JP5257646B2 - Dispersion, dispersion manufacturing method, calcium phosphate hollow particle manufacturing method, calcium phosphate porous body manufacturing method, calcium phosphate composite fine particle manufacturing method, and use thereof - Google Patents

Description

  The present invention relates to a dispersion, a calcium phosphate hollow particle, a calcium phosphate porous body, a calcium phosphate composite fine particle, a production method thereof, and use thereof. More specifically, it does not contain a dispersant other than calcium phosphate, and is a stable dispersion, and calcium phosphate hollow particles, porous calcium phosphate, calcium phosphate composite fine particles produced using the dispersion, and production methods thereof, As well as their use.

  Conventionally, calcium phosphate (hereinafter referred to as “CaP”) typified by hydroxyapatite (hereinafter referred to as “HAp”) has been used in various modes.

  For example, CaP particles are used as a dispersant for suspension polymerization.

Patent Documents 1 and 2 propose a method of producing a dispersion in which styrene is suspended in water using CaP as a dispersion stabilizer when suspension polymerization of styrene is performed. In Patent Document 3, a dispersion of a vinyl compound monomer is prepared by using CaP and a surfactant together as a suspension stabilizer, and then the suspension polymerization reaction system is heat-treated, whereby the suspension of the vinyl compound is treated. A method for carrying out turbid polymerization has been proposed. Patent Document 4 proposes a method for producing an apatite sol useful as a dispersant for suspension polymerization. Patent Document 5 proposes a method for producing a stabilizer for suspension polymerization in which an apatite slurry having CaO / P ₂ O ₅ of 1.30 (Ca / P = 1.66 molar ratio) is subjected to a powerful shear dispersion treatment.

  Further, CaP hollow particles and porous bodies are attracting attention for their use as pharmaceutical carriers and catalyst carriers. For example, the following method has been proposed as a method for producing CaP hollow particles.

  Non-Patent Document 1 discloses a method for producing CaP hollow particles by spray drying a CaP raw material aqueous solution and adjusting conditions such as a raw material concentration and a spray speed.

  In Non-Patent Document 2 and Patent Document 6, the surface of the vaterite-type (dissolved in water) calcium carbonate particles produced in advance is phosphorylated in a methanol medium to coat the calcium carbonate with calcium phosphate, Thereafter, a method for producing hollow CaP fine particles by dissolving calcium carbonate in water is disclosed.

  In Non-Patent Document 3, an ionic polymer hollow particle produced by forming a laminated film of an ionic polymer on the surface of a previously produced manganese carbonate particle and then dissolving and removing the manganese carbonate with an aqueous hydrochloric acid solution. A method for producing CaP hollow particles by precipitating calcium phosphate on the walls of the ionic polymer hollow particles using the above is disclosed.

  As a method for producing a CaP porous body, the following methods have been proposed.

  Non-Patent Document 4 discloses a method for producing porous CaP particles having a plurality of cavities therein by precipitating CaP on the surface of a lithium borate-calcium porous glass particle produced in advance. ing.

  In Patent Document 7, gelation is performed by adding an alkali to an acidic collagen aqueous solution, and then carbonated apatite particles are mixed to obtain a hydrous composite gel composed of carbonate apatite and collagen, and the obtained hydrous composite gel is centrifuged. A method of obtaining a sponge-like porous carbonate apatite / collagen composite by removing water appropriately through a separator, freezing, and then freeze-drying is disclosed.

  Non-Patent Document 5 and Patent Document 8 disclose a method for producing porous CaP by mixing carbon beads having a particle diameter of about 150 μm and fibrous CaP and firing the mixture at 1300 ° C. for 5 hours to burn carbon. ing.

  Patent Document 9 discloses a method for producing a porous dry body by freezing a slurry in which ceramic powder and an additive having a specific functional group are dispersed in water from one direction, and sublimating the frozen water under reduced pressure. It is disclosed.

  In Non-Patent Document 6, HAp is precipitated in the aqueous phase of an olive oil dispersion stabilized with casein protein, filtered under reduced pressure, dried to separate water, and then extracted with hexane or supercritical carbon dioxide. Thus, a method for producing an HAp-containing porous body is disclosed.

By the way, in recent years, CaP has attracted attention as a biomaterial because of its high biocompatibility. Therefore, a dispersion using CaP as described above, hollow particles of CaP (hereinafter simply referred to as “CaP hollow particles”), porous body of CaP (hereinafter simply referred to as “CaP porous body”). Is expected as a mode of expanding the use of CaP as a biomaterial.
Japanese Patent Publication No. 29-1298 (announced March 11, 1954) JP 30-30490 (announced September 13, 1955) Shoko 47-23666 (announced July 1, 1972) JP 2006-82985 (published March 30, 2006) JP 7-102005 (April 18, 1995) JP-A-11-171514 (released June 29, 1999) JP2003-169845 (released on June 17, 2003) JP-A-2004-284933 (released on October 14, 2004) JP 2005-1943 (released January 6, 2005) P. Luo, TG Nieh, Preparing hydroxyapatite powders with controlled morphology, Biomaterials, 1996, vol. 17, 1959-1964 Hiroki Ueda, Kuniyuki Nitta, Takuya Nakajima, Yoichi Hirohama, Hidemitsu Kasahara, Minoru Hanasaki, Goro Genyoshi, Creation of morphology-controlled hydroxyapatite using calcium carbonate as a seed, inorganic materials, 1998, vol. 5, 28-35 DG Shchukin, GB Sukhorukov, H. Mohwald, Biomimetic fabrication of nanoengineered hydroxyapatite / polyelectrolyte composite shell, Chem. Mater., 2003, vol. 15, 3947-3950. Q. Wang, W. Huang, D. Wang, BW Darvell, DE Day, MN Rahaman, Preparation of hollow hydroxyapatite microspheres, Journal of Materials Science.Materials in Medecine, 2006, vol. 17, 641-646. Mamoru Aizawa, Hiroko Ueno, Kiyoji Itaya, Fabrication of porous sheet for cell culture using fibrous apatite, Material integration, 1999. vol. 12 pp. 75-77. C. Ritzoulis, N. Scoutaris, K. Papademetriou, S. Stavroulias, C. Panayiotou, Milk protein-base emulsion gels for bone tissue engineering, Food Hydrocolloids, 2005, vol. 19, 575-581.

  However, when producing a dispersion using the conventional CaP, it is necessary to add a surfactant in addition to CaP.

  For example, Patent Documents 1 and 2 require the use of HAp in combination with a surfactant, polyphosphate, or the like in order to improve the reproducibility and reliability of HAp as a dispersion stabilizer. In Patent Document 3, CaP and a surfactant are used in combination. In Patent Document 4, sodium hexametaphosphate is added to the apatite sol. In Patent Document 5, sodium dodecylbenzenesulfonate is added when an apatite slurry is used as a stabilizer for suspension polymerization. In Patent Document 5, since an expensive facility called an ultra-high pressure emulsifier / disperser is required, the apatite slurry becomes expensive.

  Thus, in the dispersion using conventional CaP, a surfactant or the like is added. That is, there has been no conventional report on a dispersion using only CaP as a dispersant and no other surfactant.

  Further, as a result of investigation by the present inventors, in the dispersion using the conventional CaP, the water component and the oil component dispersed in the dispersion are collected in about 1 to 12 hours, and the dispersion takes a long time. A stable structure cannot be maintained.

  This causes troubles when a dispersion using CaP is used as a biomaterial such as a drug carrier. For example, when a poorly water-soluble drug is administered into the body, even if a dispersion of a poorly water-soluble drug is prepared using CaP, it cannot be stored for a long period of time. Need to be administered. In addition, when the dispersion is broken early in the living body, the poorly water-soluble drug is separated, and the absorption efficiency may be reduced.

  Furthermore, since the surfactant is a component that may be toxic to the living body, using a dispersion in which CaP and the surfactant are used in combination may cause toxicity to the living body. For example, even if the dispersion of the above-mentioned poorly water-soluble drug is produced by a conventional method using CaP, it is necessary to use a low molecular surfactant (low molecular dispersion stabilizer). However, as described above, surfactants may be toxic. Therefore, it is desired to produce a dispersion using only CaP without using a surfactant or the like.

  In order to solve these problems, a technique for stabilizing the dispersion by using only CaP as a dispersant and allowing CaP to be efficiently adsorbed on the surface of oil droplets is required. However, such a technique has not existed conventionally.

  By the way, conventional CaP hollow particles and porous bodies require complicated operations for their production. Moreover, it has a problem that it cannot be applied to a living body because of its unstable structure.

  For example, in the method for producing CaP hollow particles described in Non-Patent Document 1, since a spray drying apparatus is required, the production cost is increased. Moreover, since calcium phosphate precipitates in the sprayed water droplets and moves to the surface of the water droplets, a hollow structure is formed, so that reproducibility is poor. Moreover, there is a possibility that the shell of CaP becomes thick because CaP gathered on the surface of the water droplet becomes a framework and maintains the hollow structure.

  The vaterite-type calcium carbonate described in Non-Patent Document 2 and Patent Document 6 does not exist in nature and is a very unstable crystal. In addition, the production of the vaterite type calcium carbonate is low in reproducibility, and the vaterite type calcium carbonate is difficult to store. Furthermore, since the vaterite type calcium carbonate contains a large amount of carbonate ions, the solubility of the hollow CaP fine particles in water increases. Therefore, in the step of dissolving calcium carbonate in water, the hollow CaP fine particles are also dissolved, and the production efficiency is lowered. Moreover, since it will melt | dissolve rapidly in the living body, when it is highly water-soluble, it cannot be used as a biomaterial.

  The hollow particles described in Non-Patent Document 3 are a mixture of an ionic polymer and CaP. Since some of these ionic polymers are toxic to living organisms, they are inappropriate as biomaterials. In addition, the number of steps required for producing the hollow particles is large, and the cost is increased.

  The porous CaP particles described in Non-Patent Document 4 are a mixture of glass and CaP. Since glass is not absorbed by the living body, the porous CaP particles cannot be used as a biomaterial.

  The sponge-like porous carbonate apatite-collagen complex described in Patent Document 7 requires collagen that may transmit infectious diseases, and therefore cannot be actively used as a biomaterial.

  Since the dispersibility of the carbon beads used in the method for producing porous CaP described in Non-Patent Document 5 and Patent Document 8 is low, the carbon beads tend to aggregate locally. Therefore, there is a problem that the distribution of pores formed in CaP by burning carbon beads tends to be non-uniform. In order to use porous CaP as a biomaterial, it is necessary to ensure a certain property. However, if the pores are non-uniform in this way, the reproducibility of the property to be exhibited is low and it is not suitable as a biomaterial.

  In the method for producing a porous dry body described in Patent Document 9, frozen water that forms pores on the porous dry body is frozen from one direction. Therefore, only pores connected in only one direction are formed on the porous dry body, and the adsorptivity and the like generally required for porous materials are inferior. Moreover, it is necessary to freeze the slurry and further sublimate the frozen water under reduced pressure. For this reason, a manufacturing process is complicated and manufacturing requires a long time.

  Non-Patent Document 6 contains many components other than HAp, such as casein protein, and therefore it is difficult to exhibit the surface properties of HAp such as biological tissue adhesion and ion adsorption. Moreover, since it is highly soluble, it cannot be used as a biomaterial.

  As described above, the dispersion, the CaP hollow particles, and the CaP porous body in which the conventional CaP is used may be difficult to use in a living body, and have problems such as a complicated manufacturing process. ing.

  The present invention has been made in view of the above problems, and an object of the present invention is to provide a method for easily producing a stable dispersion without using a dispersant other than CaP such as a surfactant. Then, it is providing the dispersion body, CaP hollow particle, and CaP porous body which are safe with respect to a biological body.

  In order to solve the above problems, the dispersion according to the present invention is a dispersion containing a hydrophilic liquid, a hydrophobic substance, and calcium phosphate, and the hydrophobic substance includes a saturated organic compound having a carbonyl group, a carbonyl group It is characterized in that it is a substance containing at least one compound selected from the group consisting of vinylene compounds having a carbonyl group, cyclic olefins having a carbonyl group, and alkanes.

