CN111514379A - Central venous catheter placed through peripheral vein and preparation method thereof - Google Patents

Central venous catheter placed through peripheral vein and preparation method thereof Download PDF

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CN111514379A
CN111514379A CN201910107798.2A CN201910107798A CN111514379A CN 111514379 A CN111514379 A CN 111514379A CN 201910107798 A CN201910107798 A CN 201910107798A CN 111514379 A CN111514379 A CN 111514379A
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unit containing
catheter
peripherally inserted
inserted central
water
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CN111514379B (en
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雷杰华
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Jiangsu Biosurf Biotech Co Ltd
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Jiangsu Biosurf Biotech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/064—Use of macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M25/0045—Catheters; Hollow probes characterised by structural features multi-layered, e.g. coated
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F226/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
    • C08F226/06—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
    • C08F226/10—N-Vinyl-pyrrolidone
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D139/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Coating compositions based on derivatives of such polymers
    • C09D139/04—Homopolymers or copolymers of monomers containing heterocyclic rings having nitrogen as ring member
    • C09D139/06—Homopolymers or copolymers of N-vinyl-pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/114—Nitric oxide, i.e. NO
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings

Abstract

The invention relates to a central venous catheter placed through a peripheral vein and a preparation method thereof, wherein the central venous catheter placed through the peripheral vein comprises the following components: the coating is formed by a coating composition, the coating composition comprises at least one photocurable polymer, wherein the photocurable polymer is formed by polymerizing components including a water-soluble photosensitive monomer and a hydrophilic monomer, and the water-soluble photosensitive monomer comprises: 1) a unit containing a photosensitive structure; 2) a unit containing a quaternary ammonium salt structure; 3) a unit containing an unsaturated bond structure; the unit containing the photosensitive structure is connected with the unit containing the quaternary ammonium salt structure through at least-C (═ O) -, and the unit containing the unsaturated bond structure is connected with the unit containing the photosensitive structure through the unit containing the quaternary ammonium salt structure. The central venous catheter placed through the peripheral vein has good long-term anticoagulation and anti-hyperplasia performance and excellent biological safety.

Description

Central venous catheter placed through peripheral vein and preparation method thereof
Technical Field
The invention belongs to the field of medical appliances, and particularly relates to the field of a central venous catheter with a hydrophilic coating and placed through a peripheral vein.
Background
The central venous catheter (also called PICC) is placed into the peripheral vein, is used as a path for monitoring, blood transfusion and fluid infusion in the operation, various treatment medicines after the operation, chemotherapy of cancer patients and parenteral nutrition, is a mature and safe medical instrument used for the central venous catheter, and is gradually popularized and popularized in China in recent years. The PICC has the advantages of simple and safe operation, high puncture success rate, long-term use, reduction of puncture pain of patients, easy acceptance by the patients and the like, and is widely applied clinically.
At present, a central venous catheter capable of being permanently indwelling comprises an indwelling catheter and a closed needle-free infusion liquid medicine connector, wherein the indwelling catheter is connected with the closed needle-free infusion liquid medicine connector through a connecting device. An indwelling catheter is positioned in the superior vena cava for providing mid-to long-term iv therapy to a patient. However, with the widespread use of PICCs, complications such as mechanical phlebitis, thrombosis, catheter prolapse, etc. have occurred.
Among the above complications, catheter-related thrombosis is one of the common complications that severely impact safe use of PICCs. The catheter-related thrombus refers to thrombus blocks formed on the vessel wall where the catheter is located and the outer wall of the catheter, and the thrombus blocks fall off to cause serious complications such as pulmonary embolism and the like, so that the catheter-related thrombus is extremely harmful. In addition, catheter blockage is a significant problem encountered in patients undergoing long-term intravenous therapy or nutrition, and often requires replacement of the catheter or re-puncture thereof, and is believed to be caused by blood clots, cellulose thrombosis, or drug deposition. Thus, there is a need for long-term topical anticoagulant and antiproliferative treatment of peripherally inserted central venous catheters.
