JP5371034B2 - Calcium phosphate bone filler and method for producing the same - Google Patents

Description

  The present invention relates to a calcium phosphate-based bone filler used for repairing a bone defect due to a fracture or the like.

  As a bone filler used for repairing a bone defect caused by a fracture or the like, an acrylic bone filler, a ceramic bone filler or the like is known. Among these, the acrylic bone filler is used after the paste-like material is filled in the portion to be repaired and then cured, but if an unpolymerized monomer remains, there may be a problem of toxicity. Moreover, it has the problem that it is not absorbed in the living body and remains in the body as a foreign substance.

  As the ceramic bone filler, there are known bone fillers using alumina, carbon, zirconia, etc., and bone fillers using hydroxyapatite, calcium phosphate, or the like. The former bone filler is chemically stable in the living body but has a problem that it is not absorbed in the living body and remains in the body as a foreign substance. On the other hand, the latter is a component similar to the component constituting the bone, and is absorbed in the living body and can be expected to play a role as a bone repair material.

  Examples of the latter bone filler include calcium phosphate compositions (Patent Document 1) composed of tetracalcium phosphate and calcium hydrogen phosphate having a predetermined particle size, bioabsorbable organic materials, apatites, tricalcium phosphate, phosphorus Bone fillers using tetracalcium acid and the like (Patent Document 2) are known. These are gradually hydrated in the presence of water, and apatites are generated and hardened, so these are filled in the place to be repaired such as fractures in a paste state and hydrated (hardened) ), The fracture site can be fixed.

JP 2007-191420 A JP 2000-262608 A

  However, the cured product of the former calcium phosphate composition may have insufficient strength. Further, in the latter bone filler, tricalcium phosphate is used, but it is common to use an α-form having high reactivity of hydration reaction. However, this α-tricalcium phosphate does not have good adhesion to bone cells, and may affect the regeneration of bone in affected areas such as fractures.

  Instead of this α-tricalcium phosphate, it is conceivable to use β-tricalcium phosphate having good adhesion to bone cells. However, this β-tricalcium phosphate has poor reactivity of hydration reaction, and even when used as a bone filler, it tends to hardly cause hydration reaction and harden.

  Accordingly, an object of the present invention is to obtain a bone filler in which a hydration reaction is sufficiently generated and cured, the cured product has sufficient strength, and has good adhesion to bone cells.

  The present invention comprises kneading a phosphate-based mixture containing calcium monohydrogen phosphate, tetracalcium phosphate, and ground β-tricalcium phosphate with a water-containing kneading liquid, β-tricalcium phosphate was ground and ground in an atmosphere containing at least one selected from water and carbon dioxide, and 1.1 mol of tetracalcium phosphate per 1 mol of calcium monohydrogen phosphate. The above-mentioned problems have been solved by using a calcium phosphate-based bone filler that contains ˜3 mol and contains 1.1 to 5 mol of the β-tricalcium phosphate.

Since the calcium phosphate bone filler according to the present invention uses β-tricalcium phosphate instead of α-tricalcium phosphate, it can maintain good adhesion to bone cells.
In addition, β-tricalcium phosphate is subjected to grinding treatment in an atmosphere containing at least one selected from water and carbon dioxide, and water molecules and carbonate ions are taken into the surface, and the reaction on this surface is performed. It has improved activity, can be cured by causing a hydration reaction in the presence of water, and can be used as a bone filler.
Furthermore, since the mixing ratio of calcium monohydrogen phosphate, tetracalcium phosphate, and specific β-tricalcium phosphate is within a predetermined range, the obtained cured product has sufficient strength.

  The calcium phosphate bone filler according to the present invention includes calcium monohydrogen phosphate (hereinafter abbreviated as “DCPD”), tetracalcium phosphate (hereinafter abbreviated as “TTCP”), and specific β-phosphorus. A phosphate-based mixture containing tricalcium acid (hereinafter, abbreviated as “TCP”) is kneaded with a water-containing kneading liquid.

