A drug coated stent and method of manufacture

Abstract

This application discloses a drug-coated stent and its preparation method, belonging to the field of medical devices. The drug-coated stent includes: a drug-coated stent substrate; an anticoagulant coating covering the surface of the drug-coated stent substrate; an intermediate coating covering the anticoagulant coating and located on the outer surface of the drug-coated stent substrate; and a drug coating coated on the outer surface of the intermediate coating, the drug coating comprising an active drug and a controlled-release polymer controlling the release rate of the active drug; the intermediate coating and the anticoagulant coating are bonded by electrostatic adsorption. The drug-coated stent provided by this application exhibits the following advantages: the anticoagulant coating stably exerts its anticoagulant effect and reduces the risk of thrombosis; the intermediate coating enhances the bonding strength between the drug coating and the anticoagulant coating and prevents its detachment; and the drug coating enables sustained release of the active drug and inhibits restenosis. These three components synergistically address both anticoagulant and anti-restenosis effects, improving the stent's therapeutic efficacy and clinical applicability. The preparation process is simple and controllable, suitable for large-scale production.

Description

Technical Field

[0001] This application relates to the field of medical device technology, and in particular to a drug-coated stent and its preparation method. Background Technology

[0002] Atherosclerosis is a major pathogenic factor for coronary heart disease, cerebral infarction, and peripheral arterial disease. Among them, intracranial atherosclerotic disease is the main cause of ischemic stroke, accounting for approximately 17%-35% of ischemic cerebrovascular events in Asians; peripheral arterial disease is a global health burden affecting 20% ​​of the population over 80 years of age, and it is showing a trend towards affecting younger people, placing a heavy burden on people's health and social development.

[0003] Currently, drug-eluting stents are the primary treatment for the aforementioned atherosclerosis-related diseases, but this treatment method has significant drawbacks. Due to the drug's inhibition of endothelialization and the foreign body nature of the stent itself, acute thrombosis is highly likely to occur after stent implantation, causing serious clinical damage. Heparin, as a commonly used anticoagulant in clinical practice, can bind to antithrombin III, inactivating coagulation factors and reducing thrombus formation. Therefore, introducing a heparin coating as an anticoagulant layer onto the surface of the implanted device can significantly reduce the incidence of thrombosis on the device surface.

[0004] Existing drug-eluting stents with anticoagulant coatings all involve co-forming an anticoagulant and an antiproliferative drug into a drug coating, from which the anticoagulant is eluted to exert its effect. However, heparin's anticoagulant effect requires its active site to be exposed in the blood and bind to antithrombin III. Encapsulating heparin within the drug coating makes it difficult to effectively expose its active site. Even if heparin is eluted from the coating, it will quickly enter the bloodstream and be metabolized, resulting in a weak anticoagulant effect on the device surface and failing to fully exert its anticoagulant effect.

[0005] In existing technologies, there are methods to fix the heparin endpoint to the device surface through an aldehyde-amine reaction, such as Carmeda bioactive surface. This method makes heparin non-elutable, exhibiting excellent anticoagulant properties. The preparation process involves alternately adsorbing cationic and anionic polymers onto the device surface, and then grafting heparin onto the outermost cationic polymer through an aldehyde-amine reaction.

[0006] However, the heparin coating prepared by this process completely covers the device surface, while drug-eluting stents require a drug coating on at least the outer surface to sustainably release anti-proliferative drugs such as rapamycin and prevent restenosis. Because the heparin coating is hydrophilic, the subsequent drug coating does not adhere firmly to the heparin coating and easily detaches from the device surface, severely affecting treatment efficacy. Therefore, it is urgent to solve this technical bottleneck. Summary of the Invention

[0007] This application discloses a drug-coated stent and its preparation method to solve the technical problems in related technologies, such as insufficient anticoagulation effect, easy detachment of drug coating, and difficulty in simultaneously achieving anticoagulation performance and anti-restenosis effect in drug-coated stents with anticoagulation coating.

[0008] To solve the above problems, this application adopts the following technical solution: In a first aspect, embodiments of this application provide a drug-eluting stent, comprising: Drug-eluting scaffold matrix; An anticoagulant coating is applied to the surface of the drug-eluting scaffold matrix. An intermediate coating is applied over the anticoagulant coating and is located on the outside of the drug-eluting scaffold matrix; A drug coating is applied to the outer surface of the intermediate coating, the drug coating comprising an active drug and a controlled-release polymer for controlling the release rate of the active drug; The intermediate coating and the anticoating coating are bonded together by charge adsorption.

[0009] Secondly, embodiments of this application provide a method for preparing a drug-eluting stent, comprising the following steps: Step S10: Clean and activate the drug-eluting scaffold substrate; Step S20: Form an amino polymer layer on the surface of the activated drug scaffold substrate; Step S30: Grafting heparin molecules with aldehyde groups at the end groups to the amino polymer layer via an amine condensation reaction to form an anticoating coating; Step S40: Apply a first polymer solution to the junction of the outer surface and side surface of the drug-eluting stent matrix with the anticoagulant coating formed, so that the first polymer solution covers and coats the anticoagulant coating on the inner surface and side surface of the drug-eluting stent matrix, and forms a first polymer layer after drying. Step S50: Apply a second polymer to the outside of the anticoagulant coating on the outer surface of the drug-eluting stent matrix, and fix the second polymer to the anticoagulant coating on the outer surface by charge adsorption; after washing, remove the complex formed after the first polymer layer and the second polymer are combined, as well as the first polymer layer that is not combined with the second polymer; after drying, form an intermediate coating on the outside of the anticoagulant coating on the outer surface of the drug-eluting stent matrix. Step S60: Apply a drug coating containing the active drug and controlled-release polymer to the outer surface of the intermediate coating.

[0010] The technical solutions adopted in the embodiments of this application can achieve the following beneficial effects: The drug-eluting stent provided in this application embodiment covers the inner and side surfaces of the drug-eluting stent substrate with an anticoagulant coating, and then sequentially applies an intermediate coating and a drug coating on the outer surface of the drug-eluting stent substrate above the anticoagulant coating. The synergistic effect of these coatings effectively solves the technical bottlenecks of insufficient anticoagulant effect and easy detachment of the drug coating in existing technologies. Specific beneficial effects are as follows: First, the anticoagulant coating covering the inner and side surfaces of the drug-eluting stent matrix can directly act on the blood contact interface, allowing the anticoagulant components to remain stably present on the device surface. This avoids the problems in existing technologies where heparin is encapsulated inside the drug coating, resulting in difficulty in exposing active sites and rapid metabolism after elution. It can continuously exert an anticoagulant effect, significantly reducing the risk of acute thrombosis caused by foreign bodies and endothelial inhibition after stent implantation, reducing clinical damage, and ensuring the safety of stent implantation.

[0011] Secondly, the intermediate coating is applied only above the anticoagulant coating on the outer surface of the drug-eluting stent matrix, effectively overcoming the defect in existing technologies where the hydrophilic properties of the heparin coating lead to weak adhesion of subsequent drug coatings. The intermediate coating serves as a connecting medium between the anticoagulant and drug coatings. On one hand, it forms a stable bond with the hydrophilic anticoagulant coating; on the other hand, it provides a suitable adhesion interface for the subsequent drug coating, enhancing the bonding strength between the drug coating and the stent as a whole, preventing the drug coating from detaching from the device surface, and ensuring stable adhesion of the drug coating to the outer surface of the stent.

[0012] Finally, the drug-eluting coating is located on the outer surface of the stent and directly contacts the vessel wall. The active drug contained within it can achieve sustained and stable release under the action of the controlled-release polymer, continuously exerting an anti-proliferative effect, effectively inhibiting the proliferation of vascular smooth muscle cells, preventing restenosis, and ensuring the long-term effectiveness of stent treatment. Simultaneously, the coatings are layered and do not interfere with each other. The inner and side surfaces of the stent are continuously protected by an anticoagulant coating, while the outer surface is protected by a drug-eluting coating that directly contacts the vessel wall to exert an anti-proliferative effect. The intermediate coating ensures the stability of the connection between the layers. These three elements work synergistically to achieve both anticoagulant and restenosis prevention effects, significantly improving the therapeutic efficacy and clinical applicability of drug-eluting stents, and solving the technical challenge of simultaneously achieving excellent anticoagulant performance and stable drug release in existing technologies. Attached Figure Description

[0013] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0014] Figure 1This is a partial planar unfolded structural diagram of the drug-eluting stent matrix in the first embodiment of this application. Figure 2 This is a partial enlarged planar structural diagram of the drug-coated stent (the drug stent substrate adopts the first embodiment) in the embodiments of this application. Figure 3 yes Figure 2 Sectional view of AA; Figure 4 yes Figure 2 Sectional view of BB; Figure 5 This is a partial planar structural diagram of a second embodiment of the drug-eluting scaffold matrix according to this application. Figure 6 This is a partial enlarged planar structural diagram of the drug-coated stent (the drug stent substrate adopts the second embodiment) in the embodiments of this application. Figure 7 yes Figure 6 Sectional view of CC; Figure 8 yes Figure 6 Sectional view of DD; Figure 9 This is a schematic diagram showing the state at the junction of the outer surface and side surface of the drug-eluting stent matrix in the first embodiment of the invention. Figure 10 This is a schematic diagram showing the state at the junction of the outer surface and side surface of the drug-eluting stent matrix in a second embodiment of the invention. Figure 11 This is a schematic diagram showing the state of applying the second polymer solution to the edge of the groove in a second embodiment of the drug-eluting scaffold matrix; Figure 12 (a) is a diagram showing the staining of the drug-coated scaffold in Example 1 as observed by the naked eye; Figure 12 (b) is a diagram showing the staining of the drug-coated stent in Example 2 as observed by the naked eye; Figure 12 (c) is a diagram showing the staining of the drug-coated stent in Comparative Example 1 as observed by the naked eye.

