Drug loading balloon catheter system

Abstract

The invention discloses a medicine carrying balloon catheter system which comprises a balloon body, the balloon body has a relative inflation state and a contraction state suitable for interventional conveying, and the balloon wall of the balloon body is provided with a pore structure. A coating containing a first active cross-linking agent and a water-soluble slow-release layer wrapping the coating are loaded on the outer wall of the balloon body; the catheter is provided with a far end and a near end which are opposite to each other, and the far end is communicated with the balloon body; the perfusion device is used for supplying a second active cross-linking agent into the balloon body in a fluid manner through the near end of the catheter; and the light source device is used for applying illumination to the first active cross-linking agent and the second active cross-linking agent. By means of the drug-loading balloon catheter system, the angiogenesis effect can be improved.

Description

Technical Field

[0001] The present application relates to the technical field of medical devices, and particularly to a drug - loaded balloon catheter system. Background Art

[0002] Angioplasty can open calcified lesions in the arterial wall and is one of the main methods for revascularization of arterial stenosis. However, when the blood vessel is dilated, the blood vessel wall will be damaged, which will trigger the formation of thrombus and the release of growth factors, and then lead to the occurrence or re - closure of restenosis. At present, the above - mentioned problems are mainly solved by implanting stents into the blood vessel. Existing vascular stents are mainly divided into two categories. One category is made of biocompatible metals, but it is easy to trigger thrombus formation and immune response, and this permanently existing stent may interfere with subsequent treatments, such as corrosion and perforation and potential aneurysms. The other category is biodegradable stents. Although the problem of the permanent existence of metal stents is solved, the degradation products will trigger serious inflammatory reactions and at the same time cause atrophy and degradation of the muscle elastic elements of the arterial wall, resulting in arterial dilation.

[0003] In recent years, forming a natural vascular stent in situ in the blood vessel has become a new treatment method. It mainly involves applying a photosensitive compound and light of a specific wavelength at a specified position in the blood vessel. The photosensitive compound can be excited under the specific light, so as to induce the rapid binding of collagen and elastin in the blood vessel wall, form a vascular stent in situ, and achieve the healing and repair of the blood vessel.

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

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

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

[0007] A balloon body, which has a relative inflated state and a contracted state suitable for interventional delivery. The wall of the balloon body has a pore structure, and the outer wall of the balloon body is loaded with a coating containing a first active cross - linker and a water - soluble sustained - release layer wrapping the coating;

[0008] A catheter, which has a relative distal end and proximal end, and the distal end is communicated with the balloon body;

[0009] A perfusion device, which is used to supply a second active cross - linker to the balloon body in a fluid manner through the proximal end of the catheter;

[0010] A light source device for applying light to a first active crosslinking agent and a 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-carboxymethyl cellulose-glycine, tryptophan-carboxymethyl cellulose-tryptophan, phenylalanine, and tyrosine-modified polyethyleneimine;

[0012] The second active crosslinking agent is at least one of naphthalimide derivatives, rose bengal, and 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, and polyvinyl alcohol.

[0014] The following also provides several optional ways, but it is not an additional limitation to the above overall solution, but only further supplementation or preference. Without technical or logical contradictions, each optional way can be combined with the above overall solution alone, or multiple optional ways can be combined with each other.

[0015] Optionally, relative to the unit balloon surface area, the coating amount of the first active crosslinking agent in the coating is 1-5 μg / mm 2 .

[0016] Optionally, the thickness of the coating 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, and 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, and polysorbate sugar alcohol.

[0021] Optionally, the first active crosslinking agent is glycine-carboxymethyl cellulose-glycine, tryptophan-carboxymethyl cellulose-tryptophan, polyethylenimine modified with phenylalanine and tyrosine, 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 crosslinking agent in the fluid is 0.1-30 mg / mL.

[0023] Optionally, the fluid further includes a drug reagent, and the drug reagent is a cell growth inhibitory drug and / or an anti-proliferative drug;

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

[0025] Optionally, the light source device includes a light source and a light guiding element. The light guiding element has a light source input end and a light emitting end, wherein the light source input end is connected to the light source, and the light emitting end is located on the outer periphery or inside the balloon body.

