Electron beam sterilization of liquid adhesive compositions

Description: TECHNICAL FIELD [Detailed description of the invention]

【0001】

[Technical field to which the invention belongs]

The present invention relates to methods of treating liquid compositions useful as biomedical adhesives and encapsulants, in particular methods of sterilizing the compositions. More specifically, the present invention relates to a method for sterilizing a monomer liquid adhesive composition, for example, a 1,1-disubstituted ethylene monomer by irradiating it with an electron beam.

【0002】

[Conventional technology]

Several methods are known as methods for sterilizing the monomer and polymer compositions.

【0003】

U.S. Pat. No. 5,530,037 by McDonnell et al. Discloses the sterilization of cyanoacrylates using gamma irradiation. In addition, it discloses several other methods, including ionizing radiation. However, most of the methods are said to be unsuitable for application to cyanoacrylate adhesives. In particular, the above '037 patent states that the electron beam accelerator has a relatively small penetrating force and is outside the container. It states that it is effective only for surface sterilization.

【0004】

US Pat. No. 2,904,392 by Pomerantz et al. Packs various chemicals, gasoline, polymeric plastics, or polymerizable monomers in film-molded bags and irradiates the bags with intense ionizing radiation. Discloses a method of sterilizing. The radiation can be obtained from a beam of high-energy electrons generated by a high-voltage electron accelerator. In the case of monomers, polymerization can occur with moderate levels of irradiation without the help of chemical catalysts or promoters. In this method, the polymerization can be carried out at a low temperature, and the obtained polymer is basically pure.

【0005】

Stehlik's U.S. Pat. No. 3,704,089 describes α-cyanoacrylic acid. The sterilization treatment of monomer esters is disclosed. After cooling the esters to preferably below the freezing point, sterilization is performed by irradiating with ionizing radiation (for example, Co60-gamma ray irradiation).

【0006】

Schmitz et al., US Pat. No. 2,921,006 states that polymerizing an organic compound using high-energy electrons, more specifically, polymerizing the compound in a liquid or solid state by irradiation with high-energy electrons. Is disclosed. The organic compound is placed in a container covered with an aluminum sheet.

【0007】

Steigerwald's U.S. Pat. No. 3,122,633 provides an apparatus for polymerizing a liquid material by dividing a polymer organic material into small volumes and irradiating the material with an electron beam source in the divided state. It is disclosed.

【0008】

Nablo's US Pat. No. 3,780,308 discloses surface sterilization and / or surface treatment of containers and other packaged articles with walls that have a high specific energy absorption rate for relatively low energy electrons. The electron beam penetrates the container wall to some extent and sterilizes the surface. On the other hand, it minimizes the generation of X-rays by substantially absorbing electrons into the wall.

【0009】

[Problems to be Solved by the Invention]

The present invention relates to a method of sterilizing a liquid adhesive composition, preferably a monomer composition, in a container using electron beam irradiation. The liquid adhesive composition in the present invention may contain a 1,1-disubstituted ethylene monomer.

【0010】

[Means for solving problems]

The present invention uses an electron beam irradiation method to sterilize a liquid adhesive composition contained in a container. In a preferred embodiment, the polymerization of the monomer or the monomeric liquid adhesive composition that affects the usefulness of the monomers does not occur substantially. The advantage of electron beam irradiation is that the liquid composition on the production line can be sterilized in a few seconds and with a penetrating force lower than that of gamma ray irradiation without causing any substantial polymerization. The sterilized liquid adhesive composition has high storage stability and excellent stability. The temperature level of the liquid adhesive composition during electron beam irradiation changes only slightly from room temperature. Also, no post-sterilization microbial testing and quarantine period is required.

【0011】

[Implementation]

An object of the present invention is to sterilize a liquid adhesive composition contained in a container by using electron beam irradiation. In an embodiment, the liquid adhesive composition is approximately 0.5-10Mrad. It is subjected to electron beam irradiation of (5 to 100 kGy), preferably about 1.0 to 5.0 Mrad (10 to 50 kGy), more preferably 2 to 3 Mrad (20 to 30 kGy). A-bomb The time is related to the intensity of the beam and is typically typically in the range of one tenth to a few seconds (depending on the speed of the conveyor), preferably less than one minute. A dosimeter can be used to measure the irradiation dose of a sample.