The DCPD refers to a compound represented by the following chemical formula (1), the TTCP refers to a compound represented by the following chemical formula (2), and the TCP refers to a compound represented by the following chemical formula (3). .
CaHPO ₄ · 2H ₂ O or CaHPO ₄ (1)
Ca ₄ (PO ₄ ) ₂ O (2)
Ca ₃ (PO ₄ ) ₂ (3)

  The above-mentioned DCPD and TTCP are not particularly limited, and commercially available products can be used. Moreover, when the particle size is large, it is preferable to grind | pulverize using grinders, such as a ball mill.

  The β-TCP is subjected to grinding treatment in an atmosphere containing at least one selected from water and carbon dioxide. By grinding in an atmosphere containing water, carbon dioxide, or both, water molecules and carbonate ions are incorporated into the ground surface of β-TCP, and the active state of the surface generated by the grinding treatment is Therefore, it can be considered that the hydration reaction is likely to occur and the curing is likely to occur when coexisting with DCPD or TTCP in the presence of water.

  As a method of the above-mentioned grinding treatment, it can be pulverized using a pulverizer such as a mortar and a ball mill. The atmosphere at the time of grinding should just be the atmosphere containing water, a carbon dioxide, or both, and normal atmosphere is sufficient.

  In addition, said grinding process may be performed only by (beta) -TCP, and may be performed after mixing DCPD, TTCP, and (beta) -TCP.

The average particle diameter of β-TCP obtained by the above grinding treatment is preferably 0.5 to 20 μm, and preferably 0.8 to 15 μm. Moreover, 3.0-10 m < ² > / g is good and the specific surface area of (beta) -TCP has preferable 3.5-7 m < ² > / g. By satisfying these ranges, when coexisting with DCPD or TTCP in the presence of water, the reactivity of the hydration reaction is improved and the composition is easily cured, and can be usefully used as a bone filler. Even when the average particle size is larger than the above range or when the specific surface area is smaller than the above range, a hydration reaction occurs when the phosphate mixture is kneaded with the kneading liquid. Since the crystallinity of the apatites thus obtained is lowered, it may be difficult to be cured. On the other hand, although the said average particle diameter may be smaller than the said range, handling may become difficult. Moreover, when the said specific surface area is larger than the said range, when the said phosphate-type mixture is knead | mixed with the said kneading | mixing liquid, there exists a possibility that it may become difficult to harden | cure sufficiently.

  The mixing ratio of the above DCPD, TTCP, and β-TCP is preferably 1.1 to 3 mol, more preferably 1.5 to 2.5 mol, and 1.8 to 2.3 with respect to 1 mol of the DCPD. Mole is more preferred. If it is out of the above range, the strength of the cured product of the obtained bone filler may not be sufficiently obtained.

  Moreover, 1.1-5 mol of said (beta) -TCP is preferable with respect to 1 mol of said DCPD, 1.5-4.5 mol is more preferable, 1.8-4.3 mol is more preferable. If it is out of the above range, the strength of the cured product of the obtained bone filler may not be sufficiently obtained.

  Furthermore, a particularly preferable range of the mixing ratio of DCPD, TTCP, and β-TCP is a molar ratio of DCPD / TTCP / β-TCP = 1 / 1.9 to 2.2 / 1.9 to 4.2. . If it is this range, the intensity | strength of the hardened | cured material of the obtained bone filler can fully be obtained.

The phosphate-based mixture containing the above-mentioned DCPD, TTCP, and β-TCP in a predetermined ratio may include octacalcium phosphate (Ca ₈ H ₂ (PO ₄ ) · 5H ₂ O) (hereinafter, It may be abbreviated as “OCP”) and an organic acid or a salt thereof. When this is added, hydrophilicity can be imparted to the obtained bone filling material, and when filling and hydration reaction (hardening) is performed on a predetermined part of the body, the bone filling material is filled and hydrated (hardening). ) The affinity of the part to be in the body can be improved. Examples of the organic acid include citric acid, aspartic acid, glutamic acid, and nucleotides.

  Examples of the nucleotide include adenosine monophosphate (AMP), adenosine diphosphate (ADP), adenosine triphosphate (ATP), guanosine monophosphate (GMP), guanosine diphosphate (GDP), guanosine triphosphate ( GTP), uridine monophosphate (UMP), uridine diphosphate (UDP), uridine triphosphate (UTP), cytidine monophosphate (CMP), cytidine diphosphate (CDP), cytidine triphosphate (CTP) , Thymidine monophosphate (TMP), thymidine diphosphate (TDP), thymidine triphosphate (TTP) and the like.

