0001]The present invention is excellent in penetration of the adherend to cancellous bone or the like, relates to hard tissue repairing composition and hard tissue repair kit is excellent in adhesion to the adherend.
BACKGROUND
[0002]Traditionally, bone, bone cement for fixation of the hard tissue and the artificial articular cartilage, etc., a bone filler used in osteoporosis therapy like, as artificial bone materials, have various hard tissue repair composition is studied ing. For example, polymethyl methacrylate, a composition comprising a methyl methacrylate, and benzoyl peroxide (polymerization initiator), have been studied composition, etc. comprising (meth) acrylate, inorganic fillers calcium phosphate, and organic peroxides (for example, Patent Document 1). However, such compositions have a high heat generation during curing, a high risk of damage to the affected tissue.
[0003]
　As hard tissue repair compositions with improved this point, for example, Patent Document 2, (meth) acrylate (A), (meth) acrylate polymer (B), a specific polymerization initiator (C) and contrast agents ( hard tissue repair composition comprising X) is disclosed. The composition has a low heat generation during curing, yet has excellent workability.
CITATION
Patent Document
[0004]
Patent Document 1: JP-A-8-224294 JP
Patent Document 2: WO 2011/062227
Summary of the Invention
Problems that the Invention is to Solve
[0005]
　The present inventors have found that in terms of macroscopic adhesion between bone tissue were considered conventional hard tissue repair composition has room for improvement. For example, if the poor penetration of the cancellous bone of the bone cement (hard tissue repairing composition), with a gap in the interface between the bone pain caused by osteolysis, become necessary exacerbated when re arthroplasty put away. This problem is very important in the art.
[0006]
　That object of the present invention is excellent in penetration of the adherend cancellous bone or the like, to provide a hard tissue repairing composition and hard tissue repair kit is excellent in adhesion to the adherend.
Means for Solving the Problems
[0007]
　The present inventors have result of intensive investigation to achieve the above object, by using the contrast medium (X) in volume average particle diameter within a specific range, found that improved adhesion to the bone tissue, the It has led to the completion of the invention. That is, the present invention is specified by the following matters.
[0008]
[1] Monomer (A), the polymer (B), polymerization initiator (C), and hard tissue repair composition comprising a volume average particle diameter 3μm or more contrast agent (X).
[0009]
[2] The following hard tissue repair composition according to claim 1 simulated bone invasive as measured by the method is less than 1.0mm.
[Measurement method for simulating bone invasive]
　simulated bone invasiveness, the polyurethane foam having air bubbles in communication (porosity 95%) impregnated with physiological saline, since gone stringing becomes dough-like in its upper surface 5 Place the minute after the composition was 30 seconds applied load at a pressure of 75 kPa, measured depth composition has penetrated a (mm).
[0010]
[3] hard tissue repair composition according to the contrast agent (X) is barium sulfate or zirconium oxide [1].
[0011]
[4] Monomer (A) is (meth) hard tissue repair composition according to an acrylate based monomer [1].
[0012]
[5] The polymer (B) is (meth) hard tissue repair composition according to an acrylate-based polymer [1].
[0013]
[6] Monomer (A) 10 ~ 45 parts by weight, the total of the polymer (B) 54.9 ~ 80 parts by weight, the polymerization initiator (C) 0.1 ~ 10 parts by weight (component (A) ~ (C) is referred to as 100 parts by mass) and hard tissue repair composition according to the contrast agent (X) 0.5 ~ [1] containing 70 parts by weight.
[0014]
[7] hard tissue repair composition according to the volume average particle size of the contrast agent (X) is 3.0 ~ 25.1μm [1].
[0015]
[8] hard tissue repair composition according to the hard volume average particle diameter of the total particles contained in the tissue repair composition is less than 32 [mu] m [1].
[0016]
[9] monomer contained in the hard tissue repair composition according to [1] (A), the polymer (B), polymerization initiator (C), and, each component of the contrast agent (X), any hard tissue repair kit having members housed is divided into three or more in combination.
The invention's effect
[0017]
　According to the present invention, excellent penetration of the adherend to cancellous bone or the like, it is possible to provide a hard tissue repairing composition and hard tissue repair kit is excellent in adhesion to the adherend.
[0018]
　According to common sense, when the polymer powder passes through the gap, towards the smaller contrast medium particle size it should easily pass through the gap. However, in the present invention, surprisingly, by using a particle size is relatively large contrast media (X), simulated bone invasive hard tissue repair composition is improved. The reason is not necessarily clear, as one of the reasons, if the particle size of the contrast agent (X) is small tends powder particles are agglomerated, there is a tendency for a larger aggregate particles, a contrast agent (X when the particle size is large because it is difficult to aggregation), simulated bone invasive it is presumed that it would to increase.
DESCRIPTION OF THE INVENTION
[0019]
　[Monomer (A)]
　Monomer (A) used in the present invention is not particularly limited, it may be a polymerizable monomer by later-described polymerization initiator (C). Monomer (A) is a monofunctional monomer according to the intended use, any of the polyfunctional monomers can be used.
[0020]
　The monomer (A), for example, can be used (meth) acrylate monomer and other vinyl compounds. Among them, the stimulation of the human body is relatively low from the point (meth) acrylate monomer is preferred. "(Meth) acrylate" in the present invention is a general term for acrylate and methacrylate. Also in general, a monomer having an acidic group, hard tissue adhesion is excellent to act as decomplexing agent further described below, the acid group in the case of using an alkyl amine complex as a polymerization initiator (C) it is also possible to allow the initiation of the polymerization reaction by using a monomer having a. Thus, for example, with respect to no acidic group (meth) acrylate monomer, a monomer having an acidic group can be improved a suitable amount in combination with adhesive.
[0021]
　Specific examples of the monofunctional (meth) acrylate monomer having no acidic group, (meth) acrylate, (meth) acrylate, (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) isobornyl acrylate of (meth) acrylic acid alkyl ester; 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) 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, erythritol mono (meth) acrylate such as hydroxyalkyl esters of (meth) acrylic acid diethylene glycol mono (meth) acrylate, triethylene glycol mono (meth) acrylate, polyethylene glycol mono (meth) acrylate, polyalkylene glycol mono (meth) and polypropylene glycol mono (meth) acrylate acrylate, 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 (main ) Acrylate, polypropylene glycol monoalkyl ether (meth) acrylate of (poly) alkylene glycol monoalkyl ether (meth) acrylate; perfluorooctyl (meth) acrylate, hexafluorobutyl (meth) acrylate and the (meth) acrylic acid fluoroalkyl ester; .gamma. (meth) acryloxy propyl trimethoxy silane, .gamma. (meth) acryloxy propyl trimethoxy silane compound having a (meth) acryloxy alkyl group such as (trimethylsiloxy) silane; tetrahydrofurfuryl (meth) having a heterocyclic ring of acrylate (meth) acrylate.
[0022]
　Specific examples of the polyfunctional (meth) acrylate monomer having no acidic group, 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, trimethylolpropane tri (meth) acrylate, poly (meth) acrylates of alkane polyols such as pentaerythritol tall tetra (meth) acrylate 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 Rikoruji (meth) acrylate, polyoxyethylene alkane polyol poly (meth) such as dipentaerythritol hexa (meth) acrylate acrylate; cycloaliphatic ring system or aromatic di (meth) acrylate represented by the following general formula (1)
[0023]
[Formula 1]

(In the formula (1), R is a hydrogen atom or a methyl group, m and n are each the number of independently 0 ~ 10, R 1 is
[0024]
[Formula 2]

is either);
[0025]
　Alicyclic represented by the following general formula (2) system or aromatic epoxy di (meth) acrylate
[0026]
[Chemical Formula 3]

(in the formula (2), R, n and R 1 are, R in the formula (1), n and R 1 are the same as);
[0027]
　Polyfunctional (meth) acrylate having a urethane bond in the molecule represented by the following formula (3)
[0028]
[Formula 4]

(In the formula (3), R is the same as R in the formula (1), R 2 is
[0029]
[Of 5]

is either. ); And the like.
[0030]
　Among the above exemplified compounds, monofunctional (meth) acrylate monomer, (meth) acrylate, (meth) and ethyl acrylate (meth) acrylic acid alkyl; 2-hydroxyethyl (meth) acrylate , 1,3-dihydroxypropyl mono (meth) acrylate, hydroxyalkyl esters of pentaerythritol mono (meth) acrylate of (meth) acrylic acid; triethylene glycol monomethyl ether (meth) acrylate, triethylene glycol mono (meth) acrylate preferred polyethylene glycol mono (meth) acrylate is.
[0031]
　Among the above exemplified compounds, polyfunctional (meth) acrylate monomer, triethylene glycol di (meth) acrylate, polyethylene glycol di (meth) di having an ethylene glycol chain in the molecule of the acrylate (meth) acrylate; formula (1) compound represented by -a
[0032]
[Formula 6]

(in the formula (1) -a, R, m and n are, R in the formula (1) is the same as m and n);
[0033]
　Following formula (2) compound represented by -a
[0034]
[Chemical Formula 7]

(In the formula (2) -a, R is the same as R in the formula (1));
[0035]
　Formula (3) compounds represented by -a
[0036]
[Formula 8]

