JP2012029832A - Surface coating and medical instrument - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a surface coating which is excellent in adhesive property to the surface of a medical instrument or others, in which the carrying amount of the anionic substance is large, and an medical instrument coated with the surface coating.SOLUTION: In the surface coating including a coating component comprising the anionic substance and a polymer material, the polymer material is a branched type polymer having a plurality of branched chains and having 2-N,N-dimethylaminoethyl methacrylate and/or the derivative of the same as a polymerizing main component, the concentration of the polymer material in the surface coating is 0.0.3 to 3 wt.%, and the ionic molar ratio of the polymer material and the anionic substance is 1/0.75 to 1/1.3.

Description

  The present invention relates to a surface coating agent that can be applied to the surface of a constituent material such as various medical devices, and a medical device coated with the surface coating agent.

  Medical devices are roughly classified into implantation equipment and surface contact equipment. Examples of the implantation device include a cardiac pacemaker, an artificial blood vessel, and a stent. Examples of the surface contact device include a dressing material and a urinary catheter. In an implantation device, affinity (biological affinity) for body tissue is required. In addition, an in vivo improvement function is imparted to the surface of an implantation device. On the other hand, since the surface contact device is in direct contact with the epidermis of a living body for a medium to long term, it is essential that there is little irritation to the skin.

  For the purpose of improving the biocompatibility of an embedded device or imparting functionality, various functional substances are attached to the surface of the embedded device. In addition, for the purpose of suppressing irritation to the skin of the surface contact device, a surface protective material such as hyaluronic acid is coated on the surface of the surface contact device. However, since hyaluronic acid is highly soluble in water, if hyaluronic acid is simply adhered to the surface of the surface contact device, it is eluted into water such as sweat and consumed.

  In order to solve this, there is a technique for fixing hyaluronic acid to the surface of a material through a chemical bond using a chemical cross-linking agent (Patent Document 1), but the chemical cross-linking agent may adversely affect a living body. In general, since a biological system is mainly composed of water, it is difficult to fix a water-soluble substance on the surface of a material applied to a living body. In general, the residual organic solvent may cause a problem in such a coating agent.

  The present applicants are water-soluble (hydrophilic) at a temperature lower than a predetermined temperature (T) as a coating agent having little influence of a chemical cross-linking agent, a residual organic solvent, etc., and not at a temperature higher than the predetermined temperature. A patent application was first filed for a coating agent with affinity for skin having water-soluble (hydrophobic) temperature responsiveness (Patent Document 2).

  In this skin affinity coating agent described in Patent Document 2, hyaluronic acid or a derivative thereof is supported on a polymer material having a branched chain obtained by polymerizing a cationic monomer and N-isopropylacrylamide or a derivative thereof. Is. This polymer material has the above temperature responsiveness because the polymer portion obtained by polymerizing N-isopropylacrylamide or a derivative thereof has a temperature dependency that becomes hydrophilic at a low temperature and hydrophobic at a high temperature. It becomes like this. That is, since the polymer material is hydrophilic (water-soluble) at a temperature lower than a predetermined temperature, the polymer material is dissolved in water and applied to a living body or a surface contact device, and then the temperature is higher than the predetermined temperature. Thus, it can be made hydrophobic (water insoluble) and can be attached to a surface contact device.

JP 7-313585 A JP 2008-245747 A

  As described above, the skin-affinity coating agent described in Patent Document 2 can suppress the influence of an organic solvent or the like on a living body, but is composed of N-isopropylacrylamide or a derivative thereof that exhibits temperature responsiveness. Since the polymer portion is electrically neutral and has little interaction with anionic substances such as hyaluronic acid, the amount of anionic substance that can be supported is not sufficient, and further improvement is desired. .

  The present invention solves the above-mentioned conventional problems, has a surface coating agent that has excellent adhesion to the surface of a medical device and the like and has a large amount of anionic substance, and a medical device coated with this surface coating agent The purpose is to provide.

  In order to solve the above problems, the present inventors have shown that 2-N, N-, which exhibits hydrophilicity at a predetermined temperature or lower, exhibits hydrophobicity at a predetermined temperature or higher, and is slightly cationic, in a process of repeated studies. Attempts were made to introduce dimethylaminoethyl methacrylate into the branched chain of the polymer material. In the case of a polymer material having 2-N, N-dimethylaminoethyl methacrylate as a structural unit, the cationic 2-N, N-dimethylaminoethyl methacrylate unit contributes to the binding with the anionic substance, and the anionic substance The loading amount of can be increased.