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

[0027] Compared with the prior art, the drug-loaded balloon catheter provided by the present application loads the first active crosslinking agent in a fluid manner and loads the second active crosslinking agent in a coating manner, and a water-soluble sustained-release layer is provided on the outer surface of the coating, which can delay the release of the second active crosslinking agent. On the one hand, it can reduce the drug loss during the delivery process. On the other hand, it can regulate the release process of the two active crosslinking agents, so that the blood vessel can fully absorb the two active crosslinking agents, and then a dense fiber can be formed under the action of light of a specific wavelength band, that is, a natural blood vessel stent, which is beneficial to improving the effect of angioplasty. Description of the Drawings

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

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

[0030] Figure 3 is an EVG staining diagram of the tissue in Application Example 1 of the present application;

[0031] Figure 4 is an EVG staining diagram of the tissue in Application Example 2 of the present application;

[0032] Figure 5 is an EVG staining diagram of the tissue in Application Example 3 of the present application;

[0033] Figure 6 This is the EVG staining diagram of the tissue in Application Example 4 of the present application;

[0034] Figure 7 This is the EVG staining diagram of the tissue in Comparative Example 1 of the present application.

[0035] The descriptions of the reference numerals in the figure are as follows:

[0036] 10. Balloon body; 11. Pore structure; 12. Coating; 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 guiding element

[0040] 50. Vessel wall;

[0041] 60. Fluid. Detailed implementation manners

[0042] Next, the technical solutions in the embodiments of the present application will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present application.

[0043] It should be noted that when a component is referred to as being "connected" to another component, it can be directly connected to the other component or there may also be an intermediate component. When a component is considered to be "disposed on" another component, it can be directly disposed on the other component or there may be an intermediate component at the same time.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0045] Reference Figure 1 、 2, an embodiment of the present application provides a balloon catheter 20 system, including a balloon body 10, a catheter 20, an infusion device 30, and a light source device 40; wherein the balloon body 10 has a relative inflated state and a contracted state suitable for interventional delivery. A coating 12 containing a first active crosslinking agent and a water-soluble sustained-release layer 13 wrapping the coating 12 are loaded on the outer wall of the balloon body 10, and the balloon wall of the balloon body 10 has a pore structure 11; the catheter 20 has opposite proximal 21 and distal 22 ends, wherein the distal 22 is in communication with the balloon body 10; the infusion device 30 is used to supply a second active crosslinking agent into the balloon body 10 in the form of a fluid 60 through the proximal end of the catheter 20; the light source device 40 is used to apply light to the first active crosslinking agent and the second active crosslinking agent.

[0046] 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. Among them, lysine-PEG-lysine and tyrosine-PEG-tyrosine refer to PEG modified with corresponding amino acids at both ends; glycine-carboxymethylcellulose-glycine and tryptophan-carboxymethylcellulose-tryptophan refer to carboxymethylcellulose modified with corresponding amino acids at both ends. The second active crosslinking agent is at least one of naphthalimide derivatives, rose bengal, and riboflavin phosphate.

[0047] Among them, the first active crosslinking agent is equivalent to building a "bridge" between non-adjacent proteins. Under the photoexcitation conditions of the first photoactivator, the amino group or polypeptide contained in the second active crosslinking agent is used to crosslink with the collagen in the blood vessel wall 50. Whether the second photoactivator participates in the crosslinking reaction itself or not, through photoactivation, it can only promote the crosslinking of adjacent collagen / elastin. After adding the first active crosslinking agent, the chain length can enable proteins farther apart to form covalent bond crosslinks, increasing the crosslinking of collagen in the blood vessel wall 50, forming a natural blood vessel scaffold, and at the same time making the fibers of the blood vessel wall 50 denser, greatly improving the effect of angioplasty.

[0048] The experimental results prove that generally, applying the second active crosslinking agent to the blood vessel first and then applying the first active crosslinking agent can form better fibers. The reason may be that the second active crosslinking agent promotes the crosslinking between adjacent proteins, and the first active crosslinking agent promotes the crosslinking between non-adjacent proteins. If the first active crosslinking agent is applied first, the non-adjacent proteins crosslink first, resulting in most adjacent proteins being unable to crosslink with each other, thus affecting the crosslinking effect.

