Ureteral stent with zwitter-ion coating and preparation method of ureteral stent

Abstract

The invention relates to a ureteral stent with a zwitterionic coating and a preparation method thereof.The ureteral stent comprises a stent body and the zwitterionic coating covering the stent body, the zwitterionic coating is formed by a zwitterionic coating composition, and the zwitterionic coating composition comprises a homopolymer or copolymer of zwitterionic and a solvent; the photocuring layer is covalently bonded on the surface of the bracket in a photocuring manner; the zwitterion is selected from phosphorylcholine; the zwitterionic copolymer is at least formed by copolymerizing a phosphorylcholine monomer and a hydrophilic monomer; or the zwitterionic copolymer is at least formed by copolymerizing the phosphorylcholine monomer, the hydrophilic monomer and the photosensitive monomer. The copolymer / homopolymer of zwitter-ions is covalently fixed on the surface of a base material in a photo-initiation mode, the coating is firm and stable, the coating with hydrophilic lubrication and zwitter-ions simultaneously can be constructed on the surface, the high lubricity function and the high anti-crystallization function are both considered, and the efficient anti-crystallization effect is synergistically achieved.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and in particular to a ureteral stent with a zwitterionic coating and its preparation method. Background Technology

[0002] Ureteral stents are indispensable medical devices in the treatment of urinary system diseases, and are widely used in various clinical scenarios such as relieving urinary tract obstruction, promoting stone expulsion, and assisting in postoperative recovery after ureteral surgery. A typical ureteral stent adopts a "double pigtail" design, with one end located in the renal pelvis and the other end located in the bladder, forming a drainage channel between the renal pelvis and the bladder, effectively reducing pressure on the urinary tract.

[0003] However, these stents are in prolonged contact with urine while in place, leading to severe scaling problems (also known as crusting). Scaling refers to the deposition of crystals and minerals from urine on the inner and outer surfaces of the ureteral stent, forming stubborn mineral deposits. Bacteria are closely related to crust formation: after stent implantation, proteins and other substances in urine quickly form an conditioning film on its surface, providing a basis for bacterial colonization. Subsequently, bacteria (especially urease-producing bacteria such as Proteus and Klebsiella) adhere to and secrete extracellular polymers to form a biofilm. This biofilm not only protects the internal bacteria from the body's immune system and antibiotic attacks, but the urease produced can also decompose urea to produce ammonia, alkalizing the urine environment (increasing pH), promoting the precipitation and deposition of crystals such as magnesium ammonium phosphate (struvite) and calcium phosphate on the stent surface, ultimately forming a crust. Furthermore, the formation of the crust provides a further haven for bacteria, exacerbating biofilm-related infections and drug resistance, creating a vicious cycle.

[0004] Ureteral stents cause multiple harms to patients: First, they significantly increase removal resistance, reducing the success rate of the procedure and potentially leading to stent rupture or ureteral injury in severe cases. Second, the rough surface formed by scale provides an ideal environment for bacterial adhesion, increasing the risk of urinary tract infections. Third, severe scale buildup can cause stent blockage, affecting urine drainage and potentially leading to kidney damage. Fourth, scale can exacerbate discomfort during indwelling, such as lower back pain and bladder irritation symptoms. These problems severely limit the clinical application of ureteral stents, especially for patients requiring long-term placement.

[0005] Traditional ureteral stents are mainly made of silicone or polyurethane. Silicone has good biocompatibility, but it has a high bacterial adhesion rate and a high coefficient of friction; polyurethane has poor biocompatibility and is prone to urinary salt deposits on its surface.

[0006] Surface coating technology is currently the main direction of antifouling research and has been widely used in clinical practice: (1) Hydrophilic coatings: Common ones include polyacrylamide, polyvinylpyrrolidone, hydrogels, etc., which reduce protein and bacterial adhesion by forming a hydrophilic surface. However, studies have shown that hydrogel-coated stents may have the same or even higher risk of crusting due to the absorption of urinary solutes. (2) Antimicrobial drug coatings: Such as triclosan, silver sulfadiazine, rifampin and other antimicrobial agent coatings, which aim to reduce the risk of biofilm formation and urinary tract infection. However, studies have found that they are not significantly different from ordinary stents in terms of biofilm formation, crusting or infection, and may lead to antibiotic resistance problems.

