JP2007319534A - Heparin coating and medical device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a heparin sustained-release agent with temperature responsiveness, which exhibits hydrophilicity at a temperature lower than a predetermined temperature (T) lower than a biological temperature, and which exhibits hydrophobicity at a temperature higher than the predetermined temperature. <P>SOLUTION: The heparin sustained-release agent is composed of a polymer material on which heparin or a heparin salt is supported. The polymer exhibits hydrophilicity at the temperature lower than the predetermined temperature (T) lower than the biological temperature, and exhibits hydrophobicity at a temperature higher than the predetermined temperature (T). The polymer material is obtained by block-polymerizing N-isopropylacrylamide to a homopolymer which is composed of a branched polymer. In the branched polymer, a compound which has three or more N,N-dialkyl-dithiocarbamyl methyl groups in the same molecule, serves as an iniferter, and a vinyl monomer is living-polymerized with the compound by light irradiation. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention can maintain excellent anticoagulability (antithrombogenicity) over a long period of time, and can be applied to living tissue or as a constituent material of various medical devices such as artificial organs and artificial blood vessels. The invention relates to a possible heparin coating and a medical device coated with this heparin coating.

  When blood comes into contact with foreign matter, it has a property of coagulating due to the action of various components in the blood. Therefore, constituent materials for medical devices used for parts that come into contact with blood, such as artificial hearts, artificial heart valves, artificial blood vessels, vascular catheters, cannulas, cardiopulmonary bypasses, vascular bypass tubes, aortic balloon pumping, transfusion devices and extracorporeal circulation circuits Is required to have high anticoagulability. However, many of the constituent materials of conventional medical devices are inevitably caused by blood coagulation when used for a long period of time, which is not sufficient in terms of anti-blood coagulation sustainability. In addition, when the above-described medical device is applied to a patient, an anticoagulant such as heparin is usually used in combination. However, for example, when heparin is administered systemically, there is a problem that the risk of generating a large number of bleeding foci increases.

  As a method for solving such a problem, various techniques for fixing heparin on the surface of the medical material or releasing it gradually have been proposed. For example, heparin is contacted with a polymer material having a cationic residue, and heparin is supported on the polymer material in an ionic bond form, and heparin or a copolymer of polyvinyl chloride and acrylic acid or methacrylic acid is used. Japanese Patent No. 3341503 describes an antithrombotic medical material for coating formed by ion-bonding the salt.

  Japanese Patent No. 2854284 describes that a polyamine or a salt thereof is immobilized on the surface of an artificial blood vessel, and heparin is immobilized on the surface of the polyamine or a salt thereof by ionic bonding.

Japanese Patent No. 3372971 describes an antithrombotic material in which heparin is ionically bound to a phospholipid in a phospholipid-polymer composite thin film formed on a substrate surface.
Japanese Patent No. 3341503 Japanese Patent No. 2854284 Japanese Patent No. 3372971

  In Japanese Patent No. 3341503, a polyvinyl chloride- (meth) acrylic copolymer carrying heparin is dissolved in a solvent and applied to an object such as a catheter. As this solvent, an organic solvent such as tetrahydrofuran is used (paragraphs 0027 to 0028 in the same publication).

  When organic solvents are used in this way, they cannot be used for surface treatments such as hybrid tissues composed of cells and synthetic or biomaterials used in regenerative medicine, or living tissues removed from hosts (cells are killed by organic solvents, etc. To get injured). Some materials themselves are vulnerable to organic solvents (such as nitrocellulose). Alternatively, when a medical device coated with a drug, such as a drug-releasing stent, is sometimes damaged by peeling off a polymer layer carrying the drug with an organic solvent.

  The present invention eliminates the above-mentioned conventional problems, and has a temperature responsiveness that is hydrophilic at a temperature lower than a predetermined temperature (T) lower than the living body temperature and becomes hydrophobic at a temperature higher than the predetermined temperature. It is an object to provide a heparin coating agent possessed.

