Composite drug sustained-release system based on biomimetic glycocalyx coating and medical catheter

Abstract

The application discloses a composite drug sustained-release system based on a biomimetic glycocalyx coating and a medical catheter. The sustained-release system comprises, in sequence, an adhesion layer, a drug storage layer and a biomimetic glycocalyx coating arranged on the surface of a base. The adhesion layer is formed by in-situ polymerization of polyphenols. The drug storage layer embeds active drugs through hydrophobic or amphiphilic polymers. The biomimetic glycocalyx coating simulates the structure of vascular endothelium and is formed by cross-linking of modified polyethylene glycol and biological macromolecules through polyphenols and metal ions. The application can realize self-repairing of damage by using the double cross-linking network of the biomimetic glycocalyx coating, and can synergistically regulate drug release kinetics through a high hydration physical barrier and the storage layer, thereby significantly reducing the friction coefficient of intervention, and also endowing the medical catheter with properties such as antithrombosis and drug sustained release, effectively inhibiting initial burst release of drugs and prolonging the release period, and significantly improving the mechanical resistance, biocompatibility and safety of the medical catheter.

Description

Technical Field

[0001] This application belongs to the field of medical material surface modification and drug sustained release technology, specifically a composite drug sustained release system and medical catheter based on a biomimetic sugar calyx coating. Background Technology

[0002] Medical catheters play a vital role in clinical diagnosis and local treatment. Particularly in the fields of cardiovascular disease and interventional oncology, drug-release catheters demonstrate significant advantages in reducing systemic toxicity through local drug delivery. Coating technology, as the core of drug-release catheters, directly impacts drug delivery efficiency, biocompatibility, and ultimately, clinical efficacy.

[0003] Currently, there is still room for improvement in the precise control of drug release rates and the effectiveness of long-term placement of medical catheter coating systems. Meanwhile, the friction between the interventional catheter and human tissue is also a significant factor affecting clinical experience; excessive friction not only reduces operative compliance but may also induce tissue trauma, infection, or thrombosis. Although adding a hydrophilic coating to the catheter surface to form a hydration layer can reduce the coefficient of friction, the stability of the adhesion between the hydrophilic coating and the substrate, as well as its intervention in the drug release process, remain key areas of focus for the industry.

[0004] Glycocalyx, a natural protective layer on the surface of human vascular endothelial cells, is composed of glycoproteins, glycolipids, and proteoglycans, and possesses excellent antithrombotic and biocompatibility properties. Utilizing biomimetic technology to mimic the glycocalyx structure provides a new direction for developing high-performance drug sustained-release systems.

[0005] However, existing related technologies still need optimization in achieving the synergy between precise drug release and super-lubricating properties. For example, CN116421361A discloses a sustained-release artificial blood vessel for rapamycin, which uses electrospinning technology to prepare PCL artificial blood vessels and utilizes heparinization followed by adsorption of rapamycin to achieve sustained drug release. Although this approach has achieved some effect in inhibiting intimal hyperplasia, there is still room for optimization in the fine-tuning of the drug release process, resulting in a need to improve the consistency of drug release duration with pre-set clinical requirements. Another example is CN117797326A, which discloses a super-lubricating coating for the surface of a medical catheter and its preparation method, which uses functional polymers such as polyvinylpyrrolidone and hyaluronic acid to reduce the coefficient of friction and improve adhesion. While this approach improves the lubrication performance of the catheter, the hydrophilic single-layer coating used in conjunction with a drug release system has limited ability to block liquid penetration, easily inducing a "burst release" phenomenon, resulting in a large release of drug in a very short time, affecting drug utilization and the safety of the treatment process. Summary of the Invention

[0006] The main objective of this application is to provide a composite drug sustained-release system and medical catheter based on a biomimetic calyx coating. By constructing a gradient composite structure consisting of an adhesion layer, a drug reservoir, and a biomimetic calyx coating on the surface of the medical catheter body, the self-healing properties provided by the hydrogen bond and coordination bond dual cross-linking network of the biomimetic calyx coating, as well as the physical confinement of drug molecules by hydrophobic or amphiphilic polymers in the drug reservoir, can be used to regulate the drug release kinetic curve and reduce the surface friction coefficient during catheter intervention, thereby overcoming the shortcomings of the prior art.

[0007] To achieve the above-mentioned objectives, this application adopts the following technical solution.

[0008] In a first aspect, this application provides a method for preparing a composite drug sustained-release system based on a biomimetic sugar calyx coating, comprising the following steps: S10: The substrate surface is cleaned and activated. The activated substrate is then immersed in a buffer solution containing polyphenolic compounds and reacted at room temperature to form an adhesive layer in situ on the substrate surface. S20: Prepare an organic solution containing a biodegradable polymer and an active drug, and apply the organic solution to the surface of the adhesive layer using a spraying or dip coating process, and form a drug reservoir after drying; S30: Mix an aqueous solution containing a polyethylene glycol derivative with catechol groups at the end (hereinafter referred to as "modified polyethylene glycol"), a biomacromolecule, and a polyphenol crosslinking agent, adjust the pH value to 7.4~8.5, and construct a biomimetic sugar calyx coating on the surface of the drug reservoir through covalent crosslinking and non-covalent interactions.

[0009] In some embodiments, the activation treatment in step S10 employs plasma treatment or ozone treatment, with a treatment time of 30 to 120 seconds, aiming to increase the oxygen-containing functional groups on the substrate surface and improve the grafting density of polyphenolic substances.

[0010] In one embodiment, the polyphenolic compound in step S10 includes at least one of dopamine, tannic acid, catechin, and epicatechin, but is not limited thereto.

