JPS62148666A - Surgical adhesive - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to surgical adhesives.

[Prior Art] Conventionally, urethane prepolymers using polytetramethylene glycol (for example, Prog
r, neurol, Surg, , Vol.
3. yen), 1113~168°Karger, Ba5
eland Year BOOk, CI+icag
o 1969) Kaorita.

[Problems to be solved by the invention] However, since the curing reaction of this product due to the reaction with body fluids is uneven, the curing speed is slow, and it is not possible to ensure sufficient strength in terms of bonding with living tissue. . Therefore, when used for adhering blood vessels, etc., there was a problem in that blood oozed out from the surrounding area, eventually leading to a large amount of bleeding.

[Means to solve the problem 1 The inventors of wood
Satisfying the compatibility (use 1q of adhesive for one round, be careful)
As a result of one study, we arrived at the present invention.

However, this Komei is: Taro j1, which is characterized by having an NCO-terminated hydrophilic urethane prepolymer (a) as a main component.
Adhesive for use (first invention): NCO-terminated hydrophilic urethane prepolymer (a) and an m-compatible dim bond, and a cyano group is bonded to the carbon atoms forming the double bond. This is a surgical adhesive (second invention) having a 1S characteristic of containing compound (b) as a main component.

In the present invention, the NCO-terminated hydrophilic urethane prepolymer (a) in J3 is a urethane prepolymer made of polyisocyanate-1 and hydrophilic polyether polyols (and other polyols). can give.

Polyneedle polyΔ-ols include compounds containing at least two active hydrogen atoms (e.g., polyΔ-ol, polyhydric phenol, etc.), ethylene oxide (hereinafter abbreviated as 0), and if necessary, other alkaline f with 1 nylene Δ21-cyto (hereinafter abbreviated as other alkylene oxide AO)
Additions can be given.

Polyols include dihydric alcohols (ethylene glycol, propylene glycol, 1,3- or 1,4-
butylene glycol, neopentyl glycol, hydrogenated bisphenol A1, hydrogenated bisphenol F, polytetramethylene glycol, polyester diol, terminal silanol polysiloxane compound, etc.), trihydric alcohol (
1-limedylol (pan, 1,2,4-butanetriol, 1,2,6-h2-1-lyl, glycerin, polyester 1-lyol, etc.), tetra-helical alcohol (diglyreline, pentaerythryl 1-hel) , sorbitol, sucrose). Examples of polyhydric phenols include bisphenols (bisphenol A, bisphenol F, bisphenol S, etc.). Preferred among these are dillilli alcohols.

As AO, fluorine 1 nylene Δ21- having 3 to 4 carbon atoms
For example, propylene oxide (hereinafter abbreviated as PO)
, butylene oxide (1.2-, 1.3-, 2.
3-Jj and 1,4-butylene oxide) and two or more of these are required. Among these, preferred is LJ: PO. When EO and AO are used for 111, they may be a random copolymer, a block copolymer, or a mixture of both. Preferably it is a random copolymer.

The bare foot (molecular weight per hydroxyl weight) of the hydrophilic polyether polyol is usually 100 to 5,000, preferably 200 to 3,000. If the equivalent weight exceeds 100), it will lack flexibility as an adhesive (if the equivalent weight exceeds 5,000), the flexibility will increase, but the workability due to the upper limit of viscosity will decrease. In practice, it is difficult to use it as a stone contact agent due to the decrease in the viscosity.

Oni 1: Shiedylene ○Right■ in the hydrophilic polyether polyol is usually 30 ffl m % or more, preferably 5
0 to 90 weight. Oxyethylene containing right ω is 30
Since the hydrophilic ability of the material with 60% +1"C is reduced, the reaction with body fluids is reduced, and the curing speed is slowed down.

In addition, it lacks bonding properties with the moisture-rich body composition and the adhesive, making it impossible to find a satisfactory adhesive for external use.

