CN116426188A

CN116426188A - Coating composition for medical device surfaces, coating and use of the coating for medical device surfaces

Info

Publication number: CN116426188A
Application number: CN202111649309.XA
Authority: CN
Inventors: 郑理方; 唐增超; 黄佳磊
Original assignee: Jiangsu Biosurf Biotech Co Ltd
Current assignee: Jiangsu Biosurf Biotech Co Ltd
Priority date: 2021-12-30
Filing date: 2021-12-30
Publication date: 2023-07-14

Abstract

The invention belongs to the field of coatings, and particularly relates to a coating composition for a medical device surface, a coating and application of the coating to the medical device surface. The coating can effectively prevent the calcium element deposition phenomenon which is difficult to avoid in the long-term use of medical instruments, particularly urinary tract intervention medical instruments, thereby ensuring the long-term lubricity of the medical instruments and avoiding the damage to patients so as to achieve the purpose of prolonging the effective use period of the medical instruments.

Description

Coating composition for medical device surfaces, coating and use of the coating for medical device surfaces

Technical Field

The invention belongs to the field of coatings, and particularly relates to a coating composition for a medical device surface, a coating and application of the coating to the medical device surface.

Background

The urinary tract intervention medical instrument comprises a catheter, a ureteral stent and the like, and is mainly used for assisting in catheterization of the lower urinary tract and the upper urinary tract of a human body. However, their use often requires periodic replacement, otherwise the constant deposition of the saline components of urine on the medical device can cause a series of problems such as infection, bleeding, etc., which can create a dual pressure on the patient both economically and physiologically.

Calcium element deposition is one of the main causes that it is difficult to use a medical device for urinary tract implantation for a long period of time. In patients with urinary stones, the proportion of stones containing calcium is as high as 95%, and the proportion of single-crystal stones caused by calcium is approximately 70% [1]. The salt composition on the surface of the medical instrument is similar to the composition of urinary calculus, so that the coating on the surface of the medical instrument is expected to prolong the effective service life of the urinary tract intervention medical instrument by avoiding the deposition of calcium element on the surface of the medical instrument.

Modifying the surface of a medical device with different functional coatings can impart a variety of specific functions to the medical device to increase its useful life.

The current modification of the coating of the urinary tract interventional medical device mainly comprises the following steps: 1) Constructing a hydrophilic anti-adhesion coating. The modification method mainly comprises the step of introducing hydrophilic substances such as hyaluronic acid, polyethylene glycol hydrogel and the like into the coating, so that the adsorption of proteins, bacteria and the like can be reduced to a certain extent, and the formation of a biological film is reduced. However, such coatings do not completely block the adhesion of proteins to bacteria, and once there is a small amount of bacteria adhering, the coating becomes a "habitat" for crusting to form a large amount of metabolic stones. 2) Constructing a bactericidal coating. The modification method mainly introduces substances such as antibiotics, bactericides and the like into the coating, and aims to kill microorganisms and bacteria and reduce the deposition of urine salt. However, in practical application, the problem of bacterial drug resistance is unavoidable, and the surface of the medical device returns to an unmodified surface after the drug is released.

Patent document CN113663142a provides a multifunctional coating suitable for urinary medical devices, which is prepared from bio-based anionic polymers and silicone quaternary ammonium salts. The document mentions that the coating has an anti-crusting effect, but it uses anionic polymers, mainly based on the hydrophilic and electronegative properties of the anionic polymers, to produce an anti-adhesion effect on bacteria and proteins, and does not pay attention to the effect of the coating on anti-calcium salt deposition. Meanwhile, the raw materials of the medical instrument show that the surface of the medical instrument has no certain lubricating property. In addition, this document exploits the electrostatic interaction between anions and cations, which is less stable than covalent interactions.

Patent document CN113633832a discloses a method for manufacturing an anti-crusting coating of a ureteral stent based on an anionic resin, wherein a coating solution prepared from the anionic resin is used for forming a coating on the ureteral stent serving as a coating substrate in a solution dipping, spraying or roller coating manner, and the coating is dried and solidified and then is combined on the ureteral stent in a covalent bond mode. However, this document still introduces the structure of the anionic polymer and still has the problem of not having lubricity.

Reference is made to:

[1].Zhangqun Ye,et al.,The Status and Characteristics of Urinary Stone Composition in China.,BJU Int,125:801-809。

disclosure of Invention

Problems to be solved by the invention

Calcium ions in urine can inevitably form insoluble matters such as calcium oxalate crystals, calcium phosphate crystals and the like on or near the surface of a urinary tract interventional medical instrument, the existing sterilization, lubrication and anti-biofilm coating can hardly fundamentally avoid the deposition of calcium elements on the surface of the medical instrument, the effective service life of the medical instrument can hardly be ensured, and even some coatings promote the deposition of calcium phosphate crystals on the surface of the medical instrument due to the introduction of anionic polymers. Therefore, the principle of avoiding the deposition of calcium element on the urinary tract interventional medical devices is the key to prolonging the effective service life of the medical devices.