[0011] In one embodiment, the concentration of the buffer solution containing polyphenolic compounds in step S10 is 1~5 mg / mL.

[0012] In one embodiment, the buffer solution in step S10 is a tris(hydroxymethyl)aminomethane hydrochloride buffer solution with a concentration of 10-50 mmol / L and a pH of 8.0-8.5.

[0013] In one embodiment, the reaction time in step S10 is 2 to 6 hours.

[0014] In some cases, the adhesive layer may also be doped with silver nanoparticles at a concentration of 1 to 5 wt%. The silver nanoparticles can be prepared in situ by reducing silver ions with polyphenols to give the coating additional antibacterial function and further reduce the risk of catheter-related infections.

[0015] In one embodiment, the adhesive layer in step S10 is dense and has a thickness of 20-100 nm, preferably 40-60 nm. This thickness provides sufficient chemically active sites without affecting the flexibility of the catheter. The thickness of the adhesive layer can be precisely controlled by adjusting the dopamine polymerization time.

[0016] According to this application, an adhesive layer rich in hydroxyl and amino groups is introduced onto the substrate surface in step S10 to provide chemical anchoring points for the subsequent drug reservoir. Taking dopamine as an example of a polyphenol compound, during the construction of the adhesive layer, dopamine undergoes auto-oxidative polymerization under alkaline conditions to form polydopamine (PDA) with a highly cross-linked structure. The catechol groups in the PDA film can form hydrogen bonds with the oxygen-containing functional groups on the substrate surface, while its active quinone groups can covalently bond with the amino or hydroxyl groups at the polymer chain ends in the drug reservoir, thereby ensuring interlayer adhesion.

[0017] In one embodiment, after the adhesive layer is formed, it is preferably ultrasonically cleaned with deionized water for 5-10 minutes to remove unbonded monomers and oligomers on the surface, ensuring the cleanliness of the interface and the bonding strength of subsequent coatings.

[0018] In one embodiment, the degradable polymer in step S20 includes a hydrophobic polymer or an amphiphilic polymer; the hydrophobic polymer may be selected from at least one of polylactic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, and polyhydroxyalkanoate; the amphiphilic polymer may be selected from at least one of polyethylene glycol monomethyl ether polylactic acid block copolymer and polyethylene glycol polycaprolactone block copolymer; and is not limited thereto.

[0019] In one embodiment, the active drug in step S20 is selected from at least one of scopolamine derivatives, rapamycin, paclitaxel, heparin, and antibiotics, but is not limited thereto.

[0020] In one embodiment, the mass ratio of the active pharmaceutical ingredient to the degradable polymer is 1:100 to 30:100.

[0021] In one embodiment, the solvent of the organic solution in step S20 includes at least one of dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, and acetone, but is not limited thereto.

[0022] In one embodiment, the total concentration of solute in the organic solution is 1 to 10 wt%.

[0023] According to this application, ultrasonic atomization spraying technology is preferably used in step S20. By controlling the nozzle moving speed to 10-50 mm / s and the spray flow rate to 0.01-0.1 mL / min, the thickness deviation of the drug reservoir along the entire length of the conduit is ensured to be less than 1 μm. This highly uniform reservoir structure is the basis for achieving precise sustained release. During the spraying process, the pressure is preferably controlled at 0.1-0.3 MPa, and nitrogen is preferably used as the carrier gas to prevent oxidative degradation of the drug during spraying. During the spraying process, the ambient humidity is preferably controlled between 40% and 50%. In addition, during the spraying process, the distance between the nozzle and the conduit surface is preferably maintained at 20-30 mm, and the conduit is rotated at a speed of 60 rpm by a turntable. This ensures that the thickness deviation of the drug reservoir in both the circumferential and axial directions is less than 0.5 μm, further ensuring the consistency of drug release behavior.

[0024] According to this application, the drug loading in the drug reservoir is achieved by adjusting the number of spraying cycles, and the total drug loading can be set between 100 and 500 μg / cm³. 2 between.

[0025] In one embodiment, the thickness of the drug reservoir is 5~20 μm.

[0026] According to this application, in step S20, a hydrophobic or amphiphilic polymer is used to encapsulate the drug, thereby restricting the free diffusion of drug molecules through the entanglement of polymer segments and hydrophobic interactions.

[0027] In some cases, the biodegradable polymers in the drug reservoir are a mixture of PLGAs of different molecular weights. By utilizing the multi-peak degradation characteristics, the accumulation of acidic products generated by the degradation of single molecular weight polymers is eliminated, and the pH stability of the local microenvironment is maintained.

[0028] In some cases, the amphiphilic polymers in the drug reservoir align outward through their hydrophilic segments, forming molecular-level interpenetration and entanglement with the outermost biomimetic calyx layer, thereby enhancing interlayer bonding.

[0029] In some cases, the drug reservoir adopts a double-layer structure, with the inner layer carrying a long-acting sustained-release drug such as rapamycin and the outer layer carrying a fast-acting drug such as heparin. The difference in degradation rate between the two polymer layers enables a dual drug delivery mode.

[0030] In some cases, a porogen at a concentration of 2-5 wt%, such as polyethylene glycol 400, can be added to the drug reservoir to form micropores through the dissolution and loss of the porogen, thereby helping to regulate the release rate of the drug in the hydrophobic matrix.

[0031] In some cases, antioxidants, such as vitamin E or butylated hydroxyanisole, may also be added to the drug reservoir at an amount of 0.1% to 0.5% of the polymer mass to protect the stability of easily oxidized drug components during coating preparation and storage.

