Drug eluting balloon catheter system

Abstract

The application discloses a drug-loaded balloon catheter system, which comprises a balloon body having opposite inflation states and a contraction state suitable for interventional delivery, a balloon wall of the balloon body being provided with a porous structure, an outer wall of the balloon body being loaded with a coating containing a first active cross-linking agent and a water-soluble sustained-release layer wrapping the coating; a catheter having opposite distal and proximal ends, wherein the distal end is in communication with the balloon body; a perfusion device for supplying a second active cross-linking agent into the balloon body in a fluid manner through the proximal end of the catheter; and a light source device for applying light to the first and second active cross-linking agents. The drug-loaded balloon catheter system can improve the effect of angioplasty.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical devices, in particular to a drug-loaded balloon catheter system. BACKGROUND

[0002] Angioplasty can open calcified lesions in the arterial wall, which is one of the main ways of arterial stenosis revascularization. However, the expansion of the blood vessel will damage the blood vessel wall, thereby causing thrombosis and the release of growth factors, which in turn leads to the occurrence of vascular restenosis or reocclusion. At present, the above problems are mainly solved by implanting a stent into the blood vessel. The existing vascular stent is mainly divided into two categories. One is made of biocompatible metal, but it is easy to cause thrombosis and immune circle, and this permanent stent may interfere with subsequent treatment, such as corrosion perforation and potential aneurysm. The other is a biodegradable stent, which solves the problem of permanent existence of the metal stent, but the degradation products will cause serious inflammatory reaction, and at the same time cause the atrophy of the muscle elastic elements of the arterial wall, leading to arterial dilation.

[0003] In recent years, in situ formation of natural vascular stent in blood vessels has become a new treatment method. It mainly applies photosensitive compounds and specific wavelength light at a specified position of the blood vessel. The photosensitive compounds can be excited under specific light, thereby inducing the rapid combination of collagen and elastin in the blood vessel wall, forming a vascular stent in situ, and achieving the healing and repair of the blood vessel.

[0004] The drug-loaded balloon catheter is an important interventional instrument for delivering photosensitive compounds to a specified position of the blood vessel. It mainly loads photosensitive compounds on the surface of the balloon body in the form of a coating, and then releases the drug by delivering the balloon body to the specified position of the blood vessel. However, part of the drug is easily lost during the delivery process, and the drug release process is not easy to control, which affects the treatment effect. SUMMARY

[0005] In view of the problems of the prior art, the present application provides a drug-loaded balloon catheter system to effectively improve the effect of vascular formation.

[0006] The drug-loaded balloon catheter system provided by the present application comprises:

[0007] a balloon body having opposite inflated and deflated states suitable for interventional delivery, the balloon wall of the balloon body having a porous structure, the outer wall of the balloon body being loaded with a coating containing a first active cross-linking agent and a water-soluble sustained-release layer wrapping the coating;

[0008] a catheter having opposite distal and proximal ends, wherein the distal end is in communication with the balloon body;

[0009] a perfusion device for supplying a second active cross-linking agent to the balloon body in the form of a fluid through the proximal end of the catheter;

[0010] a light source device for applying light to the first active crosslinking agent and the second active crosslinking agent;

[0011] The first active crosslinking agent is at least one of lysine-PEG-lysine, tyrosine-PEG-tyrosine, polylysine, lysine-tryptophan copolymer, glycine-carboxymethylcellulose-glycine, tryptophan-carboxymethylcellulose-tryptophan, phenylalanine and tyrosine modified polyethyleneimine.

[0012] The second active crosslinking agent is at least one of naphthalimide derivative, rose Bengal, riboflavin phosphate.

[0013] The water-soluble sustained-release layer comprises a sustained-release material, and the sustained-release material is at least one of polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000, povidone K90, povidone K20, shellac, iopromide, polysorbate sugar alcohol, polyvinyl alcohol.

[0014] The following also provides several optional modes, but not as an additional limitation to the above general scheme, just a further supplement or preferred, without technical or logical contradiction, each optional mode can be combined with the above general scheme, but also can be combined between multiple optional modes.

[0015] Optionally, the coating amount of the first active crosslinking agent in the coating layer is 1-5 μg / mm 2 .

[0016] Optionally, the thickness of the coating layer is 5-20 μm.

[0017] The thickness of the water-soluble sustained-release layer is 5-50 μm.

[0018] Optionally, the pore size of the pore structure is 3-16 μm; the number of pores on the surface of the balloon body is 100-1000.

[0019] Optionally, the first active crosslinking agent is lysine-PEG-lysine and / or tyrosine-PEG-tyrosine, and the sustained-release material is at least one of polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000.

[0020] Optionally, the first active crosslinking agent is polylysine and / or lysine-tryptophan copolymer, and the sustained-release material is at least one of polyethylene glycol 20000, shellac, polysorbate sugar alcohol.

