JP5236900B2 - Method for producing tricalcium phosphate and method for producing calcium phosphate curable composition - Google Patents

Description

  The present invention relates to a method for producing tricalcium phosphate and a method for producing a calcium phosphate curable composition.

  The calcium phosphate curable composition is a living implantable medical material that mixes several types of calcium phosphate cement powders having different Ca / P ratios and an organic acid salt and hardens like a bone cement. This calcium phosphate curable composition is prepared by the operator performing the above mixing operation in an operating field.

  Conventionally, for example, tribasic calcium phosphate is used as the calcium phosphate cement powder contained in the calcium phosphate curable composition. Therefore, in order to obtain tricalcium phosphate having excellent physical properties, various methods for producing tricalcium phosphate have been developed. For example, a method for producing tricalcium phosphate having excellent biocompatibility is known by mixing raw materials in an aqueous solution having a water temperature of 30 ° C. or lower and firing the product at 700 ° C. or higher (for example, Patent Document 1). ).

  However, in such a production method, the particle diameter of the resulting tricalcium phosphate is large. Moreover, the particle diameter of the obtained tribasic calcium phosphate had a large variation for each production lot. Therefore, when preparing a calcium phosphate curable composition using this tricalcium phosphate, there is a problem that the fluidity of the composition is affected and a calcium phosphate curable composition having a certain consistency cannot be obtained. Yes. As a result, there is also a problem that a certain curing time cannot be obtained.

JP-A-4-321507

  An object of the present invention is to produce a tribasic calcium phosphate having a small particle size and to provide a calcium phosphate curable composition having excellent reproducibility of consistency.

Such an object is achieved by the present inventions (1) to (10) below.
(1) A method for producing tricalcium phosphate by reacting a calcium compound and phosphoric acid or a salt thereof at a holding temperature of 12 to 15 ° C. to produce tricalcium phosphate using a wet synthesis method ,
The method for producing tribasic calcium phosphate, wherein the reaction is performed while controlling the temperature so that the holding temperature varies within a range of ± 2 ° C.

  Thereby, since holding temperature hardly fluctuates, tricalcium phosphate with a small particle size can be obtained.

(2) The method for producing tricalcium phosphate according to (1) above, comprising a firing step of firing the tricalcium phosphate.
Thereby, the specific surface area of tricalcium phosphate can be controlled.

(3) The method for producing tricalcium phosphate according to (1) or (2) above, wherein the specific surface area of the obtained tricalcium phosphate is 1.05 to 1.30 m ² / g.
Thereby, tricalcium phosphate with high reactivity can be obtained.

(4) The method for producing tricalcium phosphate according to any one of the above (1) to (3), wherein a Ca / P ratio of the obtained tricalcium phosphate is 1.4 to 1.6.
Thereby, tricalcium phosphate with high affinity with respect to a living body can be obtained.

  (5) When the particle size distribution of the obtained tricalcium phosphate is measured by a laser diffraction / scattering method to obtain a particle size distribution curve, the particle size distribution curve is 90% of the total volume of the tricalcium phosphate. The method for producing tricalcium phosphate according to any one of the above (1) to (4), wherein the particle size of the dots is 40 to 55 μm.

  Thereby, since the particle size of the point which becomes 90% converted from powder with a small volume is small, many tricalcium phosphates with a small particle size can be obtained.

  (6) The method for producing tricalcium phosphate according to any one of the above (1) to (5), wherein the obtained tricalcium phosphate comprises 40 to 70% of particles having a particle diameter of 10 to 80 μm.

  Thereby, since many tricalcium phosphate exists in the range of 10-80 micrometers, the tertiary calcium phosphate with which the particle size was equal can be obtained.

(7) The method for producing tricalcium phosphate according to any one of (1) to (6), wherein the temperature management is performed using a refrigerant jacket.
Thereby, since a refrigerant | coolant carries out cooling control of reaction, temperature management can be performed correctly.

(8) a first step of producing tricalcium phosphate by reacting a calcium compound and phosphoric acid or a salt thereof at a holding temperature of 12 to 15 ° C. using a wet synthesis method ;
A second step of firing the tricalcium phosphate;
A method for producing a calcium phosphate curable composition comprising a third step of mixing the calcined powder mainly composed of tricalcium phosphate and an organic acid or a salt thereof,
The method of producing a calcium phosphate curable composition, wherein the reaction in the first step is performed while temperature control is performed so that the holding temperature varies within a range of ± 2 ° C.