[0032] In one embodiment, the drying process of the drug reservoir preferably employs gradient temperature-controlled drying, comprising: drying at 25°C for 2 hours, then increasing the temperature to 40°C for 4 hours, and finally treating in a vacuum drying oven at 50°C for 12 hours to completely remove residual organic solvents until the solvent residue is below 0.05%. Gradient temperature-controlled drying prevents rapid solvent evaporation, which could lead to pinholes or cracks on the coating surface. The initial 25°C drying aims to slowly remove most of the solvent, maintaining the uniform arrangement of polymer segments; the subsequent temperature increase is used to thoroughly remove residual solvent molecules encapsulated deep within the polymer matrix. This drying process is preferably carried out in a cleanroom, and the air velocity is preferably controlled at 0.3~0.5 m / s to prevent airborne particles from interfering with the surface smoothness of the drug reservoir. After drying, the disappearance of solvent peaks in the drug reservoir can be detected using methods such as infrared spectroscopy to ensure thorough solvent removal and avoid chemical irritation to biological tissues.

[0033] In one embodiment, the preparation process of the biomimetic sugar calyx coating in step S30 specifically includes: S301: Dissolve a polyethylene glycol derivative with a terminal catechol group in deionized water to prepare a modified polyethylene glycol solution with a concentration of 5~20 mg / mL. S302: Dissolve chitosan or polylysine in acetic acid solution or phosphate buffer to prepare a biomacromolecule solution with a concentration of 2~10 mg / mL; S303: Mix the modified polyethylene glycol solution and the biomacromolecule solution at a volume ratio of 1:5 to 5:1, add a polyphenol crosslinking agent with a concentration of 0.5 to 2 mg / mL, and then allow the resulting mixed reaction solution to react at 30 to 45°C for 4 to 12 hours.

[0034] Furthermore, the molecular weight of the polyethylene glycol derivative with terminal catechol groups is 2000-20000. Preferably, the structural formula of the polyethylene glycol derivative with terminal catechol groups contains at least two catechol functional groups.

[0035] Furthermore, the polyethylene glycol derivative with catechol groups at the end can be obtained by reacting polyethylene glycol diacid with dopamine hydrochloride in the presence of condensing agent EDC / NHS.

[0036] Specifically, polyethylene glycol diacid with a molecular weight of 2000-20000 and dopamine hydrochloride can be dissolved in an organic solvent at a mass ratio of 1:0.5-1:1.5, and a condensing agent can be added. The reaction is carried out at room temperature in the dark. After the reaction is completed, the resulting reaction mixture is dialyzed against deionized water for 2-4 days, and then freeze-dried. The grafting rate of the obtained product is controlled between 80% and 95% to ensure sufficient catechol groups for subsequent crosslinking and self-repair. The reaction process is monitored by proton nuclear magnetic resonance spectroscopy to ensure the accurate introduction of functional groups.

[0037] Furthermore, the organic solvent includes, but is not limited to, dimethyl sulfoxide.

[0038] Furthermore, the condensing agent includes EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide) and NHS (N-hydroxysuccinimide).

[0039] Furthermore, the concentration of the acetic acid solution can be 1%. The phosphate buffer solution can be PBS with a pH of 7.4 and a concentration of 0.01 mol / L.

[0040] Furthermore, in step S301, the concentration of the polyethylene glycol derivative containing catechol groups at the end is preferably adjusted to 10-15 mg / mL. Within this concentration range, the pore size of the cross-linked network formed by the coating is distributed between 50 and 200 nm, which can effectively intercept drug molecules with a molecular weight greater than 1000 Daltons, thereby achieving controlled release of medium and large molecular drugs.

[0041] Furthermore, when the biomolecule is chitosan, the degree of deacetylation of the chitosan in the biomimetic calyx coating is greater than 90%, and the molecular weight is 50,000 to 150,000, to ensure that the coating has a moderate swelling rate and good mechanical strength under physiological pH conditions.

[0042] Furthermore, when the biomolecule is polylysine, its molecular weight is preferably 10,000 to 50,000. A higher molecular weight helps to increase the cohesive force of the coating and improve its peel strength.

[0043] In one embodiment, the polyphenol crosslinking agent includes at least one of tannic acid, gallic acid, and proanthocyanidins, but is not limited thereto. The polyphenol crosslinking agent forms a three-dimensional network through hydrogen bonding between polyphenol hydroxyl groups and polyethylene glycol segments and biomolecular segments. More preferably, the polyphenol crosslinking agent is a mixture of tannic acid and dopamine in a molar ratio of 1:2 to 2:1, utilizing the multi-site crosslinking ability of tannic acid and the strong adhesion of dopamine to optimize the overall performance of the coating.

[0044] In one embodiment, step S303 further includes adding a metal salt to the mixed reaction solution until the concentration of the metal ions is 0.1~1 mmol / L; the metal salt includes at least one of ferric chloride and zinc chloride. The metal ions can form coordination bonds with the aforementioned polyphenolic hydroxyl groups.

[0045] For example, in step S30, the metal salt added to the mixed reaction solution is ferric chloride, and the Fe ion concentration is 0.5 mmol / L. The coordination complex formed by Fe ions and catechol groups increases the crosslinking point density of the coating, so that the swelling rate of the coating in physiological saline is controlled between 150 and 200%, ensuring that the coating has both good lubricity and sufficient physical barrier strength.

