JP2000288081A - Anti-thrombotic mucopolysaccharide-treated blood flow contact medical member, and method for producing the blood flow contact medical member - Google Patents

Abstract

(57) [Problem] To provide a blood flow contact medical member with a quaternary ammonium salt and at least one kind of antithrombotic mucopolysaccharide, for example, heparin, on a blood flow contact surface of a medical member. Combine
As a result, as compared with the known art, the elution of the complex from the blood flow contact surface is further suppressed, the time for the onset of the antithrombotic effect is further extended, and the hydrophilicity of the blood flow contact surface is increased, thereby priming. The present invention provides a blood flow contact medical member and a method of manufacturing the same, which facilitates priming even in a component having a shape in which blood flow is easily retained, and a blood flow contact surface of the blood flow contact medical member. A blood flow contact medical member, which is obtained by irradiating an applied complex of a quaternary ammonium salt and at least one kind of antithrombotic mucopolysaccharide with ultraviolet light, and a method for producing the same.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a quaternary ammonium salt for the purpose of (1) improving antithrombotic properties and suppressing blood activation, (2) improving hydrophilicity and priming operability. The present invention relates to an antithrombotic mucopolysaccharide in which a complex of an antithrombotic mucopolysaccharide is bonded to a blood flow contact surface of an artificial lung circuit, for example, an antithrombotic mucopolysaccharide, particularly heparin-treated blood flow contact medical member, and a method for producing the same. .

[0002]

2. Description of the Related Art Heparin is an anticoagulant well known and widely used since ancient times. This is a kind of acidic mucopolysaccharide produced by the living body and has the effect of inhibiting the activation of endogenous coagulation factors. Methods for using heparin as an anticoagulant include:
There is a method of physically adsorbing heparin to the surface of 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 (Japanese Patent Application Laid-Open No. 5-500314). , Tokuhei 2-36267). However, these methods also have problems in short-term elution of heparin, operability during priming, and bubble removal.

[0003]

SUMMARY OF THE INVENTION The present invention provides a blood flow contact medical member with a quaternary ammonium salt and at least one kind of antithrombotic mucopolysaccharide, for example, heparin, which is more firmly attached to the blood flow contact surface of the medical member. Binding, thereby further suppressing the elution of the complex from the blood flow contact surface, prolonging the onset of the antithrombotic effect, and increasing the hydrophilicity of the blood flow contact surface, as compared to the known art. It is an object of the present invention to provide a blood flow contact medical member which can be easily primed even in a component having a shape in which the priming is increased and particularly easy to retain the blood flow, and a method of manufacturing the same.

[0004]

SUMMARY OF THE INVENTION The first object of the present invention is to solve the above-mentioned problems by providing a quaternary ammonium salt and at least one kind of antithrombotic applied to a blood flow contact surface of a blood flow contact medical member. Another object of the present invention is to provide a member for blood flow contact medical treatment, which is obtained by irradiating a complex of sex mucopolysaccharide, particularly heparin, with ultraviolet light.

A second aspect of the present invention is to apply a quaternary ammonium salt and a complex of at least one antithrombotic mucopolysaccharide, particularly heparin, to a blood flow contact surface of a blood flow contact medical member, An object of the present invention is to provide a method for producing a blood flow contact medical member treated with mucopolysaccharide, which comprises irradiating an applied surface with ultraviolet light.

[0006] The blood flow contact medical member of the present invention, which has been subjected to the ultraviolet ray treatment, is compared with the aforementioned blood flow contact medical member of the prior art.
The elution of mucopolysaccharide from the blood flow contact surface is further suppressed, and not only the expression time of the antithrombotic effect can be extended further, but also the hydrophilicity of the blood flow contact surface is achieved. The complex and the base material, which further suppressed the elution of the antithrombotic mucopolysaccharide from the blood flow contact surface and could further extend the time of onset of the antithrombotic effect,
It is presumed that crosslinks were formed between the complexes.