  Thereby, since tricalcium phosphate with a small particle size can be obtained, a calcium phosphate curable composition having a certain consistency can be obtained with good reproducibility.

  (9) The manufacturing method of the calcium-phosphate curable composition as described in said (8) whose consistency of the said calcium-phosphate curable composition is 23.5-26.5 mm.

  Thereby, since a calcium phosphate curable composition becomes moderate consistency, a calcium phosphate curable composition can be favorably used as a bone cement.

  (10) The method for producing a calcium phosphate curable composition according to (8) or (9), wherein the curing time of the calcium phosphate curable composition is 6 to 9 minutes.

  Thereby, since the calcium phosphate curable composition hardens quickly, the calcium phosphate curable composition is highly useful as a bone cement.

  According to the present invention, since the reaction holding temperature hardly varies, it is possible to produce tricalcium phosphate having a small particle size. Therefore, it is possible to obtain a calcium phosphate curable composition having a certain consistency and curing time with little variation among production lots.

  Hereinafter, the manufacturing method of the tricalcium phosphate of this invention and the manufacturing method of a calcium-phosphate curable composition are demonstrated in detail.

  In addition, since the manufacturing method of the tribasic calcium phosphate of this invention is integrated in the manufacturing method of the calcium phosphate curable composition of this invention, it explains in full detail by description of the manufacturing method of a calcium phosphate curable composition.

<Method for producing calcium phosphate curable composition>
The method for producing a calcium phosphate curable composition of the present invention comprises a first step of producing a tricalcium phosphate by reacting a calcium compound with phosphoric acid or a salt thereof at a predetermined temperature, and a first step of firing the tricalcium phosphate. And a third step of mixing the calcined tricalcium phosphate and an organic acid or a salt thereof.

Hereinafter, each process is demonstrated in order.
(1) First Step Any method such as a wet synthesis method, a dry synthesis method, or a hydrothermal synthesis method may be used for the production of tertiary calcium phosphate, but at least one of a calcium compound and phosphoric acid or a salt thereof. It is preferable to use a wet synthesis method in which is used as a solution. This makes it possible to synthesize tribasic calcium phosphate easily and efficiently without requiring expensive production equipment.

  When the wet synthesis method is used, examples of the calcium compound include calcium chloride, calcium nitrate, calcium sulfate, calcium phosphate, calcium acetate, calcium carbonate, calcium bicarbonate, calcium oxalate, calcium oxide, and calcium hydroxide. These can be used in combination of two or more.

  Of these calcium compounds, calcium hydroxide is particularly preferable. Since calcium hydroxide dissolves in water and completely dissociates into hydroxide ions and calcium ions, it can efficiently react with phosphoric acid or a salt thereof.

  The amount of the calcium compound used is preferably 0.3 to 12 mol, and more preferably 1.2 to 6 mol. Thereby, it reacts with phosphoric acid or its salt without excess and deficiency, and tricalcium phosphate can be obtained with good yield.

Examples of the phosphate in this step include potassium monohydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen hydrogen phosphate, sodium dihydrogen phosphate, sodium metaphosphate, sodium pyrophosphate, ammonium phosphate. , Potassium pyrophosphate, magnesium phosphate, silver phosphate, zirconium phosphate and the like. These can be used in combination of two or more.
Of these phosphates or phosphoric acids, phosphoric acid is particularly preferred.

  The amount of phosphoric acid or a salt thereof used is preferably 0.2 to 8 mol, and more preferably 0.8 to 4 mol. Thereby, since it reacts with a calcium compound without excess and deficiency, tricalcium phosphate can be obtained with a sufficient yield.

  Hereinafter, the case where the thing which has calcium hydroxide as a main component and the thing which has phosphoric acid as a main component is used as a calcium compound is demonstrated.

In this case, the tricalcium phosphate is synthesized, for example, by dropping and mixing a phosphoric acid (H ₃ PO ₄ ) solution in a suspension of calcium hydroxide (Ca (OH) ₂ ) in a container. .