Therefore, for urinary medical devices, there is still a need for a surface coating that can achieve lubrication and crystallization resistance, while having good stability with the substrate, being less prone to falling off, and having good biocompatibility.

The invention aims to avoid the problems of a series of infection, crusting, bleeding and the like caused by the deposition of calcium element on the surface of the urinary tract intervention medical instrument, thereby effectively prolonging the effective service life of the medical instrument. Meanwhile, the lubricity of the coating is improved while the calcium deposition resistant coating is constructed, and the friction force of the coating when the coating is contacted with human tissues in the use process is reduced.

Solution for solving the problem

The invention synthesizes a cationic monomer homopolymer or a cationic monomer-hydrophilic monomer copolymer through free radical homo-polymerization or copolymerization reaction, and uses the homopolymer or the copolymer as a coating, thereby being coated on the surface of a medical instrument. Wherein the cationic monomer is effective to generate a positive potential in urine to repel calcium ions and competitively complex with oxalate ions and phosphate ions to avoid the deposition of calcium. Under the condition of using hydrophilic monomers, the hydrophilic monomers can effectively enhance the lubricity of the medical instrument so as to ensure that the medical instrument has good lubricity in the interventional and taking-out processes and avoid injury to patients.

Specifically, the invention provides the following technical scheme.

[1] A coating composition for a medical device surface, wherein the coating composition comprises 0.1 to 20% by mass of a polymer and 80 to 99.9% by mass of a solvent, based on the total mass of the coating composition;

wherein the polymer is prepared from the following raw materials in parts by mass: 0.1-2 parts of polymerization initiator, 0-100 parts of hydrophilic monomer and 10-200 parts of cationic monomer.

[2] The coating composition according to [1], wherein the hydrophilic monomer is selected from one or more of unsaturated carboxylic acid, unsaturated carboxylic acid ester, unsaturated acid hydroxyalkyl ester, unsaturated acid anhydride, unsaturated amide, unsaturated lactam; preferably, the hydrophilic monomer is selected from one or more of (meth) acrylic acid, (meth) acrylamide, vinyl pyrrolidone, hydroxyethyl (meth) acrylate, vinyl acetate, maleic acid, maleic anhydride, fumaric acid, fumaric anhydride, dimethylacrylamide; more preferably, the hydrophilic monomer is selected from the group consisting of vinyl pyrrolidone.

[3] The coating composition according to [1] or [2], wherein the cationic monomer is one or more selected from the group consisting of quaternary ammonium salt monomers, guanidine monomers, quaternary phosphonium salt monomers, chitosan and vinyl lysine.

[4] The coating composition according to [1] or [2], wherein the polymerization initiator is selected from one or more of azodicarbonyl valeric acid, cyclohexanone peroxide, benzoyl peroxide, dicumyl peroxide, azobisisobutyronitrile, ammonium persulfate.

[5] The coating composition according to [1] or [2], wherein the solvent is one or more selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, glycerol, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide.

[6] The coating composition according to [1] or [2], wherein the structure of the polymer is as follows:

wherein n is an integer of 1 to 5000, m is an integer of 1 to 5000, and n: m= (10 to 20) in terms of molar ratio; x is Br or Cl; r is R ₁ is-O-or-NH-; r is R ₂ Is an alkyl group having 1 to 12 carbon atoms.

[7] A coating for a medical device surface, characterized by being formed of the coating composition according to any one of [1] to [6 ].

[8] The use of the coating composition according to any one of [1] to [6] for lubrication and anti-calcium deposition on a medical device surface.

[9] The use according to [8], wherein the medical device is one or more selected from the group consisting of a silicone catheter, a latex catheter, a polyurethane catheter, a thermoplastic polyurethane catheter, a silicone ureteral stent, a latex ureteral stent, and a thermoplastic polyurethane ureteral stent.

ADVANTAGEOUS EFFECTS OF INVENTION

According to the invention, the coating with lubricity and calcium deposition resistance is coated on the surface of the medical instrument, so that the phenomenon of calcium element deposition which is difficult to avoid in long-term use of the medical instrument, particularly the urinary intervention medical instrument, can be effectively prevented, the long-term lubricity of the medical instrument is ensured, the damage to a patient is avoided, and the purpose of prolonging the effective service life of the medical instrument is achieved. In particular, the present invention has the following advantageous effects.

1. The coating with lubricity and calcium deposition resistance can be used for carrying out surface modification on various urinary tract intervention medical instruments through various curing methods, such as a light curing method, and can be prevented from falling off under the condition of urine soaking, so that the long-term lubrication and calcium element deposition resistance of different medical instruments are provided;

2. the coating with lubricity and calcium deposition resistance can form positive potential on the surface of the medical instrument so as to prevent calcium elements from gathering and depositing on the surface of the medical instrument, preferably, cations can destroy negative potential on the surface of bacteria so as to kill the bacteria and prevent the bacteria from adhering on the surface of the medical instrument;

3. the medical device coated with the coating with lubricity and calcium deposition resistance can still keep lower friction after being soaked in urine for a long time, ensure that the medical device is kept lubricated in the process of taking out the medical device after long-term use, and avoid injuring patients. In addition, the hydrophilic monomer optionally used in the invention can effectively avoid the adhesion of protein on the surface of the medical instrument and endow the medical instrument with anti-fouling performance.

