The present invention is excellent in various properties required for a composition for repairing hard tissue (for example, adhesion to an adherend such as an artificial joint, penetration into an adherend such as cancellous bone, reduction of the amount of eluted monomer). The present invention relates to a hard tissue repair composition and a hard tissue repair kit.
Background technology
[0002]
　Conventionally, various hard tissue repair compositions have been used as bone cement for fixing hard tissues such as bone and cartilage to artificial joints, or as bone fillers and artificial bone materials used for treatment of osteoporosis. It has been considered. For example, compositions containing polymethylmethacrylate, methylmethacrylate, and benzoyl peroxide (polymerization initiator), inorganic fillers such as (meth) acrylate and calcium phosphate, and compositions containing organic peroxides have been studied. (For example, Patent Document 1). However, such a composition generates a large amount of heat during curing, and there is a high risk of damaging the affected tissue.
[0003]
　As a hard tissue repair composition having improved this point, for example, Patent Document 2 describes a hard tissue containing (meth) acrylate (A), (meth) acrylate polymer (B), and a specific polymerization initiator (C). Tissue repair compositions are disclosed. This composition generates less heat during curing and is excellent in workability.
Prior art literature
Patent documents
[0004]
Patent Document 1: Japanese Patent Application Laid-Open No. 8-224294
Patent Document 2: International Publication No. 2011/062227
Outline of the invention
Problems to be solved by the invention
[0005]
　When the hard tissue repair composition is used, for example, for fixing an artificial joint to a bone, the hard tissue repair composition in a soft mass (dough) state before hardening is implanted in the medullary cavity, and is pressurized and deformed. After that, it is completely cured (polymerized).
[0006]
　The hard tissue repair composition is usually prepared at the site of use (for example, at the site of treatment) by mixing a plurality of components immediately before use. Immediately after this mixing, the hard tissue repair composition is in the form of a slurry, which adheres to the latex gloves of the user (for example, the practitioner) in a stringy manner. Then, after a while after the preparation, the composition for repairing the hard tissue becomes a soft mass (dough). The time point at which this soft lump (fabric) state is reached is qualitatively identified as the time point at which it no longer adheres to the user's latex gloves in a stringy manner. The composition for repairing hard tissue in a soft mass (dough) state is easy to handle because it has an appropriate viscosity and fluidity, and exhibits a good fixing force even after implantation.
[0007]
　The composition for repairing hard tissue is generally used when it is in the soft mass (dough) state described above. The formation of a hard tissue repair composition into a soft mass (dough) state is usually referred to as "doughing", and the time required to reach a soft mass (dough) state is usually referred to as "dough time". ) ”.
[0008]
　A composition for repairing a hard tissue having a long dough forming time is inferior in terms of work efficiency. In addition, the composition for repairing hard tissue that has not been made into a dough is difficult to handle. Moreover, when a hard tissue repair composition in a non-fabricated state is implanted, for example, in the medullary cavity, the composition cannot maintain a shape suitable for fixing the artificial joint and the bone, and the composition and the artificial joint cannot be maintained. And / or a gap may be created at the interface with the bone tissue, resulting in inadequate fixation of the prosthesis. This inadequate fixation is likely to cause loosening and wear of the artificial joint, which may cause pain and infection in the patient. In addition, when revision surgery of an artificial joint is required, the physical burden on the patient is great. Therefore, poor adhesion between the fabricized hard tissue repair composition and the artificial joint and poor penetration into the bone tissue are not preferable from the viewpoint of ensuring patient safety and reducing the burden.
[0009]
　In addition, the present inventors considered that there is room for improvement in the conventional hard tissue repair composition in terms of macroadhesion with bone tissue. For example, if bone cement (a composition for repairing hard tissue) has poor penetration into cancellous bone, a gap will be created at the interface with the bone, causing pain due to osteolysis, and if it worsens, revision surgery will be required. It ends up.
[0010]
　Further, the unpolymerized monomer component contained in the hard tissue repair composition may remain in the polymer and be eluted in the living body. For example, it is known that when the residual monomer in the hard tissue repair composition is eluted in the living body, it is harmful to the tissues and cells of the living body and causes a decrease in blood pressure. In particular, in addition to the blood pressure lowering caused by another cause at the time of treatment, the blood pressure lowering effect caused by the monomer eluted in the living body may cause arrhythmia or myocardial ischemia. Such a large amount of eluted monomer is not preferable from the viewpoint of ensuring the safety of the patient at the time of use (during the treatment) and after the use (after the treatment).
[0011]
　An object of the present invention is to obtain various properties required for a hard tissue repair composition (for example, adhesion to an adherend such as an artificial joint, penetration into an adherend such as cancellous bone, reduction of the amount of eluted monomer). It is an object of the present invention to provide an excellent hard tissue repair composition and a hard tissue repair kit.
Means to solve problems
[0012]
　As a result of diligent studies to solve the above problems, the present inventors used the polymer powder (B) containing the polymer powder having an aspect ratio within a specific range, and used the polymer powder (B) for the entire particles of the hard tissue repair composition. We have found that it is very effective to optimize the cumulative ratio of aspect ratios, and completed the present invention. That is, the present invention is specified by the following matters.
[0013]
　[1] A composition for repairing a hard tissue containing a monomer (A), a polymer powder (B) and a polymerization initiator (C), wherein the
　polymer powder (B) has an aspect ratio of 1.10 or more.
　Of the components contained in the hard tissue repair composition containing the coalesced powder (Bx), the cumulative ratio of the powder particles having an aspect ratio of 1.00 or more and less than 1.10 in the entire powder particles is 75 cumulative% or less. A composition for repairing hard tissue.
[0014]
　[2] Of the components contained in the hard tissue repair composition, the cumulative ratio of powder particles having an aspect ratio of 1.00 or more and less than 1.10 in the entire powder particles is 2.5 to 65 cumulative% [1]. The composition for repairing hard tissue according to.
[0015]
　[3] The polymer powder (B) contains a polymer powder (Bx) having an aspect ratio of 1.10 or more and 1.90 or less, and the overall aspect ratio of the polymer powder (B) is 1.11 or more. The composition for repairing hard tissue according to [1], which is .80 or less.
[0016]
　[4] The composition for repairing a hard tissue according to [1], wherein the monomer (A) is a (meth) acrylate-based monomer.
[0017]
　[5] The composition for repairing a hard tissue according to [1], wherein the polymer powder (B) is a (meth) acrylate-based polymer powder.
[0018]
　[6] The composition for repairing a hard tissue according to [1], wherein the polymerization initiator (C) contains an organoboron compound (c1).
[0019]
　[7] Monomer (A) 10 to 45 parts by mass, polymer powder (B) 54.9 to 80 parts by mass, and polymerization initiator (C) 0.1 to 10 parts by mass (components (A) to (C)) The composition for repairing a hard tissue according to [1], which comprises (with a total of 100 parts by mass).
[0020]
　[8] The composition for repairing hard tissue according to [1], which further comprises a contrast medium (X).
[0021]
　[9] The composition for repairing hard tissue according to [8], wherein the amount of the contrast medium (X) is 0.01 to 70 parts by mass (the total of the components (A) to (C) is 100 parts by mass). thing.
[0022]
　[10] The composition for repairing hard tissue according to [1], which further contains antibacterial agent particles (Y).
[0023]
　[11] The hard tissue repair according to [10], wherein the amount of the antibacterial agent particles (Y) is 0.01 to 30 parts by mass (the total of the components (A) to (C) is 100 parts by mass). Composition.
[0024]
　[12] Each component of the monomer (A), the polymer powder (B) and the polymerization initiator (C) contained in the hard tissue repair composition according to [1] is divided into three or more in any combination. A hard tissue repair kit with a member that has been accommodated.
The invention's effect
[0025]
　According to the present invention, various properties required for a composition for repairing hard tissue (for example, adhesion to an adherend such as an artificial joint, penetration into an adherend such as cancellous bone, reduction of the amount of eluted monomer) are satisfied. An excellent hard tissue repair composition and a hard tissue repair kit can be provided.
Mode for carrying out the invention
[0026]
　[Monomer (A)]
　The monomer (A) used in the present invention is not particularly limited as long as it is a monomer that can be polymerized by the polymerization initiator (C) described later. As the monomer (A), either a monofunctional monomer or a polyfunctional monomer can be used depending on the purpose of use.
[0027]
　As the monomer (A), for example, a (meth) acrylate-based monomer and other vinyl compounds can be used. Of these, (meth) acrylate-based monomers are preferable because they are relatively less irritating to the human body. In the present invention, "(meth) acrylate" is a general term for acrylate and methacrylate. In general, a monomer having an acidic group has excellent adhesion to a hard tissue, acts as a decomplexing agent described later, and has an acidic group when an alkylborane-amine complex is used as the polymerization initiator (C). It is also possible to initiate the polymerization reaction by using a monomer having. Therefore, for example, an appropriate amount of a monomer having an acidic group can be used in combination with a (meth) acrylate-based monomer having no acidic group to improve the adhesiveness.
[0028]
　Specific examples of the monofunctional (meth) acrylate-based monomer having no acidic group include methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, and butyl (meth) acrylate. Hexyl acrylate, 2-ethylhexyl (meth) acrylate, dodecyl (meth) acrylate, lauryl (meth) acrylate, cyclohexyl (meth) acrylate, benzyl (meth) acrylate, isobornyl (meth) acrylate, etc. (Meta) acrylic acid alkyl ester; 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 3-hydroxypropyl (meth) acrylate, 4-hydroxybutyl (meth) acrylate, 5-hydroxypentyl ( Meta) acrylate, 6-hydroxyhexyl (meth) acrylate, 1,2-dihydroxypropyl mono (meth) acrylate, 1,Hydroxyalkyl esters of (meth) acrylic acids such as 3-dihydroxypropyl mono (meth) acrylate, erythritol mono (meth) acrylate; diethylene glycol mono (meth) acrylate, triethylene glycol mono (meth) acrylate, polyethylene glycol mono (meth) Polyalkylene glycol mono (meth) acrylates such as acrylates and polypropylene glycol mono (meth) acrylates; ethylene glycol monomethyl ether (meth) acrylates, ethylene glycol monoethyl ether (meth) acrylates, diethylene glycol monomethyl ether (meth) acrylates, triethylene glycols. (Poly) alkylene glycol monoalkyl ether (meth) acrylates such as monomethyl ether (meth) acrylate, polyethylene glycol monomethyl ether (meth) acrylate, polypropylene glycol monoalkyl ether (meth) acrylate; perfluorooctyl (meth) acrylate, hexafluoro Fluoroalkyl esters of (meth) acrylic acids such as butyl (meth) acrylate; (meth) acryloxy such as γ- (meth) acryloxipropyltrimethoxysilane, γ- (meth) acryloxipropyltri (trimethylsiloxy) silane Silane compounds having an alkyl group; (meth) acrylates having a heterocycle such as tetrahydrofurfuryl (meth) acrylate can be mentioned.
[0029]
　Specific examples of the polyfunctional (meth) acrylate-based monomer having no acidic group include ethylene glycol di (meth) acrylate, propylene glycol di (meth) acrylate, butylene glycol di (meth) acrylate, and neopentyl glycol di ( Poly (meth) acrylates of alcan polyols such as meth) acrylates, hexylene glycol di (meth) acrylates, trimethylpropantri (meth) acrylates, pentaerythritol tetra (meth) acrylates; diethylene glycol di (meth) acrylates, triethylenes. Glycoldi (meth) acrylate, polyethylene glycol di (meth) acrylate, dipropylene glycol di (meth) acrylate, polypropylene glycol di (meth) acrylate, dibutylene glycol di (meth) acrylate, dipentaerythritol hexa (meth) acrylate, etc. Polyoxyalkane polyol poly (meth) acrylate; alicyclic or aromatic di (meth) acrylate represented by the following general formula (1)
[0030]
[Chemical

formula 1] (In formula (1), R is a hydrogen atom or a methyl group, m and n are independently numbers of 0 to 10, and R 1 is
[0031]
It is one of [Chemical 2]

);
[0032]
　Alicyclic or aromatic epoxy di (meth) acrylate represented by the following general formula (2)
[0033]
[Chemical

formula 3] (In formula (2), R, n and R 1 are the same as R, n and R 1 in the formula (1) );
[0034]
　Polyfunctional (meth) acrylate having a urethane bond in the molecule represented by the following formula (3)
[0035]
[Chemical

formula 4] (In equation (3), R is the same as R in the equation (1), and R 2 is
[0036]
It is one of [Chemical 5]

