JP2003079717A - Blood flow-contacting medical metallic member and method of manufacturing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a blood flow-contacting medical metallic material which is capable of more additionally suppressing the elution of a composite of a quaternary ammonium salt and at least one antithrombotic mucopolysaccharides, for example, heparin from the blood flow contact surface and enhancing the hydrophilicity of the blood-contacting surface of the blood flow-contacting medical metallic material by more firmly fastening the above composite to the blood contact surface and to provide a method of manufacturing the same. SOLUTION: The blood flow contacting medical metallic material comprising subjecting the composite of the quaternary ammonium salt and at least one antithrombotic mucopolysaccharides applied to the blood contact surface of the blood flow-contacting medical metallic material to an irradiation treatment with UV rays from 180 to 365 nm in main wavelength and from 2 to 48 J/cm<2> UV ray doses and the method of manufacturing the same.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a quaternary ammonium salt and an anti-quaternary ammonium salt for the purpose of (1) improving hydrophilicity, improving priming operability (2) improving antithrombotic property, and suppressing blood activation. A metal member for blood flow contact medical treatment with a complex of thrombotic mucopolysaccharide, for example, an antithrombotic mucopolysaccharide fixed to the blood flow contact surface of a heat exchanger of an artificial lung, particularly a metal member for blood contact medical treatment treated with heparin, and The present invention relates to a manufacturing method thereof.

[0002]

2. Description of the Related Art Heparin is a blood anticoagulant that has been well known and widely used since ancient times. This is a kind of acidic mucopolysaccharide produced by the living body and has an action of inhibiting the activation of endogenous coagulation factors. As a method of using heparin as an anticoagulant, there is a method of physically adsorbing heparin on the blood flow contact surface, for example, a method of applying a complex of a quaternary ammonium salt and heparin to the blood flow contact surface is known. (Tokuhyo Hyo 5-500314, Hokuhoku 2-36267). However, since these methods cannot be expected to significantly improve hydrophilicity, there is a problem in operability during priming and air bubble removability. In addition, since the complex of quaternary ammonium salt and heparin is eluted in a short period of time, it is difficult to maintain the antithrombotic effect for a long period of time.

[0003]

SUMMARY OF THE INVENTION According to the present invention, a complex of a quaternary ammonium salt and at least one antithrombotic mucopolysaccharide, such as heparin, is more firmly fixed to the blood flow contact surface of a medical metal member. As a result, as compared with the above-mentioned known technique, the elution from the blood flow contact surface of the complex or the like is further suppressed, the hydrophilicity of the blood flow contact surface is increased to facilitate priming, and the antithrombotic effect is obtained. It is an object of the present invention to provide a metal member for blood flow medical treatment capable of further prolonging the expression time and a method for producing the same.

[0004]

The first object of the present invention is, in order to solve the above-mentioned problems, a quaternary ammonium salt applied to the blood flow contact surface of a metal member for blood flow contact medical treatment and at least one anti-corrosion agent. It is an object of the present invention to provide a metal member for blood flow contact medical treatment, which comprises a thrombotic mucopolysaccharide, particularly a complex of heparin, which is irradiated with ultraviolet rays.

In the second aspect of the present invention, ultraviolet light is applied to a complex of a quaternary ammonium salt and at least one antithrombotic mucopolysaccharide, particularly heparin, applied to the blood flow contact surface of a metal member for blood flow contact medical treatment. An object of the present invention is to provide a method for producing a medical metal member treated with mucopolysaccharide, which is characterized by being irradiated.

[0006] The ability to suppress the elution of the quaternary ammonium salt and mucopolysaccharide from the blood flow contact surface can be achieved by the ATR.
As a result of confirmation by (total reflection attenuation spectroscopy) and XPS (X-ray photoelectron spectroscopy), irradiation treatment with ultraviolet rays increased the molecular weight due to the formation of cross-linking bonds in the complex, resulting in a decrease in solubility. It is speculated that

The degree of the dissolution inhibiting effect adopted in the present invention is such that the dissolution rate of the quaternary ammonium salt shown in Example 2 is 30% or less as compared with the case where the complex treatment and the irradiation treatment are not performed. Those are preferable.

