JP2008056513A - Manufacturing method of calcium phosphate particle, almost spherical calcium phosphate particle, use of phosphorous ester or phosphoric ester and phosphoric acid source - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a controlling method of a calcium phosphate particle controlling an individual calcium phosphate particle by a more excellent form-controlling method, and to provide the calcium phosphate particle having a new form, the use of phosphorous alkoxide or phosphoric alkoxide suitable for above or the like and a phosphoric acid source. <P>SOLUTION: A manufacturing method of the calcium phosphate particle is provided wherein a vesicle-shaped molecular template is formed in a liquid by mixing of a cationic surfactant molecule and an anionic surfactant molecule and the calcium phosphate is formed by allowing a calcium source to react with the phosphoric acid source on the surface of the surfactant molecule forming the molecular template, as a result, an almost spherical calcium phosphate particle having a particle diameter of 40 nm to 200 nm or 500 nm to 2,000 nm and also having a hollow structure is obtained. A phosphorous alkoxide or a phosphoric alkoxide may be used as the phosphoric acid source. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing calcium phosphate particles, the use of substantially spherical calcium phosphate particles (phosphite) phosphate, and a phosphate source.

  Conventionally, studies on calcium phosphate particles and methods for producing calcium phosphate particles have been made. There are various conventional methods for producing calcium phosphate particles, such as a wet method using an in-liquid reaction such as an aqueous solution reaction, a dry method in which heat and pressure are applied, and a hydrothermal method. In many cases, a reaction in liquid such as an aqueous solution reaction is used. There is apatite particles which are calcium phosphate particles.

  Apatite is known as a material excellent in biocompatibility, and apatite is attracting attention as an artificial bone grafting material because it is composed of a component that is very similar to a substance constituting the bone of the human body. In addition, apatite is a reinforcing material for biological ceramics, a filler for bone defects, an exchanger for heavy metal ions, a filler for column chromatography, an adsorbent for biopolymers such as proteins and nucleic acids, and amino acids, antibacterial and deodorant. It is applied to a wide variety of fields as materials for use.

Among hydroxyapatite (hereinafter also referred to as HAp) particles among apatites, there are reports of Patent Documents 1 and 2 below. Hydroxyapatite is represented by the general formula Ca ₁₀ (PO ₄ ) ₆ (OH) _2−x · nH ₂ O (0 ≦ n ≦ 2.5, 0 ≦ x ≦ 2.5).

  Patent Document 1 discloses a method of forming a W / O microemulsion phase using a surfactant-water-nonpolar organic liquid and synthesizing hydroxyapatite particles as calcium phosphate particles in the solution. In this system, the shape of the hydroxyapatite particles and the orientation of the particles are controlled by controlling the temperature, and it is reported that spherical, rod-shaped and columnar hydroxyapatite particles of several tens of nm to several μm can be prepared. Has been.

  Patent Document 2 discloses a method of synthesizing hydroxyapatite particles in a short time and under mild conditions by reacting α-type tricalcium phosphate with an alkali metal hydrogen phosphate in the presence of water.

Here, the biomaterial will be described. Conventionally, alumina (Al ₂ O ₃ ) having excellent wear resistance and biocompatibility has been used as an artificial bone. However, when alumina is implanted in the body, it is covered with a fibrous connective tissue, and there are few portions that are in direct contact with bone, and it may not be chemically bonded to bone. This often has the same problem not only in alumina but also in bioceramics, which will be described later, which have been studied so far. On the other hand, since calcium phosphate such as hydroxyapatite is a main component of living hard tissues such as bone, it is known to bind chemically strongly to bone. In addition, animal experiments have shown that calcium phosphates such as hydroxyapatite do not encapsulate with a fibrous coating even when implanted in the body, and bind directly to new bone. ing.

  This will be described in detail. Conventionally, as an alternative material for parts that are subjected to large loads such as tibia and femur, metal materials such as stainless steel, cobalt-chromium alloy, titanium alloy, ceramics such as ultra high molecular weight polyethylene, alumina, zirconia, etc. have been used. However, the ceramics as described above that are used as a substitute for living body hard tissue are called bioceramics. This bioceramic is high-strength and can be broadly classified into bioinert ceramics that exist stably in the living body and bioactive ceramics that directly bond with living bone in the living body. The bioinert ceramic is excellent in affinity with a living body, but hardly bonds directly. For this reason, when bioinert ceramics are used as an implant material, a thin connective tissue is formed at the interface where the implant material is in contact with a living tissue such as bone, and is fixed to the surrounding bone by mechanical fitting. However, it has been reported that loosening or falling off may occur due to long-term use. In contrast, calcium phosphates such as hydroxyapatite (HAp) and β-tricalcium phosphate (β-TCP) have excellent biocompatibility and osteoconductivity. It has been clinically applied as a tooth root. For example, it has been reported that when HAp is implanted into a living body as a bone grafting material, bone repair is quickly performed using this as a scaffold, and it exhibits excellent bone conduction ability to directly bond to new bone. In addition, β-TCP is also reported to have a feature of being decomposed in vivo and gradually replacing new bone.

JP 2002-137910 A JP 2001-348212 A

  As described above, calcium phosphate materials are attracting attention as biomaterials and the like, but there are many problems related to the manufacturing method, such as improvement in accuracy of shape control.

  The method described in Patent Document 2 does not specifically disclose a method for controlling the shape of each generated hydroxyapatite particle.

  Moreover, although the method of controlling the shape of the produced | generated individual hydroxyapatite particle | grains is disclosed about the said patent document 1, the interface of water and oil is utilized using O / W emulsion or W / O emulsion. This is used to control the morphology of hydroxyapatite particles. In this form control method, it is usual that the shape of the hydroxyapatite particles is changed, and it is often impossible to generate the hydroxyapatite particles until the properties of the hydroxyapatite particles such as a spherical shape and a hollow structure can be fully utilized.

  In particular, hydroxyapatite particles are expected to be used as carriers in drug delivery systems due to their properties such as biocompatibility and adsorption ability. However, in order to encapsulate drugs, hydroxyapatite particles have a capsule shape with a hollow structure. It is desirable that In addition, the particle size is preferably about 200 nm or less that can be accommodated in human capillaries. However, the methods described in Patent Documents 1 and 2 generally do not provide a method for producing hydroxyapatite particles that satisfy these conditions.