[0007] The hydrophilicity is achieved by IR or ES.
As a result of the confirmation by CA, it is presumed that this is based on the introduction of hydrophilic groups such as —COO, —CO, and —OH into the blood flow contact surface by the irradiation treatment with ultraviolet rays. In addition, the degree of formation of the hydrophilicity, water permeability height measurement,
It can be obtained by methods such as contact angle measurement and wet area measurement, and details of these methods will be described in Examples.
The degree of hydrophilicity employed in the present invention was determined by the evaluation of hydrophilicity by contact angle measurement shown in Example 2 as 68.2 ± 1.
1.7 to 32.1 ± 6.7 degrees, the hydrophilicity evaluation by measuring the wetting area shown in Example 3 was 130% to 734% as compared with the case where the composite treatment and the irradiation treatment were not performed. It is preferred that the evaluation of hydrophilicity by measuring the water permeability shown in Example 4 is about 3.5 ± 0.6 cm to 0.5 ± 0.6 cm. In addition, since the hydrophilic group is introduced into the blood flow contact surface, for example, in the priming operation of the blood flow contact medical member, an operation such as hitting the member is often necessary in order to remove bubbles. In addition, the blood flow contact member of the present invention has an improved hydrophilicity on the treated surface and is excellent in removing bubbles during priming operation.

[0008] The antithrombotic mucopolysaccharide used in the present invention comprises:
Preferable examples include one of antithrombotic polysaccharides containing sulfuric acid bonded in an ester-like manner, which is composed of a sulfuric acid ester of D-glucosamine and D-glucuronic acid in an α (1.4) bond. It is listed as.

The quaternary ammonium salts used in the present invention include those having the following structure.

Embedded image (Wherein R 1, R 2 and R 3 are an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms, and R 4 is an alkyl group having 1 to 25 carbon atoms. And each may be the same or different).

[0010]

Embedded image (In the formula, 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 or bromo. Specific examples of the quaternary ammonium salt having the structure of Chemical Formula 2 include benzyldimethyl myristyl ammonium chloride, benzyldimethyl stearyl ammonium chloride, and a mixture thereof. If the quaternary ammonium salt having the structure of Chemical Formula 2 is too hydrophobic, it is difficult to dissolve in a polar solvent,
If it is difficult to handle, and if the hydrophilicity is large, on the other hand, it is difficult to bond to a hydrophobic substrate, and therefore, those having an alkyl carbon chain of 14 to 18 are preferable because they have appropriate hydrophobicity.

The quaternary ammonium salt and the antithrombotic mucopolysaccharide complex are required to have the quaternary ammonium salt in the complex in order to achieve a good effect. 53 to 77% by weight of the total amount of the complex, preferably 60%
７０70% by weight.

The complex of the quaternary ammonium salt and the antithrombotic mucopolysaccharide used in the present invention is dissolved in an organic solvent such as isopropanol or a mixture of isopropanol and other lower alcohols, benzene, DMF, THF and chloroform. It is used in the form of a solution or an aqueous dispersion. In addition, the preferable amount of application varies depending on the type of the base material constituting the blood flow contact medical member to be applied.For example, in the case of an arterial filter which is a product related to cardiopulmonary bypass, from the viewpoint of efficacy and safety. When the base material of the blood flow contact medical member is PC (polycarbonate), 0.027-0.
076 (IU / cm ² ), and when the substrate is PET,
0.087 to 0.217 (IU / cm ² ) is preferable.

The amount of UV irradiation increases the hydrophilicity of the mucopolysaccharide-treated substrate with an increase in the amount of the applied antithrombotic mucopolysaccharide. The improvement in sex remains at a certain point and does not increase any further. Also, under the condition of the same irradiation amount of ultraviolet rays,
The blood flow contact surface showed higher hydrophilicity as the amount of the applied antithrombotic mucopolysaccharide increased.

