WO2013129722A1

WO2013129722A1 - Tissue adhesive for wound closure and preparation method thereof

Info

Publication number: WO2013129722A1
Application number: PCT/KR2012/001958
Authority: WO
Inventors: Hyun Jung Kim; Il Kyu Park; Yeo Jin Jun; Yong Ki Kim
Original assignee: Genewel Co., Ltd
Priority date: 2012-02-28
Filing date: 2012-03-19
Publication date: 2013-09-06
Also published as: KR101201984B1

Abstract

The present invention relates to a tissue adhesive for wound closure and a preparation method thereof, wherein the tissue adhesive comprises an acrylate-based monomer and a urethane acrylate-based polymer as an acrylate-based compound, and has improved biocompatibility and elasticity as well as a high adhesive strength even when applied on a frequently movable body portion upon wound closure.

Description

TISSUE ADHESIVE FOR WOUND CLOSURE AND PREPARATION METHOD THEREOF

The present invention relates to a tissue adhesive for wound closure and a preparation method thereof, and more particularly, to a tissue adhesive and a preparation method thereof in which the tissue adhesive comprises an acrylate-based monomer and an urethane acrylate-based polymer, as an acrylate-based compound, and has improved biocompatibility and elasticity as well as a high adhesive strength even when applied on a frequently movable body portion upon wound closure.

A wound is a type of injury in which the tissue of a body is damaged, and chiefly refers to an injury where the skin or mucous membrane is damaged. Wounds are caused by normal activities in life, accidents, sports practices, or surgery. For closure of a wound, a number of techniques are employed, including sutures, tapes, staples, tissue adhesives, and so forth.

Particularly, tissue adhesives are a type of medical device used for closing damaged wounds with simple manipulations instead of using sutures and increasingly preferred because of ease of handling and relatively little scars left after surgery. The active ingredient of tissue adhesives used for wound closure is a cyanoacrylate-based compound, which is cured through polymerization caused by water and includes ethyl cyanoacrylate, butyl cyanoacrylate, or octyl cyanoacrylate.

However, the conventional cyanoacrylate-based tissue adhesives have such a poor flexibility as to readily become brittle after being cured, consequently with difficulty in use for a frequently moving part of the body for wound closure, and also to induce tissue toxicity pertaining to formaldehyde formation when degraded. To overcome this problem, many solutions have been suggested that employ using a mixture of cyanoacrylate-based tissue adhesives each having a different alkyl substituent, or adding a plasticizer or a biodegradable substance to the cyanoacrylate-based tissue adhesives to endow the cured tissue adhesives with flexibility and to alleviate toxicity by control of the degradation time or reduction of the content of the cyanoacrylate-based monomer.

The cyanoacrylate-based tissue adhesive disclosed in Korean Patent No. 10-0523662 involves dissolving a copolymer formed from a glycolide monomer, a D,L-lactide monomer and a polyethylene glycol monomer in a cyanoacrylate monomer to acquire improved flexibility and alleviated toxicity as well as biodegradability and biocompatibility. However, this tissue adhesive has flexibility improved only to a negligible extent, relative to the conventional octyl cyanoacrylate adhesive.

The cyanoacrylate-based tissue adhesive disclosed in U.S. Patent No. 5,998,472 acquires adhesion time control and improved flexibility by mixing two cyanoacrylate-based monomers each having a different alkyl substituent. However, using a mixture of cyanoacrylate-based monomers without addition of a plasticizer or a biodegradable substance encounters a limitation to achieve adhesion time control and improved flexibility.

The cyanoacrylate-based tissue adhesive disclosed in WO96/06884 has flexibility improved, but to a negligible degree, by adding dioctyl phthalate as a biocompatible plasticizer to a cyanoacrylate-based monomer.

Accordingly, the inventors of the present invention have repeatedly performed researches and experiments to provide superior properties than have ever been acquired by the prior art to contrive the present invention.

It is therefore an object of the present invention to provide a tissue adhesive comprising an acrylate-based monomer and a urethane acrylate-based polymer as an acrylate-based compound, and has improved biocompatibility and elasticity as well as a high adhesive strength even when applied on a frequently movable body portion upon wound closure.