[0015] In the figure: 10, drug-eluting stent matrix; 101, cylindrical wave ring; 1011, wave bar; 1012, wave crest; 1013, wave trough; 102, connector; 20, anticoagulant coating; 30, drug coating; 40, intermediate coating; 50, microinjection system; 60, groove; 70, first polymer layer. Detailed Implementation

[0016] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions of this application will be described in detail below. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. Based on the embodiments in this application, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0017] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and are not used to describe a specific order or sequence. It should be understood that such use of terms can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0018] The drug-eluting stents containing an anticoagulant coating 20 in the related technologies have two major drawbacks: first, heparin is encapsulated within the drug coating 30, making it difficult to expose the active sites and resulting in insufficient anticoagulation effect; second, the hydrophilic nature of the heparin coating makes the subsequent drug coating 30 poorly adhered and prone to falling off, making it difficult to achieve both anticoagulation and anti-restenosis effects.

[0019] Based on this, a first aspect of this application provides a drug-coated stent, comprising: Drug-eluting scaffold matrix 10; An anticoagulant coating 20 covers the surface of the drug-eluting scaffold substrate 10; An intermediate coating 40 covers the anticoagulant coating 20 and is located on the outside of the drug-eluting scaffold substrate 10; A drug coating 30 is applied to the outer surface of the intermediate coating 40, and the drug coating 30 contains an active drug and a controlled-release polymer for controlling the release rate of the active drug. The intermediate coating 40 and the anti-coating coating 20 are bonded together by charge adsorption.

[0020] It is understandable that by achieving the bonding between the intermediate coating 40 and the anticoagulant coating 20 through charge adsorption, a stable connection can be formed by the interaction between charges, solving the interfacial bonding problem caused by the hydrophilicity of the anticoagulant coating 20 (heparin coating), enabling the intermediate coating 40 to adhere tightly to the surface of the anticoagulant coating 20, providing a stable adhesion basis for the subsequent drug coating 30, further preventing the drug coating 30 from falling off, and ensuring the continuity of drug release.

[0021] In some embodiments, the anticoagulant coating 20 fixes the heparin endpoints to the surface of the drug-eluting scaffold matrix 10 via an aldehyde-amine reaction. It is understood that fixing the heparin endpoints via the aldehyde-amine reaction makes heparin non-elutable and stably present on the scaffold surface, ensuring that its active sites are fully exposed to exert their anticoagulant effect.

[0022] In some embodiments, the drug-eluting stent substrate 10 is formed by connecting multiple axially arranged cylindrical wave-shaped rings 101 via connectors 102. Each cylindrical wave-shaped ring 101 is formed by connecting multiple wave rods 1011 circumferentially to form a continuous bending structure. The bending connection of adjacent wave rods 1011 forms a wave crest 1012 or a wave trough 1013. The connectors 102 connect the wave crests 1012 and troughs 1013, troughs 1013 and troughs 1013, or wave crests 1012 and wave crests 1012 of adjacent cylindrical wave-shaped rings 101. The intermediate coating 40 covers the anticoagulant coating 20 of the cylindrical wave-shaped rings 101, and the intermediate coating 40 is located on the outer side of the drug-eluting stent substrate 10 (the "outer side" refers to the side of the drug-eluting stent substrate 10 that is radially away from the vascular lumen and in contact with the vascular wall, while the inner side is the side facing the vascular lumen and in contact with blood flow). The drug coating 30 covers the outer surface of the intermediate coating 40. That is, the intermediate coating 40 and the drug coating 30 are only disposed on the outer surface of the stent matrix to achieve targeted drug release to the blood vessel wall. It should be noted that the definitions of peak 1012 and trough 1013 are view-dependent; the defined peak 1012 and trough 1013 will differ depending on the observation direction. For example, using... Figure 1 Taking the planar unfolded structure of the drug-eluting stent substrate 10 as an example, when viewed along the axial direction of the drug-eluting stent substrate 10, the upwardly convex bend connection is the peak 1012, and the downwardly concave bend connection is the trough 1013. The definitions of peak 1012 and trough 1013 in this application are based on this viewing angle. The specific structure of the drug-eluting stent substrate 10 is prior art in this field and will not be described in detail here.

[0023] In some embodiments, a groove 60 is provided on the outer surface of the wave rod 1011, the intermediate coating 40 covers the inner wall and bottom surface of the groove 60, and the drug coating 30 covers the outer surface of the intermediate coating 40. It is understood that providing the groove 60 and having the intermediate coating 40 cover the inner wall and bottom surface of the groove 60 increases the adhesion area of ​​the intermediate coating 40, improves the bonding strength between the intermediate coating 40 and the anticoagulant coating 20 on the drug-eluting stent substrate 10, and simultaneously, the groove 60 structure can limit the intermediate coating 40, further enhancing its stability and providing a more reliable adhesion interface for the drug coating 30, ensuring stable adhesion and continuous drug release.

[0024] In some embodiments, the groove 60 is positioned to avoid the apex positions of the crests 1012 and troughs 1013.

[0025] In some embodiments, the drug-eluting stent matrix 10 is made of a biocompatible metal or metal alloy; for example, the metal alloy is selected from stainless steel, nickel-titanium alloy, cobalt-chromium alloy, platinum-chromium alloy, biodegradable magnesium alloy, or titanium-tantalum alloy.

[0026] A second aspect of this application provides a method for preparing a drug-coated stent, comprising the following steps: Step S10: Clean and activate the drug-eluting stent substrate 10. In this step, the cleaning and activation process removes impurities and oil stains from the stent surface, while also improving the surface activity and increasing the surface roughness, laying the foundation for the firm adhesion of the subsequent amino polymer layer, ensuring that the subsequent amino polymer layer is tightly bonded to the drug-eluting stent substrate 10, and preventing the coating from falling off.

[0027] Step S20: An amino polymer layer is formed on the surface of the activated drug-eluting scaffold substrate 10. In this step, the amino polymer is uniformly covered on the surface of the drug-eluting scaffold substrate 10 to construct a stable linking layer, providing sufficient amino active sites for subsequent grafting of heparin molecules and ensuring the smooth progress of the amine condensation reaction.

[0028] Step S30: Grafting heparin molecules with aldehyde groups at the end of the terminal group to the amino polymer layer through an amine condensation reaction to form an anticoagulant coating 20; In this step, the aldehyde group at the end of the heparin molecule undergoes an amine condensation reaction with the amino group of the amino polymer layer, and the heparin molecule is stably grafted onto the surface of the drug-eluting scaffold substrate 10 to form a firmly bonded and non-detachable anticoagulant coating 20.

[0029] Step S40: A first polymer solution is applied to the junction of the outer surface and side surface of the drug-eluting stent substrate 10, where the anticoagulant coating 20 has been formed. This first polymer solution covers and coats the anticoagulant coating 20 on the inner surface and side surface of the drug-eluting stent substrate 10. After drying, a first polymer layer 70 is formed. In this step, the first polymer solution covers the anticoagulant coating 20 on the inner surface and side surface of the drug-eluting stent substrate 10. The first polymer layer 70 formed after drying protects the anticoagulant coating 20 in this area, preventing it from bonding with the second polymer in subsequent steps, thus ensuring the integrity of the anticoagulant coating 20 on the inner surface and side surface of the drug-eluting stent substrate 10. For the method of applying the first polymer solution, please refer to [link to relevant documentation]. Figure 9 and Figure 10 ; Figure 9 This is a schematic diagram showing the state at the junction of the outer surface and the side surface of the drug stent substrate 10 in the first embodiment of this application, where the first polymer solution is applied. Figure 10This is a schematic diagram showing the state of applying the first polymer solution to the junction of the outer surface and side surface of the drug-eluting stent substrate 10 in a second embodiment. In this diagram, region A corresponds to the outer surface of the stent, that is, the side that directly contacts the blood vessel wall after the stent is implanted; region B corresponds to the inner surface of the stent; and region C corresponds to the side surface of the stent. The first polymer solution is applied from the left side of the paper shown in the diagram, and the application operation must also be completed simultaneously at the corresponding symmetrical position on the right side of the paper to achieve uniform and aligned coating of the junction area of ​​the outer surface and side surface of the stent in the circumferential direction; so that the inner surface and both sides of the drug-eluting stent substrate 10 have the first polymer layer 70.

