JP5363744B2 - Calcium phosphate composition and method for producing the same - Google Patents

Description

  The present invention relates to a calcium phosphate composition. In particular, the present invention relates to a calcium phosphate composition suitable for medical materials and a method for producing the same.

Hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ) obtained by sintering a calcium phosphate composition has a composition close to that of inorganic components such as bones and teeth, and has a property of directly binding to bone Since it has activity, it has been reported to be used as a material for repairing bone defects and bone voids. However, such a material composed of hydroxyapatite has excellent biocompatibility, but it may be difficult in terms of moldability to be applied to a part having a complicated form.

  On the other hand, among the calcium phosphate compositions, the cement type, that is, the curable calcium phosphate composition, is gradually converted into bioabsorbable hydroxyapatite in the living body and in the oral cavity and further integrated with the living hard tissue while maintaining the form. It is known to get. Such a calcium phosphate composition is not only excellent in biocompatibility, but also has moldability, so that it can be easily applied to a part having a complicated form.

  For example, JP 2007-190226 A (Patent Document 1) discloses a calcium phosphate composition comprising tetracalcium phosphate particles having an average particle diameter of 5 to 30 μm and calcium hydrogen phosphate particles having an average particle diameter of 0.1 to 5 μm. The calcium phosphate composition is characterized in that the tetracalcium phosphate particles contain 2 to 20% by weight of particles having a particle size of 1.5 μm or less. It is said that the time from setting a solution containing water as a main component to the calcium phosphate composition to cure, that is, the curing time is within an appropriate range when used in clinical settings, and the sealing property is good. . However, further improvement has been desired not only when sufficient sequestering properties are obtained.

JP 2007-190226 A

  The present invention has been made in order to solve the above problems, and when used in a clinical field, the time from the addition of a liquid agent to a calcium phosphate composition until curing, that is, the curing time is within an appropriate range, And it aims at providing the calcium-phosphate composition with favorable marginal sealing property. Moreover, it aims at providing the manufacturing method and use of such a calcium-phosphate composition.

The above-mentioned problem is a calcium phosphate composition containing calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F), wherein the calcium phosphate particles (A) are tetracalcium phosphate particles (A1) and acidic calcium phosphate. It consists of particles (A2), and the blending ratio (A1 / A2) of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2) is 40/60 to 60/40 in molar ratio, and calcium phosphate particles (A) 100 This is solved by providing a calcium phosphate composition containing 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) based on parts by weight.

At this time, the acidic calcium phosphate particles (A2) is Ru preferably der to be anhydrous calcium hydrogen phosphate particles. It is also a preferred embodiment that the calcium phosphate composition is a powder.

Furthermore, the above-described problem is a medical kit comprising a powder containing calcium phosphate particles (A) and a condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F) and a liquid mainly composed of water. A) is composed of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2), and the mixing ratio (A1 / A2) of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2) is 40 / By providing a medical kit that is 60-60 / 40 and contains 0.5-30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to 100 parts by weight of calcium phosphate particles (A) Solved. Moreover, the said subject is a medical kit which consists of the powder containing calcium phosphate particle | grains (A), and the aqueous solution or aqueous dispersion containing the condensed polyphosphoric acid or its salt (F) of molecular weight 300-50000, Comprising: ) Consists of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2), and the blending ratio (A1 / A2) of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2) is 40/60 in molar ratio. 60 / a 40, also by providing a medical kit which comprises 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to the calcium phosphate particles (a) 100 parts by weight of Solved.

Moreover, the said subject is a manufacturing method of the calcium phosphate composition powder containing calcium phosphate particle (A) and condensed polyphosphoric acid or its salt (F) of molecular weight 300-50000, Comprising: A calcium phosphate particle (A) is tetracalcium phosphate. It consists of particles (A1) and acidic calcium phosphate particles (A2), and the blending ratio (A1 / A2) of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2) is 40/60 to 60/40 in molar ratio. And 0.5 to 30 parts by weight of condensed polyphosphoric acid or salt (F) thereof per 100 parts by weight of calcium phosphate particles (A), and calcium phosphate particles (A) and condensed polyphosphoric acid or salt (F) thereof in powder form It is solved by providing a method for producing a calcium phosphate composition powder characterized by mixing in the state described above.

Moreover, the said subject is a manufacturing method of the calcium-phosphate composition paste containing calcium phosphate particle (A) and condensed polyphosphoric acid or its salt (F) of molecular weight 300-50000, Comprising: A calcium-phosphate particle (A) is a tetracalcium phosphate particle. (A1) and acidic calcium phosphate particles (A2), the blending ratio (A1 / A2) of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2) is 40/60 to 60/40 in molar ratio, Adding a liquid mainly composed of water to a powder of a calcium phosphate composition containing 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to 100 parts by weight of calcium phosphate particles (A), and kneading. It is solved by providing a method for producing a calcium phosphate composition paste characterized by the above. Moreover, the said subject is a manufacturing method of the calcium-phosphate composition paste containing calcium phosphate particle (A) and condensed polyphosphoric acid or its salt (F) of molecular weight 300-50000, Comprising: A calcium-phosphate particle (A) is a tetracalcium phosphate particle. (A1) and acidic calcium phosphate particles (A2), the blending ratio (A1 / A2) of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2) is 40/60 to 60/40 in molar ratio, An aqueous solution or aqueous dispersion containing 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to 100 parts by weight of calcium phosphate particles (A) is added to the powder containing calcium phosphate particles (A) and kneaded. This problem can also be solved by providing a method for producing a calcium phosphate composition paste.

