A ureteral stent with a zwitterionic coating and a method of making the same

Abstract

The present application relates to a kind of zwitterionic coating ureteral stent and its preparation method, ureteral stent includes stent and the zwitterionic coating of covering on stent, zwitterionic coating is formed by zwitterionic coating composition, zwitterionic coating composition includes zwitterionic homopolymer or copolymer and solvent, and covalently bound to the surface of stent in photocuring mode;Zwitterionic is selected from phosphorylcholine;Zwitterionic copolymer is at least formed by phosphorylcholine monomer and hydrophilic monomer copolymerization;Or zwitterionic copolymer is at least formed by phosphorylcholine monomer, hydrophilic monomer and photosensitive monomer copolymerization.The homopolymer / copolymer of zwitterionic is covalently fixed on substrate surface by photo-initiated mode in the present application, coating is firm and stable, and can construct the coating of hydrophilic lubrication-zwitterionic existing simultaneously on surface, give consideration to high lubricity function and high anti-crystallization function, synergistically exert efficient anti-crystallization effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical devices, in particular to a ureteral stent with a zwitterionic coating and a preparation method thereof. BACKGROUND

[0002] Ureteral stents are indispensable medical devices in the treatment of urinary system diseases, and are widely used in relieving urinary obstruction, promoting stone discharge, and assisting postoperative recovery of ureter, etc. in various clinical scenarios. Typical ureteral stents adopt a "double pigtail" design, one end of which is located in the renal pelvis and the other end is located in the bladder, forming a drainage channel between the renal pelvis and the bladder, which effectively reduces the pressure of the urinary tract.

[0003] However, these stents will be in contact with urine for a long time during in vivo indwelling, leading to serious fouling problems (also known as encrustation). Fouling refers to the deposition of crystals and minerals in urine on the inner and outer surfaces of the ureteral stent, forming stubborn mineral deposits. Bacteria are closely related to the formation of encrustation: after stent implantation, proteins and other substances in urine will quickly form a conditioning film on the surface of the stent, providing a basis for bacterial colonization; then bacteria (especially urease-producing bacteria such as Proteus, Klebsiella, etc.) adhere and secrete extracellular polymeric substances to form a biofilm, which not only protects the internal bacteria from the body's immune system and antibiotic attack, but also produces urease to decompose urea into ammonia, alkalizing the urine environment (increasing pH), promoting the precipitation of magnesium ammonium phosphate (struvite), calcium phosphate and other crystals on the surface of the stent, and finally forming encrustation. In addition, the formation of encrustation further provides a shelter for bacteria, exacerbating biofilm-related infections and drug resistance, forming a vicious cycle.

[0004] Fouling problems cause multiple hazards to patients: first, fouling can significantly increase the removal resistance, reduce the success rate of removal, and in severe cases, may cause stent rupture or ureteral injury; second, the rough surface formed by fouling provides an ideal environment for bacterial adhesion, increasing the risk of urinary tract infection; third, severe fouling can cause stent blockage, affecting urine drainage, and thus causing kidney damage; fourth, fouling can also exacerbate the discomfort of patients during indwelling, such as waist pain, bladder irritation, etc. The existence of these problems seriously limits the clinical application effect of ureteral stents, especially for patients who need long-term indwelling.

[0005] Traditional ureteral stents are mainly made of silicone or polyurethane materials. Silicone materials have good biocompatibility, but have high bacterial adhesion rate and large friction coefficient; polyurethane materials have poor biocompatibility and are prone to form urinary salt deposits on the surface.

[0006] Surface coating technology is the main direction of current anti-encrustation research and has been widely used in clinical practice: (1) Hydrophilic coating: common ones include polyacrylamide, polyvinylpyrrolidone, hydrogel, etc. By forming a hydrophilic surface to reduce protein and bacterial adhesion. But studies have shown that due to the absorption of urine solutes, hydrogel-coated stents may have the same or even higher risk of encrustation. (2) Antibacterial drug coating: such as triclosan, silver sulfadiazine, rifampicin and other antibacterial agent coatings, aimed at reducing the risk of biofilm formation and urinary tract infection. But studies have found that they have no significant difference from ordinary stents in biofilm formation, encrustation or infection, and may cause antibiotic resistance problems.

[0007] Zwitterionic polymer carries equal amounts of positive and negative charges in each repeating unit, but as a whole it is electrically neutral. 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 layer of bound water constitutes a physical barrier that can effectively weaken the non-specific interactions (such as hydrophobic interaction, electrostatic force) between bacteria and the material surface, thereby preventing the initial adhesion of bacteria. Studies have shown that this hydration is more stable and more stable than the hydration layer formed by hydrogen bonds in traditional non-ionic hydrophilic materials (such as polyethylene glycol PEG).

