阅读说明：本技术 官能化的亲水聚合物、包含其的亲水涂层溶液和医用导管 (Functionalized hydrophilic polymer, hydrophilic coating solution and medical catheter comprising the same ) 是由 陈雪生 李亚南 赵开 马晓意 于 2019-11-07 设计创作，主要内容包括：本发明提供了一种官能化的亲水聚合物、包含其的亲水涂层溶液和医用导管。该官能化的亲水聚合物的主链为N-乙烯基吡咯烷酮与丙烯酰基单体的无规共聚物；所述丙烯酰基单体上包括能与异氰酸酯基反应的官能团,其全部或部分与异氰酸酯丙烯酸乙酯中的异氰酸酯基反应连接。包含其的亲水涂层溶液通过光引发剂引发官能化亲水聚合物的直接聚合反应可形成交联的亲水聚合物涂层,从而避免了由于亲水聚合物本身不参与交联而造成亲水涂层在使用过程中脱落向周围环境扩散的问题,特别是在应用于医用导管时,低分子迁移的亲水涂层极大降低了后期不良反应的发生。(The present invention provides a functionalized hydrophilic polymer, a hydrophilic coating solution comprising the same, and a medical catheter. The main chain of the functionalized hydrophilic polymer is a random copolymer of N-vinyl pyrrolidone and an acryloyl monomer; the acryloyl monomer comprises a functional group capable of reacting with isocyanate groups, and the whole or part of the acryloyl monomer reacts and is connected with the isocyanate groups in the isocyanate ethyl acrylate. The hydrophilic coating solution containing the hydrophilic polymer can form a cross-linked hydrophilic polymer coating through direct polymerization reaction of the functionalized hydrophilic polymer initiated by the photoinitiator, so that the problem that the hydrophilic coating falls off and diffuses to the surrounding environment in the use process due to the fact that the hydrophilic polymer does not participate in cross-linking is avoided, and particularly when the hydrophilic coating solution is applied to a medical catheter, the hydrophilic coating with low molecular migration greatly reduces the occurrence of later adverse reactions.)

1. A functionalized hydrophilic polymer characterized in that the backbone of the functionalized hydrophilic polymer is a random copolymer of N-vinylpyrrolidone and an acryloyl monomer; the acryl monomer includes a functional group capable of reacting with an isocyanate group, which is wholly or partially connected by reacting with an isocyanate group of an unsaturated monomer having an isocyanate group.

2. The functionalized hydrophilic polymer of claim 1, wherein the functional groups capable of reacting with isocyanate groups comprise: a carboxylic acid group, a hydroxyl group, or an amino group;

the unsaturated monomer with isocyanate group is isocyanate ethyl acrylate and isocyano ethyl methacrylate.

3. The functionalized hydrophilic polymer of claim 1, wherein the functionalized hydrophilic polymer has a molecular weight of 8000 to 5000000;

preferably, the functionalized hydrophilic polymer has a molecular weight of 200000 to 1300000.

4. The functionalized hydrophilic polymer of claim 1, wherein the mass of the acryloyl monomer is 10% or less of the total weight of N-vinylpyrrolidone and acryloyl monomer;

preferably, the mass of the acryloyl monomer is less than or equal to 5 percent of the total weight of the N-vinyl pyrrolidone and the acryloyl monomer.

5. The functionalized hydrophilic polymer of any one of claims 1-4, wherein the acryloyl monomer is acrylic acid, methacrylic acid, acrylamide, methacrylamide, hydroxyethyl acrylate, or hydroxyethyl methacrylate.

6. A process for the preparation of a functionalized hydrophilic polymer according to any one of claims 1 to 5, comprising the following steps:

s1, carrying out free radical polymerization reaction on N-vinyl pyrrolidone and an acryloyl monomer to obtain a random copolymer of the two monomers;

reacting the random copolymer obtained from S2 and S1 with unsaturated monomers with isocyanate groups to obtain the functionalized hydrophilic polymer, namely, polyvinyl pyrrolidone polymer with double bonds;

preferably, the conditions of the radical polymerization reaction in S1 are: heating to react under the action of an initiator in a protective gas atmosphere, and precipitating and drying after the reaction is finished to obtain the random copolymer;

preferably, the initiator is azobisisobutyronitrile, benzoyl peroxide and lauroyl peroxide, and the addition amount of the initiator is 0.1-5% of the total weight of the N-vinyl pyrrolidone and the acryloyl monomer;

preferably, the shielding gas is nitrogen, helium or argon; the heating temperature is 50-90 ℃, and the reaction time is 4-6 hours.