This reaction is represented by the following formula (I).
10Ca (OH) ₂ + 6H ₃ PO ₄ → 2Ca ₅ (PO ₄ ) ₃ (OH) + 18H ₂ O (I)

Here, if the progress of the synthesis is insufficient, an unreacted substance (Ca (OH) ₂ ) exists as an impurity in a slurry-like mixture (hereinafter simply referred to as “slurry”). Become.

Further, when the reaction is further continued, tricalcium phosphate (TCP) is produced by the reaction represented by the following formula (II).
3Ca ₅ (PO ₄ ) ₃ (OH) + H ₃ PO ₄ → 5Ca ₃ (PO ₄ ) ₂ + 3H ₂ O (II)

  The reaction time in the reaction between such a calcium compound and phosphoric acid or a salt thereof is, for example, preferably 0.5 to 5 hours, and more preferably 1 to 4 hours.

  When the reaction time is in such a range, the calcium compound and phosphoric acid or a salt thereof react with each other without excess or deficiency, so that tricalcium phosphate can be obtained with high yield.

  When reaction time is too shorter than the lower limit of the said range, there exists a possibility that reaction with a calcium compound and phosphoric acid or its salt may not be enough.

  If the reaction time is too longer than the upper limit of the above range, the reaction between the calcium compound and phosphoric acid or a salt thereof does not proceed any further, which may be inefficient.

  The atmosphere in which the calcium compound reacts with phosphoric acid or a salt thereof is not particularly limited, and examples thereof include an air atmosphere and an inert gas atmosphere such as nitrogen or argon. Of these, an air atmosphere is preferable. Since the reaction atmosphere is an air atmosphere, no special equipment or device such as an inert gas cylinder is required, so that the production operation of tricalcium phosphate can be facilitated.

  The reaction between a calcium compound and phosphoric acid or a salt thereof is an exothermic reaction. Therefore, when the reaction between the calcium compound and phosphoric acid or a salt thereof proceeds, the temperature of the reaction increases with time. That is, at the start of the reaction, for example, even if the reaction temperature is set to 35 ° C., the temperature rises with the progress of the reaction, so the reaction temperature may reach 40 ° C. at the end of the reaction. It is likely that the temperature is higher during the reaction.

  Therefore, the particle diameter of the obtained tribasic calcium phosphate becomes large, which has a problem of affecting the physical properties of the calcium phosphate curable composition described later. In order to solve this problem, the temperature during the reaction is controlled.

  Hereinafter, the reaction temperature in the reaction between the calcium compound and phosphoric acid or a salt thereof, which is a feature of the present invention, will be described in detail.

  The set temperature of the reaction between the calcium compound and phosphoric acid or a salt thereof is preferably a certain temperature within the range of 12 to 15 ° C, more preferably a certain temperature within the range of 13 to 14 ° C.

  Since the set temperature of the reaction is within such a range, the set temperature is set to a relatively low temperature, so that the increase in the reaction temperature during the reaction time can be moderated, and the temperature management described later is easy. can do.

  If the set temperature of the reaction is too lower than the lower limit of the above range, the reactivity between the calcium compound and phosphoric acid or a salt thereof may be reduced, and the yield of tricalcium phosphate may be reduced. In addition, the reaction solution may freeze and the reaction itself may not proceed.

  When the set temperature of the reaction is too higher than the upper limit of the above range, the reaction temperature reaches a high temperature in a short time due to the heat of reaction between the calcium compound and phosphoric acid or a salt thereof to obtain tricalcium phosphate having a small particle size. You may not be able to.

  In the present invention, the temperature is controlled so that the actual temperature of the reaction varies within the range of ± 2 ° C. of the preset temperature from the start to the end of the reaction between the calcium compound and phosphoric acid or its salt. The temperature is preferably controlled so as to vary within a range of ± 0.8 ° C.

  In other words, the temperature is controlled from the start to the end of the reaction so that the actual temperature of the reaction does not exceed the range of ± 2 ° C. of the set temperature and the reaction is performed within the range of the set temperature ± 2 ° C. Further, it is preferable that the temperature is controlled so that the reaction is performed within the range of the set temperature ± 0.8 ° C. without the actual temperature of the reaction exceeding the range of the set temperature ± 0.8 ° C.

  As described above, when the reaction is performed within the above range, an exothermic reaction between the calcium compound and phosphoric acid or a salt thereof is suppressed, and the reaction temperature does not increase, so that tricalcium phosphate having a small particle size can be obtained. .

