JP2849676B2 - Method for producing carbonated hydroxyapatite whiskers - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a carbonated hydroxyapatite whisker. More specifically, the present invention relates to a method for producing a carbonated hydroxyapatite whisker having a long average length, which is useful as a biomaterial, particularly as a filler for a bone defect.

BACKGROUND OF THE INVENTION Hydroxyapatite is one of the calcium phosphate compounds represented by Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ . The hydroxyapatite is a main component of bone or root in a living body, and is known to have high biocompatibility.
In recent years, utilizing the excellent biocompatibility of the hydroxyapatite, for example, it has been proposed to use a filler for a bone defect, a dental prosthesis, an aggregate of a dental cement, etc. Some are commercialized.

Among the above-mentioned applications, when hydroxyapatite is used as a filler for a bone defect, the new bone tissue penetrates into the gaps of the filled hydroxyapatite particles to form a chemical bond with the hydroxyapatite, It is believed that it takes up hydroxyapatite to form new bone tissue. The gap is required to have a major axis of 100 μm or more.

In order to use hydroxyapatite in the above-mentioned applications, it is preferable that the hydroxyapatite is in a textured form. Conventionally, fibrous hydroxyapatite or apatite-like substance is
Melting the phosphoric acid and calcium components of the raw material,
Alternatively, it is manufactured by dispersing calcium phosphate in an aqueous binder solution, extruding from a nozzle having pores, and spinning. The above technology is disclosed in
117621, 58-54023, 61-75817, and 61
-106166.

By the production method using the above-mentioned spinning method, fibrous hydroxyapatite or apatite-like substance can be obtained. However, the above-mentioned method for producing hydroxyapatite uses a spinning method that requires complicated means and requires a special apparatus for spinning, and cannot be said to be an industrially advantageous method.

On the other hand, the present inventors have found that by heating a solution containing a phosphate and a calcium salt in the presence of urea, carbonate-containing hydroxyapatite can be obtained in the form of whiskers directly in an aqueous solution. A patent for a novel carbonate-containing hydroxyapatite whisker and a method for producing the same have already been filed by the present applicant (see Japanese Patent Application No. 63-295824).

The carbonated hydroxyapatite whiskers described in the above specification have the following formula: l / {(a + b) / 2} (1 is the length of the whisker, a is the thickness of the whisker, and b is the width of the whisker. Are shown in the range of 20 to 200, and the length is 20 to 150 μm.
Whiskers in the range.

Most of the carbonated hydroxyapatite whiskers are hydroxyapatite, which is a main component of bone or tooth root, and the portion substituted by carbonic acid also retains the hydroxyapatite type molecular structure. It has good biocompatibility. Further, since the whiskers can form a relatively large gap due to entanglement of the whiskers,
The new bone tissue can easily enter the gap, and the whisker and the new bone tissue can be integrated to promote the formation of new bone.

However, in order to use a carbonated hydroxyapatite whisker as described above, particularly as a filler for a bone defect, it is desirable that the average length be further longer.

[Object of the Invention] An object of the present invention is to provide a method for producing a carbonated hydroxyapatite whisker which can easily produce a carbonated hydroxyapatite whisker having a long average length in a short time.

[Summary of the Invention] The present invention provides an aqueous solution containing a calcium salt and phosphoric acid and / or a phosphate, which is heated at a temperature of 70 ° C or more and less than 90 ° C in the presence of urea, and has an average length of 100 µm or more. The first step of producing the octacalcium phosphate whisker, and the reaction product solution containing the octacalcium phosphate whisker obtained in the first step is heated at a temperature of 90 to 180 ° C. in the presence of water to obtain an average. A second step of producing a carbonate-containing hydroxyapatite whisker having a length of 50 μm or more.

Preferred embodiments of the method for producing a carbonated hydroxyapatite whisker of the present invention are as follows.

(1) The method for producing a carbonated hydroxyapatite whisker, wherein the first and second steps are performed in an acidic aqueous solution.