  The heparin coating agent of the present invention is a heparin coating agent comprising a polymer material supporting heparin or a salt thereof, and the polymer material is hydrophilic at a temperature lower than a predetermined temperature (T) lower than a living body temperature, It is characterized by being hydrophobic at a temperature higher than the predetermined temperature (T).

  The polymer material is preferably a block copolymer of a cationic monomer and N-isopropylacrylamide.

  The molecular weight of this cationic homopolymer is preferably 2,000 to 500,000.

  The molecular weight of this block copolymer is preferably 3,000 to 600,000.

  The predetermined temperature (T) is preferably a temperature between 25 and 35 ° C.

  The cationic homopolymer is a branched polymer in which a compound having three or more N, N-dialkyl-dithiocarbamylmethyl groups in the same molecule is used as an iniferter, and a vinyl monomer is light-irradiated by living polymerization. Preferably there is.

  The compound having three or more N, N-dialkyl-dithiocarbamylmethyl groups in the same molecule has a benzene ring as a nucleus and three or more N, N-dialkyl-dithio as a branched chain in this nucleus. Those having a carbamylmethyl molecular group bonded thereto are preferred.

  This vinyl monomer is preferably 3-N, N-dimethylaminopropylacrylamide.

  The medical device of the present invention is coated with the heparin coating agent of the present invention.

  Since the heparin coating agent of the present invention is hydrophilic and water-soluble at a temperature lower than the above-mentioned predetermined temperature, it is dissolved in water and applied to a living body or a medical device, and then a temperature higher than the predetermined temperature. As a result, it becomes hydrophobic (water-insoluble) and adheres to a living body or a medical device.

  Since this heparin coating agent does not use an organic solvent, it can be applied to a hybrid material or a living body.

  The heparin coating agent of the present invention is based on a polymer material which is hydrophilic at a temperature lower than a predetermined temperature (T) lower than the living body temperature and is hydrophobic at a temperature higher than the predetermined temperature (T). This is loaded with heparin or a salt thereof.

  Examples of heparin salts include heparin sodium and benzalkonium heparin.

  As the polymer material, there is a branched polymer obtained by using a compound having three or more N, N-dialkyl-dithiocarbamylmethyl molecular groups in the same molecule as an iniferter and then subjecting the vinyl monomer to light irradiation living polymerization. Is preferred.

  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 a compound having three or more N, N-dialkyl-dithiocarbamylmethyl groups in the same molecule, three or more N, N-dialkyl-dithiocarbamylmethyl groups are bonded as a branched chain to the benzene ring. These are preferred, and specific examples are as follows. That is, as a 3-branched chain, 1,3,5-tri (bromomethyl) benzene and sodium N, N-dithiocarbamate (sodium N, N-dithiocarbamate) can be obtained by addition reaction in ethanol. , 3,5-tri (N, N-dithiocarbamylmethyl) benzene, and four branched chains include 1,2,4,5-tetrakis (bromomethyl) benzene and sodium N, N-dithiocarbamylate ( 1,2,4,5-tetrakis (N, N-dithiocarbamylmethyl) benzene obtained by addition reaction with sodium N, N-dithiocarbamate) in ethanol. Hexakis (N, N-dithio) obtained by addition reaction of bromomethyl) benzene and sodium N, N-dithiocarbamate in ethanol Rubamirumechiru) is a benzene.

  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 a halogenated alkylene, and particularly preferably benzene, toluene, chloroform or methylene chloride, especially chloroform.

As the monomer to be polymerized to this iniferter, vinyl monomers such as vinyl monomers, acrylic acid derivatives, styrene derivatives and the like are particularly suitable. Specifically, 3-N, N-dimethylaminopropylacrylamide CH ₂ ═CHCONHC ₃ H ₆ N (CH ₃ ) ₂ is preferred.

  In order to react the iniferter with the monomer, a raw material solution containing the iniferter and the monomer is prepared, and a light-irradiated product is produced to produce a reaction product in which the monomer is bonded to the iniferter.