  According to the above configuration, in the dispersion, one of the hydrophilic liquid and the hydrophobic substance is present as a dispersion medium, the other as a dispersoid, and CaP as a dispersant. That is, a substance containing at least one compound selected from a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane has a molecule capable of interacting with CaP. Since it has inside, CaP adsorb | sucks stably to the interface of a hydrophilic liquid and the said hydrophobic substance. Therefore, CaP functions as a dispersant and can form a dispersion.

  For this reason, the dispersion according to the present invention can be easily produced without requiring the use of a dispersant other than CaP, such as a surfactant.

  In addition, the dispersion according to the present invention is extremely stable because the dispersoid in the dispersion does not assemble for 24 hours or more.

  Furthermore, even a hydrophobic substance that does not form a dispersion with a mixture of CaP and a hydrophilic liquid may be a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane. By dissolving a substance containing at least one compound selected from the above, a dispersion can be easily formed without using a surfactant or the like.

  Therefore, since it can be easily produced, a dispersion having a low cost and a stable structure and containing no surfactant can be provided.

  In the dispersion according to the present invention, the saturated organic compound having a carbonyl group is more preferably a saturated fatty acid ester.

  According to the above configuration, CaP is attracted to the interface between the saturated fatty acid ester and the hydrophilic liquid by electrostatic interaction between the carbonyl group and the calcium ion or phosphate ion on the surface of the CaP. It is more stable and dense. Therefore, a more stable dispersion can be provided.

  In the dispersion according to the present invention, the saturated organic compound having a carbonyl group is more preferably methyl myristate.

  According to the above configuration, CaP is stable and has a high concentration at the interface between the hydrophilic liquid and methyl myristate because an electrostatic interaction between the carbonyl group and the calcium ion on the surface of CaP generates an attractive force. Can be compact. Therefore, a more stable dispersion can be provided.

  In the dispersion according to the present invention, the alkane is more preferably at least one alkane selected from the group consisting of alkanes having 5 to 30 carbon atoms.

  According to the above configuration, CaP can be stably and densely concentrated at the interface between the hydrophilic liquid and the alkane having 5 to 30 carbon atoms. Therefore, a more stable dispersion can be provided.

  In the dispersion according to the present invention, the alkane is more preferably dodecane and / or hexane.

  According to the above configuration, CaP can be stably and densely concentrated at the interface between the hydrophilic liquid and n-dodecane or n-hexane. Therefore, a more stable dispersion can be provided. In addition, when it describes with "A and / or B" in this specification, it shall mean A, B, or A and B.

  In the dispersion according to the present invention, the saturated organic compound having a carbonyl group is more preferably a biodegradable polymer having a carbonyl group.

  According to said structure, even if it is a case where the hydrophobic substance which cannot form a dispersion even if it mixes with the mixture of CaP and a hydrophilic liquid is used, without using surfactant etc., a dispersion Can be formed. Furthermore, by using a biodegradable polymer as a saturated organic compound having a carbonyl group, the biocompatibility and safety of the resulting dispersion can be improved. Therefore, it is possible to provide a dispersion that can be obtained easily and has higher biocompatibility and safety.

  Even when a hydrophobic substance that cannot form a dispersion even when mixed with a mixture of CaP and a hydrophilic liquid is used, an interface can be obtained by using a liquid in which a biodegradable polymer having a carbonyl group is dissolved. The knowledge that a dispersion can be easily formed without using an activator or the like has not been known so far, and it is a fact that a person skilled in the art cannot expect. The above findings have been found for the first time by the inventors' diligent efforts and unique ideas. Therefore, it can be said that the present invention includes a technical idea based on the above-described novel findings.

  In the dispersion according to the present invention, the biodegradable polymer is more preferably polylactic acid.

  According to said structure, polylactic acid has high biocompatibility and the safety | security with respect to a biological body. In addition, an electrostatic interaction between a carbonyl group contained in polylactic acid and calcium ions on the surface of CaP generates an attractive force, so that the interface between the hydrophobic substance in which polylactic acid is dissolved and the hydrophilic liquid is placed on the CaP. Can exist densely and stably. Furthermore, polylactic acid is available at low cost among biodegradable polymers. Accordingly, a stable dispersion having high biocompatibility and safety can be provided at a low cost.

  In the dispersion according to the present invention, the calcium phosphate is more preferably calcium phosphate having an average particle diameter of 1 nm to 1000 nm.

  According to said structure, since nanometer size CaP is used, the particle | grains of CaP can exist more densely in the interface of a hydrophilic liquid and a hydrophobic substance. Therefore, a more efficient and stable dispersion can be provided.

  In the dispersion according to the present invention, the calcium phosphate is more preferably hydroxyapatite.

  According to said structure, since HAp close | similar to the bone | frame and tooth | gear component of a biological body is used, the dispersion | distribution which further improved biocompatibility and safety | security can be provided.

  In the dispersion according to the present invention, the calcium phosphate is more preferably a sintered body of hydroxyapatite.

  According to the above configuration, the HAp sintered body that is close to the bone and tooth components of the living body and whose structure is stabilized by sintering is used, so that biocompatibility and safety are high, and stable dispersion is achieved. The body can be provided.

  In the dispersion according to the present invention, the hydrophilic liquid or the hydrophobic substance as a dispersion medium is a dispersion containing the first droplet and the second droplet in the dispersion medium, and the first droplet is Of the hydrophilic liquid and the hydrophobic substance, the one that is not the dispersion medium is coated with the calcium phosphate, and is dispersed in the dispersion medium. When the dispersion medium is the hydrophilic liquid, the hydrophilic liquid is coated, and when the dispersion medium is the hydrophobic substance, the hydrophobic substance is coated with the calcium phosphate. It may be dispersed in one drop.

  According to said structure, the droplet is further disperse | distributing in the droplet disperse | distributed in the dispersion medium. By using such a dispersion, for example, particles in which useful substances are dispersed can be easily produced. That is, by dissolving an arbitrary substance in a hydrophilic liquid or a hydrophobic substance that is further dispersed in the droplets dispersed in the dispersion medium and evaporating the dispersion medium, the particles are Can be obtained. And in said structure, since such a particle | grain is obtained even if surfactant is not used, it is suitable as a biomaterial.

  In order to solve the above problems, a method for producing a dispersion according to the present invention is a method for producing a dispersion containing a hydrophilic liquid, a hydrophobic substance, and calcium phosphate, and includes a saturated organic compound having a carbonyl group, a carbonyl group And a hydrophobic substance containing at least one compound selected from a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane, a hydrophilic liquid, and calcium phosphate.

  According to the above configuration, it is possible to produce a dispersion in which one of the hydrophilic liquid and the hydrophobic substance is used as a dispersion medium, the other is used as a dispersoid, and CaP is present as a dispersant. And the said dispersion body can be simply manufactured, without using dispersing agents other than CaP, such as surfactant. Furthermore, the dispersion is extremely stable with no dispersoid in the dispersion assembled for 24 hours or more. Further, even when a hydrophobic substance that cannot form a dispersion even when mixed with a mixture of CaP and a hydrophilic liquid is used, a surfactant or the like can be obtained by dissolving a saturated organic compound having a carbonyl group. A dispersion can be easily produced without using the. Furthermore, the dispersion can be produced simply by mixing a hydrophilic liquid, a hydrophobic substance, and CaP. Therefore, a stable dispersion can be easily produced.

  In the method for producing a dispersion according to the present invention, the dispersion contains at least one compound selected from a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane. A dispersion in which the first droplets are dispersed in the dispersion medium, and the second droplets are dispersed in the first droplet, using a hydrophobic substance or a hydrophilic liquid as a dispersion medium, By mixing the hydrophobic substance, the hydrophilic liquid, and the calcium phosphate to make the dispersion medium the hydrophilic liquid, the hydrophilic liquid is used, and the dispersion medium is the hydrophobic substance. Wherein the second droplet formed by coating the hydrophobic substance with the calcium phosphate is dispersed in the hydrophilic liquid and the hydrophobic substance that is not the dispersion medium. A first droplet formed by coating the first dispersion with calcium phosphate by mixing the first mixing step for producing the dispersion, the first dispersion, the dispersion medium, and the calcium phosphate. May include a second mixing step of producing a second dispersion dispersed in the dispersion medium.

  According to said structure, the dispersion in which the droplet further disperse | distributed in the droplet disperse | distributed in the dispersion medium can be simply manufactured by performing the mixing process twice.

  In the method for producing a dispersion according to the present invention, it is more preferable to use a hydrophobic material in which a saturated organic compound having a carbonyl group is mixed in advance.

  According to said structure, even if it is a case where the hydrophobic substance which cannot form a dispersion even if it mixes with the mixture of CaP and a hydrophilic liquid is used, the saturated organic compound which has a carbonyl group is said hydrophobic substance Dispersing the composition in a solution makes it possible to easily produce a dispersion without using a surfactant or the like.

  In order to solve the above problems, a method for assembling a dispersoid according to the present invention includes a hydrophilic liquid, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane. A hydrophobic substance containing at least one compound selected from the group consisting of calcium phosphate and one of the hydrophilic liquid and the hydrophobic substance as a dispersion medium, the other as a dispersoid, and calcium phosphate as a dispersant. It is characterized by mixing an acidic compound into the dispersion.

  According to said structure, pH of a hydrophilic liquid falls by mixing an acidic compound. CaP is suitably dissolved in an acid, particularly a liquid having a pH of less than 5. Therefore, when the pH of the hydrophilic liquid is lowered, CaP adsorbed on the interface between the hydrophilic liquid and the hydrophobic substance is dissolved in the hydrophilic liquid. Then, the droplets of the hydrophobic substance dispersed in the hydrophilic liquid or the drops of the hydrophilic liquid dispersed in the hydrophobic substance cannot maintain the shape of the drops. Therefore, the dispersoid in the dispersion can be easily assembled by adding the acidic compound.

  If the method for collecting dispersoids according to the present invention is used, for example, it becomes easy to recover crude oil with high viscosity, which is difficult to be pumped by an underground pump. First, water and CaP are mixed with crude oil to form a dispersion to lower the viscosity. Here, when a dispersion is not formed only by mixing CaP, a dispersion is formed by mixing a saturated organic compound having a carbonyl group dissolved in the oil and then mixing CaP. And after pumping up the said dispersion body with a pump etc. and moving to a collection tank etc., an acidic compound is mixed and a water component and an oil component are separated and collection | recovery of only an oil component is made easy.

  Moreover, according to said structure, since it becomes possible to discharge | release the oil inside a dispersion by dissolving CaP under acidic conditions, it is applicable as a carrier of a drug delivery system.

  In order to solve the above problems, the method for redispersing a dispersoid according to the present invention includes a hydrophilic liquid, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having an carbonyl group, and an alkane. A hydrophobic substance containing at least one compound selected from the group consisting of calcium phosphate and one of the hydrophilic liquid and the hydrophobic substance as a dispersion medium, the other as a dispersoid, and calcium phosphate as a dispersant. An alkaline compound is mixed with the liquid in which the dispersoid is collected by mixing an acidic compound with the dispersion.

  According to said structure, pH of a hydrophilic liquid becomes high by mixing an alkaline compound. Since CaP is difficult to dissolve in a liquid having a pH of 5 or more, it precipitates from the hydrophilic liquid. Therefore, CaP is adsorbed at the interface between the hydrophilic liquid and the hydrophobic substance so as to be concentrated. Therefore, by mixing the alkaline compound, the dispersoid is dispersed again in the dispersion medium to obtain a dispersion. be able to.

  For example, if the method for redispersing a dispersoid according to the present invention is used, CaP used for recovering the oil described above can be reused. That is, in the method for assembling a dispersoid according to the present invention described above, a hydrophilic liquid that is acidic and dissolves CaP is mixed with crude oil. In addition, a dispersion can be formed by adding an alkaline compound and mixing by stirring. Therefore, the oil can be recovered in the same manner as the oil recovery method described in the method for collecting dispersoids according to the present invention described above.