【0012】

There are several electron beam irradiation sources. The two main groups of electron beam accelerators are (1) Dynamitrons with insulated iron core transformers and (2) Radio frequency (RF) linear accelerators (linacs). The Dynamitron is a particle accelerator (4.5 MeV) designed to energize electrons. High-energy electrons are generated and accelerated by the electrostatic field of the electrodes of the accelerator arranged within the length of the glass-insulated beam tube (accelerator tube). These electrons pass through extensions such as the discharge beam tube and the beam carrier (drift pipe) and are sent to the magnetic deflector to generate a "scanning" beam prior to leaving the vacuum enclosure from the beam window. The irradiation dose is adjusted by controlling the scanning ratio, beam current and conveyor speed.

【0013】

The liquid adhesive composition is placed in, at least partially, electron beam permeable containers, including, but not limited to, glass, plastic and film molded containers. In an embodiment of the invention, the container may be sealed or may have an opening. Examples of glass containers include, but are not limited to, ampoules, vials, syringes, pipettes, applicators and the like. Penetration of electron beam irradiation is a function of the container. If the penetration from the fixed electron beam side is not sufficient, the container may be turned inside out or rotated to allow sufficient penetration. Alternatively, the irradiation amount distribution and the penetration irradiation amount of the product loading portion are obtained by using an irradiation amount diagram in which the electron beam source may be moved to the fixed container side. From this, the minimum and maximum irradiation parts in the product can be known.

【0014】

In the embodiment, the container containing the liquid adhesive composition may be irradiated with an electron beam to sterilize the container, and then the container may be subjected to gamma ray irradiation. For example, the container may be boxed with other containers that require sterilization. Then, the entire box is sterilized. In addition to gamma irradiation, the entire box is sterilized chemically (eg, with ethylene oxide or hydrogen peroxide vapor), physically (eg, dry heat), or by other methods such as microwave or electron beam irradiation. May be good.

【0015】

The liquid composition of the embodiment is preferably a monomer adhesive composition. In embodiments, the monomer is a 1,1-disubstituted ethylene monomer, such as an α-cyanoacrylate. The rate. The preferred monomeric compositions of the invention and the polymers made therein are useful in tissue adhesives, sealants for bleeding prevention or covering open wounds, and other biomedical applications. For example, lining up surgically incised or traumatically torn tissue, controlling bleeding from wounds, helping drug delivery, burn bandages, and repair and regeneration of living tissue. Will find use in.

【0016】

Conventional surgical adhesive compositions have contained plasticizers that have the opposite effect of reducing film strength. Contrary to what was previously believed, it has been found that the film strength (eg toughness) under certain conditions does not decrease with the addition of large amounts of plasticizer. Depending on the particular acid degradation inhibitor and the purity of the monomers used in the adhesive composition, adding a large amount of plasticizer will result in increased toughness of the adhesive formed on the wound. The acid decomposition inhibitor does not significantly affect the polymerization of the monomers of the composition, and increases the film strength as the amount of the plasticizer increases.

【0017】

The monomers used in the present invention can be easily polymerized to make polymers. For example, anion polymerization and free radical polymerization. Such monomers include, but are not necessarily required, monomers that make biodegradable polymers. See, for example, US Pat. No. 5,328,687. Incorporated herein with reference to the patent. Defined here As it is said, "tissue poisoning" refers to the reverse response of tissue, such as inflammation due to the presence of toxic substances in the tissue.

【0018】

The 1,1-disubstituted ethylene monomer includes, but is not limited to, a monomer having the following chemical formula. (I) HRC = CXY Here, X and Y are both strongly electron-withdrawing groups, and R is H, -CH = CH, or C when both X and Y are cyano groups.₁-C₄It is an alkyl group.

【0019】

Examples of monomers within the range of Chemical Formula (I) include α-cyanoacrylates, cyanide. Vinylidene chloride, C of vinylidene cyanide₁-C₄Alkyl homologue, dialkylmethi Lemmalonate, acylacrylonitrile, vinyl sulfinate and CH₂Contains vinyl sulfonic acid represented by = CX'Y'. Where X'is -SO₂R'or -SO₃R'and Y'are -CN, -COOR', -COCH₃, -SO₂R'or -SO₃R'and R'is H Is a hydrocal building.

