JPH0622561B2 - Surgical adhesive - Google Patents

Description

TECHNICAL FIELD The present invention relates to a surgical adhesive.

[Prior Art] Conventionally, urethane prepolymers using polytetramethylene glycol as a surgical adhesive (for example, Progr.
eurol. Surg. Vol. 3, PP. 116 ~ 168, Karger, Basela
nd Yearn Book, Chicago 1969).

[Problems to be Solved by the Invention] However, this compound has a non-uniform curing reaction due to a reaction with a body fluid, so that the curing rate becomes slow, and sufficient strength cannot be obtained in terms of bondability with biological tissues. Therefore, when it is used for adhesion of blood vessels and the like, there has been a problem that blood oozes out from the peripheral portion and finally a large amount of bleeding occurs.

[Means for Solving the Problems] The present inventors have arrived at the present invention as a result of intensive studies to obtain a surgical adhesive that satisfies a high curing rate and a bondability with living tissues.

That is, the present invention comprises: a surgical adhesive (first invention), which is mainly composed of an NCO-terminated hydrophilic urethane prepolymer (a) from p-phenylene diisocyanate and hydrophilic polyether polyols; And NCO-terminated hydrophilic urethane prepolymers from p-phenylene diisocyanate and hydrophilic polyether polyols
A surgical adhesive comprising (a) and a compound (b) having a polymerizable double bond and having a cyano group bonded to a carbon atom forming the double bond as main components (first 2 invention).

In the present invention, NCO-terminated hydrophilic urethane prepolymer
As (a), a urethane prepolymer from p-phenylene diisocyanate [hereinafter abbreviated as PPDI] (or polyisocyanates mainly composed of PPDI), hydrophilic polyether polyols (and other polyols if necessary) is used. can give.

The polyether polyols include compounds having at least two active hydrogens (for example, polyol, polyhydric phenol, etc.) and ethylene oxide (hereinafter abbreviated as EO).
And, if necessary, an adduct with other alkylene oxide (hereinafter, other alkylene oxide is abbreviated as AO).

As the polyol, a dihydric alcohol (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, polyestertriol, etc.) and tetra- to octahydric alcohols (diglycerin, pentaerythritol, sorbitol, sucrose, etc.). Examples of polyphenols include bisphenols (bisphenol A, bisphenol F, bisphenol S, etc.). Among these, a dihydric alcohol is preferable.

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 double or more thereof. Of these, PO is preferred. When EO and AO are used in combination, they may be random copolymers, block copolymers, or a mixed system of both. A random copolymer is preferred.

Equivalent weight of hydrophilic polyether polyol (molecular weight per hydroxy group) is usually 100 to 5,000, preferably 200 to 3,000.
Is. When the equivalent weight is less than 100, it lacks flexibility as a surgical adhesive; when it exceeds 5,000, it is practically used as a surgical adhesive due to increased flexibility but reduced workability due to increased viscosity. Will be difficult.

The oxyethylene content in the hydrophilic polyether polyol is usually 30% by weight or more, preferably 50 to 90% by weight. When the content of oxyethylene is less than 30% by weight, the hydrophilic ability is lowered, the reactivity with body fluid is lowered, and the curing rate is slowed. In addition, the adhesiveness to a living tissue rich in water is also lacking, and a satisfactory surgical adhesive cannot be obtained.

Other polyols optionally used with the hydrophilic polyether polyols include low molecular weight polyols and / or hydrophobic polyols. Specific examples thereof include the above-mentioned polyols (given as the raw material of the hydrophilic polyether polyol) and their AO adducts. When used in combination, the content of oxyethylene in all polyols is usually 30% by weight or more, preferably 50 to
90% by weight.

The equivalent weight of the entire polyol (average) is usually 100 to 5,000, preferably 200 to 3,000.

As the polyisocyanate used for producing the prepolymer (a), PPDI is preferable, but polyisocyanates mainly containing PPDI can also be used. As the polyisocyanate mainly composed of PPDI, a combination of PPDI and a small proportion (usually 50% by weight or less, preferably 30% by weight or less) of other polyisocyanates can be used. Examples of other polyisocyanates include aliphatic polyisocyanates (hexamethylene diisocyanate, lysine diisocyanate, etc.), alicyclic polyisocyanates (dicyclohexylmethane diisocyanate, isophorone diisocyanate, etc.), aromatic polyisocyanates [tolylene diisocyanate (TDI), diphenylmethane Diisocyanate (MDI), naphthylene diisocyanate, xylylene diisocyanate, etc.] and mixtures thereof. Among the other polyisocyanates, preferred are aromatic diisocyanates, and particularly preferred are TDI and MDI.

