JPH0768044B2 - Tetracalcium phosphate powder having apatite coating, method for producing the same, and tetracalcium phosphate-based curable composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to a tetracalcium phosphate powder having an apatite coating useful as a medical material, a dental material, etc., a tetracalcium phosphate curable composition having an apatite coating, and It relates to their manufacturing method.

In this specification, "part" and "%" mean "part by weight" and "% by weight", respectively.

Problems hydroxyapatite prior art _{is, Ca 10-z (HPO 4} ) z (PO 4) 6-z (OH) 2-z · n H 2 O ( where, n = 0~2.5, z = 0 It is a kind of calcium phosphate-based compound having a chemical composition represented by the formula (1) to (1) and most closely resembling the main components of teeth and bones in a living body, and is useful as a biomaterial.

In addition to hydroxyapatite, fluorapatite whose OH group is substituted with fluorine, carbonate apatite substituted with carbonic acid, and the like also have similar effects. In the present specification, these apatites are simply referred to as apatite.

On the other hand, tetracalcium phosphate represented by the composition formula Ca ₄ (PO ₄ ) ₂ O is also easily converted into compounds similar to the main components of bones and teeth in the body in the presence of water and acid. It has properties and is also useful as a biomaterial.

Apatite has been attracting attention as a biocompatible material for a long time and has already been put to practical use. However, apatite is a chemically very stable compound. Therefore, even if the powder is mixed with an aqueous solution of an organic acid or an inorganic acid, physiological saline, etc., it does not have curability. Therefore, when it is used as an artificial bone, a bone filling material, etc., it is molded beforehand. Or, it is necessary to use it in a granular form, and it is not necessarily easy to use clinically.
As a substance that eliminates these drawbacks, it has high chemical activity,
Tetracalcium phosphate, which has the property of being easily hardened at room temperature, has come to the fore, and the following methods have been proposed as the hardening method.

(1) A method of obtaining a curable composition by mixing with an aqueous solution of a TCA cycle organic acid such as citric acid or malonic acid.

(2) A method of obtaining a curable composition by mixing physiological saline, phosphate buffer or the like with an aqueous solution having a composition similar to the interstitial fluid in the body.

(3) A method of obtaining a curable composition by mixing with a polysaccharide aqueous solution.

(4) A method of obtaining a curable composition by mixing with an aqueous solution of a homopolymer or a copolymer of an unsaturated organic acid.

(5) By appropriately combining the methods (1) to (4),
A method of obtaining a curable composition.

The curable composition obtained by these methods is usually provided to clinicians in the form of a combination of a powder material and a liquid agent.
And, it is necessary for the clinician to knead and mix them at the time of treatment to make them paste-like or clay-like so that they can be used in any form, and after the treatment, they quickly harden and firmly adhere to the affected area. It is necessary to be immobilized on the skin and express excellent bioactivity. However, the above (1) to (5)
These required performances cannot be satisfied by any of the above methods. That is, since tetracalcium phosphate, which is the main component of the powder material, has a high chemical activity and is an alkaline substance, when it is mixed with an acidic aqueous solution, the curing reaction proceeds promptly and the appropriate softness is maintained for a certain period of time. It is difficult to obtain a uniform composition to hold.

Therefore, in order to prolong the time until the composition hardens, the acid concentration of the liquid agent is lowered or the water content in the composition is increased to secure the time for the therapeutic operation.
Further, in powder materials, attempts have been made to suppress the hardening reaction of tetracalcium phosphate as much as possible by blending apatite, tetracalcium phosphate, calcium monohydrogen phosphate and the like. However, even though these methods also markedly reduce the properties of the tetracalcium phosphate-based curing composition, no improvement in the curing reaction property to the extent of compensating for it is observed, and a fundamental improvement is required. I haven't arrived.

Attempts have also been made to mix tetracalcium phosphate powder with a neutral or near-neutral aqueous solution, but in this case, the curing reaction rate is significantly slowed down, and the tetracalcium phosphate-based cured composition is obtained. Not only is not expressed, but the resulting composition exhibits alkalinity and may be present as an irritant in the living body.