[0008] Phosphorylcholine (PC) is a kind of zwitterion, which is one of the main components of the outer layer of human cell membrane. The phosphate group in its molecular structure carries a negative charge and can form hydrogen bonds with water molecules; the choline group further enhances the affinity with water. This structure makes the phosphorylcholine coating have extremely high hydrophilicity. When this coating is applied to the surface of the ureteral stent, it actually simulates the natural environment of the human cell surface, giving the stent better biocompatibility, reducing the body's foreign body rejection reaction and inflammatory response to the stent, thereby indirectly reducing the risk of deposition caused by inflammation.

[0009] Bacterial adhesion to the material surface is the key to the formation of biofilm, which can accelerate and aggravate encrustation. Phosphorylcholine coating can also effectively inhibit bacterial adhesion and prevent biofilm formation. Studies have shown that such coatings have good effect on reducing the adhesion of common urinary pathogens such as Escherichia coli.

[0010] In the prior art, US20220125570A1 only generally mentions that a ureteral stent device is coated with a biocompatible coating capable of reducing encrustation, which includes phosphorylcholine, but does not disclose the specific structure of phosphorylcholine and the way of combination; other prior arts basically adopt the method of surface-initiated polymerization (also known as the method of grafting-from), which first needs to fix the initiator on the surface of the substrate, and then the coating liquid will include phosphorylcholine monomer (MPC), lubricity monomer, and the monomer will directly polymerize on the surface modified by the initiator, but the polymerization process control is complex, the byproduct of homopolymer may be produced, the batch repeatability is low, and strict waterless and anaerobic conditions are usually required.

[0011] In addition, the lack of lubricity of the ureteral stent is also a core pain point in clinical practice. For example, the lack of lubricity of the stent causes mechanical damage and bleeding when rubbing against the mucosa, and the increased friction force may participate in the displacement process, affecting the drainage effect; the large pushing resistance increases the difficulty of the operation and the risk of mucosal damage; and the removal may be blocked due to encrustation, which is directly related to the postoperative comfort, complication rate and overall treatment effect of the patient. SUMMARY

[0012] Therefore, it is necessary to provide a ureteral stent with a zwitterionic coating and a preparation method thereof to solve the above technical problems in the prior art. The zwitterionic copolymer / homopolymer is covalently fixed on the surface of the substrate by light initiation, the coating is firm and stable, and a coating with both hydrophilic lubricity and zwitterions can be constructed on the surface, which takes into account the high lubricity function and high anti-crystallization function, and synergistically plays an efficient anti-crystallization effect.

[0013] To solve the above technical problems, a technical solution adopted by the present application is as follows:

[0014] A ureteral stent with a zwitterionic coating, comprising a stent and a zwitterionic coating covering the stent, wherein the zwitterionic coating is formed by a zwitterionic coating composition, the zwitterionic coating composition comprises a zwitterionic homopolymer or copolymer and a solvent, and is covalently combined with the surface of the stent in a light-cured manner;

[0015] The zwitterion is selected from phosphorylcholine;

[0016] The zwitterionic copolymer is formed by copolymerization of at least a phosphorylcholine monomer and a hydrophilic monomer; or

[0017] The zwitterionic copolymer is formed by copolymerization of at least a phosphorylcholine monomer, a hydrophilic monomer and a photosensitive monomer.

[0018] Preferably, the zwitterionic coating is formed by light curing of a coating composition comprising a zwitterionic copolymer.

[0019] Preferably, the hydrophilic monomer is selected from one or more of unsaturated carboxylic acid or carboxylic acid salt, unsaturated carboxylic ester, unsaturated acid hydroxyalkyl ester, unsaturated acid anhydride, unsaturated amide, unsaturated lactam.

[0020] Preferably, the hydrophilic monomer is selected from one or more of (meth)acrylic acid, (meth)acrylamide, vinylpyrrolidone, hydroxyethyl (propyl) (meth)acrylate, vinyl acetate, maleic acid, maleic anhydride, fumaric acid, fumaric anhydride, dimethyl acrylamide.

[0021] Preferably, the hydrophilic monomer is selected from vinylpyrrolidone;

[0022] The phosphorylcholine monomer is 2-methacryloyloxyethyl phosphorylcholine;

[0023] The photosensitive monomer is selected from a Norrish Type II photosensitive monomer, and the Norrish Type II photosensitive monomer comprises an unsaturated bond.