  However, in this polymer material, 2-N, N-dimethylaminoethyl methacrylate units are easily hydrolyzed even in an aqueous solution at room temperature, and are converted into a hydrophilic polymer by the effect of the generated anionic functional group, Since it was no longer hydrophobic, it was considered unsuitable as a polymer material for surface coating agents.

  Accordingly, as a result of repeated studies on a method for suppressing hydrolysis of 2-N, N-dimethylaminoethyl methacrylate units, the present inventors have found that this polymer material has 2-N, N-dimethylaminoethyl methacrylate as a structural unit. It has been found that hydrolysis of 2-N, N-dimethylaminoethyl methacrylate units can be suppressed by controlling the mixing ratio between the concentration of and an anionic substance.

  The present invention has been achieved on the basis of such findings, and the gist thereof is as follows.

  The surface coating agent of the present invention (Claim 1) is a surface coating agent comprising a coating component comprising an anionic substance and a polymer material, wherein the polymer material comprises 2-N, N-dimethylaminoethyl methacrylate and / or A branched polymer having a plurality of branched chains whose main component is a derivative thereof, the concentration of the polymer material in the surface coating agent being 0.05 to 0.3% by weight, and the polymer material and an anion The ion molar ratio to the active substance is 1 / 0.75 to 1 / 1.3.

  The surface coating agent according to claim 2 is the surface coating agent according to claim 1, wherein the molecular weight of 2-N, N-dimethylaminoethyl methacrylate and / or its derivative unit per one branched chain is the molecular weight per one branched chain. It is characterized by being 90% or more.

  The surface coating agent according to claim 3 is characterized in that, in claim 1 or 2, the branched chain consists only of 2-N, N-dimethylaminoethyl methacrylate and / or a derivative unit thereof.

  The surface coating agent according to claim 4 is the aqueous solution according to any one of claims 1 to 3, which is an aqueous solution containing the coating component.

  The surface coating agent according to claim 5 is the surface coating agent according to any one of claims 1 to 4, wherein the anionic substance is hyaluronic acid, chondroitin sulfate, glucuronic acid, galactosamine sulfate, sulfated isuronic acid, sulfated glucosamine, neuraminic acid. N-acetylneuraminic acid, O-acylneuraminic acid, sialic acid, polyalginic acid, dextran sulfate, heparan sulfate, polyphosphoric acid, argatroban, aspirin, panaldine, pravix, pertal, warfarin, dabigatran, and derivatives thereof It is characterized by being at least one selected.

  The surface coating agent according to claim 6 is the compound according to any one of claims 1 to 5, wherein the polymer material is a compound having three or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule. This is a branched polymer obtained by subjecting at least 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof to light irradiation living polymerization.

  The surface coating agent according to claim 7 is the surface coating agent according to claim 6, wherein the compound having three or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule has a benzene ring as a nucleus and the nucleus as a branched chain. Three or more of the N, N-disubstituted dithiocarbamylmethyl groups are bonded.

  The surface coating agent according to claim 8 is characterized in that, in any one of claims 1 to 7, the molecular weight of the polymer material is 5,000 to 500,000.

  The surface coating agent according to claim 9 is the surface coating agent according to any one of claims 1 to 8, wherein the coating component is hydrophilic at a temperature lower than a predetermined temperature (T) and is higher than the predetermined temperature (T). It is characterized by being hydrophobic at temperature.

  The surface coating agent of claim 10 is characterized in that, in claim 9, the predetermined temperature (T) is a temperature between 25 and 37 ° C.

  A medical device according to the present invention (invention 11) is coated with the surface coating agent according to any one of claims 1 to 10.

  In the present invention, 2-N, N-dimethylaminoethyl methacrylate and / or its derivative (hereinafter referred to as 2-N, N-dimethylaminoethyl methacrylate and / or derivative) in the surface coating agent is simply referred to as “DMAEM”. The concentration of the polymer material composed of a branched polymer having a plurality of branched chains whose main component is polymerization) may be 0.05 to 0.3% by weight, and the polymer material and anionic substance By suppressing the ion molar ratio of 1 / 0.75 to 1 / 1.3, the hydrolysis of the structural unit derived from DMAEM in the branched chain (hereinafter sometimes referred to as “DMAEM unit”) is suppressed. It is possible to apply to the surface coating agent a polymer material having DMAEM having a slight cationic property and having excellent anionic substance loading efficiency. It is possible.