Due to the above reasons, the tetracalcium phosphate is a material suitable for use as a medical material and a dental material, but has a difficulty in handling and physical properties are not sufficiently exhibited, It has not yet been put to practical use as a tetracalcium phosphate-based curable composition having satisfactory properties.

Means for Solving the Problems The present inventor has conducted extensive studies in view of the current state of the art as described above, and as a result, in the case of coating the surface of the tetracalcium phosphate powder with a coating of apatite, It has been found that a material having both characteristics can be obtained and the problems of the prior art can be greatly reduced or substantially eliminated. It was also found that the curable composition obtained from the tetracalcium phosphate having the apatite coating film thus obtained has physical properties not inferior to known curable compositions.

That is, the present invention is the following tetracalcium phosphate powder,
Provided is a method for producing the same and a tetracalcium phosphate-based hardening composition: Tetracalcium phosphate powder having an apatite coating.

A method for producing a tetracalcium phosphate powder having an apatite coating, which comprises subjecting the tetracalcium phosphate powder to a hydration reaction treatment.

A tetracalcium phosphate-based curable composition comprising 100 parts of the above-mentioned tetracalcium phosphate powder and 5 to 80 parts of an acid aqueous solution (as an acid).

The aqueous acid solution is (a) TCA cycle carboxylic acid, (b) phosphoric acid, (c) general formula (In the formula, n is 50 to 50000) A homopolymer of acrylic acid represented by: (d) General formula (In the formula, 1 is 5 to 10, m is 1 to 5, and n is 50 to 50,000), and an acrylic acid-itaconic acid copolymer represented by the formula: (In the formula, 1 is 5 to 10, m is 1 to 5, and n is 50 to 50,000) 30 to 70% of at least one acrylic acid-fumaric acid copolymer represented by the above item. Tetracalcium phosphate curable composition.

The tetracalcium phosphate used in the present invention is not particularly limited in terms of its production method and the like, but it is preferable that the content of apatite, calcium oxide, etc. is as low as possible. Such high-purity tetracalcium phosphate can be produced, for example, by the solid phase reaction method described below in which CaCO ₃ powder and CaHPO ₄ .2H ₂ O powder are mixed and fired.

2CaCO ₃ + 2CaHPO ₄ · 2H ₂ O → Ca ₄ (PO ₄ ) ₂ O + 2CO ₂ + 5H ₂ O In the method for producing a tetracalcium phosphate powder having an apatite coating according to the present invention, first, tetracalcium phosphate is pulverized to a predetermined particle size. To do. The particle size is not particularly limited,
When used as a powder for a curable composition, usually 20
It is preferable to adjust to less than or equal to μm, and about 5 μm on average.

Then, such tetracalcium phosphate powder is subjected to a hydration reaction. The hydration reaction proceeds even by contacting tetracalcium phosphate powder with water, but in order to accelerate the reaction,
You may heat at about 80-100 degreeC, preferably to about 95 degreeC, or you may add a reaction accelerator to water. As the reaction accelerator, organic acids such as citric acid, lactic acid, tartaric acid, succinic acid and salts thereof; inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid and salts thereof; neutral to weakly alkaline such as phosphate buffer PH adjusting agents of These reaction promoters are usually used in the form of an aqueous solution having a concentration of 1% or less. In this hydration reaction, an apatite film is formed on the surface of the tetracalcium phosphate powder by the following reaction.

3Ca ₄ (PO ₄ ) ₂ O + 3H ₂ O → Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ + 2Ca (OH) ₂ apatite is very stable in an alkaline aqueous solution, so long as an apatite film can be formed, The treated water is preferably alkaline. PH of treated water is 7-8
In the following cases, octacalcium phosphate may be produced in addition to apatite. Since octacalcium phosphate is a precursor of apatite, the coating does not necessarily have to be high-purity apatite.For example, a mixture of apatite and octacalcium phosphate or a high-purity octacalcium phosphate coating may be used. However, there is no problem in practical use. In the above reaction, since calcium hydroxide is eluted into the treated water at the same time as the formation of apatite, it is not necessary to add a basic substance, but an apatite film is well formed even in an aqueous solution adjusted to be alkaline in advance. . Once the apatite coating is formed, the rate of the above reaction decreases sharply, so unless water or acid aqueous solution is newly added,
The powder surface is not activated. Therefore, deterioration of the quality of the tetracalcium phosphate particles due to excessive progress of the reaction does not occur.

