Drug-loaded microsphere, drug-loaded balloon, preparation method of drug-loaded balloon and controlled-release drug balloon catheter

Abstract

The invention relates to the field of medical catheters, and discloses a drug-loaded microsphere, a drug-loaded balloon, a preparation method of the drug-loaded balloon and a controlled-release drug balloon catheter. The drug-loaded microsphere comprises a temperature-sensitive agent, silk fibroin and a drug, the gram weight ratio of the temperature-sensitive agent to the silk fibroin ranges from 1: 1 to 1: 5; the silk fibroin comprises beta-folded crystals; the content range of beta-folded crystals in the silk fibroin is 20%-60%. The drug release rate of the drug-loaded microspheres and the temperature are in a linear relation, accurate controlled release of the drug can be achieved by controlling the temperature of the drug-loaded microspheres, insufficient drug delivery or excessive drug delivery is avoided, and meanwhile drug loss in the drug delivery process is reduced.

Description

Technical Field

[0001] The present application relates to the technical field of medical catheters, and in particular to a drug-loaded microsphere, a drug-loaded balloon and a preparation method thereof, and a controlled-release drug balloon catheter. Background Art

[0002] The main technical bottleneck that limits the wider application of drug-eluting balloons in the field of coronary artery treatment, peripheral vascular and neurovascular disease treatment is that the drug balloons currently on the market rely on passive diffusion of drugs when the balloon is expanded and briefly contacts the blood vessel wall to achieve the purpose of drug administration. This results in the inability to accurately control the amount of drug entering the lesion and the loss of drugs during the balloon's passage through the bloodstream. Most use liposomes as drug inclusion bodies, which to a certain extent reduces the loss of drugs in the blood, but still relies on physical contact or similar compatibility principles to passively diffuse into tissues, and does not solve the problem of precise controllable, rapid and quantitative release of drugs at the lesion site. Either the drug is overloaded, causing tissue damage while treating the disease; or the drug is insufficiently loaded, affecting the therapeutic efficacy. Therefore, precise controlled release of drugs is a technical problem that needs to be solved urgently. Summary of the invention

[0003] The present application discloses a drug-loaded microsphere and a preparation method thereof, a drug-loaded balloon and a preparation method thereof, and a controlled-release drug balloon catheter, which are used to realize precise controlled release of drugs by utilizing the linear relationship between drug release rate and temperature.

[0004] In order to achieve the above objectives, this application provides the following technical solutions: In a first aspect, an embodiment of the present application provides a drug-loaded microsphere, comprising: a thermosensitive agent, silk fibroin, and a drug; the weight ratio of the thermosensitive agent to the silk fibroin is in the range of 1:1-1:5; The silk fibroin includes β-pleated crystals; the content of β-pleated crystals in the silk fibroin ranges from 20% to 60%.

[0005] The components of the drug-loaded microspheres include a thermosensitive agent, silk fibroin and a drug; wherein the silk fibroin includes β-pleated crystals. The weight ratio of the thermosensitive agent to the silk fibroin and the content of the β-pleated crystals in the silk fibroin both affect the thermosensitive properties of the drug-loaded microspheres. The weight ratio of the thermosensitive agent to the silk fibroin is in the range of 1:1-1:5, and the content of the β-pleated crystals in the silk fibroin is in the range of 20%-60%. The drug release rate of the drug-loaded microspheres is linearly related to the temperature. By controlling the temperature of the drug-loaded microspheres, precise controlled release of the drug can be achieved, avoiding insufficient or excessive administration, and reducing drug loss during administration.

[0006] In some embodiments, the weight ratio of the thermosensitive agent to the silk fibroin is 1:1, and the content of β-pleated crystals in the silk fibroin ranges from 20% to 32%; Alternatively, the weight ratio of the thermosensitive agent to the silk fibroin is 1:2, and the content of β-pleated crystals in the silk fibroin is in the range of 26%-40%; Alternatively, the weight ratio of the thermosensitive agent to the silk fibroin is 1:3, and the content of β-pleated crystals in the silk fibroin is in the range of 31%-46%; Alternatively, the weight ratio of the thermosensitive agent to the silk fibroin is 1:4, and the content of β-pleated crystals in the silk fibroin is in the range of 38%-52%; Alternatively, the weight ratio of the thermosensitive agent to the silk fibroin is 1:5, and the content of β-pleated crystals in the silk fibroin is in the range of 43%-60%.

[0007] In some embodiments, the thermosensitive agent includes one or more of a gelatin-pullulan composite material, poly (N-isopropylacrylamide), a metal organic framework and a thermosensitive hydrogel composite.

[0008] In some embodiments, the drug comprises one or more of paclitaxel, rapamycin, docetaxel, rapamycin CD34 antibody, arginine-glycine-aspartic acid peptide, siRNA targeting TGF-β, and miRNA.

[0009] In some embodiments, the drug-loaded microspheres include a wrapping layer, and the wrapping layer includes the thermosensitive agent and the silk fibroin; The wrapping layer covers the outside of the drug.

[0010] In some embodiments, the drug-loaded microspheres have a particle size range of 1 μm-8 μm and a wall thickness of 10 nm-5000 nm.

[0011] In a second aspect, an embodiment of the present application provides a drug-loaded balloon, comprising: a bare balloon and a drug-loaded coating coated on the outer surface of the bare balloon; the drug-loaded coating comprises the drug-loaded microspheres as described in any one of the first aspects.

[0012] In some embodiments, the bare balloon is a non-compliant balloon or a semi-compliant balloon; And / or, the bare balloon is a rapid exchange balloon or a non-rapid exchange balloon.

[0013] In a third aspect, an embodiment of the present application further provides a controlled-release drug balloon catheter, comprising: a catheter and the drug-loaded balloon as described in the second aspect; The catheter comprises a catheter body and a three-way catheter seat connected to the first end of the catheter body; the catheter body comprises an inner layer, an intermediate layer and an outer layer; an instrument cavity is formed inside the inner layer; a first filling channel is formed between the intermediate layer and the inner layer, and a second filling channel is formed between the outer layer and the intermediate layer; The three-way catheter seat includes a first joint and a second joint, the first joint is communicated with the first filling channel, and the second joint is communicated with the second filling channel; The bare balloon is connected to the outer layer and is located at the second end of the catheter body; the interior of the bare balloon is in communication with the second filling channel; The middle layer is provided with a balloon filling channel, and the balloon filling channel is connected with the first filling channel and the interior of the bare balloon.