  The content of the complex is preferably 0.5 to 10.0% by weight, and preferably 1.0 to 5.0% by weight with respect to the total amount of the DCPD, TTCP, and β-TCP. If the amount is less than the above range, the effect of adding the composite may not be obtained. On the other hand, when it is more than the above range, the content of the phosphate-based mixture in the bone filler may be reduced, and the strength of the resulting cured bone filler may be reduced.

  As a method for producing a complex of the OCP and an organic acid or a salt thereof, α-TCP, DCPD, and the organic acid or a salt thereof are mixed in water, and a temperature of 40 to 60 ° C. A method of hydrating for -24 hours is mentioned.

  The phosphate-based mixture containing the above-mentioned DCPD, TTCP, and β-TCP in a predetermined ratio is kneaded with a water-containing kneading liquid to become a paste, which becomes a bone filler. This phosphate-based mixture undergoes a hydration reaction in the presence of water to cause a formation reaction of hydroxyapatite and is cured. Therefore, from the stage of kneading with a water-containing kneading liquid, the hydration reaction, that is, Curing begins to occur. For this reason, when filling the bone filling material into a bone repair site such as a fracture, a paste is prepared by adding a predetermined amount of kneading liquid to the phosphate mixture and kneading it immediately. Is preferably filled.

  The kneading agent needs to contain water, and may be water alone or an aqueous solution of an alkali phosphate. Examples of such alkali phosphates include disodium monohydrogen phosphate. By adding this alkali phosphate, the strength of the cured bone filler obtained can be improved.

  The amount of water in the kneading agent is preferably 50 to 100% by weight, and preferably 70 to 90% by weight, based on the phosphate mixture. If the amount is less than the above range, it may be difficult to form a paste. On the other hand, when the amount is more than the above range, the viscosity of the obtained paste is lowered, and there is a possibility that flow out may occur when filling the portion to be repaired of bone such as a fracture. It may be difficult to hold the bone filler.

  Moreover, 1.0-5.0 weight% is preferable with respect to the said phosphate-type mixture, and, as for the usage-amount of the said alkali phosphate, 2.0-3.0 weight% is preferable. If the amount is less than the above range, the effect of adding the alkali phosphate may not be obtained. On the other hand, when it is more than the above range, the content of the phosphate-based mixture in the bone filler may be reduced, and the strength of the resulting cured bone filler may be reduced.

  Further, as the above-mentioned kneading agent, a hydrophobic amino acid such as glycine, alanine, leucine, isoleucine, valine or the like may be added in addition to or together with the alkali phosphate other than water. By adding this hydrophobic amino acid, it is possible to suppress the occurrence of lumps when a kneading agent is added to the phosphate mixture, and to improve the moldability of the bone filler.

  The amount of the hydrophobic amino acid used is preferably 0.5 to 2.0% by weight, more preferably 0.8 to 1.5% by weight, based on the phosphate mixture. If the amount is less than the above range, the effect of adding a hydrophobic amino acid may not be obtained. On the other hand, when it is more than the above range, the content of the phosphate-based mixture in the bone filler may be reduced, and the strength of the resulting cured bone filler may be reduced.

  Even when the alkali phosphate salt and the hydrophobic amino acid are used together, the respective amounts described above are preferably used.

Next, the present invention will be described in more detail using examples.
<Evaluation method>
[Strength test (compressive strength)]
The obtained paste was poured into a concave portion of a Teflon (registered trademark) mold having a cylindrical concave portion with an inner diameter of 4.0 mm and a height of 10.0 mm, and left at room temperature for 1 hour. The pellet was removed. At least five of the same pellets were prepared.
The obtained pellet was immediately immersed in physiological saline in a glass bottle with a lid and capped. Then, it was left in a constant temperature room maintained at 38 ° C.
And about the pellet which does not immerse in the physiological saline (the pellet after 0-day progress), the pellet after 1-day immersion, the pellet after 3-day immersion, the pellet after 7-day immersion, and the pellet after 30-day immersion, a compression tester ( Compressive strength was measured using Imada Co., Ltd. (Digital Force Gauge ZP (Z2) type).

