TW201534359A - Cyanoacrylate adhesive and manufacturing method thereof - Google Patents

Abstract

A manufacturing method for a cyanoacrylate adhesive comprises the steps of (a) providing an adhesive base including a first cyanoacrylate monomer; (b) providing a thickener including polycyanoacrylate, in which the polycyanoacrylate is made by the process comprising: providing a second cyanoacrylate monomer, adding ammonium hydroxide or alcoholic solution to perform polymerization, heating and drying the polymerized product at 30 to 100 DEG C and vaporizing to remove the ammonium hydroxide or alcoholic solution; and (c) adding the thickener into the adhesive base. By using the thickener without containing an initiator or a promoter, the premature polymerization of the cyanoacrylate monomer can be prevented in the cyanoacrylate adhesive manufactured therewith, and the viscosity achieved can be widely applied to medical and surgical purposes.

Description

Cyanoacrylate adhesive and preparation method thereof

The present invention relates to a binder and a method of manufacturing the same, and more particularly to a cyanoacrylate adhesive for sealing a wound and a method of manufacturing the same.

The treatment of general wounds is applied with anti-inflammatory and anti-microbial drugs, so that the wound can heal naturally without being infected, but for larger and deeper wounds, surgical sutures are used to draw adjacent skin. Connect and heal as soon as possible. Compared to skin suture surgery, tissue adhesives are currently the more common method of application for sealing wounds.

The so-called tissue adhesive is applied to the skin of the wound by a liquid adhesive. When it is hardened, it is like a glue to connect and bond the skin adjacent to the wound to achieve the aforementioned suturing effect. Since the epidermal tissue will proliferate, the hardened adhesive will fall off with the epidermis after about five to ten days, and some tissue adhesives will be absorbed after a certain period of time. Compared with the traditional skin suture surgery, which is time-consuming and causes pain to the patient, the tissue adhesive is convenient to use, saves time, does not require anesthesia and has less pain, and the wound is more beautiful, so for the auxiliary treatment of general shallow wound or deep wide wound, The medical approach to using tissue adhesives is already the best option. In addition, it can be used to fill ulcers, joints between tissues or as a link between tissue and implants, and has been applied in a considerable field.

The preferred tissue adhesive must have the following characteristics: (1) it must be viscous when applied to the wound, that is, it will not spread to the undesired position due to the flow, and it can be converted into a short time. The solidified state is used to bond the wound; (2) it can adhere to the tissue in the state of water, and has certain bonding strength, tensile strength and toughness; (3) has good biocompatibility, is non-toxic and does not cause Immune reaction; (4) biodegradable, can be decomposed by natural metabolism; (5) As a repair growth template for cellular tissue to promote healing.

Currently available tissue adhesives include three major categories: (1) cyanoacrylate adhesive; (2) fibrin glue; and (3) protein crosslinked (protein crosslinked) Glue). Among them, the source of blood fibrin glue is mostly animal or human blood. Although it has good biocompatibility, there are doubts about viral infection in use, and its adhesion strength is relatively weak, only about 3~4N. /cm ² , a big disadvantage for use. As for the protein adhesive, although it has high biocompatibility and biodegradability, it also has the doubt of viral infection. In contrast, cyanoacrylate adhesives can be polymerized quickly within a few tens of seconds, and have a high strength of adhesion, which is excellent for immediate hemostasis or healing of large wounds.

The cyanoacrylate adhesive is generally applied to the wound in the form of a monomeric cyanoacrylate. When it is in contact with the moisture on the surface of the wound, an anionic polymerization is carried out to form a long and strong chain. The skin is glued. Because of the low viscosity of the cyanoacrylate monomer, when it is applied to the wound site, it is often distributed to the undesired area or the inner layer of the wound due to the fluid overflow, in addition to the damage of adjacent organs. Affect the healing of some wounds. In order to improve the viscosity, the prior art utilizes polycyanoacrylate as a thickener to increase the viscosity of the adhesive. However, in general polymerization of polycyanoacrylate, for example, when hydrogenation is used as a starting agent, it is necessary to neutralize with an acid, and if the hydrogencarbonate is not completely removed and is present in the polycyanoacrylate, When it is added with a cyanoacrylate monomer, it will cause pre-mature polymerization of the cyanoacrylate monomer, so that the cyanoacrylate monomer can not effectively bond with the skin, and the macro-reduction is greatly reduced. It seals the effectiveness of the wound.

