JPH0473066A - Adhesive for surgery - Google Patents

Abstract

PURPOSE:To harden and bond an isocyanate terminal prepolymer uniformly on an organism by using a specified amount of a certain organic solvent jointly therewith. CONSTITUTION:An isocyanate terminal urethane performer has a polyisocyanate compound reacted with polyoles to include a urethane prepolymer with a terminal of the polyoles capped by the polyisocyanate compound. An organic solvent to be used jointly with the urethane prepolymer is a hydrophilic organic solvent which is compatible with the urethane prepolymer used, inert to an isocyanate group in substance at a normal temperature and water soluble while being non-toxin pharmaceutically. Such an organic solvent play a role to lower viscosity of the urethane prepolymer used jointly, impart a hydrophilic property thereto and improve a wetting property or the like to a biotissue. An amount to be used of the organic solvent is normally 1-100 part wt. per 100 part wt. of the urethane performer.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to surgical adhesives, and more particularly to surgical adhesives based on incyanate-terminated urethane prepolymers.

Conventionally, as a surgical adhesive that has been put into practical use clinically,
Cyanoacrylate, Biopond (cyanoacrylate dispersed with fine rubber particles and further diisocyanate added), and fibrin glue are known. The unique feature of ananoacrylate adhesives is that the polymerization reaction starts with a very small amount of water, and the curing reaction is completed instantly.
The cured product is very hard, brittle, inflexible, degrades quickly in the body, has poor durability, and has drawbacks such as being a very fluid liquid and difficult to handle. Furthermore, although Biopond has improved flexibility, it has drawbacks such as the fact that it takes several hours to harden. Furthermore, bio-derived fibrin glue has the disadvantage that it is significantly inferior to the synthetic adhesives in terms of adhesive effect, adhesion speed, etc.

Therefore, research has recently been conducted to develop a new elastic adhesive for pharmaceutical use to replace this adhesive. Adhesives have been proposed (see JP-A-62-148666 and JP-A-62-290465).

The principle of curing and bonding of the urethane adhesive proposed above in a living body is based on the reaction between the terminal amino group and the terminal isocyanate group generated by the reaction between the isocyanate group at the end of the prepolymer and water in the living body. Possible factors include the high molecular weight ratio due to the accompanying chain extension reaction, and the chemical bonding between the amino group of the biological protein and the isocyanate group at the end of the prepolymer with the biological tissue. The above-mentioned process of increasing the molecular weight (curing) involves the following three kinetic processes: the rate of diffusion of water in the living body into the prepolymer, the reaction rate of amino group formation due to the reaction between water and isocyanate groups, and , is the chain extension reaction rate due to the reaction between amino groups and isocyanate groups. - It is known that the reaction between water and inocyanate groups is slower than the reaction between amine groups and isocyanate groups. The concentration of water is high at the interface between the living body and the adhesive, and water is generally present in excess for the polymerization reaction of the prepolymer. If this excess water quickly diffuses into the prepolymer, curing of the adhesive will proceed. At this time, if the diffusion rate of water is slower than the reaction rate of water and incyanate, a film due to high molecular weight is formed on the portion of the prepolymer that comes into contact with water, and as a result, water diffusion is inhibited there and curing does not proceed. Therefore, in order to increase the curing rate of the adhesive and obtain a uniform cured product, the composition of the prepolymer needs to be such that it increases the rate of water diffusion. On the other hand, if the water diffusion rate is too fast, only water exists near the incyanate groups of the prepolymer (the amount of water in the adherend is greater than the amount of water required for the chain extension reaction of the prepolymer). ) may occur. In this case, the prepolymer becomes amine-terminated by the reaction between isocyanate groups and water, but there are no isonoanate groups with which the amine ends should react, and therefore, it cannot be cured.

The proposed adhesive made of a solvent-free liquid reactive urethane prepolymer does not take into consideration the excessive presence of water in living organisms, and has the disadvantage that a sufficient adhesive effect cannot be obtained.

The present inventors have conducted intensive research to overcome the drawbacks of the previously proposed urethane adhesives and develop a urethane surgical adhesive that can quickly and uniformly harden and adhere in living organisms. The present inventors have discovered that the above object can be achieved by using an isocyanate-terminated prepolymer in combination with a specific amount of certain organic solvents, and have completed the present invention.