[Measurement of average particle size]
HORIBA, Ltd. product: LA-920 was used to measure the average particle size.
[Specific surface area measurement]
Made by Mountec: Measured by BET method using NM-Model1210.

<Raw materials used>
DCPD: Wako Pure Chemical Industries, Ltd .: reagent grade, TTCP: Wako Pure Chemical Industries, Ltd .: reagent grade, α-TCP: Taihei Chemical Industry Co., Ltd., β-TCP ... Taihei Chemical Industry Co., Ltd. ) Made by disodium monohydrogen phosphate ... Wako Pure Chemical Industries, Ltd .: reagent grade, glycine ... Wako Pure Chemical Industries, Ltd .: reagent grade, citric acid ... Wako Pure Chemical Industries, Ltd .: reagent grade・ Aspartic acid: Wako Pure Chemical Industries, Ltd .: reagent special grade ・ Adenosine monophosphate: Wako Pure Chemical Industries, Ltd .: reagent special grade

[Production of complex of OCP and organic acid or salt thereof]
In 40 ml of water heated to 40-60 ° C., 10 mmol of α-TCP, 10 mmol of DCPD, and 10 mmol of an organic acid selected from citric acid, aspartic acid and adenosine monophosphate were added, and the temperature was maintained for 24 hours. Produced by stirring in the state.
The obtained complex of OCP and citric acid is called “OCP-Cit”, the complex of OCP and aspartic acid is called “OCP-Asp”, and the complex of OCP and adenosine monophosphate is OCP− This is called AMP.

Example 1
[Trimming of β-TCP]
β-TCP (4.0 g) was weighed and stirred at room temperature for 7 hours, 24 hours, and 72 hours using an automatic mortar stirrer (manufactured by Nippon Ceramics Co., Ltd., ANM-1000, mortar manufactured by Agate).
The obtained ground β-TCP was subjected to X-ray diffraction measurement, infrared absorption measurement, and differential thermal measurement (thermogravimetric measurement). Moreover, those average particle diameters and specific surface areas were measured. The results are shown in FIGS.

  Moreover, 20 ml of water was added to 2.0 g of the obtained ground β-TCP and stirred, and a hydroxyapatite (HAp) formation reaction was performed at 90 ° C. The HAp production rate (conversion rate (%)) after 3 hours, 6 hours, 15 hours and 24 hours was calculated from the results of X-ray diffraction measurement. The result is shown in FIG. In addition, FIG. 5 shows an X-ray diffraction peak after β-TCP has completely reacted (after generation of apatites is completed).

(Examples 2-16, Comparative Examples 1-3)
DCPD, TTCP, and β-TCP stirred for 24 hours are mixed in the amounts shown in Table 1, and if necessary, OCP-Cit, OCP-Asp, OCP-AMP are added in the amounts shown in Table 1. did.
Subsequently, the kneading liquid shown in Table 1 was added and kneaded to obtain a paste.
Said strength test was done using the obtained paste. The results are shown in Tables 1-3.

(Comparative Example 4)
The above-mentioned strength test was performed using BIOPEX-R (trade name, manufactured by Pentax Co., Ltd., hereinafter referred to as “Biopex”) as a bone filler. The results are shown in Table 1.

(result)
[About grinding of β-TCP]
In Example 1, β-TCP grinding was studied.
As shown in the change in the X-ray diffraction peak of FIG. 1, the X-ray diffraction peak intensity decreased with the grinding time of β-TCP. This indicates that the crystallinity of β-TCP is lowered, and the surface of β-TCP particles is made amorphous.
In addition, as shown in the change in the infrared absorption chart of FIG. 2, absorption of water and carbon ions was observed with the grinding time. It is considered that water and carbonate ions were taken into the surface of β-TCP by the grinding of β-TCP.
Furthermore, as shown in the change in the differential calorimetry chart of FIG. 3, there was a tendency that the weight loss due to heating increased as the grinding time increased. This is probably because water and carbonate ions taken into the surface of β-TCP were volatilized by heating during grinding.

