Adhesive composition for hard tissue repair and hard tissue repair kit

Abstract

The adhesive composition for hard tissue repair contains a polymerizable monomer (A), a polymer powder (B), a polymerization initiator (C) and a filler (D), and the hard tissue repair kit contains the adhesive composition for hard tissue repair, and the polymerization initiator (C) contains 100 parts by weight of an alkoxydialkyl boron having a purity of 97% or more (including 97%) and 0.2 to 5 parts by weight of an alcohol having a boiling point of 60°C to 180°C. The polymerization initiator (C) does not smoke, burn or ignite even when it comes into contact with paper, porous fiber material, etc. in air, has high fluidity, can be easily accurately taken in small amounts, and provides high polymerization to the polymerizable composition, thereby providing an adhesive composition suitable for hard tissue repair. The repair kit is made by separating or premixing the components (A), (B), (C), and (D) of the adhesive composition for hard tissue repair and other necessary components as necessary and storing them in three or more members.

Description

[Technical Field]

[0001] The present invention relates to an adhesive composition for hard tissue repair and a hard tissue repair kit containing the adhesive composition for hard tissue repair. More specifically, the present invention relates to an adhesive composition for hard tissue repair that has high curing and adhesive properties, and a polymerization initiator used therefor that has improved safety against ignition when attached to paper or the like. [Background technology]

[0002] Adhesive compositions using tributylboron as a polymerization initiator are known to have good adhesive properties for biological hard tissues (see Patent Document 1). However, trialkylboron is an extremely unstable substance in air, and when exposed to air, it reacts rapidly with oxygen and ignites, making it unsuitable for normal clinical use. For this reason, various technologies have been proposed to improve the safety of trialkylboron against ignition.

[0003] Patent Document 2 discloses a method for improving safety against fire by adding a hydrophobic, viscous substance such as petrolatum, paraffin, or silicone (silicone oil) to trialkylborane or its derivatives, and, if necessary, an adsorbent such as silicic acid or alumina, to form a paste.

[0004] Patent Document 3 discloses a dental or surgical adhesive that uses a product (partially oxidized trialkylboron) obtained by reacting 0.3 to 0.9 moles of oxygen with trialkylboron as a polymerization initiator.

[0005] The invention of Patent Document 3 proposes a polymerization initiator that minimizes the activity of trialkylborane to improve safety against ignition, but because this polymerization initiator is a liquid / gas phase reaction between tributylborane and oxygen, it is difficult to obtain a stable product, which affects the stable curing rate of the adhesive composition. In addition, ignition potential could not be completely suppressed.

[0006] Patent Document 4 proposes a polymerization initiator prepared by adding organic oligomers or organic polymers such as silicone oil, wax, oligoesters, and oligoamides to an organoboron compound to form a uniform mixture. However, the large amount of additives reduces the activity of the polymerization initiator and increases its viscosity, making it difficult to obtain the correct amount to be used.

[0007] Patent Documents 5 and 6 propose a method of improving safety against fire by adding a polymer of an alkyl (meth)acrylate to tributyl boron or partially oxidized tributyl boron to form a paste. However, the addition of a large amount of additive tends to reduce the activity of the polymerization initiator, and at the same time, it may be difficult to obtain the correct amount of initiator composition to be used from the paste-like composition.

[0008] Patent Document 7 proposes a mixture containing, as a main component, alkylalkoxide boron obtained by reacting trialkylboron with alkyl alcohol, or a polymerization initiator whose safety is improved by further adding a polar organic compound or an inert diluent, in response to the flammability of trialkylboron; however, these proposals are still not sufficient.

[0009] Patent Document 8 proposes a method of improving safety by adding an aprotic solvent, or further an inert liquid or solid organic oligomer or polymer, to tributylboron or partially oxidized tributylboron. However, the addition of a large amount of additive tends to reduce the activity of the polymerization initiator, and the addition of the organic oligomer or polymer increases the viscosity of the initiator composition, which may make it difficult to obtain the correct amount to be used.

[0010] Patent Document 9 proposes a method of improving safety by adding specific alkanes and alcohols to tributylboron or partially oxidized tributylboron to suppress ignition. However, the effects of alkanes contained in the polymerization initiator, which cannot be absorbed or decomposed by the human body, on human health are unknown, and the addition of large amounts of additives tends to reduce the activity of the polymerization initiator. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] :Toku-Kokoku No. 14318-1967 [Patent Document 2] : JP 48-11892 [Patent Document 3] : JP 49-5143 [Patent Document 4] : JP 58-084803 [Patent Document 5] : JP 3-264509 [Patent Document 6] :CN1642933A [Patent Document 7] : JP 5-253284 [Patent Document 8] : JP 9-110913 [Patent Document 9] :CN1909870A

[0012] As described above, conventional adhesive compositions for hard tissue repair have room for improvement in terms of safety in use, convenience, and biosafety.

[0013] Invention Contents The object of the present invention is to provide a polymerization initiator and an adhesive composition suitable for hard tissue repair, which do not emit smoke, burn or ignite even when in contact with paper, porous fibrous materials, etc. in the air, have high fluidity, can be easily dispensed in small amounts accurately, can reduce adverse effects on the human body, and further impart high polymerizability to a polymerizable composition and can harden the polymerizable composition within a short period of time.

[0014] As a result of extensive research to achieve the above object, the inventors have found that by using an initiator composition comprising a specific high-purity organoboron compound and a specific small amount of alcohol, it is possible to suppress ignition and maintain high fluidity and high polymerization activity, and have completed the present invention. The technology used in the present invention is as follows.

