JPH06100410A - Calcium phosphate-based filler - Google Patents

Abstract

PURPOSE:To obtain a calcium phosphate-based filler which is packed in a deficient part or a void part of bone or tooth formed by diseased or surgical cause and integrated with hard tissue of organism with time. CONSTITUTION:A kneaded solution of tetracalcium phosphate powder, octacalcium phosphate powder and an aqueous solution of an organic acid, etc., is mixed with about 0.33mol% octacalcium phosphate based on tetracalcium phosphate remaining in a hardened material to give a calcium phosphate-based filler which contains no calcium hydroxide and consists substantially only of hydroxyapatite.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is to fill a defective portion or a void portion of bone and tooth caused by a pathological or surgical cause to facilitate the generation of new bone, and after the passage of time, it easily becomes a hard tissue of a living body. The present invention relates to a calcium phosphate-based filler that is integrated with.

[0002]

2. Description of the Related Art As a hard tissue substitute in the dental field, zinc phosphate cement, polycarboxylic acid cement, glass ionomer cement and the like have been conventionally used. In the medical field, methacrylate-based bone cement is used as a coalescing filler. However, these substitute materials are not biocompatible because they are different from the components of bone and tooth. Therefore, in order to solve the problem of poor biocompatibility, artificial bone made of alumina single crystal or alumina sintered body, which has relatively good compatibility with the living body, an artificial joint,
Artificial bones, artificial tooth roots, and the like made of an artificial tooth root or a sintered body of hydroxyapatite have been proposed.

Further, a cured product obtained by kneading α-tricalcium phosphate powder, which is said to be a precursor of hydroxyapatite, with an aqueous solution of an inorganic salt or an organic acid polymer (for example, JP-A-59-182263). Gazette)
Alternatively, a cured product obtained by kneading tetracalcium phosphate powder with an aqueous solution of acids (see, for example, JP-A-62-62).
-72363) is also known.

[0004]

However, the above-mentioned conventional techniques have the following drawbacks, respectively.
Although a biological tissue substitute composed of an alumina single crystal, an alumina sintered body, or a hydroxyapatite sintered body is suitable for use as an implant material, it is a kneading filler for the defect or void of bone and tooth. Alternatively, it has a drawback that it cannot be used as a bonding material. In addition, tricalcium phosphate powder or tetracalcium phosphate powder,
A cured product obtained by kneading with an aqueous solution of an acid or the like has a degree of biocompatibility obtained by converting most of the cured product into hydroxyapatite in a living body in a relatively short period of time. Unreacted tricalcium phosphate or tetracalcium phosphate gradually reacts with water to produce phosphoric acid or calcium hydroxide,
This is not preferable because it locally gives an acid or alkaline stimulus.

[0005]

The present invention is a calcium phosphate-based filler comprising tetracalcium phosphate, octacalcium phosphate and a kneading solution, which is based on tetracalcium phosphate remaining in the cured product. It relates to a calcium phosphate-based filler characterized by using about 0.33 mol% octacalcium phosphate. A cured product comprising a kneading solution of tetracalcium phosphate and an aqueous solution of an organic acid or an aqueous solution of an unsaturated carboxylic acid polymer is already well known. In this system, the concentration of the kneading liquid is usually about 20 to 60% by weight, and the powder-liquid ratio is in the range of 1.0 to 3.0, from the practical viewpoints such as curing time and cured product strength. . In these practical numerical ranges, the amount of tetracalcium phosphate is excessive with respect to the amount of the organic acid that is a curing agent, and the excess amount of tetracalcium phosphate is water (even when the kneading solution is not an aqueous solution, , Especially in the mouth, where there is always water around) to form calcium hydroxide. This calcium hydroxide production reaction is an equilibrium reaction that depends on the hydrogen ion concentration, and calcium hydroxide is produced stepwise, but in the end, all excess tetracalcium phosphate reacts with water. Then, hydroxyapatite and calcium hydroxide are converted into hydroxyapatite and calcium hydroxide, and this calcium hydroxide is sequentially reacted with octacalcium phosphate after generation to generate hydroxyapatite and water. And 1 mol of octacalcium phosphate and 1 mol of water react with each other to form 4 mol of hydroxyapatite).

