JPH0643263B2 - Curable composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel curable composition for filling bone defects and voids of a living body, or tooth defects. More specifically, it is a curable composition that promptly forms a hydroxyapatite cured product upon contact with water and becomes a filler having excellent affinity.

[Conventional technology]

In the surgical and orthopedic fields, bone defects or voids are caused by traffic accidents, bone tumor resection, etc., and in the dental field, alveolar pyorrhea, alveolar bone resorption, tooth extraction, and carotid tooth resection. Filling of such bone defects or voids,
Various materials such as self-bones, polymers, metals, and ceramics are used for prosthesis. Among them, autologous bone is excellent in bone forming ability and has little rejection reaction.
However, the autologous bone must be collected from the normal tissue of the person, which is not only a great pain in the operation,
There are many cases where a sufficient amount cannot be secured.

Therefore, in recent years, hydroxyapatite has begun to be used as a material to replace autologous bone. Hydroxyapatite is obtained by synthesizing or burning animal bones to remove organic components, and it is known that its biocompatibility is extremely sick. However, it has been pointed out that when hydroxyapatai is used as a filler in the form of fine powder or granules, blood also leaks out as a foreign substance after body fluid or after suturing.

As a method for solving the above problems, a composition in which a mixture of tetracalcium phosphate and another calcium phosphate salt, as a powder, or by kneading and filling with water to form hydroxyapatite, and further hardening, is obtained. Proposed. (USP4518430) However, since the curing time of this composition is as slow as 20 to 30 minutes, leakage due to blood or body fluid in the case of bone filling, or the problem that the composition cannot be transferred to the next operation when used as a tooth backing material Points are pointed out. Therefore, as a method to accelerate the curing time,
Hydroxy obtained from fluorides such as sodium fluoride and calcium fluoride, or calcium hydroxide and phosphoric acid, or calcium salts such as calcium nitrate and calcium acetate, from phosphates such as potassium hydrogen phosphate and ammonium hydrogen phosphate. Addition of apatite is under consideration. However, fluoride has a problem of toxicity when used as a filling material in the body, and since the addition of the hydroxyapatite requires a large amount of 24-43%,
There is a problem that the operability is very poor or the compressive strength is lowered.

[Means for solving problems]

The present inventors have conducted intensive studies to solve the above problems. As a result, the Ca / P atomic ratio of tetracalcium phosphate was 1.
A curable composition consisting of calcium phosphate of less than 67, wherein the composition contains tetracalcium phosphate and a Ca / P atomic ratio of
It was found that by adding hydroxyapatite and / or its precursor obtained by the reaction with calcium phosphate of less than 1.67, curing time can be remarkably accelerated without causing problems such as toxicity and operability. Has been completed.

The present invention relates to tetracalcium phosphate, calcium phosphate having a Ca / P atomic ratio of less than 1.67, and tetracalcium phosphate and Ca / P.
A curable composition comprising hydroxyapatite and / or a precursor thereof (hereinafter collectively referred to as HAP reaction product) obtained by reaction with calcium phosphate having an atomic ratio of less than 1.67.

The tetracalcium phosphate (hereinafter abbreviated as C4P) used in the curable composition of the present invention may be produced by any method. The raw materials are CaCO ₃ , CaO, Ca (OH) as a Ca source.
₂ , as a P source, P ₂ O ₅ , H ₃ PO ₄ , NH ₄ H ₂ PO ₄ , (NH ₄ ) ₂ HPO ₄ , Ca and P
CaHPO ₄ · 2H ₂ O, CaHP ₄ , Ca (H ₂ PO ₄ ) ₂ , Ca ₂ P ₂ containing both
O ₇ etc. are considered and there are various production methods depending on the raw material, but γ-Ca ₂ P ₂ O ₇ obtained by firing known CaHPO ₄ .2H ₂ O is Ca
A dry manufacturing method of mixing with CO ₃ and firing is preferable.