  When the set temperature fluctuates beyond the above range, the exothermic reaction between the calcium compound and phosphoric acid or a salt thereof cannot be suppressed, so the temperature during the reaction rises to obtain tricalcium phosphate with a small particle size. You may not be able to.

  As a temperature management method for carrying out the reaction within such a set temperature range, for example, the reaction system is cooled by a refrigerant jacket, a water bath, an ice bath or the like using a refrigerant such as water, alternative chlorofluorocarbon or carbon dioxide. A method is mentioned. As a specific method, for example, the reaction vessel in which the calcium compound reacts with phosphoric acid or a salt thereof is cooled by the above method.

  Among those listed as the temperature management method, it is preferable to manage using a refrigerant jacket. Unlike the water bath and ice bath, the refrigerant jacket flows in the jacket, so that the refrigerant at a constant temperature always comes into contact with the reaction vessel, and the temperature control of the set temperature can be accurately performed.

  This refrigerant jacket is formed in a spiral shape so as to cool the entire reaction vessel. Thereby, the cooling efficiency of reaction can be raised.

Moreover, temperature control can also be performed, putting a reaction container in a water bath and flowing water in a water bath.
By examining the particle size distribution of the tricalcium phosphate obtained in this way, it is possible to confirm particle size and particle size variation.

  The method for measuring the particle size distribution is not particularly limited, and examples thereof include a sedimentation method, a sieving method, a counting method, and a laser diffraction / scattering method. Of these, the laser diffraction / scattering method is preferred. Thereby, since the range which can be measured at once is wide, a high-resolution result can be obtained in a short time with good reproducibility.

  When the particle size distribution curve of tribasic calcium phosphate is obtained using a laser diffraction / scattering method, the particle size at which the total volume of tribasic calcium phosphate in the particle size distribution curve is 90% (hereinafter simply referred to as “90% diameter”). .) Is preferably 40 to 55 μm, and more preferably 45 to 53 μm.

  When the 90% diameter is in such a range, the particle diameter of the tricalcium phosphate in the entire volume becomes small, so that desired physical properties can be obtained when the calcium phosphate curable composition described later is used.

  If the 90% particle size is too larger than the upper limit of the above range, the particle size of the tricalcium phosphate in the total volume becomes large, so that it may not be possible to obtain desired physical properties when the calcium phosphate curable composition described later is used. There is.

  Further, when the particle size distribution curve is obtained by using the laser diffraction / scattering method, it is preferable that the tribasic calcium phosphate having a particle size of 10 to 80 μm occupies 40 to 70%, more preferably 45 to 60%. preferable.

  When the tricalcium phosphate having a particle diameter of 10 to 80 μm is in such a range, approximately half of the tricalcium phosphate having a particle diameter in the above-mentioned range in the entire volume is present. Tribasic calcium phosphate can be obtained.

  If the tricalcium phosphate having a particle size of 10 to 80 μm is too smaller than the lower limit value of the above range, there is little tricalcium phosphate having a particle size in the range of the total volume, so that a large amount of tricalcium phosphate having a large particle size may be obtained. There is.

  Further, when the particle size distribution curve is obtained using a laser diffraction / scattering method, it is preferable that the tricalcium phosphate having a particle size of 80 to 700 μm accounts for 15% or less of the whole.

  Thereby, since there is little quantity of the tribasic calcium phosphate with a large particle size, when preparing the calcium-phosphate curable composition mentioned later, a desired physical property can be obtained.

  If the tricalcium phosphate having a particle size of 80 to 700 μm is too larger than the above value, a large amount of tricalcium phosphate having a large particle size will be present. Therefore, when preparing the calcium phosphate curable composition described later, There is a possibility that physical properties cannot be obtained.

  The obtained tricalcium phosphate preferably has a Ca / P ratio of 1.4 to 1.6, and more preferably 1.45 to 1.55. When the Ca / P ratio is in such a range, tricalcium phosphate having high affinity for a living body can be obtained.

(2) Second Step This step is a step of baking the tricalcium phosphate obtained in the first step in a baking furnace.

  The firing temperature of tricalcium phosphate is preferably 1150 to 1600 ° C, and more preferably 1200 to 1500 ° C.