The method for producing calcium phosphate hollow particles according to the present invention is characterized by including the following steps (i) and (ii) in order to solve the above problems:
(i) a hydrophilic substance, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and a hydrophobic substance containing at least one compound selected from alkane, and calcium phosphate And a step of producing a dispersion by mixing with
(ii) A step of firing the dispersion.

  According to the above configuration, the hydrophilic liquid and the hydrophobic substance contained in the dispersion are removed, and the fired CaP remains. And the CaP hollow particle which has the empty hole derived from the droplet currently formed with CaP can be obtained.

  Therefore, it is possible to provide CaP hollow particles that are formed of highly bioabsorbable CaP and have fine pores.

  In the method for producing calcium phosphate hollow particles according to the present invention, it is more preferable to include (iii) a step of drying the dispersion before the step (ii).

  By drying the dispersion, the dispersion medium in the dispersion is removed by evaporation. And it can prevent that hollow particle fuse | melts by baking after removing the said dispersion medium. Moreover, it can prevent that the shape of a CaP hollow particle collapses by raising the temperature of the heat added to CaP in steps.

  In order to solve the above-mentioned problems, the calcium phosphate hollow particles according to the present invention are calcium phosphate hollow particles obtained by the above-described method for producing calcium phosphate hollow particles according to the present invention.

  According to said structure, the CaP hollow particle which is formed with the bioabsorbable CaP and has a fine hole can be provided.

The method for producing a porous calcium phosphate according to the present invention is characterized by including the following steps (iv) to (vi) in order to solve the above problems:
(iv) a hydrophobic substance containing at least one compound selected from a hydrophilic liquid, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane, and calcium phosphate And a step of producing a dispersion by mixing with
(v) concentrating droplets dispersed in the dispersion;
(vi) A step of firing the dense droplets.

  According to the above configuration, the hydrophilic liquid and the hydrophobic substance in the dispersion are removed by evaporation by baking, and only CaP remains. And CaP particle | grains are fuse | melted by baking in a dense state so that CaP particle | grains may contact, and a CaP porous body can be obtained.

  Moreover, since CaP which forms the said CaP porous body is CaP which coat | covered the fine droplet disperse | distributed in a dispersion, it has many holes about the magnitude | size of the said droplet.

  Therefore, a CaP porous body formed of CaP having high bioabsorbability and having many fine pores can be easily obtained.

  In the method for producing a calcium phosphate porous body according to the present invention, it is more preferable to include (vii) a step of drying the dispersion before the step (vi).

  By drying the dispersion, the temperature of the heat applied to CaP increases stepwise, so that the CaP porous body can be prevented from collapsing.

  In order to solve the above problems, the calcium phosphate porous body according to the present invention is a calcium phosphate porous body obtained by the above-described method for producing a calcium phosphate porous body according to the present invention.

  According to said structure, the CaP porous body which is formed with highly bioabsorbable CaP and has many fine pores can be provided.

In order to solve the above problems, a method for producing calcium phosphate composite fine particles according to the present invention is a method for producing calcium phosphate composite fine particles in which an arbitrary substance is coated with calcium phosphate, and includes the following (viii) and (ix) It is characterized by including steps:
(Viii) a hydrophobic liquid containing at least one compound selected from a hydrophilic liquid, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane, and calcium phosphate And a step of producing a dispersion by mixing with
(Ix) A step of drying the dispersion.

  According to the above configuration, by preparing a dispersion in which an arbitrary substance is dissolved in a hydrophilic liquid or a hydrophobic substance, and drying the dispersion according to the purpose, the arbitrary substance is made of CaP. Coated CaP composite fine particles can be produced. Therefore, it is possible to provide CaP composite fine particles in which various kinds of substances are coated with CaP. Since CaP is excellent in biocompatibility, even if the arbitrary substance is a drug having low biocompatibility, the arbitrary substance can be taken into the living body.

  Therefore, it is possible to provide a CaP composite fine particle that can favorably adhere a substance having low biocompatibility to a living body and can be easily produced.

  In the method for producing calcium phosphate composite fine particles according to the present invention, the dispersion produced in the step (viii) comprises a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having an carbonyl group, and an alkane. The first droplet is dispersed in the dispersion medium using a hydrophobic substance containing at least one compound selected from the above or a hydrophilic liquid as the dispersion medium, and the second droplet is dispersed in the first droplet. Is a dispersion in which the step (viii) comprises mixing the hydrophobic substance, the hydrophilic liquid, and the calcium phosphate to make the dispersion medium the hydrophilic liquid. When the hydrophilic liquid is the hydrophobic substance and the dispersion medium is the hydrophobic substance, the second droplet formed by coating the hydrophobic substance with the calcium phosphate contains the hydrophilic liquid and the hydrophilic liquid. A first mixing step of forming a first dispersion that is dispersed in the non-dispersion medium of the aqueous material, mixing the first dispersion, the dispersion medium, and the calcium phosphate; A first mixing step in which the first droplet formed by coating the first dispersion with calcium phosphate forms a second dispersion that is dispersed in the dispersion medium. In the step, the manufacturing method may be such that at least one of the hydrophilic liquid and the hydrophobic substance is mixed with the arbitrary substance in advance.

  According to said structure, the calcium-phosphate composite microparticles | fine-particles in which the useful substance was disperse | distributed inside can be manufactured easily. For example, if an arbitrary substance is dissolved in a hydrophilic liquid or a hydrophobic substance that is further dispersed in drops dispersed in a dispersion medium, and the dispersion medium is evaporated, the calcium phosphate composite fine particles It can be manufactured easily. Moreover, since it is not necessary to use a surfactant, calcium phosphate composite fine particles suitable as a biomaterial can be obtained.

  In the method for producing calcium phosphate composite fine particles according to the present invention, in the step (viii), the arbitrary substance is preferably mixed in advance with the hydrophilic liquid or the hydrophobic substance.

  According to the above configuration, the arbitrary substance is dissolved in the hydrophilic liquid or the hydrophobic substance in advance after being sufficiently mixed and dissolved, so that the arbitrary substance is dissolved. It is possible to suppress loss due to remaining without increasing the productivity of the CaP composite fine particles.

  In order to solve the above problems, the calcium phosphate composite fine particles according to the present invention are calcium phosphate composite fine particles obtained by the above-described method for producing calcium phosphate composite fine particles according to the present invention.

  According to said structure, the substance with low biocompatibility can be made to make good affinity with a biological body, and the CaP composite fine particle which can be manufactured simply can be provided.

  In order to solve the above-mentioned problems, the biomaterial according to the present invention includes the dispersion according to the present invention.

  According to said structure, since the dispersion using CaP excellent in biocompatibility is included, the biomaterial excellent in biocompatibility can be provided.

  Moreover, in order to solve the said subject, the biomaterial which concerns on this invention is characterized by including the calcium-phosphate porous body which concerns on said this invention.

  According to said structure, since the CaP porous body excellent in biocompatibility is included, the biomaterial excellent in biocompatibility can be provided.

  Moreover, in order to solve the said subject, the biomaterial which concerns on this invention is characterized by including the calcium-phosphate hollow particle which concerns on said this invention.

  According to said structure, since the CaP hollow particle excellent in biocompatibility is included, the biomaterial excellent in biocompatibility can be provided.

  Moreover, in order to solve the said subject, the biomaterial which concerns on this invention is characterized by including the calcium-phosphate composite fine particle which concerns on said this invention.

  According to said structure, since the CaP composite fine particle excellent in biocompatibility is included, the biomaterial excellent in biocompatibility can be provided.

  The drug carrier according to the present invention is characterized by including the biomaterial according to the present invention as described above in order to solve the above problems.

  According to said structure, since the biomaterial which concerns on the said invention is included, the drug carrier excellent in biocompatibility can be provided.

  The cell culture material according to the present invention is characterized by including the biomaterial according to the present invention described above in order to solve the above-described problems.

  According to said structure, since the biomaterial which concerns on the said invention is included, the cell culture material excellent in biocompatibility can be provided.

  The medical material according to the present invention is characterized by including the biomaterial according to the present invention described above in order to solve the above-described problems.

  According to said structure, since the biomaterial which concerns on the said invention is included, the medical material excellent in biocompatibility can be provided.

  The dental material according to the present invention includes the biomaterial according to the present invention as described above in order to solve the above-described problems.

  According to said structure, since the biomaterial which concerns on the said invention is included, the dental material excellent in biocompatibility can be provided.

  As described above, according to the dispersion according to the present invention and the method for producing the dispersion according to the present invention, it is possible to provide a dispersion that can be easily produced, is stable, and does not contain a surfactant. There is an effect that can be.

  In addition, according to the method for assembling a dispersoid according to the present invention, there is an additional effect that the dispersoids in the dispersion can be easily assembled.

  In addition, according to the method for redispersing a dispersoid according to the present invention, the dispersoid can be dispersed again in a dispersion medium to obtain a further dispersion.

  Moreover, according to the manufacturing method of the calcium-phosphate hollow particle which concerns on this invention, there exists the further effect that the CaP hollow particle formed with the bioabsorbable CaP and having a fine hole can be provided.

  In addition, according to the method for producing a calcium phosphate porous body according to the present invention, a further effect that a CaP porous body formed of highly bioabsorbable CaP and having many fine pores can be easily obtained. Play.

  Further, according to the method for producing calcium phosphate composite fine particles according to the present invention, it is possible to provide a CaP composite fine particle that can favorably adhere a substance having low biocompatibility to the living body and can be easily produced. There is a further effect.

  Moreover, according to the present invention, there is a further effect that a biomaterial excellent in biocompatibility, particularly a drug carrier, a cell culture material, a medical material, and a dental material can be provided.

  The embodiment of the present invention will be described as follows. Note that the present invention is not limited to this.

[Dispersion and production method thereof according to the present invention]
The dispersion according to the present invention is a dispersion containing a hydrophilic liquid, a hydrophobic substance, and calcium phosphate. The hydrophobic substance includes a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, and a carbonyl group. Any substance containing at least one compound selected from cyclic olefins and alkanes may be used.

  That is, in the dispersion according to the present invention, one of the hydrophilic liquid and the hydrophobic substance serves as a dispersion medium, the other serves as a dispersoid, and CaP serves as a dispersant. For example, a hydrophilic liquid becomes a dispersion medium, a hydrophobic substance becomes a dispersoid, and CaP coats the surface of the hydrophobic substance to form droplets. In other words, it is possible to obtain a dispersion in which droplets of a hydrophobic substance coated with CaP are dispersed in a hydrophilic liquid. Similarly, a dispersion in which droplets of a hydrophilic liquid coated with CaP are dispersed can be obtained using a hydrophobic substance as a dispersion medium. Which dispersion can be obtained varies depending on the type and volume ratio of the hydrophilic liquid and the hydrophobic substance, temperature, pressure, container wall properties, and the like.

  Further, since CaP is stably and densely concentrated at the interface between the hydrophilic liquid and the hydrophobic substance, a stable dispersion containing no dispersant other than CaP, for example, a surfactant, can be obtained. For example, when the hydrophobic substance contains at least one compound among a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, and a cyclic olefin having a carbonyl group, the carbonyl group in the compound and the CaP surface Due to electrostatic interaction with the calcium ions, they attract each other and gather at the interface.

  In this specification, the “dispersion” means a substance containing fine particles and a medium, in which the fine particles are dispersed in the medium. Specifically, in the present specification, one of a hydrophilic liquid and a hydrophobic substance is a dispersion medium, and the other is a fine droplet as a dispersoid, which is dispersed in the dispersion medium. Further, in this specification, “dispersoid” means fine particles dispersed in a dispersion. Since the dispersoid dispersed in the dispersion medium is coated with CaP, the dispersoid dispersed in the dispersion and coated with CaP may be simply referred to as “droplets”. The “dispersion medium” means a medium in which fine particles are dispersed.

  In the present specification, the “hydrophilic liquid” means water or a liquid having affinity for water and capable of uniformly mixing an arbitrary amount with water.