  The details of the mechanism that can suppress hydrolysis of DMAEM units by mixing the polymer material and the anionic substance at the ionic molar ratio is not clear, but when mixed at a predetermined ionic molar ratio, Due to the electrical affinity between the branched-chain DMAEM unit and the anionic substance, an anionic substance is present in the vicinity of the DMAEM unit, and this anionic substance inhibits the access of water molecules, resulting in hydrolysis. It is thought that it becomes difficult to occur.

  In the present invention, the molecular weight of the DMAEM unit per one branched chain is preferably 90% or more of the molecular weight per one branched chain (Claim 2). In particular, the branched chain includes only the DMAEM unit. (Claim 3) The greater the amount of DMAEM units contained in the branched chain, the higher the cationicity of the branched chain. Therefore, the affinity with the anionic substance is improved, and the amount of the anionic substance supported in the polymer material is increased.

  The surface coating agent of the present invention can be an aqueous solution in which a coating component that is a complex of a polymer material and an anionic substance is dissolved in water (Claim 4). It is possible to reduce the influence on the living body without using the organic solvent.

  Examples of the anionic substance supported on the polymer material include hyaluronic acid, chondroitin sulfate, glucuronic acid, galactosamine sulfate, sulfated isuronic acid, sulfated glucosamine, neuraminic acid, N-acetylneuraminic acid, O-acylneuraminic acid, and sialic acid. , Polyalginic acid, dextran sulfate, heparan sulfate, polyphosphoric acid, argatroban, aspirin, panaldine, pravix, pertal, warfarin, dabigatran, and derivatives thereof are preferable (Claim 5). ). When the hyaluronic acid, polyalginic acid, heparan sulfate, polyphosphoric acid, and derivatives thereof are used, the biocompatibility of the surface of the medical device can be improved. When dextran sulfate and derivatives thereof are used, In addition, LDL (bad cholesterol) adsorption performance can be imparted to the surface of medical devices, and when argatroban, aspirin, panaldin, pravix, pertal, warfarin, dabigatran, and derivatives thereof are used, antithrombotic action on the material surface Can be granted.

  The polymer material used in the present invention is a branched polymer in which a compound having three or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule is used as an iniferter, and at least DMAEM is subjected to light irradiation living polymerization. Preferably, the compound having 3 or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule has a benzene ring as a nucleus and 3 or more as branched chains in this nucleus. Those having an N, N-disubstituted dithiocarbamylmethyl group bonded thereto are preferred (Claim 7).

  The molecular weight of the polymer material used in the present invention is preferably 5,000 to 500,000 (Claim 8). When the molecular weight of the polymer material is within this range, the amount of the anionic substance supported can be sufficient, and the adhesion of the surface coating agent to a medical device or the like can be improved.

  The coating component according to the present invention is preferably hydrophilic at a temperature lower than the predetermined temperature (T), and preferably hydrophobic at a temperature higher than the predetermined temperature (T). (T) is preferably a temperature between 25 and 37 ° C. (claim 10).

  The medical device of the present invention (Claim 11) is a medical device coated with the surface coating agent of the present invention, and is excellent in adhesion and long-term stability of the surface coating agent. Can last for a long time.

It is a graph which shows the relationship between the temperature and light transmittance of a 6-branch polymer solution.

  Hereinafter, embodiments of the present invention will be described in detail.

[Surface coating agent]
The surface coating agent of the present invention is a coating component comprising a polymer material having a plurality of branched chains containing 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof (DMAEM) as a main component of polymerization and an anionic substance. The concentration of the polymer material in the surface coating agent is 0.05 to 0.3% by weight, and the ion molar ratio of the polymer material to the anionic substance is 1 / 0.75 to 1 /1.3.
In the present specification, the ionic molar ratio is a ratio between the number of moles of positive charges in the polymer material and the number of moles of negative charges in the anionic substance.

  According to the present invention, as described above, hydrolysis of the structural unit derived from DMAEM can be suppressed. As a result, the coating component becomes hydrophobic, so that the surface of the medical device is stable over a long period of time. It becomes possible to adhere to. Further, a sufficient amount of an anionic substance can be stably supported by the cationic DMAEM unit.