[0024] Preferably, in the zwitterionic copolymer, the molar ratio of the hydrophilic monomer to the phosphorylcholine monomer is (0.5-10):1.

[0025] In the zwitterionic copolymer, the molar concentration of the photosensitive monomer in the zwitterionic copolymer is 0.08-12%.

[0026] Preferably, the number average molecular weight of the zwitterionic copolymer is 5,000-500,000.

[0027] Preferably, after being soaked in a urine environment for 4 weeks, the zwitterion-coated ureteral stent has a surface calcium salt deposition that is reduced by more than 50% compared to a non-coated ureteral stent.

[0028] Preferably, the zwitterion-coated ureteral stent has a surface friction coefficient of 0.5 or less.

[0029] To solve the above technical problems, another technical solution adopted by the present application is:

[0030] A preparation method of a zwitterion-coated ureteral stent as described above, comprising the following steps:

[0031] Synthesis of the copolymer: the hydrophilic monomer and the phosphorylcholine monomer are copolymerized in a certain proportion under the action of a polymerization initiator to form a copolymer.

[0032] Preparation of the coating composition: the copolymer is dissolved in a solvent and a small molecule photoinitiator is added, and mixed thoroughly; the mass fraction of the copolymer is 0.5%-10% based on the total amount of the coating composition; the mass fraction of the small molecule photoinitiator is 0.05%-1%;

[0033] Preparation of the coating: the coating composition is coated on the surface of the ureteral stent, and curing is completed under light, thereby obtaining the ureteral stent with the zwitterionic coating.

[0034] To solve the above technical problems, the present application adopts another technical solution:

[0035] A preparation method of the ureteral stent with the zwitterionic coating as described above, comprising the following steps:

[0036] Synthesis of the copolymer: hydrophilic monomers, phosphorylcholine monomers and photosensitive monomers are copolymerized in a certain proportion under the action of a polymerization initiator, thereby forming a copolymer;

[0037] Preparation of the coating composition: the copolymer is dissolved in a solvent and mixed thoroughly; the mass fraction of the copolymer is 0.5%-10% based on the total amount of the coating composition;

[0038] The photosensitive monomer is selected from a Norrish Type II photosensitive monomer;

[0039] Preparation of the coating: the coating composition is coated on the surface of the ureteral stent, and curing is completed under light, thereby obtaining the ureteral stent with the zwitterionic coating.

[0040] 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, dimethyl sulfoxide;

[0041] The small molecule photoinitiator is selected from a Norrish II type photosensitive initiator; wherein the Norrish II type photosensitive initiator is selected from the group consisting of benzophenone, xanthone, a derivative of benzophenone, a blend of benzophenone and a derivative of benzophenone, Michler's ketone, ethyl Michler's ketone, thioxanthone, isopropyl thioxanthone, benzoin, anthraquinone, coumarin or a combination of these photosensitive initiators;

[0042] The polymerization initiator is selected from one or more of azobis cyanovaleric acid, cyclohexanone peroxide, benzoyl peroxide, dicumyl peroxide, azobisisobutyronitrile, ammonium persulfate.

[0043] Due to the adoption of the above technical solutions, the present application has the following advantages compared with the prior art:

[0044] The application covalently fixes the zwitterion, especially the copolymer / homopolymer of phosphorylcholine to the surface of the substrate by light initiation, the coating is firm and stable, and the hydrophilic and lubricating polymer components can be copolymerized, the content of the two components can be adjusted, and the coating with the coexistence of hydrophilic lubrication and zwitterion can be constructed on the surface, and the efficient anti-crystallization effect is synergistically exerted. In addition, the surface of the ureteral stent is covalently fixed by light curing, especially the Norrish type Ⅱ photosensitizer is used to combine with the substrate by hydrogen abstraction, which can exert significant substrate anchoring ability and improve the firmness of the coating.

[0045] In the application, the design of the photosensitive unit in the terpolymer can use the polymer as a macromolecular photoinitiator, thereby firmly combining the coating to the surface of the substrate, preventing the residual precipitation of small molecule photoinitiators, and effectively improving the safety of the coating, which is very important for medical devices. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 The test result graph of the long-term calcium deposition of the surface of Example 4 and Comparative Example 1 is shown in the figure;

[0047] Figure 2 The test result graph of the long-term calcium deposition of the surface of Examples 1-2 and Comparative Examples 2-3 is shown in the figure;

[0048] Figure 3 The calcium deposition amount graph of the surface of the medical device of Example 1 and Comparative Example 1 is shown in the figure;

[0049] Figure 4 The stent surface antibacterial adhesion performance detection effect graph of Example 4 and Comparative Example 1 is shown in the figure. DETAILED DESCRIPTION

[0050] In order to make the above-mentioned purposes, features and advantages of the application more obvious and easy to understand, the specific embodiments of the application will be described in detail below with reference to the accompanying drawings. In the following description, a large number of specific details are set forth in order to facilitate a full understanding of the application. However, the application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without departing from the spirit of the application, so the application is not limited by the specific embodiments disclosed below.

