of the balloon body; and a second braided thread extending axially along the balloon body and interlacing with the first braided thread and surrounding the first braided thread at least once at each interlacing point.

[0013] Optionally, the mesh yarn of the braided mesh is wound spirally around the outer periphery of the balloon body, and two adjacent windings are a first winding circle and a second winding circle, each winding circle having an undulating peak-and-valley structure and wound and connected to each other.

[0014] Optionally, the braided mesh comprises: The balloon includes a plurality of parallel-arranged first mesh lines and second mesh lines, each of which extends along the circumferential direction of the balloon body and is spaced apart along the axial direction of the balloon body; The second mesh wires extend along the axial direction of the balloon body, interlacing with each of the first mesh wires and wrapping around the first mesh wire at least once at each interlacing point.

[0015] Optionally, the balloon body is loaded with a drug by a solid coating method, and the drug-loaded balloon catheter further comprises: an optical fiber module inserted into the tube body and having a light-emitting portion extending to the adjacent balloon body; an auxiliary material and a photosensitizer are applied to the surface of the balloon body by a coating method, and the photosensitizer is a polypeptide dendrimer modified with a naphthalene imide compound; The photosensitizer activates and crosslinks collagen and elastin with light of a wavelength of 400 to 460 nm, The auxiliary material includes an active drug and a sustained-release material encapsulating the active drug, wherein the active drug is at least one of paclitaxel, rapamycin, zotarolimus, tacrolimus, everolimus, temsirolimus, zotarolimus, umirolimus, docetaxel, protein-bound paclitaxel, and protein-bound dexamethasone.

[0016] Optionally, the method for preparing the photosensitizer comprises: Step 1: protecting some of the amino groups of a polypeptide dendrimer; and step 2, in which the partially amino-protected polypeptide dendrimer and the naphthalimide compound are added to a mixed solution of an organic base and an organic solvent, and the resulting mixture is reacted at 70 to 150°C for 1 to 32 hours, and the photosensitizer is obtained after post-treatment. the organic base is at least one of N,N-diisopropylethylamine, sodium tert-butoxide, and potassium tert-butoxide; The organic solvent is at least one of isopropyl alcohol, hexafluoro-2-propanol, methanol, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, dichloromethane, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, and hexamethylphosphoramide.

[0017] Optionally, a photosensitizer is applied to the surface of the balloon body by a coating method, and the method includes the steps of dispersing or dissolving the photosensitizer in a solvent to prepare a solution and coating the surface of the balloon body with the solution; The solvent is at least one of ethanol, acetic acid, acetone, butylated hydroxytoluene, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, and water.

[0018] Optionally, the solvent is a mixture of ethanol, acetic acid, and water, and the volume ratio of each component in the solvent is ethanol:acetic acid:water=80-90:19-9:1.

[0019] Optionally, the concentration of the photosensitizer in the solution is between 6.25 and 125 μM / mL. Optionally, the solution further comprises an auxiliary material, and the mass ratio of the auxiliary material to the photosensitizer is 0.3-10. Optionally, in the auxiliary materials, the mass ratio of the active drug to the sustained-release material is 1:1-20. Optionally, the mass ratio of the photosensitizer to the active drug is 1:0.2-5.

[0020] Optionally, the solution further comprises a stabilizer, the stabilizer being at least one of an antioxidant and a Lewis acid; the antioxidant is at least one of tromethamine and butylated hydroxytoluene, and the mass ratio of the antioxidant to the photosensitizer is 0.05 to 1:100; The cation of the Lewis acid is at least one of Na+, K+, Mg+, and Ca+, and the molar ratio of the Lewis acid to the photosensitizer is 0.8 to 3.

[0021] Optionally, the coating method includes spraying and / or dipping, and the amount of photosensitizer applied on the surface of the balloon body is 0.0012 to 37.5 μM / mm 2 is.

[0022] Optionally, a drug coating is disposed on the surface of the balloon body, and an active ingredient of the drug coating comprises riboflavin and / or a riboflavin salt; The drug-loaded balloon catheter further includes a light-guiding material, one end of which is a light-emitting end extending to the balloon body and the other end of which is a light-input end extending through the catheter to the proximal end.

[0023] Optionally, the drug coating deposition method includes: The method involves preparing a drug coating solution in advance, applying the solution to the surface of the balloon body, and drying it.

[0024] Optionally, the balloon body is loaded with a drug using a solution infiltration method, and the drug-loaded balloon catheter comprises: the wall of the balloon body has a pore structure; a fluid containing riboflavin and / or a riboflavin salt, the fluid being output from the pore structure to the surrounding environment of the balloon body and for maintaining the inflation state of the balloon body; and a light guide having one end being a light emitting end extending to the balloon body and the other end being a light input end extending through the catheter to the proximal end.

[0025] Optionally, the pore structure has a pore size of 5 to 100 μm; The porosity of the surface of the balloon body is 30 to 80%.

[0026] Optionally, the fluid is in the form of a solution, the solvent of which is water; Calculated as total riboflavin, the fluid has a concentration of 0.2 to 60 mg / mL.

[0027] The present application also provides a method for making the drug-loaded balloon catheter, A step of placing a drug-containing microneedle raw material solution in the micropores of the rigid substrate and forming the microneedle in situ; wrapping a braided mesh around a balloon body; injecting a fluid into the balloon body to expand the balloon body; Applying an adhesive onto the balloon body or the microneedles, and rolling the balloon body onto the rigid substrate to adhere the microneedles to the surface of the balloon body.

[0028] Optionally, the solvent of the microneedle raw material solution is water, and the solute is at least one of chitosan, sodium alginate, polyethylene glycol, PLGA, PCL, PMMA, PGA, PLA, PEA, gelatin, and hyaluronic acid.

[0029] Optionally, the adhesive is a water-soluble redissolvable adhesive.

[0030] Optionally, before or after injecting fluid into the balloon body to expand it, a mandrel is inserted into the balloon body and the mandrel is manipulated to drive the balloon body to roll onto the rigid substrate.

[0031] The present application also provides a method for making the drug-loaded balloon catheter, wrapping a braided mesh around a balloon body; injecting a fluid into the balloon body to expand the balloon body; Dropping a UV-curable adhesive onto the surface of the balloon body or the interlacing points of the cells of the braided mesh, and applying an electric field or a magnetic field in a specific direction to harden the UV-curable adhesive into the shape of a microneedle; A step in which the microneedle-shaped UV-curable adhesive is solidified by UV light irradiation to form microneedles; and spraying or dip-coating the drug onto the surface of the microneedles.

[0032] The present application further provides a balloon catheter system, a balloon body having a corresponding inflated state and a deflated state suitable for interventional delivery, the balloon body having a pore structure in the wall for allowing fluid to pass therethrough; a tube body having opposing distal and proximal ends, the distal end of which is connected to the balloon body; a drug delivery device connected to the proximal end of the catheter for supplying a fluid, the fluid including riboflavin and / or a riboflavin salt; a light guide having one end being a light emitting end extending to the balloon body and the other end being a light input end extending through the catheter to the proximal end; The light source device is connected to the light input end of the light guide member by an optical path.

[0033] The present application provides a method for producing a vascular in situ stent, administering a first reagent to a predetermined location within a blood vessel, the first reagent including riboflavin and / or a riboflavin salt; The method includes a step of irradiating the predetermined position with light to excite the first reagent, and causing the first reagent to act on the predetermined position to form a vascular in situ stent.

[0034] Optionally, when administering the first reagent, possible methods include: A method for preparing and delivering a solution directly to a predetermined location via an interventional device; or coating and delivering to a predetermined location via an interventional device using a solid encapsulation method; When the first reagent is in the form of a solution, the concentration of the first reagent is 0.2 to 60 mg / mL when calculated as total riboflavin.

[0035] Optionally, the wavelength of the irradiated light is 300-700 nm, and the intensity of the irradiated light is 5-500 mW / cm 2 and the light irradiation time is 0.1 to 30 minutes. The present invention also provides the application of riboflavin and riboflavin salts in the preparation of vascular in-situ stent drugs, in which riboflavin and / or riboflavin salts are applied to a predetermined location, and then a vascular in-situ stent is formed at the predetermined location by photoexcitation.

[0036] The drug-loaded balloon catheter with microneedles provided by the present application can effectively dilate calcified blood vessels, especially severely calcified blood vessels, and when the balloon body is filled with pressure, the microneedles can be effectively pushed into the walls of calcified blood vessels or narrow ducts such as the digestive tract, cervix, and airway, thereby providing treatment through the sustained release of the drug.

[0037] The improved photosensitizer balloon catheter system provided in the present application can increase the utilization efficiency of the photosensitizer compound by improving the structure and coating method of the photosensitizer on the surface of the photodynamic balloon body.

[0038] The present invention uses an interventional device to transport or deliver riboflavin to the blood vessel wall, and uses light to activate riboflavin and crosslink it with proteins and polypeptides in the blood vessel wall, thereby generating endogenous microstents in situ on the blood vessel wall to replace implanted stents, thereby effectively reducing thrombus formation and immunogenicity, and the in situ formed microstents can keep the blood vessel in an expanded shape after surgery and prevent restenosis of the blood vessel. [Brief explanation of the drawings]

[0039] [Figure 1] 1 is a schematic diagram of a drug delivery balloon catheter according to an embodiment of the present application. [Figure 2] FIG. 2 is an enlarged view of a balloon body portion of a drug-loaded balloon catheter according to an embodiment of the present application. [Figure 3] FIG. 1 is a schematic diagram of a microneedle of a drug-loaded balloon catheter in accordance with an embodiment of the present application. [Figure 4a] FIG. 1 is a schematic diagram of a first type of braided mesh of the drug-loaded balloon catheter of the present application. [Figure 4b] FIG. 1 is a schematic diagram of a first type of braided mesh of the drug-loaded balloon catheter of the present application (microneedles omitted). [Figure 5] FIG. 1 is a schematic diagram of a second type of braided mesh of the drug-loaded balloon catheter of the present application. [Figure 6] FIG. 1 is a schematic diagram of a third type of braided mesh of the drug-loaded balloon catheter of the present application. [Figure 7] FIG. 1 is a schematic diagram of a substrate having micropores used in a first type of method for fabricating a drug-loaded balloon catheter in one embodiment of the present application. [Figure 8] FIG. 1 is a schematic diagram of a first type of method for fabricating a drug-loaded balloon catheter after the mandrel is inserted into the balloon body and the microneedles are rotated and bonded in one embodiment of the present application. [Figure 9] FIG. 10 is a schematic diagram of a first method for fabricating a drug-loaded balloon catheter after a mandrel is inserted into the balloon body and microneedles are rolled and bonded in one embodiment of the present application (different from the braided mesh form in FIG. 8). [Figure 10] 1 is a schematic diagram of a second type of fabrication method for the drug-loaded balloon catheter of the present application (microneedles are located at the intersections of cells of the braided mesh). [Figure 11] 1 is a structural schematic diagram of a drug-loaded balloon catheter system according to one embodiment. FIG. [Figure 12] FIG. 11 shows histological staining of experimental groups characterizing the vascular repair effect. [Figure 13] FIG. 10 is a histological staining image of a control group characterizing the vascular repair effect. [Figure 14] 1 is a flowchart of the present method for producing a vascular in situ stent. [Figure 15] 1 is a schematic structural diagram of a drug-loaded balloon catheter based on photocuring in one embodiment. FIG. [Figure 16] 1 is a schematic structural diagram of a drug-loaded balloon catheter used for a vascular in-situ stent in one embodiment. [Figure 17] 1 is a schematic structural diagram of a light-curing balloon catheter system used to create a vascular in situ stent in one embodiment. [Figure 18] 1 is a structural schematic diagram of an occlusion balloon catheter in one embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0040] Hereinafter, the embodiments of the present application will be described in detail with reference to the accompanying drawings. Note that the following embodiments are merely examples of the present application and do not limit the technical scope of the present application. All other embodiments that can be obtained by those skilled in the art based on the embodiments of the present application without departing from the scope of the present application are also within the scope of the present application.