[0046] In the construction of the biomimetic sugar calyx coating, taking tannic acid as the polyphenol crosslinking agent and Fe ions as the metal ions as an example, the tannic acid molecule contains a large number of galloyl groups, which can form a dense hydrogen bond network with the catechol groups on the modified polyethylene glycol and the amino groups on the chitosan. Simultaneously, the introduction of Fe ions induces the formation of metal-polyphenol coordination bonds. These coordination bonds are reversible, forming the mechanical basis for the coating's self-healing properties. When the coating is subjected to mechanical shearing and microcracks are generated, water molecules induce microscopic migration of polymer segments, and the broken coordination bonds and hydrogen bonds reform at the new contact surface, thereby closing the cracks.

[0047] In some cases, sodium hyaluronate with a concentration of 0.1 to 0.3 wt% can be added to the mixed reaction solution in step S303. The introduction of sodium hyaluronate can increase the viscoelasticity of the coating and further simulate the mechanical properties of natural sugar calyx.

[0048] Preferably, the reaction temperature in step S30 is controlled at around 37°C to simulate the human body temperature environment, so that the chemical structure of the coating reaches the most stable equilibrium state under physiological conditions.

[0049] Preferably, in step S30, the pH value of the reaction system is controlled between 7.8 and 8.2 to optimize the polyphenol oxidation rate, so that the coating can form a more uniform intermolecular cross-linking network during the film formation process.

[0050] In one embodiment, the biomimetic sugar calyx coating may also embed a fluorescent tracer or contrast agent, such as iodofol or sodium fluorescein, for real-time monitoring of the coating's integrity or drug release area via imaging techniques during intervention.

[0051] In one embodiment, after completing step S30, the composite drug sustained-release system is placed in an environment with a relative humidity of 60% to 90% for 12 to 24 hours to allow the biomimetic sugar calyx coating to fully hydrate.

[0052] In one embodiment, the biomimetic sugar calyx coating has a thickness of 1~5μm and its surface microstructure exhibits a uniform honeycomb microporous structure with a pore size of 100~300nm. This structure is beneficial for capturing and stabilizing the hydration layer and improving lubrication durability.

[0053] The biomimetic calyx coating constructed in step S30 simulates the natural structure of the vascular endothelial surface, containing numerous hydrogen bonds and metal coordination bonds. When the coating is subjected to mechanical damage, the broken non-covalent bonds rearrange and close in an aqueous environment, restoring the integrity of the coating within 5-15 minutes. Furthermore, the biomimetic calyx coating exhibits a mass loss rate of less than 2% after being subjected to scouring under simulated blood flow conditions (shear force of approximately 1.5 Pa) for 24 hours, demonstrating excellent scouring stability.

[0054] In one embodiment, the total thickness of the composite drug sustained-release system is controlled at 10~30μm to ensure sufficient drug loading and lubrication without significantly altering the outer diameter and permeability of the catheter.

[0055] In the multi-layered composite structure of the compound drug sustained-release system described in this application, the biomimetic calyx coating serves as the outermost layer. Its highly hydrated state forms a physical barrier that increases the resistance to water penetration into the drug reservoir, slowing down the drug dissolution rate and preventing initial burst release. Release experiments were conducted on the composite system in simulated physiological saline. The results showed that in the first 24 hours, the drug release was less than 7% of the total amount. From day 3 to day 28, the drug maintained a constant release rate, with daily release fluctuations of less than 10%. Compared to a single-layer hydrophilic coating, the burst release effect was reduced by more than 80%, effectively prolonging the drug's duration of action. Furthermore, the compound drug sustained-release system of this application exhibits good biocompatibility. According to ISO 10993 standards, the cytotoxicity level is 0-1, with no hemolysis or sensitization.

[0056] Secondly, this application provides a composite drug sustained-release system based on a biomimetic calyx coating, wherein the composite drug sustained-release system is prepared by the method described above. The composite drug sustained-release system includes an adhesion layer, a drug reservoir, and a biomimetic calyx coating sequentially stacked on a substrate surface.

[0057] Furthermore, the adhesive layer is bonded to the polar groups on the matrix surface by covalent bonds generated by polyphenol oxidative polymerization; the drug molecules in the drug reservoir are uniformly dispersed in the polymer matrix; and the biomimetic calyx coating has a highly branched network structure.

[0058] Furthermore, the biomimetic sugar calyx coating has a contact angle of less than 20° in an aqueous environment, and its surface friction coefficient is between 0.01 and 0.05.

[0059] Furthermore, the biomimetic sugar calyx coating possesses self-healing properties, which are achieved through the synergistic effect of dynamic covalent or non-covalent bonds. When scratches occur on the surface, some hydrogen bonds break under shear force, absorbing energy and preventing crack propagation. After the force is removed, under the influence of water molecule induction and Brownian motion of polyethylene glycol segments, the broken functional groups re-contact and recombine, thereby restoring macroscopic properties. The repair time is 5-15 minutes.

[0060] The composite drug sustained-release system described in this application has a drug release curve that conforms to a first-order kinetic equation or a zero-order kinetic equation. By adjusting the polymer molecular weight of the drug reservoir and the degree of cross-linking of the biomimetic glycocalyx layer, the release half-life can be adjusted between 7 and 45 days.

[0061] Thirdly, this application provides a medical catheter, including a catheter body and the aforementioned composite drug release system based on a biomimetic calyx coating, wherein the composite drug release system uniformly covers the outer wall of the catheter body.

[0062] Furthermore, the material of the catheter body includes at least one of polyurethane, polyvinyl chloride, silicone rubber, latex, nylon, and polyether block amide, and is not limited thereto.

[0063] In some cases, the medical catheters include, but are not limited to, stroke thrombectomy catheters, microcatheters, urinary catheters, endotracheal tubes, or gastric tubes.