  In the present specification, the “hydrophobic substance” means a substance such as a liquid, gel, solid, etc., which cannot uniformly mix an arbitrary amount with water, such as oil. In the present specification, the term “vinylene compound” and “cyclic olefin” refers to the “vinylene compound” and “cyclic olefin” described in Takayuki Otsu, Chemistry of Revised Polymer Synthesis, Chemistry Dojin, 1968, p. 35, respectively. Intended.

  The hydrophilic liquid contained in the dispersion according to the present invention is not particularly limited, and examples thereof include water, methanol, ethanol, etc. Among them, water is preferable. Water is easily available, has no burden on the human body and the environment, and when the dispersion is used for the production of a CaP porous body or the like described later, it is necessary to remove the hydrophilic liquid, This is because it is easy to remove water. Moreover, it is preferable that the pH of the hydrophilic liquid contained in the dispersion according to the present invention is high. Specifically, it is preferably 5 or more, more preferably 7.7 or more. CaP is soluble in a hydrophilic liquid having a low pH, but if the pH of the hydrophilic liquid is 5 or more, CaP can be prevented from dissolving in the hydrophilic liquid.

  The hydrophobic substance contained in the dispersion according to the present invention includes at least one compound selected from a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane. As long as it is a substance to be contained, it is not particularly limited. That is, the hydrophobic substance contained in the dispersion according to the present invention includes at least one selected from a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane. The compound itself may be sufficient and the said compound may be the substance mixed with the other hydrophobic substance by melt | dissolution or dispersion | distribution etc. Of these compounds, saturated organic compounds having a carbonyl group and alkanes are preferred. Hereinafter, for simplicity of explanation, “at least one compound selected from a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane” is simply referred to as “carbonyl group”. Saturated organic compound having

  The saturated organic compound having a carbonyl group is not particularly limited. For example, myristate such as methyl myristate, trimethyl acetate such as methyl trimethylacetate, pentyl acetate, isopentyl acetate, octyl acetate, etc. Acetic acid esters, propionic acid esters such as methyl propionate, methyl butyrate, ethyl butyrate, butyric acid esters such as pentyl butyrate, valeric acid esters such as pentyl valerate and pentyl valerate, salicylic acid esters such as methyl salicylate, ethyl caproate, etc. Caproic acid ester, etc., heptanoic acid ester, octanoic acid ester, nonanoic acid ester, decanoic acid ester, dodecanoic acid ester, tetradecanoic acid ester, pentadecanoic acid ester, hexadecanoic acid ester, heptadecanoic acid ester, octene Decanoic acid ester, nonadecanoic acid ester, icosanoic acid ester, docosanoic acid esters, tetracosanoic acid esters, hexacosanoic acid esters, octacosanoic esters, preferably saturated fatty acid ester of triacontanoic acid esters, inter alia methyl myristate is preferred. If a saturated fatty acid ester is used, the stability of the resulting dispersion is improved, and it is possible to obtain a stable dispersion in which a hydrophilic liquid and a hydrophobic substance are not separated even after a long period of time after production. it can. For example, when methyl myristate is used, a stable dispersion that can be stored for 6 months or more can be obtained.

  The alkane is not particularly limited, but is preferably an alkane having 5 to 30 carbon atoms, more preferably dodecane and hexane, and particularly preferably n-dodecane and n-hexane. If an alkane having 5 to 30 carbon atoms is used, the stability of the resulting dispersion is improved, and a stable dispersion in which the hydrophilic liquid and the hydrophobic substance are not separated even after a long period of time after production. You can get a body. In addition, alkanes that are liquid at normal temperature are preferred, but the alkane used is not limited as long as the alkane does not freeze the hydrophilic liquid because the freezing point of the used alkane is below the freezing point of the hydrophilic liquid used. Absent. In addition, since it is a liquid at normal temperature if it is C5-C17 alkane, it is easy to handle and the dispersion concerning this invention can be obtained simply. Moreover, even if it is C18-C30 alkane, if the said alkane is dissolved using another solvent and the said solvent is used, the dispersion concerning this invention can be obtained.

  In addition, even a hydrophobic substance that does not form a dispersion even when mixed with a mixture of a hydrophilic liquid and CaP is mixed by dissolving or dispersing the substance containing the saturated organic compound having the carbonyl group. Thus, when the hydrophobic substance is used, the dispersion according to the present invention can be obtained. The hydrophobic substance can maintain hydrophobicity even when mixed with a saturated organic compound having a carbonyl group, and can be uniformly mixed with the saturated organic compound having a carbonyl group. For example, dichloromethane, toluene, chloroform, 1-undecanol may be used, and a drug for treating inflammation described later may be used.

  The saturated organic compound having a carbonyl group to be mixed with a hydrophobic substance that does not form a dispersion even when mixed with the mixture of the hydrophilic liquid and CaP described above is not particularly limited. Preferably, it is a biodegradable polymer that is a saturated organic compound. Biodegradable polymers that are saturated organic compounds having a carbonyl group include polylactic acid (PLA), polyglycolic acid, polydioxanone, glycolide-lactide copolymer, glycolide-trimethylene carbonate copolymer, glycolide-ε-caprolactone copolymer. Polymer, poly-3-hydroxybutyric acid (PHB), 3-hydroxybutyric acid-3-hydroxyvaleric acid copolymer (PHBV), polybutylene succinate (PBS), polycaprolactone (PLC), cellulose acetate (PH) heavy Examples of the polymer include polyethylene succinate (PESu), polyester amide, and modified polyester. Among them, polylactic acid is preferable. If a biodegradable polymer is used, the biocompatibility such as bioabsorbability of the dispersion according to the present invention can be improved.

  In the case where a hydrophobic substance is used as the dispersion medium, when using a hydrophobic substance in which CaP is difficult to disperse, polylactic acid is mixed in advance with the hydrophobic substance, and CaP modified with polylactic acid is used as a dispersant. More preferably, it is used.

  The method for modifying CaP with polylactic acid is not particularly limited. For example, in the Example mentioned later, rod-shaped CaP was modified with polylactic acid by heat-treating a mixture of polylactic acid and rod-shaped CaP in a solid state. Further, heat treatment may be performed in a state where polylactic acid and rod-like CaP are dissolved or suspended in the solution, or polylactic acid may be grafted onto the CaP surface by polymerizing lactic acid (monomer) in the presence of CaP. . The method of modifying CaP with polylactic acid is described in X. Qui, L. Chen, J. Hu, J. Sun, Z. Hong, A. Liu, X. Chen, X. Jing, Journal of Polymer Science: Part A: Polymer Chemistry, 2006, Vol. 43 5177-5185, Z. Hong, P. Zhang, A. Liu, Li. Chen, X. Chen, Z. Jing, Journal of Biomedical Materials Research, 2007, Vol. 81A , 515-522, etc.

The form and type of CaP used in the dispersion according to the present invention are not particularly limited, and may be appropriately selected depending on the use of the dispersion. For example, HAp (Ca ₁₀ (PO ₄ ) ₆ ( _OH) 2), tricalcium phosphate _{(Ca 3 (PO 4) 2} ), calcium metaphosphate _{(Ca (PO 3) 2)} , Ca 10 (PO 4) 6 F 2, Ca 10 (PO 4) 6 Cl 2 , etc. Is mentioned. Among them, HAp is preferable because of high biocompatibility, and a sintered body of HAp is more preferable.

  The CaP is preferably nanometer-sized particles having an average particle diameter of 1 nm to 1000 nm. When nanometer-sized CaP particles are used, CaP is concentrated at a higher concentration and more stably at the interface between the hydrophilic liquid and the hydrophobic substance, so that a more stable dispersion can be obtained. Moreover, a dispersion having a small diameter of droplets dispersed in the dispersion can be obtained. The shape of the nanometer-sized CaP particles is not particularly limited, and may be appropriately selected from various shapes such as a spherical shape, a rod shape, and a fiber shape.

  The CaP may be artificially produced by a conventionally known production method such as a wet method, a dry method, a hydrolysis method, or a hydrothermal method, and may be naturally derived from bone, teeth, or the like. It may be. In addition, CaP may contain a compound in which a portion of CaP hydroxide ions and / or phosphate ions is substituted with carbonate ions, chloride ions, fluoride ions, and the like. For example, CaP produced by the method for producing CaP described in JP-A-2006-130007 can be used in the present invention.

  The nanometer-sized CaP particles may be obtained by a conventionally known method. For example, the nanometer-sized CaP particles may be obtained by mixing a phosphate such as ammonium phosphate with an aqueous solution of calcium salt such as calcium nitrate. At this time, it is preferable to select the calcium salt and the phosphate in a combination that does not cause precipitation other than CaP. Moreover, the particle | grains of CaP of various shapes can be obtained with the method and pH of adding a phosphate. If phosphate is added all at once, spherical CaP particles are obtained, and if alkaline phosphate solution is continuously dropped, rod-like CaP particles are obtained, and neutral phosphate solution is continuously added. Then, fiber-like CaP particles can be obtained.

  In the present specification, the “average particle diameter” is intended to mean the average of the diameters of the individual particles in the entire particle group, but in the case of rod-shaped particles or fiber-shaped particles, the long diameter of the individual particles. The average of the whole particle group and the average of the short diameter particle group of each individual particle. In the present specification, cage-like CaP particles are referred to as “rod-like particles”, and those having a major axis of 1 μm or more are referred to as “fiber-like particles”.

  The method for producing a dispersion according to the present invention may include a step of mixing a hydrophobic substance containing the saturated organic compound having a carbonyl group, a hydrophilic liquid, and calcium phosphate. For example, the dispersion according to the present invention can be produced by stirring the above-described hydrophilic liquid, hydrophobic substance, and CaP. The stirring may be performed by a conventionally known device or method. For example, a stirrer such as a homogenizer, a shaker, an ultrasonic emulsifying device, an electric emulsifying device, a shirasu porous glass membrane emulsifying device, a microchannel emulsifying device, or the like may be used. Well, you can shake it by hand. Further, the stirring conditions such as the stirring speed and the stirring time may be appropriately set according to the type of the hydrophilic liquid and the hydrophobic substance to be used.

  When producing a dispersion according to the present invention using a hydrophobic substance that does not form a dispersion even when mixed with the mixture of the hydrophilic liquid and CaP described above, the hydrophilic liquid, the hydrophobic substance, What is necessary is just to mix CaP, the saturated organic compound etc. which have the said carbonyl group etc. by melt | dissolving or disperse | distributing previously. In addition, the hydrophobic substance may be mixed with the saturated organic compound having the carbonyl group in advance.

  The volume ratio of the content of the hydrophilic liquid and the hydrophobic substance used in the method for producing a dispersion according to the present invention may be appropriately set according to the use of the dispersion and the type of the hydrophilic liquid and the hydrophobic substance. That's fine. When a hydrophilic liquid is used as a dispersion medium, the volume ratio is preferably 99.9: 0.1 to 40:60, and more preferably 99: 1 to 50:50. When a hydrophobic substance is used as a dispersion medium, the volume ratio of the hydrophilic liquid to the hydrophobic substance is preferably 0.1: 99.9 to 60:40, more preferably 1:99 to 50: 50. The combination of hydrophilic liquid and hydrophobic substance, which is the dispersion medium and which is the dispersoid, is also affected by the type of hydrophilic liquid and hydrophobic substance. The trader easily understands this point from the combination.

  The mass of CaP used in the method for producing a dispersion according to the present invention is preferably 0.01 to 20% by mass with respect to the mass of the liquid or substance used as a dispersion medium among the hydrophilic liquid and the hydrophobic substance. More preferably, it is 0.1 to 10% by mass.

  The dispersion according to the present invention is limited to a so-called O / W type dispersion or W / O type dispersion in which one of a hydrophilic liquid and a hydrophobic substance is used as a dispersion medium and the other is used as a dispersoid. Is not to be done. That is, the dispersion according to the present invention is a dispersion including the first droplet and the second droplet in the dispersion medium using the hydrophilic liquid or the hydrophobic substance as a dispersion medium. However, the one that is not the dispersion medium among the hydrophilic liquid and the hydrophobic substance is coated with the calcium phosphate and dispersed in the dispersion medium, and the second droplet However, when the dispersion medium is the hydrophilic liquid, the hydrophilic liquid is coated, and when the dispersion medium is the hydrophobic substance, the hydrophobic substance is coated with the calcium phosphate, It may be dispersed in the first droplet.