Preferably, in S2, the isocyanate ethyl acrylate is in excess relative to the acrylic-based monomer; the reaction temperature in S2 is 50-90 ℃; the reaction time is 4-6 hours.

7. A hydrophilic coating solution, comprising: a functionalized hydrophilic polymer of any one of claims 1-5, a photoinitiator, and a solvent;

preferably, the mass content of the functionalized hydrophilic polymer in the hydrophilic coating solution is 1-20%;

preferably, the photoinitiator is a free radical photoinitiator;

preferably, the mass content of the photoinitiator in the hydrophilic coating solution is 0.1-10%;

preferably, the hydrophilic coating solution further comprises: a functionalized monomer, oligomer, or polymer;

the functionalized monomer, oligomer or polymer is monofunctional acrylate, monofunctional methacrylate, difunctional acrylate monomer, difunctional methacrylate monomer, trifunctional acrylate monomer, trifunctional methacrylate monomer, multifunctional acrylate monomer, aliphatic urethane acrylate, aliphatic urethane methacrylate, aromatic urethane acrylate, epoxy acrylate or epoxy methacrylate;

the monofunctional methacrylate is 2-phenoxyethyl methacrylate or isobornyl methacrylate;

the difunctional acrylate monomer is 1, 6-hexanediol diacrylate, alkoxylated hexanediol diacrylate, tripropylene glycol diacrylate, polyethylene glycol (400) diacrylate, dipropylene glycol diacrylate, (3) ethoxylated bisphenol A diacrylate, (4) ethoxylated bisphenol A diacrylate, (10) ethoxylated bisphenol A diacrylate, tricyclodecane dimethanol diacrylate or (2) propoxylated neopentyl glycol diacrylate;

the difunctional methacrylate monomer is ethoxylated bisphenol A dimethacrylate, triethylene glycol dimethacrylate, ethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, 1, 3-butanediol dimethacrylate, (2) ethoxylated bisphenol A dimethacrylate or (10) ethoxylated bisphenol A dimethacrylate;

the trifunctional acrylate monomer is (6) propoxylated trimethylolpropane triacrylate, tris (2-hydroxyethyl) isocyanuric acid triacrylate, pentaerythritol triacrylate, (3) ethoxylated trimethylolpropane triacrylate, (3) propoxylated trimethylolpropane triacrylate, (9) propoxylated trimethylolpropane triacrylate, (3) propoxylated glycerol triacrylate or (15) ethoxylated trimethylolpropane triacrylate;

the trifunctional methacrylate monomer is trimethylolpropane trimethacrylate;

the multifunctional acrylate monomer is pentaerythritol tetraacrylate;

preferably, the mass content of the solvent in the hydrophilic coating solution is more than or equal to 70 percent;

preferably, the solvent is an organic solvent soluble in water;

preferably, the solvent is an alcohol;

preferably, the alcohol is a C1-C4 alcohol;

preferably, the C1-C4 alcohol is one or a combination of methanol, ethanol and isopropanol;

preferably, the solvent further comprises water, and the mass content of water in the hydrophilic coating solution is 0 to 80% excluding 0.

8. A method for preparing the hydrophilic coating solution of claim 7, comprising the steps of: the components were mixed and stirred at room temperature to form a homogeneous solution.

9. Use of a functionalized hydrophilic polymer according to any one of claims 1 to 5 or a hydrophilic coating solution according to claim 7 in an article comprising a hydrophilic or lubricious coating;

preferably, the hydrophilic or lubricious coating containing article is a medical device.