In the prior art, in order to prevent the formation of catheter-related thrombus, an antithrombotic coating is usually coated on the outer wall of the catheter, and an anticoagulant is generally loaded on the surface of a material in a direct soaking mode. However, in the process of long-term use, the anticoagulant on the outer wall surface of the catheter is easy to fall off, so that the outer wall surface of the catheter loses the anticoagulant function, and therefore, a long-term effective anticoagulant and antiproliferative coating needs to be formed on the surface of the central venous catheter placed through a peripheral vein.
CN101987223A discloses a peripherally inserted central venous catheter, which comprises an antibacterial layer and an anticoagulant layer on the outer side of a body, wherein the coating is prepared by soaking the body in a functional molecule (antibacterial or anticoagulant) solution, then taking out the body, and removing the closure, thus obtaining the functionalized peripherally inserted central venous catheter. The method enables the surface of the catheter to adsorb functional molecules through soaking, but the obtained surface coating is easy to fall off and remain in the body, thereby causing potential safety hazards.
CN107456611A discloses a method for preparing an anticoagulant composite coating on the surface of a medical device, which comprises treating the surface of a biomedical device with a silane coupling agent, and then soaking the treated surface in an aqueous solution containing an anticoagulant, thereby forming a hydrogel anticoagulant coating on the surface by crosslinking. The surface of the obtained material has better anticoagulation performance, but a coating solution of the material contains a small amount of micromolecule plasticizer and cross-linking agent, and the migration of molecular fragments and unreacted micromolecule components is still a bigger problem.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the defects and shortcomings of the prior art, the invention provides the central venous catheter placed through the peripheral vein and the preparation method thereof, and the central venous catheter has good long-term anticoagulation and anti-hyperplasia performance and excellent biological safety.
Means for solving the problems
The invention relates to a central venous catheter placed through a peripheral vein, comprising: a pipe body and a coating layer formed on a surface of the pipe body, the coating layer being formed of a coating composition including at least one photocurable polymer, wherein,
the photocurable polymer is polymerized by components comprising water-soluble photosensitive monomers and hydrophilic monomers,
the water-soluble photosensitive monomer contains: 1) a unit containing a photosensitive structure; 2) a unit containing a quaternary ammonium salt structure; 3) a unit containing an unsaturated bond structure;
the unit containing the photosensitive structure is connected with the unit containing the quaternary ammonium salt structure through at least-C (═ O) -, and the unit containing the unsaturated bond structure is connected with the unit containing the photosensitive structure through the unit containing the quaternary ammonium salt structure.
The peripherally inserted central catheter according to the present invention, said water-soluble photosensitive monomer having the structure of formula (I):
Figure BDA0001967128560000031
wherein: r1＝CH3Or H; r2And R3Each independently selected from a straight chain alkyl group of 1 to 20 carbon atoms or a branched alkyl group of 3 to 20 carbon atoms; x is halogen; n is 1-10; m is 1-4; f is 1-3.
According to the peripherally inserted central venous catheter, the hydrophilic monomer comprises one or more of unsaturated carboxylic acid, unsaturated carboxylate, unsaturated carboxylic ester, unsaturated acid hydroxyalkyl ester, unsaturated anhydride, unsaturated amide, unsaturated lactam and alkylene oxide.
The peripherally inserted central catheter according to the invention, wherein the water-soluble photosensitive monomer is contained in an amount of 0.01 to 20 wt% based on the total mass of the hydrophilic monomer.
The peripherally inserted central catheter according to the invention further comprises an NO catalyst in the coating composition, typically in an amount of 0.01-10% by weight of the coating composition
The number average molecular weight of the photo-curable polymer is 5-70 ten thousand when the catheter is placed into a central venous catheter through a peripheral vein.
The peripherally inserted central catheter according to the invention has a coating thickness of 1-20 μm.
