JP2000290633A - Adhesive for organism tissue - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an adhesive for organism tissue which has a good adhesive strength and high safety, by adding a water-soluble chitin derivative to gelatin as a paste component. SOLUTION: This adhesive for organism tissues comprises (A) a paste agent containing (i) a collagen protein partial hydrolyzate (preferably gelatin soluble in <=80 deg.C hot water) and (ii) a water-soluble chitin derivative (preferably chitosan or carboxymethylchitin having an acetylation degree of about 45 to about 55%) as main components and (B) a cross-linking agent containing a difunctional to multi-functional aldehyde (preferably a dialdehyde selected from the group consisting of glyoxal, succinaldehyde, glutaraldehyde and malealdehyde) as a main component. The adhesive is preferably used as a kit comprising the first pack charged with the component i and the component ii as main components and the second pack charged with the component iii as a main component.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a living tissue adhesive. More specifically, it is excellent in hemostatic performance and adhesive performance comprising a glue component mainly composed of a collagen protein partial hydrolyzate as a main component and a crosslinking agent mainly composed of bifunctional or polyfunctional aldehydes. The present invention also relates to a biological tissue adhesive having excellent safety.

[0002]

2. Description of the Related Art Conventionally, various adhesives have been proposed as adhesives for living tissues, of which cyanoacrylate, fibrin glue and gelatin-resorcin-bifunctional aldehyde are used in actual clinical practice. .

[0003]

The characteristics of tissue adhesives conventionally used in clinical settings are as follows. First, cyanoacrylate-based adhesives have good adhesive speed and adhesive strength, but have a soft adhesive surface. It has been a serious problem that the compound has been lost and there is a risk that a substance that is not preferable for safety may be generated by decomposition in a living body. As for fibrin glue, it is considered that there is no problem in terms of safety because the product is derived from the living body, so the product due to biodegradation is poor, but the adhesive strength is poor and the risk of virus infection by the biological material is also high. There are problems that cannot be ignored. In the case of gelatin-resorcin-bifunctional aldehydes, the adhesive strength is satisfactory, but highly toxic formaldehyde is used as a cross-linking aldehyde, and unreacted substances adversely affect biological tissues. The use of resorcinol, which can cause illness, is limited to only those treatments that require urgency. Therefore, development of an adhesive for living tissue having good adhesive strength and higher safety has been awaited in many clinical settings.

[0004]

The present invention is as follows. An adhesive for living tissue comprising a glue mainly composed of a collagen protein partial hydrolyzate and a water-soluble chitin derivative and a crosslinking agent mainly containing a bifunctional or polyfunctional aldehyde. The adhesive for living tissue as described above, wherein the collagen protein partial hydrolyzate is gelatin soluble in warm water of 80 ° C. or lower. The water-soluble chitin derivative has an acetylation rate of about 45%
Or a chitosan or carboxymethyl chitin in the range of from about 55% to about 55%. The biological tissue adhesive according to any one of the above items, wherein the bifunctional to polyfunctional aldehyde is a dialdehyde selected from the group consisting of glyoxal, succinaldehyde, glutaraldehyde, and malealdehyde. An adhesive kit for living tissue, comprising a first container filled with a collagen protein partial hydrolyzate and a water-soluble chitin derivative as main components, and a second container filled with a bifunctional or polyfunctional aldehyde as a main component.

According to the present invention, by adding a water-soluble chitin derivative to gelatin as a sizing agent component, an adhesive strength which cannot be obtained with gelatin alone is realized, and the amount of gelatin used is greatly reduced, thereby reducing the amount of gelatin used. High adhesiveness can be obtained with the amount of paste. As a result, it is expected that the amount of foreign matter to the living body can be reduced, and that the recovery of the wound can be improved. In addition, as a bifunctional or polyfunctional aldehyde as a crosslinking agent, glutaraldehyde, glyoxal, or the like conventionally used in the field of cardiovascular surgery and the like is mainly used, avoiding use of highly toxic formaldehyde.

[0006] Gelatin is preferably used as a partial hydrolyzate of collagen protein, which is one of the main components of the sizing agent of the present invention, which is produced by a known production method and usually has a weight-average molecular weight. 10,000 to 70,0
It is about 00 and at least soluble in warm water.
Furthermore, it is essential that the source of the raw material is clear, that is, it is not contaminated by the mad cow disease pathogen.

The water-soluble chitin derivative which is the other main component of the sizing agent of the present invention is chitin partially deacetylated or chitosan partially acetylated by a known method and has an acetylation rate of about 45%. % To about 55%. Partially deacetylated carboxymethyl chitin is also preferably used.

The crosslinking agent component used in the present invention includes:
Di- or polyfunctional aldehydes, i.e., dialdehydes selected from the group consisting of glyoxal, succinaldehyde, glutaraldehyde, and malealdehyde;
Furthermore, polyfunctional aldehydes derived from natural products, such as dextran dialdehyde, saccharides oxidized with m-periodate, and Genipin, can also be used as low-toxicity crosslinking agents.

