JPH0237785B2 - - Google Patents

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, Progr.neurol.Surg., Vol.3, PP.116~
168, Karger, Baseland Yearn Book,
Chicago 1969). [Problems to be Solved by the Invention] However, with this product, the curing reaction due to the reaction with body fluids is uneven, so the curing speed is slow, and sufficient strength cannot be obtained in terms of bondability 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 for Solving the Problems] The present inventors have conducted intensive studies to obtain a surgical adhesive that satisfies fast curing speed and bonding properties with living tissue, and as a result, has arrived at the present invention. That is, the present invention provides: A surgical adhesive (first invention) characterized in that the main component is an NCO-terminated hydrophilic urethane prepolymer (a); A surgical adhesive (second invention) characterized in that the main component is a compound (b) having a double bond and having a cyano group bonded to the carbon atom forming the double bond. In the present invention, examples of the NCO-terminated hydrophilic urethane prepolymer (a) include urethane prepolymers made of polyisocyanates and hydrophilic polyether polyols (and other polyols if necessary). Polyether polyols include compounds having at least two active hydrogens (for example, polyols, polyhydric phenols, etc.), ethylene oxide (hereinafter abbreviated as EO) and, if necessary, other alkylene oxides (hereinafter other alkylene oxides).
(abbreviated as AO). As polyols, dihydric alcohols (ethylene glycol, propylene glycol, 1,3-
or 1,4-butylene glycol, neopentyl glycol, hydrogenated bisphenol A, hydrogenated bisphenol F, polytetramethylene glycol,
polyester diol, terminal silanol polysiloxane compound, etc.), trihydric alcohol (trimethylolpropane, 1.2.4-butanetriol,
1.2.6-hexanetriol, glycerin, polyester triol, etc.), tetrahydric to octahydric alcohols (diglycerin, pentaerythritol, sorbitol, sucrose, etc.). Polyvalent phenols include bisphenols (bisphenol A, bisphenol F, bisphenol S, etc.)
can be given. Among these, preferred are dihydric alcohols. Examples of AO include alkylene oxides having 3 to 4 carbon atoms, such as propylene oxide (hereinafter abbreviated as PO), butylene oxide (1.2-, 1.3-, 2.3- and 1.4-butylene oxide), and two or more thereof. Among these, preferred is PO. When EO and AO are used in combination, a random copolymer, a block copolymer, or a mixture of both may be used. Preferably it is a random copolymer. The equivalent weight (molecular weight per hydroxyl group) of the hydrophilic polyether polyol is usually 100 to 5,000, preferably 200 to 3,000. If the equivalent weight is less than 100, it lacks flexibility as a surgical adhesive; if it exceeds 5,000, the flexibility increases but the workability decreases due to increased viscosity, so it cannot be used as a surgical adhesive in practice. becomes difficult. The oxyethylene content in the hydrophilic polyether polyol is usually 30% by weight or more, preferably 50% by weight or more.
~90% by weight. When the oxyethylene content is less than 30% by weight, the hydrophilic ability decreases, so the reactivity with body fluids decreases and the curing speed becomes slow. Also,
It also lacks bonding properties with moisture-rich living tissues, making it impossible to obtain a satisfactory surgical adhesive. Other polyols that may be used along with the hydrophilic polyether polyol include low molecular weight polyols and/or hydrophobic polyols. Specific examples of these are listed above (as raw materials for hydrophilic polyether polyols).