To achieve the object of the present invention, there is provided a tissue adhesive for wound closure comprising an acrylate-based monomer and a urethane acrylate-based polymer, as an acrylate-based compound.

Further, there is provided a method for preparing a tissue adhesive for wound closure comprising the steps of: preparing an urethane acrylate-based polymer and mixing it with an acrylate-based monomer to prepare a mixed solution; agitating the mixed solution under a temperature of 15 to 35 ℃ for 8 to 15 hours to yield an elastic solution having an inter-penetrating network structure between the urethane group in the urethane acrylate-based polymer and the acrylate-based monomer; and drying the elastic solution to obtain a tissue adhesive.

Hereinafter, the present invention is described in more details.

The present invention has a technical feature comprising an acrylate-based monomer and a urethane acrylate-based polymer, where the acrylate-based monomer is represented by the following Formula 1:

[Formula 1]

CH₂=C(CCN)-CO0-R₁

Wherein, R₁ is an alkyl group having 2 to 12 carbon atoms.

The said acrylate-based monomer of the Formula 1 may include, if not limited to, ethyl cyanoacrylate, propyl cyanoacrylate, isopropyl cyanoacrylate, butyl cyanoacrylate, isobutyl cyanoacrylate, pentyl cyanoacrylate, isopentyl cyanoacrylate, hexyl cyanoacrylate, isohexyl cyanoacrylate, heptyl cyanoacrylate, octyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, nonyl cyanoacrylate, decyl cyanoacrylate, undecyl cyanoacrylate, dodecyl cyanoacrylate, and mixtures thereof.

Further, the longer the alkyl group of the substituent R₁, the more delay the degradation time for alleviating toxicity and enhance the flexibility of the cured adhesive.

In particular, it is preferable to mix 80 to 99 parts by weight of an acrylate-based monomer having a higher alkyl group containing 6 to 12 carbon atoms with 1 to 20 parts by weight of an acrylate-based monomer having a lower alkyl group containing 2 to 5 carbon atoms, as such mixing ratio is contributed to reduce of the reaction time considering solubility.

Further, it is more preferable to mix 90 to 99 parts by weight of an acrylate-based monomer having a higher alkyl group containing 6 to 12 carbon atoms with 1 to 10 parts by weight of an acrylate-based monomer having a lower alkyl group containing 2 to 5 carbon atoms, as such mixing ratio is contributed to improve hardness and elasticity even a small amount of the acrylate-based polymer.

Considering the solubility of the urethane acrylate-based polymer, the acrylate-based monomer of the Formula 1 is preferably used in an amount of 80 to 99.9 parts by weight, more preferably 90 to 99.9 parts by weight, and most preferably 99 to 99.9 parts by weight, based on total 100 parts by weight for tissue adhesive.

Further, the urethane acrylate-based polymer functions as a plasticizer for the acrylate-based monomer of the Formula 1 and provides any easily blending together with elasticity enough to prevent the adhesive from any brittle after a curing process.

Considering the solubility for easily blending, it is preferably that the urethane acrylate-based polymer has a weight average molecular weight (Mw) of 1,000 to 50,000, and more preferably 5,000 to 20,000.

The urethane acrylate-based polymer may be synthesized using acryl polyol and isocyanate as principal raw materials by prepolymer synthesis method.

More specifically, polytetramethylene glycol, ethylene glycol, and hydroxymethyl methacrylate are added and then gradually heated to about 65 ℃ under agitation.

To the solution, an aliphatic isocyanate compound (e.g., isophorone diisocyanate)is added, and the resultant solution is gradually heated and kept to a temperature of about 110 ℃.

After 3 hours with keeping the temperature, the value of NCO% in the isocyanate group measured. When the value of NCO% decreases below a theoretical value of 5, the solution is cooled down with a cool water to terminate the reaction.

Subsequently, the polyol is diluted with ethylacetate and ethanol to facilitate the reaction between the prepolymer having a terminal NCO group and m-phenylene diamine.

