JPS624042B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a polyion complex (hereinafter abbreviated as PC) with excellent antithrombotic properties, which is composed of dextran sulfate, heparin, chondroitin sulfate, and a deacetylated product of carboxymethyl chitin or a salt thereof, and the polyion complex. Concerning the manufacturing method of Tsukusu. PC is a complex obtained by reacting a positively charged polymer electrolyte and a negatively charged polymer electrolyte in a solvent. This PC reaction is very interesting as a reaction model for biological systems, as typified by the interaction between polysaccharides and proteins in living organisms. In recent years, materials obtained using this PC reaction have been attracting attention as functional materials for medical treatment or living organisms, such as dialysis membranes and ultrafiltration materials. When using a PC material as a biomaterial, it is essential that the constituent components of the PC or itself are compatible with the living body, non-toxic, and stable. In this respect, chitin is chemically and biologically stable and safe, and
If a PC were developed, it would be revolutionary. However, since chitin is extremely highly crystalline and has strong aminoacetyl group bonds, there is no solvent that can dissolve, disperse, or swell it as well as cellulose. That is, examples of solvents for chitin include dichloroacetic acid, sulfuric acid, and formic acid.
These solvents are associated with a decrease in the molecular weight and decomposition of chitin, and also have many problems in handling such as waste liquid treatment. Therefore, in order to solubilize chitin in a solvent, attempts have been made to synthesize soluble chitin derivatives by, for example, alkylation or acetylation treatment. However, so far only chitosan, which is a deacetylated product of chitin, and its derivatives have been proposed as solvent-soluble substances, and chitosan and sulfated polyvinyl alcohol have been proposed as chitin-based PC.
PC (JP-A-50-8879) and PC of chitosan and sulfated cellulose (JP-A-50-123179) have been provided. In the process of intensive research into the development of the use of chitin, the present inventors discovered that among chitin derivatives, deacetylated products of carboxymethyl chitin or its salts are soluble in acid or alkaline aqueous solutions, and that the deacetylated products are carboxymethyl chitin. It is an amphoteric polymer electrolyte that has both groups and amino groups, and can be obtained by reacting it with either dextran sulfate, heparin, or chondroitin sulfate.
It was discovered that PC has excellent biocompatibility and biostability as well as excellent antithrombotic properties,
This has led to the present invention. That is, the present invention provides a novel PC with excellent antithrombotic properties, which is obtained by reacting a deacetylated product of carboxymethyl chitin or its salt, which is amphoteric, with dextran sulfate, heparin, or chondroitin sulfate, and a method for producing the same. It provides: The deacetylated carboxymethyl chitin used in the present invention can be obtained, for example, by the following procedure. That is, chitin represented by the general formula () obtained by separating and purifying the shells of arthropods such as crabs and shrimps by conventional methods is carboxymethylated by reacting with monochloroacetic acid, etc., to obtain the general formula ( ) to obtain carboxymethyl chitin or a salt thereof containing the structural unit.

【formula】

[Formula] or

[Formula] (In the formula, M represents hydrogen, an alkali metal, an alkaline earth metal, or an ammonium group.) Carboxymethyl chitin or a salt thereof in the present invention is carboxymethyl per unit structure N-acetyl-D-glucosamine. The group is 0.1 to 1.0, preferably 0.3 to 1.0. Next, the carboxymethyl chitin or its salt is heated in an alkaline aqueous solution such as sodium hydroxide or potassium hydroxide to de-N-acetylate it, and the amphoteric polyelectrolyte soluble in the aqueous solvent of the present invention, that is, carboxymethyl A deacetylated product of chitin or its salt can be obtained. The degree of deacetylation of the deacetylated product of the present invention is 0.1 to 1.0, preferably 0.3 to 1.0. An example of producing a deacetylated product of carboxymethyl chitin is disclosed in Japanese Patent Application No. 161391/1983. The present invention also includes the contents disclosed in Japanese Patent Application No. 53-161391. Examples of typical structural units exhibiting cationic properties of the deacetylated carboxymethyl chitin of the present invention are as follows (the formulas are schematically shown).