(2) The method for producing a carbonated hydroxyapatite whisker, wherein the first step is performed at a temperature of 75 to 85 ° C.

(3) The method for producing a carbonated hydroxyapatite whisker, wherein an octacalcium phosphate whisker having an average length of 150 µm or more is generated in the first step.

(4) The method for producing a carbonated-containing hydroxyapatite whisker, wherein the second step is performed at a temperature of 95 to 130 ° C.

(5) The method for producing a carbonated hydroxyapatite whisker, wherein the second step comprises producing a carbonated hydroxyapatite whisker having an average length of 100 μm or more.

(6) In the above second step, the following formula; l / {(a + b) / 2} (where l represents the length of the whisker, a represents the thickness of the whisker, and b represents the width of the whisker) A method for producing a carbonated hydroxyapatite whisker, comprising producing a carbonated hydroxyapatite whisker having an indicated aspect ratio of 20 to 200.

[Effect of the Invention] The production method of the present invention is a method capable of easily producing a long carbonated hydroxyapatite whisker having an average length of 50 µm or more.

The carbonate-containing hydroxyapatite whiskers produced by the production method of the present invention have a longer average length than conventional carbonate-containing hydroxyapatite whiskers, so that they are easily entangled with each other, and a degree to which new bone tissue can penetrate. The gap can be easily formed, and therefore, can be suitably used as a biomaterial for filling a bone defect.

In addition, the above-mentioned carbonate-containing hydroxyapatite whiskers can be used for producing molded articles having various shapes such as a sheet shape and a cylindrical filter paper shape by utilizing the property of being easily entangled with each other.

[Detailed Description of the Invention] As described above, the method for producing a carbonated hydroxyapatite whisker of the present invention comprises the first step of producing an octacalcium phosphate whisker, and the octaphosphate obtained in the first step. The method is characterized by comprising a second step of producing a carbonated hydroxyapatite whisker from a calcium whisker.

In the first step of the present invention, an aqueous solution containing a calcium salt and phosphoric acid and / or phosphate is subjected to 70 ° C. in the presence of urea.
This is a step of heating at a temperature of less than 90 ° C. to generate octacalcium phosphate whiskers having an average length of 100 μm or more.

Examples of the calcium salt include calcium nitrate, calcium chloride, calcium carbonate, and the like, with calcium nitrate being particularly preferred.

Examples of the phosphate include diammonium hydrogen phosphate,
Disodium hydrogen phosphate, dipotassium hydrogen phosphate, ammonium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium phosphate, or hydrates of these can be mentioned. Diammonium hydrogen is preferred.

The phosphoric acid and the phosphate may be used alone or in combination.

The ratio of the amount of the calcium salt and the amount of the phosphoric acid and / or the phosphate to be used is usually a molar ratio of Ca to P (Ca / P) of 1.1 to 1.1.
It is preferably in the range of 3.0, and more preferably in the range of 1.67 ± 0.34. This is because, in the composition [Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ] of hydroxyapatite, which is the basic substance of the carbonated hydroxyapatite obtained in the second step, the molar ratio of stoichiometric Ca and P Due to the ratio (Ca / P) being 1.67.

The urea acts as a precipitant, and ammonia generated by the decomposition of the urea functions to adjust the pH of the reaction solution and to form a uniform precipitate of octacalcium phosphate whiskers. Also, carbonate that occurs simultaneously with the ammonia by the decomposition of urea, dissolved in the reaction solution in the first step, PO ₄ ^3- or O of hydroxyapatite produced in the second step
H ^- serves to partially and substituted to produce a carbonated hydroxyapatite of.

The amount of the urea used is preferably in the range of 0.2 to 1.0 mol based on 0.1 mol of the phosphoric acid and / or phosphate of the hydroxyapatite raw material. The amount of urea used is phosphate
When the amount is less than the above range with respect to 0.1 mol, the pH adjustment becomes insufficient, and the desired product may not be obtained. When the amount of urea used is larger than the above range, the whiskers to be formed tend to further agglomerate to give a squirrel-like shape.