[0041] To better describe and illustrate the embodiments of the present application, reference may be made to one or more drawings; however, any additional details or examples used to illustrate the drawings should not be considered as limitations on the scope of any of the inventions, embodiments or preferred forms of the present application.

[0042] For clarity, when a component is said to be "connected" to another component, the component may be directly connected to the other component, or there may be intermediate components present. When a component is said to be "attached" to another component, the component may be directly attached to the other component, or there may also be intermediate components present.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0044] The present application provides a drug-loaded balloon catheter, including:

[0045] a tube body having opposite distal and proximal ends for transporting a fluid into the body of the balloon; a balloon body secured to the distal end of the tube body and in communication with the tube body, the balloon body having a hollow structure and a corresponding inflated state and a deflated state suitable for interventional delivery; The balloon body is loaded with a drug, and the drug loading method is one of solid embedding, solid coating, and solution infiltration.

[0046] The drugs are loaded onto the balloon body of the balloon catheter in the present application by different methods. In addition to the different loading methods, the types of drugs applied to the different loading methods are also different.

[0047] First, with reference to Figures 1 to 10, a method for drug loading using the solid embedding method will be described in detail. Simply put, using the solid embedding method means fixing microneedles containing drugs to the surface of the balloon body. Below, the drug-loaded balloon catheter obtained by this loading method will be referred to as a drug-loaded microneedle balloon dilation catheter, and its manufacturing method will also be described in detail.

[0048] As shown in Figures 1 and 2, the drug-loaded microneedle balloon dilatation catheter includes:

[0049] a tube body 100 having opposed distal and proximal ends 110 and 120; A balloon body 200 having a hollow structure is fixed to the distal end 110 of the tube body 100. The balloon is made of a polymer material and is wound around the balloon body 200. The balloon has a large number of cells, each of which has a width of X and a length of Y, and the ratio of X:Y=1:0.5 to 2 is satisfied. The cell area S is 1 to 50 mm 2 a braided mesh 300; and drug-loaded microneedles 400 disposed on the surface of the balloon body 200 and positioned within the cells of the braided mesh 300 and / or at the interlacing points of the cells.

[0050] In the present application, the outside of the balloon body 200 is wrapped with a braided mesh 300, which has cells. When the balloon body 200 is inflated under high pressure, the braided mesh 300 can suppress deformation of the balloon body 200, thereby allowing the balloon body 200 to inflate evenly and reducing the phenomenon of blood vessel tearing. At the same time, when the balloon body 200 is inflated under high pressure, the braid restrains the peripheral portion of the balloon body 200 within the cells, causing the microneedles 400 to bulge outward, forcing the microneedles 400 into the affected blood vessel wall and gradually releasing the drug within the affected blood vessel wall.

[0051] 2, the balloon body 200 has a constant diameter portion 210 located in the center along the axial direction and tapered reduced diameter portions 220 at both ends. The ends of the two reduced diameter portions 220 away from the constant diameter portion 210 converge onto the tube body 100. The material of the balloon body 200 may be at least one of PA, Pebax, and PU.

[0052] 1, 2, 3, and 4, multiple microneedles 400 are dispersed within each cell, with the distance between any two adjacent microneedles 400 within the cell being 30 μm to 3 mm (D in FIG. 4a), and the height of the microneedles 400 being 25 to 2000 μm. Preferably, the distance between any two adjacent microneedles 400 is 1 mm to 3 mm, and the height of the microneedles 400 is 25 to 1000 μm. More preferably, the distance between any two adjacent microneedles 400 is 1 mm to 3 mm, and the height of the microneedles 400 is 100 to 500 μm.

[0053] The microneedles 400 may be located within the cells of the braided mesh, or at the interweaving points of the cells, or may be distributed simultaneously within the cells and at the interweaving points of the cells, with no significant difference between these distribution locations.

[0054] The spacing and height of the microneedles 400 must be set taking into account the limitations of the processing technology, and must achieve the maximum possible drug loading capacity, while also taking into account the ability of the blood vessels to withstand the forces that would be imposed on them.

[0055] As shown in FIG. 3 , the microneedle 400 has a sharp tip that can be inserted into a target object. However, the tip should not be too sharp to prevent damage to the wall of the folded balloon body 200 when it is inserted into the human body. In one embodiment, the microneedle 400 is conical, with a base diameter of 30 to 1000 μm and a base angle α of the cone in the range of 45°≦α<90°. Furthermore, the base angle α of the cone in the range of 45°≦α<70°. The microneedle 400 can also have other shapes, such as a polygonal pyramid shape. The microneedle 400 can also adopt various forms available in existing technology, such as a solid microneedle 400 or a multi-layered microneedle 400.

[0056] The braided mesh 300 is woven from filament material, and the cross section of a single filament material may be circular, with a diameter of 10 to 200 μm, or the cross section of the filament material may be rectangular, with a length of 10 to 300 μm and a width of 10 to 100 μm.

[0057] The filamentary material is made of a high-strength medical polymer material, such as nylon, polyether block polyamide, polyamide, etc., which meets the high-pressure filling requirements of the balloon body 200 and ensures safety and effectiveness during pressurized use of the balloon body 200. The filamentary material itself can be woven directly or twisted before being woven.

[0058] The braided mesh 300 can be fixed to the surface of the balloon body 200 using an adhesive, such as polyurethane or polyvinyl chloride, which can be cured by natural curing or UV curing. The material and bonding method used for the braided mesh 300 in this application can effectively improve the flexibility of the balloon body 200.

[0059] The first kind of braiding method of the braided mesh, refer to Figures 4a and 4b, the braided mesh includes:

[0060] a first braided thread 311 wound spirally around the outer periphery of the balloon body 200; and a second braided thread 312 extending along the axial direction of the balloon body 200, interlacing with the first braided thread 311 and surrounding the first braided thread 311 at least once at each interlacing point.

[0061] The first braided thread 311 is spirally wrapped around the balloon body 200 from one end of the balloon body 200 to the other, which allows for more direct force transmission when the balloon body 200 is inflated, and the braided mesh 300 has good integrity and cooperation, thus allowing for higher inflation pressures to be applied, i.e., more uniform inflation at higher pressures.

[0062] The second braiding thread 312 is used to regulate the position of the first braiding thread 311 and prevent the first braiding thread 311 from overlapping in the axial direction due to uneven force.

[0063] Referring to FIG. 4a, after the balloon body 300 is filled with liquid, under the constraint of the braided mesh, the peripheral wall of the balloon body surface within each cell becomes slightly convex, and the microneedles located thereon are pushed into the blood vessel or plaque.

[0064] As shown in Figure 2, a single thread is wound spirally in the axial direction, with W1 representing the peaks and W2 representing the valleys, or it can be a straight line. L1 and L2 are the adjacent widths, L1:L2=1.2:1 to 1:1.2, the number of L1 is N, of which N=2 to 6, and the number of L2 is N-1 to N+1. H1=1.5mm to 5mm.

[0065] The second type of braiding method of the braided mesh is shown in FIG. 5. Each cell of the braided mesh 300 has a width of X and a length of Y, and satisfies X:Y=1:0.5-2. The area of ​​each cell is 1-50 mm. 2 The larger area cells ensure that the balloon body 200 forms a pronounced pillow-like projection upon inflation. The width, length, and area of ​​each cell are measured on the unfolded plane of the braided mesh 300.

[0066] Furthermore, in each cell, the cell having a size ratio of X:Y=1:1.5 is approximately "short and thick", which can constrain the balloon body 200 to form a clear pillow-like protrusion, and the contact area of ​​the pillow-like protrusion with the blood vessel is increased.

[0067] The area of ​​each cell is preferably 2 to 38 mm 2 , and when the balloon body 200 is expanded, the balloon body 200 can be constrained to form a larger pillow.

[0068] There are different ways to weave the braided mesh 300. For example, in one embodiment, the mesh yarn of the braided mesh 300 is spirally wound around the outer periphery of the balloon body 200, with two adjacent windings being a first winding circle C1 and a second winding circle C2, each having an undulating peak-and-valley structure and connected to each other, such that the first winding circle C1 has a connected peak A1 and a connected valley A1, and the second winding circle C2 has a connected peak A2 and a connected valley A2, as shown in Figure 5. In this embodiment, the peaks and valleys are relative to each other, and can constrain the balloon body 200 to form obvious pillows and grooves during the inflation process of the balloon body 200.

[0069] Furthermore, in two adjacent circles, the valley B2 in the second winding circle C2 straddles two adjacent peaks A1 in the first winding circle C1, with the valleys and peaks aligned. Compared to two adjacent winding circles in which the peaks of one circle intertwine with two adjacent valleys of the other circle, the size of the cells of the braided mesh 300 in this embodiment is more uniform, which can constrain the balloon body 200 to form relatively uniform pillow-like protrusions and grooves during the inflation process of the balloon body 200.

[0070] To form effective pillow-like protrusions and grooves, in one embodiment, the width of the peaks is W1, the width of the valley regions is W2, and the W1:W2 ratio is 1:0.8-1.2. Furthermore, the spacing H1 between two adjacent peaks is 1.5-5 mm. Peaks and valleys appear in pairs, and there may be 1-6 pairs. Referring to FIG. 5, in this embodiment, a single winding circle is arranged along the circumferential direction of the balloon body 200, with inflection points between the peaks and valleys. The width of a single peak (valley) is the linear distance between the inflection points at both ends. The length Y of each cell is approximately equal to the peak width W1, and the width X is approximately equal to the peak (or valley) spacing H1.

[0071] Referring to FIG. 6, another embodiment provides a braiding method for a braided mesh 300. The braided mesh 300 includes first mesh lines L1 and second mesh lines L2, each of which is arranged in parallel. Each first mesh line L1 extends circumferentially around the balloon body 200. The first mesh lines L1 are spaced apart along the axial direction of the balloon body 200, with the axial spacing being the cell width X. To form multiple cells, the second mesh lines L2 extend axially around the balloon body 200 and interweave with each first mesh line L1. At each interweaving point Z, the second mesh lines L2 are wound around the corresponding first mesh line L1 at least once. The distance between two interweaving points Z of a single first mesh line is the cell length Y. In this embodiment, the axial direction and the circumferential direction are relative directions within the balloon body 200 and are interchangeable. The cells formed by the braiding method of this embodiment are approximately diamond-shaped or rectangular, and their four corners become interweaving points Z with the first mesh line L1 and the second mesh line L2. During the inflation process of the balloon body 200, each cell restrains the balloon body 200 to form pillow-like protrusions, and these interweaving points Z form a certain gap between each pillow-like protrusion.