These polyisocyanates are crude polyisocyanates such as crude TDI, crude MDI [crude diaminodiphenylmethane {condensation product of formaldehyde and aromatic amine or mixture thereof: diaminodiphenylmethane and a small amount (for example, 5 to 20% by weight) of a trifunctional or higher functional compound. Mixture with polyamine} phosgene compound: polyallyl polyisocyanate (PAPI)]. Alternatively modified polyisocyanates such as liquefied M
It can also be used as DI (carbodiimide modified, trihydrocarbyl phosphate modified, etc.), or can be used together.

NCO from PPDI (or polyisocyanates mainly composed of PPDI) and polyether polyols
In the reaction for obtaining the terminal hydrophilic urethane prepolymer (a), the NCO group / OH group ratio is usually 1.5 to 5.0, preferably 1.
7 to 3.0.

By reacting PPDI (or polyisocyanates mainly composed of PPDI) and polyether polyols, N
The method for obtaining the CO-terminated hydrophilic urethane prepolymer (a) may be an ordinary method, and the reaction may be carried out in the presence of a catalyst.

The other polyol may be mixed with the hydrophilic polyether polyol to produce the prepolymer, or the hydrophilic polyether polyol and the other polyol may be sequentially reacted in any order to produce the prepolymer. . Further, a urethane prepolymer made from a hydrophilic polyether polyol may be blended with a urethane prepolymer made from another polyol. For example, a urethane prepolymer made from a hydrophilic polyether polyol may be blended with a low molecular weight polyol (having a molecular weight of 50 per hydroxyl group). ~ 500) urethane prepolymer can be blended to adjust the viscosity. When using a polyisocyanate mainly composed of PPDI, it is preferable to react the PPDI so that it comes to the terminal of the prepolymer (a) (other polyisocyanates are reacted in the initial stage of prepolymer production).

The isocyanate group content of the NCO-terminated hydrophilic urethane prepolymer (a) is usually 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, and the curing rate and the bondability to a living body are reduced. If it is more than 10% by weight, the obtained adhesive has a high curing speed, but the cured product is stiff and lacks flexibility,
It has a drawback that it cannot follow the movement of the living body.

Examples of 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) include, for example, cyano (meth) Acrylic acid [refers to cyanoacrylic acid or cyanomethacrylic acid. The same description is used below], cyano (meth) acrylic acid ester (such as methyl cyanoacrylate, ethyl cyanoacrylate, and isobutyl cyanoacrylate), (meth) acrylonitrile, cyano (meth) acrylonitrile, and two or more of these. A mixture can be given. Of these, preferred are cyanoacrylates, and particularly preferred are methyl cyanoacrylate, ethyl cyanoacrylate, and isobutyl cyanoacrylate.

N from PPDI and hydrophilic polyether polyols
In the CO-terminated hydrophilic urethane prepolymer (a) and the compound (b) having a polymerizable double bond and having a cyano group bonded to the carbon atom forming the double bond, the content of (a) is
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 rate will be extremely high, but the flexibility and the bondability with living tissue will deteriorate. On the other hand, when (b) is used in an amount of 10% or more, a fast curing rate can be obtained, and it can be applied to adhesion of blood vessels which requires fast hardening. Further, the predetermined hardness that follows the movement of the living body can be obtained by changing the mixing ratio of (a) and (b). Adhesives with a high content of (a) are effective because adhesion of blood vessels requires flexibility, and the content of (a) was reduced for adhesion around bones and bones, and a little hardness was added. Adhesives are effective.

In the adhesive of the present invention, if necessary, a filler (for example, carbon black, red iron oxide, calcium silicate, sodium silicate, titanium oxide, acrylic resin powder, various ceramic powders, etc.), a softening agent (for example, DBP). ,
DOP, TCP, tributoxyethyl phosphate, other various esters, etc.), stabilizers (eg trimethyldihydroquinone, phenyl-β-naphthylamine, P
-Isopropoxydiphenylamine, diphenyl-P-phenylenediamine, etc.) can be added. The compounding amount thereof is usually 0 to 20% by weight, preferably 0 to 5% by weight, based on the adhesive of the present invention.

The NCO-terminated hydrophilic urethane prepolymer (a) from PPDI and hydrophilic polyether polyols, which are the main components of the adhesive of the present invention, also has a polymerizable double bond used in the second invention and The compound (b) in which a cyano group is bonded to the carbon atom forming the double bond also undergoes rapid polymerization due to the presence of a small amount of water, for example, water in the air to form a tough film. Needless to say, it is necessary to use anhydrous other compounding agents, and it is preferable to shut off the air during the production. The obtained adhesive can be stored for a long period of time, for example, by filling it in a container such as an ampoule with air blocked.