[0064] Furthermore, the medical catheter is an interventional surgical catheter with a soft tip design. The composite drug sustained-release system also covers the edge of the tip, reducing the mechanical stimulation of the blood vessel wall by the catheter tip through improved lubrication performance.

[0065] In some cases, the outer packaging of the medical catheter may also contain an immersion solution, which is sterile saline or an aqueous solution containing 10% glycerol, so that the catheter is pre-lubricated after removal.

[0066] Fourthly, this application provides a method for preparing a medical catheter, comprising: uniformly covering the composite drug sustained-release system on the outer wall of the medical catheter body using the method for preparing the composite drug sustained-release system based on the biomimetic calyx coating, and then equilibrating it in an environment with a relative humidity of 60% to 90% for 12 to 24 hours.

[0067] The coverage length of the composite drug sustained-release system based on the biomimetic calyx coating on the catheter body is set according to clinical needs. For example, for thrombectomy catheters, the coverage length is usually 30-50 cm from the distal end of the catheter, covering the main part that enters the microvessels.

[0068] Furthermore, the medical catheter can be sterilized with ethylene oxide or gamma rays before packaging. Due to the stability of the coating structure, the sterilization process has an impact of less than 3% on the drug content and coating lubrication performance.

[0069] In the construction of the adhesive layer, taking dopamine as an example of a polyphenolic compound, dopamine undergoes oxidative polymerization under weakly alkaline conditions to form a polydopamine (PDA) film. This film contains a large number of ortho-quinone and catechol structures, which can form chemical bonds with the terminal functional groups of the amphiphilic polymer in the drug reservoir through Michael addition or Schiff base reaction. This chemical anchoring effect between layers avoids the risk of coating delamination or peeling during long-term catheter placement. Specifically, the peel strength between the adhesive layer and the catheter body is greater than 10 N / cm, ensuring that the coating does not detach under extreme vascular tortuosity conditions.

[0070] In drug reservoirs, drugs such as scopolamine derivatives exist in solid solution or microcrystalline form. The degradation rate of the matrix can be controlled by adjusting the ratio of lactic acid to glycolic acid in polylactic-co-glycolic acid copolymer (PLGA) (e.g., 50:50–75:25). When the PLGA ratio is 75:25, the matrix's hydrophobicity increases, and the water penetration rate slows down. Combined with the barrier effect of the biomimetic sugar calyx coating, the daily release of drugs such as rapamycin can be controlled between 1% and 2% of the total drug load, maintaining a long-lasting anti-proliferative effect.

[0071] In the biomimetic calyx coating, biomolecules such as chitosan have partially protonated amino groups on their molecular chains at pH 7.4, generating electrostatic repulsion with negatively charged plasma proteins. This, combined with the steric hindrance effect of polyethylene glycol segments, reduces protein adsorption on the duct surface to 10 μg / cm³. 2 The following is an explanation of the biomimetic design that enables the catheter to exhibit excellent blood compatibility during intervention, reducing the risk of thrombosis.

[0072] According to this application, the medical catheter solves the problems of excessively rapid drug release and insufficient adhesion in existing coatings through the synergistic effect of its three-layer composite structure. The adhesive layer utilizes the strong adhesion of polyphenols to form a stable transition interface on low-energy surfaces such as polyurethane or silicone rubber. The drug reservoir layer, through the physical barrier effect of the polymer material, restricts the release of drug molecules within a range limited by polymer degradation or swelling. The outermost biomimetic calyx coating not only captures water molecules to form a dynamic hydration layer through highly hydrophilic segments, reducing tissue friction during intervention, but more importantly, its dense cross-linked network acts as a "valve" to regulate the ingress rate of water molecules and the outward diffusion rate of drug molecules, thereby achieving stable drug release over a period of more than 30 days.

[0073] Furthermore, this coating mimics the glycocalyx structure of endothelial cell surfaces, reducing fibrinogen adsorption and platelet activation, thus improving the biocompatibility of the catheter in the circulatory system. During preparation, the cross-linking density of the biomimetic glycocalyx coating is adjusted by controlling the concentration of the polyphenol cross-linking agent and the type of metal ions. At higher cross-linking densities (e.g., tannic acid concentration of 2 mg / mL and iron ion concentration of 1 mmol / L), the coating enhances its barrier effect against large molecule drugs (such as heparin), prolonging the release cycle. At lower cross-linking densities (e.g., tannic acid concentration of 0.5 mg / mL), the coating focuses more on providing superlubricating properties. This adjustability allows the sustained-release system to adapt to drug release requirements in different clinical scenarios.

[0074] For stroke thrombectomy procedures, catheters need to be frequently bent and advanced within complex cerebral blood vessels. The biomimetic calyx coating in this application, due to the introduction of reversible hydrogen bonds and coordination bonds, exhibits a certain degree of polymer chain migration capability when microcracks are generated by shear force or compression, achieving structural healing through the re-closure of non-covalent bonds. Experiments show that after 100 repeated bends in a simulated vascular environment, the coating maintains over 98% integrity, and the drug release rate deviation is less than 5%.

[0075] The preparation method provided in this application is stable and easy to scale up for production, and the prepared catheters have excellent clinical applicability.

[0076] Fifthly, this application provides an interventional surgical system, including the aforementioned medical catheter and its associated handle, guidewire, imaging device, etc.