[0051] In the description of the present application, the meaning of "a plurality of" is two or more, unless otherwise explicitly and specifically limited. In the present application, " / " represents the meaning of "or".

[0052] 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 application belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting of the application. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0053] The present application 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, the zwitterionic coating composition comprises a zwitterionic homopolymer or copolymer and a solvent, and is covalently bonded to the surface of the stent in a photocuring manner;

[0054] The zwitterion is selected from phosphorylcholine;

[0055] The zwitterionic copolymer is formed by copolymerization of at least a phosphorylcholine monomer and a hydrophilic monomer; or

[0056] The zwitterionic copolymer is formed by copolymerization of at least a phosphorylcholine monomer, a hydrophilic monomer and a photosensitive monomer.

[0057] In a specific embodiment, the zwitterionic coating is formed by photocuring of a coating composition comprising a zwitterionic copolymer.

[0058] In a specific embodiment, the hydrophilic monomer is selected from one or more of an unsaturated carboxylic acid or carboxylic acid salt, an unsaturated carboxylic ester, an unsaturated acid hydroxyalkyl ester, an unsaturated acid anhydride, an unsaturated amide, and an unsaturated lactam.

[0059] Preferably, the hydrophilic monomer is selected from one or more of (meth)acrylic acid, (meth)acrylamide, vinylpyrrolidone, hydroxyethyl (propyl) (meth)acrylate, vinyl acetate, maleic acid, maleic anhydride, fumaric acid, fumaric anhydride, and dimethylacrylamide.

[0060] More preferably, the hydrophilic monomer is selected from vinylpyrrolidone.

[0061] In a specific embodiment, the phosphorylcholine monomer is 2-methacryloyloxyethyl phosphorylcholine.

[0062] In a specific embodiment, the photosensitive monomer is selected from a Norrish Type II photosensitive monomer, the Norrish Type II photosensitive monomer comprises an unsaturated bond. Further, the unsaturated bond includes a double bond. Specifically, the Norrish Type II photosensitive monomer can be selected from the photosensitive monomers described in CN110790871A.

[0063] In a specific embodiment, the mole ratio of the hydrophilic monomer to the phosphoryl choline 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. The present application needs to balance the lubricity and anti-crystallization performance. The hydrophilic monomer can provide better lubricity, and the phosphoryl choline monomer can provide anti-crystallization performance. The applicant found that if the phosphoryl choline monomer is too small, the anti-crystallization performance is not good, and vice versa, if the phosphoryl choline monomer is too large, the lubricity will be lost.

[0064] In a specific embodiment, the mole 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%, 5%.

[0065] In a specific embodiment, the number average molecular weight of the zwitterionic copolymer is 5,000-500,000, preferably 10,000-300,000, and more preferably 20,000-200,000. If the number average molecular weight of the zwitterionic copolymer is too large, the viscosity is too high, and if the number average molecular weight is too small, the lubricity is not enough.

[0066] In a specific embodiment, after soaking in urine for 4 weeks, the surface calcium salt deposition of the zwitterionic-coated ureteral stent is reduced by more than 50% compared to the uncoated ureteral stent.

[0067] In a specific embodiment, the surface friction coefficient of the zwitterionic-coated ureteral stent is 0.5 or less, and more preferably 0.2 or less.

[0068] In a specific embodiment, after 30 cycles of friction test, the surface lubricity of the zwitterionic-coated ureteral stent is maintained, which is manifested as a friction coefficient of 0.5 or less, and preferably 0.2 or less.

[0069] The present application also provides a preparation method of the zwitterionic-coated ureteral stent as described above, comprising the following steps:

[0070] Synthesis of copolymer: the hydrophilic monomer and the phosphoryl choline monomer are mixed in a certain proportion, and under the action of a polymerization initiator, copolymerization is initiated to form a copolymer;

[0071] Preparation of the coating: the coating composition is coated on the surface of the ureteral stent, and curing is completed under light conditions, thereby obtaining the ureteral stent with the zwitterionic coating.