[0072] Furthermore, along the axial direction of the balloon body 200, the lengths of two adjacent cells (first cell 321 and second cell 322) in the braided mesh 300 are Y1 and Y2, respectively, and Y1:Y2 is 1:0.8 to 1.2.

[0073] In the case of a single balloon body 200, if the braided mesh 300 is too dense, the cells will be relatively small (compared to a sparse braided mesh 300), making it difficult to form pillow-like protrusions, resulting in a less pronounced effect of the drug-loaded microneedles. If the cells of the braided mesh 300 are too sparse, fewer pillow-like protrusions will be formed, preventing the balloon body 200 from effectively dispersing pressure on the vascular plaque. Therefore, it is necessary to set an appropriate number of cells. For example, in one embodiment, the balloon body 200 has a diameter of 4 mm and a length of 5 cm.

[0074] Typically, the number of cells in the braided mesh 300 along the axial direction of the balloon body 200 is 10 to 34, and the number of cells in the braided mesh 300 along the circumferential direction of the balloon body 200 is 2 to 16.

[0075] The drug-loaded microneedle balloon dilation catheter provided by the present application uses a high-strength braided mesh 300 to constrain the balloon body 200, and the cell area of ​​the braided mesh 300 is relatively large, so that the balloon body 200 forms obvious pillow-like protrusions under high pressure, and each pillow-like protrusion has a certain amount of gap, thereby realizing effective shaping of the balloon body 200 and enabling the balloon body 200 to dilate severely calcified blood vessels.

[0076] The present application also provides a method for making a drug-loaded microneedle balloon dilatation catheter, comprising the steps of:

[0077] A step of placing a drug-containing raw material liquid of the microneedle 400 in the micropore 510 of the rigid substrate 500 and forming the microneedle 400 in situ; A step of wrapping a braided mesh around the balloon body 200; injecting a fluid (which may be a liquid or a gas) into the balloon body 200 to expand the balloon body 200; The method includes applying an adhesive onto the balloon body 200 or the microneedles 400, and rolling the balloon body 200 onto the rigid substrate 500 to adhere the microneedles 400 to the surface of the balloon body 200.

[0078] The structure of the rigid substrate 500 is shown in Figure 2. The rigid substrate 500 is made of silicon material, and the thickness of the substrate 500 is 1200 to 1500 micrometers. The shape and height of the micropores 510 on the substrate 500 are the same as those of the microneedles 400. That is, the micropores 510 are mold cavities for the microneedles 400. The raw material liquid for the microneedles 400 is injected into the micropores 510 and solidified on the spot to form the microneedles 400.

[0079] In the process of placing the drug-containing microneedle 400 raw material solution in the micropores 510 of the rigid substrate 500, the rigid substrate 500 having the micropores 510 can be immersed in the drug-containing microneedle 400 raw material solution, and the drug-containing microneedle 400 raw material solution is placed in the micropores 510 by centrifugation or pressurization, and the rigid substrate 500 is dried (vacuum drying, oven drying, freeze drying, and other drying methods can be used) to form the microneedles 400 in situ within the micropores 510. When freeze drying or vacuum drying is used, a porous structure is formed within the microneedles 400, which is beneficial for drug release within the microneedles 400.

[0080] The micropores 510 on the rigid substrate 500 not only have the same shape and height as the microneedles 400, but the arrangement of the micropores 510 is also the same as the expected arrangement of the microneedles 400 on the balloon body 200, i.e., when the balloon body 200 rolls on the rigid substrate 500, the adhesive position of the microneedles 400 can be reversed between the step of wrapping the braided mesh 300 located within the cell around the balloon body 200 and the step of injecting a fluid into the balloon body 200 to expand the balloon body 200, and the braided mesh 300 and the balloon body 200 can be adhesively fixed.

[0081] The solvent of the raw material solution of the microneedles 400 is water, and the solute is at least one of chitosan, sodium alginate, polyethylene glycol, PLGA, PCL, PMMA, PGA, PLA, PEA, gelatin, and hyaluronic acid. The drug content in the raw material solution of the microneedles 400 is 1 to 10 wt %. More preferably, the drug content in the raw material solution of the microneedles 400 is 1 to 5 wt %.

[0082] The drug-loaded microneedles 400 are adhered to the outer surface of the balloon body 200 using a water-soluble adhesive, which dissolves immediately upon contact with the blood in the body, allowing the microneedles 400 to be detached from the outer surface of the balloon body and left in place on the inner wall of a blood vessel; for example, the water-soluble adhesive is polyethylene glycol hydrogel.

[0083] In this application, the burst pressure of the balloon body 200 is 30 to 45 atm, preferably 30 to 40 atm. If the burst pressure exceeds 40 atm, all narrow blood vessels can be dilated. After the balloon body dilates the blood vessel, the microneedles 400 are inserted into the blood vessel and the balloon body 200 is slightly rotated, and the drug is gradually released, leaving the loaded microneedles 400 on the blood vessel wall.

[0084] In actual use, before the balloon body 200 is inflated, the microneedles 400 are hidden within the folded flaps of the balloon body 200. After the balloon body 200 is inflated and pushes the microneedles 400 into the vascular wall, maintaining this state for 0.2 to 10 minutes, the nominal pressure of the balloon body 200 is reduced to -0.5 atm, blood enters the gap between the balloon body 200 and the vascular wall, dissolves the adhesive securing the microneedles 400, and the microneedles 400 fall off the wall of the balloon body 200 and are left in the vascular wall, achieving a sustained release effect.

[0085] The microneedles 400 can be detached from the balloon body 200 and left at the lesion site to gradually release the therapeutic drug, thereby avoiding any adverse effects on the human body.

[0086] The raw material liquid of the microneedle 400 is preferably made of a material that is biodegradable in the body, and the microneedle 400 is placed in a blood vessel or plaque to slowly release a drug, and after releasing the drug, the microneedle 400 itself can decompose, and the decomposition time varies depending on the material.

[0087] In one embodiment, for example, chitosan is first dissolved in an acetic acid solution with a mass fraction of 1% (or pH=5.5±0.5) to obtain a chitosan solution with a mass fraction of 3%, an acid-soluble drug is dissolved in the chitosan solution, a rigid substrate 500 having microporosity 510 is placed in the chitosan solution, and the rigid substrate 500 is centrifuged at 8000 rpm for 5 minutes while being completely immersed in the solution, and upon completion, the rigid substrate 500 is removed, excess chitosan solution on the surface of the rigid substrate 500 is scraped off, and the rigid substrate 500 is freeze-dried at -80°C to obtain a microneedle 400 loaded with a drug.

[0088] The adhesive is a water-soluble redissolvable adhesive. The adhesive is a water-soluble medical adhesive, such as polyethylene glycol hydrogel. When it comes into contact with blood in the body, the polyethylene glycol hydrogel dissolves within 10 minutes, allowing the microneedles 400 to be inserted into the blood vessel wall and slowly release the drug into the blood vessel.

[0089] Referring to Figures 8 and 9, before or after injecting a fluid into the balloon body 200 to expand it, a mandrel 600 is inserted into the balloon body 200, and the mandrel 600 is manipulated to drive the balloon body 200 to roll onto the rigid substrate 500.

[0090] The mandrel 600 is operated to drive the balloon body 200 to roll onto the rigid substrate 500, and the microneedles 400 are adhered to the surface of the balloon body 200. Figures 8 and 9 focus on the arrangement of the microneedles 400 within the cells, and the number of microneedles 400 is treated sparsely, while the actual number of microneedles 400 is greater, and the arrangement density of the microneedles 400 can be seen in Figure 4a.

[0091] The present application also provides a method for making the drug-loaded microneedle balloon dilatation catheter, comprising the steps of:

[0092] A step of wrapping the braided mesh 300 around the balloon body 200; injecting a fluid (which may be a liquid or a gas) into the balloon body 200 to expand the balloon body 200; A step of dropping a UV-curable adhesive onto the surface of the balloon body 200 or the interlacing points of the cells of the braided mesh 300, and applying an electric field 500 or a magnetic field in a specific direction to harden the UV-curable adhesive into the shape of a microneedle; A step in which the microneedle-shaped UV-curable adhesive is solidified by UV light irradiation to form microneedles; and spraying or dip-coating the drug onto the surface of the microneedles.

[0093] Because the balloon body 200 has a roughly cylindrical structure, the specific direction of the electric field or magnetic field does not change, and the UV-curable adhesive on the balloon body 200 can be formed into the shape of a microneedle by rotating the balloon body 200. Once the microneedle shape is obtained, it is cured and shaped, and then rotated to the next position. Alternatively, by changing the direction of the electric field or magnetic field, the entire UV-curable adhesive on the balloon body 200 can be formed into the shape of a microneedle. After the microneedle shape is formed, it is cured, and then the direction of the electric field or magnetic field is changed.

[0094] Because the action of an electric field is necessary for UV-curing adhesives to form the shape of microneedles, UV-curing adhesives must be conductive, i.e., they must be able to sense electric field signals. Non-conductive UV-curing adhesives can be made conductive by adding 5 to 30% conductive material (such as graphite, iron powder, or aluminum powder).

[0095] The UV-curable adhesive can be at least one of an epoxy acrylate adhesive, a polyurethane acrylate adhesive, a polyether acrylate adhesive, a polyester acrylate adhesive, and an acrylic resin adhesive.

[0096] The amount of UV-curable adhesive to be applied is 0.5 to 3 μL, and it can be applied within the cells of the braided mesh or at the interlacing points of the cells of the braided mesh.

[0097] The UV-curable adhesive is shaped into microneedles under the action of an electric or magnetic field. The strength of the electric or magnetic field is determined by the fluidity and conductivity of the UV-curable adhesive. For a particular UV-curable adhesive, the strength of the electric or magnetic field is determined to stretch the UV-curable adhesive into microneedles with a height of 25 to 2000 μm. The electric or magnetic field strength system can be an electrostatic system as disclosed in TW293787B or another system capable of generating the required energy.

[0098] The wavelength of the ultraviolet light irradiated for curing and shaping is within the range of 10 to 400 nm, and after irradiation, the UV-curable adhesive in the shape of the microneedle is cured and crosslinked to become the microneedle 400 .

[0099] The surface of the microneedle 400 is sprayed or dip-coated with a drug to form a drug-loaded microneedle, and the drug can be selected according to actual needs. During use, the microneedle 400 presses against the blood vessel wall, directly releasing the drug into the blood vessel wall, and then the drug-loaded microneedle balloon dilation catheter is pulled out of the body.