  The firing time of tricalcium phosphate is preferably 1 to 10 hours, and more preferably 2 to 6 hours.

  When the firing temperature and firing time are within such ranges, volumetric contraction of tricalcium phosphate occurs, so that the tertiary calcium phosphate is densified and the mechanical strength can be increased.

The specific surface area of the fired tricalcium phosphate is preferably 1.05~1.30m ² / g, more preferably 1.10~1.25m ² / g.

  When the specific surface area is in such a range, the contact area with the organic acid or a salt thereof mixed in the third step to be described later becomes an appropriate size, so that a calcium phosphate curable composition having a certain consistency is obtained. Can do.

  If the specific surface area of the tribasic calcium phosphate is too smaller than the lower limit of the above range, the contact area between the tribasic calcium phosphate and the organic acid or salt thereof may be small, and a calcium phosphate curable composition with good consistency may not be obtained. There is.

  If the specific surface area of the tricalcium phosphate is too larger than the upper limit of the above range, the contact area between the tricalcium phosphate and the organic acid or salt thereof becomes too large, and the curing time of the calcium phosphate curable composition may be too short. There is.

(3) Third Step This step is a step of mixing the calcined tricalcium phosphate obtained in the second step and an organic acid or a salt thereof.

  The organic acid in this step is not particularly limited. For example, monocarboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, phthalic acid, etc. And oxymonocarboxylic acids such as hydroxybutyric acid, lactic acid and salicylic acid, oxydicarboxylic acids such as malic acid and tartaric acid, and oxytricarboxylic acids such as citric acid. These can be used in combination of two or more. Of these, dicarboxylic acids are preferable, and succinic acid is more preferable.

  Since the organic acid is a dicarboxylic acid, since the dicarboxylic acid has two carboxyl groups in the molecule, it has a high function of capturing tricalcium phosphate, and the tricalcium phosphate is uniformly distributed in the calcium phosphate curable composition. Can be dispersed.

  Further, since the organic acid is succinic acid, succinic acid is stable and non-toxic, and can be used safely as bone cement.

  Examples of the organic acid salt in this step include sodium acetate, sodium oxalate, sodium succinate, sodium lactate, sodium tartrate, sodium citrate, calcium propionate, calcium malonate, calcium malate, and potassium aspartate. It is done. These can be used in combination of two or more.

  Of these organic acid salts, sodium succinate is more preferable. Since the organic acid salt is sodium succinate, sodium succinate has high solubility in water, so that a calcium phosphate curable composition can be easily prepared. Moreover, since sodium succinate is stable and non-toxic, it can be safely used as bone cement.

  The amount of the organic acid or its salt used is preferably 0.01 to 0.1 mol, more preferably 0.03 to 0.06 mol.

The amount of organic acid or a salt thereof used as a solution is preferably 0.1 to 0.8 times (g) based on the weight (g) of tricalcium phosphate, and is 0.2 to 0.00. It is more preferable that the amount is 6 times (g).
Thereby, since there is much quantity of a tertiary calcium phosphate in a calcium-phosphate curable composition, the slurry-like calcium-phosphate curable composition which has desired consistency can be obtained.

  This calcium phosphate curable composition can be obtained, for example, by mixing tricalcium phosphate and a solution of an organic acid or a salt thereof in a container.

  In addition to these components, a compound such as sodium chondroitin sulfate that controls cell characteristics such as cell adhesion, migration, differentiation, and proliferation may be added.

  The time and temperature at which the tricalcium phosphate and the organic acid or salt thereof are mixed are not particularly limited as long as the calcium phosphate curable composition becomes a slurry.

  The consistency of the calcium phosphate curable composition thus obtained is preferably 23.5 to 26.5 mm, and more preferably 24 to 26 mm.

  When the consistency of the calcium phosphate curable composition is within such a range, it becomes an appropriate consistency as bone cement, so it can be easily injected into affected areas such as bone defects and bones, and hardens early after injection. Can be made.

  If the consistency of the calcium phosphate curable composition is too smaller than the lower limit of the above range, the calcium phosphate curable composition has a high viscosity and may not be efficiently injected into the bone.

  If the consistency of the calcium phosphate curable composition is greater than the upper limit of the above range, the viscosity of the bone calcium phosphate curable composition is low, so that it takes a long time to cure the calcium phosphate curable composition when injected into bone. It may take.