  The concentration of the monomer in the raw material solution is preferably 70% by weight or more, for example, 70 to 99% by weight.

  The concentration of the iniferter is preferably about 10 to 1000 mM.

The wavelength of the irradiated light is preferably 300 to 400 nm. The irradiation time of the light depends on the irradiation intensity, about 1 to 60 minutes are preferred, about 1 to 30 minutes at a low irradiation intensity of about 1μW ^/ cm ² ~10mW ^/ cm 2 is particularly preferred.

  In addition, you may perform a 2nd light irradiation process further after this light irradiation process (1st light irradiation process). That is, the solution containing the reaction product is diluted with an alcohol, preferably an alcohol solution of the above monomer. As the alcohol, methanol or ethanol, particularly methanol is preferable. The monomer concentration in the alcohol solution is preferably about 100 mM to 5 M as the final concentration.

  It is preferable to add 5 to 500 parts by volume of the alcohol solution to 1 part by volume of the reaction product-containing liquid from the first light irradiation step.

  The diluted solution thus diluted with the alcohol solution is subjected to the second light irradiation step, and the monomer is further polymerized with respect to the reaction product. In this case, any irradiation light source may be used as long as it includes light having a wavelength of 240 to 400 nm. For example, a low-pressure mercury lamp or a high-pressure mercury lamp can be used. The light irradiation time is preferably about 10 minutes to 120 minutes.

  Since the target branched polymer is produced in the reaction solution by this light irradiation, the cationic homopolymer comprising the branched polymer is obtained by purification as necessary.

  The molecular weight of this branched polymer depends on the number of branched chains, but is preferably 2,000 to 500,000, particularly 2,000 to 150,000, and particularly 2,000 to 100,000.

  N-isopropylacrylamide is block-copolymerized with the cationic polymer composed of the branched polymer thus produced to obtain a target polymer material. This polymer chain of N-isopropylacrylamide has a temperature dependency that becomes hydrophilic at a low temperature and hydrophobic at a high temperature, so that the polymer material has the temperature responsiveness.

In order to block copolymerize N-isopropylacrylamide, the branched polymer synthesized as described above is dissolved in a solvent such as methanol, mixed with N-isopropylacrylamide, and polymerized by irradiation with light. That's fine. The concentration of the branched polymer in the solution when starting the polymerization reaction is preferably about 0.01 to 10% by weight, and the concentration of N-isopropylacrylamide is preferably about 0.3 to 30% by weight. The light irradiation conditions are preferably a light wavelength of 250 to 400 nm, an irradiation time of 1 to 150 minutes, and an irradiation intensity of about 100 to 10,000 μW / cm ² .

  The molecular weight of this block copolymer (polymer material) is preferably 3,000 to 600,000, particularly preferably 3,000 to 150,000.

  In order to support heparin or a salt thereof on the polymer material, heparin or a salt thereof may be added to a low temperature aqueous solution of the polymer material and mixed. At this time, it is preferable to add heparin or its salt in an amount of 0.01 to 30 parts by weight, particularly 0.1 to 10 parts by weight, based on 1 part by weight of the polymer material. It can adjust suitably according to the surface state. In general, if the amount of heparin or a salt thereof is more than 10 parts by weight, the water solubility of the heparin coating agent becomes high even near the human body temperature, making it difficult to fix to the material surface. On the other hand, when the amount of heparin or a salt thereof added is less than 0.1 parts by weight, the antithrombotic effect becomes poor.

  A heparin coating agent in which 0.1 to 5 parts by weight of heparin or a salt thereof is supported on a polymer material is water-insoluble at a temperature higher than about 30 ° C and water-soluble at a temperature lower than about 30 ° C.

