KR20050079158A - Cyanoacrylate composition for tissue adhesive - Google Patents

Abstract

The present invention relates to a cyanoacrylate-based tissue adhesive composition, cyanoacrylate monomer; And a copolymer dissolved in the cyanoacrylate monomer, wherein a glycolide monomer, a D, L-lactide monomer, and a polyethylene glycol monomer are polymerized. The tissue adhesive composition according to the present invention is a biodegradable and biocompatible tissue adhesive, which not only relieves the toxicity to biological tissues but also exhibits an appropriate viscosity so that it does not easily flow to the surroundings when the tissue is closed. In addition, the tissue adhesive composition of the present invention is suitable for use beyond skin wrinkles because it is not easily broken after curing.

Description

Cyanoacrylate composition for tissue adhesive

The present invention relates to a cyanoacrylate-based tissue adhesive composition having biodegradability and biocompatibility.

Tissue adhesive (Tissue adhesive) is a suture method that is widely used in recent years due to the advantages such as easy and quick to apply, do not need to remove the suture, and less scar after the procedure. The component mainly used for showing the adhesiveness of the tissue adhesive is a cyanoacrylate-based compound. That is, tissue adhesives containing cyanoacrylate-based monomers such as methylcyanoacrylate, butylcyanoacrylate, and octylcyanoacrylate are cured by a polymerization reaction after the procedure to seal external wounds or bleed internally. Hemostatic.

However, in the case of using only cyanoacrylate monomer as a tissue adhesive, it tends to be easily broken after curing, so it is difficult to use beyond the skin wrinkles. Problems have been pointed out that gloves and the like are adhered to the sutures and the surrounding area. Therefore, in order to solve this problem, by adding and dissolving a biodegradable polymer material in the cyanoacrylate monomer, it increases the viscosity of the adhesive, gives flexibility to the cured adhesive and at the same time lowers the amount of cyanoacrylate monomer A method of mitigating toxicity has been proposed.

US 6,103,778 discloses a cyanoacrylate adhesive composition in which a biodegradable copolymer composed of lactide and caprolactone or lactide, ε-caprolactone and polyethylene glycol as a thickening agent is disclosed. However, these copolymer thickeners include ε-caprolactone, so the decomposition rate in the body is too slow, and the solubility in cyanoacrylate monomers is low. In addition, US Pat. No. 6,224,622 discloses a cyanoacryl in which a glycolide is a component and a three-component copolymer composed of two components selected from the group consisting of lactide, ε-caprolactone, paradioxanone, and trimethylene carbonate. A rate-based tissue adhesive composition is disclosed. However, copolymers containing ε-caprolactone, paradioxanone, and trimethylene carbonate also have low solubility in cyanoacrylate monomers, making it difficult to dissolve at high concentrations, thereby providing little flexibility in hardening adhesives. .

Therefore, the technical problem to be achieved by the present invention is a biodegradable and biocompatible tissue adhesive that solves the problems of the prior art, not only to mitigate toxicity to biological tissues but also exhibit an appropriate viscosity to easily flow down to the surroundings during tissue closure And it is to provide a cyanoacrylate-based tissue adhesive composition that does not easily break even after curing.

The present invention to solve the above technical problem is cyanoacrylate monomer; It provides a cyanoacrylate-based tissue adhesive composition comprising a; and a polymer dissolved in the cyanoacrylate monomer, a copolymer of a glycolide monomer, a D, L- lactide monomer and a polyethylene glycol monomer is polymerized. The cyanoacrylate-based tissue adhesive composition of the present invention is a biodegradable and biocompatible tissue adhesive, and the toxicity to biological tissue is not only alleviated but also exhibits an appropriate viscosity so that it does not easily flow to the surroundings when the tissue is closed. In addition, the tissue adhesive composition of the present invention is suitable for use beyond skin wrinkles because it is not easily broken after curing.

