JP3340002B2 - Hard tissue repair composition and device for supplying the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition for repairing hard tissue used as a bone cement, a bone filling material, an artificial bone, or the like.
And a method for supplying a composition for repairing hard tissue.

[0002]

2. Description of the Related Art Conventionally, a powder comprising polymethyl methacrylate and benzoyl peroxide (polymerization initiator) for fixing an artificial joint, methyl methacrylate and N, N-dimethyl-p
Bone cements with solutions consisting of tertiary amines (promoters) such as toluidine have been used. This bone cement is used at the time of surgery, by mixing a powder and a liquid just before fixing an artificial joint, filling the obtained mixture into an affected area using a dispenser called a cement gun, and curing the used mixture. . However, in such bone cement,
Methyl methacrylate toxicity causes a decrease in patient blood pressure during surgery, heat generated during polymerization causes damage to the patient's tissue, and fixed artificial joints become loose over time because polymethyl methacrylate does not adhere to hard tissue Since the powder and the liquid are mixed immediately before use, the odor of methyl methacrylate fills the operating room and is harmful.If the mixing of the powder and the liquid is not performed quickly, the mixture starts to harden, and the mixture can be used as bone cement. Disappear,
If the mixing of the powder and the liquid agent is insufficient, the strength of the cured product obtained is low, and there is a problem that the artificial joint cannot be firmly fixed to hard tissue.

For the purpose of improving the biocompatibility of bone cement, Japanese Patent Publication No. 54-42384 discloses a composition comprising polymethyl methacrylate and methyl methacrylate and a biomaterial having an apatite crystal phase excellent in biocompatibility. A bone cement comprising active glass has been proposed, and Japanese Patent Publication No. 62-503148 discloses a bone cement comprising di (meth) acrylate and inorganic filler particles at least partially partially absorbed by bone. Has been proposed.

[0004] The above bone cements are characterized by using a biocompatible filler.
In particular, the latter bone cement has the advantage of not using methyl methacrylate, which is problematic in terms of toxicity and adhesive strength. However, although these bone cements may provide good results from the viewpoint of biocompatibility, they are not always satisfactory from the viewpoint of operability.

That is, from the viewpoint of operability, it is necessary to perform quick and thorough mixing in order to simultaneously solve seemingly contradictory problems such as the above-mentioned problems, and to facilitate filling of the diseased part. It is also necessary that the bone cement before hardening has an appropriate fluidity.

In addition, as a practical bone cement, in addition to having sufficient adhesive strength between the hardened material and hard tissue, the hardened material is required to have a sufficient water resistance in order to maintain an appropriate strength in vivo for a long period of time. It is necessary to have the property.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a composition for repairing hard tissue which satisfies the above-mentioned properties required for practical bone cement, and is excellent in biocompatibility and operability. Aim. Still another object of the present invention is to provide a method for supplying the composition for repairing hard tissue.

[0008]

Means for Solving the Problems The present inventors have developed a calcium phosphate-based inorganic powder which has excellent biocompatibility and good adhesion to bone, and a polymerizable monomer which gives a cured product sufficient mechanical strength and water resistance. Have been found that the composition for hard tissue repair composed of a paste obtained by mixing at a specific ratio meets the above-mentioned object, and as a result of further investigation, the present invention has been completed. .

That is, the present invention relates to a calcium phosphate-based inorganic powder (hereinafter abbreviated as inorganic powder), a polymerizable monomer mixture (hereinafter abbreviated as monomer mixture), and an organic peracid.
A paste (A) comprising the compound, inorganic powder, directly amino group in the monomer mixture and the aromatic ring bonded
And a paste (B) containing a tertiary amine , and each paste has a consistency of 20 to 27 mm.
Ri, inorganic powder in the paste, the organic silane coupling
Primary treatment with a heating agent and heat treatment at 300-800 ° C.
Next, secondary treatment with an organic silane coupling agent
The powder content is 75 to 85% by weight,
Each of the polymerizable monomer mixtures has a general formula (1):

[0010]

Embedded image

(Wherein R ¹ and R ² may be the same or different and each represents a hydrogen atom or a methyl group, and p represents an integer of 1 to 4); ):

[0012]

Embedded image

(Wherein, R ³ and R ⁴ may be the same or different, each represents a hydrogen atom or a methyl group, m and n are each an integer of 1 to 5, and m + n = 2 to 2)
6), and the content of the monomer represented by the general formula (1) in the composition is 40 to 65% by weight of the total monomer mixture. A composition for repairing hard tissue is provided.