It is confirmed by IR (infrared spectroscopy) or XPS (X-ray photoelectron spectroscopy) that the hydrophilicity is achieved. As a result, it is confirmed that C It is assumed that this is based on the introduction of a hydrophilic functional group such as ═O. The degree of hydrophilicity formation can be determined by a method such as wetted area measurement, and details of the measurement method will be shown in Examples. The degree of hydrophilicity adopted in the present invention is such that the hydrophilicity evaluation by measuring the wetted area shown in Example 3 is 150% or more as compared with the case where the complex treatment and the irradiation treatment are not performed. preferable. Further, since a hydrophilic group is introduced into the blood flow contact surface, for example, when priming a medical metal member such as a bellows tube, it is often necessary to tap the member to remove bubbles. However, the medical metal member of the present invention has improved hydrophilicity on the treated surface, and is excellent in bubble removal property during priming.

The antithrombotic mucopolysaccharide used in the present invention is
One of polysaccharides having an antithrombotic property containing an ester-like sulfate group, which is composed of α- (1.4) -bonded sulfate ester of D-glucosamine and D-glucuronic acid is preferable. As an example.

Examples of the quaternary ammonium salt used in the present invention include those having the structure of the following chemical formula 1.

[Chemical 1] (In the formula, R1, R2, and R3 are alkyl groups having 1 to 12 carbon atoms, aryl groups having 6 to 12 carbon atoms, or aralkyl groups having 7 to 20 carbon atoms, and R4 is 1 to 2 carbon atoms.
5 alkyl groups, which may be the same or different, are particularly preferable.

[0011]

[Chemical 2] (In the formula, X is halogen, and R is an alkyl group having 1 to 25 carbon atoms.) The anion of the quaternary ammonium salt is preferably a halogen anion, and the halogen is preferably chloro, bromo, or the like. Specific examples of the quaternary ammonium salt having the structure of Chemical Formula 2 include benzyl dimethyl myristyl ammonium chloride, benzyl dimethyl stearyl ammonium chloride, or a mixture thereof. The quaternary ammonium salt having the structure of Chemical formula 2 is difficult to handle because it is difficult to dissolve in a polar solvent when the hydrophobicity is too large, and therefore, those having an alkyl carbon chain length of 14 to 18 have suitable hydrophobicity and are preferable. .

The complex of the quaternary ammonium salt and the antithrombotic mucopolysaccharide has a quaternary ammonium salt content in order to achieve its good effect. 50 to 80% by weight of the total amount of the complex, preferably 6
0 to 70% by weight.

The complex of the quaternary ammonium salt and the antithrombotic mucopolysaccharide used in the present invention is dissolved in isopropanol or a mixture of isopropanol and a nonpolar solvent such as hexane, or an organic solvent such as DMF, THF or chloroform. It is used in the form of a solution or an aqueous dispersion.

The hydrophilicity of the composite-treated medical metal member is increased by the irradiation amount of the ultraviolet rays, but the degree thereof depends on the applied amount and the ultraviolet irradiation amount, and the hydrophilicity of the stainless steel used for the heat exchange part of the artificial lung is increased. , 0.1 to 0.
4 IU / cm ² is preferred. For those that have not been irradiated with ultraviolet rays, the improvement in hydrophilicity remains constant even if the coating amount is increased,
It does not increase any further.

Further, the preferable range of the ultraviolet irradiation amount is
Although it depends on the kind of the complex of the quaternary ammonium salt and the antithrombotic mucopolysaccharide, it is mainly determined in consideration of the safety of the blood flow contact member. Considering the elution of the complex, the quaternary ammonium salt, and the antithrombotic mucopolysaccharide, the UV irradiation dose was 2 to 48 J at the dominant wavelength of 253.7 nm.
/ Cm ² is preferable, and 6 to 24 J / cm ² is more preferable. That is, if the irradiation amount of ultraviolet rays is less than the above range, the complex is eluted from the base material much and the quaternary ammonium salt causes hemolysis, which is not preferable. On the contrary, if the irradiation amount of ultraviolet rays exceeds the above range, elution of the antithrombotic mucopolysaccharide increases, which is not preferable. The UV irradiation dose in the present invention is shown by the following (A). UV irradiation amount (J / cm ² ) = UV irradiation intensity (W / cm ² ) × time (sec) (A)