[0007] Each repeating unit of a zwitterionic polymer carries an equal amount of positive and negative charges, but is electrically neutral as a whole. These positively and negatively charged groups can bind to surrounding water molecules through strong electrostatic interactions, forming a dense and stable "hydration layer" or "hydration layer" on the material surface. This bound water layer constitutes a physical barrier that effectively weakens non-specific interactions (such as hydrophobic interactions and electrostatic forces) between bacteria and the material surface, thereby preventing initial bacterial adhesion. Studies have shown that this hydration is stronger and more stable than the hydration layer formed by hydrogen bonds in traditional nonionic hydrophilic materials (such as polyethylene glycol PEG).

[0008] Phosphorylcholine (PC) is a zwitterion and a major component of the outer layer of human cell membranes. Its molecular structure contains negatively charged phosphate groups that can form hydrogen bonds with water molecules; the choline groups further enhance its affinity for water. This structure gives phosphorylcholine coatings extremely high hydrophilicity. When this coating is applied to the surface of a ureteral stent, it effectively mimics the natural environment of human cell surfaces, giving the stent better biocompatibility, reducing the body's rejection and inflammatory responses to the stent, and thus indirectly reducing the risk of deposition caused by inflammatory stimulation.

[0009] Bacterial adhesion to material surfaces is crucial for biofilm formation, and biofilms accelerate and exacerbate crust formation. Phosphorylcholine coatings can also effectively inhibit bacterial adhesion and prevent biofilm formation. Studies have shown that such coatings are effective in reducing the adhesion of common urinary tract pathogens such as Escherichia coli.

[0010] In the prior art, US20220125570A1 only vaguely mentions that the ureteral stent device is coated with a biocompatible coating that can reduce crusting. The coating includes phosphorylcholine, but does not disclose the specific structure of phosphorylcholine and the way it is attached. Other prior art basically adopts the surface-initiated polymerization method (i.e., the grafting-from method). This method first requires fixing the initiator on the substrate surface, and then the coating solution includes phosphorylcholine monomer (MPC) and lubricating monomers. The monomers directly undergo polymerization on the surface modified by the initiator. However, this method has a complex polymerization process control, may produce homopolymer byproducts, has low batch-to-batch repeatability, and usually requires strict anhydrous and oxygen-free conditions.

[0011] In addition, the lack of lubrication of ureteral stents is also a core pain point in clinical practice. For example, the lack of lubrication can cause mechanical damage and bleeding due to friction between the stent and the mucosa. Increased friction may participate in the displacement process and affect the drainage effect. Furthermore, the high resistance to pushing increases the difficulty of the operation and the risk of mucosal damage. During removal, the stent may be obstructed by scale, which directly affects the patient's postoperative comfort, the incidence of complications, and the overall treatment effect. Summary of the Invention

[0012] Based on this, it is necessary to address the aforementioned technical problems in the existing technology by providing a ureteral stent with a zwitterionic coating and its preparation method. The zwitterionic copolymer / homogene is covalently fixed to the substrate surface by photoinitiation, resulting in a firm and stable coating. Furthermore, it is possible to construct a coating on the surface that simultaneously contains hydrophilic lubrication and zwitterionic components, thus achieving both high lubricity and high anti-crystallization functions and synergistically exerting a highly efficient anti-crystallization effect.

[0013] To solve the above technical problems, the present invention adopts the following technical solution: A ureteral stent with a zwitterionic coating includes a stent and a zwitterionic coating covering the stent. The zwitterionic coating is formed by a zwitterionic coating composition comprising a homopolymer or copolymer of zwitterions and a solvent, and is covalently bonded to the surface of the stent by photocuring. The zwitterion is selected from phosphorylcholine; The zwitterionic copolymer is formed by copolymerization of at least phosphorylcholine monomer and hydrophilic monomer; or The zwitterionic copolymer is formed by copolymerization of at least phosphorylcholine monomer, hydrophilic monomer and photosensitive monomer.

[0014] Preferably, the zwitterionic coating is formed by photocuring a coating composition comprising a zwitterionic copolymer.

[0015] Preferably, the hydrophilic monomer is selected from one or more of unsaturated carboxylic acids or carboxylates, unsaturated carboxylic esters, unsaturated acid hydroxyalkyl esters, unsaturated acid anhydrides, unsaturated amides, and unsaturated lactams.

[0016] Preferably, the hydrophilic monomer is selected from one or more of (meth)acrylic acid, (meth)acrylamide, vinylpyrrolidone, (meth)acrylic acid hydroxyethyl (propyl) propylene, vinyl acetate, maleic acid, maleic anhydride, fumaric acid, fumaric anhydride, and dimethacrylamide.