This reaction is represented by the reaction formula _{2CaHPO 4 · 2H 2 O → γ} -Ca 2 P 2 O 7 + 5H 2 O Ca 2 P 2 O 7 + 2CaCO 3 → Ca 2 P 2 O 9 + 2CO 2, 1200 ℃ or higher After firing, quenching outside the furnace or firing at 1200 ° C or higher in a nitrogen atmosphere,
Pure C4P without transfer to hydroxyapatite
Is obtained.

Moreover, in the present invention, Ca / C which is mixed with the above-mentioned C4P
Calcium phosphate with a P molar ratio of less than 1.67 (hereinafter referred to as HPC
Abbreviated as P. ), Various ones can be used. For example, Ca
(H ₂ PO ₄ ) ₂・ H ₂ O, CaHPO ₄・ 2H ₂ O, CaHPO ₄ ,, Ca ₈ H ₂ (PO ₄ ) ₆・ 5H ₂ O, C
a ₃ (PO ₄ ) ₂ and Ca ₂ P ₂ O ₇ can be mentioned, of which CaHPO ₄・ 2H ₂
O and CaHPO ₄ are particularly preferable in terms of mechanical properties, operability and storage stability of the cured product. For example, HPCP as CaHPO ₄
・ When 2H ₂ O is used, the reaction formula is represented by the following formula, and hydroxyapatite is produced.

In _{2Ca 4 P 2 O 9 + 2CaHPO} 4 · 2H 2 O → Ca 10 (PO 4) 6 (OH) 2 + 2H 2 O The present invention, mixing ratio Ca / P molar ratio of the mixture of the above HPCP and C4P is 1.3 It is preferable to adjust the ratio to 1.8 so that hydroxyapatite can be efficiently produced and the strength of the obtained cured product is increased.

The HPCP and C4P are generally used in powder form. The particle size and shape in this case are not particularly limited, but HPCP has an average particle size of less than 50 μm, preferably 0.1 to 10 μm, in order to accelerate the curing speed and to improve the powder-liquid ratio in the mixing with water. It is preferable to use C4P having an average particle size of 0.1 to 100 μm, preferably 0.5 to 50 μm. Further, the shape is particularly preferably spherical.

The characteristic of the cured composition of the present invention is that HPCP and C4P described above are used.
In addition, it is to contain the HAP reaction product.

In the present invention, the HAP reaction product may be all hydroxyapatite, but it is particularly preferable that a part or all thereof is a hydroxyapatite precursor. The HAP reaction product containing such a hydroxyapatite precursor can be used without particular limitation as long as it is produced in the process of reacting HPCP with C4P in the presence of water.
Among them, in X-ray diffraction, the peak height of C4P as a raw material is about 90% or less before reaction, preferably 10 to 80%.
The one in which the reaction is stopped in this state is preferable because it has an excellent effect of shortening the curing time of the resulting curable composition.

Further, as the HPCP, CaHPO ₄ .2H ₂ O among the above examples is used.
And CaHPO ₄ are preferred.

The method for producing the HAP reaction product is not particularly limited. If a typical manufacturing method is illustrated, C4P and HPCP are Ca
A method may be mentioned in which the mixture mixed so that the / P atomic ratio is 1.3 to 1.8 is relaxed with water and then dried during the reaction. The mixing ratio of the mixture and water is 10/1 to 1/1
The range of 0, more preferably 5/1 to 1/2 is suitable. The holding temperature after kneading is not limited as long as it is 0 ° C. or higher, but a range of 20 to 60 ° C. is preferable in view of reaction rate and drying.

Since the reaction of the kneaded product of C4P, HPCP and water proceeds in the presence of water, the reaction can be stopped by drying in the middle of the reaction to remove water. The drying method is not particularly limited, freeze-drying method, organic solvent immersion method,
A spray drying method, a heating concentration method and the like are generally used.
Among them, the freeze-drying method and the organic solvent immersion method are preferable as the method capable of stopping the reaction in a short time. In the freeze-drying method, the kneaded product is frozen in a freezer, dry ice, liquid nitrogen or the like and then dehydrated in a vacuum to obtain a HAP reaction product. The organic solvent immersion method is an organic solvent soluble in water,
For example, the kneaded product is immersed in methanol, ethanol, isopropyl alcohol, acetone or the like to dehydrate and stop the reaction. Subsequently, HA is filtered and dried.
A P reaction product can be obtained.