It is an object of the present invention to provide a method for producing a cyanoacrylate adhesive which can easily remove an initiator used in a polymerization process of a monomer in a cyanoacrylate adhesive when preparing a tissue adhesive, and can be prepared in advance. There is no thickener present in the starter.

A second object of the present invention is to provide a cyanoacrylate adhesive capable of preventing premature polymerization of a thickener remaining in a cyanoacrylate adhesive. The method can improve the shortcomings of the conventional adhesive due to the excessive reaction of the thickener, thereby destroying the skin bonding effect.

In order to achieve the foregoing objects, the present invention provides a method for producing a cyanoacrylate adhesive, the steps comprising: (a) providing a binder matrix comprising a first cyanoacrylate monomer; (b Providing a thickener, the thickener comprising polycyanoacrylate, wherein the polycyanoacrylate is produced by: providing a second cyanoacrylate monomer; adding ammonium hydroxide (ammonium) Hydrating or alcohol aqueous solution; heating and drying the polymerization product at 30 ° C to 100 ° C, and volatilizing to remove the ammonium hydroxide or the alcohol; and (c) adding the thickener to the binder In the matrix.

In one embodiment, the method for producing a cyanoacrylate adhesive, wherein the first cyanoacrylate monomer or the second cyanoacrylate monomer is selected from the group consisting of alkyl 2-cyanoacrylates (alkyl 2-cyanoacrylate), cycloalkyl-2-cyanoacrylate, fluoroalkyl-2-cyanoacrylate, fluorocycloalkyl-2- Fluorocycloalkyl-2-cyanoacrylate, alkoxyalkyl-2-cyanoacrylate, alkoxycycloalkyl-2-cyanoacrylate And a group consisting of fluoroalkoxyalkyl-2-cyanoacrylate, but is not limited thereto.

In another embodiment, the method for producing a cyanoacrylate adhesive, wherein the first cyanoacrylate monomer or the second cyanoacrylate monomer may be selected from n-butyl cyanoacrylate (n-butyl cyanoacrylate), 2-octyl cyanoacrylate, and ethyl cyanoacrylate, but not limited thereto.

In another embodiment, the method for producing a cyanoacrylate adhesive, wherein the thickener in the cyanoacrylate adhesive may be 0.5 to 25% by weight, preferably 1 to 10% by weight. The optimum is 1 to 5% by weight.

In one embodiment, the method for producing a cyanoacrylate adhesive, wherein the aqueous ammonium hydroxide solution is 0.01 to 1% by weight, preferably 0.01 to 0.1% by weight, and the ammonium hydroxide and the first The weight ratio of the dicyanoacrylate monomer may be 1:50 to 1:80, preferably 1:60~1:70, but not limited to this.

In one embodiment, the method for producing a cyanoacrylate adhesive, wherein the alcohol may be selected from the group consisting of methanol, ethanol, propanol, butanol, and any mixture thereof, but is not limited thereto. However, in order to prevent the heating temperature from being excessively high, methanol, ethanol, propanol or a combination thereof having a relatively low boiling point is preferred.

In one embodiment, the method for producing a cyanoacrylate adhesive, wherein the alcohol is ethanol, the aqueous ethanol solution may be 0.1 to 1.5% by weight, preferably 0.1 to 0.6% by weight, and the ethanol and the ethanol are The weight ratio of the second cyanoacrylate monomer may be 1:5 to 1:15, preferably 1:8 to 1:12, but not limited thereto.

In another embodiment, the method for producing a cyanoacrylate adhesive, wherein the step may further comprise a plasticizer, a colorant, a radical stabilizer, and an anion stabilizer. Wherein, the plasticizer may be selected from the group consisting of glycerol esters, fatty acid esters, citric esters, sebacic esters, cellulose esters, and poly Group of glycol glycol ethers, for example: glycerol triacetate, glycerol tripropionate, glycerol tributyrate, trihexanoic acid glycerol Tricaproin, trivalerin, trilacrin, tributyl citrate (tributyl 2-acetylcitrate), ethyl myristate, meat Isobutyl myristate, ethyl stearate, methyl sebacate, ethyl sebacate, ethylcellulose or Polyethylene glycol diethers, but not limited to this.