Further, the present invention provides a method for supplying the above-mentioned composition for repairing hard tissue.

The term "hard tissue" used in the present invention refers to bone, cartilage,
A hard tissue in a living body such as a joint or a tooth.

The expression "excellent in operability" as used in the present invention means that each of the pastes (A) and (B) constituting the composition for repairing hard tissue has an appropriate fluidity or consistency. I do.

The consistency of the paste is such that a certain amount of paste is
It is expressed by the diameter (mm) which spreads after a certain time when a certain pressure is applied between two glass plates. The preferred consistency of the paste is 4 ml of 0.5 ml paste at 25 ° C.
When a pressure of 0 g is applied, the diameter after 30 seconds is 20 mm or more and 27 mm or less.

In particular, when the consistency of the paste is in the above range, the paste can be uniformly mixed, the obtained composition for repairing hard tissue has an appropriate fluidity, and the composition can be easily filled into an affected part. It is preferable to be able to carry out. In particular, when a dispenser described later is used, the above two operations of mixing and filling can be performed simultaneously.

The fluidity of the paste is quantitatively defined by the force required to extrude a fixed amount of paste filled in a container of a fixed shape at a constant speed. Specifically, the inner diameter 1
3 mm, a cylinder having an outlet diameter of 3.5 mm was filled with the material, and a piston inserted into the cylinder at 25 ° C. was inserted into the cylinder by 5 mm.
It is expressed as the force required to push at a speed of / min. The paste having appropriate fluidity preferably has an extrusion force of 2N or less, more preferably 1N or less. When the fluidity of the paste is in the above range, the force required for performing the mixing and filling operations described above is small, and the operation can be easily performed with one hand.

If the flowability of the paste is too high, the paste drips from the dispenser and flows out of the application site, and if the flowability is too low, the paste is difficult to extrude from the dispenser and cannot be sufficiently injected into the application site. , All have poor operability.

The inorganic powder used in the present invention includes, for example, dicalcium phosphate, octacalcium phosphate, α-
Examples include tricalcium phosphate, β-tricalcium phosphate, tetracalcium phosphate, and hydroxyapatite. Among them, α-tricalcium phosphate, β-tricalcium phosphate and hydroxyapatite have excellent biocompatibility. And preferred.

In the present invention, the content of the inorganic powder in each of the pastes (A) and (B) needs to be within the range of 75 to 85% by weight in the paste.

When the content of the inorganic powder in each paste is less than 75% by weight, the surface of the inorganic powder is often covered with a polymer, so that adhesion to bone is inhibited and good biocompatibility is not exhibited. When hardening the composition for hard tissue repair,
There are drawbacks such as an increase in the amount of heat generated by polymerization, which is likely to cause damage to the patient's tissue, and insufficient strength of the cured product. On the other hand, the content of the inorganic powder in each paste was 85% by weight.
Exceeding the above range, the fluidity of the paste is lowered, and in some cases, a uniform repair composition cannot be obtained, and the excellent operability aimed at by the present invention cannot be realized.

It is desirable that the component and content of the inorganic powder in the paste (A) and the component and content of the inorganic powder in the paste (B) are the same.

The particle diameter of the inorganic powder used in the present invention is 0.1.
It is preferably from 1 to 100 μm, more preferably from 0.1 to 100 μm.
50 μm. By setting the particle diameter of the inorganic powder to have such a wide distribution, the content of the inorganic powder in the paste can be further increased.

Further, the inorganic powder is preferably a dense body. The term “dense body” as used herein refers to a substance having substantially no pores and having a pore volume of 0.
It means that the amount is 1 ml / g or less. If the inorganic powder has a pore volume within the above range, the monomer mixture is not absorbed into the pores of the inorganic powder when mixed with the monomer mixture, and contains the inorganic powder as described above. A high amount of the repair composition can be obtained.

