JPH053916A - Coating material for electrolyte sensor for blood - Google Patents

Abstract

PURPOSE:To improve the antithrombogenic property and permeability of electrolyte by mixing high polymer raw material which is rich in mechanical strength and has water retaining property with quaternary ammonium salt heparinate to form a coating material for an electrolyte sensor for blood. CONSTITUTION:High polymer raw material which is rich in mechanical strength and has water retaining property, polyethylene oxide segmented nylon 610 (hereinafter referred to as PEO-Nylon 610) and quaternary ammonium salt heparinate, for example, a heparinate compound such as benzal chloride conium or the like are mixed to form a coating material for an electrolyte sensor for blood. In this case, the molecular weight of PEO is 2000-600, and the weight ratio is about 20-80%. The material is coated on an electrolyte sensor for blood. Thus, heparin is continuously emitted for a long time so as to transmit electrolyte enough.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a heparin sustained-release material used by coating the surface of an electrolyte sensor in blood.

[0002]

Medical devices used in blood include blood vessel catheters, cannulas, heart-lung machines, blood vessel bypass tubes, aortic balloon pumping, monitoring tubes and the like.

It is well known that, in general, when a medical material is brought into contact with blood, the blood is easily coagulated and a thrombus is formed on the surface of the material.

To prevent this, synthetic polymers have been studied for the purpose of designing a material that reduces the adhesion of blood components and weakens the interaction with blood components, and molding or applying this to medical devices for use. Has been done. For example, silicone-based polymers, fluorine-based polymers, polyhydroxymethylmethacrylate, polyvinyl alcohol, ethylene vinyl alcohol copolymers, segmented polyurethane with hydrophilic-hydrophobic microdomain structure, and the like. Also, a method of physically or chemically binding a physiologically active substance that prevents blood coagulation to the surface of the material to exert antithrombotic property by using this force has been studied.

In reality, the function of synthetic polymers cannot be said to be sufficient depending on the conditions of use, and it seems that they can be used in combination with physiologically active substances such as heparin.

On the other hand, heparin acts on antithrompine 3 which is a blood coagulation inhibitor, and remarkably enhances the inhibitory effect of antithrompin 3, and is therefore used as a powerful and reliable method for preventing thrombosis. However, when administered systemically, there is a risk that many hemorrhagic foci are generated, and the half-life in the body is not so long as 4 to 6 hours, and continuous administration is required. For this reason, studies have been conducted to immobilize heparin on a material for the purpose of preventing blood coagulation and achieving medical purposes by releasing heparin systemically without releasing it systemically.

For example, a mixture of polymer and heparin

[0008] In this case, since heparin is water-soluble, if it is applied to the surface of the polymer, it will dissolve immediately and lose its effect. Therefore, it is devised that the material is sufficiently kneaded and gradually leached to the surface. A solution of an ionic bond complex of a quaternary ammonium salt and heparin is applied to the surface of the medical device. Alternatively, a mixed solution of a suitable polymer and an ionic bond complex is formed or applied to the surface of another medical device. A cationic residue is chemically introduced into the polymer, and heparin is ionically bonded thereto. Heparin is covalently attached to the polymer. And so on.

Materials widely used in clinical practice today (eg, silicone rubber, polycarbonate, Teflon,
The surface of polyethylene, soft polyvinyl chloride, etc.) can be easily heparinized. That is, the surfaces of various cardiovascular catheters, thermodilution measuring catheters, drainage tubes, aortic bypass tubes, guide wires, etc. are heparinized and used clinically. However, since this is only applied to the surface of the material, heparin elutes in a short time, the antithrombotic property does not continue, and it is said that it is about one day at most.

In order to improve the drawback of (1), heparin is bound to the inside of the material and polyvinyl chloride is grafted with a copolymer of methoxypolyethylene glycol methacrylate and quaternized dimethylaminoethyl methacrylate, and heparin is ionically bonded to the grafted copolymer. Is sold by Toray Industries, Inc. under the trademark Anthron.

[0011] Although the elution of heparin is small, it seems that it has not yet been put into practical use due to the problem that the anticoagulant activity of heparin is reduced by covalent bonding.

[0012] The point is that an effective amount of heparin is continuously released for a long period of time, which is considered to be sufficiently expected for practical use.

[0013]

As a material used for the blood electrolyte sensor, when applied to the sensor surface, thrombus formation is prevented on the sensor surface, and responsiveness reduction due to thrombus does not occur and it is applied to the sensor surface. It is necessary that the applied material is sufficiently permeable to the electrolyte and the like in blood and does not deteriorate the response of the sensor.

From this point of view, when the heparinized material is examined, it can be expected that the prevention of blood coagulation can be expected but the permeability is insufficient. That is, although the conventional heparinized materials have some clinical usefulness in terms of antithrombotic properties, they are still insufficient for blood electrolyte sensors.

In order to solve these drawbacks, the present inventor has arrived at the present invention as a result of extensive studies on a material that can be expected from both aspects of antithrombogenicity and permeability such as an electrolyte.