[0015] That is, the adhesive composition for hard tissue repair of the present invention contains a polymerizable monomer (A), a polymer powder (B), and a polymerization initiator (C), and the polymerization initiator (C) contains 100 parts by weight of an alkoxydialkylboron having a purity of 97% or more (including 97%) and 0.2 to 5 parts by weight of an alcohol having a boiling point of 60°C to 180°C; the polymerizable monomer (A) may be a (meth)acrylate or a combination of a (meth)acrylate and a polymerizable monomer having an acidic group; and the polymer powder (B) is at least one polymer selected from the group consisting of a homopolymer of alkyl (meth)acrylate, a copolymer of alkyl (meth)acrylate, a copolymer of alkyl (meth)acrylate and other polymerizable monomers, a copolymer of alkyl (meth)acrylate and alkylene di(meth)acrylate, and a copolymer of alkyl (meth)acrylate and a butadiene-based polymerizable monomer.

[0016] The alkoxydialkylboron contained in the polymerization initiator (C) is butoxydibutylboron, and the alcohol contained therein is ethanol.

[0017] The adhesive composition for hard tissue repair contains 20 to 70 parts by weight of a polymerizable monomer (A), 20 to 70 parts by weight of a polymer powder (B), and 1 to 20 parts by weight of a polymerization initiator (C) (total of 100 parts by weight of (A), (B), and (C)).

[0018] The adhesive composition for hard tissue repair further contains a filler (D) in an amount of usually 20 to 150 parts by weight per 100 parts by weight of the total amount of the polymerizable monomer (A), the polymer powder (B), and the polymerization initiator (C). The filler (D) is an inorganic filler, an organic filler, or an organic-inorganic composite filler that is insoluble or does not swell in the polymerizable monomer (A).

[0019] The hard tissue repair kit further comprises the polymerizable monomer (A), polymer powder (B), polymerization initiator (C), and filler (D) of the adhesive composition for hard tissue repair according to claims 1 to 4, divided into the polymerizable monomer (A) and a portion of the polymer powder (B), the polymerization initiator (C), and the other portion of the polymer powder (B), and stored in three components; alternatively, the polymerizable monomer (A) and filler (D), the polymer powder (B), and polymerization initiator (C), and stored in three components; or alternatively, the polymerizable monomer (A), polymerization initiator (C), polymer powder (B), and filler (D), and stored in three components.

[0020] According to the present invention, a polymerization initiator is obtained which does not emit smoke, burn or ignite even when it comes into contact with paper, porous fibrous materials, etc. in the air, has excellent fluidity and is easy to collect in small amounts, reduces adverse effects on the human body, and imparts high polymerizability to a polymerizable composition, and by using this initiator, an adhesive composition suitable for hard tissue repair can be obtained.

[0021] It is generally believed that the reactivity of alkylborons with oxygen, i.e., the flammability of alkylborons when they come into contact with oxygen, is proportional to their polymerization initiation ability. However, in the present invention, surprisingly, a polymerization initiator composed of a high-purity alkoxydialkylboron and a specific small amount of alcohol of the present invention exhibits polymerization activity equivalent to that of trialkylboron and its partial oxides, despite being less flammable than trialkylboron and its partial oxides. While the reason for this is not entirely clear, one possible reason is that the polymerization initiator composed of an alkoxydialkylboron and a specific small amount of alcohol of the present invention reacts relatively mildly with oxygen compared to trialkylboron and its partial oxides. Therefore, the portion of the initial radical species generated by the reaction with oxygen that does not react with each other and contribute to polymerization initiation is relatively small, making it more effective for initiating polymerization.

[0022] As shown in Examples 1 and 2 and Comparative Examples 1 and 2 in Table 1, a mixture of tributylboron partial oxide and butoxydibutylboron can burn the filter paper and even ignite it when it comes into contact with the filter paper, whereas the polymerization initiator of the present invention, which is composed of high-purity butoxydibutylboron and a small amount of ethanol, does not emit smoke when it comes into contact with the filter paper, and does not cause the filter paper to burn or ignite, yet it exhibits polymerization activity equivalent to that of the mixture of tributylboron partial oxide and butoxydibutylboron.

[0023] MODE FOR CARRYING OUT THE INVENTION Polymerizable monomer (A) The polymerizable monomer (A) of the present invention can be used without any particular limitation as long as it can be polymerized with the polymerization initiator composition (C) described below. Furthermore, either a monofunctional polymerizable monomer or a polyfunctional polymerizable monomer can be used as the polymerizable monomer (A) depending on the purpose of use.

[0024] Examples of the polymerizable monomer (A) include (meth)acrylates and other vinyl compounds. Among these polymerizable monomers (A), (meth)acrylates are preferred because they are relatively less irritating to the human body (note that (meth)acrylates collectively refer to acrylates and methacrylates). Furthermore, among the polymerizable monomers (A), it is preferred to use them in combination with a polymerizable monomer having an acidic group because they have excellent adhesion to hard tissues and metals such as titanium for hard tissue repair.