In order to obtain a stable repair composition by uniformly mixing the calcium phosphate-based inorganic powder and the organic monomer mixture used in the present invention, it is preferable to introduce an organic group to the surface of the inorganic powder. As the means, treatment with an organic silane coupling agent can be mentioned. In particular, a heat treatment is performed after the inorganic powder is firstly treated with an organic silane coupling agent, and further subjected to a second treatment with an organic silane coupling agent, so that a repair composition having appropriate fluidity is obtained, and the cured product is obtained. The strength of is increased. This is considered to be due to the fact that silicon silane is introduced into the surface of the inorganic powder by performing an organic silane coupling treatment and a heat treatment on the silicon-free calcium phosphate-based inorganic powder, and the second organic silane molecule is bonded to this. .

As the organic silane coupling agent, for example, γ-methacryloxypropyltrimethoxysilane,
γ-methacryloxypropyltriethoxysilane, γ-
Methacryloxypropyl-tris (β-methoxyethoxy) silane, γ-aminopropyltriethoxysilane, and the like. The silane coupling agent used in the two organic silane treatments may be the same or different, but the second treatment is a silane coupling agent having a polymerizable double bond such as γ-methacryloxypropyltrimethoxysilane. The use of a ring agent is more preferable because the bond with the cured product becomes stronger. The heat treatment performed between the two silane treatments may be any temperature at which the organic silane coupling agent introduced in the first silane treatment can be thermally decomposed. At a high temperature, the composition or structure of the inorganic powder may change. Therefore, the heat treatment temperature is desirably 300 ° C. to 800 ° C.

The monomer mixture used in the present invention has the general formula (1):

[0030]

Embedded image

(Wherein R ¹ and R ² may be the same or different and each represents a hydrogen atom or a methyl group, and p represents an integer of 1 to 4); ):

[0032]

Embedded image

(Wherein, R ³ and R ⁴ may be the same or different, each represents a hydrogen atom or a methyl group, m and n are each an integer of 1 to 5, and m + n = 2 to 2)
6).

The monomer represented by the general formula (1) is a liquid having high fluidity, and is necessary for dissolving other monomers and uniformly mixing with the inorganic powder to form a stable repair composition. Component. This monomer is hydrophilic and slightly remains on the surface of the cured product due to the polymerization inhibitory action of the surrounding oxygen. When the monomer is dissolved in the surrounding water, particles of the inorganic powder having affinity for the hard tissue are formed around the hardened material. Direct contact with the organization,
It is considered that they bond with each other and the adhesiveness to hard tissue becomes strong.

FIG. 1 is a surface scanning electron micrograph of a plate-like cured product made from the repair composition of the present invention (the composition of Example 1 described later). As is clear from this photograph, inorganic particles are exposed on the surface of the cured product made from the composition of the present invention. On the other hand, FIG.
23 is a surface scanning electron micrograph of a cured product obtained from the composition disclosed in No. 23 (composition of Comparative Example 3 described later).
This composition does not contain the monomer of the general formula (1) which is an essential component in the present invention. Therefore, the inorganic particles on the surface of the cured product are covered with the polymer, and the inorganic particles cannot directly adhere to the hard tissue in the body. It is considered that the adhesiveness to the adhesive is poor.

As the monomer (1) represented by the general formula (1), for example, ethylene glycol dimethacrylate,
Examples thereof include diethylene glycol dimethacrylate, triethylene glycol dimethacrylate, and propylene glycol dimethacrylate. Among them, triethylene glycol dimethacrylate is preferable.

Further, the monomer represented by the general formula (2) is a liquid having low fluidity, and is necessary for forming a stable repair composition while holding the inorganic powder. This monomer is also hydrophobic and is a necessary component for improving the water resistance of the cured product.

As the monomer (2), for example, 2,2-
Bis (4-methacryloxyethoxyphenyl) propane, 2,2-bis (4-methacryloxypolyethoxyphenyl) propane, 2,2-bis (4-methacryloxypolypropoxyphenyl) propane and the like are included, and among them, 2,2-bis (4-methacryloxyethoxyphenyl) propane is preferred.