In another embodiment, the method for producing a cyanoacrylate adhesive, wherein the step further sterilizes the cyanoacrylate adhesive.

In the embodiment of the present invention, an aqueous solution of ammonium hydroxide or an alcohol as a starting agent for polymerization of a cyanoacrylate monomer can be easily removed by heating by using a lower boiling point characteristic, and it is not necessary to carry out conventional knowledge. Neutralization reaction. Therefore, the thickener comprising the polycyanoacrylate can be prepared to completely remove the initiator, so that when a cyanoacrylate monomer as a matrix is added, premature polymerization can be avoided, and Skin tissue produces the best bond And the sealing effect, and can extend the shelf life of the adhesive.

The embodiments of the present invention are further described in the following description, and the embodiments of the present invention are set forth to illustrate the present invention, and are not intended to limit the scope of the present invention. In the scope of the invention, the scope of protection of the invention is defined by the scope of the appended claims.

In the embodiment of the present invention, a thickener comprising polycyanoacrylate (polymerized by a second cyanoacrylate monomer) is prepared, and then the thickener is added to the monomer containing the cyanoacrylate (first cyanide). The acrylate base binder is stirred to produce a desired cyanoacrylate adhesive.

Wherein, the first cyanoacrylate monomer or the second cyanoacrylate monomer may be an alkyl 2-cyanoacrylate, a cycloalkyl-2-cyanoacrylate or a fluoroalkyl-2-cyanoacrylate Ester, fluorocycloalkyl-2-cyanoacrylate, alkoxyalkyl-2-cyanoacrylate, alkoxycycloalkyl-2-cyanoacrylate or fluoroalkyloxyalkyl-2-cyano Acrylate. In order that the polymer of the second cyanoacrylate monomer is easily dissolved in the first cyanoacrylate monomer, the first cyanoacrylate monomer and the second cyanoacrylate monomer are preferably of the same kind. Body, but not limited to this, can be selected according to the desired viscosity.

The thickener may be added to the low boiling point initiator, such as ammonium hydroxide or an aqueous alcohol solution, but is not limited thereto. By virtue of its low boiling point, it can be easily removed by evaporation during subsequent heating. Wherein, the alcohol may be selected from the group consisting of methanol, ethanol, propanol, butanol and any mixture thereof, but is not limited thereto. However, in order to prevent the heating temperature from being excessively high, methanol, ethanol, propanol or a combination thereof having a relatively low boiling point is preferred.

In addition, a thickener formed by polymerization of a second cyanoacrylate monomer The polycyanoacrylate may have a weight average molecular weight of 5,000 to 4,000,000, preferably 5,000 to 1,000,000.

On the other hand, a plasticizer may be further added to the binder to adjust its viscosity and soften it. The plasticizer may be selected from the group consisting of glycerides, fatty acid esters, citrate esters, sebacates, cellulose esters, and polyethylene glycol ethers, for example, triacetin, glycerol tripropionate, Triglyceride, trihexanoate, glyceryl trivalerate, glyceryl tricaprate, tributyl citrate, ethyl myristate, isobutyl myristate, stearic acid Ethyl ester, dimethyl sebacate, diethyl sebacate, ethyl cellulose or polyethylene glycol diether, but is not limited thereto.

Hereinafter, the method of the present invention will be described by way of examples, the steps and reaction conditions and the results thereof are merely exemplified, and the relevant conditions can be adjusted according to different yields and desired effects.

Example 1: Preparation of polycyanoacrylate polymer A

1800 ml of deionized water was taken, and 0.7 g (about 0.04% by weight) of ammonium hydroxide (NH ₄ OH) was added and stirred for about 3 minutes. Thereafter, 32 ml of n-butyl cyanoacrylate (nBCA monomer, Chemistry Co.) was taken and added dropwise to the diluted ammonium hydroxide solution. After continuous stirring for 0.5 hours, the polycyanoacrylate polymer A was gradually polymerized. The polycyanoacrylate polymer A was then poured out and dried under vacuum at 65 ° C for 8 hours. The molecular weight after measurement by a gel chromatography was 57,300.