  In addition, since calcium phosphates such as hydroxyapatite (HAp) and β-tricalcium phosphate (β-TCP) are basically fragile materials, when the sintered body is used for artificial bones and dental roots, Mechanical strength is likely to be a problem. HAp and β-TCP dense bodies tend to have sufficient compressive strength compared to bones and teeth, but have a problem that their fracture toughness, tensile strength, bending strength, etc. tend to be insufficient. ing. In addition, these dense bodies have a higher elastic modulus than actual bones, and there are concerns about adverse effects such as thinning and thinning of the surrounding bones, and they tend to be difficult to use in areas where load is applied. is there. Therefore, in order to further improve these problems, there is a demand for a method for producing calcium phosphate particles, in which individual calcium phosphate particles are controlled and produced by a better form control method.

  The present invention has been made in view of solving the above-mentioned problems and the like, and is a method for producing calcium phosphate particles capable of controlling individual calcium phosphate particles by a more excellent form control method, and a substantially spherical calcium phosphate particle having a new shape. The main object of the present invention is to use a phosphorous ester suitable for the above and to provide a phosphoric acid source.

  The present invention relates to a method for producing calcium phosphate particles, the molecular template forming step of forming a vesicle-shaped molecular template in a liquid by mixing a cationic surfactant molecule and an anionic surfactant molecule, and the molecular template And a production step of producing calcium phosphate by reacting a calcium source and a phosphate source on the surface of the surfactant molecule forming the surface.

  The calcium phosphate is preferably apatite.

  The calcium phosphate is preferably hydroxyapatite.

  The calcium source is preferably one or more salts selected from the group consisting of calcium nitrate, calcium carbonate, calcium chloride, calcium hydroxide, calcium acetate and the like.

  The phosphoric acid source is selected from the group consisting of phosphoric acid, primary sodium phosphate, secondary sodium phosphate, primary potassium phosphate, secondary potassium phosphate, primary ammonium phosphate, secondary ammonium phosphate, etc. It is preferable that the salt is one or more kinds of salts.

  The particle size of the molecular template is preferably 20 nm to 200 nm.

  The reaction time in the production step is preferably 60 minutes to 90 minutes.

  The method for producing the calcium phosphate particles depends on the correlation between the previously determined composition ratio of the cationic surfactant molecule and the anionic surfactant molecule and the rate of formation of calcium phosphate. It is preferable to include a selection step of selecting the composition ratio between the activator molecule and the anionic surfactant molecule.

  In the method for producing the calcium phosphate particles, it is preferable that the phosphate source contains a phosphate alkoxide.

  It is preferable to use triethyl phosphite as the phosphate ester.

  The present invention is a substantially spherical calcium phosphate particle having a diameter of 40 nm to 200 nm and a hollow structure.

  The present invention is substantially spherical calcium phosphate particles having a diameter of 500 nm to 2000 nm and a hollow structure.

  The calcium phosphate is preferably apatite.

  The calcium phosphate is preferably hydroxyapatite.

  In addition, the present invention is characterized by the use of (phosphite) phosphate alkoxide as the phosphate source when the calcium phosphate particles are produced by reacting the phosphate source with the calcium source.

  In addition, the present invention is a phosphoric acid source for producing calcium phosphate particles by reacting a phosphoric acid source and a calcium source, and includes (phosphite) phosphoric acid alkoxide.

The present invention relates to a method for producing calcium phosphate particles capable of controlling individual calcium phosphate particles by a more excellent form control method, substantially spherical calcium phosphate particles having a new shape, use of a (sub) phosphate suitable for the above, phosphorus An acid source can be provided.

  The present inventor paid attention to the form control using a molecular assembly formed by a surfactant in a single solvent such as water as a template as a more excellent form control method of calcium phosphate particles, and calcium phosphate using this form control method. The method for producing particles (template method) was studied earnestly. As a result, in an anionic / cationic surfactant mixed system, an electrostatic interaction acts between the hydrophilic groups of the surfactant to form a surfactant having a quasi-double-chain structure, and has a form different from that of a single system. In addition, the shape of the molecular assembly changes greatly depending on the composition ratio, and the formation of a wide variety of molecular aggregates such as rod-like micelles, vesicles, liquid crystals, and precipitates can be controlled. In regions containing a large amount of surfactant, this anionic / cationic surface activity can be obtained by taking advantage of the fact that vesicles that are closed endoplasmic reticulum can be specifically formed using this pseudo-double-stranded structure. By using the template method with the nanomolecular assembly formed by the agent mixture system as a template, it is easy to prepare a material having a specific structure such as a regular pore structure or a hollow structure. Found that can be appropriately controlled more shapes calcium particles. In particular, since capsules of calcium phosphate particles having a hollow structure can release inclusions selectively and stepwise, fields in which the inclusions can be selectively and stepwise released (for example, cosmetics and pharmaceutical fields). Is particularly useful.

  Moreover, this inventor was able to find that the calcium phosphate particle which has a new shape can be provided if the form control method of the said calcium phosphate particle is used. For example, it has been found that calcium phosphate particles having a capsule shape having a hollow structure and / or particle diameters of 40 to 200 nm and calcium phosphate particles having a more controlled shape can be provided.

  Hereinafter, the calcium phosphate particles and the method for producing calcium phosphate particles according to the present embodiment will be described. In addition, this embodiment is only one form for implementing this invention, and this invention is not limited by this embodiment.

"Calcium phosphate particles and method for producing the same"
The method for producing calcium phosphate particles according to the present embodiment includes a molecular template forming step of forming a vesicle-shaped molecular template in a liquid by mixing a cationic surfactant molecule and an anionic surfactant molecule; And a generation step of generating calcium phosphate by reacting a calcium source and a phosphate source on the surface of the surfactant molecule to be formed.