In the present invention, the composition of the monomer mixture is an important requirement for achieving excellent operability. That is, the content of the monomer represented by the general formula (1) needs to be 40 to 65% by weight of the total monomer mixture, and is preferably in the range of 45 to 60% by weight.
When the content of the monomer represented by the general formula (1) exceeds 65% by weight of the total monomer mixture, the obtained paste has poor stability and inorganic powder is separated from the paste. On the other hand, when the content of the monomer represented by the general formula (1) is less than 40% by weight of the total monomer mixture, the fluidity of the paste becomes too low, and the excellent operability aimed at by the present invention is realized. Can not.

The monomer represented by the general formula (2) is added so that the total amount of the monomer represented by the general formula (1) and the third component described later is 100% by weight.

The above monomer mixture contains a hydrophobic dimethacrylate such as 2,2-bis [4- (3-methacryloxy-2-hydroxypropoxy) phenyl] propane (hereinafter abbreviated as Bis-GMA), , 2-
Bis (4-methacryloxyphenyl) propane or the like can be added as a third component. The term "hydrophobic" as used herein means that the saturated solubility in physiological saline at 37 ° C. is 500.
It means those below ppm.

Such hydrophobic dimethacrylates are used in the range from 0 to 30% by weight of the total monomer mixture.

It is desirable that the monomer mixture forming the paste (A) and the monomer mixture forming the paste (B) have the same composition.

The polymerization initiator and the polymerization accelerator used in the present invention, when used alone, do not initiate polymerization at room temperature for a short period of time, but when they are mixed, radicals are generated to function to cure the monomer mixture. Things.

Examples of the polymerization initiator include, for example, organic peroxides, preferably diacyl peroxides and peroxyesters. Benzoyl peroxide, 2,4-dichlorobenzoyl peroxide, m-
Tolyl peroxide, t-butylperoxybenzoate, di-t-butylperoxyisophthalate, 2,
5-dimethyl-2,5-di (benzoylperoxy) hexane, 2,5-dimethyl-2,5-di [(o-benzoyl) benzoylperoxy] hexane, 2,5-dimethyl-2,5-di [(O-benzoyl) benzoylperoxy] hexyne-3,3,3 ′, 4,4′-tetra (t-butylperoxycarbonyl) benzophenone and the like are used.

As the polymerization accelerator, a tertiary amine in which an amino group is directly bonded to an aromatic ring is preferable, and N, N-dimethyl-p-toluidine, N, N-dimethylaniline,
N-methyl-N- (2-hydroxyethyl) aniline,
N, N-di (2-hydroxyethyl) aniline, N, N
-Di (2-hydroxyethyl) -p-toluidine, N,
N-di (2-hydroxypropyl) aniline, N, N-
Di (2-hydroxypropyl) -p-toluidine and the like are used.

These polymerization initiators and polymerization accelerators are
It is necessary to use an amount sufficient to sufficiently cure the monomer mixture, and usually each is used in the range of 0.1 to 2% by weight based on the monomer mixture.

In the present invention, when both pastes are mixed, curing of the surface of the mixture may be delayed due to the effect of oxygen in the air. To prevent this, a photopolymerization initiator is further added to the paste. If this is done, it becomes possible to harden even from the surface by light irradiation, and in particular, in the case of a bone cement for artificial joint fixation, fixation can be performed in a short time. As such a photopolymerization initiator, a combination of camphorquinone and an amine can be used.

The composition for repairing hard tissue of the present invention is preferably sterilized. The monomer mixture and the inorganic powder are separately sterilized, and the two may be mixed to form a paste. After formation, it may be sterilized. The sterilization method may be appropriately selected from known methods such as EOG sterilization and filtration.

The mixing ratio of the paste (A) and the paste (B) is not particularly limited, but is 1:10 to 10: 1 by volume.
And most preferably 1: 1.