Example 2: Preparation of cyanoacrylate adhesive A

285 g of 2-octyl cyanoacrylate (2-OCA monomer having a viscosity of 6 cP at 20 ° C) was placed in a round bottom flask, and the rotor was started to rotate at 200 RPM. 15 g of the polycyanoacrylate polymer A prepared in Example 1 was slowly poured and heated at 100 ° C for 60 minutes to form a cyanoacrylate adhesive A. After measurement by a capillary viscometer, the viscosity was 43 cP at 20 °C.

Example 3: Preparation of cyanoacrylate adhesive B

285 g of 2-octyl cyanoacrylate (2-OCA monomer having a viscosity of 6 cP at 20 ° C) was placed in a round bottom flask, and the rotor was started to rotate at 200 RPM. Slowly pour 15 g of the polycyanoacrylate polymer A prepared in Example 1, and then slowly pour 15 g of 2-ethyl citrate The cyanoacrylate adhesive B can be formed by heating tributyl 2-acetylcitrate at 100 ° C for 60 minutes. After measurement by a capillary viscometer, the viscosity was 39 cP at 20 °C.

Example 4: Preparation of polycyanoacrylate polymer B

1800 ml of deionized water was taken, and 1 g (about 0.06% by weight) of ammonium hydroxide (NH ₄ OH) was added and stirred for about 3 minutes. Thereafter, 32 ml of n-butyl cyanoacrylate (nBCA monomer, Chemistry Co.) was taken and added dropwise to the diluted ammonium hydroxide solution. After continuously stirring for 0.5 hours, the polycyanoacrylate polymer B was gradually polymerized. The polycyanoacrylate polymer B was then poured out and dried under vacuum at 65 ° C for 8 hours. The molecular weight after the measurement by gel chromatography was 41,200.

Example 5: Preparation of cyanoacrylate adhesive C

285 g of 2-octyl cyanoacrylate (2-OCA monomer having a viscosity of 6 cP at 20 ° C) was placed in a round bottom flask, and the rotor was started to rotate at 200 RPM. 15 g of the polycyanoacrylate polymer B prepared in Example 4 was slowly poured and heated at 100 ° C for 60 minutes to form a cyanoacrylate adhesive C. After measurement by a capillary viscometer, the viscosity was 31 cP at 20 °C.

Example 6: Preparation of cyanoacrylate adhesive D

285 g of 2-octyl cyanoacrylate (2-OCA monomer having a viscosity of 6 cP at 20 ° C) was placed in a round bottom flask, and the rotor was started to rotate at 200 RPM. 15 g of the polycyanoacrylate polymer B prepared in Example 4 was slowly poured, and then 15 g of 2-tributium 2-acetylcitrate was slowly poured and heated at 100 ° C for 60 minutes. Then, cyanoacrylate adhesive D can be formed. After measurement by a capillary viscometer, the viscosity was 28 cP at 20 °C.

Example 7: Accelerated Aging Test of Cyanoacrylate Adhesive B

0.8 ml of cyanoacrylate adhesive B was placed in 300 aluminum tubes and sealed and sterilized for testing. The above samples were divided into 5 groups (first to fifth groups), 60 in each group, respectively, according to the following Table 1, simulated in 60 ° C environment for accelerated aging test at different time intervals at 20 ° C, and then at 20 ° C Viscosity was measured and the results are also shown in Table 1.

Example 8: Wound seal strength test of cyanoacrylate adhesive B

After the aging test was carried out in Example 7, the wound sealing strength test was further carried out. According to ASTM F2458, each sample was applied to the wound produced by the pig skin incision, and then the wound was opened. power. At the time of application, each sample was uniformly applied to an area of 2.5 cm X 1.0 cm adjacent to two cut pig skins, and two pieces of pig skin were adhered, and each sample was tested for 10 samples. The bonded sample is placed in a sealed plastic bag and placed at about 30 ° C (± 1 ° C) for about 1 hour (± 15 minutes). After the adhesive is hardened, it can be taken out for strength test. The test results are shown in Table 1 above.