A method of preparing a peripherally inserted central catheter in accordance with the present invention comprises: and forming the coating composition on the surface of the tube body of the peripherally inserted central venous catheter, and curing under the condition of light.
According to the preparation method provided by the invention, the light source used in illumination is any one of a UV light source, a visible light source and an infrared light source.
According to the preparation method, the light source is a UV light source, and the intensity of ultraviolet light during curing is 5-25mW/cm2And the curing time is 2-7 minutes.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention forms a stable hydrophilic coating with anticoagulation and anti-proliferation performance on the surface of a tube body which is placed into a central venous catheter through a peripheral vein in a photocuring mode. The surface of the constructed hydrophilic coating can effectively resist protein nonspecific adsorption, can stably release NO, can effectively inhibit the activation and aggregation of platelets on the surface of a material, and plays a better anticoagulation function, thereby inhibiting the activation and aggregation of the platelets on the surface of an implant material.
Meanwhile, the released NO can inhibit the adhesion and growth of smooth muscle cells, so that the obtained central venous catheter placed through a peripheral vein can achieve the effects of anticoagulation and anti-hyperplasia.
Drawings
FIG. 1A graph showing the results of the anticoagulation test in example 1 and comparative example 1
FIG. 2A graph showing the results of the anti-proliferative test of example 1 and comparative example 1
Detailed Description
The technical solution of the present invention will be described in detail with reference to the following examples.
The term "monomer" in the present invention means any chemical species that can be characterized by a chemical formula with polymerizable groups (including (meth) acrylate groups) that can be polymerized into oligomers or polymers to increase molecular weight. The molecular weight of the monomers can generally be calculated simply from the given formulae.
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: C1-C6 linear, branched or cyclic alkyl, aryl, -OH, -CN, halogen, amine, amide, alcohol, ether, thioether, sulfone and its derivatives, sulfoxide and its derivatives, carbonate, isocyanate, nitrate and acrylate.
The term "unit" in the present invention means not only a functional group (e.g., photosensitive group, quaternary ammonium salt group, unsaturated group) but also an additional chemical group having a small influence on the functional group, such as alkyl group, alkylene group, etc.
The term "polymer" in the present invention refers to a molecule containing two or more repeating units, in particular, a polymer may be formed from two or more monomers, which may be the same or different, and when used in the present invention, the term also includes oligomers or prepolymers. The term "molecular weight" in the present invention refers to the number average molecular weight (Mn), defined as Mn as determined by light scattering, optionally in combination with size exclusion chromatography SEC.
The term "curing" is understood in the present invention as: physical or chemical hardening or solidification, or curing by chemical reaction, such as radiation curing, thermal curing or curing with the addition of curing molecules, initiators, by any method such as heating, cooling, drying, crystallization.
The term "photocuring" can be achieved in the present invention in the following exemplary manner: the photoinitiation process occurs via irradiation with light or UV radiation in the wavelength range from 100nm to 600 nm. Illumination sources that may be used are sunlight or artificial lamps or lasers. 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.
Central venous catheter placed through peripheral vein
In accordance with the present invention, there is provided a central venous catheter for placement through a peripheral vein, comprising: a pipe body and a coating layer formed on a surface of the pipe body, the coating layer being formed of a coating composition including at least one photocurable polymer, wherein,
the photocurable polymer is polymerized by components comprising water-soluble photosensitive monomers and hydrophilic monomers,
the water-soluble photosensitive monomer contains: 1) a unit containing a photosensitive structure; 2) a unit containing a quaternary ammonium salt structure; 3) a unit containing an unsaturated bond structure;
the unit containing the photosensitive structure is connected with the unit containing the quaternary ammonium salt structure through at least-C (═ O) -, and the unit containing the unsaturated bond structure is connected with the unit containing the photosensitive structure through the unit containing the quaternary ammonium salt structure.
Pipe body
In the present invention, the tube body for inserting the central venous catheter through the peripheral vein is not particularly limited, and may be any peripheral venous insertion central venous catheter used in the art, for example, a commercially available uncoated peripheral venous insertion central venous catheter.
