WO2010140634A1 - Tube-shaped calcium phosphate and process for production thereof - Google Patents

Tube-shaped calcium phosphate and process for production thereof Download PDF

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WO2010140634A1
WO2010140634A1 PCT/JP2010/059385 JP2010059385W WO2010140634A1 WO 2010140634 A1 WO2010140634 A1 WO 2010140634A1 JP 2010059385 W JP2010059385 W JP 2010059385W WO 2010140634 A1 WO2010140634 A1 WO 2010140634A1
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calcium
calcium phosphate
aqueous solution
suspension
tube
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PCT/JP2010/059385
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French (fr)
Japanese (ja)
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田辺　克幸
暁光 飯田
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日鉄鉱業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/04—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium
    • B01J20/048—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium containing phosphorus, e.g. phosphates, apatites, hydroxyapatites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
    • B01J20/282—Porous sorbents

Definitions

  • the present invention relates to a tubular (tubular) hollow particle of calcium phosphate. More specifically, tube-like hollow particles of calcium phosphate having an average tube cross-sectional diameter of 100 nm or less, which can be expected as functional materials such as biomaterials, chromatographic fillers, catalyst materials, and fluorescent materials, and tubes of calcium phosphate
  • the present invention relates to a method for producing a hollow particle.
  • phosphate ore which is a raw material for phosphoric acid or phosphorus fertilizer.
  • apatite (Ca 10 (PO 4 ) 6 (OH, F, Cl) 2 ) used in a large amount as a phosphor raw material can be said to be the most well-known calcium phosphate among them.
  • apatite examples include hydroxyapatite (HAp) having a hydroxyl group as an anion, fluorine apatite (FAp) containing fluorine, and chlorine apatite (CAp) containing chlorine.
  • HAp hydroxyapatite
  • FFP fluorine apatite
  • CAp chlorine apatite
  • Carbonate-containing apatite containing carbonate radicals by substituting a part of these anions or phosphate radicals is known as being close to living hard tissues.
  • hydroxyapatite and carbonic acid-containing hydroxyapatite are attracting attention from the viewpoint of application to substitute materials for biological hard tissues such as bones and teeth and to chromatographic packing materials.
  • calcium phosphate other than apatite amorphous calcium phosphate, octacalcium phosphate (Ca 8 H 2 (PO 4 ) 6 ⁇ 5 H 2 O), tricalcium phosphate (Ca 3 (PO 4 ) 2 ), tetracalcium phosphate (Ca 4 (PO 4 ) 2 O), calcium monohydrogen phosphate, and the like.
  • the calcium monohydrogen phosphate includes a hydrous CaHPO 4 ⁇ 2H 2 O (brushite) and an anhydrous CaHPO 4 (monetite). There is.
  • tricalcium phosphate is known to have a high temperature type ⁇ phase and a low temperature type ⁇ phase ( ⁇ -, ⁇ -Ca 3 (PO 4 ) 2 ), physical properties, solubility, The biocompatibility is similar to hydroxyapatite. Further, since TCP has a property of slowly changing to hydroxyapatite in the presence of moisture, it is said that it has good biocompatibility and is suitable for bone tissue regeneration.
  • the precipitation method is a synthesis method in which a calcium salt aqueous solution and a phosphate aqueous solution are mixed under basic conditions.
  • the hydrolysis method is a method of synthesizing by hydrolyzing CaHPO 4 .2H 2 O or the like.
  • the hydrothermal synthesis method is known mainly as a method for synthesizing large crystals
  • fine particles can also be synthesized by mixing a calcium nitrate aqueous solution and an ammonium hydrogen phosphate aqueous solution and performing a hydrothermal treatment.
  • sol-gel method There is a sol-gel method as a more special method.
  • a mixed solution of water, acetic acid and ethanol is dropped into a mixed solution of an ethylene glycol solution of calcium diethoxide and an ethanol solution of triethyl phosphite, followed by hydrolysis and polycondensation to form a plate-like water solution.
  • This is a method of synthesizing acid apatite.
  • a tube structure having a nano-sized cross section (usually a size of 100 nm or less) which is the most important as the tubular calcium phosphate of the present invention is referred to as a “nanotube” with the recent progress of nanotechnology.
  • nanotubes Some of the “nanotubes” reported so far are made of carbon, titania, silica, tungsten oxide, etc., and they are carbon nanotubes (CNT), titania nanotubes, silica nanotubes, oxides based on their constituent elements and morphology.
  • CNT carbon nanotubes
  • titania nanotubes titania nanotubes
  • silica nanotubes oxides based on their constituent elements and morphology.
  • organic nanotubes called tungsten nanotubes. And these particles express the peculiar function derived from the constituent element, structure, and form, and application to various fields is examined.
  • FED field emission display
  • flat fluorescent tube cold cathode tube cathode
  • cathode cold cathode
  • X-ray generation source semiconductor material
  • integrated circuit high-speed switching element
  • fuel cell electrode interatomic It is expected to be used for force microscope probes, nanotweezers, high-strength materials, etc.
  • titanium oxide nanotubes with a diameter of several nanometers having an anatase type crystal structure have been synthesized, and various applications based on various properties such as magnetism, optical properties, and chemical catalyst properties are considered.
  • various properties such as magnetism, optical properties, and chemical catalyst properties are considered.
  • doping with metals and metal compounds it has been confirmed that the optical band gap is increased, the heat-resistant temperature is improved, and the electric resistance value is lowered. Research on gas sensors is also underway.
  • Tungsten oxide nanotubes which have become a hot topic recently, have an outer diameter of 300 to 1000 nm and a length of 2 to 20 ⁇ m, which is slightly larger than what is called a nanotube, but about 8 times that of conventional nitrogen-doped titanium oxide under visible light. It is said that the photocatalytic activity is doubled.
  • the application area of “nanotubes” is wide as electronic materials, electrode materials, chemical catalysts, photocatalysts, optical materials, templates, and reinforcing materials, and further development and expansion of application fields are expected in the future.
  • Patent Document 1 discloses a hollow sphere having at least one opening prepared by using a foaming agent or a binder in calcium phosphate, and a manufacturing method thereof. And wet.
  • the hollow spheres obtained in the examples have a particle diameter of 30 to 250 ⁇ m and an opening diameter of 10 to 40 ⁇ m.
  • Patent Document 2 discloses a hollow capsule made of tricalcium phosphate and hydroxide apatite and a method for producing the same. There, an aqueous suspension of calcium carbonate and an aqueous solution of a water-soluble phosphate or a water-soluble salt thereof are reacted to form a calcium phosphate crystal layer on the surface of the calcium carbonate particles, and then a water-insoluble calcium phosphate salt or an aqueous solution thereof. There has been proposed a method in which the suspension is reacted to elute calcium carbonate inside to form a wall material of tricalcium phosphate and / or a hydroxyapatite crystal layer.
  • Patent Document 3 discloses a calcium phosphate having an oval spherical hollow structure having an average particle diameter of 2.0 ⁇ m or less converted to a sphere examined by a scanning electron microscope by using vaterite-type calcium carbonate as a core material. Yes.
  • Patent Documents 4 and 5 regarding the tubular calcium phosphate directly related to the present invention.
  • the average particle diameter of the long diameter (length) of the tubular particles is 0.1 to 1000 ⁇ m
  • the average particle diameter of the short diameter (outer diameter) is 0.05 to 100 ⁇ m
  • the particle diameter is 0.02 to 95 ⁇ m
  • the inner diameter / outer diameter ratio is 0.05 to 0.95.
  • Patent Document 4 “average value of volume of tube-shaped composite synthetic inorganic fine particles measured by electron micrograph” is described. The particles satisfy the shape factor f divided by “the volume calculated from the average particle diameter of the major axis of the tube-shaped composite synthetic inorganic fine particles measured by an electron micrograph”.
  • needle-like core particles having an average major axis diameter of 0.6 to 750 ⁇ m and an average minor axis diameter of 0.12 to 50 ⁇ m are mixed with orthophosphoric acid, an aqueous solution of sodium phosphate and calcium chloride, fluoride An aqueous sodium solution is dropped, and the core particles are treated with hydroxyapatite, calcium monohydrogen phosphate, amorphous calcium phosphate, etc., and then treated with an organic acid and / or an inorganic acid to dissolve and remove the core particles to form a tube.
  • a number of examples have been disclosed for preparing inorganic particulates.
  • the average length of the calcium phosphate-based tubular fine particles obtained in many of the examples is 0.6 to 750 ⁇ m, the average outer diameter is 0.14 to 56 ⁇ m, and the average inner diameter is 0.08 to 38 ⁇ m.
  • the smallest tubular fine particles can be produced in Example 9, in which extremely small tubular fine particles are obtained as compared with other examples, but each average particle size is still 0.6 ⁇ m in major axis, The outer diameter is 0.14 ⁇ m and the inner diameter is 0.09 ⁇ m.
  • Example 4 has the smallest average inside diameter, it is still 0.08 ⁇ m.
  • Patent Document 5 is the same as that of Patent Document 4, and is the largest of the calcium phosphate-based tubular fine particles obtained in the examples, with an average major axis of 800 ⁇ m, an average outer diameter of 56 ⁇ m, and an average inner diameter. Is 38 ⁇ m, the smallest particle has an average major axis of 0.5 ⁇ m, an average outer diameter of 0.12 ⁇ m, and an average inner diameter of 0.07 ⁇ m.
  • the reference 4 and 5 conceptually disclose calcium phosphate-based tubular fine particles having an average particle diameter as described above, they are actually in the present invention.
  • tubular calcium phosphate having an average value of the outer diameter of the minor axis of 30 nm to 100 nm and an average value of the inner diameter of the minor axis of 29 nm to 99 nm, and a technique for producing the same is not disclosed.
  • Non-Patent Document 1 the size of the major axis is 10 ⁇ m and the minor axis is about 1 to 2 ⁇ m synthesized by phosphorylating calcium carbonate (aragonite) with calcium monohydrogen phosphate dihydrate and then dissolving the calcium carbonate with acetic acid.
  • phosphorylating calcium carbonate aragonite
  • acetic acid calcium monohydrogen phosphate dihydrate
  • macaroni-like hollow aggregates have been reported.
  • flaky particles have been confirmed by an electron microscope. From the element ratio of the characteristic X-rays of P and Ca detected from the EDX spectrum, it is assumed that it is calcium deficient hydroxyapatite (DAp). Yes.
  • Patent Document 6 discloses rod-shaped hollow polymer particles having an average major axis of 0.1 to 1000 ⁇ m, an average minor axis of 0.01 to 100 ⁇ m, and an aspect ratio of 3 to 100.
  • This particle is a core / shell-like organic-inorganic composite with a rod-like inorganic particle containing calcium phosphate on the surface of calcium carbonate as a core, and an organic polymer as a shell, and only the rod-like inorganic fine particles are dissolved and removed. Then, it is manufactured by a method characterized by hollowing.
  • the particles obtained in the examples have an average major axis of 2.2 to 25.1 ⁇ m, an average minor axis of 0.6 to 1.2 ⁇ m, and an aspect ratio of 3.7 to 22.8.
  • JP 63-198970 A Japanese Patent Laid-Open No. 10-202093 Japanese Patent Laid-Open No. 11-171514 JP 7-196305 A JP-A-7-196314 JP 2001-253966 A
  • tubular (also called tubular or macaroni) calcium phosphate has been disclosed or reported so far, but in actual production, the major axis is in the micron to submicron size, the average of the minor axis. It is a “microtube” having an outer diameter of 0.12 ⁇ m or more and an average inner diameter of 0.07 ⁇ m or more, and so-called “calcium phosphate nanotubes” that can be said to be nano-sized have not been known.
  • those manufacturing methods are such that calcium phosphate is precipitated on the outer surface of the core particle, and the core particle is dissolved and removed by treatment with an organic acid or an inorganic acid in the latter half of the manufacturing process to produce a tube-like particle.
  • an aqueous solution (or suspension) containing phosphoric acid and an aqueous solution (or suspension) containing calcium without using the core particles and without dissolving and removing the core particles with acid. Not what you want.