From the results of Table 1, it can be found that although the viscosity of the cyanoacrylate adhesive B gradually increases with time, its sealing strength to the wound is only reduced after 12 months under the aging test, and even After 18 months, it still has a sealing strength of 8.3 N. Therefore, it can be seen that the cyanoacrylate adhesive prepared by the present invention can avoid the problem of premature polymerization caused by the retention of the initiator. The adhesive has the desired viscosity and has a long shelf life while still maintaining a certain degree of wound sealing effect.

Example 9: Preparation of polycyanoacrylate polymer C

Take 1800 ml of deionized water, add 5 g of ethanol (about 0.3% by weight), and stir for about 3 minutes. Thereafter, 32 ml of n-butyl cyanoacrylate (nBCA monomer, Chemistry Co.) was taken and added dropwise to the diluted ethanol solution. After continuously stirring for 0.5 hours, the polycyanoacrylate polymer C was gradually polymerized. The polycyanoacrylate polymer C was then poured out and dried under vacuum at 65 ° C for 8 hours. The molecular weight after measurement by a gel chromatography was 64,300.

Example 10: Preparation of cyanoacrylate adhesive E

285 g of 2-octyl cyanoacrylate (2-OCA monomer having a viscosity of 6 cP at 20 C) was placed in a round bottom flask, and the rotor was started to rotate at 200 RPM. 15 g of the polycyanoacrylate polymer C prepared in Example 9 was slowly poured and heated at 100 ° C for 60 minutes to form a cyanoacrylate adhesive E. After measurement by a capillary viscometer, the viscosity was 47 cP at 20 °C.

Example 11: Preparation of cyanoacrylate adhesive F

285 g of 2-octyl cyanoacrylate (2-OCA monomer having a viscosity of 6 cP at 20 ° C) was placed in a round bottom flask, and the rotor was started to rotate at 200 RPM. 15 g of the polycyanoacrylate polymer C prepared in Example 9 was slowly poured, and then 15 g of 2-tributic 2-acetylcitrate was slowly poured and heated at 100 ° C for 60 minutes. The cyanoacrylate adhesive F can be formed. After measurement by a capillary viscometer, the viscosity was 43 cP at 20 °C.

Example 12: Preparation of polycyanoacrylate polymer D

1800 ml of deionized water was taken, 1.8 g of sodium hydrogencarbonate (about 0.1% by weight) was added, and the mixture was stirred for about 3 minutes. Thereafter, 32 ml of n-butyl cyanoacrylate (nBCA monomer, Chemistry Co.) was taken and added dropwise to the diluted sodium hydrogencarbonate solution. After continuous stirring for 0.5 hours, the polycyanoacrylate polymer D was gradually polymerized. The polycyanoacrylate polymer D is first rinsed with deionized water for several times, then neutralized with sodium bicarbonate contained therein with 0.1 N hydrochloric acid, and rinsed again with deionized water several times, followed by polycyanide. The acrylate polymer D was taken out and dried under vacuum at 65 ° C for 8 hours. The molecular weight after the measurement by a gel chromatography was 43,100.

Example 13: Preparation of cyanoacrylate adhesive G

285 g of 2-octyl cyanoacrylate (2-OCA monomer having a viscosity of 6 cP at 20 ° C) was placed in a round bottom flask, and the rotor was started to rotate at 200 RPM. 15 g of the polycyanoacrylate polymer D prepared in Example 12 was slowly poured, and then 15 g of 2-tributic 2-acetylcitrate was slowly poured and heated at 100 ° C for 60 minutes. The cyanoacrylate adhesive G can be formed. After measurement by a capillary viscometer, the viscosity was 31 cP at 20 °C.

Example 14: Accelerated Aging Test of Cyanoacrylate Adhesive G

0.8ml of cyanoacrylate adhesive G was placed in 300 aluminum tubes and densely Prepare for testing after sterilization. The above samples were divided into 5 groups (sixth to tenth groups), each group of 60, according to the following Table 2, simulated in 60 ° C environment for accelerated aging test at different time intervals at 20 ° C, and then at 20 ° C Viscosity was measured and the results are also shown in Table 2.