[0017] Preferably, the hydrophilic monomer is selected from vinylpyrrolidone; The phosphorylcholine monomer is 2-methacryloyloxyethyl phosphorylcholine; The photosensitive monomer is selected from Norrish II type photosensitive monomers, which contain unsaturated bonds.

[0018] Preferably, in the zwitterionic copolymer, the molar ratio of the hydrophilic monomer to the phosphorylcholine monomer is (0.5~10):1; In the zwitterionic copolymer, the molar concentration of the photosensitive monomer in the zwitterionic copolymer is 0.08-12%.

[0019] Preferably, the number-average molecular weight of the zwitterionic copolymer is 5,000 to 500,000.

[0020] Preferably, after soaking in urine for 4 weeks, the ureteral stent with zwitterionic coating has a surface calcium salt deposition reduction of more than 50% compared to the uncoated ureteral stent.

[0021] Preferably, the surface friction coefficient of the ureteral stent with zwitterionic coating is below 0.5.

[0022] To solve the above technical problems, another technical solution adopted by the present invention is: A method for preparing a zwitterional ion-coated ureteral stent as described above includes the following steps: Synthesis of copolymers: Hydrophilic monomers and phosphorycholine monomers are copolymerized in a certain proportion under the action of a polymerization initiator to form copolymers; Preparation of the coating composition: Dissolve the copolymer in a solvent, add a small molecule photoinitiator, and mix thoroughly; based on the total amount of the coating composition, the mass fraction of the copolymer is 0.5%-10%; the mass fraction of the small molecule photoinitiator is 0.05%-1%. Preparation of coating: The coating composition is applied to the surface of the ureteral stent and cured under light to obtain a ureteral stent with zwitterionic coating.

[0023] To solve the above technical problems, another technical solution adopted by the present invention is: A method for preparing a zwitterional ion-coated ureteral stent as described above includes the following steps: Synthesis of copolymers: Hydrophilic monomers, phosphorylcholine monomers and photosensitive monomers are copolymerized in a certain proportion under the action of a polymerization initiator to form copolymers; Formulation of the coating composition: The copolymer is dissolved in a solvent and thoroughly mixed; the copolymer has a mass fraction of 0.5%-10% based on the total amount of the coating composition; The photosensitive monomer is selected from Norrish type II photosensitive monomers; Preparation of coating: The coating composition is applied to the surface of the ureteral stent and cured under light to obtain a ureteral stent with zwitterionic coating.

[0024] Preferably, the solvent is selected from one or more of water, methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; The small molecule photoinitiator is selected from Norrish II type photoinitiators; wherein the Norrish II type photoinitiator is selected from the group consisting of: benzophenone, xanthonesone, derivatives of benzophenone, blends of benzophenone and benzophenone derivatives, Mistral ketone, ethyl Mistral ketone, thioxanthonesone, isopropyl thioxanthonesone, benzoyl, anthraquinone, coumarin, or combinations of these photoinitiators; The polymerization initiator is selected from one or more of azobiscyanopentanoic acid, cyclohexanone peroxide, benzoyl peroxide, diisopropylbenzene peroxide, azobisisobutyronitrile, and ammonium persulfate.

[0025] Due to the adoption of the above technical solutions, the present invention has the following advantages compared with the prior art: This invention covalently fixes zwitterions, especially copolymers / homopolymers of phosphorycholine, onto the substrate surface via photoinitiation. The resulting coating is robust and stable, and can copolymerize hydrophilic lubricating polymeric components. The content of both components is adjustable, and a coating exhibiting both hydrophilic lubrication and zwitterionic properties can be constructed on the surface, synergistically providing a highly effective anti-crystallization effect. Furthermore, covalent fixation to the ureteral stent surface via photocuring, particularly using a Norrish II photosensitizer, allows for hydrogen abstraction and binding to the substrate, significantly enhancing substrate anchoring ability and improving coating adhesion.

[0026] The design of the photosensitive unit in the terpolymer of this invention allows the polymer to act as a macromolecular photoinitiator, thereby enabling the coating to be firmly bonded to the substrate surface and preventing the residual precipitation of small molecule photoinitiators, effectively improving the safety of the coating, which is extremely important for medical devices. Attached Figure Description

[0027] Figure 1 The graph shows the test results of long-term calcium deposition on the surface of Example 4 and Comparative Example 1; Figure 2 The graph shows the test results of long-term calcium deposition on the surfaces of Examples 1-2 and Comparative Examples 2-3; Figure 3 This is a graph showing the amount of calcium deposition on the surface of the medical devices in Example 1 and Comparative Example 1. Figure 4 The images show the results of testing the antibacterial adhesion performance of the scaffold surface in Example 4 and Comparative Example 1. Detailed Implementation

[0028] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0029] In the description of this application, "multiple" means two or more, unless otherwise explicitly specified. In this application, " / " means "or".