Drawings

Fig. 1 is a graph showing the effect of calcium deposition resistance on the surface of ureteral stents prepared in example 1 and comparative examples 1 to 3.

Fig. 2 is a graph of the long-term (15 days) anti-calcium deposition effect of the ureteral stent surface prepared in example 1.

Fig. 3 is a graph of the average friction coefficient of the ureteral stent surface prepared in example 1 and comparative example 1.

Fig. 4 is a graph of antibacterial property test of the ureteral stent surface prepared in example 1 and comparative example 1.

Detailed Description

The technical scheme of the present invention will be described in detail with reference to specific embodiments.

The term "monomer" in the context of the present invention means any chemical substance that can be characterized by a chemical formula with a polymerizable group (including (meth) acrylate groups) that can polymerize into an oligomer or polymer to increase molecular weight. The molecular weight of the monomers can generally be calculated simply from the chemical formulae given.

In the present invention, the term "polymer" means a molecule containing two or more repeating units, and in particular, a polymer may be formed of two or more identical or different monomers, and when used in the present invention, the term also includes an oligomer or prepolymer. In the present invention the term "molecular weight" refers to the number average molecular weight (Mn), which is defined as Mn as determined by light scattering, optionally in combination with size exclusion chromatography SEC.

Hereinafter, when a moiety of a molecule is described as "optionally substituted" or "substituted", this means that the moiety may be substituted with one or more substituents selected from the group consisting of: c (C) ₁ -C ₆ Straight, branched or cyclic alkyl, aryl, -OH, -CN, halogen, amine, amide, alcohol, ether, thioether, sulfone and derivatives thereof, sulfoxide and derivatives thereof, carbonate, isocyanate, nitrate and acrylate.

In the present invention the term "curing" is understood as: physical or chemical hardening or solidification is caused by any method such as heating, cooling, drying, crystallization, or solidification caused by chemical reactions, such as radiation curing, thermal curing or addition of curing molecules, initiators.

The term "photo-curing" in the present invention may be achieved by the following exemplary means: the photoinitiation process occurs via irradiation with light or UV radiation in the wavelength range from 100nm to 600 nm. The irradiation source that can be used is sunlight or an artificial lamp or laser. For example, high, medium or low pressure mercury lamps, and xenon and tungsten lamps are advantageous. Also excimer, solid state and diode based lasers are advantageous. Diode-based light sources are generally advantageous for initiating chemical reactions.

< coating composition >

The present invention provides a coating composition for a medical device surface, the coating composition comprising 0.1 to 20% by mass, preferably 2 to 6% by mass of a polymer and 80 to 99.9% by mass, preferably 94 to 98% by mass of a solvent, based on the total mass of the coating composition; wherein the polymer is prepared from the following raw materials in parts by mass: 0.1-2 parts of polymerization initiator, 0-100 parts of hydrophilic monomer and 10-200 parts of cationic monomer.

Polymer (A)

The invention aims to synthesize a cationic monomer homopolymer or a cationic monomer-hydrophilic monomer copolymer through free radical homo-polymerization or copolymerization reaction, and the homopolymer or the copolymer is used as a coating layer to be coated on the surface of a medical instrument.

Hydrophilic monomers

In the present invention, the hydrophilic monomer means a monomer capable of dissolving 1g or more in 100g of water at 25 ℃. The hydrophilic monomer is selected from one or more of unsaturated carboxylic acid, unsaturated carboxylic acid ester, unsaturated acid hydroxyalkyl ester, unsaturated anhydride, unsaturated amide and unsaturated lactam; preferably, the hydrophilic monomer is selected from one or more of (meth) acrylic acid, (meth) acrylamide, vinyl pyrrolidone, hydroxyethyl (meth) acrylate, vinyl acetate, maleic acid, maleic anhydride, fumaric acid, fumaric anhydride, dimethylacrylamide; more preferably, the hydrophilic monomer is selected from the group consisting of vinyl pyrrolidone.

In the present invention, the hydrophilic monomer is used in an amount of 0 to 100 parts by mass, preferably 20 to 80 parts by mass.

The hydrophilic monomer can effectively enhance the lubricity of the medical instrument so as to ensure that the medical instrument has good lubricity in the interventional and taking-out processes and avoid the injury to patients.

In the present invention, the hydrophilic monomer is optionally used, and the cationic polymer synthesized using the cationic monomer is effective in avoiding the phenomenon of calcium element deposition on the surface of the medical device even in the case where the hydrophilic monomer is not used.