The first and second steps of the present invention are preferably performed in an acidic aqueous solution. In particular, it is preferable to perform the first step so that the pH at the start of the reaction is 3.9 or less and is as high as possible. Examples of the acid that can be used for the acidic aqueous solution include nitric acid, hydrochloric acid, and acetic acid, and nitric acid is particularly preferable. The concentration of the acid is usually in the range from 0.2 to 1.0 mol /.

In carrying out the first step of the present invention, first, a calcium salt, phosphoric acid and / or phosphate, and urea are dissolved in an acidic aqueous solution to prepare a reaction raw material liquid. The pH of the reaction raw material liquid can be adjusted by adding the above-mentioned acid, ammonia, or aqueous ammonia to the reaction raw material liquid.

Next, the reaction raw material liquid is charged into a reaction tank and heated at a temperature of 70 ° C. or more and less than 90 ° C., preferably at a temperature of 75 to 85 ° C. to cause a reaction.

The reactor used in the first step does not need to be a pressurized vessel in order to perform the first step at a temperature within the above range, but the same reactor is used for the first step and the second step. Since the second step of the present invention is conveniently performed under pressure, it is preferable that the container is a pressurized container that can perform the second step. In the present invention, since the first step and the second step are performed in an acidic aqueous solution, the material of the reaction tank needs to be acid-resistant.

In the reaction in the first step, the pH of the reaction solution changes due to ammonia and carbonic acid generated by the thermal decomposition of urea, and phosphoric acid generated by partial decomposition of the product.
It can be tracked by continuously measuring the pH. Next, the relationship between the change over time in the pH of the reaction solution and the product will be described.

First, at the beginning of the reaction, the pH increases due to ammonia generated by the thermal decomposition of urea. The pH of the reaction solution rises
In the pH range of 3.5 to 4.2, precipitation of particulate crystals of calcium hydrogen phosphate (CaHPO ₄ , sometimes abbreviated as DCPA) occurs, and at the same time, the pH slightly decreases.

After the precipitation of DCPA crystals, the pH of the reaction solution increases again, and the pH reaches a maximum value in the range of 5.2 to 6.0. During the rise of the above pH, the reaction solution of the supernatant of the precipitation of the DCPA, octacalcium phosphate _{(Ca 8 H 2 (PO 4} ) 6 · 5H 2 O, may be abbreviated as follows OCP) of Whiskers generate. The formation of whiskers of OCP continues until the pH reaches the maximum value mentioned above. As long as the reaction temperature of the first step is maintained in the above range, the OCP does not convert to other substances, and the OCP whiskers grow in the longitudinal direction and gradually become longer as the reaction time becomes longer. The pH of the reaction solution slightly decreases after reaching the maximum value.

If the reaction temperature of the first step is lower than the above range, OCP
Whisker generation rate is slow or conversion to OCP does not proceed sufficiently, and if it is higher than the above range, OCP is converted to hydroxyapatite, OCP whiskers grow insufficiently and the average length of OCP is short. You get a whisker.

By performing the first step for 8 hours or more, preferably for 15 hours or more, the average length is 100 μm or more, preferably 150 μm or more.
OCP whiskers of μm or more can be generated.
In general, the longer the reaction time of the first step, the more OC
Although the average length of the P whiskers increases, the growth rate of the OCP whiskers gradually decreases, so it is not advisable to make the reaction time too long.
A reaction time of less than about an hour is appropriate.

In the first step, the reaction solution may or may not be stirred.However, after the growth of the OCP whiskers has started, stirring the reaction solution will reduce the average length of the OCP whiskers. Is preferred. Therefore, it is preferable to stir gently in order to carry out the reaction of the reaction raw materials uniformly for about 1 to 2 hours at the beginning of the first step, and then to advance the first step without stirring.

The generation of OCP in the first step of the present invention can be confirmed from the powder X-ray diffraction diagram of the intermediate product in the first step. From the powder X-ray diffraction diagram of the intermediate product, it is confirmed that DCPA is also present in the intermediate product of the first step.