. );
[0037]
　Among the above exemplified compounds, examples of the monofunctional (meth) acrylate-based monomer include alkyl (meth) acrylates such as methyl (meth) acrylate and ethyl (meth) acrylate; 2-hydroxyethyl (meth) acrylate. Hydroxyalkyl esters of (meth) acrylic acids such as 1,3-dihydroxypropyl mono (meth) acrylates and erythritol mono (meth) acrylates; triethylene glycol monomethyl ether (meth) acrylates, triethylene glycol mono (meth) acrylates and the like. Polyethylene glycol mono (meth) acrylate is preferred.
[0038]
　Among the above-exemplified compounds, examples of the polyfunctional (meth) acrylate-based monomer include di (meth) having an ethylene glycol chain in the molecule such as triethylene glycol di (meth) acrylate and polyethylene glycol di (meth) acrylate. Acrylate; a compound represented by the following formula (1) -a
[0039]
[Chemical

formula 6] (R, m and n in the formula (1) -a are the same as R, m and n in the formula (1));
[0040]
　Compound represented by the following formula (2) -a
[0041]
[Chemical

formula 7] (In formula (2) -a, R is the same as R in formula (1));
[0042]
　Compound represented by the following formula (3) -a
[0043]
[Chemical

formula 8] (R in the formula (3) -a is the same as R in the formula (1));
is preferable.
[0044]
　Two or more of these (meth) acrylate-based monomers may be used in combination.
[0045]
　Specific examples of the monomer having an acidic group include (meth) acrylic acid and its anhydride, 1,4-di (meth) acryloxyethyl pyromellitic acid, and 6- (meth) acryloxyethyl naphthalene 1,2,6. -Tricarboxylic acid, N- (meth) acryloyl-p-aminobenzoic acid, N- (meth) acryloyl-o-aminobenzoic acid, N- (meth) acryloyl-m-aminobenzoic acid, N- (meth) acryloyl- 5-Aminosalicylic acid, N- (meth) acryloyl-4-aminosalicylic acid, 4- (meth) acryloxiethyl trimellitic acid and its anhydride, 4- (meth) acryloxybutyltrimellitic acid and its anhydride, 4 -(Meta) acryloxyhexyl trimellitic acid and its anhydride, 4- (meth) acryloyloxydecyltrimellitic acid and its anhydride, 2- (meth) acryloyloxybenzoic acid, 3- (meth) acryloyloxybenzoic acid , 4- (Meta) acryloyloxybenzoic acid, β- (meth) acryloyloxyethyl hydrogen succinate, β- (meth) acryloyloxyethyl hydrogen maleate, β- (meth) acryloyloxyethyl hydrogen phthalate, 11 -A monomer having a carboxylic acid group such as (meth) acryloyloxy-1,1-undecandicarboxylic acid, p-vinylbenzoic acid or an anhydride group thereof; (2- (meth) acryloxyethyl) phosphoric acid, (2-) Monomer having a phosphoric acid group such as (meth) acryloxyethylphenyl) phosphoric acid, 10- (meth) acryloxidecylphosphoric acid; sulfonic acid such as p-styrene sulfonic acid and 2-acrylamide-2-methylpropane sulfonic acid. Examples include a monomer having a group. Of these, 4-metaacryloxyethyltrimellitic acid and its anhydrides are preferred.
[0046]
　Two or more kinds of these monomers having an acidic group may be used in combination. In addition, the monomer having an acidic group can also be used as a calcium salt.
[0047]
　The blending amount of the monomer (A) is preferably 10 to 45 parts by mass, more preferably 20 to 45 parts by mass, and more preferably 25 to 36 parts by mass (the total of the components (A) to (C) is 100 parts by mass. To do). The lower limit of each of the above ranges is significant in terms of exhibiting characteristics such as ease of application, operability, and penetration into bone tissue. The upper limit is significant in that properties such as adhesive strength, mechanical properties, and toughness are exhibited, and / or the amount of residual monomer and / or the amount of eluted monomer can be reduced. When the monomer (A) contains a monomer having an acidic group, the amount of the monomer having an acidic group is preferably 0.005 to 30% by mass, more preferably 0.01, based on 100% by mass of the total of the monomers (A). ~ 25% by mass. However, the use of the monomer having an acidic group is optional, and the composition for repairing a hard tissue of the present invention may or may not contain a monomer having an acidic group.
[0048]
　[Polymer powder (B)]
[0049]
　The type of the polymer powder (B) used in the present invention is not particularly limited, but a part or all of the monomer units constituting the polymer powder (B) are a part of the monomer (A) described above. It is preferable that the monomer unit is derived from the same type of monomer as the monomer of the above or all the monomers. In the present invention, "polymer" is a general term for homopolymers and copolymers. As the polymer powder (B), for example, a (meth) acrylate-based polymer and other vinyl-based polymers can be used. Of these, (meth) acrylate-based polymers are preferable.
[0050]
　Specific examples of the (meth) acrylate-based polymer include polymethyl (meth) acrylate, polyethyl (meth) acrylate, methyl (meth) acrylate / ethyl (meth) acrylate copolymer, and methyl (meth) acrylate / butyl (meth). Non-crosslinked polymers such as acrylate copolymers and methyl (meth) acrylate / styrene copolymers; methyl (meth) acrylate / ethylene glycol di (meth) acrylate copolymers, methyl (meth) acrylate / triethylene glycol di ( Examples thereof include crosslinked polymers such as meta) acrylate copolymers, copolymers of methyl (meth) acrylate and butadiene-based monomers, and polymers that partially form calcium salts. Further, it may be an organic / inorganic composite in which a metal oxide or a metal salt is coated with a non-crosslinked polymer or a crosslinked polymer.
[0051]
　As the polymer powder (B), one kind of polymer powder may be used alone, or a mixture of a plurality of kinds of polymer powders may be used.
[0052]
　In the present invention, the polymer powder (B) contains a polymer powder (Bx) having an aspect ratio of 1.10 or more, and among the components contained in the hard tissue repair composition, the aspect ratio of the entire powder particles. The cumulative ratio of powder particles having a value of 1.00 or more and less than 1.10 is 75 cumulative% or less. The effects on various properties in the present invention (for example, adhesion to an adherend such as an artificial joint, penetration into an adherend such as cancellous bone, reduction of the amount of eluted monomer) are mainly exhibited due to these. ..
[0053]
　In the present invention, "adhesion" means the adhesive force and / or the adhesive force of the hard tissue repair composition to an adherend such as an artificial joint or bone tissue. For example, even when an adherend such as an artificial joint is made of metal, the composition for repairing hard tissue of the present invention exhibits excellent adhesion. However, the type of adherend is not limited to this. The composition for repairing hard tissue of the present invention can be used, for example, for adhesion between hard tissues, filling into hard tissues, adhesion and / or adhesion between hard tissues and metal artificial objects, and other structures such as hard tissues and soft tissues. Excellent adhesion and / or adhesion with bone cement used for fixing hard tissues such as bone and cartilage to artificial joints, filling material for bone defects, bone filling material, artificial bone, etc. Express sex. Hereinafter, the reason why the effect of the present invention can be obtained will be described.
[0054]
　(Adhesion to adherends such as artificial joints)
　Generally, the molecular structure of the polymer powder (B) is similar to the molecular structure of the monomer (A), so that the polymer powder (B) is the monomer (A). Partially dissolves in. Therefore, the mixed solution thickens faster than the case of only thickening due to the polymerization reaction. Further, it is generally known that when the viscosity of the mixed solution is increased, the termination reaction between the growth radical species is less likely to occur, and the polymerization rate is increased. This is called the cage effect (Trommsdorf effect).
[0055]
　The polymer powder (BX) having a large aspect ratio (aspect ratio of 1.10 or more) used in the present invention is a polymer having a small aspect ratio (aspect ratio of 1.00 or more and less than 1.10). Since it is more easily dissolved in the monomer (A) than the powder (By), the composition tends to thicken faster and the dough forming time tends to be shortened due to the effect of accelerating the polymerization rate due to the cage effect.
[0056]
　Further, in the present invention, the cumulative ratio (%) of the powder particles having an aspect ratio of 1.00 or more and less than 1.10 in the entire powder particles is moderately low. That is, the proportion of powder particles having a large aspect ratio (powder particles having an aspect ratio of 1.10 or more) is moderately high. Among the powder particles having a large aspect ratio, the polymer powder (BX) having a particularly large aspect ratio exhibits the effect of shortening the dough forming time as described above. Further, the powder particles having a large aspect ratio tend to increase the viscosity of the composition as compared with the powder particles having a small aspect ratio due to the shape of the powder particles even if the material is insoluble in the monomer (A). Therefore, if the proportion of powder particles having a large aspect ratio is high, the dough forming time tends to be short.
[0057]
　The short doughing time means that it takes a short time for each component to be uniformly mixed in a desired composition to form a homogeneous soft mass state. Further, the composition for repairing hard tissue having excellent homogeneity is superior in operability as compared with the composition having inferior homogeneity, and a decrease in a substantial contact area with an adherend such as an artificial joint is suppressed. There is a tendency. Moreover, the composition for repairing a hard tissue having excellent homogeneity is in a state of a desired composition (optimal blending ratio from the viewpoint of each characteristic) at any location. From these points, it is considered that the anchoring effect associated with the polymerization reaction of the composition is sufficiently exhibited, and the effect of improving the adhesion to the adherend such as an artificial joint in the soft mass (fabric) state can be obtained.
[0058]
　(Invasion into adherends such as cancellous bone) The
　hard tissue repair composition is a slurry-like composition (slurry containing powder and liquid) in which the polymerization reaction has not yet sufficiently proceeded immediately after preparation. The flow characteristics of this slurry-like composition have a great influence on the invasion into an adherend such as cancellous bone. In general, slurry-like fluids include Newtonian fluids whose flow characteristics (viscosity) do not change without being affected by shear stress (shear stress) and non-Newtonian fluids whose flow characteristics change under the influence of the effects. It is known that some Newtonian fluids exhibit dilatancy. Dilatancy is a characteristic that the viscosity of a fluid increases as the shear stress increases. For example, when a slurry-like composition is allowed to penetrate into an adherend such as cancellous bone, shear stress is generated at the contact surface between the fluid and the adherend. Therefore, a fluid that exhibits remarkable dilatancy is not preferable as a hard tissue repair composition because its viscosity increases when it invades the adherend.
[0059]
　On the other hand, the polymer powder (Bx) having a large aspect ratio used in the present invention tends to have less gaps between particles even when stress is applied from the outside as compared with the polymer powder having a small aspect ratio. It is considered that a fluid in which such a gap is unlikely to occur is unlikely to exhibit dilatancy. Further, powder particles having a large aspect ratio other than the polymer powder (Bx) also tend to have less gaps between the particles, and it is considered that the fluid is less likely to exhibit dilatancy. As a result, an increase in the viscosity of the slurry-like composition is suppressed, and the permeability to an adherend such as cancellous bone is improved.
[0060]
　(Reduction of Elution Monomer Amount)
　As described above, in general, the mixed solution of the polymer powder (B) and the monomer (A) thickens faster than the case of only thickening due to the polymerization reaction. In addition, the polymerization rate is increased due to the cage effect. As a result, the amount of eluted monomers is usually reduced from the surface of the hard tissue repair composition without being polymerized.
[0061]
　However, when the water content is excessively present in the living body, the polymerization activity of the polymerization initiator (C) tends to decrease, the polymerization reaction itself tends to be inhibited, and the water content has a molecular structure significantly different from that of the polymer powder (B). Due to the influence of the above, the solubility of the polymer powder (B) in the monomer (A) is lowered, and the cage effect tends not to be sufficiently exhibited. In this case, the amount of eluted monomers cannot be sufficiently reduced.
[0062]
　On the other hand, in the present invention, the polymer powder (BX) having a large aspect ratio is easily dissolved in the monomer (A), so that the polymer powder (Bx) (even when excessive water is present in the living body) ( The decrease in solubility of B) in the monomer (A) tends to be suppressed. As a result, it is considered that the cage effect is sufficiently exhibited, the polymerization reaction is promoted, and the amount of eluted monomers is reduced.
[0063]
　Further, when an organic boron compound (C1), which will be described later, is used as the polymerization initiator (C), the composition with the body fluid or spinal fluid contained in the living tissue with which the implanted hard tissue repair composition is in direct contact is used. Since the polymerization reaction proceeds from the interface, it is considered that the amount of unpolymerized monomer is further reduced and the amount of eluted monomer is reduced. It is presumed that the reason why the polymerization reaction proceeds from the interface is that the polymerization activity ability is increased or maintained by the dissolved oxygen contained in the water existing at the interface with the body fluid or the cerebrospinal fluid.
[0064]
　(Other property 1: Shortening of dough time) As
　described above, in general, the mixed solution of the polymer powder (B) and the monomer (A) is only thickened by the polymerization reaction. It thickens faster than it does. In addition, the polymerization rate is increased due to the cage effect. As a result, as described above, the dough formation time tends to be shortened.
[0065]
　(Other property 2: Reduction of residual monomer amount)
　As described above, the polymer powder (BX) having a large aspect ratio is easily dissolved in the monomer (A), so that even if the water content in the living body is excessive, it is excessive. Even if it is present, the decrease in solubility of the polymer powder (B) in the monomer (A) tends to be suppressed. As a result, it is considered that the cage effect is sufficiently exhibited, the polymerization reaction is promoted, and the amount of residual monomer is reduced.
[0066]
　(Other characteristic 3: Dischargeability from filling device)