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0031] The present invention provides a ureteral stent with a zwitterionic coating, comprising a stent and a zwitterionic coating covering the stent. The zwitterionic coating is formed by a zwitterionic coating composition comprising a homopolymer or copolymer of zwitterions and a solvent, and is covalently bonded to the surface of the stent by photocuring. The zwitterion is selected from phosphorycholine; zwitterionic copolymers are formed by copolymerization of at least phosphorycholine monomers and hydrophilic monomers; or The zwitterionic copolymer is formed by copolymerization of at least phosphorylcholine monomer, hydrophilic monomer and photosensitive monomer.

[0032] In one specific embodiment, the zwitterionic coating is formed by photocuring a coating composition comprising a zwitterionic copolymer.

[0033] In a specific embodiment, the hydrophilic monomer is selected from one or more of unsaturated carboxylic acids or carboxylates, unsaturated carboxylic esters, unsaturated acid hydroxyalkyl esters, unsaturated acid anhydrides, unsaturated amides, and unsaturated lactams.

[0034] Preferably, the hydrophilic monomer is selected from one or more of (meth)acrylic acid, (meth)acrylamide, vinylpyrrolidone, (meth)acrylic acid hydroxyethyl (propyl) propylene, vinyl acetate, maleic acid, maleic anhydride, fumaric acid, fumaric anhydride, and dimethacrylamide.

[0035] More preferably, the hydrophilic monomer is selected from vinylpyrrolidone.

[0036] In one specific embodiment, the phosphorylcholine monomer is 2-methacryloyloxyethyl phosphorylcholine.

[0037] In a specific embodiment, the photosensitive monomer is selected from Norrish II type photosensitive monomers, which contain unsaturated bonds. Further, the unsaturated bonds include double bonds. Specifically, the Norrish II type photosensitive monomer can be selected from the photosensitive monomer described in publication number CN110790871A.

[0038] In a specific embodiment, the molar ratio of the hydrophilic monomer to the phosphorylcholine monomer in the zwitterionic copolymer is (0.5~10):1; preferably (0.6~6):1; more preferably (1~3):1, and more specifically 1:1, 1.3:1, 1.5:1, 1.7:1, 2:1, 2.4:1, 2.7:1, 3:1. This invention requires a balance between lubricity and anti-crystallization properties. The hydrophilic monomer provides good lubricity, while the phosphorylcholine monomer provides anti-crystallization properties. The applicant found that if there is too little phosphorylcholine monomer, the anti-crystallization properties are poor; conversely, if there is too much phosphorylcholine monomer, the lubricity is compromised.

[0039] In a specific embodiment, the molar concentration of the photosensitive monomer in the zwitterionic copolymer is 0.08-12%, preferably 0.5-8%, more preferably 1-5%, and more specifically 1%, 1.3%, 1.7%, 2%, 2.5%, 3%, 3.4%, 3.8%, 4.2%, 4.5%, or 5%.

[0040] In a specific embodiment, the number-average molecular weight of the zwitterionic copolymer is 5,000 to 500,000, preferably 10,000 to 300,000, and more preferably 20,000 to 200,000. If the number-average molecular weight of the zwitterionic copolymer is too large, the viscosity will be too high; if the molecular weight is too small, the lubricity will be insufficient.

[0041] In one specific embodiment, after immersion in urine for 4 weeks, the ureteral stent with zwitterionic coating showed a reduction of more than 50% in surface calcium salt deposition compared to the uncoated ureteral stent.

[0042] In a specific embodiment, the surface friction coefficient of the ureteral stent with zwitterionic coating is less than 0.5, more preferably less than 0.2.

[0043] In a specific embodiment, after 30 cycles of cyclic friction testing, the surface lubricity of the ureteral stent with zwitterionic coating is maintained as a coefficient of friction of 0.5 or less, preferably 0.2 or less.

[0044] The present invention also provides a method for preparing a ureteral stent with a zwitterionic coating as described above, comprising the following steps: Synthesis of copolymers: Hydrophilic monomers and phosphorycholine monomers are copolymerized in a certain proportion under the action of a polymerization initiator to form copolymers; Preparation of the coating composition: Dissolve the copolymer in a solvent and add a small molecule photoinitiator, then mix thoroughly; based on the total amount of the coating composition, the mass fraction of the copolymer is 0.5%-10%; the mass fraction of the small molecule photoinitiator is 0.05%-1%. Coating preparation: The coating composition is applied to the surface of the ureteral stent and cured under light to obtain a ureteral stent with zwitterionic coating.