[Production of HAp by β-TCP hydration reaction]
In the X-ray diffraction peak shown in FIG. 1, it was found that the HAp peak (31.8 °) increased and the milled β-TCP peak (29.0 °) decreased with the milling time. Therefore, the conversion rate from ground β-TCP to HAp was calculated, and the result is shown in FIG. As a result, it was found that the longer the grinding time, the faster the reaction rate to HAp.
Subsequently, in FIG. 5, the hydration reaction was performed using β-TCP subjected to grinding for each grinding time, and the X-ray diffraction peak of the obtained HAp was shown. As a result, when the grinding time was short (7 hours), the obtained peak became sharp. That is, apatites with good crystallinity were obtained. On the other hand, as the grinding time became longer, the resulting peak became broader. That is, it became clear that the crystallinity of the obtained apatites was lowered.

[Strength of bone filler]
In Examples 2 to 16 and Comparative Examples 1 to 4, the strength of the bone filler was examined.
As shown in Table 2, in the results of Examples 2 to 4, it was found that the strength of the bone filler in the present invention was sufficient. In particular, when β-TCP is 2 mol times to 3 mol times with respect to DCPD (Examples 3 and 4), the compression strength is 38 MPa and the sufficient strength is obtained when the immersion time is 3 days or more. It was.
Moreover, in Examples 2-4, especially in Example 4, it became clear that the compressive strength equivalent to the biopex which is a conventional product is obtained.
On the other hand, as in Comparative Examples 1 to 3, when the content of DCPD is greater than or equal to the content of TTCP, or when the content is greater than or equal to the content of β-TCP, it has become clear that sufficient compressive strength is difficult to obtain. .
Next, in the results of Examples 4 to 13, in the case of adding a complex of OCP and an organic acid or a salt thereof as a phosphate-based mixture, particularly when the immersion time is long, The same compressive strength as when not added is obtained. For this reason, it turned out that the affinity with a body can be improved more and the bone filler which has sufficient compressive strength can be obtained.
Moreover, in Examples 4 and 14-16, even if glycine is added, the compressive strength close | similar to the case where it does not add is obtained. For this reason, it turned out that it is possible to obtain the bone filler which has better moldability and sufficient compressive strength.

Change of X-ray diffraction peak with change of grinding time of β-TCP Change in infrared absorption chart with grinding time of β-TCP Change in differential calorimetry chart with grinding time of β-TCP Graph of conversion from milled β-TCP to HAp X-ray diffraction peak of HAp obtained by performing hydration reaction using β-TCP subjected to grinding for a predetermined grinding time

Claims (5)

A bone filler formed by kneading a phosphate-based mixture containing calcium monohydrogen phosphate, tetracalcium phosphate and ground β-tricalcium phosphate with a water-containing kneading liquid,
The β-tricalcium phosphate is milled in an atmosphere containing at least one selected from water and carbon dioxide, the average particle size is 0.1 to 20 μm, and the specific surface area is 3.0 to 10 m ² / g,
A calcium phosphate-based bone filler containing 1.1 to 3 mol of the tetracalcium phosphate and 1.1 to 5 mol of the β-tricalcium phosphate with respect to 1 mol of the calcium monohydrogen phosphate. The water-containing kneading liquid is an aqueous solution of an alkali metal phosphate, and the amount of the alkali metal phosphate used is 1.0 to 5.0% by weight based on the phosphate mixture. The calcium phosphate bone filler according to claim 1 . The phosphate-based mixture contains a complex of octacalcium phosphate and an organic acid or a salt thereof,
Its content, calcium hydrogen phosphate of the above, tetracalcium phosphate, and the total amount of β- tricalcium phosphate, according to claim 1 or 2 is 0.5 to 10.0 wt% Calcium phosphate bone filler. The calcium phosphate bone filler according to claim 3 , wherein the organic acid is an acid selected from citric acid, aspartic acid, glutamic acid, and nucleotides. The water-containing kneading liquid contains a hydrophobic amine acid, and the amount of the hydrophobic amino acid used is 0.5 to 2.0% by weight based on the phosphate mixture. 5. The calcium phosphate bone filler according to any one of items 1 to 4 .

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