  A preferred embodiment of the calcium phosphate composition is a medical composition, and is particularly suitable as a bone cement or a dental filler.

  When the calcium phosphate composition of the present invention is used in a clinical setting, the time from the addition of a solution to the calcium phosphate composition until it is cured, that is, the curing time is within an appropriate range, and the marginal sealing property is good. . Therefore, it is suitable for medical materials, and particularly suitable for bone cement and dental fillers.

  The calcium phosphate composition of the present invention includes calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F).

  The calcium phosphate composition containing the calcium phosphate particles (A) is cured when kneaded in the presence of water. At this time, in addition to the calcium phosphate particles (A), by further containing condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F), the sealing property of the site filled with the calcium phosphate composition paste while maintaining strong compressive strength. Was found to be significantly improved. Although the reason for this is not necessarily clear, the following mechanism is presumed.

  That is, when preparing a calcium phosphate composition paste containing calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F), condensed polyphosphoric acid or a salt thereof uniformly dispersed in the calcium phosphate composition It is considered that (F) and calcium ions are combined and gelled. At this time, when the calcium phosphate composition containing condensed polyphosphoric acid or a salt thereof (F) is a powder composition, condensed polyphosphoric acid or a salt thereof (F) is obtained by kneading the powder composition and a liquid agent. Is believed to dissolve and gel. Moreover, when using the aqueous solution or aqueous dispersion containing condensed polyphosphoric acid or its salt (F) as a liquid agent, it gelatinizes by knead | mixing the powder containing a calcium phosphate particle (A), and the said aqueous solution or aqueous dispersion. I think that. Next, when the calcium phosphate composition paste is filled into bones, teeth, etc., the gel is deposited in the gaps between the particles contained in the filled paste to close the gaps, so that the marginal sealing property is improved. It is.

  The calcium phosphate particles (A) used in the present invention are not particularly limited. For example, tetracalcium phosphate particles (A1), acidic calcium phosphate particles (A2), hydroxyapatite particles, fluorinated apatite particles, carbonate-containing apatite particles, Calcium-deficient hydroxyapatite particles, tricalcium phosphate particles, octacalcium phosphate and the like can be mentioned, and one or more of these are used.

  The average particle size of the calcium phosphate particles (A) used in the present invention is preferably 0.5 to 30 μm. When the average particle size is less than 0.5 μm, not only the viscosity of the paste obtained by mixing with the liquid agent becomes too high, but also the strength of the cured product may be reduced. The average particle diameter of the calcium phosphate particles (A) is more preferably 2 μm or more, and even more preferably 5 μm or more. On the other hand, when the average particle size exceeds 30 μm, the paste properties obtained by mixing with the liquid agent may not be preferable, such as insufficient viscosity. Further, when used as a dental root canal filling material or the like, the tip of the nozzle may be clogged when injecting into a narrow transplantation site using a syringe. The average particle diameter of the calcium phosphate particles (A) is more preferably 25 μm or less, and even more preferably 20 μm or less. Here, the average particle diameter of the calcium phosphate particles (A) used in the present invention is the entire particles that can constitute the calcium phosphate particles (A) such as tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2). It is measured and calculated using a laser diffraction particle size distribution measuring device.

  The calcium phosphate composition of the present invention contains 0.5 to 30 parts by weight of condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F) with respect to 100 parts by weight of the calcium phosphate particles (A). As described above, the present inventors have found that a calcium phosphate composition having a curing time in an appropriate range and having a good sealing property can be provided by containing a certain amount of condensed polyphosphoric acid or a salt thereof (F). . When the content of condensed polyphosphoric acid or a salt thereof (F) is less than 0.5 parts by weight, the curing time may be long and the operability at the clinical site may be affected, and the sealing property may be deteriorated. It is preferably at least part by weight, more preferably at least 2 parts by weight. On the other hand, when the content of condensed polyphosphoric acid or a salt thereof (F) exceeds 30 parts by weight, the curing time is long and the operability at the clinical site may be affected, and the sealing property may be deteriorated. The amount is preferably at most 26 parts by weight, more preferably at most 26 parts by weight.

  The condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F) used in the present invention is not particularly limited, and linear condensed polyphosphoric acid or a salt thereof obtained by dehydrating condensation of orthophosphoric acid or a cyclic polyphosphoric acid or a salt thereof. And polyphosphoric acid in which P—O—P bonds are connected in an amorphous form in a network or a salt thereof. Examples of the linear condensed polyphosphoric acid or a salt thereof include tripolyphosphoric acid, tetrapolyphosphoric acid, pentapolyphosphoric acid, hexapolyphosphoric acid or a salt thereof. Examples of the cyclic polyphosphoric acid or a salt thereof include trimetaphosphoric acid, tetrametaphosphoric acid, hexametaphosphoric acid or a salt thereof. Furthermore, examples of the polyphosphoric acid or salt thereof in which the P—O—P bonds are connected in a network-like manner include ultrapolyphosphoric acid or a salt thereof. As the salt, alkali metal salts such as sodium salt and potassium salt, acidic condensed phosphate which is a mixed salt of alkali metal ions and hydrogen ions, and the like are preferably used.

