JP2005095346A - Material for cement, and cement - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a material for cement and cement which harden without accompanying a pH change at the time of hardening, and have good biocompatibility and compression strength. <P>SOLUTION: This material for cement contains a fine crystal in which an inositol phosphate, a phytic acid or their salt is adsorbed on the surface of a calcium compound. Alternatively, the material for cement comprises a fine crystal of hydroxyapatite and the inositol phosphate or the phytic acid or their salt. For this cement, one of the materials for cement is kneaded in an aqueous solvent, and is hardened. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a cement material and cement.

Calcium phosphate is a group of bioactive materials having almost the same composition and structure as inorganic substances found in hard tissues such as vertebrate bones and teeth, and exhibiting biocompatibility.
In particular, hydroxyapatite does not cause rejection of the living body or necrosis even when implanted in the living body, and has the property of being easily assimilated and adhered to the living hard tissue. ing. The material forms of hydroxyapatite include dense bodies, porous bodies, granules, cement, and the like, but apatite cement that can be molded into an arbitrary shape is a material that is expected to develop in the future.

  However, it is known that the conventional apatite cement has a long setting time and a long bone induction period of 4 to 5 weeks from the time it is embedded in the living body until the adhesion and bonding to the living hard tissue starts. Since this property is related to patient pain, it is regarded as one of the drawbacks of the current apatite cement (Patent Document 1). Moreover, the conventional apatite cement has a fault weak in bending strength (nonpatent literature 1). In addition, since the conventional apatite cement is accompanied by an acid / base reaction when it is cured, there is a problem that local pH fluctuation occurs before it is cured in the living body, and an inflammatory reaction is induced.

  In addition, cement made of β-tricalcium phosphate is used as a part for transplanted bone collection or as a replacement material after tumor resection, but it is widely used for long bones that support high loads such as the femur and tibia. Adaptation to deficiency has not been established yet. This is because a bone bonding force sufficient to withstand excessive stress generated at the interface between the loaded long tubular bone and the artificial bone cannot be obtained in a short period of time. The cement made of β-tricalcium phosphate is gradually replaced with living bone, but it takes a long time, so that it is difficult to use it for the load part without other fixing materials in actual treatment (Non-patent Document 2). ).

Japanese Patent Laid-Open No. 5-229807 Takafumi Kanazawa "Rin", pages 65-86 (Kenseisha, 1997) The Chemical Society of Japan, 6th edition, Chemical Handbook, Applied Chemistry II, page 1485 (Maruzen, 2003)

  The problem to be solved by the present invention is to provide a cement material and cement which are cured without changing pH during curing and have good biocompatibility and compressive strength.

The above object of the present invention has been achieved by the following means.
(1) A cement material comprising microcrystals in which inositol phosphate or phytic acid or a salt thereof is adsorbed on the surface of a calcium compound,
(2) The cement material according to (1), wherein the molar ratio of inositol phosphate or phytic acid or a salt thereof and a calcium compound is 0.001 to 0.1,
(3) The cement material according to (1) or (2), wherein the calcium compound is calcium phosphate and / or calcium carbonate,
(4) The cement material according to (3), wherein the calcium phosphate is hydroxyapatite,
(5) A cement material, characterized by comprising hydroxyapatite microcrystals and inositol phosphate or phytic acid, or a salt thereof,
(6) Cement characterized in that the cement material according to any one of (1) to (5) is kneaded in an aqueous solvent and cured.

  The material for cement of the present invention hardens without causing a change in pH, and gives a cement excellent in biocompatibility and compressive strength. The cement according to the present invention is filled in a bone defect or void, facilitates the generation of new bone, and easily integrates with the hard tissue of a living body.