[0077] In summary, this application integrates adhesion enhancement, controlled drug release, superlubrication, and biomimetic functions through a multi-layered composite design, constructing a highly stable and functionally integrated medical catheter coating system. This system addresses the technical shortcomings of simple hydrophilic coatings, such as poor drug barrier properties and susceptibility to burst release. Furthermore, a self-healing mechanism enhances the coating's mechanical tolerance during complex interventional procedures. This system is not only suitable for stroke thrombectomy catheters but can also be extended to peripheral vascular stents, non-vascular interventional catheters, and other medical device fields, providing safer and more efficient device options for clinical interventional treatment, and possesses broad application prospects and clinical value. Detailed Implementation

[0078] The embodiments or implementations described in this specification adopt a progressive approach, with each embodiment focusing on its differences from other embodiments. In the description of this specification, the terms "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with an implementation or example that are included in at least one implementation or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same implementation or example. Furthermore, the specific features, structures, materials, or characteristics described can be combined in any suitable manner in one or more implementations or examples.

[0079] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined with "first" or "second" may explicitly or implicitly include at least one of that feature.

[0080] In the description of this application, "multiple" means at least two, such as two, three, etc., unless otherwise expressly and specifically limited.

[0081] This application provides a composite drug sustained-release system and medical catheter based on a biomimetic calyx coating. Through precise hierarchical design and material selection, a high-performance interventional catheter coating system is achieved, which keeps the initial and continuous frictional forces of the catheter at extremely low levels during intervention, solving the problem of frictional damage during catheter intervention. Furthermore, the biomimetic hierarchical structure enables precise control of drug release, resulting in significant sustained-release characteristics. This provides technical support for long-term local treatment and overcomes the shortcomings of existing technologies, such as easy coating peeling, sudden drug release, and poor lubrication durability. It provides a reliable solution for the surface functionalization of high-precision interventional medical devices, which is conducive to significantly improving the clinical application value of interventional medical devices.

[0082] The technical solution of this application will be described in detail below with reference to specific embodiments.

[0083] Example 1 This embodiment provides a method for preparing a medical catheter, the surface of which has a composite drug release system based on a biomimetic calyx coating (hereinafter referred to as a composite coating). The specific steps of the preparation method are as follows: S10: Construction of the adhesion layer.

[0084] A medical catheter body made of polyurethane was selected and placed in a plasma treatment instrument for activation treatment for 60 seconds at a power of 100W and an oxygen flow rate of 20 sccm. The activated catheter body was then immersed in a buffer solution containing dopamine. The buffer solution was a 20 mmol / L Tris-HCl buffer solution with a pH of 8.5. The dopamine concentration was 2 mg / mL. The reaction was carried out at room temperature (25°C) for 4 hours, resulting in in-situ polymerization of a polydopamine adhesion layer on the substrate surface. After the reaction was complete, the catheter was removed, ultrasonically cleaned with deionized water for 5 minutes to remove physically adsorbed monomers, and then dried at 40°C. The thickness of this adhesion layer was approximately 45 nm.

[0085] S20: Construction of the drug reservoir. An organic solution containing the biodegradable polymer PLGA (lactide to glycolide molar ratio of 75:25, molecular weight 80,000) and the active drug rapamycin was prepared. Dichloromethane was used as the solvent, with PLGA at a mass percentage concentration of 4% and rapamycin to PLGA at a mass ratio of 10:100. An ultrasonic atomization spraying process was used, with a spraying pressure of 0.2 MPa and high-purity nitrogen as the carrier gas. The nozzle movement speed was 30 mm / s, and the spray flow rate was 0.05 mL / min. By controlling the number of spraying cycles, a drug reservoir with a thickness of approximately 12 μm was formed on the surface of the adhesive layer. After coating, the delivery tube was dried at 25 °C for 2 h, then heated to 40 °C for 4 h, and finally treated in a vacuum drying oven at 50 °C for 12 h to ensure that the solvent residue was less than 0.05%.

[0086] S30: Construction of a biomimetic sugar calyx coating.

[0087] S301: Polyethylene glycol diacid with a molecular weight of approximately 18,000-20,000 and dopamine hydrochloride were dissolved in dimethyl sulfoxide at a mass ratio of 1:1. Condensing agents EDC and NHS were added, and the reaction was carried out at room temperature in the dark for 24 hours. After the reaction, the solution was placed in a dialysis bag and dialyzed against deionized water for 3 days. The target product was obtained by freeze-drying. The grafting rate of the catechol groups was approximately 88% as determined by 1H NMR spectroscopy. Then, the polyethylene glycol with the catechol groups grafted at the ends was dissolved in deionized water to prepare a modified polyethylene glycol solution with a concentration of 10 mg / mL.

[0088] S302: Prepare a biological macromolecule solution by dissolving chitosan (95% degree of deacetylation, molecular weight 100,000) in a 1% (w / w) acetic acid solution at a concentration of 5 mg / mL.

[0089] S303: Modified polyethylene glycol solution and chitosan solution were mixed at a volume ratio of 1:1. Tannic acid was added as a polyphenol crosslinking agent, with a final concentration of 1 mg / mL in the mixture. Ferric chloride solution was then added to achieve an iron ion concentration of 0.5 mmol / L. The pH of the mixture was adjusted to 8.0. The drug reservoir-modified catheter was immersed in this mixture and reacted at 37°C for 8 hours. After the reaction, the catheter was removed and placed in an environment with a relative humidity of 80% for 18 hours to allow the outer coating to fully hydrate, forming a 3 μm thick biomimetic sugar calyx coating.