[0014] In some embodiments, the controlled-release drug balloon catheter further comprises a precision temperature control device; The precision temperature control device comprises a liquid reservoir, a temperature sensor, a temperature controller and a liquid supplier; The liquid reservoir is in communication with the first connector, and a first control valve is provided between the liquid reservoir and the first connector for controlling the flow rate of liquid delivered from the liquid reservoir to the first connector; The temperature sensor is arranged inside the liquid reservoir and is used to collect the temperature of the liquid inside the liquid reservoir; The liquid supplier is in communication with the liquid reservoir via the temperature controller, and the temperature controller is connected to the temperature sensor signal for regulating the temperature of the liquid inside the liquid reservoir.

[0015] In some embodiments, the temperature controller includes a first flow channel and a second flow channel in parallel and a semiconductor cooling plate located between the first flow channel and the second flow channel, the first flow channel passes through a heating area of ​​the semiconductor cooling plate, and the second flow channel passes through a cooling area of ​​the semiconductor cooling plate; The liquid supplier is in communication with the liquid reservoir through the first flow channel and the second flow channel in parallel; The precision temperature control device further comprises a second control valve, which is arranged between the liquid reservoir and the first flow channel and the second flow channel in parallel; The second control valve is connected to the temperature sensor signal, and is used to adjust the temperature of the liquid inside the liquid reservoir by adjusting the liquid flow rates of the first flow channel and the second flow channel.

[0016] In some embodiments, the precision temperature control device further includes a controller, and the temperature sensor, the first control valve, the semiconductor refrigeration plate, and the second control valve are all connected to the controller signal.

[0017] In a fourth aspect, the present application also provides a method for preparing drug-loaded microspheres, comprising: A nanoemulsion of a thermosensitive agent and silk fibroin is prepared by a polyethylene glycol emulsification method within a preset temperature range; The drug and silk fibroin emulsion is prepared by polyethylene glycol emulsification method within a preset temperature range, and the polyethylene glycol is eluted by centrifugation to obtain nano-gel particles; The prepared nanoemulsion and the nanogel particles are mixed, and then the polyethylene glycol is eluted by centrifugation to obtain drug-loaded particles; The drug-loaded microspheres are obtained by inducing and regulating the content of beta-folded crystals in silk fibroin in a physical manner on the drug-loaded particles.

[0018] In a fifth aspect, the present application also provides a method for preparing a drug-loaded balloon, comprising: A nanoemulsion of a thermosensitive agent and silk fibroin is prepared by a polyethylene glycol emulsification method within a preset temperature range; The drug and silk protein emulsion is prepared by polyethylene glycol emulsification method within a preset temperature range, and the polyethylene glycol is eluted by centrifugation to obtain nano-gel particles; The prepared nanoemulsion and nanogel particles are mixed and then coated on the surface of the bare balloon after the polyethylene glycol is eluted by centrifugation to form a drug-loaded coating on the surface of the bare balloon; The drug-loaded balloon is obtained by inducing and regulating the content of beta-folded crystals in the silk fibroin in the drug-loaded coating in a physical manner. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 A cross-sectional view of the internal structure of a drug-loaded microsphere provided in an embodiment of the present application; Figure 2 The graph is the relationship between different temperatures and the percentage of drug release content of drug-loaded microspheres in the total amount (20S); Figure 3 A schematic diagram of the internal structure of a drug-loaded balloon provided in an embodiment of the present application Figure 1 ; Figure 4 A schematic diagram of the internal structure of a drug-loaded balloon provided in an embodiment of the present application Figure 2 ; Figure 5 A schematic diagram of the structure of a controlled-release drug balloon catheter provided in an embodiment of the present application; Figure 6 A schematic diagram of the structure of a catheter body in a controlled-release drug balloon catheter provided in an embodiment of the present application; Figure 7 A schematic diagram of an axial cross-section of a catheter body in a controlled-release drug balloon catheter provided in an embodiment of the present application; Figure 8 An enlarged view of a precision temperature control device in a controlled-release drug balloon catheter provided in an embodiment of the present application; Fig. 9 A control principle diagram of a controlled drug release balloon catheter provided in an embodiment of the present application; Fig.10 A flow chart of a method for preparing drug-loaded microspheres provided in an embodiment of the present application; Fig.11 A flow chart of a method for preparing a drug-loaded balloon provided in an embodiment of the present application; Fig.12 The drug release concentration curves at different temperatures within 20S; Fig.13 The drug release content curves at different temperatures within 20S; Fig.14 It is a curve diagram showing the relationship between the percentage of drug release content in the total amount within 20 seconds at different temperatures; Fig.15 It is the fitting curve diagram of the percentage of drug release content in the total amount within 20S at different temperatures; Icons: 100-drug-loaded microspheres; 110-drug; 120-wrapping layer; 200-drug-loaded balloon; 210-bare balloon; 220-drug-loaded coating; 310-catheter; 320-precision temperature control device; 330-first control valve; 340-pressure relief valve; 311-catheter body; 312-three-way catheter seat; 321-liquid reservoir; 322-temperature sensor; 323-temperature controller; 324-liquid supply; 325-pressure pump; 326-second control valve; 327-controller; 3111-inner layer ;3112-middle layer;3113-outer layer;3121-first joint;3122-second joint;3211-overflow valve;3231-first flow channel;3232-second flow channel;3233-semiconductor refrigeration plate;3234-insulation layer;3241-first interface;3242-second interface;3243-third interface;3244-fourth interface;3111a-instrument cavity;3112a-first filling channel;3112b-balloon filling channel;3113a-second filling channel. DETAILED DESCRIPTION

[0020] The following will combine the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application. Among them, in the description of the embodiments of the present application, unless otherwise specified, " / " means or, for example, A / B can mean A or B; "and / or" in the text is only a description of the association relationship of associated objects, indicating that there can be three relationships, for example, A and / or B can mean: A exists alone, A and B exist at the same time, and B exists alone. In addition, in the description of the embodiments of the present application, "multiple" refers to two or more than two.

[0021] In the following, the terms "first" and "second" are used for descriptive purposes only and are not to be understood as suggesting or implying relative importance or implicitly indicating the number of the indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features, and in the description of the embodiments of the present application, unless otherwise specified, "plurality" means two or more.

