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 a particular mixing ratio of the polymer powder (b1) in volume average particle diameter within a specific range, to improve adhesion to the bone tissue found that, it has led to the completion of the present invention. That is, the present invention is specified by the following matters.
[0008]
[1] Monomer (A), the volume average particle diameter of 27 ~ 80 [mu] m of the polymer powder (b1) a polymer powder containing 54 wt% or more (B), and hard tissue repair composition comprising a polymerization initiator (C) Stuff.
[0009]
[2] hard tissue repair composition according to the following simulated bone invasive as measured by the method it is 1.0mm or more [1].
[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 volume average particle diameter 3.0μm below the contrast agent further comprises a (X) [1].
[0011]
[4] Monomer (A) is (meth) hard tissue repair composition according to an acrylate based monomer [1].
[0012]
[5] the polymer powder (B) is (meth) hard tissue repair composition according to an acrylate-based polymer powder [1].
[0013]
[6] Monomer (A) 10 ~ 45 parts by weight, of the polymer powder (B) 54.9 ~ 80 parts by weight, the polymerization initiator (C) 0.1 ~ 10 parts by weight (component (A) ~ (C) total and 100 parts by weight), and hard tissue repair composition according to [1] comprising 0 to 70 parts by weight contrast agent (X).
[0014]
[7] [1] to monomers contained in hard tissue repair composition according (A), polymer powder (B), and each component of the polymerization initiator (C) is more than three in any combination hard tissue repair kit having members housed divided into.
The invention's effect
[0015]
　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.
[0016]
　According to common sense, when the polymer powder passes through the gap, towards the small polymer powder particle size it should easily pass through the gap. However, in the present invention, surprisingly, by using a relatively large amount of relatively large polymer powder (b1) is the particle diameter, simulated bone invasive hard tissue repair composition is improved. The reason is not necessarily clear, as one of the reasons, when the particle size of the polymer powder (b1) is less tends powder particles are agglomerated, there is a tendency for a larger aggregate particles, polymer powders (b1) because when the particle diameter is large is difficult to aggregate, simulated bone invasive it is presumed that it would to increase. As another one of the reasons, when the particle size of the polymer powder (b1) is greater moderately inhibited polymerization reaction rate because time is relatively long dissolving the monomer (A), the result as a composition invasive to cancellous bone is inferred that it would be improved.
DESCRIPTION OF THE INVENTION
[0017]
　[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.
[0018]
　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.
[0019]
　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.
[0020]
　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)
[0021]
[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
[0022]
[Formula 2]

is either);
[0023]
　Alicyclic represented by the following general formula (2) system or aromatic epoxy di (meth) acrylate
[0024]
[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);
[0025]
　Polyfunctional (meth) acrylate having a urethane bond in the molecule represented by the following formula (3)
[0026]
[Formula 4]

(In the formula (3), R is the same as R in the formula (1), R 2 is
[0027]
[Of 5]

is either. ); And the like.
[0028]
　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.
[0029]
　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
[0030]
[Formula 6]

(in the formula (1) -a, R, m and n are, R in the formula (1) is the same as m and n);
[0031]
　Following formula (2) compound represented by -a
[0032]
[Chemical Formula 7]

(In the formula (2) -a, R is the same as R in the formula (1));
[0033]
　Formula (3) compounds represented by -a
[0034]
[Formula 8]