  • the average value of the outer diameter of the minor axis is 30 nm or more and 100 nm or less, the inner diameter of the minor axis
  • the tubular calcium phosphate having an average value of 29 nm or more and 99 nm or less there is no specific disclosure of the tubular calcium phosphate having an average value of 29 nm or more and 99 nm or less, and a technique for producing the same is not disclosed.
  • the average value of the outer diameter of the short axis is 30 nm or more and 100 nm or less.
  • tubular calcium phosphate having an average inner diameter of 29 nm to 99 nm there is no tubular calcium phosphate having an average inner diameter of 29 nm to 99 nm, and a technique for producing it has not been developed.
  • the present inventors have made a “nanotube” made of calcium phosphate that has never been made, that is, calcium phosphate having a smaller tube structure than ever before, specifically, a short diameter
  • the inventors of the present invention have intensively studied to synthesize “calcium phosphate nanotubes” having an average outer diameter and an average inner diameter that are unprecedented, and reached the present invention.
  • an object of the present invention is to provide an unprecedented smaller “calcium phosphate nanotube”.
  • the manufacturing method is not complicated, using core particles as before, and requiring a step of dissolving and removing the core particles with an organic acid or an inorganic acid in a later step. It is an object of the present invention to provide a simpler method that does not require the above.
  • the present invention provides nano-sized tubular calcium phosphate and a method for producing tubular calcium phosphate, and the tubular calcium phosphate has an average value of a major axis (length) of 200 nm or more and 1000 nm or less, and an outer diameter of a minor axis.
  • the average value is 30 nm or more and 100 nm or less
  • the average inner diameter of the minor axis is 29 nm or more and 99 nm or less.
  • the inner diameter / outer diameter ratio of the minor axis is 0.7 or more and less than 1.0.
  • Such tubular calcium phosphate has a shape and size that could not be produced by conventional techniques, and the tubular calcium phosphate is relatively stable among calcium phosphates and is a promising water as a biomaterial.
  • An X-ray diffraction pattern close to acid apatite is shown.
  • the hydroxyapatite referred to here includes a carbonate-containing hydroxyapatite in which a hydroxyl group or a part of a phosphate group is substituted with a carbonate group.
  • the manufacturing method is characterized by synthesizing by reacting an aqueous solution or suspension containing phosphoric acid as a phosphorus raw material with an aqueous solution or suspension containing a calcium compound as a calcium raw material.
  • the phosphorus raw material is an aqueous solution or suspension selected from the group consisting of phosphoric acid, condensed phosphoric acid and salts thereof, calcium monohydrogen phosphate, and the calcium raw material is calcium hydroxide, calcium carbonate, basic carbonate An aqueous solution or suspension selected from the group consisting of calcium is preferred.
  • the phosphorus raw material is a phosphoric acid aqueous solution and the calcium raw material is calcium hydroxide and / or a calcium carbonate suspension, so that cations and anions other than calcium phosphate are not mixed, and it is also preferable in terms of economy. .
  • the tubular calcium phosphate having a nano-sized minor axis of the present invention that is, “calcium phosphate nanotube”, has an average major axis (length) of the tube of 200 nm to 1,000 nm, an average outer diameter of the minor axis of 30 nm to 100 nm, and a minor axis.
  • the average inner diameter is not less than 29 nm and not more than 99 nm, which has a shape and size that have not been known before.
  • the calcium phosphate constituting the tube-shaped particles is preferably close to the hydroxyapatite, and in that case, it can be said to be a very promising material that can be expected to be applied as a biomaterial or a functional material.
  • the manufacturing method of the tubular calcium phosphate of this invention is using the phosphate ion and calcium ion, controlling reaction conditions, without using a core particle and dissolving and removing a core particle with an organic acid or an inorganic acid. Unlike the method of using core particles as in the conventional manufacturing method, and dissolving and removing the particles with organic acid or inorganic acid in the subsequent process, it is industrial. It is also a simple method.
  • FIG. 2 is a scanning electron micrograph of calcium phosphate nanotubes synthesized in Example 1.
  • FIG. 2 is a powder X-ray diffraction pattern of the calcium phosphate nanotubes synthesized in Example 1.
  • FIG. 4 is a transmission electron micrograph of calcium phosphate nanotubes synthesized in Example 4.
  • the average value of the long diameter (length) of the tube is 200 nm to 1000 nm
  • the average value of the short diameter is 30 nm to 100 nm
  • the average value of the short diameter is 29 nm to 99 nm.
  • the average aspect ratio is 4 to 20, and it has a shape and size that cannot be manufactured by the conventional technique.
  • the average wall thickness of the tube is preferably 1 nm to 15 nm
  • the average inner diameter / outer diameter is preferably 0.7 to less than 1.0.
  • an aqueous solution or suspension containing phosphoric acid is reacted with an aqueous solution or suspension containing calcium, and the aqueous solution or suspension containing phosphoric acid is phosphoric acid, condensed phosphorus.
  • It can be prepared using an acid or a salt thereof (for example, calcium monohydrogen phosphate) and the like.
  • condensed phosphoric acid such as pyrophosphoric acid reacts with water to form phosphoric acid, and thus is substantially equivalent to phosphoric acid.
  • the phosphate include sodium, potassium, or ammonium salts such as pyrophosphoric acid, hexametaphosphoric acid, or tripolyphosphoric acid.
  • calcium monohydrogen phosphate there are hydrous CaHPO 4 ⁇ 2H 2 O (brushite) and anhydrous CaHPO 4 (monetite), both of which can be used, and in the examples described later, Often generated as a body.
  • These phosphorus materials can be used alone or in appropriate combinations, and in that case, they may be aqueous solutions or suspensions.
  • Examples of the calcium compound include calcium hydroxide, calcium carbonate, basic calcium carbonate, calcium chloride, calcium sulfate and the like.
  • Various calcium carbonates such as calcite, aragonite, or vaterite having different crystal structures are known, such as amorphous calcium carbonate or hydrated calcium carbonate, but any of them may be used.
  • phosphoric acid which is an aqueous solution without containing unnecessary elements in the product as the phosphorus raw material, or condensed phosphoric acid, calcium hydroxide, calcium carbonate, Or it is preferable to select and combine from basic calcium carbonate.
  • First method While stirring an aqueous phosphoric acid (salt) solution at room temperature, a calcium compound is added and dissolved to prepare an aqueous calcium phosphate solution or suspension. This aqueous solution or suspension is added to a separately prepared calcium compound aqueous solution or suspension while maintaining the temperature in the range of 30 to 70 ° C.
  • Second method An aqueous phosphoric acid (salt) solution is added while stirring an aqueous calcium compound solution or suspension maintained at a liquid temperature in the range of 30 to 70 ° C. The obtained suspension is cooled to 20 ° C. or lower, and an aqueous phosphoric acid (salt) solution is added again. Next, the obtained suspension is heated to 30 to 70 ° C. and kept for 0 to 25 hours for aging.
  • Third method An aqueous phosphoric acid (salt) solution is added while stirring an aqueous calcium compound solution or suspension maintained at a liquid temperature in the range of 0 to 20 ° C. The resulting suspension is warmed to 30-70 ° C. and kept for 0-30 hours for aging.
  • Method 4 Aqueous solution or suspension containing a calcium compound maintained at a liquid temperature in the range of 30 to 70 ° C. while stirring, an aqueous solution of phosphoric acid (salt) is added, and the mixture is kept for 0 to 30 hours for aging.
  • Fifth method A mixed suspension of calcium monohydrogen phosphate and a calcium compound is aged by holding at a temperature of 30 to 70 ° C. for 1 to 50 hours.
  • the reaction system when adding an aqueous phosphate solution or suspension, it is preferably added dropwise.
  • the reaction system may maintain a high pH of 10 or more. Therefore, the pH of the reaction system is adjusted to 5. with an acid such as hydrochloric acid as necessary. It is preferable to adjust to 5 to 7.5.
  • the aging time depends on the reaction conditions at that time, and in the second method, the third method, and the fourth method, aging may not be required in the reaction at a relatively high temperature. It is listed as time.
  • the particles obtained by these methods all have an average outer diameter of 30 to 100 nm, an average inner diameter of 29 to 99 nm, an average wall thickness of 1 to 15 nm, and an average inner diameter / outer diameter ratio.
  • a diffraction pattern very close to that of hydroxyapatite (JCPDS card number 01-072-1243) or carbonate-containing hydroxyapatite (JCPDS card number 00-19-272), which is a kind of calcium phosphate was exhibited.
  • the present invention will be described more specifically with reference to a plurality of examples. However, the present invention is not limited to these examples, and it is understood that the present invention is understood by the claims. Nor. In each of the following examples, the measurement results of the outer diameter, inner diameter, wall thickness, and major diameter (length) of the nanotube product are average values of a total of ten products observed in the electron micrograph.
  • Example 1 ⁇ Preparation of calcite> 1 L of tap water was put into a cylindrical separable flask having a capacity of 3 liters, and 150 g of industrial quicklime was put therein. The mixture was allowed to stand for 10 minutes and then stirred for 20 minutes, and coarse particles were removed with a 100 mesh sieve. Tap water was added to the calcium hydroxide suspension thus obtained so that the liquid volume would be 2 L, the temperature was adjusted to 15 ° C., and carbon dioxide was introduced at a flow rate of 1.0 L / min while stirring at 500 rpm. A suspension of the site was prepared, and the solid content concentration of the slurry was adjusted to 5.0% by mass. The calcite suspension (or slurry) thus obtained was used in the following steps of Example 1. Further, Examples 2 to 5 and Example 8 were used.
  • Example 2 (Second method) 1 kg of calcite suspension having a solid content of 5.0% by mass is placed in a beaker having a capacity of 3 liters, and maintained at 50 ° C. while stirring at 300 rpm, and 250 mL of 4.25% by mass phosphoric acid aqueous solution is added at 8 mL / min. It was dripped at a speed. Next, the obtained slurry was cooled to 10 ° C., 450 mL of a 4.25% by mass phosphoric acid aqueous solution was added dropwise at a rate of 8 mL / min, and then heated to 50 ° C. at a rate of 40 ° C./hour, and left as it was.
  • the product was found to be a tube-shaped particle having an outer diameter of 60 nm, an inner diameter of 50 nm, and a major axis (length) of 300 to 400 nm.
  • Example 3 (Third method) Into a beaker with a capacity of 3 liters, 1 kg of a calcite suspension having a solid content concentration of 5.0% by mass is maintained at 10 ° C. while stirring at 300 rpm, and 700 mL of a 4.25% by mass phosphoric acid aqueous solution is added at 8 mL / min. It was dripped at a speed. The product obtained slurry thus a mixture of the examined by X-ray diffraction calcite and CaHPO 4 ⁇ 2H 2 O (brushite ). The slurry was heated to 50 ° C. at a rate of 40 ° C./hour and held for 20 hours. When the product was observed with a scanning electron microscope, it was found to be a tube-shaped particle having an outer diameter of 60 nm, an inner diameter of 50 nm, and a major axis (length) of 300 to 400 nm.
  • Example 4 (Third method) A 608 g slurry of calcite having a solid content concentration of 5.0% by mass was placed in a separable flask having a volume of 3 liters, and a solution obtained by suspending reagent calcium hydroxide in 735 g of tap water was added thereto while stirring the slurry. Subsequently, the mixture was adjusted and maintained at 10 ° C. while stirring at 300 rpm, and 700 g of a 5.0 mass% phosphoric acid aqueous solution was dropped at a rate of 18 mL / min.
  • the product obtained slurry thus a mixture of the examined by X-ray diffraction calcite and CaHPO 4 ⁇ 2H 2 O (brushite ).
  • the slurry was heated to 50 ° C. at a rate of 2 ° C./min and held there for 5 hours.
  • the result was as shown in FIG. 3, which was a tube-like shape having an outer diameter of 40 to 90 nm, a wall thickness of 1 to 2 nm, and a long diameter (length) of 400 to 700 nm.
  • the particles were in the form.