As another method for carrying out the hydration reaction, a) a method of contacting with steam, b) a method of using water in the atmosphere to react at high temperature, and c) a method of combining a) and b) are also effective. Is.

In the method a), if the temperature of water vapor is 100 ° C. or lower,
The treatment time is almost the same as the treatment in water. At 100 ° C or higher, the treatment time is shortened as the temperature rises. For example, in the case of air blending steam and tetracalcium phosphate powder at 300 ° C, the treatment time of 1 to 120 seconds is sufficient. Is 30 to 60 seconds.

In the method of b), tetracalcium phosphate is about 300 ° C to 120 ° C.
It utilizes the property of actively absorbing moisture in the atmosphere and converting it to apatite in the range of 0 ° C. For example, 50
When air blending the air heated to 0 ° C. and the tetracalcium phosphate powder, the treatment time is from 1 second to
120 seconds is sufficient, preferably 30 to 60 seconds.

The method c) is a method of performing the surface treatment while controlling the partial pressure of water vapor in the atmosphere and the temperature, and the method a) and the method b).
It can be said to be a combination of and. For example, in the case of air blending air having a water vapor partial pressure of 15 Torr at 350 ° C. and tetracalcium phosphate powder, a treatment time of 1 second to 120 seconds is sufficient, and preferably 30 seconds to 6 seconds.
0 seconds.

Furthermore, the following method is effective as a method for producing a tetracalcium phosphate powder having a double structure without subjecting it to a hydration reaction.

a) A method of adsorbing and immobilizing ultrafine apatite on the surface of tetracalcium phosphate particles.

b) A method in which apatite is made into a liquid form and attached (or vapor-deposited) and immobilized on the surface of tetracalcium phosphate particles.

The advantage of these methods is that the surface coating material is not limited to apatite. That is, any substance may be used as long as it is a substance that is gradually dissolved in the acidic aqueous solution. However, when used as a biomaterial, a substance harmless to the living body (for example, tricalcium phosphate,
It is preferred to use (e.g. calcium monohydrogen phosphate).

In the tetracalcium phosphate-based curable composition according to the present invention, the tetracalcium phosphate powder having the apatite coating formed as described above is admixed with 5 to 80% (as acid) of the organic acid aqueous solution of the powder weight. Can be obtained. The particle size of the tetracalcium phosphate powder formed with the apatite coating is also
Usually, it is preferably 20 μm or less, and about 5 μm on average.

The following can be used as the organic acid.

(A) TC such as citric acid, tartaric acid, malonic acid, malic acid, maleic acid, lactic acid, succinic acid, fumaric acid, ascorbic acid, succinic acid, gluconic acid, glutaric acid and pyruvic acid
A cycle carboxylic acids.

(B) phosphoric acid, (c) general formula (In the formula, n is 50 to 50000) A homopolymer of acrylic acid represented by the formula:

(D) General formula (In the formula, 1 is 5 to 10, m is 1 to 5, and n is 50 to 50,000.) An acrylic acid-itaconic acid copolymer.

(E) General formula (In the formula, 1 is 5 to 10, m is 0 to 5, and n is 50 to 50,000.) An acrylic acid-fumaric acid copolymer.

These acids can be used alone or in the form of a mixture of two or more kinds, and are usually used in the form of an aqueous solution containing pure water having a concentration of about 30 to 70% as a solvent.

The tetracalcium phosphate-based curable composition thus obtained, unlike conventional products, does not impair any of the physical properties specific to tetracalcium phosphate and has sufficient useful properties of tetracalcium phosphate. It is possible to further improve those physical properties while exhibiting the above. Therefore, such a curable composition is useful as a biomaterial such as a medical material or a dental material.

Effects of the Invention According to the present invention, the following remarkable effects are obtained.