Cationic monomer

In the invention, the cationic monomer is selected from one or more of quaternary ammonium salt monomer, guanidine monomer, quaternary phosphonium salt monomer, chitosan and vinyl lysine.

Specifically, as the cationic monomer, for example, quaternary ammonium salt type monomers such as diallylamine, dimethyldiallylammonium chloride, diethyldiallylammonium chloride, (meth) acryloyloxyethyltrimethylammonium chloride, acryloyloxyethyldimethylbenzyl ammonium chloride, 3- [ [2- (methacryloyloxy) ethyl ] dimethylammonium group ] propane-1-sulfonate and the like; guanidine monomers such as guanidine, metformin, diphenylguanidine, tetramethylguanidine, etc.; quaternary phosphonium salt monomers such as triphenylphosphine, tetraphenylphosphine bromide, methyltriphenylphosphine bromide, ethyltriphenylphosphine bromide, benzyltriphenylphosphine chloride, etc.; a chitosan; vinyl lysine, and the like.

The cationic monomers can effectively generate positive potential in urine, so as to repel calcium ions and complex with oxalate ions and phosphate ions to avoid the deposition of calcium elements.

In the present invention, the cationic monomer is used in an amount of 10 to 200 parts by mass, preferably 30 to 150 parts by mass.

Polymerization initiator

As the polymerization initiator, a radical initiator is used in the present invention, and the radical initiator means a substance which generates a radical upon application of activation energy, and includes heat-activated initiators such as organic peroxides, organic hydroperoxides, and azo compounds. In the invention, the polymerization initiator is selected from one or more of azodicarbonyl valeric acid, cyclohexanone peroxide, benzoyl peroxide, dicumyl peroxide, azodiisobutyronitrile and ammonium persulfate. In a preferred embodiment of the present invention the polymerization initiator is azobisisobutyronitrile.

In the present invention, the amount of the polymerization initiator is 0.1 to 2 parts by mass, preferably 0.5 to 1.5 parts by mass.

Other components

In the synthesis of the polymers of the present invention, other components may be added in addition to the above-listed raw material components, as long as these components do not affect and alter the properties and functions of the cationic monomer-hydrophilic monomer copolymer of the present invention. For example, in addition, a small amount of an amino-modified unsaturated carboxylic acid ester salt may be added as a modifying monomer in the synthesis of the polymer for the subsequent graft modification, and examples of the modifying monomer include 2-aminoethylmethacrylate hydrochloride, 2-aminopropyl methacrylate hydrochloride, and the like. It should be noted that the anionic monomers are not used in the present invention to prepare the polymer.

In the synthesis of the polymers of the present invention, in addition to hydrophilic monomers and cationic monomers, photosensitive monomers may also be added to promote immobilization of the synthesized polymers on the surface of medical devices by photocuring. Through a light curing mode, stable coating of the polymer on the surface of the medical instrument can be simply and efficiently finished. Meanwhile, by introducing the photosensitive monomer into the polymer chain, the addition of the photosensitive agent in the later stage can be reduced, and the migration of the photosensitive agent can be avoided. Examples of the photosensitive monomer include substituted or unsubstituted α -hydroxyalkylbenzophenone type photoinitiators. More specifically, the α -hydroxyalkyl benzophenone photoinitiator can have the structure of formula (I): r is R ³ -Ph-C(＝O)-C(R ¹ )(R ² )OH(I)。

Wherein: r is R ¹ 、R ² Independently selected from hydrogen, C ₁ -C ₆ Alkyl, phenyl, C ₁ -C ₆ Alkoxy or R ¹ 、R ² Forms a cyclohexyl ring together with the carbon atoms to which they are attached; r is R ³ Selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Hydroxyalkyl, -OCH ₂ CH ₂ -OR ₄ ；R ₄ Selected from hydrogen, C ₁ -C ₆ An alkyl group.

Specifically, the α -hydroxyalkyl benzophenone photoinitiator may be selected from the group consisting of 2-hydroxy-2-methyl-1-phenyl-1-propanone, 1-hydroxy-cyclohexyl-phenyl-methanone, 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl-propiophenone, 2-hydroxy-2-methyl-1- (4-isopropylphenyl) -1-propanone, 2-hydroxy-2-methyl-1- (4-tert-butylphenyl) -1-propanone; preferably, any one selected from 2-hydroxy-2-methyl-1-phenyl-1-propanone, 1-hydroxy-cyclohexyl-phenyl-methanone, 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylbenzophenone, 2-hydroxy-2-methyl-1- (4-isopropylphenyl) -1-propanone, 2-hydroxy-2-methyl-1- (4-tert-butylphenyl) -1-propanone; from the viewpoint of improving the initiating activity and yellowing resistance, 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylpropionacetone is more preferable.