Thus, according to the present invention, (a) 100 parts by weight of an isocyanate-terminated urethane prepolymer; (b) compatible with the prepolymer, substantially inert to isocyanate groups at room temperature, and Provided is a surgical adhesive characterized by containing 1 to 100 parts by weight of a pharmaceutically non-toxic organic solvent that is soluble in the surgical adhesive.

Hereinafter, the surgical adhesive of the present invention will be explained in more detail.

(a) Incyanate-terminated urethane prepolymer The isonanate-terminated urethane prepolymer that can be used in the present invention is a urethane prepolymer obtained by reacting a polyol with a polyisocyanate compound and capping the ends of the polyol with a polyisocyanate compound. Included.

Polyols used in the preparation of such urethane prepolymers include polyether polyols and polyester polyols, with polyether polyols being generally preferred.

Polyether polyols include, for example, ethylene glycol, propylene glycol,
．． Those obtained by adding alkylene oxides such as ethylene oxide, propylene oxide, butylene oxide to dihydric alcohols such as 4-ethylene glycol and neopentyl glycol, such as polyethylene oxide, polypropylene oxide, poly(ethylene oxide propylene oxide) ) copolymers. These polyether polyols generally have about 200 to
It can have a molecular weight within the range of about 3,000, preferably about 400 to about 1000.

On the other hand, the polyisocyanate compound that can be used for end-capping the polyols can be of any type, such as aliphatic, alicyclic, aromatic, or a mixture of two or more of these. Specific examples include hexamethylene diisocyanate, inphorone diisocyanate, dicyclohexylmethane diisocyanate, tolylene diisocyanate, diphenylmethane diisocyanate, and the like. Among them, tolylene diisocyanate,
Aromatic diisonanates such as diphenylmethane diisocyanate are preferred.

The reaction between the polyols and the polyisocyanate compound can be carried out by a method known per se. For example, the reaction between the polyols and the polyisocyanate compound can be carried out using
Mixed within a range where the H molar ratio is greater than 1 and less than or equal to 2,
The reaction can be carried out without a solvent or by reacting in a suitable solvent such as toluene, tetrahydrofuran or methyl ethyl ketone.

(b) Organic solvent The organic solvent used in combination with the urethane prepolymer is compatible with the urethane prepolymer used and is substantially inert to isocyanate groups at room temperature (usually,
(contains no active hydrogen atoms), is a hydrophilic organic solvent that is soluble in water and pharmaceutically non-toxic.

Here, "soluble in water" means that it is miscible with water in any proportion at a temperature within the range of 20 to 40°C.

Such an organic solvent plays the role of lowering the viscosity of the urethane prepolymer used in combination, imparting hydrophilicity, and improving wettability to living tissues. It does not necessarily have to be hydrophilic like the urethane prepolymers used in adhesives.

The terminal isocyanate moiety of the prepolymer is generally hydrophobic, and by using it in combination with a specific hydrophilic organic solvent according to the present invention, the penetration and diffusion of water in the living body into the adhesive can be moderately controlled, resulting in a urethane prepolymer. In addition to uniform curing of the polymer, the reaction with active hydrogen of hydrophilic functional groups such as carboxyl groups, hydroxyl groups, and amine groups contained in living tissue also occurs smoothly, achieving an elastic bond with excellent adhesive effects. be able to.

Hydrophilic organic solvents that can be used for such purposes include:
Examples include α-pyrrolidone, N-methyl-σ-pyrrolidone, dimethyl sulfoxide, ε-caprolactone, γ-butyrolactone, among others, α-pyrrolidone,
Hydrophilic polar organic solvents such as N-methyl-σ-pyrrolidone and dimethylsulfonoxide are suitable.

The amount of the organic solvent to be used can vary depending on the type of urethane prepolymer used in combination, but is generally l-1 per 100 parts by weight of the urethane prepolymer.
00 parts by weight, preferably 10 to 30 parts by weight. If the amount of organic solvent used is less than 1 part by weight, the urethane prepolymer will not be cured uniformly, and if it exceeds 100 parts by weight, the curing time will become longer and the flexibility of the cured product will tend to be adversely affected. It will be done.

(c) Other additives The adhesive of the present invention can basically consist of the above-mentioned urethane prepolymer (a) and organic solvent (b), but if necessary, a curing catalyst may be added. , a foam stabilizer, etc. may be blended as appropriate.