The cement material of the present invention will be described.
In the present invention, microcrystals in which inositol phosphate or phytic acid or a salt thereof is adsorbed on the surface of a calcium compound are used as a cement material (hereinafter also referred to as “cement material I”).
Here, the microcrystal of the calcium compound refers to a crystal having an average particle diameter of about 1 μm to about 1 mm. Prior to adsorption, the microcrystals are preferably used after being purified by a recrystallization method, if necessary. In addition, it is preferable to use a calcium compound having a uniform particle size by classifying the microcrystals by dry sieving or the like.
In order to adsorb inositol phosphate or phytic acid or a salt thereof on the surface of the calcium compound, a microcrystal of the calcium compound is immersed in a dilute solution of inositol phosphate or phytic acid or a salt thereof. Inositol phosphate or phytic acid or a salt thereof is considered to be chemically adsorbed on the microcrystal surface of the calcium compound.
The adsorption operation will be described in detail later.

  As the calcium compound, calcium phosphate, calcium carbonate and the like are preferably used. These may be used alone or in combination of two. When one kind is used alone, it is preferable to use calcium phosphate.

  As calcium phosphate, hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate, γ-tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, non- Crystalline calcium phosphate is preferred, and hydroxyapatite is more preferred. These may be used alone or in combination of two or more.

The method for producing hydroxyapatite (hereinafter also referred to as “HAp”) used for the cement material I of the present invention is not particularly limited, and any method may be used. Examples of the method for producing hydroxyapatite include a dry method, a semi-dry method, and a wet method.
The case where the hydroxyapatite microcrystals used in the present invention are produced by a wet process will be described. When a solution containing phosphate ions such as ammonium phosphate previously adjusted to weak alkalinity is dropped into a solution containing calcium ions such as calcium nitrate previously adjusted to alkalinity, and aging while maintaining alkalinity, gel-like hydroxyapatite is formed. can get. As the alkali for adjusting the pH of the solution, ammonia is preferably used. By heating the gel-like hydroxyapatite, microcrystals of hydroxyapatite can be obtained. In order to prevent carbon dioxide in the air from being taken into hydroxyapatite microcrystals, the series of operations is preferably performed in an inert gas atmosphere such as nitrogen gas. In this method, the purity of the material used is reflected in the purity of the resulting hydroxyapatite microcrystals. Therefore, if a high-purity material is used, high-purity hydroxyapatite microcrystals can be obtained.

  The average particle diameter of the hydroxyapatite microcrystals used in the cement material I of the present invention is preferably 1 to 500 μm, more preferably 10 to 250 μm, and particularly preferably 10 to 50 μm.

Examples of inositol phosphates include inositol monophosphate, inositol diphosphate, inositol triphosphate, inositol tetraphosphate, inositol pentaphosphate, and phytic acid (inositol hexaphosphate). Inositol hexaphosphate is usually called phytic acid.
The salt of inositol phosphate or phytic acid is preferably an alkali metal salt or an alkaline earth metal salt, such as sodium salt, potassium salt, magnesium salt, calcium salt, barium salt and the like.
Among these, phytic acid, phytic acid sodium salt, or phytic acid potassium salt is preferable, and phytic acid sodium salt or phytic acid potassium salt is more preferably used.
There are several types of sodium phytate having different crystal water contents, such as sodium phytate 38 hydrate, sodium phytate 47 hydrate, sodium phytate 12 hydrate, and the like. However, any of them can be preferably used.

The method for producing phytic acid (hereinafter also referred to as “IP ₆ ”) or alkali metal phytic acid used in the cement material I of the present invention is not particularly limited, and may be produced by any method. For example, phytic acid sodium salt (hereinafter also referred to as “IP ₆ Na”) is obtained by extracting defatted plant seed powder with dilute hydrochloric acid, precipitating it from the extract into insoluble copper salt, iron salt, etc. It can be obtained by changing to a sodium salt and adding alcohol to cause precipitation.

  After the microcrystals of the calcium compound are mixed with the inositol phosphate or phytic acid or an aqueous solution thereof and adsorbed on the surface of the microcrystals, the microcrystals are separated and dried to obtain inositol phosphate or phytic acid or Microcrystals (cement material I) in which those salts are adsorbed on calcium compounds can be obtained.