[0045] The present invention also provides another method for preparing a ureteral stent with a zwitterionic coating as described above, comprising the following steps: Synthesis of copolymers: Hydrophilic monomers, phosphorylcholine monomers and photosensitive monomers are copolymerized in a certain proportion under the action of a polymerization initiator to form copolymers; Formulation of the coating composition: Dissolve the copolymer in a solvent and mix thoroughly; the copolymer mass fraction is 0.5%-10% based on the total amount of the coating composition; Coating preparation: The coating composition is applied to the surface of the ureteral stent and cured under light to obtain a ureteral stent with zwitterionic coating.

[0046] In a specific embodiment, the photosensitive monomer is selected from Norrish II type photosensitive monomers, which contain unsaturated bonds. Further, the unsaturated bonds include double bonds. Specifically, the Norrish II type photosensitive monomer can be selected from the photosensitive monomer described in publication number CN110790871A.

[0047] In a specific embodiment, the solvent is selected from one or more of water, methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0048] In a specific embodiment, the small molecule photoinitiator is selected from Norrish II type photoinitiators; wherein the Norrish II type photoinitiator is selected from the group consisting of: benzophenone, xanthonesone, derivatives of benzophenone, blends of benzophenone and benzophenone derivatives, Mistral ketone, ethyl Mistral ketone, thioxanthonesone, isopropylthioxanthonesone, benzoyl, anthraquinone, coumarin, or combinations of these photoinitiators.

[0049] In a specific embodiment, the polymerization initiator is selected from one or more of azobiscyanopentaic acid, cyclohexanone peroxide, benzoyl peroxide, diisopropylbenzene peroxide, azobisisobutyronitrile, and ammonium persulfate.

[0050] In a specific embodiment, the coating composition can be applied to the surface of the ureteral stent by one or more of the following methods: brushing, dipping, extracting, spraying, pouring, and scraping.

[0051] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0052] Example 1 Step 1: Synthesis of Polymer 1 55 parts by mass of N-vinylpyrrolidone (NVP), 25 parts by mass of 2-methacryloyloxyethylphosphorylcholine (MPC), and 7.5 parts by mass of benzophenone acrylate were added to a reactor. 250 parts by mass of water were added, and the mixture was stirred until homogeneous. The reactor was then heated to 60°C and maintained for 15 minutes. 0.25 parts by mass of azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water were added. The reaction was stopped after stirring for 2 hours. 1000 parts by mass of acetone were added as a precipitant. After precipitation, the insoluble residue was dried at 80°C for 2 hours to obtain polymer 1. The number-average molecular weight (Mn) of polymer 1, as determined by GPC, was 154k, and the polydispersity index (PDI) was 2.23.

[0053] Step 2: Preparation of Coating Composition 1 Take polymer 1 from step one, dissolve it with 50% by mass ethanol, and prepare a coating solution with a polymer mass fraction of 3%, which is coating composition 1.

[0054] Step 3: Preparation of coating and ureteral stent products The above-mentioned coating solution was applied to the surface of a thermoplastic polyurethane ureteral stent using a dip-coating method, achieving a strength of 20 mw / cm. 2 The sample was cured under 365 nm ultraviolet light for 5 min, and then air-dried to obtain a thermoplastic polyurethane ureteral stent with a coating formed by coating composition 1 on its surface.

[0055] Example 2 Step 1: Synthesis of Polymer 2 55 parts by mass of N-vinylpyrrolidone and 25 parts by mass of 2-methacryloyloxyethylphosphorylcholine (MPC) were added to a reactor, followed by 250 parts by mass of water. After stirring until homogeneous, the mixture was heated to 60°C and maintained for 15 minutes. Then, a solution of 0.25 parts by mass of azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. The reaction was stopped after stirring for 2 hours. 1000 parts by mass of acetone were added as a precipitant. After precipitation, the insoluble residue was dried at 80°C for 2 hours to obtain polymer 2.

[0056] Step 2: Preparation of Coating Composition 2 Take polymer 2 from step one, dissolve it with 50% by mass ethanol, prepare a coating solution with a polymer mass fraction of 3%, and add 2-hydroxybenzophenone (0.5% by mass based on the total amount of the coating composition) as a photoinitiator, mix it evenly to obtain the coating solution, which is the coating composition 2.