[0072] Preparation of the coating: the coating composition is coated on the surface of the ureteral stent, and curing is completed under light conditions, thereby obtaining the ureteral stent with the zwitterionic coating.

[0073] The application further provides still another preparation method of the ureteral stent with the zwitterionic coating as described above, comprising the following steps:

[0074] Synthesis of the copolymer: the hydrophilic monomer, the phosphorylcholine monomer and the photosensitive monomer are copolymerized in a certain proportion under the action of a polymerization initiator, thereby forming the copolymer.

[0075] Preparation of the coating: the coating composition is coated on the surface of the ureteral stent, and curing is completed under light conditions, thereby obtaining the ureteral stent with the zwitterionic coating.

[0076] Preparation of the coating: the coating composition is coated on the surface of the ureteral stent, and curing is completed under light conditions, thereby obtaining the ureteral stent with the zwitterionic coating.

[0077] In a specific embodiment, the photosensitive monomer is selected from a Norrish Type II photosensitive monomer, and the Norrish Type II photosensitive monomer comprises an unsaturated bond. Further, the unsaturated bond comprises a double bond. Specifically, the Norrish Type II photosensitive monomer can be selected from the photosensitive monomers described in CN110790871A.

[0078] 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, dimethyl sulfoxide.

[0079] In a specific embodiment, the small-molecule photoinitiator is selected from a Norrish II type photosensitive initiator; wherein the Norrish II type photosensitive initiator is selected from the group consisting of benzophenone, xanthone, a derivative of benzophenone, a blend of benzophenone and a derivative of benzophenone, Michler's ketone, ethyl Michler's ketone, thioxanthone, isopropyl thioxanthone, benzoin, anthraquinone, coumarin or a combination of these photosensitive initiators.

[0080] In a specific embodiment, the polymerization initiator is selected from one or more of azobis cyanovaleric acid, cyclohexanone peroxide, benzoyl peroxide, dicumyl peroxide, azobisisobutyronitrile, ammonium persulfate.

[0081] In a particular embodiment, the coating composition can be applied to the surface of the ureteral stent by one or more of brushing, dip coating, dip extraction, spraying, pouring, and doctor blading.

[0082] The present application is described in detail below with reference to the accompanying drawings and specific embodiments.

[0083] Example 1

[0084] Step 1: Synthesis of Polymer 1

[0085] Into a reactor, 55 parts by mass of N-vinylpyrrolidone (NVP), 25 parts by mass of 2-methacryloyloxyethyl phosphorylcholine (MPC) and 7.5 parts by mass of benzophenone acrylate were added, 250 parts by mass of water was added, and after stirring to dissolve uniformly, heated to 60°C, and after maintaining for 15 minutes, 0.25 parts by mass of a solution of azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. After continuing to stir for 2 hours, the reaction was stopped, 1000 parts by mass of acetone was added as a precipitant, and after precipitation, the insoluble material was dried at 80°C for 2 hours to obtain Polymer 1. The Polymer 1 obtained was measured by GPC to have a number average molecular weight Mn of 154k, and a PDI (polydispersity index) of 2.23.

[0086] Step 2: Preparation of Coating Composition 1

[0087] The Polymer 1 from Step 1 was stirred and dissolved in ethanol with a concentration of 50% by mass, and a coating liquid with a polymer mass fraction of 3% was prepared, which was Coating Composition 1.

[0088] Step 3: Preparation of Coating and Ureteral Stent Product

[0089] The above coating liquid was applied to the surface of a thermoplastic polyurethane ureteral stent by dip coating, and cured using 365 nm ultraviolet light with an intensity of 20 mw / cm 2 for 5 minutes, and the sample after curing was left to dry in the air, to obtain a thermoplastic polyurethane ureteral stent with a coating formed from Coating Composition 1 on the surface.

[0090] Example 2

[0091] Step 1: Synthesis of Polymer 2

[0092] Into a reactor, 55 parts by mass of N-vinylpyrrolidone (NVP), 25 parts by mass of 2-methacryloyloxyethyl phosphorylcholine (MPC) and 7.5 parts by mass of benzophenone acrylate were added, 250 parts by mass of water was added, and after stirring to dissolve uniformly, heated to 60°C, and after maintaining for 15 minutes, 0.25 parts by mass of a solution of azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. After continuing to stir for 2 hours, the reaction was stopped, 1000 parts by mass of acetone was added as a precipitant, and after precipitation, the insoluble material was dried at 80°C for 2 hours to obtain Polymer 1. The Polymer 1 obtained was measured by GPC to have a number average molecular weight Mn of 154k, and a PDI (polydispersity index) of 2.23.