　For example, when a slurry-like fluid is discharged from a discharge nozzle, shear stress is generated at the contact surface between the fluid and the contacted body, and as a result, pressure loss occurs. (Energy loss) occurs. In particular, in general filling instruments such as cement mixers for orthopedics, cement injectors for orthopedics, cement dispensers for orthopedics, and cement guns, from the syringe part (large diameter part) to the discharge nozzle part (small diameter part). Since the inner diameter (cross-sectional area) is remarkably reduced everywhere, when the hard tissue repair composition shows remarkable dilatancy, the pressure loss (energy loss) at the place where the cross-sectional area is reduced becomes large and the ejection property is discharged. Will decrease. On the other hand, as described above, the polymer powder (BX) having a large aspect ratio and other powder particles having a large aspect ratio used in the present invention tend to have less gaps between the particles, and the fluid is dilatancy. Is considered to be difficult to express. As a result, the increase in viscosity of the slurry-like composition is suppressed, and the discharge property tends to be improved.
[0067]
　(Other property 4: Toughness)
　Generally, the fracture of the hard tissue repair composition after curing occurs due to the stress concentration caused in the defects contained in the composition. The defects include, for example, defects due to impurities contained in each component such as monomer (A), polymer powder (B), and polymerization initiator (C), and additional components such as contrast agent (X) and colorant. Defects due to defects, defects due to non-uniform structure such as voids, voids, weld lines, etc. generated in the mixing operation for preparing the composition for hard tissue repair, non-uniform height of high molecular weight components contained in the cured composition There is a defect due to the following structure. The fracture toughness value is an index of resistance to the start or progress of fracture of the composition. In general, as a method for improving the fracture toughness of a resin material, there is a method of adding various components such as rubber particles, a thermoplastic resin, and an inorganic filler. It is important that the interface between these additive components and the resin material is firmly adhered and / or adhered. When the physical properties of the additive component and the resin material are significantly different, the adhesion and / or adhesion of the interface tends to be insufficient, the interface peeling tends to occur, and as a result, the fracture toughness value tends to decrease. On the other hand, in the present invention, the type of the polymer powder (B) can be selected according to the type of the monomer (A), that is, the polymer powder (B) having the same or similar basic molecular structure can be selected. It's easy. If the basic molecular structure is the same or similar, the uniformity of the interface after preparation of the hard tissue repair composition is also excellent, so that interface peeling is unlikely to occur. Furthermore, if a polymer powder (Bx) having a large aspect ratio is used, even if the composition is cracked, the effect of physical wedges and / or cross-linking can be reduced by the aspect ratio. Since it is more easily expressed than a composition using only a polymer powder having a small aspect ratio, the growth of cracks tends to be suppressed. The effect of improving toughness is considered to be exhibited by suppressing this crack growth.
[0068]
　The polymer powder (B) may contain, for example, only the polymer powder (Bx) having an aspect ratio of 1.10 or more, but in particular, the polymer powder having an aspect ratio of 1.10 or more. Various properties (for example, for example) required for a hard tissue repair composition to contain (Bx) and a polymer powder (By) having an aspect ratio of 1.00 or more and less than 1.10. It is preferable in terms of improving the various characteristics described above). Hereinafter, the blending amount of the polymer powder (Bx) and the polymer powder (By) will be described.
[0069]
　Considering various properties such as adhesion to an adherend (for example, an artificial joint), the polymer powder (BX) and the polymer powder (By) are mixed to obtain 100% by mass of the polymer powder (B). When prepared, the blending amount of the polymer powder (Bx) is preferably 3.0% by mass or more, more preferably 4.0 to 70% by mass, and more preferably 5.0 to 60% by mass. The blending amount of the polymer powder (By) is preferably 97.0% by mass or less, more preferably 30 to 96.0% by mass, and more preferably 40 to 95.0% by mass. When the polymer powder (Bx) having a large aspect ratio is used in such a specific amount or more, the solubility of the polymer powder (B) in the monomer (A) is appropriately maintained, and a sufficient thickening effect and a sufficient thickening effect are obtained. It is preferable in that it exhibits a cage effect (Polymersdorf effect), shortens the dough forming time, and improves various properties such as operability of the hard tissue repair composition. Further, the use of the polymer powder (Bx) having a large aspect ratio in such a specific amount or less enables the preparation of a homogeneous hard tissue repair composition by suppressing significant thickening, and an adherend. It is preferable in that it suppresses a decrease in the anchoring effect due to a substantial reduction in the contact area with the object, and improves various characteristics such as adhesion to an adherend (for example, an artificial joint).
[0070]
　Further, considering various properties such as permeability to an adherend (for example, sponge bone), the polymer powder (Bx) and the polymer powder (By) are mixed to produce 100 mass of the polymer powder (B). In the case of preparing%, the blending amount of the polymer powder (Bx) is preferably 1.0 to 45% by mass, more preferably 6.0 to 45% by mass, and more preferably 10 to 45% by mass. .. The blending amount of the polymer powder (By) is preferably 55 to 99.0% by mass, more preferably 55 to 94.0% by mass, and more preferably 55 to 90% by mass. When the polymer powder (Bx) having a large aspect ratio is used in such a specific amount or more, the expression of dilatancy is suppressed and various properties such as penetration into an adherend (for example, cancellous bone) are improved. It is preferable in that respect. In addition, the use of the polymer powder (Bx) having a large aspect ratio in a specific amount or less suppresses significant thickening and provides various properties such as permeability to an adherend (for example, cancellous bone). It is preferable in terms of improvement.
[0071]
　Further, in consideration of various characteristics such as reduction of the amount of eluted monomers, when the polymer powder (Bx) and the polymer powder (By) are mixed to prepare 100% by mass of the polymer powder (B), The blending amount of the polymer powder (Bx) is preferably 1.0 to 70% by mass, more preferably 5.0 to 60% by mass, and particularly preferably 10 to 55% by mass. The blending amount of the polymer powder (By) is preferably 30 to 99.0% by mass, more preferably 40 to 95.0% by mass, and more preferably 45 to 90% by mass. Using a polymer powder (Bx) having a large aspect ratio in an amount equal to or more than a specific amount causes a sufficient cage effect (Trommsdorf effect) and improves various properties such as reduction of the amount of eluted monomers. Is preferable. Further, the use of the polymer powder (Bx) having a large aspect ratio in such a specific amount or less enables the preparation of a homogeneous hard tissue repair composition by suppressing significant thickening, and cures. It is preferable in that it suppresses an increase in non-uniform structure on the surface and / or inside of the object and improves various properties such as a reduction in the amount of eluted monomers.
[0072]
　In the hard tissue repair composition of the present invention, the cumulative ratio of particles having an aspect ratio of 1.00 or more and less than 1.10 in the entire polymer particles (B) or the entire powder particles is within a predetermined range. It is preferable in that it improves various properties (for example, the properties described above) required for the hard tissue repair composition. Hereinafter, the cumulative ratio thereof will be described.
[0073]
　Considering various characteristics such as adhesion to an adherend (for example, an artificial joint), the polymer powder particles (B) having an aspect ratio of 1.00 or more and less than 1.10 in the entire polymer powder (B) (100 cumulative%). The cumulative ratio of −y) is preferably 86 cumulative% or less, more preferably 3.5 to 80 cumulative%. Increasing the cumulative ratio of polymer powder particles (By) having a small aspect ratio to such a specific ratio or more enables the preparation of a homogeneous hard tissue repair composition by suppressing significant thickening. It is preferable in that it suppresses a decrease in the anchoring effect due to a reduction in a substantial contact area with the adherend and improves various characteristics such as adhesion to the adherend (for example, an artificial joint). Further, by setting the cumulative ratio of the polymer powder particles (By) having a small aspect ratio to such a specific ratio or less, the solubility of the polymer powder (B) in the monomer (A) can be appropriately maintained. It is preferable in that it exhibits a sufficient thickening effect and a cage effect (Polymersdorf effect), shortens the dough forming time, and improves various properties such as operability of the hard tissue repair composition.
[0074]
　In addition, considering various properties such as permeability to an adherend (for example, cancellous bone), polymer powder particles having an aspect ratio of 1.00 or more and less than 1.10 in the entire polymer powder (B) (100 cumulative%). The cumulative ratio of (By) is preferably 15 to 55 cumulative%, more preferably 20 to 50 cumulative%. Increasing the cumulative ratio of polymer powder particles (By) having a small aspect ratio to such a specific ratio or more suppresses significant thickening, and various factors such as permeability to adherends (for example, cancellous bone). It is preferable in terms of improving the characteristics. Further, setting the cumulative ratio of the polymer powder particles (By) having a small aspect ratio to such a specific ratio or less suppresses the development of dilatancy, and the invasion into the adherend (for example, cancellous bone) and the like. It is preferable in that it improves various characteristics of.
[0075]
　Further, in consideration of various characteristics such as reduction of the amount of eluted monomers, the polymer powder particles (By) having an aspect ratio of 1.00 or more and less than 1.10 in the entire polymer powder (B) (100 cumulative%). The cumulative ratio is preferably 15 to 55 cumulative%, more preferably 20 to 50 cumulative%. Increasing the cumulative ratio of polymer powder particles (By) having a small aspect ratio to such a specific ratio or more enables the preparation of a homogeneous hard tissue repair composition by suppressing significant thickening. , It is preferable in that it suppresses an increase in non-uniform structure on the surface and / or inside of the cured product and improves various properties such as a reduction in the amount of eluted monomers. Further, setting the cumulative ratio of the polymer powder particles (By) having a small aspect ratio to such a specific ratio or less causes a sufficient cage effect (Trommsdorf effect) to be exhibited, and the amount of eluted monomers can be reduced. It is preferable in terms of improving various characteristics.
[0076]
　The composition for repairing hard tissue of the present invention may contain powder particles other than the polymer powder (B). In that case, it is preferable to consider the cumulative ratio (%) of the powder particles having an aspect ratio of 1.00 or more and less than 1.10 in the entire powder particles among each component contained in the hard tissue repair composition. Examples of the powder particles other than the polymer powder (B) include a contrast agent (X), an antibacterial agent particle (Y), and a polymerization initiator (C), which will be described later. As will be described later, the polymerization initiator (C) may be in a liquid state or in a solid state (for example, in a powder state). The powdery polymerization initiator is mixed with the polymer powder (B) or supported on the polymer powder (B). Therefore, the powdery polymerization initiator corresponds to powder particles other than the polymer powder (B). That is, the "whole powder particles" contained in the hard tissue repair composition means that all of the powder particles other than the polymer powder (B) and the polymer powder (B) as exemplified above are included.
[0077]
　Considering various properties such as adhesion to an adherend (for example, an artificial joint), the total of all powder particles (polymer powder (B) and other powder particles) among each component contained in the hard tissue repair composition The cumulative ratio of powder particles having an aspect ratio of 1.00 or more and less than 1.10 in (100 cumulative%) is 75 cumulative% or less, preferably 70 cumulative% or less, more preferably 2.5 to 65 cumulative%, and more. It is preferably 3.0 to 60 cumulative%. Increasing the cumulative ratio of powder particles having an aspect ratio of 1.00 or more and less than 1.10 to such a specific ratio or more enables the preparation of a homogeneous hard tissue repair composition by suppressing significant thickening. It is preferable in that it suppresses a decrease in anchoring effect due to a reduction in a substantial contact area with an adherend and improves various characteristics such as adhesion to an adherend (for example, an artificial joint). Further, by setting the cumulative ratio of the powder particles having an aspect ratio of 1.00 or more and less than 1.10 to such a specific ratio or less, the solubility of the polymer powder (B) in the monomer (A) is appropriately maintained. It is preferable in that it exhibits a sufficient thickening effect and a cage effect (Polymersdorf effect), shortens the dough forming time, and improves various properties such as operability of the hard tissue repair composition.
[0078]
　In addition, considering various properties such as permeability to an adherend (for example, sponge bone), among the components contained in the hard tissue repair composition, all the powder particles (polymer powder (B) and other powder particles) The cumulative ratio of powder particles having an aspect ratio of 1.00 or more and less than 1.10 is 75 cumulative% or less, preferably 2.5 to 55 cumulative%, and more preferably 3.0 to 3.0. It is 40 cumulative%, more preferably 3.0 to 35 cumulative%. Increasing the cumulative ratio of powder particles having an aspect ratio of 1.00 or more and less than 1.10 to such a specific ratio or more suppresses significant thickening and suppresses penetration into adherends (for example, cancellous bone). It is preferable in terms of improving various characteristics. Further, setting the cumulative ratio of powder particles having an aspect ratio of 1.00 or more and less than 1.10 to such a specific ratio or less suppresses the development of dilatancy and infiltrates into an adherend (for example, cancellous bone). It is preferable in terms of improving various characteristics such as.
[0079]