Here, the molecular weight of condensed polyphosphoric acid or a salt thereof (F) refers to the weight average molecular weight, measured under the following conditions using gel permeation chromatography, and converted using a calibration curve of standard polyethylene glycol. Can be obtained.
Column: TSK-GEL column (α-2500 + α-4000 + α-6000) manufactured by Tosoh Corporation
Mobile phase: DMSO + 10 mmol / L LiBr
Temperature: 25 ° C
Flow rate: 1 mL / min
Sample concentration, amount: 0.1% by weight, 20 μL
Detector: Differential refractive index detector (RID)

  In addition, the condensed polyphosphoric acid or salt (F) used in the present invention has a molecular weight in the range of 300 to 50,000, and this makes the curing time in an appropriate range and calcium phosphate having good sealing properties. A composition is obtained. When the molecular weight of the condensed polyphosphoric acid or its salt (F) is less than 300, the curing time may be long and the operability at the clinical site may be affected, and the sealing property may be deteriorated, and may be 320 or more. Preferably, it is 450 or more. On the other hand, when the molecular weight exceeds 50000, the viscosity of the liquid agent may increase, so that the kneading property with the powder may be lowered. The content is preferably 35000 or less, more preferably 30000 or less, and 28000 or less. More preferably it is.

  The calcium phosphate composition of the present invention preferably further contains an alkali metal salt (C) of phosphoric acid. As a result, the curing time can be further shortened, so that the operability is improved and the blocking property can be improved. Although it does not specifically limit as alkali metal salt (C) of phosphoric acid to be used, Disodium monohydrogen phosphate, dipotassium monohydrogen phosphate, dilithium monohydrogen phosphate, monosodium dihydrogen phosphate, dihydrogen phosphate Monopotassium, trisodium phosphate, tripotassium phosphate and the like can be mentioned, and one or more of these can be used. Especially, it is preferable that the alkali metal salt (C) of phosphoric acid is monosodium monohydrogen phosphate and / or monosodium dihydrogen phosphate from a viewpoint of the safety | security and the ease of acquisition of a highly purified raw material.

  The calcium phosphate particles (A) used in the present invention are preferably composed of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2). When the calcium phosphate composition containing the tetracalcium phosphate particles (A1) and the acidic calcium phosphate particles (A2) is kneaded in the presence of water, a thermodynamically stable hydroxyapatite is generated and cured. By containing 0.5 to 30 parts by weight of condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F) in the calcium phosphate composition containing tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2). A calcium phosphate composition having a suitable time and good sequestering properties can be obtained.

The manufacturing method of the tetracalcium phosphate [Ca ₄ (PO ₄ ) ₂ O] particles (A1) used in the present invention is not particularly limited. Commercially available tetracalcium phosphate particles may be used as they are, or may be used by appropriately pulverizing and adjusting the particle diameter. As a pulverization method, a method similar to the pulverization method of acidic calcium phosphate particles (A2) described later can be employed.

  The average particle diameter of the tetracalcium phosphate particles (A1) is preferably 0.5 to 30 μm. When the average particle size is less than 0.5 μm, the dissolution of the tetracalcium phosphate particles (A1) becomes excessive, resulting in an increase in pH in the aqueous solution and the smooth precipitation of hydroxyapatite. There is a risk that the mechanical strength will decrease. The average particle size is more preferably 2 μm or more. On the other hand, when the average particle size exceeds 30 μm, the paste obtained by mixing with the liquid agent may not exhibit sufficient viscosity, or the paste property may be unfavorable, for example, the feeling of roughness may be increased. Further, when used as a dental root canal filling material or the like, the tip of the nozzle may be clogged when injecting into a narrow transplantation site using a syringe. The average particle size is more preferably 25 μm or less. Here, the average particle diameter of the tetracalcium phosphate particles (A1) used in the present invention is measured and calculated using a laser diffraction particle size distribution measuring apparatus.

The acidic calcium phosphate particles (A2) used in the present invention are anhydrous anhydrous calcium monohydrogen phosphate [CaHPO ₄ ] particles, anhydrous calcium dihydrogen phosphate [Ca (H ₂ PO ₄ ) ₂ ] particles, acidic pyro Even if it is calcium phosphate [CaH ₂ P ₂ O ₇ ], calcium monohydrogen phosphate dihydrate [CaHPO ₄ .2H ₂ O] particles and calcium dihydrogen phosphate monohydrate [Ca ( H ₂ PO ₄ ) ₂ .H ₂ O] particles may be used, but an anhydride is preferably used, and anhydrous calcium monohydrogen phosphate [CaHPO ₄ ] particles are more preferably used. In the present invention, the number of moles of phosphate radicals is the number of moles of acidic calcium phosphate particles (A2). The average particle size of the acidic calcium phosphate particles (A2) is preferably 0.1 to 5 μm. When the average particle size is less than 0.1 μm, the viscosity of the paste obtained by mixing with the liquid may be too high, and more preferably 0.5 μm or more. On the other hand, when the average particle diameter exceeds 5 μm, the acidic calcium phosphate particles (A2) are difficult to dissolve in the liquid agent, so that the dissolution of the tetracalcium phosphate particles (A1) becomes excessive and the pH of the aqueous solution increases, thereby increasing the hydroxy value. Precipitation of apatite may not be smooth, and the mechanical strength of the cured product may be reduced. The average particle size is more preferably 2 μm or less. The average particle diameter of the acidic calcium phosphate particles (A2) is calculated in the same manner as the average particle diameter of the tetracalcium phosphate particles (A1).