In the cyanoacrylate tissue adhesive composition of the present invention, the content of the copolymer dissolved in the cyanoacrylate monomer is preferably 5 to 30% by weight of the cyanoacrylate monomer.

In the cyanoacrylate tissue adhesive composition of the present invention, as the cyanoacrylate monomer, a cyanoacrylate monomer having 2 to 6 carbon atoms of an alkyl group and a cyanoacrylate monomer having 8 to 12 carbon atoms of an alkyl group are used. The use of a mixture in a weight ratio of 1: 1 to 60:40 further reduces the toxicity of the adhesive and improves its flexibility.

In addition, the addition of a carboxyl group-containing compound such as glycolic acid, lactic acid, maleic acid, fumaric acid, polyethylene glycol biscarboxymethyl ether to the cyanoacrylate tissue adhesive composition of the present invention does not affect toxicity, adhesion time, adhesive strength, and the like. Without this, the stability of the adhesive is improved.

Hereinafter, the cyanoacrylate tissue adhesive composition according to the present invention will be described in detail.

The cyanoacrylate tissue adhesive composition of the present invention is a cyanoacrylate monomer; And a copolymer dissolved in the cyanoacrylate monomer, wherein a glycolide monomer, a D, L-lactide monomer, and a polyethylene glycol monomer are polymerized.

The cyanoacrylate monomer is a main component of the tissue adhesive, and may be used as long as it is a cyanoacrylate-based monomer that can be cured by a polymerization reaction after the procedure to seal external wounds or bleed internal bleeding. In particular, as a cyanoacrylate monomer, a mixture of a cyanoacrylate monomer having 2 to 6 carbon atoms of an alkyl group and a cyanoacrylate monomer having 8 to 12 carbon atoms of an alkyl group is mixed at a weight ratio of 99: 1 to 60:40. Will further reduce the toxicity of the adhesive and improve its flexibility. That is, in the cyanoacrylate monomer represented by the following Chemical Formula 1, the short alkyl group (C ₂ ~ C ₆ ) compound can be spontaneously anion polymerization proceeds to shorten the adhesion time, the alkyl group is relatively long Compounds (C ₈ to C ₁₂ ) delay the degradation time to mitigate the toxicity of the adhesive and at the same time improve the flexibility of the cured adhesive.

CH ₂ = C (CN) -CO-OR

In Formula 1, R is an alkyl group of C ₂ ~ C ₁₂ .

Examples of the cyanoacrylate monomer having 2 to 6 carbon atoms in the alkyl group include ethyl cyanoacrylate, propylcyanoacrylate, isopropylcyanoacrylate, butylcyanoacrylate, isobutylcyanoacrylate, and pentylcyano. Acrylate, isopentylcyanoacrylate, hexylcyanoacrylate, isohexylcyanoacrylate, and the like. Examples of the cyanoacrylate monomer having 8 to 12 carbon atoms in the alkyl group include heptylcyanoacrylate and octyl. Cyanoacrylate, 2-ethylhexyl cyanoacrylate, nonylcyanoacrylate, decylcyanoacrylate, undecylcyanoacrylate, dodecylcyanoacrylate, etc. can be illustrated.

The cyanoacrylate monomer having 2 to 6 carbon atoms of the alkyl group and the cyanoacrylate monomer having 8 to 12 carbon atoms of the alkyl group are preferably in a weight ratio of 99: 1 to 60:40 in consideration of the strength and flexibility of the adhesive. More preferably, the mixture is used in a weight ratio of 95: 5 to 70:30.

The cyanoacrylate tissue adhesive composition according to the present invention includes a copolymer obtained by polymerizing a glycolide monomer, a D, L-lactide monomer and a polyethylene glycol monomer as a polymer thickener dissolved in a cyanoacrylate monomer. .

These copolymers have good solubility in cyanoacrylate monomers and have an appropriate viscosity so that the adhesive does not easily flow to the surroundings when the tissue is closed. It also gives flexibility to the adhesive so that it does not break easily even after the adhesive has cured. Looking at the properties of the copolymer of the present invention in detail.