Mention may be made of polyols and their AO adducts. When used together, the oxyethylene content in the total polyol is usually 30% by weight or more, preferably 50~
It is 90% by weight. The equivalent weight of the entire polyol (average) is usually 100~
5000, preferably 200-3000. Examples of polyisocyanates include aliphatic polyisocyanates (hexamethylene diisocyanate, lysine diisocyanate, etc.), alicyclic polyisocyanates (dicyclohexylmethane diisocyanate, isophorone diisocyanate, etc.), aromatic polyisocyanates [tolylene diisocyanate (TDI), diphenyl, etc.] methane diisocyanate (MDI), p-phenylene diisocyanate, naphthylene diisocyanate, xylylene diisocyanate, etc.] and mixtures thereof. Among these, aromatic diisocyanates are preferred, and TDI and MDI are particularly preferred. These polyisocyanates include crude polyisocyanates such as crude TDI, crude MDI [crude diaminodiphenylmethane {condensation product of formaldehyde and aromatic amines or mixtures thereof: diaminodiphenylmethane and a small amount (e.g. 5-20% by weight)] It can also be used as a phosgene compound (polyallyl polyisocyanate (PAPI)), a mixture with a trifunctional or more functional polyamine. or modified polyisocyanates such as liquefied MDI
(Carbodiimide modified, trihydrocarbyl phosphate modified, etc.)
Moreover, these can also be used together. In the reaction for obtaining the NCO-terminated hydrophilic urethane prepolymer (a) from polyisocyanates and polyether polyols, the NCO group/OH group ratio is usually 1.5 to 5.0, preferably 1.7 to 3.0. The method of reacting polyisocyanates and polyether polyols to obtain the NCO-terminated hydrophilic urethane prepolymer (a) may be a conventional method, and the reaction may be carried out in the presence of a catalyst. Other polyols may be mixed with hydrophilic polyether polyols to produce prepolymers, or hydrophilic polyether polyols and other polyols may be reacted sequentially in any order to produce prepolymers. . Also, urethane prepolymers from hydrophilic polyether polyols and urethane prepolymers from other polyols may be blended; for example, urethane prepolymers from hydrophilic polyether polyols are mixed with low-molecular-weight polyols (molecular weight per hydroxyl group: It is possible to adjust the viscosity by blending a urethane prepolymer of ~500). The isocyanate group content of the NCO-terminated hydrophilic urethane prepolymer is 1 to 10% by weight, 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 amount is more than 10% by weight, although the resulting adhesive has a fast curing speed, the cured product is hard and lacks flexibility, and has the disadvantage of not being able to follow the movements of living organisms. The compound (b) having a polymerizable double bond and having a cyano group bonded to the carbon atom forming the double bond used in the present invention (second invention) is as follows:
For example, cyano(meth)acrylic acid [cyanoacrylic acid or cyanomethacrylic acid]. The same description will be used below], cyano(meth)acrylic esters (methyl cyanoacrylate, ethyl cyanoacrylate, isobutyl cyanoacrylate, etc.), (meth)acrylonitrile, cyano(meth)acrylonitrile, and two or more of these A mixture can be mentioned. Preferred among these are cyanoacrylates, and particularly preferred are methyl cyanoacrylate, ethyl cyanoacrylate, and isobutyl cyanoacrylate. In the compound (b) which has a polymerizable double bond with the NCO-terminated hydrophilic urethane prepolymer (a) and has a cyano group bonded to the carbon atom forming the double bond, the content of (a) is as follows: It is usually 20 to 90%, preferably 30 to 70%, based on the total weight of (a) and (b). If the content of (a) is less than 20%, the curing speed is extremely fast, but the flexibility and bonding properties with living tissue decrease.