【0020】

The preferred monomer of formula (I) used in the present invention is α-cyanoacrylate. The monomer is known in the art and has a chemical formula. [Chemical 1]

<img file="JP2002503522A_D0001.tif" />It is represented by. Where R²Is hydrogen, R³Is a hydrocarbyl or substituted hydrocarbyl group, ie the chemical formula is -R⁴ -OR⁵ -OR⁶And R⁴Is a 1,2-alkylene group with 2 to 4 carbon atoms, R⁵Is an alkylene group with 2 to 4 carbon atoms, R⁶Is an alkyl group with 1 to 6 carbon atoms, or has a chemical formula [Chemical 2]

<img file="JP2002503522A_D0002.tif" />It is represented by R⁷But [Chemical 3]

<img file="JP2002503522A_D0003.tif" />Or -C (CH)₃)₂- so n is 1 to 10, preferably 1 to 5 carbon atoms, R⁸Is the organic part.

【0021】

Examples of suitable hydrocarbyl and substituted hydrocarbyl groups include 1-16. Linear or branched chain alkyl group with carbon atom; linear or branched chain C substituted with acyloxy group, haloalkyl group, alkoxy group, halogen atom, cyano group, or haloalkyl group₁-C₁₆Alkyl group; with 2 to 16 carbon atoms Includes straight-chain or branched-chain alkenyl groups; straight-chain or branched-chain alkynyls with 2 to 12 carbon atoms; cycloalkyls; aralkyls; alkylaryls; and aryls.

【0022】

Organic part R⁸May be substituted or unsubstituted, linear, branched, cyclic, saturated, unsaturated or aromatic. In the example of the organic part, C₁-C₈Al Kill part, C₂-C₈Alkenyl part, C₂-C₈Alkyne part, C₃-C₁₂Cyclo fat Includes family parts, aryl parts such as phenyl and substituted phenyl, and aralkyl parts such as benzyl, methylbenzyl and phenylethyl. Other organic moieties include substituted hydrocarbon moieties such as halo (eg, chloro-, fluoro-, and bromo-substituted hydrocarbons) and oxy- (eg, alkoxy-substituted hydrocarbon) substituted hydrocarbon moieties. Preferred organic radicals are alkyl, alkenyl and alkynyl moieties with 1 to 8 carbon atoms, and halo-substituted derivatives thereof. Particularly preferably, it is an alkyl moiety having 4 to 6 carbon atoms.

【0023】

In the monomer of cyanoacrylate of chemical formula (II), R³Is 1 to 10 carbons Alkyl group with atoms or chemical formula-AOR⁹In the family of, A is a divalent straight chain or branched chain alkylene or oxyalkylene part having 2 to 8 carbon atoms, and R⁹Is a straight or branched chain alkyl part with 1 to 8 carbon atoms.

【0024】

Chemical formula-AOR⁹Examples of groups represented by are 1-methoxy-2-propyl, 2-butoxyethyl, isopropoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

【0025】

The preferred α-cyanoacrylate monomer used in the present invention is 2-octylsis. Anoacrylate, dodecyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, butyl cyanoacrylate, methyl cyanoacrylate, 3-methoxybutyl cyanoacrylate, 2-butoxyethyl cyanoacrylate, 2-isopropoxyethyl cyanoacrylate, or 1-methoxy-2- Butyl cyanoacrylate Relate.

【0026】

The α-cyanoacrylate of formula (II) can be prepared by a known method. As a reference For example, there are US Pat. Nos. 2,721,858 and 3,254,111. It is as follows. For example, α-cyanoacrylate is an alkyl cyanoacrylate. Is prepared by reacting with formaldehyde in the presence of a basic catalyst in a non-aqueous organic solvent, and then thermally decomposing the anhydrous intermediate polymer in the presence of a polymerization inhibitor. The α-shi Ananoacrylate monomers prepared with a low water content and basically no impurities are desirable for biomedical applications.