　In addition, considering various characteristics such as reduction of the amount of eluted monomers, the entire powder particles among the components contained in the hard tissue repair composition (total 100 cumulative% of the polymer powder (B) and other powder particles). The cumulative ratio of powder particles having an aspect ratio of 1.00 or more and less than 1.10 is 75 cumulative% or less, preferably 70 cumulative% or less, more preferably 2.5 to 65 cumulative%, and more preferably 2. It is 5 to 55 cumulative%, more preferably 4.0 to 40 cumulative%, and more preferably 4.0 to 35 cumulative%. Increasing the cumulative ratio of powder particles with an aspect ratio of 1.00 or more and less than 1.10 to such a specific ratio or more enables the preparation of a homogeneous hard tissue repair composition by suppressing significant thickening. It is preferable in that it suppresses an increase in the non-uniform structure on the surface and / or inside of the cured product and improves various properties such as a reduction in the amount of eluted monomers. Further, setting the cumulative ratio of the polymer powder particles (By) having a small aspect ratio to such a specific ratio or less causes a sufficient cage effect (Trommsdorf effect) to be exhibited, and the amount of eluted monomers can be reduced. It is preferable in terms of improving various characteristics.
[0080]
　The aspect ratio of the polymer powder (Bx) is 1.10 or more, and is preferably 1.10 or more and 1.90 or less, more preferably, from the viewpoint of improving various properties required for the hard tissue repair composition. Is 1.15 or more and 1.80 or less. Setting the aspect ratio of the polymer powder (Bx) to such a specific ratio or more facilitates, for example, developing the desired solubility of the polymer powder (Bx) in the monomer (A). , It is preferable in terms of improving various characteristics. Further, setting the aspect ratio of the polymer powder (Bx) to such a specific ratio or less means that, for example, the desired solubility of the polymer powder (Bx) in the monomer (A) is excessively high. It is possible to prevent the polymer powder (B) or the powder particles from becoming excessively cohesive, and as a result, the operability of the hard tissue repair composition and the like are suppressed. It is preferable in terms of improving various characteristics.
[0081]
　The aspect ratio of the polymer powder (By) is 1 or more and less than 1.10, and is preferably 1.00 or more and 1.05 or less from the viewpoint of improving various properties required for the hard tissue repair composition. be. Setting the aspect ratio of the polymer powder (By) to 1.05 or less means that, for example, the desired solubility of the polymer powder (Bx) in the monomer (A) becomes excessively high. It suppresses or suppresses the cohesiveness of the polymer powder (B) or the entire powder particles from becoming excessively high, and as a result, improves various properties such as operability of the hard tissue repair composition. Preferred in terms of points.
[0082]
　When the polymer powder (B) contains the polymer powder (BX) and the polymer powder (By), the aspect ratio of the entire polymer powder (B) is required for the hard tissue repair composition. From the viewpoint of improving various characteristics, it is preferably 1.11 or more and 1.80 or less, more preferably 1.15 or more and 1.80 or less, and more preferably 1.15 or more and 1.75 or less. Keeping the aspect ratio of the entire polymer powder (B) within such a specific range, for example, maintains the solubility of the polymer powder (B) in the monomer (A) at an appropriate level, or makes it heavy. It is preferable in that the cohesiveness of the combined powder (B) or the entire powder particles is maintained at an appropriate level, and as a result, various properties such as operability of the hard tissue repair composition are improved.
[0083]
　The method for measuring the aspect ratio and the cumulative ratio (%) described above is as described in the column of Examples described later.
[0084]
　Weight average molecular weight of polymer powder (B) (that is, weight average molecular weight of the polymer when one kind of polymer is used alone, and weight average of the whole mixture when a mixture of two or more kinds of polymers is used. The molecular weight) is preferably 40,000 to 6 million, more preferably 50,000 to 5 million, and more preferably 75,000 to 2 million, from the viewpoint of improving various properties required for the hard tissue repair composition. It is more preferably 75,000 to 880,000, and more preferably 100,000 to 400,000. Keeping the weight average molecular weight of the polymer powder (B) within such a specific range, for example, maintains the solubility of the polymer powder (B) in the monomer (A) at an appropriate level and has a thickening effect. It is preferable in that the cage effect (Polymer powder effect) is controlled, and as a result, the operability of the hard tissue repair composition is improved. Moreover, if the operability is improved, it becomes easier to obtain a composition for repairing a hard tissue having excellent homogeneity, and as a result, the adhesion to the adherend, the penetration into the adherend, and the amount of eluted monomers are reduced. , The flexural modulus, tensile strength, compressive strength, flexural strength, toughness (surface dissipation energy limit value) and other characteristics of the hard tissue repair composition after curing tend to be improved.
[0085]
　Volume average particle size of the polymer powder (B) (that is, when a kind of polymer powder is used alone, the volume average particle size of the polymer powder, or when a mixture of two or more kinds of polymer powders is used, The volume average particle size of the entire mixture) is preferably 7 to 120 μm, more preferably 10 to 118 μm, and more preferably 15 to 77 μm from the viewpoint of improving various properties required for the hard tissue repair composition. Keeping the volume average particle size of the polymer powder (B) within such a specific range, for example, maintains the solubility of the polymer powder (B) in the monomer (A) at an appropriate level and thickens it. It is preferable in that the effect and the cage effect (Polymer powder effect) are controlled, and as a result, the operability of the hard tissue repair composition is improved. Moreover, if the operability is improved, it becomes easier to obtain a composition for repairing a hard tissue having excellent homogeneity, and as a result, the adhesion to the adherend, the penetration into the adherend, and the amount of eluted monomers are reduced. , The flexural modulus, tensile strength, compressive strength, flexural strength, toughness (surface dissipation energy limit value) and other characteristics of the hard tissue repair composition after curing tend to be improved.
[0086]
　The blending amount of the polymer powder (B) is preferably 54.9 to 80 parts by mass, more preferably 56.7 to 73.7 parts by mass, from the viewpoint of improving various properties required for the hard tissue repair composition. Parts, more preferably 59.7 to 70.7 parts by mass (the total of the components (A) to (C) is 100 parts by mass). Keeping the blending amount of the polymer powder (B) within such a specific range, for example, maintains the solubility of the polymer powder (B) in the monomer (A) at an appropriate level and has a thickening effect and a thickening effect. It is preferable in that the cage effect (Polymer powder effect) is controlled, and as a result, the operability of the hard tissue repair composition is improved. Moreover, if the operability is improved, it becomes easier to obtain a composition for repairing a hard tissue having excellent homogeneity, and as a result, the adhesion to the adherend, the penetration into the adherend, and the amount of eluted monomers are reduced. , Various properties such as flexural modulus, tensile strength, compressive strength, flexural strength, toughness (surface dissipation energy limit value) of the hard tissue repair composition after curing tend to be improved.
[0087]
　[Polymerization Initiator (C)]
　The polymerization initiator (C) used in the present invention is not particularly limited, and various known compounds can be used. Among them, the organoboron compound (c1) and the organic peroxide are preferable, and the organoboron compound (c1) is more preferable. The organoboron compound (c1) tends to shorten the dough formation time as compared with other polymerization initiators. It is considered that the reason is that the polymerization reaction proceeds from the interface with the surrounding air in which the composition for repairing the hard tissue comes into direct contact, and the stringing disappears at an early stage to form a soft mass (dough) state. Further, it is also considered that the polymerization activity ability is increased or maintained by the dissolved oxygen in water even if the composition for repairing the hard tissue contains water.
[0088]
　As organic peroxides, for example, diacyl peroxides such as diacetyl peroxide, diisobutyl peroxide, didecanoyl peroxide, benzoyl peroxide (BPO), and succinate peroxide; diisopropylperoxydicarbonate, di-2- Peroxydicarbonates such as ethylhexyl peroxydicarbonate and diallyl peroxydicarbonate; peroxyesters such as tert-butylperoxyisobutyrate, tert-butylneodecanate and cumemperoxyneodecanate; acetylcyclohexyl Examples thereof include peroxide sulfonates such as sulfonyl peroxide.
[0089]
　The organic peroxide may be used as a redox initiator in combination with a tertiary amine or sulfinic acid or an alkali metal salt thereof and a tertiary amine. Of these, benzoyl peroxide (BPO) and N, N-dimethyl-p-toluidine and benzoyl peroxide (BPO) and N, N-dihydroxyethyl-p-toluidine are preferably used.
[0090]
　It is preferable that a tertiary amine such as N, N-dimethyl-p-toluidine or N, N-dihydroxyethyl-p-toluidine is added to the monomer (A) in advance for use. The amount added is preferably 5.0 parts by mass or less, more preferably 0.1 to 3.0 parts by mass, and more preferably 0.25 to 2.6 parts by mass (monomer (A) and tertiary). The total with amine is 100 parts by mass). When a tertiary amine is used, radical species are generated by electron transfer even at room temperature, so that the polymerization reaction can be easily started without heating.
[0091]
　As the organoboron compound (c1), for example, trialkylboron, alkoxyalkylborone, dialkylborane, partially oxidized trialkylborone, and alkylborane-amine complex can be used.
[0092]
　Specific examples of trialkylboron include triethylboron, tripropylboron, triisopropylboron, tributylboron, tri-sec-butylboron, triisobutylboron, tripentylboron, trihexylboron, triheptylboron, and trioctylboron. Examples thereof include trialkylboron having an alkyl group having 2 to 8 carbon atoms, such as tricyclopentylboron and tricyclohexylboron. The alkyl group may be any of a linear alkyl group, a branched alkyl group and a cycloalkyl group, and the three alkyl groups contained in trialkylboron may be the same or different.
[0093]
　Specific examples of alkoxyalkylboron include monoalkoxydialkylboron such as butoxydibutylboron and dialkoxymonoalkylboron. The alkyl group of alkoxyalkylboron and the alkyl portion of the alkoxy group may be the same or different.
[0094]
　Specific examples of dialkylborane include dicyclohexylborane and diisoamylborane. The two alkyl groups contained in the dialkylborane may be the same or different. Further, the two alkyl groups contained in the dialkylborane may be bonded to form a monocyclic structure or a bicyclo structure. Such compounds include, for example, 9-borabicyclo [3.3.1] nonane.
[0095]
　The partially oxidized trialkylboron is a partial oxide of trialkylboron. Of these, partially oxidized tributylboron is preferable. The amount of oxygen added to 1 mol of trialkylboron is preferably 0.3 to 0.9 mol, more preferably 0.4 to 0.6 mol.
[0096]
　Specific examples of the alkylborane amine complex include triethylborane diaminopropane (TEB-DAP), triethylborane diethylenetriamine (TEB-DETA), tri-n-butylborane 3-methoxypropylamine (TnBB-MOPA), and tri. -N-butylborane diaminopropane (TnBB-DAP), tri-sec-butylborane diaminopropane (TsBB-DAP), methylaminoethoxydiethylborane (MAEDEB), methylaminoethoxydicyclohexylborane (MAEDCB) and derived from these Derivatives can be mentioned. These alkylborane-amine complexes can be used alone or in combination of two or more.
[0097]
　When the alkylborane-amine complex is used as the polymerization initiator (C), it is preferable to further use a decoupling agent together with the monomer (A). As used herein, the term "coordinating agent" refers to a compound capable of liberating alkylborane from an alkylborane-amine complex, which allows the liberation of the alkylborane to initiate a polymerization reaction.
[0098]
　As a suitable decoupling agent, for example, any acid or a monomer having an acidic group (a monomer having an acidic group used as the above-mentioned monomer (A)) can be used. Suitable acids include Lewis acids (eg SnCl 4 , TiCl 4 ), Bronsted acids (eg, carboxylic acids, HCl, H 2 SO 4 , H 3 PO 4 , phosphonic acid, phosphinic acid, silicic acid). Be done. Suitable carboxylic acids include those represented by the general formula R-COOH, in which R is a hydrogen atom and an alkyl group having 1 to 8 carbon atoms (preferably an alkyl group having 1 to 4 carbon atoms). , An alkenyl group having 2 to 8 carbon atoms (preferably an alkenyl group having 2 to 4 carbon atoms), an alkynyl group having 2 to 8 carbon atoms (preferably an alkynyl group having 2 to 4 carbon atoms), or an alkynyl group having 6 to 10 carbon atoms. It shows an aryl group (preferably an aryl group having 6 to 8 carbon atoms). The alkyl group, alkenyl group, and alkynyl group in R may be linear or branched. The aliphatic group in R may be saturated or unsaturated. The aryl group in R may be substituted with a substituent such as an alkyl group, an alkoxy group or a halogen atom, or may be unsubstituted. Examples of the acid exemplifying the carboxylic acid represented by the above general formula include acrylic acid, methacrylic acid, acetic acid, benzoic acid and p-methoxybenzoic acid. Specific examples of the monomer having an acidic group are as described in the section of the above-mentioned monomer (A), and among them, 4-metaacryloxyethyltrimellitic acid and its anhydride are preferable.
[0099]
　Among these organic boron compounds (c1), tributylboron or partially oxidized tributylboron is preferable, and partially oxidized tributylboron is more preferable. When tributylboron and partially oxidized tributylboron are used as the organoboron compound (c1), not only the operability is improved, but also the reactivity tends to be appropriate for a living body having water. Further, when tributylboron or partially oxidized tributylboron is used as the organoboron compound (c1), the reaction starts even in a place having a large amount of water such as a living body, and the reaction proceeds. Therefore, the interface between the composition and the living body. In this case, the monomer is unlikely to remain, and therefore, it is extremely harmless to the living body. These organoboron compounds (c1) can be used alone or in combination of two or more.
[0100]
　The organoboron compound (c1) may further contain an aprotic solvent. When the organoboron compound (c1) is diluted with an aprotic solvent, the exothermic property of the ignitable organoboron compound (c1) becomes milder, the ignitability is suppressed, and the mixture is mixed during transportation, storage, and storage. It becomes easier to handle the time. Further, since sudden heat generation can be suppressed, even when an extremely large amount of the hard tissue repair composition is used, the damage to the tissue in contact with the hard tissue repair composition tends to be reduced. The boiling point of the aprotic solvent at 1 atm is usually 30 ° C. to 150 ° C., preferably 50 ° C. to 120 ° C. Setting the boiling point of the aprotic solvent to such a specific temperature or higher suppresses the volatilization or scattering of the aprotic solvent from the polymerization initiator during transportation or storage, and generates heat of the organoboron compound (c1). It is preferable in that it sufficiently suppresses property and flammability. Further, lowering the boiling point of the aprotic solvent to such a specific temperature or lower reduces the residual amount of the aprotic solvent in the cured product obtained from the hard tissue repair composition, and reduces the residual amount of the aprotic solvent with respect to the affected part of the cured product. It is preferable in terms of improving various properties such as adhesive strength, flexural modulus, tensile strength, compressive strength, and flexural strength.