[0057] Step 3: Preparation of coating and ureteral stent products The final coating solution obtained above was applied to the surface of a thermoplastic polyurethane ureteral stent using a dip-coating method, with a strength of 20 mw / cm. 2 The sample was cured under 365 nm ultraviolet light for 5 min, and then air-dried to obtain a thermoplastic polyurethane ureteral stent with a coating formed by coating composition 2 on its surface.

[0058] Example 3 The difference between this embodiment and Embodiment 1 is that a silicone ureteral stent is used instead of the thermoplastic polyurethane ureter in Embodiment 1, while the remaining steps and component ratios are the same as in Embodiment 1.

[0059] Example 4 Step 1: Synthesis of Polymer 3 27 parts by mass of N-vinylpyrrolidone, 25 parts by mass of 2-methacryloyloxyethylphosphorylcholine (MPC), and 2.3 parts by mass of a polymerizable photosensitive monomer [refer to patent CN201810870339.5, specific structure as follows] were added to a reactor. 250 parts by mass of water were added, and after stirring until homogeneous, the mixture was heated to 60°C and maintained for 15 minutes. Then, 0.25 parts by mass of azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. The reaction was stopped after stirring for 2 hours. 1000 parts by mass of acetone were added as a precipitant. After precipitation, the insoluble residue was dried at 80°C for 2 hours to obtain polymer 3.

[0060] Polymerizable photosensitive monomers Steps two and three are the same as in Example 1, resulting in a thermoplastic polyurethane ureteral stent with a coating formed by coating composition 3 on its surface.

[0061] Comparative Example 1 This comparative example is an uncoated thermoplastic polyurethane ureteral stent.

[0062] Comparative Example 2 Step 1: Synthesis of Polymer 4 55 parts by mass of N-vinylpyrrolidone and 7.5 parts by mass of benzophenone acrylate were added to a reactor, followed by 250 parts by mass of water. After stirring until homogeneous, the mixture was heated to 60°C and maintained for 15 minutes. Then, 0.25 parts by mass of azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. The reaction was stopped after stirring for 2 hours. 1000 parts by mass of acetone were added as a precipitant. After precipitation, the insoluble residue was dried at 80°C for 2 hours to obtain polymer 4.

[0063] Step 2: Preparation of coating composition 4 Take polymer 4 from step one, dissolve it with 50% by mass ethanol, and prepare a coating solution with a polymer mass fraction of 3%, which is coating composition 4.

[0064] Step 3: Preparation of coating and ureteral stent products The above-mentioned coating solution was applied to the surface of a thermoplastic polyurethane ureteral stent using a dip-coating method, achieving a strength of 20 mw / cm. 2 The sample was cured under 365 nm ultraviolet light for 5 minutes. After curing, the sample was placed in the air to dry, thus obtaining a thermoplastic polyurethane ureteral stent with a coating formed by coating composition 4 on its surface.

[0065] Comparative Example 3 The thermoplastic polyurethane ureteral stent was ultrasonically cleaned sequentially with acetone, ethanol, and deionized water for 30 minutes, and then dried with nitrogen. The cleaned stent was then immersed in an acetone solution containing 2% benzophenone (BP) at 50°C for 10 minutes, and then removed and cleaned. Next, 25 parts by weight of MPC and 55 parts by weight of NVP were dissolved in 250 parts by weight of deionized water, and the solution was purged with nitrogen for 30 minutes to remove oxygen. The stent treated in step one was then immersed in the monomer solution and irradiated with 365 nm ultraviolet light (20 mW / cm²) for 5 minutes under nitrogen protection to induce surface graft polymerization of the monomers. This yields a coated thermoplastic polyurethane ureteral stent formed by surface-initiated polymerization.

[0066] Comparative Example 4 Referring to Example 1, 4.4 parts by weight of N-vinylpyrrolidone, 50 parts by weight of 2-methacryloyloxyethyl phosphorylcholine (MPC), and 2.65 parts by weight of benzophenone acrylate were added to a reactor. 250 parts by weight of water were added, and the mixture was stirred until homogeneous. The reactor was then heated to 60°C and maintained for 15 minutes. 0.25 parts by weight of azobisisobutyronitrile (AIBN) dissolved in 1 part by weight of water were then added. The reaction was stopped after stirring for 2 hours. 1000 parts by weight of acetone were added as a precipitant. After precipitation, the insoluble residue was dried at 80°C for 2 hours to obtain polymer 5.

[0067] Steps two and three are the same as in Example 1, resulting in a thermoplastic polyurethane ureteral stent with a coating formed by coating composition 5 on its surface.