Other polyols that are necessary together with the hydrophilic polyether polyol include the low molecular weight polyol d3.
and/or hydrophobic polyols. Specific examples of these include the polyols mentioned above (mentioned as raw material 1 of hydrophilic polyether polyols) and their AO (=J additives).When used together, the oxy The ethylene content is usually 30% by weight or more, preferably 50 to 1% by weight.

The equivalent weight of the entire polyol is usually 100 to 5.0.
00. Preferably it is 200-3,000.

Examples of polyisocyanes 1 to 1 include aliphatic polyisocyanes 1 to 1 (hekyrimethylene diisocyanate, lysine diisocyanate 1 to etc.), alicyclic polyisocyanes 1 to 1 (dicyclohexylmethane diisocyanate 1 to
-, isophorone diisocyanate 1~, etc.), aroma/Iχ
Polyisocyanate-1 to [tolylene diisocyanate (T
D I ”), diphenylmethane diisocyanate-1-
(MDI), I)-phenylene diisosifune 1,
Examples include naphdilene diisocyanene-1-, 2-1-silylene diisocyanate-1.sudo] and combinations thereof. Among these, preferred are 1 and L-aromatic cyisocyanene-1, and particularly preferred are TDI and MD.
It is I.

These polyisocyanes 1 to 1 are added to crude polyisocyanes 1, for example, by crude TDI, crude MDI, crude diaminodiphenylmethane (a condensation product of bormaldehyde and aromatic/JX amine or a mixture thereof, diaminodiphenylmethane, 20 Q 'j'H96)
3-functional (IF, mixture with the above bo-1 noamines) phosgene compound: to polyarylboriisocyanate I (PAP
I)].

or modified polyisocyanates such as liquefied NII
It can be used as DI (carposiimide modified, 1-copper, 1-lihydrocarbyl small sulfate modified, etc.), and these can also be used as IJ1.

NCO-terminated hydrophilic 1-cretane prepolymer from polyisocyanates and polyether polyols? −(
In the reaction of 1q of a), the N00 base 10+-t clouding is usually 1.5-5.01, preferably 1.7-3,0.

NCO-terminated hydrophilic urethane prepolymer (
The method for converting 1q of a) may be any conventional method, and the reaction may be carried out in the presence of a catalyst.

Sen's polyol is a hydrophilic polyether polyol)
The prepolymer may be prepared after kneading, or the prepolymer may be prepared by sequentially reacting the hydrophilic polyether polyol and other polyols in any order. Alternatively, a urethane prepolymer from a hydrophilic polyneedle polyA-ru is blended with a urethane prepolymer from another polyΔ-ol, for example, a 1-tarethane prepolymer from a hydrophilic polyether polyol is mixed with a low-molecular-weight polyol (hydroxyl It is possible to adjust the viscosity by blending a urethane prepolymer with m8 molecules (H50 to 500).

The isocyanate content of the NCO-terminated hydrophilic urethane prepolymer is 1 to 1, preferably 2 to 8% by weight. If it is less than 1% by weight,
The reactivity of the adhesive becomes low, resulting in a decrease in curing speed and a decrease in bondability with living organisms. When the IQ single ff is more than 1%, although the obtained adhesive has a fast curing speed, the cured product is hard and lacks flexibility, and has the disadvantage that it cannot follow the movements of a living body.

The compound (b) having a polymerizable divalent bond and having a cyano group bonded to the carbon atom forming the double bond, which is used in conjunction with the present invention (second invention), includes, for example, cyano ( meth)acrylic acid (refers to cyanacrylic acid or cyanomethacrylic acid. The same description will be used hereinafter), cyano(meth)acrylic% 1 stel (ethyl cyanoacrylate, ethyl cyanoacrylate, isobutyl cyanacrylate, etc.), (Meta) Acryloni 1 ~ Lil, Cyano (
meta)acryloni 1 heliyl d'3 and mixtures of two or more thereof are required. Preferred among these are cyanacrylic esters, and particularly preferred are medyl cyanacrylate, ethyl cyanacrylate,
J3 and isobutel cyanoacrylate.