10. A medical catheter comprising a hydrophilic coating; the hydrophilic coating layer is obtained by subjecting the hydrophilic coating solution of claim 7 to a one-time coating and curing process;

preferably, the base material of the medical catheter is a nylon tube;

preferably, the primary coating and curing process comprises:

immersing the base material into the prepared hydrophilic coating solution, lifting the base material when the base material is 2/3 immersed in the solution, and then placing the base material under an ultraviolet light source for curing; the actual light intensity of the ultraviolet curing light source is more than 40mW/cm²The curing time is 100-.

Technical Field

The invention relates to the field of medical materials, in particular to a functionalized hydrophilic polymer, a hydrophilic coating solution containing the functionalized hydrophilic polymer and a medical catheter.

Background

With the development of medical technology, medical catheters are widely applied clinically and play a critical role in improving the medical technology level. A general medical catheter is made of polymer materials such as rubber, silica gel, polyvinyl chloride, polyethylene, polypropylene, nylon, etc., and when the catheter is used in a human body, a series of reactions, such as blood coagulation, bacterial adsorption, and tissue damage caused by friction, are brought about. Therefore, it is critical that the catheter has improved surface biocompatibility and lubricity in addition to its desired mechanical properties. By lubricating the surface of the catheter, on one hand, the friction between the catheter and the surface of the tissue in the pushing or withdrawing process is reduced, and the pain of a patient is relieved; on the other hand, the method can effectively reduce bacterial adhesion and protein adsorption and improve the biocompatibility of the material surface.

The surface of the catheter is coated with the lubricant, so that friction force can be reduced, and smoothness is improved, but the lubricant needs to be coated when the catheter is used, the using amount and the operation process of the lubricant are not well mastered, the operation process influences cleaning of the catheter, and most importantly, the lubricant can fall off from the surface of the catheter and stays in tissues, so that adverse effects are brought.

Hydrophilic coatings that become lubricious upon wetting are widely studied, particularly for medical devices, and it is desirable to minimize the amount of migrateable materials that can find their way into human tissue, which can potentially be harmful. An effective way to reduce the amount of migrateable coating is to crosslink the active ingredient in the coating by curing, so that the coating adheres better to the surface of the catheter to resist mechanical or frictional forces applied to the surface.

CN101812265A discloses a hydrophilic coating solution comprising a modified polyurethane dispersion matrix polymer, a hydrophilic polymer and a reactive cross-linking agent; CN101934101A discloses a hydrophilic coating solution comprising an adhesive layer and a hydrophilic layer, wherein the adhesive layer is a crosslinked polyurethane coating obtained by crosslinking hydrophilic polyurethane with a crosslinking agent, and the wetting layer is a hydrophilic high molecular polymer. They are characterized in that the network polymer formed by polyurethane and cross-linking agent forms the skeleton of the coating, the linear hydrophilic polymer is distributed in the network polymer skeleton to increase the lubricity of the coating, the network polyurethane cross-linking polymer and the linear hydrophilic polymer form semi-interpenetrating network structure, although the solution can be realized by single-layer coating or double-layer coating, the hydrophilic polymer is only combined with the network cross-linking polymer by hydrogen bonding force or van der waals force and steric hindrance effect, the combination is not firm, and the hydrophilic polymer can migrate to the outside of the coating once the coating is wetted.

WO2006056482, WO2007065722, WO2009112548 disclose a hydrophilic coating solution for forming a coating on a substrate surface having a crosslinked polymer, the hydrophilic coating solution being characterized in that an oligomer or polymer capable of undergoing a crosslinking reaction is polymerized by a Norrish type i photoinitiator to obtain a crosslinked underlayer, and further coating the surface of the underlayer with a functional linear polymer solution, the linear functional polymer being linked to the crosslinked polymer underlayer by a grafting reaction of the Norrish type i photoinitiator. WO2016200337a1 improves on the above invention by using amphiphilic polymers to make the base layer, which increases the bond strength to different substrates. Although the invention realizes the chemical bond combination of all the effective components of the coating and reduces the migration of the polymer to the outside of the coating, the invention can not ensure that all the linear functional polymers are completely combined with the base layer through the grafting reaction, and the coating and the base material can be firmly combined through two coating and curing processes.