(1) An apatite film can be formed on the surface of tetracalcium phosphate powder by a simple operation without requiring a special device.

(2) The tetracalcium phosphate powder coated with apatite has stable quality over a long period of time, is excellent in weathering resistance, and is excellent in storage stability.

(3) While maintaining various useful properties of tetracalcium phosphate as a biomaterial, physical and engineering properties are also improved.

(4) By controlling various conditions of the surface treatment, a composition having various curing characteristics can be obtained, so that the range of application of tetracalcium phosphate as a biomaterial is widened.

Examples Hereinafter, reference examples, examples and comparative examples will be shown to further clarify the features of the present invention.

Reference Example 1 Powdered CaCO ₃ having an average particle size of about 5 μm and CaHPO ₄ .2H ₂ O were mixed at a molar ratio of Ca / P = 2, and molded to obtain 1600 in air.
Maximum particle size of 20μm after firing at ℃ for 3 hours to obtain a sintered body
Then, the powder was pulverized to an average particle size of about 5 μm to obtain tetracalcium phosphate powder.

The X-ray diffraction result of the product is shown in FIG. From the results shown in FIG. 1, it is clear that the product is a high-purity product consisting essentially of tetracalcium phosphate.

In the following examples, the high-purity tetracalcium phosphate thus produced was used.

Example 1 To 10 g of tetracalcium phosphate powder, 20 g of purified water at 95 ° C. was added,
Make 7 sets of sealed samples, and cure them in a 95 ° C constant temperature bath for 1 hour, 3 hours, 24 hours, respectively.
Remove after 7, 14, 30 and 60 days
After drying at 5 ° C, the obtained powder was subjected to X-ray diffraction measurement.
The results are shown in FIGS.

From FIGS. 2A to 2G, it can be seen that tetracalcium phosphate is gradually converted into hydroxyapatite. It is also found that tetracalcium phosphate is relatively stable and continues to exist for a long period of time even in hot water.

Example 2 2 g of tetracalcium phosphate powder was dispersed in purified water 1 and
After heating at ℃ and 95 ℃ for 5 hours, it was filtered off and air-dried for 24 hours, and the obtained powder was subjected to X-ray diffraction.

The X-ray diffraction results of the product are shown as H and I in FIG.

From the results shown in FIG. 2, it is clear that the tetracalcium phosphate according to the present invention stably exists even in excess water.

Example 3 20 g of purified water was added to 10 g of tetracalcium phosphate powder, and surface treatment was performed under the conditions (combination of temperature and time) shown in Table 1, followed by filtration and air drying for 24 hours. A curable composition powder was obtained. The numbers 1 to 40 in Table 1 indicate sample numbers.

Next, a citric acid aqueous solution having a concentration of 40% was mixed with the above powder to obtain a curable composition, and the curing time of each was measured. The mixing ratio of the powder material and the aqueous solution is 2.3 g / ml.

The results are shown in Table 2.

Example 4 100 g of tetracalcium phosphate powder was mixed with 200 g of distilled water at 95 ° C.
After stirring for 1 hour and separating, the mixture was dried at 105 ° C. for 24 hours, and the obtained tetracalcium phosphate powder having an apatite coating was mixed under the following conditions to obtain a curable composition.

(B) Aqueous solution with citric acid concentration of 40% powder / liquid ratio = 2.4 (g / m
l) was mixed.

(B) An aqueous solution having a citric acid concentration of 40% and a polyacrylic acid concentration of 5% was mixed at a powder / liquid ratio of 2.2 (g / ml).

(C) An aqueous solution having a citric acid concentration of 38%, a tartaric acid concentration of 1% and a polyacrylic acid concentration of 2.5% was mixed at a powder / liquid ratio of 2.2 (g / ml).

(D) An aqueous solution having a citric acid concentration of 29%, a malonic acid concentration of 10% and a polyacrylic acid concentration of 2.5% was mixed at a powder / liquid ratio of 2.3 (g / ml).

(E) An aqueous solution having a citric acid concentration of 40% and a phosphoric acid concentration of 20% was mixed at a powder / liquid ratio of 2.0 (g / ml).

