JP3082503B2 - Precursor for artificial bone production and method for producing artificial bone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a precursor which is excellent in biocompatibility and osteoconductivity, has a dense and excellent strength, and gives an apatite artificial bone which is less harmful to the living body. The present invention relates to a method for producing an artificial bone.

[0002]

2. Description of the Related Art As an artificial bone material used for repairing bone defects or filling voids in orthopedic surgery, oral surgery, dentistry, plastic surgery, etc., calcium phosphate-based apatite has been widely used. Typically,
Hydroxyapatite [Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ], fluorine apatite [Ca ₁₀ (PO ₄ ) ₆ F], carbonate apatite [Ca ₁₀ (PO ₄ ) ₆ (CO ₂ )], β · Ca ₃ ( PO ₄ ) ₂ ,
α · Ca ₃ (PO ₄ ) _{2 and the} like are known.

[0003] Of these, fluorine apatite is the most stable chemically and thermally. However, since fluorine apatite is highly toxic when it may be released, it is strictly controlled as a biomaterial. Need. Α ・ Ca ₃ (PO
₄ ) ₂ cannot be used alone because it has high solubility and its stability in the living body is not so good. Even when used in combination with other apatites, quantitative control is required.

On the other hand, hydroxyapatite and carbonate apatite are currently most widely used because they have good in vivo stability, have no toxicity problem, and are easy to handle. The problem remains that the ratio of is difficult to become atomic stoichiometry. And Ca
If the / P atomic ratio exceeds 10/6, excess CaO is generated during the firing process, which adversely affects the affinity in vivo. When the Ca / P atomic ratio is less than 10/6, C
a ₃ (PO ₄ ) ₂ is produced, which becomes α · Ca ₃ (PO ₄ ) ₂ under firing conditions of 1200 ° C. or higher, which has poor initial osteoconductivity when formed into a fired body, Lack of bone suitability. That is, the above-mentioned CaO or α · Ca ₃ (PO ₄ ) ₂
Is eluted before the bone is formed, which delays the bonding with the bone and causes a problem of insufficient osteoconductivity. In order to avoid such a problem, it is conceivable to perform low-temperature sintering at 1200 ° C. or lower. However, in order to obtain sufficient strength by such low-temperature sintering, expensive molding equipment such as a high-temperature isostatic press (HIP) is required. Will be needed.

On the other hand, it has been confirmed that when hydroxyapatite or carbonate apatite contains a third component such as Mg, stable β.Ca ₃ (PO ₄ ) ₂ is produced even under high-temperature firing conditions of about 1400 ° C. However, on the other hand, if Mg is contained in an excessive amount, there is a risk of showing carcinogenicity. If Mg is contained, it becomes easily amorphous and the affinity with the living body is poor, so it is enough to avoid such problems The mixing and baking must be repeated, and it takes a long time to manufacture. Mg ₃ (PO ₄ ) ₂ itself has high solubility in vivo,
However, since strict management is required in terms of manufacturing, it has hardly been practically used. Also, β
Ca ₃ (PO ₄ ) ₂ alone lacks stability in vivo,
It has been confirmed that a mixture with apatite has better bone conduction than apatite alone.

[0006]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned circumstances, and its object is to provide hydroxyapatite or carbonate apatite with M as a third component.
While enjoying the advantages of containing g, the above problems caused by the addition of Mg are eliminated, the elution of the Mg component is suppressed, and the problem of harm to living organisms is eliminated. An object of the present invention is to provide a precursor capable of providing an artificial bone and a method capable of efficiently producing the artificial bone.

[0007]

Means for Solving the Problems The precursor for producing an artificial bone according to the present invention, which can solve the above-mentioned problems, comprises hydroxyapatite and / or carbonate apatite containing Ca, Mg and P as constituent elements. It has a gist in that it contains Mg in an amount satisfying the following requirements as a main component.

Mg content: 0.1-0.5% by weight Atomic ratio of Ca, Mg, P: 1.50 ≦ (Ca + Mg) / P ≦
1.67 This precursor is prepared by reacting phosphoric acid, calcium hydroxide, calcium carbonate, etc. and a Mg source (magnesium hydroxide, magnesium carbonate, etc.) in an aqueous or non-aqueous solution, or using trimethyl phosphate, calcium ethoxy, etc. If the synthesis is performed by a sol-gel method using a metal alkoxide such as Mg, Mg becomes a solid solution in the apatite crystal structure at this synthesis stage, and the elution of Mg after firing can be further reduced. If these Mg-containing apatites are fired at 1200 to 1450 ° C., there is no elution of Mg, excellent biocompatibility and osteoconductivity, and dense and excellent strength, and it is possible to obtain artificial bones that are less harmful to living organisms. .

