JPH10191902A - Gelatin gel, production of gelatin gel, medical bioadhesive material and production of medical bioadhesive material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a gel which forms a secure gal exhibiting adhesiveness in vital tissues, is excellent in the hemostasis of a wound surface, eliminates the danger of a virus infection, is harmless and has no problems in safety by mixing specific compds. with gelatin. SOLUTION: This gel is obtd. by mixing the gelatin soln. and the soln. of at least one kind of the compds. selected from compds. of formula I (R2 , R3 , R5 , R6 are H, alkyl; Z1 , Z2 are the nonmetal atom groups necessary for forming a pyrolopyridine ring; R1 , R4 are groups having acid bases; L is methine; X<-> is anion; (m) is 3, 4; (n) is 1, 2, n=1 when an intra-molecular salt is formed) and/or formula II (R7 , R8 are H, alkyl; R9 is an H molecule, halogen, univalent org. group; K is halogen, OH, alkyl group, etc.; (p) is 0 to 4; R10 is a group substd with an acid).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a gelatin gel used for an adhesive or a hemostatic agent for a living tissue, a method for producing a gelatin gel, a medical bioadhesive material used for an adhesive or a hemostatic agent for a living tissue, and a medical bioadhesive material. And a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, as an adhesive or hemostatic agent for living tissue, fibrin glue which utilizes the fact that fibrinogen, which is a water-soluble plasma protein, is limitedly degraded by the enzymatic action of thrombin and the degraded fibrin is molecularly associated and gelled. In addition, cyanoacrylate-based adhesives, gelatin pastes for crosslinking gelatin and resorcinol with formalin, and the like have been used.

[0003]

The cyanoacrylate-based adhesive has a problem that the bonding speed is too high and the bonding operation is difficult.
Although the adhesive strength is large, the cured polymer is too hard, and thus has a drawback that the hemostasis of the wound surface becomes insufficient, and that formalin is produced along with the decomposition, but this is harmful. In addition, fibrin glue has disadvantages such as low adhesive strength and a risk of virus infection because the raw material is derived from human blood. In addition, gelatin paste in which gelatin and resorcinol are crosslinked with formalin has drawbacks such as insufficient strength and harmfulness of formalin. Recently, in order to solve the problem of harmful effects of formalin, a gelatin-based adhesive in which gelatin is crosslinked using a polyanion such as polyglutamic acid and carbodiimide has been reported (JP-A-7-163860).

[0004] However, carbodiimides are chemically active on carboxyl groups, and there is a concern about safety for living tissues.

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a strong gel is formed by mixing certain compounds with gelatin. The present invention was found to exhibit adhesiveness, and the present invention was completed.

Accordingly, an object of the present invention is to provide a gelatin gel and a method for producing a gelatin gel which are excellent in hemostasis on a wound surface, free from the risk of viral infection, harmless, and have no problem in safety to living tissue. An object of the present invention is to provide a medical bioadhesive material and a method of manufacturing the medical bioadhesive material.

[0007]

The object of the present invention is achieved by the following constitution.

[0008] 1. A gelatin gel comprising gelatin and at least one compound selected from a compound represented by the following general formula (I) and / or a compound represented by the following general formula (II).

[0009]

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In the formula, R ₂ , R ₃ , R ₅ and R ₆ represent a hydrogen atom or an alkyl group, and Z ₁ and Z ₂ each represent a group of non-metallic atoms necessary for forming a pyrrolopyridine ring. R ₁ and R ₄
Represents a group having an acid group. L represents a methine group, and X ⁻ represents an anion. m represents an integer of 3 or 4, and n represents an integer of 1 or 2. When the present compound forms an inner salt, n = 1.

[0011]

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In the formula, R ₇ and R ₈ each represent a hydrogen atom or an alkyl group. R ₉ is a hydrogen molecule, a halogen atom or 1
Represents a valent organic group. K represents a group selected from a halogen atom, a hydroxyl group, an alkyl group, an alkoxyl group, a carboxyl group and a sulfonic acid. p is 0, 1, 2, 3
Or an integer of 4. R ₁₀ represents a group substituted with an acid.