The phosphate-based calcium particles are not particularly limited and can be appropriately selected and employed. Hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ), β-tricalcium phosphate, apatite (apatite) In the chemical formula of hydroxyapatite, anions such as carbonate group (CO ₃ ^2- ), oxygen group (O ^2- ), fluorine group (F ⁻ ), and chlorine group (Cl ⁻ ) are located at the position of hydroxyl group (OH ⁻ ). (Including substituted ones) as the main component, monocalcium phosphate monohydrate, monocalcium phosphate anhydride, dicalcium phosphate dihydrate, dicalcium phosphate anhydride, tetracalcium phosphate , Calcium orthophosphate, CaHPO ₄ , Ca ₃ (PO ₄ ) ₂ , Ca ₄ O (PO ₄ ) ₂ , CaP ₄ O ₁₁ , Ca (PO ₃ ) ₂ , Ca ₂ P ₂ O ₇ , Ca (H ₂₎ Examples thereof include particles containing PO ₄ ) ₂ , Ca ₂ P ₂ O ₇ , Ca (H ₂ PO ₄ ) ₂ .H ₂ O as a main component.

  The cationic surfactant molecule and the anionic surfactant molecule are not particularly limited and can be appropriately selected and used as long as they can form a vesicle-shaped molecular template in a liquid.

Examples of the cationic surfactant molecule include cetyltrimethylammonium bromide (CH ₃ (CH ₂ ) ₁₅ N (CH ₃ ) ₃ Br: CTAB), quaternary ammonium salt type [for example, tetraalkyl (C4-100) ammonium salt (E.g., lauryl trimethyl ammonium chloride, didecyl dimethyl ammonium chloride, dioctyl dimethyl ammonium bromide and stearyl trimethyl ammonium bromide), trialkyl (C3-80) benzyl ammonium salts (e.g., lauryl dimethyl benzyl ammonium chloride (benzalkonium chloride), alkyl ( C2-60) pyridinium salts (eg cetylpyridinium chloride), polyoxyalkylene (C2-4) trialkylammonium salts (eg polyoxye) Tylene trimethylammonium chloride) and sapamine type quaternary ammonium salts (eg stearamide ethyl diethyl methyl ammonium methosulfate)] and amine salt types [eg higher aliphatic amines (C12-60, eg laurylamine, stearylamine, cetylamine, cure) Inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid) or organic acids (C2-22, eg acetic acid, propionic acid, lauric acid, oleic acid, benzoic acid, succinic acid, adipic acid and azelain) Acid) salts, inorganic acid (above) salts such as EO adducts of aliphatic amines (C1-30) or organic acid (above) salts and tertiary amines (C3-30, eg triethanolamine monostearate) Rate and stearamide ethyl diethyl And inorganic acids methylethanolamine) (described above) salts or organic acids (as mentioned above) salt] can be exemplified.

Examples of the anionic surfactant molecule include sodium octyl sulfate (CH ₃ (CH ₂ ) ₇ SO ₄ Na: SOS) or a salt thereof, carboxylic acid (eg, C8-22 saturated or unsaturated fatty acid and ether carboxylic acid) or Salts thereof, sulfate esters [e.g. higher alcohol sulfates (e.g. sulfate esters of C8-18 aliphatic alcohols) and higher alkyl ether sulfates [e.g. EO of C8-18 aliphatic alcohols (1-10 mol) ) Sulfuric acid ester salts of adducts]], sulfonates [C10-20, such as alkyl benzene sulfonates (eg, sodium dodecylbenzene sulfonate), alkyl sulfonates, alkyl naphthalene sulfonates, dialkyl ester sulfosuccinates, hydro Carbon (eg Al , Α-olefin) sulfonate and Igepon T type] and phosphate esters [eg higher alcohol (C8-60) EO adduct phosphate ester and alkyl (C4-60) phenol EO adduct phosphate ester salt Further, as the above-mentioned salts, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, alkylamine (C1-20) salts and alkanolamine (C2-12, for example mono-, di- and triethanolamine) salts And so on.

  A liquid for forming a vesicle-shaped molecular template by mixing a cationic surfactant molecule and an anionic surfactant molecule is not particularly limited and can be appropriately selected and used. Water, aqueous solution, inorganic solvent And organic solvents.

  The total concentration of the cationic surfactant molecule and the anionic surfactant molecule can be appropriately selected without particular limitation as long as it is a total concentration capable of forming a vesicle-shaped molecular template. It can be mentioned that it is 20 mM-120 mM.

  The composition ratio between the cationic surfactant molecule and the anionic surfactant molecule is not particularly limited as long as it is a composition ratio for forming a vesicle-shaped molecular template. Activator molecule: Anionic surfactant molecule having a ratio of 1: 9 to 3: 7 is preferable because it is a phase formed only by vesicles.

  The method of forming a vesicle-shaped molecular template using a cationic surfactant molecule and an anionic surfactant molecule is not particularly limited and can be appropriately selected and employed. For example, the following formula (1) The method can also be judged using the critical filling parameter (CP) shown in FIG.

Here, v is the volume of the hydrophilic group of the surfactant, a ₀ is the area occupied by the hydrophilic group, and l _c is the maximum effective chain length of the hydrophobic group.

  The molecular assembly formed is determined by the critical packing parameter (CP) value. When CP <1/3, the molecule is conical, so that the spherical micelle is 1/3 <CP <1/2, and the rod-like micelle is 1 It is known that bilayer vesicles in a case of / 3 <CP <1 and bilayer membranes on a plane in a geometrical stable form when CP = ˜1. When CP> 1, reverse micelles are formed.

  It is preferable to confirm whether or not a vesicle-shaped molecular template is formed after the molecular template forming step. The confirmation method is not particularly limited and can be appropriately selected and adopted. For example, a method for visually confirming that a color specific to a vesicle-shaped molecular template is visually generated, using a cryo-TEM And a method of directly observing the vesicle.

  Further, it is preferable to confirm whether the vesicle-shaped molecular template has a desired particle size after the molecular template forming step. The confirmation method is not particularly limited and can be appropriately selected and employed. For example, a method of confirming particle size distribution measurement of a surfactant aqueous solution by a dynamic light scattering method, using cryo-TEM For example, the vesicle diameter can be confirmed by directly observing the vesicle.

The particle size of the molecular template may be determined depending on factors such as the size of the calcium phosphate particles to be produced. For example, the calcium phosphate particles may be 40 nm to 200 nm.
For this purpose, it is preferable that the particle size of the molecular template is 20 nm to 200 nm.