[0049] Considering the physical and chemical properties of the drug itself, the first active cross-linking agent is selected to be loaded in the form of the coating 12, and the second active cross-linking agent is loaded in the form of the fluid 60. To regulate the release of the two active cross-linking agents, a water-soluble sustained-release layer 13 is provided 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. On the other hand, it can delay the release of the first active cross-linking agent, and the delay time of the release depends on the material and thickness of the water-soluble sustained-release layer 13. The water-soluble sustained-release layer 13 includes a sustained-release material, and the sustained-release material 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 one embodiment, the thickness of the water-soluble sustained-release layer 13 is 5 to 50 μm, such as 20 to 40 μm, or 20 to 30 μm. The greater the thickness, the longer the release delay of the first active cross-linking agent. Therefore, in vascular treatment, the second active cross-linking agent is first applied to the blood vessel by the fluid 60 for a period of time. During this period, the first active cross-linking agent is basically not released or partially released due to the wrapping of the water-soluble sustained-release layer 13. After this period, the first active cross-linking agent is completely exposed and released in large quantities. When releasing the first active cross-linking agent, 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 ends. Or after the second active cross-linking agent is delivered, the balloon body 10 is inflated with physiological saline to keep the pressure of the balloon body to ensure 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 photoactive cross-linking can be regulated.

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

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

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

[0054] The fluid 60 may further include pharmaceutical reagents, such as cell growth inhibitory drugs and / or anti-proliferative drugs. The cell growth inhibitory drugs include at least one of rapamycin, sirolimus, everolimus, zotarolimus, 42-(dimethylphosphinyl)rapamycin (deforolimus), deforolimus, biolimus, umirolimus, and tacrolimus. The anti-proliferative drugs include at least one of paclitaxel, protaxel, and docetaxel. The concentration of the pharmaceutical reagent in the fluid 60 is 1 to 10 mg / mL, such as 2 to 8 mg / mL, or 2 to 5 mg / mL. The solvent used for the pharmaceutical reagent is a mixture of water and polyethylene glycol, where the polyethylene glycol is, for example, polyethylene glycol with a molecular weight of 8000, i.e., polyethylene glycol 8000.

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

[0056] To ensure the wrapping effect of the coating 12, in one embodiment, the first active cross-linking 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. For example, the sustained-release material is polyethylene glycol 8000:polyethylene glycol 10000 with a mass ratio of 1.25:1, or polyethylene glycol 8000:polyethylene glycol 20000 with a mass ratio of 2:1.

[0057] In another embodiment, the first active cross-linking agent is glycine-carboxymethyl cellulose-glycine, tryptophan-carboxymethyl cellulose-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 is povidone K90 at 35 mg / mL, or povidone K90:povidone K20 with a mass ratio of 1:4.

[0058] The light source device 40 includes a light source 41 and a light guiding element 42. The catheter 20 element has an input end of the light source 41 and a light emitting end, where the input end of the light source 41 is connected to the light source 41, and 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 cooperates with the application of the first active cross-linking agent and the second active cross-linking agent to irradiate the blood vessel to promote tissue protein cross-linking.

[0059] Regarding the preparation of the drug-loaded balloon 10, the coating of the first active crosslinking agent and the water-soluble sustained-release layer 13 can be formed on the surface of the balloon coating 12 by means of spraying, infiltration or spin coating 12 process. The first active crosslinking agent and the water-soluble sustained-release layer 13 are respectively prepared into coating 12 solutions in advance by using solvents. The solvent can include organic solvents and water. The organic solvents are at least one of isopropanol, ethanol, acetonitrile, methanol, ethyl acetate, and acetone. The volume ratio of water to the organic solvent is (0.05-0.5):1.

[0060] There are various structural types of the catheter 20. In one embodiment, the catheter 20 includes an inner tube and an outer tube sleeved with each other. The balloon 10 is fixed to the distal end of the outer tube and communicates with the inside of the outer tube. The radial gap between the inner tube and the outer tube provides a fluid 60 passage, and the catheter 20 components 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 crosslinking agent in the form of fluid 60 and loads the second active crosslinking agent in the form of coating 12, and a water-soluble sustained-release layer 13 is provided on the outer surface of the coating 12, which can delay the release of the second active crosslinking agent. On the one hand, it can reduce the drug loss during the delivery process. On the other hand, it can regulate the release process of the two active crosslinking agents, so that the blood vessels can fully absorb the two active crosslinking agents, and then dense fibers can be formed under the action of light of a specific wavelength band, that is, a natural vascular stent, which is beneficial to improving the effect of angioplasty.

