JP2000005296A - Adhesive for medical treatment - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain enough gel strength for bonding tissues by constituting an adhesive from a film of a poly-ion complex formed from a poly-cationic material and a poly-anionic material. SOLUTION: This adhesive is formed from a film of poly-ion complex formed from a poly-cationic material and a poly-anionic material. Since a cationic group included in the poly-cationic material reacts with an anionic group of the poly-anionic material in the presence of water to from the gel-like poly-ion complex, the adhesive can be formed from this film. For example, a hydrochloric acid solution of a poly-allylamine and a distilled water solution of sodium alginate are mixed on a glass plate, and are made to flow extending to a thin layer to be naturally dried. The adhesive is formed from the film, and enough strength can be obtained by this constitution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a medical adhesive comprising a polyion complex film formed from a polycationic substance and a polyanionic substance.
The medical adhesive of the present invention is a film that adheres to the surface of a tissue when it absorbs blood or a biological tissue exudate in an affected part and gels, and is particularly suitably used as a tissue adhesive for a surgical operation.

[0002]

2. Description of the Related Art Conventionally, as a tissue adhesive for surgical operation,
The following are known. A typical example is a so-called fibrin glue composed of fibrinogen, blood coagulation factor XIII and thrombin.
At present, several companies are commercially available, but all of them use human plasma-derived fibrinogen, and thus have a problem that the possibility of infection with a pathogen such as a virus cannot be ruled out. Further, it is necessary to mix several kinds of materials immediately before use, and there is still a problem in operability.

Although a cyanoacrylate-based tissue adhesive is commercially available, it has a high curing speed and high adhesive strength, but lacks flexibility after curing, and produces harmful formaldehyde when decomposed in vivo. Has been pointed out as a problem. In addition, tissue adhesives consisting of gelatin, resorcinol and formaldehyde have recently been launched in Japan, which also has the problem of formaldehyde toxicity. In addition, it is necessary to mix several types of reagents immediately before use, which is not satisfactory in terms of operability.

Further, Japanese Patent Application Laid-Open No. 62-290465 discloses a tissue adhesive using a diisocyanate urethane prepolymer. Not converted. As described above, conventional tissue adhesives have problems of biological safety such as infectivity, sensitization, toxicity, etc., and problems of operability.

[0005] It is well known that when a polycationic substance and a polyanionic substance are mixed in the coexistence of water, a polyion complex is quickly formed, and the polyion complex is used in a wide variety of fields including pharmaceuticals and medical devices. ing. For example, JP-A-53-11069
No. 3 discloses a hemostatic agent in which a polymer complex obtained by reacting an anionic partially substituted dextran with a cationically substituted polysaccharide is in the form of powder, granules or tablets. JP-A-61-73665 discloses a wound protecting agent which forms a film by spraying an aqueous solution of a polyanionic material and an aqueous solution of a polycationic material to which an aqueous solution of a calcium salt is added. However, in these methods of using polyion complex, the gel itself cannot be expected to have strength because the polyion complex powder is applied to the affected area or a solution is mixed at the affected area to form a polyion complex. Not suitable.

JP-A-3-278538 discloses an agent for promoting periodontal tissue regeneration containing a polyelectrolyte complex as an active ingredient, which is injected into a periodontal pocket. Is not listed. JP-A-8-224293 discloses a wound treatment multilayer body having a structure in which chitosan, alginic acid, chitin and a support are successively stacked. However, the wound treatment multilayer body is produced by placing a previously produced chitosan-alginate complex on a chitin dispersion layer or a chitin layer formed on a support and drying the chitosan-alginate complex. Since the alginic acid complex is produced without dissolving chitosan and alginic acid in water, chitosan and alginic acid in the wound treatment multilayer body do not form a polyion complex.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to adhere to an affected area after applying the blood or tissue exudate from the affected area to the gel after applying the adhesive to the affected area, and have sufficient gel strength for tissue adhesion. An object of the present invention is to provide a medical adhesive.
Another object of the present invention is to provide a medical adhesive excellent in operability that does not require pretreatment such as mixing and dissolving during surgery or the like. Still another object of the present invention is to provide a medical adhesive excellent in biosafety without concern about infectivity and sensitization.