After all, the calcium phosphate filler of the present invention contains octacalcium phosphate in an amount of about 0.33 mol% with respect to the tetracalcium phosphate which has not reacted with the curing agent and remains in the cured body. By the reaction, a calcium phosphate-based cured product that does not substantially contain calcium hydroxide and that finally consists essentially of hydroxyapatite is obtained. The reaction system produced by the cured product of the present invention is very complicated, and it is not possible to obtain a cured product produced solely from hydroxyapatite. The word “substantially” means the theoretical atomic ratio of calcium and phosphorus of hydroxyapatite (hereinafter, C
1.67 (referred to as a / P ratio), the cured product obtained by the present invention has a Ca / P ratio of 1.50 by elemental analysis.
It means in the range of 1.80.

The tetracalcium phosphate powder used in the present invention may be prepared by any method. For example, calcium hydrogen phosphate dihydrate and calcium carbonate may be used in a molar ratio. 1: 1 to mix evenly, 1250-
It is obtained by firing at a temperature in the range of 1650 ° C., preferably around 1600 ° C. for about 2 hours, and finely pulverizing the obtained tetracalcium phosphate with a ball mill or the like to obtain fine powder having a particle size of 44 μm or less. The octacalcium phosphate powder is obtained by, for example, uniformly mixing 0.33 to 0.40 mol of calcium carbonate with 1 mol of calcium hydrogen phosphate dihydrate, and purifying water at a temperature of 40 to 60 ° C. After reacting for 12 hours or more, filtering and drying, the obtained octacalcium phosphate is finely pulverized with a ball mill or the like to obtain fine powder having a particle size of 44 microns or less.

On the other hand, the kneading solution includes (1) an aqueous solution of an organic acid such as citric acid, malic acid, tartaric acid, malonic acid, lactic acid, glutaric acid, phytic acid, tricarballylic acid and tannic acid, and (2) acrylic acid. Acid, itaconic acid, fumaric acid, homopolymers or copolymers of unsaturated organic acids such as maleic acid, (3)
Orthophosphoric acid, pyrophosphoric acid, aqueous solution of inorganic acid such as hydrochloric acid, (4)
One or more selected from higher fatty acids such as palmitic acid, stearic acid, oleic acid, linoleic acid and linoleic acid, (5) alkyl glycols such as ethylene glycol and propylene glycol, or polyalkylene glycols such as polyethylene glycol and polypropylene glycol, or A mixture of two or more kinds can be used. Of these, preferred is an aqueous solution of an organic acid. For example, a 25 to 50 wt% aqueous solution of citric acid is preferred, and
About 20% by weight or less of citric acid in this aqueous solution may be replaced with malic acid, malonic acid, acrylic acid polymer or the like. Further, if necessary, a trace amount of an antibacterial agent such as chlorhexidine salt and benzalkonium chloride may be added.

In the present invention, for example, when an aqueous solution of citric acid is used as a kneading solution, the calcium ion of tetracalcium phosphate and the carboxyl group of citric acid are 1: 1.
However, excess tetracalcium phosphate reacts with water to produce calcium hydroxide. The amount of this excess tetracalcium phosphate was calculated from the amount of tetracalcium phosphate used, the concentration of the kneading liquid and the powder-liquid ratio, and about 0.33 mol% of the amount of octacalcium phosphate was calculated. use. The Ca / P of the cured product kneaded and cured by such an amount ratio is usually in the range of about 1.65 to 1.70, which confirms that the cured product substantially consists of hydroxyapatite. .

[0010]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples. In the following Examples and Comparative Examples, the conversion rate to hydroxyapatite was determined by adding a certain amount of standard substance (α- to a powder mixture containing hydroxyapatite).
Was added alumina), and measuring X-ray diffraction intensity of the mixture, the content of hydroxyapatite in the powder mixture: the diffraction intensity of the powder mixture containing X hydroxyapatite: I _HAp alpha-alumina diffraction intensity: as I _S , I _HAp / I _S values were plotted on the vertical axis and X values were plotted on the horizontal axis. A calibration curve was prepared, the diffraction intensity of the obtained cured product was measured, and the calibration curve was determined from this calibration curve.