[0030] Step S50: A second polymer is applied to the outside of the anticoagulant coating 20 on the outer surface of the drug-eluting stent substrate 10. The second polymer is fixed to the anticoagulant coating 20 on the outer surface by charge adsorption. After washing, the complex formed by the combination of the first polymer layer 70 and the second polymer, as well as the first polymer layer 70 that is not combined with the second polymer, are removed. After drying, an intermediate coating 40 is formed on the outside of the anticoagulant coating 20 on the outer surface of the drug-eluting stent substrate 10. In this step, the second polymer and the anticoagulant coating 20 on the outer surface of the drug-eluting stent substrate 10 achieve stable bonding through strong charge adsorption. The complex formed by the second polymer and the first polymer is removed by washing. The first polymer layer 70 that is not combined with the second polymer is also removed by washing. Free second polymer that is not combined with any substance is also removed during washing. Finally, a stable intermediate coating 40 is formed only on the outside of the anticoagulant coating 20 on the outer surface of the drug-eluting stent substrate 10. This does not damage the anticoagulant coating 20 on the inner and side surfaces, and provides a stable adhesion interface for the subsequent drug coating 30. The thickness of the intermediate coating 40 is only required to achieve effective adhesion. For example, the thickness of the intermediate coating 40 is 0.1~200nm.

[0031] Step S60: Apply a drug coating 30 containing an active drug and a controlled-release polymer to the outer surface of the intermediate coating 40. In this step, the active drug and the controlled-release polymer are mixed and applied to the surface of the intermediate coating 40 to form the drug coating 30. The controlled-release polymer can control the slow and sustained release of the active drug, continuously exert its anti-proliferative effect, inhibit vascular restenosis, and work synergistically with the inner surface anticoagulant coating 20 to improve the safety and effectiveness of stent treatment.

[0032] In some embodiments, in step S50, the first polymer layer 70 and the second polymer are bonded together by ionic bonds to form a composite. It is understood that ionic bonds have strong binding forces, enabling the first polymer and the second polymer to bond quickly and stably to form a composite, facilitating the removal of the entire composite from the support surface during subsequent washing.

[0033] In some embodiments, in step S40, the first polymer is selected from one or more of polyacrylic acid, dextran sulfate, sodium alginate, hyaluronic acid, polyaspartic acid, polyglutamic acid, sodium carboxymethyl cellulose, carbomer, and hydroxypropyl methylcellulose acetate succinate. It is understood that the above polymers all possess good water solubility and film-forming properties, enabling the formation of a uniform and dense first polymer layer 70 on the inner and side surfaces of the drug-eluting stent substrate 10, effectively coating the anticoagulant coating 20 in this area. Simultaneously, these polymers carry a negative charge, allowing them to form stable ionic bonds with the subsequent second polymer, providing a structural basis for the formation and removal of the complex, and ensuring the protective effect on the anticoagulant coating 20 on the inner and side surfaces of the drug-eluting stent.

[0034] In some embodiments, in step S40, the mass percentage concentration of the first polymer in the first polymer solution is 0.3% to 2%.

[0035] In some embodiments, during step S40, when the first polymer solution is applied, it is allowed to flow along the stent surface under gravity and cover the inner and side surfaces. It is understood that gravity allows the first polymer solution to flow naturally, achieving complete coverage of the stent's inner and side surfaces without additional complex operations, ensuring no areas are missed; simultaneously, it reduces damage to the anticoagulant coating 20 on the drug-eluting stent surface from external forces, ensuring the structural integrity of the anticoagulant coating 20.

[0036] In some embodiments, in step S40, the drying is performed at a temperature of 40°C to 120°C for 10 to 15 hours.

[0037] Please see Figure 11 In some embodiments, when applying the second polymer solution in step S50, for the drug stent substrate 10 with grooves 60 on the outer surface of the wave rod 1011, the second polymer solution is applied from the edge of the groove 60 toward the inside of the groove 60, and the second polymer solution is coated around the circumference of the edge of the groove 60 to form an intermediate coating 40. The intermediate coating 40 covers the inner wall and bottom surface of the groove 60, and the second polymer solution can flow naturally along the inner wall surface of the groove 60 under the action of gravity, thereby completely covering the inner wall surface and bottom surface of the groove 60. It can be understood that this embodiment utilizes gravity to achieve the natural spreading of the second polymer solution, which can uniformly fill the groove 60 structure without additional complex operations, ensuring the complete coverage and uniformity of the intermediate coating 40 in the groove 60, while precisely controlling the coating to be distributed only in the groove 60 area, avoiding covering or damaging the anticoagulant coating 20 on the inner surface and sides of the stent, simplifying the process and improving the stability of the coating quality.

[0038] In some embodiments, in step S50, the second polymer is selected from one or more of polylysine, polyarginine, protamine, polyornithine, polyethyleneimine, and N,N-dimethylaminoethyl methacrylate. It is understood that these polymers are all positively charged and can form a stable bond with the negatively charged anticoagulant coating 20 (heparin coating) through electrostatic adsorption, ensuring that the second polymer is firmly fixed on the anticoagulant coating 20 on the outer surface of the drug-eluting stent substrate 10. Simultaneously, these polymers have good biocompatibility, do not irritate vascular tissue, and have excellent film-forming properties, forming a stable intermediate coating 40, providing a reliable adhesion interface for the subsequent drug coating 30.

[0039] In some embodiments, in step S50, the mass percentage concentration of the second polymer in the second polymer solution is 0.3% to 2%.

[0040] Based on the negative charge characteristics of the first polymer and the positive charge properties of the second polymer, a flexible and stable combination relationship can be formed between them without limiting a specific combination. The first polymer and the second polymer can be used in any combination. Since the first polymer has negative charge characteristics and the second polymer has positive charge characteristics, regardless of the choice of any combination of the first polymer and any combination of the second polymer, a stable ionic complex can be formed through the electrostatic interaction of positive and negative charges. This does not affect the coating and protective function of the first polymer on the inner surface and side anti-coating coating 20 of the scaffold, nor does it damage the electrostatic adsorption effect of the second polymer on the outer surface anti-coating coating 20 or the film-forming stability of the intermediate coating 40. For example, any combination of polyacrylic acid and polylysine, dextran sulfate and polyethyleneimine, sodium alginate and polyarginine can be used to achieve the process goal of "complex formation-removal" while ensuring the structural integrity and functional effectiveness of the intermediate coating 40.

[0041] In addition to the specific types of the first and second polymers explicitly listed above, the technical solution of this application is not limited to this scope, and other first and second polymers may also be used, as long as the following core requirements are met: For the first polymer, it must meet the following requirements: good water solubility (can dissolve rapidly in aqueous solution to form a homogeneous solution), excellent film-forming properties (can form a dense coating layer on the stent surface), negative charge (can combine with the second polymer through ionic bonds to form a removable complex), and biocompatibility (does not affect the biosafety of subsequent stent implantation). The second polymer must meet the following requirements: it must be positively charged (able to form electrostatic adsorption with the negatively charged heparin coating and the first polymer respectively), biocompatible (no vascular tissue irritation), have stable film-forming properties (able to form a uniform intermediate coating 40), and provide a stable adhesion interface for the subsequent drug coating 30 (without adverse reactions with the drug or controlled-release polymer). Other polymers that meet these core requirements can replace the types listed above to achieve the technical objective of "protecting the inner surface and side anticoagulant coating 20 of the stent and constructing a stable intermediate coating 40" in this application, without requiring substantial adjustments to the existing preparation process.

[0042] In some embodiments, in step S50, the washing process includes water washing (which may be ultrasonic washing); the second polymer carries a positive charge, and the anticoagulant coating 20 carries a negative charge. The second polymer is electrostatically bonded to the anticoagulant coating 20 on the outer surface of the drug-eluting stent substrate 10. It is understood that electrostatic adsorption is highly specific and stable, allowing the second polymer to be precisely fixed to the anticoagulant coating 20 on the outer surface of the stent, without bonding to the anticoagulant coating 20 on the inner surface or sides covered by the first polymer layer 70. Water washing thoroughly removes the complex, unbonded first polymer layer 70, and free second polymer without damaging the coating structure already formed on the stent surface, ensuring the purity and stability of the intermediate coating 40, while avoiding damage to the drug-eluting stent substrate 10.

[0043] In some embodiments, in step S50, the drying is performed at a temperature of 40°C to 120°C for 10 to 15 hours.

[0044] In some embodiments, in step S20, the formation of the amino polymer layer includes: immersing the activated drug-eluting stent substrate 10 in an amino-rich polymer solution to form an amino polymer layer on the surface of the drug-eluting stent; the polymer used to prepare the amino-rich polymer solution is selected from at least one of polyethyleneimine, chitosan, polyallylamine, polyallylamine hydrochloride, poly-L-arginine, poly-L-arginine hydrochloride, poly-L-lysine, and poly-L-lysine hydrobromide. It is understood that the surface of the activated drug-eluting stent substrate 10 has high activity. Immersion allows the amino-rich polymer to fully contact the surface of the drug-eluting stent substrate 10, uniformly adhere, and form an amino polymer layer. This provides sufficient amino active sites for subsequent grafting of heparin molecules, ensuring the smooth occurrence of the amine condensation reaction and laying the foundation for the stable formation of the anticoagulant coating 20.

[0045] In some embodiments, in step S20, when the activated drug-eluting scaffold substrate 10 is immersed in an amino-rich polymer solution, the immersion temperature is 40°C to 120°C, the immersion time is 0.5 hours to 24 hours, and the mass percentage concentration of the polymer solution is 2% to 20%. It is understood that controlling the immersion temperature, time, and solution concentration within this range allows the amino polymer to fully dissolve and uniformly adhere to the surface of the drug-eluting scaffold substrate 10, forming an amino polymer layer of suitable thickness and tight bonding. Excessive temperature or concentration can lead to an excessively thick and uneven coating, while insufficient temperature or short time can result in inadequate polymer adhesion, affecting the subsequent heparin molecule grafting effect.