[0008]

Means for Solving the Problems The present inventors have intensively studied means for solving the above-mentioned problems, and as a result, a medical device comprising a film of a polyion complex formed from a polycationic substance and a polyanionic substance. The present inventors have found that the above problems can be solved by providing an adhesive, and have completed the present invention.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The polycationic substance according to the present invention has a plurality of cationic groups in its molecule, and can form a gel-like polyion complex with the polyanionic substance described below in the presence of water. No particular limitation is imposed as long as the polyion complex can exert a biological tissue adhesive action and has little adverse reaction to the living body, and in particular, is decomposed after the affected tissue is cured and absorbed into the living body. As described above, a substance having bioabsorbability is preferable. As the polycationic substance, those having such a property that the polycationic substance can be dissolved or swelled in water and the cationic group is positively charged in water are preferably used.

The cationic group includes, for example, an amino group;
Monoalkylamino groups such as methylamino group and ethylamino group; dialkylamino groups such as dimethylamino group and diethylamino group; imino groups; guanidino groups; and the like. Substances having an amino group are preferred.

Known polycationic substances may be used, and preferred are basic polysaccharides such as chitosan and aminated cellulose; basic polysaccharides such as polylysine, polyarginine, and a copolymer of lysine and arginine. Examples include homopolymers or copolymers of amino acids; basic vinyl polymers such as polyvinylamine and polyallylamine, and salts thereof (hydrochloride, acetate, etc.).
Among these, basic polysaccharides, derivatives thereof (such as acetylated products), and salts thereof are more preferable, and chitosan is preferable as the basic polysaccharide. Chitosan is a deacetylated product of chitin, and the degree of deacetylation is preferably in the range of 40 to 100%, more preferably in the range of 45 to 90%, from the viewpoint of bioabsorbability and water solubility.
More preferably, it is within the range of 80%. Further, a crosslinked polymer obtained by crosslinking the above-mentioned polycationic polymer can also be used. As a method for crosslinking the polycationic polymer, any of known methods can be used. When the polycationic polymer has an amino group, a method of crosslinking the polycationic polymer by subjecting the amino group of the polycationic polymer to a condensation reaction with a dicarboxylic acid is preferable.

The molecular weight of the polycationic substance is not particularly limited, but as the molecular weight increases, the viscosity of the solution increases during film production, making casting difficult.
The viscosity of the polycationic substance (1% aqueous solution measured at 20 ° C.) is 1
It is preferably 5,000 cp or less.
It is more preferably not more than p.

Further, as a preferable example of the polycationic substance, a low molecular weight diamine or polyamine can be used. For example, compounds having two amino groups in one molecule such as diaminoalkanes such as diaminoethane, diaminopropane, diaminobutane, diaminopentane, and diaminohexane; N- (lysyl) -diaminoethane; N '-(diridyl) -diaminoethane, N- (lysyl) -diaminohexane, N, N'-
Use a compound having 3 to 4 amino groups in one molecule, such as a mono- or diridylaminoalkane such as (diridyl) -diaminohexane, or a compound having 5 or more amino groups in one molecule. It is also possible. Further, in the medical adhesive of the present invention, two or more kinds of polycationic substances can be used.

The polyanionic substance has a plurality of anionic groups in its molecule, and can form a gel-like polyion complex with the polycationic substance in the presence of water. There is no particular limitation as long as it can exert a biological tissue adhesive action and has little adverse reaction to the living body. It is preferable that the substance has absorbability.
The polyanionic substance has such a degree of hydrophilicity that it can be dissolved or swelled in water, and a substance having a property of being negatively charged by dissociation of an anionic group in water is preferably used. You.