[0022] In a first aspect, the present application provides a drug-loaded microsphere, comprising: a thermosensitive agent, silk fibroin, and a drug; the weight ratio of the thermosensitive agent to the silk fibroin is in the range of 1:1-1:5; Silk fibroin includes β-pleated crystals; the content of β-pleated crystals in silk fibroin ranges from 20% to 60%.

[0023] The components of the drug-loaded microspheres include a thermosensitive agent, silk fibroin and a drug; wherein the silk fibroin includes β-pleated crystals. The weight ratio of the thermosensitive agent to the silk fibroin and the content of the β-pleated crystals in the silk fibroin affect the thermosensitive properties of the drug-loaded microspheres. When the weight ratio K of the thermosensitive agent to the silk fibroin is in the range of 1:1-1:5, and the content of the β-pleated crystals in the silk fibroin is in the range of 20%-60%, the drug release rate of the drug-loaded microspheres is linearly related to the temperature. By controlling the temperature of the drug-loaded microspheres, precise controlled release of the drug can be achieved, avoiding insufficient or excessive administration, and reducing drug loss during administration.

[0024] In some embodiments, the weight ratio K of the thermosensitive agent to the silk fibroin is 1:1, and the content of β-pleated crystals in the silk fibroin ranges from 20% to 32%. For example, the content of β-pleated crystals in the silk fibroin is 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, etc.

[0025] In some embodiments, the weight ratio K of the thermosensitive agent to the silk fibroin is 1:2, and the content of β-pleated crystals in the silk fibroin ranges from 26% to 40%. For example, the content of β-pleated crystals in the silk fibroin is 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, etc.

[0026] In some embodiments, the weight ratio K of the thermosensitive agent to the silk fibroin is 1:3, and the content of β-pleated crystals in the silk fibroin ranges from 31% to 46%. For example, the content of β-pleated crystals in the silk fibroin is 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, etc.

[0027] In some embodiments, the weight ratio K of the thermosensitive agent to the silk fibroin is 1:4, and the content of β-pleated crystals in the silk fibroin ranges from 38% to 52%. For example, the content of β-pleated crystals in the silk fibroin is 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, etc.

[0028] In some embodiments, the weight ratio K of the thermosensitive agent to the silk fibroin is 1:5, and the content of β-pleated crystals in the silk fibroin ranges from 43% to 60%. For example, the content of β-pleated crystals in the silk fibroin is 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, etc.

[0029] In some embodiments, the thermosensitive agent includes one or more of a gelatin-pullulan composite material, poly(N-isopropylacrylamide) (PNIPAM for short), a metal organic framework and a thermosensitive hydrogel composite.

[0030] In the gelatin-pullulan composite material, gelatin is more sensitive to temperature, while pullulan is relatively stable. The combination of the two can balance the temperature sensitivity to a certain extent and improve the stability of the material.

[0031] The most notable property of poly(N-isopropylacrylamide) is its sensitivity to temperature, with a lower critical solution temperature (LCST), which is usually around 32°C. Below the LCST, PNIPAM dissolves in water; above the LCST, it precipitates out of water to form a gel or precipitate.

[0032] Metal-Organic Frameworks (MOFs) are porous crystalline materials formed by self-assembly of metal ions or metal clusters and organic ligands through coordination bonds. Thermosensitive hydrogels are hydrogel materials that undergo phase changes within a specific temperature range, and poly(N-isopropylacrylamide) (PNIPAM) is a common one. This type of hydrogel absorbs water and expands at low temperatures, and loses water and shrinks at high temperatures. The composite material formed by combining metal-organic frameworks (MOFs) with thermosensitive hydrogels combines the advantages of both, showing unique physicochemical properties and multifunctionality. Due to the thermosensitive properties of hydrogels, the composite material can exhibit different structural and functional states at different temperatures. For example, at low temperatures, the hydrogel expands and the effective surface area of ​​MOFs increases; at high temperatures, the hydrogel shrinks, resulting in the partial closure or exposure of the MOFs pores, thereby changing the adsorption and release behaviors. The metal-organic framework and thermosensitive hydrogel composite is used as a controlled release carrier in drug delivery systems to regulate the release rate of drugs by controlling the temperature. For example, at normal body temperature (37°C), the hydrogel is in a contracted state, limiting drug release; when the local temperature rises, the hydrogel expands, accelerating drug release.

[0033] In some embodiments, the drug comprises one or more of paclitaxel, rapamycin, docetaxel, rapamycin CD34 antibody, arginine-glycine-aspartic acid peptide, siRNA targeting TGF-β, miRNA.

[0034] Among them, RGD peptide (Arg-Gly-Asp peptide) is a small peptide containing three amino acids: arginine (Arg), glycine (Gly) and aspartic acid (Asp), and its sequence is arginine-glycine-aspartic acid. siRNA (small interfering RNA) targeting TGF-β is a method that uses RNA interference (RNAi) technology to specifically inhibit the expression of transforming growth factor-β (TGF-β). miRNA (microRNA) is a small RNA molecule with a length of about 20-25 nucleotides. It regulates gene expression by complementary pairing with target mRNA, resulting in mRNA degradation or translation inhibition.

[0035] In some embodiments, Figure 1 As shown, the drug-loaded microsphere 100 includes a wrapping layer 120 , and the wrapping layer 120 includes a thermosensitive agent and silk fibroin; the wrapping layer 120 is coated on the outside of the drug 110 .

[0036] In one embodiment, the drug-loaded microspheres are nanofiber hydrogels whose drug release rate in a specific temperature range is linearly responsive to temperature, and the drugs are encapsulated inside the gel.

[0037] In some embodiments, the drug-loaded microspheres have a particle size range of 1 μm-8 μm and a wall thickness of 10 nm-5000 nm.

[0038] The material of the drug-loaded microspheres is a polymer material with good biocompatibility or a completely degradable polymer material, which will not remain in the body or cause harm. The particle size of the drug-loaded microspheres is 1μm, 2μm, 3μm, 4μm, 5μm, 6μm, 7μm, 8μm, etc. The particle size of the drug-loaded microspheres is less than 8μm, and blood vessel blockage is not likely to occur.

[0039] The wall thickness of the drug-loaded microspheres is 10nm, 50nm, 100nm, 500nm, 1000nm, 5000nm, etc. The drug-loaded microspheres with thinner walls are relatively sensitive to temperature. When subjected to different temperatures, they are easy to fall off the balloon surface and break, and can be used for immediate drug release. The drug-loaded microspheres with thicker walls are not easy to break when subjected to the same temperature, and can be used for slow release of drugs at the lesion site.