In the present invention, ultraviolet irradiation is most preferable as compared with radiation and electron beams. The reason is that the ultraviolet irradiation device is excellent in safety, the irradiation operation itself is easier than other irradiation devices, and the irradiation maintenance and management are simple. The UV irradiator used in the present invention may have a wavelength range of 180 to 365 nm,
It is more preferable to use an irradiating device having a wavelength of around 253.7 nm as a main wavelength, since a measuring device for the wavelength can be obtained easily and cheaply as compared with a measuring device for a shorter wavelength.

According to the metal member for medical treatment of blood flow contact with ultraviolet ray of the present invention, the elution of the quaternary ammonium salt and the mucopolysaccharide from the surface of blood flow contact is compared with the metal member for medical treatment of the known art. Not only can it be further suppressed and the time of manifestation of the antithrombotic effect can be further extended, but also a hydrophilic function can be secured on the blood flow contact surface.

[0018]

EXAMPLES The present invention will be described in more detail below with reference to examples.

Example 1 Preparation of Quaternary Ammonium Salt / Heparin Complex (1) The ratio of the amount of sodium heparin to the quaternary ammonium salt was 1: 3.2. (2) Preparation of Heparin Sodium Solution A required amount of heparin sodium is collected to a concentration of 5.64 mg.
It was dissolved in 0.03M NaCl aqueous solution so that the concentration became / ml. (3) Preparation of quaternary ammonium salt solution A required amount of the quaternary ammonium salt was collected, and the concentration was 9.90 m.
It was dissolved in 0.03M NaCl aqueous solution so that the concentration became g / ml. (4) Each of the preparations of (2) and (3) above is 40
After heating to 60 ° C, the mixture was mixed and stirred for several minutes. (5) A quaternary ammonium salt / heparin complex was formed by allowing the solution prepared in (4) above to stand in a greenhouse (40 to 60 ° C.) for several hours. (6) The quaternary ammonium salt-heparin complex obtained in (5) above contains a quaternary ammonium salt at a maximum of 73.
5% by weight, minimum 58.6% by weight, maximum 3 heparin
It contained 4.8% by weight and a minimum of 29.4% by weight. This complex was found to dissolve in polar organic solvents such as ethanol, isopropyl alcohol, THF.

Example 2 Evaluation of Elution Suppression Effect by UV Irradiation After the stainless plate was treated with the quaternary ammonium salt / heparin complex obtained in the above Example 1, UV irradiation was carried out. Ultraviolet irradiation dose 2.4 J / cm ² irradiation on plate 1,
Same as 6.0 J / cm ² irradiation, plate 2, same 12 J / cm
² irradiation was used as plate 3, only the treatment with quaternary ammonium salt / heparin complex was performed, and the plate not irradiated with ultraviolet light (hereinafter referred to as plate 4) was used as a test sample, and each plate was immersed in 2M NaCl aqueous solution. The degree of elution of the quaternary ammonium salt and heparin was measured. The elution amount of the quaternary ammonium salt and heparin was measured from each of the plates, and the elution amount of the plate was adjusted to 10
The ratio is shown as 0.

[Table 1]

Example 3 Hydrophilicity Evaluation by Measuring Wet Area A stainless steel plate was treated with the quaternary ammonium salt / heparin complex obtained in Example 1 above and then irradiated with ultraviolet rays. In addition to the plates 1, 2 and 3, the amount of UV irradiation is 2
The plate 4 was irradiated with 4 J / cm ² and the plate 5 was used after degreasing. 20 μl of distilled water having a water temperature of 20 to 25 ° C. was dropped on each plate surface as a test solution, and immediately the water droplet was photographed from a certain height, and the area was measured. The plate 5 was shown as a control.