  As an embodiment of the dispersion, for example, a dispersion in which drops of a hydrophobic substance are dispersed in a hydrophilic liquid that is a dispersion medium, and drops of the hydrophilic liquid are dispersed in the drops of the hydrophobic substance. (Hereinafter referred to as “W / O / W type dispersion” for convenience of explanation). At this time, the hydrophilic liquid serving as the dispersion medium and the hydrophilic liquid dispersed in the droplets of the hydrophobic substance may be the same or different. Further, an arbitrary substance may be dissolved in the hydrophilic liquid dispersed in the droplets of the hydrophobic substance depending on the use of the dispersion.

  Further, as another embodiment, for example, a dispersion in which drops of a hydrophilic liquid are dispersed in a hydrophobic substance that is a dispersion medium, and drops of the hydrophobic substance are dispersed in the drops of the hydrophilic liquid. (Hereinafter referred to as “O / W / O type dispersion” for convenience of explanation). Similar to the W / O / W type dispersion, the hydrophobic substance serving as the dispersion medium and the hydrophobic substance dispersed in the droplets of the hydrophilic liquid may be the same or different. Also good. In addition, an arbitrary substance may be dissolved in the hydrophobic substance dispersed in the droplet of the hydrophilic liquid depending on the use of the dispersion.

  If a dispersion in which droplets are further dispersed in droplets dispersed in a dispersion medium is used, particles in which useful substances are dispersed can be easily produced. For example, if any useful substance is dissolved in a hydrophilic liquid or a hydrophobic substance that is further dispersed in drops dispersed in a dispersion medium, and the dispersion medium is evaporated, the particles can be easily Can be manufactured. Moreover, since such particles can be obtained without using a surfactant, particles suitable as a biomaterial can be obtained. The particles are an embodiment of the calcium phosphate composite fine particles according to the present invention.

  Such an O / W / O type dispersion or W / O / W type dispersion may be produced by the following production method. That is, in the method for producing a dispersion according to the present invention, the dispersion is at least one selected from a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane. Dispersion in which the first droplet is dispersed in the dispersion medium, and the second droplet is dispersed in the first droplet, using a hydrophobic substance containing one compound or a hydrophilic liquid as a dispersion medium When the dispersion medium is the hydrophilic liquid by mixing the hydrophobic substance, the hydrophilic liquid, and the calcium phosphate, the hydrophilic liquid is used, and the dispersion medium is used as the hydrophobic substance. The second droplet formed by coating the hydrophobic substance with the calcium phosphate is dispersed in the hydrophilic liquid and the hydrophobic substance that is not the dispersion medium. A first mixing step for producing a first dispersion, the first dispersion, the dispersion medium, and the calcium phosphate are mixed, whereby the first dispersion is coated with calcium phosphate. And a second mixing step for producing a second dispersion in which one droplet is dispersed in the dispersion medium.

  For example, in the case of producing the above-mentioned W / O / W type dispersion, the hydrophobic substance, the combination of the hydrophobic substance and the hydrophilic liquid in which the hydrophobic substance serves as a dispersion medium, A hydrophilic liquid and calcium phosphate are mixed to prepare a dispersion (first dispersion). Next, a dispersion (second dispersion) is prepared by mixing the first dispersion, calcium phosphate, and a hydrophilic liquid. The second dispersion thus obtained is the aforementioned W / O / W type dispersion.

  Similarly, when producing the above-mentioned O / W / O type dispersion, the hydrophobic substance, which is a combination of the hydrophobic substance and the kind and volume of the hydrophilic liquid in which the hydrophilic liquid serves as a dispersion medium, The hydrophilic liquid and calcium phosphate are mixed to prepare a dispersion (first dispersion). Next, a dispersion (second dispersion) is prepared by mixing the first dispersion, calcium phosphate, and a hydrophobic substance. The second dispersion thus obtained is the aforementioned W / O / W type dispersion.

  As described above, according to the method for producing a dispersion according to the present invention, a dispersion in which droplets are further dispersed in droplets dispersed in a dispersion medium can be easily produced by two mixing steps.

  The preferred conditions for the hydrophilic liquid, the hydrophobic substance, and the calcium phosphate relating to the W / O / W type dispersion or the O / W / O type dispersion as the dispersion according to the present invention apply the matters described so far. it can.

[Method of assembling dispersoid and redispersion of dispersoid according to the present invention]
In the method for assembling the dispersoid according to the present invention, an acidic compound may be mixed with the dispersion according to the present invention. When the pH of the hydrophilic liquid in the dispersion according to the present invention is lowered, CaP as the dispersant is dissolved in the hydrophilic liquid. As a result, the dispersoid cannot be dispersed in the dispersion medium, and the dispersoid collects. In the present specification, “dispersoids gather” means that the dispersion is lost in stability, and the dispersoids forming droplets are united to form a continuous layer. In other words, “dispersoids gather” means that dispersoids that have lost stability collide and merge to become one, and as a result, the dispersoids that have been dispersed become one. To do.

  The acidic compound used in the method for assembling the dispersoid according to the present invention is not particularly limited, but is preferably an acid that does not form a calcium salt insoluble in water when mixed with calcium ions. Nitric acid and hydrochloric acid are preferred. The pH of the hydrophilic liquid is preferably 5 or less, and more preferably 4 or less. At this time, the lower limit value of the pH is not limited as long as the reactor used in carrying out the dispersoid assembly method according to the present invention can withstand.

  In addition, the method of mixing the acidic compound in the method for assembling the dispersoid according to the present invention is not particularly limited. For example, it may be added, or may be added and lightly stirred and then allowed to stand. Good.

  In the redispersion method of the dispersoid according to the present invention, an alkaline compound may be mixed into the liquid in which the dispersoid is collected by the dispersoid assembly method according to the present invention.

  When the pH of the hydrophilic liquid contained in the liquid is increased, CaP dissolved in the hydrophilic liquid is precipitated. Thereby, for example, a droplet of a hydrophobic substance is formed in a hydrophilic liquid, and the dispersion is formed again by dispersing the droplet. In the present specification, it is referred to as “redispersion” that the aggregate of dispersoids is dispersed again in the dispersion medium to form a dispersion.

  The alkaline compound used in the method for redispersing a dispersoid according to the present invention is not particularly limited, but an alkaline compound that does not form a phosphate insoluble in water is preferable. Examples of the alkaline compound that does not form a phosphate insoluble in water when mixed with phosphate ions include alkali metal hydroxides, among which sodium hydroxide and potassium hydroxide are preferred. In addition, even if it is an alkaline compound which forms a phosphate insoluble in water, the phosphate may function as a dispersant, and at this time, the dispersoid redispersion method according to the present invention is preferably carried out. be able to. Thus, although the phosphate insoluble in water is formed, magnesium hydroxide, zinc hydroxide, etc. are mentioned as an alkaline compound in which the phosphate functions as a dispersant. Further, the pH of the hydrophilic liquid is preferably 5 or more, and more preferably 7.7 or more. At this time, the upper limit value of the pH is not limited as long as the reactor used in the redispersion can withstand.

  In the method for redispersing a dispersoid according to the present invention, the liquid in which the dispersoid is collected can be redispersed satisfactorily by adding an alkaline compound, for example, by stirring and mixing. . The stirring may be performed according to the description of the stirring of the hydrophilic liquid, the hydrophobic substance, and CaP in the method for producing the dispersion according to the present invention.

  The dispersoid assembly method and dispersoid redispersion method according to the present invention can be performed repeatedly. That is, by repeating the mixing of the acidic compound, the mixing of the alkaline compound, and the mixing of the acidic compound in the reactor containing the dispersion according to the present invention, the assembly of the dispersoid, redispersion, and assembly of the dispersoid are repeated. be able to.

  This facilitates, for example, the recovery of highly viscous crude oil that is difficult to pump with underground pumps. That is, water and CaP are mixed with crude oil to form a dispersion to lower the viscosity. Here, when a dispersion is not formed only by mixing CaP, a dispersion is formed by mixing a saturated organic compound having a carbonyl group dissolved in the oil and then mixing CaP. And after pumping up the said dispersion body with a pump etc. and moving to a collection tank etc., an acidic compound is mixed, a water component and an oil component are divided, and collection | recovery of only an oil component is made easy. Furthermore, the CaP used for recovering the oil described above can be reused. That is, in the method for assembling a dispersoid according to the present invention described above, a hydrophilic liquid that is acidic and dissolves CaP is mixed with crude oil. Then, a dispersion can be formed by mixing an alkaline compound. Therefore, the oil can be recovered in the same manner as the oil recovery method described in the method for collecting dispersoids according to the present invention described above. Thus, since CaP can be used repeatedly, crude oil with high viscosity can be recovered easily at low cost.

[Calcium phosphate hollow particles according to the present invention]
The method for producing calcium phosphate hollow particles (CaP hollow particles) according to the present invention may include the following steps (i) and (ii):
(I) a hydrophilic substance, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and a hydrophobic substance containing at least one compound selected from alkane, and calcium phosphate And a step of producing a dispersion by mixing with
(Ii) A step of firing the dispersion.

  When the dispersion according to the present invention is baked, the hydrophilic liquid and the hydrophobic substance are removed, and CaP forming the droplets dispersed in the dispersion remains. Therefore, CaP hollow particles having a hollow structure derived from the shape of the droplet can be obtained. At this time, if the above-described nanometer-sized CaP particles are used in the method for producing CaP hollow particles according to the present invention, extremely thin shell CaP hollow particles can be obtained. The thickness of the shell is the thickness of one CaP particle, for example, a thickness of 1 nm to 1000 nm. In addition, a large number of through holes are formed on the shell. This is a hole derived from a gap between CaP particles, and the diameter of the through hole varies depending on the firing temperature described later. The higher the firing temperature, the smaller the diameter of the through hole, and the lower the firing temperature, the larger the diameter of the through hole. For example, when the firing temperature is 500 ° C., a through hole having a diameter of 100 nm to 500 nm is formed.

  In the present specification, the term “hollow particle” is intended to mean a particle consisting of only a substance constituting the shell, the inside of which is empty. That is, the CaP hollow particles according to the present invention are particles in which the shell is formed of CaP and the inside is empty.

  In the method for producing CaP hollow particles according to the present invention, the step (i) may be performed according to the description of the method for producing a dispersion according to the present invention described above.

  Further, in the step (i), a biodegradable polymer which is a saturated organic compound having a carbonyl group as a hydrophobic substance is produced by producing a dispersion in which droplets of a hydrophobic substance are dispersed in a hydrophilic liquid. It is preferable to use a hydrophobic substance in which is dissolved. Even after the hydrophobic substance and the hydrophilic liquid evaporate in the firing process, the biodegradable polymer remains until it thermally decomposes and maintains the shape of CaP that has covered the droplets. Therefore, spherical CaP hollow particles can be suitably obtained.

  In the method for producing CaP hollow particles according to the present invention, the step (ii) is performed after the step (i). In the step (ii), the temperature for firing the dispersion is not limited as long as the hydrophilic liquid and the hydrophobic substance can be removed from the dispersion by transpiration, thermal decomposition, or the like. For example, a range of 500 ° C. or more and 2000 ° C. or less is preferable, and a range of 800 ° C. or more and 1500 ° C. or less is more preferable. If it is 500 degreeC or more, CaP is sintered and the CaP hollow particle of a stable structure can be obtained. If it is 2000 degrees C or less, in each CaP hollow particle, it can prevent that CaP which comprises the said CaP hollow particle fuse | melts, and a shape collapses.

  Further, in the step (ii), it is preferable to perform firing so that the droplets in the dispersion are not concentrated. For example, the dispersion is preferably applied to a flat plate and then baked, and the applied thickness is preferably as thin as possible, but is not limited thereto. As in the step (vi) described later, it is not necessary to perform the step of concentrating droplets. For example, the CaP hollow particles according to the present invention can be produced even if the dispersion obtained in the step (i) is baked as it is. It is possible to do.