Further, the preferable range of the irradiation amount of the ultraviolet rays differs depending on the type of the base material and the type of the complex of the quaternary ammonium salt and the antithrombotic mucopolysaccharide. Determined in consideration of safety. Therefore, irradiation of a product in which the complex is applied to a blood contacting member having a blood contacting surface made of a polymer material such as polypropylene, silicone, or polyethylene or stainless steel or the like is performed by ultraviolet irradiation and material deterioration (safety). ) Is taken into account to determine the preferred range of UV light,
It is 1 to 5 J / cm ² at a wavelength around 3.7 nm. For example, in the case of the coating amount as described above, the preferable UV irradiation amount for imparting hydrophilicity to the polyester mesh and the polycarbonate mesh used for the blood filter is 1.2 to 4.2 (wavelength around 253.7 nm, respectively). J
/ cm ² ) 1.8 to 3.6 at a wavelength of around 253.7 nm
(J / cm ² ).

In addition, the disposable medical device is not limited to the blood contact member to which the present invention is applied. In the disposable medical device, the amount of the mucopolysaccharide complex to be applied is determined in consideration of the elution of the complex from the substrate and the change in the pH value of the substrate. Then, the amount of ultraviolet irradiation is preferably 1 to 5 J / cm2 at a wavelength of 253.7 nm. That is, if the amount of ultraviolet irradiation is less than the above range, the complex is eluted from the base material much, and the dissolution test or the hemolysis test based on the disposable product which defines the product quality and test method for safety etc. On the contrary, when the UV irradiation amount is larger than the above range, the change in the reference pH value becomes large, which is not preferable. Note that the amount of irradiation of ultraviolet rays in the present invention is defined by the following formula (A). UV irradiation dose (J / cm ² ) = UV irradiation intensity (mW / cm ² ) × time (sec) （1000 (A)

In the present invention, ultraviolet irradiation is most preferable as compared with radiation and electron beam for the following reasons. (1) The ultraviolet irradiation device is excellent in safety, the irradiation operation itself is easier than other radiation irradiation devices, and irradiation maintenance and management are simple. (2) When ultraviolet rays such as γ-rays are used, the substrate irradiated with the ultraviolet rays in order to suppress the deterioration of the material is required to have a uniform grade for the deterioration. However, the blood flow contact member, which is the object of the present invention, especially the product used in connection with cardiopulmonary bypass has a large number of parts, and it is very difficult and costly to mold it with a uniform grade substrate. On the other hand, the ultraviolet irradiation employed in the present invention can suppress the deterioration of the material lower than other ultraviolet rays, so that the deterioration of the base material due to the irradiation is small,
Since it is not necessary to select a radiation-resistant grade uniform material as the base material constituting the blood flow contact member, the degree of freedom in designing the blood flow contact member can be increased and the cost can be reduced. (3) Third, it is possible to locally modify the surface. Ultraviolet rays such as radiation will penetrate most medical substrates, so it is extremely difficult to partially hydrophilize the product coated with the complex by irradiation of ultraviolet rays such as radiation, or to improve the dissolution property. Although it is difficult, ultraviolet rays are harder to penetrate the base material than radiation. Therefore, it is possible to modify the surface of only a necessary part of the blood flow contact member by partially irradiating. As the ultraviolet irradiation device used in the present invention, a device having a wavelength range of 180 to 365 nm can be used. However, if an irradiation device mainly having a wavelength of about 253.7 nm is used, a measuring device for the wavelength will have a shorter wavelength. It is more preferable because it can be easily and inexpensively obtained as compared with a measuring device.

The antithrombotic mucopolysaccharification treatment of the blood flow contact medical member of the present invention can be applied to any part or material of the blood flow contact medical member. Components, specifically blood pumps,
Heparinization treatment of a heat exchanger, a circuit tube, an arterial filter, a membrane oxygenator, a pump tube, a blood reservoir, a cannula and the like can be mentioned.