【0027】

Α-Cyanoacrylate of chemical formula (II), R³Is the chemical formula-R⁴ -OR⁵ -OR⁶Family members can be prepared by the method disclosed in US Pat. No. 4,364,876 of Kimura et al. It Is as follows. In the method of Kimura et al., α-Cyanoacrylate is cyano. It is prepared by cyanoacetate obtained by esterifying acetic acid with alcohol or transesterifying cyanoalkyl acetic acid with alcohol. That is, in order to obtain a condensate, cyanoacetate is condensed with formaldehyde or para-formaldehyde in the presence of a catalyst at a monomer ratio of 0.5 to 1.5: 1, preferably 0.8 to 1.2: 1. The condensation reaction mixture is depolymerized either directly or after removing the condensation catalyst to obtain a crude cyanoacrylate. Then, the crude cyanoacrylate is distilled to obtain a high-purity cyanoacrylate.

【0028】

Α-Cyanoacrylate of chemical formula (II), R³Is the chemical formula [Chemical 4]

<img file="JP2002503522A_D0004.tif" />Those who have are disclosed in U.S. Pat. No. 3,995,641 of Kronenthal et al. Can be prepared by method. It is as follows. In the method of Kronenthal et al., The α-cyanoacrylate reacts an alkyl ester of α-cyanoacrylic acid with a cyclic 1,3-diene to form Diels-Alder adduction, which is subjected to alkaline hydrolysis and then the corresponding. Acidify to make α-cyanoacrylate adducts. The α-cyanoacrylic acid adduct is the corresponding carboalkoxymethyl / α-cyanoac Esterification with alkylbromoacetate is preferred to obtain the relate adduct. Alternatively, the α-cyanoacrylic acid adduct may react with thionyl chloride to convert to the α-cyanoacrylic halogenated adduct. α-Cyanoacrylic Ha The logging adduct is then the corresponding carboalkoxymethyl α-cyanoa. Clirate adduct or carboalkoxy alkyl α-cyanoacrely To obtain an adduct, react with alkyl hydroxyacetate or methyl-substituted alkyl hydroxyacetate. The cyclic 1,3-diene block group is finally removed and the carboalkoxy methyl α-cyanoacrylate adduct is added. Alternatively, a carboalkoxy / alkyl / α-cyanoacrylate adduct can be added. The product is heated with a slight deficiency of maleic anhydride to convert it to the corresponding carboalkoxy alkyl α-cyanoacrylate.

【0029】

In the example of chemical formula (II), the chemical formula [Chemical 5]

<img file="JP2002503522A_D0005.tif" />Includes cyanopentadienoates and α-cyanoacrylates. Where Z is -CH = CH₂And R³Is as already defined. In chemical formula (III), R³Alkyl groups of 1 to 10 carbon atoms, such as 2-cyanopenta-2,4-dienoate, react the appropriate 2-cyanoacetate with acrolein in the presence of a catalyst such as zinc chloride. Can be prepared. This method of preparing 2-cyanopenta-2,4-dienoic acid ester For example, it is disclosed in US Pat. No. 3,554,990. It is as follows.

【0030】

A preferred monomer is an alkyl α-cyanoacrylate, more preferably an octyl α-cyanoacrylate, and particularly preferably a 2-octyl α cyanoacrylate. The monomers used in the present invention are of high purity and should contain very few impurities (eg medical grade). The compositions of the present invention can contain at least one plasticizer, which imparts flexibility to the polymerized monomers formed on the scratches and cuts. The plasticizer preferably contains little or no water and should not have a significant effect on the polymerization of the monomers.

【0031】

Other compositions are exemplified in US Pat. Nos. 5,259,835 and 5,328,687, and US Patent Application Nos. 08 / 609,921, 08 / 714,288, 08 / 909,845, 08 / 755,007, 08 / 920,876 and 08 / 488,411. All of these are referenced and included here.

【0032】

Suitable plasticizers include acetyltributylcitrate ester, dimethylsebacic acid ester, triethylphosphate, tri (2-ethylhexyl) phosphate, tri (p-cresyl) phosphate, glyceryl, triacetate, glyceryl tributyrate, diethylsebacic acid ester. , Dioctyl adipate, isopropyl myristart, butyl steerate, lauric acid, trioctyl remelitat, dioctyl glutarate, and mixtures thereof. Preferred plasticizers are tributyl citrate ester and acetyl tributyl citrate ester. Specifically, suitable plasticizers include polyethylene glycol (PEG) esters and polymerizable plasticizers such as capped PEG esters or ethers, polyester glutarates and polyester adipates.