In the second step of the present invention, the reaction product solution containing the octacalcium phosphate whisker obtained in the first step is heated at a temperature of 90 to 180 ° C. in the presence of water to form a carbonate having an average length of 50 μm or more. And forming a hydroxyapatite whisker containing.

The second step of the present invention is a step of simply heating the reaction product liquid obtained in the first step to a temperature of 90 to 180 ° C. Therefore, the first step and the second step of the present invention may be performed in different reaction tanks, but both steps are performed in the same reaction tank without removing the contents from the reaction tank after the completion of the first step. It is preferable to increase the temperature of the contents to a predetermined temperature.

In the second step, the pH of the reaction solution was gradually reduced to pH 6.
In the meantime, the DCPA and OCP are hydrolyzed to produce hydroxyapatite, but the reaction solution contains carbonic acid generated by the decomposition of urea as described above. Therefore, a carbonate-containing hydroxyapatite in which a part of PO ₄ ^3- or OH ⁻ of the hydroxyapatite is replaced by carbonic acid (CO ₃ ^2- ) is generated. Substitution by the carbonate, of each molecule PO ₄ ^3-
Or OH ^- may be either is substituted structure, both may be substituted structure. The carbonic acid-containing hydroxyapatite whisker contains carbonic acid usually in the range of 2 to 7% by weight in a bonded state of the above structure.

The fact that the carbonate-containing hydroxyapatite whisker contains carbonic acid in the bonded state of the above structure can be confirmed by measuring the infrared absorption (IR) spectrum of the whisker by the KBr method. In the above IR spectrum, generally, hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH)
OH ₂₎ ^- is CO ₃ ^2- absorption of substituting for the 1540 cm ^-1 and around 88
0cm around ^-1, the absorption of CO ₃ ^2- substituted with PO ₄ ^3- is 1420 cm ^-1
In the vicinity, the absorption of CO ₃ ^2- substituted with both OH ^- and PO ₄ ^3- is observed around 1460 cm ^-1 , respectively. Further, the carbonic acid content of the above carbonate-containing hydroxyapatite whisker can be calculated by comparing the intensity of the absorption of CO ₃ ^2- with the other absorption of hydroxyapatite in the above-mentioned IR spectrum.

In the second step, the OCP produced in the first step is a whisker with a long average length, and in the second step, the OCP whisker is changed to a carbonated hydroxyapatite whisker while maintaining its shape. Produces a carbonated hydroxyapatite whisker with a long average length.

The heating temperature in the second step is a temperature in the range of 90 to 180 ° C, preferably 95 to 130 ° C, particularly preferably 105 to 125 ° C. When the heating temperature is lower than the above range, it takes a long time to convert to a carbonate-containing hydroxyapatite whisker, and when the heating temperature is higher than the above range, the average length of the generated carbonate-containing hydroxyapatite whisker becomes short.
In the second step, it is necessary that water is present in the system, and therefore, when the heating temperature in the second step is higher than 100 ° C., it may be performed under pressure in a pressure-resistant reaction tank. is necessary.

The heating time in the second step can be shortened as the heating temperature is increased, and as the heating time is increased, the average length of the generated carbonated hydroxyapatite whiskers decreases.

Therefore, in the second step of the present invention, the desired conversion rate to the carbonated hydroxyapatite whisker and the average length of the carbonated hydroxyapatite whisker (50 μm or more)
The heating temperature and the heating time should be determined in consideration of, for example, the heating time is preferably 10 to 25 hours when the heating temperature is 95 ° C, and 2 to 6 hours when the heating temperature is 120 ° C. .

After the completion of the second step, the product is washed with water, dehydrated and dried to obtain a carbonated hydroxyapatite whisker.

According to the present invention, the average length is 50 μm or more, preferably 10 μm or more.
Carbonic acid-containing hydroxyapatite whiskers of 0 μm or more, more preferably 120 μm or more, can be produced. The average length is a number average length.