[0021] Optionally, the first active cross-linking agent is glycine-carboxymethyl cellulose-glycine, tryptophan-carboxymethyl cellulose-tryptophan, phenylalanine and tyrosine modified polyethyleneimine, and the sustained-release material is at least one of povidone K90, povidone K20 and polyvinyl alcohol.

[0022] Optionally, the concentration of the second active cross-linking agent in the fluid is 0.1-30 mg / mL.

[0023] Optionally, the fluid further comprises a pharmaceutical agent, which is a cell growth inhibiting drug and / or an anti-proliferative drug.

[0024] The concentration of the pharmaceutical agent in the fluid is 5-30 mg / mL.

[0025] Optionally, the light source device comprises a light source and a light guide element, the light guide element has a light source input end and a light emitting end, the light source input end is connected with the light source, and the light emitting end is located at the outer periphery of the balloon body or in the balloon body.

[0026] Optionally, the catheter comprises an inner tube and an outer tube which are sleeved with each other, the balloon body is fixed to the distal end of the outer tube and communicates with the inner part of the outer tube, the radial gap between the inner tube and the outer tube provides a fluid channel, and the light guide element is fixed to the inner wall or the outer wall of the inner tube.

[0027] Compared with the prior art, the drug-loaded balloon catheter provided by the application loads the first active cross-linking agent in a fluid manner and loads the second active cross-linking agent in a coating manner, and a water-soluble sustained-release layer is arranged on the outer surface of the coating, which can delay the release of the second active cross-linking agent, on the one hand, can reduce the loss of drugs during delivery, and on the other hand, can regulate the release process of the two active cross-linking agents, so that the blood vessel can fully absorb the two active cross-linking agents, and then can form a dense fiber under the action of light in a specific wave band, that is, a natural blood vessel stent, which is beneficial to improve the effect of the blood vessel forming operation. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 FIG. 1 is a structural schematic diagram of a drug-loaded balloon catheter system in an embodiment of the application;

[0029] Figure 2 FIG. 2 is a partial schematic diagram of a balloon body in the application;

[0030] Figure 3 FIG. 3 is an EVG staining diagram of a tissue in application example 1 of the application;

[0031] Figure 4 FIG. 4 is an EVG staining diagram of a tissue in application example 2 of the application;

[0032] Figure 5 FIG. 5 is an EVG staining diagram of a tissue in application example 3 of the application;

[0033] Figure 6 EVG staining chart organized in Example 4 of the present application;

[0034] Figure 7 EVG staining chart organized in Comparative Example 1 of the present application.

[0035] Reference numerals in the drawings are explained as follows:

[0036] 10, balloon body; 11, porous structure; 12, coating layer; 13, water-soluble sustained-release layer

[0037] 20, catheter; 21, proximal end; 22, distal end;

[0038] 30, perfusion device;

[0039] 40, light source device; 41, light source; 42, light guide element

[0040] 50, blood vessel wall;

[0041] 60, fluid. DETAILED DESCRIPTION

[0042] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0043] It should be noted that when a component is referred to as being "connected" with another component, it can be directly connected with the other component or there can be a middle component. When a component is referred to as being "disposed on" another component, it can be directly disposed on the other component or there can be a middle component.

[0044] 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 in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0045] Reference Figure 1 , 2An embodiment of the present application provides a balloon catheter system 20, which comprises a balloon body 10, a catheter 20, a perfusion device 30 and a light source device 40; wherein the balloon body 10 has opposite inflated and contracted states suitable for interventional delivery, the outer wall of the balloon body 10 is loaded with a coating 12 containing a first active cross-linking agent and a water-soluble sustained-release layer 13 wrapping the coating 12, and the balloon wall of the balloon body 10 has a porous structure 11; the catheter 20 has opposite proximal and distal ends 21 and 22, wherein the distal end 22 is in communication with the balloon body 10; the perfusion device 30 is used to supply a second active cross-linking agent to the balloon body 10 in the form of a fluid 60 through the proximal end of the catheter 20; and the light source device 40 is used to apply light to the first and second active cross-linking agents.

[0046] The first active cross-linking agent is at least one of lysine-PEG-lysine, tyrosine-PEG-tyrosine, polylysine, lysine-tryptophan copolymer, glycine-carboxymethyl cellulose-glycine, tryptophan-carboxymethyl cellulose-tryptophan, and phenylalanine and tyrosine modified polyethyleneimine. The lysine-PEG-lysine and the tyrosine-PEG-tyrosine refer to PEGs with corresponding amino acids at both ends; the glycine-carboxymethyl cellulose-glycine and the tryptophan-carboxymethyl cellulose-tryptophan refer to carboxymethyl celluloses with corresponding amino acids at both ends. The second active cross-linking agent is at least one of naphthalimide derivative, rose Bengal and riboflavin phosphate.