[0009]

As described above, in the present invention, hydroxyapatite and / or carbonate apatite are the main components, and a predetermined amount of Mg is dissolved in this to form a stable β. Ca ₃ (PO ₄₎ yielding _2, dense _{β · Ca 3 (PO 4)} 2 and biocompatibility of two-phase mixture of apatite and to obtain a precursor that gives a good sintered compact bone conduction The reasons for determining the above constituent requirements are as follows.

That is, the Mg content in apatite is 0.1 to 0.5
If the amount of Mg is insufficient, the formation of α · Ca ₃ (PO ₄ ) ₂ when firing at a temperature of 1200 ° C. or more cannot be prevented if the amount of Mg is insufficient. This is because the effect of improving bone conductivity cannot be ensured. On the other hand, M
When the amount of g exceeds 0.5% by weight, the amount of Mg solid solution in the apatite crystal structure is saturated to generate MgO, which remains as a soluble component even after firing, which is an obstacle pointed out in the prior art. Can not be avoided.

FIG. 1 shows the results obtained by sintering various amounts of Mg with respect to hydroxyapatite or carbonate apatite at 1200 ° C. for 120 minutes, and examining the amount of sintering of the resulting sintered body in physiological saline and bone conduction. From this figure, it can also be seen that by setting the Mg content to 0.1% by weight or more, excellent osteoconduction can be ensured while suppressing elution of the sintered body. However, when the amount of Mg exceeds 0.5% by weight, the dissolution of Mg is rapidly increased, and the possibility of carcinogenicity is caused, and the biocompatibility of the sintered body is deteriorated.
It must be kept below 0.5% by weight.

The atomic ratio of (Ca + Mg) / P is 1.50 to
The reason defined in the range of 1.67 is that β · Ca ₃ (PO ₄ ) ₂ is generated while preventing the generation of CaO, and the sintered compact is mixed with a two-phase mixed composition of apatite and β · Ca ₃ (PO ₄ ) _2. If the temperature is less than the above range, the stability as β · Ca ₃ (PO ₄ ) ₂ when sintered at a high temperature of 1200 ° C. or more becomes poor, and dense and stable apatite and β · Ca ₃ (PO ₄ ) It becomes difficult to obtain a sintered compact having a two-phase mixed composition with _2, and if it exceeds the above range, CaO is generated, the biocompatibility of the sinterable molded body is reduced, and osteoconduction is also deteriorated.

Table 1 shows that the amount of Mg added to hydroxyapatite or carbonate apatite was 0.2% by weight.
, And calcined at 1200 ° C. for 2 hours while changing the atomic ratio of (Ca + Mg) / P to β in the obtained sintered body.
-It is a result of examining the generation rate of Ca ₃ (PO ₄ ) ₂ . As is clear from this table, (Ca + Mg)
When / P is set in the range of 1.50 to 1.67, dense and stable β · Ca ₃ (PO ₄ ) ₂ can be generated in the sintered product. However, if it is less than 1.50, Ca ₂ P ₂ O ₇ is generated, and no generation of β · Ca ₃ (PO ₄ ) ₂ is observed.
Even when it exceeds 67, β · Ca ₃ (PO ₄ ) ₂ is not generated, and the sintered product has a mixed composition of hydroxyapatite and CaO.

[0014]

[Table 1]

The method for producing the precursor according to the present invention is not particularly limited, but the most preferred is, for example, phosphoric acid esters such as phosphoric acid and triethyl phosphate and calcium chloride, Ca carboxylate, calcium alkoxide and the like.
This is a method in which a solution is reacted with an Mg source (Mg chloride or a carboxylate such as magnesium acetate or the like) in an aqueous or non-aqueous solvent while maintaining the alkalinity, or a reaction is performed by a sol-gel method. If such a method is adopted, the crystal structure in the apatite generation stage will have M
g is taken in a solid solution state, and M
As a result of the easy diffusion and movement of g, Mg is homogeneously dispersed and shifts to a newly generated phase, so that elution of Mg can be prevented more reliably.

By the above-mentioned solution reaction, Mg-dissolved hydroxyapatite or Mg-dissolved carbonate apatite precipitates in the form of fine powder, and the Mg-dissolved apatite is subjected to vacancy defects by the subsequent compacting and sintering processes. In order to obtain a dense molded article free from defects, it is preferable to adjust the solution reaction conditions (solution concentration, type of solvent, temperature, etc.) so that primary particles can be obtained in the form of fine particles having a major axis of 5 μm or less. When it is obtained as a coarse particle, it is of course possible to pulverize it and adjust it to a suitable particle size.