[0046] In some embodiments, in step S30, the formation of the anticoagulant coating 20 includes: immersing a drug scaffold with an amino polymer layer on its surface in a reaction solution containing heparin molecules with aldehyde end groups; grafting heparin molecules onto the amino polymer layer via an amine condensation reaction to form the anticoagulant coating 20; and controlling the areal density of the anticoagulant coating 20 to be 0.5 μg / cm³. 2 Up to 50 μg / cm 2 Understandably, the reducing agent can promote the amine condensation reaction between the aldehyde group at the end of the heparin molecule and the amino group of the amino polymer layer, so that the heparin molecule is stably grafted onto the surface of the scaffold through chemical bonds, forming a firmly bonded and non-detachable anticoagulant coating 20, ensuring that the active sites of heparin are fully exposed and exert a long-lasting anticoagulant effect.

[0047] In some embodiments, in step S30, the heparin molecule is selected from at least one of heparin, its pharmaceutically acceptable salts, low molecular weight heparin, and terminal-modified heparin. It is understood that such heparin-like substances all possess good anticoagulant activity, can be stably grafted onto the amino polymer layer via amine condensation reactions, and can effectively bind to antithrombin III to exert an anticoagulant effect; at the same time, these substances have good biocompatibility, do not irritate vascular tissue, and are compatible with the in vivo environment after stent implantation.

[0048] In some embodiments, in step S30, when the drug-eluting scaffold substrate 10 with an amino polymer layer on its surface is immersed in a reaction solution containing heparin molecules with aldehyde end groups, the immersion temperature is 40°C to 65°C, and the immersion time is 0.5 hours to 48 hours; the mass percentage concentration of heparin molecules in the reaction solution is 0.1% to 5%. It is understood that reaction parameters within this range ensure that the amine condensation reaction proceeds sufficiently, allowing heparin molecules to be uniformly and stably grafted onto the amino polymer layer, forming an anticoagulant coating 20 with appropriate thickness and stable anticoagulant effect; deviations from the parameters may lead to insufficient reaction, insufficient heparin grafting, or uneven coating, affecting the anticoagulant effect.

[0049] In some embodiments, in step S60, the controlled-release polymer is selected from degradable polymers, non-degradable polymers, or a combination of both. It is understood that controlled-release polymers can encapsulate active drugs and control the drug release rate through their own properties, achieving sustained and stable release of the active drug; degradable polymers can gradually degrade in vivo, avoiding long-term foreign body residue, while non-degradable polymers can provide a more sustained drug release effect. The combination of both can balance drug release duration and in vivo biocompatibility, ensuring that the drug continuously exerts its anti-proliferative effect and inhibits vascular restenosis.

[0050] In some embodiments, the biodegradable polymer is selected from lactide, trimethylene carbonate, glycolide, poly(L-lactide), racemic polylactic acid, polylactide-co-glycolic acid, poly(L-lactide-co-glycolic acid), poly(L-lactide-co-ε-caprolactone), poly(L-lactide-co-trimethylene carbonate), polytrimethylene carbonate, polycaprolactone, poly(glycolic acid-trimethylene carbonate), poly(lactide-glycolic acid-trimethylene carbonate), polyhydroxybutyrate, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), polyhydroxyvalerate, polyhydroxybutyrate / polyhydroxyvalerate copolymer, polyhydroxyalkanoate, polyorthoester, polyanhydride, polyimino carbonate, tyrosine-derived polycarbonate, and tyrosine-derived poly... Acrylates, iodinated tyrosine-derived polycarbonates, brominated tyrosine-derived polycarbonates, iodinated tyrosine-derived polyacrylates, brominated tyrosine-derived polyacrylates, polyamide esters, polycarbonate copolymers, lactone-based polymers, poly(propylene fumarate-co-ethylene glycol) copolymers, polyanhydride esters, silk-elastin polymers, polyphosphazenes, aliphatic polyurethanes, polyhydroxy acids, polyether esters, polyphenol peptides, poly(alkylene oxalate), polyaspartic acid, polyglutamic acid polymers, poly(p-dioxanone), poly(β-dioxanone), asymmetric 3,6-substituted poly(1,4-dioxane-2,5-dione), polyalkyl-2-cyanoacrylates, polydihydropyran, poly(β-maleic acid), polyfatty acid esters, and poly(β-alkanoic acid) are one or more of these. Understandably, these biodegradable polymers have good biocompatibility and in vivo degradability. After the stent is implanted, it can gradually degrade into non-toxic metabolites, avoiding long-term foreign body residue that could irritate vascular tissue. At the same time, it has excellent film-forming properties and drug compatibility, which can effectively encapsulate active drugs. By regulating the drug release rhythm through its own degradation rate, it ensures slow and sustained drug release, guarantees the long-lasting anti-proliferative effect, and adapts to the physiological environment in the body.

[0051] In some embodiments, the non-degradable polymer is selected from one or more of polyaryletherketone, polyetheretherketone, polyimide, polyethylene, polypropylene, polyethylene terephthalate, polybutyl methacrylate, polycarbonate, polyphenylene sulfone, polyethersulfone, polyetherimide, polyurethane, polyamide, nylon, polyvinyl chloride, polytetrafluoroethylene, fluorinated ethylene propylene copolymer, ethylene-tetrafluoroethylene copolymer, PFA, polyvinylidene fluoride, polyvinylidene fluoride-hexafluoropropylene copolymer, and acryloylbutadiene styrene. It is understood that such non-degradable polymers have high mechanical strength and good stability, maintaining structural integrity for a long time and providing stable carrier support for the drug coating 30; they also have good biocompatibility, do not trigger significant immune rejection reactions, and can control the drug release rate through their own structural characteristics, achieving long-term stable release of active drugs. This makes them suitable for scenarios with high requirements for controlled drug release time, ensuring the long-term therapeutic effect of the stent.

[0052] In some embodiments, in step S60, the active drug is selected from one or more of rapamycin, rapamycin derivatives, ABT-578, zotalimus, everolimus, eutrimolimus, desfolimus, tesiromolimus, tacrolimus, pimecrolimus, nitric oxide synthase, C3 exoenzyme, RhoA inhibitors, A3 agonists, CB2 agonists, 17-AAG, Hsp90 antagonists, tyrosine phosphorylation inhibitors, cathepsin S inhibitors, paclitaxel and its derivatives, paclitaxel, docetaxel, corticosteroids, dexamethasone, ceramides, dimethylsphingosine, ether-linked diglycerides, ether-linked phosphatidic acids, dihydrosphingosine, estrogens, takazole, takazole analogs, actinomycin D, prostaglandins, vitamin A, probucol, palmastat, statins, tramidil, mitomycin C, cytochalasin B, antiangiogenic agents, and antibodies. Understandably, these active drugs all have good anti-vascular smooth muscle cell proliferation effects, which can inhibit vascular wall proliferation and prevent restenosis after stent implantation. At the same time, they have good compatibility with controlled-release polymers, can be effectively encapsulated and stably loaded in the drug coating 30, and are slowly released under the regulation of the controlled-release polymer, continuously exerting pharmacological effects. They work synergistically with the anticoagulant coating 20 on the inner surface of the stent to improve the safety and effectiveness of stent therapy and meet the treatment needs of ischemic vascular diseases.

[0053] Based on the properties of the aforementioned controlled-release polymers (degradable, non-degradable, and combinations thereof) and their functional compatibility with active pharmaceutical ingredients, drugs and controlled-release polymers can be used in any combination. Regardless of the choice of any one or more combinations of degradable and non-degradable polymers as the controlled-release carrier, and their pairing with any one or more active pharmaceutical ingredients, the core objective of "carrier encapsulation-drug sustained release" can be achieved: the controlled-release polymer, through its film-forming properties and drug compatibility, can stably load the active pharmaceutical ingredient and form a uniform drug coating 30; the active pharmaceutical ingredient, under the rate regulation of the controlled-release polymer, can be continuously released and exert its anti-proliferative effect, and different combinations will not interfere with each other's core functions. For example, racemic polylactic acid (degradable) can be combined with zotamoxetine, or polyetheretherketone (non-degradable) can be combined with paclitaxel, etc., which can ensure the long-term effectiveness and stability of drug release, while also taking into account biocompatibility or mechanical support requirements, adapting to the treatment needs in different clinical scenarios.

[0054] In addition to the specific types of active pharmaceutical ingredients and controlled-release polymers explicitly listed above, the technical solution of this application is not limited to this scope, and other pharmaceutical ingredients and controlled-release polymers may also be used, as long as the following core requirements are met: For active drugs, they must meet the following requirements: clear anti-vascular smooth muscle cell proliferation activity (able to inhibit abnormal proliferation of the vascular wall and prevent restenosis after stent implantation), good biocompatibility (no obvious vascular tissue irritation or immunogenicity, and no additional inflammation or toxicity), and good compatibility with controlled-release polymers (can be effectively encapsulated by controlled-release polymers without aggregation, degradation or loss of pharmacological activity). For controlled-release polymers, if they are biodegradable, they must meet the following requirements: excellent biocompatibility (degradation products are non-toxic and metabolizable), controllable biodegradability in vivo (degradation rate matches drug release requirements), and good film-forming and drug-loading capacity (able to form a uniform coating and stably load the drug). If they are non-biodegradable, they must meet the following requirements: adequate mechanical strength and structural stability (able to maintain coating integrity for a long time), good biocompatibility (no risk of long-term foreign body irritation), and stable drug-controlled release performance (able to regulate the slow release of the drug through its own structure). If it is a combination of both, it must meet the core requirements of the above-mentioned biodegradable and non-biodegradable polymers, and the combination must not have synergistic toxicity, nor affect the drug release regulation effect and biosafety of each polymer.