To the prepolymer thus obtained, a diluted solution of m-phenylene diamine and ethanol (e.g., 1:1 weight ratio) is added dropwise, in order to induce a reaction between the m-phenylene diamine and the terminal isocyanate group of the prepolymer for polymerization, and thus obtain an urethane acrylate-based polymer as a clear, colorless and sticky liquid.

According to the prepolymer synthesis method, the polytetramethylene glycols may include, if not limited to, at least one selected from polytetramethylene glycol, polyethylene oxide polyol, polypropylene oxide polyol, and polyethylene propylene oxide copolymer polyol; the ethylene glycols may include, if not limited to, at least one selected from ethylene glycol, propylene glycol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, diethylene glycol, triethylene glycol, and polyethylene glycol; and the (meth)acrylates may include, if not limited to, at least one selected from (meth)acrylate, hydroxyethyl methacrylate, hydroxymethyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, tetrahydrofuryl methacrylate, glycerol monomethacrylate, glycerol dimethacrylate. trimethylol propane trimethacrylate, ethylene glycol dimethacrylate, and polyethylene glycol dimethacrylate. At least one polytetramethylene glycol, at least one ethylene glycol, and at least one methacrylate are added at a molar ratio of 1 : 0.5 : 0.5 to 1 : 0.99 : 0.01, and the mixture is gradually heated to 40 to 80 ℃ under agitation.

To the solution is added at least one aliphatic isocyanate compound (e.g., isophorone diisocyanate, diphenylmethane diisocyanate, 1,6-hexamethylene diisocyanate, 1,5-naphthalene diisocyanate, 4,4-dicyclohexylmethane diisocyanate, 2,2,4-trimethyl hexamethylene diisocyanate, 2,4,4-trimethyl hexamethylene diisocyanate, etc.). The resultant solution is gradually heated and kept in the range of 80 to 130 ℃.

After 1 to 5 hours with keeping the temperature, the value of NCO% in the isocyanate group is measured. In consideration of the molecular weight, elasticity and tactile characteristics, when the theoretical value of NCO% drops below 5, the mixture is cooled down with cooling water to terminate the reaction and yield a prepolymer having a terminal NCO group. The theoretical value of NCO% is determined by titration. More specifically, the prepolymer sample thus obtained is collected and dissolved in 0.1N-dibutylamine and a defined volume of a solvent, and the resultant solution is diluted with isopropylalcohol and titrated with 0.1N-HCl to measure the theoretical value of NCO%.

Subsequently, amine is added to the prepolymer to terminate the reaction, because the prepolymer still contains a reactive NCO group. Here, ethanol and acetate may also be added as solvents in order to make the prepolymer having a high viscosity into a solution having a low viscosity and thereby to facilitate blending (reaction) with the amine.

As a diluted solution of m-phenylene diamine and ethanol (for example, weight ratio of 1:1) is added dropwise to the resultant prepolymer having a terminal NCO group, the m-phenylene diamine reacts with the terminal isocyanate group of the prepolymer to form an urethane acrylate-based polymer having a -NH-CO-O- group as a clear, colorless and sticky liquid.

The urethane acrylate-based polymer thus obtained is then blended with an acrylate-based monomer of the Formula 1 to yield a mixed solution. As urethane is immiscible with the acrylate-based monomer of the Formula 1, the urethane acrylate-based polymer is used to introduce acrylate to the main chain of the urethane, making the urethane miscible with the acrylate monomer.

The content of the urethane acrylate-based polymer is preferably 0.1 to 20 parts by weight, more preferably 0.1 to 10 parts by weight, and most preferably 0.1 to 1 part by weight, based on total 100 parts for tissue adhesive. The content of the urethane acrylate-based polymer is defined considering that the hardness of the cured acrylate-based monomer of the Formula 1 can be controlled by addition of the urethane acrylate-based polymer. The content below the defined range is not sufficient to provide good effects, whereas the content above the defined range may reduce the strength of the wound connection upon wound closure by excessively increased malleability of the product.

Subsequently, the compounded solution is agitated at 15 to 35 ℃ for 8 to 15 hours, preferably at the room temperature for about 12 hours, to prepare an elastic solution having an inter-penetrating network structure between the urethane group of the urethane acrylate-based polymer and the acrylate-based monomer.

