JPS6248630A - Heparin-containing ion complex - Google Patents

Abstract

PURPOSE:To provide the titled complex capable of imparting antithrombogenic property to the necessary part in living body without deteriorating the function of the body, by bonding heparin with glycidyl trialkyl ammonium halide through ionic bond. CONSTITUTION:The objective novel complex is composed of heparin and glycidyl trialkyl ammonium halide (e.g. glycidyl trimethyl ammonium chloride) bonded together through ionic bond. An antithrombogenetic material or an anticoagulant is indispensable for the remedy of circulatory diseases. Heparin is being used singly for the purpose, however, the agent is liable to cause hemorrage and sometimes cause uncontrollable bleeding. The complex of the present invention can be produced in the form of easily handleable solution simply by mixing a heparin solution with a solution of glycidyl trialkyl ammonium halide. When the solution of the complex is brought into contact with the inner wall of a blood vessel, only the inner surface can be made locally anti-thrombogenetic while keeping the thrombogenetic property of the outer surface of the vessel.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a heparin-containing ionic complex consisting of heparin and glycidyl trialkylammonium halide that imparts novel antithrombotic properties.

(Prior art) Antithrombotic materials or anticoagulants are essential for the treatment of circulatory system diseases. Conventionally, heparin was administered alone, but this often caused a tendency for bleeding. There were adverse effects such as the blood becoming unstoppable when bleeding occurred. The present inventor has studied various materials with continuous antithrombotic properties that are free from such drawbacks (for example,
7-65054, Japanese Patent Application No. 60-163028, and Japanese Patent Application No. 60-163028) We have recently discovered a new medical material that imparts novel antithrombotic properties.

(Problems to be Solved) The present invention provides antithrombotic properties to natural polymers and synthetic polymer materials using a simple method,
To provide a novel anti-blood medical material that imparts anti-blood properties to tu) without impairing the functions of the living body.

(Means for Solving the Problems) The present invention is a heparin-containing ionic complex imparting antithrombotic properties, characterized by ionic bonding of heparin and glycidyl trialkylammonium halide. However, the glycidyl trialkylammonium halide in the present invention is a quaternizing agent having an epoxy group, particularly glycidyl trialkylammonium halide (GTMA).
C) etc. are advantageous. GTMAC is toxic when injected into living organisms alone, but shows no toxicity when formed into an ionic complex with heparin, so the complex of the present invention can be safely used in living organisms.

The ionic complex of the present invention can be easily obtained by mixing an aqueous heparin solution and an aqueous glycidyl trialkylammonium halide solution.

That is, the heparin concentration is 0.01 to 20%, preferably 0.1
The ionic complex can be easily prepared in the form of an aqueous solution by mixing ~5% heparin aqueous solution with a glycidyltrialkylammonium halide aqueous solution having a glycidyl trialkylammonium halide concentration of 0.001 to 15%, preferably 0.01 to 3%. You can get it at The solvent used to produce the complex of the present invention is not limited to water, but any solvent that dissolves heparin or glycidyl trialkylammonium halide can be used, and various buffer solutions can also be used. Further, the ion complex solution of the present invention may contain an excess of either heparin or ammonium halide, which does not participate in complex formation, in addition to the ion complex.

Since the ionic complex of heparin and glycidyl trialkylammonium halide of the present invention has an epoxy group, it easily reacts with various active hydrogens such as amino groups, carboxyl groups, and hydroxyl groups, resulting in natural polymer materials or synthetic polymers. Heparinization can be performed on molecular materials. Specifically, materials for heparinization include collagen, gelatin, cellulose, dextran, and chitosan.

These include partial hydrolysates of 2-hydroxyethyl methacrylate, polyvinyl alcohol, and polymethyl methacrylate.

Furthermore, blood vessels in which a thrombus has formed can be made to have antithrombotic properties again by being heparinized in 5 situ. That is, after the blood clot is removed, both ends of the necessary part of the blood vessel are closed off, the complex of the present invention is injected into this lumen, and after the reaction is completed, the unreacted material is washed thoroughly to perform a complicated surgery. The heparinized blood vessels obtained in this way are diluted with ionically bound heparin to prevent blood clotting, and endothelial cells gradually proliferate until natural antithrombotic properties are achieved. The antithrombotic effect of heparin is sustained.

Next, one embodiment of the present invention will be explained in detail with reference to examples.

Example Glycidyltrimethylammonium chloride (GT
MAC) Ig was dissolved in 100 ml of water to obtain a GTMAC solution.Meanwhile, 1.5 g of heparin was dissolved in 100 ml of water to obtain a heparin solution, and the GTMAC solution and the heparin solution were mixed. An inventive ionic complex was obtained.

A portion of a dog's jugular vein was tied at both ends to the length of ioam, and the vessel wall was incised to a length of approximately 2 m, and a brush was inserted into the incision to scrape off endothelial cells. This area has lost its antithrombotic properties due to the removal of endothelial cells.Next, the ionic complex solution of the present invention is injected into this blood vessel to cause the endothelial cells to detach and react with the exposed surfaces of collagen and elastic fibers. Excess solution was removed after minutes. Heparinization of the blood vessel wall, which had lost endothelial cells, was then completed by washing five times with physiological saline, and the incision was then sutured to restore blood flow.

After the endothelial cells were detached, those that were not treated with the ionic complex solution were used as the control standard. The control control immediately formed a thrombus and was occluded within 5 minutes. When heparinized with the ionic complex of the present invention, no thrombus was formed at all, and after 2 weeks, it was covered again with endothelial cells and showed good healing.

(Effects) As described above, the ionic complex of the present invention is easy to handle because it can be obtained in a solution state by simply mixing a heparin solution and a glycidyltrialkylammonium halide solution, and It is possible to heparinize the necessary parts of various synthetic polymer materials and natural polymer materials, and in particular, by bringing the ionic complex solution of the present invention into contact with the inner surface of the blood vessel and causing a reaction, the outer surface of the blood vessel can be locally treated with thrombi. This has the effect of making only the inner surface antithrombotic while maintaining its properties.

Claims (1)

[Scope of Claims] 1. A heparin-containing ionic complex imparting antithrombotic properties characterized by ionic bonding of heparin and glycidyl trialkylammonium halide.
C) Heparin-containing ionic complex 3 imparting antithrombotic properties according to claim 1, wherein the heparin-containing ionic complex is in the form of a mixed solution consisting of heparin and glycidyl trialkylammonium halide. Heparin-containing ionic complex imparting antithrombotic properties according to scope 1