The thus obtained precursor in the form of fine powder is dried, formed into a predetermined shape, preliminarily calcined if necessary, and then calcined at 1200 to 1450 ° C. for about 1 to 3 hours under atmospheric pressure. A natural artificial bone can be obtained. If the sintering temperature is less than 1200 ° C., it is difficult to obtain a dense sintered product, not only the strength becomes insufficient, but also the elution of the artificial bone itself becomes high, the bone conduction becomes unstable, and furthermore, the cell is poorly eaten. And the stability of the generated bone becomes worse.

On the other hand, if the calcination temperature exceeds 1450 ° C., different phases are precipitated for both hydroxyapatite and β.Ca ₃ (PO ₄ ) ₂ structures, and the amount of Mg eluted increases, resulting in osteoconduction and In vivo stability deteriorates.

[0019]

EXAMPLES Hereinafter, the structure and operation and effect of the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples, and the present invention is applicable to the above and following points. The present invention can be appropriately modified and implemented within the scope of the invention, and all of them are included in the technical scope of the present invention.

EXAMPLE A predetermined amount of phosphoric acid, calcium hydroxide and magnesium hydroxide were added to water, and the pH was maintained at 11 while stirring vigorously.
The reaction was carried out at 2 ° C. for 2 hours. After completion of the reaction, the product was filtered and washed to obtain Mg solid solution hydroxyapatite. When the Mg content and the (Ca + Mg) / P atomic ratio of each obtained product were examined by elemental analysis, the results shown in Table 1 were obtained.
Further, when these were subjected to X-ray powder diffraction, it was confirmed that each was a single phase of hydroxyapatite.

This Mg-dissolved hydroxyapatite (precursor for producing artificial bone) powder is granulated to 0.6 to 1 mm, and is granulated in an air furnace.
Baking was performed at 1200 ° C. for 2 hours. The phase constitution and β · Ca ₃ (PO ₄ ) ₂ content of the obtained fired product were determined by X-ray diffraction, and the results are shown in Table 1.

[0022]

[Table 2]

As is clear from Table 2, before sintering of Nos. A to E (precursors) all have a hydroxyapatite phase, but in Nos. A to D (Examples), While the resulting phase has a two-phase mixed composition of hydroxyapatite and β · Ca ₃ (PO ₄ ) ₂ , No. E (comparative example)
CaO is observed in the sintered product.

Each of the obtained sintered products was subjected to the following in vitro test, and the elution amount and the pH of the aqueous solution were examined. The Mg elution was 0.5 ppm or less in all cases. Was about 7.5, while No. E was pH 10 or more. In addition, when an implanting test was performed on rabbit hip bone using each of the sintered products, it was confirmed that all had good bone conduction except for No. E.

For comparison, the same experiment as above was carried out except that the addition of Mg was omitted. As a result, all of the calcined products were α.Ca ₃ (PO ₄ ) ₂ . Elution was observed about three times as much as Nos. A to D, confirming that the formation of bone was significantly delayed.

(In vitro test) The precursor was press-molded,
It is fired at 1200 ° C. to obtain a dense body having a porosity of 0.4% or less. This is cut out to a size of 1 cm square × 1 mm, the surface is polished to Ra = 0.2 μm, and then immersed in 50 cc of physiological saline and kept at 37 ° C. for 30 days. 1
Days, 3 days, 7 days, 14 days, 30 days
The increments of a, Mg and P are measured.

Comparative Example CaCO ₃ containing 5% MgCO ₃ and phosphoric acid were mixed in an agate mortar for 30 minutes, and reacted at 1100 ° C. for 2 hours.
When this was subjected to X-ray diffraction, unreacted CaO and partially soluble Ca ₂ P ₂ O ₇ were recognized. This is wet pulverized again for 30 minutes using alcohol and then at 1100 ° C. for 2 minutes.
By firing for a time and repeating the same operation three times, a sintered body having a two-phase mixed composition of hydroxyapatite and β · Ca ₃ (PO ₄ ) _{2 was} finally obtained.

[0028]

According to the present invention, an apatite-based artificial bone having excellent biocompatibility and osteoconductivity, having a high density and excellent strength, having a low dissolution property and being less harmful to the living body is constructed. The given precursor and artificial bone can be produced efficiently.

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between the Mg content and the amount of Ca eluted into physiological saline.

Claims (3)

(57) [Claims] 1. A precursor for producing an artificial bone, comprising hydroxyapatite and / or carbonate apatite containing Ca, Mg and P as constituent elements as a main component, and containing Mg in an amount satisfying the following requirements. . Mg content: 0.1 to 0.5% by weight Atomic ratio of Ca, Mg, P: 1.50 ≦ (Ca + Mg) / P ≦
1.67 2. The precursor for producing an artificial bone according to claim 1, wherein the precursor is synthesized by an aqueous or non-aqueous solution reaction or a sol-gel method. 3. A method for producing an artificial bone, comprising firing the precursor according to claim 1 at 1200 to 1450 ° C. under atmospheric pressure.