(Formula (3) in -a, R is the formula (1) is the same as R in);
are preferred.
[0037]
　These (meth) acrylate monomer may be used in combination of two or more.
[0038]
　Specific examples of the monomer having an acidic group, (meth) acrylic acid and its anhydride, 1,4-di (meth) acryloxy ethyl pyromellitic acid, 6- (meth) acryloxy ethyl naphthalene 1,2,6 - tricarboxylic acid, N- (meth) acryloyl -p- amino 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 anhydride thereof, 4- (meth) acryloxy-butyl trimellitic acid and its anhydride, 4 - (meth) acryloxy hexyl trimellitic acid and its anhydride, 4- (meth) acryloxydecyltrimellitic acid and its anhydride, - (meth) acryloyloxy-benzoic acid, 3- (meth) acryloyloxy-benzoic acid, 4- (meth) acryloyloxy-benzoic acid, beta-(meth) acryloyloxyethyl hydrogen succinate, beta-(meth) acryloyloxyethyl Hydro Gemma oleate, beta-(meth) acryloyloxyethyl hydrogen phthalate, 11- (meth) acryloyloxy-1,1-undecane dicarboxylic acid, having a carboxylic acid group or anhydride group such as a p- vinylbenzoic acid monomer; (2- (meth) acryloxyethyl) Hosuhorikku acid, (2- (meth) acryloxyethyl phenyl) Hosuhorikku acid, 10- (meth) acryloxy monomer having a phosphoric acid group such as tridecyl phosphite Holic acid; p- styrene sulfonic acid, 2-acrylamide -2 Include monomers having a sulfonic acid group such as methyl propane sulfonic acid. Among them, 4-methacryloxyethyl trimellitic acid and anhydrides thereof are preferred.
[0039]
　These monomers having acidic groups may be used in combination of two or more. Further, a monomer having an acidic group can also be used as a calcium salt.
[0040]
　The amount of the monomer (A) is a preferably 10 to 45 parts by weight, more preferably 20 to 45 parts by weight, particularly preferably a total of 100 parts by weight of 25-36 parts by weight (component (A) ~ (C) is to). The lower limits of the above-mentioned range, easy and operability of the coating, there is a significant intrusion, etc. point into the bone tissue. Upper limit, adhesion strength is significant in terms of such mechanical properties. If the monomer (A) comprises a monomer having an acidic group, the amount of the monomer having an acidic group is preferably 0.01 to 20% by weight, based on the monomers (A) total 100% by weight.
[0041]
　[Polymer (B)]
　The type of polymer (B) used in the present invention is not particularly limited, some or all of the monomer units constituting the polymer (B) is a monomer as described above (A ) is a monomer unit resulting from the same types of monomers and a portion of the monomer or all of the monomers in it is preferred. "Polymer" in the present invention is a general term for homopolymers and copolymers. The polymer (B), for example, can be used (meth) acrylate polymers and other vinyl polymer. Among them, (meth) acrylate-based polymers are preferred.
[0042]
　Specific examples of the (meth) acrylate-based polymer, polymethyl (meth) acrylate, polyethyl (meth) acrylate, methyl (meth) acrylate ethyl (meth) acrylate copolymer, methyl (meth) acrylate-butyl (meth) acrylate copolymer, methyl (meth) non-crosslinked polymer of an acrylate-styrene copolymer; methyl (meth) acrylate of ethylene glycol di (meth) acrylate copolymer, methyl (meth) acrylate triethylene glycol di ( meth) acrylate copolymer, and polymer forming the (meth) crosslinked polymers and partially calcium salt of a copolymer of methyl acrylate and butadiene monomers. The metal oxide or metal salt may be a non-crosslinked polymer or coated with a crosslinked polymer organic-inorganic composite.
[0043]
　Form of the polymer (B) is not particularly limited, is preferably a powder. It polymer powder may be used one polymer powder alone or may be a mixture of plural kinds of polymer powder. Among them, it is preferable that the specific surface area and / or volume-average particle diameter using a mixture of two or more of the polymer powder varies.
[0044]
　Form of each particle of the polymer powder used as the polymer (B) is spherical, but may be any of amorphous, it is preferable to use a mixture of polymer powder spherical polymer powder and amorphous. Spherical particles specific surface area is relatively small, since the amorphous particles have a relatively large specific surface area, it can be distinguished by the difference in specific surface area. In the present invention, as the polymer powder of sphere, a specific surface area of 0.05 ~ 0.5 m 2 it is preferred to use a polymer powder / g (b1), as the polymer powder of amorphous, specific surface area of 1 .5 ~ 4.5 m 2 it is preferred to use a polymer powder / g (b3). Furthermore, spherical polymer powder (b1) and an amorphous polymer powder (b3) of the intermediate forms a having specific surface area 0.51 ~ 1.2 m 2 be used in conjunction / g of the polymer particles (b2) It is also preferred. Method of measuring the specific surface area is as described in the column of Examples described later.
[0045]
　The specific surface area of the polymer powder (b1) is 0.05 ~ 0.5 m 2 was / g, preferably 0.1 ~ 0.4 m 2 is / g. The specific surface area of the polymer powder (b2) is 0.51 ~ 1.2 m 2 was / g, preferably 0.7 ~ 1.1 m 2 is / g. The specific surface area of the polymer powder (b3) is 1.5 ~ 4.5 m 2 was / g, preferably 2.5 ~ 3.5 m 2 is / g.
[0046]
　The weight average molecular weight of the polymer powder (b1) is preferably 10,000 to 5,000,000, more preferably 50,000 to 1,540,000, particularly preferably 100K-500K. The weight average molecular weight of the polymer powder (b2) is preferably 10,000 to 5,000,000, more preferably 50,000 to 1,660,000, particularly preferably 100K-500K. The weight average molecular weight of the polymer powder (b3) is preferably from 150,000 to 5,000,000, more preferably 200,000 to 1,150,000, particularly preferably from 240,000 to 670,000. Measurement method of weight average molecular weight is as described in the column of Examples described later, the molecular weight of the polystyrene equivalent value determined by gel permeation chromatography (GPC).
[0047]
　The volume average particle size of the polymer powder (b1) is preferably 12.7 ~ 77 m, more preferably 15 ~ 45 [mu] m, particularly preferably 17.5 ~ 35 [mu] m. The volume average particle size of the polymer powder (b2) is preferably 1 ~ 15 [mu] m, more preferably 3.5 ~ 10 [mu] m. The volume average particle size of the polymer powder (b3) is preferably 0.3 ~ 60 [mu] m, more preferably 7.5 ~ 50 [mu] m, particularly preferably 15.7 ~ 40 [mu] m. Method for measuring the volume average particle diameter is as described in the column of Examples described later.
[0048]
　The weight average molecular weight of the polymer (B) (i.e. the weight average molecular weight of the case of using a type of polymer alone the polymer, weight average molecular weight of the mixture as a whole, when using the mixture of two or more polymers ) is preferably from 50,000 to 5,000,000, more preferably from 75,000 to 2,000,000, particularly preferably from 75,000 to 880,000, and most preferably from 100,000 to 400,000. Polymer (B) is a volume average particle size (i.e. type of polymer powder volume average particle diameter of the polymer powder in the case of using alone or a mixture of two or more of the polymer powder when in powder form the volume average particle size of the mixture as a whole when used) is preferably 10 ~ 80 [mu] m, more preferably 15 ~ 45 [mu] m, particularly preferably 15 ~ 30 [mu] m.
[0049]
　The amount of the polymer (B), preferably 54.9 to 80 mass parts, more preferably 56.7 to 73.7 parts by weight, particularly preferably 59.7 to 70.7 parts by weight (component (A) is ~ total to 100 parts by weight of (C)). The amount of the polymer (B) polymer powder in 100 wt% (b1) is preferably 50.5 to 95 mass%, more preferably 53 to 85 wt%. The amount of polymer powder (b2) is preferably 0 to 33.5% by%, and more preferably 0 to 25 mass%. The amount of polymer powder (b3) is preferably from 5 to 49.5 wt%, more preferably 15 to 47 wt%.
[0050]
　Of the polymer (B), the content of the polymer powder having a volume average particle diameter of 2.0μm greater is preferably from greater than 70 wt%, more preferably 80 mass% or more, 90 wt% by particularly preferably more.
[0051]
　[Polymerization Initiator (C)]
　is not particularly restricted but the polymerization initiator used in the present invention (C), can be used various known compounds. Among them, the organic peroxide is preferably an organic boron compound, an organic boron compound is particularly preferable.
[0052]
　As the organic peroxides, e.g., diacetyl peroxide, diisobutyl peroxide, di-decanoyl peroxide, benzoyl peroxide (BPO), diacyl peroxides such as succinic acid peroxide; diisopropyl peroxydicarbonate, di-2 ethylhexyl peroxydicarbonate, peroxy dicarbonates such as diallyl peroxydicarbonate; tert- butylperoxy isobutyrate, peroxy esters such as tert- butyl neodecanate, cumene peroxyneodecanoate; acetyl cyclohexyl peroxides sulfonates such as sulfonyl peroxide and the like.
[0053]
　Organic peroxide, tertiary amine, or may be used in combination with the sulfinic acid or its alkali metal salts and a tertiary amine as a redox initiator. Among them, benzoyl peroxide (BPO) N, N-dimethyl-p-toluidine, and benzoyl peroxide (BPO) N, -p- N- dihydroxyethyl toluidine are preferred.
[0054]
　N, N- dimethyl -p- toluidine, N, tertiary amines such as N- dihydroxyethyl -p- toluidine, it is preferable to preliminarily added to use the monomer (A). The addition amount thereof is preferably 5.0 parts by mass or less, more preferably 0.1 to 3.0 mass parts, and particularly preferably 0.25 to 2.6 parts by weight (monomer (A) and the tertiary the sum of the amine and 100 parts by weight). Since radicals are generated by electron transfer even at room temperature under Using tertiary amines, even without heating it can be started easily polymerization reaction.
[0055]
　As the organic boron compounds, e.g., trialkyl boron, alkoxyalkyl boron, dialkyl borane, partially oxidized trialkyl boron, an alkyl borane-amine complex may be used.
[0056]
　Specific examples of trialkyl boron, triethyl boron, tri-propyl borate, triisopropyl borate, tributylboron, tri -sec- butylborohydride, triisobutyl borate, Toripenchiruhou arsenide, trihexyl borate, triheptyl borate, trioctyl borate, tricyclopentylphosphine boron, and trialkyl boron having an alkyl group having 2 to 8 carbon atoms of tricyclohexyl borate arsenide. Alkyl group is a straight-chain alkyl groups, branched alkyl groups may be any of the cycloalkyl group, the three alkyl groups contained in the trialkyl boron may or may not be the same.
[0057]
　Specific examples of alkoxyalkyl boron, monoalkoxy dialkyl boron of butoxy dibutyl borate arsenide include dialkoxyalkyl monoalkyl boron. Alkyl groups having an alkoxyalkyl boron, may be the same or different from the alkyl portion of the alkoxy group.
[0058]
　Specific examples of dialkyl borane, dicyclohexyl borane, include diisoamylborane. Two alkyl groups of the dialkyl borane may be the same or different. Two alkyl groups contained in the dialkyl borane may form a monocyclic structure or a bicyclo structure bonded. Such compounds, such as 9-borabicyclo [3.3.1] is nonane.
[0059]
　The partial oxidation trialkylboron a partial oxide of trialkyl boron. Among these, partial oxidation tributylboron are preferred. The amount of oxygen added to the trialkylboron 1 mole, preferably 0.3 to 0.9 mol, more preferably 0.4-0.6 moles.
[0060]
　Specific examples of the alkyl amine complex, triethylborane-diaminopropane (TEB-DAP), triethyl borane diethylenetriamine (TEB-DETA), tri -n- butyl borane-3-methoxypropylamine (TnBB-MOPA), tri -n- butyl borane-diaminopropane (TnBB-DAP), tri -sec- butyl borane-diaminopropane (TsBB-DAP), methylaminoethoxy diethyl borane (MAEDEB), induced methylaminoethoxy dicyclohexyl borane (MAEDCB) and from these derivatives, and the like. These alkyl amine complex may be used alone or in combination.
[0061]
　When the alkyl amine complex is used as the polymerization initiator (C), it is preferable to use a decomplexing agent further with the monomer (A). The "de-complexing agent" means a compound capable of liberating alkyl borane alkyl amine complex, to allow initiation of polymerization by free alkyl borane.
[0062]
　Suitable decomplexing agents, for example, any acid, or a monomer having an acidic group (monomer having an acidic group used as the above-mentioned monomer (A)) can be used. Suitable acids include Lewis acids (e.g., SnCl 4 , TiCl 4 ), Bronsted acids (e.g., carboxylic acids, HCl, H 2 SO 4 , H 3 PO 4 , phosphonic acid, phosphinic acid, silicic acid). and the like. Suitable carboxylic acids include those represented by the general formula R-COOH. In this formula, R represents a hydrogen atom, an alkyl group (preferably an alkyl group having 1 to 4 carbon atoms) having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms (preferably 2 carbon atoms - 4 alkenyl groups), alkynyl groups (preferably an alkynyl group having 2 to 4 carbon atoms of 2 to 8 carbon atoms), or C 6 -C 10 -aryl group (preferably an aryl of 6 to 8 carbon atoms a group). The alkyl group in R, an alkenyl group, an alkynyl group may be linear, it may be branched. Aliphatic group in R may be a saturated or may be unsaturated. Aryl group for R is an alkyl group, may be substituted with a substituent such as an alkoxy group or a halogen atom, it may be unsubstituted. Specific examples of the acid represented by the general formula, acrylic acid, methacrylic acid, acetic acid, benzoic acid, p- methoxybenzoic acid. Specific examples of the monomer having an acidic group, among the above-mentioned monomer (A), 4-methacryloxyethyl trimellitic acid and anhydrides thereof are preferred.
[0063]