[0062] Preparation Example 1

[0063] Drug-loaded balloon:

[0064] (1) First active crosslinking agent: Dissolve lysine-PEG-lysine in a solution, and the concentration of lysine-PEG-lysine is 20 mg / mL. Ultrasonically oscillate until the drug solution is completely dissolved, and evenly cover the surface of the balloon with the drug solution by spraying method, and the coating amount is 2 μg / mm 2 , and the coating thickness is 8 μm after drying.

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

[0066] Fluid: Dissolve polyethylene glycol 8000 in a solvent, and the solvent is selected as water:ethanol = 1:1 (volume ratio). Prepare a solution with a concentration of 5 mg / mL, dissolve riboflavin phosphate:rapamycin = 1:1 (mass ratio) in the solution, and prepare a medicated solution with a concentration of 5 mg / mL. Ultrasonic for 3 - 5 min to completely dissolve each drug.

[0067] Preparation Example 2

[0068] Drug-loaded balloon:

[0069] (1) First active cross-linking agent: Dissolve polylysine powder in water to prepare a solution with a concentration of 20 mg / mL. Ultrasonic oscillate until the medicated solution is completely dissolved, and evenly cover the surface of the balloon with the medicated solution by spraying method, and the coating amount is 2 μg / mm 2 , and the coating thickness is 12 μm after drying.

[0070] (2) Sustained-release material: Dissolve polyethylene glycol 20000:shellac = 1:1 in water, heat it to complete dissolution at 150 °C on an electric hot plate and wait for the solution to cool. After the surface of the balloon is air-dried, evenly wrap the sustained-release material on the surface of the balloon by spraying method, and the coating amount is 3 μg / mm 2 , and the coating thickness is 25 μm after drying.

[0071] Fluid: Dissolve polyethylene glycol 8000 in a solvent, and the solvent is selected as ethanol. Dissolve riboflavin phosphate:paclitaxel = 1:1 (mass ratio) in the solution, and prepare a medicated solution with a concentration of 5 mg / mL. Ultrasonic for 3 - 5 min to completely dissolve each drug.

[0072] Preparation Example 3

[0073] Drug-loaded balloon:

[0074] (1) First active cross-linking agent: Dissolve glycine-carboxymethyl cellulose-glycine in water to prepare a 20 mg / mL solution. Ultrasonic oscillate until the medicated solution is completely dissolved, and evenly cover the surface of the balloon with the medicated solution by spraying method, and the coating amount is 2 μg / mm 2 , and the coating thickness is 10 μm after drying.

[0075] (2) Sustained-release material: Dissolve polyvinylpyrrolidone K90:polyvinylpyrrolidone K20 = 1:4 in water, heat it to complete dissolution at 150 °C on an electric hot plate and wait for the solution to cool. After the surface of the balloon is air-dried, evenly wrap the sustained-release material on the surface of the balloon by spraying method, and the coating amount is 3 μg / mm 2 , and the coating thickness is 22 μm after drying.

[0076] Fluid: Dissolve polyethylene glycol 8000 in a solvent. The solvent is water:ethanol = 1:1 (volume ratio). Prepare a solution with a concentration of 5 mg / mL. Dissolve rose bengal:rapamycin = 1:1 (mass ratio) in the solution to prepare a medicated solution with a concentration of 5 mg / mL. Ultrasonic for 3 - 5 min to completely dissolve each drug.

[0077] Preparation Example 4

[0078] Drug - loaded balloon:

[0079] (1) First active cross - linker: Dissolve lysine - PEG - lysine in the solution. The concentration of lysine - PEG - lysine is 20 mg / mL. Ultrasonic oscillation until the medicated solution is completely dissolved, and evenly cover the surface of the balloon with the medicated solution by spraying method. The coating amount is 2 μg / mm 2 , and the coating thickness is 9 μm after drying.

[0080] Fluid: Dissolve polyethylene glycol 8000 in a solvent. The solvent is water:ethanol = 1:1 (volume ratio). Prepare a solution with a concentration of 5 mg / mL. Dissolve riboflavin phosphate:rapamycin = 1:1 (mass ratio) in the solution to prepare a medicated solution with a concentration of 5 mg / mL. Ultrasonic for 3 - 5 min to completely dissolve each drug.