2. Producing the gelatin gel, wherein a gelatin solution and a solution of at least one compound selected from the compound represented by the general formula (I) and / or the compound represented by the general formula (II) are mixed. Method.

3. A bioadhesive material for medical use, comprising gelatin and a compound which forms a gel by non-covalently bonding to gelatin.

4. A method for producing a medical bioadhesive material, comprising mixing a gelatin solution and a solution of a compound which forms a gel by non-covalently binding to gelatin.

5. A medical bioadhesive material comprising gelatin and at least one compound selected from the compounds represented by the general formula (I) and / or the compound represented by the general formula (II).

Hereinafter, the present invention will be described in more detail.

The gelatin used in the present invention is prepared from collagen by a conventional method, and may be acid-treated gelatin, alkali-treated gelatin, or enzyme-treated gelatin. Further, a water-soluble gelatin decomposition product decomposed to a molecular weight of about 10,000 may be used. Preferably, acid-treated gelatin or alkali-treated gelatin may be used, and more preferably, alkali-treated gelatin. The origin is not particularly limited, and those derived from cattle, horses, pigs, and humans are used. Generally, those derived from bovine bones and skin are used,
Those having poor immunogenicity to humans are preferred.

In the present invention, the compound which forms a gel by non-covalently bonding to gelatin is at least one selected from the compounds represented by the above general formula (I) and / or the compounds represented by the above general formula (II). One kind of compound.

In the general formula (I), R ₂ , R ₃ , R
₅ and R ₆ represent a hydrogen atom or an alkyl group, and Z ₁ and Z ₂
Represents a group of nonmetallic atoms necessary for forming a pyrrolopyridine ring. R ₁ and R ₄ represent a group having an acid group. L represents a methine group, and X ⁻ represents an anion. m represents an integer of 3 or 4, and n represents an integer of 1 or 2. When the present compound forms an inner salt, n = 1.

The alkyl group represented by R ₂ , R ₃ , R ₅ and R ₆ is preferably a lower alkyl group having 4 or less carbon atoms.

The non-metallic atomic groups Z ₁ and Z ₂ necessary for forming a pyrrolopyridine ring include, for example, the following (A):
(B) and (C) are mentioned, and among these, (A) is particularly preferable.

[0023]

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Z ₁ and Z ₂ may have a substituent,
Examples of the substituent include a sulfo group (including a salt), a carboxyl group (including a salt), a hydroxyl group, a cyano group, and a halogen atom.

Examples of the acid group of R ₁ and R ₄ include a sulfonic acid group, a carboxylic acid group and a phosphonic acid group, and these acid groups include salts thereof. Particularly, a sulfonic acid group and a salt thereof are preferable. Salts include alkali metal salts such as sodium and potassium, ammonium, triethylamine,
Organic ammonium salts such as pyridine can be mentioned. R ₁ and R ₄ having an acid group are preferably an alkyl group or an aryl group substituted with an acid group.

The methine group represented by L may also have a substituent. Examples of the substituent include a substituted or unsubstituted lower alkyl group having 1 to 5 carbon atoms, a halogen atom, an aryl group and an alkoxyl group. No.

[0027] by X ^- anion represented is not particularly limited, a halogen ion, p- toluenesulfonate ion, such as ethyl sulfate ions.

Specific examples of the compound represented by formula (I) of the present invention are shown below, but the present invention is not limited thereto.

[0029]

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[0030]

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[0031]

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In the general formula (II), R ₇ and R
₈ represents a hydrogen atom or an alkyl group, respectively. R ₉ represents a hydrogen molecule, a halogen atom or a monovalent organic group. K represents a group selected from a halogen atom, a hydroxyl group, an alkyl group, an alkoxyl group, a carboxyl group and a sulfonic acid. p represents an integer of 0, 1, 2, 3 or 4. R ₁₀ is
Represents a group substituted with an acid.