The curing catalyst that can be blended is preferably one that is pharmaceutically non-toxic, especially an aliphatic carboxylic acid metal salt type,
Among these, carlum salts and sodium salts of aliphatic carboxylic acids are preferred. Examples of aliphatic carboxylic acids that form such metal salts include acetic acid, propionic acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, valmitic acid, stearic acid, malonic acid, succinic acid, Examples include glutamic acid, adipic acid, maleic acid, glycolic acid, lactic acid, malic acid, and tartaric acid.

The amount of the above curing catalyst used is usually 1 part of the urethane prepolymer.
10 parts by weight or less per 00 parts by weight, preferably 0.1 to 5 parts by weight
It can be expressed in parts by weight.

Further, a foam stabilizer may be added as necessary for the purpose of controlling the size of carbon dioxide bubbles generated during urea bond formation.

The surgical adhesive provided by the present invention cures rapidly in a short period of time even in the presence of excess water in a living body, and the cured product is highly flexible and has excellent adhesive properties.

Therefore, the surgical adhesive of the present invention can be used, for example, to join tissues together, to stop bleeding, to embolize, which was conventionally performed using sutures.
It can be widely used for coating, reinforcement, etc.

Next, the present invention will be explained in more detail with reference to Examples.

Examples 1 to 3 (1) Preparation of urethane prepolymer T-80 [2,4-tolylene diisocyanate/2,6-tolylene diisocyanate 80] was placed in a four-bottle flask equipped with a cooling tube.
/20 mixture, manufactured by Sumitomo Bayer Urethane Co., Ltd.] 348
．． Take 3g and stir at room temperature. Carpo wax on this #
400 [Polyethylene glycol, average molecular weight 400
, manufactured by Kokusan Kagaku Co., Ltd.] 400 g was dropped. 80 minutes after dripping
The temperature was raised to 1°C and stirring was continued for 3 hours to obtain a prepolymer. The NCO content of the obtained prepolymer was measured by the dibutylamine method and was found to be 12.8% (theoretical amount 13
．． 4%).

(2) Preparation of adhesive To 10 g of the prepolymer obtained in the above (1), 3 g of α-pyrrolidone, N-methyl α-pyrrolidone, or dimethyl sulfoxide was added and mixed as a hydrophilic organic solvent. In addition, as a catalyst, 1 part of potassium octoate was added to TG-
400 [Polyether polyol, manufactured by Mitsui Nisso Co., Ltd.]
0.1 g of the catalyst obtained by dissolving in 1 part was used.

(3) Adhesion test (a) The adhesive composition thus obtained was tested at a temperature of 25
The mixture was applied to beef (25°C) that had been heated to 25°C and lightly wiped with water, and immediately the uncoated beef was pressed against the coated surface to cure the adhesive. Column (a) of Table 1 shows the curing time and degree of adhesion.

(b) Next, 2 g of water was added to each of the above catalyst-free compositions, stirred, and then applied onto a glass plate and cured at a curing temperature of 25°C. After foaming started due to the curing reaction, the glass plate was applied from above. Cover the top and bottom glass plates with clips to a thickness of about 2mm.
A sheet-like cured product was obtained.

The amount of water is approximately 8 times the molar ratio of the incyanato groups contained in the prepolymer log, and 16 times the amount required for the chain extension reaction. The length of the obtained sheet is 6 cm and the width is 1 cm.
A test piece was taken and a tensile test was carried out at a pulling speed of 100 m.
m/m and temperature (25°C), and the apparent density, breaking strength, and breaking elongation were determined. The results are shown in column (b) of Table 1.

As a comparative example, a prepolymer without the addition of an organic solvent was tested by curing it on beef or with water under the same conditions as in the above example. The results are also shown in Table 1 below.

Claims (1)

[Claims] 1. (a) Isocyanate-terminated urethane prepolymer 1
(b) 1 to 100 parts by weight of an organic solvent that is compatible with the prepolymer, is substantially inert to isocyanate groups at room temperature, is soluble in water, and is pharmaceutically non-toxic. A surgical adhesive characterized by containing: 2. The surgical adhesive according to claim 1, wherein the organic solvent is α-pyrrolidone, N-methyl-α-pyrrolidone, dimethyl sulfoxide, or a mixture thereof. 3. Claim 1 further containing 10 parts by weight or less of a curing catalyst.
Surgical adhesive as described. 4. The surgical adhesive according to claim 2, wherein the curing catalyst is a potassium salt or a sodium salt of an aliphatic carboxylic acid.