[0081] Preparation Example 5

[0082] Drug - loaded balloon:

[0083] (1) First active cross - linker: Dissolve polylysine powder in water to prepare a solution with a concentration of 20 mg / mL. Ultrasonic oscillation until the medicated solution is completely dissolved, and evenly cover the surface of the balloon with the medicated solution by spraying method. The coating amount is 2 μg / mm 2 , and the coating thickness is 11 μm after drying.

[0084] Fluid: Dissolve polyethylene glycol 8000 in a solvent. The solvent is ethanol. Dissolve riboflavin phosphate:paclitaxel = 1:1 (mass ratio) in the solution to prepare a medicated solution with a concentration of 5 mg / mL. Ultrasonic for 3 - 5 min to completely dissolve each drug.

[0085] Preparation Example 6

[0086] Drug - loaded balloon:

[0087] (1) First active cross - linker: Dissolve glycine - carboxymethyl cellulose - glycine in water to prepare a 20 mg / mL solution. Ultrasonic oscillation until the medicated solution is completely dissolved, and evenly cover the surface of the balloon with the medicated solution by spraying method. The coating amount is 2 μg / mm 2 , and the coating thickness is 12 μm after drying.

[0088] Fluid: Dissolve polyethylene glycol 8000 in a solvent. The solvent is water: ethanol = 1:1 (volume ratio). Prepare a solution with a concentration of 5 mg / mL. Dissolve rose bengal: rapamycin = 1:1 (mass ratio) in the solution to prepare a medicated solution with a concentration of 5 mg / mL. Ultrasonic for 3 - 5 min to completely dissolve the drug.

[0089] Preparation Example 7

[0090] Drug-loaded balloon:

[0091] (1) First active cross-linking agent: Dissolve lysine-PEG-lysine in the solution. The concentration of lysine-PEG-lysine is 20 mg / mL. Ultrasonic oscillate until the medicated solution is completely dissolved, and evenly cover the surface of the balloon with the medicated solution by spraying method. The coating amount is 2 μg / mm 2 , and the coating thickness is 9 μm after drying.

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

[0093] Fluid: Dissolve polyethylene glycol 8000 in a solvent. The solvent is water: ethanol = 1:1 (volume ratio). Prepare a solution with a concentration of 5 mg / mL. Dissolve riboflavin phosphate: rapamycin = 1:1 (mass ratio) in the solution to prepare a medicated solution with a concentration of 5 mg / mL. Ultrasonic for 3 - 5 min to completely dissolve each drug.

[0094] Preparation Example 8

[0095] Drug-loaded balloon:

[0096] (1) First active cross-linking agent: Dissolve polylysine powder in water to prepare a solution with a concentration of 20 mg / mL. Ultrasonic oscillate until the medicated solution is completely dissolved, and evenly cover the surface of the balloon with the medicated solution by spraying method. The coating amount is 2 μg / mm 2 , and the coating thickness is 11 μm after drying.

[0097] (2) Sustained-release material: Dissolve polyethylene glycol 20000: shellac = 1:1 in water, and heat it on an electric hot plate at 150 °C until it is completely dissolved and then wait for the solution to cool. After the surface of the balloon is air-dried, evenly wrap the sustained-release material on the surface of the balloon by spraying method. The coating amount is 1 μg / mm 2 , and the coating thickness is 19 μm after drying.

[0098] Fluid: Dissolve polyethylene glycol 8000 in a solvent, and the solvent is selected as ethanol. Dissolve riboflavin phosphate: paclitaxel = 1:1 (mass ratio) in the solution to prepare a medicated solution with a concentration of 5 mg / mL. Ultrasonic for 3 - 5 min to completely dissolve each drug.

[0099] Preparation Example 9

[0100] Drug - loaded balloon:

[0101] (1) First active cross - linker: Dissolve glycine - carboxymethyl cellulose - glycine in water to prepare a 20 mg / mL solution. Ultrasonic oscillate until the medicated solution is completely dissolved, and then use the spraying method to evenly cover the surface of the balloon with the medicated solution, and the coating amount is 2 μg / mm 2 , and the coating thickness is 12 μm after drying.