In the hard tissue repair composition of the present invention,
If the paste (A) containing the polymerization initiator and the paste (B) containing the polymerization accelerator are not uniformly mixed, the strength of the cured product will be poor. However, if the mixing is time-consuming, the curing starts before being applied to the affected part, Becomes unusable. Incorporation of air bubbles also causes poor strength. Furthermore, it is necessary to prevent mixing of various bacteria from the air or the like during mixing, and to prevent monomer vapor from volatilizing into the air. Furthermore, since the two pastes begin to harden when mixed, they need to be stored in separate containers, and it is desirable that they can be easily mixed when used. Therefore, two containers for separately storing both pastes, an extrusion mechanism for discharging the paste from the two containers, a discharge hole of the container, and a method for introducing and uniformly mixing both pastes discharged from the discharge holes. It is most suitable for the purpose of the present invention to use the feeding device having the static mixer mechanism described above.

The specific method is described in the literature [SD Chen et al., “Static Mixing Handbook-All about Static Mixing Process-” (Sogo Chemical Laboratory, 1
973), pages 9 to 15]. By using this apparatus, uniform mixing of the two pastes (A) and (B) and aseptic filling of the affected composition with the obtained composition in a short time can be efficiently performed.

When the composition for repairing hard tissue is applied to an affected area using this static mixer, if the fluidity of the paste is too low, it becomes difficult to discharge the paste, and if the fluidity is too high, the tip of the mixer becomes difficult. From the paste, or the shapeability of the paste becomes poor. Therefore,
The supply method of the present invention is characterized in that a paste composition having an appropriate consistency is combined with a supply device for uniformly mixing the paste and injecting the paste into an affected part.

FIG. 3 shows an example of an apparatus used for mixing pastes. This device includes a dispenser 1, a mixer unit 2, a syringe 3 filled with paste (A), a pair of syringes 3 'filled with paste (B), and a plunger 4. By pulling the trigger of the dispenser 1, the plunger 4 is pushed in, and each paste in the syringe 3, 3 ′ has a common discharge hole 5.
Through the mixer 2. Mixer part 2
Has a built-in blade for continuously performing separation and mixing. The paste is completely mixed when passing through the mixer section 2, and is directly connected to the outlet of the mixer section 2 or through a tube of a desired length. Injected into the affected area.

Since such a device is used in contact with a tissue in a patient's body, it is preferable that the device is sterilized. The sterilization method may be appropriately selected from known methods such as EOG sterilization and autoclave sterilization. Further, it is desirable that the mixer section 2 and the syringes 3, 3 'be disposable.

[0056]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 (Production of hydroxyapatite powder) Reference [E. Hayek and H. Newesel, "Inorganic Synthesis"
VII ", McGraw-Hill, New York (1963), such that the molar ratio of Ca / PO ₄ according to the methods described in the 63 page] is 1.67, monohydrogen aqueous ammonium phosphate, an aqueous solution of calcium nitrate and aqueous ammonia Was mixed and heated to synthesize hydroxyapatite. The obtained hydroxyapatite was centrifugally dehydrated, dried at 80 ° C., calcined at 1100 ° C. for 2 hours, and then pulverized with a ball mill to obtain an average particle size of 4 μm. Diameter 0.1-50 μm, density 3.27 g / m
1, a hydroxyapatite powder having a pore volume of 0.057 ml / g was obtained.

The obtained hydroxyapatite powder 400
g was added to 240 ml of an acetone solution of 8 g of γ-methacryloxypropyltrimethoxysilane, and the mixture was stirred at room temperature for 1 hour, acetone was distilled off under reduced pressure, dried at room temperature, and further heat-treated at 750 ° C. for 2 hours. Next, the powder was added to a toluene solution (600 ml) of 8 g of γ-methacryloxypropyltrimethoxysilane, and the mixture was heated under reflux for 3 hours, and toluene was distilled off under reduced pressure, followed by drying at room temperature.