[0100] In one embodiment, 2 μL of acrylic resin adhesive (i.e., UV-curable adhesive) with a viscosity of 60,000 ps is added dropwise to the intersection of the warp and weft threads of the braided mesh (see Figure 10), an electric field is applied to the outside of the balloon body to form the shape of a microneedle, and the adhesive is solidified by irradiating it with 275 nm ultraviolet light for 15 seconds to form the microneedle.

[0101] The drug-loaded microneedle balloon dilation catheter provided by the present application can effectively dilate calcified blood vessels, especially severely calcified blood vessels, and when the balloon body is filled with pressure, the microneedles can be effectively pushed into the walls of calcified blood vessels or narrow tracts such as the digestive tract, cervix, and airways, thereby providing treatment through the sustained release of the drug.

[0102] This application provides two methods for manufacturing drug-loaded microneedle balloon dilation catheters, of which the microneedles manufactured using a substrate are adhered to the outer surface of the balloon body using a water-soluble adhesive, and the microneedles are separated from the balloon body and placed within the target object, particularly suitable for areas such as the digestive tract and cervix. The microneedles manufactured using a UV-curable adhesive cannot be separated from the surface of the balloon, but the drug coated on the surface of the microneedle can be pushed into the target object through the microneedle, thereby administering the drug to the target object and applying it to areas such as blood vessels.

[0103] Below, with reference to Figures 11 to 13, we will explain in detail about drug-loaded balloon catheters in which drugs are loaded using a solid coating method. In Figures 11 to 13, the drug coatings loaded on the solid coatings all contain a photosensitive material, i.e., a photosensitizer. The drug-loaded balloon catheter has been improved to improve the performance of the photosensitive material, and this mainly relates to the methods for preparing and loading the photosensitive material.

[0104] A method for preparing a photosensitive material having a blood vessel repair function, comprising the steps of: Step 1: protecting some of the amino groups of a polypeptide dendrimer; and step 2 of adding the partially amino-protected polypeptide dendrimer and the naphthalimide compound to a mixed solution of an organic base and an organic solvent, reacting them at 70 to 150°C for 1 to 32 hours, and obtaining a photosensitive material after post-treatment.

[0105] The organic base is at least one of N,N-diisopropylethylamine, sodium tert-butoxide, and potassium tert-butoxide.

[0106] The organic solvent is at least one of isopropyl alcohol, hexafluoro-2-propanol, methanol, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, dichloromethane, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, and hexamethylphosphoramide.

[0107] A naphthalimide compound is a photosensitive material. In the present application, the naphthalimide compound is chemically reacted with a polypeptide dendrimer, and the naphthalimide compound is connected to the polypeptide dendrimer via a chemical bond. Based on the regular structure of the polypeptide dendrimer, the naphthalimide compound is collected on the peptide dendrimer, which improves the aggregation degree of the naphthalimide compound and improves the local light utilization efficiency.

[0108] When the polypeptide dendrimer modified with a naphthalimide compound enters the body, it penetrates the extracellular matrix of the blood vessel wall, approaches elastin and collagen within the blood vessel, and generates an excited state through the catalytic action of light, inducing cross-linking of proteins near the naphthalene imide compound, thereby performing the function of repairing the blood vessel.

[0109] The support and aggregation effect of the polypeptide dendrimer on the naphthalimide compound improves the permeability of the naphthalimide compound into the vascular wall, allowing it to penetrate the vascular wall more quickly and tending to be distributed uniformly within the blood vessels in a shorter period of time.

[0110] The polypeptide dendrimer is a dendrimer that has an amino group and can undergo nucleophilic substitution reactions, and is at least one of an arginine-based dendrimer, a lysine-based dendrimer, a glutamic acid-based dendrimer, and a proline-based dendrimer.

[0111] Lysine-based dendrimers are as follows: JPEG2025530802000002.jpg101170 or JPEG2025530802000003.jpg96170

[0112] The lysine-based dendrimer is a lysine-arginine dendrimer, the molecular structure of which is shown below. JPEG2025530802000004.jpg77170

[0113] In step 1, some of the amino groups of the polypeptide dendrimer are protected. When the polypeptide dendrimer is a lysine-arginine dendrimer, the molecular structure after the amino groups are protected is as follows: JPEG2025530802000005.jpg78170

[0114] The naphthalene imide compound is a derivative of 1,8-naphthalene diimide.

[0115] Derivatives of 1,8-naphthalimide include dimers, polymers, isomers, and salt forms thereof, for example, 1,8-naphthalimide dimer, the polypeptide dendron dendrimer molecule is a lysine-arginine dendrimer molecule, and the structural formula of the photosensitizer is as follows: JPEG2025530802000006.jpg63170

[0116] Step 1 of protecting some of the amino groups of the polypeptide dendrimer comprises the following steps: Step 1-1: Protecting different amino groups of the polypeptide dendrimer using Cbz, Boc, and Pbf; and Step 1-2, in which Cbz is deprotected (Cbz is deprotected with Pd / C methanol solution) to obtain a polypeptide dendrimer with partially protected amino groups.

[0117] JPEG2025530802000007.jpg51170

[0118] In step 2, the partially amino-protected polypeptide dendrimer and the naphthalimide compound are added to a mixed solution of an organic base and an organic solvent, and reacted at 70 to 100°C for 4 to 32 hours, to obtain a photosensitive material after post-treatment.

[0119] In step 2, the molar ratio of the polypeptide dendrimer to the naphthalene imide compound is 1:3 to 1:6, and preferably 1:4. In step 2, the ratio of the organic base to the organic solvent used is 40 mol:30 to 90 mL. In step 2, the ratio of the polypeptide dendrimer to the organic solvent is 4 mol:30-90 mL. In step 2, the synthesis of the naphthalene imide compound includes the following steps:

[0120] A. One amino group of the triethylene glycol amino group is protected with Boc to obtain a one-side protected tert-butyltrimethylene glycol amino group. B. The one-side protected tert-butyltrimethylene glycol amino group and 4-bromo-1,8-naphthalenedicarboxylic acid anhydride are added to ethanol to form an ethanol solution, and the ethanol solution is heated to 30 to 90°C and reacted for 1 to 18 hours to obtain a first product. C. N,N-diisopropylethylamine and dimethyl sulfoxide (DMSO) are added to the one-side protected tert-butyltriethylene glycol amino group and 4-bromo-1,8-naphthalenedicarboxylic anhydride to form a mixed solution, and the mixed solution is reacted at 70 to 150°C for 1 to 32 hours to obtain a second product. D. The first product is deprotected by Boc deprotection in trifluoroacetic acid and dichloromethane, the pH is adjusted to 6.5-8, stirring is performed for 5-15 minutes, and extraction with dichloromethane is performed to obtain the deprotected first product. E. The deprotected first product and second product are dissolved in ethanol, heated to 30 to 90°C, and reacted for 1 to 18 hours to obtain a naphthalene imide compound.

[0121] The reaction scheme from step B to step E is as follows: JPEG2025530802000008.jpg69170

[0122] In Step B, the molar ratio of the mono-protected tert-butyltrimethylene glycol amino group to 4-bromo-1,8-naphthalenedicarboxylic anhydride is 1:1-3, preferably 1:1-2.

[0123] In step B, the ratio of 4-bromo-1,8-naphthalenedicarboxylic anhydride to ethanol used is 1 mol:0.8 to 1.1 L.

[0124] In step B, after the reaction is completed, the first product is obtained by washing with 30 mL of deionized water, filtering, and drying under vacuum.

[0125] In Step B, the molar ratio of the mono-protected tert-butyltrimethylene glycol amino group to 4-bromo-1,8-naphthalenedicarboxylic anhydride is 1:1.

[0126] In Step C, the ratio of 4-bromo-1,8-naphthalenedicarboxylic anhydride, N-diisopropylethylamine, and dimethyl sulfoxide used is 1 mol:2 mol:7-8 L.

[0127] In step C, after the reaction is complete, a second product is obtained by vacuum drying.

[0128] In step D, the pH is adjusted to 6.5-8 using saturated aqueous sodium bicarbonate solution.

[0129] In Step E, the molar ratio of the second product to the third product is 1:1.

[0130] In step 2, post-processing includes the following steps, performed in order: a. Extract with dichloromethane or chloroform. b. The extracted organic phase is separated and purified by silica gel column chromatography or HPLC separation to obtain a naphthaleneimide-crosslinked polypeptide dendrimer. c. Naphthalene imide cross-linked polypeptide dendrimer is deprotected to Boc and Pbf. d. After evaporation on a rotary evaporator, adjust the pH to 6.5-8, stir for 5-15 minutes, extract with dichloromethane, and dry under vacuum to obtain the photosensitizer. In step a, when dichloromethane or chloroform is used for extraction, the amount of dichloromethane or chloroform is 15 to 50 mL.

[0131] In step c, the naphthalene imide-bridged polypeptide dendrimer is deprotected by Boc and Pbf in a mixed solvent of trifluoroacetic acid and dichloromethane.

[0132] In step d, the pH is adjusted to 6.5-8 using saturated aqueous sodium bicarbonate solution.

[0133] Referring to FIG. 11, the balloon catheter system includes:

[0134] a tube body having opposed proximal and distal ends; a balloon body fixed to the distal end of the tube body; and an optical fiber module having a light-emitting portion inserted within the tube body and extending to the adjacent balloon body.

[0135] An auxiliary material and a photosensitizer are placed on the surface of the balloon body by coating, and the photosensitizer is a polypeptide dendrimer modified with a naphthalene imide compound.

[0136] The photosensitizer crosslinks collagen and elastin by activating them with light of wavelengths of 400 to 460 nm. The auxiliary material includes an active drug and a sustained-release material encapsulating the active drug, wherein the active drug is at least one of paclitaxel, rapamycin, zotarolimus, tacrolimus, everolimus, temsirolimus, zotarolimus, umirolimus, docetaxel, protein-bound paclitaxel, and protein-bound dexamethasone.

[0137] The surface of the balloon body 200 is coated with an auxiliary material and a photosensitizer, of which the photosensitizer is activated by light of 400-460 nm wavelength and can crosslink collagen and elastin in organs and / or tissues (such as blood vessels), forming a microstent in situ. The auxiliary material contains an active drug, such as a therapeutic drug for vascular disease, which is released into the blood vessel and / or onto the blood vessel wall via the balloon body 200 and is absorbed by cells.

[0138] The dosage of the active drug is determined based on the pathological condition. However, experiments have shown that even when the planned dosage is administered, the expected therapeutic effect is not achieved. Research has shown that the active drug is released into the bloodstream quickly from the surface of the balloon 200, and the concentration of the free active drug in the body does not change ideally, meaning that the concentration of the free active drug decreases faster than the rate at which the drug is utilized by cells. Furthermore, it has been found that the rapid decrease in the concentration of the free active drug is due to the fact that the free active drug is easily decomposed by light with a wavelength of 400-460 nm. Once all the active drug is released into the bloodstream, some of the free active drug is not absorbed by cells in time and is decomposed by light, becoming ineffective. To solve this technical problem, the auxiliary materials also include a sustained-release material encapsulating the active drug, which protects the active drug, reduces its loss, and improves its utilization.