　Among the organic boron compound, tributylboron, preferably partial oxidation tributylboron, especially partial oxidation tributylboron is more preferable. Tributylboron, if the partial oxidation tributylboron used as the organic boron compound, not only the operability is improved, tend to have a suitable reactivity to a living body having a water. In the case of using tributylboron, the partial oxidation tributylboron organic boron compound, the reaction in high moisture places like the living body starts, since the reaction proceeds, the monomers may remain at the interface between the adhesive and biological Nikuku, is extremely small for damage resistance of the living body. These organoboron compounds may be used alone or in combination.
[0064]
　Organic boron compounds may further comprise an aprotic solvent. When the organic boron compound is diluted with an aprotic solvent, pyrogenic becomes milder organic boron compound having a pyrophoric, suppresses pyrophoric, during transportation, it is easy to handle during storage and mixing . Further, it is possible to suppress a rapid heat generation, in a very large amount of hard tissue even when using a repair composition, the damage is less prone to the tissue in contact with hard tissue repair composition. Boiling point at 1 atm of aprotic solvent is usually 30 ° C. ~ 0.99 ° C., preferably from 50 ℃ ~ 120 ℃. If the boiling point is less than the above range, there is a tendency that an aprotic solvent from the polymerization initiator in the transport or during storage is volatile, will be scattered like, fire suppression effect of the organic boron compound is reduced. Further, if the boiling point exceeds the above range, the residual aprotic solvent into a cured product formed from the hard tissue repair composition of the present invention is increased, the adhesive strength to the affected part of the cured product, flexural modulus , tensile strength, compressive strength, tend to physical properties such as bending strength becomes poor.
[0065]
　Examples of the aprotic solvents, hydroxy group which reacts with the organic boron compound does not have a group containing active hydrogen such as a mercapto group, a solvent capable of forming a homogeneous solution and the organic boron compound is preferable.
[0066]
　Examples of the aprotic solvents, such as pentane, hexane, cyclohexane, heptane, benzene, hydrocarbons such as toluene; fluorobenzene, 1,1-dichloroethane, 1,2-dichloroethane, halogenated hydrocarbons such as freon; diethyl ether , diisopropyl ether, ethylene glycol dimethyl ether and tetrahydrofuran; acetone, methyl ethyl ketone, ketones such as diethyl ketone; methyl acetate, ethyl acetate, esters such as isopropyl acetate. Among them, pentane, hexane, saturated aliphatic hydrocarbons, ethers and heptane, esters are preferred, hexane, diisopropyl ether, ethyl acetate is more preferable. These aprotic solvents may be used alone or in combination.
[0067]
　The content of the aprotic solvent, to the organic boron compound to 100 parts by mass, preferably 30 to 80 parts by mass. When the content of the aprotic solvent is less than the above range, sufficient dilution effect is obtained, the effect of suppressing heat generation or ignition tends not sufficient. On the other hand, if the content of the aprotic solvent is more than the above range tend to lower the polymerization initiation ability of the polymerization initiator (C).
[0068]
　Organic boron compound, in addition to the aprotic solvent, or may contain an alcohol in place of the aprotic solvent. By adding an alcohol to the organic boron compound, a tendency that the reaction of an organic boron compound becomes more gentle without decreasing the polymerization activity, scorching or ignition of the case of contact with members such as paper in the air is suppressed is there.
[0069]
　Boiling point at 1 atmosphere of alcohol is generally 60 ° C. ~ 180 ° C., preferably from 60 ℃ ~ 120 ℃. If the boiling point is less than the above range, there is a tendency that an aprotic solvent from the polymerization initiator composition during transport or storage is volatile, will be scattered, fire suppression effect of the organic boron compound is reduced. On the other hand, if the boiling point exceeds the above range, the hardness setting time of the tissue repair composition tends to become longer, the adhesive strength to the affected part of the cured product, flexural modulus, tensile strength, compressive strength, flexural strength there is a tendency that the physical properties and the like becomes poor.
[0070]
　Specific examples of the alcohol include methanol, ethanol, n- propanol and isomers thereof, n- butanol and isomers thereof, n- pentanol and isomers thereof, n- hexanol and isomers thereof, n- heptanol and its isomers body, and the like. Among them, having 4 or less of the alcohol carbon atoms, i.e. methanol, ethanol, n- propanol and its isomers, and n- butanol and isomers thereof are preferable, ethanol, n- propanol are more preferred. These alcohols may be used alone or in combination.
[0071]
　The content of alcohol, to the organic boron compound to 100 parts by mass, 0.01 to 40 parts by weight, preferably 0.1 to 30 parts by weight, more preferably 0.5 to 20 parts by weight. When the content of the alcohol is less than the above range, sufficient dilution effect is obtained, the effect of suppressing heat generation or ignition tends not sufficient. On the other hand, when it exceeds the above range, there is a tendency to lower than necessary polymerization initiation ability of the polymerization initiator.
[0072]
　When used in combination with alcohol and aprotic solvent, the content of the aprotic solvent, to the organic boron compound to 100 parts by mass, preferably 5 to 40 parts by weight, more preferably 10 to 30 parts by weight, particularly preferably is 10 to 25 parts by weight. When the content of the aprotic solvent is less than the above range, there is a tendency effect of suppressing heat generation or ignition is not sufficient. On the other hand, when it exceeds the above range, there is a tendency to lower the polymerization initiation ability of the polymerization initiator (C).
[0073]
　The amount of the polymerization initiator (C) is a monomer (A), with respect to 100 parts by weight of the polymer (B) and a polymerization initiator (C), preferably 0.1 to 10 parts by weight, more preferably 1.0-7.0 parts by weight, particularly preferably 2.1 to 4.3 parts by weight. When the amount of the polymerization initiator (C) is less than the above range, the polymerization hardly proceeds, there is a tendency that the curing time is slow. On the other hand, when it exceeds the above range, may cause deterioration in viscosity by dilution, it could adversely affect the safety, and also rapid polymerization proceeds rapidly polymerized and cured product is formed envisaged It is.
[0074]
　[Contrast medium (X)]
　The volume average particle size of the contrast agent used in the present invention (X) is a 3μm or more, preferably 3.0 ~ 25.1μm, more preferably 3.0 ~ 18.0, in particular preferably 3.5 to 15.5 and most preferably 4.0 ~ 13.0μm. Such relatively large volume average particle size of the contrast agent (X) is less likely to aggregate, as a result improves the invasive to cancellous bone of the composition, is considered to be excellent in adhesion to the adherend. Method for measuring the volume average particle diameter is as described in the column of Examples described later.
[0075]
　Type of contrast medium (X) is not particularly limited. Examples include barium sulfate, zirconium oxide, bismuth carbonate, calcium tungstate, yttrium, iodine compounds. Among them, hard tissue applications, especially from the point where there is a record of use to the bone cement, barium sulphate, zirconium oxide is preferred. Contrast medium (X) is preferably solely is to form particles. Further, the surface is uncoated (e.g., not covered by titanium dioxide and the like) are preferable.
[0076]
　The amount of contrast medium (X), the monomer (A), with respect to 100 parts by weight of the polymer (B) and a polymerization initiator (C), preferably 0.5 to 70 parts by mass, more preferably 0 .5 to 45 parts by weight, particularly preferably from 2.5 to 33.8 parts by weight, and most preferably from 4.5 to 22.5 parts by weight.
[0077]
　Contrast medium (X) is internally without being sealed and / or adsorption of the polymer (B), hard tissue when the repairing composition is prepared, the liquid component prior to curing (monomer (A), polymerization initiator ( it is preferably dispersed in C) or the like). Of the contrast agent (X), preferably more than 80 mass% are dispersed in the liquid component, more preferably more than 90 mass% are dispersed in the liquid component, the liquid component is more than 95 wt% particularly preferred to be dispersed in, and most preferably particularly preferably more than 99 mass% are dispersed in the liquid component.
[0078]
　Contrast medium (X) is preferably not encapsulated and / or adsorbed on the inside of the polymer (B). It Among contrast medium (X), the amount of the polymer inside the encapsulation and / or adsorbed by that contrast agents (B) (X) is preferably 20 wt% or less, 10 wt% or less still more preferably, particularly preferably 1 mass% or less is a polymer (B), and most preferably 0.1 wt% or less.
[0079]
　Of the liquid components contained in the hard tissue repair composition of the present invention, desirably more than 50 wt% is monomer (A), preferably more than 60 wt% is monomer (A), 70 wt% or more preferably a monomer (a) is particularly preferably more than 80 wt% is monomer (a), and most preferably more than 90 wt% is monomer (a).
[0080]
　Liquid components contained in the hard tissue repair composition of the present invention (provided that the polymer (excluding liquid in B) in the) of the content of water is preferably 20 mass% or less, 10 wt % preferably less, more preferably at most 5.0 mass%, particularly preferably at most 3.0 wt%, and most preferably not more than 1.5 mass%.
[0081]
　Of the total of the liquid component contained in the hard tissue repair composition of the present invention, the amount of water is desirably 25% by mass or less, and preferably 15 wt% or less, at 10 wt% or less more preferably in, particularly preferably at most 5.0 mass%, and most preferably not more than 3.0 mass%.
[0082]
　[Other Components]
　hard tissue repair composition of the present invention optionally may contain a polymerization inhibitor. Specific examples of the polymerization inhibitor, hydroquinone, hydroquinone compounds such as dibutyl hydroquinone, hydroquinone monomethyl ether, 2,6-di -tert- butylphenol, 2,6-di -tert- butyl -p- phenols such as cresol , catechol, pyrogallol, benzoquinone, 2-hydroxy-benzoquinone, p- methoxyphenol, t- butyl catechol, butylated hydroxy anisole, butylated hydroxy toluene, t-butylhydroquinone. Among them, a mixture of hydroquinone monomethyl ether and 2,6-di -tert- butyl -p- cresol is preferred. In view of its own stability, sometimes hydroquinone monomethyl ether. Polymerization inhibitors may be used alone or in combination.
[0083]
　The addition amount of the polymerization inhibitor with respect to hard tissue repairing total composition, preferably 1 ~ 1500 ppm, more preferably 5 ~ 1000 ppm, particularly preferably 5 ~ 500 ppm. The amount of polymerization inhibitor (D), relative to the monomer (A), 10 ~ 5000ppm, more preferably 25 ~ 1000 ppm, particularly preferably 25 ~ 500 ppm.
[0084]
　Hard tissue repair composition of the present invention optionally may contain an ultraviolet absorber. Specific examples of the ultraviolet absorber is 2- (2'-hydroxy-5'-methylphenyl) benzotriazole, 2- (3 ', 5'-di -tert- butyl-2'-hydroxyphenyl) benzotriazole, 2- (5'-tert-butyl-2'-hydroxyphenyl) benzotriazole, 2- (2'-hydroxy-5 '- (1,1,3,3-tetramethylbutyl) phenyl) benzotriazole, 2- (3 ', 5'-di -tert- butyl-2'-hydroxyphenyl) -5-chloro-benzotriazole, 2-(3'-tert-butyl-2'-hydroxy-5'-methylphenyl) -5 chlorobenzotriazole, 2- (3'-sec-butyl-5'-tert-butyl-2'-hydroxyphenyl) benzotriazole, 2- (2'-hydroxy-4'-octoxyphenyl) benzotriazole, 2- ( ', 5'-di -tert- amyl-2'-hydroxyphenyl) benzotriazole, 2- (3', 5'-bis (alpha, alpha-dimethylbenzyl) -2'-hydroxyphenyl) benzotriazole, 2- (3'-tert-butyl-2'-hydroxy-5 '- (2-octyloxycarbonylethyl) phenyl) -5-chloro-benzotriazole, 2- (3'-tert-butyl-5' - [2- ( 2-ethylhexyl oxy) carbonyl ethyl] -2'-hydroxyphenyl) -5-chloro-benzotriazole, 2- (3'-tert-butyl-2'-hydroxy-5 '- (2-methoxycarbonylethyl) phenyl) - 5-chloro-benzotriazole, 2- (3 ' -tert- butyl-2'-hydroxy-5 '- (2-methoxycarbonylethyl) phenyl) benzotriazole, 2- (3'-tert-butyl-2'-hydroxy-5' - (2-octyloxycarbonylethyl ) phenyl) benzotriazole, 2- (3'-tert-butyl-5 '- [2- (2-ethylhexyl oxy) carbonyl ethyl] -2'-hydroxyphenyl) benzotriazole, 2- (3'-dodecyl -2 '- hydroxy-5'-methylphenyl) benzotriazole, 2- (3'-tert-butyl-2'-hydroxy-5' - (2-iso-octyloxycarbonylethyl) phenyl) benzotriazole 2,2' methylene - bis [4- (1,1,3,3-tetramethylbutyl) -6-benzotriazol-2-yl phenol] and mixtures, 2- [3'-tert- Butyl-5 '- (2-methoxycarbonylethyl) -2'-hydroxyphenyl] transesterification product of a benzotriazole with polyethylene glycol 300, [[R-CH 2 CH 2 -COOCH 2 ] 3 ] 2 - (wherein, R is 3'-tert-butyl-4'-hydroxy-5'-2H-benzotriazol-2-yl) benzotriazole compounds such as;
　2, 4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-octoxybenzophenone, 2-hydroxy-4-decyl oxy benzophenone, 2-hydroxy-4-dodecyloxy benzophenone, 2-hydroxy-4- benzyloxy, 2,2 ', 4,4'-tetra hydroxybenzophenone, 2,2'-benzophenone compounds such as dihydroxy-4,4'-dimethoxy benzophenone;
　salicylate 4-tert-butylphenyl salicylate, phenyl salicylate, octyl salicylate phenyl, dibenzoyl resorcinol, bi (4-tert-butyl-benzoyl) resorcinol, benzoyl resorcinol, 2,4-di -tert- butylphenyl 3,5-di -tert- butyl-4-hydroxybenzoate, hexadecyl 3,5-di -tert- butyl-4 - hydroxybenzoate, octadecyl 3,5-di -tert- butyl-4-hydroxybenzoate, benzoic acid 2-methyl-4,6-di -tert- butylphenyl, benzoate 3,5-di -tert- butyl-4 - hydroxybenzoate;