On the other hand, by using 10% or more of (b) in combination, a fast curing speed can be obtained, and it can be applied to blood vessel adhesion, etc., which require fast curing properties. Further, a predetermined hardness that follows the movement of a living body can be obtained by changing the mixing ratio of (a) and (b). Adhesives with a high content of (a) are effective for adhering blood vessels because flexibility is required, and adhesives with a high content of (a) are effective for adhering bones and their surroundings. Adhesive is effective. The adhesive of the present invention may optionally contain fillers (for example, carbon black, red iron oxide, calcium silicate, sodium silicate, titanium oxide, acrylic resin powder, various ceramic powders, etc.),
Softeners (e.g. DBP, DOP, TCP, tributoxyethyl phosphate, and various other esters), stabilizers (e.g. trimethyldihydroquinone, phenyl-β-naphthylamine, P-isopropoxydiphenylamine, diphenyl-P
-phenylenediamine, etc.) can be blended. The amount of these compounds is usually 0 to 20% by weight, preferably 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 polymerizable double bond, which is used in the second invention, and has a cyano group on the carbon atom forming the double bond. compound (b) combined with
In both cases, the presence of a small amount of moisture, such as moisture in the air, causes rapid polymerization and forms a strong film, so it is necessary to use anhydrous main ingredients as well as other ingredients. It is preferable to shut off air during manufacturing as well. The obtained adhesive can be stored for a long period of time by filling it into a container such as an ampoule that is sealed from air. When joining living tissues with the adhesive of the present invention in a surgical operation, the application method includes, for example,
Methods include using a brush, tweezers, a special spatula, and spraying using Freon or nitrogen gas. As a method of adhering tissues,
Direct adhesive method in which adhesive is applied directly to the incision; a thin piece of cloth or cotton-like material such as Dacron, oxidized cellulose, collagen, or polyurethane, or a piece of tissue such as vein, fascia, or muscle is placed on the affected area and adhesive is applied. Covering and adhesion methods include; suture fixation methods in which sutures are placed partially and adhesive is applied to seal the remaining joints; In addition, the adhesive of the present invention can be used not only for joining living tissues, but also as a coating material for aneurysms, a plug material, and a sealing material for cerebrospinal fluid leakage by utilizing its flexibility and bonding properties with living tissues. It can be used by methods such as application to the skin or injection using a catheter or the like. [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 refers to polyethylene oxide,
PPO stands for polypropylene oxide, PEG stands for polyethylene glycol, PPG stands for polypropylene glycol, and PTMG stands for polytetramethylene glycol. The NCO-terminated hydrophilic urethane prepolymer was obtained by mixing and stirring polyisocyanates 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 prepolymers and cyano compounds used in Examples and Comparative Examples are as follows. (1) Prepolymer A ₁ : TDI and polyether polyol (PEO-
NCO-terminated hydrophilic urethane prepolymer (NCO content 2.5%) obtained by reacting PPO random copolymer, average molecular weight 3000, oxyethylene content 80%). (2) Prepolymer A ₂ : MDI and polyether polyol (PEO-
NCO-terminated hydrophilic urethane prepolymer (NCO content 3.5%) obtained by reacting PPO random copolymer, average molecular weight 4000, oxyethylene content 60%). (3) Prepolymer A ₃ : TDI, polyether polyol [PEG (average molecular weight 2000) 80 parts and PPG (average molecular weight 200)
20 parts of NCO
Terminal hydrophilic urethane prepolymer (NCO content 6.4%). (4) Prepolymer A ₄ : TDI and polyether polyol (PTMG)
-PEO block copolymer, average molecular weight 2000,
NCO-terminated hydrophilic urethane prepolymer (NCO content: 6.7%) obtained by reacting NCO-terminated hydrophilic urethane prepolymer (oxyethylene content: 50%). (5) Prepolymer: NCO-terminated urethane prepolymer (NCO content 6.2%) obtained by reacting TDI and PTMG (average molecular weight 1000). (6) Prepolymer: NCO-terminated urethane prepolymer (NCO content 2.5%) obtained by reacting TDI with a PEO-PPG random copolymer (average molecular weight 3000, oxyethylene content 20%). (7) Prepolymer: TDI and polyether polyol (PEO-
NCO-terminated hydrophilic urethane prepolymer (NCO content 2.5%) obtained by reacting PPO random copolymer, average molecular weight 3000, oxyethylene content 10%). (8) Cyano compound: ECA: Ethyl cyanoacrylate MCA: Methyl cyanoacrylate BCA: Isobutyl cyanoacrylate Examples 1 to 4 Surgical adhesive consisting of prepolymers A ₁ , A ₂ , A ₃ or A ₄ . Example 5 A surgical adhesive obtained by dehydrating, mixing and stirring 50 parts of prepolymer A ₁ and 50 parts of ECA. Example 6 Surgical adhesive obtained by dehydrating, mixing and stirring 70 parts of prepolymer A ₂ and 30 parts of MCA. Example 7 Surgical adhesive obtained by dehydrating, mixing and stirring 50 parts of prepolymer _A3 and 50 parts of BCA. Example 8 Surgical adhesive obtained by dehydrating and stirring 40 parts of prepolymer _A4 and 60 parts of ECA. Comparative Example 1 Adhesive whose main component is ECA. Comparative Example 2 Surgical adhesive consisting of prepolymer. Comparative Example 3 Surgical adhesive consisting of prepolymer. Comparative Example 4 7 parts of nitrile rubber (nitrile content 38-40%) was dissolved in 50 parts of dehydrated and dried nitromethane, and
Obtained by adding 7 parts of ECA and 1 part of TDI and mixing and stirring.