  The method for producing acidic calcium phosphate particles (A2) having such an average particle diameter is not particularly limited, and may be used as long as a commercially available product is available, but it is preferable to further grind the commercially available product. There are many. In that case, a pulverizing apparatus such as a ball mill, a likai machine, or a jet mill can be used. Moreover, acidic calcium phosphate raw material powder is pulverized with a liquid medium such as alcohol using a lykai machine, a ball mill or the like to prepare a slurry, and the resulting slurry is dried to obtain acidic calcium phosphate particles (A2). it can. A ball mill is preferably used as the pulverizer at this time, and alumina or zirconia is preferably used as the material of the pot and ball.

  As described above, by increasing the average particle diameter of the tetracalcium phosphate particles (A1) compared to the average particle diameter of the acidic calcium phosphate particles (A2), the solubility of both is balanced, and the pH of the aqueous solution is set to be medium. By maintaining in the vicinity of the property, it is possible to smoothly produce hydroxyapatite crystals and improve the mechanical strength of the cured product. Specifically, the average particle size of (A1) is more preferably 2 times or more than the average particle size of (A2), more preferably 4 times or more, and particularly preferably 7 times or more. . On the other hand, the average particle size of (A1) is more preferably 35 times or less than the average particle size of (A2), more preferably 30 times or less, and particularly preferably 25 times or less.

  Although the mixing ratio (A1 / A2) of the tetracalcium phosphate particles (A1) and the acidic calcium phosphate particles (A2) is not particularly limited, it is used in a mixing ratio such that the molar ratio is in the range of 40/60 to 60/40. It is preferred that Thereby, a calcium phosphate composition having high mechanical strength of the cured product can be obtained. The blending ratio (A1 / A2) is more preferably 45/55 to 55/45, and most preferably 50/50.

  The calcium phosphate composition of the present invention may contain components other than calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F) as long as the effects of the present invention are not impaired. For example, a thickener can be mix | blended as needed. This is for improving the moldability or uniform filling property of the calcium phosphate composition paste. Examples of the thickener include carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene glycol, polyacrylic acid, polyacrylate, polyglutamic acid, polyglutamate, polyaspartic acid, polyasparagine. Acid salts, starches other than cellulose, alginic acid, alginates, hyaluronic acid, hyaluronic acid salts, polysaccharides such as pectin, chitin, chitosan, acidic polysaccharide esters such as propylene glycol alginate, collagen, gelatin and derivatives thereof 1 or 2 or more selected from macromolecules such as proteins of carboxymethyl cell in terms of solubility in water and viscosity Over scan sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, alginic acid, alginates, chitosan, at least one selected from the group consisting of polyglutamic acid and polyglutamic acid salt is preferred. A thickener can be mix | blended with a calcium phosphate powder, can be mix | blended with a liquid agent, or can be mix | blended with the paste in kneading | mixing.

  An X-ray contrast medium may be included as necessary. This is because the monitoring of the filling operation of the calcium phosphate composition paste and the change after the filling can be traced. Examples of the X-ray contrast agent include one or more selected from barium sulfate, bismuth nitrate, bismuth carbonate, bismuth oxide, ytterbium fluoride, iodoform, barium apatite, barium titanate, and the like. The X-ray contrast agent can be blended with calcium phosphate powder, blended with a liquid agent, or blended into a paste being kneaded.

  In addition, any pharmacologically acceptable drug or the like can be added, such as a disinfectant, an anticancer agent, an antibiotic, an antibacterial agent, a blood circulation improving agent such as actosine or PEG1, a growth factor such as bFGF, PDGF, or BMP, Cells that promote the formation of hard tissue such as cells, odontoblasts, and undifferentiated bone marrow-derived stem cells can be added.

  The calcium phosphate composition of the present invention contains calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F). The calcium phosphate composition of the present invention is preferably a powder. At this time, calcium phosphate composition powder is manufactured by mixing calcium phosphate particles (A) and condensed polyphosphoric acid or a salt thereof (F) in a powder state. Preferably, tetracalcium phosphate particles (A1), acidic calcium phosphate particles (A2), and condensed polyphosphoric acid or a salt thereof (F) are mixed in a powder state. The method for mixing is not particularly limited, and for example, a jet mill, a lye machine, a ball mill, a bead mill, a planetary mill, a hybridizer, a mechano-fusion, a kneading extruder, a high-speed rotary mill, and the like can be used. A raikai machine, a ball mill, a planetary mill, and a high-speed rotary mill are used, and a high-speed rotary mill is more preferably used. At this time, it is also possible to mix in the presence of a liquid medium containing no water such as alcohol. Moreover, after mixing condensed polyphosphoric acid or its salt (F) separately with respect to two or more types of calcium phosphate particles, it can also be implemented as a preferable aspect that this two or more types of calcium phosphate particles are further mixed.