[0101]
　As the aprotic solvent, a solvent that does not have a group containing active hydrogen such as a hydroxy group or a mercapto group that reacts with the organoboron compound (c1) and can form a uniform solution with the organoboron compound (c1) can be used. preferable.
[0102]
　Examples of the aproton solvent include hydrocarbons such as pentane, hexane, cyclohexane, heptane, benzene and toluene; halogenated hydrocarbons such as fluorobenzene, 1,1-dichloroethane and 1,2-dichloroethane, so-called freon; diethyl. Ethers such as ether, diisopropyl ether, ethylene glycol dimethyl ether and tetrahydrofuran; ketones such as acetone, methyl ethyl ketone and diethyl ketone; esters such as methyl acetate, ethyl acetate and isopropyl acetate can be mentioned. Among these, saturated aliphatic hydrocarbons such as pentane, hexane and heptane, ethers and esters are preferable, and hexane, diisopropyl ether and ethyl acetate are more preferable. These aprotic solvents can be used alone or in combination of two or more.
[0103]
　The content of the aprotic solvent is preferably 30 to 80 parts by mass with respect to 100 parts by mass of the organic boron compound (c1). Setting the content of the aprotic solvent to such a specific temperature or higher sufficiently dilutes the organoboron compound (c1) and sufficiently suppresses the exothermic and ignitability of the organoboron compound (c1). preferable. Further, it is preferable to set the content of the aprotic solvent to such a specific temperature or lower from the viewpoint of suppressing a decrease in the polymerization initiation ability of the organoboron compound (c1).
[0104]
　The organoboron compound (c1) may contain alcohol in addition to or in place of the aprotic solvent. By adding alcohol to the organoboron compound (c1), the reaction by the organoboron compound (c1) becomes more gentle without lowering the polymerization activity, and even if it touches a member such as paper in the air, it burns or ignites. It tends to be easier to suppress.
[0105]
　The boiling point of alcohol at 1 atm is usually 60 ° C. to 180 ° C., preferably 60 ° C. to 120 ° C. Raising the boiling point of the alcohol above such a specific temperature suppresses the volatilization or scattering of the aprotic solvent from the polymerization initiator during transportation or storage, and causes the organoboron compound (c1) to generate heat and ignite. It is preferable in that the sex is sufficiently suppressed. Further, lowering the boiling point of the alcohol to such a specific temperature or lower reduces the residual amount of the aprotic solvent in the cured product obtained from the hard tissue repair composition, and the adhesive strength of the cured product to the affected area. It is preferable in terms of improving various characteristics such as flexural modulus, tensile strength, compressive strength, and flexural strength.
[0106]
　Examples of alcohols include methanol, ethanol, n-propanol and its isomers, n-butanol and its isomers, n-pentanol and its isomers, n-hexanol and its isomers, n-heptanol and its isomers. Can be mentioned. Among them, alcohols having 4 or less carbon atoms, that is, methanol, ethanol, n-propanol and isomers thereof, and n-butanol and isomers thereof are preferable, and ethanol and n-propanol are more preferable. These alcohols can be used alone or in combination of two or more.
[0107]
　The alcohol content is usually 0.01 to 40 parts by mass, preferably 0.1 to 30 parts by mass, and more preferably 0.5 to 20 parts by mass with respect to 100 parts by mass of the organoboron compound (c1).
[0108]
　When the alcohol and the aprotic solvent are used in combination, the content of the aprotic solvent is preferably 5 to 40 parts by mass, preferably 10 to 30 parts by mass with respect to 100 parts by mass of the organic boron compound (c1). It is by mass, more preferably 10 to 25 parts by mass.
[0109]
　The blending amount of the polymerization initiator (C) is preferably 0.1 to 10 parts by mass, based on 100 parts by mass of the total of the monomer (A), the polymer powder (B), and the polymerization initiator (C). It is preferably 1.0 to 7.0 parts by mass, and more preferably 2.1 to 4.3 parts by mass. When the blending amount of the polymerization initiator (C) is contained in a certain amount or more, the component of the unpolymerized monomer (A) remains in the composition due to the development of the desired polymerization initiating ability of the polymerization initiator. And / or because it is possible to reduce elution from the composition, it is preferable from the viewpoint that safety to the living tissue can be easily ensured. Further, when the content is less than a certain content, it is preferable because it is possible to suppress rapid polymerization progress and / or heat generation and prevent rapid formation of a cured polymerization product. Further, when the polymerization initiator (C) is a liquid, it is preferable from the viewpoint that deterioration of operability due to an excessive decrease in viscosity can be suppressed.
[0110]
　[Contrast Agent (X)]
　The composition for repairing hard tissue of the present invention may contain a contrast agent (X). The volume average particle size of the contrast medium (X) is preferably 0.15 to 25.1 μm, more preferably 0.45 to 18.0 μm. The fact that the volume average particle size of the contrast agent (X) is within a certain range means that the contrast agent (Z) and / or the entire powder particles (total 100 cumulative% of the polymer powder (B) and other powder particles). It is preferable from the viewpoint that the cohesiveness of the hard tissue repair composition can be maintained appropriately and the desired operability of the hard tissue repair composition can be easily expressed. ..
[0111]
　The type of the contrast agent (X) is not particularly limited, and examples thereof include barium sulfate, zirconia oxide, bismuth carbonate, calcium tungstate, itribium, and an iodine compound. Among them, barium sulfate and zirconia oxide are preferable because they have a track record of being used for hard tissues, especially as bone cement.
[0112]
　The amount of the contrast agent (X) to be blended is preferably 0 to 70 parts by mass, more preferably 0. It is 01 to 70 parts by mass, more preferably 0.01 to 45 parts by mass, more preferably 2.5 to 33.8 parts by mass, and more preferably 4.5 to 22.5 parts by mass.
[0113]
　[Antibacterial Agent Particles (Y)]
　The composition for repairing hard tissue of the present invention may contain antibacterial agent particles (Y). Specific examples of antibacterial agents include antibiotics, elemental iodine, solid polyvinylpyrrolidone iodine, polyvinylpyrrolidone iodine; tribromophenol, trichlorophenol, tetrachlorophenol, nitrophenol, 3-methyl-4-chloro-phenol, 3,5. -Dimethyl-4-chlorophenol, phenoxyethanol, dichlorophenol, o-phenylphenol, m-phenylphenol, p-phenylphenol, 2-benzyl-4-chlorophenol, 2,4-dichloro-3,5-dimethylphenol, 4-Chlorotimol, chlorphene, triclosan, fentichlor, phenol, 2-methylphenol, 3-methylphenol, 4-methylphenol, 4-ethylphenol, 2,4-dimethylphenol, 2,5-dimethylphenol, 3 , 4-dimethylphenol, 2,6-dimethylphenol, 4-n-propylphenol, 4-n-butylphenol, 4-n-amylphenol, 4-tert-amylphenol, 4-n-hexylphenol, 4-n -Heptylphenols, monoalkylhalophenols, polyalkylhalophenols, aromatic halophenols, and phenolic compounds such as ammonium salts, alkali metal salts and alkaline earth metal salts thereof; silver nitrate, hexachlorophene, melbromin and the like. Of these, antibiotics are preferred.
[0114]
　Antibiotics are substances produced by microorganisms or chemically synthesized substances that inhibit the growth of other microorganisms. In addition, this definition of antibiotic also includes chemically converted substances produced by microorganisms or chemically synthesized.
[0115]
　Specific examples of antibiotics include gentamicin, gentamicin sulfate, tobramycin, tobramycin sulfate, amikacin, amikacin sulfate, dibekacin, dibekacin sulfate, vancomycin, vancomycin hydrochloride, daptomycin, albekacin, arbekacin sulfate, phosphomycin, cefazoline, Examples include cefazoline sodium salt, minocycline, clindamicin, colistin, linezolide, tetracycline hydrochloride, tetracycline hydrate, oxytetracycline and erythromycin. Among them, it is preferable to contain one or more antibiotics selected from the group consisting of gentamicin, tobramycin, amikacin, dibekacin, vancomycin, daptomycin, and pharmacologically acceptable salts thereof.
[0116]
　When daptomycin and a pharmacologically acceptable salt of daptomycin are used as antibacterial agent particles (Y), it is further desirable to use them together with a filler having a sustained release of calcium, among the inorganic fillers described below. The daptomycin derivative bound to the calcium element or ion invades and binds to the cell membrane of the bacterium, which promotes depolarization in the cell membrane and causes the bacterium to die by losing the membrane potential, thereby improving the antibacterial property. Tend to do. These calcium sustained release fillers can be used alone or in combination of two or more.
[0117]
　The volume average particle size of the antibacterial agent particles (Y) is preferably less than 250 μm, more preferably 1.0 to 200 μm, and more preferably 2.5 to 150 μm.
[0118]
　The blending amount of the antibacterial agent particles (Y) may be appropriately determined according to the type thereof, but is preferable with respect to a total of 100 parts by mass of the monomer (A), the polymer powder (B) and the polymerization initiator (C). Is 30 parts by mass or less, more preferably 0.01 to 30 parts by mass, more preferably 1.0 to 30 parts by mass, more preferably 1.2 to 25 parts by mass, and more preferably 1.4 to 20 parts by mass. be.
[0119]
　[Polysaccharide (Z)]
　The composition for repairing hard tissue of the present invention may contain a polysaccharide (Z). Specific examples of the polysaccharide (Z) include sucrose, lactose, maltose, trehalose, tullanose, cellobiose, raffinose, meregitos, maltotriose, acarbose, stachyose, starch, glycogen, cellulose, carboxymethyl cellulose, dextrin, glucan, and xyloglucan. , Fructan, chitin, chitosan, agarose, carrageenan, hyaluronic acid, pectin, glucomannan, chondroitin sulfate, alginic acid, pullulan and derivatives derived from them and / or pharmacologically acceptable salts. These polysaccharides can be used alone or in combination of two or more. In particular, when used in combination with the antibacterial agent particles (Y) described above and / or a filler having a sustained release of calcium described below, the antibacterial activity tends to be improved and / or the harmfulness to the living body tends to be reduced.
[0120]
　The blending amount of the polysaccharide (Z) may be appropriately determined according to the type thereof, but is preferably based on 100 parts by mass of the total of the monomer (A), the polymer powder (B) and the polymerization initiator (C). It is 40 parts by mass or less, more preferably 0.1 to 30 parts by mass or less.
[0121]
　[Other Ingredients]
　The composition for repairing hard tissue of the present invention may contain a polymerization inhibitor, if necessary. Examples of the polymerization inhibitor include hydroquinone compounds such as hydroquinone and dibutylhydroquinone, phenols such as hydroquinone monomethyl ether, 2,6-di-tert-butylphenol, and 2,6-di-tert-butyl-p-cresol, and catechol. , Pyrogalol, benzoquinone, 2-hydroxybenzoquinone, p-methoxyphenol, t-butylcatechol, butylated hydroxyanisole, butylated hydroxytoluene and t-butylhydroquinone. Of these, a mixture of hydroquinone monomethyl ether and 2,6-di-tert-butyl-p-cresol is preferable. In addition, hydroquinone monomethyl ether may be preferable from the viewpoint of stability of itself. The polymerization inhibitor can be used alone or in combination of two or more.
[0122]
　The amount of the polymerization inhibitor added is preferably 1 to 1500 ppm, more preferably 5 to 1000 ppm, and more preferably 5 to 500 ppm with respect to the total amount of the hard tissue repair composition. The amount of the polymerization inhibitor added is 10 to 5000 ppm, more preferably 25 to 1000 ppm, and more preferably 25 to 500 ppm with respect to the monomer (A).
[0123]
　The composition for repairing hard tissue of the present invention may contain an ultraviolet absorber, if necessary. Specific examples of the ultraviolet absorber include 2- (2'-hydroxy-5'-methylphenyl) benzotriazole, 2- (3', 5'-di-tert-butyl-2'-hydroxyphenyl) benzotriazole, and the like. 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-chlorobenzotriazole, 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- (3', 5'-di-tert-amyl-2'-hydroxyphenyl) benzotriazole, 2- (3', 5'-bis (α, α-dimethylbenzyl) -2'-hydroxyphenyl) benzotriazole, 2- (3'-tert-butyl-2'-hydroxy-5'-(2-octyloxycarbonylethyl) phenyl) -5-chlorobenzotriazole, 2- (3'-tert-butyl-5'-[2 -(2-Ethylhexyloxy) carbonylethyl] -2'-hydroxyphenyl) -5-chlorobenzotriazole, 2- (3'-tert-butyl-2'-hydroxy-5'-(2-methoxycarbonylethyl) phenyl )-5-Chlorobenzotriazole, 2- (3' 2 CH 2 -COOCH 2 ] 3 ] 2 - (wherein, R = 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-decyloxybenzophenone, 2-Hydroxy-4-dodecyloxybenzophenone, 2-Hydroxy-4- Benzophenone compounds such as benzyloxybenzophenone, 2,2', 4,4'-tetrahydroxybenzophenone and 2,2'-dihydroxy-4,4'-dimethoxybenzophenone;
　4-tert-butylphenyl salicylate, phenyl salicylate, octyl salicylate Phenyl, dibenzoylresorcinol, bis (4-tert-butylbenzoyl) resorcinol, benzoylresorcinol, 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, and 2-methyl-4,6-di-tert-butylphenyl benzoate, and benzoate Acid 3,5-di-tert-butyl-4-hydroxybenzoate;
　Bis sevacinate (2,2,6,6-tetramethylpiperidyl), bis succinate (2,2,6,6-tetramethylpiperidyl), bis sevacinate (1,2,2,6,6-pentamethyl) Piperidine), bis (1,2,2,6,6-pentamethylpiperidyl) n-butyl-3,5-di-3-tri-butyl-4-hydroxybenzylmalonate, 1-hydroxyethyl-2,2, Condensation product of 6,6-tetramethyl-4-hydroxypiperidine and succinic acid, N, N'-bis- (2,2,6,6-tetramethyl-4-piperidyl) hexamethylenediamine and 4-th. Condensation product with 3-octylamino-2,6-dichloro-1,3,5-s-triazine, tris- (2,2,6,6-tetramethyl-4-piperidyl) nitrilotriacetate, tetrakis- (2,2,6,6-tetramethyl-4-piperidyl) 2,2,6,6-Tetramethyl-4-piperidyl) -1,2,3,4-butanetetraoate, 1,1'-(1,2-ethanediyl) bis (3,3,5,5) -Tetramethylpiperazinone), 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-3-butylbenzyl) malonate, 3-n-octyl-7,7,9,9- Tetramethyl-1,3,8-triazaspiro [4.5] decane-2,4-dione, bis sebacate (1-octyloxy-2,2,6,6-tetramethylpiperidyl), bis succinate (1) -Octyloxy-2,2,6,6-tetramethylpiperidyl), N, N'-bis- (2,2,6,6-tetramethyl-4-piperidyl) hexamethylenediamine and 4-morpholino-2, Condensation product with 6-dichloro-1,3,5-triazine, 2-chloro-4,6-di- (4-n-butylamino-2,2,6,6-tetramethylpiperidyl) -1, 3,5-triadidine and 1,Condensation product with 2-bis (3-aminopropylamino) ethane, 2-chloro-4,6-di- (4-n-butylamino-1,2,2,6,6-pentamethylpiperidyl)- Condensation product of 1,3,5-triazine and 1,2-bis (3-aminopropylamino) ethane, 8-acetyl-3-dodecyl-7,7,9,9-tetramethyl-1,3, 8-Triazospiro [4.5] decane-2,4-dione, and 3-dodecyl-1- (2,2,6,6-tetramethyl-4-piperidyl) pyrrolidine-2,5-dione, and 3- Hindered amine compounds such as dodecyl-1- (1,2,2,6,6-pentamethyl-4-piperidyl) pyrrolidine-2,5-dione;