Production Example 1 [Tetracalcium Phosphate Powder (hereinafter referred to as Powder I)] An equimolar mixture of calcium hydrogen phosphate dihydrate and calcium carbonate was sufficiently mixed to be uniform, and the mixture was heated to 1600 ° C.
After baking at the temperature of 2 hours, it was taken out into the open air and rapidly cooled. The fired product was crushed with a ball mill to obtain a powder or granule having a diameter of 44 microns or less. X-ray diffraction of the powder and granules was measured, and it was confirmed to be tetracalcium phosphate. Production Example 2 [Octocalcium phosphate powder (hereinafter referred to as powder II)] A mixture of 1 mol of calcium hydrogen phosphate dihydrate and 0.365 mol of calcium carbonate was sufficiently mixed to be uniform, and 40 A hydration reaction was carried out in purified water at ℃ for 24 hours, followed by filtration, washing with water several times, and drying. The product was crushed with a ball mill to give a powder or granule having a diameter of 44 microns or less. X of powder
The line diffraction was measured, and it was confirmed to be octacalcium phosphate.

Examples 1 to 3 A mixture of powder I and powder II in the proportions shown in Table 1 was mixed with a 45% by weight aqueous solution of citric acid as a kneading solution at a powder-liquid ratio of 1.5 and kneaded to obtain The cured product thus obtained was immersed in a HEPES buffer solution (artificial saliva). The cured product was taken out from the buffer solution after 3 days, 10 days and 30 days, and the conversion rate to hydroxyapatite was measured by the X-ray internal standard method. The results are shown in Table 1. In Examples 1 and 2, the conversion rate is 99.6%,
In Example 3, it was 100%, and it was confirmed that the cured product substantially consisted of hydroxyapatite.

[0013]

[Table 1]

Production Example 3 [β-tricalcium phosphate (hereinafter referred to as powder III)]
A mixture of 1 mol of β-calcium pyrophosphate obtained by calcining calcium hydrogen phosphate dihydrate at 850 ° C. for 7 hours and 1 mol of calcium carbonate was sufficiently mixed to obtain a uniform temperature of 1050 ° C. After calcination for 24 hours, the calcined product was crushed with a ball mill to obtain a powder or granule having a diameter of 44 microns or less. X-ray diffraction of the granular material was measured, and it was confirmed that it was β-tricalcium phosphate. Comparative Example 1 A mixture of 1 mol of powder I and 1.25 mol of powder III was mixed with a 45 wt% aqueous solution of citric acid as a kneading liquid at a powder-liquid ratio of 1.
The mixture was mixed and kneaded in 5, and the obtained cured product was measured for conversion to hydroxyapatite in the same manner as in the examples. As a result, the conversion rate was as low as 26.1% after 3 days, 30.8% after 10 days, and 66.6% after 30 days.

Comparative Example 2 A cured product was obtained in the same manner as in Comparative Example 1 except that 0.65 mol of calcium hydrogen phosphate dihydrate was used in place of the powder III, and the conversion rate to hydroxyapatite was obtained. It was measured. As a result, the conversion rate was as low as 52.9% after 3 days, 79.6% after 10 days, and 85.3% after 30 days. Comparative Example 3 A cured product was obtained in the same manner as in Comparative Example 1 except that only 1 mol of powder I was used as the powder, and the conversion rate to hydroxyapatite was measured. As a result, the conversion rate is 1 after 3 days.
7.0%, 22.1% after 10 days, 81.9 after 30 days
% Was low.

[0016]

EFFECTS OF THE INVENTION The calcium phosphate-based filler of the present invention does not produce an alkaline substance that causes local irritation, and the hardened material is substantially composed of hydroxyapatite, and therefore has excellent biocompatibility. ing. In addition, unlike a material such as an alumina sintered body that cannot be applied except as an implant material, it can be used as a kneading filler or a bonding material for a defective portion or void of bone and tooth.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Narumi Une 3-10 Nakamiyakitamachi, Hirakata-shi, Osaka Ube Industries Ltd. Hirakata Laboratory

Claims (1)

[Claims] 1. A calcium phosphate filler comprising tetracalcium phosphate, octacalcium phosphate and a kneading solution, which is about 0.33 mol% phosphoric acid based on the tetracalcium phosphate remaining in the cured product. A calcium phosphate-based filler characterized by using octacalcium.