JPH01301543A - Curable composition - Google Patents

Abstract

PURPOSE:To obtain a curable composition, consisting of tetracalcium phosphate, calcium phosphate at a prescribed atomic ratio (Ca/P) and hydroxyapatite prepared by reaction of both and capable of rapidly forming a cured product of hydroxyapatite and providing a filler having excellent affinity. CONSTITUTION:The above-mentioned curable composition is constituted of tetracalcium phosphate (C4P), calcium phosphate (HPCP) at <1.67 atomic ratio (Ca/P) and hydroxyapatite and/or precursor (HAP reaction product) obtained by reaction of both the afore-mentioned phosphates. If the mixing ratio of the mixture of the above-mentioned HPCP with the C4P is regulated so as to provide 1.3-1.8 molar ratio (Ca/P), the HAP is efficiently produced to enhance the strength of the cured product. The HPCP and C4P are used in a powdery form. The HPCP having <50mum average particle diameter and the C4P having 0.1-100mum average particle diameter are respectively preferably used.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel curable composition for filling bone defects and voids in living organisms, or tooth defects.

Specifically, it is a curable composition that rapidly forms a cured hydroxyapatite upon contact with water and becomes a filler with excellent affinity.

[Conventional technology]

In the field of surgery and orthopedics, bone defects or voids occur due to traffic accidents, bone tumor resection, etc., and in the field of dentistry, due to alveolar pyorrhea, alveolar bone resorption, tooth extraction, caries removal, etc. Filling such bone defects or voids,
Various materials are used for prosthetics, such as bone bones, polymers, metals, and ceramics. Among these, autologous bone is extremely superior in terms of its excellent osteogenic ability and low rejection reaction.

However, autologous bone must be harvested from the patient's normal tissue, which not only involves great pain during surgery, but also
In many cases, it is not possible to secure sufficient quantities.

Therefore, in recent years, hydroxyapatite has begun to be used as a material to replace autologous bone. Hydroxyapatite can be synthesized or obtained by burning animal bones and removing organic components, and is known to have very high biocompatibility. However, when hydroxyapatite is used as a filler in the form of fine powder or granules, it has been pointed out that there is a problem that blood may leak out due to body fluids or leak as foreign matter even after suturing.

As a method to solve the above problems, a composition that generates hydroxyapatite and hardens by filling a mixture of tetracalcium phosphate and other calcium phosphate salts either as powder or after kneading with water is proposed. Proposed. (USP 4s18430)L However, this composition has a slow curing time of 20 to 30 minutes, which prevents leakage due to blood and body fluids during bone filling, or when used as a tooth lining material, making it impossible to proceed to the next operation. Problems such as these have been pointed out. Therefore, as a way to speed up the curing time,
Fluorides such as sodium fluoride and calcium fluoride, or calcium hydroxide and phosphoric acid, or calcium salts such as calcium nitrate and calcium acetate, and hydroxyl obtained from phosphates such as potassium hydrogen phosphate and ammonium hydrogen phosphate. Addition of apatite, etc. is being considered. However, when using fluoride as a filler in the body, there is a problem that it is harmful, and addition of the above-mentioned hydroxyapatite requires a large amount of 24 to 43%.
There are problems such as extremely poor operability and decreased compressive strength.

[Means for solving problems]

The present inventors have conducted extensive research in order to solve the above problems. As a result, the tetracalcium phosphate hca/P atomic ratio was 1.
．． In a curable composition comprising calcium phosphate having a Ca/P atomic ratio of less than 1.67, hydroxyapatite and/or its precursor obtained by the reaction of tetracalcium phosphate and calcium phosphate having a Ca/P atomic ratio of less than 1.67 is added to the composition. It was discovered that by doing so, the curing time can be significantly accelerated without causing problems such as toxicity and operability, and the present invention has been completed.

In the present invention, tetracalcium phosphate has a Ca/P atomic ratio of 1.
Hydroxyapatite and/or its precursor obtained by the reaction of calcium phosphate and tetracalcium phosphate with a Ca/P atomic ratio of less than 1.67 (hereinafter collectively referred to as HAP reaction products) This is a curable composition consisting of:

Tetracalcium phosphate (hereinafter abbreviated as C4P) used in the curable composition of the present invention may be produced by any method. The raw material is CaC0, as a Ca source.
CaO1Ca (OH) t, P2O5゜H as P source
2PO4, NHJzPO4, (NH4)11) IPO4
, Ca1lPO4・2HzO containing both Ca and P
, CaHPa, Ca(HzPOn)z, Ca2Pz
Although there are various manufacturing methods depending on the raw materials, γ- obtained by calcining known CaHPO4.2H,O
A dry manufacturing method in which Ca, P, and 07 are mixed and fired with CaCO5 is suitable.