In the surgical operation, when the biological tissues are joined with the adhesive of the present invention, examples of the application method include a method using a writing brush, tweezers, a special spatula, and a method using spraying using Freon or nitrogen gas. As a method for adhering tissue, a direct adhesive method in which an adhesive is directly applied to the incision; thin cloth pieces such as Dacron, oxidized cellulose, collagen, polyurethane, etc., and cotton-like material, and tissue pieces such as veins, fascia, and muscle are affected. Then, there is a coating adhesion method of applying an adhesive; a suture fixing method of applying an adhesive so that a suture is partially applied to seal the remaining joints.
Further, the adhesive of the present invention can be applied not only to the joining of living tissues but also to the pipe portion as a coating substance for an aneurysm or the like by utilizing the flexibility and the bondability with living tissues, or as a sealing substance for sealing plugs, cerebrospinal fluid leakage, etc. It can be used by a method such as application of a drug or injection using a catheter.

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

In the following, PEO is polyethylene oxide, PPO is polypropylene oxide, PEG is polyethylene glycol, PPG is polypropylene glycol, and PTMG is polytetramethylene glycol.

The NCO-terminated hydrophilic urethane prepolymer was obtained by mixing and stirring polyisocyanates and polyether polyol dehydrated under reduced pressure and reacting at a temperature of 80 ° C. for 8 hours.

Parts in the examples and comparative examples are parts by weight.

The prepolymers and cyano compounds used in the examples and comparative examples are as follows.

(1) Prepolymer A ₁ : PPCO and a polyether polyol (PEO-PPO random copolymer, average molecular weight 3,000, oxyethylene content 80%) obtained by reacting NCO-terminated hydrophilic urethane prepolymer (NCO Content rate 2.5%).

(2) Prepolymer A ₂ : PPDI and polyether polyol (PEO-PPO
NCO-terminated hydrophilic urethane prepolymer (NCO content rate 3.5%) obtained by reacting with a random copolymer, average molecular weight 4,000, oxyethylene content 60%).

(3) Prepolymer A ₃ : An NCO-terminated hydrophilic urethane prepolymer obtained by reacting PPDI with a polyether polyol [a mixture of 80 parts of PEG (average molecular weight 2,000) and 20 parts of PPG (average molecular weight 200)] Polymer (NCO content 6.4%).

(4) Prepolymer A ₄ : PPDI and polyether polyol (PTMG-PE
NCO-terminated hydrophilic urethane prepolymer (NCO content 6.7%) obtained by reacting an O block copolymer, average molecular weight 2,000, oxyethylene content 50%).

(5) Prepolymer B ₁ : NDI-terminated hydrophilic urethane prepolymer obtained by reacting TDI with a polyether polyol (PEO-PPO random copolymer, average molecular weight of 3,000, oxyethylene content of 80%) ( NCO content 2.5%).

(6) Prepolymer B ₂ : NCO-terminated hydrophilic urethane prepolymer obtained by reacting MDI with a polyether polyol (PEO-PPO random copolymer, average molecular weight 4,000, oxyethylene content 60%) ( NCO content 3.5%).

(7) Prepolymer B _3: TDI and, [mixture of PEG (average molecular weight: 2,000) 80 parts of PPG (average molecular weight 200) 20 parts] Polyether polyols and obtained by reacting, NCO-terminated hydrophilic urethane prepolymer Polymer (NCO content 6.4%).

(8) Prepolymer B ₄ : TDI and polyether polyol (PTMG-PEO
NCO-terminated hydrophilic urethane prepolymer (NCO content 6.7%) obtained by reacting a block copolymer with an average molecular weight of 2,000 and oxyethylene content of 50%.

(9) Prepolymer I: NCO-terminated urethane prepolymer obtained by reacting TDI with PTMG (average molecular weight 1000) (NCO content 6.
2%).

(10) Prepolymer II: TDI and PEO-PPG random copolymer (average molecular weight
NCO terminated urethane prepolymer (NCO content 2.5, obtained by reacting with 3000, oxyethylene content 20%)
%).

(11) Prepolymer III: TDI and polyether polyol (PEO-PPO random copolymer, (average molecular weight 3,000, oxyethylene content 10%), obtained by reacting NCO-terminated hydrophilic urethane prepolymer ( NCO content 2.5%).

(12) Cyano compound: ECA: ethyl cyanoacrylate MCA: methyl cyanoacrylate BCA: isobutyl cyanoacrylate Examples 1 to 4 A surgical adhesive comprising prepolymers A ₁ , A ₂ , A ₃ or A ₄ .

Example 5 A surgical adhesive obtained by dehydration mixing and stirring 50 parts of prepolymer A _{1 and} 50 parts of ECA.

Reference Examples 1 to 5 In Examples 1 to 5, the prepolymers A ₁ , A ₂ and A _{3 were used.}
Alternatively, instead of A ₄ , prepolymer B ₁ ,
Surgical adhesive using B ₂ , B ₃ or B ₄ .

Comparative Example 1 An adhesive containing ECA as a main component.

Comparative Example 2 Surgical adhesive consisting of Prepolymer I.