[0018]

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

Example 1 Preparation of Benzalkonium Chloride (Quaternary Ammonium Salt) -Heparin Complex (1) The ratio of sodium herine to quaternary ammonium salt was 1: 3.2. (2) Adjustment of heparin sodium A required amount of heparin sodium was fractionated, and 0.03 M NaC
dissolved in 1 aqueous solution. The concentration at that time is 5.64 mg / m
l. (3) Adjustment of Quaternary Ammonium Salt A required amount of the quaternary ammonium salt was taken and dissolved in a 0.03 M NaCl aqueous solution. The concentration at that time is adjusted to 9.9 mg / ml. (4) The adjusted products of (2) and (3) were
After heating to ６０60 ° C., they were mixed and heated with stirring for several minutes. (5) Transfer the solution prepared in (4) to a heating chamber (40 to 6).
(0 ° C.) for several hours to form a benzalkonium chloride (quaternary ammonium salt) / heparin complex. (6) The benzalkonium chloride (quaternary ammonium salt) -heparin complex obtained in the above (5) contains benzalkonium chloride (quaternary ammonium salt) at a maximum value of 69.
It contained 79% by weight, a minimum of 59.81% by weight, a maximum of 38.9% by weight of heparin and a minimum of 29.5% by weight. This complex has been found to have limited solubility in polar organic solvents such as methanol, ethanol and isopropyl alcohol, or in organic solvents including said solvents.

Example 2 Evaluation of Hydrophilicity by Contact Angle Measurement After the polycarbonate sheet was treated with the benzalkonium chloride (quaternary ammonium salt) / heparin complex obtained in Example 1, ultraviolet irradiation (1.2 to 1.2) was performed. 3.6 J / cm2)
Only the treated sheet (hereinafter, referred to as sheet 1) and the benzalkonium chloride (quaternary ammonium salt) / heparin complex of the sheet 1 are subjected to ultraviolet irradiation (1.2 to 3.6 J / cm 2). The untreated sheet (hereinafter referred to as sheet 2) and the sheet 1 treated with benzalkonium chloride (quaternary ammonium salt) -heparin complex were also irradiated with ultraviolet rays (1.2 to 3.6 J / cm).
2) A sheet that was not treated (hereinafter, referred to as sheet 3) was used as a test sheet.

A water solution having a water temperature of 20
20 μl of reverse osmosis water at ２５25 ° C. was added dropwise. Ten seconds after dropping, the contact angle was measured at a contact angle measurement of θ = 2 tan ⁻¹ (2 h / △) (h: height of the drop, Δ: diameter of the drop). Sheet 1 68.2 ± 11.7 to 32.1 ± 6.7 degrees Sheet 2 71.2 ± 5.3 to 75.8 ± 5.8 degrees Sheet 3 85.2 ± 4.0 degrees

Example 3 Evaluation of Hydrophilicity by Measurement of Wet Area Sheet 1, Sheet 2 and Sheet 3 were used as test sheets. 20 μl of reverse osmosis water at a water temperature of 20 to 25 ° C. was used as a test solution on each of these sheet surfaces (the ultraviolet irradiation was performed at 1.2 to 7.2 J / cm 2) as in Example 2.
Was added dropwise. Four minutes after the dropping, the wet area of the dropping solution was measured by photography from a certain height. Contact angle measurement: The contact angle was measured at θ = 2 tan ⁻¹ (2 h / △) (h: height of the droplet, Δ: diameter of the droplet). In addition, the height of the photograph was evaluated in the case of the sheet 1 and the sheet 2 using the case of the sheet 3 as a control, and thus the height of the photograph was set to an arbitrary height. Sheet 1 130% to 734% Sheet 2 115% to 138%