[0040] In some embodiments, the temperature response interval of the drug-loaded microspheres is 5-45° C. Within the range of 5-45° C., the drug release rate of the drug-loaded microspheres is linearly related to the temperature. By providing the temperature environment required by the drug-loaded microspheres, the purpose of precise drug release is achieved.

[0041] Taking paclitaxel as an example, the relationship curve of the mass release ratio of drug-loaded microspheres within 20 seconds (S) at different temperatures within the temperature range of 5-45°C is as follows: Figure 2 As shown, it can be clearly seen that in the range of 5-25°C, the linear relationship between the mass release ratio of the drug microspheres and the temperature is very good.

[0042] In a second aspect, the present application embodiment provides a drug-loaded balloon 200, such as Figure 3 and Figure 4 As shown, it includes: a bare balloon 210 and a drug-loaded coating 220 coated on the outer surface of the bare balloon 210; the drug-loaded coating 220 includes the drug-loaded microspheres as described in any one of the first aspects.

[0043] In some embodiments, the bare balloon 210 is a non-compliant balloon or a semi-compliant balloon; And / or, the bare balloon 210 is a rapid exchange balloon or a non-rapid exchange balloon.

[0044] In one embodiment, the bare balloon 210 may be made of a polymer material or a mixed material such as thermoplastic polyurethane (TPU), nylon, etc. At 5-45°C, the size change of the bare balloon material is less than 5%, the elastic modulus change is less than 5%, and the hardness decreases by about 5A as the temperature increases. The change will not affect the performance of the bare balloon itself, but can affect the surface connection between the drug-loaded microspheres and the bare balloon, and promote the separation of the two.

[0045] Thirdly, Figure 5 As shown, the embodiment of the present application further provides a controlled-release drug balloon catheter, comprising: a catheter 310 and a drug-loaded balloon 200; the drug-loaded balloon 200 is the drug-loaded balloon 200 in the embodiment of the second aspect; or, the drug-loaded balloon 200 comprises a bare balloon 210 and a drug-loaded coating 220 coated on the outer surface of the bare balloon 210, and the drug-loaded coating 220 is the drug-loaded microsphere in any embodiment of the first aspect; like Figure 6 and Figure 7 As shown, the catheter 310 includes a catheter body 311 and a three-way catheter seat connected to the first end of the catheter body 311; the catheter body 311 includes an inner layer 3111, an intermediate layer 3112 and an outer layer 3113; an instrument cavity 3111a is formed inside the inner layer 3111; a first filling channel 3112a is formed between the intermediate layer 3112 and the inner layer 3111, and a second filling channel 3113a is formed between the outer layer 3113 and the intermediate layer 3112; The three-way catheter seat 312 includes a first joint 3121 and a second joint 3122, the first joint 3121 is connected to the first filling channel 3112a, and the second joint 3122 is connected to the second filling channel 3113a; The bare balloon 210 is connected to the outer layer 3113 and is located at the second end of the catheter body 311; the interior of the bare balloon 210 is connected to the second filling channel 3113a; The middle layer 3112 is provided with a balloon filling channel 3112 b , and the balloon filling channel 3112 b is connected to the first filling channel 3112 a and the interior of the bare balloon 210 .

[0046] In one embodiment, the controlled drug release balloon catheter includes a catheter 310 and a drug-loaded balloon 200, the drug-loaded balloon 200 includes a bare balloon 210 and a drug-loaded coating 220 coated on the outer surface of the bare balloon 210, and the drug-loaded coating 220 includes the drug-loaded microspheres in the first embodiment.

[0047] In another embodiment, the controlled drug release balloon catheter includes a catheter 310 and a drug-loaded coating 220. The catheter 310 includes a catheter body 311, a three-way catheter seat 312, and a bare balloon 210 welded to one end of the catheter body 311 away from the three-way catheter seat 312. The outer surface of the bare balloon 210 is coated with a drug-loaded coating 220, and the drug-loaded coating 220 includes the drug-loaded microspheres in the first aspect of the embodiment.

[0048] In one embodiment, Figure 6 and Figure 7 As shown, the catheter 310 is composed of an inner layer 3111, an intermediate layer 3112, an outer layer 3113, a balloon, and a three-way catheter seat 312. The inner layer 3111 isolates the instrument channel. There is a first filling channel 3112a between the intermediate layer 3112 and the inner layer 3111. There are two groups of symmetrical small holes with a diameter of 1 mm at the overlap between the intermediate layer 3112 and the balloon, which serve as channels for filling the balloon. The outer layer 3113 is directly welded to the balloon, and there is a second filling channel 3113a (pressure relief channel) between the outer layer 3113 and the intermediate layer 3112. The head end of the inner layer 3111 is connected to the head end of the intermediate layer 3112, the head end of the balloon is connected to the head end of the intermediate layer 3112, and the tail end of the balloon is connected to the head end of the outer layer 3113. There are three channels inside the three-way catheter seat 312, namely, the intermediate channel, the first channel connected to the first joint 3121, and the second channel connected to the second joint 3122. The inner layer 3111 is bonded to the side wall of the middle channel of the three-way catheter seat 312, the middle layer 3112 is bonded to the side wall of the first channel of the three-way catheter seat 312, and the outer layer 3113 is bonded to the side wall of the second channel of the three-way catheter seat 312, thereby forming an effective reflux.

[0049] In some embodiments, Figure 8 As shown, the controlled-release drug balloon catheter also includes a precision temperature control device 320; the precision temperature control device 320 includes a liquid reservoir 321, a temperature sensor 322, a temperature controller 323 and a liquid supply device 324; the liquid reservoir 321 is connected to the first joint 3121, and a first control valve 330 is provided between the liquid reservoir 321 and the first joint 3121, which is used to control the flow rate of liquid delivered from the liquid reservoir 321 to the first joint 3121; the temperature sensor 322 is arranged inside the liquid reservoir 321, and is used to collect the temperature of the liquid inside the liquid reservoir 321; the liquid supply device 324 is connected to the liquid reservoir 321 through the temperature controller 323, and the temperature controller 323 is connected to the temperature sensor 322 signal, which is used to adjust the temperature of the liquid inside the liquid reservoir 321.

[0050] In one embodiment, the controlled-release drug balloon catheter includes a catheter 310 and a precision temperature control device 320; the precision temperature control device 320 is connected to a first connector 3121 in the catheter 310, and is used to provide a liquid of a preset temperature to the catheter 310. In one embodiment, the liquid provided by the precision temperature control device 320 is physiological saline, and in another embodiment, the liquid provided by the precision temperature control device 320 is a developer.