This reaction is 2CaHPOa・2HzO−T CazPzOy +
58zOCazPzOt + 2CaCO3-Ca2
It is shown by the reaction formula of P2O, + 2CO2, and is either quenched outside the furnace after firing at 1200°C or higher, or heated at 1200°C in a nitrogen atmosphere.
If fired at temperatures below -F, pure C4P can be obtained without being transformed into hydroxyapatite.

In addition, in the present invention, Ca mixed with the above-mentioned C4P
/P molar ratio of less than 1.67 calcium phosphate (hereinafter referred to as
Various types of HPCP (abbreviated as HPCP) can be used. For example, Ca(HzPOi)i・HgO, CaHPO4゜2
HzO+ Ca) IP04. Caalt(PO4)b・
5) 1zO1Caz(POs)z+C'a z P z
'o? Among them, Ca11P04・2
112 o.

CaHPOa is particularly suitable in terms of mechanical properties, operability, and storage stability of the cured product. For example, as HPCP
When aHPO4.2■20 is used, the reaction formula is expressed as the following formula, and hydroxyapatite is produced.

2 CaaPzOq + 2CaHPO4・2HzO−
Calo(POa>b(OH)t + 21bO In the present invention, the mixing ratio of the mixture of HPCP and C4P described above may be adjusted so that the Ca/P molar ratio is 1.3 to 1.8. This is preferred in order to efficiently generate hydroxyapatite and increase the strength of the resulting cured product.

Moreover, the above-mentioned HPCP and C4P are used in powder form in -g. In this case, the particle size and shape are not particularly limited, but in order to accelerate the curing speed and improve the powder-liquid ratio when mixed with water, HPcp has an average particle size of less than 50μ, preferably 0.1 to 10μ. It is preferable to use particles having an average particle size of 0.1 to 100 μm, preferably 0.5 to 50 μm, respectively. Further, the shape is particularly preferably spherical.

The characteristics of the cured composition of the present invention are the above-mentioned HPCP and C
It contains HAP reaction products along with 4P.

In the present invention, the HAP reaction product may be entirely hydroxyapatite, but it is particularly preferable that part or all of it 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 and C4P in the presence of water.

Among them, in X-ray diffraction, the peak height of the raw material C4P is about 90% or less, preferably 10 to 80% of that before reaction.
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.

In addition, among the above-mentioned examples, examples of HPCP include Ca)lP
O4.2)1go and Ca)1PO4 are preferred.

The method for producing the HAP reaction product is not particularly limited. To give an example of a typical manufacturing method, C4P and HPCP are
An example of the method is to knead a mixture with water so that the a/P atomic ratio is 1.3 to 1.8, and then dry the mixture during the reaction. The mixing ratio of the mixture and water is 10/1-
A range of 1/10, more preferably 571 to 1/2 is suitable. The holding temperature after kneading is not limited as long as it is 0°C or higher, but considering the reaction rate and drying, it is 20 to 60°C.
A range of is suitable.

Since the reaction of the mixture of C4P, HPCP and water proceeds in the presence of water, the reaction can be stopped by drying during the reaction and removing water. The drying method is not particularly limited, but may include freeze-drying, organic solvent immersion,
Spray drying methods, heating concentration methods, etc. are generally used.

Among these, the freeze-drying method and the organic solvent immersion method are suitable as methods that can stop the reaction in a short time. In the freeze-drying method, a HAP reaction product can be obtained by freezing a kneaded product in a freezer, dry ice, liquid nitrogen, etc., and then dehydrating it in vacuum. The organic solvent immersion method uses an organic solvent that is soluble in water,
For example, the kneaded product is immersed in methanol, ethanol, isopropyl alcohol, acetone, etc. to dehydrate and stop the reaction. Next, filter and dry the HA.
A P reaction product can be obtained.

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

In the present invention, the HAP reaction product is HPCP and C4
Rather than complete hydroxyapatite obtained by reaction with P, it is more effective and preferable to add one containing its precursor or only the precursor.

In the present invention, the proportion of the HAP reaction product to be used varies somewhat depending on the purpose of use and at which stage the HAP reaction product is added, but in general, it is hydroxyapatite and/or The precursor is 0.1% relative to the total amount of HPCP and C4P.
~20 Wtχ, preferably 0.2~1 Ovtχ is suitable. That is, when the proportion of the HAP reaction product used is less than the above range, the effect of shortening the curing time is small, and when it is greater, the strength of the cured product tends to decrease.