According to the X-ray diffraction analysis of the above reaction, the peak of the raw material is small in the initial stage of the kneading, but the peak of the product does not appear, and hydroxyapatite is gradually produced after a certain period of time or longer. Therefore, it is considered that an amorphous substance having a composition close to that of hydroxyapatite is formed in the initial stage of kneading, and the hydroxyapatite precursor can be left by removing water in the process.

In the present invention, the HAP reaction product includes HPCP and C4P.
It is preferable to add the one containing the precursor thereof or the addition of only the precursor thereof, rather than the complete hydroxyapatite obtained by the reaction with

In the present invention, the use ratio of the HAP reaction product is slightly different depending on the purpose of use and the stage of the addition of the HAP reaction product, but in general, unreacted raw materials such as hydroxyapatite and / or hydroxyapatite excluding C4P and / or C4P are generally used. The precursor is 0.1-2 with respect to the total amount of HPCP and C4P.
0 wt%, preferably 0.2-10 wt% is suitable. That is, H
When the use ratio of the AP reaction product is less than the above range, the effect of shortening the curing time is small, and when it is more than the above range, the strength of the cured product tends to decrease.

Other components may be added to the curable composition of the present invention, if necessary, within a range that does not significantly affect the curability. For example, it is preferable to add 10 to 50 parts by weight of barium sulfate, barium glass, strontium glass, zirconia, iodoform or the like to 100 parts by weight of the curable composition in order to impart X-ray contrast. Also,
Silica, calcium fluoride, titanium dioxide, calcium hydroxide, alumina, in order to adjust the operability and strength,
Sodium phosphate, ammonium phosphate and the like can be added.

Depending on the purpose of use, the curable composition of the present invention may be used in the form of powder as it is for reaction curing with water in the body, or may be used by kneading with a kneading solution in advance. When a kneading solution is used, water or physiological saline is generally used. Further, other components can be added to the kneading liquid, if necessary. For example, it is preferable to add 0.001 to 50% of phosphoric acid, sodium fluoride, carboxylic acid, a polymer having a carboxyl group or the like in order to adjust the curing time.

In addition, the curable composition of the present invention can be made into a one-paste solution by previously mixing a liquid organic compound as a kneading liquid, and after being embedded in a tooth or in the body, it is cured by reacting with a body fluid.

The powder-liquid ratio of the powder of the hydraulic composition of the present invention to the kneading liquid may be appropriately determined so as to obtain a suitable viscosity depending on the application.
Generally, the viscosity of the obtained kneaded product after 1 minute of kneading is from 10 to 10.
The powder-liquid ratio may be adjusted so that it is within the range of 10,000 poise, preferably 100 to 7,000 poise. For example, when used as a root canal filling material, the viscosity of the kneaded product is 1
It is desirable to adjust the powder-liquid ratio so that it is from 00 to 5000 voise.

[Action]

In the present invention, the reason why the addition of the HAP reaction product shortens the curing time of the resulting curable composition is not clear, but the present inventors have found that the HAP reaction product merely serves as a crystal nucleus. Not only that, it acts as a promoter for crystal growth, and it is considered that the time for forming crystals is shortened as compared with the case of only C4P and HPCP or the case of adding hydroxyapatite obtained by another method. .

〔effect〕

The effect composition of the present invention, by adding the HAP reaction product to the curable component consisting of C4P and HPCP, without impairing the properties such as operability, safety and strength,
The curing time can be effectively shortened. Therefore, a dental restoration material such as a backing material, a cemented cement, a filling cement, a root canal filling material, a covering material, a periodontal vocket filling material, or a bone filling material,
It can be suitably used as an orthopedic repair material such as bone cement.

〔Example〕

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples. still,
The definitions of the various quantities relating to the properties of the materials shown in the text and the examples and the measuring methods thereof are as follows.

(1) Average particle size Disperse the obtained particles in isopropyl alcohol,
It was measured with a particle size distribution meter (CAPA-500, manufactured by Horiba Ltd.). The measuring principle is the centrifugal sedimentation method.