It is an object of the present invention to provide a material which releases heparin continuously for a certain period of time to exhibit antithrombogenicity and has good permeability to electrolytes and the like, which is suitable as a coating material for an electrolyte sensor in blood. .

[0017]

[Means for Solving the Problems] An ionic bond complex of a quaternary ammonium salt and heparin is a material that is easy to use because it dissolves in various organic solvents and can be easily applied to medical materials. As shown, the permeability of electrolytes is not sufficient, and the elution of heparin occurs rapidly in biological fluids, and the antithrombotic effect cannot be expected to continue. It's difficult.

On the other hand, a material having suitable mechanical strength and moisture retention when formed into a film is generally known. This can be expected as an ion permeable material. For example, polyethylene oxide segmented nylon 610 (hereinafter P
EO-Nylon 610) is configured as shown in FIG. That is, the nylon segment works effectively for forming a film, shares the mechanical strength of the film, and the polyethylene oxide segment forms a favorable ion permeation channel by containing water, so that a film with good responsiveness is formed when coated on the sensor. . However, from the viewpoint of the blood coagulation preventing function, it is inferior to the quaternary ammonium salt-heparin and the ionic bond complex, and is not sufficient. Therefore, the inventors of the present application conducted a diligent study under the idea that the advantages of the two could be utilized by mixing them to compensate for their disadvantages, and as a result, a mixed film of both was effective for a blood electrolyte sensor. It has been found that it can be a different coating.

That is, the present invention is a material for a sensor for cleaning in blood which is a mixture of a polymer material having high mechanical strength and water content and a quaternary ammonium salt heparinate.

Here, as the quaternary ammonium salt,
Benzalkonium chloride, tridodecyl ammonium chloride, methyl tricaprylammonium chloride,
Examples include cetylpyridinium chloride, cetyltrimethylammonium bromide, cetylammonium bromide and the like. Each of these has a quaternary ammonium residue and ionically bonds with an anion residue of heparin to form a water-insoluble complex (hereinafter abbreviated as heparinized compound).
The quaternary ammonium salt is not limited to those listed above.

PEO-Nylon610 is

[Chemical 1] It is a polymer compound composed of repeating units of (A), which is a crystalline-amorphous block copolymer composed of a hydrophilic polyethylene oxide (abbreviated as PEO) segment portion (A) and a hydrophobic nylon 610 segment portion (B). By changing the molecular weight or weight ratio of (A), polymers having different mechanical strength and ion permeability can be obtained.

What is used in the present invention is PEO.
Has a molecular weight of 1000 to 6000, preferably 2000 to 6000, and a weight ratio of 10 to 90%, preferably 20 to 80%. If the molecular weight and weight ratio of PEO are small, it becomes difficult for the ions to pass, and if the molecular weight of PEO is large, the ions can easily pass but the mechanical strength becomes weak. Dissolved 2w / v% of those with different weight ratio hexafluoroisopropanol in the case of PEO of molecular weight 3000 as an example, which I _S F
The results of comparing the response time to the pH change in the buffer by dropping two drops from the injection needle on the gate surface of ET are shown in FIGS. 2 to 4. When the PEO ratio is 0%, the response is extremely poor (FIG. 2). ), And the responsiveness improves as the PEO ratio increases to 21% and 51.5% (Figs. 3 and 4). The ratio of the heparinized product-PEO-Nylon 610 mixed solution applied to the surface of the electrolyte sensor is 1 to 90%, preferably 10 to 80% as a heparinized product. When the ratio of the heparinized product is too large, the film forming property is deteriorated, the responsiveness is deteriorated, the release of heparin occurs rapidly, and the antithrombotic effect cannot be expected to continue. When the ratio of heparinized product is small, the responsiveness is improved but the antithrombotic property is decreased.

The concentration as a mixed solution is 0.1 to 40%, preferably about 1 to 30%. When the concentration is low, the antithrombotic effect is not achieved, and when the concentration is high, there are drawbacks such as difficulty in application and poor responsiveness.

[0024]

When the present invention is applied to a blood electrolyte sensor and used, it releases heparin continuously for a long time and sufficiently permeates the electrolyte.

[0025]

【Example】

Example 1 The heparinized product was dissolved in a mixed solvent of 3 volumes of methylene chloride and 2 volumes of hexachloroisopropanol to 2 w / v% and I _S
On the gate insulating film (silicon nitride) of the FET (ion sensor having a gate insulating field effect transistor structure), three drops were dropped with an injection needle and the solvent was evaporated to cover the heparinized product. When the response of this I _S FET to the pH change was examined in the buffer, the PH change PH6.86 → P
95% response to H9.18 took 3 minutes.

Further, PEO-Nylon610 (PEO molecular weight 30
00, the same concentration of the mole fraction 51.5%) in the same solvent dissolving I _S
The FET gate insulating film is coated with 3 drops by an injection needle to evaporate the solvent and to change the pH in the same manner (PH6.86 → PH9.18).
When the responsiveness to was examined, 95% response was shown in 15 seconds.