[0102] (2) Sustained - release material: Dissolve polyvinylpyrrolidone K90: polyvinylpyrrolidone K20 = 1:4 in water, heat it on a hot plate at 150 °C until completely dissolved, and wait for the solution to cool. After the surface of the balloon is air - dried, use the spraying method to evenly wrap the sustained - release material on the surface of the balloon, and the coating amount is 1 μg / mm 2 , and the coating thickness is 20 μm after drying.

[0103] Fluid: Dissolve polyethylene glycol 8000 in a solvent, and the solvent is selected as water: ethanol = 1:1 (volume ratio). Prepare a 5 mg / mL solution, dissolve rose bengal: rapamycin = 1:1 (mass ratio) in the solution to prepare a medicated solution with a concentration of 5 mg / mL. Ultrasonic for 3 - 5 min to completely dissolve each drug.

[0104] Example 1 Sustained - release Test

[0105] Take six bare balloons with a specification of 3.0×15 and record their initial mass m 0 , prepare one balloon by each of the methods described in Preparation Examples 1, 2, and 3 above, and then use the first active cross - linker described in Preparation Examples 1 - 3 above and the drug - loaded balloons of Preparation Examples 4 - 6 (i.e., without covering the sustained - release material) as controls. Record the mass of the balloon + drug coating as m 1 , and record the mass of the balloon + drug coating + sustained - release layer as m 2 . Flush the balloon with normal saline at a flow rate of 220 mm / s for 35 s, put the balloon in an oven at 50 °C and dry it for 2 h, and weigh and record it as m 3 .

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

[0107] Table 1 Sustained - release Test Results

[0108]

[0109] Take six bare balloons with a specification of 3.0×15 and record their initial mass M 0 , prepare balloons by the methods described in Preparation Examples 1, 2, 3, 7, 8, and 9 above. After the first active crosslinking agent drug coating is air-dried, weigh it and record as M 1 , measure its thickness with a laser diameter gauge and record as Thickness 1. Then spray the corresponding sustained-release layer and air-dry it, and weigh it and record as M 2 , measure its thickness with a laser diameter gauge and record as Thickness 2. Flush the balloon with normal saline at a flow rate of 220 mm / s, and use a timer (detecting every 3 s) to record the time required for the balloon mass to decrease to only the mass m of the first active crosslinking agent drug coating 1 . The test results are shown in Table 2 below:

[0110] Table 2 Test Results

[0111]

[0112] Application Example 1

[0113] Use a porcine peripheral artery model to study the effectiveness of the drug balloon. In the porcine peripheral artery model, push the balloon body of Preparation Example 1 into the blood vessel, expand the compressed balloon body by perfusing the second active crosslinking agent fluid, with a pressure of 6 atm. Then, while maintaining the balloon body pressure, the light guide element emits light with a wavelength of 450 nm, and the photocuring time is 1 minute. Until the second active crosslinking agent delivery is completed, use normal saline to maintain the balloon in a filled state. As the sustained-release material dissolves, the first active crosslinking agent is released and then photocured for 2 minutes. After illumination, withdraw the balloon body from the blood vessel. Observe the morphology of elastic fibers and collagen fibers in the tissue sections of each sample after EVG staining under a microscope, see Figure 3 .

[0114] Application Example 2

[0115] Use a porcine peripheral artery model to study the effectiveness of the drug balloon. In the porcine peripheral artery model, push the balloon body of Preparation Example 2 into the blood vessel, expand the compressed balloon body by perfusing the second active crosslinking agent fluid, with a pressure of 6 atm. Then, while maintaining the balloon body pressure, the light guide element emits light with a wavelength of 450 nm, and the photocuring time is 1 minute. Until the second active crosslinking agent delivery is completed, use normal saline to maintain the balloon in a filled state. As the sustained-release material dissolves, the first active crosslinking agent is released and then photocured for 2 minutes. After illumination, withdraw the balloon body from the blood vessel. Observe the morphology of elastic fibers and collagen fibers in the tissue sections of each sample after EVG staining under a microscope, see Figure 4 .