In addition, materials suitable for use in the manufacture of central venous catheters for placement via a peripheral vein include polymers such as silicone, polyurethane, PVC, and the like.
Photocurable polymers
The present invention also provides a photocurable polymer. The coating is prepared by copolymerizing a water-soluble photosensitive monomer and a hydrophilic monomer, and has a photosensitive structural unit which can be used as a macromolecular photoinitiator, so that the use of a micromolecular photoinitiator can be reduced when the coating is prepared into a coating composition, the problems of residue, migration and the like of the micromolecular photoinitiator in a coating can be solved, and the coating has excellent biological safety and compatibility and is suitable for the medical field.
< Water-soluble photosensitive monomer >
The water-soluble photosensitive monomer contains: 1) a unit containing a photosensitive structure; 2) a unit containing a quaternary ammonium salt structure; 3) a unit containing an unsaturated bond structure; the unit containing a photosensitive structure is linked to the unit containing a quaternary ammonium salt structure at least through-C (═ O) -and the unit containing an unsaturated bond structure is linked to the unit containing a photosensitive structure at least through the unit containing a quaternary ammonium salt structure.
The molecular structure of the water-soluble photosensitive monomer contains quaternary ammonium salt ions and double bonds besides a photoinitiation unit (namely a unit of a photosensitive structure), so that the photosensitive monomer has water solubility and polymerizability, has good compatibility with aqueous resin, and can be polymerized onto a macromolecular chain of the resin, thereby effectively overcoming the defect that small molecules are easy to migrate to the surface of a product.
The existence of the quaternary ammonium salt can greatly improve the water solubility and simultaneously has certain antibacterial property. The unit containing a quaternary ammonium salt structure contains a quaternary ammonium salt group, and may contain several alkylene groups in addition to the quaternary ammonium salt group.
The unit having an unsaturated bond may be a polymerizable group having a double bond. Such reactive groups may allow the photoactive unit to be incorporated into the backbone of the polymer in the form of a repeating unit via free radical polymerization. The unit containing an unsaturated bond may be selected from units having a (meth) acrylate group. The existence of the polymerizable group can overcome the problems of toxicity and high mobility of the conventional small-molecule photoinitiator, promote the photoinitiator to be anchored in a polymer network, improve the material performance by copolymerizing with other monomers, and inhibit the undesirable volatilization caused by the residue of the small-molecule photoinitiator.
In the present invention, the unit having a photosensitive structure is directly bonded to the quaternary ammonium salt structure through a carbonyl group (-C (═ O) -), and the unit having an unsaturated bond is directly bonded to the unit having a photosensitive structure through the quaternary ammonium salt-containing structural unit. The connection mode provides the greatest opportunity for interaction among all structural units, is favorable for energy transfer, can generate free radical active species more and more quickly, and improves the initiation efficiency.
In a preferred embodiment of the present invention, the water-soluble photosensitive monomer has the following structural formula:
formula (I)
Figure BDA0001967128560000071
Wherein: r1＝CH3Or H; r2And R3Each independently selected from a straight chain alkyl group of 1 to 20 carbon atoms or a branched chain alkyl group having 3 to 20 carbon atoms; x is halogen; n is 1-10; m is 1-4; f is 1-3; preferably, R2And R3Similarly, X is bromo, n ═ 1, m ═ 1, f ═ 1; more preferably, R2And R3Is methyl or ethyl, X is bromine, n is 1, m is 1, and f is 1. The selection of the groups and the molecular chain length in the general formula is mainly the requirements of viscosity, initiation rate and mobility of the comprehensive product.
Further preferably, suitable water-soluble photosensitive monomers according to the present invention include one or more compounds of the following structure:
Figure BDA0001967128560000081
the water-soluble photosensitive monomer is obtained by performing acyl halide treatment on the molecular terminal of a compound containing a photosensitive structure, and then reacting the compound with (methyl) acrylate containing a tertiary amine group.