[0047] The first active cross-linking agent is equivalent to bridging between non-adjacent proteins, and under the light excitation condition of the first photoactivator, the amino group or polypeptide contained in the second active cross-linking agent is cross-linked with the collagen in the blood vessel wall 50. Whether the second photoactivator participates in the cross-linking reaction or not, the second photoactivator can only promote the cross-linking between adjacent collagen / elastin through light activation. After the first active cross-linking agent is added, the length of the chain can make the proteins far away from each other form covalent bond cross-linking, increase the cross-linking of the collagen in the blood vessel wall 50, form a natural blood vessel stent, and make the fibers of the blood vessel wall 50 more dense, thereby greatly improving the effect of angioplasty.

[0048] The experimental results prove that, generally, the second active cross-linking agent is applied to the blood vessel first, and then the first active cross-linking agent is applied, which can form better fibers. The reason may be that the second active cross-linking agent promotes the cross-linking between adjacent proteins, and the first active cross-linking agent promotes the cross-linking between non-adjacent proteins. If the first active cross-linking agent is applied first, the non-adjacent proteins are cross-linked first, which leads to the fact that most of the adjacent proteins cannot be cross-linked with each other, thereby affecting the cross-linking effect.

[0049] From the physical and chemical properties of the drug itself, the first active cross-linking agent is loaded in the form of coating 12, and the second active cross-linking agent is loaded in the form of fluid 60. In order to regulate the release of the two active cross-linking agents, a water-soluble sustained-release layer 13 is arranged on the surface of the coating 12. On the one hand, the water-soluble sustained-release layer 13 can reduce the damage of the first active cross-linking agent during the delivery of the balloon body 10, and on the other hand, it can delay the release of the first active cross-linking agent, and the delay time depends on the material and thickness of the water-soluble sustained-release layer 13. The water-soluble sustained-release layer 13 comprises a sustained-release material, which can be selected from one or more of polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000, povidone K90, povidone K20, shellac, iopromide, polysorbate sugar alcohol, and polyvinyl alcohol.

[0050] In an embodiment, the thickness of the water-soluble sustained-release layer 13 is 5-50 μm, for example, 20-40 μm, and for example, 20-30 μm. The greater the thickness, the longer the delay of the release of the first active cross-linking agent. Therefore, in the treatment of blood vessels, the second active cross-linking agent is first applied to the blood vessels by using the fluid 60 for a period of time, and during this period of time, the first active cross-linking agent is not released or partially released due to the wrapping of the water-soluble sustained-release layer 13. After this period of time, the first active cross-linking agent is completely exposed and released in large quantities. When the first active cross-linking agent is released, the fluid 60 containing the second active cross-linking agent can be continuously delivered to keep the balloon body 10 inflated until the release of the first active cross-linking agent is completed. Alternatively, after the delivery of the second active cross-linking agent is completed, the balloon body 10 is inflated with physiological saline to keep the balloon body under pressure, thereby ensuring the release of the first active cross-linking agent on the balloon body. According to the expected treatment effect, the application process of the first active cross-linking agent and the second active cross-linking agent can be regulated.

[0051] The balloon body 10 is made of a light-transmitting material, for example, nylon PA, PEBAX, polyethylene terephthalate PET, polyethylene PE, polypropylene PP, polyvinyl chloride PVC, and polycarbonate PC.

[0052] The coating amount of the first active cross-linking agent in the coating 12 is 1-5 μg / mm 2 , for example, 2-4 μg / mm 2 , relative to the unit surface area of the balloon. The thickness of the coating 12 is 5-20 μm, for example, 8-20 μm, and for example, 12-18 μm.

[0053] The solvent used by the second active cross-linking agent is water, and the pH is adjusted to form a buffer solution as needed. The concentration of the second active cross-linking agent in the fluid 60 is 0.1-30 mg / mL, for example, 15-20 mg / mL, and for example, 5-10 mg / mL.

[0054] The fluid 60 can also include a pharmaceutical agent, such as a cytostatic agent and / or an anti-proliferative agent. The cytostatic agent can be at least one of rapamycin, sirolimus, everolimus, zotarolimus, deforolimus, biolimus, umirolimus, and tacrolimus. The anti-proliferative agent can be at least one of paclitaxel, protaxel, and docetaxel. The concentration of the pharmaceutical agent in the fluid 60 can be 1-10 mg / mL, such as 2-8 mg / mL, and such as 2-5 mg / mL. The solvent for the pharmaceutical agent can be a mixture of water and polyethylene glycol, such as polyethylene glycol with a molecular weight of 8000, i.e., macrogol 8000.

[0055] The pore structure 11 affects the release of the fluid 60. In one embodiment, the pore size of the pore structure 11 is 3-16 μm, such as 3-10 μm, and such as 3-7 μm. The number of pores on the surface of the balloon body 10 can be 100-1000, such as 200-800, and such as 320-600.