As examples of photosensitive monomers, for example, benzophenone-type photoinitiators are also possible. Specifically, the benzophenone photoinitiator may be selected from any one of benzophenone, benzophenone acrylate, 4-fluoro-4' -hydroxybenzophenone, 4-methylbenzophenone, 4-ethylbenzophenone, 4-hydroxybenzophenone, and 4-bromomethylbenzophenone. In the present invention, from the viewpoint of improving the photocurability, benzophenone acrylate is preferably used.

In the case of synthesizing a polymer using a photosensitive monomer, the amount of the photosensitive monomer is 1 to 10 parts by mass, preferably 3 to 8 parts by mass. The dosage can ensure that the polymer is firmly fixed on the surface of the medical instrument through photo-curing and is not easy to fall off.

Polymerization

The polymer of the present invention is prepared by a free radical polymerization process including, but not limited to, conventional free radical polymerization, living controlled free radical polymerization, preferably the polymer is prepared by conventional free radical polymerization processes. The polymer of the present invention is prepared in a certain medium, including but not limited to solution polymerization, emulsion polymerization, inverse emulsion polymerization, suspension polymerization, bulk polymerization, preferably the polymer is completed by solution polymerization from the viewpoint of easy operation, and more preferably the polymer is completed by homo-polymerization or copolymerization in an aqueous solution from the viewpoint of environmental protection. In one embodiment of the invention, the optional hydrophilic monomer, the cationic monomer and the optional other components are dissolved in water, a free radical initiator is added into the system, oxygen is removed, and the reaction is carried out at a certain temperature to obtain the polymer.

As a non-limiting example, the method of synthesizing the polymer of the present invention includes: weighing 5-20 parts of cationic monomer, 50-100 parts of hydrophilic monomer and 100-2000 parts of solvent in a reactor, stirring and dissolving uniformly, heating to 30-90 ℃ and keeping for 10-30 minutes. Rapidly adding a solution containing 0.1-2 parts of a polymerization initiator and 10-20 parts of a solvent, and keeping the temperature for reaction for 1-5 hours. After the reaction is finished, the reaction mixture is transferred and fully mixed with 500 to 20000 parts of precipitant, and the precipitated product is taken out and dried for 3 to 8 hours at 50 to 100 ℃ to obtain the polymer.

Polymer

The present invention preferably uses the hydrophilic monomer and the cationic monomer to undergo a radical copolymerization reaction to obtain the polymer, and as a non-limiting example, the structure of the polymer is as follows:

wherein n is an integer of 1 to 5000, preferably an integer of 10 to 3000, m is an integer of 1 to 5000, preferably an integer of 10 to 3000, n: m= (10 to 20), preferably 12 to 18, in terms of molar ratio; x is Br or Cl; r is R ₁ is-O-or-NH-; r is R ₂ Is an alkyl group having 1 to 12 carbon atoms.

As the alkyl group, there may be exemplified those known in the art such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, isomers of these groups and the like.

The structure of the polymer is not limited to the present invention, and for example, in the case of synthesizing a polymer using the above-described photosensitive monomer, the structure of the polymer of the present invention may contain a photosensitive monomer unit in addition to a hydrophilic monomer unit and a cationic monomer unit. For example, in the case of synthesizing a polymer using only cationic monomers, the structure of the polymer of the present invention contains only cationic monomer units.

Solvent (S)

The coating composition of the present invention comprises a solvent, preferably one or more selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, glycerol, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide.

Lubricating additives such as surfactants, waxes, lubricants, soaps and detergents may also be added to the coating composition as desired. These lubricious additives do not increase the coating too much in osmolarity but can increase lubricity on wetting and reduce adhesion, their low solubility in water helps to retain them in the coating. Other additives may include polyelectrolytes, wetting agents, leveling agents, defoamers, film forming aids, thickeners, pigments, antimicrobial agents, colorants, surfactants, and the like. Preferably, the coating composition of embodiments of the present invention achieves good lubricity, firmness and calcium deposition resistance without the addition of additional optional components other than the polymer, solvent.

< coating >

In the present invention, the coating composition described above is used to form a coating for medical devices. The coating is formed, for example, by: the coating composition of the present invention is applied, for example dip-coated, to the surface of a medical device, cured by solvent evaporation, or a film forming aid is added thereto to form on the surface of a medical device by thermal curing, or it is exposed to electromagnetic radiation, preferably ultraviolet radiation, to excite the photosensitive monomer units in the polymer to cure the coating composition. The ultraviolet intensity is 5-50 mW/cm during curing ² The time for curing the coating composition is 2 to 10 minutes.

The coating composition may be applied by one or more of brushing, dipping, spraying, flow coating, knife coating, and the thickness of the coating on the medical device is preferably in the range of 1 to 20 μm, preferably 2 to 18 μm. The thickness of the coating can be controlled by: changing the soak time, changing the draw rate, or changing the viscosity of the coating composition and the number of coating steps.