  Accordingly, an aqueous solution of heparin coating agent having a temperature lower than about 30 ° C., for example, about 10 to 25 ° C. (concentration is preferably about 3 to 150 mg / mL) is attached to a living body or a medical device by application or the like. By raising the temperature to a high temperature and drying it as necessary, a water-insoluble coating carrying heparin or a salt thereof is formed. In the case of a living body, the temperature increase at this time is performed by the body temperature of the living body.

This medical device is used for parts that come into contact with blood, such as an artificial heart, an artificial heart valve, an artificial blood vessel, a blood vessel catheter, a blood vessel stent, a cannula, an artificial heart lung, a blood vessel bypass tube, an aortic balloon pumping, a blood transfusion device, and an extracorporeal circuit. Examples thereof include medical devices to be used. When applied to a medical device, it is preferable to deposit about 0.1 to 30 mg of heparin coating agent per 1 cm ² of the surface of the medical device.

Example 1
i) Synthesis of iniferter According to the following reaction formula, 1,2,4,5-tetrakis (NN-diethyldithiocarbamylmethyl) benzene was synthesized as follows.

  2.0 g of 1,2,4,5-tetrakis (bromomethylbenzene) and 12.0 g of sodium N, N-diethyldithiocarbamate were added to 10 mL of ethanol and stirred at room temperature for 4 days under light shielding. The precipitate was filtered, dried under reduced pressure, dissolved in 40 mL of chloroform, extracted with 50 mL of water, and sodium bromide was removed. After repeating this operation three times, the chloroform layer was dried with about 10 g of magnesium sulfate for 24 hours, filtered, added with n-hexane, purified by recrystallization, and a slightly light blue 1, White crystals of 2,4,5-tetrasakis (N, N-diethyldithiocarbamylmethyl) benzene were obtained (yield 90%).

The measurement results of ¹ H NMR (in CDCl ₃ ) are σ7.48 (s, 2H, Ar—H), σ4.57 (s, 2H × 4, Ar—CH ₂ S—), σ4.03 (q, 2H). × 4, N—CH ₂ −, J = 10.7 Hz), σ 3.72 (q, 2H × 4, N—CH ₂ −, J = 10.7 Hz), σ 1.26 to 1.31 (t, 3H) × _8, became _{-CH 2 -CH 3, J = 6.6Hz} ).

ii) Synthesis of cationic homopolymer comprising 4-branched star polymer by photopolymerization According to the following reaction formula, 1,2,4,5-tetrakis (N, N-diethyldithiocarbamyl ( A cationic homopolymer composed of poly (3-N, N-dimethylaminopropylacrylamide) (hereinafter sometimes referred to as pDMAPAAm) was synthesized.

That is, 0.43 g of 1,2,4,5-tetrasakis (N, N-diethyldithiocarbamylmethyl) benzene synthesized by i) above was dissolved in 10 mL of toluene, and 3-N, N-dimethylaminopropylacrylamide was dissolved. 5.2 g of (3-N, N-DMAPAAm) was added and mixed, and the total amount was adjusted to 20 mL with toluene. After purging with high purity nitrogen gas for 5 minutes with vigorous stirring in a quartz cell, ultraviolet light was irradiated with a 200 W high pressure mercury lamp for 30 minutes. The irradiation intensity was adjusted to 1 mW / cm ² (250 nm) using an illuminometer (UVR-1, TOPCON, Tokyo, Japan). The polymerization solution is concentrated with an evaporator, purified by reprecipitation of the polymer with diethyl ether, dissolved in a small amount of water, filtered through a 0.2 μm filter, and lyophilized to obtain a 4-branched star homopolymer 1,2. , 4,5-tetrakis (N, N-diethyldithiocarbamyl (poly (3-N, N-dimethylaminopropylacrylamide) (pDMAPAAm)) was obtained (polymerization rate 40%) with a molecular weight of GPC. Was measured to be 3700.