[0025] Examples of monofunctional (meth)acrylates having no acidic group include alkyl (meth)acrylates such as methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, butyl (meth)acrylate, hexyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, dodecyl (meth)acrylate, lauryl (meth)acrylate, cyclohexyl (meth)acrylate, benzyl (meth)acrylate, and isobornyl (meth)acrylate; 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, and the like. Hydroxyalkyl esters of (meth)acrylic acid such as acrylate, 3-hydroxypropyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, 5-hydroxypentyl (meth)acrylate, 6-hydroxyhexyl (meth)acrylate, 1,2-dihydroxypropyl mono(meth)acrylate, 1,3-dihydroxypropyl mono(meth)acrylate, and erythritol mono(meth)acrylate; diethylene glycol mono(meth)acrylate, triethylene glycol mono(meth)acrylate, and polyethylene glycol Examples of the (meth)acrylate include polyalkylene glycol mono(meth)acrylates such as cholesteryl mono(meth)acrylate and polypropylene glycol mono(meth)acrylate; (poly)alkylene glycol monoalkyl ether (meth)acrylates such as ethylene glycol monomethyl ether (meth)acrylate, ethylene glycol monoethyl ether (meth)acrylate, diethylene glycol monomethyl ether (meth)acrylate, triethylene glycol monomethyl ether (meth)acrylate, polyethylene glycol monomethyl ether (meth)acrylate, and polypropylene glycol monoalkyl ether (meth)acrylate; fluoroalkyl esters of (meth)acrylic acid such as perfluorooctyl (meth)acrylate and hexafluorobutyl (meth)acrylate; silane compounds having a (meth)acryloxyalkyl group such as γ-(meth)acryloxypropyltrimethoxysilane and γ-(meth)acryloxypropyltri(trimethylsiloxy)silane; and (meth)acrylates having a heterocycle such as tetrahydrofurfuryl (meth)acrylate.

[0026] Examples of polyfunctional (meth)acrylates having no acidic group include poly(meth)acrylates of alkane polyols such as ethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, butylene glycol di(meth)acrylate, neopentyl glycol di(meth)acrylate, hexylene glycol di(meth)acrylate, 2-hydroxypropyl di(meth)acrylate, trimethylolpropane tri(meth)acrylate, and pentaerythritol tetra(meth)acrylate; and polyoxyalkane polyol poly(meth)acrylates such as diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, polyethylene glycol di(meth)acrylate, dipropylene glycol di(meth)acrylate, polypropylene glycol di(meth)acrylate, dibutylene glycol di(meth)acrylate, and dipentaerythritol hexa(meth)acrylate. Alicyclic or aromatic di(meth)acrylate represented by the following formula (1): [ka] (In the above formula (1), R represents a hydrogen atom or a methyl group, m and n represent numbers of 0 to 10 which may be the same or different, and R 1 teeth [ka] ); Aliphatic or aromatic di(meth)acrylate having a hydroxyl group in the molecule, represented by the following formula (2): [ka] (In the above formula (2), R represents a hydrogen atom or a methyl group, n represents a number from 0 to 10, and R 1 teeth [ka] ); and polyfunctional (meth)acrylates having a urethane bond in the molecule represented by the following formula (3): [ka] (In the above formula (3), R represents a hydrogen atom or a methyl group, and R 1 teeth [ka] ); Examples include:

[0027] Among these (meth)acrylates, preferred monofunctional (meth)acrylates include alkyl (meth)acrylates such as methyl (meth)acrylate and ethyl (meth)acrylate; hydroxyalkyl esters of (meth)acrylic acid such as 2-hydroxyethyl (meth)acrylate, 1,3-dihydroxypropyl mono(meth)acrylate and erythritol mono(meth)acrylate; and polyethylene glycol mono(meth)acrylates such as triethylene glycol monomethyl ether (meth)acrylate and triethylene glycol mono(meth)acrylate.

[0028] Examples of polyfunctional (meth)acrylates include di(meth)acrylates having an ethylene glycol chain in the molecule, such as triethylene glycol di(meth)acrylate and polyethylene glycol di(meth)acrylate; and compounds represented by the following formula (1-a): [ka] (In formula (1)-a, R, m, and n are defined as in formula (1)); A compound represented by the following formula (2)-a: [ka] (In formula (2)-a, the definition of R is the same as in formula (2)); A compound represented by the following formula (3)-a: [ka] (In formula (3)-a, the definition of R is the same as in formula (3)); etc. are preferred.

[0029] These (meth)acrylates can be used alone or in combination of two or more.

[0030] Examples of polymerizable monomers having an acidic group include (meth)acrylic acid and its anhydride, 1,4-di(meth)acryloxyethylpyromellitic acid, 6-(meth)acryloxyethylnaphthalene, 1,2,6-tricarboxylic acid, N-(meth)acryloyl-p-aminobenzoic acid, N-(meth)acryloyl-o-aminobenzoic acid, N-(meth)acryloyl-m-aminobenzoic acid, N-(meth)acryloyl-5-aminosalicylic acid, N-(meth)acryloyl-4-aminosalicylic acid, 4-(meth)acryloxyethyltrimellitic acid and its anhydride, 4-(meth)acryloxybutyltrimellitic acid and its anhydride, 4-(meth)acryloxyhexyltrimellitic acid and its anhydride, 4-(meth)acryloxydecyltrimellitic acid and its anhydride, 2-(meth)acryloyloxybenzoic acid, Examples of the monomer include monomers having a carboxylic acid group or an anhydride group thereof, such as 3-(meth)acryloyloxybenzoic acid, 4-(meth)acryloyloxybenzoic acid, β-(meth)acryloyloxyethyl hydrogen succinate, β-(meth)acryloyloxyethyl hydrogen maleate, β-(meth)acryloyloxyethyl hydrogen phthalate, 11-(meth)acryloyloxy-1,1-undecanedicarboxylic acid, and p-vinylbenzoic acid; monomers having a phosphoric acid group, such as (2-(meth)acryloxyethyl)phosphoric acid, (2-(meth)acryloxyethylphenyl)phosphoric acid, and 10-(meth)acryloxydecylphosphoric acid; and polymerizable monomers having a sulfonic acid group, such as p-styrenesulfonic acid and 2-acrylamido-2-methylpropanesulfonic acid.

[0031] Among these polymerizable monomers having an acidic group, 4-methacryloxyethyltrimellitic acid and its anhydride are preferred.