[0051] The precision temperature control device 320 includes a liquid reservoir 321, a temperature sensor 322, a temperature controller 323 and a liquid supply 324. The liquid supply 324 is connected to the temperature controller 323, and is used to collect liquid and also to provide liquid to the temperature controller 323. The liquid enters the liquid reservoir 321 after being temperature-controlled by the temperature controller 323. The liquid reservoir 321 serves as a buffer structure for the liquid, and a temperature sensor 322 is arranged inside the liquid reservoir 321. The temperature sensor 322 is used to collect the temperature of the liquid inside the liquid reservoir 321. A first control valve 330 is arranged on the pipeline between the liquid reservoir 321 and the first joint 3121. When the temperature sensor 322 detects that the temperature of the liquid inside the liquid reservoir 321 reaches the preset temperature, the first control valve 330 opens, and the liquid inside the liquid reservoir 321 is input into the first filling channel 3112a through the first connector 3121, so as to achieve the purpose of controlling the temperature in the first filling channel 3112a, thereby precisely controlling the drug release of the drug coating 220 on the drug-loaded balloon 200.

[0052] In one embodiment, Figure 8 As shown, a pressure pump 325 is also provided between the liquid supplier 324 and the temperature controller 323 .

[0053] In one embodiment, the second connector 3122 in the catheter 310 is connected to a pressure relief valve 340 for ensuring a pressure difference between the first filling channel 3112a and the second filling channel 3113a so as to expand the drug-loaded balloon 200 to a desired size.

[0054] In one embodiment, Figure 8 As shown, the liquid reservoir 321 is provided with an overflow valve 3211 to ensure that the internal pressure of the liquid reservoir 321 is constant.

[0055] In some embodiments, the temperature controller 323 includes a first flow channel 3231 and a second flow channel 3232 in parallel and a semiconductor cooling plate 3233 located between the first flow channel 3231 and the second flow channel 3232. The first flow channel 3231 passes through the heating area of ​​the semiconductor cooling plate 3233, and the second flow channel 3232 passes through the cooling area of ​​the semiconductor cooling plate 3233. The liquid supply device 324 is connected to the liquid storage device 321 through a first flow channel 3231 and a second flow channel 3232 in parallel; The precision temperature control device 320 further includes a second control valve 326 , which is disposed between the liquid reservoir 321 and the parallel first and second flow channels 3231 and 3232 ; The second control valve 326 is connected to the temperature sensor 322 for controlling the temperature of the liquid inside the liquid reservoir 321 by adjusting the liquid flow rates of the first flow channel 3231 and the second flow channel 3232 .

[0056] In one embodiment, Figure 8 As shown, the thermostat 323 includes a liquid inlet and two liquid outlets, the liquid inlet of the thermostat 323 is connected to the liquid supply 324, and the two liquid outlets are connected to the second control valve 326. In one embodiment, the first control valve 326 includes two two-position three-way valves, each of which has three interfaces. In the first two-position three-way valve, the first interface is connected to a liquid outlet of the thermostat 323, the second interface is connected to the liquid inlet of the reservoir 321, and the third interface is connected to the liquid supply 324. In the second two-position three-way valve, the first interface is connected to another liquid outlet of the thermostat 323, the second interface is connected to the liquid inlet of the reservoir 321, and the third interface is connected to the liquid supply 324. Exemplarily, the two-position three-way valve is an electromagnetic proportional valve.

[0057] Semiconductor refrigerator, also known as thermoelectric cooler (TEC), is a semiconductor device based on the Peltier effect, which realizes heating or cooling function by changing the direction of electric current.

[0058] A first flow channel 3231 is formed between the liquid inlet and one liquid outlet of the thermostat 323, and a second flow channel 3232 is formed between the liquid inlet and the other liquid outlet of the thermostat 323. A semiconductor cooling plate 3233 is arranged inside the thermostat 323, and the semiconductor cooling plate 3233 has a heating area and a cooling area. The first flow channel 3231 passes through the heating area, and the second flow channel 3232 passes through the cooling area. The liquid passing through the first flow channel 3231 is heated by the heating area and then heated up, and the liquid passing through the second flow channel 3232 is cooled by the cooling area and then cooled down. The first control valve 326 achieves the purpose of controlling the temperature of the liquid inside the liquid reservoir 321 by controlling the liquid flow rate of the first flow channel 3231 entering the liquid reservoir 321 and the liquid flow rate of the second flow channel 3232 entering the liquid reservoir 321.

[0059] In one embodiment, Figure 8 As shown, and refer to Figure 5The liquid supply device 324 has a first interface 3241, a second interface 3242, a third interface 3243 and a fourth interface 3244. The first interface 3241 is connected to the third interface of the first two-position three-way valve; the second interface 3242 is connected to the third interface of the second two-position three-way valve; the third interface 3243 is connected to the overflow valve 3211; and the fourth interface 3244 is connected to the pressure relief valve 340.

[0060] In one embodiment, the thermostat 323 further includes an outer insulation layer 3234 to prevent heat loss and achieve energy saving.

[0061] In some embodiments, Fig. 9 As shown, the precision temperature control device 320 also includes a controller 327 , and the temperature sensor 322 , the first control valve 330 , the semiconductor cooling plate 3233 , and the second control valve 326 are all connected to the controller 327 via signals.

[0062] In one embodiment, the controller 327 is a programmable logic controller (PLC). The controller 327 is connected to the semiconductor cooling plate 3233 by signal to adjust the heat generation of the semiconductor cooling plate 3233. The controller 327 is connected to the second control valve 326 by signal to adjust the flow rate of the liquid flowing into the liquid reservoir 321 from the first flow channel 3231 and the second flow channel 3232, thereby adjusting the liquid temperature inside the liquid reservoir 321. The internal temperature information of the liquid reservoir 321 collected by the temperature sensor 322 is sent to the controller 327, so that the controller 327 can adjust the working state of the second control valve 326 and the first control valve 330 according to the feedback information of the temperature sensor 322. When the temperature sensor 322 feedbacks that the temperature of the liquid inside the liquid reservoir 321 reaches the preset temperature, the controller 327 controls the first control valve 330 to open.

[0063] It should be noted that the precision temperature control device 320 is not inside the human body, there are no components in the catheter 310, the size of the catheter 310 is controllable, the catheter is more miniaturized, and can be adapted to more vascular locations such as neurovascular use, and has wide adaptability to human blood vessels.