【0033】

The compositions of the present invention may also contain at least one acidic stabilizer that inhibits polymerization. Such stabilizers may also include a mixture of anionic stabilizers and radical stabilizers.

【0034】

Suitable anionic stabilizers include sultone (eg α-chloro-α-hydroxy-o-toluenesulfonic acid-γ-sultone), sulfur dioxide, sulfuric acid, sulfonic acid, lactone, trisulfonated boron, acetic acid or Examples include, but are not limited to, organic acids such as phosphoric acid, alkylsulfuric acid, alkylsulfuric acid, 3-sulfoleno, alkylsulfone, alkylsulfoxide, mercaptan, and alkylsulfides, and mixtures thereof. Preferred anion stabilizers are acidic stabilizers of organic acids such as acetic acid or phosphoric acid. Specifically, the amount of sulfur dioxide stabilizer is less than 100 ppm, preferably 5 to 75 ppm, more preferably. It is about 20 to 50 ppm. The amount of sultone and / or trifluoroacetic acid is about 500-3000 ppm.

【0035】

Suitable radical stabilizers include hydroquinone, hydroquinone monomethyl ether, catechol, pyrogallol, benzoquinone, 2-hydroxybenzoquinone, p-methoxyphenol, t-butylcatechol, butylated hydroxyanisole (BHA), butylated hydroxytoluene, and Examples thereof include t-butylhydroquinone. Specifically, the amount of BHA is about 1000-5000 ppm.

【0036】

The pKa ionization constants of suitable acidic stabilizers in water range from -12 to 7, about -5 to about 7, preferably about -3.5 to about 6, and more preferably about 2 to about 5.5. For example, suitable acid stabilizers include hydrogen sulfide (pKa7.0), carbonic acid (pKa6.4), triacetylmethane (pKa5.9), acetic acid (pKa4.8), benzoic acid (pKa4.2), 2,4-Dinitrophenol (pKa4.0), picric acid (pKa3.7), nitrite (pKa3.3), hydrofluoric acid (pKa3.2), chloroacetic acid (pKa2.9), phosphoric acid (pKa2. 2), dichloroacetic acid (pKa1.3), trichloroacetic acid (pKa0.7), 2,4,6-trinitrophenol (picric acid) (pKa0.3), trifluoroacetic acid (pKa0.2), sulfuric acid (pKa- 3.0), and mixtures thereof can be exemplified. Specifically, the amount of trifluoroacetic acid is about 500 to 1500 ppm.

【0037】

When the acid stabilizer is added to the adhesive composition, the plasticizer is added from about 0.5% to about 16% by weight, preferably from about 3% to about 9% by weight, and more preferably from about 5% by weight to about. When added in an amount of 7% by weight, it imparts better film strength (eg, toughness) than polymerized monomers comprising plasticizers and acid stabilizers beyond the above range.

【0038】

The concentration of acid stabilizer used can vary depending on the strength of the acid. For example, when acetic acid is used, concentrations of 80-200 ppm (wt / wt), preferably 90-180 ppm (wt / wt), and more preferably 100-150 ppm (wt / wt) can be used. When a stronger acid such as phosphoric acid is used, a concentration range of 20-80 ppm (wt / wt), preferably 30-70 ppm (wt / wt) and more preferably 40-60 ppm (wt / wt) can be used. Specifically, the amount of trifluoroacetic acid is about 100 to 3000 ppm, preferably 500 to 1500 ppm. More specifically, the amount of phosphoric acid is about 10-200 ppm, preferably about 50-150 ppm, and more preferably about 75-125 ppm.

【0039】

Other compositions are exemplified in US Pat. Nos. 5,624,669, 5,582,834, 5,575,997, 5,514,371, 5,514,372, 5,259,835 and 5,328,687. All of these are referenced and incorporated here. The compositions of the present invention may also include at least one biocompatible agent that is effective in reducing the level of active formaldehyde concentration that occurs during biodegradation of the polymer in vivo (in the present specification, "reducing formaldehyde concentration". Agent "). Preferably, this ingredient is a formaldehyde scavenger -It is a compound. Formaldehyde scavenger compounds useful in the present invention include sulfites; bisulfites; mixtures of sulfites and bisulfites; ammonium sulfites; amines; amides; imides; nitriles; carbonates; alcohols; mercaptans; proteins; amines. , A mixture of amides and proteins; active methylene compounds such as compounds with cyclic ketones and b-dicarbonyl groups; and without carbonyl groups and with NH groups, the rings are made of nitrogen or carbon atoms and the rings are Unsaturated, or saturated or unsaturated when condensed to a phenyl group, the NH group is attached to a carbon or nitrogen atom, which is double-bonded directly to another carbon or nitrogen atom. Examples thereof include bonded heterocyclic compounds.