  About the production | generation process which makes a calcium source and a phosphate source react and produces | generates calcium phosphate, what produces calcium phosphate can be suitably selected and used for a calcium source and a phosphate source, without being specifically limited.

Examples of the calcium source include calcium nitrate (Ca (NO ₃ ) ₂ ), calcium carbonate (CaCO ₃ ), calcium chloride (CaCl ₂ ), calcium hydroxide (Ca (OH) ₂ ), or calcium acetate (Ca (CH _3). One or more salts selected from the group consisting of COO) ₂ ) and the like can be mentioned. These calcium sources may be used alone or in combination.

Examples of the phosphate source include phosphoric acid (H ₃ PO ₄ ), primary sodium phosphate (NaH ₂ PO ₄ ), secondary sodium phosphate (Na ₂ HPO ₄ ), and primary potassium phosphate (KH ₂ PO _4). ), Dibasic potassium phosphate (K ₂ HPO ₄ ), primary ammonium phosphate (NH ₄ H ₂ PO ₄ ) or dibasic ammonium phosphate ((NH ₄ ) ₂ HPO ₄ ), etc. One or more kinds of salts can be mentioned. These phosphoric acid sources may be used alone or in combination.

The pH of the reaction solution for producing calcium phosphate by reacting the calcium source and the phosphate source can be selected as appropriate. For example, the range of pH 8 to pH 12 prevents the following impurities from being mixed. Therefore, it is suitable from the viewpoint of promoting the production of calcium phosphate. When the pH is less than 8, the hardly soluble calcium phosphate compound which is an impurity in the reaction solution is mainly CaHPO ₄ .2H ₂ O (DCPD) or CaHPO ₄ at pH 4 to ₆ and Ca ₈ H ₂ (PO at pH 6 to 7). ₄ ) ₆ 5H ₂ O (OCP) is likely to occur. On the other hand, when the pH exceeds 12, calcium hydroxide Ca (OH) _{2 which} is an impurity in the reaction solution is easily generated.

  Although the temperature of the reaction liquid at the time of making a calcium source and a phosphate source react and producing | generating calcium phosphate can be selected suitably, it can mention the range of 20-30 degreeC, for example.

  Although the reaction time at the time of making a calcium source and a phosphate source react and producing | generating calcium phosphate can be selected suitably and can be employ | adopted, the range for 60 minutes-90 minutes can be mentioned, for example. If it is this reaction time, it can prevent suitably that it becomes the filling structure which calcium phosphate produced | generated to the inside of a particle | grain, and it is easy to maintain a hollow structure.

  Further, it is preferable to appropriately stir the reaction solution during the formation of calcium phosphate.

  After the production step, a calcium phosphate particle / vesicle template complex solution is obtained. After the production step, filtration may be performed to remove aggregates.

  It is also possible to remove the vesicle template from the calcium phosphate particles to obtain calcium phosphate particles alone. The method for removing the vesicle template from the calcium phosphate particles is not particularly limited and can be appropriately selected and employed. Examples thereof include a method of thermally decomposing the vesicle template by a baking treatment.

  With the method for producing calcium phosphate particles according to the present embodiment, individual calcium phosphate particles can be controlled by a more excellent form control method. That is, in the anionic / cationic surfactant mixed system, electrostatic interaction acts between the hydrophilic groups of the surfactant to form a surfactant having a pseudo double chain structure, and has a different form from the single system. Depending on the composition ratio, the shape of the molecular assembly changes greatly, and the formation of a wide variety of molecular aggregates such as rod-like micelles, vesicles, liquid crystals, and precipitates can be controlled. In a region where the active agent is contained in a large amount, a method for producing calcium phosphate particles utilizing advantages such as the ability to specifically form vesicles that are closed endoplasmic reticulum can be provided. Thereby, calcium phosphate particles having a new shape such as fine particles having a hollow structure can be provided.

  It is particularly suitable as a method for obtaining substantially spherical calcium phosphate particles having a particle size of 40 nm to 200 nm and having a hollow structure.

  These calcium phosphate particles have a particle diameter of about 200 nm or less and can fit in human capillaries. In addition, since it has a capsule shape having a hollow structure, it can enclose drugs and the like and can be applied as a carrier of a drug delivery system. In particular, apatite having a high biocompatibility, particularly hydroxyapatite is preferable.

  Moreover, the substantially spherical calcium phosphate particles produced according to the present embodiment can be appropriately selected and used without any particular limitation. For example, if it is apatite, it is a high-strength apatite composite for human body transplantation, bone filler and apatite particles for use as a filler for rubber and paper, apatite particles suitable for proteins supplied to the human body or pharmaceutical mediators It is useful as apatite particles containing various metal ions and anions or various catalysts that can be used as antibacterial and deodorant materials.

  In addition, when the present inventors use a phosphate ester as a phosphate source, the formation rate of calcium phosphate can be suppressed and the shape of the particle can be made closer to a true spherical shape. By using an ester, the reaction can be selectively caused in the vicinity of the template vesicle surface or in the bilayer of surfactant molecules forming the vesicle, and as close to the vesicle surface as possible rather than in solution. It has been found that the production efficiency can be improved by raising it with a bilayer membrane.

  To make calcium phosphate particles, calcium phosphate particles are produced by reacting and producing a phosphoric acid source such as phosphoric acid as described above, but this production reaction is very likely to occur and has a high reaction rate. is there. Therefore, the phosphoric acid source and the calcium source react with each other before reaching the vicinity of the surface of the vesicle as a template, and calcium phosphate particles are likely to be generated. Therefore, the reaction rate can be suppressed by using a phosphate ester that cannot be directly reacted with a calcium source as it is and can be converted into a phosphate source capable of reacting with a direct calcium source such as phosphoric acid. Can do. This prevents the phosphoric acid source and calcium source from reacting easily before reaching the vesicle surface, which is the template, and easily produces calcium phosphate particles, and also suppresses the production rate itself, In the calcium phosphate crystal growth process, the hollow structure can be maintained, and the shape can be controlled such that the particle shape can be made closer to a true spherical shape.

  Furthermore, since the phosphate ester is hydrophobic, it is more likely to be selectively collected near the vesicle surface, which is a template made of a surfactant molecule having a hydrophobic group, than in an aqueous solution. You will gather selectively. By this selective concentration action, calcium phosphate particles in which a phosphate source and a calcium source react with each other are also generated by being selected in the vicinity of the vesicle surface or in a bilayer, thereby improving selectivity.