Examples of the anionic group include a carboxyl group, a sulfate group, a sulfonic group, and a phosphate group. As the polyanionic substance, a substance having two or more carboxyl groups in one molecule is particularly preferable. .

Preferred examples of the polyanionic substance used in the present invention include natural acidic polysaccharides having an anionic group such as a carboxyl group and a sulfate group such as alginic acid, hyaluronic acid, chondroitin sulfate, dextran sulfate and pectin, and derivatives thereof. An acidic polysaccharide artificially synthesized by binding an anionic group to a polysaccharide having no anionic group such as a carboxyl group or a sulfate group in nature, such as cellulose, dextran, and starch, for example, carboxymethyl cellulose, carboxymethyl Dextran, carboxymethyl starch, carboxymethyl chitosan, sulfated cellulose, sulfated dextran, derivatives thereof; polyglutamic acid, polyaspartic acid, homopolymers of acidic amino acids such as a copolymer of glutamic acid and aspartic acid, or Polymers; acidic vinyl polymers, such as polyacrylic acid, and their salts (alkali metal salts such as sodium salts). Further, a crosslinked polymer obtained by crosslinking these polyanionic polymers can also be used. As a method for crosslinking the polyanionic polymer, any of known methods can be used. When the polyanionic polymer has a carboxyl group, a method of crosslinking by performing a condensation reaction of the carboxyl group of the polyanionic polymer with a diamine is preferable.

The acidic polysaccharide derivative is obtained by reacting a part or all of the hydroxyl groups of the acidic polysaccharide with acetic acid, nitric acid, sulfuric acid, phosphoric acid, or the like; Examples include compounds esterified with low molecular alcohols such as ethylene glycol and propylene glycol, and specifically, ethylene glycol alginate, propylene glycol alginate, ethylene glycol hyaluronate, propylene glycol hyaluronate and the like. . The degree of esterification in these derivatives is not particularly limited, but if the degree of esterification is too high, the ratio of carboxyl groups, that is, the anionicity decreases, and the mechanical properties of the polyion complex formed between the polycationic substance and the polycation complex are reduced. Strength tends to decrease,
The degree of esterification is preferably 80% or less, and 30%
It is more preferable that:

Examples of the salt of the acidic polysaccharide or a derivative thereof include a salt of the acidic polysaccharide or a derivative thereof and a monovalent ion, for example, an alkali metal salt such as a sodium salt and a potassium salt; an ammonium salt. As the polyanionic substance, acidic polysaccharides, derivatives thereof, and salts thereof are particularly preferable. Alginic acid, derivatives thereof (specifically, propylene glycol alginate),
Their salts (eg alkali metal salts such as sodium salts)
Is preferred.

The molecular weight of the polyanionic substance is not particularly limited, but as the molecular weight increases, the viscosity of the solution increases during the production of the film, making casting difficult.
The viscosity of the polyanionic substance (1% aqueous solution measured at 20 ° C.) is 1
5,000 cp or less, preferably 5,000 cp or less.
It is more preferably not more than p.

It is also possible to use a low molecular compound having two or more anionic groups in one molecule as a polyanionic substance. For example, two or more compounds in one molecule such as succinic acid and malonic acid can be used. Compounds having a carboxyl group are exemplified. Further, in the medical adhesive of the present invention, two or more kinds of polyanionic substances can be used.

The combination of the polycationic substance and the polyanionic substance used in the present invention may be any combination as long as it forms a polyion complex and gels when mixed in the presence of water. From the viewpoint of properties, it is preferable that at least one of the polycationic substance and the polyanionic substance is a bioabsorbable polymer.

The mixing ratio of the polycationic substance and the polyanionic substance may be any mixing ratio that forms a polyion complex and gels when mixed in the presence of water. Alternatively, an excess amount of a polycationic or polyanionic substance can be mixed with the other to form a polyion complex.