Example 15: Wound seal strength test of cyanoacrylate adhesive G

After the aging test was carried out in Example 14, the wound sealing strength test was further carried out. According to ASTM F2458, each sample was applied to the wound produced by the pig skin incision, and then the wound was opened. power. At the time of application, each sample was uniformly applied to an area of 2.5 cm X 1.0 cm adjacent to two cut pig skins, and two pieces of pig skin were adhered, and each sample was tested for 10 samples. The bonded sample is placed in a sealed plastic bag and placed at about 30 ° C (± 1 ° C) for about 1 hour (± 15 minutes). After the adhesive is hardened, it can be taken out for strength test. The test results are shown in Table 2 above.

From the results of Table 2, it can be found that the sealing strength of the cyanoacrylate adhesive G to the wound has dropped to 7.5N after 12 months, and after 18 months, it is suddenly reduced to only A seal strength of about 6N. Therefore, it is known that a cyanoacrylate adhesive which is prepared by mixing a polycyanoacrylate thickener prepared by a conventional initiator with a neutralization reaction and a cyanoacrylate monomer is present. The problem of premature polymerization has a significant detrimental effect on wound sealing strength and shortens the shelf life of the adhesive. However, by the thickener prepared by the aqueous solution of ammonium hydroxide or alcohol in the present invention, the problem of premature polymerization can be overcome, and the desired viscosity can be widely applied to medical treatment and surgery.

Claims (12)

A method for producing a cyanoacrylate adhesive, the method comprising the steps of: (a) providing a binder matrix, the binder matrix comprising a first cyanoacrylate monomer; (b) providing a thickener, the thickening The method includes a polycyanoacrylate, wherein the polycyanoacrylate is produced by: providing a second cyanoacrylate monomer; adding an ammonium hydroxide or an alcohol aqueous solution to carry out a polymerization reaction; And heating and drying the polymerization product at 30 ° C to 100 ° C, and volatilizing to remove the ammonium hydroxide or the alcohol; and (c) adding the thickener to the binder matrix. The method for producing a cyanoacrylate adhesive according to claim 1, wherein the first cyanoacrylate monomer or the second cyanoacrylate single system is selected from the group consisting of alkyl 2-cyanoacrylate. Ester, cycloalkyl-2-cyanoacrylate, fluoroalkyl-2-cyanoacrylate, fluorocycloalkyl-2-cyanoacrylate, alkoxyalkyl-2-cyanoacrylate, alkoxy A group consisting of a cycloalkyl-2-cyanoacrylate and a fluoroalkyloxyalkyl-2-cyanoacrylate. The method for producing a cyanoacrylate adhesive according to claim 2, wherein the first cyanoacrylate monomer or the second cyanoacrylate single system is selected from n-butyl cyanoacrylate a group consisting of octyl 2-cyanoacrylate and ethyl cyanoacrylate. The method for producing a cyanoacrylate adhesive according to claim 1, wherein the thickener is 0.5 to 25% by weight of the cyanoacrylate adhesive. The method for producing a cyanoacrylate adhesive according to claim 4, wherein the thickener is 1 to 10% by weight of the cyanoacrylate adhesive. The method for producing a cyanoacrylate adhesive according to claim 5, wherein the thickener is 1 to 5% by weight of the cyanoacrylate adhesive. The method for producing a cyanoacrylate adhesive according to claim 4, wherein the aqueous ammonium hydroxide solution is 0.01 to 1% by weight. The method for producing a cyanoacrylate adhesive according to claim 4, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, butanol, and any mixture thereof. The method for producing a cyanoacrylate adhesive according to claim 8, wherein the alcohol is ethanol, and the aqueous ethanol solution is 0.1 to 1.5% by weight. The method for producing a cyanoacrylate adhesive according to claim 1, wherein the cyanoacrylate adhesive is further sterilized. The method for producing a cyanoacrylate adhesive according to claim 1, further comprising a plasticizer, a colorant, a radical stabilizer or an anion stabilizer. A cyanoacrylate adhesive prepared by the method described in claim 1, 2 or 3.