  The (sub) phosphate ester can be appropriately selected without particular limitation as long as it has the property of being converted into a phosphate source that can directly react with a calcium source in a solution. An example is triethyl phosphite. As a (phosphite) ester, triethyl phosphite undergoes a hydrolysis reaction under milder conditions than triisopropyl phosphite, and also has a slower hydrolysis reaction than trimethyl phosphite. is there.

  Here, in order to be a phosphoric acid source that can directly react with a calcium source, it is necessary to be a phosphoric acid solution such as orthophosphoric acid or orthophosphorous acid. Moreover, as conditions which can be converted into the phosphoric acid source which can react directly with a calcium source, it is usually necessary to be a (phosphite) phosphate ester having a methoxy group or an ethoxy group.

  Thereby, when the calcium phosphate particles are produced by reacting the phosphate source with the calcium source, the use of the (phosphite) phosphate ester as the phosphate source indicates that the calcium phosphate particles in the vesicle template of the present embodiment Without limiting to the production, various calcium phosphate particles can be produced while suppressing the reaction rate. Phosphoric acid source used when phosphoric acid source and calcium source are reacted to produce calcium phosphate particles. When (phosphite) phosphate is included, the reaction rate of various conventionally known methods for producing calcium phosphate particles is suppressed. Thus, various calcium phosphate particles can be produced. For example, it is a substantially spherical calcium phosphate particle having a diameter of 500 nm to 2000 nm and a hollow structure. With calcium phosphate particles having a particle size of 500 nm or more, the crystal growth rate is large and the crystal grows to the inside to form a packed structure, but the reaction rate can be suppressed by using (phosphite) phosphate as a phosphate source. It is possible to form calcium phosphate particles having a hollow structure.

  Further, the present inventor has found that there is a correlation between the composition ratio of the cationic surfactant molecule and the anionic surfactant molecule and the production rate of calcium phosphate.

  As a result, the correlation between the composition ratio of the cationic surfactant molecule and the anionic surfactant molecule and the formation rate of calcium phosphate is obtained as a correlation data by sampling, for example, several samples. If the system selects the composition ratio of the desired cationic surfactant molecule and anionic surfactant molecule according to the correlation, the shape and size of the desired calcium phosphate particles can be obtained. become. That is, when there is a desired shape, appearance structure, size, etc., of a hollow structure or a packed structure of calcium phosphate particles, a cationic surfactant molecule and an anion based on the correlation with the calcium phosphate formation rate obtained in advance. Shape and appearance such as hollow structure and packed structure of calcium phosphate particles desired to be obtained by calculating the composition ratio with the surfactant surfactant molecule and adopting the cationic surfactant molecule and the anionic surfactant molecule of this composition ratio Structure and size can be obtained.

  For the correlation, for example, the size of calcium phosphate particles per unit time is obtained with respect to the composition ratio of the cationic surfactant molecule and the anionic surfactant molecule, and the production rate calculated from the calcium phosphate production rate is used. You can also.

  Using the generation rate used in this way, the composition ratio of a certain cationic surfactant molecule and an anionic surfactant molecule is analyzed to determine the generation rate, and the cationic surfactant molecule is analyzed. And the composition ratio and production rate of the anionic surfactant molecule are plotted. Preferably, for a plurality of solid templates in which the composition ratio between the cationic surfactant molecule and the anionic surfactant molecule is changed, the composition rate is analyzed to determine how much the composition rate is, and the cationic surfactant molecule It is preferable to obtain a correlation between a plurality of plots of the composition ratio and the production rate of the anionic surfactant molecule.

  The obtained correlation is preferably stored in a storage device or the like in advance. The storage device is not particularly limited, but is not particularly limited as long as it is a device that can store a correlation such as a read-only storage device (ROM or the like) or a readable / writable storage device (RAM or the like).

  The selection method for obtaining calcium phosphate particles having a desired shape may be any suitable method for selecting the composition ratio between the cationic surfactant molecule and the anionic surfactant molecule according to the correlation acquired in advance. .

  Examples of the manufacturing method include a manufacturing method using a system using a computer that executes a processing flow as shown in FIG. Depending on the correlation between the pre-stored composition ratio of the cationic surfactant molecule and the anionic surfactant molecule and the formation rate for the shape and size of the calcium phosphate particles to be produced, A computer program is loaded that includes a step of selecting a composition ratio between the surfactant molecule and the anionic surfactant molecule.

  The CPU in the computer is requested by an input means such as a keyboard to manufacture calcium phosphate particles having a size and shape desired by the manufacturer who manufactures the calcium phosphate particles (S1). The CPU in the computer should select the composition ratio between the cationic surfactant molecule and the anionic surfactant molecule in order to obtain the calcium phosphate particles of the desired size and shape in terms of the production rate. The storage device that stores the information is accessed (S2), and the correlation stored in the storage device is read (S3). The CPU determines how much of the composition ratio between the cationic surfactant molecule and the anionic surfactant molecule can be obtained based on the read correlation (S4). The composition ratio information of the cationic surfactant molecule and the anionic surfactant molecule determined by the CPU is the composition ratio of the cationic surfactant molecule and the anionic surfactant molecule. It is transmitted to the sorting device for sorting (S5). The sorting device sorts the composition ratio between the appropriate cationic surfactant molecule and the anionic surfactant molecule based on the information (S6). Using the selected composition ratio of the cationic surfactant molecule and the anionic surfactant molecule, calcium phosphate particles having a shape and size desired by the manufacturer are obtained by the method for producing calcium phosphate particles according to the present embodiment. (S7).

  Select the composition ratio between the cationic surfactant molecule and the anionic surfactant molecule to obtain calcium phosphate particles of the shape (including structure) and size desired by the manufacturer using the above system. Will be able to. It is possible to easily obtain substantially spherical calcium phosphate particles having a particle diameter of 40 nm to 200 nm and having a hollow structure.