[0056] To ensure the encapsulation effect of the coating 12, in one embodiment, the first active crosslinking agent is lysine-PEG-lysine and / or tyrosine-PEG-tyrosine, and the sustained release material is at least one of macrogol 8000, macrogol 10000, and macrogol 20000. For example, the sustained release material can be macrogol 8000:macrogol 10000 in a mass ratio of 1.25:1, and such as macrogol 8000:macrogol 20000 in a mass ratio of 2:1.

[0057] In another embodiment, the first active crosslinking agent is glycine-carboxymethylcellulose-glycine, tryptophan-carboxymethylcellulose-tryptophan, and polyethyleneimine modified with phenylalanine and tyrosine, and the sustained release material is at least one of povidone K90, povidone K20, and polyvinyl alcohol. For example, the sustained release material can be 35 mg / mL of povidone K90, and such as povidone K90:povidone K20 in a mass ratio of 1:4.

[0058] The light source device 40 includes a light source 41 and a light guide element 42. The catheter 20 element has a light source 41 input end connected to the light source 41 and a light emitting end. The light emitting end is located on the outer periphery of the balloon body 10 or inside the balloon body 10. Preferably, the light emitting end is located on the outer periphery of the balloon body 10, so that light can be applied to the blood vessel without passing through the balloon body 10. The light source device 40 is used in conjunction with the application of the first active crosslinking agent and the second active crosslinking agent to irradiate the blood vessel and promote the crosslinking of the tissue proteins.

[0059] The preparation of the drug-loaded balloon body 10 can form the coating 12 of the first active cross-linking agent and the water-soluble sustained-release layer 13 on the surface of the balloon coating 12 by spraying, soaking or rotary coating 12 process. The first active cross-linking agent and the water-soluble sustained-release layer 13 are respectively prepared into a coating 12 liquid by using a solvent in advance. The solvent can be a solvent including an organic solvent and water, and the organic solvent is at least one of isopropyl alcohol, ethanol, acetonitrile, methanol, ethyl acetate, and acetone, and the volume ratio of water and organic solvent is (0.05-0.5):1.

[0060] The catheter 20 has various structural types. In an embodiment, the catheter 20 includes an inner tube and an outer tube which are sleeved with each other, the balloon body 10 is fixed to the distal end of the outer tube and communicates with the inside of the outer tube, and the radial gap between the inner tube and the outer tube provides a fluid 60 channel. The elements of the catheter 20 can be fixed to the inner wall or the outer wall of the inner tube.

[0061] The drug-loaded balloon catheter 20 provided in the present application loads the first active cross-linking agent in the form of fluid 60 and the second active cross-linking agent in the form of coating 12, and sets the water-soluble sustained-release layer 13 on the outer surface of the coating 12, which can delay the release of the second active cross-linking agent, reduce the loss of drugs during delivery on the one hand, and regulate the release process of the two active cross-linking agents on the other hand, so that the blood vessel can fully absorb the two active cross-linking agents, and then form a dense fiber under the action of light in a specific wave band, i.e. a natural blood vessel stent, which is beneficial to improve the effect of blood vessel formation.

[0062] Preparation Example 1

[0063] Drug-loaded balloon:

[0064] (1) The first active cross-linking agent: lysine-PEG-lysine is dissolved in a solution, and the concentration of lysine-PEG-lysine is 20 mg / mL. Ultrasonic oscillation is performed until the drug solution is completely dissolved. The drug solution is uniformly coated on the surface of the balloon by spraying, and the coating amount is 2 μg / mm 2 , and the coating thickness after drying is 8 μm.

[0065] (2) Sustained-release material: polyethylene glycol 8000: polyethylene glycol 10000 = 1.25:1 (mass ratio) is dissolved in water to prepare a solution with a concentration of 60 mg / mL. After the drug solution on the surface of the balloon is completely air-dried and dried, the sustained-release material is uniformly coated on the surface of the balloon by spraying, and the coating amount is 3 μg / mm 2 , and the coating thickness after drying is 20 μm.

[0066] Fluid: Polyethylene glycol 8000 was dissolved in solvent, which was selected from water: ethanol = 1:1 (volume ratio). A solution of 5 mg / mL was prepared, and riboflavin phosphate: rapamycin = 1:1 (mass ratio) was dissolved in the solution to prepare a drug solution with a concentration of 5 mg / mL. Ultrasonic oscillation was performed for 3-5 min to completely dissolve the drugs.

[0067] Preparation Example 2

[0068] Drug-loaded balloon:

[0069] (1) First active crosslinking agent: Polylysine powder was dissolved in water to prepare a solution with a concentration of 20 mg / mL. Ultrasonic oscillation was performed until the drug solution was completely dissolved. The drug solution was uniformly coated on the surface of the balloon by spraying, and the coating amount was 2 μg / mm 2 , and the coating thickness was 12 μm after drying.