Disclosure of Invention

In order to solve the above technical problems, the present invention provides a functionalized hydrophilic polymer, a hydrophilic coating solution and a medical catheter comprising the same. When the hydrophilic coating solution containing the functionalized hydrophilic polymer is applied to the medical catheter coating, only one coating and curing process is needed, and the coating solution has low migratable objects and good binding force with a base material.

In order to achieve the purpose, the invention adopts the following technical scheme:

the first aspect of the present invention provides a functionalized hydrophilic polymer having a backbone of a random copolymer of N-vinylpyrrolidone and an acryloyl monomer;

the acryl monomer includes a functional group capable of reacting with an isocyanate group (-NCO), which is wholly or partially attached by reacting with an isocyanate group of an unsaturated monomer having an isocyanate group.

The functionalized hydrophilic polymer provided by the invention is polyvinyl pyrrolidone (PVP) with double bonds, and the double bond group is acrylate group or alkyl acrylate group. The polyvinylpyrrolidone segment in the resulting functionalized hydrophilic polymer provides the hydrophilicity of the polymer, while the functionalized segment with double bonds can fix the polymer chains to the surface of the substrate by cross-linking reaction of the double bonds.

Preferably, the functional group capable of reacting with an isocyanate group (-NCO) includes: carboxylic acid group (-COOH), hydroxyl group (-OH) or amino group (-NH)₂)；

The unsaturated monomer with isocyanate group is isocyanate ethyl acrylate and isocyano ethyl methacrylate.

Preferably, the functionalized hydrophilic polymer has a molecular weight of 8000 to 5000000; more preferably from 200000 to 1300000.

Preferably, the mass of the acryloyl monomer is less than or equal to 10%, preferably less than or equal to 5%, of the total weight of the N-vinylpyrrolidone and the acryloyl monomer.

The N-vinyl pyrrolidone and the acryloyl monomer can be mixed and copolymerized in any proportion, the mass of the acryloyl monomer limited by the invention is within 10 percent of the total mass of all monomers of a main chain, so that the N-vinyl pyrrolidone is in a main structure in the main chain of a final polymer, and the addition of the acryloyl monomer is used for providing a group capable of reacting with an isocyanate group, and further functionalizing the molecular chain of the polymer to form a double bond with a crosslinking function.

Preferably, the acryl monomer is acrylic acid (MA), methacrylic acid (MAA), acrylamide, methacrylamide, hydroxyethyl acrylate, or hydroxyethyl methacrylate (HEMA), and the like.

In a second aspect, the present invention provides a method for preparing the above functionalized hydrophilic polymer, comprising the steps of:

s1, carrying out free radical polymerization reaction on N-vinyl pyrrolidone (NVP) and an acryloyl monomer to obtain a random copolymer of the two monomers; the reaction formula is as follows:

wherein R is₁is-H or alkyl; the alkyl group is preferably-CH₃；

R₂is-OH, -NH₂，–O(CH₂)_nOH。

The random copolymer obtained from S2 and S1 reacts with unsaturated monomer with isocyanate group to obtain the functionalized hydrophilic polymer, namely polyvinyl pyrrolidone polymer with double bond.

As a preferred embodiment of the present invention, the reaction formula when ethyl isocyanate acrylate is used as the unsaturated monomer having an isocyanate group is as follows:

preferably, the conditions of the radical polymerization reaction in S1 are: and in a protective gas atmosphere, under the action of an initiator, heating for reaction, and after the reaction is finished, precipitating and drying to obtain the random copolymer.

Preferably, the initiator is Azobisisobutyronitrile (AIBN), Benzoyl Peroxide (BPO), Lauroyl Peroxide (LPO) added in an amount of 0.1% to 5% by weight based on the total weight of the N-vinyl pyrrolidone and the acryl monomer.

Preferably, the shielding gas is nitrogen, helium or argon; nitrogen is preferred, which is protective and inexpensive.

The heating temperature is 50-90 ℃, and the reaction time is 4-6 hours.