  In the present invention, the concentration of the polymer material in the surface coating agent is preferably about 0.05 to 0.3% by weight, particularly about 0.05 to 0.15% by weight. When the concentration of the polymer material in the surface coating agent is lower than the lower limit, a uniform coating film cannot be obtained. When the concentration is higher than the upper limit, the polymer material and the anionic substance are described later. Even if it mixes by ion molar ratio of this, hydrolysis of a DMAEM unit cannot be suppressed. When the concentration of the polymer material in the surface coating agent is within the above range, hydrolysis of DMAEM units is effectively suppressed, and handling properties when applying the surface coating agent are good, and a thin and uniform coating film is formed. Can be formed.

<Coating ingredients>
The ion molar ratio of the polymer material constituting the coating component according to the present invention to the anionic substance is preferably about 1 / 0.75 to 1 / 1.3, particularly preferably about 1 / 0.85 to 1 / 1.15. When this ion molar ratio is outside the above range, hydrolysis of DMAEM units in the polymer material cannot be sufficiently suppressed. Moreover, when there are few anionic substances, the bioaffinity effect cannot fully be acquired, and when there are too many anionic substances, manufacturing cost will rise. By setting the ion molar ratio between the polymer material and the anionic substance within the above range, it is possible to obtain sufficient biocompatibility while suppressing hydrolysis of the DMAEM unit.

  In order to prepare the coating component, an anionic substance may be added to and mixed with a low temperature aqueous solution of the polymer material, and the anionic substance may be supported on the polymer material.

  The coating component obtained by mixing the polymer material and the anionic substance at the predetermined concentration becomes hydrophilic at a temperature lower than the predetermined temperature (T) and becomes hydrophobic at a temperature higher than the predetermined temperature (T). The predetermined temperature (T) is preferably 25 to 37 ° C, particularly 30 to 35 ° C.

  When the predetermined temperature is 30 ° C., an aqueous solution of a surface coating agent at a temperature lower than 30 ° C., for example, about 10 to 25 ° C. is attached to a living body or a medical device by application, etc. By raising the temperature and drying as necessary, a water-insoluble coating carrying an anionic substance is formed. In the case of a living body, the temperature rise at this time is performed by a non-contact type heating device such as infrared rays or illumination light or the body temperature of the living body.

≪Polymer material≫
The polymer material used in the present invention is preferably a compound obtained by using a compound having three or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule as an iniferter, and subjecting the iniferter to at least DMAEM light irradiation living polymerization.

  In this specification, the iniferter is a polymerization initiator that generates radicals upon irradiation with light, a function as a chain transfer agent, a function that bonds with the growth terminal to stop the growth, and a polymerization when light irradiation stops. It is a molecule that functions as a polymerization initiator / termination agent for stopping.

  As an aromatic compound having three or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule as an iniferter, the N, N-disubstituted dithiocarbamylmethyl group, preferably N, N A compound in which three or more dialkyldithiocarbamylmethyl groups are bonded as a branched chain is preferable, and specific examples are as follows. That is, the tri-branched compound is obtained by addition reaction of 1,3,5-tri (bromomethyl) benzene and sodium N, N-dialkyldithiocarbamate (sodium N, N-dialkyldithiocarbamate) in ethanol. 1,3,5-tri (N, N-dialkyldithiocarbamylmethyl) benzene, and four-branched compounds include 1,2,4,5-tetrakis (bromomethyl) benzene and N, N-dialkyldithiocarbamic acid 1,2,4,5-tetrakis (N, N-dialkyldithiocarbamylmethyl) benzene obtained by addition reaction of sodium (sodium N, N-dialkyldithiocarbamate) in ethanol, 6-branched compound As hexakis (bromomethyl) benzene and N, N-dialkyldithio Rubamin sodium (sodium N, N-dialkyldithiocarbamate) and the hexakis obtained by addition reaction in ethanol (N, N-dialkyldithiocarbamate carbamylmethyl) include benzene. Here, the alkyl group of the dialkyl moiety contained in the N, N-dialkyldithiocarbamylmethyl group is preferably an alkyl group having 2 to 18 carbon atoms such as an ethyl group, but is not limited to an alkyl group. It may be an aromatic hydrocarbon group such as a group. That is, not only N, N-dialkyldithiocarbamylmethyl group but also N, N-substituted by aliphatic hydrocarbon group and / or aromatic hydrocarbon group including N, N-diaryldithiocarbamylmethyl group and the like. A di-substituted dithiocarbamylmethyl group can achieve the object.