[0032] These polymerizable monomers having an acidic group can be used alone or in combination of two or more kinds.

[0033] In the polymerizable monomer (A), the amount of the monofunctional (meth)acrylate monomer blended is preferably 80 parts by weight or more, more preferably 90 parts by weight or more, and even more preferably 95 parts by weight or more.

[0034] When a polymerizable monomer having an acidic group is blended into the polymerizable monomer (A), it is preferably contained in an amount of 1 to 20 parts by weight per 100 parts by weight of the total polymerizable monomers contained in the adhesive composition for hard tissue repair of the present invention.

[0035] The blending amount of the polymerizable monomer (A) is preferably 20 to 70 parts by weight, more preferably 30 to 65 parts by weight, and even more preferably 35 to 60 parts by weight, per 100 parts by weight of the total of the polymerizable monomer (A), the polymer powder (B), and the polymerization initiator (C).

[0036] If the amount of polymerizable monomer added is less than the above range, the operability and the permeability into the adhesive composition tend to be poor, whereas if the amount of polymerizable monomer added exceeds the above range, the early adhesive strength and mechanical properties tend to be poor.

[0037] Polymer powder (B) The polymer powder (B) in the present invention is not particularly limited, and any polymer powder that dissolves or swells in the polymerizable monomer (A) can be used. Examples of such polymer (B) include alkyl(meth)acrylate polymers and other ethylene-based polymers. Among these, alkyl(meth)acrylate polymers, such as homopolymers of alkyl(meth)acrylate, copolymers of alkyl(meth)acrylate, copolymers of alkyl(meth)acrylate and other polymerizable monomers, copolymers of alkyl(meth)acrylate and alkylene di(meth)acrylate, and copolymers of alkyl(meth)acrylate and butadiene-based polymerizable monomers, are preferred. These polymer powders can be used alone or in combination.

[0038] Specific examples of alkyl (meth)acrylate polymers include non-crosslinkable polymers such as polymethyl (meth)acrylate, polyethyl (meth)acrylate, methyl (meth)acrylate-ethyl (meth)acrylate copolymer, methyl (meth)acrylate-butyl (meth)acrylate copolymer, and methyl (meth)acrylate-styrene copolymer; and crosslinkable polymers such as methyl (meth)acrylate-ethylene glycol di(meth)acrylate copolymer, methyl (meth)acrylate-triethylene glycol di(meth)acrylate copolymer, and copolymers of methyl (meth)acrylate and butadiene-based monomers.

[0039] The blending amount of the polymer powder (B) is preferably 20 to 70 parts by weight, more preferably 30 to 65 parts by weight, and even more preferably 35 to 60 parts by weight, per 100 parts by weight of the total of the polymerizable monomer (A), the polymer powder (B), and the polymerization initiator (C).

[0040] Polymerization initiator (C) The polymerization initiator (C) of the present invention contains 100 parts by weight of an alkoxydialkylboron having a purity of 97% or more (including 97%) and 0.2 to 5 parts by weight of an alcohol having a boiling point of 60°C to 180°C.

[0041] Specific examples of the alkoxydialkylboron include ethoxydiethylboron, ethoxydipropylboron, ethoxydibutylboron, ethoxydipentylboron, propoxydiethylboron, propoxydipropylboron, propoxydibutylboron, propoxydipentylboron, butoxydiethylboron, butoxydipropylboron, and butoxydibutylboron. Among these alkoxydialkylborons, ethoxydibutylboron, propoxydibutylboron, and butoxydibutylboron are preferred. More preferred are propoxydibutylboron and butoxydibutylboron, and particularly preferred is butoxydibutylboron.

[0042] These alkoxydialkylborons can be used alone or in combination of two or more.

[0043] The purity of the alkoxydialkylborane of the present invention is preferably 97% or more, more preferably 98% or more, and particularly preferably 98.5% or more. Surprisingly, when the purity of the alkoxydialkylborane of the present invention reaches a certain level or higher, the addition of a small amount of a specific alcohol clearly suppresses its smoke generation and flammability while maintaining the same level of polymerization activity.

[0044] Alkoxydialkylboranes are prepared by reacting trialkylboranes with the corresponding alcohols. The preparation of alkoxydialkylboranes by the reaction of trialkylboranes with alcohols must be carried out under oxygen-shielding conditions, and is also affected by the reaction temperature. Therefore, typically, only a mixture (primary product) consisting primarily of the target alkoxydialkylborane is obtained. The high-purity alkoxydialkylboranes of the present invention can be obtained by further subjecting the primary product to reduced-pressure distillation.

[0045] Alkoxydialkylboranes can also be prepared by the reaction of trialkylboranes with an oxidizing agent such as oxygen. In the case of the oxidation reaction of trialkylboranes using oxygen, the reaction conditions, such as the oxygen blowing rate and the liquid stirring rate, must be strictly controlled because the reaction is a gas-liquid heterophase reaction. The reaction product obtained by the oxidation reaction of trialkylboranes with oxygen is usually a mixture primarily composed of the target alkoxydialkylborane. The high-purity alkoxydialkylboranes of the present invention can be obtained by further subjecting the mixture to a reduced-pressure distillation process.

[0046] Specific examples of the alcohol having a boiling point of 60°C to 180°C include methanol, ethanol, n-propanol or an isomer thereof, n-butanol or an isomer thereof, n-pentanol or an isomer thereof, and n-hexanol or an isomer thereof. Among these alcohols, alcohols having 4 or less carbon atoms are preferred, and ethanol and n-propanol are particularly preferred. These alcohols may be used alone or in combination of two or more.