[0068] Characterization methods: (1) Testing of the resistance to calcium salt deposition on the surface of medical devices The simulated artificial urine and the method for detecting the anti-calcium salt deposition performance involved in this invention refer to "YY / T 0872-2013 Ureteral Stent Test Method" and reference 1.

[0069] Literature[1] Gilmore, BF et al. Models for the assessment of biofilm and encrustation formation on urological materials. In Biomaterials and TissueEngineering in Urology; Woodhead Publishing Limited&CRC Press LLC: Sawston,UK, 2009; pp. 59–81. (2) Test for long-term calcium deposition on the surface of medical devices The medical devices of Example 4 and Comparative Example 1 were immersed in 10 mL of simulated artificial urine and shaken at 37°C and 60 rpm for up to 28 days. The urine was changed every 48 hours, and the surface crystallization was observed using an optical microscope.

[0070] from Figure 1 It can be seen that even after prolonged (28 days) immersion, the surface of the medical device in Example 4 remained smooth and showed no significant calcium deposition. In contrast, the uncoated ureteral stent in Comparative Example 1 developed a thick layer of crystals (crust) on its surface after 28 days of immersion.

[0071] The medical devices of Examples 1-2 and Comparative Examples 2-3 were immersed in 10 mL of simulated artificial urine and agitated at 37°C and 60 rpm for up to 14 days. The urine was changed every 48 hours, and the surface crystallization was observed using an optical microscope.

[0072] from Figure 2 It can be seen that even after long-term (14 days) immersion, the medical devices in Examples 1 and 2 did not exhibit severe calcium deposition compared to Comparative Examples 2 and 3. Comparative Example 2, lacking phosphorylcholine components, still formed a thicker crystalline layer after 14 days of immersion. Comparative Example 3, using surface polymerization, could not effectively control the ratio of exposed phosphorylcholine components to hydrophilic monomer components, thus also exhibiting more severe crystallization.

[0073] (3) Determination of calcium deposition on the surface of medical devices The amount of calcium deposition on the surface of the medical devices in Example 1 and Comparative Example 1 was determined according to the method in reference [2]. The results are as follows: Figure 3 As shown. Specifically, the crust on the surface of the medical device was dissolved with hydrochloric acid solution, and the calcium element was quantitatively characterized using an enzyme-linked immunosorbent assay (ELISA) reader to obtain the amount of calcium deposited on the surface of the medical devices in Example 1 and Comparative Example 1.

[0074] Reference [2]: Liu Hua, Continuous determination of calcium and magnesium content in chlorate industrial brine by ultraviolet spectrophotometry [J], Chemical Engineering and Equipment, 2007, 000(006):79-82.

[0075] (4) Testing of the lubrication performance of surface coatings on medical devices The lubrication performance of the coatings in Examples 1-3 and Comparative Examples 1 and 4 was tested according to the standard T / CSBME 021-2020 Evaluation Method for Lubrication Performance of Hydrophilic Coatings for Urinary Catheters. The results are shown in Table 1.

[0076] Table 1. Test data on the coating lubrication performance of Examples 1-3 and Comparative Examples 1 and 4. As can be seen from the table above, the surface coatings of the medical devices in Examples 1-3 of this invention have good lubrication properties, and the coatings on the stent surface remain stable after 30 cycles of friction, demonstrating their excellent adhesion. In contrast, Comparative Example 4 has relatively low proportions of hydrophilic monomers, resulting in poorer lubrication.

[0077] (5) Test method for antibacterial adhesion performance Referring to the 2020 edition of the Pharmacopoeia of the People's Republic of China, Volume IV, and YY / T0923-2014 "Test Method for Microbial Intrusion at Needle-Free Interfaces of Fluid Pathways and Blood Pathways," the antibacterial adhesion performance of the stent surface in Example 4 and Comparative Example 1 was tested. The test results are as follows: Figure 4 As shown, the left side is a microscope image, and the right side is a SEM image. The images demonstrate that the sample coated with the coating of this invention exhibits antibacterial adhesion properties.

[0078] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0079] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A ureteral stent with a zwitterionic coating, characterized in that, The invention includes a support and a zwitterionic coating covering the support, the zwitterionic coating being formed from a zwitterionic coating composition comprising a zwitterionic homopolymer or copolymer and a solvent, and being covalently bonded to the surface of the support by photocuring. The zwitterion is selected from phosphorylcholine; The zwitterionic copolymer is formed by copolymerization of at least phosphorylcholine monomer and hydrophilic monomer; or The zwitterionic copolymer is formed by copolymerization of at least phosphorylcholine monomer, hydrophilic monomer and photosensitive monomer.