The carbonated hydroxyapatite whiskers produced according to the present invention have the following formula: l / {(a + b) / 2} (where l is the length of the whisker, a is the thickness of the whisker, and b is the whisker Are shown in the range of 20 to 200.

The carbonated hydroxyapatite whiskers produced according to the present invention are heated to a temperature range of 800-1300 ° C., preferably about 1 ° C.
Decarboxylate by heating to 200 ° C and then quenching,
Hydroxyapatite containing no carbonic acid can be produced. Although the hydroxyapatite obtained by the above decarboxylation tends to decrease in weight as compared to the carbonated hydroxyapatite whisker, the shape of the whisker is well maintained.

The carbonated hydroxyapatite whisker and the hydroxyapatite whisker obtained by decarboxylation of the whisker as described above can be particularly preferably used as a filler for a bone defect, and can also be used as an artificial bone, an artificial joint, or a bone. Replacement materials, osteosynthesis materials, artificial blood vessels, artificial trachea, artificial roots, dental cement,
Various biomaterials such as transdermal terminals; biochemical applications such as column packing for chromatography for biopolymers and carrier for cell culture; dentifrice for tooth decay prevention; catalysts such as phenol synthesis catalyst and styrene polymer dispersant Ion exchangers such as heavy metal collectors and fluorine collectors; various sensors such as humidity sensors and gas sensors; and phosphors. Hydroxyapatite is stable up to about 1300 ° C in the air, so it is also used as a heat insulating material.

Further, by subjecting the suspension of the carbonate-containing hydroxyapatite whisker to suction filtration or centrifugal separation, a molded product made of a carbonate-containing hydroxyapatite whisker having various shapes such as a sheet shape and a cylindrical filter paper shape is obtained. Can be.

The carbonic acid-containing hydroxyapatite whisker molded article, and the OCP whisker molded article, a filter material such as protein,
There are uses such as an ion exchanger and a sintered body for artificial aggregate.

 Next, examples of the present invention will be described.

In each example, the product was identified by measuring X-ray diffraction and infrared absorption (IR) spectra. In addition, observation of the form of the product obtained in each example was performed using a scanning electron microscope.

[Example 1] Calcium nitrate tetrahydrate, phosphoric acid and urea were converted to calcium nitrate tetrahydrate 0.167 mol /, phosphoric acid 0.1 mol /,
And urea at a concentration of 0.5 mol /
It was dissolved in nitric acid to prepare 35 solutions. Next, aqueous ammonia was added to this solution to adjust the pH of the solution to 2.2 to prepare a reaction raw material liquid. This reaction raw material liquid was charged into a 50-capacity jacketed reactor (stainless steel, inner surface Teflon coating) provided with a reflux condenser and a heater inside.

By heating the contents of the reaction vessel with a heater, raising the temperature of the contents to 80 ° C. in about 1 hour, and maintaining the temperature of the contents at 80 ° C. for 22 hours from the charging of the reaction raw material liquid. The first step was performed.

After the end of the first step, whiskers are generated in the contents of the reaction tank, and a part of the whiskers is sampled,
When its X-ray diffraction (FIG. 1) and infrared (IR) absorption spectrum (FIG. 2) were measured, it was confirmed that the whiskers were octacalcium phosphate whiskers.
When the length of the whisker was observed with a scanning electron microscope, the length of the whisker had a frequency distribution as shown in FIG. 3, and the length of the whisker included a maximum of 300 μm. Was 190 μm.

Then, the reaction vessel was sealed while the contents obtained in the first step were placed in the reaction vessel, the contents of the reaction vessel were raised to 120 ° C., and the temperature was maintained at that temperature for 2 hours, whereby the second step was carried out. Done.

After the completion of the second step, the contents are taken out of the reaction vessel, and the whisker-like solid is washed with distilled water and ethanol, filtered off, dried at 120 ° C., and 494 g of the whisker-like solid (collection based on the used calcium nitrate). %: 84%).