The copolymer contained in the adhesive composition of the present invention contains a biodegradable glycolide and a D, L-lactide component, and the copolymer containing these components contains a caprolactone, paradioxanone and trimethylenecarbonate component. It is better in solubility in cyanoacrylate monomers than copolymers. However, copolymers containing glycolide and D, L-lactide are relatively inferior in flexibility to the adhesive after curing, and the flexibility of the adhesive is clearly improved by the polyethylene glycol component introduced into the copolymer. The polyethylene glycol component is included in the copolymer as a biocompatible material that is metabolized in vivo and discharged out of the body, thereby improving the flexibility of the tissue adhesive after curing.

It is preferable that the molar ratio of D, L-lactide and a glycolide component in a copolymer is 90/10-50/50. The higher the content ratio of the D, L-lactide component, the higher the amorphous region, so that the solubility of the copolymer in the cyanoacrylate monomer and the flexibility of the adhesive containing the same are improved, and the higher the content ratio of the glycolide component, the faster the degradability. . In addition, the total content of the D, L-lactide and glycolide components and the polyethylene glycol component in the copolymer is preferably 99/1 to 5/95, more preferably 95: 5 to 60:40 Included to the extent possible. If the content ratio of polyethylene glycol is increased, the flexibility is increased, but the solubility in cyanoacrylate is lowered, and phase transition phenomenon may occur in which the adhesive surface applied to the skin is cracked after curing.

As a copolymer of this invention, it is preferable to use the block copolymer which consists of polylactic-co-glycolide, polyethyleneglycol, and polylactic-co-glycolide. Such a copolymer may be represented by the following formula (2).

[O-CH (CH ₃ ) -CO] x- [O-CH ₂ -CO] y- [O-CH ₂ CH ₂ ] z- [O-CH ₂ -CO] y- [O-CH (CH ₃ ) -CO] x

Wherein x, y and z are each an integer in the range of 10 to 10 ^3, respectively.

The weight average molecular weight of the copolymer contained in the cyanoacrylate tissue adhesive composition of the present invention is preferably 5,000 to 200,000, more preferably 10,000 to 100,000. When the molecular weight of the copolymer is lower than 5,000, the amount of the copolymer added for the appropriate viscosity increases, thereby increasing the adhesion time when the adhesive is applied, there is a fear that the adhesive strength is also lowered. In addition, when the molecular weight is 200,000 or more, the viscosity may be excessively increased even in a small amount of mixing, and thus the toxicity reduction and the improvement of flexibility to be achieved in the present invention may be insufficient, and even when the adhesive is applied, it may be difficult to apply uniformly.

The cyanoacrylate tissue adhesive composition of the present invention may include an anionic polymerization inhibitor, a radical polymerization inhibitor, and the like, which are commonly used for storage stability of the composition before the procedure. As the anionic polymerization inhibitor, sulfur dioxide, sulfonic acid, lactone, boron fluoride, phosphoric acid, acetic acid, benzoic acid, carbonic acid, formic acid, and the like may be used alone or in combination of one or more thereof. Ether, catechol, pyrogallol, benzoquinone, paramethoxyphenol, etc. can be used individually or in mixture of 1 or more types.

In particular, it is preferable to add a biocompatible carboxyl group-containing compound such as glycolic acid, lactic acid, maleic acid, fumaric acid, polyethylene glycol biscarboxymethyl ether to the cyanoacrylate tissue adhesive composition of the present invention as a stabilizer. That is, in the case of containing the polymer thickener such as the cyanoacrylate-based tissue adhesive composition of the present invention, the stability is more required than the single composition of the cyanoacrylate monomer, and thus the amount of the anionic polymerization inhibitor is further added. Is common. However, as the amount of the anionic polymerization inhibitor such as sulfur dioxide increases, the toxicity is also increased. The addition of the biocompatible carboxyl group-containing compound described above can alleviate this problem without affecting the adhesion time, adhesion strength, etc. Can be. The addition amount of the carboxyl group-containing compound is preferably 10 to 5,000 ppm, more preferably 50 to 1,000 ppm.