Reference Example 2 (Determination of Composition of Polymerizable Monomer Mixture) Triethylene glycol dimethacrylate (hereinafter abbreviated as TEGDMA) as a monomer represented by the general formula (1) is represented by a general formula (2). 2,2-bis (4-methacryloxyethoxyphenyl) as the monomer to be used
Propane (hereinafter abbreviated as bis-MEPP)
And bis-GMA was used as the third dimethacrylate, and these were mixed at the weight ratio shown in Table 1. 0.3% by weight of benzoyl peroxide and 20% by weight of this monomer mixture were obtained in Reference Example 1. Hydroxyapatite powder (80 parts by weight) was added and mixed well in a mortar to prepare a paste. The obtained paste was 13 mm in inner diameter and the outlet diameter was 3.
The force required for filling the cylinder into a 5-mm cylinder and pushing the piston inserted into the cylinder at a speed of 5 mm / min using an Instron universal testing machine was measured. The results are shown in Table 1.

[0060]

[Table 1]

In Table 1,-indicates that sedimentation of the hydroxyapatite powder was observed. When the content of TEGDMA in the monomer mixture was 25% by weight or less, the fluidity of the monomer mixture was low and the monomer mixture and the hydroxyapatite powder could not be uniformly mixed.

As a result, in order to obtain a hard tissue repair composition having excellent operability while keeping the extrusion force at 2 N or less, the ratio of TEGDMA to the total monomer mixture should be 40 to 65.
It has been found that it is necessary to make the weight%.

Example 1 (Preparation of paste) 50 parts by weight of TEGDMA, Bis-
20 parts by weight of MEPP and 30 parts by weight of Bis-GMA were mixed, and 0.3 part by weight of benzoyl peroxide and 80 parts by weight of the hydroxyapatite powder obtained in Reference Example 1 were added to 20 parts by weight of this monomer mixture, and mixed well in a mortar. Thus, a paste (A1) was prepared. A paste (B1) was prepared by mixing 20 parts by weight of the same monomer mixture with 0.4 parts by weight of N, N-di (2-hydroxyethyl) -p-toluidine and 80 parts by weight of hydroxyapatite powder.
Was prepared.

(Evaluation of Water Resistance of Cured Product) Equal amounts of the paste (A1) and the paste (B1) obtained above were mixed using a dispenser shown in FIG. 3, and the obtained composition was placed in a Teflon tube. Extruded and cured, 3mm in diameter,
A cured product of a round bar having a length of 25 mm was obtained.

The obtained cured product was immersed in a physiological saline solution at 37 ° C. and stored for a certain period of time. The weight of the cured product before and after storage was measured, and the water absorption was calculated.

The bending strength of the cured product was measured at room temperature and in air by a three-point support method (head speed: 1 mm / min) with a distance between supports of 20 mm using an Instron strength tester.

Table 2 shows the results.

[0068]

[Table 2]

As shown in Table 2, the water absorption of the cured product was very low, and the mechanical strength of the cured product was maintained even when immersed in a physiological saline solution. It is clear that they have.

(Measurement of calorific value during curing) Internal volume 2.8 m
A chromel-alumel thermocouple was fixed to the outside of a 1 glass sample bottle. Equal amounts of the obtained paste (A1) and paste (B1) were put into the sample bottle and mixed, and the maximum temperature due to heat generation during curing was measured. The result was 46 ° C. 4.9 minutes after the start of mixing.

(Effect of Monomer (1)) A composition obtained by mixing equal amounts of the obtained pastes (A1) and (B1)
A sheet-shaped cured product was obtained by polymerizing at room temperature for 10 minutes between two Teflon sheets, and then immediately washed with water to remove an uncured layer on the surface.

Gold was vapor-deposited on the obtained plate-like cured product, and the surface was observed with a scanning electron microscope. The results are shown in FIG.

As is apparent from FIG. 1, a large number of hydroxyapatite particles (white portions in the photograph) were observed on the surface of the obtained cured product.

(Effect of Surface Treatment of Inorganic Particle ) Equal amounts of the obtained pastes (A1) and (B1) are mixed and cured,
A round bar with a diameter of 3 mm and a length of 28 mm, and a diameter of 4 mm and a length of 4 m
m round bar was obtained.

For the former of the obtained test pieces, the bending strength (using an Instron strength tester, the distance between fulcrums was 20 mm)
And the compression strength (using an Instron strength tester, head speed: 2 mm / min) was measured at room temperature and in air for the latter (all 10 samples). .