[Table 2]

Example 4 Hydrophilicity Evaluation Based on Bubble Removal Performance FIG. 1 is a schematic diagram illustrating a hydrophilicity evaluation device based on bubble removal performance. In the evaluation device shown in FIG. 1, a stainless steel bellows tube 2 is arranged in a hollow housing 1, and a liquid filled in the housing 1 is introduced from an introduction port 3,
The device is configured to be discharged from the discharge port 4. The evaluation method is as follows: The following (A) and (B) stainless steel bellows tubes are installed as a sample in the device, and 2 L is put in the device.
Tap water is circulated at a flow rate of / min and 50 ml in it
Inflate the air once. By hitting the device, air bubbles adhering to the surface of the bellows tube were removed, and the number of hits of the device required for removal was recorded up to 200 times for evaluation. Sample (A) is not treated with the quaternary ammonium salt / heparin complex, and sample (B) is treated with the quaternary ammonium salt / heparin complex. The hydrophilicity evaluation for each of the samples was as follows. Sample (A): Bubbles cannot be removed even if tapped 200 times or more Sample (B): Bubbles removed after 45 times

[0023]

According to the present invention, the complex of the quaternary ammonium salt and the antithrombotic mucopolysaccharide is more firmly fixed to the blood flow contact surface of the metal member for blood flow contact medical treatment. It is possible to provide the metal member for blood flow contact medical treatment in which the elution from the metal member for blood flow contact medical treatment is further suppressed and the hydrophilicity of the blood flow contact surface is improved. As a result, it is possible to further extend the time for the antithrombotic effect of the metal member for blood flow contact medical treatment to be prolonged.
In addition, even in the case of a medical device using a metal member for blood flow contact medical treatment, particularly a medical device having a shape in which bubbles in the filling liquid are likely to stay, the bubble removal performance is enhanced during the priming operation, and priming operability is improved. The effect is improved.

[Brief description of drawings]

FIG. 1 is a schematic diagram illustrating a hydrophilicity evaluation device based on bubble removal performance in Example 4.

[Explanation of symbols]

1. housing 2. Stainless steel bellows 3. Entrance 4. Vent

Claims (9)

[Claims] 1. A complex of a quaternary ammonium salt and at least one antithrombotic mucopolysaccharide applied to the blood flow contact surface of a medical metal member, which is irradiated with ultraviolet rays. Blood flow contact medical metal parts. 2. The metal member for blood flow contact medical treatment according to claim 1, wherein the at least one antithrombotic mucopolysaccharide is heparin. 3. The metal member for blood flow contact medical treatment according to claim 1, wherein the dominant wavelength of ultraviolet rays is 180 to 365 nm. 4. The dominant wavelength of ultraviolet rays is 180 to 365 nm.
4. The metal member for blood flow contact medical treatment according to any one of claims 1 to 3, wherein the amount of ultraviolet rays to be irradiated is 2 to 48 J / cm ² . 5. The hydrophilicity as measured by the wetted area is 1.5 times or more the wetted area of the metal member for blood flow contact medical treatment which is not irradiated with ultraviolet rays, and the wetted area is at least 1.5 times the wetted area. Blood flow contact medical metal parts. 6. The elution of the quaternary ammonium salt in the amount of the complex of the quaternary ammonium salt applied to the blood flow contact surface of the medical metal member and at least one antithrombotic mucopolysaccharide complex. The metal member for blood flow contact medical treatment according to any one of claims 1 to 5, wherein the ratio is 30% or less compared to that of the composite body not irradiated with ultraviolet rays. 7. A medical metal member is coated with a complex of a quaternary ammonium salt and at least one antithrombotic mucopolysaccharide on a blood flow contact surface, and the coated surface is irradiated with ultraviolet rays. A method for producing a metal member for blood flow contact medical treatment. 8. The method for producing a metal member for blood flow contact medical treatment according to claim 7, wherein the main wavelength of ultraviolet rays is 180 to 365 nm. 9. The dominant wavelength of ultraviolet rays is 180 to 365 nm.
10. The method for producing a metal member for blood flow contact medical treatment according to claim 8, wherein the amount of ultraviolet rays to be irradiated is 2 to 48 J / cm ² .