[0047] The blending amount of the alcohol in the polymerization initiator of the present invention is in the range of 0.2 to 5 parts by weight per 100 parts by weight of high-purity alkoxydialkylboron. It is preferably 0.3 to 4.5 parts by weight, more preferably 0.5 to 4 parts by weight. If the blending amount of the alcohol is below the lower limit of the above range, the sufficient suppression effect against smoke generation and fire tends to be poor. If the blending amount of the alcohol is above the upper limit of the above range, the polymerization ability of the polymerization initiator tends to be low.

[0048] The amount of the polymerization initiator (C) to be blended is preferably 1 to 20 parts by weight, more preferably 2 to 15 parts by weight, and even more preferably 3 to 10 parts by weight, per 100 parts by weight of the total of the polymerizable monomer (A), the polymer powder (B), and the polymerization initiator (C).

[0049] Filler (D) The filler (D) of the present invention is not particularly limited, and an inorganic filler, an organic filler, or an organic-inorganic composite filler that is not dissolved or swelled in the polymerizable monomer (A) can be used.

[0050] Examples of the inorganic filler (D) include metal oxide powders such as zirconium oxide, bismuth oxide, titanium oxide, zinc oxide, and aluminum oxide particles; metal salt powders such as calcium carbonate, calcium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, bismuth carbonate, calcium phosphate, zirconium phosphate, and barium sulfate; hydroxide apatite, carbonate apatite, and anhydrous calcium hydrogen phosphate; glass fillers such as silica glass, aluminum-containing glass, barium-containing glass, strontium-containing glass, and zirconium silicate glass; fillers with sustained silver ion release properties, and fillers with sustained fluorine release properties. These inorganic fillers can be used alone or in combination.

[0051] In order to obtain a strong bond between the inorganic filler and the resin, it is preferable to use an inorganic filler that has been subjected to a surface treatment such as silane treatment or polymer coating.

[0052] The amount of filler (D) in the composition of the present invention is preferably 20 to 150 parts by weight, more preferably 30 to 120 parts by weight, even more preferably 35 to 100 parts by weight, and particularly preferably 40 to 80 parts by weight, per 100 parts by weight of the total of the polymerizable monomer (A), the polymer powder (B), and the polymerization initiator (C).

[0053] Other ingredients The adhesive composition for hard tissue repair of the present invention may contain a polymerization inhibitor, if necessary. Examples of polymerization inhibitors include hydroquinone compounds such as hydroquinone and dibutylhydroquinone, phenols such as hydroquinone monomethyl ether, 2,6-di-tert-butylphenol and 2,6-di-tert-butyl-p-cresol, catechol, pyrogallol, benzoquinone, 2-hydroxybenzoquinone, p-methoxyphenol, tert-butylcatechol, butylated hydroxyanisole, butylated hydroxytoluene, and tert-butylhydroquinone. The polymerization inhibitors may be used alone or in combination. Among these, a mixture of hydroquinone monomethyl ether and 2,6-di-tert-butyl-p-cresol is preferably used.

[0054] The polymerization inhibitor is usually added to the polymerizable monomer (A). The amount of the polymerization inhibitor added is preferably 10 to 1000 ppm, more preferably 20 to 500 ppm, and even more preferably 25 to 200 ppm, relative to the polymerizable monomer (A).

[0055] The adhesive composition for hard tissue repair of the present invention may further contain an ultraviolet absorber, if necessary. Examples of ultraviolet absorbers include benzotriazole compounds. The amount of the ultraviolet absorber added is preferably 5 to 500 ppm, more preferably 10 to 200 ppm, based on the polymerizable monomer (A).

[0056] The adhesive composition for hard tissue repair of the present invention may further contain, as needed, anti-infective agents, antibacterial agents, antiviral agents, hemostatic agents, platelet activators, bone morphogenetic factors, bone growth factors, synthetic peptides with hemostatic activity, and other pharmaceutical or therapeutic ingredients.

[0057] The adhesive composition for hard tissue repair of the present invention may further contain, if necessary, a colorant for visually clearly distinguishing the adhesive composition for repair from the surrounding hard tissue.

[0058] Hard Tissue Repair Kit The hard tissue repair composition of the present invention is typically used by mixing the components prior to use. The polymerizable monomer (A), polymer powder (B), polymerization initiator (C), filler (D), and other optional components can be stored individually or in any combination in three or more separate components to form a hard tissue repair kit. For example, the kit can be stored in three separate components: Component 1, which contains a mixture of the polymerizable monomer (A) and other optional components (e.g., polymerization inhibitor, UV absorber, etc.); Component 2, which contains a mixture of the polymer powder (B) or the polymer powder (B) with the filler (D) and other optional components (e.g., anti-infective, antibacterial, colorant, etc.); and Component 3, which contains a mixture of the polymerization initiator (C) and other optional components.

[0059] When mixing the above components, there are no particular restrictions on the order of mixing, and from the viewpoint of achieving better performance of the resulting adhesive composition for hard tissue repair, it is desirable to first mix the polymerizable monomer (A) and other components that may be included as needed for member 1 with the polymerization initiator (C) and other components that may be included as needed for member 3, and then mix the polymer powder (B) of member 2, or the polymer powder (B) with the filler (D) and other components that may be included as needed.

[0060] The material for the member 1 containing the polymerizable monomer (A) and other components that may be added as needed is preferably one that is made of a material that prevents the evaporation and scattering of the polymerizable monomer, such as a sealable resin container with gas barrier properties, a metal-plastic composite laminated membrane bag, or a glass ampoule; the material for the member 2 containing the polymer powder (B), or the polymer powder (B) and the filler (D) and other components that may be added as needed, is preferably a resin or glass container with good sealing properties to prevent moisture absorption, a breathable resin nonwoven fabric that can be sterilized with ethylene oxide (EO) or hydrogen peroxide, or sterilized paper; the material for the member 3 containing the polymerization initiator (C) and other components that may be added as needed is preferably one that is made of a material that prevents the polymerization initiator from coming into contact with air and leaking, such as a sealable metal container with gas barrier properties, a metal-plastic composite laminated membrane bag, or a glass ampoule.