  By applying on the flat plate, it is possible to suppress the fusion of CaP that has formed the droplets dispersed in the dispersion and CaP that has formed other droplets. Furthermore, by applying thinly, it is possible to prevent a plurality of droplets dispersed in the dispersion from overlapping in the vertical direction of the flat plate and fusing the droplets together. The flat plate used here is not particularly limited as long as it can withstand the firing temperature described above. For example, the bottom of an evaporating dish, a petri dish or the like made of a material such as glass, stainless steel, or alumina is flat. A reactor may be used.

  Moreover, in the manufacturing method of the CaP hollow particle which concerns on this invention, it is preferable to include the process of (iii) drying the said dispersion | distribution before the process of said (ii) after the process of said (i). It is possible to prevent CaPs from fusing together by drying the dispersion, removing the dispersion medium, and firing. Moreover, it can prevent that the shape of a CaP hollow particle collapses by raising the temperature of the heat added to CaP in steps.

  In the step (iii), the temperature and pressure for drying the dispersion are not limited as long as the dispersion medium in the dispersion can be evaporated. In addition, the droplets dispersed in the dispersion remaining after the dispersion medium is removed by drying in the step (iii) is an embodiment of the CaP composite fine particles according to the present invention described later. I can say that.

[Calcium phosphate porous body according to the present invention]
The method for producing a calcium phosphate porous body (CaP porous body) according to the present invention may include the following steps (iv) to (vi):
(Iv) a hydrophobic liquid containing at least one compound selected from a hydrophilic liquid, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane, and calcium phosphate And a step of producing a dispersion by mixing with
(V) a step of concentrating the droplets dispersed in the dispersion;
(Vi) A step of firing the dense droplets.

  By firing the droplets dispersed in the dispersion according to the present invention, the hydrophilic liquid and the hydrophobic substance are removed, and the fired CaP remains. Furthermore, since CaP particles are densely packed, CaP particles are fused. Thereby, a CaP porous body can be obtained.

  In the present specification, the “porous body” is a substance having a large number of fine pores, and a sponge-like porous material in which a large number of fine pores are connected in a complex manner in a substance serving as a skeleton. Include in its meaning.

  That is, according to the method for producing a CaP porous body according to the present invention, a sponge-like porous body having CaP as a skeleton can be suitably obtained. In addition, the CaP porous body according to the present invention has pores with different sizes such as pores (micrometer size) derived from a droplet of a hydrophobic substance and pores (nanometer size) between CaP particles. .

According to the method for producing a CaP porous body according to the present invention, a CaP porous body having a porosity of 70% to 99% and an apparent density of 0.03 to ³ × 10 ⁻⁵ g / cm ³ is preferably obtained. be able to.

  In the method for producing a CaP porous body according to the present invention, the step (iv) may be performed according to the description of the method for producing a dispersion according to the present invention described above.

  In the method for producing a CaP porous body according to the present invention, the step (v) is performed after the step (iv), and then the step (vi) is performed.

  In the step (v), the method for concentrating the droplets dispersed in the dispersion obtained in the step (iv) is not particularly limited. And CaP) alone may be recovered, and the dispersion may be subjected to centrifugation, vacuum filtration, and pressure filtration. In addition, after filtration, the gap between the collected droplets may be reduced by a hydraulic press or a hydraulic press, and the collected droplets may be further adhered to each other.

  In the step (vi), the temperature for firing the dispersion is not limited as long as the hydrophilic liquid and the hydrophobic substance can be removed from the dispersion by transpiration or thermal decomposition. For example, a range of 500 ° C. or more and 2000 ° C. or less is preferable, and a range of 800 ° C. or more and 1500 ° C. or less is more preferable. If it is 500 degreeC or more, CaP will be sintered and the CaP porous body of a stable structure can be obtained. If it is 2000 degrees C or less, the reduction | decrease of the number of holes and a magnitude | size by CaP fuse | melting can be prevented, and the CaP porous body which has more and a micro pore of a size can be obtained.

  In the method for producing CaP hollow particles according to the present invention, it is preferable to include (vii) a step of drying the dispersion after the step (iv) and before the step (vi). By raising the temperature added to CaP step by step, it is possible to prevent the CaP porous body from collapsing.

  In the step (vii), the temperature and pressure for drying the dispersion are not limited as long as the temperature and pressure can evaporate the dispersion medium in the dispersion. In addition, the droplets dispersed in the dispersion remaining after the dispersion medium is removed by drying in the step (vii) is an embodiment of the CaP composite fine particles according to the present invention described later. I can say that.

[Calcium phosphate composite fine particles according to the present invention]
The method for producing calcium phosphate composite fine particles (CaP composite fine particles) according to the present invention may include the following steps (viii) and (ix):
(Viii) a hydrophobic liquid containing at least one compound selected from a hydrophilic liquid, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane, and calcium phosphate And a step of producing a dispersion by mixing with
(Ix) A step of drying the dispersion.

  In this specification, “calcium phosphate composite fine particles (CaP composite fine particles)” means particles in which an arbitrary substance other than CaP is coated with CaP.

  That is, according to the method for producing CaP composite particles according to the present invention, CaP composite particles coated with an arbitrary substance can be obtained. Moreover, according to the method for producing CaP composite particles according to the present invention, for example, CaP composite particles having an average particle diameter of 1 μm to 1 cm can be obtained favorably.

  The substance to be coated with CaP is not limited as long as it has solubility or dispersibility in at least one of a hydrophilic liquid and a hydrophobic substance, and may be appropriately selected according to the application. That's fine.

  That is, the arbitrary substance may be a hydrophilic liquid, a saturated organic compound having a carbonyl group, or the like, or may be a substance other than these. For example, when an arbitrary substance is a hydrophilic liquid or a saturated organic compound having a carbonyl group, a dispersion in which the arbitrary substance becomes a dispersoid may be produced in the step (viii). When the substance is a substance other than a saturated organic compound having a carbonyl group, the arbitrary substance may be dissolved in a hydrophilic liquid or a saturated organic compound having a carbonyl group, which becomes a dispersoid. . As described above, the above-mentioned arbitrary substance may be included in the dispersoid of the dispersion produced in the step (viii).

  For example, a drug may be used as the arbitrary substance. CaP composite fine particles in which a drug is coated with CaP can release the drug gradually in a living body for a long time. This is because CaP has high biocompatibility but is not a substance that dissolves immediately in the water in the living body.

  In addition, if CaP composite microparticles coated with a CaP agent for treating inflammation are used, inflammation can be efficiently treated. That is, as described above, it is known that CaP is soluble in water having a low pH and has a low pH in the vicinity of inflamed cells. Therefore, since the CaP composite fine particles are preferentially dissolved in the vicinity of the inflamed cells, the inflammation can be efficiently treated.

  Thus, the CaP composite fine particles obtained by the present invention can be applied to DDS. In the present invention, a drug that can be used as a substance coated with CaP is not limited. For example, adriamycin, paclitaxel, irinotecan, transforming growth factor, epidermal growth factor, adrenomedullin, basic fibroblast growth Factor, vascular endothelial growth factor, bone morphogenetic protein and the like.

  In the method for producing CaP composite fine particles according to the present invention, in the step (viii), when a hydrophilic liquid is selected as the arbitrary substance, the hydrophobicity includes CaP and the saturated organic compound having the carbonyl group. A dispersion may be obtained by mixing a substance and the arbitrary substance.

  In addition, when a substance that is soluble or dispersible in a hydrophilic liquid is selected as the arbitrary substance, a hydrophobic substance containing CaP, a saturated organic compound having the carbonyl group, and the like, A dispersion may be obtained by mixing with a hydrophilic liquid.

  Further, when a saturated organic compound having a carbonyl group is selected as the optional substance, if the optional substance is a liquid, the arbitrary substance, a hydrophilic liquid, and CaP are mixed and dispersed. If the desired substance is not a liquid, the desired substance, a hydrophobic substance capable of dissolving or dispersing the desired substance, a hydrophilic liquid, and CaP are mixed. To obtain a dispersion.

  In addition, when a hydrophobic substance other than the saturated organic compound having the carbonyl group is selected as the arbitrary substance, the arbitrary substance and a carbonyl group capable of dissolving or dispersing the arbitrary substance What is necessary is just to mix a saturated organic compound etc. which have A, a hydrophilic liquid, and CaP and to obtain a dispersion.

  Alternatively, the dispersion may be produced by mixing the above-mentioned arbitrary substance with a hydrophobic substance containing a hydrophilic liquid or a saturated organic compound having a carbonyl group by dissolving or dispersing in advance.

  That is, no matter what substance is selected as an arbitrary substance, a dispersion in which the dispersoid of the hydrophilic liquid and the hydrophobic substance includes the arbitrary substance may be manufactured. .

  In addition, what is not demonstrated about the manufacturing method of the dispersion in the process of said (viii) should just be performed according to description of the manufacturing method of the dispersion concerning this invention mentioned above.

  In the method for producing CaP composite fine particles according to the present invention, the step (ix) is performed after the step (viii).

In the step (ix), the temperature and pressure for drying the dispersion are not particularly limited, but the temperature and pressure at which the dispersion medium in the dispersion produced in the step (viii) can be evaporated. It may be. For example, in the step (viii), when a dispersion using a dispersion medium as a hydrophilic liquid is manufactured, the temperature may be any temperature at which the hydrophilic liquid can be evaporated. Further, it may be left alone at room temperature, or after removing the dispersion medium to some extent by filtration or the like, the remaining dispersion medium may be removed from the collected filtrate. Further, the hydrophobic substance used as the dispersoid may be evaporated according to the use of the CaP composite fine particles, but the step (ix) is not limited as long as it is a step of drying the dispersion medium.
Similarly, in the step (viii), when a dispersion using a dispersion medium as a hydrophobic substance is manufactured, the temperature may be any temperature at which the hydrophobic substance can be evaporated. At this time, the hydrophilic liquid used as the dispersoid may be evaporated according to the use of the CaP composite fine particles. In any case, the temperature for drying the dispersion is preferably lower than the temperature at which the arbitrary substance is removed by evaporation or thermal decomposition.

  Also, CaP composite fine particles in which an arbitrary hydrophilic substance is dispersed in oil coated with CaP, and CaP composite fine particles in which an arbitrary hydrophobic substance is dispersed in a hydrophilic liquid coated with CaP This is the category of the calcium phosphate composite fine particles according to the present invention.

  Such CaP composite fine particles can also be produced by the method for producing CaP according to the present invention. At this time, in the method for producing CaP composite fine particles according to the present invention, the dispersion produced in the step (viii) includes a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, and a cyclic olefin having a carbonyl group. And a hydrophobic substance containing at least one compound selected from alkanes or a hydrophilic liquid as a dispersion medium, the first droplet is dispersed in the dispersion medium, and the first droplet is dispersed in the first droplet. 2 is a dispersion in which the step (viii) is a mixture of the hydrophobic substance, the hydrophilic liquid, and the calcium phosphate, whereby the dispersion medium is mixed with the hydrophilic liquid. The second droplet formed by coating the hydrophilic liquid with the calcium phosphate when the dispersion medium is the hydrophobic substance. A first mixing step of forming a first dispersion that is dispersed in the non-dispersing substance of the active substance, mixing the first dispersion, the dispersion medium, and the calcium phosphate, A first mixing step in which the first droplet formed by coating the first dispersion with calcium phosphate forms a second dispersion that is dispersed in the dispersion medium. In the step, the manufacturing method may be such that at least one of the hydrophilic liquid and the hydrophobic substance is mixed with the arbitrary substance in advance.

  For example, a case where CaP composite fine particles in which an arbitrary hydrophilic substance is dispersed in a hydrophobic substance coated with CaP will be described in detail as follows.