Example 4 Evaluation of Hydrophilicity by Measurement of Water Permeability Height As a test method, an apparatus shown in FIG. 1 was used, and the following processes (1) to (5) were employed. (1) An adhesive is applied to the end surface of the connector 3 having an inner diameter of 12 mm. (2) A polyester mesh 2 of the following (A), (B) or (C) is adhered to the adhesive surface as a sample. (3) FIG. Connect to the device and fill the solution to the end face of the polyester mesh. (4) At the cylindrical location 1, the test solution is 1.5 cm / min.
(5) Record the solution filling height when the sample was broken through. In the test method, the diameter of the cylindrical portions 1 and 4 was 2.8.
cm, and the two cylindrical portions 1 and 4 are in communication so that the liquid can move freely. In addition, as a test solution, 20 to 25
C. reverse osmosis water was used. As a sample, a polyester mesh having a mesh pore size is used. Sample (A) is heparin-treated + UV irradiation (1.2 to 7.2), sample (B) is only heparin-treated, and sample (C) is Neither heparin treatment nor UV irradiation is performed. Evaluation of hydrophilicity by measuring the water permeability height for each sample,
It was as follows. Sample (A): 3.5 ± 0.6 cm
０．５0.5 ± 0.6 cm Sample (B): 3.4 ± 0.6 cm to 2.8 ± 1.0 cm Sample (C): 9.9 ± 1.2 cm

[0024]

According to the present invention, a complex of a quaternary ammonium salt and heparin is more firmly bound to a blood flow contact surface of a blood flow contact medical member, whereby the complex can be removed from the blood flow contact medical member. It is possible to provide a heparin-treated blood flow contact medical member in which elution is further suppressed, the time for developing the antithrombotic effect can be further extended, and the hydrophilicity of the blood flow contact surface is also improved, and a method for producing the same. Was.

[Brief description of the drawings]

FIG. 1 is a view for explaining an apparatus for measuring a water permeation height in Example 4.

[Explanation of symbols]

 1 Cylindrical place 2 Polyester mesh 3 Connector 4 Cylindrical place

Claims (10)

[Claims] The present invention is characterized in that a complex of a quaternary ammonium salt and at least one antithrombotic mucopolysaccharide applied to a blood flow contact surface of a blood flow contact medical member is irradiated with ultraviolet light. Blood flow contact medical member. 2. The method of claim 2, wherein the at least one antithrombotic mucopolysaccharide is
The blood flow contact medical member according to claim 1, which is heparin. 3. The blood flow contact medical member according to claim 1, wherein the ultraviolet light has a wavelength of about 253.7 nm. 4. The blood flow contact medical member according to claim 1, wherein the irradiation amount of the ultraviolet light is 1 to 5 J / cm ² at a wavelength of about 253.7 nm. 5. A hydrophilicity measured by a contact angle of 68.2 ± 1.
The blood flow contact medical member according to claim 1, wherein the angle is 1.7 to 32.1 ± 6.7 degrees. 6. The hydrophilicity measured by the wetting area is 1.3 to 7.3 of the wetting area of the blood flow contact medical member not irradiated with ultraviolet light.
The blood flow contact medical member according to any one of claims 1 to 5, which has a wet area four times as large. 7. The hydrophilicity measured by the water permeability height is 3.5.
The thickness is ± 0.6 cm to 0.5 ± 0.6 cm.
The medical member for blood flow contact according to any one of the above. 8. A fourth blood flow contact surface of the blood flow contact medical member.
A method for producing a blood flow contact medical member, comprising applying a coating solution containing a quaternary ammonium salt and at least one antithrombotic mucopolysaccharide, and irradiating the applied surface with ultraviolet rays. 9. The method according to claim 8, wherein the ultraviolet light has a wavelength of about 253.7 nm. 10. The method for producing a blood flow contact medical member according to claim 8, wherein the amount of ultraviolet irradiation is 1 to 5 J / cm ² at a wavelength of about 253.7 nm.