[0061] The component for storing the hard tissue repair kit of the present invention may also be a container (e.g., adhesive composition extruder, mixing container, adhesive composition injector, etc.) that can directly fill and apply the hard tissue repair adhesive composition obtained by mixing the components to affected hard tissues such as bone and cartilage, soft tissues, and artificial repair materials such as titanium, ceramic, and stainless steel. For example, the polymerizable monomer (A) of the present invention and other components that may be added as needed are placed inside an adhesive composition extruder, and in use, the polymerizable monomer (A) is brought into contact with and mixed with the polymerization initiator (C), polymer powder (B), or the polymer powder (B) and filler (D) and other components that may be added as needed, and then directly filled or applied to the affected area or prosthesis for repair; or the inside of the composition extruder is divided into two chambers by a partition or spacer, and the polymerizable monomer (A) and other components that may be added as needed, and the polymerization initiator (C) and other components that may be added as needed, are placed in each chamber, and in use, the partition is broken or moved or the spacer is removed, and the polymerizable monomer (A) is brought into contact with and mixed with the polymerization initiator (C), and then further filled with the polymer powder (B), or the polymer powder (B). or a mixing container in which the interior of a composition extruder is divided into three chambers by partitions or spacers, each chamber containing a polymerizable monomer (A) and other components that may be included as needed, a polymer powder (B) or a polymer powder (B) and a filler (D) and other components that may be included as needed, and a polymerization initiator (C) and other components that may be included as needed, and in which, upon use, the partitions are broken or moved or the spacers are removed to bring the polymerizable monomer (A) into contact with and mix it with the polymerization initiator (C), and the polymer powder (B) or a polymer powder (B) and a filler (D) and other components that may be included as needed, and then the mixture is directly filled or applied to the affected area or a restorative prosthesis.

[0062] The hard tissue repair kit of the present invention may further contain a disinfectant such as alcohol or a solution for pretreatment intended to improve adhesion.

[0063] When storing each component in a hard tissue repair kit, each component may be sterilized using electromagnetic waves such as ultraviolet rays or ethylene oxide, preferably under conditions that do not alter the components (e.g., do not harden the polymerizable monomers). [Example]

[0064] The present invention will be described in more detail below based on examples, however, the present invention is not limited to these examples.

[0065] The abbreviations used below represent the following compounds. MMA: methyl methacrylate 4-META: 4-methacryloxyethyl trimellitic anhydride p-(MMA / BuMA): Copolymer of methyl methacrylate and butyl methacrylate (particle size 68 μm, MMA content approximately 25% by weight)

[0066] Example 1 (1) Preparation of polymerization initiator 1 In a nitrogen atmosphere, 182 g of tributylborane was poured into a reaction vessel, the temperature of the reaction contents was kept below 80°C, and 74 g of anhydrous n-butyl alcohol was added dropwise with stirring. The temperature was then slowly raised with stirring to reflux. After 24 hours, heating was stopped, and a butoxydibutylboron mixture was obtained. In a nitrogen atmosphere, the butoxydibutylboron mixture was distilled under reduced pressure at 92-94°C / 8 mmHg, and the fraction was collected. Gas chromatography confirmed that the product was butoxydibutylboron with a purity of 97.6%. This product was designated butoxydibutylboron 1.

[0067] In a nitrogen atmosphere, 100 parts by weight of the above butoxydibutylboron 1 was poured into a mixing vessel, and 3 parts by weight of absolute ethanol was slowly added dropwise while stirring to obtain polymerization initiator 1. The obtained polymerization initiator was stored in a nitrogen box.

[0068] (2) Ignition test 0.5 ml of the polymerization initiator obtained in (1) above was dropped onto a filter paper (Whatman, No. 3) at 23°C ± 2°C, and the state of ignition and burning was observed.

[0069] (3) Collectability test The polymerization initiator was dripped from the syringe and the dripping condition was visually judged. If it dripped drop by drop and there was no stringiness or air bubbles mixed in, it was judged as good collection; if the droplets dripped in a series, there was viscous stringiness, air bubbles mixed in, or it was impossible to drip, it was judged as poor collection.

[0070] (4) Polymerization activity test (curing time measurement) 1) In a room with a room temperature of 25°C ± 2°C, 8 drops (0.18 g) of polymerizable monomer consisting of MMA / 4-META = 95 / 5 (weight ratio) and 2 drops (0.011 to 0.015 g) of polymerization initiator were placed in a dappen dish, 0.16 g of p-MMA (number average molecular weight 400,000, average particle size approximately 25 μm) was added, and the mixture was lightly mixed for 10 seconds to make resin mud.

[0071] 2) A thin layer of Vaseline was applied to a glass plate, and a Teflon ring (outer diameter 13 mm, inner diameter 10 mm, thickness 5 mm) similarly coated with a thin layer of Vaseline was placed on top, and resin mud was poured into it.

[0072] 3) Within 30 seconds of starting mixing, the specimen was placed in an incubator at 37±2°C and 100% humidity, and a Vigor needle was gently dropped onto the surface of the specimen to check whether a needle mark was left. The time from the start of mixing until the needle mark disappeared on the specimen was recorded as the setting time.

[0073] The results are shown in Table 1.