　Sebacic acid bis (2,2,6,6-tetramethyl piperidyl) succinate bis (2,2,6,6-tetramethyl piperidyl) sebacate bis (1,2,2,6,6-pentamethyl piperidyl), bis (1,2,2,6,6-pentamethyl-piperidyl) n- butyl-3,5-di - tert - butyl-4-hydroxybenzyl malonate, 1-hydroxyethyl-2,2, 6,6-condensation product of tetramethyl-4-hydroxypiperidine and succinic acid, N, N'-bis - (2,2,6,6-tetramethyl-4-piperidyl) hexamethylenediamine 4- three - condensation product of octyl-2,6-dichloro-1,3,5-s-triazine, tris - (2,2,6,6-tetramethyl-4-piperidyl) nitrilotriacetate, tetrakis - ( 2,2,6,6-tetramethyl-4-Piperi Le) -1,2,3,4-butane tetraoleate benzoate, 1,1 '- (1,2-ethanediyl) bis (3,3,5,5-tetramethyl piperazinone), 4-benzoyl-2 , 2,6,6-tetramethylpiperidine, 4-stearyloxy-2,2,6,6-tetramethylpiperidine, bis (1,2,2,6,6-pentamethyl-4-piperidyl) 2-n- butyl-2- (2-hydroxy-3,5-di - tert - butylbenzyl) malonate, 3-n-octyl-7,7,9,9-tetramethyl-1,3,8-triazaspiro [4. 5] decane-2,4-dione, sebacic acid bis (1-octyloxy-2,2,6,6-tetramethyl-piperidyl) succinate bis (1-octyloxy-2,2,6,6-tetramethyl methyl piperidyl), N, N'-bis - (2,2,6,6-tetramethyl-4-piperidyl) hexane The condensation product of diamine and 4-morpholino-2,6-dichloro-1,3,5-triazine, 2-chloro-4,6-di - (4-n-butylamino-2,2,6, 6-tetramethyl-piperidyl) -1,3,5-triazine and 1,
　4,4'-octyloxy-oxanilide, 2,2'-diethoxy-oxanilide, 2,2'-di-octyloxy-5,5'-di -tert- butyl oxanilide, 2,2'-di dodecyloxy-5,5'-di -tert- butyl-oxanilide, 2-ethoxy-2'-ethyloxanilide, N, N'-bis (3-dimethylaminopropyl) oxalamide, 2-ethoxy-5- tert- butyl-2'-ethyloxanilide and 2-ethoxy-2'-ethyl-5,4'-di -tert- butyl oxanilide and mixtures thereof, o- and p- methoxy -, o- and p- ethoxy - oxalamide compounds such a mixture of disubstituted oxanilides;
　2,4,6-tris (2-hydroxy-4-octyloxy phenyl) -1,3,5-triazine, 2- (2-hydroxy-4-octyloxyphenyl) -4,6-bis (2,4 - dimethylphenyl) -1,3,5-triazine, 2- (2,4-dihydroxyphenyl) -4,6-bis (2,4-dimethylphenyl) -1,3,5-triazine, 2,4 bis (2-hydroxy-4-propyloxy phenyl) -6- (2,4-dimethylphenyl) -1,3,5-triazine, 2- (2-hydroxy-4-octyloxy) -4,6 bis (4-methylphenyl) -1,3,5-triazine, 2- (2-hydroxy-4-dodecyloxyphenyl) -4,6-bis (2,4-dimethylphenyl) -1,3,5 triazine, 2- [2-hydroxy-4- (2-hydro Shi-3-butyloxy-propyloxy) phenyl] -4,6-bis (2,4-dimethylphenyl) -1,3,5-triazine, 2- [2-hydroxy-4- (2-hydroxy-3- octyloxy-propyloxy) phenyl] -4,6-bis (2,4-dimethylphenyl) -1,3,5-triazine, 2- [4-dodecyloxy / tridecyloxy - (2-hydroxypropyl) oxy -2 - hydroxyphenyl] -4,6-bis (2,4-dimethylphenyl) -1,3,5-triazine, 2- (2-hydroxyphenyl) -1,3,5-triazine compound;
　Triphenyl phosphite, diphenyl alkyl phosphites, phenyl dialkyl phosphites, tris (nonylphenyl phosphite), trilauryl phosphite, trioctadecyl phosphite, distearyl pentaerythrityl diphosphite, tris - (2,4-di - tert - butylphenyl) phosphite, diisodecyl pentaerythrityl diphosphite, bis - (2,4-di - tert - butylphenyl) pentaerythrityl diphosphite, bis - (2,6-di - Part three - butyl-4-methylphenyl) pentaerythrityl diphosphite, bis - isodecyloxy pentaerythrityl diphosphite, bis - (2,4-di - tert - butyl-6-methylphenyl) pentaerythrityl diphosphite, bis (2,4,6-tri - tert - Bed Butylphenyl) pentaerythrityl diphosphite, tristearyl sorbitan tilt Li phosphite, tetrakis (2,4-di - tert - butylphenyl) 4,4'-biphenylene diphosphonite, 6-iso-octyloxy-2,4, 8,10 tetra - tert-butyl -12H- dibenzo [d, g] -1,3,2- dioxaphosphocin, 6-fluoro-2,4,8,10-tetra - tert - butyl -12 - methyldibenzo [d, g] -1,3,2- dioxaphosphocine, bis - (2,4-di - tert - butyl-6-methylphenyl) methyl phosphite, bis (2,4-di - tert - phosphite compound or phosphonite compound butyl-6-methylphenyl) ethyl phosphite, and the like. Of these, benzotriazole compounds are preferable.
[0085]
　The addition amount of the ultraviolet absorber, the monomer (A), preferably 10 ~ 1,000 ppm, more preferably 100 ~ 800 ppm. By adding the ultraviolet absorber, coloring of a liquid containing the monomer is suppressed, the storage stability of the monomer itself tends to be improved.
[0086]
　Examples of other ingredients, further soft agents, plasticizers.
[0087]
　The soft material, for example, natural rubber, rubber such as synthetic rubbers, and elastomers such as a thermoplastic elastomer. Flexibility of hard tissue repair composition by such a soft material can be enhanced. Specific examples of synthetic rubbers include EPT (ethylene propylene terpolymer) it is. Specific examples of the thermoplastic elastomer, styrene elastomer, vinyl chloride elastomer, olefin elastomer, polyester elastomer, polyamide elastomer, a urethane-based elastomer. The molecular weight of the elastomer is usually 1,000 to 1,000,000, preferably from 2,000 to 500,000. Glass transition point (Tg) of the elastomer, typically 20 ° C. or less, preferably 0 ℃ less.
[0088]
　Examples of plasticizers include citric acid esters, isocitrate esters, tartaric acid esters, malic acid esters, lactic esters, glycerol esters, hydroxycarboxylic acid esters such as glycolic acid esters, trimellitic acid trimethyl, dibenzoate diethylene glycol, malonic diethyl, o- acetyl triethyl citrate, benzyl butyl phthalate, di-benzoic acid dipropylene glycol, diethyl adipate, o- acetyl tributyl citrate, dimethyl sebacate, include alkylene glycol diester.
[0089]
　The addition amount of the soft material and plasticizer, may be suitably determined depending on the type, in the whole composition hard tissue repair, usually 0-30 wt%, preferably 0 to 20 mass%, more preferably from 0 to 10 % by mass.
[0090]
　Hard tissue repair composition of the present invention optionally may contain a preservative. Examples of preservatives include methylparaben, methylparaben sodium, ethylparaben, propylparaben, propylparaben sodium, butylparaben, cresol, chlorocresol, resorcinol, 4-n-hexylresorcinol, 3a, 4,7,7a-tetrahydro - 2 - ((trichloromethyl) thio)-1H-isoindole-1,3 (2H) - dione, benz monkey benzalkonium chloride, sodium benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol butanol, potassium dehydroacetate, o- phenylphenol, phenol, phenylethyl alcohol, benzoic acid, potassium sorbate, sodium benzoate, sodium dehydroacetate, sodium propionate, Sol Bi Phosphate, thimerosal, thymol, phenylmercuric borate, phenylmercuric nitrate, phenylmercuric compounds such as phenylmercuric acetate, and formaldehyde.
[0091]
　Other components, further anti-infective agents, antibiotics, antibacterial agents, antiviral agents, analgesics, formulation of analgesics, appetite suppressants, anti-helminth agents, anti-arthritic agents, antiasthmatics, anticonvulsants, depressants, anti-diuretics, anti-diarrheal drugs, antihistamines, anti-inflammatory agents, anti-migraine drug, control vomiting agents, anti-neoplastic agents, anti-Parkinson's disease drugs, antipruritic drugs, antipsychotics, antipyretics, antispasmodics anticholinergics, sympathomimetics, cardiovascular agents, antiarrhythmic agents, antihypertensives, diuretics, vasodilators, immunosuppressants, muscle relaxants, parasympatholytics, awakening agents, sedatives, tranquilizers, cholinergic, chemotherapeutic agents, radiopharmaceuticals, osteoinductive agents, bladder quiescent heparin neutralizers, procoagulants, hemostatic agents, Kisanshin derivatives, hormones, proteins synthesized by naturally occurring or genetically engineered , polysaccharides, glycoproteins, lipoproteins, oligo Kureochido, antibody, antigen, vasopressin, vasopressin analogs, epinephrine, selectin, procoagulant poison, plasminogen activator inhibitor, platelet activating agents, osteogenesis factor, bone growth factors, synthetic peptides having hemostatic activity, and other it is pharmaceutically or therapeutically components. By containing these components, hard tissue repair composition of the present invention can be used in drug delivery systems and regenerative medicine.
[0092]
　Examples of antimicrobial agents, elemental iodine, solid polyvinylpyrrolidone iodine, polyvinyl pyrrolidone iodine; tribromophenol, trichlorophenol, tetra chlorophenol, nitrophenol, 3-methyl-4-chloro - phenol, 3,5-dimethyl - 4-chlorophenol, phenoxyethanol, dichlorophen, o- phenylphenol, m- phenylphenol, p- phenylphenol, 2-benzyl-4-chlorophenol, 2,4-dichloro-3,5-dimethylphenol, 4-chloro thymol, Kurorufen, triclosan, Fen Ji crawl, phenol, 2-methylphenol, 3-methylphenol, 4-methylphenol, 4-ethylphenol, 2,4-dimethylphenol, 2,5-dimethylphenol, , 4-dimethylphenol, 2,6-dimethylphenol, 4-n-propyl phenol, 4-n-butylphenol, 4-n-amyl phenol, 4-tert-amyl phenol, 4-n-hexyl phenol, 4-n - heptyl phenol, monoalkyl halophenol, polyalkyl halophenol, aromatic halophenols, and their ammonium salts, phenolic compounds such as alkali metal salts and alkaline earth metal salts; silver nitrate, hexachlorophene, include merbromin.
[0093]
　Examples of antibiotics, gentamicin, gentamicin sulfate, tobramycin, tobramycin sulfate, amikacin, amikacin sulfate, dibekacin, dibekacin sulfate, vancomycin, vancomycin hydrochloride, fosfomycin, cefazolin, cefazolin sodium, minocycline, Kurinda mycin, colistin, linezolid, tetracycline hydrochloride, tetracycline hydrate include oxytetracycline and erythromycin.
[0094]
　The addition amount of the antibiotic, may be suitably determined depending on the type, the total 100 wt% of the polymer (B), polymerization initiator (C) and contrast agents (X), usually 0 to 30 mass% , preferably 0 to 20% by weight, more preferably 0 to 10 mass%.
[0095]
　Hard tissue repair composition of the present invention, for the purpose of promoting tissue repair, osteogenic factors, bone growth factors, and other may contain a pharmaceutically or therapeutically component.
[0096]
　Other components, further there is a perfume. Specific examples of the perfume, range oil, grapefruit oil, lemon oil, lime oil, clove oil, oil of wintergreen, peppermint oil, peppermint spirit, banana distillate, cucumber distillate, honey distillate, rose the water, menthol, anethole, alkyl salicylate, benzaldehyde, monosodium glutamate, ethyl vanillin, thymol, include vanillin.
[0097]
　Examples of other ingredients, further clarity visual distinction between surrounding bone tissue, improvement in adhesion, enhanced physical properties such as compressive strength, or near by active radical species supplement to the bone tissue for the purpose of reducing the invasiveness, inorganic filler (excluding the X-ray contrast agents described above), an organic filler, an organic composite filler, there is a colorant.
[0098]
　Specific examples of the inorganic filler, bismuth oxide, titanium oxide, zinc oxide, metal oxide powder such as aluminum oxide particles; metal salt powder such as zirconium phosphate; silica glass, aluminum-containing glasses, barium-containing glass, strontium-containing glass, glass filler, such as zirconium silicate glass; fillers having silver sustained release filler having a calcium sustained release: include fillers having a fluoride-releasing. From the viewpoint of forming a strong bond between the inorganic filler after curing and the monomer (A), silane-treated inorganic filler is preferably subjected to a surface treatment such as a polymer coating. These inorganic fillers may be used alone or in combination.
[0099]
　Specific examples of colorants, Red No. 2 and Aluminum Lake, Red No. 3 and Aluminum Lake, Red No. 102 and aluminum lakes, 104 Red No. (1) and its aluminum lakes or barium lakes, 105 Red No. (1) and its aluminum lake, red No. 106 and aluminum lake, yellow No. 4 and aluminum lakes or barium lakes or zirconium lake, yellow No. 5 and aluminum lakes or barium lakes or zirconium lakes, green No. 3 and its aluminum lake, blue 1 and aluminum lakes or barium lakes or zirconium lakes, blue No. 2 and aluminum lake, red No. 201, red No. 202, red No. 203, red No. 204, red No. 205, red 2 No. 6, Red No. 207, Red No. 208, Red 213, Red 214, Red 215, Red 218, Red 219 No. 220 Red No. red 221, Red 223 No., Red No. 225, Red No. 226 , red No. 227 and aluminum lake, red No. 228, 230 red No. (1) and its aluminum lakes, 230 red No. (2) and its aluminum lake, red 231 No. and aluminum lake, red No. 232 and its aluminum lake, orange No. 201, orange No. 203, orange No. 204, orange No. 205 and aluminum lakes or barium lakes or zirconium lake, orange No. 206, No. orange 207 and aluminum lake, yellow No. 201 , of yellow No. 202 (1) and its aluminum Umureki, of Yellow No. 202 (2) and its Aluminum Lake, Yellow No. 203 and aluminum lakes or barium lakes or zirconium lake, Yellow No. 204, Yellow No. 205, Green No. 201 and Aluminum Lake, green 202, Green # 204 No. and aluminum lake, green No. 205 and aluminum lakes or zirconium lakes, blue No. 201, blue No. 202 and its barium lake, blue 203 No., Blue No. 204, Blue No. 205 and Aluminum Lake, brown No. 201 and Aluminum Lake, Purple No. 201, Red No. 401 and Aluminum Lake, Red No. 404, Red No. 405, Red 501 No., Red No. 502, and As aluminum lake, red 503 No. and aluminum lake, red 504 No. and aluminum lake, red No. 505, red 506 No. and aluminum lake, orange No. 401, orange 402 No. and aluminum lakes or barium lake, orange color No. 403, yellow No. 401, yellow 402 No. and aluminum lakes, yellow No. 403 (1) and its aluminum lake, yellow No. 404, yellow No. 405, yellow 406 No. and aluminum lake, yellow 407 No. and Al Niumureki, green No. 401, green 402 No. and aluminum lakes or barium lake, blue No. 403, Blue No. 404, Purple No. 401 and Aluminum Lake, black No. 401 and aluminum lakes; chlorophyll, chlorophyllin, malachite green, crystal violet , brilliant green, cobalt phthalocyanine, carotene, and induction derivatives vitamin B12 and from these. These colorants may be used alone or in combination.
[0100]
　The addition amount of the coloring agent may be appropriately determined depending on the type, the total 100 wt% of the polymer (B), polymerization initiator (C) and contrast agents (X), usually 0-5% by weight , preferably 0 to 2 mass%, more preferably 0 to 1 mass%.
[0101]
　[Hard tissue repairing Composition
　hard tissue repair composition of the present invention, the monomer (A), the polymer (B), polymerization initiator (C), is included, as a contrast medium (X) and other necessary It is prepared by mixing the components. The composition can be used by applying, for example, in the affected area. Note that the "hard tissue repair composition" in the present invention, the adhesion of the hard tissues together, filling into hard in tissue, hard tissue and titanium, ceramics, adhesive and / or adhesion to the artifact, such as stainless steel, hard which is used in the adhesive and / or adhesion to the other tissue such as tissue and soft tissue, adhesion between the tooth and the filling (i.e., dental applications) are not included.