The measurement results of ¹ H NMR (in CDCl ₃ ) are as follows: σ 3.10-3.39 (br, —NH—CH ₂ —), σ 2.25-2.42 (br, —CH ₂ —N (CH ₃ ) _{2), σ2.21 (br, -N} (CH 3) 2), σ1.48-1.76 (br, -CH 2 -CH -, - CH 2 -CH 2 -CH 2 -) became.

iii) Synthesis of polymer material (4-branched pDMAPAAm-b-pNIPAM) by block copolymerization of N-isopropylacrylamide with cationic homopolymer According to the following reaction formula, tetrakis (N, N-diethyldithio) Carbamyl (poly (3-N, N-dimethylaminopropylacrylamide) -block-poly- (N-isopropylacrylamide) (hereinafter sometimes referred to as pDMAPAAm-b-pNIPAM) was synthesized.

  That is, 645 mg of the 4-branched pDMAPAAm homopolymer synthesized in the above ii) was dissolved in 10 mL of methanol, and 1.2 g of N-isopropylacrylamide (NIPAM) was mixed to adjust the total amount to 20 mL with methanol. Photo-irradiation polymerization was performed under the same conditions as in ii), and purification was performed in a methanol / diethyl ether system to obtain a polymer material composed of a block polymer of 4-branched pDMAPAAm and poly N-isopropylacrylamide (pNIPAM) (polymerization) 80%). The molecular weight was measured to be 9,300 by GPC.

The measurement result of ¹ H NMR (in CDCl ₃ ) is as follows: σ 3.10-3.39 (br, —NH—CH ₂ —), σ 2.25-2.42 (br, —CH ₂ —N (CH ₃ ) _{2), σ2.21 (br, -N} (CH 3) 2), σ1.48-1.76 (br, -CH 2 -CH -, - CH2-CH 2 -CH 2 -), σ1.08- _{1.23 (br, -CH- (CH 3} ) 2) became.

iv) Ion complexation with heparin The polymer material (4-branched pDMAPAAm-b-pNIPAM) synthesized in the above iii) and heparin could be mixed in an aqueous solution to form an ion complex. In order to make water-insoluble or sparingly soluble as an antithrombotic agent, the mixing ratio with heparin was determined as follows. The relationship between the absorbance and temperature of a solution in which 20 mg of 4-branched pDMAPAAm-b-pNIPAM and heparin were dissolved in 2 mL of water in the range of 0 mg to 200 mg was plotted, and the cloud point was measured. It was recognized that the cloud point shifted to a low temperature region when the amount of heparin introduced was large. In order to be insoluble in water near the human body temperature, the amount of heparin needed to be about 50 mg or less.

v) Coating treatment 20 mg of the above polymer material (4-branched pDMAPAAm-b-pNIPAM block copolymer) and 15 mg of heparin were dissolved in water to adjust the total volume to 2 mL. 10 μL of this solution was homogeneously cast onto a 2 cm × 3 cm square PET film and dried by a dryer to carry out coating treatment. The film was placed on a plate temperature-controlled at 37 ° C., and the contact angle was measured. The contact angle in this state was 15 °, and the hydrophilicity phenomenon of the film surface presumed to be caused by heparin was confirmed. When this film was continuously washed with warm water of 37 ° C., the contact angle of the surface gradually increased with the washing time and reached a plateau at about 44 °. Although the contact angle of the PET film approached 74 °, it was confirmed that heparin was insolubilized and fixed.

vi) Confirmation of antithrombogenicity Human peripheral blood was collected, and immediately applied onto a PET film as it was, and then rinsed lightly with physiological saline after a period of time to observe surface thrombus adhesion. In the PET film, thrombus generation was confirmed in about 5 minutes, but in the coated PET film, thrombus generation was not confirmed even after 20 minutes.

Comparative Example 1
(N, N-dithiocarbamylmethyl) benzene was synthesized in the same manner as i) of Example 1 except that bromomethylbenzene was used instead of 1,2,4,5-tetrakis (bromomethylbenzene). . The purified product was a colorless liquid, and the yield was about 93%.