  • Example 5 (Third method) A 608 g slurry of calcite having a solid content concentration of 5.0% by mass was placed in a separable flask having a volume of 3 liters, and a solution obtained by suspending reagent calcium hydroxide in 735 g of tap water was added thereto while stirring the slurry. Subsequently, the mixture was adjusted and maintained at 10 ° C. while stirring at 300 rpm, and 700 g of a 5.0 mass% phosphoric acid aqueous solution was dropped at a rate of 18 mL / min. This slurry was heated to 30 ° C. at a rate of 2 ° C./minute and kept for 20 hours for aging.
  • the product When the product was observed with a transmission electron microscope, it was particles in the form of a tube having an outer diameter of 40 to 90 nm, a wall thickness of 1 to 2 nm, and a major axis (length) of 300 to 600 nm.
  • Example 6 ⁇ Preparation of Aragonite> 2 L of tap water was put into a cylindrical separable flask having a volume of 3 liters, and 150 g of reagent calcium hydroxide was put therein. This calcium hydroxide suspension was prepared at 25 ° C., and carbon dioxide was introduced at a flow rate of 1.0 L / min while stirring at 300 rpm to prepare an aragonite suspension. The solid content concentration of the slurry was 10 Adjusted to 0.0 mass%. The aragonite suspension (or slurry) thus obtained was used in the following steps of Example 6 and Example 9.
  • This slurry was heated to 50 ° C. at a rate of 2 ° C./min and held there for 4 hours.
  • the product was observed with a transmission electron microscope, it was found to be a tube-shaped particle having an outer diameter of 50 to 80 nm, a wall thickness of 1 to 2 nm, and a major axis (length) of 300 to 800 nm.
  • Example 7 ⁇ Preparation of basic calcium carbonate> 1 L of tap water was put into a cylindrical separable flask having a capacity of 3 liters, and 150 g of industrial quicklime was put therein. The mixture was allowed to stand for 10 minutes and then stirred for 20 minutes, and coarse particles were removed with a 100 mesh sieve. Tap water was added to the calcium hydroxide suspension thus obtained so that the liquid volume was 2 L, and the temperature was adjusted to 10 ° C., and carbon dioxide was introduced at a flow rate of 0.2 L / min while stirring at 500 rpm. A suspension of basic calcium carbonate was prepared, and the solid content concentration of the slurry was adjusted to 5.0 mass%. The basic calcium carbonate suspension (or slurry) thus obtained was used in the following steps of Example 7.
  • Method 4 Into a beaker with a capacity of 3 liters, 1000 mL of a basic calcium carbonate slurry having a solid concentration of 5.0% by mass was adjusted and maintained at 50 ° C. while stirring at 300 rpm, and 600 mL of a 5.0% by mass phosphoric acid aqueous solution was added. The solution was added dropwise at a rate of 8.0 mL / min, and the temperature of 50 ° C. was maintained as it was for 18 hours.
  • Example 8 (Method 4) In a separable flask with a volume of 3 liters, 313 g of a calcite slurry having a solid content concentration of 5.0% by mass, 7.7 g of reagent calcium hydroxide, and 800 g of tap water are placed, adjusted and maintained at 10 ° C. while stirring at 300 rpm. Then, 700 g of a 5.0 mass% sodium pyrophosphate aqueous solution was added dropwise at a rate of 8.0 mL / min, and then 2N hydrochloric acid was added dropwise to adjust the pH to a range of 6.5 to 7.0. And then aged for 5 hours. When the product was observed with a scanning electron microscope, tube-shaped particles having an outer diameter of 50 to 70 nm, a wall thickness of 3 to 8 nm, and a major axis (length) of 500 to 800 nm were formed.
  • Example 9 (Fifth method) 1000 mL of a suspension of aragonite readjusted to a solid content concentration of 5.0% by mass in a 2 liter beaker was added and mixed with 37.5 g of reagent calcium monohydrogen phosphate (brushite) while stirring at 300 rpm. While stirring as it is, the slurry temperature at that time was heated to 50 ° C. and aged for 20 hours. When the product was observed with a scanning electron microscope, particles having a tubular shape with an outer diameter of 40 to 60 nm, a wall thickness of 2 to 10 nm, and a major axis (length) of 300 to 700 nm were produced.
  • the tubular calcium phosphate of the present invention has a hollow structure called a “nanotube” having a nano-sized aperture, and exhibits various functions and effects derived from its size and shape. That is, a chromatographic filler, fluorescent material, adsorbent, filter agent, filter aid, sustained release body, fragrance, liquid absorbent, microorganism breeding material, microorganism carrier, chemical catalyst, catalyst carrier, photocatalyst function improving material, pharmaceutical carrier
  • a chromatographic filler fluorescent material, adsorbent, filter agent, filter aid, sustained release body, fragrance, liquid absorbent, microorganism breeding material, microorganism carrier, chemical catalyst, catalyst carrier, photocatalyst function improving material, pharmaceutical carrier
  • plant growth agents, molding aids, ceramic raw materials, various carriers, applications as functional fillers such as plastics, rubber, paints, inks or sealing materials and papermaking can be expected.
  • Hydroxyapatite is particularly excellent in biocompatibility, and the tubular structure is expected to be well integrated with living tissue, so biomaterials, medical materials, dental materials, biocompatible coating materials, bioscaffolding materials, It is considered promising in applications to fields such as gene delivery carriers or biofunctional materials.
  • this invention was demonstrated along the specific aspect, the deformation

Abstract

Disclosed are tube-shaped hollow particles which are characterized by having an average longer diameter (length) of 200 to 1000 nm inclusive, an average outer diameter of shorter diameters of 30 to 100 nm inclusive, and an average inner diameter of the shorter diameters of 29 to 99 nm inclusive. Also disclosed is a process for producing the tube-shaped hollow particles, which is characterized by comprising reacting an aqueous solution or suspension containing phosphoric acid with an aqueous solution or suspension containing a calcium compound. The tube-shaped hollow particles have nano-sized cross-section diameters, and are therefore expected to be used as a functional material such as a biomaterial, a filler for chromatography or a fluorescent material.

Description

チューブ状リン酸カルシウム及びその製造方法Tubular calcium phosphate and method for producing the same
　本発明は、リン酸カルシウムのチューブ状（管状）中空粒子に関する。より詳しくは、生体材料、クロマト用充填剤、触媒材料、蛍光材料等の機能性材料として期待できる、チューブの平均断面径が１００ｎｍ以下のナノサイズであるリン酸カルシウムのチューブ状中空粒子、及びリン酸カルシウムのチューブ状中空粒子の製造方法に関する。 The present invention relates to a tubular (tubular) hollow particle of calcium phosphate. More specifically, tube-like hollow particles of calcium phosphate having an average tube cross-sectional diameter of 100 nm or less, which can be expected as functional materials such as biomaterials, chromatographic fillers, catalyst materials, and fluorescent materials, and tubes of calcium phosphate The present invention relates to a method for producing a hollow particle.
　リン酸カルシウムは、リン酸あるいはリン肥の原料であるリン鉱石の主成分として種々のものが古くより知られている。そして蛍光体原料として大量に使用されているアパタイト（Ｃａ１０（ＰＯ４）６（ＯＨ，Ｆ，Ｃｌ）２）は、その中でも最も良く知られたリン酸カルシウムといえる。 Various types of calcium phosphate have long been known as the main component of phosphate ore, which is a raw material for phosphoric acid or phosphorus fertilizer. And apatite (Ca 10 (PO 4 ) 6 (OH, F, Cl) 2 ) used in a large amount as a phosphor raw material can be said to be the most well-known calcium phosphate among them.
　このアパタイトには、陰イオンに水酸基を有する水酸アパタイト（ＨＡｐ）、フッ素を含むフッ素アパタイト（ＦＡｐ）、塩素を含有する塩素アパタイト（ＣＡｐ）がある。また生体硬組織に近いものとして、これらの陰イオンあるいはリン酸根の一部を置換して炭酸根を含有した炭酸含有アパタイトが知られている。
　近年になり、骨や歯などの生体硬組織の代替材料やクロマトの充填材への応用という観点から、特に水酸アパタイトや炭酸含有水酸アパタイトが注目されている。 Examples of the apatite include hydroxyapatite (HAp) having a hydroxyl group as an anion, fluorine apatite (FAp) containing fluorine, and chlorine apatite (CAp) containing chlorine. Carbonate-containing apatite containing carbonate radicals by substituting a part of these anions or phosphate radicals is known as being close to living hard tissues.
In recent years, hydroxyapatite and carbonic acid-containing hydroxyapatite are attracting attention from the viewpoint of application to substitute materials for biological hard tissues such as bones and teeth and to chromatographic packing materials.
　アパタイト以外のリン酸カルシウムとしては、非晶質リン酸カルシウム、リン酸八カルシウム（Ｃａ８Ｈ２（ＰＯ４）６・５Ｈ２Ｏ）、リン酸三カルシウム（Ｃａ３（ＰＯ４）２）、リン酸四カルシウム（Ｃａ４（ＰＯ４）２Ｏ）及びリン酸一水素カルシウム等があり、そのリン酸一水素カルシウムには、含水物のＣａＨＰＯ４・２Ｈ２Ｏ（brushite）と無水物のＣａＨＰＯ４（monetite）とがある。 As calcium phosphate other than apatite, amorphous calcium phosphate, octacalcium phosphate (Ca 8 H 2 (PO 4 ) 6 · 5 H 2 O), tricalcium phosphate (Ca 3 (PO 4 ) 2 ), tetracalcium phosphate (Ca 4 (PO 4 ) 2 O), calcium monohydrogen phosphate, and the like. The calcium monohydrogen phosphate includes a hydrous CaHPO 4 · 2H 2 O (brushite) and an anhydrous CaHPO 4 (monetite). There is.
　これらのうちリン酸三カルシウム（ＴＣＰ）には高温型のα相と低温型であるβ相とが知られており（α－、β－Ｃａ３（ＰＯ４）２）、物性、溶解性、生体親和性が水酸アパタイトに似ているという特徴がある。またＴＣＰは水分の存在下でゆっくりと水酸アパタイトに変化する性質を有していることから、生体適合性が良く骨組織再生に適しているといわれている。 Among these, tricalcium phosphate (TCP) is known to have a high temperature type α phase and a low temperature type β phase (α-, β-Ca 3 (PO 4 ) 2 ), physical properties, solubility, The biocompatibility is similar to hydroxyapatite. Further, since TCP has a property of slowly changing to hydroxyapatite in the presence of moisture, it is said that it has good biocompatibility and is suitable for bone tissue regeneration.
　アパタイトの合成方法としては、沈殿法、加水分解法、水熱合成法等の湿式合成法や固相反応による乾式法による合成が検討されている。沈殿法は塩基性条件下でカルシウム塩水溶液とリン酸塩水溶液との混合を行なう合成方法である。加水分解法は、ＣａＨＰＯ４・２Ｈ２Ｏなどを加水分解することにより合成する方法である。水熱合成法は主として大型の結晶を合成する方法として知られているが、硝酸カルシウム水溶液とリン酸水素アンモニウム水溶液とを混合して水熱処理を行なうことにより微粒子を合成することもできる。 As a method for synthesizing apatite, wet synthesis methods such as precipitation method, hydrolysis method, hydrothermal synthesis method and the like, and synthesis by a dry method using a solid phase reaction are being studied. The precipitation method is a synthesis method in which a calcium salt aqueous solution and a phosphate aqueous solution are mixed under basic conditions. The hydrolysis method is a method of synthesizing by hydrolyzing CaHPO 4 .2H 2 O or the like. Although the hydrothermal synthesis method is known mainly as a method for synthesizing large crystals, fine particles can also be synthesized by mixing a calcium nitrate aqueous solution and an ammonium hydrogen phosphate aqueous solution and performing a hydrothermal treatment.
　さらに特殊な方法としてゾル－ゲル法がある。この方法は、カルシウムジエトキシドのエチレングリコール溶液と亜リン酸トリエチルのエタノール溶液の混合液に、水と酢酸とエタノールとの混合液を滴下して加水分解と重縮合を行って板状の水酸アパタイトを合成する方法である。 There is a sol-gel method as a more special method. In this method, a mixed solution of water, acetic acid and ethanol is dropped into a mixed solution of an ethylene glycol solution of calcium diethoxide and an ethanol solution of triethyl phosphite, followed by hydrolysis and polycondensation to form a plate-like water solution. This is a method of synthesizing acid apatite.