In the present invention, gelatin and a water-soluble chitin derivative are used as main components of the sizing agent. The concentration of gelatin in an aqueous solution is preferably about 5 to 50% by weight, more preferably 10 to 30% by weight. Preferably, the water-soluble chitin derivative is about 0.1 to about 10% by weight, more preferably about 0.1% by weight.
It ranges from 3 to about 5% by weight.

The bifunctional to polyfunctional aldehyde of the present invention is preferably used in an aqueous solution in the range of about 1 to about 20% by weight.

The adhesive for living tissue of the present invention is prepared by aseptically preparing an aqueous paste solution containing gelatin and a water-soluble chitin derivative as main components and filling the container under aseptic conditions, or filling the container with the paste aqueous solution in advance. After that, it is sterilized to prepare a paste, and an aqueous solution of one or two or more bifunctional or polyfunctional aldehydes is prepared under aseptic conditions, and filled in a container under aseptic conditions, or A cross-linking agent is prepared by filling an aqueous solution of an aldehyde into the mixture and then sterilizing it.

In actual bonding of a living tissue, a glue is applied to the living tissue in the same manner as a known adhesive, a crosslinking agent is added, and the bonded portion is pressed and cured. The concentration of the cross-linking agent and the amount added to the sizing agent vary depending on the composition and concentration of the sizing agent to be used, but it is desirable that the curing is adjusted so that sufficient curing is achieved in about 1 to about 5 minutes.

In the present invention, the sizing agent and the cross-linking agent are filled in a vial or a syringe, and if necessary, are enclosed with a deoxidizer and the like, and are packaged in a packaging material that does not allow oxygen to pass therethrough.

[0014]

The present invention will be described in more detail with reference to the following examples.

Example 1 20 parts by weight of gelatin for food and 0.5 parts by weight of chitosan (trade name: Koyo Chitosan DAC-50) having an acetylation ratio of 50% were dissolved in 79.5 parts by weight of distilled water for injection to prepare a paste solution. Prepared (Glue A). Separately, glutaraldehyde is 10% by weight, 5% by weight, and
An aqueous solution containing 2.5% by weight was prepared to obtain a crosslinking agent solution.

Example 2 1 part by weight of chitosan (trade name: Koyo Chitosan DAC-50) having 30% by weight of gelatin for food and 50% of acetylation ratio was dissolved in 69 parts by weight of distilled water for injection to prepare a paste solution. Prepared (Glue B).

Example 3 25 parts by weight of gelatin for food and 5 parts by weight of partially deacetylated carboxymethyl chitin (trade name: Koyo CM chitin) were dissolved in 70 parts by weight of distilled water for injection to prepare a paste solution. (Glue C).

Comparative Example 1 40 parts by weight of gelatin for food was dissolved in 60 parts by weight of distilled water for injection to prepare a paste solution of gelatin alone (referred to as paste D).

[Adhesion strength test] A commercially available bovine pericardium patch (trade name: tissue guard) was cut into a width of 1 cm and a length of 5 cm to obtain a material for an adhesion strength test. Moisture on the surface of the test piece was removed as much as possible with a filter paper, and 0.1 g of the paste prepared in Examples 1 to 3 was applied to 1 cm 2 at one end, and then 10 μl of the crosslinker of a predetermined concentration prepared in Example 1 was added thereto. Immediately, attach another piece of adhesive so that the adhesive surface is 1 cm, put a weight of 100 g on the adhesive surface, press for 2 minutes, remove the weight, then leave it for 3 minutes, and then pull it out (test machine: TENSILON made by TOYO BALDWIN) RTM
100 at a pulling speed of 3 cm / min). Table 1 shows the results.

[0020]

[Table 1]

Continued on the front page F term (reference) 4C081 AC04 BA11 BB04 CC05 CD091 CD121 CD151 CE08 DA15 DC12 4J040 BA141 BA142 BA161 BA162 HB17 JA02 JA13 JB11 KA16 LA06 LA11 MA14 NA02

Claims (5)

[Claims] 1. An adhesive for living tissue comprising a paste mainly composed of a collagen protein partially hydrolyzed substance and a water-soluble chitin derivative and a crosslinking agent mainly composed of a bifunctional or polyfunctional aldehyde. 2. The adhesive for living tissue according to claim 1, wherein the collagen protein partial hydrolyzate is gelatin soluble in hot water at 80 ° C. or lower. 3. The adhesive for living tissue according to claim 1, wherein the water-soluble chitin derivative is chitosan or carboxymethyl chitin having an acetylation ratio in a range of about 45% to about 55%. 4. The living body according to claim 1, wherein the bifunctional to polyfunctional aldehyde is a dialdehyde selected from the group consisting of glyoxal, succinaldehyde, glutaraldehyde, and malealdehyde. Tissue adhesive. 5. A biological tissue comprising a first container filled with a collagen protein partial hydrolyzate and a water-soluble chitin derivative as main components, and a second container filled with a bifunctional or polyfunctional aldehyde as a main component. Adhesive kit.