  When the calcium phosphate composition containing the calcium phosphate particles (A) and condensed polyphosphoric acid or a salt thereof (F) of the present invention is a powder composition, when used in a medical field, a liquid containing water as a main component, that is, a liquid agent Kneaded to obtain a calcium phosphate composition paste, which can be used by filling or coating a desired part. The liquid containing water as a main component may be pure water, or an aqueous solution or water dispersion containing other components. As the components to be mixed with water, phosphoric acid, sodium phosphate monobasic phosphate, sodium phosphate monobasic sodium phosphate and the like, mixtures thereof, potassium phosphates, ammonium phosphates, N, PH buffering agents such as N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid, N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid, sodium fluoride, potassium fluoride, ammonium fluoride, etc. And water-soluble polyhydric alcohols such as glycerin and propylene glycol. Among these, from the viewpoint of safety, it is preferable to blend sodium phosphate salts such as disodium monohydrogen phosphate and monosodium dihydrogen phosphate, and mixtures thereof.

  Further, the present invention is not directed to a calcium phosphate composition containing calcium phosphate particles (A) and condensed polyphosphoric acid or a salt thereof (F), but to a powder containing calcium phosphate particles (A). A calcium phosphate composition paste can also be obtained by mixing an aqueous solution or aqueous dispersion containing F). That is, an aqueous solution or aqueous dispersion containing 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to 100 parts by weight of calcium phosphate particles (A) is added to the powder containing calcium phosphate particles (A). A calcium phosphate composition paste is produced by kneading. Depending on the type of the condensed polyphosphoric acid or salt (F) used, the viscosity of the aqueous solution or aqueous dispersion containing the (F) may increase, making it difficult to knead. Therefore, in this case, the content of (F) in the aqueous solution or aqueous dispersion is preferably 20 parts by weight or less, and 15 parts by weight or less with respect to 100 parts by weight of the calcium phosphate particles (A). More preferred.

  Thus, when manufacturing a calcium phosphate composition paste, a method of kneading a calcium phosphate powder composition containing condensed polyphosphoric acid or a salt thereof (F) and a liquid agent may be employed, and calcium phosphate particles (A) You may employ | adopt the method of mixing the aqueous solution or aqueous dispersion containing condensed polyphosphoric acid or its salt (F) with the powder containing this. However, as described above, when the content of (F) in the aqueous solution or aqueous dispersion is increased, the viscosity increases, and thus kneading may be difficult. Therefore, when preparing a calcium phosphate composition paste by adding a large amount of condensed polyphosphoric acid or a salt thereof (F), a calcium phosphate powder composition containing condensed polyphosphoric acid or a salt thereof (F) and a liquid agent are kneaded. It is preferable to adopt the method to do.

  The mass ratio between the calcium phosphate composition and the liquid agent (calcium phosphate composition / liquid agent) in preparing the calcium phosphate composition paste is not particularly limited, but is preferably 1 to 6, more preferably 3 to 5. . After sufficiently kneading so that the calcium phosphate composition and the liquid agent are uniformly mixed, a desired part is immediately filled or applied. In this case, since the hardening time of the calcium phosphate composition is within an appropriate range, the operability when kneading with the liquid agent is good.

  The calcium phosphate composition of the present invention can be used by filling or coating a desired site as a calcium phosphate composition paste as described above. At this time, the calcium phosphate composition paste is usually prepared at a medical site. Therefore, it is a medical kit comprising a powder containing calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F) and a liquid mainly composed of water. One. Another embodiment of the present invention is a medical kit comprising a powder containing calcium phosphate particles (A) and an aqueous solution or aqueous dispersion containing condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F). One.

  The calcium phosphate composition of the present invention is suitably used for various medical uses. For example, it is suitably used as a bone cement for bonding or fixing. When the calcium phosphate composition of the present invention is used for the above-mentioned purposes, it has excellent paste filling properties, can be filled into every corner of a complex shape, and can be used as a hard tissue restoration material such as teeth and bones. Is preferred. In addition, as a dental filler, when filling a calcium phosphate composition in an affected area where dentinal tubules are present on the surface, such as a cutting root canal, etc., the hydroxyapatite crystals are efficiently precipitated inside the pores, thereby providing sealing performance. It is good and is particularly preferably used as a root canal filling material or a root canal restoration material. Further, since the paste itself is converted into hydroxyapatite within a short period of time in the living body or in the oral cavity, and integration with the living hard tissue occurs, it is excellent in biocompatibility.