2. The ureteral stent with zwitterionic coating according to claim 1, characterized in that, The zwitterionic coating is formed by photocuring a coating composition containing a zwitterionic copolymer.

3. The ureteral stent with zwitterionic coating according to claim 1, characterized in that, The hydrophilic monomer is selected from one or more of the following: unsaturated carboxylic acids or carboxylates, unsaturated carboxylic esters, unsaturated acid hydroxyalkyl esters, unsaturated acid anhydrides, unsaturated amides, and unsaturated lactams.

4. The ureteral stent with zwitterionic coating according to claim 3, characterized in that, The hydrophilic monomer is selected from one or more of (meth)acrylic acid, (meth)acrylamide, vinylpyrrolidone, (meth)acrylate, vinyl acetate, maleic acid, maleic anhydride, fumaric acid, fumaric anhydride, and dimethacrylamide.

5. The ureteral stent with zwitterionic coating according to claim 4, characterized in that, The hydrophilic monomer is selected from vinylpyrrolidone; The phosphorylcholine monomer is 2-methacryloyloxyethyl phosphorylcholine; The photosensitive monomer is selected from Norrish II type photosensitive monomers, which contain unsaturated bonds.

6. The ureteral stent with zwitterionic coating according to claim 1, characterized in that, In the zwitterionic copolymer, the molar ratio of the hydrophilic monomer to the phosphorylcholine monomer is (0.5~10):1; In the zwitterionic copolymer, the molar concentration of the photosensitive monomer in the zwitterionic copolymer is 0.08-12%.

7. The ureteral stent with zwitterionic coating according to claim 1, characterized in that, The number-average molecular weight of the zwitterionic copolymer is 5,000 to 500,000.

8. The ureteral stent with zwitterionic coating according to claim 1, characterized in that, After immersion in urine for 4 weeks, the ureteral stent with zwitterionic coating showed a reduction of more than 50% in surface calcium salt deposition compared to the uncoated ureteral stent.

9. The ureteral stent with zwitterionic coating according to claim 1, characterized in that, The surface friction coefficient of the ureteral stent with zwitterionic coating is below 0.

5.

10. A method for preparing a ureteral stent with a zwitterionic coating as described in any one of claims 1 to 9, characterized in that, Includes the following steps: Synthesis of copolymers: Hydrophilic monomers and phosphorycholine monomers are copolymerized in a certain proportion under the action of a polymerization initiator to form copolymers; Preparation of the coating composition: Dissolve the copolymer in a solvent, add a small molecule photoinitiator, and mix thoroughly; based on the total amount of the coating composition, the mass fraction of the copolymer is 0.5%-10%; the mass fraction of the small molecule photoinitiator is 0.05%-1%. Preparation of coating: The coating composition is applied to the surface of the ureteral stent and cured under light to obtain a ureteral stent with zwitterionic coating.

11. A method for preparing a ureteral stent with a zwitterionic coating as described in any one of claims 1 to 9, characterized in that, Includes the following steps: Synthesis of copolymers: Hydrophilic monomers, phosphorylcholine monomers and photosensitive monomers are copolymerized in a certain proportion under the action of a polymerization initiator to form copolymers; Preparation of the coating composition: Dissolve the copolymer in a solvent and mix thoroughly; the copolymer has a mass fraction of 0.5%-10% based on the total amount of the coating composition; The photosensitive monomer is selected from Norrish type II photosensitive monomers; Preparation of coating: The coating composition is applied to the surface of the ureteral stent and cured under light to obtain a ureteral stent with zwitterionic coating.

12. The method for preparing a ureteral stent with a zwitterionic coating according to claim 10 or 11, characterized in that, The solvent is selected from one or more of water, methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; The polymerization initiator is selected from one or more of azobiscyanopentanoic acid, cyclohexanone peroxide, benzoyl peroxide, diisopropylbenzene peroxide, azobisisobutyronitrile, and ammonium persulfate.

13. The method for preparing a ureteral stent with a zwitterionic coating according to claim 10, characterized in that, The small molecule photoinitiator is selected from Norrish II type photoinitiators; wherein the Norrish II type photoinitiator is selected from the group consisting of: benzophenone, xanthonesone, derivatives of benzophenone, blends of benzophenone and benzophenone derivatives, Mistral ketone, ethyl Mistral ketone, thioxanthonesone, isopropylthioxanthonesone, benzoyl, anthraquinone, coumarin, or combinations of these photoinitiators.

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