[0055] Other drugs and controlled-release polymers that meet the core requirements can replace the types listed above to achieve the technical objective of "long-acting sustained release of drugs and inhibition of vascular restenosis" in this application, without requiring substantial adjustments to the existing drug coating 30 preparation process.

[0056] In some embodiments, step S60, the formation of the drug coating 30 specifically includes: Fix the vascular stent to be sprayed onto a support shaft with a diameter that matches its diameter; A drug spraying solution is prepared by mixing and dissolving an active drug, a controlled-release polymer, and an organic solvent, wherein: the mass ratio of the active drug to the controlled-release polymer is 1:(0.1~10); and the mass ratio of the active drug to the organic solvent is 1:(10~200). The drug coating solution is uniformly sprayed onto the outer surface of the vascular stent, for example, by ultrasonic spraying, gas spraying, or piezoelectric inkjet printing, ultimately achieving an active drug loading of 0.5 μg / mm² on the outer surface of the vascular stent. 2 Up to 1.0 μg / mm 2 ; The coated vascular stents were subjected to natural drying and constant temperature drying processes in sequence to obtain drug-coated stents.

[0057] In some embodiments, the natural drying is natural drying in air at room temperature for 1.5 to 2.5 hours; the constant temperature drying is drying at a temperature of 40°C to 50°C for 10 to 15 hours.

[0058] In some embodiments, the organic solvent is selected from at least one of acetone, tetrahydrofuran, ethyl acetate, propyl acetate, butyl acetate, ethanol, acetonitrile, dichloromethane, chloroform, and dimethyl sulfoxide.

[0059] The following detailed embodiments illustrate this application in more detail. It should also be understood that the following embodiments are for further explanation only and should not be construed as limiting the scope of protection of this application. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of this application fall within the scope of protection of this application. The specific process parameters, etc., in the following embodiments are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the range based on the description herein, and are not necessarily limited to the specific values ​​in the embodiments below.

[0060] I. Example: Examples 1 to 9 all employ the following methods: Figure 1 The drug-eluting scaffold substrate 10 shown has no groove 60 on the outer surface of the cylindrical wave ring 101. Example 1:

[0061] This application provides a method for preparing a drug-coated stent, comprising the following steps: Step S10: Take a cobalt-chromium alloy vascular stent and use it as the drug-eluting stent substrate 10. After ultrasonic washing with acetone, ethanol, purified water and isopropanol respectively, it is then treated with oxygen plasma for 30 minutes to obtain an activated vascular stent.

[0062] Step S20: Immerse the activated vascular stent in a 5% (w / w) aqueous solution of polyethyleneimine (weight average molecular weight of 25,000 Daltons) at 40°C for 24 hours, then remove it and rinse it with purified water to obtain a vascular stent with a polyethyleneimine layer on its surface.

[0063] Step S30: Form an anti-condensation coating 20 Step S301: Dissolve 1g of sodium heparin in 300mL of purified water and cool the solution to 0°C in an ice bath; add 10mg of sodium nitrate while stirring, then add 1M hydrochloric acid dropwise to adjust the pH of the solution to 3; maintain the low temperature of 0°C and stirring for 2 hours; after the reaction is complete, purify by dialysis and then freeze-dry to obtain sodium heparin with aldehyde groups at the end.

[0064] Step S302: Dissolve sodium heparin with aldehyde end groups at a concentration of 2% by mass in purified water to prepare a reaction solution. Immerse a vascular stent with a polyethyleneimine layer on its surface in the reaction solution, ensuring complete submersion, and react at 50°C for 36 hours. After the reaction, remove the vascular stent and rinse it thoroughly with purified water to obtain a vascular stent with a sodium heparin coating grafted onto its inner, side, and outer surfaces. This sodium heparin coating is the anticoagulant coating 20. The areal density of the sodium heparin coating is 35 μg / cm³ as determined by the toluidine blue colorimetric method. 2 .

[0065] Step S40: Weigh sodium hyaluronate (weight-average molecular weight of 20,000 Daltons) and dissolve it in purified water to prepare a first polymer solution with a mass percentage concentration of 0.5%; apply the first polymer solution to the junction of the outer surface and side surface of the cylindrical corrugated ring 101 using a micro-injection system 50. (See [link to relevant documentation]). Figure 9 (When using) Figure 5 When referring to the drug-eluting scaffold substrate 10 shown, please refer to... Figure 10 The first polymer solution is applied from the left side of the paper shown in the figure. Under the action of gravity, the first polymer solution flows and spreads in the direction of arrow a. At the same time, the application operation must also be completed simultaneously at the corresponding symmetrical position on the right side of the paper. The first polymer solution completely covers the heparin coating on the inner surface and two sides of the drug-eluting stent substrate 10. The stent is placed in a 50°C oven and dried for 12 hours to form the first polymer layer 70 (formed on the outside of the anticoagulant coating 20) on the inner surface and two sides of the drug-eluting stent substrate 10.

[0066] Step S50: Weigh out polyarginine (weight average molecular weight of 30,000-70,000 Daltons) and dissolve it in purified water to prepare a second polymer solution with a mass percentage concentration of 0.5%. After applying this solution to the outer surface of the stent (the second polymer solution can still be applied using a micro-injection system 50), immediately place the stent in purified water for ultrasonic washing at a power of 360W, a frequency of 40kHz, and a washing time of 5min to remove the complex formed by polyarginine and sodium hyaluronate, as well as the first polymer layer 70 that has not reacted with polyarginine and excess polyarginine. Subsequently, place the stent in a 50℃ oven to dry for 12h, finally obtaining a vascular stent in which only the heparin coating on the outer surface of the stent is combined with polyarginine, i.e., the intermediate coating 40 (thickness of 10-30nm), while the heparin coating on the inner surface and sides of the stent remains intact and is not covered by polymer.

[0067] Step S60: Place the vascular stent obtained in step S60 onto the outside of the support shaft (the outer diameter of the support shaft matches the inner diameter of the vascular stent); weigh 50 mg of rapamycin and 50 mg of racemic polylactic acid (intrinsic viscosity 0.7~1.0 dl / g), dissolve them in 1600 mg of acetone to prepare a drug spraying solution; use ultrasonic spraying, setting the following spraying process parameters: spraying air pressure 1.5 PSI, spraying power 1.0 W, injection rate 40 μL / min, nozzle-stent distance 12.5 mm, uniformly spray the drug spraying solution onto the outer surface of the stent, so that the rapamycin loading on the outer surface of the stent reaches 0.7 μg / mm. 2 The drug-coated stent was air-dried for 2 hours after spraying, and then placed in a 50°C oven for 12 hours to obtain the drug-coated stent. Example 2:

[0068] This application provides a method for preparing a drug-coated stent, comprising the following steps: Step S10: Take a cobalt-chromium alloy vascular stent and use it as the drug-eluting stent substrate 10. After ultrasonic washing with acetone, ethanol, purified water and isopropanol respectively, it is then treated with oxygen plasma for 30 minutes to obtain an activated vascular stent.

[0069] Step S20: Immerse the activated vascular stent in a 20% (w / w) aqueous solution of chitosan (weight average molecular weight of 100,000 Daltons) at 65°C for 0.5 hours, then remove it and rinse it with purified water to obtain a vascular stent with a chitosan layer on its surface.

[0070] Step S30: Form an anti-condensation coating 20 Step S301: Dissolve 1g of heparin calcium in 300mL of purified water and cool the solution to 0°C in an ice bath; add 10mg of sodium nitrate while stirring, then add 1M hydrochloric acid dropwise to adjust the pH of the solution to 3; maintain the low temperature of 0°C and stirring for 2 hours; after the reaction is complete, purify by dialysis and then freeze-dry to obtain heparin calcium with aldehyde groups at the end.

[0071] Step S302: Heparin calcium with aldehyde end groups was dissolved in purified water at a mass percentage concentration of 0.1% to prepare a reaction solution. A vascular stent with a chitosan layer on its surface was immersed in the reaction solution, ensuring complete submersion, and the reaction was carried out at 65°C for 0.5 hours. After the reaction, the vascular stent was removed and thoroughly rinsed with purified water to obtain a vascular stent with a heparin calcium coating grafted onto its inner, side, and outer surfaces. This heparin calcium coating is the anticoagulant coating 20. The areal density of the heparin calcium coating was determined to be 35 μg / cm³ using the toluidine blue colorimetric method. 2 .