The carboxyl group-containing compound stabilizer may be used alone, but is preferably used in combination with an anionic polymerization inhibitor and a radical polymerization inhibitor.

In addition, the cyanoacrylate-based tissue adhesive composition of the present invention is a dye (D & C violet No. 2, D & C Green No. 6, FD & C Blue No. .2, etc.) may be added.

Hereinafter, the present invention will be described in detail with reference to Examples. However, embodiments according to the present invention can be modified in many different forms, the scope of the present invention should not be construed as limited to the embodiments described below. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Preparation Example 1 Preparation of Butyl Cyanoacrylate

0.005 mol of piperidine is dissolved in 5 mol of methanol and 0.2 mol of methoxyethyl ether with 1 mol of paraformaldehyde and basic catalyst, and the reaction is performed at about 100 DEG C while adding 1 mol of butylcyanoacetate. The solvent was removed by azeotropic distillation by adding benzene. The anion polymerization inhibitor and radical polymerization inhibitor were added to the butylcyanoacrylate in the form of oligomer. Distillation was carried out to obtain butylcyanoacrylate. Confirmation of the prepared cyanoacrylate was confirmed using ¹ H-NMR (Bruker AVANCE DPX 400, manufactured by Bruker Co., Ltd.), and purity (99% or more) was confirmed by GC (Hewlett-Packard Co.-HP6890).

Preparation Example 2 Preparation of Octyl Cyanoacrylate

Octylcyanoacrylate was obtained in the same manner as in Production Example 1 except that octylcyanoacetate was used instead of butylcyanoacetate. Confirmation of the prepared octylcyano acrylate was confirmed by ¹ H-NMR (Bruker AVANCE DPX 400, manufactured by Bruker Co., Ltd.), purity (99% or more) was confirmed by GC (Hewlett-Packard Co.-HP6890).

Preparation Example 3 Preparation of D, L-Lactide / Glycolide / Polyethylene Glycol Copolymer

50 g of purified polyethylene glycol was placed in a 1 L flask and dried in a vacuum bath at 120 ° C. for 2 hours. After adding 0.05 g (diluted in toluene solution) of tin 2-ethylhexanoate to the reactor, the toluene was removed at 120 ° C. for about 30 minutes and then cooled to a slightly lower temperature. 404 g of purified D, L-lactide and 95.5 g of glycolide were added, followed by reaction at 130 ° C. for 6 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to 70 ° C. and the resulting polymer was dissolved in a chloroform solvent. 1 The solution was extracted with normal hydrochloric acid solution, the catalyst was decomposed and washed with distilled water, and the solution from which the catalyst and by-products were removed was slowly added dropwise to cold diethyl ether. Subsequently, in order to remove the residual solvent of the precipitated block copolymer, it was vacuum dried for 3 days in a 90 ℃ vacuum oven. The composition of the D, L-lactide / glycolide / polyethylene glycol copolymer using ¹ H-NMR was 69/21/10 by weight ratio, and the molecular weight was 34,760.

Comparative Examples 1 and 2

To prepare a tissue adhesive composition with no copolymer added to the components and contents shown in Table 1. That is, sulfur dioxide and hydroquinone were added to each monomer of butylcyanoacrylate or octylcyanoacrylate, and then stirred for 24 hours to prepare a tissue adhesive.

Examples 1-14

To prepare a tissue adhesive composition in which the copolymer is dissolved in the components and contents shown in Table 1 below.

Property Test of Tissue Adhesives

The physical properties of the tissue adhesive composition prepared by the above method were measured and shown in Table 2 as follows.

(1) adhesive strength

Using a tensile strength analyzer (Instron-4204), the stainless steel was bonded with an adhesive of about 0.03 mL so that the adhesive area was 1 cm ² according to ASTM D1002, and measured after 24 hours at 37 ° C. and 75% relative humidity. It was.