< use of coating composition >

The invention also relates to the use of said coating composition for lubrication and anti-calcium deposition on the surface of medical devices. As described above, the invention can form a coating with lubricity and calcium deposition resistance by homo-polymerizing cationic monomers to form homopolymers or copolymerizing hydrophilic monomers and cationic monomers to form copolymers, wherein the coating can form positive potential on the surface of a medical instrument so as to prevent calcium elements from gathering and depositing on the surface of the medical instrument, and meanwhile, cations can destroy negative potential on the surface of bacteria so as to kill the bacteria and prevent the bacteria from adhering on the surface of the medical instrument. The coating of the present invention has a significant effect of providing excellent lubricity and calcium deposition resistance to the surface of the medical device.

In the invention, the medical instrument is one or more selected from a silicone catheter, a latex catheter, a polyurethane catheter, a thermoplastic polyurethane catheter, a silicone ureteral stent, a latex ureteral stent and a thermoplastic polyurethane ureteral stent.

Examples

The invention is illustrated by the following examples, which are given by way of illustration only and not by way of exhaustive illustration, as will be understood by those skilled in the art.

The simulated artificial urine related by the invention is prepared according to YY/T0872-2013 ureteral stent test method.

Example 1

Step one: synthesis of Polymer 1

55 parts by mass of N-vinylpyrrolidone, 25 parts by mass of acryloyloxyethyl trimethyl ammonium chloride (DAC) and 7.5 parts by mass of benzophenone acrylate were added to the reactor, 250 parts by mass of water was added thereto, and after stirring and dissolving uniformly, the mixture was heated to 60℃and after holding for 15 minutes, a solution of 0.25 part by mass of Azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. After stirring for 2 hours, the reaction was stopped, 1000 parts by mass of acetone was added as a precipitant, and insoluble matter was taken after precipitation and dried at 80℃for 2 hours to obtain Polymer 1.

Step two: preparation of coating composition 1

And (3) stirring and dissolving the polymer 1 in the step (I) by using 50 mass percent ethanol to prepare a coating solution with the mass percent of the polymer being 3%, namely the coating composition 1.

Step three: preparation of coatings and medical devices

The coating liquid is coated on the surface of the thermoplastic polyurethane ureteral stent by a leaching method, and the using strength is 20mw/cm ² And (3) curing for 5 minutes, and airing the cured sample in the air to obtain the thermoplastic polyurethane ureteral stent with the surface coated with the coating formed by the coating composition 1.

Example 2

The procedure was the same as in example 1 except that a latex urinary catheter was used instead of the thermoplastic polyurethane ureter of example 1.

Example 3

The procedure was the same as in example 1 except that a silicone urinary catheter was used instead of the thermoplastic polyurethane ureter of example 1.

Example 4

Step one: synthesis of Polymer 2

55 parts by mass of N-vinylpyrrolidone, 25 parts by mass of acryloyloxyethyl trimethyl ammonium chloride (DAC) were added to the reactor, 250 parts by mass of water was added thereto, and after stirring and dissolving uniformly, the mixture was heated to 60℃and kept for 15 minutes, a solution of 0.25 part by mass of Azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. After stirring for 2 hours, the reaction was stopped, 1000 parts by mass of acetone was added as a precipitant, and insoluble matter was taken after precipitation and dried at 80℃for 2 hours to obtain Polymer 2.

Step two: preparation of coating composition 2

And (3) stirring and dissolving the polymer 2 in the step (I) by using 50 mass percent ethanol to prepare a coating solution with the polymer mass percent of 3%, adding polyurethane emulsion in an equal volume ratio, and adding 2-hydroxybenzophenone (the dosage is 0.5wt% of the polymer 2) as a photoinitiator, so that the coating solution is obtained after uniform mixing, namely the coating composition 2.

Step three: preparation of coatings and medical devices

By leachingThe finally obtained coating liquid is coated on the surface of a thermoplastic polyurethane ureteral stent, and the using strength is 20mw/cm ² And (3) curing for 5 minutes, and airing the cured sample in the air to obtain the thermoplastic polyurethane ureteral stent with the surface coated with the coating formed by the coating composition 2.

Example 5

Step one: synthesis of Polymer 2

Polymer 2 was obtained in the same manner as in step one of example 4.

Step two: preparation of coating composition 3

And (3) stirring and dissolving the polymer 2 in the step (I) by using 50 mass percent ethanol to prepare a coating solution with the polymer mass percent of 3 percent, and uniformly mixing the coating solution to obtain the coating composition 3.

Step three: preparation of coatings and medical devices

And (3) coating the finally obtained coating liquid on the surface of the thermoplastic polyurethane ureteral stent by a leaching method, and airing and curing the coating liquid in air to obtain the thermoplastic polyurethane ureteral stent with the surface coated with the coating formed by the coating composition 3.

Example 6

Step one: synthesis of Polymer 2

Polymer 2 was obtained in the same manner as in step one of example 4.