Preferably, in S2, the isocyanate ethyl acrylate is in excess relative to the acrylic-based monomer, generally 1.2 times or more the molar amount of the acrylic-based monomer; the reaction temperature in S2 is 50-90 ℃; the reaction time is 4-6 hours.

In a third aspect, the present invention provides a hydrophilic coating solution comprising: the invention provides in a first aspect a functionalized hydrophilic polymer, a photoinitiator and a solvent.

The polyvinylpyrrolidone segment in the functionalized hydrophilic polymer of the invention provides hydrophilicity of the polymer, and the functionalized segment with double bonds fixes a polymer chain on the surface of the substrate through the cross-linking reaction of the double bonds, so that the hydrophilic coating solution is combined with the substrate more firmly when being applied.

Preferably, the mass content of the functionalized hydrophilic polymer in the hydrophilic coating solution is 0-90%, excluding 0; more preferably 1-20%, and is more beneficial to the implementation of the coating process.

Preferably, the photoinitiator is any available radical photoinitiator, including benzoin and derivatives (such as benzoin, benzoin bis-methyl ether, benzoin ethyl ether, benzoin isopropyl ether, benzoin butyl ether), benzils (such as benzophenone, α -dimethoxy- α -phenylacetophenone), alkylbenzophenones (such as α -diethoxyacetophenone, α -hydroxyalkyl phenone, α -aminoalkylphenone), acylphosphine oxides (such as aroylphosphine oxide, bis-benzoylphenylphosphine oxide), benzophenones (such as benzophenone, 2, 4-dihydroxybenzophenone, Michler ketone), thioxanthones (such as thiopropoxythioxantrone, isopropylthioxanthone), commonly used radical photoinitiators of Gellidon, TPO (2,4,6 (trimethylbenzoyl) diphenylphosphine oxide), TPO (2,4,6 (2,6 (trimethylbenzoyl) diphenyl phosphine oxide), TPO-L (2,4, 6-trimethylbenzoylethyl benzoylphosphonate), 2-methyl-1- [ 4-benzyl ] benzophenone), Gellic-2- (2-isopropyl) benzophenone), Gellic-isopropyl-2-isopropyl-benzoylbenzophenone { 1- [ 4-propyl ] -2- (1-ethyl-4-propyl ] -2-ethyl-benzoylbenzophenone), Ge4-methyl-ethyl-benzoylbenzophenone (1-ethyl-4-methyl-phenyl-ethyl-p-ethyl-5-ethyl-benzoate), poly (1-ethyl-5-ethyl-4-ethyl-phenyl-ethyl-p-ethyl-phenyl-ethyl-benzoate), poly-ethyl-p-ethyl-5-ethyl-p-ethyl-p-ethyl-benzoate), poly (1-ethyl-p-ethyl-p-ethyl-p-ethyl-p-.

The photoinitiators may be used alone or in combination. The embodiment of the invention adopts the commonly used Irgacure 2959.

Preferably, the photoinitiator is contained in the hydrophilic coating solution in an amount of 0.1 to 10% by mass.

Preferably, the hydrophilic coating solution further comprises: a functionalized monomer, oligomer, or polymer. The addition of functionalized monomers, oligomers or polymers can further improve the adhesion of the hydrophilic coating to the substrate.