In a compound (b) having an associative double bond with the NCO-terminated hydrophilic urethane prepolymer (a) and having a cyano group bonded to the carbon atom forming the two-set bond, a3 is added to (a)
Containment ■ is ILI for the combination of (a) and (b).

It is 20-90%, preferably 30-70%. (a)
If the content is less than 2096, the curing speed is extremely fast, but the flexibility and bonding properties with living tissues are reduced. on the other hand,
(b>10% or more (By using Jf, a fast curing speed can be obtained, and it can be applied to blood vessels that require fast hardening. Also, a predetermined hardening rate that follows the movement of the living body can be obtained. Hardness can be obtained by changing the mixing ratio of (a) and (b).Since flexibility is necessary for adhering blood vessels, adhesives with a high m content (a) are effective, and Adhesives with reduced hardness and a little hardness in (a) are effective for adhesion around bones.

Note that the adhesive of the present invention may contain fillers (for example, carbon black, pen color, calcium chloride,
Silicic acid - Thulium titanium oxide, acrylic 1/1
At the end of fat dressing, various Relamic 4'! J) powder, etc.), softeners (
For example, DBP, DOP, TCP, trib-1~xyethylphosphate-1~, various esters thereof), stabilizers (for example, trimedeldihydroquinone, phenyl-
β-naphthylamine, P-isopropoxydiphenylamine, diphenyl-p-phenylenediamine, etc.) can be blended. The blending amount of these components is usually 0 to 20% by weight, and 0 to 5% by weight, based on the adhesive of the present invention.

In the adhesive of the present invention, the NCO-terminated hydrophilic urethane prepolymer (a), which is the main component, also has a monopolymerizable double bond used in the second invention, and a cyan group is added to the carbon atom forming the two-handed bond. The combined compound (b) also rapidly aggregates in the presence of trace amounts of moisture, such as moisture in the air, forming a strong film, so the main component is Moraro/υ and other compounding agents. It is also necessary to use an anhydrous material, and it is preferable to keep air out during production. The cured adhesive can be stored for a long period of time by, for example, filling it in a container such as an ampoule that is sealed from air.

When bonding biological tissue with the adhesive of the present invention in external oblique surgery, examples of application methods include methods using a brush, tweezers, a special spatula, and a method using a spray using Freon or nitrogen gas. Tissue adhesion methods include direct adhesion, in which adhesive is applied directly to the incision;
Examples include the covering adhesion method, in which a piece of tissue such as muscle is placed on the affected area, and adhesive is applied; suture fixation method, in which a suture is partially applied and adhesive is applied to seal the remaining joint. It will be done. In addition, the adhesive of the present invention can be used not only for bonding living tissue, but also as a coating material or a sealing material for aneurysm etc. by utilizing its flexibility and bonding properties with living tissue.
:0 It can be used as a sealing material to prevent liquid leakage by applying it to a tube or injecting it using a catheter, etc.

[Examples] The present invention will be further described below with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

In the following, PEO represents polyethylene oxide, PPO represents polypropylene oxide, PEG represents polyethylene glycol, PPG represents polypropylene glycol, and PTMG represents polytetra-ramethylene glycol.

The NCO-terminated hydrophilic urethane prepolymer was obtained by mixing and stirring polyisocyanes 1 to 'lJ'i and polyether polyol dehydrated under reduced pressure, and reacting the mixture at a temperature of 80°C for 8 hours.

Parts in Examples and Comparative Examples are parts by weight.

The prepolymer rice cyano compounds used in the Examples and Comparative Examples are as follows.