[0070] (2) Sustained-release material: Polyethylene glycol 20000: shellac = 1:1 was dissolved in water, and the solution was heated on a hot plate at 150°C until it was completely dissolved. After the surface of the balloon was air-dried, the sustained-release material was uniformly coated on the surface of the balloon by spraying, and the coating amount was 3 μg / mm 2 , and the coating thickness was 25 μm after drying.

[0071] Fluid: Polyethylene glycol 8000 was dissolved in solvent, which was selected from water: ethanol = 1:1 (volume ratio). A solution of 5 mg / mL was prepared, and riboflavin phosphate: rapamycin = 1:1 (mass ratio) was dissolved in the solution to prepare a drug solution with a concentration of 5 mg / mL. Ultrasonic oscillation was performed for 3-5 min to completely dissolve the drugs.

[0072] Preparation Example 3

[0073] Drug-loaded balloon:

[0074] (1) First active crosslinking agent: Glycine-carboxymethyl cellulose-glycine was dissolved in water to prepare a solution with a concentration of 20 mg / mL. Ultrasonic oscillation was performed until the drug solution was completely dissolved. The drug solution was uniformly coated on the surface of the balloon by spraying, and the coating amount was 2 μg / mm 2 , and the coating thickness was 10 μm after drying.

[0075] (2) Sustained-release material: Povidone K90: povidone K20 = 1:4 was dissolved in water, and the solution was heated on a hot plate at 150°C until it was completely dissolved. After the surface of the balloon was air-dried, the sustained-release material was uniformly coated on the surface of the balloon by spraying, and the coating amount was 3 μg / mm 2 , and the coating thickness was 22 μm after drying.

[0076] Fluid: Polyethylene glycol 8000 was dissolved in solvent, solvent was selected as water: ethanol = 1:1 (volume ratio). A solution of 5 mg / mL was prepared, rose Bengal: rapamycin = 1:1 (mass ratio) was dissolved in the solution, a drug solution of 5 mg / mL was prepared. Ultrasonic 3-5 min, each drug was completely dissolved.

[0077] Preparation Example 4

[0078] Drug-loaded balloon:

[0079] (1) The first active crosslinking agent: lysine-PEG-lysine was dissolved in solution, the concentration of lysine-PEG-lysine was 20 mg / mL. Ultrasonic oscillation until the drug solution was completely dissolved, the drug solution was uniformly covered on the surface of the balloon by spraying method, the coating amount was 2 μg / mm 2 , the coating thickness was 9 μm after drying.

[0080] Fluid: Polyethylene glycol 8000 was dissolved in solvent, solvent was selected as water: ethanol = 1:1 (volume ratio). A solution of 5 mg / mL was prepared, rose Bengal: rapamycin = 1:1 (mass ratio) was dissolved in the solution, a drug solution of 5 mg / mL was prepared. Ultrasonic 3-5 min, each drug was completely dissolved.

[0081] Preparation Example 5

[0082] Drug-loaded balloon:

[0083] (1) The first active crosslinking agent: polylysine powder was dissolved in water to prepare a solution with a concentration of 20 mg / mL. Ultrasonic oscillation until the drug solution was completely dissolved, the drug solution was uniformly covered on the surface of the balloon by spraying method, the coating amount was 2 μg / mm 2 , the coating thickness was 11 μm after drying.

[0084] Fluid: Polyethylene glycol 8000 was dissolved in solvent, solvent was selected as water: ethanol = 1:1 (volume ratio). A solution of 5 mg / mL was prepared, rose Bengal: rapamycin = 1:1 (mass ratio) was dissolved in the solution, a drug solution of 5 mg / mL was prepared. Ultrasonic 3-5 min, each drug was completely dissolved.

[0085] Preparation Example 6

[0086] Drug-loaded balloon:

[0087] (1) The first active crosslinking agent: glycine-carboxymethyl cellulose-glycine was dissolved in water to prepare a solution with a concentration of 20 mg / mL. Ultrasonic oscillation until the drug solution was completely dissolved, the drug solution was uniformly covered on the surface of the balloon by spraying method, the coating amount was 2 μg / mm 2 , the coating thickness was 12 μm after drying.

[0088] Fluid: Polyethylene glycol 8000 was dissolved in solvent, solvent was selected as water: ethanol = 1:1 (volume ratio). A solution of 5 mg / mL was prepared, rose Bengal: rapamycin = 1:1 (mass ratio) was dissolved in the solution, a drug solution of 5 mg / mL was prepared. Ultrasonic 3-5 min, the drug was completely dissolved.