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

Depending on the purpose of use, the curable composition of the present invention may be used as a powder and cured by reaction with moisture in the body, or it may be used after being kneaded with a kneading liquid in advance.

When using a kneading solution, water or physiological saline is generally used. Moreover, other components can be added to the kneading liquid as necessary. For example, in order to adjust the curing time, 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.

Furthermore, the cured composition of the present invention can be made into a paste by using a liquid organic compound as a kneading liquid in advance, and after being implanted in the body or in the body, it can be cured by reacting with body fluids.

The powder-liquid ratio of the powder of the hydraulic composition of the present invention and the kneading liquid may be determined as appropriate to obtain a suitable viscosity depending on the application.

Generally, the viscosity of the resulting kneaded product after 1 minute of kneading is lO~
The powder/liquid ratio may be adjusted to be 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 material is 1
It is desirable to adjust the powder/liquid ratio so that it becomes 0.00 to 5000 voids.

[For production]

In the present invention, the reason why the curing time of the resulting curable composition is shortened by the addition of the HAP reaction product is not clear, but the present inventors believe that the HAP reaction product merely acts as a crystal nucleus. This is thought to be due to the fact that it not only acts as a crystal growth accelerator, so the time for crystal formation is shorter than when using only C4P and HPCP or when adding hydroxyapatite obtained by other methods. .

〔effect〕

The curable composition of the present invention effectively increases the curing time without impairing properties such as operability, safety, and strength by adding a HAP reaction product to the curable component consisting of C4P and HPCP. Can be shortened. Therefore, it is suitable as a dental restorative material such as backing material, luting cement, filling cement, root canal filling material, covering material, periodontal pocket filling material, or orthopedic restorative material such as bone filling material and bone cement. It can be used for.

〔Example〕

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples. still,
The definitions of various quantities related to the properties of materials shown in the text and in the examples and the methods for measuring them are as follows.

(11 average particle size The obtained particles are dispersed in isopropyl alcohol,
Measurement was performed using a particle size distribution meter (CAPA-500, manufactured by Horiba, Ltd.). The measurement principle is centrifugal sedimentation.

(2) Using a structural X-ray diffraction measurement device (JEOL Ltd.) to measure the reaction product X
Linear diffraction was measured to identify the remaining amount of raw materials and the structure of the reaction product.

(3) Curing time of kneaded product A polyvinyl chloride mold with an inner diameter of 20 mm and a thickness of 3 mm was filled with the kneaded product kneaded for 1 minute, and its surface was flattened. When 2 minutes and 30 seconds had passed from the start of kneading, the mixture was transferred to a constant temperature bath at a temperature of 37° C. and a relative humidity of 100%. Then, a Gilmore needle weighing 114.12 g (needle cross-sectional area 4
．． 91 fin) was gently dropped onto the surface of the test piece, and the time when no needle marks were left was defined as the curing time starting from the start of kneading.

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

That is, the kneaded product kneaded for 1 minute was placed in a mold, 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 are cylindrical with 12 cranes x 6 dragons φ. After that, this test piece was further kept in distilled water at 37°C for 23 hours, and then processed using a universal testing machine Tensilon (manufactured by Toyo Baldwin) at a crosshead speed of 0.5 hours per minute until the test piece was crushed. I pressed it.

The crushing resistance at this time was defined as the compressive strength (kgloll).

Production Example 1 CaHPO, -2H□O was calcined at 500°C for 2 hours to obtain rCazPz07. This powder and CaCO3 powder were mixed at a ratio of 1:2 (molar ratio), fired in air at 1400°C for 2 hours, and then rapidly cooled outside the furnace. The generated powder is C
It was confirmed from X-ray diffraction that it was 4P. This C4P was ground in an alumina ball mill for 10 hours. Pass this through a sieve with a mesh size of 250 mesh, and CAPFA
A powder (average particle size: 5.3 μm) was obtained.

The above C4P and calcium hydrogen phosphate dihydrate (average particle size 5.2717 m) were mixed so that the Ca/P atomic ratio was 1.67. Add this mixture and ion exchange water to 2.0
2 minutes and 30 seconds after starting kneading, the relative humidity was 1.
00%, transferred to a constant temperature bath at 37°C, and 15 minutes after starting kneading,
After 30 minutes, 1 hour, 3 hours, 5 hours, 10 hours, and 24 hours, a portion of the kneaded product was taken out and frozen with liquid nitrogen to stop the reaction. This sample was transferred to a vacuum desiccator, freeze-dried using a vacuum pump, and then pulverized using a ball mill to obtain a reaction product (average particle size: 2.2 μm).