[0139] The sustained-release material in the auxiliary material is at least one of shellac, polyethylene glycol, magnesium stearate, povidone, alginic acid, ethyl cellulose, guar gum, gum arabic, hydroxypropyl methylcellulose, methyl cellulose, polyvinylpyrrolidone, corn starch, calcium stearate, mineral oil, sodium stearyl fumarate, sodium benzoate, sodium lauryl sulfate, and stearic acid. More preferably, the sustained-release material is povidone K90.

[0140] 11 , the tube body 100 may be a multi-lumen tube. For example, in one embodiment, the tube body 100 has at least a guidewire lumen 130, a fluid supply lumen 140, and a receiving lumen. The guidewire lumen 130 opens at both ends of the tube body 100 to allow a guidewire to pass through. One end of the fluid supply lumen 140 opens at the proximal end 120 of the tube body 100, and the other end communicates with the interior of the balloon body 200. The inflation of the balloon body 200 is driven by supplying a fluid to the fluid supply lumen 140. After inflation, the coating on the surface of the balloon body 200 can be quickly released. The optical fiber module 340 is inserted into the receiving lumen, and its light-emitting portion 330 is adjacent to the balloon body 200. This proximity is mainly due to the fact that the distance over which the light emitted from the optical fiber module 340 acts on the balloon body 200 is short, ensuring the range and intensity of irradiation, and the photosensitive agent crosslinks with the collagen fibers in the vascular wall to form a vascular microstent with a certain supporting ability, so that the vascular wall remains expanded even after the balloon body 200 is pulled out of the blood vessel.

[0141] The tube body 100 comprises multiple tubes sleeved together, with the inside of each tube and / or the radial gap between the inner and outer tubes 170 being used to provide a guidewire lumen 130, a delivery lumen 140 and a receiving lumen, which may be combined into one or may be separate.

[0142] For example, in one embodiment, the multiple tubes include an inner layer tube 160 and an outer layer tube 170, of which the inner layer tube 160 provides the guidewire lumen 130, the gap between the inner layer tube 160 and the outer layer tube 170 provides the fluid delivery lumen 140, and the receiving lumen is provided by an independent tube or shares the gap between the inner layer tube 160 and the outer layer tube 170, and the independent tube is disposed in the gap between the inner layer tube 160 and the outer layer tube 170.

[0143] The receiving lumen is also provided by an extension tube located in the radial gap between the inner tube 160 and the outer tube 170, the distal end 120 of the extension tube extending into the balloon body 200 and secured to the inner tube 160.

[0144] Examples of materials for the tube body 100 and the balloon body 200 include nylon (PA), PEBAX, PEEK, PU, ​​PVC, and silicone.

[0145] The optical fiber module 340 includes an illuminating device 310 and an optical fiber body 320, the illuminating device 310 being attached externally to the tube body 100, one end (proximal end 110) of the optical fiber body 320 being connected to the illuminating device 310, and the other end (distal end 120) being inserted into the receiving lumen and extending to the vicinity of the balloon body 200, with the light emitting section 330 being located at this end.

[0146] The optical fiber body 320 is a plastic optical fiber or a glass optical fiber, and has a diameter of 0.1 to 0.5 mm. The optical fiber body 320 can be movably disposed within the tube body 100 or can be fixed within the tube body 100. The fixing position can be adjusted depending on the specific structure of the tube body 100, and the fixing method can be adhesive or welding. For example, if the receiving lumen shares the gap between the inner tube 160 and the outer tube 170, the distal end 120 of the optical fiber body 320 can be fixed to the outer wall of the inner tube 160 or the inner wall of the outer tube 170 (see FIG. 11 ). If the receiving lumen is provided by an extension tube, the portion of the distal end 120 of the optical fiber body protruding from the receiving lumen is fixed to the outer wall of the inner tube 160.

[0147] The photosensitizer and active drug are released through the catheter system of the balloon body 200, and the active drug is wrapped in a sustained-release material with a photoprotective effect, which reduces the loss rate of the free active drug in the body due to photodegradation and increases the availability of the effective drug, thereby ensuring the effectiveness of the effective drug.

[0148] The surface of the balloon body may be plasma treated or coated with a hydrophilic material before applying the coating.

[0149] Plasma treating the surface of the balloon body or coating it with a hydrophilic material slows down the release of the drug on the balloon, and the drug release rate when coated with a hydrophilic material is slower than the drug release rate when plasma treated.

[0150] The photosensitizer is applied to the surface of the balloon body by a coating method, which includes the following steps: dispersing or dissolving the photosensitizer in a solvent to prepare a solution, and then coating the surface of the balloon body.

[0151] The solvent is at least one of ethanol, acetic acid, acetone, butylated hydroxytoluene, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, and water.

[0152] The solvent is a mixture of ethanol, acetic acid, and water, and the volume ratio of each component in the solvent is ethanol:acetic acid:water=80-90:19-9:1. The solvent was a mixture of ethanol, acetic acid, and water, and the volume ratio of each component in the solvent was ethanol:acetic acid:water=89:10:1. The concentration of the photosensitizer in the solution is 6.25 to 125 μM / mL, and more preferably 12.5 to 25 μM / mL. The solution further comprises an auxiliary material, and the mass ratio of the auxiliary material to the photosensitizer is 0.3-10, more preferably the mass ratio of the auxiliary material to the photosensitizer is 1:1. Among the auxiliary materials, the mass ratio of the active drug to the sustained-release material is 1:1-20. The mass ratio of the photosensitizer to the active drug is 1:0.2-5.

[0153] The solution further includes a stabilizer that is at least one of an antioxidant and a Lewis acid. The antioxidant is at least one of tromethamine and butylated hydroxytoluene, and the weight ratio of the antioxidant to the photosensitizer is 0.05 to 1:100. The cation of the Lewis acid is at least one of Na+, K+, Mg+, and Ca+. The molar ratio of the Lewis acid to the photosensitizer is 0.8 to 3. The coating method includes spraying and / or dipping, and the coating amount of the photosensitizer on the surface of the balloon body is 0.0012-37.5 μM / mm 2 More preferably, the coverage of the photosensitizer on the balloon surface is 0.05 μM / mm 2 is.

[0154] Example 1: Preparation of naphthalene imide compound The synthesis of naphthalene imide compounds includes the following steps: (1) One amino group of the triethylene glycol amino group is protected with Boc to obtain a one-side protected tert-butyltrimethylene glycol amino group. (2) 0.02 mol of the mono-protected tert-butyltrimethylene glycol amino group and 0.02 mol of 4-bromo-1,8-naphthalenedicarboxylic acid anhydride are added to 20 mL of ethanol to form an ethanol solution, and the ethanol solution is heated to 80°C and reacted for 22 hours to obtain a first product. (3) 0.02 mol of the mono-protected tert-butyltriethylene glycol amino group and 0.02 mol of 4-bromo-1,8-naphthalenedicarboxylic acid anhydride are added to 0.04 mol of N,N-diisopropylethylamine and 150 mL of dimethyl sulfoxide to form a mixed solution, and the mixed solution is reacted at 80°C for 1.5 hours to obtain a second product. (4) The first product is deprotected by Boc deprotection in trifluoroacetic acid and dichloromethane, the pH is adjusted to 6.5-8, the mixture is stirred for 5-15 minutes, and the mixture is extracted with dichloromethane to obtain the deprotected first product. (5) The deprotected first product and second product are dissolved in 55 mL of ethanol, heated to 80°C, and reacted for 2 hours to obtain a naphthalene imide compound.

[0155] Example 2: Preparation of photosensitive material A method for preparing a photosensitive material with vascular repair function, comprising the steps of: (1) Lysine-arginine dendrimer was prepared using the divergent method, and its molecular structure is as follows: JPEG2025530802000009.jpg78170(2) Different amino groups of the lysine-arginine dendrimer were protected using Cbz, Boc, and Pbf, and the molecular structure after the amino groups were protected is shown below. JPEG2025530802000010.jpg97170(3) Deprotect Cbz with Pd / C methanol solution to obtain a Cbz-deprotected dendrimer. (4) 1 mole of the deprotected Cbz dendrimer and 4 moles of the naphthalene imide compound prepared in Example 1 are dissolved in 90 mL of dimethyl sulfoxide (organic solvent), 40 mL of N,N-diisopropylethylamine (organic base) is added, the mixture is heated to 80°C, and the mixture is stirred for 2 hours to react. (5) After the reaction is complete, the reaction mixture is extracted with 30 mL of dichloromethane, and the organic phase is separated by column chromatography (silica gel: 200-300 mesh, eluent: ethyl acetate / ethanol = 100:1) and dried in vacuo to obtain a photosensitive material protected with Boc and Pbf. (6) The photosensitive material protected with Boc and Pbf is added to a mixed solvent of trifluoroacetic acid and dichloromethane for deprotection. (7) After evaporation on a rotary evaporator, saturated sodium bicarbonate is added dropwise to adjust the pH to 7, the mixture is stirred for 15 minutes, extracted with dichloromethane, and dried in vacuo to obtain a photosensitive material.

[0156] Example 3: Preparation of photosensitive material coating on the surface of the balloon body The photosensitive material with blood vessel repair function prepared in Example 2 was dissolved in an ethanol solution to give a concentration of 3.75 × 10 -3 A 5 μg / mm solution was prepared and applied to the surface of the balloon. 2and dried for 5 hours to obtain a balloon catheter having a photosensitive material coating.

[0157] Performance Criteria 1.Transparency characteristics Experimental group: The blood vessel was cut into 2x2cm slices with the inner surface facing up and moistened with 0.9% saline. The photosensitive material with vascular repair function prepared in Example 1 was dripped onto the inner surface of the blood vessel at 1mg / mL. After a certain period of time, the remaining liquid on the inner surface of the blood vessel was wiped off, and the penetration depth into the blood vessel was examined using a laser confocal microscope.

[0158] Control group: Cut the blood vessel into 2x2cm slices with the inner surface facing up and moisten with 0.9% saline. Add 1mg / mL of the third product of Example 1 to the inner surface of the blood vessel. After a certain period of time, wipe off the remaining liquid on the inner surface of the blood vessel and examine the penetration depth into the blood vessel using a laser confocal microscope. JPEG2025530802000011.jpg20170As shown in Table 1, the photosensitive material in the experimental group had good permeability into the vascular wall, penetrated into the vascular wall quickly, and tended to be distributed uniformly within the blood vessel in a shorter period of time.

[0159] 2. Vascular repair effect Experimental group: After a portion of the blood vessel was sampled and its diameter was measured, the balloon catheter with the intelligent photosensitive material coating prepared in Example 3 was inserted into the blood vessel, the balloon body was loaded to the nominal pressure, the blood vessel was inflated, the laser was then turned on at 2.5W, and the balloon body was removed after 1 minute. The dilated portion of the blood vessel was sampled and histologically stained to observe the cross-linking of elastic fibers and collagen fibers within the blood vessel. The cross-linking state is shown in Figure 12. At the same time, the diameter change of the dilated portion of the blood vessel was measured.