  First, an arbitrary hydrophilic substance is dissolved in a hydrophilic liquid, and the hydrophilic liquid, the hydrophobic substance, and CaP are mixed to form a drop of the hydrophilic liquid in the hydrophobic substance. A dispersion in which is dispersed (first dispersion) is produced. Next, a dispersion (second dispersion) in which droplets of the first dispersion are dispersed in the hydrophilic liquid is produced by mixing the first dispersion, the hydrophilic liquid, and CaP. . When the dispersion medium (hydrophilic liquid) is evaporated by drying the second dispersion, CaP composite fine particles in which any hydrophilic substance is dispersed in a hydrophobic substance coated with CaP can be obtained. it can.

  Further, for example, a case where CaP composite fine particles in which an arbitrary hydrophobic substance is dispersed in a hydrophilic liquid coated with CaP will be described in detail as follows.

  First, an arbitrary hydrophobic substance is dissolved in the hydrophobic substance, and the hydrophobic substance, a hydrophilic liquid, and CaP are mixed, whereby the hydrophobic substance drops in the hydrophilic liquid. A dispersion in which is dispersed (first dispersion) is produced. Next, by mixing the first dispersion, the hydrophobic substance, and CaP, a dispersion (second dispersion) in which the droplets of the first dispersion are dispersed in the hydrophobic substance is manufactured. . When the dispersion medium (hydrophobic substance) is evaporated by drying the second dispersion, CaP composite fine particles in which a hydrophobic substance is dispersed in a hydrophilic liquid coated with CaP can be obtained. it can.

  In this example, an arbitrary substance is preliminarily mixed with the substance that becomes the second droplet, but the present invention is not limited to this. The arbitrary substance may be mixed with the substance that becomes the first drop, or may be mixed with both the substance that becomes the first drop and the second drop.

[Use of Dispersion, CaP Porous Material, CaP Hollow Particle, and CaP Composite Fine Particle According to the Present Invention]
The biomaterial according to the present invention may include the above-described dispersion, CaP porous body, CaP hollow particles, and CaP composite fine particles according to the present invention.

  In this specification, “biological material” intends a material of a product such as equipment or medicine used for a living body.

  The biomaterial according to the present invention can be suitably used particularly as a drug carrier, cell culture material, medical material, and dental material.

  For example, in the dispersion according to the present invention, when a drug is contained in dispersed droplets, CaP serving as the shell of the droplets has high biocompatibility and is thus well absorbed by the living body. Further, in the dispersion according to the present invention, if the culture medium component is used as a dispersion medium, the cells are well cultured on CaP having high biocompatibility, and thus can be used as a cell culture material.

  The CaP porous body and CaP hollow particles according to the present invention can be used as a drug carrier. For example, by including a drug therein, the drug can be gradually released in a living body for a longer period of time. Moreover, the CaP porous body and CaP hollow particles according to the present invention have high biocompatibility and high cell adhesion. Therefore, if these are used as cell culture materials and mixed in the medium, living cells can be cultured well on CaP porous bodies and CaP hollow particles.

  The CaP composite fine particles according to the present invention can be used as a drug carrier. For example, when the CaP composite fine particles according to the present invention having a biodegradable polymer in the shell and further containing a drug as the above arbitrary substance, the drug is gradually released in a living body for a longer period of time. be able to. As described above, the CaP composite fine particles containing a drug can be used as a drug itself having high bioabsorbability.

  Moreover, the CaP composite fine particles according to the present invention can be suitably used as a cell culture material. As will be shown in Examples described later, the CaP composite fine particles according to the present invention have high cell adhesiveness. Therefore, the CaP composite fine particles according to the present invention can be suitably used as a scaffold for culturing cells, for example. Further, when a growth factor is contained in the shell, elution of the growth factor can be controlled by pH or the like, so that it can be used as a cell culture material capable of controlling the cell growth rate. That is, when the pH around the CaP composite fine particles is lowered, the elution of the medium components increases, and when the pH is increased, the elution of the medium components is suppressed.

  In the present specification, “cell culture material” means a material used as a scaffold for cells during cell culture.

  Since the biomaterial according to the present invention is close to components of bones and teeth of a living body, in the medical field, for example, a cell scaffold material for regenerative medicine (tissue engineering), a blood purification material, It can be widely used as a dental material or medical material such as an embolic therapy material, a bone filler, a dental filler, a drug sustained-release agent and the like.

  Examples will be shown below, and the embodiments of the present invention will be described in more detail. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects are possible in detail. Further, the present invention is not limited to the above-described embodiments, and various modifications can be made within the scope shown in the claims, and the present invention is also applied to the embodiments obtained by appropriately combining the disclosed technical means. It is included in the technical scope of the invention. In addition, all of the academic literatures and patent literatures described in this specification are incorporated herein by reference.

[Example 1; Production of CaP used as dispersant]
CaP particles having a spherical, rod-like, or fiber-like form were synthesized by a wet method. The synthesis method of each particle is shown below. In addition, Ca (NO ₃ ) ₂ aqueous solution, (NH ₄ ) ₂ HPO ₄ aqueous solution, and aqueous ammonia described later are all Ca (NO ₃ ) ₂ .4H ₂ O, (NH ₄ ) manufactured by Wako Pure Chemical Industries, Ltd. ₂ HPO ₄ , 25% aqueous ammonia was used.

(Spherical CaP)
A Ca (NO ₃ ) ₂ aqueous solution (42 mM; 800 mL) adjusted to pH 12 with aqueous ammonia was poured into a 1 L flask connected with a condenser and a semicircular stirring blade, and kept at 25 ° C. To this flask, (NH ₄ ) ₂ HPO ₄ aqueous solution (100 mM; 200 mL) adjusted to pH 12 with aqueous ammonia was added all at once at 25 ° C. Thereafter, the flask was stirred for 10 hours to obtain spherical CaP.

(Rod-like CaP)
A Ca (NO ₃ ) ₂ aqueous solution (42 mM; 800 mL) adjusted to pH 12 with aqueous ammonia was poured into a 1 L flask equipped with a condenser and a semilunar stirring blade, and kept at 80 ° C. (NH ₄ ) ₂ HPO ₄ aqueous solution (100 mM; 200 mL) adjusted to pH 12 with aqueous ammonia was added to this flask at a rate of 10 mL / h at 80 ° C. Thereafter, the flask was stirred for 24 hours to obtain rod-shaped CaP.

(Fibrous CaP)
A Ca (NO ₃ ) ₂ aqueous solution (42 mM; 800 mL) whose pH was not adjusted was poured into a 1 L flask equipped with a condenser and a semicircular stirring blade, and kept at 80 ° C. At 80 ° C., (NH ₄ ) ₂ HPO ₄ aqueous solution (100 mM; 200 mL) without pH adjustment was added to the flask at a rate of 10 mL / h. Thereafter, the flask was stirred for 24 hours to obtain fibrous CaP.

  In addition, all obtained CaP was wash | cleaned by centrifuging and substituting the medium with pure water.

  Next, each obtained CaP was observed with a scanning electron microscope. The results are shown in FIG. FIG. 1 is a diagram showing the results of observation of each CaP obtained in this example with a scanning electron microscope, (a) shows a scanning electron microscope image of the spherical CaP, and (b) shows the rod-like shape. A scanning electron microscope image of CaP is shown, and (c) shows a scanning electron microscope image of the fibrous CaP.

  The scanning electron microscope was observed at a magnification of 30000 times or 95000 times using a model name JSM-6301F manufactured by JEOL Ltd.

  From FIG. 1, it was confirmed that spherical CaP, rod-like CaP, and fiber-like CaP were obtained.

  Moreover, the particle diameter and density of each obtained CaP were measured. The particle diameter of each CaP was determined from the image obtained by observation with the above-described scanning electron microscope. The density of each CaP was measured at room temperature in a dry state using a pycnometer (manufactured by Micrometrics, model name Accu Pyc 1300). The results of measuring the particle size and density of each CaP are shown in Table 1.

As a result, the average particle diameter of spherical CaP was 40 nm, and the coefficient of variation was 17%. The average particle diameter of the rod-shaped CaP was 410 nm (variation coefficient 50%), short diameter 80 nm (variation coefficient 18%), and the aspect ratio was 5.1. The average particle size of the fiber-like CaP was 2320 nm in the major axis (variation coefficient 58%), 100 nm in the minor axis (36% variation coefficient), and the aspect ratio was 24. Density of particles determined from the pycnometer, the spherical CaP particles 2.72 g / cm ^3, the rod-shaped CaP 3.01 g / cm ^3, was 3.00 g / cm ³ in the fibrous CaP.

Next, the zeta potential of the obtained spherical CaP was measured. The zeta potential is measured by dispersing spherical CaP in 10 mM KNO ₃ aqueous solution and adjusting pH using HNO ₃ or KOH aqueous solution, and then using a zeta potential measuring device (Malvan, model name Nano ZS ZEN 3600). And performed at room temperature. The zeta potential showed a typical sigmoidal curve and was shown to have an isoelectric point near pH 5.9. At pH 3.5 or less, the spherical CaP nanoparticles were dissolved in water and became a colorless and transparent ionic aqueous solution.

Example 2 Production of Dispersion Using CaP as Dispersant
In this example, a dispersion was prepared using rod-like CaP obtained by the method described in Example 1 as a dispersant.

First, water was used as the hydrophilic liquid, and rod-like CaP was mixed with water so as to have a solid content concentration of 1% by mass to prepare a dispersion in which CaP was dispersed in water. The dispersion (5 mL) was weighed into a sample bottle (15 mL), the pH was adjusted using HNO ₃ and an aqueous KOH solution, and 5 mL of a hydrophobic substance was gently mixed into the sample bottle. Next, the mixture was stirred for 2 minutes at 12,000 rpm and 20 ° C. using a homogenizer (manufactured by IKA, model name Ultra-Turrax T-18) to obtain a dispersion. In the following examples, all of the hydrophilic liquid used for producing the dispersion is water.

  The hydrophobic substances (hereinafter referred to as “oil”) used in this example are n-dodecane, methyl myristate, 1-undecanol, toluene, n-hexane, chloroform, dichloromethane, and methyl trimethylacetate. As n-dodecane, methyl myristate, and 1-undecanol, those manufactured by Aldrich were used. As n-hexane, chloroform, and dichloromethane, those manufactured by Fisher Scientific were used, and methyl trimethylacetate manufactured by Lancaster Synthesis was used. .

  Next, the type and stability evaluation of each dispersion using each oil described above, observation of oil droplets of each dispersion, and measurement of the size thereof were performed.

  The type of dispersion was evaluated using a conductivity meter (Hana model Primo 5) or by dropping the dispersion in water and oil. When a conductivity meter is used, the case where the conductivity is 1 mS / cm or more is an oil-in-water dispersion (the dispersion medium is water and the dispersoid is oil), and the case where the conductivity is 1 mS / cm or less. It was judged as a water droplet type dispersion (dispersion medium was oil and dispersoid was water). Also, the dispersion is dropped into water, the system in which the dispersion is quickly dispersed is judged as an oil-in-water type, the dispersion is dropped into oil, and the system in which the dispersion is quickly dispersed is referred to as a water-in-oil type. It was judged.

  The stability of the oil-in-water dispersion was evaluated from the ratio of the oil dispersed in the dispersion without being aggregated after standing for 24 hours obtained from the following formula (1).

100- (B / A × 100)% Formula (1)
Here, A is the volume of the charged hydrophobic substance, and B is the volume of the oil layer formed by collecting the oil in the dispersion after being left for 24 hours.

  For observation of oil droplets in the dispersion, an optical microscope (James Switch MP3502, Prior Scientific Instruments Ltd.) equipped with a digital camera (Nikon Coolpix 4500) was used. In addition, a laser diffraction / scattering method (Malvern Mastersizer 2000) was used to measure the size of the oil droplets.

  Table 2 shows the results of measuring the type and stability of each dispersion and the size of the oil droplets.

  When methyl myristate or methyl trimethylacetate was used as the oil, the dispersion was stably present even after being left for 24 hours, and the stability was 100%. When n-dodecane or n-hexane was used, a stable dispersion in which 70% or more of the oil phase after being allowed to stand for 24 hours was dispersed was obtained. When toluene, chloroform, or dichloromethane was used, only millimeter-sized huge oil droplets were formed, and a dispersion could not be obtained. When 1-undecanol was used, after stirring with a homogenizer, the water layer and the oil layer immediately separated, and a dispersion could not be obtained.