The curable composition thus obtained was measured for (1) curing time, (2) crushing strength (kg f / cm ² ) after 24 hours and (3) film thickness according to the test method of JIST6602. did.

The results are as shown in Table 3.

Table 3 Mixing conditions (1) (2) (3) (a) 6 minutes 30 seconds 984 24 μm (b) 6 minutes 30 seconds 1239 29 μm (c) 5 minutes 30 seconds 1019 38 μm (d) 5 minutes 30 seconds 1123 25 μm (E) 4 minutes 45 seconds 1472 41 μm Comparative Example 1 A curable composition was obtained in the same manner as in Example 4 except that tetracalcium phosphate which was not surface-treated was used.

The results measured in the same manner as in Example 4 are as shown in Table 4. In Table 4, (a) to (e) and (1) to (3) mean the same items as in Table 3.

Table 4 Mixing conditions (1) (2) (3) (a) Within 30 seconds Unmeasurable measurement Unavailable (b) Within 30 seconds Unavailable measurement Unavailable (ha) Within 30 seconds Unavailable measurement (d) Within 30 seconds Unmeasurable Unmeasurable (e) Within 30 seconds Unmeasurable Unmeasurable As is clear from the results shown in Table 4, under the same solvent admixture conditions as in Example 4, all compositions were almost instantaneous. It cures within a short enough time and is easy to handle.
It was not possible to obtain a soft curable composition.

Comparative Example 2 By using tetracalcium phosphate without surface treatment, the amount of an acidic aqueous solution mixed to obtain a curable composition whose physical properties can be measured was increased, and the rest was cured under the same mixing conditions as in Example 4. A sex composition was obtained.

(F) Powder / liquid ratio of the aqueous solution of (a) of Example 4 = 1.5 (g / m
l) was mixed.

(G) Powder / liquid ratio of the aqueous solution of (b) of Example 4 = 1.5 (g / m
l) was mixed.

(H) Powder / liquid ratio = 1.5 (g / m) of the aqueous solution of (c) of Example 4
l) was mixed.

(I) Powder / liquid ratio of the aqueous solution of (d) of Example 4 = 1.5 (g / m
l) was mixed.

(G) Powder / liquid ratio = 1.5 (g / m) of the aqueous solution of (e) of Example 4
l) was mixed.

The results are shown in Table 5.

Table 5 Mixing conditions (1) (2) (3) (f) 4 minutes 593 46 μm (g) 3 minutes 50 seconds 612 52 μm (ch) 3 minutes 05 seconds 623 73 μm (ri) 2 minutes 40 seconds 671 107 μm (nu ) 1 minute 55 seconds 819 113 μm

[Brief description of drawings]

FIG. 1 is a chart showing the X-ray diffraction results of the tetracalcium phosphate powder used in each example of the present application. FIG. 2 is a chart showing the X-ray diffraction results of the tetracalcium phosphate powder having the apatite coating obtained in Example 1 of the present application. FIG. 3 is a chart showing the X-ray diffraction results of the tetracalcium phosphate powder having the apatite coating obtained in Example 2 of the present application.

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Claims (4)

[Claims] 1. A tetracalcium phosphate powder having an apatite coating. 2. A method for producing a tetracalcium phosphate powder having an apatite coating, which comprises subjecting the tetracalcium phosphate powder to a hydration reaction treatment. 3. A tetracalcium phosphate-based curable composition comprising 100 parts of the tetracalcium phosphate powder of claim 1 and 5 to 80 parts of an aqueous acid solution (as an acid). 4. An aqueous acid solution comprising: (a) TCA cycle carboxylic acid, (b) phosphoric acid, (c) general formula (In the formula, n is 50 to 50000) A homopolymer of acrylic acid represented by: (d) General formula (In the formula, 1 is 5 to 10, m is 1 to 5, and n is 50 to 50,000), and an acrylic acid-itaconic acid copolymer represented by the formula: (In the formula, 1 is 5 to 10, m is 1 to 5, and n is 50 to 50,000) 30 to 70% of at least one acrylic acid-fumaric acid copolymer represented by the formula: Tetracalcium phosphate curable composition.