[0072] Step S40: Weigh polyacrylic acid (weight average molecular weight of 450,000 Daltons) and dissolve it in purified water to prepare a first polymer solution with a mass percentage concentration of 2%; apply the first polymer solution to the junction of the outer surface and side surface of the cylindrical corrugated ring 101 using a micro-injection system 50 (see [link to product details]). Figure 9 The first polymer solution is applied from the left side of the paper shown in the figure. Under the action of gravity, the first polymer solution flows and spreads in the direction of arrow a. At the same time, the application operation must also be completed simultaneously at the corresponding symmetrical position on the right side of the paper. The first polymer solution completely covers the heparin coating on the inner surface and two sides of the drug-eluting stent substrate 10. The stent is placed in a 60°C oven and dried for 10 hours to form the first polymer layer 70 (formed on the outside of the anticoagulant coating 20) on the inner surface and two sides of the drug-eluting stent substrate 10.

[0073] Step S50: Weigh polylysine (weight average molecular weight of 150,000~300,000 Daltons) and dissolve it in purified water to prepare a second polymer solution with a mass percentage concentration of 2%. After applying this solution to the outer surface of the stent, immediately place the stent in purified water for ultrasonic washing at an ultrasonic power of 360W, an ultrasonic frequency of 40kHz, and an ultrasonic washing time of 5min to remove the complex formed by polylysine and polyacrylic acid, and at the same time remove the first polymer layer 70 that has not reacted with polylysine and excess polylysine. Subsequently, place the stent in a 60℃ oven to dry for 10h, and finally obtain a vascular stent in which only the heparin coating on the outer surface of the stent is combined with polylysine, that is, the intermediate coating 40 (thickness of 40~60nm), and the heparin coating on the inner surface and sides of the stent remains intact and is not covered by polymer.

[0074] Step S60: Place the vascular stent obtained in step S60 onto the outside of the support shaft (the outer diameter of the support shaft matches the inner diameter of the vascular stent); weigh 50 mg of zotamolimus and 500 mg of poly(lactic-co-glycolic acid) (weight-average molecular weight of 60,000~100,000 Daltons, where the molar ratio of lactide to glycolide is 75:25), dissolve them in 500 mg of ethyl acetate to prepare a drug spraying solution; use ultrasonic spraying, setting the following spraying process parameters: spraying pressure 1.5 PSI, spraying power 1.0 W, injection rate 40 μL / min, and nozzle-stent distance 12.5 mm, uniformly spray the drug spraying solution onto the outer surface of the stent, so that the zotamolimus loading on the outer surface of the stent reaches 0.7 μg / mm. 2 The drug-coated stent was air-dried for 2 hours after spraying, and then placed in a 50°C oven for 12 hours to obtain the drug-coated stent. Example 3:

[0075] This application provides a method for preparing a drug-coated stent, comprising the following steps: Step S10: Take a nickel-titanium alloy vascular stent and use it as the drug-eluting stent substrate 10. After ultrasonic washing with acetone, ethanol, purified water and isopropanol respectively, it is then treated with oxygen plasma for 30 minutes to obtain an activated vascular stent.

[0076] Step S20: Immerse the activated vascular stent in a 2% (w / w) aqueous solution of polyallylamine (weight average molecular weight of 25,000 Daltons) at 50°C for 12 hours, then remove it and rinse it with purified water to obtain a vascular stent with a polyallylamine layer on its surface.

[0077] Step S30: Form an anti-condensation coating 20 Step S301: Dissolve 1g of potassium heparin in 300mL of purified water and cool the solution to 0°C in an ice bath; add 10mg of sodium nitrate while stirring, then add 1M hydrochloric acid dropwise to adjust the pH of the solution to 3; maintain the low temperature of 0°C and stirring for 2 hours; after the reaction is complete, purify by dialysis and then freeze-dry to obtain potassium heparin with aldehyde groups at the end.

[0078] Step S302: Take heparin potassium with aldehyde end groups and dissolve it in purified water at a mass percentage concentration of 5%. After thorough dissolution, prepare a reaction solution. Immerse the vascular stent with a polyallylamine layer on its surface into the reaction solution, ensuring that the stent is completely submerged. React at 40°C for 48 hours. After the reaction, remove the vascular stent and rinse it thoroughly with purified water to obtain a vascular stent with a heparin potassium coating grafted onto its inner, side, and outer surfaces. This heparin potassium coating is the anticoagulant coating 20. The areal density of the heparin potassium coating is 35 μg / cm³ as determined by the toluidine blue colorimetric method. 2 .

[0079] Step S40: Weigh sodium alginate (weight-average molecular weight of 100,000 Daltons) and dissolve it in purified water to prepare a first polymer solution with a mass percentage concentration of 0.3%; apply the first polymer solution to the junction of the outer surface and side surface of the cylindrical corrugated ring 101 using a micro-injection system 50 (see [link to product details]). Figure 9 The first polymer solution is applied from the left side of the paper shown in the figure. Under the action of gravity, the first polymer solution flows and spreads in the direction of arrow a. At the same time, the application operation must also be completed simultaneously at the corresponding symmetrical position on the right side of the paper. The first polymer solution completely covers the heparin coating on the inner surface and two sides of the drug-eluting stent substrate 10. The stent is placed in a 40°C oven and dried for 15 hours to form the first polymer layer 70 on the inner surface and two sides of the drug-eluting stent substrate 10 (formed on the outside of the anticoagulant coating 20).

[0080] Step S50: Weigh polyethyleneimine (weight-average molecular weight of 25,000 Daltons) and dissolve it in purified water to prepare a second polymer solution with a mass percentage concentration of 0.3%. After applying this solution to the outer surface of the stent, immediately place the stent in purified water for ultrasonic washing at an ultrasonic power of 360W, an ultrasonic frequency of 40kHz, and an ultrasonic washing time of 5min to remove the complex formed by polyethyleneimine and transparent sodium alginate, and at the same time remove the first polymer layer 70 that has not reacted with polyethyleneimine and excess polyethyleneimine. Subsequently, place the stent in a 40℃ oven to dry for 15h, finally obtaining a vascular stent in which only the heparin coating on the outer surface of the stent is combined with polyethyleneimine, i.e., the intermediate coating 40 (thickness of 80~100nm), and the heparin coating on the inner surface and sides of the stent remains intact and is not covered by polymer.

[0081] Step S60: Place the vascular stent obtained in step S60 onto the outside of the support shaft (the outer diameter of the support shaft matches the inner diameter of the vascular stent); weigh 50 mg everolimus and 250 mg polyaryletherketone (weight-average molecular weight 50,000~100,000 Daltons), dissolve them in 1500 mg tetrahydrofuran to prepare a drug spraying solution; use ultrasonic spraying, setting the following spraying process parameters: spraying pressure 1.5 PSI, spraying power 1.0 W, injection rate 40 μL / min, nozzle-stent distance 12.5 mm, uniformly spray the drug spraying solution onto the outer surface of the stent, so that the everolimus loading on the outer surface of the stent reaches 0.7 μg / mm. 2 The drug-coated stent was air-dried for 2 hours after spraying, and then placed in a 50°C oven for 12 hours to obtain the drug-coated stent. Example 4:

[0082] This application provides a method for preparing a drug-coated stent. The difference between this embodiment and Embodiment 1 is that in step S20, the amino-rich polymer solution is an aqueous solution of polyallylamine hydrochloride (weight-average molecular weight of 25,000 Daltons) with a mass percentage concentration of 10%. In step S302, sodium heparin with aldehyde groups at the end is taken and dissolved in purified water at a mass percentage concentration of 3%. After complete dissolution, a reaction solution is prepared. In step S40, dextran sulfate (weight average molecular weight 20,000 Daltons) is weighed and dissolved in purified water to prepare a first polymer solution with a mass percentage concentration of 0.5%. In step S50, protamine sulfate is weighed and dissolved in purified water to prepare a second polymer solution with a mass percentage concentration of 0.5%. In step S60, 50 mg of Emulolimus and 50 mg of polyetheretherketone (weight average molecular weight of 100,000 Daltons) are weighed and dissolved in 2500 mg of propyl acetate to prepare a drug spraying solution. The procedure was the same as in Example 1, resulting in a drug-coated stent. Example 5:

[0083] This application provides a method for preparing a drug-coated stent. The difference between this embodiment and Embodiment 1 is that in step S20, the amino-rich polymer solution is an aqueous solution of poly-L-arginine hydrochloride (weight-average molecular weight of 30,000 to 70,000 Daltons) with a mass percentage concentration of 15%. In step S40, hyaluronic acid (weight-average molecular weight of 20,000 Daltons) is weighed and dissolved in purified water to prepare a first polymer solution with a mass percentage concentration of 1%. In step S50, polyornithine (weight average molecular weight of 30,000-70,000) is weighed and dissolved in purified water to prepare a second polymer solution with a mass percentage concentration of 1%. In step S60, 50 mg of desfomol and 100 mg of polyarylene ether (weight average molecular weight 100,000 Daltons) are weighed and dissolved in 5,000 mg of ethanol to prepare a drug spraying solution. The procedure was the same as in Example 1, resulting in a drug-coated stent. Example 6:

[0084] This application provides a method for preparing a drug-coated stent. The difference between this embodiment and Embodiment 1 is that in step S20, the amino-rich polymer solution is an aqueous solution of poly-L-lysine (weight-average molecular weight 150,000-300,000 Daltons) with a mass percentage concentration of 3%. In step S40, polyaspartic acid (weight-average molecular weight of 23,000 Daltons) is weighed and dissolved in purified water to prepare a first polymer solution with a mass percentage concentration of 1.5%. In step S50, N,N-dimethylaminoethyl methacrylate (weight average molecular weight of 20,000 Daltons) is weighed and dissolved in purified water to prepare a second polymer solution with a mass percentage concentration of 1.5%. In step S60, 50 mg of everolimus and 5 mg of polycarbonate (molecular weight 45,000 Daltons) are weighed and dissolved in 1500 mg of chloroform to prepare a drug spraying solution. The procedure was the same as in Example 1, resulting in a drug-coated stent. Example 7:

[0085] This application provides a method for preparing a drug-coated stent. The difference between this embodiment and Embodiment 1 is that in step S20, the amino-rich polymer solution is an aqueous solution of poly-L-arginine (weight-average molecular weight of 30,000 to 70,000 Daltons) with a mass percentage concentration of 5%. In step S40, sodium carboxymethyl cellulose (weight average molecular weight of 25,000 Daltons) is weighed and dissolved in purified water to prepare a first polymer solution with a mass percentage concentration of 0.5%. In step S60, 50 mg of ceramide and 50 mg of polyhydroxyalkanoate (weight average molecular weight of 50,000 Daltons) are weighed and dissolved in 10,000 mg of dimethyl sulfoxide to prepare a drug spraying solution. The procedure was the same as in Example 1, resulting in a drug-coated stent. Example 8:

[0086] This application provides a method for preparing a drug-coated stent. The difference between this embodiment and Embodiment 1 is that in step S20, the amino-rich polymer solution is an aqueous solution of poly-L-lysine hydrobromide (weight-average molecular weight of 30,000 to 70,000 Daltons) with a mass percentage concentration of 8%. In step S40, carbomer (model carbomer 940) is weighed and dissolved in purified water to prepare a first polymer solution with a mass percentage concentration of 0.5%. In step S60, 50 mg of probucol and 50 mg of polycaprolactone (weight average molecular weight of 40,000 to 100,000 Daltons) are weighed and dissolved in 2000 mg of tetrahydrofuran to prepare a drug spraying solution. The procedure was the same as in Example 1, resulting in a drug-coated stent. Example 9:

[0087] This application provides a method for preparing a drug-coated stent. The difference between this embodiment and Embodiment 1 is that in step S40, hydroxypropyl methylcellulose acetate succinate (weight-average molecular weight of 100,000 Daltons) is weighed and dissolved in purified water to prepare a first polymer solution with a mass percentage concentration of 0.5%. In step S60, 50 mg of tropidil and 50 mg of trimethylene carbonate (weight-average molecular weight of 100,000 Daltons) are weighed and dissolved in 2500 mg of dichloromethane to prepare a drug spraying solution. The procedure was the same as in Example 1, resulting in a drug-coated stent.

[0088] II. Comparative Example: Comparative Example 1: This application provides a method for preparing a drug-coated stent, comprising the following steps: Steps S10 to S30: are exactly the same as steps S10 to S30 in Example 1.

[0089] Step S40: Weigh polyarginine (weight average molecular weight 30,000~70,000 Daltons) and dissolve it in purified water to prepare a polyarginine solution with a mass percentage concentration of 0.5%; apply the solution to the outer surface of the stent and dry the stent in a 50°C oven for 12 hours to obtain a vascular stent.

[0090] Step S50: The vascular stent obtained in step S40 is fitted onto the outside of the support shaft (the outer diameter of the support shaft matches the inner diameter of the vascular stent); 50 mg of rapamycin and 50 mg of racemic polylactic acid are weighed and dissolved in 1600 mg of acetone to obtain a drug spraying solution; ultrasonic spraying is used, with the following spraying process parameters set: spraying air pressure 1.5 PSI, spraying power 1.0 W, injection rate 40 μL / min, and nozzle-stent distance 12.5 mm. The drug spraying solution is uniformly sprayed onto the outer surface of the stent, so that the rapamycin loading on the outer surface of the stent reaches 0.7 μg / mm. 2 The drug-coated stent was air-dried for 2 hours after spraying, and then placed in a 50°C oven for 12 hours to obtain the drug-coated stent.

[0091] III. Experimental Examples: 1. Heparin coating staining experiment Drug-coated stents prepared in Examples 1 to 9 and the drug-coated stent prepared in Comparative Example 1 were used for heparin coating staining experiments. The specific experimental procedures were as follows: Each drug-coated stent was immersed in a 0.02% (w / w) toluidine blue solution at room temperature (20°C to 25°C) for 2 minutes. After immersion, the residual solution on the surface of each drug-coated stent was gently blotted dry with sterile filter paper (avoiding scratching the coating). Finally, each drug-coated stent was placed under an optical microscope (200x magnification) to observe the staining, recording the color development state, uniformity, and presence of blank unstained areas on the inner surface and sides of the drug-coated stent. The experimental results are shown in Table 1 below. Figure 12 (a) Figure 12 (b) and Figure 12 As shown in (c): Table 1 Results of heparin coating staining experiment Combined with Table 1 and Figure 12 (a) Figure 12 (b) and Figure 12 The experimental observation results in (c) are used to analyze the heparin coating retention effect of the drug-eluting stent of this application as follows: (1) Verification of the integrity of the heparin coating in the example Please see Figure 12 (a) Figure 12 (b) and Figure 12 (c) Figure 12 (a) Figure 12 (b) and Figure 12(c) The drug-coated scaffolds prepared in Examples 1, 2 and 1 respectively were characterized by toluidine blue specific staining. Toluidine blue can specifically bind to the acidic mucopolysaccharide groups in heparin molecules and turn purple, which can be used to visually characterize the integrity of the heparin coating.

[0092] The drug-coated stent prepared in Example 1 exhibited a relatively uniform purple positive color after specific staining with toluidine blue on both its inner and side surfaces. Toluidine blue specifically binds to the acidic mucopolysaccharide groups in heparin molecules, resulting in a purple color. This staining result indicates that the heparin coating on the inner and side surfaces of the stent in Example 1 remained intact and undamaged, without being covered or destroyed by subsequent coating processes, thus laying the structural foundation for the continued anticoagulant effect of heparin. The staining results of Example 2 were essentially consistent with those of Example 1, with the inner and side surfaces of the stent also showing a uniform purple positive color, indicating that its heparin coating also remained intact.

[0093] Examples 3 to 9 show drug-coated stents prepared according to the core process of this application. After toluidine blue staining, the staining results are basically consistent with those of Example 1. The inner surface and sides of the stents show relatively uniform purple positive color development, and no staining loss or abnormal fading occurs (the relevant staining result images are consistent with those of Examples 1 and 2, and no separate figures are shown). This result fully demonstrates that the process parameter selection and coating combination design of this application have good universality and stability, and can stably achieve complete retention of the heparin coating on the inner surface and sides of the stent under different process conditions.

[0094] (2) Control of heparin coating destruction in Comparative Example 1 Please see Figure 12 (c) Figure 12 (c) The characterization results of the drug-coated stent prepared in Comparative Example 1 after toluidine blue specific staining. As a control, the drug-coated stent in Comparative Example 1, after being treated with the same toluidine blue staining, only showed vague purple positive staining in the two areas marked by the red arrows. The rest of the stent showed the background color of the stent substrate itself, with no obvious purple coloration. This result indicates that the process of Comparative Example 1 failed to effectively protect the anticoagulant coating 20 on the inner surface / side of the stent. Most of the heparin coating was covered or destroyed by subsequent coatings, resulting in severe masking of the anticoagulant active sites and failure to perform normal antithrombotic function. This contrasts sharply with the example, further verifying the effectiveness of the process in ensuring the integrity of the heparin coating.

[0095] The above experimental results fully demonstrate that the technical solution of this application, through a differentiated coating preparation process (layered anticoagulant coating 20, intermediate coating 40, and drug coating 30), effectively protects and preserves the integrity of the heparin coating on the inner surface and sides of the stent while promoting stable adhesion of the drug coating 30 to the outer surface of the stent. This avoids the technical defects of existing technologies where the heparin coating is covered or damaged. The complete preservation of the heparin coating ensures that heparin is continuously exposed to the blood and exerts its anticoagulant effect, fundamentally improving the antithrombotic ability of the drug-eluting stent and effectively reducing the risk of acute thrombosis after stent implantation. Meanwhile, the stable adhesion of the drug coating 30 ensures the long-term sustained-release effect of the active drug, achieving the dual clinical goals of antithrombosis and anti-restenosis. In summary, the technical solution of this application significantly improves the clinical safety and therapeutic efficacy of drug-eluting stents, meeting the clinical treatment needs of related vascular diseases.

[0096] The above description is merely a specific embodiment of this application, but the scope of protection of this application is not limited thereto. Any changes or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this application should be included within the scope of protection of this application.

Claims

1. A drug-coated stent, characterized in that, include: Drug-eluting scaffold matrix; An anticoagulant coating is applied to the surface of the drug-eluting scaffold matrix. An intermediate coating is applied over the anticoagulant coating and is located on the outside of the drug-eluting scaffold matrix; A drug coating is applied to the outer surface of the intermediate coating, the drug coating comprising an active drug and a controlled-release polymer for controlling the release rate of the active drug; The intermediate coating and the anticoating coating are bonded together by charge adsorption.