  Hereinafter, the present invention will be described more specifically with reference to examples. In this example, the average particle size of the calcium phosphate particles (A), the tetracalcium phosphate particles (A1) and the acidic calcium phosphate particles (A2) is determined by a laser diffraction particle size distribution analyzer (“SALD-2100 type” manufactured by Shimadzu Corporation). ) And the median diameter calculated from the measurement results was taken as the average particle diameter. Moreover, the molecular weight of condensed polyphosphoric acid or its salt (F) was measured using the gel permeation chromatography as mentioned above, and was represented by the weight average molecular weight converted using the calibration curve of standard polyethylene glycol.

[Example 1]
(1) Preparation of calcium phosphate composition Tetracalcium phosphate particles (A1) used in this experiment were prepared as follows. Commercially available anhydrous calcium hydrogen phosphate particles (Product No. 1430, manufactured by JTBaker Chemical Co.) and calcium carbonate particles (Product No. 1288, manufactured by JTBaker Chemical Co.) were added to water so as to be equimolar, After stirring for 1 hour, the cake-like equimolar mixture obtained by filtration and drying is heated in a calciner (Model 51333, Lindberg, Watertown, WI) at 1500 ° C. for 24 hours, and then brought to room temperature in a desiccator. A TTCP (tetracalcium phosphate) mass was prepared by cooling. Next, the obtained TTCP lump was roughly crushed with a mortar, and then fined and the TTCP lump were removed by sieving to adjust the particle size within a range of 0.5 to 3 mm to obtain crude tetracalcium phosphate particles. Furthermore, the tetracalcium phosphate particles (A1) (average particle size 21.2 μm) used in this example are 100 g of crude tetracalcium phosphate particles and 300 g of zirconia balls having a diameter of 20 mm. In addition to “Type A-3 HD Pot Mill” manufactured by Nikkato Co., Ltd.), it was obtained by grinding for 2 hours 30 minutes at a rotational speed of 200 rpm.

  As an example of acidic calcium phosphate particles (A2), anhydrous calcium monohydrogen phosphate particles (A2) (average particle size 1.1 μm) used in this experiment are commercially available anhydrous calcium hydrogen phosphate particles (JTBaker Chemical Co., Ltd.). 50 g of an average particle size of 10.3 μm, 120 g of 95% ethanol (“Ethanol (95)” manufactured by Wako Pure Chemical Industries, Ltd.), and 240 g of zirconia balls having a diameter of 10 mm are made of 400 ml of an alumina grinding pot ( In addition to “Type A-3 HD Pot Mill” manufactured by Nikkato Co., Ltd.), the slurry obtained by performing wet pulverization for 24 hours at a rotational speed of 120 rpm was distilled off ethanol with a rotary evaporator and then dried at 60 ° C. for 6 hours. And vacuum drying at 60 ° C. for 24 hours.

  145.8 g of the above-mentioned tetracalcium phosphate particles (A1), 54.2 g of anhydrous calcium monohydrogen phosphate particles (A2), and 40 g of (A1) and (A2) sodium ultrapolyphosphate (manufactured by Taihei Chemical Industrial Co., Ltd., molecular weight 26200) ) Is added to a high-speed rotary mill (“SM-1” manufactured by ASONE Corporation) and mixed for 3 minutes at a rotating blade speed of 3000 rpm to obtain a calcium phosphate powder composition. It was. At this time, the average particle diameters of the tetracalcium phosphate particles (A1) and the anhydrous calcium monohydrogen phosphate particles (A2) before and after mixing are not substantially changed. The average particle diameter of the calcium phosphate particles (A) obtained by mixing the tetracalcium phosphate particles (A1) and the anhydrous calcium monohydrogen phosphate particles (A2) at the above ratio was 16.8 μm.

(2) Measurement of curing time The measurement of the curing time of the calcium phosphate composition obtained in (1) above was measured by a method according to ISO6876 (Dental root canal sealing materials). A calcium phosphate composition paste was prepared by precisely weighing 1 g of the calcium phosphate composition, adding 0.25 g of a 0.2 M Na ₂ HPO ₄ aqueous solution thereto, and kneading the mixture (mixing weight ratio (powder / liquid) at this time was 4). Is). This calcium phosphate composition paste was filled into a stainless steel ring mold having a cavity with an inner diameter of 10 mm and a height of 2 mm placed on a glass plate in a cabinet adjusted to 37 ° C. and relative humidity of 98%, and the upper part of the paste was spatula It was made smooth using. Next, every 180 seconds after the end of the kneading, every 10 seconds, the indicator having a flat end having a weight of 100 g and a diameter of 2 mm is gently lowered vertically to the vertical surface of the calcium phosphate composition paste, This operation was repeated until no longer visible, and the time until the needle tip trace disappeared after kneading was measured (n = 5). The setting time of the calcium phosphate composition obtained in Example 1 was 13 minutes 34 seconds ± 21 seconds.