The medical adhesive of the present invention can be produced by drying a polyion complex cast in a thin layer to form a film. The polyion complex cast in a thin layer is, for example, a polycationic substance and a polyanionic substance are separately dissolved in water or another solvent and mixed and then cast into a thin layer or while casting in a thin layer. A method of mixing or casting one solution in a thin layer and then mixing the other solution, dissolving either the polycationic substance or the polyanionic substance in water or another solvent, and adding the other solution to the solution. Is dissolved and then cast in a thin layer, or in a thin layer while dissolving, or a method in which one is cast in a thin layer and then the other is added, a polycationic substance and a polyanionic substance are added. Mix in powder state and dissolve in water or other solvent and then cast in thin layer, or dissolve in water or other solvent and cast in thin layer, or spray mixed powder in thin layer Back water Method of dissolving by adding other solvents, either polycationic substances or polyanionic material to the powder, the other a dry film was sprayed with the above powder thereto,
It can be produced by a method of dissolving in water or another solvent.

As a method for drying the polyion complex cast in a thin layer, polycationic substances,
Any method can be employed as long as it does not cause alteration of the polyanionic substance and the generated polyion complex, and examples thereof include a natural drying method, a reduced pressure drying method, a solvent displacement drying method, a heating drying method, and a blast drying method. Can be mentioned.

When the polycationic or polyanionic substance forming the polyion complex used for the medical adhesive of the present invention has tissue adhesiveness, the polycationic substance or polyanionic substance may be provided on one side of the film. By distributing the derived portion more, higher tissue adhesiveness can be obtained. In the case of manufacturing a medical adhesive formed by laminating polyion complex films, a portion derived from a polycationic substance is provided on one surface of the film, and the other is obtained in order to obtain adhesiveness between the laminated films. A film of a polyion complex in which a portion derived from a polyanionic substance is more distributed on the surface is preferably used. In this way, by distributing more of the portion derived from the polycationic substance or the part derived from the polyanionic substance of the polyion complex on at least one surface of the film, tissue adhesion, between each film constituting the laminated film Can be improved in adhesiveness.

As a method for producing a polyion complex film in which a portion derived from a polycationic substance or a portion derived from a polyanionic substance is more distributed on at least one surface of the film, a method for producing a film of a polyion complex may be used. Any method can be adopted as long as the method can distribute a portion derived from the polycationic substance or a portion derived from the polyanionic substance onto the target surface more. For example, a method of separately dissolving a polycationic substance and a polyanionic substance in water or another solvent, first casting one of them in a thin layer, and then casting the other in a thin layer, followed by drying, A method in which one of a conductive substance and a polyanionic substance is made into a dry film, and the other is coated with a solution dissolved in water or another solvent on the dry film and then dried, and either one of a polycationic substance or a polyanionic substance is used. A solution in which water or another solvent is dissolved is cast in a thin layer, a method of spraying and dissolving the other of the powders thereon, and then drying, forming a polycationic substance and a polyanionic substance as dry films, respectively. It can be carried out by, for example, a method of dissolving in a water or other solvent in a state of being overlapped.

In any case, any solvent may be used as the solvent for dissolving the polycationic substance and the polyanionic substance, as long as the solvent dissolves the polycationic substance and the polyanionic substance. Water or an aqueous solution of an inorganic salt is suitable from the viewpoint of generating more charges in the polycationic substance and the polyanionic substance. The concentration of the polycationic substance and the polyanionic substance in the solution is not particularly limited, and may be appropriately adjusted and set according to each production method.

At least one of the polycationic substance and the polyanionic substance used in the production of the medical adhesive of the present invention is a salt, and the polyion is removed by removing a counter ion of the cationic group or the anionic group of the salt. When the solubility of the cationic substance or the polyanionic substance in water is reduced, the mechanical strength of the medical adhesive is improved by removing a counter ion contained in the polyion complex film after forming the film. be able to.