【0040】

Bisulfites and sulfites useful as formaldehyde scavenger compounds in the present invention include alkali metal salts such as lithium, sodium and potassium salts, and ammonium salts. For example, sodium bisulfite, potassium bisulfite, lithium bisulfite, ammonium bisulfite, sodium sulfite, potassium sulfite, lithium sulfite, ammonium sulfite and the like.

【0041】

Examples of amines useful in the present invention are aliphatic and aromatic amines such as aniline, benzidine, aminopyrimidine, toluene-diamine, triethylenediamine, diphenylamine, diaminodiphenylamine, hydrazine and hydrazide.

【0042】

Suitable proteins include collagen, gelatin, casein, soy protein, plant protein, keratin and sardine. A protein that can be preferably used in the present invention is casein.

【0043】

Amides suitable for use in the present invention are preferred amides, such as urea, cyanamide, acrylamide, benzamide and acetamide. Suitable alcohols can be exemplified by phenol, 1,4-butanediol, d-sorbitol, and polyvinyl alcohol. Suitable compounds having a b-dicarbonyl group include malonic acid, acetylacetone, ethylacetone, acetate, malonamide, diethylmalonate, or other marron esters. Cyclohexanone or cyclopentanone can be exemplified as the cyclic ketone that can be preferably used in the present invention.

【0044】

Heterocyclic compounds suitable for use as formaldehyde scavengers in the present invention are disclosed, for example, in US Pat. No. 4,127,382 (Perry). And refer to this and import it here. Examples of such heterocyclic compounds include benzimidazole, 5-methylbenzimidazole, 2-methylbenzimidazole, indole, pyrrole, 1,2,4-triazole, indoline, benzotriazole, indoline and the like.

【0045】

The formaldehyde scavenger preferably used in the present invention is sodium bisulfite.

【0046】

In the practice of the present invention, a formaldehyde concentration reducing agent, such as a formaldehyde scavenger compound, is added to the cyanoacrylate in an effective amount. This "effective amount" is an amount sufficient to reduce the amount of formaldehyde produced during subsequent biodegradation of the polymerized cyanoacrylate in vivo. This amount depends on the type of active formaldehyde concentration reducing agent and can be easily determined by those skilled in the art without undue experimentation.

【0047】

Formaldehyde concentration reducing agents can be used in free form or in microcapsule form in the present invention, other compositions are exemplified by US Patent Application No. 08 / 714,288, which is incorporated herein by reference in its entirety. .. When placed in microcapsules, the formaldehyde concentration-reducing agent is continuously released from the microcapsules throughout the biodegradation of the cyanoacrylate polymer in vivo.

【0048】

For the purposes of the present invention, a microencapsulated formaldehyde concentration reducing agent is preferred. The reason for this is that according to this aspect, the polymerization of the cyanoacrylate monomer is inhibited or substantially reduced by the formaldehyde concentration reducing agent, which improves the storage stability and facilitates the handling of the monomer composition during use. Is.

【0049】

Microencapsulation of formaldehyde scavengers can be achieved by many known microencapsulation methods. For example, microencapsulation dissolves the coating polymer in a volatile solvent (eg, methylene chloride) at a polymer concentration of about 6% by weight; the formaldehyde scavenger compound in the form of particles is stirred into the coating polymer / solvent solution. Add below to a scavenger concentration of 18% by weight; slowly add surfactant-containing mineral oil solution to the polymer solution under rapid stirring; evaporate the volatile solvent under stirring; remove the stirrer It can be done by separating the solid from the mineral oil; washing and drying the fine particles. The size of these fine particles is about 0.001 to about 1000 microns.