[0090] Example 2 This embodiment is basically the same as Example 1, except that: in step S20, the active drug is heparin sodium, the biodegradable polymer is the amphiphilic polymer polyethylene glycol monomethyl ether-polylactic acid (mPEG-PLA), and the solvent is chloroform. In step S301, polyethylene glycol diacid with a molecular weight of 2000-3000 and dopamine hydrochloride are dissolved in dimethyl sulfoxide at a mass ratio of 1:0.5, and condensing agents EDC and NHS are added. The reaction is carried out at room temperature in the dark for 24 hours. After the reaction is completed, the solution is placed in a dialysis bag and dialyzed in deionized water for 3 days, and then freeze-dried to obtain polyethylene glycol with catechol groups grafted at the ends. In step S303, no metal salt solution is added, and the coating is constructed solely by the hydrogen bond network formed by polyphenol crosslinking.

[0091] Example 3 This embodiment is basically the same as Example 1, except that: in step S10, tannic acid is used as the polyphenol compound. In step S301, polyethylene glycol diacid with a molecular weight of 8000-10000 and dopamine hydrochloride are dissolved in dimethyl sulfoxide at a mass ratio of 1:1.5, and condensing agents EDC and NHS are added. The reaction is carried out at room temperature in the dark for 24 hours. After the reaction is completed, the solution is placed in a dialysis bag and dialyzed in deionized water for 3 days, and then freeze-dried to obtain polyethylene glycol with catechol groups grafted at the ends. In step S302, polylysine (molecular weight of about 30000) is used as the biomolecule. In step S303, a mixture of tannic acid and dopamine (mass ratio of about 1:1) is used as the polyphenol crosslinking agent, and the iron ion concentration is adjusted to about 1.0 mmol / L.

[0092] Example 4 This embodiment provides a method for preparing a medical catheter, the surface of which has a composite drug release system (hereinafter referred to as composite coating) with a double-layer drug reservoir structure. The preparation method specifically includes the following steps: Step S10: Same as in Example 1.

[0093] Step S20 consists of two spraying steps: the first step involves spraying a solution containing rapamycin and PLGA (75:25) to form the inner reservoir; the second step involves spraying a solution containing heparin and PLGA (50:50) to form the outer reservoir.

[0094] In step S30, sodium hyaluronate with a concentration of 0.2 wt% is added to the mixed solution to increase the viscoelasticity of the coating.

[0095] Comparative Example 1 This comparative example prepares a single-layer drug-loaded coating medical catheter. Following step S20 in Example 1, an organic solution containing PLGA and rapamycin was directly sprayed onto the cleaned polyurethane catheter surface, but without constructing an adhesive layer or a biomimetic calyx coating.

[0096] Comparative Example 2 This comparative example prepares a double-coated medical catheter lacking an adhesive layer. A drug reservoir and a biomimetic calyx coating are constructed on the catheter surface (specific operation is the same as in Example 1), but the adhesive layer modification in step S10 is not performed.

[0097] Comparative Example 3 This comparative example prepares a double-coated medical catheter lacking a biomimetic calyx coating. An adhesion layer and a drug reservoir are constructed on the catheter surface (steps are the same as in Example 1), but the biomimetic calyx coating modification in step S30 is not performed.

[0098] Performance testing and characterization The following performance tests were conducted on the catheter systems prepared in the above embodiments and comparative examples: 1. Surface lubricity test: The coefficient of friction of the coating surface was measured using a friction coefficient tester in a physiological saline environment.

[0099] 2. Drug release kinetics: The catheter segment was placed in phosphate-buffered saline (PBS) at pH 7.4 and shaken at 37°C and 100 rpm. Samples were taken periodically, and the cumulative release of rapamycin was determined by high-performance liquid chromatography (HPLC).

[0100] 3. Self-healing performance test: A scratch with a depth of about 2μm was made on the surface of the biomimetic sugar calyx coating, and the surface was immersed in deionized water. The scratch closure time was observed by optical microscope.

[0101] 4. Adhesion strength test: The peel strength between the coating and the substrate was determined using the scratch test method. The test data are shown in Table 1 below.

[0102] Table 1. Performance test results of composite coatings on the surfaces of various medical catheters in the embodiments and comparative examples of this application.

[0103] Note: The data in the table above is the average value after multiple tests on multiple samples.

[0104] As can be seen from the experimental data in the table above, Examples 1-4 significantly reduced the friction coefficient of the catheter surface by constructing a three-layer composite structure. Example 3, due to the use of a high metal ion crosslinking density and a tannic acid / dopamine mixed crosslinking agent, exhibited the lowest friction coefficient and the strongest peel strength. Regarding drug release, Comparative Examples 1-3 all showed significant burst release within 24 hours, while the initial release amount of Examples 1-4 was controlled below 7%, and a stable release rate was maintained over a 28-day period.

[0105] Furthermore, regarding the specific application of thrombectomy catheters for stroke, this application coats the composite system onto a 40 cm distal region of the catheter. Pushing tests were conducted in a simulated vascular tortuosity model. After 50 pushes, the coating on the catheter of Example 1 showed no visible peeling, and scanning electron microscopy (SEM) revealed that the surface microstructure remained intact. The catheter of Example 1 was sterilized with ethylene oxide (EO). The EO concentration was set at 600 mg / L, the temperature at 45°C, the humidity at 50%, and the treatment time at 4 hours. Post-sterilization testing revealed that the rapamycin content retention rate was 98.5%, and the lubricating performance of the biomimetic calyx coating did not significantly decrease, demonstrating the composite system's tolerance to commonly used clinical sterilization processes.

[0106] Furthermore, the sodium hyaluronate (molecular weight 1-2 million) added in Example 4, with its extremely high water retention capacity, forms a highly swollen hydrated layer on the outermost surface of the coating. This structure not only further reduces the coefficient of friction to approximately 0.015, but also significantly inhibits the adsorption of fibrinogen on the duct surface (adsorption amount less than 5 μg / cm³). 2 This improves blood compatibility.