When the counter ion of the cationic group is removed, an alkaline solution such as an aqueous solution of a base such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, or ammonia may be used. When removing the counter ion, the polyion complex film is immersed in an acidic solution such as an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, citric acid, malic acid, and tartaric acid, and then removed with an appropriate solvent. Washing and drying are preferred. The solvent used for washing is not particularly limited as long as it is a solvent that can be wet without dissolving the polyion complex film.From the viewpoint of efficiently dissolving the counter ion in the film and enhancing the washing effect, water or water is used. Aqueous solutions of inorganic salts such as sodium chloride, calcium chloride and sodium acetate are preferred. An organic solvent such as ethanol, methanol, or acetone can be added to the alkaline solution, the acidic solution, or the solvent used for washing in order to prevent the polyion complex from swelling and reducing the mechanical strength.

In the case of removing a counter ion having high volatility, a method of heating a polyion complex film to such an extent that the polycationic substance or polyanionic substance constituting the film is not deteriorated may be adopted. it can.

The medical adhesive of the present invention may have a form in which two or more polyion complex films are laminated from the viewpoint of improving the mechanical strength. The number of films to be laminated is preferably 2 to 15 and more preferably 2 to 10 from the viewpoint of water absorption of the film and flexibility of the film in a dry state. In addition, two or more kinds of films can be laminated, whereby the medical adhesive can have properties such as mechanical strength, tissue adhesiveness, and bioabsorbability of the polyion complex constituting each film. .

The medical adhesive obtained by laminating polyion complex films is prepared by laminating the films to be laminated with an appropriate solvent and superimposing them, or by laminating the films and moistening them with an appropriate solvent and then drying them. Can be manufactured. As the solvent for wetting the film, any solvent can be used as long as it is a solvent that does not dissolve the polyion complex film, but from the viewpoint of the adhesion due to the charge of each film, water or inorganic solvent can be used. Aqueous solutions of salts are suitable. Further, to the above-mentioned solvent, a suitable polycationic substance or polyanionic substance can be added for bonding the superposed surfaces, and an organic solvent such as ethanol, methanol, acetone or the like can be added to prevent swelling of the polyion complex. Can be added.

Although the thickness of the polyion complex film is not particularly limited, it is preferably 0.5 mm or less from the viewpoint of water absorption and flexibility in a dry state.
More preferably, it is 2 mm or less. In addition, when the water content of the polyion complex film is high, the water absorption of the film when applied to the affected area is reduced. Therefore, the water content of the film is preferably 60% or less, more preferably 30% or less. .

The medical adhesive of the present invention is suitably used particularly as a tissue adhesive for surgery. For example, adhesion of skin, adhesion of incisions of parenchymal organs such as liver and spleen, intestinal tract,
Anastomosis of the fallopian tubes, adhesion of dura, pleura, fascia, peritoneum and other membranes,
It is used as an adhesive for stopping hemorrhage from parenchymal organs, a suture assisting agent for stopping bleeding from a suture hole at the time of suturing, an adhesive for preventing air leakage from the lung, and the like.

As a method of using the medical adhesive of the present invention, any method can be used as long as it is capable of absorbing water such as blood and tissue fluid and gelling after adhering to the affected part. be able to. For example, the medical adhesive of the present invention may be adhered to a diseased part to be bonded in a dry state, and gelled by absorbing water such as blood and tissue fluid in the diseased part. In addition, when the affected part has a small amount of water and insufficient gelation, after applying the medical adhesive of the present invention to the affected part, it is possible to replenish moisture from the outside and promote gelation of the adhesive. . As the water to be replenished from the outside, any solution can be used as long as it is harmless to the affected area, but physiological saline or Ringer's solution is appropriate.

[0036]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited thereto.