All of which are commercially available functionalized monomers, oligomers, or polymers; comprises the following steps: monofunctional acrylates, such as: methoxypolyethylene glycol monoacrylate, alkoxylated phenol acrylate, 2 (2-ethoxy) ethyl acrylate, tetrahydrofuran acrylate, 2-phenoxyethyl acrylate, isodecyl acrylate, caprolactone acrylate, isobornyl acrylate, trimethylolpropane formal acrylate, alkoxylated nonylphenol acrylate; monofunctional methacrylates, such as: 2-phenoxyethyl methacrylate, isobornyl methacrylate; difunctional acrylate monomers, such as: 1, 6-hexanediol diacrylate, alkoxylated hexanediol diacrylate, tripropylene glycol diacrylate, polyethylene glycol (400) diacrylate, dipropylene glycol diacrylate, (3) ethoxylated bisphenol a diacrylate, (4) ethoxylated bisphenol a diacrylate, (10) ethoxylated bisphenol a diacrylate, tricyclodecane dimethanol diacrylate, (2) propoxylated neopentyl glycol diacrylate; difunctional methacrylate monomers, such as: ethoxylated bisphenol a dimethacrylate, triethylene glycol dimethacrylate, ethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, 1, 3-butanediol dimethacrylate, (2) ethoxylated bisphenol a dimethacrylate, and (10) ethoxylated bisphenol a dimethacrylate; trifunctional acrylate monomers, such as: (6) trimethylolpropane propoxylate triacrylate, trimethylolpropane triacrylate, tris (2-hydroxyethyl) isocyanuric acid triacrylate, pentaerythritol triacrylate, (3) ethoxylated trimethylolpropane triacrylate, (3) propoxylated trimethylolpropane triacrylate, (9) propoxylated trimethylolpropane triacrylate, (3) glycerol propoxylate triacrylate, (15) ethoxylated trimethylolpropane triacrylate; trifunctional methacrylate monomers, such as: trifunctional acid esters, trimethylolpropane trimethacrylate; multifunctional acrylate monomers, such as: pentaerythritol tetraacrylate. And aliphatic urethane acrylate, aliphatic urethane methacrylate, aromatic urethane acrylate, epoxy methacrylate, and the like. Preference is given to polymers or oligomers having a polarity close to that of the substrate.

The hydrophilic coating solution also contains a sufficient amount of solvent to disperse or dissolve the other components of the formulation. The solvent should be low in toxicity, volatile and capable of having the polymer dissolved or at least dispersed therein. The solvent is preferably a polar liquid in order to dissolve or disperse the hydrophilic polymer well.

Preferably, the solvent is an organic solvent soluble in water.

Preferably, the organic solvent is an alcohol; more preferably C1-C4 alcohol, such as one or more of methanol, ethanol and isopropanol.

Preferably, the solvent may also include water, and the solvent further includes water, and the mass content of water in the hydrophilic coating solution is 0 to 80% excluding 0. More preferably between 0 and 60 wt%.

Preferably, the mass content of the solvent in the hydrophilic coating solution is more than or equal to 70 percent. The content of the solvent in the hydrophilic coating solution is preferably 80% by weight or more in view of handling properties (low viscosity) and/or in order to facilitate the application of the composition to obtain a coating of a desired thickness.

The fourth aspect of the present invention provides a method for preparing the above hydrophilic coating solution, comprising the steps of: the components were mixed and stirred at room temperature to form a homogeneous solution.

The hydrophilic coating solution can obtain a coating with good bonding force with a base material and low migratable objects through one-time coating and curing processes.

In a fifth aspect the invention provides the use of a functionalized hydrophilic polymer or hydrophilic coating solution as described above in an article comprising a hydrophilic or lubricious coating.

Preferably, the hydrophilic or lubricious coating containing article is a medical device.

A sixth aspect of the present invention provides a medical catheter comprising a hydrophilic coating; the hydrophilic coating is obtained by subjecting the above hydrophilic coating solution to a one-time coating and curing process.

Preferably, the base material of the medical catheter is a nylon tube.

Preferably, the primary coating and curing process comprises:

immersing the base material into the prepared hydrophilic coating solution, lifting the base material when the base material is 2/3 immersed in the solution, and then placing the base material under an ultraviolet light source for curing; the actual light intensity of the ultraviolet curing light source is more than 40mW/cm²The curing time is 100-.

The hydrophilic coating solution can form a cross-linked hydrophilic polymer coating by initiating the direct polymerization reaction of the functionalized hydrophilic polymer through the photoinitiator, thereby avoiding the problem that the hydrophilic coating falls off and diffuses to the surrounding environment in the use process because the hydrophilic polymer does not participate in cross-linking, and particularly when the hydrophilic coating solution is applied to a medical catheter, the hydrophilic coating with low molecular migration greatly reduces the occurrence of later adverse reactions.

Detailed Description

The technical solutions of the present invention will be described in detail below in order to clearly understand the technical features, objects, and advantages of the present invention, but the present invention is not limited to the practical scope of the present invention.