[0089] Preparation Example 7

[0090] Drug-loaded balloon:

[0091] (1) The first active crosslinking agent: lysine-PEG-lysine was dissolved in solution, the concentration of lysine-PEG-lysine was 20 mg / mL. Ultrasonic oscillation until the drug solution was completely dissolved, the drug solution was uniformly coated on the surface of the balloon by spraying method, the coating amount was 2 μg / mm 2 , the coating thickness was 9 μm after drying.

[0092] (2) Sustained-release material: polyethylene glycol 8000: polyethylene glycol 10000 = 1.25:1 (mass ratio) was dissolved in water to prepare a solution of 60 mg / mL. After the drug solution on the surface of the balloon was completely air-dried and dried, the sustained-release material was uniformly coated on the surface of the balloon by spraying method, the coating amount was 1 μg / mm 2 , the coating thickness was 18 μm after drying.

[0093] Fluid: Polyethylene glycol 8000 was dissolved in solvent, solvent was selected as water: ethanol = 1:1 (volume ratio). A solution of 5 mg / mL was prepared, rose Bengal: rapamycin = 1:1 (mass ratio) was dissolved in the solution, a drug solution of 5 mg / mL was prepared. Ultrasonic 3-5 min, the drug was completely dissolved.

[0094] Preparation Example 8

[0095] Drug-loaded balloon:

[0096] (1) The first active crosslinking agent: polylysine powder was dissolved in water to prepare a solution of 20 mg / mL. Ultrasonic oscillation until the drug solution was completely dissolved, the drug solution was uniformly coated on the surface of the balloon by spraying method, the coating amount was 2 μg / mm 2 , the coating thickness was 11 μm after drying.

[0097] (2) Sustained-release material: polyethylene glycol 20000: shellac = 1:1 was dissolved in water, heated to complete dissolution on the electric heating plate at 150°C, and the solution was cooled. After the balloon surface was air-dried, the sustained-release material was uniformly coated on the surface of the balloon by spraying method, the coating amount was 1 μg / mm 2 , the coating thickness was 19 μm after drying.

[0098] Fluid: Polyethylene glycol 8000 was dissolved in solvent, which was selected as ethanol. The drug solution was prepared by dissolving riboflavin phosphate: paclitaxel = 1:1 (mass ratio) in the solution with a concentration of 5 mg / mL. The solution was ultrasonically oscillated for 3-5 min to completely dissolve the drugs.

[0099] Preparation Example 9

[0100] Drug-loaded balloon:

[0101] (1) First active cross-linking agent: Glycine-carboxymethyl cellulose-glycine was dissolved in water to prepare a solution with a concentration of 20 mg / mL. The solution was ultrasonically oscillated until the drug solution was completely dissolved. The drug solution was uniformly coated on the surface of the balloon by spraying, and the coating amount was 2 μg / mm 2 . After drying, the coating thickness was 12 μm.

[0102] (2) Sustained-release material: Povidone K90: povidone K20 = 1:4 was dissolved in water, and the solution was heated on a hot plate at 150°C until it was completely dissolved. After the surface of the balloon was air-dried, the sustained-release material was uniformly coated on the surface of the balloon by spraying, and the coating amount was 1 μg / mm 2 . After drying, the coating thickness was 20 μm.

[0103] Fluid: Polyethylene glycol 8000 was dissolved in solvent, which was selected as water: ethanol = 1:1 (volume ratio). A solution with a concentration of 5 mg / mL was prepared, and rose Bengal: rapamycin = 1:1 (mass ratio) was dissolved in the solution to prepare a drug solution with a concentration of 5 mg / mL. The solution was ultrasonically oscillated for 3-5 min to completely dissolve the drugs.

[0104] Sustained-release test of Example 1

[0105] Six bare balloons with a size of 3.0 x 15 were taken to record their initial mass m0. One balloon was prepared by each of the methods described in Preparation Examples 1, 2, and 3 above, and the drug-loaded balloon without the sustained-release material prepared in Preparation Examples 1-3 above was used as a control. The mass of the balloon + drug coating was recorded as m1, and the mass of the balloon + drug coating + sustained-release layer was recorded as m2. The balloon was flushed with normal saline at a flow rate of 220 mm / s for 35 s, and then placed in a 50°C oven to dry for 2 h, and the mass was recorded as m3.