[0074] Example 2 (1) Preparation of polymerization initiator 2 In a nitrogen atmosphere, 182 g of tributylborane was poured into a reaction vessel, and 0.5 molar oxygen equivalents of dry air were blown onto the surface of the reaction liquid over 6 hours while stirring, so as not to raise the temperature of the reaction contents above 40°C, to obtain partially oxidized tributylboron. In a nitrogen atmosphere, the partially oxidized tributylboron was distilled under reduced pressure at 92-94°C / 8 mmHg, and the fraction collected was found to be butoxydibutylboron with a purity of 97.2%. This was designated butoxydibutylboron 2.

[0075] In a nitrogen atmosphere, 100 parts by weight of the butoxydibutylboron 2 was poured into a mixing vessel, and 3 parts by weight of absolute ethanol was slowly added dropwise while stirring to obtain a polymerization initiator 2. The obtained polymerization initiator was stored in a nitrogen box.

[0076] Evaluation was carried out in the same manner as in Example 1. The results are shown in Table 1.

[0077] [Table 1]

[0078] Examples 3 to 4 As the polymerization initiator (C), polymerization initiator 1 was used in the blending amount shown in Table 1, and the composition was evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0079] Comparative Example 1 The butoxydibutylboron mixture of Example 1 was used as the polymerization initiator (C), and evaluation was carried out in the same manner as in Example 1. The results are shown in Table 1.

[0080] Comparative Example 2 As the polymerization initiator (C), the partially oxidized tributylboron of Example 2 was used, and evaluation was carried out in the same manner as in Example 1. The results are shown in Table 1.

[0081] Comparative Examples 3 to 7 As the polymerization initiator (C), an initiator composition in the amount shown in Table 1 was used, and evaluation was carried out in the same manner as in Example 1. The results are shown in Table 1.

[0082] Example 5 (Adhesion strength to hard tissue) (1) Under water, the labial side of a bovine front tooth was cut with coarse emery paper to expose a flat enamel surface, and then polished with 600-grit emery paper to form an adhesive surface. After drying, the adhesive surface was treated with a phosphoric acid etching solution containing 35% by weight of phosphoric acid for 10 seconds, rinsed with water for 10 seconds, and air-dried for 15 seconds. After that, a piece of cellophane tape with a 4 mm diameter hole was applied to the adhesive surface to determine the adhesive area. (2) A resin slurry was prepared in the same blending ratio as in the polymerization activity test in Example 1(4). (3) This resin mud was applied to the adhesive surface prepared in (1), and an acrylic rod was attached to prepare a sample for the adhesion test. The sample for the adhesion test was left at room temperature for 30 minutes, and then immersed in distilled water at 37°C for 24 hours. A tensile test was then conducted to measure the adhesive strength between the acrylic rod and the tooth structure. The adhesive strength was the average value measured for five test pieces. The adhesive strength was 10.9 MPa.

[0083] Example 6 (Adhesion strength to hard tissue) As the polymerization initiator (C), polymerization initiator 2 of Example 2 was used and evaluation was carried out in the same manner as in Example 5. The results are shown in Table 1. The adhesive strength was 10.7 MPa.

[0084] The hard tissue repair composition of the present invention is typically used by mixing the components prior to use. The polymerizable monomer (A), polymer powder (B), polymerization initiator (C), filler (D), and other optional components can be stored individually or in any combination in three or more separate components to form a hard tissue repair kit. For example, the kit can be stored in three separate components: Component 1, which contains a mixture of the polymerizable monomer (A) and other optional components (e.g., polymerization inhibitor, UV absorber, etc.); Component 2, which contains a mixture of the polymer powder (B) or the polymer powder (B) with the filler (D) and other optional components (e.g., anti-infective, antibacterial, colorant, etc.); and Component 3, which contains a mixture of the polymerization initiator (C) and other optional components.

[0085] When mixing the above components, there are no particular restrictions on the order of mixing, and from the viewpoint of achieving better performance of the resulting adhesive composition for hard tissue repair, it is desirable to first mix the polymerizable monomer (A) and other components that may be included as needed for member 1 with the polymerization initiator (C) and other components that may be included as needed for member 3, and then mix the polymer powder (B) of member 2, or the polymer powder (B) with the filler (D) and other components that may be included as needed.

[0086] The member 1 for storing the polymerizable monomer (A) and other components that may be included as needed is preferably made of a material that prevents the polymerizable monomer from volatilizing or scattering, such as a sealable resin container with gas barrier properties, a metal-plastic composite laminated membrane bag, or a glass ampoule; the member 2 for storing the polymer powder (B), or the polymer powder (B) and the filler (D) and other components that may be included as needed, is preferably made of a resin or glass container with good sealing properties to prevent moisture absorption, a breathable resin nonwoven fabric that can be sterilized with ethylene oxide (EO) or hydrogen peroxide, or sterilized paper; the member 3 for storing the polymerization initiator (C) and other components that may be included as needed is preferably made of a material that prevents the polymerization initiator from coming into contact with air and leaking, such as a sealable metal container with gas barrier properties, a metal-plastic composite laminated membrane bag, or a glass ampoule.