The alkyl groups represented by R ₇ and R ₈ include:
It is preferably an alkyl group having 1 to 4 carbon atoms, which may have a substituent or may be unsubstituted. Examples of the substituent atom and substituent include a halogen atom, a hydroxyl group, a sulfonic acid group, and the like.

Examples of the monovalent organic group represented by R ₉ include an alkyl group, an alkoxyl group, a carboxyl group, a nitro group, an amino group, a cyano group, an aryl group, an amide group, a hydroxyl group and a sulfonyl group. And these may have a substituent. The substituent atom represented by K is preferably a halogen atom, and is preferably substituted at the meta position with respect to the amino group.

The acid group of R ₁₀ includes a sulfonic acid group, a carboxylic acid group, a phosphonic acid group and the like, and these acid groups include salts thereof. Particularly, a sulfonic acid group and a salt thereof are preferable.

Examples of the group substituted with the acid group represented by R ₁₀ include an alkyl group and an aryl group, and these may have a substituent. Particularly, an alkyl group having 1 to 4 carbon atoms or a phenyl group is preferable, and a phenyl group is particularly preferable.

Specific examples of the compound represented by formula (II) of the present invention are shown below, but the present invention is not limited thereto.

[0038]

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[0039]

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The compound represented by the general formula (I) and the compound represented by the general formula (II) may be used alone or simultaneously.

The gelatin gel of the present invention is prepared by the following method.

[Preparation of Gelatin Solution] In general, a method of preparing an aqueous gelatin solution can be used. That is, a small amount of water is added to gelatin to swell, then an aqueous medium is added and the gelatin is heated to about 50 ° C. to dissolve the gelatin. The compound represented by the general formula (I) and / or the compound represented by the general formula (I) of the present invention which forms a gel by non-covalent bonding with gelatin.
A solution of at least one compound selected from the compounds represented by I) (hereinafter, also simply referred to as the compound of the present invention) is prepared. When the compound is hardly soluble in water, the compound may be dissolved in a water-soluble organic solvent such as ethanol which does not irritate living tissues and then dissolved in an aqueous medium.

The solution in which gelatin or the compound of the present invention is dissolved may contain a suitable buffer such as a phosphate buffer or a borate buffer, or may contain a suitable salt such as sodium chloride or potassium chloride. May be included. Also, sugars,
It may contain lipids, amino acids, proteins and the like.

Further, it may contain a preservative, an antibacterial agent and the like.

A gelatin gel can be formed by mixing a gelatin solution and a solution of the compound of the present invention at an appropriate concentration.
0.1-50% by weight gelatin aqueous solution and 0.01-30%
It is preferred to mix the compound solutions in weight% at a ratio of 1: 100 to 100: 1.

When used as a biological tissue adhesive or a hemostatic agent, the gelatin solution and the compound solution of the present invention may be mixed and added to the target wound before gelation, or the gelatin solution may be added to the target wound. After the addition, the compound solution may be added, or the compound solution may be added to a target wound portion, and then the gelatin solution may be added. Further, the gelatin solution and the compound solution of the present invention may be simultaneously added to the target wound. Gelatin and the compound mix to form a gel on the target wound, which acts as a medical bioadhesive material. The functions of the medical bioadhesive material include a biological tissue adhesive, a hemostatic agent, a wound filler, and the like.

The mechanism of the formation of the gelatin gel of the present invention is based not on gel formation by a chemical covalent bond reaction as in the case of using formalin or carbodiimide, but on non-covalent bonds such as ionic bonds, hydrophobic bonds or hydrogen bonds. is assumed.

Accordingly, the gel formed by mixing the compound of the present invention and a gelatin which forms a gel by non-covalently bonding with the gelatin of the present invention can be prepared by using chemically active formalin or carbodiimide. In comparison, the irritation to living tissue is extremely poor.

[0049]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the embodiments of the present invention are not limited thereto.

Example 1 a) Preparation of Medical Bioadhesive Material 2 g of alkali-treated gelatin (manufactured by Konica Gelatin) was dissolved in 10 ml of pure water to prepare a 20% by weight gelatin solution. Further, 0.5 g of Exemplified Compound I-1) was added to pure water 10
The resulting mixture was dissolved in 5 ml of a gelling agent (1).