  When phosphate ester is used as the phosphate source in the above system, the formation rate of calcium phosphate is suppressed, the hollow structure can be maintained even during the long calcium phosphate crystal growth process, and the particle shape can be made closer to a true spherical shape. Furthermore, by using a hydrophobic ester, the reaction can be selectively caused in the vicinity of the vesicle surface as a template or in a bilayer film of surfactant molecules forming the vesicle. The generation efficiency can be improved by causing it to occur in the vicinity of the vesicle surface or in a bimolecular film as much as possible instead of in the solution.

  Hereinafter, the present embodiment will be described more specifically with reference to examples of the production method of hydroxyapatite particles among calcium phosphate particles, but the present invention is not limited to these examples.

"Example 1"
Anionic sodium octyl sulfate (CH ₃ (CH ₂ ) ₇ SO ₄ Na: SOS) and cationic cetyltrimethylammonium bromide (CH ₃ (CH ₂ ) ₁₅ N (CH ₃ ) ₃ Br in 25 ml of ultrapure water: CTAB) was added at various composition ratios (SOS: CTAB = 9: 1, 8: 2, 7: 3) to a total concentration of 60 mM and dissolved.

  From the visual observation of the prepared aqueous surfactant solution, the pale color that is peculiar to the vesicle solution was visually confirmed at all the mixing ratios, and thus the formation of vesicles was visually confirmed.

  Next, in order to confirm the particle size of the vesicle, the particle size distribution of the aqueous surfactant solution was measured by the dynamic light scattering method. As a result, the vesicle size was about any mixture ratio studied in the SOS / CTAB mixed system. It was found to be 60 nm.

"Example 2"
Attempts were made to prepare hydroxyapatite particles in the aqueous surfactant solution prepared in Example 1.

<Preparation and Evaluation Results of HAp / Surfactant Composite Particles Using H ₃ PO ₄ as Phosphate Source>
CaCl ₂ and H ₃ PO ₄ were added to the surfactant aqueous solution, and the pH was adjusted to 8 using an aqueous sodium hydroxide solution. Thereafter, the mixture was stirred for various times and the aggregate was collected by filtration to obtain a hydroxyapatite particle / vesicle composite solution.

  First, the stirring time (reaction time) was 12 hours, and hydroxyapatite particles were prepared in solutions prepared at various SOS / CTAB mixing ratios. FIG. 1 shows the results of dynamic light scattering measurement of the obtained hydroxyapatite particle / vesicle composite solution, and FIG. 2 shows the results of transmission electron microscope observation.

  From FIG. 1, peaks derived from particles and aggregates of about 150 nm were confirmed at a mixing molar ratio of SOS: CTAB of 8: 2, 7: 3, but by setting the mixing ratio to 9: 1, the uniformity of about 100 nm was confirmed. It has been found that simple nanoparticles can be prepared.

  Further, from FIG. 2, spherical particles having a particle diameter of about 200 nm were confirmed, but a hollow structure could not be confirmed. This is presumably because the particle growth of hydroxyapatite particles progressed to the inside of the vesicle. Therefore, it has been found that it is necessary to shorten the reaction time and suppress the growth of hydroxyapatite particles.

  Next, in order to suppress particle growth of the hydroxyapatite particles, the stirring time (reaction time) was set to 1 hour, and hydroxyapatite particles were similarly prepared. FIG. 3 shows the results of dynamic light scattering measurement of the obtained hydroxyapatide / vesicle composite solution, and together with the results of FIG.

  From Table 1, it was confirmed that the particle size was reduced by setting the stirring time to 1 h. This is presumably due to the fact that the progress of the reaction was suppressed as the stirring time decreased.

  Next, the obtained solution was observed with a transmission electron microscope. FIG. 4 shows the results of observation with a transmission electron microscope of particles prepared with stirring at a mixing ratio of 8: 2, 1 h. From FIG. 4, since spherical particles having a hollow structure with a particle diameter of about 100 nm were confirmed, hydroxyapatite particle / surfactant composite particles using vesicles as templates were successfully prepared.

  From the above results, the form and size of the particles that can be prepared vary depending on the mixing ratio of the surfactant, but since many spherical particles are generated, the vesicle serves as a template and the calcium phosphate particles have a hollow structure. Is considered to be generated.

"Example 3"
Attempts were made to prepare hydroxyapatite particles in the aqueous surfactant solution prepared in Example 1.

<Preparation and evaluation results of HAp / surfactant composite particles using triethyl phosphite: P (OC ₂ H ₅ ) ₃ as a phosphoric acid source>
P (OC ₂ H ₅ ) ₃ was added to the surfactant aqueous solution, stirred for 1 hour, and adjusted to pH 12 using an aqueous sodium hydroxide solution. Thereafter, an aqueous CaCl ₂ solution was added and stirred for 24 hours to obtain a calcium phosphate particle / vesicle composite solution.

  The transmission electron microscope observation result of the particle | grains obtained in FIGS. 5-8 is shown.

5 to 8, spherical particles of 500 nm to 2000 nm (2 μm) were confirmed. Further, in FIGS. 5 and 6, the inside is brighter than the end of the particle and the electron beam is easily transmitted, so that it is considered to be a hollow shape. Therefore, it was confirmed that spherical calcium phosphate particles having a hollow structure were generated.
When a phosphoric acid source that reacts directly with a calcium source is used without using a phosphate ester as the phosphoric acid source, the crystal growth proceeds to the inside, so it is considered that the hollow structure is not maintained even after 24 hours. It is done. On the other hand, it was found that when phosphate ester is used as the phosphate source, the formation rate of calcium phosphate can be suppressed, the shape of the particles can be made closer to a true sphere, or a hollow structure can be formed.

Reference example
Hereinafter, preparation of mesoporous HAp particles using hexagonal liquid crystal as a template is shown as a reference example.

<Sample> Cetyltrimethylammonium chloride (CH ₃ (CH ₂ ) ₁₅ N (CH ₃ ) ₃ Cl: CTAC, manufactured by Aldrich) was used as the cationic surfactant.

As the anionic surfactant, sodium dodecyl sulfate (CH ₃ (CH ₂ ) ₁₁ SO ₄ Na: SDS, manufactured by Wako Pure Chemical Industries, Ltd.) was used.

Calcium chloride (CaCl ₂ , manufactured by Wako Pure Chemical Industries, Ltd.) and phosphoric acid (H ₃ PO _4, manufactured by Wako Pure Chemical Industries, Ltd.) were used as HAp precursors.