  The above iniferter is almost insoluble in polar solvents such as alcohol, but is easily soluble in nonpolar solvents. The nonpolar solvent is preferably a hydrocarbon, an alkyl halide or an alkylene halide, particularly preferably benzene, toluene, chloroform or methylene chloride, especially toluene.

  In order to react the iniferter with the DMAEM, a raw material solution containing the iniferter and the DMAEM is prepared and irradiated with light to thereby generate a reaction product in which DMAEM is bound to the iniferter.

  The concentration of DMAEM in the raw material solution is preferably 0.5 M or more, for example, 0.5 M to 2.5 M, and the concentration of iniferter is preferably about 1 to 20 mM.

The wavelength of the irradiated light is preferably 250 to 400 nm. For example, a fluorescent lamp, a short arc xenon lamp, a low pressure mercury lamp, a high pressure mercury lamp, or the like can be used. The irradiation time of the light depends on the irradiation intensity, about 1 to 90 minutes are preferred, about 1 to 60 minutes at a low irradiation intensity of about 1μW ^/ cm ² ~10mW ^/ cm 2 is particularly preferred. When light irradiation is performed using a commercially available fluorescent lamp, it is preferable to perform light irradiation for about 1 to 100 hours.

  By this light irradiation, the target branched polymer is produced in the reaction solution. Therefore, by purifying as necessary, a polymer chain composed of DMAEM units is introduced into the branched chain portion, and the end of the branched chain is N, A homopolymer which is an N-disubstituted dithiocarbamylmethyl group is obtained.

  The molecular weight per branched chain of this branched polymer is preferably about 100 to 60,000, particularly about 200 to 30,000. This molecular weight can be adjusted by controlling the light irradiation time. That is, by extending the reaction time, the polymerization reaction can be advanced to obtain a branched polymer having a large molecular weight.

  In addition, in this specification, molecular weight means the number average molecular weight of polyethylene glycol conversion by GPC (gel permeation chromatography).

  The branched chain of the branched polymer is preferably a homopolymer consisting of only one monomer having the above-mentioned DMAEM as a monomer. However, a block copolymer or a random copolymer in which one or more monomers different from DMAEM and DMAEM are introduced. It may be a copolymer.

As other monomers in this case, vinyl monomers such as acrylic acid derivatives and styrene derivatives are suitable. Specifically, N, N-dimethylacrylamide, methoxyethyl (meth) acrylate, 3-N, N- Dimethylaminopropylacrylamide CH ₂ = CHCONHC ₃ H ₆ N (CH ₃ ) ₂ , 4-N, N-dimethylaminostyrene, and at least one vinyl monomer selected from the group consisting of 4-aminostyrene derivatives In particular, cationic vinyl monomers such as 3-N, N-dimethylaminopropylacrylamide CH ₂ ═CHCONHC ₃ H ₆ N (CH ₃ ) ₂ are preferable. These vinyl monomers may be used alone or in combination of two or more.

  To react an iniferter with a different monomer from DMAME and DMAEM, a raw material solution containing monomers other than the iniferter, DMAEM, and DMAEM is prepared in the same manner as in the case of reacting the iniferter with DMAEM. Is irradiated with light to obtain a random copolymer in which monomers other than DMAEM and DMAEM are bonded to the iniferter.

In addition, to the above iniferter, first, DMAEM is block-polymerized to form a homopolymer, and then 3-N, N-dimethylaminopropylacrylamide is block-polymerized to the homopolymer, and the base end side of the branched chain is The block polymer of DMAEM may be a branched chain composed of 3-N, N-dimethylaminopropylacrylamide block polymer on the tip side of the branched chain. Thus, when making a branched chain into a block copolymer of two or more types of monomers, the order of polymerization with respect to the iniferter is arbitrary.
In either case, the end of the branched chain is an N, N-disubstituted dithiocarbamylmethyl group.

  As described above, when DMAEM and a monomer other than DMAEM are reacted, the molecular weight of DMAEM units per branched chain is 90% or more, particularly 95-100% of the molecular weight per branched chain. It is preferable that Since the DMAEM unit is cationic, the more DMAEM units contained in the branched chain, the higher the affinity between the polymer material and the anionic substance, and the higher the amount of the anionic substance supported.