Adhesion strength = adhesion strength of metal to metal (stainless steel)

(2) flexibility

According to ASTM D3111 method, the adhesive was poured into the molder using a Hardness Tester D Type (Teclock Co.-GS 709N), cured for 72 hours at 37 ° C and 75% RH, and then width 2cm and thickness 5mm. Specimens were made and measured under load 5kgf.

(3) viscosity

Using a viscometer (Brookfield-viscometer DV-II) was measured at sp15, 100rpm at 23 ± 0.5 ℃ according to the method of ASTM D 2556.

(4) Bonding time

In accordance with JIS K6861, the adhesive area of 1 cm ² was applied to the stainless steel plate, and then 0.03 mL of adhesive was administered, and the minimum time that the adhesive force can be endured was measured when the two plates applied a weight of 5 kg while adhering with a load of 2 kgf.

Referring to the results of Table 2, the tissue adhesive (Examples 1 to 14) in which the copolymer according to the present invention is dissolved does not flow to the surroundings when the tissue is sealed by applying a viscosity to the adhesive, unlike the tissue adhesive of the comparative example.

On the other hand, the tissue adhesives of the example shows better adhesive strength than the tissue adhesive of the comparative example. Cyanoacrylate monomers undergo a volume reduction of 10 to 15% upon polymerization and curing, resulting in a decrease in strength due to internal stresses resulting from the dissolution of the copolymer to compensate for this internal stress. Although there was no big change according to silver composition, when the molecular weight of a copolymer is large or the addition amount exceeds 20 weight%, it tends to be delayed slightly. The flexibility of the adhesive improves as the amount of copolymer is increased. When the content of the adhesive is adjusted to about 10-15% in consideration of the adhesion time and the adhesive strength, the flexibility may be improved along with the improvement of the existing physical properties. have. In particular, when a mixture of butylcyanoacrylate and octylcyanoacrylate was used, it was found that the most improved effect of flexibility.

Testing the Toxic Effects of Tissue Adhesives

Cytotoxicity test was performed to compare the toxicity of the tissue adhesive composition according to the present invention with the product consisting of butylcyanoacrylate and octylcyanoacrylate. Cytotoxicity was obtained by incubating the mouse fibroblast L-929 at a concentration of 1 × 10 ⁴ cells / well according to the cytotoxicity test method of ISO 10993-5, and then using 1 g of a cured adhesive with 5 ml of a single strength minium essential medium. , MEM) was extracted for 24 hours at 37 ℃. The extracts were diluted to various concentrations, then each was added to a well and incubated for 3 days in the same environment. To this was added dimethylthiazolyl diphenyltetrazolium (MTT) solution again and incubated for 4 hours at 37 ℃, 5% CO ₂ environment. Then, immediately after removing the MTT solution from the well and adding dimethyl sulfoxide (DMSO) again, the UV value was measured at 540 nm using an ELISA reader. Relative cell activity is shown in Table 3 with a non-toxic negative control of 100.

Referring to Table 3, it can be confirmed that the tissue adhesive dissolving the copolymer according to the present invention in cyanoacrylate is less toxic than the tissue adhesive using only butylcyanoacrylate or octylcyanoacrylate alone. In particular, as in Example 12, the improvement of toxicity was the best in the adhesive in which a copolymer was dissolved in a cyanoacrylate monomer mixed with butylcyanoacrylate and octylcyanoacrylate.

Test of Flexibility Improvement of Tissue Adhesives by Polyethylene Glycol Content Change of Copolymer

In order to confirm the effect of improving the flexibility of the polyethylene glycol-incorporated copolymer for the tissue adhesive, copolymers of Table 4 having similar molecular weights but different polyethylene glycol content ratios were prepared, and mixed with cyanoacrylate in a 10 weight ratio, respectively. And then cured. The hardness of the cured adhesive was measured and shown in Table 4.