　ところで、本発明のチューブ状リン酸カルシウムとして最も重要となるナノサイズ（通常は１００ｎｍ以下の大きさのことをいう）の断面を有するチューブ構造は、近年のナノテクノロジーの進展に伴い「ナノチューブ」と称され、世界で注目を集めている。これまでに報告された「ナノチューブ」には、カーボン、チタニア、シリカ、酸化タングステン等を材料とするものがあり、それらは構成元素と形態から、カーボンナノチューブ（ＣＮＴ）、チタニアナノチューブ、シリカナノチューブ、酸化タングステンナノチューブなどと呼ばれ、さらには有機系のナノチューブに関する報告も見られる。そしてこれらの粒子は、その構成元素や構造、形態に由来する特有の機能を発現し、様々な分野への応用が検討されている。 By the way, a tube structure having a nano-sized cross section (usually a size of 100 nm or less) which is the most important as the tubular calcium phosphate of the present invention is referred to as a “nanotube” with the recent progress of nanotechnology. , Attracting attention in the world. Some of the “nanotubes” reported so far are made of carbon, titania, silica, tungsten oxide, etc., and they are carbon nanotubes (CNT), titania nanotubes, silica nanotubes, oxides based on their constituent elements and morphology. There are reports on organic nanotubes called tungsten nanotubes. And these particles express the peculiar function derived from the constituent element, structure, and form, and application to various fields is examined.
　例えば、カーボンナノチューブにおいては、電界放出ディスプレー（ＦＥＤ）、平面蛍光管、冷陰極管のカソード（陰極）デバイス、Ｘ線発生源、半導体素材、集積回路、高速スイッチング素子、燃料電池の電極、原子間力顕微鏡の探針、ナノピンセット、高強度材料等々への活用が期待されている。 For example, in the case of carbon nanotubes, field emission display (FED), flat fluorescent tube, cold cathode tube cathode (cathode) device, X-ray generation source, semiconductor material, integrated circuit, high-speed switching element, fuel cell electrode, interatomic It is expected to be used for force microscope probes, nanotweezers, high-strength materials, etc.
　チタニアナノチューブでは、アナターゼ型の結晶構造をなす直径数ｎｍの酸化チタンナノチューブが合成されており、磁性、光学特性、化学触媒特性等の各種の特性に基づいた種々の応用が考えられている。また、金属や金属化合物をドープすることにより、光学的バンドギャップの拡大、耐熱温度の向上、電気抵抗値の低下などが確認されているほか、ガスセンサーとしての研究も進められている。 As titania nanotubes, titanium oxide nanotubes with a diameter of several nanometers having an anatase type crystal structure have been synthesized, and various applications based on various properties such as magnetism, optical properties, and chemical catalyst properties are considered. In addition, by doping with metals and metal compounds, it has been confirmed that the optical band gap is increased, the heat-resistant temperature is improved, and the electric resistance value is lowered. Research on gas sensors is also underway.
　最近話題となっている酸化タングステンナノチューブは、外径が３００～１０００ｎｍ、長さが２～２０μｍであり、ナノチューブと呼ぶにはやや大きいが、可視光下において従来の窒素ドープ型酸化チタンの約８倍の光触媒活性を発現しているといわれる。
　このように「ナノチューブ」の応用領域は，電子材料、電極材料、化学触媒、光触媒、光学材料、テンプレート、強化素材と幅広く、今後さらなる応用分野の発展・拡大が期待されている。 Tungsten oxide nanotubes, which have become a hot topic recently, have an outer diameter of 300 to 1000 nm and a length of 2 to 20 μm, which is slightly larger than what is called a nanotube, but about 8 times that of conventional nitrogen-doped titanium oxide under visible light. It is said that the photocatalytic activity is doubled.
As described above, the application area of “nanotubes” is wide as electronic materials, electrode materials, chemical catalysts, photocatalysts, optical materials, templates, and reinforcing materials, and further development and expansion of application fields are expected in the future.
　本発明の対象物質であるリン酸カルシウムについても中空構造をなす粒子に関し種々の技術が開発され開示されている。まず、中空球状粒子としては、特許文献１にリン酸カルシウムに発泡剤又は結合剤を使用して調製した少なくとも１個の開口を有する中空球と、その製造方法が開示されており、その方法には乾式と湿式とがある。実施例で得られた中空球の粒子径は３０～２５０μｍであり、開口径は１０～４０μｍである。 Various techniques have been developed and disclosed for particles having a hollow structure with respect to calcium phosphate, which is a target substance of the present invention. First, as hollow spherical particles, Patent Document 1 discloses a hollow sphere having at least one opening prepared by using a foaming agent or a binder in calcium phosphate, and a manufacturing method thereof. And wet. The hollow spheres obtained in the examples have a particle diameter of 30 to 250 μm and an opening diameter of 10 to 40 μm.
　特許文献２には、第三リン酸カルシウムと水酸化アパタイトからなる中空カプセル及びその製造方法が開示されている。そこには炭酸カルシウムの水性懸濁液と水溶性リン酸類あるいはその水溶性塩の水溶液とを反応させて、リン酸カルシウムの結晶層を炭酸カルシウム粒子表面に形成させた後、水不溶性リン酸カルシウム塩あるいはその水性懸濁液を反応させて内部の炭酸カルシウムを溶出させ、第三リン酸カルシウム及び／又は水酸化アパタイト結晶層の壁材を形成させる方法が提案されている。 Patent Document 2 discloses a hollow capsule made of tricalcium phosphate and hydroxide apatite and a method for producing the same. There, an aqueous suspension of calcium carbonate and an aqueous solution of a water-soluble phosphate or a water-soluble salt thereof are reacted to form a calcium phosphate crystal layer on the surface of the calcium carbonate particles, and then a water-insoluble calcium phosphate salt or an aqueous solution thereof. There has been proposed a method in which the suspension is reacted to elute calcium carbonate inside to form a wall material of tricalcium phosphate and / or a hydroxyapatite crystal layer.
　特許文献３には、バテライト型炭酸カルシウムを核材として使用することにより、走査型電子顕微鏡により調べた球に換算した平均粒子径が２．０μｍ以下の楕円球状の中空構造のリン酸カルシウムが開示されている。 Patent Document 3 discloses a calcium phosphate having an oval spherical hollow structure having an average particle diameter of 2.0 μm or less converted to a sphere examined by a scanning electron microscope by using vaterite-type calcium carbonate as a core material. Yes.
　本発明に直接関連するチューブ状のリン酸カルシウムに関しては、特許文献４、５がある。これらの特許文献では、チューブ状粒子の長径（長さ）の平均粒子径は０．１～１０００μｍ、短径（外径）の平均粒子径は０．０５～１００μｍ、短径（内径）の平均粒子径は０．０２～９５μｍ、内径／外径比は０．０５～０．９５であり、特許文献４では「電子顕微鏡写真により測定したチューブ状複合体合成無機微粒子の体積の平均値」を「電子顕微鏡写真により測定したチューブ状複合体合成無機微粒子の長径の平均粒子径より算出した体積」で除した形状係数ｆを満足する粒子であるとしている。 There are Patent Documents 4 and 5 regarding the tubular calcium phosphate directly related to the present invention. In these patent documents, the average particle diameter of the long diameter (length) of the tubular particles is 0.1 to 1000 μm, the average particle diameter of the short diameter (outer diameter) is 0.05 to 100 μm, and the average of the short diameter (inner diameter). The particle diameter is 0.02 to 95 μm, and the inner diameter / outer diameter ratio is 0.05 to 0.95. In Patent Document 4, “average value of volume of tube-shaped composite synthetic inorganic fine particles measured by electron micrograph” is described. The particles satisfy the shape factor f divided by “the volume calculated from the average particle diameter of the major axis of the tube-shaped composite synthetic inorganic fine particles measured by an electron micrograph”.
　そして、前記特許文献４では、長径の平均径が０．６～７５０μｍ、短径の平均径が０．１２～５０μｍの針状のコア粒子にオルト燐酸、燐酸ナトリウムと塩化カルシウムの水溶液、フッ化ナトリウムの水溶液等を滴下し、コア粒子をヒドロキシアパタイト、燐酸一水素カルシウム、アモルファス燐酸カルシウム等で処理し、その後、有機酸及び／又は無機酸で処理することでコア粒子を溶解除去してチューブ状の無機微粒子を調製する多くの実施例が開示されている。 In Patent Document 4, needle-like core particles having an average major axis diameter of 0.6 to 750 μm and an average minor axis diameter of 0.12 to 50 μm are mixed with orthophosphoric acid, an aqueous solution of sodium phosphate and calcium chloride, fluoride An aqueous sodium solution is dropped, and the core particles are treated with hydroxyapatite, calcium monohydrogen phosphate, amorphous calcium phosphate, etc., and then treated with an organic acid and / or an inorganic acid to dissolve and remove the core particles to form a tube. A number of examples have been disclosed for preparing inorganic particulates.
　その多くの実施例で得られた燐酸カルシウム系のチューブ状微粒子の平均長径は０．６～７５０μｍ、平均外径は０．１４～５６μｍ、平均内径は０．０８～３８μｍとなっている。最も小さなチューブ状微粒子が製造できるのが実施例９であり、そこでは他の実施例に比し、極端に小さなチューブ状微粒子が得られているものの、それでも各平均粒子径は長径０．６μｍ、外径０．１４μｍ、内径０．０９μｍである。なお、平均内径が一番小さいのは実施例４であるが、それでも０．０８μｍである。 The average length of the calcium phosphate-based tubular fine particles obtained in many of the examples is 0.6 to 750 μm, the average outer diameter is 0.14 to 56 μm, and the average inner diameter is 0.08 to 38 μm. The smallest tubular fine particles can be produced in Example 9, in which extremely small tubular fine particles are obtained as compared with other examples, but each average particle size is still 0.6 μm in major axis, The outer diameter is 0.14 μm and the inner diameter is 0.09 μm. In addition, although Example 4 has the smallest average inside diameter, it is still 0.08 μm.
　特許文献５についても調製方法は特許文献４と同様であり、その実施例で得られた燐酸カルシウム系のチューブ状微粒子の中で最も大きい粒子で平均長径は８００μｍ、平均外径は５６μｍ、平均内径は３８μｍ、最も小さい粒子で平均長径は０．５μｍ、平均外径は０．１２μｍ、平均内径は０．０７μｍとなっている。
　以上のとおりであるから、引用文献４及び５には、概念的には前記のとおりの平均粒径の燐酸カルシウム系のチューブ状微粒子は開示されているものの、実際には本発明にあるような短径の外径の平均値が３０ｎｍ以上１００ｎｍ以下、短径の内径の平均値が２９ｎｍ以上９９ｎｍ以下のチューブ状リン酸カルシウムについては開示するところはなく、それを製造する技術も開示されていない。 The preparation method of Patent Document 5 is the same as that of Patent Document 4, and is the largest of the calcium phosphate-based tubular fine particles obtained in the examples, with an average major axis of 800 μm, an average outer diameter of 56 μm, and an average inner diameter. Is 38 μm, the smallest particle has an average major axis of 0.5 μm, an average outer diameter of 0.12 μm, and an average inner diameter of 0.07 μm.
As described above, although the reference 4 and 5 conceptually disclose calcium phosphate-based tubular fine particles having an average particle diameter as described above, they are actually in the present invention. There is no disclosure of tubular calcium phosphate having an average value of the outer diameter of the minor axis of 30 nm to 100 nm and an average value of the inner diameter of the minor axis of 29 nm to 99 nm, and a technique for producing the same is not disclosed.