An exemplary reaction scheme for the water-soluble photosensitive monomer is as follows:
Figure BDA0001967128560000082
wherein R is1And R2The same as the definition of the general formula (I).
< hydrophilic monomer >
In the present invention, the hydrophilic monomer is mainly used to provide hydrophilicity to the photocurable polymer. The hydrophilic monomer is not particularly limited as long as it is a monomer that can dissolve 1g or more in 100g of water at 25 ℃. The hydrophilic monomer comprises one or more than two of unsaturated carboxylic acid, unsaturated carboxylate, unsaturated carboxylic ester, unsaturated acid hydroxyalkyl ester, unsaturated anhydride, unsaturated amide, unsaturated lactam and alkylene oxide.
As the hydrophilic monomer, vinylpyrrolidone is preferable. The structure of vinyl pyrrolidone (NVP) gives it and the polymers formed from it special properties: it is readily polymerized; the polymer formed by the polymer has excellent hydrophilicity, complexing ability, physiological compatibility and chemical stability; has no irritation to skin; has strong solubilization, can increase the water solubility of some substances which are basically insoluble in water but have pharmacological activity, and is suitable for medical use. Therefore, when vinylpyrrolidone is used as the hydrophilic monomer, the resulting hydrophilic coating has a better lubricating effect, and the specific phenotype is that the frictional force is low, and the frictional force hardly changes as the number of cycles increases.
Wherein the content of the water-soluble photosensitive monomer is 0.01-20 wt% of the total mass of the hydrophilic monomer.
< polymerization of Water-soluble photosensitive monomer and hydrophilic monomer >
The photocurable polymer is prepared by free radical polymerization of a water-soluble photosensitive monomer and a hydrophilic monomer. Wherein, the free radical polymerization includes but is not limited to common free radical polymerization and living controllable free radical polymerization.
The free-radical polymerization is carried out in a medium, such as solution polymerization, emulsion polymerization, inverse emulsion polymerization, suspension polymerization, bulk polymerization. From the viewpoint of ease of handling, it is preferable that the photocurable hydrophilic polymer is polymerized from a solution, and from the viewpoint of environmental protection, it is more preferable that the photocurable polymer is copolymerized in an aqueous solution. In one embodiment of the present invention, a photocurable polymer is obtained by dissolving a water-soluble photosensitive monomer and a hydrophilic monomer in water, adding a radical initiator into the system, removing oxygen, and reacting at a specific temperature.
The total monomers are contained in the aqueous solution in a concentration of 10 to 50 wt%, preferably 10 to 30 wt%, more preferably 12 to 20 wt%, based on the total weight of the aqueous solution.
The radical initiator in the polymerization reaction means a substance which generates radicals upon application of activation energy, and includes heat-activated initiators such as organic peroxides, organic hydroperoxides and azo compounds. Representative examples of such initiators include, but are not limited to, benzoyl peroxide, t-butyl perbenzoate, diisopropyl peroxydicarbonate, cumene hydroperoxide, azobisisobutyronitrile, and the like. The thermal initiators are generally used in amounts of from 0.02 to 0.05% by weight, based on the total mass of the monomers.
The photocurable polymer preferably has a number average molecular weight of at least 5 ten thousand, preferably a relatively high molecular weight, in order to reduce migration, but preferably 70 ten thousand or less in order to facilitate application of the coating. In order to obtain a hydrophilic coating having good lubricating properties even after many cycles, the photocurable polymer preferably has a number average molecular weight of 5 to 70 ten thousand, more preferably 10 to 50 ten thousand, and most preferably 30 to 40 ten thousand.
Coating composition
The coating composition of the present invention comprises at least one of the above-mentioned at least one photocurable polymer.
In addition, the coating composition of the present invention may further include a solvent and a NO catalyst.