[0160] Control group: After a portion of the blood vessel was sampled and its diameter measured, a balloon catheter coated with 1,8-naphthalimide was inserted into the blood vessel, and the balloon was placed up to the nominal pressure to expand the blood vessel. The laser was then turned on at 2.5 W, and the balloon was removed after 1 minute. The expanded portion of the blood vessel was sampled and stained for histological examination to observe the cross-linking of elastic and collagen fibers within the blood vessel. The cross-linking state is shown in Figure 12. At the same time, the diameter change of the expanded portion of the blood vessel was measured. JPEG2025530802000012.jpg20170

[0161] As shown in Figure 12, histological staining analysis showed that the collagen and elastin in the vascular membrane of the experimental group were in a cross-linked state, and the blood vessels maintained compliance. As shown in Figure 13, most of the collagen and elastin in the vascular membrane of the control group was destroyed, and the blood vessels lost compliance.

[0162] The balloon catheter system provided in the above examples can improve the utilization efficiency of the photosensitizing compound by improving the structure and coating method of the photosensitizing agent on the surface of the photodynamic balloon body. Below, in combination with Figures 14 to 18, a drug-loaded balloon catheter that delivers drugs using solid coating and solution infiltration methods will be described in detail. The drug delivered by the drug-loaded balloon catheter described below is mainly riboflavin. Below, a method for forming an in situ stent in a blood vessel using a drug-loaded balloon catheter, a drug-loaded balloon catheter, and a light-curing balloon catheter system for producing a vascular in situ stent will be described in detail.

[0163] As shown in FIG. 14, a method for producing a vascular in-situ stent provided in one embodiment of the present invention includes the following steps.

[0164] Step S10 of administering a first reagent to a predetermined location in the blood vessel 70, the first reagent including riboflavin and / or a riboflavin salt; and step S20 of irradiating the predetermined position with light to excite the first reagent, which then acts on the predetermined position to form a vascular in-situ stent.

[0165] In step S10, the riboflavin salt is riboflavin 5'-(dihydrogen phosphate) monosodium salt dihydrate, and the riboflavin (C17H20N4O6) content should be 74.0% to 79.0%.

[0166] When administering the first reagent, a solution may be prepared and delivered directly to the desired location via the interventional device, or the first reagent may be delivered to the desired location via the interventional device using a coating, solid embedding, or the like.

[0167] Examples of the interventional device include a syringe needle, a microporous balloon, and a tube body 20. When administering the first reagent, the device can block the upstream and downstream blood flow at a predetermined position, thereby achieving precise local drug delivery. In one embodiment, the active ingredient of the first reagent includes at least riboflavin, and the concentration of riboflavin in the solution is 0.2 to 60 mg / mL.

[0168] In another embodiment, the active ingredient of the first reagent is riboflavin, and the concentration thereof is 0.2 to 1.6 mg / mL, preferably 0.2 to 1.2 mg / mL.

[0169] In another embodiment, the active ingredient of the first reagent is a riboflavin salt, and the total concentration converted to riboflavin is 5 to 60 mg / mL. In step S20, the wavelength of the irradiated light is 300 to 700 nm. The intensity of the irradiated light is 5 to 500 mW / cm. 2 , preferably 100 to 500 mW / cm 2 , and more preferably 500 mW / cm 2 The light irradiation time is 0.1 to 30 minutes, preferably 3 to 10 minutes, and more preferably 5 minutes.

[0170] The method for producing an in situ vascular stent provided in this embodiment can be used to deliver a drug to a target site (i.e., a predetermined location) in a tissue such as a blood vessel 70. The riboflavin and / or riboflavin salt in the first reagent is an anti-restenosis agent. After the first reagent is applied to the predetermined location, light is irradiated to activate the riboflavin, causing it to bind to collagen or other proteins in the tissue wall, thereby forming an in situ vascular stent at the predetermined location. Such an in situ vascular stent is an "endogenous" stent, and compared to current implantable metal stents and polymer-finished stents, it helps to eliminate post-operative problems associated with implantable devices, such as poor compatibility, immunogenicity, thrombosis, and inflammation.

[0171] As shown in FIG. 15, one embodiment of the present invention also provides a photocuring-based drug-loaded balloon catheter, which includes a balloon body 10 and a tube body 20, wherein the balloon body 10 has a corresponding inflated state and a deflated state suitable for interventional delivery, and the tube body 20 has opposing distal and proximal ends 22 and 21, and the distal end 22 is connected to the balloon body 10 and transports fluid into the balloon body 10 to inflate the deflated balloon body 10.

[0172] A drug coating 60 is applied to the surface of the balloon body 10, and when the balloon body 10 is inflated, the surface acts on the vascular wall 71, distributing the drug to the vascular wall 71. In this embodiment, the active ingredients of the drug coating 60 include riboflavin and / or riboflavin salt. These two drugs are anti-restenosis agents, and when subjected to specific optical excitation, they bind to collagen or other proteins in the tissue wall, forming an in-situ vascular stent at a predetermined location. To form the in-situ vascular stent, the drug-loaded balloon catheter further includes a light-guiding member 30, such as an optical fiber, having one end serving as a light-emitting end 31 extending to the balloon body 10 and the other end serving as a light-input end 32 extending through the tube body 20 to the proximal end 21. The light-emitting end 31 can emit light of a specific wavelength, which penetrates the inner wall of the balloon body 10 and acts on the vascular wall 71 (indicated by the arrow in FIG. 15 ), activating the riboflavin.

[0173] There are many ways to deliver drug coating 60, for example, in one embodiment, methods for delivering drug coating 60 include the following.

[0174] A solution of the drug coating 60 is prepared in advance, and the solution is applied to the surface of the balloon body 10 and dried to obtain the drug coating 60.

[0175] The concentration of the active ingredient in the solution is 0.2 to 1.2 mg / mL calculated as riboflavin. The amount of application per unit area of ​​the balloon body affects the in situ stent formation effect in the blood vessel, and in one embodiment, the amount of application per unit area of ​​the balloon body is 0.05 to 20 μg / mm in terms of riboflavin. 2 This ensures the formation of a microstent with high adhesive strength, and effectively prevents restenosis of the blood vessel 70.

[0176] In one embodiment, drug coating 60 further comprises a carrier, which can be at least one of polyethylene glycol, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polysorbate, polyvinylpyrrolidone, magnesium stearate, urea, trihexyl 2-(butyryloxy)propane-1,2,3-tricarboxylate, iopromide, ethylcellulose, methylparaben, ethylparaben, acetyl tributyl citrate, glyceryl stearate, shellac, and pectin.

[0177] In one embodiment, the method of delivering drug coating 60 includes: The carrier, active ingredient and solvent are mixed to form the drug coating 60 solution. For example, the carrier is dispersed in a solvent in advance, and the active ingredient is added to the dispersion and mixed. In one implementation, the method of delivering the drug coating 60 includes the following. A solution of the active ingredient and a carrier solution are prepared separately in advance, and the active ingredient solution is applied to the surface of the balloon body and then dried. After drying, the carrier solution is applied next. The solution-formed coating of the carrier functions to protect the drug coating 60 and to provide sustained release of the active ingredient.

[0178] The solvent of each of the above solutions is at least one of water, methanol, ethanol, formic acid, acetic acid, acetonitrile, isopropanol, acetone, ethyl acetate, n-hexane, cyclohexane, dichloromethane, methyl acetate, butyl acetate, carbon tetrachloride, butanone, and n-heptane.

[0179] The application method may be spray coating or dip coating. The application method of the active ingredient solution and the carrier solution may be different.

[0180] As shown in FIG. 16, the drug-loaded balloon catheter for vascular in situ stenting provided in one embodiment of the present invention includes a balloon body 10, a tube body 20, and a light-guiding material 30, wherein the balloon body 10 has a corresponding expanded state and a deflated state suitable for interventional delivery, the balloon wall 11 of the balloon body 10 has a pore structure 12, the tube body 20 has opposite distal and proximal ends 22 and 21, the distal end 22 is connected to the balloon body 10, one end of the light-guiding material 30 is a light-emitting end 31 extending to the balloon body 10, and the other end is a light-input end 32 extending through the tube body 20 to the proximal end 21.

[0181] The drug-loaded balloon catheter further contains a fluid, including riboflavin and / or a riboflavin salt. The fluid can be transported through the tube body 20 to the balloon body 10, expanding the deflated balloon body 10. The fluid in the balloon body 10 then flows out through the pore structure 12 and is output to the environment surrounding the balloon body 10 (the direction of the fluid is indicated by the arrow in FIG. 16). The output fluid travels with the blood flow and enters the blood vessel wall 71. The light-emitting end 31 is controlled to emit light beams of a specific wavelength. These light beams pass through the balloon wall 11 of the balloon body 10 and act on the blood vessel wall 71 (indicated by the wave in FIG. 16), activating the riboflavin, which then binds to collagen or other proteins in the tissue on the wall, forming an in-situ vascular stent in place.

[0182] The pore size of the pore structure 12 affects the rate at which fluid is output from the balloon body 10 to the surrounding environment. Therefore, the pore size of the pore structure 12 must not be too large to avoid the release (loss) of the drug carried by the balloon body 10 before the balloon body 10 reaches the pressure required to dilate the blood vessel 70. The pore size must also not be too small; otherwise, the drug release rate from the balloon body 10 after dilating the blood vessel 70 will be too slow. In one embodiment, the pore size of the pore structure 12 is 5 to 100 μm, preferably 10 to 80 μm, and more preferably 30 to 50 μm. The porosity of the surface of the balloon body 10 is 30 to 80%, preferably 40 to 70%, and even more preferably 45 to 60%.

[0183] The fluid is in the form of a solution, the solvent of which is water, a phosphate buffer solution, a sodium chloride solution or physiological saline.

[0184] The concentration of the fluid, calculated as total riboflavin, is 0.2 to 1.2 mg / mL, and it can be released and fixed to the vessel wall 71 to form a stable vascular in-situ stent.

[0185] 17 , a light-curing balloon catheter system for producing a vascular in situ stent provided in one embodiment of the present invention includes a balloon body 10, a tube body 20, a drug delivery device 40, a light guide 30, and a light source device 50. The tube body 20 has opposing distal and proximal ends 22 and 21. The balloon body 10 has a deflated state and an inflated state suitable for corresponding interventional delivery. The balloon wall 11 has a pore structure 12 for fluid passage. The balloon body 10 is connected to the distal end 22 of the tube body 20. The drug delivery device 40 is connected to the proximal end 21 of the tube body 20 to supply a fluid, which in this embodiment includes riboflavin and / or a riboflavin salt. The light guide 30 has one end as a light-emitting end 31 extending to the balloon body 10 and the other end as a light input end 32 extending through the tube body 20 to the proximal end 21. The light source device 50 is connected to the light input end 32 of the light guide 30 by an optical path.

[0186] During operation, the deflated balloon body 10 is inserted into the target site (predetermined position) of the blood vessel 70, and the fluid delivered through the drug delivery device 40 is delivered to the balloon body 10 via the tube body 20. The balloon body 10 then expands, exposing the pore structure 12, and the fluid is discharged from the pore structure 12 into the environment surrounding the balloon body 10. The discharged fluid travels with the blood flow and enters the blood vessel wall 71, and the light source device 50 excites the light-emitting end 31 to emit light of a specific wavelength, activating riboflavin, which then binds with collagen and other proteins in the wall tissue, thereby forming a blood vessel in situ at the predetermined position.