In Table 4, PLGA is a lactide / glycolide copolymer and PLGA-PEG-PLGA is a lactide / glycolide / polyethyleneglycol copolymer.

As shown in the results of Table 4, it can be seen that the tissue adhesive to which the copolymer containing polyethylene glycol is added is more flexible after curing than the tissue adhesive to which the copolymer without polyethylene glycol is added. The higher the content ratio of polyethylene glycol, the more the flexibility was further improved.

Solubility Test of Copolymer to Cyanoacrylate Monomer

In order to evaluate the solubility of the copolymer dissolved in the tissue adhesive composition of the present invention, a copolymer having a component different from that of the copolymer of the present invention was synthesized, and the solubility in butylcyanoacrylate was shown in Table 5. . Synthesis of all the copolymers was carried out in the same manner as the method for producing block copolymers of D, L-lactide / glycolide / polyethylene glycol. The solubility of the copolymer in butylcyanoacrylate was visually observed and evaluated as follows according to the amount of butylcyanoacrylate for dissolving 1 g of the copolymer transparently.

1 ~ 10g: Melt well

10 ~ 30g: Melt

30 ~ 100g: slightly soluble

100-1000 g: Hard to melt

As shown in Table 5, the solubility of the copolymer in the butylcyanoacrylate monomer was most excellent in the D, L-lactide / glycolide / polyethyleneglycol copolymer of the present invention.

As described above, the tissue adhesive composition according to the present invention is a biodegradable and biocompatible tissue adhesive, which not only relieves the toxicity to biological tissues but also exhibits an appropriate viscosity so that it does not easily flow to the surroundings when the tissue is closed. In addition, since the tissue adhesive composition of the present invention is not easily broken after curing, it is suitable for use over skin wrinkles, and thus, it is useful as a tissue adhesive used in the body such as hemostatic agents, vascular sutures, fixation of dental and orthopedic implants, and the like. Can be.

Claims (9)

Cyanoacrylate monomers; And A polymer dissolved in the cyanoacrylate monomer, a copolymer formed by polymerizing a glycolide monomer, a D, L-lactide monomer and a polyethylene glycol monomer; cyanoacrylate tissue adhesive composition comprising a. The method of claim 1, The content of the copolymer is cyanoacrylate-based tissue adhesive composition, characterized in that 5 to 30% by weight of the cyanoacrylate monomer. The method of claim 1, The copolymer is a cyanoacrylate-based tissue adhesive composition, characterized in that it comprises D, L-lactide and glycolide in a molar ratio of 90:10 to 50:50. The method according to claim 1 or 3, The copolymer is cyanoacrylate-based tissue adhesive composition, characterized in that the total content of D, L- lactide and glycolide and the polyethylene glycol content in a weight ratio of 95: 5 ~ 60:40. The method of claim 1, The cyanoacrylate monomer is characterized by consisting of a cyanoacrylate monomer having 2 to 6 carbon atoms of the alkyl group and a cyanoacrylate monomer having 8 to 12 carbon atoms of the alkyl group in a weight ratio of 99: 1 to 60:40. A cyanoacrylate-based tissue adhesive composition. The method of claim 1, The copolymer is a cyanoacrylate-based tissue adhesive composition, characterized in that the block copolymer consisting of polylactic-co-glycolide, polyethylene glycol, polylactic-co-glycolide. The method of claim 1, A cyanoacrylate-based tissue adhesive composition, further comprising a carboxyl group-containing compound. The method of claim 7, wherein The carboxyl group-containing compound is cyanoacrylate-based tissue adhesive composition, characterized in that it comprises any one or more selected from the group consisting of glycolic acid, lactic acid, maleic acid, fumaric acid, polyethylene glycol bis carboxymethyl ether. The method of claim 7, wherein The content of the carboxyl group-containing compound is cyanoacrylate-based tissue adhesive composition, characterized in that 10 to 5,000ppm.