[0064] The controlled-release drug balloon catheter provided in the embodiments of the present application can be used for local delivery of various therapeutic agents, and can reach any location in the human body, such as coronary arteries, nerve vessels, and peripheral blood vessels, using a guidewire or a guide catheter. The controlled-release drug balloon catheter has the characteristics of large drug loading capacity, high drug loading efficiency, high drug absorption utilization rate, and precise and controllable drug release. More importantly, the controlled-release drug balloon catheter is equipped with a precision temperature control device, which provides temperature energy from the balloon filling injection hole. The path through which energy is transferred is fixed (determined by the balloon model), and the medium for energy transfer is controllable (such as saline or developer). The entire temperature control process is dynamic, which provides the possibility for a more precise controlled release process.

[0065] In one embodiment, the catheter 310 in the controlled-release drug balloon catheter is inserted into the target position of the human body, the precision temperature control device 320 is left outside the human body, and the liquid in the liquid supply device 324 is sent to the temperature controller 323 through the pressure pump 325. The temperature controller 323 has two flow channels, namely the first flow channel 3231 and the second flow channel 3232, which pass through the heating area and the cooling area of ​​the semiconductor refrigeration plate 3233 respectively. When the flow rate of the two flow channels is stable, a constant temperature difference can be provided on both sides. The outlets of the two flow channels are respectively provided with a two-position three-way electromagnetic proportional valve. The liquid inlet of the electromagnetic proportional valve is connected to the liquid outlet of the temperature controller 323, and one of the liquid outlets of the electromagnetic valve is connected to the liquid reservoir 321 and the other is connected to the liquid supply device 324. The flow rate of the two liquid outlets can be adjusted by the controller 327, such as a PLC controller, to keep the flow rate through the temperature controller 323 constant. The liquids of the two flow channels enter the liquid reservoir 321 through the electromagnetic proportional valve. The liquid reservoir 321 has three interfaces, the first interface is connected to the second control valve 326, the second interface is connected to the first control valve 330 such as a stop valve, and the third interface is connected to the overflow valve 3211, and the overflow valve 3211 is connected to the third interface 3243 of the liquid supply device 324. The overflow valve 3211 can set the required pressure to effectively control the constant pressure of the entire liquid reservoir 321. The liquid reservoir 321 has a temperature probe, that is, a temperature sensor 322. The temperature sensor 322 detects the temperature of the liquid in the liquid reservoir 321 and can be fed back to the controller 327. The controller 327 can control the constant temperature of the liquid in the liquid reservoir 321 by adjusting the switches of the two electromagnetic proportional valves. When the temperature of the liquid reservoir 321 reaches the target temperature, the check valve and the pressure relief valve 340 are opened while the overflow valve 3211 is closed, and the liquid enters the catheter 310 through the filling injection hole, and the liquid passes through the first filling channel 3112a-drug-loaded balloon 200-second filling channel 3113a-filling injection hole. During the whole process, the inside of the catheter 310 is a complete loop and the liquid keeps flowing. One end of the filling injection hole is connected to the second filling channel 3113a, and the other end is connected to the pressure relief valve 340. The pressure relief valve 340 is connected to the liquid supplier 324 through the fourth interface 3244. The overflow valve 3211 and the pressure relief valve 340 can set the same required pressure, effectively control the pressure of the filling injection hole, and then accurately control the surface temperature of the drug-loaded balloon 200 through the flowing liquid, wherein the filling size of the drug-loaded balloon 200 is achieved by controlling the pressure difference of the two filling injection holes by the overflow valve 3211 and the pressure relief valve 340. The drug-loaded coating 220 on the surface of the drug-loaded balloon 200 changes from solid (or gel state) to liquid state at different temperatures, or the porous structure on the surface of the thermosensitive agent changes (the pore size becomes larger / smaller), thereby controlling the drug-loaded coating 220 to fall off from the naked balloon 210 and the drug release rate. At the same time, the change in temperature will cause the molecular diffusion rate on the surface of the drug-loaded microspheres to change, thereby achieving the purpose of controlling the drug release rate at the target position.

[0066] In a fourth aspect, the present application also provides a method for preparing drug-loaded microspheres, such as Fig.10 As shown, the specific steps include: S1001, preparing a nanoemulsion of a thermosensitive agent and silk fibroin by a polyethylene glycol emulsification method within a preset temperature range; S1002, preparing a drug and silk fibroin emulsion by a polyethylene glycol emulsification method within a preset temperature range, and eluting the polyethylene glycol by centrifugation to obtain nano-gel particles; S1003, mixing the prepared nanoemulsion and nanogel particles, and then eluting the polyethylene glycol by centrifugation to obtain drug-loaded particles; S1004. The drug-loaded particles are physically induced and regulated to obtain the β-folded crystal content in the silk fibroin to obtain drug-loaded microspheres.

[0067] In one embodiment, the preset temperature range in S1001 and S1002 is 15-25° C. The thermosensitive agent is poly(N-isopropylacrylamide (PNIPAM)). The drug is paclitaxel. The physical induction method in S1004 is water vapor, ethanol fumigation, etc.

[0068] In a fifth aspect, the present application also provides a method for preparing a drug-loaded balloon, such as Fig.11 As shown, the specific steps include: S1101, preparing a nanoemulsion of a thermosensitive agent and silk fibroin by a polyethylene glycol emulsification method within a preset temperature range; S1102, preparing a drug and silk fibroin emulsion by a polyethylene glycol emulsification method within a preset temperature range, and eluting the polyethylene glycol by centrifugation to obtain nano-gel particles; S1103, mixing the prepared nanoemulsion and nanogel particles, eluting the polyethylene glycol by centrifugation, and then coating the mixture on the surface of the bare balloon to form a drug-loaded coating on the surface of the bare balloon; S1104. The drug-loaded coating is physically induced and regulated to obtain the β-folded crystal content in the silk fibroin to obtain the drug-loaded capsule.

[0069] In one embodiment, the preset temperature range in S1101 and S1102 is 15-25° C. The thermosensitive agent is poly(N-isopropylacrylamide (PNIPAM)). The drug is paclitaxel. The physical induction method in S1104 is water vapor, ethanol fumigation, etc.