[0102]
　Upon mixing of these components, the order of mixing is not limited. From the viewpoint of stability of the obtained hard tissue repairing composition is more excellent, first monomer (A) and a polymerization initiator (C) were mixed, followed by the contrast agent (X) is blended polymer (B) preferably mixed with the monomer (a), polymerization initiator (C) and contrast agent (X) that is mixed polymers formulated with (B) at the same time is more preferable.
[0103]
　If hard tissue repair composition of the invention includes a polymerization inhibitor from the viewpoint of stability is more excellent in the resulting composition, a mixture of first monomer (A) and the polymerization inhibitor, and a polymerization initiator ( C) were mixed, followed by the contrast agent (X) is blended polymer (B) is preferred that by mixing
laid, a mixture of a polymerization inhibitor monomer (a), polymerization initiator (C), and, it is more preferable to mix the contrast agent (X) is blended polymer (B) at the same time.
[0104]
　Hard tissue repair composition of the present invention, simulated bone invasive to be measured by the following method is preferably 1.0mm or more, more preferably 1.0 ~ 6.0 mm. Thus hard tissue repair composition will be more excellent adhesion to the bone tissue.
　(Measurement method of simulating bone invasive)
　simulated bone invasiveness, polyurethane foam having a bubble that communicates (porosity 95%) in saline (manufactured by Wako Pure Chemical Industries, Ltd., trade name 0.01 mol / L phosphate buffer impregnated with saline), placing the composition after 5 minutes gone stringing becomes dough shape on its upper surface for 30 seconds applied load at a pressure of 75 kPa, depth composition has penetrated a (mm) taking measurement.
[0105]
　Particles contained in the hard tissue repair composition of the present invention (specifically, the polymer (B), the contrast agent (X) and other particles in the case of a powder form) the volume average particle diameter of the whole, preferably is 32μm or less, more preferably 15 ~ 26 .mu.m. When the volume average particle diameter of the whole particles exceeds 26 .mu.m, poor simulated bone invasive above. Method for measuring the volume average particle diameter is as described in the column of Examples described later.
[0106]
　Of the particles contained in the hard tissue repair composition of the present invention, the amount of contrast medium (X) is preferably less than 1.0 wt% to 20 wt%, 1.5 wt% or more 19 wt % preferably less, and particularly preferably not more than 2.0 mass% to 18 mass%.
[0107]
　Prior to curing the hard tissue repair composition of the present invention, for example, dry heat treatment, steam, ethylene oxide (EO), treatment using a gas such as hydrogen peroxide, filtration, or the like process using the liquid processing before filling to the affected area a good hard tissue repair compositions may be sterilized by, it may be disinfected beforehand affected area surface with antiseptic solution such as alcohol. Moreover, prior to filling the hard tissue repair composition to the affected area, it may be pretreated for the purpose of improving the adhesion to the affected area. As the liquid for preprocessing, for example saline.
[0108]
　[Hard tissue repair kit]
　hard tissue repair composition of the present invention is the form and performance by elapsed long period changes, if there is a risk that the effect of the present invention is impaired, the monomer (A), the polymer (B), polymerization initiator (C), all the components included as necessary contrast medium (X) and others, is divided into three or more in any combination, to accommodate them each three or more members , it can be saved as hard tissue repair kit. Each component may be a hard tissue repair composition are mixed immediately before use. The means for containing the monomer (A) and the polymerization initiator (C), preferably members to prevent their volatilization and scattering sealable resin containers or glass ampoules having gas barrier properties and specific examples thereof are and the like. Specific examples of the means for containing the polymer (B), sealing performance can be prevented moisture absorption makes sterilization by good resin containers and glass containers, gas such as ethylene oxide (EO) or hydrogen peroxide it resin nonwoven fabric having a venting properties, sterile paper.
[0109]
　Hard Tissues repair kit, the monomer (A) and a mixture of components contained depending on the other necessary, contrast medium (X) polymer that is blended is (B) and a mixture of components contained depending on the other necessary If, divided into three mixtures of components contained polymerization initiator (C) and other optionally, hard tissue repair kit is preferably accommodated in three members each. However hard tissue repair kit is not limited to this, for example, a mixture of components contained monomer (A) and other optionally, the mixture of components contained polymer (B) and other optionally a mixture of components contained as necessary contrast medium (X) and others, is divided into four of a mixture of components contained depending on the polymerization initiator (C) and other necessary were housed four members each also may in hard tissue repair kit, the monomer (a), a mixture of components contained as necessary contrast medium (X) and others, a mixture of the components contained polymer (B) and other optionally, divided into three mixtures of components contained polymerization initiator (C) and other optionally, each may be a hard tissue repairing kit housed in three members. Hard tissue repair kit having three or more members of these components are housed can be provided as a product.
[0110]
　When using hard tissue repair kit, for example, a mixture of components contained depending on the monomer (A) and other necessary, a polymerization initiator (C) and a mixture of components contained depending on the other necessary mixed , it is preferable to mix followed by a mixture of ingredients that contrast medium (X) is optionally included to polymer powder (B) and other compounding. It is also possible to mix them at the same time. Such admixing at to easily obtained hard tissue repair compositions with a more stable performance.
[0111]
　Hard tissue repair kit, member for accommodating the respective components (e.g., resin containers, glass ampules) as well as members for mixing takes out the respective components (e.g., cement gun, the mixing vessel, mixing dish, cement injection vessel, cylinder) may have.
[0112]
　In hard tissue repair kit, inside one chamber (mixing vessel) is separated into three or more by a partition or spacer, its components in a separate three or more locations may be accommodated. Further hard tissue repair kit, after the monomer (A) and a polymerization initiator (C) the contrast medium (X) is brought into contact with the polymer which is blended (B) by destruction or transfer or removal of the spacer of the partition wall it may have a stirring unit for mixing the components by operating the stirring blade. Such hard tissue repair kit, it is easy task as compared with the case of mixing taking out the respective components from each container. It is also useful in that it facilitates the work further utilizing a jig cement gun or the like for filling directly to the affected area a composition from the chamber (mixing vessel).
[0113]
　Hard tissue bone repair composition, hard tissue such as a lesion and a soft tissue, such as cartilage, and other titanium, ceramics, with respect to a jig to be used in applying the artifact, such as stainless steel, pre-polymerization initiator (C) some components or may be allowed to contain a whole. In this case, the monomer just prior to use (A), polymer powder (B), and to prepare the hard tissue repair composition by contacting the component with the fixture included depending on the other necessary, which is directly to fill in the affected area.
[0114]
　The jig for filling the hard tissue repair composition to the affected area, include, for example, cement gun.
[0115]
　Hard tissue repair kit, for example, may have a solution for the pretreatment for the purpose of improving the disinfectant and adhesion, such as alcohols previously mentioned.
[0116]
　When housing the components in a hard tissue repair kit, preferably each component is not altered (e.g. monomer not cured) condition may be sterilized each component by an electromagnetic wave such as visible light.
Example
[0117]
　Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.
[0118]
　(1) a specific surface area
　The specific surface area of the polymer powder is subjected to vacuum degassing at room temperature as a pretreatment, using an apparatus BELSORP-mini (manufactured by Microtrac Bell), the nitrogen gas adsorption method under liquid nitrogen temperature It was measured Te.
[0119]
　(2) The weight average molecular weight (Mw) of
　polymer powder was dissolved in reagent grade tetrahydrofuran (Wako Pure Chemical Industries, Ltd.), the solution was filtered with a hydrophobic 0.45μm polytetrafluoroethylene filter. The solution after the filtration and sample, high performance liquid chromatography (manufactured by Shimadzu Corporation, LC-10AD), separation column (PLgel (10μm) MIXED-B × 2), with a detector (Shodex Co., RI-101) Te, the weight average molecular weight of the polymer powder (Mw) was measured (in terms of standard polystyrene).
[0120]
　(3) The volume average particle diameter D50
　reagent grade methanol (manufactured by Wako Pure Chemical Industries, Ltd., the solvent refractive index 1.33) as a dispersing solvent, or 0.2 wt% hexametaphosphate sodium phosphate solution (manufactured by Wako Pure Chemical Industries, Ltd., the solvent refractive using the rate 1.33), polymer powder or contrast agent in ultrasonic homogenizer for 5 minutes (output 25W) is dispersed. The dispersion as a sample, a particle size distribution analyzer (Microtrac Inc., Microtrac MT3300EXII) and according to the concentration conditions in the device Loading Loading Index appropriate amount range, and (when 100%, 65mL / sec) circulation rate of 50% under the conditions of , polymer powder, contrast agents, and was measured volume average particle diameter D50 of the entire particles included in the composition.
[0121]
　(4) simulated bone invasive
　for simulating bone invasiveness, cancellous simulated bone of polyurethane foam having a bubble that communicates (Human Body trade name SAW1522-507, porosity 95%) in saline (OR by Wako pure Chemical Industries, Ltd., trade name 0.01 mol / L phosphate buffered saline) impregnated with, gone stringing becomes dough shape topped with composition after 5 minutes on the upper surface, 30 seconds at a pressure of 75kPa and applied load, the depth composition has penetrated a (mm) was measured.
[0122]
　(5) adhesion to the pig femur
　for adhesion to the pig femur was filled with an appropriate amount of the composition after 5 minutes gone stringing becomes dough-like intrathecally pig femur edible while applying a load of 200 g, the temperature 37 ° C., relative to an environment of humidity of 95% RH compositions allowed to cure for 24 hours, 5 mm / min rate load values required to hollowing out from porcine femur (N ) was measured. The evaluation method was "Canadian Journal of Surgery, 54 (2011 ) 33-38, Stephen Hunt, Craig Stone, Shane Seal " in reference to. Incidentally, pig femur edible, previously cut with the length 10 mm, intrathecal saline (manufactured by Wako Pure Chemical Industries, Ltd., trade name 0.01 mol / L phosphate buffered saline) was thoroughly washed with, a range of 10 ~ 25 mm (the average value of the minimum and maximum values) the inner diameter of the medullary canal, was used to confirm that there are no scratches or cracks.
[0123]
　[Example 1a ~ 6a, Comparative Examples 1a ~ 6a]
　Examples 1a ~ 6a, in Comparative Examples 1a ~ 6a, methyl methacrylate as monomer (A), polymethyl methacrylate (specific surface area as spherical polymer powder (b1) = 0.32 m 2 /G,Mw=12.1 ten thousand, the volume average particle diameter D50 = 21.9μm), polymethyl methacrylate (specific surface area = 2.9 m as an amorphous polymer powder (b3) 2 / g, Mw = 44.2 million in a volume average particle diameter D50 = 21.3μm), as a polymerization initiator (C), 85 wt% of the partial oxidation tributylboron and 15 wt% ethanol mixture (manufactured by Mitsui Chemicals, Inc., part number BC- S1i) and total 100% by mass of (polymerization initiator (C)), using barium sulfate (manufactured by Sakai Chemical Industry Co., Ltd.) as a contrast agent (X).
[0124]
　In first compounding ratio shown in Table 1 and 2, the polymer (B) and contrast agent (X) to uniformly disperse the mixture to prepare, also Separately from this, the monomer (A) in 5mL glass sample tube the polymerization initiator mixture (C) was prepared. Then, a polypropylene container (Matsukazesha trade name tray resin miscible instrument) using and silicone rubber spatula, mixed for 60 seconds a mixture of the two at 23 ° C.. The resulting mixture was allowed to stand appropriate time, to obtain a hard tissue repairing composition became stringy disappears dough-like. Using this composition was evaluated for adhesion to the simulated bone invasive and pig femur. The results are shown in Tables 1 and 2.
[0125]
　The mixing ratio shown in parentheses for each component in the table is the ratio relative to the total 100 parts by weight of component (A) ~ (C) (parts by weight). The compounding ratio of component (b1) and (b3) is a polymer powder (B) ratio relative to the 100 weight% (wt%).
[0126]
[Table 1]