(3) Measurement of marginal leakage distance 1 g of the calcium phosphate composition obtained in (1) above is precisely weighed, and 0.25 g of a 0.2M Na ₂ HPO ₄ aqueous solution is added thereto and kneaded to obtain a calcium phosphate composition paste. It was prepared (mixing weight ratio (powder / liquid) at this time is 4), and used for measurement of marginal leakage distance. The measurement of the marginal leakage distance was carried out according to the microleakage test method of ISO / TS11405 (2nd edition, dental material-bonding test to dental material). After removing the root and pulp of the extracted bovine tooth of the single root canal, the root part was closed with a dental composite resin (“AP-X” manufactured by Kuraray Medical). Next, the center of the cheek side was polished with # 80 and then with # 2000 polishing paper to produce a flat enamel surface. A cavity having a diameter of about 3 mm and a depth of about 2.5 mm was prepared on the surface of the enamel using a dental high-speed handpiece, the paste was filled in the cavity, and the temperature was 37 ° C. and the relative humidity was 98%. It was cured by storing for 4 hours under conditions. Next, this sample was stored in distilled water at 37 ° C. for 24 hours, then immersed in a 0.2% basic fuchsin solution adjusted to pH 7.2, and stored at 25 ° C. for 24 hours. Next, the center of the cavity is cut using a water-cooled diamond blade (“Isomet” manufactured by Bühler Ltd), and the cross-section is observed using a microscope (manufactured by Keyence), and the interface between the tooth substance and the material The distance at which the dye penetrated the deepest in FIG. 5 was defined as the edge leakage distance (n = 5). The marginal leakage distance of the calcium phosphate composition obtained in Example 1 was 0.63 ± 0.26 mm. The obtained results are summarized in Table 1.

[Example 2]
In Example 1, 145.8 g of tetracalcium phosphate particles (A1) and 54.2 g of anhydrous calcium monohydrogen phosphate particles (A2) were mixed to prepare a calcium phosphate powder composition, and (A1) and ( Example 1 except that 0.25 g of an aqueous solution containing sodium ultrapolyphosphate was added and kneaded so that the content of sodium ultrapolyphosphate was 0.6 parts by weight with respect to 100 parts by weight of A2) in total. Then, a calcium phosphate composition paste was prepared and evaluated. The obtained results are summarized in Table 1.

Example 3
In Example 1, a calcium phosphate composition paste was prepared and evaluated in the same manner as in Example 1 except that the content of sodium ultrapolyphosphate was 25 parts by weight. The obtained results are summarized in Table 1.

[Examples 4 and 5]
In Example 1, a calcium phosphate composition paste was prepared and evaluated in the same manner as in Example 1 except that 20 parts by weight of each of the following condensed polyphosphates was used instead of ultrapolyphosphate sodium. The obtained results are summarized in Table 1.
Example 4: Sodium hexametaphosphate (manufactured by Taihei Chemical Industrial Co., Ltd., (NaPO ₃ ) _n , Na _{n + 2} P _n O _{3n + 1} , molecular weight 15300)
Example 5: Sodium pentapolyphosphate (manufactured by Phosphor Chemical Co., Ltd., Na ₇ P ₅ O ₁₆ , molecular weight 572)

Example 6
In Example 1, the calcium phosphate composition was the same as in Example 1 except that the molar ratio (A1 / A2) of the tetracalcium phosphate particles (A1) to the anhydrous calcium monohydrogen phosphate particles (A2) was 0.7. A paste was prepared and evaluated. The obtained results are summarized in Table 1. The average particle diameter of the calcium phosphate particles (A) obtained by mixing the tetracalcium phosphate particles (A1) and the anhydrous calcium monohydrogen phosphate particles (A2) at the above ratio was 11.9 μm.

[Comparative Example 1]
In Example 1, evaluation was performed in the same manner as in Example 1 except that sodium ultrapolyphosphate was not added. The obtained results are summarized in Table 1.

[Comparative Example 2]
In Example 1, calcium phosphate composition paste in the same manner as in Example 1 except that 20 parts by weight of disodium monohydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd., molecular weight 143) was used instead of ultrapolysodium phosphate. Were prepared and evaluated. The obtained results are summarized in Table 1.

[Comparative Example 3]
In Example 1, a calcium phosphate composition paste was prepared in the same manner as in Example 1 except that 20 parts by weight of acidic sodium pyrophosphate (Rin Chemical Industry Co., Ltd., molecular weight 266) was used instead of ultrapolysodium phosphate. And evaluated. The obtained results are summarized in Table 1.

[Comparative Example 4]
In Example 2, the calcium phosphate composition was carried out in the same manner as in Example 2 except that 0.25 g of an aqueous solution containing sodium ultrapolyphosphate was added and kneaded so that the content of sodium ultrapolyphosphate was 0.25 parts by weight. A paste was prepared and evaluated. The obtained results are summarized in Table 1.

[Comparative Examples 5 and 6]
In Example 1, the calcium phosphate composition paste was performed in the same manner as in Example 1 except that the content of sodium ultrapolyphosphate was 0.25 parts by weight (Comparative Example 5) and 35 parts by weight (Comparative Example 6), respectively. Were prepared and evaluated. The obtained results are summarized in Table 1.

[Comparative Example 7]
A calcium phosphate composition paste was prepared and evaluated in the same manner as in Example 1 except that 20 parts by weight of sodium metaphosphate prepared in the following manner was used instead of ultrapolyphosphate. The obtained results are summarized in Table 1.