The inter-penetrating network structure in the elastic solution is illustrated in FIG. 5. As shown in FIG. 5, the urethane group of the urethane acrylate-based polymer holds the acrylate-based monomer, so that the tissue adhesive of the present invention with enhanced elasticity becomes less brittle than the conventional tissue adhesives. This is demonstrated by the results of the elasticity evaluation as presented by the graph of FIG. 2.

Subsequently, the elastic adhesive solution is cured with water through a simple drying process into a solid adhesive, which meets adhesive requirements, including both an adhesive strength in the range of 1.5 to 2 kgf/cm² and an elastic coefficient in the range of 2,000 to 3,000 (G´), and thus may be used as a tissue adhesive without an additional processing.

Accordingly, the present invention advantageously makes a tissue adhesive miscible (easy to blend) and secure elasticity after being cured.

The term "frequently movable body portion" as used herein refers to, if not limited to, knees, neck, shoulders, hands, and so forth.

The tissue adhesive for wound closure according to the present invention, due to its good bioadhesiveness and high elasticity, provides a high adhesive strength even when applied to a frequently movable body portion for wound closure, and does not become brittle after being cured. It also provides a preparation method for tissue adhesive with high economical efficiency.

FIG. 1 is a graph showing the experimental results evaluating four tissue adhesives in regard to shear adhesive strength (see FIG. 1a) and wound closure strength (see also FIG. 1b), where an urethane cyanoacrylate tissue adhesive blended with 0.5% urethane acrylate is equivalent in wound closure strength but superior in shear adhesive strength to the other three tissue adhesives.

FIG. 2 is a graph showing the experimental results evaluating four tissue adhesives in regard to elasticity, where the urethane cyanoacrylate tissue adhesive blended with 0.5% urethane acrylate is superior in elasticity to the other three tissue adhesives, so that it does not become brittle even when applied on a frequently movable body portion for wound closure.

FIG. 3 is a graph showing the experimental results evaluating four tissue adhesives in regard to adhesion time, where the 0.5% urethane acrylate tissue adhesive is equivalent in adhesion time to the other three tissue adhesives.

FIG. 4 is a graph showing the experimental results evaluating the amount of formaldehyde released from four tissue adhesives, where the amount of formaldehyde released from the 0.5% urethane acrylate tissue adhesive has an insignificant effect on the blending of urethane acrylate.

FIG. 5 is a mimetic diagram showing the inter-penetrating network structure in an elastic solution as formed when an urethane acrylate polymer is blended with a cyanoacrylate monomer.

The present invention may, however, be embodiment in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the present invention to those skilled in the art.

[Preparation Example 1]

An urethane acrylate-based polymer was synthesized as follows:

1 mole (34.6 g) of polytetramethylene glycol, 0.9 mole (1.65 g) of ethylene glycol, and 0.1 mole (10.85 g) of hydroxy ethyl methacrylate were mixed together, and the mixed solution was gradually heated to about 65 ℃ under agitation.

To the mixed solution was added 3 moles (18.01 g) of isophorone diisocyanate, and the resultant mixed solution was gradually heated and kept with a temperature of about 110 ℃. After 3 hours under the temperature, the mixed solution of isocyanate and polyol was measured in regard to the value of NCO% in the isocyanate group. When the theoretical value of NCO% drops below 5, the solution was cooled down with a cooling water to terminate the reaction.

To facilitate the reaction between the prepolymer having a terminal NCO group and 1 mole of m-phenylene diamine, the polyol was diluted with 20 parts by weight of ethyl acetate and 80 parts by weight of ethanol. To the prepolymer thus obtained was added dropwise a diluted solution of m-phenylene diamine and ethanol (weight ratio of 1:1), causing a reaction between the m-phenylene diamine and the terminal isocyanate group of the prepolymer to yield an urethane acrylate-based polymer having a molecular weight (Mw) of 20,000 as a clear, colorless and sticky liquid.

[Preparation Example 2]

The procedures were performed in the same manner as described in Preparation Example 1, excepting that 0.5 mole of ethylene glycol and 0.5 mole of hydroxy ethyl methacrylate were used to prepare an urethane acrylate-based polymer having a molecular weight (Mw) of 20,000.