  In the present invention, since the polymer material functions as a carrier for an anionic substance and also functions as an anchor for adhesion to a medical device or the like, it is preferable that the branched polymer of the polymer material has more branched chains. The number of branched chains is preferably 4 or more, particularly 6.

  Further, the molecular weight of the polymer material is preferably about 5,000 to 500,000, particularly about 25,000 to 150,000 in order to effectively obtain the above functions.

≪Anionic substances≫
As anionic substances, hyaluronic acid, chondroitin sulfate, glucuronic acid, galactosamine sulfate, sulfated isuronic acid, sulfated glucosamine, neuraminic acid, N-acetylneuraminic acid, O-acylneuraminic acid, sialic acid, polyalginic acid, dextran sulfate And anionic compounds such as heparan sulfate, polyphosphoric acid, argatroban, aspirin, panaldine, pravix, pertal, warfarin, dabigatran, and derivatives thereof. In particular, when hyaluronic acid, polyalginic acid, heparan sulfate, polyphosphoric acid, and derivatives thereof are used, it is possible to obtain a surface coating agent with high biocompatibility, and dextran sulfate and derivatives thereof are used. In some cases, a surface coating agent having high LDL (bad cholesterol) adsorptivity can be obtained. In the case of using argatroban, aspirin, panalgin, pravix, pertal, warfarin, dabigatran, and derivatives thereof, an antithrombotic action can be imparted to the material surface. Examples of the derivative of the anionic substance include sodium salt, potassium salt, and ammonium salt of the anionic substance. In the present invention, one of the anionic substances may be used alone, or two or more may be used in combination.

[Medical equipment]
Examples of the medical device of the present invention include surface contact devices such as dressing materials and urinary catheters. Further, it may be an implantation device such as an artificial heart, an artificial heart valve, an artificial blood vessel, a vascular catheter, a vascular stent, a cannula, an artificial heart lung, a vascular bypass tube, an aortic balloon pumping, a blood transfusion device, and an extracorporeal circuit.

When the surface coating agent of the present invention is applied to a medical device, it is preferable to adhere about 0.1 to 30 mg of the surface coating agent of the present invention per 1 cm ² of the surface of the medical device. This adhesion amount can be adjusted by the coating component concentration in the surface coating agent, the coating amount of the coating agent (one coating amount, the number of times of coating), a cleaning operation, and the like.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist.

(1) Synthesis of iniferter 1,2,3,4,5,6-hexakis (N, N-diethyldithiocarbamylmethyl) benzene as an iniferter was synthesized as follows.

  5.0 g of 1,2,3,4,5,6-hexakis (bromomethylbenzene) and 34.0 g of sodium N, N-diethyldithiocarbamate were added to 100 mL of ethanol, and the mixture was stirred at room temperature for 4 days in the dark. . The precipitate was filtered, poured into 3 L of methanol, stirred for 30 minutes, and then filtered. This operation was repeated a total of 4 times. Dissolve the precipitate in 200 mL of chloroform, add 100 mL of methanol, warm to 50 ° C., filter by heat, store in the refrigerator for 15 hours to recrystallize, wash the crystals with a large amount of methanol after filtration did. The crystals were dried at room temperature under reduced pressure to obtain white 1,2,3,4,5,6-hexakis (N, N-diethyldithiocarbamylmethyl) benzene needle-like crystals (yield 90%). This crystal was analyzed by high performance liquid chromatography, and it was confirmed that the raw material was not contained in the crystal and that the crystal was a single substance.

The measurement result of ¹ H-NMR (in CDCl ₃ ) is as follows: δ 1.26-1.31 ppm (t, 36H, CH ₂ CH ₃ ), δ 3.69-3.77 ppm (q, 12H, N (CH ₂ CH _{3 2} ), δ 3.99-4.07 ppm (q, 12H, N (CH ₂ CH ₃ ) ₂ ), δ 4.57 ppm (s, 12H, Ar—CH ₂ ).

(2) Synthesis of 6-branched polymer 1,2-3,4-5,6-hexakis [(N, N-diethyldithiocarbamyl) poly using 2-N, N-dimethylaminoethyl methacrylate as a monomer (2-N, N-dimethylaminoethyl methacrylate) methyl] benzene was synthesized.