  Sodium hydroxide (NaOH, manufactured by Kanto Chemical Co., Inc.) was used as a pH adjuster for the surfactant / HAp precursor mixed solution.

Ultrapure water (> 18.2 MΩcm ⁻¹ ) was used as the solvent.

"Reference Example 1"
<Preparation and Evaluation Results of HAp / Surfactant Composite Particles Using Cationic Surfactant>
CaCl ₂ and H ₃ PO ₄ were added to various concentrations of the CTAC aqueous solution, and the pH was adjusted to 8 using NaOH. Thereafter, the mixture was stirred for various times, and the obtained product was filtered, washed, and dried (120 ° C., 10 h) to obtain HAp / surfactant composite particles.

  The structural characteristics and crystallinity of the obtained particles were evaluated using an X-ray diffractometer (manufactured by Rigaku Corporation, RINT1100, CuKα ray). The measurement sample used was finely ground with a mortar.

  The structure of the obtained particles was evaluated by observation with a transmission electron microscope (TEM) (manufactured by Hitachi High-Technologies Corporation, H-7650). As the sample, a product finely ground with a mortar was dispersed in a small amount of ethanol, a few drops were dropped on a carbon reinforced collodion film-attached copper mesh (manufactured by Oken Shoji), and dried.

  In order to examine the influence of the surfactant concentration as a template on the structural properties of HAp, HAp / surfactant composite particles were prepared by changing the CTAC concentration in the range of 60-780 mM. The powder X-ray diffraction measurement (XRD) results of the obtained particles are shown in FIGS. As a comparative sample, HAP-100 (manufactured by Taihei Chemical Industrial Co., Ltd.) was used as a commercially available HAp, and the XRD measurement results were shown.

  From FIG. 9, no peak due to the regular pore structure was confirmed in all particles. From this, it was suggested that the CTAC concentration as a template has no influence on the structural characteristics.

  On the other hand, from FIG. 10, since the peak attributed to HAp was confirmed in all the particles, it was found that the obtained particles were HAp. However, since crystallization of HAp is progressing in any particle, it is considered that this crystallization inhibits the formation of a regular pore structure.

  From the above results, it was suggested that crystallization of HAp inhibits the formation of a regular pore structure. Therefore, in the subsequent experiments, a method for suppressing crystallization by fixing the CTAC concentration to 60 mM was examined.

  In order to suppress crystallization of HAp, the HAC / surfactant composite particles were prepared by fixing the CTAC concentration at 60 mM and changing the stirring time in the range of 0-24 h. The powder X-ray diffraction measurement (XRD) results of the obtained particles are shown in FIGS.

  From FIG. 11, no peak due to the regular pore structure was observed in any of the particles. This suggested that the stirring time had no effect on the structural properties.

  On the other hand, from FIG. 12, it was confirmed that the crystallinity of HAp slightly decreased as the stirring time decreased, but it was confirmed that crystallization progressed even at the stirring time of 0 h. . From this, it was confirmed that it was difficult to suppress crystallization of HAp by the stirring time.

  From the above results, it was confirmed that HAp crystallizes even in a short reaction time. This may be because HAp is generated not in the template micelle surface but in bulk.

"Reference Example 2"
<Preparation and evaluation results of HAp / surfactant composite particles using anionic surfactant>
H ₃ PO ₄ was added to various concentrations of SDS aqueous solution, and the pH was adjusted to 12 using NaOH. Thereafter, an aqueous calcium chloride solution was added and stirred for 24 hours, and the resulting product was filtered, washed, and dried (120 ° C., 10 hours) to obtain HAp / surfactant composite particles. In addition, preparation was performed under room temperature and 60 degreeC heating.

  The structural characteristics and crystallinity of the obtained particles were evaluated using an X-ray diffractometer (manufactured by Rigaku Corporation, RINT1100, CuKα ray). The measurement sample used was finely ground with a mortar.

  The structure of the obtained particles was evaluated by observation with a transmission electron microscope (TEM) (H-7650, manufactured by Hitachi High-Technologies Corporation). For the sample, the product finely ground with a mortar was dispersed in a small amount of ethanol, and a few drops were dropped onto a carbon reinforced collodion film-attached copper mesh (manufactured by Oken Shoji) and dried.

  In order to examine the influence of the surfactant concentration on the structural properties of HAp, HAp / surfactant composite particles were prepared by changing the SDS concentration in the range of 8-96 mM. The powder X-ray diffraction measurement (XRD) results of the obtained particles are shown in FIGS. As a comparative sample, HAP-100 (manufactured by Taihei Chemical Industrial Co., Ltd.) was used as a commercially available HAp, and the XRD measurement results were shown.

  From FIG. 13, only the particles prepared with an SDS concentration of 96 mM confirmed a peak due to the lamellar structure. The inter-surface distance was calculated from the diffraction angle of the primary peak using the Bragg equation, and was found to be about 3.09 nm.

  On the other hand, from FIG. 14, a peak attributed to HAp was confirmed in all particles. However, a peak that appears to be an impurity was also confirmed in particles prepared at an SDS concentration of 96 mM. From this, it was found that the particles prepared with an SDS concentration of 96 mM contained some impurities.

  Subsequently, TEM observation was performed to confirm the structure of the particles prepared at an SDS concentration of 96 mM. The TEM observation result is shown in FIG.

  From FIG. 15, a regular layered structure was confirmed. Further, the inter-surface distance estimated from the TEM image was about 3 nm, which was found to be almost in agreement with the XRD measurement result.

  From the above results, it was speculated that the particles prepared at an SDS concentration of 96 mM were HAp / surfactant composite particles having a lamellar structure although some impurities were observed.

  It is known that SDS and calcium ions react in an aqueous solution at room temperature and precipitate as calcium didodecyl sulfate (CaDDS). Therefore, in order to investigate the influence of the particles, CaDDS particles were prepared and XRD measurement was performed. A comparison was made between the CaDDS prepared in FIGS. 16 and 17 and the prepared particles (SDS concentration 96 mM) by XRD patterns.

  In FIG. 16, the peak attributed to the lamellar structure coincided with the impurity peak in FIG. 17. Thus, it was confirmed that the lamellar structure and the impurity confirmed above were attributed to precipitated CaDDS.