  In the case of using an aqueous solution of inositol phosphate or phytic acid, it is preferable to add an alkaline aqueous solution to the aqueous solution in advance and adjust the pH to preferably 6 to 11, more preferably 6 to 8. The aqueous alkali solution used for adjusting the pH is not particularly limited, and examples thereof include an aqueous sodium hydroxide solution and an aqueous potassium hydroxide solution.

The concentration of the aqueous solution of inositol phosphate or phytic acid or a salt thereof is preferably 0.001 to 0.25M, more preferably 0.001 to 0.05M.
The molar ratio of inositol phosphate or phytic acid or a salt thereof to a calcium compound is preferably 0.001 to 0.1, and more preferably 0.001 to 0.05.

  There is no particular limitation on the method of adsorption, and an aqueous solution of inositol phosphate or phytic acid salt in which microcrystals such as hydroxyapatite are immersed is appropriately stirred and shaken to complete the adsorption, and then allowed to stand. Separate the microcrystals. The mixing temperature is preferably 20 to 90 ° C, and more preferably 20 to 40 ° C. The mixing time is preferably 2 to 24 hours, and more preferably 2 to 5 hours. The hydroxyapatite adsorbed with phytic acid or the like is preferably used after being separated and dried.

  The drying temperature is preferably 4 to 80 ° C, more preferably 4 to 40 ° C. The drying time is preferably 12 to 48 hours, more preferably 12 to 24 hours.

The cement material I prepared by the above method is composed of microcrystals (hereinafter also referred to as “IP ₆ HAp”) in which inositol phosphate, phytic acid or a salt thereof is adsorbed on the surface of a calcium compound. In particular, the adsorption of inositol phosphate or phytic acid or a salt thereof to hydroxyapatite microcrystals can be approximated to a uniform adsorption of a monolayer from the Langmuir plot of the adsorption isotherm.

  In the present invention, unlike the above-mentioned cement material I, a simple mixture of hydroxyapatite microcrystals and inositol phosphate, phytic acid, or a salt thereof is also referred to as a cement material (hereinafter referred to as “cement material II”). ) Can also be used. The term “mixture” as used herein means that the hydroxyapatite fine crystals and the fine powder of inositol phosphate, phytic acid, or salts thereof were merely mechanically mixed. The cement material II may contain a third component as necessary, in addition to the hydroxyapatite microcrystals and the fine powder of inositol phosphate, phytic acid or salts thereof.

  In the cement material II, the same hydroxyapatite and inositol phosphate, phytic acid, or salts thereof as in the cement material I can be used.

Next, the cement of the present invention will be described.
The cement material I or II of the present invention is kneaded in an aqueous solvent and used as a paste. As the aqueous solvent, water is mainly used, but a solvent to which a solvent miscible with water such as ethanol is added can also be used.
Cement can be prepared by filling the kneaded cement material into an affected area such as a bone defect and curing it. As the cement material, the cement material I is preferably used rather than the cement material II. The cement material I is excellent in terms of the obtained strength and short curing time.

As the kneading time, it is preferable to complete the operations from kneading to filling within 3 minutes. The pH of the aqueous solvent is preferably pH 6 to 11, more preferably water having a pH of 6 to 8.
The weight ratio of the cement material and the aqueous solvent is not particularly limited, but is preferably 1 / 0.50 to 1 / 0.80.

  When kneading the cement material of the present invention in an aqueous solvent, depending on the disease to be applied, polysaccharides such as starch, glycosaminoglycan, alginic acid, chitin, chitosan, heparin, collagen, gelatin, and derivatives thereof, etc. Physiologically active substances such as proteins, anti-rheumatic therapeutic agents, anti-inflammatory agents, antibiotics, antitumor agents, osteoinductive factors, retinoic acid and retinoic acid derivatives may be added.

When the above-mentioned paste is filled in an affected part such as a bone defect part, it begins to harden in 2 to 3 minutes and hardens within about 10 minutes to become cement. The cement is replaced by new bone and is integrated with the living hard tissue.
Unlike the conventional apatite cement, the cement of the present invention does not cause an acid / base reaction at the time of curing, so there is no pH change before and after curing. Therefore, the cement of the present invention is less likely to cause an inflammatory reaction.