  46.0 mg of 1,2,3,4,5,6-hexakis (N, N-diethyldithiocarbamylmethyl) benzene synthesized according to (1) above was dissolved in 20 mL of chloroform, and 2-N, N-dimethyl was dissolved. Aminoethyl methacrylate 8.0g was added and mixed, and the whole quantity was adjusted to 50 mL with chloroform. After purging with high-purity nitrogen gas (G1 grade, flow rate: 2 L / min) for 10 minutes with vigorous stirring in a 1 mm thick soft glass cell, the tube of a round tube fluorescent lamp (O-shaped) (Toshiba: FCL30L) The glass cell and the magnetic stirrer were placed inside, and the fluorescent lamp light was irradiated for 96 hours from the entire circumference of the side surface of the glass cell. The color of the solution after light irradiation was light yellow. The polymerization solution was concentrated with an evaporator, the polymer was reprecipitated with n-hexane, n-hexane was decanted, and the precipitate was dissolved in chloroform. The solvent was removed by evaporation to form a film on the inner wall surface of the flask. The film was purified by washing with a mixed solution of diethyl ether / n-hexane (v / v: 1/1) to obtain the intended 6-branched polymer. It was 26,000 (Mw / Mn = 2.0) when the number average molecular weight which used polyethylene glycol of this polymer as a standard substance was measured by GPC. The molecular weight per branched chain was calculated to be 4159.

(3) Cloud point evaluation 20 mg of the 6-branched polymer synthesized in (2) above was dissolved in water, immediately after dissolution (Experimental Example 1), 1 hour after dissolution (Experimental Example 2), and 3 hours later (Experimental Example 3) The cloud point (LCST) of the polymer was measured by measuring the light transmittance at 30 to 40 ° C. of the solution after 5 hours (Experimental Example 4) and after 24 hours (Experimental Example 5). Asked. The results are shown in FIG.

  In all the experimental examples, the solution became cloudy due to an increase in temperature, which indicates that the polymer has temperature sensitivity. In addition, since the cloud point increased in proportion to the retention time from dissolution to measurement, and a volatile low molecular weight amine compound was formed in the solution with the passage of time, it was divided into 6 branches over time. It can be seen that the 2-N, N-dimethylaminoethyl methacrylate unit in the mold polymer is hydrolyzed in an aqueous solution and the desolvation property is gradually lost.

(4) Preparation of composite (coating component) and evaluation of cloud point The 6-branched polymer synthesized in (2) above and sodium hyaluronate were mixed in an aqueous solution to form a composite. In this example, each solution was prepared so that the final concentration of the 6-branched polymer was 0.15% by weight. Further, mixing was carried out so that the ion molar ratio of the tertiary amine functional group in the six-branched polymer and the anionic functional group in sodium hyaluronate was 1.0 / 0.3 to 1.0 / 4.0. The light transmittance at 30 to 45 ° C. was quickly measured to determine the cloud point of the composite. Further, as a blank, the cloud point of a solution in which only the 6-branched polymer was dissolved was also obtained in the same manner.

  The number of moles of positive charges (ions) in the 6-branched polymer solution is obtained by dividing the weight of the DMAEM unit in the 6-branched polymer solution by the molecular weight per one positive charge (DMAEM molecular weight) 157. It can ask for. The number of moles of negative charges (ions) in the sodium hyaluronate solution can be determined by dividing the weight of sodium hyaluronate in the solution by the molecular weight of 399 per negative charge.

  In this experiment, the higher the concentration of sodium hyaluronate, the higher the cloud point. The cloud point immediately after mixing was 33-35 ° C. when a solution in which the ion molar ratio of the positive charge of the 6-branched polymer to the negative charge of sodium hyaluronate was 1 / 0.75 to 1 / 1.3 was used. The cloud point after 24 hours from mixing was also less than 36 ° C. That is, it can be seen that the complex formed under these conditions is stable in water. It is considered that this complex can be stably attached to the surface of a medical device or the like.

  On the other hand, when a solution having an ionic molar ratio of the positive charge of the 6-branched polymer and the negative charge of sodium hyaluronate is less than 1 / 0.6 and a solution having a ratio of 1 / 1.6 or more, the cloud point immediately after mixing is Although it was 32 degreeC and 35 degreeC, respectively, the cloud point 24 hours after mixing changed to about 42 degreeC. This is presumably because the structure of the 6-branched polymer was changed by the influence of the concentration of sodium hyaluronate, the water molecules easily approached the branched chain, and the branched chain was gradually hydrolyzed.