　4,4'-Dioctyloxyoxanilide, 2,2'-diethoxyoxanilide, 2,2'-dioctyloxy-5,5'-di-tert-butyloxanilide, 2,2'-di Dodecyloxy-5,5'-di-tert-butyloxanilide, 2-ethoxy-2'-ethyloxanilide, N, N'-bis (3-dimethylaminopropyl) oxalamide, 2-ethoxy-5- A mixture of tert-butyl-2'-ethyloxanilide and 2-ethoxy-2'-ethyl-5,4'-di-tert-butyloxanilide, o- and p-methoxy-, and o-. And oxalamide compounds such as a mixture of p-ethoxy-disubstituted oxanilide;
　2,4,6-tris (2-hydroxy-4-octyloxyphenyl) -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-propyloxyphenyl) -6- (2,4-dimethylphenyl) -1,3,5-triazine, 2- (2-hydroxy-4-octyloxyphenyl) -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-hydroxy-3-butyloxypropyloxy) phenyl] -4,6-bis (2,4-dimethylphenyl) -1,3,5-triazine, 2- [2-Hydroxy-4- (2-hydroxy-3-octyloxypropyloxy) phenyl] -4,6-bis (2,4-dimethylphenyl) -1,3,5-triazine, and 2- [4- Dodecyl / tridecyloxy- (2-hydroxypropyl) oxy-2-hydroxyphenyl] -4,6-bis (2,4-dimethylphenyl) -1,3,5-triazine and other 2- (2-hydroxyphenyl) ) -1,3,5-triazine compound;
　For example, triphenylphosfit, diphenylalkylphosfit, phenyldialkylphosfit, tris (nonylphenylphosfit), trilaurylphosfit, trioctadecylphosfit, distearylpentaerythrityl diphosfit, tris- (2,4) -Di-tri-butylphenyl) phosfit, diisodecylpentaerythrityl diphosfit, bis- (2,4-di-3-butylphenyl) pentaerythrityl diphosfit, bis- (2,6-di) -Tri-butyl-4-methylphenyl) pentaerythrityl diphosfit, bis-isodecyloxypentaerythrityl diphosfit, bis- (2,4-di-3-butyl-6-methylphenyl) penta Ellis lithyl diphosfit, bis (2,4,6-tri-3-butylphenyl) pentaerythrityl diphosfit, tristearyl sorbitil diphosfit, tetrakis (2,4-di-3-butylphenyl) 4,4'-Biphenylenediphosphonite, 6-isooctyloxy-2,4,8,10-tetra-tertiary butyl-12H-dibenzo [d, g] -1,3,2-dioxaphosphocin, 6-Fluoro-2,4,8,10-Tetra-3-thi-butyl-12-methyldibenzo [d, g] -1,3,2-dioxaphosphocin, bis- (2,4-di-th) Examples thereof include phosfit compounds such as 3-butyl-6-methylphenyl) methylphosfit and bis (2,4-di-3-butyl-6-methylphenyl) ethylphosfit, or phosphonite compounds. Of these, benzotriazole compounds are preferred.
[0124]
　The amount of the ultraviolet absorber added is preferably 1000 ppm or less, more preferably 800 ppm or less, and more preferably 500 ppm or less with respect to the monomer (A). By adding the ultraviolet absorber in this way, the coloring of the liquid containing the monomer is suppressed, and the storage stability of the monomer itself tends to be improved.
[0125]
　Examples of other components further include softeners and plasticizers.
[0126]
　Examples of the softener include rubbers such as natural rubber and synthetic rubber, and elastomers such as thermoplastic elastomers. Such a soft agent can increase the flexibility of the hard tissue repair composition. Examples of the synthetic rubber include EPT (ethylene propylene terpolymer). Examples of the thermoplastic elastomer include styrene-based elastomers, vinyl chloride-based elastomers, olefin-based elastomers, polyester-based elastomers, polyamide-based elastomers, and urethane-based elastomers. The molecular weight of the elastomer is usually 10 to 1,000,000, preferably 2000 to 500,000. The glass transition point (Tg) of the elastomer is usually 20 ° C. or lower, preferably 0 ° C. or lower.
[0127]
　Examples of the plasticizer include hydroxycarboxylic acid esters such as citric acid ester, isocitrate ester, tartrate acid ester, malic acid ester, lactic acid ester, glycerate ester and glycolic acid ester; trimethyl trimeritoate, diethylene glycol dibenzoate and malonic acid. Examples thereof include diethyl, triethyl o-acetylcitrate, benzylbutyl phthalate, dipropylene glycol dibenzoate, diethyl adipate, tributyl o-acetylcitrate, dimethyl sebacate, and alkylene glycol diester.
[0128]
　The amount of the softener and the plasticizer added is appropriately selected depending on the type of material, but is usually 0 to 30% by mass, preferably 0 to 20% by mass, more preferably 0 to 20% by mass in the entire hard tissue repair composition. Is 0 to 10% by mass.
[0129]
　Examples of other components further include preservatives. Specific examples of preservatives include methylparaben, methylparaben sodium, ethylparaben, propylparaben, propylparaben sodium, butylparaben; cresol, chlorocresol; resorcinol, 4-n-hexylresorsinol, 3a, 4,7,7a-tetrahydro-. 2-((Trichloromethyl) thio) -1H-isoindole-1,3 (2H) -dione; benzzarkonium chloride, sodium benzalkonium chloride, benzethonium chloride; benzoic acid, benzyl alcohol, cetylpyridinium chloride, chloro Butanol, dehydroacetic acid, o-phenylphenol, phenol, phenylethyl alcohol, potassium benzoate, potassium sorbate, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, timol, phenylmercury borate and phenylnitrate Examples thereof include phenyl mercury compounds such as mercury and phenyl mercury acetate, and formaldehyde.
[0130]
　Examples of other ingredients include analgesics, analgesic formulations, appetite suppressants, antipsychotics, antiarthritis, antiasthmatics, anticonvulsants, antidepressants, antidiuretics, antidiarrhea, antihistamines. Drugs, anti-inflammatory drugs, anti-bias headache drugs, anti-vomiting drugs, anti-neoplastic drugs, anti-Parkinson's disease drugs, antipruritic drugs, antipsychotic drugs, antipyretics, antispasmodics, anticholinergic drugs, sympathomimetics, heart Vascular drugs, anti-arrhythmic drugs, antihypertensive drugs, diuretics, vasodilators, immunosuppressants, muscle relaxants, parasympathetic blockers, stimulants, analgesics, tranquilizers, cholinergic agents, chemotherapeutic agents, Radiopharmaceuticals, bone-inducing drugs, bladder-quiescent heparin neutralizers, blood clots, hemostatic agents, xanthine derivatives, hormones, naturally occurring or genetically synthesized proteins, glycoproteins, lipoproteins, oligonucleotides, antibodies, Antigens, vasopressin, vasopressin analogs, epinephrine, selectins, blood clot-promoting toxins, plasminogen activator inhibitors, platelet activators, osteogenic factors, bone growth factors, synthetic peptides with analgesic properties, and other pharmaceutical or other pharmaceutical or Therapeutic ingredients are mentioned. By including these components, the composition for repairing hard tissue of the present invention can also be used for drug delivery systems and regenerative medicine applications.
[0131]
　The hard tissue repair composition may further contain bone forming factors, bone growth factors, and other pharmaceutical or therapeutic ingredients, for example, for the purpose of promoting tissue repair.
[0132]
　Examples of other ingredients include range oil, grapefruit oil, lemon oil, lime oil, clove oil, winter green oil, peppermint oil, peppermint spirit, banana distillate, cucumber distillate, honey distillate, rose. Examples include fragrances such as water, menthol, anetol, alkyl salicylate, benzaldehyde, monosodium glutamate, ethyl vanillin, timol, and vanillin.
[0133]
　Examples of other components include, for example, clarification of visual distinction from surrounding bone tissue, improvement of adhesion, enhancement of properties such as compressive strength, and harmfulness to surrounding bone tissue by supplementing active radical species. Inorganic fillers (excluding the above-mentioned X-ray contrast medium), organic fillers, organic composite fillers, and colorants may be further contained for the purpose of reducing the amount of the above-mentioned.
[0134]
　Examples of the inorganic filler include metal oxide powders such as bismuth oxide, titanium oxide, zinc oxide, and aluminum oxide particles; metal salt powders such as zirconium phosphate; silica glass, aluminum-containing glass, barium-containing glass, and strontium. Examples include glass fillers such as contained glass and zirconium silicate glass; fillers having a sustained release of silver, fillers having a sustained release of calcium: and fillers having a sustained release of fluorine. From the viewpoint of forming a strong bond between the cured inorganic filler and the monomer (A), it is preferable to use an inorganic filler that has been subjected to surface treatment such as silane treatment or polymer coating. These inorganic fillers can be used alone or in combination of two or more.
[0135]
　Examples of the filler having sustained calcium release include calcium dihydrogen phosphate, calcium dihydrogen phosphate monohydrate, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tricalcium phosphate, and octacalcium phosphate. Calcium, Hydroacid Apatite, Fluorine Apatite, Chlorine Apatite, Carbonated Hydrous Acid Apatite, Calcium Gluconate, Calcium Glucronate, Calcium Lactate, Calcium Acetate, Calcium Sorbate, Calcium Sulfate Dihydrate, Calcium Sulfate Hemihydrate, α -Tricalcium phosphate, β-tricalcium phosphate can be mentioned. These fillers having sustained release of calcium can be used alone or in combination of two or more, and the above-mentioned pharmacologically acceptable salts of daptomycin and daptomycin are used as antibacterial agent particles (Y), and these sustained-release calcium salts. When used with a filler having calcium, it tends to improve antibacterial properties. Further, when used in combination with the above-mentioned antibacterial agent particles (Y) and / or the above-mentioned polysaccharide (Z), the antibacterial property tends to be improved and / or the harmfulness to the living body tends to be reduced.
[0136]
　Rium Lake, Blue 203, Blue 204, Blue 205 and its Aluminum Lake, Brown 201 and its Aluminum Lake, Purple 201, Red 401 and its Aluminum Lake, Red 404, Red 405, Red 501, Red No. 502 and its aluminum lake, Red No. 503 and its aluminum lake, Red No. 504 and its aluminum lake, Red No. 505, Red No. 506 and its aluminum lake, Yellow color 401, Yellow color 402 and its aluminum lake, Or barium lake, orange 403, yellow 401, yellow 402 and its aluminum lake, yellow 403 (1) and its aluminum lake, yellow 404, yellow 405, yellow 406 and its aluminum lake, yellow 407 and its aluminum lake, green 401, green 402 and its aluminum lake, or barium lake, blue 403, blue 404, purple 401 and its aluminum lake, black 401 and its aluminum lake, chlorophyll, chlorophyllin , Malakite green, crystal violet, brilliant green, cobalt phthalocyanine, carotene, vitamin B12 and derivatives derived from these. These colorants can be used alone or in combination of two or more.
[0137]
　The amount of the colorant added is appropriately selected depending on the type, but usually, the total amount of the composition for repairing hard tissue is 100% by mass, that is, the monomer (A), the polymer powder (B), the polymerization initiator (C), and the like. And, usually 0 to 5% by mass, preferably 0 to 2% by mass, more preferably 0 to 2% by mass, based on 100% by mass of the total of the polymerization agent (X) and / or the antibacterial agent particles (Y) and other components contained as necessary. Is 0 to 1% by mass.
[0138]
　[Hard Tissue Repair Composition]
　The hard tissue repair composition of the present invention is obtained by mixing a monomer (A), a polymer powder (B), a polymerization initiator (C), and other components contained as necessary. Prepared. The composition can be used by applying it to the affected area. In the present invention, the "hard tissue repair composition" refers to adhesion between hard tissues, filling into hard tissues, adhesion between hard tissues and artificial materials such as titanium, ceramics, and stainless steel, hard tissues and soft tissues, and the like. It is used for adhesion to other tissues and does not include adhesion between teeth and fillings (ie, for dental use).
[0139]
　When each of these components is mixed, the order in which they are mixed is not limited, but the monomer (A) and the polymerization initiator (C) are first selected from the viewpoint of better stability of the obtained hard tissue repair composition. It is preferable to mix the polymer powder (B) containing the contrast agent (X) and the antibacterial agent particles (Y), preferably the monomer (A), the polymerization initiator (C), and the contrast agent. It is more preferable to simultaneously mix the polymer powder (B) containing (X) and the antibacterial agent particles (Y).
[0140]
　When the composition for repairing a hard structure of the present invention contains a polymerization inhibitor, first, a mixture of the monomer (A) and the polymerization inhibitor, and the polymerization initiator (C) are obtained from the viewpoint that the stability of the obtained composition is more excellent. ), And then the polymer powder (B) containing the contrast agent (X) and the antibacterial agent particles (Y), preferably a mixture of the monomer (A) and the polymerization inhibitor, and a polymerization initiator. It is more preferable to simultaneously mix (C) and the polymer powder (B) containing the contrast agent (X) and the antibacterial agent particles (Y).
[0141]
　Before curing the hard tissue repair composition of the present invention, it may be sterilized by treatment with a gas such as dry heat, steam, ethylene oxide (EO), hydrogen peroxide, filtration, liquid or the like. Further, the surface of the affected area may be disinfected with a disinfectant solution such as alcohol in advance before the hard tissue repair composition is filled in the affected area. Further, before filling the affected portion with the composition for repairing hard tissue, pretreatment may be performed for the purpose of improving the adhesion with the affected portion, for example. Examples of the pretreatment liquid include physiological saline.
[0142]
　[Hard Tissue Repair Kit] When
　the hard tissue repair composition of the present invention changes in form and performance over a long period of time and may impair the effects of the present invention, the monomer (A) and the polymer powder (B) A hard tissue repair kit in which all the components used for hard tissue repair, which consist of the polymerization initiator (C) and other components contained as necessary, are divided alone or in any combination and stored in three or more members. It can be stored as a hard tissue repair composition and mixed before use. Examples of the storage member include a sealable resin container having a gas barrier property and a glass ampoule in order to prevent the monomer (A) and the polymerization initiator (C) from volatilizing and scattering. As a member for storing the polymer powder (B), a well-sealed resin and a glass container for preventing moisture absorption, or a resin for sterilization with a gas such as ethylene oxide (EO) or hydrogen peroxide. Examples include non-woven fabric and sterile paper.
[0143]
　Examples of the method for preserving the above components include a mixture of the monomer (A) and other components contained as necessary, a polymer powder (B) containing a contrast agent (X) and antibacterial agent particles (Y), and the like. It is preferable to divide and store the mixture of other components contained as necessary, the polymerization initiator (C), and the mixture of other components contained as necessary. Other than that, for example, a mixture of monomer (A) and other components contained as required, polymer powder (B) and a mixture of other components contained as required, contrast agent (X) and other necessary components. Divided into five parts: a mixture of components contained accordingly, a mixture of antibacterial drug particles (Y) and other components contained as required, a polymerization initiator (C) and a mixture of other components contained as required. Preservation method, monomer (A), contrast agent (X), antibacterial agent particles (Y) and other optionally contained mixture, polymer powder (B) and other optionally contained mixture It is also possible to divide and store the mixture of the polymerization initiator (C) and other components contained as necessary in three parts.