(2) Structure X of the reaction product was measured using an X-ray diffractometer (JEOL).
The line diffraction was measured to identify the residual amount of the raw material and the structure of the reaction product.

(3) Curing time of kneaded product A polyvinyl chloride mold having an inner diameter of 20 mm and a thickness of 3 mm was filled with the kneaded product kneaded for 1 minute to flatten the surface. When 2 minutes and 30 seconds had passed from the start of kneading, the mixture was transferred into a constant temperature bath having a temperature of 37 ° C. and a relative humidity of 100%. After that, Gilmour needle weighing 114.12 g (needle cross-sectional area 4.91 mm)
Was gently dropped on the surface of the test piece, and the time when no needle mark was left was counted from the start of kneading as the curing time.

(4) Compressive strength According to the crushing resistance test of zinc phosphate cement of JIS T-66002.

That is, the kneaded product kneaded for 1 minute was put into a mold, and the kneaded product was kept in a constant temperature bath at a temperature of 37 ° C. and a relative humidity of 100% for 1 hour, and then the cured product was taken out from the mold. The size and shape of the test piece is a cylinder of 12 mm × 6 mmφ. After that, this test piece was further kept in distilled water at 37 ° C for 23 hours, and then pressed using a universal testing machine Tensilon (manufactured by Toyo Baldwin Co., Ltd.) at a crosshead speed of 0.5 mm per minute until the test piece was crushed. did. The crushing resistance at this time was defined as compressive strength (kg / cm ² ).

Production Example 1 CaHPO ₄ .2H ₂ O was calcined at 500 ° C. for 2 hours to obtain γ-Ca ₂ P ₂ O ₇ . This powder and CaCO ₃ powder were mixed at a ratio of 1: 2 (molar ratio), calcined in air at 1400 ° C. for 2 hours, and then rapidly cooled outside the furnace. It was confirmed by X-ray diffraction that the produced powder was C4P. Place this C4P on an alumina ball mill,
Grinded for 10 hours. This was passed through a sieve with a 250 mesh opening to obtain C4P powder (average particle size 5.3 μm).

The above C4P and calcium hydrogen phosphate dihydrate (average particle size: 5.2 μm) were mixed so that the Ca / P atomic ratio was 1.67. This mixture and ion-exchanged water were kneaded at a powder-liquid ratio of 2.0, and 2 minutes 30 seconds after the start of kneading, the relative humidity was 100% and the temperature was 37 ° C.
15 minutes, 30 minutes, 1 hour, 3 hours, 5 hours, 10 hours, and 24 hours after the start of the kneading, a part of the kneaded product was taken out and washed with liquid nitrogen. Freeze and stop the reaction. Transfer this sample to a vacuum dessicator,
After freeze-drying with a vacuum pump, it was pulverized with a ball mill (average particle size: 2.2 μm) to obtain a reaction product.

The residual ratio of C4P in the reaction product by X-ray diffraction (29.2
The peak ratio before and after kneading) and the state of hydroxyapatite formation were measured to determine the proportion of HAP reaction product. The results are shown in Table 1.

Example 1 Comparative Example 1 C4P of Production Example 1 and calcium hydrogen phosphate anhydrous were replaced with Ca /
The P atomic ratio was 1.67. Obtained from this mixture and Preparation 1. The reaction products of NO.1-1 to NO.1-4 were mixed so that the HAP reaction product would be 2 wt% of the whole to obtain a curable composition. The ratio of each curable composition to ion-exchanged water and powder liquid
The mixture was kneaded at 2.5 and the curing time, operability and compressive strength were measured. The results are shown in Table 2. For comparison, Comparative Example 1 shows the results obtained without adding the HAP reaction product.

Example 2 Comparative Example 2 C4P of Production Example 1 and calcium hydrogen phosphate dihydrate were mixed with Ca.
The P / P atomic ratio was 1.67. No. 1 of Production Example 1 was added to this mixture.
The curable composition was prepared by adding the reaction products of 1-3 such that the HAP reaction products were in the proportions shown in Table 3, respectively. This was kneaded with physiological saline at a powder / liquid ratio of 2.5, and the curing time was measured. The measurement results are shown in Table 3. As a comparative example, the result when the reaction product is not added is shown in Comparative Example 2.
Shown in.