[0087] The component for storing the hard tissue repair kit of the present invention may also be a container (e.g., adhesive composition extruder, mixing container, adhesive composition injector, etc.) that can directly fill and apply the hard tissue repair adhesive composition obtained by mixing the components to affected hard tissues such as bone and cartilage, soft tissues, and artificial repair materials such as titanium, ceramic, and stainless steel. For example, the polymerizable monomer (A) of the present invention and other components that may be added as needed are placed inside an adhesive composition extruder, and in use, the polymerizable monomer (A) is brought into contact with and mixed with the polymerization initiator (C), polymer powder (B), or the polymer powder (B) and filler (D) and other components that may be added as needed, and then directly filled or applied to the affected area or a prosthesis for repair; or the inside of the composition extruder is divided into two chambers by a partition or spacer, and the polymerizable monomer (A) and other components that may be added as needed, and the polymerization initiator (C) and other components that may be added as needed, are placed in each chamber, and in use, the partition is broken or moved or the spacer is removed to bring the polymerizable monomer (A) into contact with and mix the polymerization initiator (C), and then the polymer powder (B) or the polymer powder (B) is filled in. or a mixing container in which the polymerizable monomer (A) and other components that may be included as needed, the polymerizable monomer (A) and other components that may be included as needed, the polymer powder (B) or the polymer powder (B) and the filler (D) and other components that may be included as needed, and the polymerization initiator (C) and other components that may be included as needed are respectively stored in three chambers, and upon use, the partitions are broken or moved or the spacers are removed to allow the polymerizable monomer (A) to be brought into contact with and mixed with the polymerization initiator (C), and the polymer powder (B) or the polymer powder (B) and the filler (D) and other components that may be included as needed, and then the polymerizable monomer (A) and the polymerization initiator (C), and the polymer powder (B) or the polymer powder (B) and the filler (D) and other components that may be included as needed, and then the polymerizable monomer (A) and the polymerization initiator (C) are directly packed or applied to the affected area or a restorative prosthesis.

[0088] As described above, according to the present invention, it is possible to provide a polymerization initiator and an adhesive composition that do not emit smoke, burn, or become flammable even when in contact with paper, porous fibrous materials, etc. in the air, have high fluidity, make it easy to accurately dispense small amounts, reduce adverse effects on the human body, and further impart high polymerizability to the polymerizable composition, making them suitable for hard tissue repair.

[0089] The above content is a comparatively good embodiment of the present invention, and does not limit the present invention. Any modifications, equivalent replacements and improvements within the concept and principle of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for producing a hard tissue repair kit, which contains a polymerizable monomer (A), a polymer powder (B), and a polymerization initiator (C), and which is divided into the polymerizable monomer (A), the polymer powder (B), and the polymerization initiator (C) and stored in three components, comprising: The method includes mixing 100 parts by weight of an alkoxydialkylboron having a purity of 97% or more (including 97%) with 0.2 to 5 parts by weight of an alcohol having a boiling point of 60°C to 180°C to obtain a polymerization initiator (C); The polymerizable monomer (A) is a (meth)acrylate or a combination of a (meth)acrylate and a polymerizable monomer having an acidic group; The method, wherein the polymer powder (B) is at least one polymer selected from the group consisting of a homopolymer of alkyl (meth)acrylate, a copolymer of alkyl (meth)acrylate, and a copolymer of alkyl (meth)acrylate and another polymerizable monomer.

2. A method for producing an adhesive composition for hard tissue repair, comprising: The method includes mixing a polymerizable monomer (A), a polymer powder (B), and a polymerization initiator (C), the above method further comprises mixing 100 parts by weight of an alkoxydialkylboron having a purity of 97% or more (including 97%) with 0.2 to 5 parts by weight of an alcohol having a boiling point of 60°C to 180°C to obtain a polymerization initiator (C); The polymerizable monomer (A) is a (meth)acrylate or a combination of a (meth)acrylate and a polymerizable monomer having an acidic group; The method, wherein the polymer powder (B) is at least one polymer selected from the group consisting of a homopolymer of alkyl (meth)acrylate, a copolymer of alkyl (meth)acrylate, and a copolymer of alkyl (meth)acrylate and another polymerizable monomer.

3. A method for producing a polymerization initiator (C) used in an adhesive composition for hard tissue repair containing a polymerizable monomer (A) and a polymer powder (B), comprising: The method includes mixing 100 parts by weight of an alkoxydialkylboron having a purity of 97% or more (including 97%) with 0.2 to 5 parts by weight of an alcohol having a boiling point of 60°C to 180°C to obtain a polymerization initiator (C); The polymerizable monomer (A) is a (meth)acrylate or a combination of a (meth)acrylate and a polymerizable monomer having an acidic group; The method, wherein the polymer powder (B) is at least one polymer selected from the group consisting of a homopolymer of alkyl (meth)acrylate, a copolymer of alkyl (meth)acrylate, and a copolymer of alkyl (meth)acrylate and another polymerizable monomer.

4. A method according to any one of claims 1 to 3, characterized in that the alkoxydialkylboron is butoxydibutylboron and the alcohol is ethanol.

5. The method according to claim 2 or 3, characterized in that the adhesive composition for hard tissue repair contains 20 to 70 parts by weight of a polymerizable monomer (A), 20 to 70 parts by weight of a polymer powder (B), and 1 to 20 parts by weight of a polymerization initiator (C) (total of 100 parts by weight of (A), (B), and (C)).

6. The method according to claim 2 or 3, wherein the adhesive composition for hard tissue repair further contains 20 to 150 parts by weight of a filler (D) per 100 parts by weight of the total amount of the polymerizable monomer (A), the polymer powder (B), and the polymerization initiator (C), and the filler (D) is an inorganic filler, an organic filler, or an organic-inorganic composite filler that is not dissolved in or swells with the polymerizable monomer (A).

7. The method according to any one of claims 1 to 3, wherein the polymer powder (B) is at least one polymer selected from the group consisting of a homopolymer of alkyl (meth)acrylate, a copolymer of alkyl (meth)acrylate, a copolymer of alkyl (meth)acrylate and alkylene di(meth)acrylate, and a copolymer of alkyl (meth)acrylate and a butadiene-based polymerization monomer.

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