(1) Prepolymer A1: TI)I and polyether polyol (PFO-PPO
A random copolymer, average molecular t, 4H3,000, was reacted with oxyethylene (1 m 80%) and 157 was obtained.
NC○-terminated hydrophilic urethane prepolymer (NCO content 2.5%).

(2) Prepolymer A2: NCO-terminated hydrophilic urethane prepolymer obtained by reacting MDI with polyether polyol (PFO-PPO random copolymer, average molecular aa, ooo, oxyethylene content FF 160%) (NCO content 3.5%
).

(3) Prepolymer A3: TDI, polyether polyol [PEG (average molecular weight FA 2,000> 80 parts) and PPG (average molecular weight 20 parts
0) a mixture with 20 parts] of NCO
Terminal hydrophilic urethane prepolymer (NCO content 6.4
%).

(4) Prepolymer A4: TDI and polyether polyol (PTMG-PEO
NCO-terminated hydrophilic urethane prepolymer (NCO content 6.7%) obtained by reacting a block copolymer, average molecular weight 2,000, oxyethylene content gi 59%).
).

(5) Prepolymer: TDI and PTMG (average molecular weight 1000) were reacted to form an NCO-powdered 4111 urethane prepolymer (11).
NCO content 6.2%).

(6) Prepolymer■: TDI and PFO-PPG random co-wheel metal wheel combination homogeneous molecule=
NCO-terminated urethane prepolymer (NCO content: 2.5%) obtained by reacting NCO-terminated urethane prepolymer (NCO content: 2.5%).

(7) Prepolymer ■: NCO-terminated hydrophilic urethane prepolymer obtained by reacting TDI with polyether polyol (PEO-PPO random copolymer, average molecular B 3,000°, oxyethylene content ff110%) (NCO content 2.5%
).

(8) Cyano compounds: ECA Ethyl diane acrylate MCA Methyl diane acrylate BCA Isobutyl diane acrylate Examples 1 to 4 Prepolymer A1. A2, A3 or A4/) adhesive for external use.

Example 5 A Yuhi j1-period adhesive obtained by dehydrating, mixing and stirring 150 parts of prepolymer A and 30 parts of ECA.

Example 6 A surgical adhesive obtained by dehydrating, mixing and stirring 270 parts of prepolymer A and 30 parts of MCA.

Example 7 Dehydrated mixing of 350 parts of prepolymer A and 50 parts of BCA 1)
Surgical adhesive obtained by stirring.

Example 8 Dehydrated mixing of 440 parts and 60 parts of ECA to prepolymer 1i
2. Surgical adhesive obtained by stirring.

Comparative example 1 Adhesive whose main component is ECA.

Comparative example 2 Adhesive for Taro 91 made of prepolymer T.

Comparative example 3 Surgical adhesive consisting of prepolymer ■.

Comparative Example 4 7 parts of nitrile rubber (38-40%) was dissolved in 50 parts of dehydrated and dried nitromethane, and ECA7
Adhesive obtained by adding 1 part of TDII and stirring 1f2 parts.

Comparative Example 5 Surgical No. 11 dressing obtained by dehydrating and stirring 150 parts of prepolymer and 30 parts of ECA.

Test Example: The carotid artery (outer diameter of about 11 mm) of an adult goat was temporarily electrically connected to a section of about 5 mm.
Make a cut in the longitudinal direction of the blood vessel and apply a small amount of adhesive for the opening. Time to hardening (6 and 5 minutes later, blood flow is resumed and the adhesion with the tissue of the incision is evaluated1i1
ri L, ta.

', 7 i1'j, In order to exclude the influence of the W surface effect due to blood coagulation and to examine the effect of the adhesive, the test was conducted under anticoagulation with heparin. The test results are listed in Table 1.

Table 1 [Results of the invention 1 NCO-terminated hydrophilic urethane prepolymer of the present invention (a)
Al, which has a high curing speed and is effective in reducing surgical time. J: For biological use 1
Since it also promotes bonding with people 11],
There is an effect of certainty that increases r7 by 1. In addition, it has a high flexibility that allows it to follow the movements of the cow's body (4).