The measurement results of ¹ H NMR (in CDCl ₃ ) are as follows: σ7.41 to 7.27 ppm (m, 5H, Ar—H), σ4.54 ppm (s, 2H, Ar—CH ₂ —S—), σ4.08 to 4.01 ppm (q, 2H, N—CH ₂ —), σ 3.72 ppm (q, 2H, N—CH ₂ —), σ 1.25 to 1.31 ppm (m, 6H, —CH ₂ —CH ₃ ) became.

  Next, a linear block polymer pDMAPAAm-b-pNIPAM was synthesized according to the above methods ii) and iii), and the coating treatment and water washing experiment on the PET film of (v) were performed. The contact angle increased from 15 ° to 74 ° just by washing lightly at 37 ° C., and it was confirmed that the coated polymer was quickly peeled off from the PET film.

  From the above, the superiority of the branched structure of the present invention was confirmed. That is, in the antithrombotic agent of the present invention, the molecule cannot be peeled off from the material surface unless all of the plurality of NIPAM polymer chains in one molecule that are hydrophobically bonded to the material surface are peeled off simultaneously. Even if the book is peeled off, if the remaining polymer chains are bonded, the once peeled polymer chains can be rebonded, which is considered to be more firmly fixed. On the other hand, the linear block polymer synthesized in Comparative Example 1 has only one p-NIPAM polymer chain in one molecule. If this P-NIPAM polymer chain peels off, the molecule peels off as it is. Therefore, it is considered weak against the cleaning process.

Example 2
[1] Synthesis of hexakis (N, N-diethyldithiocarbamylmethyl) benzene 5 g of hexakis (bromomethyl) benzene and 31.8 g of sodium N, N-diethyldithiocarbamate were added to 1 L of ethanol and stirred at room temperature for 4 days. The precipitate was filtered, dried under reduced pressure, dissolved in 200 mL of chloroform, 150 mL of water was added thereto, and liquid-liquid extraction was performed to remove sodium bromide. After repeating this operation three times, the chloroform layer was dried over magnesium sulfate for 24 hours. After filtration, recrystallization was carried out by adding n-hexane to obtain white crystals of hexakis (N, N-diethyldithiocarbamylmethyl) benzene having a slightly light blue color (yield 90%).

The measurement result of ¹ H NMR (in CDCl ₃ ) is δ 1.26-1.31 (t, 36H, J = 6.9 Hz, -CH ₂ SC (S) N (CH ₂ CH ₃ ) ₂ ), 3.71-4.01 (wq, _{24H, J = 6.9Hz, -CH 2} SC (S) N (CH 2 CH 3) 2), was _{4.57 (s, 12H, -CH 2} SC (S) NEt 2).

[2] Synthesis of 6-branched pDMAPAAm homopolymer The monomer 3-N, N-dimethylaminopropylacrylamide was purified by distillation under reduced pressure. 8.7 mg of hexakis (N, N-diethylthiocarbamylmethyl) benzene is dissolved in 20 mL of chloroform, 3.9 g of 3-N, N-dimethylaminopropylacrylamide is added and mixed, and the whole amount is diluted with chloroform. Adjusted to 50 mL. Purge with high purity nitrogen gas for 5 minutes with vigorous stirring in a quartz cell. Light irradiation was performed for 10 minutes with a 200 W high-pressure mercury lamp. The illuminance was adjusted to 1 mW / cm ² (250 nm) using an illuminometer (UVR-1, TOPCON, Tokyo, Japan). The polymerization solution was concentrated by an evaporator and purified by reprecipitation with diethyl ether. This is dissolved in a small amount of water, filtered through a 0.2 μm filter, and freeze-dried to give hexakis {N, N-diethyldithiocarbamyl-poly (3-N, N-dimethylaminopropylacrylamide) -methyl} benzene. (6-branch type pDMAPAAm homopolymer) was obtained (polymerization rate 40%).