[0127]
[Table 2]

[0128]
　As shown in Table 1 and 2, hard tissue repair compositions of Examples 1a ~ 6a using a volume average particle diameter is large barium sulfate as a contrast medium (X) is in close contact with the simulated bone invasive and pig femur sex was excellent. The hard tissue repairing composition, improvement in adhesion can be expected when used in the treatment of a patient as a bone cement.
[0129]
　On the other hand, hard tissue repair compositions of Comparative Examples 1a ~ 6a using a volume average particle diameter is small barium sulfate as a contrast medium (X) is, the adhesion between the simulated bone invasive and pig femur was inferior. In Comparative Example 1a ~ hard hard tissue repair compositions the volume average particle diameter of the total particles contained in the tissue repair composition has the largest Comparative Example 6a in 6a includes a simulated bone invasive and pig femur adhesion was the most inferior. This result, the volume average particle diameter of the total particles contained in the hard tissue repairing composition is too large, it can be seen that the adhesion between the simulated bone invasive and pig femur conversely tends to decrease.
[0130]
　[Example 1b and Comparative Example 1b]
　contrast medium (X) as a zirconia having a volume average particle diameter shown in Table 3 in place of barium sulfate (Pure Chemical Co., Ltd., trade name zirconium (IV), and from Aldrich except for using trade name Zirconium (IV)), the hard tissue repairing composition in the same manner as in example 4a was prepared and evaluated. The results are shown in Table 3.
[0131]
[table 3]