[0093] Step two: Preparation of coating composition 2

[0094] Take the polymer 2 in step one, stir and dissolve with 50 mass% concentration of ethanol, prepare a coating liquid with polymer mass fraction of 3%, and add 2-hydroxybenzophenone (the amount is 0.5% of the mass fraction based on the total amount of the coating composition) as a photoinitiator, mix uniformly to obtain a coating liquid, which is coating composition 2.

[0095] Step three: Preparation of coating and ureteral stent product

[0096] The final coating liquid obtained above is coated on the surface of the thermoplastic polyurethane ureteral stent by dip coating method, and cured for 5 min using 365 nm ultraviolet light with intensity of 20 mw / cm 2 The sample after curing is placed in air to dry, and a thermoplastic polyurethane ureteral stent coated with a coating layer formed by coating composition 2 on the surface is obtained.

[0097] Example 3

[0098] The difference between this example and example 1 is that a silica gel ureteral stent is used instead of the thermoplastic polyurethane ureteral stent in example 1, and the rest of the steps and component proportions are the same as in example 1.

[0099] Example 4

[0100] Step one: Synthesis of polymer 3

[0101] Add 27 parts by mass of N-vinylpyrrolidone, 25 parts by mass of 2-methacryloyloxyethyl phosphorylcholine (MPC), and 2.3 parts by mass of a polymerizable photosensitive monomer

refer to patent CN201810870339.5, the specific structure is as follows

[0102]

[0103] Polymerizable photosensitive monomer

[0104] Step two and step three are the same as in example 1, and a thermoplastic polyurethane ureteral stent coated with a coating layer formed by coating composition 3 on the surface is obtained.

[0105] Comparative example 1

[0106] The comparative example is a thermoplastic polyurethane ureteral stent without coating.

[0107] Comparative Example 2

[0108] Step 1: Synthesis of polymer 4

[0109] Into a reactor, 55 parts by mass of N-vinyl pyrrolidone and 7.5 parts by mass of benzophenone acrylate were added, 250 parts by mass of water was added, after stirring and dissolving uniformly, heated to 60°C, after keeping for 15 minutes, 0.25 parts by mass of azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. After continuing stirring for 2 hours, the reaction was stopped, 1000 parts by mass of acetone was added as a precipitant, after precipitation, the insoluble material was dried at 80°C for 2 hours, to obtain polymer 4.

[0110] Step 2: Preparation of coating composition 4

[0111] The polymer 4 in step 1 was stirred and dissolved with 50% by mass concentration of ethanol, and a coating liquid with a polymer mass fraction of 3% was prepared, which was coating composition 4.

[0112] Step 3: Preparation of coating and ureteral stent product

[0113] The above coating liquid was coated on the surface of the thermoplastic polyurethane ureteral stent by dip coating method, and cured for 5 minutes using 365 nm ultraviolet light with an intensity of 20 mW / cm 2 The sample after curing was left to dry in air, to obtain a thermoplastic polyurethane ureteral stent coated with a coating formed by coating composition 4 on the surface.

[0114] Comparative Example 3

[0115] The thermoplastic polyurethane ureteral stent was sequentially cleaned with acetone, ethanol and deionized water for 30 minutes, and dried with nitrogen. The cleaned stent was immersed in an acetone solution containing 2% benzophenone (BP) at 50°C for 10 minutes, and then taken out for cleaning. Then 25 parts by mass of MPC and 55 parts by mass of NVP were dissolved in 250 parts by mass of deionized water, and deoxygenated for 30 minutes with nitrogen. The stent after step 1 was immersed in the monomer solution, and irradiated with 365 nm ultraviolet light with an intensity of 20 mW / cm² for 5 minutes under nitrogen protection, to make the monomer graft polymerize on the surface. A thermoplastic polyurethane ureteral stent with a coating formed by surface-initiated polymerization was obtained.

[0116] Comparative Example 4

[0117] Referring to Example 1, 4.4 parts by mass of N-vinylpyrrolidone, 50 parts by mass of 2-methacryloyloxyethyl phosphorylcholine (MPC) and 2.65 parts by mass of benzophenone acrylate were added to a reactor, 250 parts by mass of water was added thereto, and after stirring to dissolve uniformly, it was heated to 60°C, and after keeping for 15 minutes, 0.25 parts by mass of a solution of azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. After continuing stirring for 2 hours, the reaction was stopped, 1000 parts by mass of acetone was added as a precipitant, and after precipitation, the insoluble matter was dried at 80°C for 2 hours to obtain polymer 5.