(Formula (3) in -a, R is the formula (1) is the same as R in);
are preferred.
[0035]
　These (meth) acrylate monomer may be used in combination of two or more.
[0036]
　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.
[0037]
　Among the monomers (A), preferably more than 90 wt% is a monofunctional (meth) acrylate monomer, more preferably more than 95 wt% is a monofunctional (meth) acrylate monomer, it is particularly preferred 100% by weight is a monofunctional (meth) acrylate monomer.
[0038]
　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.
[0039]
　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.
[0040]
　[Polymer powder (B)]
　The type of polymer powder (B) used in the present invention is not particularly limited, some or all of the monomer units constituting the polymer powder (B) has been described previously it is preferably a monomer unit resulting from the same types of monomers and a portion of the monomer or all of the monomers in the monomer (a). "Polymer" in the present invention is a general term for homopolymers and copolymers. The polymer powder (B), for example, can be used (meth) acrylate polymers and other vinyl polymer. Among them, (meth) acrylate-based polymers are preferred.
[0041]
　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.
[0042]
　Polymer powder (B) contains a volume average polymer powder particle size 27 ~ 80μm (b1) 54% by mass or more. Polymer powder (B), the polymer powder (b1) may be used alone or may be used a mixture of one or more of the polymer powder is different from the polymer powder (b1). 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.
[0043]
　Form of each particle of the polymer powder (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 particular, each particle of the polymer powder (b1) is spherical, that is, towards a small specific surface area preferably. The specific surface area is time to dissolve the monomer (A) becomes relatively long smaller, because the polymerization reaction rate can be suppressed more effectively. The specific surface area of the polymer powder (b1) is preferably 0.05 ~ 0.5 m 2 is / g. Further, 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.
[0044]
　The specific surface area of the polymer powder (b1) is preferably ~ 0.5 m 0.05 2 / g, more 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.
[0045]
　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).
[0046]
　The volume average particle size of the polymer powder (b1) is 27 ~ 80 [mu] m, preferably 28.5 ~ 58 .mu.m, more preferably 30.5 ~ 50 [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.
[0047]
　The weight average molecular weight of the polymer powder (B) (i.e. the weight average molecular weight of the case of using a type of polymer alone the polymer, also mixtures overall weight average in the case of using a mixture of two or more polymers molecular weight) is preferably 50000 to 5000000, more preferably 75000 to 2000000, particularly preferably from 75,000 to 880,000, and most preferably from 100,000 to 400,000. The volume average particle diameter of the polymer powder in the case of using the volume average particle size of the polymer powder (B) (i.e., a kind of polymer powder alone, when a mixture of two or more polymer powder the volume average particle diameter of the total mixture) is preferably 10 ~ 80 [mu] m, more preferably 15 ~ 45 [mu] m, particularly preferably 20 ~ 45 [mu] m.
[0048]
　The amount of polymer powder (B) is preferably 54.9 to 80 mass parts, more preferably 56.7 to 73.7 parts by weight, particularly preferably from 59 to 68.6 parts by weight (component (A) ~ is the sum of the 100 parts by weight of (C)). The amount of polymer powder (B) polymer powder in 100 wt% (b1) is preferably 50.5 to 95 mass%, more preferably 53 to 85% by weight, particularly preferably 53 to 75 mass% . The amount of polymer powder (b2) is preferably from 0 to 33.5% by weight, more preferably 0 to 25% by weight, particularly preferably 5.7 to 25 mass%, most preferably 9.7 to 25 mass% it is. The amount of polymer powder (b3) is preferably from 5 to 49.5 wt%, more preferably 15 to 47 wt%, particularly preferably 15-37% by weight.
[0049]
　[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.
[0050]
　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.
[0051]
　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.
[0052]
　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.
[0053]
　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.
[0054]
　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.
[0055]
　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.
[0056]
　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.
[0057]
　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.
[0058]
　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.
[0059]
　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.
[0060]
　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.
[0061]
　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.
[0062]
　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.
[0063]
　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.
[0064]
　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.
[0065]
　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).
[0066]
　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.
[0067]
　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.
[0068]
　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.
[0069]
　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. Content of alcohol, in the case of 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.
[0070]
　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).
[0071]
　The amount of the polymerization initiator (C) per 100 parts by weight of the monomer (A), polymer powder (B) and a polymerization initiator (C), preferably 0.1 to 10 parts by weight, more preferably 1.0 to 7.0 mass parts, and 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.
[0072]
　[Contrast medium (X)]
　hard tissue repair composition of the present invention may comprise a contrast medium (X). The volume average particle size of the contrast agent (X) is preferably less than 3.0 [mu] m, more preferably 0.15 ~ 2.5 [mu] m, particularly preferably 0.45 ~ 2.0 .mu.m, and most preferably 0.7-1. it is 0μm. Particularly, in the present invention, a relatively large volume average increase invasiveness into cancellous bone particle size of the polymer powder (b1) composition so used is, even if the contrast medium (X) are aggregated as a result reduction of invasive tends not noticeable. Accordingly, in the present invention is also advantageous in that inexpensive contrast agent volume average particle size is not too large (X) without problems be used.
[0073]
　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 as a 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.
[0074]
　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.
[0075]
　The amount of contrast medium (X), the monomer (A), with respect to 100 parts by weight of the polymer powder (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.
[0076]
　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).
[0077]
　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%.
[0078]
　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%.
[0079]
　[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.
[0080]
　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.
[0081]
　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 and bis (2,4-di - tert - phosphite compound or phosphonite compound butyl-6-methylphenyl) ethyl phosphite, and the like. Of these, benzotriazole compounds are preferable.
[0082]
　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.
[0083]
　Examples of other ingredients, further soft agents, plasticizers.
[0084]
　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.
[0085]
　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.
[0086]
　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.
[0087]
　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.
[0088]
　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 pharmaceutical or therapeutic components and the like. By containing these components, hard tissue repair composition of the present invention can be used in drug delivery systems and regenerative medicine.
[0089]
　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.
[0090]
　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.
[0091]
　The addition amount of the antibiotic, may be suitably determined depending on the type, the polymer powder (B), per 100 wt% of the polymerization initiator (C) and contrast agents (X), usually 0 to 30 mass %, preferably 0 to 20% by weight, more preferably 0 to 10 mass%.