【0050】

Coating polymers for microencapsulating formaldehyde concentrations are preferably subject to biocorrosion in vivo at the same or faster rates as cyanoacrylate polymers are formed from monomers and have a lower inherent water content. It takes that. Such "biological corrosion" can occur as a result of the physical or chemical destruction of the encapsulating material. For example, it occurs as a result of the encapsulating material being destroyed by changing from solid to solute in the presence of body fluids, or by biodegrading the encapsulating material by agents present in the body.

【0051】

Coating materials that can be used to microencapsulate formaldehyde concentrations include polyglycolic acid, polylactic acid, poly-1,4-dioxa-2-one, polyoxalate, polycarbonate, polyglycolic acid and poly. Copolemer of lactic acid, polycaprolactone, poly-b-hydroxybutyrate, copolymer of epsilon-caprolactone and delta-valerolactone, copolymer of epsilon-caprolactone and DL-dilactide, and esters such as polyester hydrogels; polyvinylpyrrolidone; polyamide; gelatin; albumin Examples include proteins; collagens; polyorthoesters, polyanhydrides; poly (alkyl-2-cyanoacrylates); polydihydropyrans; polyacetals; polyphosphazene; polyurethanes; polydioxynones; celluloses and starches.

【0052】

Examples of the surfactant that can be added to the mineral oil include commercially available surfactants represented by "Triton x-100", "Tween 20", and "Tween 80".

【0053】

The compositions of the present invention can contain one or more auxiliary substances such as thickeners, agents, etc., which can improve the medical usefulness of special medical monomers.

【0054】

Suitable thickeners include polycyanoacrylate, polylactic acid, poly-1,4-dioxa-2-one, polyoxalate, polyglycolic acid, lactic acid-glycolic acid copolymer, polycaprolactone, lactic acid-caprolactone copolymer, poly. Examples thereof include -3-hydroxybutyl acid, polyorthoester, polyalkyl acrylate, copolymer of alkyl acrylate and vinyl acetate, polyacyl methacrylate, and copolymer of alkyl methacrylate and butadiene. Examples of the alkyl methacrylate and alkyl acrylate include poly-2-ethylhexyl methacrylate and poly-2-ethylhexyl acrylate, polybutyl methacrylate and polybutyl acrylate, and various acrylate monomers such as poly (butyl methacrylate-CO-methyl acrylate). And a copolymer of methacrylate monomer can be exemplified.

【0055】

In order to improve the bonding strength of the adhesive formed from the composition of the present invention, a bifunctional monomer cross-linking agent can be added to the monomer of the present invention. Such cross-linking agents are known. See, for example, US Pat. No. 3,940,362 of Overhults, which is incorporated herein by reference. Examples of suitable cross-linking agents include alkyl bis (2-cyanoacrylate), triallyl isocyanurate, alkylene diacrylate, alkylene dimethacrylate, trimethylolpropane triacrylate, and alkyl bis (2-cyanoacrylate). A catalytic amount of an amine-activated free radical initiator or rate modifier can be added to initiate polymerization or alter the rate of polymerization of the cyanoacrylate monomer / crosslinker blend.

【0056】

Specifically, the adhesive composition may additionally comprise a thermal and / or light (eg, visible or ultraviolet) activation initiator and accelerator. These initiate cross-linking of the cyanoacrylate composition containing the compound of formula (I).

【0057】

One of ordinary skill in the art can easily select a special initiator for a particular system without undue experimentation. Suitable polymerization initiators for cyanoacrylate compositions include detergent compositions; surfactants such as polysorbate 20 (eg Tween 20).^TM), Polysorbate 80 (eg Tween 80)^TM), And nonionic surfactants such as poroxamer, cationic surfactants such as tetrabutylammonium bromide, benzalconium chloride or its pure constituents, stannous octoate (tin (II) 2-ethylhexanoate). And anionic surfactants such as sodium tetradecyl sulfate and amphoteric or amphoteric surfactants such as dodecyldimethyl (3-sulfopropyl) ammonium hydroxide, internal salts; amines such as imidazole, tryptamine, urea, arginine and povidine, Imines and amides; phosphines such as triphenylphosphine and triethylphosphite, phosphite and phosphonium salts; alcohols such as ethylene glycol, methyl gallate, ascorbic acid, tannin and tannic acid; Inorganic bases and salts such as sodium silicate; sulfur compounds such as thiourea and polysulfide; polymerizable cyclic ethers such as monencin, nonactin, crown ether, calix arene and polymerizable epoxides; cyclic and acyclic ethers such as diethylcarbonate. Carbonate; Aliquat 336 phase transition catalysts; organometallic compounds, manganese acetylacetonates and radical initiators can be exemplified, but not limited to these. Cobalt naphthenate can be used as an accelerator for peroxides.