  Since the cement of the present invention has a short setting time, the treatment time can be shortened and the patient's pain can be reduced. The cement of the present invention can be used for treatment of fractures, osteoporosis, rheumatoid arthritis and the like.

<Example 1>
(1) Classification of hydroxyapatite Hydroxyapatite (manufactured by Taihei Kagaku) was classified into the following five stages using sieves having openings of 150 μm, 75 μm, 53 μm and 37 μm.

(2) Preparation of cement material I (IP ₆ HAp) 50 g of phytic acid aqueous solution (3.0 mM, pH 7.3, 0.15 mmol) was added to 2.5 g (2.49 mmol) of the classified hydroxyapatite obtained above. And shaken for 5 hours. IP ₆ HAp was collected by suction filtration and dried under reduced pressure for 24 hours.

(3) Measurement of phytic acid saturated adsorption amount The pH of aqueous phytic acid solution prepared to various concentrations was adjusted to pH 7 using an aqueous sodium hydroxide solution, and hydroxyapatite (specific surface area 35 m ² / g) was added to 10 mL of these solutions. 0.3 g of each was added and incubated using a shaking incubator (37 ° C., 100 times / min). Thereafter, solid-liquid separation was performed, and the phosphorus concentration in the supernatant was measured by ICP to calculate the amount of phytic acid adsorbed on hydroxyapatite. Moreover, when the saturated adsorption amount of phytic acid with respect to hydroxyapatite was calculated | required from Langmuir plot, it was 15 mg / g.

<Example 2>
Water was mixed with the IP ₆ HAp prepared in Example 1 at a solid-liquid ratio of 1 / 0.60 (weight ratio), kneaded for 1 minute, and then filled into a molding machine. After uniaxial pressure molding (0.8 MPa), it was cured by standing for 1 day to prepare a cylindrical cement having a diameter of 5 mm and a height of 7 to 8 mm.
The compressive strength of the hardened cement (IP ₆ HAC) was evaluated.
The compressive strength was calculated by using a strength tester manufactured by Yasuda Seiki Seisakusho at a crosshead speed of 0.5 mm / min and dividing the maximum load at break by the cross-sectional area of the test piece.
Further, hydroxyapatite (made by Taihei Kagaku, unclassified) (HAp) not adsorbing phytic acid was cured by the same operation as above to prepare cement (HAC). The compressive strength of cement (HAC) was measured and used as a control.
The results are shown in Table 2 below.

ＩＰ_６ＨＡｐ−Ｅを硬化させたセメントＩＰ_６ＨＡＣ−Ｅの圧縮強度が一番大きく、対照のＨＡＣの約３倍の強度を示した。

The compressive strength of the cement IP ₆ HAC-E in which IP ₆ HAp-E was cured was the highest, indicating about three times the strength of the control HAC.

<Example 3>
(Influence of solid-liquid ratio on compressive strength)
Water was mixed with the IP ₆ HAp prepared in Example 1 at a solid-liquid ratio of 1 / 0.50 to 1 / 1.20, kneaded for 1 minute, and then filled into a molding machine. After uniaxial pressure molding (0.8 MPa), it was cured by standing for 1 day to prepare a cylindrical cement having a diameter of 5 mm and a height of 7 to 8 mm. The compressive strength of the hardened cement (IP ₆ HAC) was evaluated in the same manner as in Example 2.
Regarding IP ₆ HAC-A and IP ₆ HAC-E, the compressive strength was greatest when the solid-liquid ratio was 1 / 0.60, and the compressive strength at that time was 6.8 MPa.