  The reproducibility of the consistency of the calcium phosphate curable composition obtained by the method for producing a calcium phosphate curable composition of the present invention preferably has a coefficient of variation (Cv value) of 0.1 to 5%. More preferably, it is 1-3%.

  Because the consistency variation coefficient is in this range, the dispersion of consistency is small, so even if calcium phosphate curable compositions are manufactured at different places, a calcium phosphate curable composition with a certain consistency is reproduced. It can be obtained with good quality.

  If the consistency coefficient of variation is too larger than the upper limit of the above range, the dispersion of the consistency becomes large. Therefore, the consistency differs every time the calcium phosphate curable composition is produced, and a calcium phosphate curable composition having a certain consistency is obtained. You may not be able to.

  Moreover, it is preferable that it is 7 to 10 minutes, and, as for the hardening time of the obtained calcium phosphate curable composition, it is more preferable that it is 7.5 to 8.5 minutes.

  When the setting time of the calcium phosphate curable composition is within such a range, the calcium phosphate curable composition is cured early, so that the calcium phosphate curable composition can be easily placed at a desired site in the bone. .

  If the curing time of the calcium phosphate curable composition is too shorter than the lower limit of the above range, the calcium phosphate curable composition may be cured before being injected into the bone.

  When the curing time of the calcium phosphate curable composition is too longer than the upper limit of the above range, it may take a long time to cure the calcium phosphate curable composition.

  Thus, the calcium phosphate curable composition obtained by the production method of the present invention can be used as a medical material for living body implants such as cements such as teeth and bones.

  As mentioned above, although the manufacturing method of the tricalcium phosphate of this invention and the manufacturing method of the calcium-phosphate curable composition were demonstrated, in the manufacturing method of this invention, the other arbitrary processes may be added.

  Hereinafter, although the manufacturing method of the tricalcium phosphate of this invention and the manufacturing method of a calcium-phosphate curable composition are demonstrated further in detail by an Example and a comparative example, this invention is not limited to this.

1. Production of calcium phosphate curable composition [Example 1]
(1) Production of tricalcium phosphate 3 mol of calcium hydroxide (manufactured by Ube Material Co., Ltd.) was placed in a 2 L container and dissolved in 1500 ml of water. In another container, 2 mol of phosphoric acid (manufactured by Lhasa Kogyo Co., Ltd.) and 200 ml of water were mixed. A container of calcium hydroxide solution was placed in the water jacket and the temperature was set at 13.5 ° C. And the phosphoric acid aqueous solution was dripped gradually, stirring a solution. After stirring for 0.5 hour, the reaction was terminated. The actual temperature during the reaction was controlled by the water jacket so that it was within the range of 13.5 ± 0.8 ° C. until the end of the reaction.

  After the completion of the reaction, the resulting slurry component was dried at 110 ° C. for 48 hours with a dryer (Daemon 62 manufactured by Yamato Kagaku Co., Ltd.) to obtain tricalcium phosphate in a yield of 95.8%.

(2) Calcination of tricalcium phosphate The obtained tricalcium phosphate was baked at 1400 ° C. for 4 hours using a baking furnace (SBL-2025 manufactured by Motoyama Co., Ltd.). Thereby, calcined tricalcium phosphate (Ca / P ratio = 1.5) was obtained.

(3) Production of Calcium Phosphate Curable Composition 90 g of calcined tricalcium phosphate was placed in a 1 L container and mixed with 30 g of 0.01 mol sodium succinate aqueous solution. This was stirred to obtain a slurry-like calcium phosphate curable composition.

[Example 2]
In Example 1, it carried out similarly to Example 1 except having made it the temperature in reaction of manufacture of a tribasic calcium phosphate being in the range of +/- 1.6 degreeC, and obtained the calcium-phosphate curable composition. The yield of tricalcium phosphate was 95.7%.

Example 3
In Example 1, it carried out similarly to Example 1 except having made the preset temperature of manufacture of a tribasic calcium phosphate into 12 degreeC, and obtained the calcium-phosphate curable composition. The yield of tricalcium phosphate was 95.8%.

Example 4
In Example 1, it carried out similarly to Example 1 except having made the preset temperature of manufacture of tricalcium phosphate into 15 degreeC, and obtained the calcium-phosphate curable composition. The yield of tricalcium phosphate was 92.4%.