[0118] Steps two and three were the same as Example 1, to obtain a thermoplastic polyurethane ureteral stent coated on the surface with a coating layer formed from coating composition 5.

[0119] Characterization method:

[0120] (1) Test of calcium salt deposition resistance on the surface of medical devices

[0121] The simulated artificial urine and the test method of calcium salt deposition resistance referred to in the present application refer to YY / T 0872-2013 Ureteral Stent Test Method and Literature 1.

[0122] Literature [1] Gilmore, B.F et al. Models for the assessment of biofilm and encrustation formation on urological materials. In Biomaterials and Tissue Engineering in Urology; Woodhead Publishing Limited & CRC Press LLC: Sawston, UK, 2009; pp. 59-81.

[0123] (2) Test of long-term calcium deposition on the surface of medical devices

[0124] The medical devices of Example 4 and Comparative Example 1 were immersed in 10 mL of simulated artificial urine, and immersed and shaken at 37°C and 60 rpm for a maximum of 28 days, the urine was replaced every 48 hours, and the surface crystallization was observed using an optical microscope.

[0125] From Figure 1 It can be seen that even after long-term (28 days) immersion, the surface of the medical device of Example 4 can still remain smooth and there is no serious calcium deposition. The ureteral stent of Comparative Example 1 without a coating layer generates a thick layer of crystals (crust layer) on the surface after 28 days of immersion.

[0126] The medical devices of Examples 1-2 and Comparative Examples 2-3 were soaked in 10 mL of simulated artificial urine, and the surface crystallization was observed using an optical microscope under the condition of 37℃, 60rpm, and soaking and shaking for a maximum of 14 days, with the urine being replaced every 48h.

[0127] From Figure 2 It can be seen that even under long-term (14 days) soaking, the surfaces of the medical devices of Examples 1 and 2 did not have serious calcium deposition relative to Comparative Examples 2 and 3. Comparative Example 2 still generated a relatively thick crystalline layer after 14 days of soaking due to the lack of a phosphorylcholine component, and Comparative Example 3 used a surface polymerization method that could not well control the ratio of the phosphorylcholine component and the hydrophilic monomer component exposed on the surface, and thus also exhibited relatively serious crystallization.

[0128] (3) Measurement of calcium deposition amount on the surface of the medical device

[0129] The calcium deposition amount on the surface of the medical devices of Examples 1 and Comparative Example 1 was measured according to the method in document [2], and the results are shown in Table 2. Figure 3 Specifically, the crust on the surface of the medical device was dissolved with a hydrochloric acid solution, and the calcium element was quantitatively characterized using an enzyme label instrument to obtain the calcium deposition amount on the surface of the medical devices of Examples 1 and Comparative Example 1.

[0130] Document [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.

[0131] (4) Detection of lubricating property of the coating on the surface of the medical device

[0132] The lubricating property of the coating of Examples 1-3 and Comparative Examples 1 and 4 was detected according to the standard “T / CSBME 021-2020 Evaluation method for lubricating property of hydrophilic coating of urinary catheter”, and the results are shown in Table 1.

[0133] Table 1: Detection data table of the lubricating property of the coating of Examples 1-3 and Comparative Examples 1 and 4

[0134]

[0135] As can be seen from the above table, the coating on the surface of the medical device of Examples 1-3 has good lubricating property, and the coating on the surface of the stent still stably exists after 30 cycles of friction, proving that it has excellent firmness. Comparative Example 4 has a relatively small proportion of hydrophilic monomers, and thus has poor lubricity.

[0136] (5) Detection method of antibacterial adhesion property

[0137] The stent surface anti-bacterial adhesion performance of Example 4 and Comparative Example 1 was detected according to the fourth part of the Pharmacopoeia of the People's Republic of China 2020 edition and YY / T0923-2014 "Microbial intrusion test method for liquid and blood needle-free interface". The detection effect is shown in Figure 1, where the left side is a microscope photo and the right side is a SEM photo. As can be seen from the figure, the sample with the coating of the application has anti-bacterial adhesion performance. Figure 4

[0138] The technical features of the above-mentioned examples can be combined arbitrarily. In order to make the description simple, all possible combinations of the technical features in the above-mentioned examples are not described, however, as long as the combination of the technical features does not exist contradictory, it should be considered as the scope of the present application.