　非特許文献１では、炭酸カルシウム（アラゴナイト）をリン酸一水素カルシウム二水和物でリン酸化した後、酢酸により炭酸カルシウムを溶解して合成された長径１０μｍ、短径１～２μｍ程度の大きさのマカロニ状中空凝集体が報告されている。このマカロニ状中空凝集体の外層部には電子顕微鏡により薄片状粒子が確認されており、ＥＤＸスペクトルから検出されたＰとＣａの特性Ｘ線の元素比からカルシウム欠損ハイドロキシアパタイト（ＤＡｐ）であるとしている。 In Non-Patent Document 1, the size of the major axis is 10 μm and the minor axis is about 1 to 2 μm synthesized by phosphorylating calcium carbonate (aragonite) with calcium monohydrogen phosphate dihydrate and then dissolving the calcium carbonate with acetic acid. Of macaroni-like hollow aggregates have been reported. In the outer layer of this macaroni-like hollow aggregate, flaky particles have been confirmed by an electron microscope. From the element ratio of the characteristic X-rays of P and Ca detected from the EDX spectrum, it is assumed that it is calcium deficient hydroxyapatite (DAp). Yes.
　特許文献６には、平均長径が０．１～１０００μｍ、平均短径が０．０１～１００μｍ、アスペクト比が３～１００を有する棒状中空重合体粒子が開示されている。この粒子は炭酸カルシウムの粒子表面にリン酸カルシウムが含有されている棒状無機粒子をコアとし、有機重合体をシェルとするコア／シェル状有機－無機複合体を生成し、棒状無機微粒子のみを溶解・除去して中空化することを特徴とする方法によって製造される。実施例で得られた粒子の平均長径は２．２～２５．１μｍ、平均短径は０．６～１．２μｍ、アスペクト比は３．７～２２．８となっている。 Patent Document 6 discloses rod-shaped hollow polymer particles having an average major axis of 0.1 to 1000 μm, an average minor axis of 0.01 to 100 μm, and an aspect ratio of 3 to 100. This particle is a core / shell-like organic-inorganic composite with a rod-like inorganic particle containing calcium phosphate on the surface of calcium carbonate as a core, and an organic polymer as a shell, and only the rod-like inorganic fine particles are dissolved and removed. Then, it is manufactured by a method characterized by hollowing. The particles obtained in the examples have an average major axis of 2.2 to 25.1 μm, an average minor axis of 0.6 to 1.2 μm, and an aspect ratio of 3.7 to 22.8.
特開昭６３－１９８９７０号公報JP 63-198970 A 特開平１０－２０２０９３号公報Japanese Patent Laid-Open No. 10-202093 特開平１１－１７１５１４号公報Japanese Patent Laid-Open No. 11-171514 特開平７－１９６３０５号公報JP 7-196305 A 特開平７－１９６３１４号公報JP-A-7-196314 特開２００１－２５３９６６号公報JP 2001-253966 A
　このように、チューブ状（管状、マカロニ状とも呼ばれる）リン酸カルシウムはこれまでも開示又は報告されているが、実際に製造されたものは、いずれもその長径はミクロン～サブミクロンサイズ、短径の平均外径は０．１２μｍ以上、平均内径は０．０７μｍ以上である「マイクロチューブ」であり、これまでナノサイズと言える所謂「リン酸カルシウムナノチューブ」と呼べるものは知られていない。 As described above, tubular (also called tubular or macaroni) calcium phosphate has been disclosed or reported so far, but in actual production, the major axis is in the micron to submicron size, the average of the minor axis. It is a “microtube” having an outer diameter of 0.12 μm or more and an average inner diameter of 0.07 μm or more, and so-called “calcium phosphate nanotubes” that can be said to be nano-sized have not been known.
　また、それらの製造方法は、コア粒子の外面にリン酸カルシウムを析出させ、製造工程の後半で有機酸や無機酸で処理することによりこのコア粒子を溶解除去してチューブ状の粒子を作製するものであり、コア粒子を使用することなく、また酸によるコア粒子の溶解除去なしにリン酸を含有する水溶液（又は懸濁液）とカルシウムを含有する水溶液（又は懸濁液）との反応のみにより製造するものではない。 In addition, those manufacturing methods are such that calcium phosphate is precipitated on the outer surface of the core particle, and the core particle is dissolved and removed by treatment with an organic acid or an inorganic acid in the latter half of the manufacturing process to produce a tube-like particle. Yes, by using only the reaction of an aqueous solution (or suspension) containing phosphoric acid and an aqueous solution (or suspension) containing calcium without using the core particles and without dissolving and removing the core particles with acid. Not what you want.
　以上のとおりであるから、リン酸カルシウム系のチューブ状微粒子に関し、本発明に最も近い技術を開示する特許文献４及び５においても、短径の外径の平均値が３０ｎｍ以上１００ｎｍ以下、短径の内径の平均値が２９ｎｍ以上９９ｎｍ以下のチューブ状リン酸カルシウムについて具体的に開示するところはなく、それを製造する技術も開示されていないのであり、現状では短径の外径の平均値が３０ｎｍ以上１００ｎｍ以下、短径の内径の平均値が２９ｎｍ以上９９ｎｍ以下のチューブ状リン酸カルシウムは存在せず、それを製造する技術も開発されていない。 As described above, regarding the calcium phosphate-based tubular fine particles, in Patent Documents 4 and 5 disclosing the technology closest to the present invention, the average value of the outer diameter of the minor axis is 30 nm or more and 100 nm or less, the inner diameter of the minor axis There is no specific disclosure of the tubular calcium phosphate having an average value of 29 nm or more and 99 nm or less, and a technique for producing the same is not disclosed. At present, the average value of the outer diameter of the short axis is 30 nm or more and 100 nm or less. There is no tubular calcium phosphate having an average inner diameter of 29 nm to 99 nm, and a technique for producing it has not been developed.
　このような事情に鑑み、本発明者らはこれまで作られたことがないリン酸カルシウムからなる「ナノチューブ」、すなわち、これまでにない、より小さなチューブ構造をしたリン酸カルシウム、具体的には、短径の平均外径及び平均内径がこれまでにない小さな「リン酸カルシウムナノチューブ」を合成すべく鋭意検討を行い、本発明に到達した。 In view of such circumstances, the present inventors have made a “nanotube” made of calcium phosphate that has never been made, that is, calcium phosphate having a smaller tube structure than ever before, specifically, a short diameter The inventors of the present invention have intensively studied to synthesize “calcium phosphate nanotubes” having an average outer diameter and an average inner diameter that are unprecedented, and reached the present invention.
　したがって、本発明は、これまでにない、より小さな「リン酸カルシウムナノチューブ」を提供することを解決すべき課題とするものである。
　また、その製造方法については、従前のようにコア粒子を使用し、後の工程で有機酸や無機酸でそのコア粒子を溶解除去する工程を必要とする複雑なものではなく、このような工程を必要としない、より簡便な方法を提供することを課題とするものである。 Therefore, an object of the present invention is to provide an unprecedented smaller “calcium phosphate nanotube”.
In addition, the manufacturing method is not complicated, using core particles as before, and requiring a step of dissolving and removing the core particles with an organic acid or an inorganic acid in a later step. It is an object of the present invention to provide a simpler method that does not require the above.
　本発明は、ナノサイズのチューブ状リン酸カルシウム及びチューブ状リン酸カルシウムの製造方法を提供するものであり、そのチューブ状リン酸カルシウムは、長径（長さ）の平均値が２００ｎｍ以上１０００ｎｍ以下、短径の外径の平均値が３０ｎｍ以上１００ｎｍ以下、短径の内径の平均値が２９ｎｍ以上９９ｎｍ以下であることを特徴とするものである。さらに短径の内径／外径比が、０．７以上１．０未満であることを特徴とするものである。
　このようなチューブ状リン酸カルシウムは、従来の技術では製造が不可能であった形状と大きさを有するものであり、そのチューブ状リン酸カルシウムは、リン酸カルシウムの中でも比較的安定で、生体材料としても有望な水酸アパタイトに近いＸ線回折パターンを示す。なお、ここでいう水酸アパタイトとは、その水酸基あるいはリン酸根の一部を炭酸根で置換した炭酸含有水酸アパタイトも含まれる。 The present invention provides nano-sized tubular calcium phosphate and a method for producing tubular calcium phosphate, and the tubular calcium phosphate has an average value of a major axis (length) of 200 nm or more and 1000 nm or less, and an outer diameter of a minor axis. The average value is 30 nm or more and 100 nm or less, and the average inner diameter of the minor axis is 29 nm or more and 99 nm or less. Furthermore, the inner diameter / outer diameter ratio of the minor axis is 0.7 or more and less than 1.0.
Such tubular calcium phosphate has a shape and size that could not be produced by conventional techniques, and the tubular calcium phosphate is relatively stable among calcium phosphates and is a promising water as a biomaterial. An X-ray diffraction pattern close to acid apatite is shown. The hydroxyapatite referred to here includes a carbonate-containing hydroxyapatite in which a hydroxyl group or a part of a phosphate group is substituted with a carbonate group.
　そして、その製造方法は、リン原料としてのリン酸を含有する水溶液又は懸濁液と、カルシウム原料としてのカルシウム化合物を含有する水溶液又は懸濁液とを反応させることにより合成することを特徴とする。
　リン原料は、リン酸、縮合リン酸、及びそれらの塩、リン酸一水素カルシウムからなる群から選ばれる水溶液又は懸濁液であり、並びにカルシウム原料は、水酸化カルシウム、炭酸カルシウム、塩基性炭酸カルシウムからなる群から選ばれる水溶液又は懸濁液であることが好ましい。
　特に、リン原料がリン酸水溶液、カルシウム原料が水酸化カルシウム及び／又は炭酸カルシウム懸濁液であることが、リン酸カルシウム以外の陽イオンや陰イオンが混入することがなく、また経済性の点でも好ましい。 And the manufacturing method is characterized by synthesizing by reacting an aqueous solution or suspension containing phosphoric acid as a phosphorus raw material with an aqueous solution or suspension containing a calcium compound as a calcium raw material. .
The phosphorus raw material is an aqueous solution or suspension selected from the group consisting of phosphoric acid, condensed phosphoric acid and salts thereof, calcium monohydrogen phosphate, and the calcium raw material is calcium hydroxide, calcium carbonate, basic carbonate An aqueous solution or suspension selected from the group consisting of calcium is preferred.
In particular, it is preferable that the phosphorus raw material is a phosphoric acid aqueous solution and the calcium raw material is calcium hydroxide and / or a calcium carbonate suspension, so that cations and anions other than calcium phosphate are not mixed, and it is also preferable in terms of economy. .
　本発明のナノサイズの短径を有するチューブ状リン酸カルシウム、すなわち「リン酸カルシウムナノチューブ」は、チューブの平均長径（長さ）が２００ｎｍ以上１０００ｎｍ以下、短径の平均外径が３０ｎｍ以上１００ｎｍ以下、短径の平均内径が２９ｎｍ以上９９ｎｍ以下であり、これは従前に知られていない形状と大きさを有するものである。特にチューブ状粒子を構成するリン酸カルシウムが水酸アパタイトに近いことがよく、その場合には生体材料や機能性材料としての応用が期待できる極めて有望な材料といえる。 The tubular calcium phosphate having a nano-sized minor axis of the present invention, that is, “calcium phosphate nanotube”, has an average major axis (length) of the tube of 200 nm to 1,000 nm, an average outer diameter of the minor axis of 30 nm to 100 nm, and a minor axis. The average inner diameter is not less than 29 nm and not more than 99 nm, which has a shape and size that have not been known before. In particular, the calcium phosphate constituting the tube-shaped particles is preferably close to the hydroxyapatite, and in that case, it can be said to be a very promising material that can be expected to be applied as a biomaterial or a functional material.
　そして、本発明のチューブ状リン酸カルシウムの製造方法は、コア粒子を使用することなく、かつ有機酸や無機酸でコア粒子を溶解除去することもなく、反応条件を制御しながらリン酸イオンとカルシウムイオンとを直接反応させることのみにより合成するものであり、従来の製造方法のようにコア粒子を使用し、後の工程で有機酸や無機酸でその粒子を溶解除去する方法とは異なり、工業的にも簡便な方法である。 And the manufacturing method of the tubular calcium phosphate of this invention is using the phosphate ion and calcium ion, controlling reaction conditions, without using a core particle and dissolving and removing a core particle with an organic acid or an inorganic acid. Unlike the method of using core particles as in the conventional manufacturing method, and dissolving and removing the particles with organic acid or inorganic acid in the subsequent process, it is industrial. It is also a simple method.
