JPS5950339B2 - Cellulose-based antithrombotic medical material - Google Patents

Description

[Detailed description of the invention] The present invention relates to a novel antithrombotic medical material.

More specifically, the present invention relates to an antithrombotic medical material made of cellulose or a derivative thereof and having urokinase immobilized on its surface.

In recent years, polymer materials have come into use in the field of medical materials, but when polymer materials are used in areas that come into direct contact with blood, such as artificial blood vessels, catheters, artificial kidneys, artificial hearts, artificial lungs, and vascular suture systems. , there is a problem of causing thrombus formation.

Thrombus formation means that a complex series of enzymatic reactions in the blood coagulation system ultimately converts fibrinogen into insoluble fibrin.

The development of conventional antithrombotic medical materials focused on this blood coagulation system and applied heparin, which acts as an inhibitor of blood coagulation enzymes, to the material surface to inhibit the conversion of fibrinogen to fibrin.

In the body, fibrin is constantly formed at a constant rate in the blood coagulation system, and at the same time, once formed, fibrin is constantly dissolved in the fibrinolytic system (fibrinolytic system), thereby maintaining an equilibrium state. .

The present inventors focused on this fibrinolytic system and studied the application of urokinase to the surfaces of various materials, and succeeded in developing a new material that is highly effective as a blood contact material.

That is, the present invention provides an antithrombotic medical material made of cellulose or its derivatives and having urokinase immobilized on its surface.

In the present invention, cellulose refers to glucose containing β-1.
4-Glucoside bonded polysaccharides such as momen, hemp,
Contained in plants such as wood.

Cellulose can be processed into various shapes such as fibers, films, membranes, permeable membranes, tubes, and powders by dissolving it as a cuprammonium solution, viscose, etc., and then regenerating it.

By esterifying or etherifying some or all of the hydroxyl groups of cellulose, it can be converted into a cellulose derivative.

Esterified derivatives of cellulose include cellulose acetate, cellulose propionate, cellulose butyrate, nitrocellulose, cellulose sulfate, cellulose phosphate,
Examples include cellulose dithiocarboxylate.

Examples of etherified derivatives of cellulose include methylcellulose, ethylcellulose, benzylcellulose, tritylcellulose, dimethylcellulose, and the like.

These cellulose derivatives can be processed into various shapes depending on the purpose, such as fibers, films, membranes, permeable membranes, tubes, and powders.

Fibrinolytic active substances in the present invention refer to synthetic and natural substances involved in fibrin dissolution, such as proteins such as urokinase, streptokinase, plasmin, brinolase, mefenamic acid, flufenamic acid, fenbutacin, oxyphenbutylene, etc. cin, indomethacin, α-n-propyl-P-bromocinnamic acid, 3-(1
・Synthetic substances such as 1,3,3-tetramethylbutyl)-salicylic acid are mentioned.

For example, urokinase can be produced by covalent bond method, ionic bond method,
It is immobilized on the surface of cellulose or its derivatives by methods such as physical adsorption.

The covalent bonding method is a method in which a covalent bond is formed between a highly reactive surface functional group and urokinase.

Examples of the reactive functional group include an amine group, a carboxyl group, an azide group, a diazonium salt group, an isocyanate group, an acid chloride group, an acid anhydride group, a formyl group, a bromoacetyl group, and a carbonate group.

These functional groups may exist before being processed into the shape of fibers, films, membranes, permeable membranes, tubes, etc., or may be introduced onto the surface through surface treatment after processing. Good too.

The ion bonding method is a method in which an ionic bond is formed between urokinase and an ion exchange group such as an ammonium group, sulfonate group, or carboxylate group present on the surface.

The physical adsorption method is a method in which the material is adsorbed onto a surface using, for example, hydrophobic bonding, van der Waalska, or the like.

The surface of a material on which urokinase is immobilized in this manner and made of cellulose or a derivative thereof exhibits excellent antithrombotic properties.

The antithrombotic medical material of the present invention is useful as an artificial blood vessel, a catheter artificial valve, an artificial heart, an artificial lung, an artificial kidney, a blood vessel suturing system, and the like.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples.

In addition, antithrombotic property refers to fibrinolytic activity (fibrinolysis).
Based on the measurements.

In other words, the joint venture, the jointly edited "Clinical Testing Law Proposal" revised 2nd edition.
Referring to the 7th edition (Metal Publishing) VI-100, measurements were made using a fibrin plate prepared by adding a thrombin physiological saline solution to a human fibrinogen aqueous solution.

The sample piece was placed on a fibrin plate and left at 37°C for 24 hours, and then the fibrinolytic activity was measured based on the degree of dissolution of the fibrin membrane around the sample piece.

When repeatedly performing activity measurements on the same sample, the sample piece was washed with physiological saline and placed on a new fibrin plate.

Example 1 A cellophane film was placed in a 2% bromcyan aqueous solution, and while stirring, a 2N-NaOH aqueous solution was added dropwise to adjust the temperature to 10-12.

The treated film was washed with cold water and then with 0.1M phosphate buffer (pH 6.2).

After washing, the film was immersed in 0.1M urokinase phosphate buffer (pH 6, 2,600 units/m1) at 7°C.
I left it for 24 hours.

The obtained film was washed with 0.1M phosphate buffer and then with physiological saline solution, and then the fibrinolytic activity was measured on a fibrin plate.

A fibrin membrane was dissolved in a circular shape of 2.4 cm in diameter around the film piece (circular with a diameter of 1 crn) on which urokinase was immobilized.

Example 2 A nacetylcellulose film was immersed in a urokinase physiological saline solution (600 units/ml), then the film was taken out and air-dried in a cold place.

Next, the air-dried film was immersed in 1% glutaralde phosphate buffer (pH 7.0), and then left at 7° C. for 16 hours.

The obtained film was washed repeatedly with physiological saline to remove unreacted urokinase and glutaraldehyde.

The urokinase-immobilized film piece (circular with a diameter of 1 cm) obtained as described above has a circumference of 2.2 cm.
The fibrin membrane was dissolved into a circular shape.

Example 3 Physiological saline solution of urokinase (1200 units/ml)
Carboxymethyl cellulose was added to 5 ml to make a slurry.

To this was added 50 mg of 1-cyclohexyl 3-(2-morpholininoethyl)-carposiimido-meth-p-)luenesulfonate, and the mixture was stirred at 7°C for 24 hours.

The product was thoroughly washed with physiological saline and then freeze-dried.

When the obtained powder was placed on a fibrin plate and activity was measured, it was observed that the fibrin film around the powder had dissolved.

Fibrinolytic activity remained even after repeated activity measurements on the same powder sample five times.

Example 4 The same procedure as in Example 3 was carried out except that aminoethyl cellulose was used instead of carboxymethyl cellulose.
Urokinase was immobilized on aminoethylcellulose.

The resulting powder showed fibrinolytic activity.

Claims (1)

[Claims] 1.An antithrombotic medical material made of cellulose or its derivatives and having urokinase immobilized on its surface.