[0092]
　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.
[0093]
　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.
[0094]
　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.
[0095]
　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.
[0096]
　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.
[0097]
　The addition amount of the coloring agent may be appropriately determined depending on the type, the polymer powder (B), per 100 wt% of the polymerization initiator (C) and contrast agents (X), usually 0-5 weight %, preferably 0 to 2 mass%, more preferably 0 to 1 mass%.
[0098]
　[Hard tissue repairing Composition
　hard tissue repair composition of the present invention, the monomer (A), polymer powder (B), polymerization initiator (C) and mixing the components contained depending Other necessary It is prepared. 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.
[0099]
　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, the monomer (A) and a polymerization initiator (C) were mixed first, followed by the contrast agent (X) is blended polymer powder (B it is preferable to) mixing the monomers (a), polymerization initiator (C), and it is more preferable to mix the polymer powder contrast agent (X) is blended with (B) at the same time.
[0100]
　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 ( mixed C), followed by preferably mixing the polymer powder formulated (B) contrast medium (X) is a mixture of a polymerization inhibitor monomer (a), polymerization initiator (C), and, mixing polymer powder contrast agent (X) is blended with (B) at the same time is more preferable.
[0101]
　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.
[0102]
　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.
[0103]
　[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 powder (B), polymerization initiator (C) and all components contained depending on the other necessary, divided into three or more in any combination, to accommodate them each three or more members, hard for tissue repair It can be saved as a 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 powder (B), sealability good resin containers or glass containers can prevent moisture absorption, sterilization by gas such as ethylene oxide (EO) or hydrogen peroxide resin non-woven fabric having a venting property be performed, sterile paper.
[0104]
　The hard tissue repairing kit, monomer (A) and a mixture of components contained depending on the other required polymer powder (B) (preferably polymer powder contrast agent (X) is blended (B)) and a mixture of the components included, as other necessary, a polymerization initiator (C) and is divided into three mixtures of components contained depending on the other necessary, hard tissue repair kit which contains three members each It is preferred. However hard tissue repair kit is not limited to this, for example, a mixture of monomers (A) and a mixture of the components included, as other necessary, the polymer powder (B) and components contained if other necessary , 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, housed in four members each may be a hard tissue repairing kit, monomer (a), a mixture with the polymer powder (B) and a mixture of components contained depending on the other necessary components contained as necessary contrast medium (X) and other If, divided into three mixtures of the components included, as a polymerization initiator (C) and other necessary, 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.
[0105]
　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 , followed by the polymer powder (B) (preferably the contrast agent (X) is to the polymer powder (B) compounded) is mixing the mixture of components contained as required and other desirable. 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.
[0106]
　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.
[0107]
　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 contacting the monomer (A) and a polymerization initiator (C) a polymer powder (B) by disruption or movement or removal of the spacer of the partition wall, each by operating the stirring blade it may have a stirring unit for mixing the components. 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).
[0108]
　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.
[0109]
　The jig for filling the hard tissue repair composition to the affected area, include, for example, cement gun.
[0110]
　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.
[0111]
　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
[0112]
　Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.
[0113]
　(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.
[0114]
　(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).
[0115]
　(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 It was measured volume average particle diameter D50 of the polymer powder and the contrast agent.
[0116]
　(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.
[0117]
　(5) setting time
　setting time, the international standard for bone cement ISO5833: 2002 - was measured at a specified conditions in (a surgical implant acrylic resin cement).
[0118]
　(6) adhesion between 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.
[0119]
　[Examples 1-11 and Comparative Examples 1-3]
　In Examples 1-11 and Comparative Examples 1-3, methyl methacrylate as monomer (A), 85 mass% of the partial oxidation tributylboron as the polymerization initiator (C) If the 15 wt% ethanol mixture (manufactured by Mitsui Chemicals, Inc., part number BC-S1i) (a total 100 wt% of the polymerization initiator (C)), barium sulfate as a contrast agent (X) (manufactured by Sakai Chemical Industry Co., Ltd.) It was used.
[0120]
　The spherical polymer powder with a large particle size (b1), polymethyl methacrylate (specific surface area = 0.17 m 2 /G,Mw=14.9 ten thousand, the volume average particle diameter D50 = 42.0μm), polymethyl methacrylate (specific surface area = 0.11 m 2 /G,Mw=14.8 ten thousand, the volume average particle diameter D50 = 76.3μm), polymethyl methacrylate (specific surface area = 0.35 m 2 /G,Mw=15.5 ten thousand, The volume average particle diameter D50 = 31.1μm), polymethyl methacrylate (specific surface area = 0.31 m 2 /G,Mw=96.5 ten thousand, the volume average particle diameter D50 = 37.1μm), polymethyl methacrylate (specific surface area = 0.25 m 2 /G,Mw=29.1 ten thousand, the volume average particle diameter D50 = 42.8μm), or polymethyl methacrylate (specific surface area = 0.20 m 2 /G,Mw=45.7 ten thousand, the volume average The particle size D50 = 40. 6 [mu] m), polymethyl methacrylate (specific surface area = 0.20 m 2 /G,Mw=38.3 ten thousand, with a volume average particle diameter D50 = 35.7μm). As the spherical polymer powder (b1 '), polymethyl methacrylate (specific surface area = 0.34 m 2 /G,Mw=136.8 ten thousand, the volume average particle diameter D50 = 21.9μm) were used.
[0121]
　The spherical-amorphous polymer powder (b2), polymethyl methacrylate (specific surface area = 0.92 m 2 /G,Mw=13.2 ten thousand, the volume average particle size D50 = 8.0 .mu.m), polymethyl methacrylate ( specific surface area = 0.75 m 2 /G,Mw=15.8 ten thousand, the volume average particle diameter D50 = 11.4), or polymethyl methacrylate (specific surface area = 0.71 m 2 /G,Mw=12.1 ten thousand It was used having a volume average particle diameter of D50 = 21.9μm). It was used.
[0122]
　The amorphous polymer powder (b3), polymethyl methacrylate (specific surface area = 2.9 m 2 /G,Mw=44.2 ten thousand, the volume average particle diameter D50 = 21.3μm) were used.
[0123]
　In first compounding ratio shown in Table 1-3, the polymer powder (B) and contrast agent (X) uniformly dispersed mixture was prepared, also apart from this, 5 mL glass sample tube in the monomer (A) the polymerization initiator mixture (C) was prepared with. 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 1-3.
[0124]
　[Examples 12 and 13]
　with a polymerization initiator (C) as benzoyl peroxide instead of the alkyl borane polymerization initiator (Aldrich Co., trade name Luperox (R) A75) in the amounts shown in Table 3, monomer (a) is a methyl methacrylate to 0.5 mass% of N, except that the addition of N- dimethyl -p- toluidine, Similarly prepared hard tissue repair composition as in example 1 and 10 ,evaluated. The results are shown in Table 3.
[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]
[table 3]