As a result, the bending strength was 118.1 ± 10.6.
MPa and compressive strength were 239 ± 13 MPa.

Comparative Example 1 The amount of heat generated during curing was measured in the same manner as in Example 1 using commercially available polymethyl methacrylate bone cement (the content of the polymerizable monomer in the total composition was 33% by weight). .

As a result, the temperature reached 76.3 ° C. 7.7 minutes after the start of mixing the powder and the liquid.

Example 2 (Preparation of paste) 50 parts by weight of TEGDMA, Bis-
20 parts by weight of MEPP and 30 parts by weight of Bis-GMA were mixed, and 0.3 part by weight of benzoyl peroxide and 75 parts by weight of the hydroxyapatite powder obtained in Reference Example 1 were added to 25 parts by weight of this monomer mixture, and mixed well in a mortar. Thus, a paste (A2) was prepared. A paste (B2) was prepared by mixing 25 parts by weight of the same monomer mixture with 0.5 parts by weight of N, N-di (2-hydroxyethyl) -p-toluidine and 75 parts by weight of hydroxyapatite powder.

(Influence of Inorganic Powder Content) Paste (A2)
And paste (B2) are mixed in equal amounts, put in a brass mold, cured at room temperature, and then left at 37 ° C. overnight to obtain a diameter of 4 m.
m, a round bar having a thickness of 4 mm was obtained.

The obtained round bar was immersed in water at 70 ° C. for 24 hours, and the water absorption was measured from the weight before and after that. The compressive strength in air after immersion was measured in the same manner as in Example 1. (10 samples)

Table 3 shows the results.

Comparative Example 2 In accordance with Japanese Patent Publication No. 62-503148, TEGDMA50
And 50 parts by weight of Bis-GMA were mixed, 1 part by weight of benzoyl peroxide and 70 parts by weight of hydroxyapatite powder were added to 30 parts by weight of the monomer mixture, and the mixture was thoroughly mixed in a mortar to prepare a paste (C). Further, 30 parts by weight of the same monomer mixture as above was mixed with 0.6 parts by weight of N, N-di (2-hydroxyethyl) -p-toluidine and 70 parts by weight of hydroxyapatite powder to prepare a paste (D).

Equal amounts of the pastes (C) and (D) were mixed, a cylindrical sample was prepared in the same manner as in Example 2, and the water absorption and the compressive strength in air after water absorption were measured (number of samples). 10).

Table 3 shows the results.

[0086]

[Table 3]

As shown in Table 3, between Example 2 and Comparative Example 2,
As a result of the t test, both the water absorption rate and the compressive strength after water absorption were the risk factors 1
% Or less, a significant difference was observed.

Comparative Example 3 According to EP 123323, Bis was used as a monomer.
-Using MEPP only, add 0.3 parts by weight of benzoyl peroxide and 80 parts by weight of hydroxyapatite powder to 20 parts by weight, mix well in a mortar and paste (E)
Was prepared. Also, N, N-
Paste (F) was prepared by mixing 0.5 parts by weight of di (2-hydroxyethyl) -p-toluidine and 80 parts by weight of hydroxyapatite powder.

Mix equal amounts of paste E and paste F,
A plate-shaped cured product was prepared in the same manner as in Example 1 (effect of monomer (1)), and a scanning electron micrograph of the surface was obtained (FIG. 2). As is clear from FIG. 2, in the cured product obtained from the composition of Comparative Example 3 in which the monomer (1) was not used, a polymer film formed from the monomer was formed on the hydroxyapatite particles.

Comparative Example 4 According to US Pat. No. 4,778,834, 10 g of hydroxyapatite was added to an aqueous solution of sodium metasilicate nonahydrate (0.1 g).
After stirring at room temperature overnight in 5 g / 70 ml, adjusted to pH 6.8 with 1 N hydrochloric acid, washing and drying, a toluene solution of γ-methacryloxypropyltrimethoxysilane (0.2 g / 1
Under reflux for 3 hours to obtain hydroxyapatite particles. Pastes (G) and (H) were obtained in the same manner as in Example 1 except that the hydroxyapatite particles thus obtained were used as the inorganic particles.