The molecular weight was measured to be 3,000 by GPC, and the measurement result of ¹ H NMR (in D ₂ O) was δ 1.00-1.70 (br, 416H, -CH ₂ CH-and-CH ₂ CH ₂ CH _2- ), 1.90 (br, 104H, -CH ₂ CH-), 2.09 (s, 624H, -N (CH ₃ ) ₂ ), 2.25 (br, 208H, -CH ₂ N (CH ₃ ) ₂ ), 2.98 (br, 208H , -CONHCH _2- ), which was confirmed to be the desired product.

[3] Synthesis of 6-branched (pDMAPAAm-co-pNIPAM) block polymer N-isopropylacrylamide was purified by recrystallization from hexane and dried under reduced pressure at room temperature.

  1.6 g of the 6-branched pDMAPAAm homopolymer synthesized in [2] was dissolved in 20 mL of methanol, 3.1 g of N-isopropylacrylamide was added and mixed, and the total amount was adjusted to 50 mL with methanol. Purge with high purity nitrogen gas for 5 minutes with vigorous stirring in a quartz cell. The polymerization solution obtained by carrying out photoirradiation polymerization under the same conditions as in [2] was concentrated by an evaporator and purified by reprecipitation with diethyl ether. This was dissolved in a small amount of water, filtered through a 0.2 μm filter, and lyophilized to obtain the desired product. The molecular weight was measured as 9,000 by GPC.

[4] Heparinization of 6-branch type (pDMAPAAm-co-pNIPAM) block polymer 20 mg of heparin was dissolved in 1 mL of water and the temperature was adjusted to 20 ° C. 20 mg of the 6-branched (pDMAPAAm-co-pNIPAM) block polymer synthesized in [3] was dissolved in 1 mL of water at 20 ° C., mixed with a heparin solution, and stirred at 20 ° C. for 30 minutes.

[5] Antithrombotic coating This solution is applied onto a 2 mm thick polypropylene resin plate, drained with a doctor knife with a clearance of 100 μm, heated to 37 ° C. to gel the solution, and then washed with water at 37 ° C. Washed. By ESCA measurement after drying, S atoms derived from heparin were confirmed on the surface. The contact angle was 70 ° after coating, compared to 90 ° for the untreated plate. When ACD-ized human whole blood was brought into contact, platelets adhered and deformed in the untreated plate, whereas platelet adhesion was not confirmed in the antithrombotic treated product.

Claims (9)

In a heparin coating agent comprising a polymer material supporting heparin or a salt thereof,
The heparin coating agent, wherein the polymer material is hydrophilic at a temperature lower than a predetermined temperature (T) lower than a living body temperature and is hydrophobic at a temperature higher than the predetermined temperature (T).   The heparin coating agent according to claim 1, wherein the polymer material is a block copolymer of a cationic monomer and N-isopropylacrylamide.   The heparin coating agent according to claim 2, wherein the molecular weight of the cationic polymer block is 2,000 to 500,000.   The heparin coating agent according to claim 3, wherein the block copolymer has a molecular weight of 3,000 to 600,000.   The heparin coating agent according to any one of claims 1 to 4, wherein the predetermined temperature (T) is a temperature between 25 and 35 ° C.   6. The cationic homopolymer according to claim 1, wherein the cationic homopolymer is an iniferter compound having three or more N, N-dialkyl-dithiocarbamylmethyl molecular groups in the same molecule. A heparin coating agent characterized by being a branched polymer obtained by light-irradiating living polymerized.   7. The compound having three or more N, N-dialkyl-dithiocarbamylmethyl molecular groups in the same molecule as defined in claim 6, wherein the benzene ring is a nucleus and three or more N, N- A heparin coating agent, wherein a dialkyl-dithiocarbamylmethyl molecular group is bonded.   8. The heparin coating agent according to claim 6, wherein the vinyl monomer is 3-N, N-dimethylaminopropylacrylamide.   A medical device coated with the heparin coating agent according to any one of claims 1 to 8.