Any solvent suitable for use in the present invention is sufficient as long as it allows coating of the coating composition having hydrophilicity on the surface. Preferably, the solvent is one or a mixture of solvents that can dissolve the above photocurable polymer to form a homogeneous solution. Examples of the solvent include one or more of water, low molecular weight alcohols (methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, propylene glycol, glycerol, etc.), ethyl acetate, N-hexane, dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetone, diethyl ether, toluene, benzene, xylene, cyclohexane, phenol. The low-cost and pollution-free solvent suitable for dissolving and mixing the uniform formula is preferably a mixture of water and isopropanol, preferably the volume ratio of the water to the isopropanol is 1:10-10:1, and the solvent suitable for dissolving and mixing the uniform formula is more preferably the volume ratio of the water to the isopropanol is 1:5-5:1, and most preferably 2:3-3: 2.
The NO catalyst suitable for the present invention is selected from cystamine, ebselen, selenocysteine, cystine, CuCl2And CuCl.The NO catalyst is generally used in an amount of 0.01 to 10%, more preferably 0.02 to 5% of the coating composition.
Other additives such as support polymers, polyelectrolytes, wetting agents, leveling agents, defoamers, coalescents, thickeners, pigments, antimicrobials, colorants, surfactants, and the like may also be added to the coating composition as desired.
Method for preparing central venous catheter placed through peripheral vein
The invention also provides a preparation method of the central venous catheter placed through the peripheral vein, which comprises the following steps: and forming the coating composition on the surface of the tube body of the peripherally inserted central venous catheter, and curing under the condition of light.
Wherein, the coating composition is formed on the surface of the tube body of the peripherally inserted central venous catheter by one or more of brushing, dip coating, spraying, pouring and blade coating.
The light source used in illumination comprises any one of a UV light source, a visible light source and an infrared light source; preferably, the light source is a UV light source and a visible light source; more preferably a source of UV light. Preferably, the intensity of ultraviolet light during curing is 5-25mW/cm2The time for curing the coating composition is 2 to 7 minutes, preferably 3 to 5 minutes.
Preferably, the peripherally inserted central catheter is placed in the cartridge containing the masking liquid composition, left to stand for 2-7min, and the catheter is pulled at a speed of 0.5-1cm/s, and the UV light intensity of the peripherally inserted central catheter with masking liquid is 5-25mW/cm2Irradiating with ultraviolet lamp for 3-5min for curing.
Wherein the coating has a thickness in the range of 1-20 μm on a peripheral venous access central venous catheter.
Examples
The present invention is described below by way of examples, which are not exhaustive, as those skilled in the art will appreciate that the examples are illustrative only.
Example 1
Synthesis of water-soluble photosensitive monomer
22.4g (100mmol) of 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylpropiophenone, 10.6g (105mmol) of triethylamine and 100mL of dichloromethane were weighed out and placed in a 250mL flask and placed in an ice-water bath to be sufficiently dissolved. A solution of 9.1mL bromoacetyl bromide (21.1g, 105mmol) in methylene chloride was slowly added dropwise to the flask over 1 h. After 0.5h of reaction under ice-bath conditions, the temperature was raised to room temperature and the reaction was continued for 10 h. After the reaction, the reaction solution was cooled to room temperature, the crude product was dissolved in dichloromethane, washed with saturated brine, hydrochloric acid (1M) and saturated sodium bicarbonate in this order for 2 times, dried over anhydrous magnesium sulfate overnight, filtered and the solvent was spin-dried, and purified by column chromatography using ethyl acetate and n-hexane as eluent to give 28.8g of 2-hydroxy-4' - (2-hydroxyethoxybromoacetate) -2-methylpropiophenone as a white solid with a yield of 84%.