The solid was measured for X-ray diffraction (FIG. 4) and infrared (IR) absorption spectrum (FIG. 5), and as a result, was confirmed to be a single phase of carbonated hydroxyapatite whiskers. Also, from the IR spectrum, the product was converted to carbonic acid.
The content was confirmed to be 5.5% by weight. When the length of this whisker was observed with a scanning electron microscope, the length of the whisker had a frequency distribution as shown in FIG. 6, including those having a maximum length of 240 μm. Is 1
It was 30 μm.

Example 2 A carbonate-containing hydroxyapatite whisker was produced in the same manner as in Example 1, except that the heating time in the second step was changed to 4 hours.

In the same manner as in Example 1, it was confirmed that the above product was a carbonated hydroxyapatite whisker, and its length was observed with a scanning electron microscope. It has a frequency distribution as shown, including a maximum of 230 μm, and an average length of 110 μm.

Example 3 A carbonated hydroxyapatite whisker was produced in the same manner as in Example 1, except that the heating time in the second step was changed to 6 hours.

In the same manner as in Example 1, the product was confirmed to be a carbonate-containing hydroxyapatite whisker, and its length was observed with a scanning electron microscope. It had a frequency distribution as shown, including those with a maximum length of 170 μm, with an average length of 70 μm.

Example 4 A carbonated hydroxyapatite whisker was produced in the same manner as in Example 1, except that the heating temperature in the second step was 95 ° C. and the heating time was changed to 24 hours.

In the same manner as in Example 1, it was confirmed that the product was a carbonate-containing hydroxyapatite whisker, and its length was observed with a scanning electron microscope. It has a frequency distribution as shown, including those with a maximum length of 300 μm, and an average length of 170 μm.

[Brief description of the drawings]

FIG. 1 is an X-ray diffraction diagram of an octacalcium phosphate whisker obtained in the first step of Example 1. FIG. 2 is an infrared absorption spectrum of the octacalcium phosphate whisker obtained in the first step of Example 1. FIG. 3 is a frequency distribution diagram of the length of octacalcium phosphate whiskers obtained in the first step of Example 1. FIG. 4 is an X-ray diffraction diagram of the carbonate a hydroxyapatite whisker obtained in the second step of Example 1. FIG. 5 is an infrared absorption spectrum of the carbonated hydroxyapatite whisker obtained in the second step of Example 1. FIG. 6 is a frequency distribution diagram of the length of carbonate-containing hydroxyapatite whiskers obtained in the second step of Example 1. FIG. 7 is a frequency distribution diagram of the length of carbonate-containing hydroxyapatite whiskers obtained in the second step of Example 2. FIG. 8 is a frequency distribution diagram of the length of carbonate-containing hydroxyapatite whiskers obtained in the second step of Example 3. FIG. 9 is a frequency distribution diagram of the length of the intermediate product obtained in the first step and the length of the carbonated hydroxyapatite whisker (final product) obtained in the second step of Example 4.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kazuhiro Segawa 8-1, Goi-minamikaigan, Ichihara-shi, Chiba Japan Lime Industry Co., Ltd. (72) Inventor Naohiko Sasaki 8-1, Goi-minamikaigan, Ichihara-shi, Chiba Japan Inside Lime Industries Co., Ltd. (72) Inventor Hitoshi Mito 8-1, Goi South Coast, Ichihara City, Chiba Prefecture Japan Lime Industry Co., Ltd. (56) References JP-A-3-28197 (JP, A) (58) Field (Int.Cl. ⁶ , DB name) C30B 1/00-35/00

Claims (1)

(57) [Claims] An aqueous solution containing a calcium salt and phosphoric acid and / or phosphate is heated at a temperature of 70 ° C. or more and less than 90 ° C. in the presence of urea to form a phosphoric acid having an average length of 100 μm or more. The first step of forming a calcium whisker, and the reaction product solution containing the octacalcium phosphate whisker obtained in the first step is heated at a temperature of 90 to 180 ° C. in the presence of water to have an average length of 50 μm. A method for producing a carbonated hydroxyapatite whisker, comprising the second step of producing the above carbonated hydroxyapatite whisker.