[0144]
　These divided components can be put into separate members, for example, a container such as an ampoule, and contained in a hard tissue repair kit to be provided as a product.
[0145]
　The composition of the hard tissue repair kit is not particularly limited as long as the morphology and performance change due to storage and there is no risk of impairing the effect of the present invention. The polymer powder (B) containing Y), a mixture of other components contained as necessary, and the polymerization initiator (C) are separately stored, and the monomer (A) and the polymerization initiator (A) are first stored. It has a structure in which C) is mixed, and then a polymer powder (B) containing a contrast agent (X) and antibacterial agent particles (Y) and a mixture of other components contained as necessary are mixed. Is preferable, a polymer powder (B) containing a monomer (A), a contrast agent (X), and antibacterial agent particles (Y), a mixture of other components contained as necessary, and a polymerization initiator (C). It is more preferable to have a structure in which the two are mixed at the same time. With such a configuration, it is easy to obtain a composition for repairing a hard tissue having more stable performance.
[0146]
　As the hard tissue repair kit, for example, the monomer (A), the polymer powder (B) containing the contrast agent (X) and the antibacterial agent particles (Y), and the polymerization initiator (C) are separately stored. Members (eg, resin containers, glass ampoules) and members for removing and mixing them from the housed members (eg, orthopedic cement mixers, orthopedic cement injectors, orthopedic cements). Examples include kits with a dispenser, cement gun, mixing vessel, mixing dish, cylinder).
[0147]
　As a hard tissue repair kit, for example, a monomer (A), a polymer powder (B) containing a contrast agent (X) and an antibacterial agent particle (Y), and a polymerization initiator (C) are mixed in one. Monomers (A) and polymerization initiators that are separately housed in chambers separated into three or more by bulkheads or spacers in the container and pre-designed bypasses in the mixing vessel by breaking, moving, or removing spacers from the bulkheads. A stirring unit through which (C) passes, comes into contact with a polymer powder (B) containing a contrast agent (X) and antibacterial agent particles (Y), and can be mixed by operating a pre-installed stirring blade. Examples include kits having.
[0148]
　A kit consisting of one mixing container in which each component is stored in three or more separated chambers divides the composition of the present invention into two or more members, typically each container, and mixes immediately before use. Compared to the method used in be.
[0149]
　In addition, a part or all of the polymerization initiator (C) component is applied in advance to the affected part such as hard tissue such as bone and cartilage, soft tissue, and other artificial materials such as titanium, ceramics, and stainless steel. It is contained in the jig used for the treatment, and immediately before use, it is cured with the monomer (A) or a mixture containing the monomer (A) and the polymerization inhibitor, the polymer powder (B), and other components contained as necessary. The composition for repairing hard tissue of the present invention can be prepared in-situ by contacting the tool and filled in the affected area as it is.
[0150]
　Examples of the jig for filling the affected area include an orthopedic cement mixer, an orthopedic cement injector, an orthopedic cement dispenser, and a cement gun.
[0151]
　The hard tissue repair kit may include, for example, the above-mentioned disinfectant solution such as alcohol or a solution for pretreatment for the purpose of improving adhesion.
[0152]
　When each component is stored in a hard tissue repair kit, it may be sterilized by electromagnetic waves such as visible light, preferably under the condition that each component does not deteriorate (for example, the monomer does not cure).
Example
[0153]
　Hereinafter, the present invention will be described in more detail based on Examples, but the present invention is not limited to these Examples.
[0154]
　(1) Aspect ratio value (Ap value) and cumulative ratio (%) For the
　Ap value and cumulative ratio (%), 2-propanol (manufactured by Daishin Chemical Co., Ltd.) is used as the dispersion solvent, and an ultrasonic bath with an output of 500 W is used. PITA-3 (manufactured by Seishin Enterprise Co., Ltd., particle size / shape distribution measurement) under the conditions of a sample liquid flow rate of 0.42 μL / sec, a carrier liquid flow rate of 416.67 μL / sec, and an observation magnification (lens magnification) of 10 times. It was measured by the dynamic image analysis method (wet) method using a device). The number of observed particles was about 10,000 per measurement. The Ap value was calculated by the following formula based on the projected image obtained by this dynamic image analysis method (wet).
　Ap value = L / W
　　L: major diameter (maximum length) (μm)
　　W: minor diameter (maximum length vertical length) (μm)
[0155]
The cumulative ratio of powder particles with an Ap value of 1.00 or more and less than 1.10 is shown by plotting the distribution of the Ap value of the powder particles obtained by measurement as the cumulative distribution (the entire distribution of the Ap value of the powder particles is 100 cumulative%). ), It was obtained by calculating the distribution ratio corresponding to the range where the Ap value is 1.00 or more and less than 1.10.
[0156]
　(2) Volume average particle size D50 The volume average particle size D50 of the
　polymer powder is a reagent special grade methanol (solvent refractive index 1.33) (manufactured by Wako Pure Chemical Industries, Ltd.) or 0.2 mass% hexametaphosphate as a dispersion solvent. Using an aqueous sodium solution (solvent refractive index 1.33) (manufactured by Wako Pure Chemical Industries, Ltd.), disperse it for 5 minutes (output 25 W) with an ultrasonic homogenizer built into the device, and under the concentration conditions within the appropriate amount range of the device Loading Index. The measurement was performed using a Microtrac MT3300EXII (microparticle distribution meter manufactured by Microtrac) at a circulation rate of 50% (at 100%, 65 mL / sec).
[0157]
　The value of the volume average particle size D50 of the polymer powder (B) used in Examples and Comparative Examples is a value of 50% of the cumulative volume average particle size of the entire polymer powder (B), and the value of the polymer powder (B-). The value of the volume average particle diameter D50 of x) is a value of 50% of the cumulative volume average particle diameter of the entire polymer powder (Bx), and the value of the volume average particle diameter D50 of the polymer powder (By). Is the cumulative value of 50% of the volume average particle diameter in the entire polymer powder (By).
[0158]
　(3) Amount of Elution Monomer (mg / g) The
　amount of Elution Monomer (mg / g) was measured under the conditions specified in the American standard ASTM F451-16 (Standard Specification for Acrylic Bone Cement) for bone cement. In the elution operation, the prepared composition for repairing hard tissue is quickly separated in the range of 0.8 to 0.9 g, and the contact area with water (eluent) is controlled to be about 0.65 cm 2. I went. The elution temperature was 37 ° C. The elution period was 7 days (168 hours) ± 15 minutes from 3 minutes after the start of preparation of the hard tissue repair composition.
[0159]
　(4) Simulated bone invasion (mm)
　Simulated bone invasion is a sponge simulated bone (manufactured by Human Body Co., Ltd., trade name SAW1522-507, porosity 95%) made of polyurethane foam having communicated air bubbles and physiological saline. (Manufactured by Wako Pure Chemical Industries, Ltd., trade name: 0.01 mol / L phosphate buffered saline) is impregnated, and the composition 5 minutes after it becomes a soft mass and no stringing is placed on the upper surface thereof, and the pressure is 75 kPa. The load was applied for 30 seconds, and the depth (mm) in which the composition penetrated was measured.
[0160]
　(5) Adhesion to
　metal (kPa) Adhesion to metal is such that the composition is placed on the upper surface of the mirror-finished SUS304 within 30 seconds after it becomes a soft mass and the stringing disappears, and the composition is applied at a pressure of 150 kPa for 30 minutes. It was measured as the resistance value required for the cured product, which was loaded and then allowed to stand for 24 ± 3 hours without applying a load, to peel off from the interface with SUS304. The resistance value is a measured value when one end of the cured composition is pushed in a direction parallel to the contact interface with SUS304 (shearing) at a test speed of 5 mm / min.
[0161]
　As the metal plate of SUS304, a mirror-surfaced SUS304 plate (part number 304 # 400 polished cutting plate) manufactured by Hakudo Co., Ltd. is used, and the operation and / evaluation environment is 23 ± 2 ° C. and the relative humidity is 40% RH or more.
[0162]
　(6)
　Fabrication time (minutes' seconds ") Measured under the conditions specified in ISO 5833: 2002 (surgical implant-acrylic resin cement), an international standard for bone cement.
[0163]
　(7) Residual Monomer Amount (%) The
　Residual Monomer Amount (%) was measured according to a predetermined measuring method for JIS T6501: 2012 “Acrylic resin for denture base (residual amount of methyl methacrylate monomer)”. The extraction time of the monomer solution was 3 hours ± 10 minutes.
[0164]
　(8) Resistance value at the time of syringe discharge (N)
　The resistance value at the time of syringe discharge is 100 mm / pusher of Neofeed (registered trademark) syringe (manufactured by Top Co., Ltd., standard 20 mL) filled with a composition for repairing hard tissue. It was measured as the resistance value when pushing at the test speed of minutes. The test was started 2 minutes and 30 seconds after the preparation of the hard tissue repair composition was started. The resistance value is the average value of the two measured values ​​when the displacement (moved distance) of the pusher is about 5 ± 3 mm and about 50 ± 5 mm.
[0165]
　(9) Surface dissipative energy limit value (G IC value) (KJ / m 2 ) The
　surface dissipative energy limit value (G IC value) is the SENB (Single-edge-notch) specified in American standard ASTM D5045-14 for plastic materials. -Measured by the blending method. The plate thickness B of the SENB test piece is 4.0 mm, and the test speed is 10 mm / min.
[0166]
　[Examples 1 to 6 and Comparative Examples 1 to 3] In
　Examples 1, 3, 4, 6 and Comparative Examples 1 and 3, methyl methacrylate was used as the monomer (A) and 85% by mass was used as the polymerization initiator (C). Partially oxidized tributylboron oxide and 15% by mass ethanol mixture (manufactured by Mitsui Chemicals, Inc., product number BC-S1i) (the total of the polymerization initiator (C) is 100% by mass), and barium sulfate (Sakai) as the contrast agent (X). (Manufactured by Chemical Industry Co., Ltd.) was used.
[0167]
　In Examples 2 and 5 and Comparative Example 2, as the monomer (A), 99.5% by mass of methyl methacrylate and 0.5% by mass of the reagent first-class N, N-dimethyl-p-toluidine (Wako Pure Chemical Industries, Ltd.) (Manufactured by), a mixture of (the total of the monomers (A) is 100% by mass), benzoyl peroxide (BPO) as the polymerization initiator (C) (manufactured by Aldrich, trade name Luperox (registered trademark) A75), and a contrasting agent ( Barium sulfate (manufactured by Sakai Chemical Industries, Ltd.) was used as X).
[0168]
　In Example 3 and Comparative Example 3, gentamicin sulfate (manufactured by Wako Pure Chemical Industries, Ltd., titer = 654 μg / mg) was used as the antibacterial agent particles (Y).
[0169]
　In Examples 1 to 6, as the polymer powder (BX), polymethylmethacrylate (aspect ratio = 1.30, weight average molecular weight Mw = 452000, volume average particle size D50 = 18.7 μm) or polymethyl Methacrylate (aspect ratio = 1.72, weight average molecular weight Mw = 457000, volume average particle size D50 = 21.7 μm) was used.
[0170]
　In Examples 1a to 1d, Examples 1h, Examples 2a to 2b, Examples 4a and Comparative Examples 1 to 3, (1) polymethylmethacrylate (aspect ratio = 1.04) as the polymer powder (By). , Weight average molecular weight Mw = 117,000, volume average particle size D50 = 8.2 μm), (2) Polymethylmethacrylate (aspect ratio = 1.04, weight average molecular weight Mw = 147,000, volume average particle size D50 = 40.5 μm) Was used in combination (mass ratio (1): (2) = 38.9: 61.1).
[0171]
　In Examples 1e to 1g, Examples 1i to 1k, Examples 2c to 2e, Examples 3, 4b to 4c and Example 5, the polymer powder (By) is polymethylmethacrylate (aspect ratio =). 1.03, weight average molecular weight Mw = 139000, volume average particle size D50 = 70.5 μm) was used.
[0172]
　In Example 6, as the polymer powder (By), (1) polymethylmethacrylate (aspect ratio = 1.04, weight average molecular weight Mw = 117,000, volume average particle size D50 = 8.2 μm), (2). Polymethylmethacrylate (aspect ratio = 1.04, weight average molecular weight Mw = 147000, volume average particle size D50 = 40.5 μm) was also used (mass ratio (1): (2) = 22.2: 77.8). ..
[0173]
　Then, the polymer powder (B) and the contrast agent (X) are prepared in advance at the blending ratios shown in Tables 1 to 3, Tables 11 to 12, Tables 18 to 19, Table 22, Tables 25 and Table 28, and if necessary, antibacterial. The mixture in which the drug particles (Y) are uniformly dispersed and the compounding ratios shown in Tables 1 to 3, Tables 11 to 12, Tables 18 to 19, Table 22, Table 25 and Table 28 in advance in a 50 mL glass sample tube. The mixed monomer (A) and the polymerization initiator (C) were mixed using a polypropylene container (manufactured by Shofu Co., Ltd., trade name: tray resin mixer) and a spatula made of silicon rubber, and described above. Each characteristic was measured by the method. The mixing time is 60 seconds. The results are shown in Tables 4-10, 13-17, 20-21, 23-24, 26-27 and 29-30.
[0174]
　The compounding ratio shown in parentheses for each component in the table is a ratio (parts by mass) based on a total of 100 parts by mass of the components (A) to (C). The compounding ratio of the components (Bx) and (By) is a ratio (mass%) based on 100% by mass of the polymer powder (B).
[0175]
　The Ap value of the polymer powder (B) in the table is a value of a cumulative 50% of the aspect ratio of the entire polymer powder (B), and the Ap value of the polymer powder (Bx) is the polymer powder (B-). x) The cumulative aspect ratio of the entire polymer powder (By) is 50%, and the Ap value of the polymer powder (By) is the cumulative 50% of the cumulative aspect ratio of the polymer powder (By).
[0176]
　In the column of "cumulative ratio (%) of powder particles having an Ap value of less than 1.10" in the table, the cumulative ratio (%) of the polymer powder (B) is the Ap value of the entire polymer powder (B). It is a value of the cumulative ratio (%) of the powder particles less than 10, and the cumulative ratio (%) of the entire powder particles is contained in the entire mixture of the polymer powder (B) and the contrast agent (X) (that is, contained in the composition). It is a value of the cumulative ratio (%) of powder particles having an Ap value of less than 1.10 in the whole particles).
[0177]
[table 1]