【formula】

【formula】

[Formula] Dextran sulfate, heparin, and chondroitin sulfate, which are the other reactants for forming PC of the present invention, may be commercially available. Since all of the ionic polymer electrolytes of the present invention are soluble in aqueous solvents, PC can be easily produced without particularly using an organic solvent.
That is, the PC of the present invention is a PC produced by dissolving the deacetylated product of carboxymethyl chitin or a salt thereof in an aqueous solvent, and mixing and stirring a solution in which dextran sulfate, heparin, or chondroitin sulfate to be reacted with this is dissolved. can be obtained by over-separation and washing with water.
The aqueous solvent used is an acid or alkali aqueous solution, and the concentration of the aqueous solution may be arbitrary in view of the relationship with the viscosity of the solution, and is usually about 0.5 to 5%. Note that when the viscosity of the solution is high, care must be taken because it tends to become non-uniform PC or gel-like. In addition, the reaction temperature in this production may be 100°C or less because an aqueous solvent is used, but preferably 5 to 100°C.
It is 40℃. Confirmation of PC formation can be performed by elemental analysis, infrared spectroscopy and solubility testing. The PC of the present invention thus obtained has an intrinsic viscosity [η sp/c] of 0.1 to 20 at 20° C. as measured by an Ubbelohde viscometer. Although it is difficult to clearly express the structure of the PC of the present invention with a chemical formula, it is possible to combine -NH3, a deacetylated product of carboxymethyl chitin, and _-NH3 , which is a deacetylated product of carboxymethyl chitin, and a -NH3 product of heparin, chondroitin, or dextran sulfate.
It is thought to be an ion-bridged network structure mainly formed by electrostatic bonds with SO ₃ or -COO. The PC obtained by the present invention is soluble in an aqueous solution with a hydrogen ion concentration (PH) that dissolves the other side of the deacetylated product of carboxymethyl chitin or its salt, and is also soluble in an aqueous solution of a neutral salt. , it has extremely good workability. Therefore, the PC of the present invention can be easily made insoluble by dissolving it in the aqueous solution, making it into a film or fiber, and then desalting it. Moreover, insolubilization can be performed by heat treatment, ultraviolet treatment, and crosslinking agent treatment. The thus obtained PC molded article of the present invention has excellent chemical resistance and heat resistance, and is stable in vivo because it is derived from natural chitin.
Since it has antithrombotic properties and ionic groups, it can be used as microcapsule materials, dialysis membranes or ultrafiltration membranes, artificial organs, surgical materials, and other moisture-breathing materials. The present invention will be described in detail below with reference to Examples. Example 1 Commercially available dextran sodium sulfate (molecular weight 50
Manufactured by Hanui Chemical, S content 18.8%) 38g with water 1
dissolve in Next, 23 g of sodium salt of deacetylated carboxymethyl chitin (degree of carboxymethylation 0.5, degree of deacetylation 1.0, intrinsic viscosity 8.5) was dissolved in 2 parts of water, and the above aqueous solution of dextran sodium sulfate was slowly added while stirring. As it goes on, it becomes cloudy and further precipitates form. This precipitate was filtered, washed with water, further washed with ethanol, and dried to obtain a white solid, with a yield of 51
g was close to 100%. From the IR spectrum at 1510 cm ^-1 −NH ₃ , 1210,
Absorption of -SO ₃ was observed at 1040 cm ^-1 , and elemental analysis revealed that the S content was 12.0%, forming a polyion complex of approximately 1:1. The intrinsic viscosity of this material was 14.5 at 20°C in a 0.1N aqueous solution of caustic soda. Example 2 46 g of the deacetylated carboxymethyl chitin from Example 1 was increased and dissolved in 2 waters, and the same amount of dextran sulfate as in Example 1 was used, and the same operations as in Example 1 were carried out. The yield was 69g, which was close to 100%. From the IR spectrum at 1510 cm ^-1 −NH ₃ , 1210,
Absorption of -SO ₃ is observed at 1040 cm ^-1 , and the absorption is larger than in Example 1. According to elemental analysis, the S content was 9.0%, and a PC with a composition of approximately 1:2 (dextran/deacetylated product) was obtained. The intrinsic viscosity of this material was 13.2 at 20°C in a 0.1N aqueous solution of caustic soda. Example 3 10 g of sodium salt of deacetylated carboxymethyl chitin (degree of carboxymethylation 0.3, degree of deacetylation 0.5, intrinsic viscosity 9.0) was dissolved in 500 c.c. of water, poured into a glass plate, and dried at 40°C. do. Add this to 1% heparin, sodium aqueous solution (manufactured by Novo)
When immersed in 200c.c. at 37℃, the surface of the film becomes cloudy and insolubilized. When this opaque film was washed with water and dried, a transparent film was obtained, which exhibited the following physical properties.

[Table] Example 4 10 g of PC obtained in Example 1 was dissolved in 200 c.c. of 5% ammonia aqueous solution, poured into a glass plate, and ammonia and water were removed at 40°C to obtain a transparent film. Ta. Example 5 10 g of sodium salt of deacetylated carboxymethyl chitin (degree of carboxymethylation 0.3, degree of deacetylation 0.5) was dissolved in 500 c.c. of water, and 1
% glutaraldehyde aqueous solution for 5 minutes, poured onto a glass plate and dried at 40°C. When the obtained film is immersed in 100 c.c. of 1% heparin sodium aqueous solution at room temperature, the surface of the film becomes cloudy and a polyion complex is formed.
When this white, cloudy, opaque film is washed with water and dried, a transparent film is obtained.

Claims (1)

[Scope of Claims] 1. At least one member selected from the group consisting of dextran sulfate, heparin, and chondroitin sulfate, and a degree of carboxymethylation of 0.1 to 1.0 per structural unit N-acetyl-D-glucosamine, and , a deacetylated product of carboxymethyl chitin or a salt thereof having a degree of deacetylation of 0.1 to 1.0 per structural unit N-acetyl-D-glucosamine, and having an intrinsic viscosity of 0.1 to 20 at 20°C. 2. Carboxymethyl chitin or a salt thereof represented by the following formula, in which the deacetylated product has a degree of carboxymethylation of 0.3 to 1.0 per structural unit N-acetyl-D-glucosamine,
[Formula] or [Formula] (In the formula, M represents hydrogen, alkali metal, alkaline earth metal, or ammonium group) Per structural unit N-acetyl-D-glucosamine
Claim 1, characterized in that it is a deacetylated product having a degree of deacetylation of 0.3 to 1.0.
Polyionic complexes as described in Section.