[0139] The above-mentioned examples only express several embodiments of the present application, the description is more specific and detailed, but it should not be understood as a limitation on the scope of the patent. It should be pointed out that for ordinary skilled in the art, without departing from the concept of the present application, a number of variations and improvements can be made, which are within the scope of the present application. Therefore, the scope of the patent protection of the present application should be subject to the appended claims.​

Claims

1. A ureteral stent with a zwitterionic coating, characterized in that, The zwitterionic coating is formed by photo-curing a coating composition comprising a zwitterionic copolymer. The zwitterion is selected from phosphorylcholine. The zwitterionic copolymer is formed by copolymerization of at least a phosphorylcholine monomer and a hydrophilic monomer; or The zwitterionic copolymer is formed by copolymerization of at least a phosphorylcholine monomer, a hydrophilic monomer and a photosensitive monomer; The number average molecular weight of the zwitterionic copolymer is 5,000-500,000. The molar ratio of the hydrophilic monomer to the phosphorylcholine monomer in the zwitterionic copolymer is (0.5-10):

1. The molar concentration of the photosensitive monomer in the zwitterionic copolymer is 0.08-12%.

2. The zwitterion-coated ureteral stent of claim 1, wherein, The zwitterionic coating is formed by photo-curing a coating composition comprising a zwitterionic copolymer.

3. The zwitterion-coated ureteral stent of claim 1, wherein, The hydrophilic monomer is selected from one or more of unsaturated carboxylic acid or carboxylic acid salt, unsaturated carboxylic ester, unsaturated acid hydroxyalkyl ester, unsaturated acid anhydride, unsaturated amide, unsaturated lactam.

4. The zwitterion-coated ureteral stent of claim 3, wherein, The hydrophilic monomer is selected from one or more of (meth)acrylic acid, (meth)acrylamide, vinylpyrrolidone, hydroxyethyl (propyl) (meth)acrylate, vinyl acetate, maleic acid, maleic anhydride, fumaric acid, fumaric anhydride, dimethyl acrylamide.

5. The zwitterion-coated ureteral stent of claim 4, wherein, The hydrophilic monomer is selected from vinylpyrrolidone. The phosphorylcholine monomer is 2-methacryloyloxyethyl phosphorylcholine. The photosensitive monomer is selected from a Norrish Type II photosensitive monomer comprising an unsaturated bond.

6. The zwitterion-coated ureteral stent of claim 1, wherein, The zwitterionic coating ureteral stent has a surface friction coefficient of 0.5 or less.

7. The zwitterion-coated ureteral stent of claim 1, wherein, The method comprises the following steps:

8. A method of making a zwitterion-coated ureteral stent as claimed in any one of claims 1 to 7, characterized in that, Synthesis of the copolymer: the hydrophilic monomer and the phosphorylcholine monomer are copolymerized in a certain proportion under the action of a polymerization initiator to form a copolymer; Preparation of the coating composition: the copolymer is dissolved in a solvent and a small molecule photoinitiator is added and mixed thoroughly; the mass fraction of the copolymer is 0.5%-10% and the mass fraction of the small molecule photoinitiator is 0.05%-1% based on the total amount of the coating composition; Preparation of the coating: the coating composition is coated on the surface of the ureteral stent and cured under light to obtain the zwitterionic coating ureteral stent. The method comprises the following steps:

9. A method of making a zwitterion-coated ureteral stent as claimed in any one of claims 1 to 7, characterized in that, Synthesis of the copolymer: the hydrophilic monomer, the phosphorylcholine monomer and the photosensitive monomer are copolymerized in a certain proportion under the action of a polymerization initiator to form a copolymer; Preparation of the coating composition: the copolymer is dissolved in a solvent and mixed thoroughly; the mass fraction of the copolymer is 0.5%-10% based on the total amount of the coating composition; The photosensitive monomer is selected from a Norrish Type II photosensitive monomer. ​ Preparation of the coating: the coating composition is coated on the surface of the ureteral stent and the curing is completed under light conditions, thereby obtaining the ureteral stent with the zwitterionic coating.

10. The method of claim 8 or 9, wherein the method further comprises the step of: The solvent is selected from one or more of water, methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide; The polymerization initiator is selected from one or more of azobis cyanovaleric acid, cyclohexanone peroxide, benzoyl peroxide, dicumyl peroxide, azobis isobutyronitrile, ammonium persulfate.

11. The method for preparing a ureteral stent with a zwitterionic coating according to claim 8, characterized in that, The small molecule photoinitiator is selected from a Norrish Type II photoinitiator; wherein the Norrish Type II photoinitiator is selected from the group consisting of benzophenone, xanthone, a derivative of benzophenone, a blend of benzophenone and a derivative of benzophenone, Michler's ketone, ethyl Michler's ketone, thioxanthone, isopropyl thioxanthone, benzil, anthraquinone, coumarin, or a combination of these photoinitiators.

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