[0070] In a sixth aspect, the present application also provides a method for preparing a controlled-release drug balloon catheter, which specifically comprises the following steps: Connect the catheter components (inner tube, middle layer, outer layer, three-way catheter seat) together; Assemble the precision temperature control device and connect it to the catheter; The drug-loaded microspheres are prepared by the above-mentioned method for preparing the drug-loaded microspheres and the spraying method, and the drug-loaded microspheres are sprayed onto the surface of the bare balloon to form the drug-loaded balloon; welding the drug-loaded balloon to the surface of the catheter; Tablet pressing, rolling, packaging, and ethylene oxide sterilization are set aside for use.

[0071] In the controlled-release drug balloon catheter provided in the embodiment of the present application, the temperature transfer process avoids the interference of human tissue, and is more accurate and stable. At the same time, no components are required to be set at the balloon tip, which also facilitates the use of precision temperature control devices in more parts of the human body and has a wider range of applications in human blood vessels.

[0072] In order to further illustrate the relationship between the drug release amount and temperature of the drug-loaded coating provided in the examples of the present application, the present application uses high-performance liquid chromatography (HPLC) quantitative analysis of paclitaxel to find out and verify that the drug release amount of the silk fibroin-PNIPAM-paclitaxel drug coating is linearly correlated with the temperature within a certain temperature range.

[0073] In one embodiment, the instruments and reagents used in the research are: The instruments include: DC-015 constant temperature water bath, HPLC system (with UV detector, Agilent 1260), chromatographic column: Agilent ZORBXSB-C18 reverse phase column, analytical balance (accuracy 0.0001g), ultrasonic cleaner, micropipette and volumetric flask, precision pipette and 50ml triangular pyramidal flask, controlled release drug balloon catheter (catheter size Ø6mmx10mm, total drug loading 360mg±5mg; PNIPAM to silk protein weight ratio K is K=1:3, β-folded crystal content 31-46%), and a timer (accuracy 0.01s).

[0074] Reagents include: paclitaxel standard (purity ≥ 98%), chromatographic grade acetonitrile, ethanol and ultrapure water.

[0075] The experimental steps include: 1. Establish a HPLC quantitative analysis method for paclitaxel and find a standard curve for quantitative analysis of paclitaxel; specifically include: Preparation of standard solutions. Stock solution (0.1 mg / mL): Accurately weigh 10.0 mg of paclitaxel standard, dissolve in ethanol and make up to 100 mL. Series of working solutions: Dilute the stock solution with ethanol to prepare standard solutions with concentrations of 0.1, 0.5, 1.0, 5.0, and 10.0 μg / mL, respectively.

[0076] Chromatographic conditions were set. Mobile phase: acetonitrile-water (50:50, V / V). Flow rate: 1.0 mL / min. Detection wavelength: 227 nm. Column temperature: 30 °C. Injection volume: 20 μL.

[0077] Data collection: Inject standard solutions of various concentrations in sequence, perform parallel determination three times, and record the average peak area.

[0078] The experimental results are shown in Table 1.

[0079] Table 1 Standard curve data The standard curve equation includes: The regression equation is: The correlation coefficient is: The linear range is 0.1-10 μg / mL.

[0080] From the above content, we can know that: a. The standard curve showed good linearity (R²>0.999), indicating that the method is suitable for quantitative analysis of paclitaxel in the range of 0.1–10 μg / mL.

[0081] b. The RSD of each concentration point was less than 2%, which proved that the method had good repeatability.

[0082] c. The selection of mobile phase ratio and detection wavelength was optimized based on the polarity and UV absorption characteristics of paclitaxel to ensure symmetrical peak shape and no interference.

[0083] The conclusion is as follows: In this experiment, a standard curve for HPLC quantitative analysis of paclitaxel was established, which has a wide linear range and high sensitivity, meeting the actual sample detection needs and providing a reliable method for the determination of paclitaxel content in samples.

[0084] 2. Determine the drug release amount of silk fibroin-PNIPAM-paclitaxel drug-loaded balloons at different temperatures by HPLC; find out the linear correlation and verify it.

[0085] The experimental steps include: a. Use a pipette to accurately transfer 30 ml of ethanol into a conical flask. The liquid level should be high enough to fully immerse the drug-coated balloon in the balloon catheter.

[0086] b. Soak the flask containing ethanol in a constant temperature water bath at 37℃.

[0087] c. The precision temperature control device is set at 5°C and the pressure is (0.5-0.8mPa), and is connected to circulate in the liquid medium (contrast agent).

[0088] d. Wait until the medium temperature stabilizes and then connect the catheter. When the balloon of the catheter is expanded and filled, immerse the balloon in the ethanol solution in the conical flask for 20 seconds.

[0089] e. 5℃, 7℃, 10℃...37℃ in sequence. Test and record the temperatures shown in Table 2.

[0090] f. Perform liquid chromatography measurement and analysis on the ethanol extract of paclitaxel in the conical flasks at different temperatures.

[0091] g. According to the standard curve, calibrate the paclitaxel content at each temperature and calculate the percentage of the released amount to the total amount.

[0092] Table 2 Data record of drug release at different temperatures (within 20S) The drug release concentration curves at different temperatures within 20S are as follows Fig.12 The drug release content curves at different temperatures within 20S are shown in Fig.13 The relationship curve of the percentage of drug release content in the total amount at different temperatures within 20S and the fitting curve are shown in Fig.14 and Fig.15 shown.

[0093] Depend on Fig.14 and Fig.15 It can be seen that the linear regression equation between temperature and percentage of drug controlled release within the temperature range (5-25°C) is: The correlation coefficient is: This experiment verified that the silk fibroin-PNIPAM-paclitaxel drug coating showed a good linear relationship in the temperature range of 5℃-25℃ (correlation coefficient: R²=0.993). The temperature of the liquid medium can be controlled by a precision temperature control device, and the temperature-sensitive properties of the drug-loaded microspheres can be used to achieve the possibility of precise drug controlled release.

[0094] Obviously, those skilled in the art can make various changes and modifications to the embodiments of the present application without departing from the spirit and scope of the present application. Thus, if these modifications and variations of the present application fall within the scope of the claims of the present application and their equivalents, the present application is also intended to include these modifications and variations.

Claims

1. A drug-loaded microsphere, characterized in that: include: A thermosensitive agent, silk fibroin and a drug; the weight ratio of the thermosensitive agent to the silk fibroin is in the range of 1:1-1:5; The silk fibroin includes β-pleated crystals; the content of β-pleated crystals in the silk fibroin ranges from 20% to 60%.