[Examples]

Example 1

0.5 part by weight of the urethane acrylate-based polymer according to Preparation Example 1 was mixed with 99.5 parts by weight of butyl cyanoacrylate as an acrylate-based monomer of the Formula 1, wherein R₂ is C₄H₉. The mixture was stirred at the room temperature for 12 hours to yield a tissue adhesive for wound closure.

Example 2

The procedures were performed in the same manner as described in Example 1, excepting that 9.5 parts by weight of butyl cyanoacrylate (wherein R₁ is C₄H₉) and 90 parts by weight of octyl cyanoacrylate (wherein R₁ is C₈H₁₇) were used instead of 99.5 parts by weight of the acrylate monomer of the Formula 1.

In comparison with Example 1, the total reaction time was 10 hours, reduced than the Example 1, whereas the elastic coefficient was increased than the Example 1.

Comparative Example 1

The procedures were performed in the same manner as described in Example 1, excepting that an acrylate where R₁ is C₄H₉ as the acrylate-based monomer of the Formula 1 was directly used as a tissue adhesive for wound closure without adding the urethane acrylate of Preparation Example 1.

Comparative Example 2

The procedures were performed in the same manner as described in Example 1, excepting that Histoacryl^® tissue adhesive (butyl cyanoacrylate, B. Broun/Germany) was used instead of the acrylate-based monomer of the Formula 1, without adding any acrylate-based polymer in Preparation Example 1.

Comparative Example 3

The procedures were performed in the same manner as described in Example 1, excepting that Dermabond^® tissue adhesive (octyl cyanoacrylate, Johnson & Johnson/U.S.A.) was used instead of the acrylate-based monomer of the Formula 1, without adding the acrylate-based polymer of Preparation Example 1.

[Evaluation of Adhesive Strength: Shear Adhesive Strength and Wound Closure Strength]

The tissue adhesives of Examples 1 and 2 and Comparative Examples 1, 2 and 3 were applied on a pig skin sample (2.5 cm x 5 cm) and evaluated in regard to shear adhesive strength (under ASTM F2255-5) and wound closure strength (under ASTM F2458-05). The results are represented in Table 1 and FIG. 1, respectively.

[Evaluation of Elasticity: Elastic Coefficient (G´)]

The tissue adhesives of Examples 1 and 2 and Comparative Examples 1, 2 and 3 were cured and cut out into films (1.5 cm x 1.5 cm), and the force exerted from a rotating spindle-type rotation plate was measured with an elasticity measuring instrument (Hakke MARS, Thermo Electron/U.S.A.) and converted to a value of elasticity. The measurement results are represented in Table 1 and FIG. 2, respectively.

[Adhesion Time]

The tissue adhesives of Examples 1 and 2 and Comparative Examples 1, 2 and 3 were measured in regard to the adhesive strength depending on the required adhesion time when applied on a pig skin sample. The results are represented in Table 1 and FIG. 3, respectively.

[Degradation Testing: Biocompatibility]

The tissue adhesives of Examples 1 and 2 and Comparative Examples 1, 2 and 3 were cured at the room temperature, eluted at 50 ℃ for 15 days (0.2 g/mL) and then measured in regard to the amount of formaldehyde in the eluent. The results are represented in Table 1 and FIG. 4, respectively.

Table 1

Div.	Example		Comparative Example
Div.	1	2	1	2	3
Shear Adhesive Strength (kgf/cm²)	2	2.2	0.8	0.8	0.75
Wound Closure Strength (kgf/cm²)	1.5	1.3	1	1	0.9
Elastic Coefficient (G')	3,120	3,289	2,120	2,045	2,581
Adhesion Time (sec)	< 15	< 15	< 15	< 15	< 15
Released Amount of Formaldehyde (ppm)	7.8	6	9.7	8.6	5.2

As can be seen from Table 1 and FIG. 1, the tissue adhesives of Examples 1 and 3 of the present invention were equivalent in wound closure strength and far superior in shear adhesive strength to those of Comparative Examples 1, 2 and 3.

Accordingly, the tissue adhesives of the present invention turned out to stay on the skin for a longer time than those of Comparative Examples 1, 2 and 3 due to equivalent wound closure strength and superior adhesive strength.