The residual proportion of C4P in the reaction product was determined by X, v1 diffraction (
The peak ratio before and after kneading at 29.2°) and the state of hydroxyapatite formation were measured, and the proportion of the HAP reaction product was determined. The results are shown in Table 1.

Example 1 Comparative Example 1 C4P and calcium hydrogen phosphate anhydride of Production Example 1 were
/P atomic ratio of 1.67. This mixture and Production Example 1
I got it. The reaction products of N11-1 to l1hl-4 were converted into HAP
The reaction products were mixed so that the total weight was 2wtχ to obtain a curable composition. Each curable composition was kneaded with ion-exchanged water at a powder/liquid ratio of 2.5, and the curing time, operability, and compressive strength were measured. The results are shown in Table 2. As a comparison,
Comparative Example 1 shows the results without adding the HAP reaction product.

Example 2 Comparative Example 2 C4P of Production Example 1 and calcium hydrogen phosphate dihydrate were
They were mixed at an a/P atomic ratio of 1.67. The reactant of Production Example 1kkl-3 was added to this mixture so that the HAP reaction products had the proportions shown in Table 3, to prepare a curable composition. This was mixed 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 results obtained when no reaction product was added are shown in Comparative Example 2.

Production Example 2 C4P from 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 mixed at a powder/liquid ratio of 2.
5, and 2 minutes and 30 seconds after the start of mixing, the relative humidity is 100%.
, and transferred to a constant temperature bath at 50°C. 15 minutes after starting kneading, 30 minutes
After minutes, 1 hour, 3 hours, 5 hours, and 10 hours, take out 20g of the kneaded material and lightly crush it to 200m+
The reaction was stopped by immersion in methanol (No. 2) and stirring. This was filtered, dried under vacuum at room temperature, and then ground in a ball mill (average particle size: 3.1 μm) to obtain a reaction product.

The residual proportion of C4P in the reaction product was determined by X-ray diffraction (29,2
The ratio of the peaks before and after kneading at 50°C and the state of hydroxyapatite formation were measured, and the proportion of the HAP reaction product was determined. The results are shown in Table 4.

Example 3 In Example 1, the reaction product of Nl14-1-11h4-4 obtained in Production Example 2 was used instead of the reaction product obtained in Production Example 1, so that the total HAP reaction product was 1.5wtχ The mixture was mixed and the same measurements were performed. The results are shown in Table 5.

Example 4 C4P of Production Example 1 and various HPCPs of Table 6 were mixed so that the Ca/P atomic ratio was 1.67, and mixed with ion-exchanged water.
．． The mixture was kneaded at a powder/liquid ratio of 5, and 2 minutes and 30 seconds after the start of kneading, the mixture was transferred to a constant temperature bath at 37° C. with a relative humidity of 100%, and freeze-dried 3 hours after the start of kneading.

Using the above reactants in place of the reactants of Example 1, HAP
The reaction products were mixed to a concentration of 1.5 wtX, 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
/P atomic ratio of 1.67, and to this mixture were added 2.10.40-Lχ of hydroxyapatite synthesized by the following dry method or wet method, respectively. This was mixed with physiological saline 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]

CatlPOa-2H20 powder and (1:acO+ powder were mixed so that the Ca/P atomic ratio was 1.67, and the mixture was heated at 70°C.
13 while blowing air containing saturated water vapor at 61 per minute.
It was baked at 00°C for 4 hours. This powder was ground in a ball mill and passed through a 250 mesh sieve to obtain a dry hydroxyapatite powder.

[Wet method hydroxyapatite]

0.5 mol/β calcium hydroxide suspension and 0.3 m
o 1/1 phosphoric acid aqueous solution with a Ca/P atomic ratio of 1.
The mixture was mixed at 40° C. and stirred for 24 hours.

The precipitate of the reaction solution was filtered and dried at 120°C.

This powder was ground in a mortar and passed through a 25 sieve sieve to obtain a wet hydroxyapatite powder (1).

2mo7! /j! Calcium nitrate solution 0.51 and 1.2
mol/7! Potassium dihydrogen phosphate solution 0.51
was added dropwise to ion-exchanged water 41 so that the pH was 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 ground in a mortar and passed through a 250 sieve sieve to obtain a wet hydroxyapatite powder (2).

・-i-1 for i-1

Claims (1)

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