[Comparative Example 1]
In Example 1, the setting temperature for the production of tribasic calcium phosphate was set to 5 ° C., and the setting temperature was kept within the range of ± 1.2 ° C. Sex composition was obtained. The yield of tricalcium phosphate was 95.6%.

[Comparative Example 2]
In Example 1, except that the set temperature for the production of tricalcium phosphate was 12 ° C. and the temperature during the reaction exceeded ± 2.0 ° C. and was within the range of ± 5.7 ° C. In the same manner as above, a calcium phosphate curable composition was obtained. The yield of tricalcium phosphate was 95.0%.

[Comparative Example 3]
In Example 1, except that the temperature during the reaction of the production of tricalcium phosphate exceeds ± 2.0 ° C. and is within the range of ± 3.5 ° C., the calcium phosphate curability is the same as in Example 1. A composition was obtained. The yield of tricalcium phosphate was 91.5%.

[Comparative Example 4]
In Example 1, the setting temperature for the production of tribasic calcium phosphate was set to 10 ° C., and the setting temperature was set within the range of ± 1.2 ° C. Sex composition was obtained. The yield of tricalcium phosphate was 96.0%.

[Comparative Example 5]
In Example 1, the setting temperature for the production of tribasic calcium phosphate was set to 17 ° C., and the setting temperature was set within the range of ± 1.2 ° C. Sex composition was obtained. The yield of tricalcium phosphate was 89.5%.

[Comparative Example 6]
In Example 1, it carried out similarly to Example 1 except not using a water flow jacket, and obtained the calcium-phosphate curable composition. Although the initial temperature of the solution was 13.5 ° C., a temperature increase of about 10 ° C. was confirmed during the reaction. The yield of tricalcium phosphate was 91.3%.

2. Evaluation (1) Tricalcium Phosphate (1-1) Particle Size Distribution The particle size distribution of the tricalcium phosphate obtained in Examples 1 to 4 and Comparative Examples 1 to 6 was measured using a laser diffraction particle size distribution measuring device (Microtrack Co., Ltd.). (Manufactured by FRA). And 90% diameter and the abundance ratio of 10-80 micrometers were obtained from the particle size distribution curve. The results are shown in Table 1.

  The 90% diameter in Table 1 is converted from a powder having a small volume, and indicates the particle diameter at the time when the total volume reaches 90%.

The measurement conditions for the particle size distribution were as shown below.
Measurement principle: Laser diffraction and scattering method Light source: Semiconductor laser (wavelength 750 nm)
Measurement method: Wet mode Measurement time: 3 minutes / time Sample amount: 0.5 to 2 g

(1-2) Specific surface area The specific surface area of the tricalcium phosphate obtained in Examples 1 to 4 and Comparative Examples 1 to 6 was measured using a specific surface area measuring device (manufactured by Mountec Co., Ltd., HMmodel-1201). . The results are shown in Table 1.

The measurement conditions for the specific surface area were as follows.
Measurement principle: BET single-point method Detector: Thermal conductivity detector (TCD)
Degassing temperature: 250 ° C
Gas used: N ₂ + He mixed gas and N ₂ gas

(2) Calcium phosphate curable composition (2-1) Consistency 1 g of the calcium phosphate curable composition obtained in Examples 1 to 4 and Comparative Examples 1 to 6 was taken and placed on a glass plate. Then, a 120 g glass plate was placed on the calcium phosphate curable composition. At this time, the length of the calcium phosphate curable composition spreading on the glass plate was measured to obtain a consistency. The results are shown in Table 1.

(2-2) Reproducibility Each of Examples 1 to 4 and Comparative Examples 1 to 6 was performed 5 times (n = 5), and the consistency was measured by the method shown in (2-1). For each of the five consistency values obtained in each Example and each Comparative Example, the standard deviation and the average value were obtained, and the coefficient of variation (Cv) was obtained by the following formula. The results are shown in Table 1.
Cv = standard deviation (Sx) × 100 / average value (x)

(2-3) Curing time 1 g of the calcium phosphate curable composition obtained in Examples 1 to 4 and Comparative Examples 1 to 6 was taken and placed in a mold. Then, the calcium phosphate curable composition was placed in an environment of 37 ° C. and humidity of 90%. The time until the calcium phosphate curable composition at this time was cured was measured. The results are shown in Table 1.