glue. Comparative Example 5 Surgical adhesive obtained by dehydrating, mixing and stirring 50 parts of prepolymer and 50 parts of ECA. Test example: The carotid artery of an adult goat (outer diameter approximately 4 mm) was temporarily tied to a length of approximately 5 mm, and the carotid artery was tied at approximately equal intervals of approximately 3 mm.
A cut was made (in the long axis direction of the blood vessel) and a small amount of surgical glue was applied. The time until hardening and the blood flow was resumed 5 minutes later, and the adhesion with the tissue of the incision was evaluated. In addition, in order to exclude the effect of hemostasis 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] [Effects of the Invention] The surgical adhesive containing the NCO-terminated hydrophilic urethane prepolymer (a) of the present invention as a main component has a fast curing speed and is effective in shortening surgical time. Furthermore, since it greatly promotes the bonding ability with living tissue, it has the effect of increasing the reliability of surgery. Furthermore, since it has high flexibility, it has the effect of being able to follow the movements of a living body. Adhesive ( The second invention) has the effect of accelerating the curing speed not only from the biological contact surface but also from the entire adhesive interior, including the inside of the adhesive, due to the rapid polymerization reaction caused by body fluids (moisture) in b and the reactivity caused by the terminal isocyanate in (a). There is. 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. As surgical adhesives, adhesives mainly composed of ethyl cyanoacrylate and adhesives prepared by dissolving tolylene diisocyanate, diene polymers, and cyanoacrylate in organic solvents have been conventionally used; Although it is excellent, the cured product is hard and lacks flexibility, and has the disadvantage that it easily peels off when a slight mechanical stress (such as pulsatile flow) is applied; Although a diene polymer is added to give properties, the diene polymer itself has no curing reactivity and does not bond with living tissue, so when used as a surgical adhesive, it has a hard time curing speed and bonding with living tissue. It is not satisfactory in terms of connectivity,
Furthermore, there was a problem in terms of the safety of the organic solvent itself necessary for dissolving the diene polymer against living tissue. On the other hand, the adhesive of the present invention does not contain any organic solvent in its components, and has the following three points: curing speed required for surgical adhesives, bondability with biological tissues, and flexibility that can follow the movements of living organisms. I am satisfied with all of the above. From the above, the application of the adhesive of the present invention to surgical operations makes it possible to use an anastomotic technique using an adhesive technique in addition to the conventional suture technique, thereby shortening the surgical time, preventing bleeding, and minimizing the risk of stenosis of blood vessels. Improvements in medical technology can be seen to have a major effect, such as the avoidance of
In addition, it has a wide range of applications, including temporary fixation prior to suturing and reliability by using suturing and adhesion in combination, and is effective in providing high reliability and performance in all surgeries.

Claims (1)

[Scope of Claims] 1. A surgical adhesive characterized by containing an NCO-terminated hydrophilic urethane prepolymer (a) as a main component. 2 (a) is a prepolymer made of polyisocyanates and hydrophilic polyether polyols,
The adhesive according to claim 1, wherein 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 other 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 (a) is a prepolymer made of polyisocyanates and hydrophilic polyether polyols,
The adhesive according to claim 5, wherein 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 The content of (a) is relative to the total weight of (a) and (b)
Adhesive according to any one of claims 5 to 9, which has a content of 20 to 90%.