実施例１で合成されたリン酸カルシウムナノチューブの走査型電子顕微鏡写真である。2 is a scanning electron micrograph of calcium phosphate nanotubes synthesized in Example 1. FIG. 実施例１で合成されたリン酸カルシウムナノチューブの粉末Ｘ線回折図である。2 is a powder X-ray diffraction pattern of the calcium phosphate nanotubes synthesized in Example 1. FIG. 実施例４で合成されたリン酸カルシウムナノチューブの透過型電子顕微鏡写真である。4 is a transmission electron micrograph of calcium phosphate nanotubes synthesized in Example 4. FIG.
　以下に、本発明の実施の形態及び詳細について説明するが、本発明はそれらによって何等限定されるものではなく、特許請求の範囲の記載によって特定されるものであることはいうまでもない。
　本発明のチューブ状リン酸カルシウムは、チューブの長径（長さ）の平均値が２００ｎｍ以上１０００ｎｍ以下、短径の外径の平均値が３０ｎｍ以上１００ｎｍ以下、短径の内径の平均値が２９ｎｍ以上９９ｎｍ以下、平均アスペクト比が４～２０であり、従来の技術では製造が不可能であった形状と大きさを有するものである。なお、そのチューブの平均壁厚は１ｎｍ以上１５ｎｍ以下、内径／外径の平均値は０．７以上１．０未満が好ましい。 Embodiments and details of the present invention will be described below, but the present invention is not limited to these embodiments, and it goes without saying that the present invention is specified by the description of the scope of claims.
In the tubular calcium phosphate of the present invention, the average value of the long diameter (length) of the tube is 200 nm to 1000 nm, the average value of the short diameter is 30 nm to 100 nm, and the average value of the short diameter is 29 nm to 99 nm. The average aspect ratio is 4 to 20, and it has a shape and size that cannot be manufactured by the conventional technique. The average wall thickness of the tube is preferably 1 nm to 15 nm, and the average inner diameter / outer diameter is preferably 0.7 to less than 1.0.
　その製造方法は、リン酸を含有する水溶液又は懸濁液とカルシウムを含有する水溶液又は懸濁液とを反応させるものであり、リン酸を含有する水溶液又は懸濁液は、リン酸、縮合リン酸、又はそれらの塩（例えば、リン酸一水素カルシウム）等を使用して調製することができる。これらの中でピロリン酸のような縮合リン酸は水と反応しリン酸となるので、実質的にはリン酸と同等である。またリン酸塩としては、ピロリン酸、ヘキサメタリン酸、又はトリポリリン酸などのナトリウム、カリウム、又はアンモニウム塩などもあげることができる。 In the production method, an aqueous solution or suspension containing phosphoric acid is reacted with an aqueous solution or suspension containing calcium, and the aqueous solution or suspension containing phosphoric acid is phosphoric acid, condensed phosphorus. It can be prepared using an acid or a salt thereof (for example, calcium monohydrogen phosphate) and the like. Among these, condensed phosphoric acid such as pyrophosphoric acid reacts with water to form phosphoric acid, and thus is substantially equivalent to phosphoric acid. Examples of the phosphate include sodium, potassium, or ammonium salts such as pyrophosphoric acid, hexametaphosphoric acid, or tripolyphosphoric acid.
　さらに、リン酸一水素カルシウムとしては、含水物のＣａＨＰＯ４・２Ｈ２Ｏ（brushite）と無水物のＣａＨＰＯ４（monetite）とがあり、いずれも使用することができ、後述する実施例においても中間体としてしばしば生成する。
　これらのリン原料は単独で使用することはもちろん、適宜組み合わせて使用することもでき、その場合は水溶液であっても懸濁液であってもよい。 Further, as calcium monohydrogen phosphate, there are hydrous CaHPO 4 · 2H 2 O (brushite) and anhydrous CaHPO 4 (monetite), both of which can be used, and in the examples described later, Often generated as a body.
These phosphorus materials can be used alone or in appropriate combinations, and in that case, they may be aqueous solutions or suspensions.
　カルシウム化合物としては、水酸化カルシウム、炭酸カルシウム、塩基性炭酸カルシウム、塩化カルシウム、又は硫酸カルシウム等があげられる。炭酸カルシウムには結晶構造の異なるカルサイト、アラゴナイト、又はバテライトをはじめ、非晶質炭酸カルシウム、又は含水炭酸カルシウム等、種々のものが知られているが、いずれを使用してもかまわない。また塩基性炭酸カルシウムとは、Ｃａ３（ＣＯ３）２（ＯＨ）２・ｎＨ２０（ｎ＝０～２）なる組成の物質である。 Examples of the calcium compound include calcium hydroxide, calcium carbonate, basic calcium carbonate, calcium chloride, calcium sulfate and the like. Various calcium carbonates such as calcite, aragonite, or vaterite having different crystal structures are known, such as amorphous calcium carbonate or hydrated calcium carbonate, but any of them may be used. Basic calcium carbonate is a substance having a composition of Ca 3 (CO 3 ) 2 (OH) 2 .nH 2 0 (n = 0 to 2).
　上記したリン原料、又はカルシウム原料の選択にあたっては、リン原料としては生成物に不用な元素が混在せず水溶液となるリン酸、又は縮合リン酸が、カルシウム原料としては水酸化カルシウム、炭酸カルシウム、又は塩基性炭酸カルシウムから選択して組み合わせることが好ましい。
　これらのリン原料とカルシウム原料とを特定の条件で反応させることにより、リン酸カルシウムナノチューブを製造でき、具体的には次のような方法をあげることができる。 In selecting the phosphorus raw material or calcium raw material described above, phosphoric acid, which is an aqueous solution without containing unnecessary elements in the product as the phosphorus raw material, or condensed phosphoric acid, calcium hydroxide, calcium carbonate, Or it is preferable to select and combine from basic calcium carbonate.
By reacting these phosphorus raw materials and calcium raw materials under specific conditions, calcium phosphate nanotubes can be produced. Specifically, the following methods can be mentioned.
　第１法：常温にてリン酸（塩）水溶液を撹拌しながら、カルシウム化合物を加え溶解して、リン酸カルシウム水溶液又は懸濁液を調製する。この水溶液又は懸濁液を、別に用意したカルシウム化合物水溶液又は懸濁液に温度を３０～７０℃の範囲で維持しながら添加する。
　第２法：液温を３０～７０℃の範囲に維持したカルシウム化合物水溶液又は懸濁液を撹拌しながら、リン酸（塩）水溶液を添加する。得られた懸濁液を２０℃以下に冷却し、再度リン酸（塩）水溶液を添加する。次に、得られた懸濁液を３０～７０℃まで加温し、そのまま０～２５時間保持し熟成する。 First method: While stirring an aqueous phosphoric acid (salt) solution at room temperature, a calcium compound is added and dissolved to prepare an aqueous calcium phosphate solution or suspension. This aqueous solution or suspension is added to a separately prepared calcium compound aqueous solution or suspension while maintaining the temperature in the range of 30 to 70 ° C.
Second method: An aqueous phosphoric acid (salt) solution is added while stirring an aqueous calcium compound solution or suspension maintained at a liquid temperature in the range of 30 to 70 ° C. The obtained suspension is cooled to 20 ° C. or lower, and an aqueous phosphoric acid (salt) solution is added again. Next, the obtained suspension is heated to 30 to 70 ° C. and kept for 0 to 25 hours for aging.
　第３法：液温を０～２０℃の範囲に維持したカルシウム化合物水溶液又は懸濁液を撹拌しながら、リン酸（塩）水溶液を添加する。得られた懸濁液を３０～７０℃まで加温し、そのまま０～３０時間保持し熟成する。
　第４法：液温を３０～７０℃の範囲に維持したカルシウム化合物を含有する水溶液又は懸濁液を撹拌しながら、リン酸（塩）水溶液を添加し、そのまま０～３０時間保持し熟成する。
　第５法：リン酸一水素カルシウムとカルシウム化合物の混合懸濁液を、３０～７０℃の温度に１～５０時間保持し熟成する。 Third method: An aqueous phosphoric acid (salt) solution is added while stirring an aqueous calcium compound solution or suspension maintained at a liquid temperature in the range of 0 to 20 ° C. The resulting suspension is warmed to 30-70 ° C. and kept for 0-30 hours for aging.
Method 4: Aqueous solution or suspension containing a calcium compound maintained at a liquid temperature in the range of 30 to 70 ° C. while stirring, an aqueous solution of phosphoric acid (salt) is added, and the mixture is kept for 0 to 30 hours for aging. .
Fifth method: A mixed suspension of calcium monohydrogen phosphate and a calcium compound is aged by holding at a temperature of 30 to 70 ° C. for 1 to 50 hours.
　上記の方法においてリン酸塩水溶液、又は懸濁液を添加するときは滴下することが好ましい。またリン原料としてリン酸塩や縮合リン酸塩を使用する場合は反応系がｐＨ１０以上の高ｐＨが維持される場合があるので、必要に応じ塩酸等の酸により、反応系のｐＨを５．５～７．５に調整することが好ましい。なお熟成時間はその時の反応条件に依存し、第２法、第３法、及び第４法において比較的高温での反応では熟成を必要としない場合があることから、そのときの熟成時間は０時間として記載している。 In the above method, when adding an aqueous phosphate solution or suspension, it is preferably added dropwise. In addition, when phosphate or condensed phosphate is used as the phosphorus raw material, the reaction system may maintain a high pH of 10 or more. Therefore, the pH of the reaction system is adjusted to 5. with an acid such as hydrochloric acid as necessary. It is preferable to adjust to 5 to 7.5. The aging time depends on the reaction conditions at that time, and in the second method, the third method, and the fourth method, aging may not be required in the reaction at a relatively high temperature. It is listed as time.
　これらの方法により得られた粒子は、いずれも、外径の平均値が３０～１００ｎｍ、内径の平均値が２９～９９ｎｍ、壁厚の平均値が１～１５ｎｍ、内径／外径比の平均値が０．７以上１．０未満、長径（長さ）の平均値が２００～１０００ｎｍのチューブ状の形態の粒子であり、Ｘ線回折により調べたところ、粒子径が小さく壁厚も薄いため幅広のピークとなったが、リン酸カルシウムの一種である水酸アパタイト（ＪＣＰＤＳカード番号　０１－０７２－１２４３）あるいは炭酸含有水酸アパタイト（ＪＣＰＤＳカード番号　００－１９－２７２）に極めて近い回折パターンを示した。 The particles obtained by these methods all have an average outer diameter of 30 to 100 nm, an average inner diameter of 29 to 99 nm, an average wall thickness of 1 to 15 nm, and an average inner diameter / outer diameter ratio. Is a tube-shaped particle with an average value of the major axis (length) of 200 to 1000 nm, and when examined by X-ray diffraction, it is wide because the particle diameter is small and the wall thickness is thin. However, a diffraction pattern very close to that of hydroxyapatite (JCPDS card number 01-072-1243) or carbonate-containing hydroxyapatite (JCPDS card number 00-19-272), which is a kind of calcium phosphate, was exhibited.
　本発明について、複数の実施例を挙げて更に具体的に説明するが、本発明は、この実施例によって何ら限定されるものではなく、特許請求の範囲によって把握されるものであることはいうまでもない。
　以下の各実施例において、ナノチューブ生成物の外径、内径、壁厚、及び長径（長さ）の測定結果は、電子顕微鏡写真で観察された生成物計１０個の平均値である。 The present invention will be described more specifically with reference to a plurality of examples. However, the present invention is not limited to these examples, and it is understood that the present invention is understood by the claims. Nor.
In each of the following examples, the measurement results of the outer diameter, inner diameter, wall thickness, and major diameter (length) of the nanotube product are average values of a total of ten products observed in the electron micrograph.