[0107] In summary, this application, through the synergistic combination of the adhesion layer, drug reservoir, and biomimetic calyx coating, not only solves the problem of lubrication persistence of interventional devices in complex vascular pathways, but also achieves precise and long-term controlled release of small and large molecule drugs through a biomimetic three-dimensional network, which has significant clinical application value.

[0108] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A method for preparing a composite drug sustained-release system based on a biomimetic calyx coating, characterized in that, Includes the following steps: S10: The substrate surface is cleaned and activated. The activated substrate is then immersed in a buffer solution containing polyphenolic compounds and reacted at room temperature to form an adhesive layer in situ on the substrate surface. S20: Prepare an organic solution containing a biodegradable polymer and an active drug, and apply the organic solution to the surface of the adhesive layer using a spraying or dip coating process, and form a drug reservoir after drying; S30: Mix an aqueous solution containing a polyethylene glycol derivative with catechol groups at the end, a biomacromolecule, and a polyphenol crosslinking agent, adjust the pH to 7.4-8.5, and construct a biomimetic calyx coating on the surface of the drug reservoir through covalent crosslinking and non-covalent interactions.

2. The method according to claim 1, characterized in that: The polyphenolic compounds mentioned in step S10 include at least one of dopamine, tannic acid, catechin, and epicatechin; And / or, the concentration of the buffer solution containing polyphenolic compounds is 1~5 mg / mL; And / or, the buffer solution is a tris(hydroxymethyl)aminomethane hydrochloride buffer solution with a concentration of 10-50 mmol / L and a pH of 8.0-8.5; And / or, the reaction time in step S10 is 2-6 hours; And / or, the thickness of the adhesive layer is 20~100nm.

3. The method according to claim 1, characterized in that: The biodegradable polymer mentioned in step S20 includes at least one of polylactic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polyhydroxyalkanoate, polyethylene glycol monomethyl ether polylactic acid block copolymer, and polyethylene glycol polycaprolactone block copolymer. And / or, the active pharmaceutical ingredient is selected from at least one of scopolamine derivatives, rapamycin, paclitaxel, heparin, and antibiotics; And / or, the mass ratio of the active drug to the degradable polymer is 1:100 to 30:100; And / or, the thickness of the drug reservoir is 5~20μm.

4. The method according to claim 1, characterized in that: The solvent of the organic solution in step S20 includes at least one of dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, and acetone; and / or the total concentration of solute in the organic solution is 1 to 10 wt%.

5. The method according to claim 1, characterized in that, The preparation process of the biomimetic sugar calyx coating in step S30 specifically includes: S301: Dissolve a polyethylene glycol derivative with a terminal catechol group in deionized water to prepare a modified polyethylene glycol solution with a concentration of 5~20 mg / mL. S302: Dissolve chitosan or polylysine in acetic acid solution or phosphate buffer to prepare a biomacromolecule solution with a concentration of 2~10 mg / mL; S303: Mix the modified polyethylene glycol solution and the biomacromolecule solution at a volume ratio of 1:5 to 5:1, add a polyphenol crosslinking agent with a concentration of 0.5 to 2 mg / mL, and then allow the resulting mixed reaction solution to react at 30 to 45°C for 4 to 12 hours.

6. The method according to any one of claims 1 and 5, characterized in that: The molecular weight of the polyethylene glycol derivative containing catechol groups at the ends is 2000~20000; And / or, the method for preparing the polyethylene glycol derivative with catechol groups at the ends includes: dissolving polyethylene glycol diacid with a molecular weight of 2000-20000 and dopamine hydrochloride in an organic solvent at a mass ratio of 1:0.5-1:1.5, adding a condensing agent, reacting at room temperature in the dark, and after the reaction is completed, dialyzing the obtained reaction mixture in deionized water for 2-4 days, and then freeze-drying; And / or, the polyphenol crosslinking agent includes at least one of tannic acid, gallic acid, and proanthocyanidins; and / or, the concentration of the acetic acid solution or phosphate buffer is 1%; And / or, the thickness of the biomimetic sugar calyx coating is 1~5μm.

7. The method according to claim 6, characterized in that: The organic solvent includes dimethyl sulfoxide; And / or, the condensing agent includes 1-ethyl-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide.

8. The method according to claim 5, characterized in that: Step S303 further includes adding a metal salt to the mixed reaction solution until the concentration of metal ions is 0.1~1 mmol / L; the metal salt includes at least one of ferric chloride and zinc chloride.

9. A composite drug sustained-release system based on a biomimetic calyx coating, characterized in that: The composite drug sustained-release system is prepared by the method described in any one of claims 1 to 8 for preparing a composite drug sustained-release system based on a biomimetic calyx coating.

10. A medical catheter, comprising a catheter body; characterized in that, Also includes: The composite drug sustained-release system based on biomimetic calyx coating as described in claim 9, wherein the composite drug sustained-release system uniformly covers the outer wall of the catheter body.

11. The medical catheter according to claim 10, characterized in that: The material of the catheter body includes at least one of polyurethane, polyvinyl chloride, silicone rubber, latex, nylon, and polyether block amide.

12. A method for preparing a medical catheter, characterized in that, include: The composite drug sustained-release system based on the biomimetic calyx coating, as described in any one of claims 1 to 8, is uniformly coated on the outer wall of the medical catheter body, and then equilibrated in an environment with a relative humidity of 60% to 90% for 12 to 24 hours.

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