On the other hand, a part of the heparinized product is used as PEO-Nyl.
In the case of replacement with on610 and 70% heparinized compound, similarly, three drops are formed on the I _S FET gate insulating film to form a coating,
When the responsiveness to the change in PH (PH6.86 → PH9.18) was examined, it was 95% and was about 1 minute.

Example 2 PEO-Nylon610 (PEO molecular weight 3000, weight ratio 5
1.5%) is dissolved in a mixed solvent of 3 volumes of methylene chloride and 2 volumes of hexachloroisopropanol to give a 0.75 w / v% solution, which is applied and dried on the inner surface of a glass test tube having an inner diameter of 10 mm and a length of 100 mm. Platelet rich plasma 0.5m
Then, 0.5 ml of M / 40 calcium chloride was added, and the time until the plasma coagulated at 37 ° C. was measured and it was 5 minutes. When the same time was measured for the uncoated glass test tube, it was 3 minutes.

On the other hand, the benzalunium chloride-heparin ion-bonded complex was dissolved in methylene chloride to 0.75 w / v% and coated on the inner surface of a glass test tube in the same manner as above, dried and then added with 0.5 ml of platelet-rich plasma and then M / 40 Ca Cl. ₂ 0.5 ml was added and the time until the plasma clots at 37 ° C was measured.
It did not solidify after 24 hours.

Example 3 The benzalunium chloride-heparin ion-bonded complex was dissolved in a mixed solvent of 3 volumes of methylene chloride and 2 volumes of hexachloropropanol to prepare a 0.75 w / v% solution.

Separately, using the same mixed solvent, benzalunium chloride-heparin ion-bonded complex and PEO-Nylon610.
(PEO molecular weight 3000, weight ratio 51.5%) was mixed and
A solution containing 75% and 1.0% was prepared.

Each solution was applied to the inner surface of a glass test tube having an inner diameter of 10 mm and a length of 100 mm, filled with 1 N sodium chloride aqueous solution and left at 37 ° C. After 50 hours, the sodium chloride aqueous solution was discarded and tested. The inner surface of the tube was thoroughly washed with ion-exchanged water and dried at 60 ° C.

0.5 ml of bovine platelet-poor plasma was added to each of the test tubes treated as described above, followed by 0.5 m of M / 40 potassium chloride.
In addition, the time required for plasma to coagulate at 37 ° C. was measured, and it was 3 minutes for the heparinized product alone.
On the other hand, in the case where the mixed film of the heparinized product and PEO-Nylon610 was applied, coagulation did not occur even after 20 hours.

Example 4 The benzalunium chloride-heparin ion-bonded complex was dissolved in a mixed solvent of 3 volumes of methylene chloride and 2 volumes of hexachloroisopropanol to prepare a 2 w / v% solution.

Separately, using the same solvent, 2 w / v% of benzalyunium chloride-heparin ion-bonded complex and 3 w / v of PEO-nylon 610 (PEO molecular weight 3000, mole fraction 51.5%).
A mixed solution containing v% was prepared. A nylon film having a diameter of 8 mm was prepared by repeating the process of immersing the nylon film in each solution, pulling it up, and drying it twice.

Each disc was immersed in 10 ml of bovine platelet-poor plasma at 37 ° C., and the change in heparin concentration in plasma was measured. Results are shown in FIG. In the case of only the benzalunium chloride-heparin ion-bound complex, rapid elution of heparin occurs, and the elution rate of heparin decreases with time. On the other hand, in the PEO-Nylon610 mixed film, the rapid elution of heparin is suppressed.

[0037]

EFFECTS OF THE INVENTION According to the present invention, a coating material for an electrolyte sensor in blood, which has excellent antithrombogenicity for a long period of time and has good permeability of electrolytes and the like, can be obtained.

[Brief description of drawings]

FIG. 1 is a diagram showing the structure of PEO-Nylon610.

FIG. 2 is a diagram showing a response time to PH change of an I _S FET coated with PEO-Nylon610 having a PEO ratio of 0%.

FIG. 3 is a graph showing a response time of an I _S FET coated with PEO-Nylon610 having a PEO ratio of 21% with respect to a change in PH.

FIG. 4 is a graph showing a response time of an I _S FET coated with PEO-Nylon610 having a PEO ratio of 51.5% with respect to a change in PH.

FIG. 5 is a view showing changes in heparin concentration in plasma when only a benzalunium chloride-heparin ion-bonded complex and a mixture of this and PEO-Nylon610 are adhered to a nylon disc and immersed in plasma.

Claims (2)

[Claims] 1. A coating material for an electrolyte sensor in blood, which is obtained by mixing a polymer material having high mechanical strength and water content with a quaternary ammonium salt heparinate. 2. The coating material for an electrolyte sensor in blood according to claim 1, wherein the polymer material is polyethylene oxide segmented nylon 610.