[0129]
[Table 4]

[0130]
　As shown in Table 1-3, the polymer powder hard tissue repair compositions of Examples 1 to 13, volume average particle diameter as a part of larger polymer powder (b1) was used in a specific amount of (B) is adhesion between the simulated bone invasive and pig femur 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.
[0131]
　Meanwhile, as shown in Table 4, the hard tissue repairing composition of Comparative Example 1 and 3 did not use the volume average particle diameter is large polymer powder (b1) is in close contact with the simulated bone invasive and pig femur sex was inferior. Hard tissue repair composition in an amount less Comparative Example 2 having a volume average particle diameter is large polymer powder (b1) also, adhesion between the simulated bone invasive and pig femur was inferior.
[0132]
　Further, as in Examples 12 and 13 were used benzoyl peroxide as the polymerization initiator, the polymerization initiator (C) as the Example 1 and 10 was used alkylborane-based polymerization initiator is compared respectively, Example 1 and towards 10 the adhesion between the 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.
[0133]
　Also, in Examples 1-13, setting time, the particle size of the polymer powder (b1), the weight average molecular weight to change the content as appropriate, by or adding an appropriate amount of the polymer powder (b2) it was able to adjust.
Industrial Applicability
[0134]
　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 volume average particle diameter of 27 ~ 80 [mu] m of the polymer powder (b1) a polymer powder containing 54 wt% or more (B), and hard tissue repair composition comprising a polymerization initiator (C).
[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, further comprising a volume average particle diameter 3.0μm of less than contrast agent (X).
[Requested item 4]
　Monomer (A) is (meth) acrylate-based hard tissue repair composition according to claim 1 is a monomer.
[Requested item 5]
　Polymer powder (B) is (meth) acrylate-based polymer powder hard tissue repair composition according to claim 1 is.
[Requested item 6]
　Monomer (A) 10 ~ 45 parts by weight, the polymer powder (B) 54.9 ~ 80 parts by weight, a total of 100 of the polymerization initiator (C) 0.1 ~ 10 parts by weight (component (A) ~ (C) the parts by weight), and the contrast agent (X) 0 ~ hard tissue repair composition according to claim 1 comprising 70 parts by weight.
[Requested item 7]
　Monomer contained in hard tissue repair composition according to claim 1 (A), polymer powder (B), and each component of the polymerization initiator (C) is divided into three or more in any combination hard tissue repair kit having members housed Te.