  As shown in Table 1, it was found that the tricalcium phosphate obtained in the examples was 90% smaller in diameter and smaller in particle size than the tricalcium phosphate obtained in the comparative example.

  Moreover, since the thing of the particle size of 10-80 micrometers exceeded the 50% of the tricalcium phosphate of an Example, it turned out that the thing of the particle diameter of 10-80 micrometers is prepared as a whole.

  In particular, it was found that the tricalcium phosphate of Example 1 had a small particle size and a particle size in the range of 10 to 80 μm.

  In contrast, it was found that the tricalcium phosphate obtained in Comparative Examples 2, 3, and 6 having a large fluctuation temperature range had a small particle size of 10 to 80 μm and a large proportion of the other particle sizes.

  On the other hand, the calcium phosphate curable compositions obtained in the examples had good consistency, good reproducibility of consistency, and good curing time.

  In particular, the calcium phosphate curable composition of Example 1 was found to have excellent consistency reproducibility, the best curing time, and excellent physical properties.

  On the other hand, the calcium phosphate curable composition obtained in the comparative example was inferior in consistency and poor in reproducibility of consistency.

  Regarding the consistency, when the difference between the maximum value and the minimum value in five trials was examined, it was 0.8 mm in Example 1 and 3.6 mm in Comparative Example 6. From this, when Example 1 and Comparative Example 6 are compared, the magnitude of variation in the temperature range during synthesis greatly affects the consistency variation, even though the holding temperature (initial temperature) is the same. It was found to affect. The difference between the maximum value and the minimum value of the consistency in the other examples was as small as 2.0 mm or less.

  From the above results, if a calcium phosphate curable composition is prepared by using the production method of the present invention, a calcium phosphate curable composition that always exhibits certain physical properties can be obtained, which is excellent as a bone cement.

Claims (10)

A method for producing tricalcium phosphate by producing a tricalcium phosphate by reacting a calcium compound with phosphoric acid or a salt thereof at a holding temperature of 12 to 15 ° C. using a wet synthesis method ,
The method for producing tribasic calcium phosphate, wherein the reaction is performed while controlling the temperature so that the holding temperature varies within a range of ± 2 ° C.   The manufacturing method of the tribasic calcium phosphate of Claim 1 which has a baking process which bakes the said tricalcium phosphate. The method for producing tricalcium phosphate according to claim 1 or 2, wherein a specific surface area of the obtained tricalcium phosphate is 1.05 to 1.30 m ² / g.   The method for producing tricalcium phosphate according to any one of claims 1 to 3, wherein the obtained calcium phosphate has a Ca / P ratio of 1.4 to 1.6.   When the particle size distribution of the obtained tricalcium phosphate is measured by a laser diffraction / scattering method to obtain a particle size distribution curve, the particle at a point that is 90% of the total volume of the tricalcium phosphate in the particle size distribution curve The method for producing tricalcium phosphate according to any one of claims 1 to 4, wherein the diameter is 40 to 55 µm.   The said tricalcium phosphate is a manufacturing method of the tricalcium phosphate in any one of Claim 1 thru | or 5 with which the particle | grains with a particle size of 10-80 micrometers occupy 40-70% of the whole.   The said temperature control is a manufacturing method of the tribasic calcium phosphate in any one of Claim 1 thru | or 6 performed using a refrigerant | coolant jacket. A first step of producing tricalcium phosphate by reacting a calcium compound and phosphoric acid or a salt thereof at a holding temperature of 12 to 15 ° C. using a wet synthesis method ;
A second step of firing the tricalcium phosphate;
A method for producing a calcium phosphate curable composition comprising a third step of mixing the calcined powder mainly composed of tricalcium phosphate and an organic acid or a salt thereof,
The method of producing a calcium phosphate curable composition, wherein the reaction in the first step is performed while temperature control is performed so that the holding temperature varies within a range of ± 2 ° C.   The method for producing a calcium phosphate curable composition according to claim 8, wherein the consistency of the calcium phosphate curable composition is 23.5 to 26.5 mm.   The method for producing a calcium phosphate curable composition according to claim 8 or 9, wherein a curing time of the calcium phosphate curable composition is 6 to 9 minutes.