Step two: preparation of coating composition 4

And (3) stirring and dissolving the polymer 2 in the step (I) by using 50 mass percent ethanol to prepare a coating solution with the mass percent of the polymer, and adding the acrylate emulsion in an equal volume ratio to uniformly mix the coating solution to obtain the coating composition 4.

Step three: preparation of coatings and medical devices

And (3) coating the finally obtained coating liquid on the surface of the thermoplastic polyurethane ureteral stent by a leaching method, and placing the thermoplastic polyurethane ureteral stent in a 60 ℃ oven for curing to obtain the thermoplastic polyurethane ureteral stent with the surface coated with the coating formed by the coating composition 4.

In both examples 5 and 6, the coating layer achieved a firm and stable bond with the substrate and had good lubricity and anti-calcium salt deposition effect. This means that the different curing modes do not affect the performance effect of the coating.

Comparative example 1

As comparative example 1, a thermoplastic polyurethane ureter without any coating was used.

Comparative example 2

Step one: synthesis of Polymer 3

55 parts by mass of N-vinylpyrrolidone, 25 parts by mass of sodium styrene sulfonate and 7.5 parts by mass of benzophenone acrylate were added to the reactor, 250 parts by mass of water was added thereto, and after stirring and dissolving uniformly, the mixture was heated to 60℃and kept for 15 minutes, and then a solution of 0.25 part by mass of Azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. After stirring for 2 hours, the reaction was stopped, 1000 parts by mass of acetone was added as a precipitant, and insoluble matter was taken after precipitation and dried at 80℃for 2 hours to obtain polymer 3.

Step two: preparation of coating composition 5

And (3) stirring and dissolving the polymer 3 in the step (I) by using 50 mass percent ethanol to prepare a coating solution with the mass percent of the polymer of 3 percent, namely the coating composition 5.

Step three: preparation of coatings and medical devices

The coating liquid is coated on the surface of the thermoplastic polyurethane ureteral stent by a leaching method, and the using strength is 20mw/cm ² And (3) curing for 5 minutes, and airing the cured sample in the air to obtain the thermoplastic polyurethane ureteral stent with the surface coated with the coating formed by the coating composition 5.

Comparative example 3

Step one: synthesis of Polymer 4

55 parts by mass of N-vinylpyrrolidone and 7.5 parts by mass of benzophenone acrylate were added to the reactor, 250 parts by mass of water was added thereto, and after stirring and dissolving uniformly, the mixture was heated to 60℃and kept for 15 minutes, and then a solution of 0.25 part by mass of Azobisisobutyronitrile (AIBN) dissolved in 1 part by mass of water was added. After stirring for 2 hours, the reaction was stopped, 1000 parts by mass of acetone was added as a precipitant, and insoluble matter was taken after precipitation and dried at 80℃for 2 hours to obtain polymer 4.

Step two: preparation of coating composition 6

And (3) stirring and dissolving the polymer 4 in the step (I) by using 50 mass percent ethanol to prepare a coating solution with the mass percent of the polymer being 3%, namely the coating composition 6.

Step three: preparation of coatings and medical devices

The coating liquid is coated on the surface of the thermoplastic polyurethane ureteral stent by a leaching method, and the using strength is 20mw/cm ² And (3) curing for 5 minutes, and airing the cured sample in the air to obtain the thermoplastic polyurethane ureteral stent with the surface coated with the coating formed by the coating composition 6.

Performance testing

(1) Testing of calcium deposition on medical device surfaces

A calcium deposition experimental apparatus was produced according to document [2 ]. The device was placed in a constant temperature oven, maintained at 37 ℃, and the medical devices of example 1 and comparative examples 1, 2, 3 were placed in the device, respectively, and continuously injected with simulated artificial urine at a flow rate of 0.5-1.5 mL/min. After 5 days, the medical devices of example 1 and comparative examples 1, 2 and 3 were removed, the surface thereof was gently rinsed with absolute ethyl alcohol, and after air-drying, the surface crystallization was observed by using an optical microscope.

Document [2]: choong SK, wood S, whitfield hn.a model to quantify encrustation on ureteric stents, urethral catheters and polymers intended for urological use, BJU int.2000sep;86 (4):414-21.

As can be seen from fig. 1, the medical device of example 1 coated with the coating composition of the present invention as a coating layer had a smooth surface and no calcium deposition. In contrast, the medical devices of comparative examples 1 to 3 all had severe calcium deposition on the surfaces. This shows that if the surface is not coated (comparative example 1) and the coating is not prepared using cationic monomers (comparative examples 2 and 3), the medical device surface cannot have good lubricity and calcium deposition resistance.

(2) Testing of long-term (15 days) calcium deposition on medical device surfaces

The medical device of example 1 was immersed in 10mL of simulated artificial urine, immersed at 37 ℃ for 15 days at 70rpm, replaced once a day, and surface crystallization was observed using an optical microscope.

As can be seen from fig. 2, the surface of the medical device of example 1 remained smooth and without severe calcium deposition even under prolonged (15 day) soaking.