2. The drug-loaded microspheres according to claim 1, characterized in that: The weight ratio of the thermosensitive agent to the silk fibroin is 1:1, and the content of β-pleated crystals in the silk fibroin is in the range of 20%-32%; Alternatively, the weight ratio of the thermosensitive agent to the silk fibroin is 1:2, and the content of β-pleated crystals in the silk fibroin is in the range of 26%-40%; Alternatively, the weight ratio of the thermosensitive agent to the silk fibroin is 1:3, and the content of β-pleated crystals in the silk fibroin is in the range of 31%-46%; Alternatively, the weight ratio of the thermosensitive agent to the silk fibroin is 1:4, and the content of β-pleated crystals in the silk fibroin is in the range of 38%-52%; Alternatively, the weight ratio of the thermosensitive agent to the silk fibroin is 1:5, and the content of β-pleated crystals in the silk fibroin is in the range of 43%-60%.

3. The drug-loaded microspheres according to claim 1, characterized in that: The thermosensitive agent includes one or more of a gelatin-pullulan composite material, poly (N-isopropylacrylamide), a metal organic framework and a thermosensitive hydrogel composite.

4. The drug-loaded microspheres according to claim 1, characterized in that: The drug includes one or more of paclitaxel, rapamycin, docetaxel, rapamycin CD34 antibody, arginine-glycine-aspartic acid peptide, siRNA targeting TGF-β, and miRNA.

5. The drug-loaded microspheres according to claim 1, characterized in that: The drug-loaded microspheres include a wrapping layer, and the wrapping layer includes the thermosensitive agent and the silk fibroin; The wrapping layer covers the outside of the drug.

6. The drug-loaded microspheres according to claim 1, characterized in that: The particle size of the drug-loaded microspheres ranges from 1 μm to 8 μm, and the wall thickness ranges from 10 nm to 5000 nm.

7. A drug-loaded balloon, characterized in that: include: A bare balloon and a drug-loaded coating coated on the outer surface of the bare balloon; the drug-loaded coating comprises the drug-loaded microspheres as described in any one of claims 1-6.

8. The drug-loaded balloon according to claim 7, characterized in that: The naked balloon is a non-compliant balloon or a semi-compliant balloon; And / or, the bare balloon is a rapid exchange balloon or a non-rapid exchange balloon.

9. A controlled drug release balloon catheter, characterized in that: include: A catheter and a drug-loaded balloon; the drug-loaded balloon is the drug-loaded balloon as claimed in claim 7; or the drug-loaded balloon comprises a bare balloon and a drug-loaded coating coated on the outer surface of the bare balloon, and the drug-loaded coating is the drug-loaded microsphere as claimed in any one of claims 1 to 6; The catheter comprises a catheter body and a three-way catheter seat connected to the first end of the catheter body; the catheter body comprises an inner layer, an intermediate layer and an outer layer; an instrument cavity is formed inside the inner layer; a first filling channel is formed between the intermediate layer and the inner layer, and a second filling channel is formed between the outer layer and the intermediate layer; The three-way catheter seat includes a first joint and a second joint, the first joint is communicated with the first filling channel, and the second joint is communicated with the second filling channel; The bare balloon is connected to the outer layer and is located at the second end of the catheter body; the interior of the bare balloon is in communication with the second filling channel; The middle layer is provided with a balloon filling channel, and the balloon filling channel is connected with the first filling channel and the interior of the bare balloon.

10. The controlled drug release balloon catheter according to claim 9, characterized in that: The controlled-release drug balloon catheter also includes a precision temperature control device; The precision temperature control device comprises a liquid reservoir, a temperature sensor, a temperature controller and a liquid supplier; The liquid reservoir is in communication with the first connector, and a first control valve is provided between the liquid reservoir and the first connector for controlling the flow rate of liquid delivered from the liquid reservoir to the first connector; The temperature sensor is arranged inside the liquid reservoir and is used to collect the temperature of the liquid inside the liquid reservoir; The liquid supplier is in communication with the liquid reservoir via the temperature controller, and the temperature controller is connected to the temperature sensor signal for regulating the temperature of the liquid inside the liquid reservoir.

11. The controlled drug release balloon catheter according to claim 10, characterized in that: The temperature controller comprises a first flow channel and a second flow channel in parallel and a semiconductor cooling plate located between the first flow channel and the second flow channel, the first flow channel passes through a heating area of ​​the semiconductor cooling plate, and the second flow channel passes through a cooling area of ​​the semiconductor cooling plate; The liquid supplier is in communication with the liquid reservoir through the first flow channel and the second flow channel in parallel; The precision temperature control device further comprises a second control valve, which is arranged between the liquid reservoir and the first flow channel and the second flow channel in parallel; The second control valve is connected to the temperature sensor signal, and is used to adjust the temperature of the liquid inside the liquid reservoir by adjusting the liquid flow rates of the first flow channel and the second flow channel.

12. The controlled drug release balloon catheter according to claim 11, characterized in that: The precision temperature control device also includes a controller, and the temperature sensor, the first control valve, the semiconductor refrigeration plate, and the second control valve are all connected to the controller by signal.

13. A method for preparing drug-loaded microspheres, characterized in that: include: A nanoemulsion of a thermosensitive agent and silk fibroin is prepared by a polyethylene glycol emulsification method within a preset temperature range; The drug and silk protein emulsion is prepared by polyethylene glycol emulsification method within a preset temperature range, and the polyethylene glycol is eluted by centrifugation to obtain nano-gel particles; The prepared nanoemulsion and the nanogel particles are mixed, and then the polyethylene glycol is eluted by centrifugation to obtain drug-loaded particles; The drug-loaded microspheres are obtained by inducing and regulating the content of beta-folded crystals in silk fibroin in a physical manner on the drug-loaded particles.

14. A method for preparing a drug-loaded balloon, characterized in that: include: A nanoemulsion of a thermosensitive agent and silk fibroin is prepared by a polyethylene glycol emulsification method within a preset temperature range; The drug and silk protein emulsion is prepared by polyethylene glycol emulsification method within a preset temperature range, and the polyethylene glycol is eluted by centrifugation to obtain nano-gel particles; The prepared nanoemulsion and nanogel particles are mixed and then coated on the surface of the bare balloon after the polyethylene glycol is eluted by centrifugation to form a drug-loaded coating on the surface of the bare balloon; The drug-loaded balloon is obtained by inducing and regulating the content of beta-folded crystals in the silk fibroin in the drug-loaded coating in a physical manner.

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