Example 1 1 g of polyallylamine (L-type, molecular weight 10,000) manufactured by Nitto Boseki Co., Ltd. was dissolved in 100 ml of 0.1 N hydrochloric acid.
And Further, sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity: 100 to 150 cp) is added to 100 ml of distilled water.
1 g was dissolved to prepare solution 2. The total amount of Solution 1 and Solution 2 was mixed on a glass plate, cast into a thin layer, and air-dried. While the film in the dry state is moistened with distilled water, 3
The sheets were stacked and air-dried again. After drying, the film was peeled from the glass plate, and the test described in Test Examples was performed.
Table 1 shows the results.

Example 2 1 g of chitosan (Chitosan 500, manufactured by Wako Pure Chemical Industries, Ltd., degree of deacetylation: 85%) was dissolved in 100 ml of 0.1 N acetic acid to obtain a solution 1. In addition, sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd .;
600 cp) of 1 g was dissolved to prepare a solution 2. After mixing the total amount of Solution 1 and Solution 2 on a glass plate and casting in a thin layer,
Blow dry. After drying, the film was peeled from the glass plate, and the test described in Test Examples was performed. Table 1 shows the results.

Example 3 1 g of chitosan (Chitosan 500, manufactured by Wako Pure Chemical Industries, Ltd., degree of deacetylation: 85%) was dissolved in 100 ml of 0.1 N acetic acid to obtain a solution 1. Also, sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., having a viscosity of 300 to
400 cp) of 1 g was dissolved to prepare solution 2. After mixing the total amount of Solution 1 and Solution 2 on a glass plate and casting in a thin layer,
Blow dry. Five films in the dry state were superposed while being moistened with distilled water, and dried by blowing air again. After drying,
The film was peeled from the glass plate, and the test described in the test example was performed. Table 1 shows the results.

Example 4 1 g of chitosan (Chitosan 500, manufactured by Wako Pure Chemical Industries, Ltd., degree of deacetylation 85%) was dissolved in 100 ml of 0.1 N acetic acid to obtain a solution 1. In addition, 1 g of dextran sodium sulfate (manufactured by Wako Pure Chemical Industries, Ltd., molecular weight: 500,000) was dissolved in 100 ml of distilled water to prepare solution 2. After mixing the total amount of Solution 1 and Solution 2 on a glass plate and casting in a thin layer,
It was dried by heating at 40 ° C. Five films in the dried state were superposed while being moistened with distilled water, and dried again by heating.
After drying, the film was peeled from the glass plate, and the test described in Test Examples was performed. Table 1 shows the results.

Example 5 A solution 1 was prepared by dissolving 1 g of chitosan (Chitosan 500, manufactured by Wako Pure Chemical Industries, Ltd., degree of deacetylation: 85%) in 100 ml of 0.1 N acetic acid. In addition, sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd .;
600 cp) of 1 g was dissolved to prepare a solution 2. The entire amount of Solution 1 and Solution 2 was layered on a glass plate in a thin layer so that Solution 1 was the lower layer and Solution 2 was the upper layer, and then blow-dried. Five films in the dry state were superposed while being moistened with distilled water, and dried by blowing air again. After drying, the film was peeled off from the glass plate, and a test described in Test Examples was performed on a surface on which a portion derived from chitosan was distributed more. Table 1 shows the results.

Example 6 1 g of chitosan (Chitosan 500, manufactured by Wako Pure Chemical Industries, Ltd., degree of deacetylation: 85%) was dissolved in 100 ml of 0.1 N acetic acid to obtain a solution 1. Also, sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., having a viscosity of 500-6
00 cp) 1 g was dissolved to obtain solution 2. The whole amount of Solution 1 and Solution 2 was laminated on a glass plate in a thin layer so that Solution 1 was the upper layer and Solution 2 was the lower layer, and then heated and dried at 40 ° C. to obtain a film. The obtained dried film together with the glass plate was immersed in a 0.1N sodium hydroxide / 60% ethanol aqueous solution for 5 minutes, washed with a 60% ethanol aqueous solution, and then dried by blowing. The film was peeled from the glass plate, and the test described in the test example was performed on a surface where a large portion derived from chitosan was distributed. Table 1 shows the results.