Comparative Example 3 Surgical adhesive composed of Prepolymer II.

Comparative Example 4 7 parts of nitrile rubber (38-40% nitrile amount) was dissolved in 50 parts of dehydrated and dried nitromethane, and 7 parts of ECA and T
An adhesive obtained by adding 1 part of DI and mixing and stirring.

Comparative Example 5 A surgical adhesive obtained by dehydration mixing and stirring 50 parts of prepolymer III and 50 parts of ECA.

Test example The carotid artery of a goat (outer diameter of about 4 mm) is temporarily ligated over a length of about 5 mm, and about 3 mm (longitudinal direction of blood vessels) cuts are made at approximately equal intervals, and a small amount of surgical adhesive is used. Applied. The blood flow was restarted after the time until hardening and after 5 minutes, and the adhesiveness of the incision to the tissue was evaluated. In addition, the test was conducted under anticoagulation with heparin to exclude the influence of the hemostatic effect due to blood coagulation and to examine the effect of the adhesive. The test results are shown in Table 1.

EFFECT OF THE INVENTION A surgical adhesive mainly composed of an NCO-terminated hydrophilic urethane prepolymer (a) from PPDI and hydrophilic polyether polyols of the present invention has a significantly high curing rate (TD
It is even faster than I-based prepolymers and MDI-based prepolymers) and is effective in shortening the operation time. Further, since the bondability with living tissue is greatly promoted, it has the effect of certainty for surgery. Moreover, since it has high flexibility, it has the effect of being able to follow the movement of the living body. Furthermore, it is more safe than TDI prepolymers.

An adhesive containing a compound (b) having a polymerizable double bond and a cyano group bonded to a carbon atom forming the double bond with the NCO-terminated hydrophilic urethane prepolymer (a) of the present invention ( The second invention is an effect of accelerating the entire curing rate not only from the biological contact surface but also the inside of the adhesive due to the rapid polymerization reaction by (b) body fluid (water) and the reactivity by (a) terminal isocyanate. There is. In addition, the reactivity of (a) and (b) greatly promotes the bondability with the living tissue as a whole, and has the effect of certainty for surgery. Moreover, since it has high flexibility, it has the effect of being able to follow the movement of the living body.

As a surgical adhesive, an adhesive containing ethyl cyanoacrylate as a main component, an adhesive obtained by dissolving tolylene diisocyanate and a diene polymer, and cyanoacrylate in an organic solvent have been conventionally used. Although it is excellent in, the cured product is hard and inflexible, and has the drawback that it can easily fall off when a little mechanical stress (such as pulsatile flow) is applied; Although the diene-based polymer is added to impart the property, the diene-based polymer itself has no curing reactivity,
When it is used as a surgical adhesive because it has no bondability with biological tissue, it is not satisfactory in terms of curing rate and bondability with biological tissue, and the organic solvent itself necessary to dissolve the diene polymer Had a problem in terms of safety for living tissues. On the other hand, the adhesive of the present invention does not contain an organic solvent in its components, and has three points of curing rate required for a surgical adhesive, bondability to a living tissue, and flexibility capable of following movement of a living body. Are all satisfied with.

From the above, the application of the adhesive of the present invention to the surgical operation makes it possible to use the anastomosis technique by the technique of adhesion in addition to the technique of conventional suturing, which shortens the operation time, prevents bleeding, and causes stenosis of the minimum blood vessel. The effect can be seen in the improvement of medical technology, such as avoidance. In addition, it has a wide range of applications such as temporary fixing prior to suturing and certainty due to the combined use of suture and adhesive,
It has the effect of imparting high credibility and high performance to all operations.

Claims (10)

[Claims] 1. A surgical adhesive comprising an NCO-terminated hydrophilic urethane prepolymer (a) composed of p-phenylenediisocyanate and hydrophilic polyether polyols as a main component. 2. The adhesive according to claim 1, wherein the isocyanate group content of (a) 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 with ethylene oxide and optionally other alkylene oxide. 4. The adhesive according to claim 2 or 3, wherein the content of oxyethylene in the hydrophilic polyether polyols is 30% by weight or more. 5. An NCO-terminated hydrophilic urethane prepolymer (a) composed of p-phenylenediisocyanate and hydrophilic polyether polyols, and a carbon atom having a polymerizable double bond and forming the double bond. A surgical adhesive comprising a compound (b) having a cyano group bonded as a main component. 6. The adhesive according to claim 5, wherein the isocyanate group content of (a) 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 with ethylene oxide and optionally other alkylene oxide. 8. The adhesive according to claim 6 or 7, wherein the content of oxyethylene 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 cyanoacrylic acid ester. 10. The method according to any one of claims 5 to 9, wherein the content of (a) is 20 to 90% with respect to the total weight of (a) and (b). Glue.