【0058】

The compositions of the present invention may further comprise fibrous reinforcing and coloring agents, i.e. dyes and pigments. Examples of suitable fibrous reinforcing agents include PGA microfibrils, collagen microfibrils, cellulose microfibrils and olefin microfibrils. Suitable colorants include 1-hydroxy-4- [4-methylphenyl-amino] -9,10-anthracene dione (D + C purple; No. 2); 6-hydroxy-5-[(4-sulfophenyl). ) Oxo] -2-naphthalene-sulfonic acid (FD + C yellow No. 6) disodium salt; 9- (0-carboxyphenyl) -6-hydroxy-2,4,5,7-tetraiodo-3H-xanthene -3-one, disodium salt, monohydrate (FD + C red No. 3); 2- (1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-iriden) -2 , 3-Dihydro-3-oxo-1H-Indol-5-Sulfonic acid disodium salt (FD + C blue No. 2); and [Phenyl-Russian ninato (2-)] copper and the like can be exemplified.

【0059】

The liquid composition of the present invention can be applied using known means such as a glass stir bar, a sterile brush, or a chemical dropper, depending on the particular requirements of the user. However, in many situations a pressurized aerosol dispense package is preferred, where the adhesive composition is in a solution containing a compatible anhydrous propellant.

【0060】

[Example]

Specific embodiments of the present invention will be described with reference to the following examples. These examples are used for illustration purposes only and are not intended to limit materials, conditions or steps.

【0061】

Table 1 shows the stabilizer concentrations for Experiment Nos. 1 to 20 in Tables 2 to 7. Table 8 shows the stabilizer concentrations for Experiment Nos. 1-27 in Tables 9-11. Tables 2 and 5 show the initial viscosities of the 2-octyl cyanoacrylate monomer composition (containing less than 5 ppm SO2 or not containing SO2) when sterilized by electron beam irradiation, respectively. Tables 3-4 show changes in viscosity over time (d indicates day) for 2-octyl cyanoacrylate compositions containing less than 5 ppm SO2 sterilized by electron beam irradiation. Tables 6 to 7 show the changes in viscosity over time for SO2-free 2-octyl cyanoacrylate compositions sterilized by electron beam irradiation. Viscosity changes are a measure of polymerization and stability of the liquid adhesive monomer composition.

【0062】

Table 9 shows the initial viscosities of 2-octyl cyanoacrylate monomer compositions containing 1500 ppm hydroquinone and 27 ppm SO2 sterilized by electron beam irradiation. Tables 10 to 11 show that the monomer composition containing the stabilizer shows excellent stability, which is represented by a small change in viscosity when sterilized by electron beam irradiation. Table 12 shows that the n-butyl cyanoacrylate monomer composition also exhibits excellent stability when sterilized by electron beam irradiation.

【0063】

Accelerated stability results performed at 80 ° C to analyze stability and storage show that 3 days at 80 ° C corresponded to about 6 months at room temperature, 6 days at 80 ° C for about 1 year at room temperature, and 80 ° C 12 days corresponds to about 2 years at room temperature. ND indicates that there is no data. Viscosity was measured at 25 ° C.

[table 1]

<img file="JP2002503522A_D0006.tif" />[Table 2]

<img file="JP2002503522A_D0007.tif" />[Table 3]

<img file="JP2002503522A_D0008.tif" />[Table 4]

<img file="JP2002503522A_D0009.tif" />[Table 5]

<img file="JP2002503522A_D0010.tif" />[Table 6]

<img file="JP2002503522A_D0011.tif" />[Table 7]

<img file="JP2002503522A_D0012.tif" />[Table 8]

<img file="JP2002503522A_D0013.tif" />[Table 9]

<img file="JP2002503522A_D0014.tif" />[Table 10]

<img file="JP2002503522A_D0015.tif" />[Table 11]

<img file="JP2002503522A_D0016.tif" />[Table 12]

<img file="JP2002503522A_D0017.tif" />