The pastes (G) and (H) obtained were mixed in equal amounts and cured, and the flexural strength and compressive strength of the test piece were measured in the same manner as in Example 1 (effect of surface treatment of inorganic particles). It was measured (10 samples).

Table 4 shows the results. The result of Example 1 is also described for reference.

[0093]

[Table 4]

[0094] Between the Comparative Example 3 and Example 4, the bending strength at t - test, with compressive strength significant difference of 1% or less risk rate was observed.

The consistency of the pastes of Example 1 and Comparative Example 4 was measured. That is, placing the glass plate of the weight 40g in each paste 0.5 ml, diameter was measured 30 seconds after the paste.

Table 5 shows the results.

[0097]

[Table 5]

The pastes (A1) and (B) of Example 1
It was confirmed that 1) can provide a composition for repairing hard tissue having fluidity suitable for extrusion from a dispenser.

[0099]

The composition for repairing hard tissue according to the present invention has high adhesiveness to bone and has sufficient water resistance. Also,
The calorific value during curing is also small, and the damage to the patient's tissue is small. Furthermore, since the paste constituting the composition for repairing hard tissue has an appropriate consistency, it is easy to uniformly mix the paste and fill the affected area with the obtained mixture by using the supply device. .

Therefore, the composition for repairing hard tissue of the present invention can be effectively used not only as a bone cement but also as a filler, a bone filler, or an artificial bone for a bone defect.

[Brief description of the drawings]

FIG. 1 is a surface electron micrograph of a plate-shaped cured product obtained from the composition obtained in Example 1.

FIG. 2 is a surface electron micrograph of a plate-shaped cured product obtained from the composition obtained in Comparative Example 3.

FIG. 3 is a schematic view (longitudinal section) of an apparatus used for mixing pastes, 1 is a dispenser, 2 is a mixer section, 3 and 3 ′ are syringes, and 4 is a plunger. is there.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Dispenser 2 Mixer part 3 and 3 'syringe 4 Plunger 5 Discharge hole

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-49083 (JP, A) JP-A-6-226178 (JP, A) JP-A-59-217666 (JP, A) 152634 (JP, U) JP 48-11156 (JP, B1) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61L 24/00-33/18

Claims (3)

(57) [Claims] 1. A paste (A) containing a calcium phosphate-based inorganic powder, a polymerizable monomer mixture and an organic peroxide , and an amino group bonded directly to the calcium phosphate-based inorganic powder, the polymerizable monomer mixture and an aromatic ring Is
And a paste (B) containing a tertiary amine , wherein each paste has a consistency of 20 to 27 mm, and the calcium phosphate-based inorganic powder in each paste contains
Primary treatment with a run coupling agent, 300-800 ° C
Heat treatment, then secondary with organic silane coupling agent
Treated, the content of the calcium phosphate-based inorganic powder ,
And each of the polymerizable monomer mixtures has a general formula (1): (Wherein R ¹ and R ² may be the same or different,
A hydrogen atom or a methyl group, p represents an integer of 1 to 4), and the following general formula (2): Wherein R ³ and R ⁴ may be the same or different,
A hydrogen atom or a methyl group, m and n are each an integer of 1 to 5 and m + n = 2 to 6), and represented by the general formula (1) A composition for repairing hard tissue, wherein the content of the monomer is 40 to 65% by weight of the total monomer mixture. 2. The monomer represented by the general formula (1) is triethylene glycol dimethacrylate, and the monomer represented by the general formula (2) is 2,2-bis (4-methacryloxyethoxyphenyl). 2. The composition for repairing hard tissue according to claim 1, wherein the composition is propane. 3. A container in which the paste A and the paste B according to claim 1 are separately stored, an extruding mechanism for discharging the paste from the two containers, a discharge hole of the two containers, and the discharge hole. 2. The apparatus for supplying a composition for repairing hard tissue according to claim 1, further comprising a static mixer mechanism for introducing and uniformly mixing the two pastes discharged from the apparatus.