Production Example 2 C4P of Production Example 1 and calcium hydrogen phosphate anhydrate (average particle size 4.3 μm) were mixed so that the Ca / P atomic ratio was 1.7. This mixture and ion-exchanged water were kneaded at a powder-liquid ratio of 2.5, and 2 minutes and 30 seconds after the start of kneading, a relative temperature of 100% and 50 ° C
It was transferred to a constant temperature bath. 15 minutes after kneading, 30 minutes after, 1
After 2 hours, 3 hours, 5 hours, and 10 hours, knead mixture 2
Each 0 g was taken out, lightly crushed, immersed in 200 m of methanol and stirred to stop the reaction. This was filtered, vacuum dried at room temperature, and then pulverized with a ball mill to obtain a reaction product (average particle size 3.1 μm).

The proportion of residual C4P in the reaction product (peak ratio before and after kneading at 29.2 °) and the state of hydroxyapatite formation were measured by X-ray diffraction to determine the proportion of HAP reaction product. The results are shown in Table 4.

Example 3 In Example 1, the reaction products of NO.4-1 to NO.4-4 obtained in Production Example 2 were replaced with HA instead of the reaction product obtained in Production Example 1.
The P reaction product was mixed so as to be 1.5 wt% of the whole, and the same measurement was performed. The results are shown in Table 5.

Example 4 C4P of Production Example 1 and various HPCPs of Table 6 were mixed so as to have a Ca / P atomic ratio of 1.67, and kneaded with ion-exchanged water at a powder-liquid ratio of 2.5, and kneading started for 2 minutes 30. Relative humidity 100 after seconds
%, The mixture was transferred to a 37 ° C. constant temperature bath and freeze-dried 3 hours after the start of kneading.

The above reactants were used in place of the reactants of Example 1 and HAP
The reaction product was mixed so as to be 1.5 wt% and the curing time was measured. The results are shown in Table 6.

Comparative Examples 3 to 5 C4P of Production Example 1 and calcium hydrogen phosphate dihydrate Ca /
The P atomic ratio was 1.67, and hydroxyapatite synthesized by the following dry method or wet method was added to the mixture at 2, 10 and 40 wt%, respectively. This with saline
The mixture was kneaded at a powder / liquid ratio of 2.5, and the curing time and operability were measured. The results are shown in Table 7.

[Dry method hydroxyapatite]

CaHPO ₄ · 2H ₂ O powder and CaCO ₃ powder were mixed so that the Ca / P atomic ratio was 1.67, and air containing saturated steam at 70 ° C was added at 6 per minute.
While blowing, it was baked at 1300 ° C. for 4 hours. This powder was crushed with a ball mill and passed through a 250-mesh sieve to obtain a dry process hydroxyapatite powder.

[Wet method hydroxyapatite]

0.5mo / calcium hydroxide suspension and 0.3mo /
The phosphoric acid aqueous solution of 4 to adjust the Ca / P atomic ratio to 1.67.
Mix at 0 ° C. and stir for 24 hours. The precipitate of the reaction solution was filtered and dried at 120 ° C. This powder was ground in a mortar and sieved with a 25-mesh sieve to obtain wet-type hydroxyapatite powder (1).

PH of 2mo / calcium nitrate solution 0.5 and 1.2mo / potassium dihydrogen phosphate solution 0.5 in ion-exchanged water 4
Was added dropwise so as to be in the range of 7.2 to 7.6, and the mixture was stirred at 40 ° C. for 24 hours. The precipitate of the reaction solution was filtered and dried at 120 ° C. This powder was crushed in a mortar and then sieved with a 250-mesh sieve to obtain a wet method hydroxyapatite powder (2).

Claims (1)

[Claims] 1. Tetracalcium phosphate having a Ca / P atomic ratio of 1.67.
Less than calcium phosphate and tetracalcium phosphate and Ca /
A curable composition comprising hydroxyapatite and / or a precursor thereof obtained by reaction with calcium phosphate having a P atom ratio of less than 1.67.