2. The drug-coated stent according to claim 1, characterized in that, The anticoagulant coating fixes the heparin endpoint to the surface of the drug-eluting scaffold substrate through an aldehyde-amine reaction. And / or, the drug-eluting stent matrix is ​​composed of multiple axially arranged cylindrical corrugated rings connected by connectors. The cylindrical corrugated rings are formed by multiple wave rods connected sequentially in the circumferential direction to form a continuous bending structure, and the bending connection of adjacent wave rods constitutes a crest or trough. The connectors are connected to the crests and troughs, troughs and troughs, or crests and crests of adjacent cylindrical corrugated rings. The intermediate coating covers the anticoagulant coating of the cylindrical corrugated rings, and the intermediate coating is located on the outside of the drug-eluting stent matrix. The drug coating covers the outer surface of the intermediate coating.

3. The drug-coated stent according to claim 2, characterized in that, The outer surface of the wave rod is provided with a groove, the intermediate coating covers the inner wall and bottom surface of the groove, and the drug coating covers the outer surface of the intermediate coating.

4. The method for preparing a drug-coated stent according to any one of claims 1-3, characterized in that, Includes the following steps: Step S10: Clean and activate the drug-eluting scaffold substrate; Step S20: Form an amino polymer layer on the surface of the activated drug scaffold substrate; Step S30: Grafting heparin molecules with aldehyde groups at the end groups to the amino polymer layer via an amine condensation reaction to form an anticoating coating; Step S40: Apply a first polymer solution to the junction of the outer surface and side surface of the drug-eluting stent matrix with the anticoagulant coating formed, so that the first polymer solution covers and coats the anticoagulant coating on the inner surface and side surface of the drug-eluting stent matrix, and forms a first polymer layer after drying. Step S50: Apply a second polymer to the outside of the anticoagulant coating on the outer surface of the drug-eluting stent matrix, and fix the second polymer to the anticoagulant coating on the outer surface by charge adsorption; After washing, the complex formed by the combination of the first polymer layer and the second polymer, as well as the first polymer layer that is not combined with the second polymer, are removed; after drying, an intermediate coating is formed on the outside of the anticoagulant coating on the outer surface of the drug-eluting stent matrix. Step S60: Apply a drug coating containing the active drug and controlled-release polymer to the outer surface of the intermediate coating.

5. The method for preparing a drug-coated stent according to claim 4, characterized in that, In step S50, the first polymer layer and the second polymer are bonded together by ionic bonds to form a complex; And / or, in step S40, the first polymer is selected from one or more of polyacrylic acid, dextran sulfate, sodium alginate, hyaluronic acid, polyaspartic acid, polyglutamic acid, sodium carboxymethyl cellulose, carbomer, and hydroxypropyl methylcellulose acetate succinate; And / or, in step S40, the mass percentage concentration of the first polymer in the first polymer solution is 0.3% to 2%; And / or, in step S40, when the first polymer solution is applied, the first polymer solution is allowed to flow along the surface of the support under gravity and cover the inner surface and the side surface.

6. The method for preparing a drug-coated stent according to claim 4, characterized in that, In step S50, the second polymer is selected from one or more of polylysine, polyarginine, protamine, polyornithine, polyethyleneimine, and N,N-dimethylaminoethyl methacrylate. And / or, in step S50, the mass percentage concentration of the second polymer in the second polymer solution is 0.3% to 2%; And / or, in step S50, the washing process includes water washing; the second polymer carries a positive charge, the anticoagulant coating carries a negative charge, and the second polymer is bonded to the anticoagulant coating on the outer surface of the drug stent matrix by electrostatic adsorption.

7. The method for preparing a drug-coated stent according to claim 4, characterized in that, In step S20, the formation of the amino polymer layer includes: immersing the activated drug scaffold matrix in an amino-rich polymer solution to form an amino polymer layer on the surface of the drug scaffold; the polymer used to prepare the amino-rich polymer solution is selected from at least one of polyethyleneimine, chitosan, polyallylamine, polyallylamine hydrochloride, poly-L-arginine, poly-L-arginine hydrochloride, poly-L-lysine, and poly-L-lysine hydrobromide. And / or, in step S30, the formation of the anticoagulant coating includes: immersing a drug-eluting scaffold substrate with an amino polymer layer on its surface in a reaction solution containing heparin molecules with aldehyde end groups; grafting heparin molecules onto the amino polymer layer via an amine condensation reaction to form an anticoagulant coating; and controlling the areal density of the anticoagulant coating to be 0.5 μg / cm³. 2 Up to 50 μg / cm 2 .

8. The method for preparing a drug-coated stent according to claim 7, characterized in that, In step S20, when the activated drug-eluting scaffold matrix is ​​immersed in an amino-rich polymer solution, the immersion temperature is 40°C to 120°C, the immersion time is 0.5 hours to 24 hours, and the mass percentage concentration of the polymer solution is 2% to 20%. And / or, in step S30, the heparin molecule is selected from at least one of heparin, its pharmaceutically acceptable salt, low molecular weight heparin, and terminal-modified heparin; And / or, in step S30, when the drug scaffold matrix with an amino polymer layer on its surface is immersed in a reaction solution containing heparin molecules with aldehyde end groups, the immersion temperature is 40°C to 120°C and the immersion time is 0.5 hours to 48 hours; the mass percentage concentration of heparin molecules in the reaction solution is 0.1% to 5%.

9. The method for preparing a drug-coated stent according to claim 4, characterized in that, In step S60, the controlled-release polymer is selected from degradable polymers, non-degradable polymers, or a combination of both; The biodegradable polymer is selected from lactide, trimethylene carbonate, glycolide, poly(L-lactide), racemic polylactic acid, polylactide-co-glycolic acid, poly(L-lactide-co-glycolic acid), poly(L-lactide-co-ε-caprolactone), poly(L-lactide-co-trimethylene carbonate), polytrimethylene carbonate, polycaprolactone, poly(glycolic acid-trimethylene carbonate), poly(lactide-glycolic acid-trimethylene carbonate), polyhydroxybutyrate, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), polyhydroxyvalerate, polyhydroxybutyrate / polyhydroxyvalerate copolymer, polyhydroxyalkanoate, polyorthoester, polyanhydride, polyimide carbonate, tyrosine-derived polycarbonate, and tyrosine-derived polyacrylic acid. The following are included in the following categories: esters, iodinated tyrosine-derived polycarbonates, brominated tyrosine-derived polycarbonates, iodinated tyrosine-derived polyacrylates, brominated tyrosine-derived polyacrylates, polyamide esters, polycarbonate copolymers, lactone-based polymers, poly(propylene fumarate-co-ethylene glycol) copolymers, polyanhydride esters, silk-elastin polymers, polyphosphazenes, aliphatic polyurethanes, polyhydroxy acids, polyether esters, polyphenolic peptides, poly(alkylene oxalate), polyaspartic acid, polyglutamic acid polymers, poly(p-dioxanone), poly(β-dioxanone), asymmetric 3,6-substituted poly(1,4-dioxane-2,5-dione), polyalkyl-2-cyanoacrylates, polydihydropyran, poly(β-maleic acid), polyfatty acid esters, and poly(β-alkanoic acid). The non-degradable polymer is selected from one or more of polyaryletherketone, polyetheretherketone, polyimide, polyethylene, polypropylene, polyethylene terephthalate, polybutyl methacrylate, polycarbonate, polyphenylsulfone, polyethersulfone, polyetherimide, polyurethane, polyamide, nylon, polyvinyl chloride, polytetrafluoroethylene, fluorinated ethylene propylene copolymer, ethylene-tetrafluoroethylene copolymer, PFA, polyvinylidene fluoride, polyvinylidene fluoride-hexafluoropropylene copolymer, and acryloylbutadiene styrene.

10. The method for preparing a drug-coated stent according to claim 4, characterized in that, In step S60, the active drug is selected from one or more of the following: rapamycin, rapamycin derivatives, ABT-578, zotalimus, everolimus, eutrimolimus, desfolimus, tesiromolimus, tacrolimus, pimecrolimus, nitric oxide synthase, C3 exoenzyme, RhoA inhibitor, A3 agonist, CB2 agonist, 17-AAG, Hsp90 antagonist, tyrosine phosphorylation inhibitor, cathepsin S inhibitor, paclitaxel and its derivatives, paclitaxel, docetaxel, corticosteroids, dexamethasone, ceramide, dimethylsphingosine, ether-linked diglycerides, ether-linked phosphatidic acid, dihydrosphingosine, estrogen, takazole, takazole analogs, actinomycin D, prostaglandins, vitamin A, probucol, palmastat, statins, tropidil, mitomycin C, cytochalasin B, antiangiogenic agents, and antibodies. And / or, in step S60, the formation of the drug coating specifically includes: Fix the vascular stent to be sprayed onto a support shaft with a diameter that matches its diameter; A drug spraying solution is prepared by mixing and dissolving an active drug, a controlled-release polymer, and an organic solvent, wherein: the mass ratio of the active drug to the controlled-release polymer is 1:(0.1~10); and the mass ratio of the active drug to the organic solvent is 1:(10~200). The drug spraying solution is uniformly sprayed onto the outer surface of the vascular stent, so that the active drug loading on the outer surface of the vascular stent reaches 0.5 μg / mm². 2 Up to 1.0 μg / mm 2 ; The coated vascular stents were subjected to natural drying and constant temperature drying processes in sequence to obtain drug-coated stents.

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