[0106] The test results are shown in Table 1 below:

[0107] Table 1 Sustained-release test results

[0108]

[0109] Take six bare balloon with size of 3.0*15 to record their initial mass M0, and prepare the balloon with each method described in the above preparation example 1, 2, 3, 7, 8, 9. After the first active crosslinking agent drug coating is dried, weigh it and record as M1, and measure its thickness with laser caliper and record as thickness 1. Then spray the corresponding sustained release layer and dry it, weigh it and record as M2, and measure its thickness with laser caliper and record as thickness 2. Flush the balloon with normal saline at a flow rate of 220 mm / s, and record the time required for the mass of the balloon to decrease to the mass of the first active crosslinking agent drug coating m1 with a timer (every 3 s). The test results are shown in Table 2 below:

[0110] Table 2 Test results

[0111]

[0112] Application Example 1

[0113] The effectiveness of the drug balloon was studied using a peripheral artery model in pigs. In the peripheral artery model of pigs, the balloon body of preparation example 1 was pushed into the blood vessel, and the compressed balloon body was expanded by the second active crosslinking agent fluid to inflate, with a pressure of 6 atm. Then, under the condition of maintaining the pressure of the balloon body, the light guide element emitted light with a wavelength of 450 nm, and the light curing time was 1 minute. After the second active crosslinking agent was delivered, the balloon was maintained in a state of filling with normal saline, and the first active crosslinking agent was released as the sustained release material dissolved. Then, the balloon was light cured for another 2 minutes, and the balloon body was removed from the blood vessel after light exposure. The morphology of elastic fibers and collagen fibers after EVG staining of tissue sections of each sample was observed under a microscope, as shown in Figure 3 .

[0114] Application Example 2

[0115] The effectiveness of the drug balloon was studied using a peripheral artery model in pigs. In the peripheral artery model of pigs, the balloon body of preparation example 2 was pushed into the blood vessel, and the compressed balloon body was expanded by the second active crosslinking agent fluid to inflate, with a pressure of 6 atm. Then, under the condition of maintaining the pressure of the balloon body, the light guide element emitted light with a wavelength of 450 nm, and the light curing time was 1 minute. After the second active crosslinking agent was delivered, the balloon was maintained in a state of filling with normal saline, and the first active crosslinking agent was released as the sustained release material dissolved. Then, the balloon was light cured for another 2 minutes, and the balloon body was removed from the blood vessel after light exposure. The morphology of elastic fibers and collagen fibers after EVG staining of tissue sections of each sample was observed under a microscope, as shown in Figure 4 .

[0116] Application Example 3

[0117] The drug balloon was studied for effectiveness using a peripheral artery model in pigs. In the peripheral artery model in pigs, the balloon body of Preparation Example 3 was pushed into the blood vessel, the balloon body in the compressed state was expanded by perfusion of the second active crosslinking agent fluid to inflate, the pressure was 6 atm, then the light guide element emitted light at a wavelength of 450 nm under the condition of maintaining the pressure of the balloon body, the light curing time was 1 minute, until the second active crosslinking agent was delivered, the balloon was maintained in the inflated state with physiological saline, the first active crosslinking agent was released as the slow-release material dissolved, and light curing was performed for another 2 minutes, after light irradiation, the balloon body was removed from the blood vessel. The morphology of elastic fibers and collagen fibers after EVG staining of tissue sections of each sample was observed under a microscope, see Figure 5 .

[0118] Application Example 4

[0119] The drug balloon was studied for effectiveness using a peripheral artery model in pigs. In the peripheral artery model in pigs, the balloon body of Preparation Example 3 was pushed into the blood vessel, the balloon body in the compressed state was expanded by perfusion of the second active crosslinking agent fluid to inflate, the pressure was 6 atm, then the light guide element emitted light at a wavelength of 450 nm under the condition of maintaining the pressure of the balloon body, the light curing time was 30 s, while the second active crosslinking agent was delivered, the first active crosslinking agent was released as the slow-release material dissolved, and light curing was performed for another 150 s, after light irradiation, the balloon body was removed from the blood vessel. The morphology of elastic fibers and collagen fibers after EVG staining of tissue sections of each sample was observed under a microscope, see Figure 6 .

[0120] Comparative Example 1

[0121] The drug balloon was studied for effectiveness using a peripheral artery model in pigs. In the peripheral artery model in pigs, the balloon body of Preparation Example 3 was pushed into the blood vessel, the balloon body in the compressed state was expanded by perfusion of the second active crosslinking agent fluid to inflate, the pressure was 6 atm, then the light guide element emitted light at a wavelength of 450 nm under the condition of maintaining the pressure of the balloon body, the light curing time was 30 s, while the second active crosslinking agent was delivered, the first active crosslinking agent was released as the slow-release material dissolved, and light curing was performed for another 150 s, after light irradiation, the balloon body was removed from the blood vessel. The morphology of elastic fibers and collagen fibers after EVG staining of tissue sections of each sample was observed under a microscope, see Figure 7 .

[0122] The application results are shown in Table 1 Figures 3 to 7 It can be seen from Table 1 that the blue-black elastic fibers and pink collagen fibers in Application Examples 1, 2, 3, and 4 are more uniform and dense than those in Comparative Example 1, indicating that under the protection of the slow-release material, the auxiliary crosslinking agent is released slowly and participates in the protein crosslinking reaction in the blood vessel wall, which more effectively protects the blood vessel from tearing during expansion and causes less tissue damage.