[0187] In one embodiment shown in Figure 18, the interventional device is a block balloon catheter including at least two balloon bodies (a first balloon body 13 and a second balloon body 14), a tube body 20 and a light-guiding material 30, in which the first balloon body 13 and the second balloon body 14 are positioned at predetermined positions upstream and downstream of the blood flow, respectively, and can block the blood flow on both sides in an inflated state to achieve localized and accurate drug delivery, and the light-emitting end 31 of the light-guiding material extends into the tube body 20 and is positioned at a position corresponding to the predetermined position.

[0188] The present invention also provides the application of riboflavin and riboflavin salts in the preparation of vascular in-situ stent drugs, in which riboflavin and / or riboflavin salts are applied to a predetermined location, and then a vascular in-situ stent is formed at the predetermined location by photoexcitation.

[0189] Some further preparation examples are given below, all reagents are commercially available.

[0190] <Preparation Example 1> Riboflavin is added to water and subjected to ultrasonic vibration to prepare a riboflavin solution with a concentration of 0.5 mg / mL, which becomes a fluid.

[0191] <Preparation Example 2> A solution was prepared by thoroughly mixing 32 mg of polyethylene glycol and 2 mL of acetic acid, to which 32 mg of riboflavin was added and subjected to ultrasonic vibration to prepare a drug coating solution. This drug coating solution was sprayed onto the surface of the balloon body, and the sprayed amount, calculated as riboflavin, was 3 μg / mm 2 This gives the drug-loaded balloon body.

[0192] <Preparation Example 3> A solution was prepared by thoroughly mixing 32 mg of polyethylene glycol and 2 mL of acetic acid. 32 mg of riboflavin was added to this solution and subjected to ultrasonic vibration to prepare a drug coating solution. This solution was applied to the balloon surface by dip coating. The applied amount, calculated as riboflavin, was 4 μg / mm 2 Thus, a drug-loaded balloon body was obtained.

[0193] <Preparation Example 4> A carrier solution was prepared by thoroughly mixing 32 mg of polyethylene glycol and 2 mL of acetic acid. 32 mg of riboflavin was added to water and ultrasonically vibrated to prepare a riboflavin solution. The riboflavin solution was first sprayed onto the surface of the balloon body and dried. The sprayed amount was calculated as riboflavin, and the sprayed amount was 3 μg / mm. 2 Then, the carrier solution is sprayed and dried. When calculated as a carrier, the spray amount is 3 μg / mm 2 Thus, a drug-loaded balloon was obtained.

[0194] <Preparation Example 5> A carrier solution was prepared by thoroughly mixing 32 mg of polyethylene glycol and 2 mL of acetic acid. 32 mg of riboflavin was added to water and ultrasonically vibrated to prepare a riboflavin solution. The balloon body was first immersed in the riboflavin solution for 30 seconds, removed and dried, and then immersed in the spray carrier solution for 30 seconds, removed and dried to obtain a drug-loaded balloon.

[0195] <Preparation Example 6> A carrier solution was prepared by thoroughly mixing 32 mg of polyethylene glycol and 2 mL of acetic acid. 32 mg of riboflavin was added to water and ultrasonically vibrated to prepare a riboflavin solution. The riboflavin solution was first sprayed onto the surface of the balloon body and dried. The sprayed amount was calculated as riboflavin, and the sprayed amount was 3 μg / mm. 2 Then, the balloon was immersed in the spray carrier solution for 30 seconds, removed, and dried to obtain a drug-loaded balloon.

[0196] <Preparation Example 7> A carrier solution was prepared by thoroughly mixing 32 mg of polyethylene glycol and 2 mL of ethanol. 32 mg of riboflavin was added to water and ultrasonically vibrated to prepare a riboflavin solution. The riboflavin solution was first sprayed onto the surface of the balloon body and dried. The sprayed amount was calculated as riboflavin, and the sprayed amount was 3 μg / mm. 2 Then, the carrier solution was sprayed and dried, and the spray amount was 3 μg / mm 2 Thus, a drug-loaded balloon was obtained.

[0197] <Preparation Example 8> A carrier solution was prepared by thoroughly mixing 32 mg of polyethylene glycol with 2 mL of ethanol. 32 mg of riboflavin was added to water and ultrasonically vibrated to prepare a riboflavin solution. The balloon body was first immersed in the riboflavin solution for 30 seconds, removed and dried, and then immersed in the spray carrier solution for 30 seconds, removed and dried to obtain a drug-loaded balloon.

[0198] <Preparation Example 9> A carrier solution was prepared by thoroughly mixing 32 mg of polyethylene glycol and 2 mL of ethanol. 32 mg of riboflavin was added to water and ultrasonically vibrated to prepare a riboflavin solution. The riboflavin solution was first sprayed onto the surface of the balloon body and dried. The sprayed amount was calculated as riboflavin, and the sprayed amount was 3 μg / mm. 2 Then, the balloon was immersed in the spray carrier solution for 30 seconds, removed, and dried to obtain a drug-loaded balloon.

[0199] <Application example 1> A pig peripheral blood vessel was immersed in PBS buffer, and the balloon body (pore diameter 50 μm, surface porosity 50%) was pushed into the blood vessel. The compressed balloon body was inflated by injecting the fluid of Preparation Example 1 at a pressure of 6 atm. Next, while maintaining the pressure of the balloon, the light-guiding material was excited by the light source device to generate 450 nm light, and the photocuring time was 5 minutes.

[0200] After irradiation, the balloon body was removed from the blood vessel, and the amount of riboflavin remaining on each balloon body after removal was measured. The specific procedure was to immerse the balloon body in a solvent containing dissolved riboflavin, ultrasonically treat it for 20 minutes, measure the concentration of riboflavin in water using high-performance liquid chromatography, calculate the amount of riboflavin remaining on the surface of the balloon body, and compare it with the initial amount applied to obtain the riboflavin residual rate (%). The results are shown in Table 1.

[0201] <Application example 2> A pig peripheral blood vessel was immersed in PBS buffer, and the balloon body of Preparation Example 6 was pushed into the blood vessel. Fluid was injected into the compressed balloon body at a pressure of 6 atm to expand it. Next, while maintaining the pressure of the balloon, the light-guiding material emitted 450 nm light, and the photocuring time was 5 minutes.

[0202] After irradiation, the balloon body was removed from the blood vessel, and the amount of riboflavin remaining on each balloon body after removal was measured. The specific procedure was to immerse the balloon body in a solvent containing dissolved riboflavin, ultrasonically treat it for 20 minutes, measure the concentration of riboflavin in water using high-performance liquid chromatography, calculate the amount of riboflavin remaining on the surface of the balloon body, and compare it with the initial amount applied to obtain the riboflavin residual rate (%). The results are shown in Table 1.

[0203] <Application example 3> A pig peripheral blood vessel was immersed in PBS buffer, and the balloon body of Preparation Example 9 was pushed into the blood vessel. Fluid was injected into the compressed balloon body at a pressure of 6 atm to expand it. Next, while maintaining the pressure of the balloon, the light-guiding material emitted 450 nm light, and the photocuring time was 5 minutes.

[0204] After irradiation, the balloon body was removed from the blood vessel, and the amount of riboflavin remaining on each balloon body after removal was measured. The specific procedure was to immerse the balloon body in a solvent containing dissolved riboflavin, ultrasonically treat it for 20 minutes, measure the concentration of riboflavin in water using high-performance liquid chromatography, calculate the amount of riboflavin remaining on the surface of the balloon body, and compare it with the initial amount applied to obtain the riboflavin residual rate (%). The results are shown in Table 1.

[0205] <Comparative Example 1> A pig peripheral blood vessel was immersed in PBS buffer, and a balloon containing no riboflavin was inserted into the vessel. The balloon was then inflated by injecting fluid at a pressure of 6 atm. While maintaining the pressure of the balloon, the light guide emitted 450 nm light for 5 minutes. After irradiation, the balloon was removed from the vessel.

[0206] <Comparative Example 2> A pig peripheral blood vessel was immersed in PBS buffer, and the balloon body of Preparation Example 6 was pushed into the blood vessel. Fluid was injected into the compressed balloon body at a pressure of 6 atm to expand it, and then, while maintaining the balloon pressure, excitation and photo-curing of the light-guiding material were not performed.

[0207] The balloon body was then removed from the blood vessel, and the amount of riboflavin remaining on each balloon body after removal was measured. The specific procedure was to immerse the balloon body in a solvent containing dissolved riboflavin, ultrasonically treat it for 20 minutes, measure the concentration of riboflavin in water using high-performance liquid chromatography, calculate the amount of riboflavin remaining on the surface of the balloon body, and compare it with the initial amount applied to obtain the riboflavin remaining rate (%). The results are shown in Table 3.

[0208] JPEG2025530802000013.jpg33170

[0209] Experimental studies using peripheral arteries in pigs demonstrated that the luminal gain after light-cured balloon catheter angioplasty and riboflavin-treated balloon angioplasty using a vascular in situ stent was significantly greater than that after angioplasty alone or without light activation. These results also confirmed that riboflavin can cross-link proteins under light activation, resulting in a denser medial fibrous network in the treated arteries. Cross-linking structural proteins such as collagen in the vessel wall helps maintain the integrity of the native vascular stent and is beneficial in the treatment of damaged or diseased arteries.

[0210] The present application proposes transporting or delivering riboflavin to the vascular wall using an interventional device such as a balloon catheter, activating the riboflavin using light irradiation and crosslinking it with proteins and polypeptides in the vascular wall, thereby generating endogenous microstents in situ in the vascular wall, replacing implanted stents and thereby effectively reducing thrombus formation and immunogenicity, and the in situ formed microstents can maintain the blood vessel in an expanded shape after surgery and prevent vascular restenosis.

[0211] The technical features of the above-described embodiments may be combined in any manner; however, for the sake of simplicity, not all possible combinations of the technical features in the above-described embodiments are described; however, unless there is a contradiction in the combinations, all are deemed to be within the scope of this specification.

[0212] It should be noted that those skilled in the art may make some modifications and improvements without departing from the concept of the present application, all of which fall within the scope of protection of the present application. Therefore, the scope of protection of this patent application should be determined by the appended claims. [Explanation of symbols]

[0213] In Figures 1 to 10: 100 tube body 110 distal end 120 proximal end 200 balloon body 210 Equal diameter part 220 Reduced diameter part 300 braided mesh 311 First Braided Yarn 312 Second Braiding Yarn 321 First Cell 322 Second Cell 400 microneedles 500 boards 510 Micropore 600 mandrels 700 electric field X cell width Y cell length Y1: Length of the first cell Y2: Length of the second cell S cell area C1 First winding circle A1 Mountain B1 valley C2 Second winding circle A2 mountain B2 Valley W1 Width of the mountain W2 Valley width H1 Mountain Spacing L1 First mesh line L2 Second mesh line Z Interlacing point. The reference symbols in FIG. 11 are explained as follows: 100 tube body 200 balloon body 130 Guidewire lumen 140 fluid delivery lumen 160 Inner layer tube 170 outer tube 340 Fiber Optic Module 310 Light-emitting device 320 Optical fiber body 330 Luminous part. The reference symbols in FIGS. 14 to 18 are explained as follows. 10 Balloon body 11 Balloon Wall 12 Pore structure 13 First balloon body 14 Second balloon body 20 Tube body 21 proximal end 22 distal end 30 Light guiding material 31 Light-emitting end 32 Optical input terminal 40 Drug delivery devices 50 Light source device 60 Drug Coating 70 Blood vessels 71 Blood vessel wall.