  In order to suppress the precipitation of CaDDS, the preparation was performed under heating at 60 ° C., which is higher than the craft point (50 ° C.) of CaDDS. 18 and 19 show the results of powder X-ray diffraction measurement (XRD) of the obtained particles.

  From FIG. 18, no peak due to the regular pore structure was confirmed, and from FIG. 19, a peak attributed only to HAp was confirmed.

  From the above results, it was confirmed that the regular pore structure was not imparted to the HAp particles themselves prepared by heating at 60 ° C. This is considered to be caused by the fact that HAp particles that grow in a columnar shape immediately after the formation of the particles are hardly generated on the micelle surface having a large curvature.

It is a figure which shows the particle diameter distribution measurement result of the hydroxyapatite particle / vesicle composite solution at the time of 12-hour stirring. It is an electron micrograph of hydroxyapatite particles / surfactant composite particles prepared by stirring with a mixing ratio of 9: 1, 12 hours. It is a particle diameter distribution measurement result of the hydroxyapatite particle / vesicle composite solution at the time of stirring for 1 hour. It is an electron micrograph of hydroxyapatite particles / surfactant composite particles prepared by stirring with a mixing ratio of 8: 2 for 1 hour. It is an electron micrograph of calcium phosphate / surfactant composite particles prepared by stirring for 24 hours with a mixing ratio of 9: 1. It is an electron micrograph of calcium phosphate / surfactant composite particles prepared by stirring for 24 hours with a mixing ratio of 9: 1. It is an electron micrograph of calcium phosphate / surfactant composite particles prepared by stirring for 24 hours with a mixing ratio of 8: 2. It is an electron micrograph of calcium phosphate / surfactant composite particles prepared by stirring for 24 hours with a mixing ratio of 7: 3. It is a figure which shows the low angle XRD pattern of the particle | grains prepared with various surfactant density | concentrations. FIG. 3 is a diagram showing wide-angle XRD patterns of particles prepared with various surfactant concentrations. It is a figure which shows the low angle XRD pattern of the particle | grains prepared with various surfactant density | concentrations. FIG. 3 is a diagram showing wide-angle XRD patterns of particles prepared with various surfactant concentrations. It is a figure which shows the low angle XRD pattern of the particle | grains prepared with various surfactant density | concentrations. FIG. 3 is a diagram showing wide-angle XRD patterns of particles prepared with various surfactant concentrations. It is a TEM photograph of the prepared particles. It is a figure which shows the low angle XRD pattern regarding the comparison of the prepared particle | grains and CaDDS. It is a figure which shows the wide angle XRD pattern regarding the comparison of the prepared particle | grains and CaDDS. It is a figure which shows the low angle XRD pattern of the particle | grains prepared with various surfactant density | concentrations. FIG. 3 is a diagram showing wide-angle XRD patterns of particles prepared with various surfactant concentrations. It is a figure explaining the processing flow concerning this embodiment.

Claims (16)

A method for producing calcium phosphate particles,
A molecular template forming step of forming a vesicle-shaped molecular template in a liquid by mixing a cationic surfactant molecule and an anionic surfactant molecule;
A method for producing calcium phosphate particles, comprising a step of reacting a calcium source and a phosphate source on the surface of a surfactant molecule forming the molecular template to generate calcium phosphate. A method for producing calcium phosphate particles according to claim 1,
The method for producing calcium phosphate particles, wherein the calcium phosphate is apatite. A method for producing calcium phosphate particles according to claim 1 or 2,
The method for producing calcium phosphate particles, wherein the apatite is hydroxyapatite. A method for producing calcium phosphate particles according to any one of claims 1 to 3,
The method for producing calcium phosphate particles, wherein the calcium source is at least one salt selected from the group consisting of calcium nitrate, calcium carbonate, calcium chloride, calcium hydroxide, calcium acetate and the like. A method for producing calcium phosphate particles according to any one of claims 1 to 4,
The phosphoric acid source is selected from the group consisting of phosphoric acid, primary sodium phosphate, secondary sodium phosphate, primary potassium phosphate, secondary potassium phosphate, primary ammonium phosphate, secondary ammonium phosphate, etc. The manufacturing method of the calcium-phosphate particle | grains which are 1 or more types of salt made. A method for producing calcium phosphate particles according to any one of claims 1 to 5,
A method for producing calcium phosphate particles, wherein the molecular template has a particle size of 20 nm to 200 nm. A method for producing calcium phosphate particles according to any one of claims 1 to 6,
The manufacturing method of the calcium phosphate particle whose reaction time in the said production | generation process is 60 minutes-90 minutes. A method for producing calcium phosphate particles according to any one of claims 1 to 7,
Depending on the correlation between the composition ratio of the cationic surfactant molecule and the anionic surfactant molecule determined in advance and the formation rate of calcium phosphate, the desired cationic surfactant molecule and the anionic surfactant are obtained. The manufacturing method of a calcium phosphate particle including the selection process which selects a composition ratio with an agent molecule | numerator. A method for producing calcium phosphate particles according to any one of claims 1 to 8,
The said phosphoric acid source is a manufacturing method of the calcium phosphate particle containing (phosphite) phosphate ester. A method for producing calcium phosphate particles according to claim 9,
A method for producing calcium phosphate particles using triethyl phosphite: P (OC ₂ H ₅ ) ₃ as the (phosphite) ester. Substantially spherical calcium phosphate particles having a particle size of 40 nm to 200 nm,
And the substantially spherical calcium phosphate particle which has a hollow structure. Substantially spherical calcium phosphate particles having a particle size of 500 nm to 2000 nm and a hollow structure. The substantially spherical calcium phosphate particles according to claim 11 or 12,
The substantially spherical calcium phosphate particles, wherein the calcium phosphate is apatite. The substantially spherical calcium phosphate particles according to claim 13,
The said apatite is a substantially spherical calcium phosphate particle which is a hydroxyapatite. When producing calcium phosphate particles by reacting a phosphate source with a calcium source,
Use of (phosphite) phosphate ester as the phosphate source.   A phosphate source for reacting a phosphate source with a calcium source to produce calcium phosphate particles, and comprising a (phosphite) phosphate ester.