When the wound area of the skin moves, the conventional tissue adhesive applied on the wound is ready to become brittle and taken off from the skin, but the tissue adhesive of the present invention can be moving more flexibly on the skin.

As can be seen from Table 1 and FIG. 2, the tissue adhesives blended with an acrylate-based polymer were superior in elasticity to the tissue adhesives of Comparative Examples 1, 2 and 3. The tissue adhesive not blended with an acrylate-based polymer as in Comparative Example 3 had poor elasticity even with a higher alkyl group introduced to provide flexibility, thereby adversely deteriorating wound closure strength when applied on a frequently movable body portion for wound closure.

As for adhesion time which is a critical factor in closure of a wound with a tissue adhesive, the use of an acrylate-based monomer alone shortened the curing time with a decrease in the length of the alkyl chain, and the addition of an acrylate-based polymer hardly affected the curing time, as shown in Table 1 and FIG. 3, respectively.

Moreover, as can be seen from Table 1 and FIG. 4, the tissue adhesives of the present invention were susceptible to hydrolysis, showing a similar behavior of releasing formaldehyde to those of Comparative Examples 1, 2 and 3.

Claims

A tissue adhesive for wound closure comprising an acrylate-based monomer and a urethane acrylate-based polymer, as an acrylate-based compound.
The tissue adhesive for wound closure as claimed in claim 1, wherein the acrylate-based monomer is represented by the following Formula 1:

[Formula 1]

CH₂=C(CCN)-CO0-R₁

wherein R₁ is an alkyl group having 2 to 12 carbon atoms.
The tissue adhesive for wound closure as claimed in claim 2, wherein the acrylate-based monomer of the above Formula 1 comprises 80 to 99 parts by weight of an acrylate-based monomer having an alkyl group having 6 to 12 carbon atoms; and 1 to 20 parts by weight of an acrylate-based monomer having an alkyl group having 2 to 5 carbon atoms.
The tissue adhesive for wound closure as claimed in claim 2, wherein the acrylate-based monomer is at least one selected from the group consisting of ethyl cyanoacrylate, propyl cyanoacrylate, isopropyl cyanoacrylate, butyl cyanoacrylate, isobutyl cyanoacrylate, pentyl cyanoacrylate, isopentyl cyanoacrylate, hexyl cyanoacrylate, isohexyl cyanoacrylate, heptyl cyanoacrylate, octyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, nonyl cyanoacrylate, decyl cyanoacrylate, undecyl cyanoacrylate, and dodecyl cyanoacrylate.
The tissue adhesive for wound closure as claimed in claim 1, wherein the urethane group supplied from the urethane acrylate-based polymer is in an amount of 0.1 to 1 wt% for the tissue adhesive.
The tissue adhesive for wound closure as claimed in claim 1, wherein the urethane acrylate-based polymer is a polymer prepared from a hydroxyl group containing acrylate and a urethane.
The tissue adhesive for wound closure as claimed in claim 6, wherein the urethane acrylate-based polymer has a weight average molecular weight (Mw) of 5,000 to 20,000, as a prepolymer synthesized from acryl polyol and isocyanate.
The tissue adhesive for wound closure as claimed in claim 1, wherein the acrylate-based monomer and the urethane acrylate-based polymer are mixed together at a weight ratio of 80 ∼ 99.9 : 0.1 ∼ 20 based on total 100 parts by weight for the tissue adhesive.
A method for preparing a tissue adhesive, comprising the steps of: preparing an urethane acrylate-based polymer and mixing it with an acrylate-based monomer to prepare a mixed solution;

agitating the mixed solution under a temperature of 15 to 35 ℃ for 8 to 15 hours to yield an elastic solution having an inter-penetrating network structure between the urethane group in the urethane acrylate-based polymer and the acrylate-based monomer; and

drying the elastic solution to obtain a biotissue adhesive.
The method as claimed in claim 9, wherein the tissue adhesive has an adhesive strength in the range of 1.5 to 2 kgf/cm², an elastic coefficient in the range of 2,000 to 3,500 (G´) and a biocompatibility.