6.9g (20mmol) of 2-hydroxy-4' - (2-hydroxyethoxybromoacetate) -2-methylpropiophenone and 0.05g of hydroquinone were dissolved in 50mL of acetonitrile and placed in a 250mL flask, and sufficiently dissolved. A solution of 50mL dimethylaminoethyl methacrylate (3.2g, 20mmol) in acetonitrile was slowly added dropwise to the flask and the reaction was carried out at 60 ℃ for 12 h. After the reaction is finished, the solvent is dried by spinning, the product is precipitated by absolute ethyl ether, and 10g of water-soluble photosensitive monomer is obtained after column chromatography purification, as shown in the structural formula 1, the water-soluble photosensitive monomer is light yellow viscous liquid, and the yield is 100%. The results of nuclear magnetic hydrogen spectroscopy (1H NMR) were as follows:
1.35ppm(m,6H,CH3-C-OH),1.98ppm(m,3H,CH3-C＝),3.30ppm(m,6H,CH3-N),3.48ppm(m,2H,-CH2-N),4.2ppm(s,2H,O＝C-CH2-),4.44-4.6ppm(m,6H,-CH2-O),6.4-6.5ppm(m,2H,＝CH2) 7.01-7.94ppm (m,4H, benzene ring).
Figure BDA0001967128560000121
Synthesis of Photocurable polymers
106.7g (0.96mol) of vinylpyrrolidone, 16.9g (0.04mol) of a water-soluble photosensitive monomer, and 0.0618g (mass fraction of the total amount of the monomers: 0.05%) of azobisisobutyronitrile were weighed out and added to a 1-liter round bottomIn the flask, 700mL of deionized water was added and dissolved by mechanical stirring. General formula of solution N2Deoxidizing in 30min, and heating the reaction bottle in oil bath at 65 ℃ to start the reaction. After 6h of reaction, the reaction solution was taken down and cooled to room temperature, precipitated in 95% ethanol, and the precipitate was dried in an oven for 36h at 35 ℃ in the dark. The polymer thus obtained had a number average molecular weight Mn of 39.6 ten thousand and a molecular weight distribution PDI of 1.91 as determined by GPC.
Preparation of the coating composition
5g of a photo-curable polymer (Mn is 39.6 ten thousand, the mole fraction of a water-soluble photosensitive monomer is 4%), 0.02% of selenocysteine are weighed and added into 95g of a deionized water/isopropanol mixed solvent (the volume ratio is 1:1), and the mixture is stirred away from light for 18h to be dissolved, so that a colorless clear solution is obtained.
Anticoagulant and antiproliferative coating and preparation of its products
The surface of a central venous catheter placed through a peripheral vein is wiped clean by dust-free paper dipped with 75% ethanol, and the central venous catheter is dried. Soaking the catheter in the material cylinder containing the above coating liquid composition, standing for 1min, pulling the catheter at 0.5cm/s, irradiating the catheter with the coating liquid with ultraviolet lamp for 5min, and curing with ultraviolet light intensity of 10mW/cm2The rotational speed of the catheter was 4 rpm. The cured samples were air dried. The thickness of the coating layer of the peripherally inserted central catheter prepared by the process is within 2-10 mu m. The obtained coated layer is placed into a central venous catheter through a peripheral vein, and performance test is carried out on the catheter without obvious unevenness through visual observation.
Comparative example 1
Will not have the aboveOf anticoagulant, antiproliferative coatingsA central venous catheter was placed via a peripheral vein as comparative example 1, and the same performance test as in example 1 was performed thereon.
Performance testing
Anticoagulation assay: samples were taken from the surfaces of the products of example 1 and comparative example 1, followed by adhesion for 2h in plasma solution to which 65. mu.M of S-nitrosoglutathione (GSNO) and 30. mu.M of L-Glutathione (GSH) were added. Then, the density of surface platelets was counted by observation under a scanning electron microscope. As shown in fig. 1, the embodimentThe surface platelet density of 1 was 95% lower than that of comparative example 1.
Anti-proliferative test: samples were taken from the central venous catheters placed through peripheral veins of example 1 and comparative example 1, cultured together with human umbilical vein smooth muscle cells, 65. mu.M of S-nitrosoglutathione (GSNO) and 30. mu.M of L-Glutathione (GSH) were added to the cell culture medium, and after 4h, 1 day and 7 days of culture, the cells on the surface were observed by immunofluorescence staining and the cell density on the surface was counted. As shown in FIG. 2, the surface human umbilical vein smooth muscle cell density of example 1 was 87% less than the surface human umbilical vein smooth muscle cell surface platelet density of comparative example 1.