0.3 ml of the gelling agent (1) was mixed with 1 ml of the gelatin solution to prepare the medical bioadhesive material (1) of the present invention. In addition, what was prepared using pure water instead of the gelling agent (1) was prepared as a comparative material (1).

B) Evaluation Three Balb / C mice (6 weeks old, female) were anesthetized, the back was shaved, and the skin was incised about 2 cm with a scalpel. About 0.3 m of the bioadhesive material (1) prepared just before the incision
After application, the wound surface was pressed and fixed from the left and right. Ten minutes later, the wound was checked for adhesion and hemostasis visually. As a comparison, the same operation as that of the medical bioadhesive material (1) was performed using the comparative material (1).

As a result, when the medical bioadhesive material (1) of the present invention was used, the wound was completely adhered to all three animals, and there was no opening and no bleeding even when the area around the wound was pulled. On the other hand, in the case of using the comparative material (1), the wound portion was opened only by lightly contacting the wound portion with all three animals, bleeding occurred, and the wound portion was not adhered.

Example 2 c) Preparation of Medical Bioadhesive Material 0.5 g of Exemplified Compound II-1 was dissolved in 10 ml of pure water to obtain a solution.
A weight% gelling agent (2) was prepared, and a bioadhesive material for medical use (2) was prepared in the same manner as in Example 1 using this. Also,
As a comparative material (2), a commercially available fibrin glue (Bolheel) was used.

D) Evaluation The same operation as in Example 1 was performed except that the medical bioadhesive material (2) and the comparative material (2) were used, and the same evaluation was performed.

As a result, as in Example 1, when the medical bioadhesive material (2) of the present invention was used, the wound was completely adhered to all three animals, and there was no opening even when the area around the wound was pulled. He did not bleed. On the other hand, when the comparative material (2) was used, when the periphery of the wound was lightly pulled, all three mice opened and bleeding, and the adhesion of the wound was not sufficient.

[0057]

According to the present invention, the gelatin gel, the method for producing the gelatin gel, the bioadhesive material for medical use, and the method for producing the bioadhesive material for medical use are excellent in hemostasis of the wound surface, there is no risk of virus infection, and there is no harm. In addition, it has an excellent effect that there is no problem in safety for living tissues.

Claims (5)

[Claims] 1. A gelatin gel comprising gelatin and at least one compound selected from the following compounds represented by the general formula (I) and / or the compound represented by the general formula (II): . Embedded image [Wherein, R ₂ , R ₃ , R ₅ and R ₆ represent a hydrogen atom or an alkyl group, and Z ₁ and Z ₂ each represent a group of non-metallic atoms necessary for forming a pyrrolopyridine ring. R ₁ and R ₄ represent a group having an acid group. L represents a methine group, and X ⁻ represents an anion. m represents an integer of 3 or 4, and n represents an integer of 1 or 2. When the present compound forms an inner salt, n = 1. [Chemical formula 2] [Wherein, R ₇ and R ₈ each represent a hydrogen atom or an alkyl group. R ₉ represents a hydrogen molecule, a halogen atom or a monovalent organic group. K represents a group selected from a halogen atom, a hydroxyl group, an alkyl group, an alkoxyl group, a carboxyl group and a sulfonic acid. p represents an integer of 0, 1, 2, 3 or 4. R ₁₀ represents a group substituted with an acid. ] 2. A method comprising mixing a gelatin solution and a solution of at least one compound selected from the compounds represented by the general formula (I) and / or the compound represented by the general formula (II). A method for producing the gelatin gel. 3. A medical bioadhesive material comprising gelatin and a compound which forms a gel by non-covalently bonding to gelatin. 4. A method for producing a bioadhesive material for medical use, comprising mixing a gelatin solution and a solution of a compound which forms a gel by non-covalently binding to gelatin. 5. A bioadhesive for medical use, comprising gelatin and at least one compound selected from the compound represented by the general formula (I) and / or the compound represented by the general formula (II). material.