Example 7 Chitosan (degree of deacetylation: 6 in 100 ml of 0.1 N acetic acid)
0%, viscosity 300-400 cp)
And In addition, sodium alginate (viscosity 500-600 cp) 1 in distilled water 100 ml
g was dissolved to prepare solution 2. The whole amount of Solution 1 and Solution 2 was laminated on a glass plate in a thin layer so that Solution 1 was the upper layer and Solution 2 was the lower layer, and then heated and dried at 40 ° C. to obtain a film. The obtained dried film together with the glass plate was immersed in a 0.1N sodium hydroxide / 60% ethanol aqueous solution for 5 minutes, washed with a 60% ethanol aqueous solution, and then dried by blowing. The film was peeled from the glass plate, and the test described in the test example was performed on a surface where a large portion derived from chitosan was distributed. Table 1 shows the results.

Comparative Example 1 1 g of polyallylamine (L-type, molecular weight 10,000) manufactured by Nitto Boseki Co., Ltd. was dissolved in 100 ml of 0.1 N hydrochloric acid, cast on a glass plate, and air-dried. After drying, the film was peeled from the glass plate, and the test described in Test Examples was performed. Table 1 shows the results.

Comparative Example 2 2 g of sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity: 300 to 400 cp) was dissolved in 100 ml of distilled water.
After casting on a glass plate, it was blow-dried. After drying, the film was peeled from the glass plate, and the test described in Test Examples was performed. Table 1 shows the results.

Comparative Example 3 1 g of polyallylamine (L-type, molecular weight 10,000) was dissolved in 100 ml of 0.1N hydrochloric acid. 10
2 g of sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity 300 to 400 cp) was dissolved in 0 ml of distilled water. The tests described in Test Examples were performed on the above-mentioned aqueous solution of polyallylamine hydrochloride and aqueous solution of sodium alginate.
However, both solutions were mixed in advance and applied to the affected area. Table 1 shows the results.

Comparative Example 4 1 g of polyallylamine (L-type, molecular weight 10,000) was dissolved in 100 ml of 0.1 N hydrochloric acid. 10
2 g of sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity 300 to 400 cp) was dissolved in 0 ml of distilled water. The tests described in Test Examples were performed on the above-mentioned aqueous solution of polyallylamine hydrochloride and aqueous solution of sodium alginate.
However, both solutions were mixed at the affected part at the time of use. Table 1 shows the results
Shown in

Comparative Example 5 Chitosan cotton (made by loosening a non-woven fabric to form a cotton) 0.8
g was dispersed in 500 ml of water, poured uniformly over a filter paper of 30 × 25 cm, and filtered to form a chitosan layer on the filter paper. An alginate nonwoven fabric having a thickness of 1 mm was placed thereon, and the chitosan layer was transferred onto the alginate nonwoven fabric. To this, 200 ml of water was added dropwise, followed by freeze vacuum drying to obtain a chitosan-alginate sheet. The test described in Test Examples was performed on the chitosan surface of this sheet. Table 1 shows the results.

Comparative Example 6 The test described in the Test Example was performed on fibrin glue (manufactured by Behringberge).

Comparative Example 7 0.13 g of sodium dextran sulfate (manufactured by Wako Pure Chemical Industries, Ltd., molecular weight: 500,000) was dissolved in 100 ml of distilled water, and hydrochloric acid was added to adjust the pH to 2.8. 50 g of chitosan (Chitosan 500, manufactured by Wako Pure Chemical Industries, Ltd.)
of distilled water, and dissolved by adding hydrochloric acid to pH 2.6.
And The above dextran sulfate sodium solution and chitosan solution were mixed at room temperature for 30 minutes, and a white precipitate was obtained from the reaction solution by centrifugation. After washing this white precipitate with water,
Vacuum drying gave a white powder. After the powder was sterilized by irradiation with 25 kGy of γ-ray, the test described in the test example was performed. Table 1 shows the results.