[0132]
　As shown in Table 3, the same applies to the case where contrast agent (X) was changed from barium sulfate zirconia, for hard tissue repair of Example 1b using a volume average particle diameter is large zirconia as contrast agents (X) composition, adhesion to the simulated bone invasive and pig femur was excellent. On the other hand, hard tissue repair composition of Comparative Example 1b using a contrast agent (X) as a volume average particle diameter is small oxidation zirconia, adhesion between the simulated bone invasive and pig femur was inferior.
[0133]
　[Example 1c ~ 3c and Comparative Examples 1c ~ 3c]
　polymerization initiator (C) as benzoyl peroxide instead of the alkyl borane-based polymerization initiator (Aldrich Co., trade name Luperox (R) A75) Table 4 and used amounts shown in 5, the monomer (a) is a methyl methacrylate to 0.5 mass% of N, was added N- dimethyl -p- toluidine, the volume average particle diameter of the barium sulfate in tables 4 and 5 except for changing as shown, the hard tissue repairing composition in the same manner as in example 4a was prepared and evaluated. The results are shown in Tables 4 and 5.
[0134]
[Table 4]

[0135]
[table 5]

[0136]
　As shown in Table 4 and 5, similarly if you change the polymerization initiator (C) alkyl borane-based polymerization initiator benzoyl peroxide, was used having a volume average particle diameter is large barium sulfate as a contrast medium (X) hard tissue repair compositions of examples 1c ~ 3c are adhesion between simulated bone invasive and pig femur was excellent. On the other hand, hard tissue repair compositions of Comparative Examples 1c ~ 3c using a volume average particle diameter is small barium sulfate as a contrast medium (X) is, the adhesion between the simulated bone invasive and pig femur was inferior.
[0137]
　Further, Example 1c ~ 3c using benzoyl peroxide as a polymerization initiator, the polymerization initiator (C) as an Example 4a ~ 6a using an alkyl borane-based polymerization initiator is compared respectively, Examples 4a ~ who 6a adhesion between simulated bone invasive and pig femur was superior. This result, as the polymerization initiator (C), than the organic peroxides such as benzoyl peroxide, towards the organoboron compound such as an alkyl borane-based polymerization initiator is found more preferable in terms of adhesion.
[0138]
　Example 1d and Comparative Example 1d]
　contrast medium (X) as a zirconia having a volume average particle diameter shown in Table 6 instead of barium sulfate (Pure Chemical Co., Ltd., trade name zirconium (IV), and from Aldrich except for using trade name Zirconium (IV)), the hard tissue repairing composition in the same manner as in example 1c was prepared and evaluated. The results are shown in Table 6.
[0139]
[Table 6]