NCO powder 4η of the present invention: hydrophilic urethane prepolymer
(a) and a compound (b) which has a polymerizable double bond and has a cyano group bonded to the carbon atom forming the double bond (second invention), Not only from the biological contact surface due to the rapid hand reaction with body fluids (moisture) and the reaction 1'l to the terminal isocyanate 1 in (a),
It has the effect of accelerating the curing speed of the entire adhesive, including the inside. In addition, the reactivity of (a) and (b) greatly promotes the bonding with living tissue as a whole, which has the effect of increasing the reliability of surgery. Moreover, since it has high flexibility, it has the effect of being able to follow the movements of a living body.

Conventionally, adhesives for external use have been used: ■Adhesives whose main component is ethyl cyanoacrylate; and ■Adhesives in which tolylene diisocyanate and diene polymer cyanoacrylate are dissolved in an organic solvent. ■Although it is superior in terms of fast curing speed, the cured product is hard and lacks flexibility, and it has the disadvantage that it easily peels off when a slight mechanical stress (such as pulsating flow) is applied. In addition, although a diene polymer is added to give flexibility, the diene polymer itself has no curing reactivity, and it is difficult to bond with living tissue and bind to biological tissues, so it cannot be used externally. When used as an adhesive, it is not different from Jl:l-/L in terms of curing speed and bonding ability with living tissue, and it is also necessary to dissolve diene polymers. There was a problem in terms of the safety of the organic solvent itself for living tissues. In contrast, the adhesive of the present invention does not contain any solvent in its components, has a curing speed required for adhesives for external use, has good bonding ability with biological tissue, and can follow the movements of living organisms. It satisfies all three points regarding flexibility.

The application of the adhesive of the present invention to the above-mentioned 11 surgeries makes it possible to use an anastomotic technique using an adhesive technique in addition to the conventional suturing technique, shortening the surgical time, and reducing the appearance of the protruding type and minimal blood vessels. Improvements in medical technology have been shown to be effective in preventing stenosis accidents and other issues. In addition, the combination of temporary fixation, suturing, and adhesion prior to suturing has a wide range of applications, such as reliability, and has the effect of imparting high reliability and high performance to all surgeries.

Claims (1)

[Claims] 1. A surgical adhesive characterized by containing an NCO-terminated hydrophilic urethane prepolymer (a) as a main component. 2. The adhesive according to claim 1, wherein (a) is a prepolymer of polyisocyanates and hydrophilic polyether polyols, and the isocyanate group content is 1 to 10% by weight. 3. The adhesive according to claim 2, wherein the hydrophilic polyether polyol is an adduct of a compound having at least two active hydrogens, ethylene oxide, and optionally another alkylene oxide. 4. The adhesive according to claim 2 or 3, wherein the oxyethylene content in the hydrophilic polyether polyol is 30% by weight or more. 5. NCO-terminated hydrophilic urethane prepolymer (a);
1. A surgical adhesive comprising as a main component a compound (b) having a polymerizable double bond and having a cyano group bonded to the carbon atom forming the double bond. 6. The adhesive according to claim 5, wherein (a) is a prepolymer of polyisocyanates and hydrophilic polyether polyols, and the isocyanate group content is 1 to 10% by weight. 7. The adhesive according to claim 6, wherein the hydrophilic polyether polyol is an adduct of a compound having at least two active hydrogens, ethylene oxide, and optionally another alkylene oxide. 8. The adhesive according to claim 6 or 7, wherein the oxyethylene content in the hydrophilic polyether polyol is 30% by weight or more. 9. The adhesive according to any one of claims 5 to 8, wherein (b) is a cyanoacrylate ester. 10. Claims 5 to 9 in which the content of (a) is 20 to 90% of the total weight of (a) and (b)
Adhesives according to any one of paragraphs.