7 g (0.06 mol) of H ₃ PO ₄ (manufactured by Wako Pure Chemical Industries, Ltd.) is added to 120 g (1.00 mol) of NaH ₂ PO ₄ (manufactured by Wako Pure Chemical Industries, Ltd.), and the mixture is heated at about 800 ° C. for 3 hours. Baked. The obtained fired product was pulverized in a mortar to obtain the target sodium metaphosphate. The molecular weight was 87500.

  As can be seen from Table 1, in Examples 1 to 6 containing 0.5 to 30 parts by weight of condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F) with respect to 100 parts by weight of calcium phosphate particles (A), nothing Compared with Comparative Example 1 which was not added, the curing time is short, and it is in an appropriate range when used in a clinical field. The marginal leakage distance is short, so that the sealing property of the filling site is good. Thus, the effect of containing a certain amount of condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F) is clear.

  In Comparative Example 2 using 20 parts by weight of disodium monohydrogen phosphate instead of condensed polyphosphoric acid or a salt thereof (F), the curing time was shorter than that in Comparative Example 1 in which nothing was added. The pigment penetrated until the edge was blocked. In Comparative Example 3 in which 20 parts by weight of acidic sodium pyrophosphate (molecular weight: 266) having a molecular weight of less than 300 was used, the curing time was slightly shorter than that in Comparative Example 1 in which nothing was added. In Comparative Example 7 using 20 parts by weight of sodium metaphosphate (molecular weight: 87500) having a molecular weight of more than 50000, the curing time was longer than that of Comparative Example 1 in which nothing was added. The pigment penetrated to the bottom of the cavity and the marginal sealing property was poor. Further, in Comparative Examples 4 to 6 in which the content of condensed polyphosphoric acid or a salt thereof (F) is not in the range of 0.5 to 30 parts by weight, the curing time is slightly shorter than Comparative Example 1 in which nothing is added. However, in Comparative Examples 4 and 5, the marginal leakage distance was only slightly improved, and in Comparative Example 6, the pigment entered the cavity bottom and the marginal sealing performance was poor.

Claims (10)

A calcium phosphate composition comprising calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F), wherein the calcium phosphate particles (A) are tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2). The blending ratio (A1 / A2) of the tetracalcium phosphate particles (A1) and the acidic calcium phosphate particles (A2) is 40/60 to 60/40 in molar ratio, with respect to 100 parts by weight of the calcium phosphate particles (A). A calcium phosphate composition containing 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F). Powder is a claim 1 calcium phosphate composition. A medical kit comprising a powder containing calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F) and a liquid mainly composed of water, wherein the calcium phosphate particles (A) are phosphoric acid. It consists of tetracalcium particles (A1) and acidic calcium phosphate particles (A2), and the blending ratio (A1 / A2) of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2) is 40/60 to 60/40 in molar ratio. , and the medical kit which comprises 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to the calcium phosphate particles (a) 100 parts by weight of. A medical kit comprising a powder containing calcium phosphate particles (A) and an aqueous solution or dispersion containing a condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F), wherein the calcium phosphate particles (A) are tetraphosphates. It consists of calcium particles (A1) and acidic calcium phosphate particles (A2), and the blending ratio (A1 / A2) of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2) is 40/60 to 60/40 in molar ratio. There, medical kit which comprises 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to the calcium phosphate particles (a) 100 parts by weight of. A method for producing a calcium phosphate composition powder comprising calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F),
The calcium phosphate particles (A) are composed of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2), and the mixing ratio (A1 / A2) of the tetracalcium phosphate particles (A1) and the acidic calcium phosphate particles (A2) is molar ratio. 40/60 to 60/40, containing 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to 100 parts by weight of calcium phosphate particles (A), and calcium phosphate particles (A) and condensed polyphosphorus A method for producing a calcium phosphate composition powder comprising mixing an acid or a salt thereof (F) in a powder state. A method for producing a calcium phosphate composition paste comprising calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F),
The calcium phosphate particles (A) are composed of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2), and the mixing ratio (A1 / A2) of the tetracalcium phosphate particles (A1) and the acidic calcium phosphate particles (A2) is molar ratio. 40/60 to 60/40 , and water is added to the powder of the calcium phosphate composition containing 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to 100 parts by weight of the calcium phosphate particles (A). A method for producing a calcium phosphate composition paste, wherein a liquid containing a main component is added and kneaded. A method for producing a calcium phosphate composition paste comprising calcium phosphate particles (A) and condensed polyphosphoric acid having a molecular weight of 300 to 50,000 or a salt thereof (F),
The calcium phosphate particles (A) are composed of tetracalcium phosphate particles (A1) and acidic calcium phosphate particles (A2), and the mixing ratio (A1 / A2) of the tetracalcium phosphate particles (A1) and the acidic calcium phosphate particles (A2) is molar ratio. 40/60 to 60/40, and an aqueous solution or aqueous dispersion containing 0.5 to 30 parts by weight of condensed polyphosphoric acid or a salt thereof (F) with respect to 100 parts by weight of calcium phosphate particles (A) A method for producing a calcium phosphate composition paste, which is kneaded in addition to the powder containing A). Claim 1 or 2 medical composition comprising a calcium phosphate composition. A bone cement comprising the calcium phosphate composition according to claim 1 or 2 . A dental filler comprising the calcium phosphate composition according to claim 1 or 2 .