[0123] Any technical features in the above-described embodiments can be combined in any manner, and for the sake of brevity, the foregoing description has not described all possible combinations of the technical features in the above-described embodiments. However, it is understood that no reference to a particular feature in a given embodiment is intended to imply that all embodiments must include that particular feature. Moreover, descriptions of a particular feature in a given embodiment does not mean that the feature is essential or critical to that embodiment. Any technical features in the different embodiments can be combined in the same drawing figure, and it can be considered that the same drawing figure discloses the combination of the embodiments involved.

[0124] The above-described embodiments only express several implementation manners of the present application, and the description is relatively specific and detailed, but it should not be understood as a limitation on the scope of the patent. It should be pointed out that for ordinary skilled persons in the art, some modifications and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the appended claims.

Claims

1. A drug-loaded balloon catheter system, characterized in that, include: The balloon has a relatively inflated state and a contracted state suitable for interventional delivery. The balloon wall has a porous structure, and the outer wall of the balloon is loaded with a coating containing a first active crosslinking agent and a water-soluble sustained-release layer encapsulating the coating. The catheter has a distal end and a proximal end, wherein the distal end communicates with the balloon body; An infusion device for supplying a second active crosslinking agent in a fluid manner into the balloon via the proximal end of a catheter; A light source device for applying light to the first and second active crosslinking agents; The first active crosslinking agent is at least one of lysine-PEG-lysine, tyrosine-PEG-tyrosine, polylysine, lysine-tryptophan copolymer, glycine-carboxymethyl cellulose-glycine, tryptophan-carboxymethyl cellulose-tryptophan, phenylalanine and tyrosine-modified polyethyleneimine. The second active crosslinking agent is at least one of naphthalimide derivative, rose red, and riboflavin phosphate; The water-soluble sustained-release layer includes a sustained-release material, which is at least one of polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000, povidone K90, povidone K20, shellac, iopromide, polysorbate, and polyvinyl alcohol. In vascular treatment, the second active crosslinking agent is first applied to the blood vessel using the fluid for a period of time. During this period, the first active crosslinking agent is not released or is only partially released due to the encapsulation of the water-soluble sustained-release layer. After this period, the first active crosslinking agent is fully exposed and released in large quantities.

2. The drug-loaded balloon catheter system according to claim 1, characterized in that, The amount of the first active crosslinking agent in the coating is 1~5 μg / mm² relative to the unit balloon surface area. 2 ; The thickness of the coating is 5~20μm; The thickness of the water-soluble sustained-release layer is 5~50μm.

3. The drug-loaded balloon catheter system according to claim 1, characterized in that, The pore size of the pore structure is 3~16μm; The number of pores on the surface of the balloon is 100 to 1000.

4. The drug-loaded balloon catheter system according to claim 1, characterized in that, The first active crosslinking agent is lysine-PEG-lysine and / or tyrosine-PEG-tyrosine, and the sustained-release material is at least one of polyethylene glycol 8000, polyethylene glycol 10000, and polyethylene glycol 20000.

5. The drug-loaded balloon catheter system according to claim 1, characterized in that, The first active crosslinking agent is polylysine and / or lysine-tryptophan copolymer, and the sustained-release material is at least one of polyethylene glycol 20000, shellac, and polysorbate.

6. The drug-loaded balloon catheter system according to claim 1, characterized in that, The first active crosslinking agent is polyethyleneimine modified with glycine-carboxymethyl cellulose-glycine, tryptophan-carboxymethyl cellulose-tryptophan, phenylalanine and tyrosine, and the sustained-release material is at least one of polyvinylpyrrolidone K90, polyvinylpyrrolidone K20 and polyvinyl alcohol.

7. The drug-loaded balloon catheter system according to claim 1, characterized in that, The concentration of the second active crosslinking agent in the fluid is 0.1~30 mg / mL.

8. The drug-loaded balloon catheter system according to claim 1, characterized in that, The fluid also includes pharmaceutical reagents, which are cell growth inhibitors and / or antiproliferative drugs; The concentration of the drug reagent in the fluid is 5~30 mg / mL.

9. The drug-loaded balloon catheter system according to claim 1, characterized in that, The light source device includes a light source and a light guide element. The light guide element has a light source input end and a light emission end, wherein the light source input end is connected to the light source, and the light emission end is located on the outer periphery or inside the balloon body.

10. The drug-loaded balloon catheter system according to claim 9, characterized in that, The catheter includes an inner tube and an outer tube that are nested together. The balloon is fixed to the distal end of the outer tube and communicates with the interior of the outer tube. The radial gap between the inner tube and the outer tube provides a fluid channel. The light guide element is fixed to the inner wall or the outer wall of the inner tube.

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