[0116] Application Example 3

[0117] Study the effectiveness of the drug balloon using a porcine peripheral artery model. In the porcine peripheral artery model, the balloon body of Preparation Example 3 was pushed into the blood vessel. The compressed balloon body was expanded and inflated by perfusing the second active cross-linking agent fluid at a pressure of 6 atm. Then, while maintaining the pressure of the balloon body, the light guide element emitted light with a wavelength of 450 nm, and the photocuring time was 1 minute until the delivery of the second active cross-linking agent was completed. The balloon was maintained in a filled state with physiological saline. As the sustained-release material dissolved, the first active cross-linking agent was released and photocuring was carried out for another 2 minutes. After irradiation, the balloon body was withdrawn from the blood vessel. Observe the morphology of elastic fibers and collagen fibers in each sample tissue section after EVG staining under a microscope. See Figure 5 。

[0118] Application Example 4

[0119] Study the effectiveness of the drug balloon using a porcine peripheral artery model. In the porcine peripheral artery model, the balloon body of Preparation Example 3 was pushed into the blood vessel. The compressed balloon body was expanded and inflated by perfusing the second active cross-linking agent fluid at a pressure of 6 atm. Then, while maintaining the pressure of the balloon body, the light guide element emitted light with a wavelength of 450 nm, and the photocuring time was 30 s. At the same time, the delivery of the second active cross-linking agent was maintained. As the sustained-release material dissolved, the first active cross-linking agent was released and photocuring was carried out for another 150 s. After irradiation, the balloon body was withdrawn from the blood vessel. Observe the morphology of elastic fibers and collagen fibers in each sample tissue section after EVG staining under a microscope. See Figure 6 。

[0120] Comparative Example 1

[0121] Study the effectiveness of the drug balloon using a porcine peripheral artery model. In the porcine peripheral artery model, the balloon body of Preparation Example 4 was pushed into the blood vessel. The compressed balloon body was expanded and inflated by perfusing the second active cross-linking agent fluid at a pressure of 6 atm. Then, while maintaining the pressure of the balloon body, the light guide element emitted light with a wavelength of 450 nm, and the photocuring time was 3 minutes. After irradiation, the balloon body was withdrawn from the blood vessel. Observe the morphology of elastic fibers and collagen fibers in each sample tissue section after EVG staining under a microscope. See Figure 7 。

[0122] See the application results in Figures 3 to 7 , it can be seen 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 sustained-release material, the auxiliary cross-linking agent is released slowly, participates in the protein cross-linking reaction in the blood vessel wall, and more effectively protects against tearing during blood vessel dilation, with less tissue damage.

[0123] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as falling within the scope described in this specification. When the technical features in different embodiments are embodied in the same drawing, the drawing can be regarded as also disclosing the combination examples of the various embodiments involved.

[0124] The above-described embodiments only represent several implementation manners of the present application. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, 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. Drug-loaded balloon catheter system, characterized in that, comprising: a balloon body having a relative inflated state and a contracted state suitable for interventional delivery, the wall of the balloon body having a pore 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; a catheter having a relative distal end and proximal end, wherein the distal end communicates with the balloon body; an infusion device for supplying a second active cross-linking agent to the balloon body in a fluid manner through the proximal end of the catheter; a light source device for applying light to the first active cross-linking agent and the second active cross-linking agent; 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, phenylalanine and tyrosine-modified polyethyleneimine; the second active cross-linking agent is at least one of naphthalimide derivatives, rose bengal, riboflavin phosphate; 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.

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

3. The drug-loaded balloon catheter system according to claim 1, characterized in that, 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.

4. The drug-loaded balloon catheter system according to claim 1, characterized in that, the first active cross-linking 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.

5. The drug-loaded balloon catheter system according to claim 1, characterized in that, the first active cross-linking 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.

6. The drug-loaded balloon catheter system according to claim 1, characterized in that, 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, polyvinyl alcohol.

7. The drug-loaded balloon catheter system according to claim 1, characterized in that, the concentration of the second active cross-linking 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 further comprises a drug reagent, and the drug reagent is a cell growth inhibitory drug and / or an anti-proliferative drug; 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 guiding element, the light guiding element has a light source input end and a light emitting end, wherein the light source input end is connected to the light source, and the light emitting end is located on the outer periphery of the balloon body 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 sleeved with each other, the balloon body is fixed to the distal end of the outer tube and communicates with the inside of the outer tube, a radial gap between the inner tube and the outer tube provides a fluid passage, and the light guiding element is fixed to the inner wall or the outer wall of the inner tube.

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