[0178]
[Table 2]

[0179]
[Table 3]

[0180]
[Table 4]

[0181]
[Table 5]

[0182]
[Table 6]

[0183]
[Table 7]

[0184]
[Table 8]

[0185]
[Table 9]

[0186]
[Table 10]

[0187]
[Table 11]

[0188]
[Table 12]

[0189]
[Table 13]

[0190]
[Table 14]

[0191]
[Table 15]

[0192]
[Table 16]

[0193]
[Table 17]

[0194]
　As shown in Tables 4 to 10 and Tables 13 to 17, the hard tissue repair compositions of Examples 1 and 2 were excellent in various properties.
[0195]
　On the other hand, the hard tissue repair compositions of Comparative Examples 1 and 2 do not contain the polymer powder (Bx) having an aspect ratio of 1.10 or more, and the aspect ratio of the entire powder particles is 1.00 or more. Due to the high cumulative ratio of powder particles less than .10, some properties were inferior.
[0196]
　Further, Example 1 in which the organoboron compound (c1) is used as the polymerization initiator (C) has some characteristics as compared with Example 2 in which benzoyl peroxide (BPO) is used as the polymerization initiator (C). It was better. For example, when the component compositions other than the polymerization initiator (C) are substantially the same, Example 1a and Example 2a, and Example 1d and Example 2b are directly compared, the amount of eluted monomers (Tables 4 and 13) and the simulated bone In terms of both permeability (Tables 5 and 14) and adhesion to metals (Tables 6 and 14), Examples 1a and 1d in which the organoboron compound (c1) was used as the polymerization initiator (C) were more suitable. It was excellent.
[0197]
[Table 18]

[0198]
[Table 19]

[0199]
[Table 20]

[0200]
[Table 21]

[0201]
　As shown in Tables 20 to 21, the hard tissue repair compositions of Example 3 were excellent in various properties.
[0202]
　On the other hand, the hard tissue repair composition of Comparative Example 3 does not contain the polymer powder (BX) having an aspect ratio of 1.10 or more, and the aspect ratio of the entire powder particles is 1.00 or more and 1.10. Due to the high cumulative ratio of less than powder particles, some properties were inferior.
[0203]
[Table 22]

[0204]
[Table 23]

[0205]
[Table 24]

[0206]
[Table 25]

[0207]
[Table 26]

[0208]
[Table 27]

[0209]
　As shown in Tables 23 to 24 and Tables 26 to 27, the hard tissue repair compositions of Examples 4 to 5 were excellent in various properties.
[0210]
　Further, Example 4 in which the organic boron compound (c1) was used as the polymerization initiator (C) had some characteristics as compared with Example 5 in which benzoyl peroxide (BPO) was used as the polymerization initiator (C). It was better. For example, when Example 4b and Example 5b, which have substantially the same composition of components other than the polymerization initiator (C), are compared, the amount of eluted monomers (Tables 23 and 26), simulated bone permeability (Tables 23 and 26), and residue. In terms of the amount of monomers (Tables 24 and 27), Example 4b using the organoboron compound (c1) as the polymerization initiator (C) was more excellent.
[0211]
[Table 28]

[0212]
[Table 29]

[0213]
[Table 30]

[0214]
　As shown in Tables 29 to 30, the hard tissue repair composition of Example 6 was excellent in various properties.
Industrial applicability
[0215]
　The composition for repairing hard tissue of the present invention includes, for example, adhesion between hard tissues, filling into hard tissues, adhesion and / or adhesion between hard tissues and artificial objects such as titanium, ceramics, and stainless steel, and hard tissues and soft tissues. Useful for bone cement, filling material for bone defects, bone filling material, artificial bone, etc. used for adhesion and / or adhesion to other tissues such as bone, and fixation of hard tissues such as bone and cartilage to artificial joints. Is.
[0216]
　Further, when the hard tissue repair composition of the present invention contains antibacterial agent particles (Y), it is also useful as a molding material for medical cement spacers and cement beads. For example, if the affected area is infected after artificial joint surgery, the inserted artificial joint may be removed. To fill the gap created by this removal, a cement spacer containing an antibiotic is usually used. In some cases, debridement (removal and cleaning of necrotic tissue) is performed without removing the artificial joint, and cement beads containing an antibacterial agent are embedded. In addition, there are reports of using flexible spacers. For example, by curing the hard tissue repair composition of the present invention in a molding mold, a cement spacer or cement beads having a desired shape can be obtained.
The scope of the claims
[Claim 1]
　A composition for repairing a hard tissue containing a monomer (A), a polymer powder (B) and a polymerization initiator (C), wherein the
　polymer powder (B) has an aspect ratio of 1.10 or more.
　Hard tissue containing Bx ) and having an aspect ratio of 1.00 or more and less than 1.10 among the components contained in the composition for repairing hard tissue is 75 cumulative% or less. Repair composition.
[Claim 2]
　The first aspect of claim 1, wherein the cumulative ratio of the powder particles having an aspect ratio of 1.00 or more and less than 1.10 in the whole powder particles among the components contained in the hard tissue repair composition is 2.5 to 65 cumulative%. Composition for repairing hard tissue.
[Claim 3]
　The polymer powder (B) contains a polymer powder (BX) having an aspect ratio of 1.10 or more and 1.90 or less, and the overall aspect ratio of the polymer powder (B) is 1.11 or more and 1.80 or less. The hard tissue repair composition according to claim 1.
[Claim 4]
　The composition for repairing a hard tissue according to claim 1, wherein the monomer (A) is a (meth) acrylate-based monomer.
[Claim 5]
　The composition for repairing a hard tissue according to claim 1, wherein the polymer powder (B) is a (meth) acrylate-based polymer powder.
[Claim 6]
　The composition for repairing a hard tissue according to claim 1, wherein the polymerization initiator (C) contains an organoboron compound (c1).
[Claim 7]
　The total of 10 to 45 parts by mass of the monomer (A), 54.9 to 80 parts by mass of the polymer powder (B), and 0.1 to 10 parts by mass of the polymerization initiator (C) (components (A) to (C)). The composition for repairing a hard tissue according to claim 1, which comprises 100 parts by mass).
[Claim 8]
　The composition for repairing hard tissue according to claim 1, further comprising a contrast agent (X).
[Claim 9]
　The composition for repairing hard tissue according to claim 8, wherein the amount of the contrast medium (X) is 0.01 to 70 parts by mass (the total of the components (A) to (C) is 100 parts by mass).
[Claim 10]
　The hard tissue repair composition according to claim 1, further comprising antibacterial agent particles (Y).
[Claim 11]
　The hard tissue repair composition according to claim 10, wherein the amount of the antibacterial agent particles (Y) is 0.01 to 30 parts by mass (the total of the components (A) to (C) is 100 parts by mass).
[Claim 12]
　Each component of the monomer (A), the polymer powder (B) and the polymerization initiator (C) contained in the hard tissue repair composition according to claim 1 is divided into three or more in any combination and contained. Hard tissue repair kit with the members.