［実施例１］
〈カルサイトの調製〉
　容量３リットルの筒型セパラブルフラスコに水道水１Ｌを入れ、その中に工業用生石灰１５０ｇを投入した。１０分間静置後２０分間撹拌して、１００ｍｅｓｈの篩により粗粒分を除去した。こうして得られた水酸化カルシウム懸濁液に液量が２Ｌとなるように水道水を加え１５℃に調整後、５００ｒｐｍで撹拌しながら炭酸ガスを１．０Ｌ／分の流速で導入して、カルサイトの懸濁液を作製し、スラリーの固形分濃度を５．０質量％に調整した。こうして得られたカルサイト懸濁液（又はスラリー）を、実施例１の以下の工程で用いた。更に、実施例２～５及び実施例８でも使用した。 [Example 1]
<Preparation of calcite>
1 L of tap water was put into a cylindrical separable flask having a capacity of 3 liters, and 150 g of industrial quicklime was put therein. The mixture was allowed to stand for 10 minutes and then stirred for 20 minutes, and coarse particles were removed with a 100 mesh sieve. Tap water was added to the calcium hydroxide suspension thus obtained so that the liquid volume would be 2 L, the temperature was adjusted to 15 ° C., and carbon dioxide was introduced at a flow rate of 1.0 L / min while stirring at 500 rpm. A suspension of the site was prepared, and the solid content concentration of the slurry was adjusted to 5.0% by mass. The calcite suspension (or slurry) thus obtained was used in the following steps of Example 1. Further, Examples 2 to 5 and Example 8 were used.
（第１法）
　脱イオン水９５７．５ｇを入れた容量２リットルのビーカーに試薬リン酸４２．５ｇを加え４．２５質量％のリン酸水溶液を調製した。このリン酸水溶液を容量２リットルのビーカーに７００ｍＬとり３００ｒｐｍで撹拌しながら、５．０質量％のカルサイト懸濁液３００ｇを加えて溶解し、リン酸カルシウム懸濁液を調製した。
　次に、容量３リットルのビーカーに固形分濃度５．０質量％のカルサイト懸濁液７００ｍＬを入れ、５０℃に保ち３００ｒｐｍで攪拌しながら、先のリン酸カルシウム懸濁液の全量を８ｍＬ／ｍｉｎの速度で滴下した。生成物を走査型電子顕微鏡で観察したところ、その結果は図１に示す通りであり、外径が６０ｎｍ、内径が５０ｎｍ、長径（長さ）が３００～４００ｎｍのチューブ状の形態の粒子であった。またＸ線回折を行なったところ、水酸アパタイトに極めて近いパターンを示した。
　なお、得られたリン酸カルシウムナノチューブの粉末Ｘ線回折図は図２に示すとおりである。 (First method)
42.5 g of reagent phosphoric acid was added to a 2-liter beaker containing 957.5 g of deionized water to prepare a 4.25% by mass phosphoric acid aqueous solution. 700 mL of this phosphoric acid aqueous solution was taken in a 2-liter beaker and stirred at 300 rpm, and 300 g of a 5.0% by mass calcite suspension was added and dissolved to prepare a calcium phosphate suspension.
Next, 700 mL of a calcite suspension having a solid content concentration of 5.0% by mass was placed in a beaker having a volume of 3 liters, and the total amount of the previous calcium phosphate suspension was adjusted to 8 mL / min while stirring at 300 rpm while maintaining the temperature at 50 ° C. It was dripped at a speed. When the product was observed with a scanning electron microscope, the result was as shown in FIG. 1. The result was a tube-shaped particle having an outer diameter of 60 nm, an inner diameter of 50 nm, and a major axis (length) of 300 to 400 nm. It was. Further, when X-ray diffraction was performed, a pattern very close to hydroxyapatite was shown.
In addition, the powder X-ray diffraction pattern of the obtained calcium phosphate nanotube is as shown in FIG.
［実施例２］
（第２法）
　容量３リットルのビーカーに固形分濃度５．０質量％のカルサイト懸濁液１ｋｇを入れ、３００ｒｐｍで撹拌しながら５０℃を維持して４．２５質量％のリン酸水溶液２５０ｍＬを８ｍＬ／ｍｉｎの速度で滴下した。次に、得られたスラリーを１０℃まで冷却し４．２５質量％のリン酸水溶液４５０ｍＬを８ｍＬ／ｍｉｎの速度で滴下し、その後、４０℃／時間の速度で５０℃まで加温しそのまま１５時間保持した。
　生成物を走査型電子顕微鏡で観察したところ、外径が６０ｎｍ、内径が５０ｎｍ、長径（長さ）が３００～４００ｎｍのチューブ状の形態の粒子であった。 [Example 2]
(Second method)
1 kg of calcite suspension having a solid content of 5.0% by mass is placed in a beaker having a capacity of 3 liters, and maintained at 50 ° C. while stirring at 300 rpm, and 250 mL of 4.25% by mass phosphoric acid aqueous solution is added at 8 mL / min. It was dripped at a speed. Next, the obtained slurry was cooled to 10 ° C., 450 mL of a 4.25% by mass phosphoric acid aqueous solution was added dropwise at a rate of 8 mL / min, and then heated to 50 ° C. at a rate of 40 ° C./hour, and left as it was. Held for hours.
When the product was observed with a scanning electron microscope, it was found to be a tube-shaped particle having an outer diameter of 60 nm, an inner diameter of 50 nm, and a major axis (length) of 300 to 400 nm.
［実施例３］
（第３法）
　容量３リットルのビーカーに固形分濃度５．０質量％のカルサイト懸濁液１ｋｇを入れ、３００ｒｐｍで撹拌しながら１０℃を維持して４．２５質量％のリン酸水溶液７００ｍＬを８ｍＬ／ｍｉｎの速度で滴下した。こうして得られたスラリー中の生成物をＸ線回折により調べるとカルサイトとＣａＨＰＯ４・２Ｈ２Ｏ（brushite）の混合物であった。このスラリーを４０℃／時間の速度で５０℃まで加温しそのまま２０時間保持した。
　生成物を走査型電子顕微鏡で観察したところ、外径が６０ｎｍ、内径が５０ｎｍ、長径（長さ）が３００～４００ｎｍのチューブ状の形態の粒子であった。 [Example 3]
(Third method)
Into a beaker with a capacity of 3 liters, 1 kg of a calcite suspension having a solid content concentration of 5.0% by mass is maintained at 10 ° C. while stirring at 300 rpm, and 700 mL of a 4.25% by mass phosphoric acid aqueous solution is added at 8 mL / min. It was dripped at a speed. The product obtained slurry thus a mixture of the examined by X-ray diffraction calcite and CaHPO 4 · 2H 2 O (brushite ). The slurry was heated to 50 ° C. at a rate of 40 ° C./hour and held for 20 hours.
When the product was observed with a scanning electron microscope, it was found to be a tube-shaped particle having an outer diameter of 60 nm, an inner diameter of 50 nm, and a major axis (length) of 300 to 400 nm.
［実施例４］
（第３法）
　容量３リットルのセパラブルフラスコに固形分濃度５．０質量％のカルサイトのスラリー６０８ｇを入れ、そのスラリーの攪拌下に、水道水７３５ｇに試薬水酸化カルシウムを懸濁させた液を加えた。引き続き３００ｒｐｍで撹拌しながら１０℃に調整及び維持して、５．０質量％のリン酸水溶液７００ｇを１８ｍＬ／ｍｉｎの速度で滴下した。こうして得られたスラリー中の生成物をＸ線回折により調べるとカルサイトとＣａＨＰＯ４・２Ｈ２Ｏ（brushite）の混合物であった。このスラリーを２℃／分の速度で５０℃まで加温しそのまま５時間保持した。
　生成物を透過型電子顕微鏡で観察したところ、その結果は図３に示す通りであり、外径が４０～９０ｎｍ、壁厚が１～２ｎｍ、長径（長さ）が４００～７００ｎｍのチューブ状の形態の粒子であった。 [Example 4]
(Third method)
A 608 g slurry of calcite having a solid content concentration of 5.0% by mass was placed in a separable flask having a volume of 3 liters, and a solution obtained by suspending reagent calcium hydroxide in 735 g of tap water was added thereto while stirring the slurry. Subsequently, the mixture was adjusted and maintained at 10 ° C. while stirring at 300 rpm, and 700 g of a 5.0 mass% phosphoric acid aqueous solution was dropped at a rate of 18 mL / min. The product obtained slurry thus a mixture of the examined by X-ray diffraction calcite and CaHPO 4 · 2H 2 O (brushite ). The slurry was heated to 50 ° C. at a rate of 2 ° C./min and held there for 5 hours.
When the product was observed with a transmission electron microscope, the result was as shown in FIG. 3, which was a tube-like shape having an outer diameter of 40 to 90 nm, a wall thickness of 1 to 2 nm, and a long diameter (length) of 400 to 700 nm. The particles were in the form.
［実施例５］
（第３法）
　容量３リットルのセパラブルフラスコに固形分濃度５．０質量％のカルサイトのスラリー６０８ｇを入れ、そのスラリーの攪拌下に、水道水７３５ｇに試薬水酸化カルシウムを懸濁させた液を加えた。引き続き３００ｒｐｍで撹拌しながら１０℃に調整及び維持して、５．０質量％のリン酸水溶液７００ｇを１８ｍＬ／ｍｉｎの速度で滴下した。このスラリーを２℃／分の速度で３０℃まで加温しそのまま２０時間保持して熟成した。
　生成物を透過型電子顕微鏡で観察したところ、外径が４０～９０ｎｍ、壁厚が１～２ｎｍ、長径（長さ）が３００～６００ｎｍのチューブ状の形態の粒子であった。 [Example 5]
(Third method)
A 608 g slurry of calcite having a solid content concentration of 5.0% by mass was placed in a separable flask having a volume of 3 liters, and a solution obtained by suspending reagent calcium hydroxide in 735 g of tap water was added thereto while stirring the slurry. Subsequently, the mixture was adjusted and maintained at 10 ° C. while stirring at 300 rpm, and 700 g of a 5.0 mass% phosphoric acid aqueous solution was dropped at a rate of 18 mL / min. This slurry was heated to 30 ° C. at a rate of 2 ° C./minute and kept for 20 hours for aging.
When the product was observed with a transmission electron microscope, it was particles in the form of a tube having an outer diameter of 40 to 90 nm, a wall thickness of 1 to 2 nm, and a major axis (length) of 300 to 600 nm.
［実施例６］
〈アラゴナイトの調製〉
　容量３リットルの筒型セパラブルフラスコに水道水２Ｌを入れ、その中に試薬水酸化カルシウム１５０ｇを投入した。この水酸化カルシウム懸濁液を２５℃に調製し、３００ｒｐｍで撹拌しながら炭酸ガスを１．０Ｌ／分の流速で導入して、アラゴナイトの懸濁液を作製し、スラリーの固形分濃度を１０．０質量％に調整した。こうして得られたアラゴナイト懸濁液（又はスラリー）を、実施例６の以下の工程及び実施例９で用いた。 [Example 6]
<Preparation of Aragonite>
2 L of tap water was put into a cylindrical separable flask having a volume of 3 liters, and 150 g of reagent calcium hydroxide was put therein. This calcium hydroxide suspension was prepared at 25 ° C., and carbon dioxide was introduced at a flow rate of 1.0 L / min while stirring at 300 rpm to prepare an aragonite suspension. The solid content concentration of the slurry was 10 Adjusted to 0.0 mass%. The aragonite suspension (or slurry) thus obtained was used in the following steps of Example 6 and Example 9.