[0140]
　As shown in Table 6, also in the case of using a zirconium oxide as a polymerization initiator (C) as and contrast agent benzoyl peroxide (X), the volume average particle diameter as contrast agents (X) is larger zirconia hard tissue repair composition of example 1d was used, adhesion between the simulated bone invasive and pig femur was excellent. On the other hand, hard tissue repair composition of Comparative Example 1d using contrast medium (X) as a volume average particle diameter is small oxidation zirconia, adhesion between the simulated bone invasive and pig femur was inferior.
Industrial Applicability
[0141]
　Hard tissue repair composition of the present invention, for example, hard tissue adhesion between, filled into hard in tissue, hard tissue and titanium, ceramics, adhesion between artifacts such as stainless steel, hard tissue and other soft tissue such as it is useful in adhesive applications and organizations. Furthermore, hard tissue repair composition of the present invention, for example, bone, bone cement used for fixation of the hard tissue and the artificial articular cartilage, etc., filler into the defect portion of the bone, bone substitute material, useful as artificial bone it is.

WE CLAIM

Monomer (A), the polymer (B), polymerization initiator (C), and hard tissue repair composition comprising a volume average particle diameter 3μm or more contrast agent (X).
[Requested item 2]
　Hard tissue repair composition according to claim 1 simulated bone invasive to be measured by the following method is not less than 1.0mm.
[Measurement method for simulating bone invasive]
　simulated bone invasiveness, the polyurethane foam having air bubbles in communication (porosity 95%) impregnated with physiological saline, since gone stringing becomes dough-like in its upper surface 5 Place the minute after the composition was 30 seconds applied load at a pressure of 75 kPa, measured depth composition has penetrated a (mm).
[Requested item 3]
　Hard tissue repair composition according to claim 1 contrast medium (X) is barium sulfate or zirconium oxide.
[Requested item 4]
　Monomer (A) is (meth) acrylate-based hard tissue repair composition according to claim 1 is a monomer.
[Requested item 5]
　Polymer (B) is (meth) acrylate-based polymer hard tissue repair composition according to claim 1 is.
[Requested item 6]
　Monomer (A) 10 ~ 45 parts by weight, the polymer (B) 54.9 ~ 80 parts by weight, total 100 weight of the polymerization initiator (C) 0.1 ~ 10 parts by weight (component (A) ~ (C) part to) and contrast medium (X) hard tissue repair composition according to claim 1 containing 0.5 to 70 parts by mass.
[Requested item 7]
　Hard tissue repair composition according to claim 1 having a volume average particle diameter of 3.0 ~ 25.1μm of the contrast agent (X).
[Requested item 8]
　Hard tissue repair composition according to claim 1 volume average particle diameter of the total particles contained in the hard tissue repairing composition is less than 32 [mu] m.
[Requested item 9]
　Monomer contained in hard tissue repair composition according to claim 1 (A), the polymer (B), polymerization initiator (C), and each component of the contrast agent (X) is 3 in any combination One or more divided hard tissue repair kit having the contained member.