  From the above results, when the concentration of the 6-branched polymer is 0.15% by weight, the mixing ratio of the 6-branched polymer and sodium hyaluronate (number of positive charges (ions) of the 6-branched polymer) And the ratio of the number of negative charges (ions) of sodium hyaluronate) is 1.0 / 0.75 to 1.0 / 1.3, the hydrolysis of the branched chain of the 6-branched polymer is suppressed. It can be seen that a stable coating layer can be formed.

(5) Coating on material surface and evaluation of hydrolysis resistance Examples 1-6, Comparative Examples 1-3
A surface coating agent comprising an aqueous solution having a concentration of 6-branched polymers shown in Table 1 and an ionic molar ratio of 6-branched polymers and sodium hyaluronate was prepared. 10 μL of this solution was uniformly cast onto a 2 × 3 cm square PE (polyethylene) film, and dried by a dryer to carry out a coating treatment, and then the PE film was washed with warm water at 37 ° C. for 24 hours. About the PE film after washing | cleaning and the PE film which has not performed the coating process, the water contact angle of the film surface was measured by Kyowa Interface Chemical Co., Ltd., CA-D, and the hydrolysis resistance of the surface coating agent was evaluated. . That is, when the contact angle of the PE film after cleaning is different from that of the untreated PE film, the contact angle of the PE film after cleaning is the contact with the untreated PE film. The same thing as a corner has no hydrolysis resistance (x). The results are shown in Table 1.

  From the results in Table 1, the surface coating agent in which the concentration of the polymer material composed of the 6-branched polymer and the ion molar ratio between the polymer material and the anionic substance are within the scope of the present invention has hydrolysis resistance, It turns out that it is useful as a surface coating agent.

Claims (11)

In a surface coating agent comprising a coating component comprising an anionic substance and a polymer material,
The polymer material is a branched polymer having a plurality of branched chains having 2-N, N-dimethylaminoethyl methacrylate and / or a derivative thereof as a polymerization main component,
The concentration of the polymeric material in the surface coating agent is 0.05-0.3 wt%;
A surface coating agent characterized by having an ion molar ratio of the polymer material to the anionic substance of 1 / 0.75 to 1 / 1.3.   2. The molecular weight of 2-N, N-dimethylaminoethyl methacrylate and / or a derivative unit thereof per one branched chain is 90% or more of the molecular weight per one branched chain according to claim 1. Surface coating agent.   3. The surface coating agent according to claim 1, wherein the branched chain is composed only of 2-N, N-dimethylaminoethyl methacrylate and / or a derivative unit thereof.   The surface coating agent according to claim 1, wherein the surface coating agent is an aqueous solution containing the coating component.   5. The anionic substance according to claim 1, wherein the anionic substance is hyaluronic acid, chondroitin sulfate, glucuronic acid, galactosamine sulfate, sulfated isuronic acid, sulfated glucosamine, neuraminic acid, N-acetylneuraminic acid, O -Be at least one selected from the group consisting of acylneuraminic acid, sialic acid, polyalginic acid, dextran sulfate, heparan sulfate, polyphosphoric acid, argatroban, aspirin, panaldin, pravix, pertal, warfarin, dabigatran, and derivatives thereof. A surface coating agent characterized by.   6. The polymer material according to claim 1, wherein the polymer material is a compound having three or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule as an iniferter. A surface coating agent characterized by being a branched polymer obtained by light-irradiating living polymerization of dimethylaminoethyl methacrylate and / or its derivative.   7. The compound according to claim 6, wherein the compound having three or more N, N-disubstituted dithiocarbamylmethyl groups in the same molecule has a benzene ring as a nucleus and three or more N, N- A surface coating agent having a di-substituted dithiocarbamylmethyl group bonded thereto.   The surface coating agent according to claim 1, wherein the polymer material has a molecular weight of 5,000 to 500,000.   9. The coating component according to claim 1, wherein the coating component is hydrophilic at a temperature lower than a predetermined temperature (T) and hydrophobic at a temperature higher than the predetermined temperature (T). Surface coating agent.   The surface coating agent according to claim 9, wherein the predetermined temperature (T) is a temperature of 25 to 37 ° C.   A medical device coated with the surface coating agent according to any one of claims 1 to 10.

Images