Test Example: Measurement of Adhesive Strength of Skin Incision An abdomen of an 8-week-old ICR mouse was incised, and an incision wound 1 cm long was made in the peritoneum. In this incision, Example 1,
2,3,4,5,6,7, Comparative Example 1, 2 or 5 sample pieces (1 × 1.5 cm) were stuck (however, the sample pieces of Examples 5, 6 and 7 were chitosan (The chitosan surface was applied to the sample section of Comparative Example 5), or the sample of Comparative Example 3, 4, 6 or 7 was applied or sprayed and adhered. One minute later, the animals were sacrificed and 1 × 2 cm strip-shaped peritoneal sections were cut out for each wound. Both ends of the strip are ligated with a nylon thread, and pulled in a direction perpendicular to the incision-adhering surface using an Autograph AGS-50A (manufactured by Shimadzu Corporation), and the tension at the time when the incision is peeled off is adhered. Strength.
Table 1 shows the adhesive strength per unit area of the sample section.

[0052]

[Table 1]

As is evident from Table 1, when the samples of Examples 1 to 7 were used, all exhibited an adhesive strength of 20 gf / cm ² or more, whereas the samples of Comparative Examples 1 and 2 exhibited When used, it was dissolved immediately after application and could not be adhered. When the samples of Comparative Examples 3 and 4 were used, they did not adhere and fell off, and when the sample of Comparative Example 5 was used, 2 gf
/ Cm ² , and 10 gf /
cm ² , and 4 gf / cm ² when using the sample of Comparative Example 7.
It showed only low adhesive strength.

[0054]

According to the present invention, after pasting on the affected area,
A medical adhesive is provided which absorbs blood or tissue exudate from the affected part and gels at the same time as the gel adheres to the affected part and has sufficient gel strength for tissue adhesion. The medical adhesive of the present invention,
It can be easily and effectively used as a tissue adhesive because it adheres to the affected tissue and gels at the same time, has high adhesion to the tissue, and is excellent in biosafety without fear of infectivity and sensitization. Can be. Furthermore, the medical adhesive of the present invention is provided as a film of a polyion complex, and is gelled with an affected tissue fluid or the like. Therefore, when used as a tissue adhesive during surgery, pretreatment such as mixing and dissolution is required. Excellent in operability.

Claims (10)

[Claims] 1. A medical adhesive comprising a polyion complex film formed from a polycationic substance and a polyanionic substance. 2. The medical adhesive according to claim 1, wherein the polycationic substance is a substance having two or more amino groups in one molecule. 3. The medical adhesive according to claim 2, wherein the substance having two or more amino groups in one molecule is a basic polysaccharide, a derivative thereof, or a salt thereof. 4. The medical adhesive according to claim 3, wherein the basic polysaccharide, a derivative thereof, or a salt thereof is chitosan, a derivative thereof, or a salt thereof. 5. The polyanionic substance is a substance having two or more carboxyl groups in one molecule.
The medical adhesive according to any one of the above. 6. The medical adhesive according to claim 5, wherein the substance having two or more carboxyl groups in one molecule is an acidic polysaccharide, a derivative thereof, or a salt thereof. 7. The medical adhesive according to claim 6, wherein the acidic polysaccharide, a derivative thereof, or a salt thereof is alginic acid, a derivative thereof, or a salt thereof. 8. The medical adhesive according to claim 1, wherein at least one of the polycationic substance and the polyanionic substance is a bioabsorbable polymer. 9. The medical treatment according to claim 1, wherein a portion derived from a polycationic substance or a part derived from a polyanionic substance of the polyion complex is more distributed on at least one surface of the film. Adhesive. 10. A medical adhesive obtained by laminating a polyion complex film formed from a polycationic substance and a polyanionic substance.