Examples 2 to 4
The NO catalyst in the coating composition of example 1 was replaced with cysteamine, ebselen, and selenocysteine respectively from cysteamine (examples 2-4, respectively). The anticoagulant and antiproliferative properties of the prepared central venous catheter placed through the peripheral vein are evaluated in the same way as in example 1, and the results are shown in table 1.
TABLE 1 Effect of the type of NO catalyst on the Performance of a peripherally inserted Central venous catheter coating
NO catalyst Platelet density/mm2 Smooth muscle cell density/mm2
Example 2 Cystamine 1205 10
Example 3 Ebselen 1120 9
Example 4 Selenocysteine 1229 8
Example 1 Selenocysteine 1000 5
As can be seen from Table 1, a stable and firm hydrophilic anticoagulation and anti-hyperplasia lubricating coating can be constructed on the surface of a central venous catheter placed through a peripheral vein by the method, and the method has good anticoagulation and anti-hyperplasia effects on different NO catalysts, wherein the selenocysteine has the best effect.

Claims (10)

1. A peripherally inserted central catheter, comprising: a pipe body and a coating layer formed on a surface of the pipe body, the coating layer being formed of a coating composition including at least one photocurable polymer, wherein,
the photocurable polymer is polymerized by components comprising water-soluble photosensitive monomers and hydrophilic monomers,
the water-soluble photosensitive monomer contains: 1) a unit containing a photosensitive structure; 2) a unit containing a quaternary ammonium salt structure; 3) a unit containing an unsaturated bond structure;
the unit containing the photosensitive structure is connected with the unit containing the quaternary ammonium salt structure through at least-C (═ O) -, and the unit containing the unsaturated bond structure is connected with the unit containing the photosensitive structure through the unit containing the quaternary ammonium salt structure.
2. The peripherally inserted central catheter of claim 1, wherein the water-soluble photoactive monomer has the structure of formula (I):
Figure FDA0001967128550000011
wherein: r1＝CH3Or H; r2And R3Each independently selected from a straight chain alkyl group of 1 to 20 carbon atoms or a branched alkyl group of 3 to 20 carbon atoms; x is halogen; n is 1-10; m is 1-4; f is 1-3.
3. The peripherally inserted central catheter of claim 1 or 2, wherein said hydrophilic monomer comprises one or more of an unsaturated carboxylic acid, an unsaturated carboxylic acid salt, an unsaturated carboxylic acid ester, an unsaturated acid hydroxyalkyl ester, an unsaturated acid anhydride, an unsaturated amide, an unsaturated lactam, and an alkylene oxide.
4. The peripherally inserted central catheter of any one of claims 1-3, wherein the water-soluble photosensitive monomer is present in an amount of from 0.01 to 20 wt.% based on the total mass of the hydrophilic monomer.
5. The peripherally inserted central catheter of any one of claims 1-4, further comprising an NO catalyst in the coating composition.
6. The peripherally inserted central catheter of any one of claims 1-5, wherein the number average molecular weight of the photocurable polymer is in the range of from 5 to 70 ten thousand.
7. The peripherally inserted central catheter of any one of claims 1-6, wherein the coating has a thickness of from 1 to 20 μm.
8. A method of making a peripherally inserted central catheter as claimed in any one of claims 1 to 7, comprising: and forming the coating composition on the surface of the tube body of the peripherally inserted central venous catheter, and curing under the condition of light.
9. The method according to claim 8, wherein the light source used for the illumination is any one of a UV light source, a visible light source, and an infrared light source.
10. The production method according to claim 8 or 9, wherein the light source is a UV light source, and the intensity of UV light at the time of curing is 5 to 25mW/cm2And the curing time is 2-7 minutes.
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