Claims

1. A drug-loaded balloon catheter, a tube body having opposite distal and proximal ends for transporting a fluid into the body of the balloon; a balloon body secured to the distal end of the tube body and in communication with the tube body, the balloon body having a hollow structure and a corresponding inflated state and a deflated state suitable for interventional delivery; The drug-loaded balloon catheter is characterized in that the balloon body is loaded with a drug, and the drug is loaded in one of the following ways: solid embedding, solid coating, and solution permeation.

2. The drug is loaded into the balloon body by a solid embedding method, and the drug-loaded balloon catheter comprises: The balloon is made of a polymer material and is wound around the balloon body. The balloon has a large number of cells, each of which has a width of X and a length of Y, and the ratio of X:Y=1:0.5 to 2 is satisfied. The area of ​​the cell is 1 to 50 mm. ２ a braided mesh, The drug-loaded balloon catheter of claim 1, further comprising drug-loaded microneedles arranged on the surface of the balloon body and positioned within the cells of the braided mesh and / or at the interweaving points of the cells.

3. The drug-loaded balloon catheter of claim 2, wherein a plurality of microneedles are dispersed within each cell, the distance between any two adjacent microneedles within a cell is 30 μm to 3 mm, and the height of the microneedles is 25 to 2000 μm.

4. a first braided thread wound spirally around the outer periphery of the balloon body; 4. The drug-loaded balloon catheter according to claim 2 or 3, further comprising a second braided thread extending along the axial direction of the balloon body, interwoven with the first braided thread, and surrounding the first braided thread at least once at each interwoven point.

5. The drug-loaded balloon catheter of claim 2 or 3, characterized in that the mesh threads of the braided mesh are wound spirally around the outer periphery of the balloon body, and two adjacent windings are a first winding circle and a second winding circle, each winding circle having an undulating peak-and-valley structure and are wound and connected to each other.

6. The balloon includes a plurality of parallel-arranged first mesh lines and second mesh lines, each of which extends along the circumferential direction of the balloon body and is spaced apart along the axial direction of the balloon body; A drug-loaded balloon catheter as described in claim 2 or 3, characterized in that the second mesh wire extends along the axial direction of the balloon body, interweaves with each first mesh wire, and at each interweaving point, surrounds the first mesh wire at that location at least once.

7. The balloon body is loaded with a drug by using a solid coating method, and the drug-loaded balloon catheter further comprises: an optical fiber module inserted into the tube body and having a light-emitting portion extending to the adjacent balloon body; an auxiliary material and a photosensitizer are applied to the surface of the balloon body by a coating method, and the photosensitizer is a polypeptide dendrimer modified with a naphthalene imide compound; The photosensitizer crosslinks collagen and elastin by activating them with light of wavelengths of 400 to 460 nm; The drug-loaded balloon catheter of claim 1, characterized in that the auxiliary material includes an active drug and a sustained-release material encapsulating the active drug, and the active drug is at least one of paclitaxel, rapamycin, zotarolimus, tacrolimus, everolimus, temsirolimus, zotarolimus, umirolimus, docetaxel, protein-bound paclitaxel, and protein-bound dexamethasone.

8. The method for preparing the photosensitizer comprises: Step 1: Protecting some of the amino groups of the polypeptide dendrimer; Step 2: adding the partially amino-protected polypeptide dendrimer and the naphthalimide compound to a mixed solution of an organic base and an organic solvent, reacting at 70 to 150°C for 1 to 32 hours, and obtaining the photosensitizer after post-treatment; the organic base is at least one of N,N-diisopropylethylamine, sodium tert-butoxide, and potassium tert-butoxide; 8. The drug-loaded balloon catheter of claim 7, wherein the organic solvent is at least one of isopropyl alcohol, hexafluoro-2-propanol, methanol, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, dichloromethane, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, and hexamethylphosphoramide.

9. The photosensitizer is applied to the surface of the balloon body by a coating method, and the method includes the steps of dispersing or dissolving the photosensitizer in a solvent to prepare a solution and coating the surface of the balloon body with the solution; 8. The drug-loaded balloon catheter of claim 7, wherein the solvent is at least one of ethanol, acetic acid, acetone, butylated hydroxytoluene, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, and water.

10. 10. The drug-loaded balloon catheter of claim 9, wherein the solvent is a mixture of ethanol, acetic acid, and water, and the volume ratio of each component in the solvent is ethanol:acetic acid:water=80-90:19-9:

1.

11. 10. The drug-loaded balloon catheter of claim 9, wherein the concentration of the photosensitizer in the solution is 6.25 to 125 μM / mL.

12. 10. The drug-loaded balloon catheter of claim 9, wherein the solution further comprises an auxiliary material, and the mass ratio of the auxiliary material to the photosensitizer is 0.3-10.

13. 13. The drug-loaded balloon catheter of claim 12, wherein the weight ratio of the active drug to the sustained-release material in the auxiliary material is 1:1-20.

14. 8. The drug-loaded balloon catheter of claim 7, wherein the mass ratio of the photosensitizer to the active drug is 1:0.2-5.

15. the solution further comprises a stabilizer, the stabilizer being at least one of an antioxidant and a Lewis acid; the antioxidant is at least one of tromethamine and butylated hydroxytoluene, and the weight ratio of the antioxidant to the photosensitizer is 0.05 to 1:100; 10. The drug-loaded balloon catheter of claim 9, wherein the cation of the Lewis acid is at least one of Na+, K+, Mg+, and Ca+, and the molar ratio of the Lewis acid to the photosensitizer is 0.8 to 3.

16. The coating method includes spraying and / or dipping, and the coating amount of the photosensitizer on the surface of the balloon body is 0.0012 to 37.5 μM / mm ２ 10. The drug-loaded balloon catheter according to claim 9, wherein:

17. a drug coating is applied to the surface of the balloon body, and the active ingredient of the drug coating includes riboflavin and / or a riboflavin salt; 2. The drug-loaded balloon catheter of claim 1, further comprising a light-guiding material, one end of which is a light-emitting end extending to the balloon body, and the other end of which is a light-input end extending through the catheter to the proximal end.

18. The method of depositing the drug coating comprises:

18. The drug-loaded balloon catheter of claim 17, further comprising: preparing a drug coating solution in advance; applying the solution to the surface of the balloon body; and drying the solution.

19. The balloon body is loaded with a drug by a solution infiltration method, and the drug-loaded balloon catheter comprises: the wall of the balloon body has a pore structure; a fluid containing riboflavin and / or a riboflavin salt, the fluid being output from the pore structure to the surrounding environment of the balloon body and for maintaining the inflation state of the balloon body; 2. The drug-loaded balloon catheter of claim 1, further comprising a light-guiding material, one end of which is a light-emitting end extending to the balloon body and the other end of which is a light-input end extending through the catheter to the proximal end.

20. The pore size of the pore structure is 5 to 100 μm, 20. The drug-loaded balloon catheter of claim 19, wherein the surface porosity of the balloon body is 30-80%.

21. the fluid is in the form of a solution, the solvent of which is water; 20. The drug-loaded balloon catheter of claim 19, wherein the concentration of the fluid is 0.2 to 60 mg / mL, calculated as total riboflavin.

22. A step of placing a drug-containing microneedle raw material solution in the micropores of the rigid substrate and forming the microneedle in situ; wrapping a braided mesh around a balloon body; injecting a fluid into the balloon body to expand the balloon body; 7. A method for producing a drug-loaded balloon catheter according to any one of claims 2 to 6, further comprising the steps of applying an adhesive onto the balloon body or the microneedles, rolling the balloon body on a rigid substrate, and adhering the microneedles to the surface of the balloon body.

23. 23. The method for producing a drug-loaded balloon catheter according to claim 22, wherein the solvent of the microneedle raw material solution is water, and the solute is at least one of chitosan, sodium alginate, polyethylene glycol, PLGA, PCL, PMMA, PGA, PLA, PEA, gelatin, and hyaluronic acid.

24. 23. The method for manufacturing a drug-loaded balloon catheter according to claim 22, wherein the adhesive is a re-dissolvable adhesive that dissolves in water.

25. 23. The method for producing a drug-loaded balloon catheter according to claim 22, wherein a mandrel is inserted into the balloon body before or after injecting a fluid into the balloon body to expand it, and the mandrel is manipulated to drive the balloon body to roll onto the rigid substrate.

26. wrapping a braided mesh around a balloon body; injecting a fluid into the balloon body to expand the balloon body; A step of dropping a UV-curable adhesive onto the surface of the balloon body or the interlacing points of the cells of the braided mesh, and applying an electric field or a magnetic field in a specific direction to harden the UV-curable adhesive into the shape of a microneedle; A step of solidifying the microneedle-shaped UV-curable adhesive by irradiating it with UV light to form microneedles; 7. The method for producing a drug-loaded balloon catheter according to claim 2, further comprising the step of spraying or dip-coating the drug onto the surface of the microneedle.

27. a balloon body having a corresponding inflated state and a deflated state suitable for interventional delivery, the balloon body having a pore structure in the wall for allowing fluid to pass therethrough; a tube body having opposing distal and proximal ends, the distal end of which is connected to the balloon body; a drug delivery device connected to the proximal end of the catheter for supplying a fluid, the fluid including riboflavin and / or a riboflavin salt; a light guide having one end being a light emitting end extending to the balloon body and the other end being a light input end extending through the catheter to the proximal end; a light source device connected to the light input end of the light guide by an optical path.

28. administering a first reagent to a predetermined location within a blood vessel, the first reagent including riboflavin and / or a riboflavin salt; a step of irradiating the predetermined location with light to excite the first reagent, and causing the first reagent to act on the predetermined location to form a vascular in situ stent.

29. Possible methods for administering the first reagent include: A method for preparing and delivering a solution directly to a predetermined location via an interventional device; or coating and delivering to a predetermined location via an interventional device using a solid encapsulation method; 29. The method for producing a vascular in situ stent according to claim 28, wherein when the first reagent is in the form of a solution, the concentration of the first reagent is 0.2 to 60 mg / mL, calculated as total riboflavin.

30. The wavelength of the irradiated light is 300 to 700 nm, and the intensity of the irradiated light is 5 to 500 mW / cm ２ The method for producing a vascular in situ stent according to claim 28, wherein the light irradiation time is 0.1 to 30 minutes.

31. 1. The use of riboflavin and riboflavin salts in the manufacture of a vascular in-situ stent drug, which comprises applying riboflavin and / or riboflavin salts to a predetermined location, and then forming a vascular in-situ stent at the predetermined location by photoexcitation.

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