<Example 4>
IP ₆ HAp-E prepared in Example 1 was mixed with water at a solid-liquid ratio of 1 / 0.60 (weight ratio), kneaded for 1 minute, and then a stainless steel mold (with a diameter of 1 cm and a height of 1.5 cm). It was filled in a columnar shape and allowed to stand in an incubator (37 ° C., humidity 100%). Measurement was performed using a bigger needle having a load of 200 g and a diameter of 2 mm, and the time until the indentation was not made was defined as the curing time.
As a control, the same operation (solid-liquid ratio 1 / 1.00) as described above was performed using hydroxyapatite (HAp).
The control HAC took about 90 minutes to fully cure, whereas IP ₆ HAC-E fully cured in about 10 minutes.

<Example 5>
(1) Preparation of biological simulated body fluid Sodium chloride (7.996 g), sodium bicarbonate (0.350 g), potassium chloride (0.224 g), potassium hydrogen phosphate trihydrate (0) in about 700 mL of distilled water 228 g), magnesium chloride hexahydrate (0.305 g), 1M hydrochloric acid (40 mL), calcium chloride (0.278 g), sodium sulfate (0.071 g) and trishydroxymethylaminomethane (6.057 g) in this order. added. After adjusting the pH to 7.40 using 1M hydrochloric acid, distilled water was added to make the total liquid volume accurately 1000 mL.
(2) Simulated biological body fluid immersion experiment The cement (IP ₆ HAC-E) prepared in Example 2 was immersed in the simulated biological fluid, and the compressive strength of the cement and the ion concentration of calcium ions or phosphorous ions in the simulated biological fluid over time were measured. Measured.
The ion concentration of calcium ions or phosphorus ions in the simulated biological fluid immersed in IP ₆ HAC-E decreased with time, and became a constant ion concentration after 6 days. This result shows that calcium phosphate is precipitated on cement (IP ₆ HAC-E). Considering the rate of change over time of the calcium ion and phosphate ion concentrations in the simulated body fluid, it is assumed that apatite is precipitated.
Moreover, when the compressive strength of the cement 30 days after being immersed in the biological simulated body fluid was measured, IP ₆ HAC-E showed compressive strength about 5 times that of HAC.

<Example 6>
Osteoblast-like cells (MC3T3-E1) (6 × 10 ⁴ cells) were seeded in polystyrene plates and cultured for 1 day. Transwell was placed in the polystyrene plate, the cement prepared in Example 2 (IP ₆ HAC-E) was added, and the number of cells after 2, 4, 6 and 8 days was counted.
The number of cells increased with time and reached a plateau after 6 days. From this result, it was found that the cement of the present invention has good biocompatibility.

<Example 7>
An aqueous solution (pH 10.7 to 10.8, 1 mL) of 0.05M phytic acid 12 sodium salt hydrate (IP ₆ Na) was added to 1 g of hydroxyapatite (manufactured by Taihei Chemical, HAp-100) (solid-liquid ratio 1 / 1.00) and then kneaded, packed in a 10 mm diameter mold and pressed at a pressure of 10 MPa. When left at room temperature for 1 day, the cement was completely cured and the compressive strength was good.

<Example 8>
An aqueous solution (pH 10.7 to 10.8, 1 mL) of 0.01 M phytic acid 12 sodium salt hydrate (IP ₆ Na) was added to 1 g of hydroxyapatite (manufactured by Taihei Chemical, HAp-100) (solid-liquid ratio 1 / 1.00) and then kneaded, packed in a 10 mm diameter mold and pressed at a pressure of 10 MPa. When left at room temperature for 1 day, the cement was completely cured and the compressive strength was good.

Claims (6)

  A cement material comprising microcrystals in which inositol phosphate or phytic acid or a salt thereof is adsorbed on the surface of a calcium compound.   The cement material according to claim 1, wherein the molar ratio of inositol phosphate or phytic acid or a salt thereof to a calcium compound is 0.001 to 0.1.   The cement material according to claim 1 or 2, wherein the calcium compound is calcium phosphate and / or calcium carbonate.   The cement material according to claim 3, wherein the calcium phosphate is hydroxyapatite.   A cement material comprising microcrystals of hydroxyapatite and inositol phosphate, phytic acid or a salt thereof.   A cement, wherein the cement material according to any one of claims 1 to 5 is kneaded in an aqueous solvent and cured.