（第３法）
　容量３リットルのセパラブルフラスコに固形分濃度１０質量％のアラゴナイトのスラリー３０７ｇを入れ、そのスラリーの攪拌下に、水道水７３５ｇに試薬水酸化カルシウムを懸濁させた液を加えた。引き続き３００ｒｐｍで撹拌しながら１０℃に調整及び維持して、５．０質量％のリン酸水溶液７００ｇを１８ｍＬ／ｍｉｎの速度で滴下した。こうして得られたスラリー中の生成物をＸ線回折により調べるとアラゴナイトとＣａＨＰＯ４・２Ｈ２Ｏ（brushite）の混合物であった。このスラリーを２℃／分の速度で５０℃まで加温しそのまま４時間保持した。
　生成物を透過型電子顕微鏡で観察したところ、外径が５０～８０ｎｍ、壁厚が１～２ｎｍ、長径（長さ）が３００～８００ｎｍのチューブ状の形態の粒子であった。 (Third method)
A 307 g slurry of aragonite having a solid content concentration of 10% by mass was placed in a separable flask having a volume of 3 liters, and a solution obtained by suspending reagent calcium hydroxide in 735 g of tap water was added thereto while stirring the slurry. Subsequently, the mixture was adjusted and maintained at 10 ° C. while stirring at 300 rpm, and 700 g of a 5.0 mass% phosphoric acid aqueous solution was dropped at a rate of 18 mL / min. The product thus obtained in the slurry was a mixture of the examined by X-ray diffraction aragonite and CaHPO 4 · 2H 2 O (brushite ). This slurry was heated to 50 ° C. at a rate of 2 ° C./min and held there for 4 hours.
When the product was observed with a transmission electron microscope, it was found to be a tube-shaped particle having an outer diameter of 50 to 80 nm, a wall thickness of 1 to 2 nm, and a major axis (length) of 300 to 800 nm.
［実施例７］
〈塩基性炭酸カルシウムの調製〉
　容量３リットルの筒型セパラブルフラスコに水道水１Ｌを入れ、その中に工業用生石灰１５０ｇを投入した。１０分間静置後２０分間撹拌して、１００ｍｅｓｈの篩により粗粒分を除去した。こうして得られた水酸化カルシウム懸濁液に液量が２Ｌとなるように水道水を加え１０℃に調整後、５００ｒｐｍで撹拌しながら炭酸ガスを０．２Ｌ／分の流速で導入して、塩基性炭酸カルシウムの懸濁液を作製し、スラリーの固形分濃度を５．０質量％に調整した。こうして得られた塩基性炭酸カルシウム懸濁液（又はスラリー）を、実施例７の以下の工程で用いた。 [Example 7]
<Preparation of basic calcium carbonate>
1 L of tap water was put into a cylindrical separable flask having a capacity of 3 liters, and 150 g of industrial quicklime was put therein. The mixture was allowed to stand for 10 minutes and then stirred for 20 minutes, and coarse particles were removed with a 100 mesh sieve. Tap water was added to the calcium hydroxide suspension thus obtained so that the liquid volume was 2 L, and the temperature was adjusted to 10 ° C., and carbon dioxide was introduced at a flow rate of 0.2 L / min while stirring at 500 rpm. A suspension of basic calcium carbonate was prepared, and the solid content concentration of the slurry was adjusted to 5.0 mass%. The basic calcium carbonate suspension (or slurry) thus obtained was used in the following steps of Example 7.
[第４法]
　容量３リットルのビーカーに固形分濃度５．０質量％の塩基性炭酸カルシウムのスラリー１０００ｍＬを入れ、３００ｒｐｍで撹拌しながら５０℃に調整及び維持して、５．０質量％のリン酸水溶液６００ｍＬを８．０ｍＬ／ｍｉｎの速度で滴下し、そのまま５０℃の温度を１８時間維持した。
　生成物を走査型電子顕微鏡で観察したところ、滴下直後でもチューブ状の粒子が少量観察され、１８時間後では、外径が６０～９０ｎｍ、壁厚が２～５ｎｍ、長径（長さ）が２００～５００ｎｍのチューブ状の形態の粒子が形成された。 [Method 4]
Into a beaker with a capacity of 3 liters, 1000 mL of a basic calcium carbonate slurry having a solid concentration of 5.0% by mass was adjusted and maintained at 50 ° C. while stirring at 300 rpm, and 600 mL of a 5.0% by mass phosphoric acid aqueous solution was added. The solution was added dropwise at a rate of 8.0 mL / min, and the temperature of 50 ° C. was maintained as it was for 18 hours.
When the product was observed with a scanning electron microscope, a small amount of tube-like particles were observed even immediately after dropping, and after 18 hours, the outer diameter was 60 to 90 nm, the wall thickness was 2 to 5 nm, and the major axis (length) was 200. Particles in the form of tubes of ˜500 nm were formed.
［実施例８］
（第４法）
　容量３リットルのセパラブルフラスコに固形分濃度５．０質量％のカルサイトのスラリー３１３ｇ、試薬水酸化カルシウム７．７ｇ、及び水道水８００ｇを入れ、３００ｒｐｍで撹拌しながら１０℃に調整及び維持して、５．０質量％のピロリン酸ナトリウム水溶液７００ｇを８．０ｍＬ／ｍｉｎの速度で滴下し、引き続き２Ｎ塩酸を滴下してｐＨ６．５～７．０の範囲に調整しながら、温度を５０℃まで上昇させ、そのまま５時間保持し熟成した。
　生成物を走査型電子顕微鏡で観察したところ、外径が５０～７０ｎｍ、壁厚が３～８ｎｍ、長径（長さ）が５００～８００ｎｍのチューブ状の形態の粒子が形成された。 [Example 8]
(Method 4)
In a separable flask with a volume of 3 liters, 313 g of a calcite slurry having a solid content concentration of 5.0% by mass, 7.7 g of reagent calcium hydroxide, and 800 g of tap water are placed, adjusted and maintained at 10 ° C. while stirring at 300 rpm. Then, 700 g of a 5.0 mass% sodium pyrophosphate aqueous solution was added dropwise at a rate of 8.0 mL / min, and then 2N hydrochloric acid was added dropwise to adjust the pH to a range of 6.5 to 7.0. And then aged for 5 hours.
When the product was observed with a scanning electron microscope, tube-shaped particles having an outer diameter of 50 to 70 nm, a wall thickness of 3 to 8 nm, and a major axis (length) of 500 to 800 nm were formed.
［実施例９］
（第５法）
　容量２リットルのビーカーに固形分濃度５．０質量％に再調整したアラゴナイトの懸濁液を１０００ｍＬ入れ、３００ｒｐｍで撹拌しながら試薬リン酸一水素カルシウム（brushite）３７．５ｇを加えて混合した。そのまま撹拌しながら、その時のスラリー温度１８℃を５０℃まで加温し２０時間熟成した。
　生成物を走査型電子顕微鏡で観察したところ、外径が４０～６０ｎｍ、壁厚が２～１０ｎｍ、長径（長さ）が３００～７００ｎｍのチューブ状の形態の粒子が生成した。 [Example 9]
(Fifth method)
1000 mL of a suspension of aragonite readjusted to a solid content concentration of 5.0% by mass in a 2 liter beaker was added and mixed with 37.5 g of reagent calcium monohydrogen phosphate (brushite) while stirring at 300 rpm. While stirring as it is, the slurry temperature at that time was heated to 50 ° C. and aged for 20 hours.
When the product was observed with a scanning electron microscope, particles having a tubular shape with an outer diameter of 40 to 60 nm, a wall thickness of 2 to 10 nm, and a major axis (length) of 300 to 700 nm were produced.
本発明のチューブ状リン酸カルシウムは、ナノサイズの口径を有するいわゆる「ナノチューブ」と呼ばれる中空構造を有するものであり、その大きさや形状に由来する様々な機能や効果を発揮するものである。
　すなわち、クロマト用充填剤、蛍光材料、吸着剤、濾過剤、濾過助剤、徐放体、芳香剤、吸液剤、微生物飼育材、微生物担体、化学触媒、触媒担体、光触媒機能向上材、医薬担体、農薬担体、植物成長剤、成形助材、セラミック原料、各種キャリアーをはじめ、プラスチック、ゴム、塗料、インキ又はシーリング材及び製紙等の機能性充填材としての用途が期待できる。特に水酸アパタイトは生体適合性に優れ、またチューブ状の構造は生体組織との一体化が充分に予想されることから、生体材料、医療材料、歯科材料、生体適合コーティング材料、生体足場材料、遺伝子デリバリー担体、又は生体機能性材料等の分野への応用で有望と考えられる。
　以上、本発明を特定の態様に沿って説明したが、当業者に自明の変形や改良は本発明の範囲に含まれる。 The tubular calcium phosphate of the present invention has a hollow structure called a “nanotube” having a nano-sized aperture, and exhibits various functions and effects derived from its size and shape.
That is, a chromatographic filler, fluorescent material, adsorbent, filter agent, filter aid, sustained release body, fragrance, liquid absorbent, microorganism breeding material, microorganism carrier, chemical catalyst, catalyst carrier, photocatalyst function improving material, pharmaceutical carrier In addition to agricultural chemical carriers, plant growth agents, molding aids, ceramic raw materials, various carriers, applications as functional fillers such as plastics, rubber, paints, inks or sealing materials and papermaking can be expected. Hydroxyapatite is particularly excellent in biocompatibility, and the tubular structure is expected to be well integrated with living tissue, so biomaterials, medical materials, dental materials, biocompatible coating materials, bioscaffolding materials, It is considered promising in applications to fields such as gene delivery carriers or biofunctional materials.
As mentioned above, although this invention was demonstrated along the specific aspect, the deformation | transformation and improvement obvious to those skilled in the art are included in the scope of the present invention.

Claims (7)

  1. 　長径（長さ）の平均値が２００ｎｍ以上１０００ｎｍ以下、短径の外径の平均値が３０ｎｍ以上１００ｎｍ以下、短径の内径の平均値が２９ｎｍ以上９９ｎｍ以下であることを特徴とするチューブ状リン酸カルシウム。 An average value of major axis (length) is 200 nm or more and 1000 nm or less, an average value of outer diameter of minor axis is 30 nm or more and 100 nm or less, and an average value of inner diameter of minor axis is 29 nm or more and 99 nm or less, .
  2. 　短径の内径／外径比の平均値が、０．７以上１．０未満である請求項１に記載のチューブ状リン酸カルシウム。 The tubular calcium phosphate according to claim 1, wherein the average value of the inner diameter / outer diameter ratio of the minor axis is 0.7 or more and less than 1.0.
  3. 　リン酸カルシウムが水酸アパタイトである請求項１に記載のチューブ状リン酸カルシウム。 The tubular calcium phosphate according to claim 1, wherein the calcium phosphate is hydroxyapatite.
  4. 　リン原料としてリン酸を含有する水溶液又は懸濁液と、カルシウム原料としてカルシウム化合物を含有する水溶液又は懸濁液とを反応させることにより合成することを特徴とする請求項１～３に記載のチューブ状リン酸カルシウムの製造方法。 4. The tube according to claim 1, wherein the tube is synthesized by reacting an aqueous solution or suspension containing phosphoric acid as a phosphorus raw material with an aqueous solution or suspension containing a calcium compound as a calcium raw material. Method for producing calcium phosphate.
  5. 　リン原料が、リン酸、縮合リン酸、及びそれらの塩、リン酸一水素カルシウムからなる群から選ばれる水溶液又は懸濁液である請求項４に記載のチューブ状リン酸カルシウムの製造方法。 The method for producing tubular calcium phosphate according to claim 4, wherein the phosphorus raw material is an aqueous solution or suspension selected from the group consisting of phosphoric acid, condensed phosphoric acid, salts thereof, and calcium monohydrogen phosphate.
  6. 　カルシウム原料が、水酸化カルシウム、炭酸カルシウム、塩基性炭酸カルシウムからなる群から選ばれる水溶液又は懸濁液である請求項４又は請求項５に記載のチューブ状リン酸カルシウムの製造方法。 The method for producing tubular calcium phosphate according to claim 4 or 5, wherein the calcium raw material is an aqueous solution or suspension selected from the group consisting of calcium hydroxide, calcium carbonate, and basic calcium carbonate.
  7. 　リン原料がリン酸水溶液、カルシウム原料が水酸化カルシウム及び／又は炭酸カルシウム懸濁液であることを特徴とする請求項４に記載のチューブ状リン酸カルシウムの製造方法。 The method for producing tubular calcium phosphate according to claim 4, wherein the phosphorus raw material is an aqueous phosphoric acid solution and the calcium raw material is calcium hydroxide and / or a calcium carbonate suspension.
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