(3) Determination of the surface calcium deposition of medical instruments

The amount of calcium deposited on the surfaces of the medical devices of example 1, example 4 and comparative examples 1, 2 and 3 was measured according to the method described in document [3], and the results are shown in Table 1 below. Specifically, the encrustation on the surface of the medical device was dissolved with a hydrochloric acid solution, and the calcium element was quantitatively characterized by using an enzyme-labeled instrument, and the calcium deposition amounts on the surfaces of the medical devices of example 1, example 4 and comparative examples 1, 2 and 3 were obtained by comparison with a standard curve (y=0.062x+0.0265, r2= 0.9991).

Document [3]: liu Hua, ultraviolet spectrophotometry to continuously measure the calcium and magnesium content of chlorate industrial brine [ J ], chemical engineering and equipment, 2007, 000 (006): 79-82.

As can be seen from table 1, the calcium deposition rate (about 54%) on the medical device surface of example 1, the calcium deposition rate (about 61%) on the medical device surface of example 4 was far lower than those of comparative example 1 (about 100%), comparative example 2 (about 469%) and comparative example 3 (about 75%).

TABLE 1

	Example 1	Example 4	Comparative example 1	Comparative example 2	Comparative example 3
						Calcium deposition Rate (%)	54	61	100	469	75

(4) Determination of the coefficient of Friction

The medical devices of example 1 and comparative example 1 were immersed in purified water for 1min, respectively, and then their friction coefficients were tested under a clamping force of 3N, repeated 30 times and the average friction coefficient was calculated.

As can be seen from fig. 3, the average friction coefficient of the medical device surface of example 1 was about 0.1, while the average friction coefficient of the medical device surface of comparative example 1 was about 1.3, i.e., the average friction coefficient of example 1 was much lower than that of comparative example 1. This shows that the use of the medical device of example 1 can significantly reduce the coefficient of friction, thereby reducing the harm to the patient due to excessive resistance in actual use. Meanwhile, the average friction coefficient of the example 1 keeps low deviation under repeated test, which shows that the coating of the invention has high mechanical property and is not easy to wear.

(5) Test of antibacterial Properties

The medical devices of comparative example 1 and example 1 were immersed in simulated urine, respectively, and were shaken at 37℃and 70rpm for 5 days, and after removal, bacteria on the surface were immobilized using a 2.5% glutaraldehyde solution, and dehydration was performed using a gradient of 85% alcohol-95% alcohol-absolute alcohol. Bacteria on the surface of the tube were observed using a scanning electron microscope.

As can be seen from fig. 4, the medical device surface of example 1 did not exhibit a more pronounced antibacterial property than the medical device surface of comparative example 1, and both surfaces were adhered with a large amount of bacteria. It is believed that the efficacy of the coating according to the invention is mainly due to the repelling effect on calcium ions and not to the antimicrobial properties. Even under the condition of certain bacterial adhesion, the coating can still achieve good effect of resisting calcium salt deposition.

Claims

1. A coating composition for medical device surfaces, characterized in that the coating composition comprises 0.1-20% by mass of polymer and 80-99.9% by mass of solvent, based on the total mass of the coating composition;

2. The coating composition of claim 1, wherein the hydrophilic monomer is selected from one or more of unsaturated carboxylic acids, unsaturated carboxylic acid esters, unsaturated acid hydroxyalkyl esters, unsaturated anhydrides, unsaturated amides, unsaturated lactams; preferably, the hydrophilic monomer is selected from one or more of (meth) acrylic acid, (meth) acrylamide, vinyl pyrrolidone, hydroxyethyl (meth) acrylate, vinyl acetate, maleic acid, maleic anhydride, fumaric acid, fumaric anhydride, dimethylacrylamide; more preferably, the hydrophilic monomer is selected from the group consisting of vinyl pyrrolidone.

3. The coating composition according to claim 1 or 2, wherein the cationic monomer is selected from one or more of quaternary ammonium salt monomers, guanidine monomers, quaternary phosphonium salt monomers, chitosan, vinyl lysine.

4. The coating composition according to claim 1 or 2, wherein the polymerization initiator is selected from one or more of azodicarbonyl valeric acid, cyclohexanone peroxide, benzoyl peroxide, dicumyl peroxide, azobisisobutyronitrile, ammonium persulfate.

5. The coating composition according to claim 1 or 2, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, glycerol, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide.

6. The coating composition according to claim 1 or 2, characterized in that the structure of the polymer is as follows:

7. A coating for medical device surfaces, characterized in that it is formed from a coating composition according to any one of claims 1 to 6.

8. Use of a coating composition according to any one of claims 1 to 6 for lubrication and anti-calcium deposition on the surface of medical devices.

9. The use according to claim 8, wherein the medical device is selected from one or more of a silicone catheter, a latex catheter, a polyurethane catheter, a thermoplastic polyurethane catheter, a silicone ureteral stent, a latex ureteral stent, a thermoplastic polyurethane ureteral stent.