[Example 3; Production of dispersion using oil for which stable dispersion was not obtained in Example 2]
In this example, dichloromethane, which was an oil for which a stable dispersion could not be obtained in Example 2, was mixed with polylactic acid, which is a biodegradable polymer of a saturated organic compound having a carbonyl group. Attempted formation.

  First, polylactic acid (MW = 150,000) was dissolved in dichloromethane at a concentration of 1% by mass with respect to dichloromethane.

  A dispersion was prepared in the same manner as in Example 2, except that the spherical CaP obtained in Example 1 was used as the dispersant and dichloromethane in which polylactic acid was dissolved was used as the oil.

  In FIG. 2, the result of having observed the dispersion obtained by the present Example is shown. In FIG. 2, (a) is a mixture of water and dichloromethane, (b) is a mixture of water and dichloromethane in which polylactic acid is dissolved, and (c) and (c ′) are mixtures of water and dichloromethane. Spherical CaP is dispersed, and (d) and (d ′) are diagrams showing spherical CaP dispersed in a mixture of water and dichloromethane in which polylactic acid is dissolved. In FIG. 2, (c ′) is a view showing a result of observing the sample bottle shown in (c), and (d ′) is a result of observing the sample bottle shown in (d) from below.

  As shown in FIG. 2, when dichloromethane in which polylactic acid was not dissolved was used, only huge oil droplets were formed and a stable dispersion was not formed. However, a stable dispersion could be obtained by dissolving polylactic acid in dichloromethane and mixing CaP in water.

  Even when polylactic acid was dissolved in dichloromethane, a dispersion could not be obtained when CaP was not present in water.

[Example 4: Evaluation of the influence of the shape of CaP on the resulting dispersion]
In this example, the influence of spherical CaP, rod-like CaP, and fiber-like CaP on the size of the oil droplets in the obtained dispersion was evaluated.

  As the oil, methyl myristate was used. In addition, as a method for producing the dispersion, the same operation as in Example 2 was performed.

  Spherical CaP, rod-like CaP, and fiber-like CaP, any of the dispersants can be stably present as 100% even after being left for 24 hours, and can be stored for more than 6 months. A stable dispersion was obtained.

  The result of observing the obtained dispersion with an optical microscope is shown in FIG. 3, and the result of measuring the oil droplet size distribution in the obtained dispersion by the laser diffraction / scattering method is shown in FIG. In FIG. 3, (a) shows a spherical CaP, (b) shows a rod-like CaP, and (c) shows an optical microscope image of a dispersion obtained using fiber-like CaP as a dispersant. Also, in FIG. 4, (a) spherical CaP, (b) rod-shaped CaP, and (c) fiber-like CaP were used as dispersants, and the oil droplet size distribution in the dispersion was measured. Results are shown. The size distribution of the oil droplets by the laser diffraction / scattering method was measured using a laser diffraction particle size distribution measuring device (manufactured by Malvern; product number Mastersizer 2000; attached to sample dispersion unit Hydro 2000SM).

  As shown in FIGS. 3 and 4, a dispersion having large oil droplets was obtained in the order of spherical CaP, rod-like CaP, and fiber-like particle CaP.

[Example 5: Evaluation of the influence of the pH of the solvent on the resulting dispersion]
In this example, the influence of the pH of water on the formation of the dispersion was examined using the dispersion medium as water.

  For the preparation of the dispersion according to this example, methyl myristate was used as the oil (dispersoid), and the spherical CaP particles obtained in Example 1 were used as the dispersant. Further, the same operation as in Example 2 was performed except that the pH of water was changed to 11.7, 11.0, 10.0, 9.0, 7.7, 6.1, 5.0, 4.0. A dispersion was prepared.

  FIG. 5 shows the result of observing the appearance of each sample bottle after 24 hours after preparing the dispersion, and FIG. 6 shows the result of observing the contents of the sample bottle with an optical microscope.

  In FIG. 5, (a) shows the pH of water 11.7, (b) shows the pH of water 11.0, (c) shows the pH of water 10.0, (d) shows the pH of water 9. 0, (e) pH of water is 7.7, (f) is pH of water 6.1, (g) is pH of water 5.0, (h) is pH of water 4.0. The appearance of the sample bottle is shown.

In FIG. 6, (a) is the pH of water 4.0, (b) is the pH of water 5.0, (c) is the pH of water 6.1, (d) is the pH of water 7. 7, (e) is the pH of water 9.0, (f) is the pH of water 10.0, (g) is the pH of water 11. The result of observing the contents of the sample bottle with an optical microscope when 0 is shown is shown.

  As shown in FIGS. 5 and 6, in all the systems having a pH of 7.7 or higher, dispersoid aggregation did not occur even after 24 hours, and the dispersion was stably present at 100%. Furthermore, all dispersions with a pH of 7.7 or higher were stable and could be stored for 6 months or longer. As in Example 4, the oil droplet diameter in the dispersion was measured by laser diffraction / scattering method. As a result, the size distribution of the oil droplet diameter was in the range of 50 to 100 μm.

  Further, as shown in FIGS. 5 and 6, in the system of pH 6.1 and pH 5.0, 1% to 10% oil (dispersoid) aggregated after 24 hours, but other oils were in the dispersion. Dispersed. In addition, a stable dispersion that can be stored for 6 months or more was obtained even in a system of pH 6.1 and pH 5.0. In addition, when the size distribution of the oil droplet diameter of the dispersion was measured using an optical microscope, it was in the range of 10 to 200 μm in the pH 6.1 system, and 20 μm to 2 mm in the pH 5.0 system. Range. In the system of pH 4.0, millimeter-sized oil droplets were formed at the interface between the oil layer and the aqueous layer after stirring, but with the progress of time, the oil droplets were absorbed into the oil layer and disappeared. Although not shown in the drawing, the operation described in Example 2 was performed using a dispersion in which the pH of water was 3.3 or lower, using methyl myristate as the oil, and using the spherical CaP particles obtained in Example 1 as the dispersant. An attempt was made to prepare a dispersion in the same manner as described above. However, spherical CaP was dissolved in water, and after stirring with a homogenizer, the oil layer and the water layer were separated within a few seconds, and stable oil droplets could not be obtained.

Example 6: Aggregation and redispersion of dispersoids by pH operation
In this example, the dispersoid in the dispersion is assembled by lowering the pH of the water (dispersion medium) of the dispersion, and then the dispersed dispersoid is redispersed by raising the pH. A study was carried out to fabricate.

  First, a dispersion using spherical CaP as a dispersant and methyl myristate as an oil (dispersoid) was prepared. The dispersion was produced in the same manner as in Example 2.

  The pH of the resulting dispersion is 7.8. Next, the dispersion was mixed with nitric acid and adjusted to pH 3.0 or lower. Next, potassium hydroxide was mixed to adjust the pH to 5.0 or more. This was repeated, and nitric acid was mixed 5 times and potassium hydroxide was mixed 4 times. The result is shown in FIG. In FIG. 7, (a) is immediately after preparation, (b) is after the first nitric acid mixing, (c) is after the first potassium hydroxide mixing, (d) is after the second nitric acid mixing, (e) is After the second potassium hydroxide mixing, (f) after the third nitric acid mixing, (g) after the third potassium hydroxide mixing, (h) after the fourth nitric acid mixing, (i) the fourth time (J) is a figure which shows the result of having observed the external appearance of the sample bottle after the nitric acid mixing of the 5th time after mixing of this potassium hydroxide.

  The dispersion produced in this example shown in FIG. 7 (a) was a stable dispersion that could be stored for 6 months or longer in a state where nitric acid was not mixed once. However, by mixing nitric acid and adjusting the pH to 3.0 or less, the oil quickly gathered within tens of seconds, and the water layer and the oil layer separated as shown in FIG. 7B. Next, when potassium hydroxide was mixed to adjust the pH to 5 or more and stirred using a homogenizer, redispersion was performed as shown in FIG. It was confirmed that this oil dispersion and oil assembly could be repeated five times. When the size distribution of the oil droplet diameter of the dispersion produced by redispersion shown in FIGS. 7C, 7E, 7G, and 7I was measured by the same operation as in Example 2, FIG. The size distribution of oil droplet diameters contained in all dispersions shown in (c), (e), (g), and (i) was in the range of 47 μm to 154 μm.

[Example 7: Porous body using CaP dispersion as template]
In this example, a CaP porous body was prepared by firing a dispersion prepared using CaP.

  First, a dispersion was prepared in the same manner as in Example 2, except that 0.05 g of the spherical CaP obtained in Example 1 was used as the dispersant and 5 ml of methyl myristate was used as the oil (dispersoid). did. Next, the obtained dispersion was filtered to separate water and obtain oil droplet particles. Next, the obtained oil droplet particles were heated to 1000 ° C. at a rate of 10 ° C./min in an electric furnace and held at 1000 ° C. for 1 hour to obtain a CaP porous body. The result of having observed the obtained CaP porous body using the scanning electron microscope is shown in FIG. The observation with a scanning electron microscope was performed in the same manner as in Example 1 except that the magnification was 1000 times.

  As shown in FIG. 8, it was confirmed that a porous body having pores having the same size as the oil droplets was obtained.

[Comparative Example 1; Comparison with Example 7]
Only the spherical CaP obtained in Example 1 was heated to 1000 ° C. at a rate of 10 ° C./min in an electric furnace and held at 1000 ° C. for 1 hour. As a result, a porous body was not obtained, and a fired body with dense CaP was obtained.

[Example 8: Preparation of CaP composite fine particles 1]
In this example and Example 9 described later, CaP composite particles containing polylactic acid in spherical CaP were produced.

  First, in a 50 ml sample bottle, 2.5 g of dichloromethane containing 1% by mass of polylactic acid is added to 25 g of water containing 0.02% by mass of the spherical CaP obtained in Example 1, and the sample bottle is stirred. A dispersion was prepared.

  The result of observing the obtained dispersion with an optical microscope is shown in FIG. A stable dispersion was obtained, and the size of the oil droplets was 30 μm.

  Next, the dispersion was allowed to stand at room temperature for 24 hours to evaporate dichloromethane. Next, by drying at 60 ° C. for 24 hours, water was evaporated to obtain CaP composite fine particles.

  The result of having observed the obtained CaP composite fine particle using the scanning electron microscope is shown in FIG. Observation with a scanning electron microscope was performed in the same manner as in Example 1 except that the magnification was 8000 times. As shown in FIG. 10, it was confirmed that spherical particles having a particle diameter of 11 μm were obtained. Formation of CaP composite fine particles in which spherical CaP was uniformly coated on the surface of polylactic acid was confirmed.

  The obtained CaP composite fine particles were dried at 60 ° C., put in a polyethylene capsule, and embedded in an epoxy resin manufactured by Agar SCIENTIFIC LTD. Next, using an ultramicrotome diamond knife (manufactured by Sumitomo Electric, product number: SK3045), the epoxy resin was cut into a thickness of 100 nm to prepare a slice. The section was observed using a transmission electron microscope (manufactured by PHILIPS, product number: CM120). The results are shown in FIG. FIG. 13 is a view showing a result of observing a cross section of the CaP composite fine particles obtained in this example using a transmission electron microscope.

  As shown in FIG. 13, it was confirmed that spherical CaP uniformly coats the surface, not the inside of the CaP composite fine particles.

[Example 9: Preparation 2 of CaP composite fine particles]
First, in a sample bottle of 50 ml capacity, 2.5 g of dichloromethane containing 5% by mass of polylactic acid is added to 25 g of water containing 0.2% by mass of spherical CaP obtained in Example 1, and the sample bottle is stirred. A dispersion was prepared.

  The obtained dispersion was allowed to stand at room temperature for 24 hours to evaporate dichloromethane to obtain CaP composite fine particles.

  FIG. 11 shows the results of observation of the obtained CaP composite fine particles using a scanning electron microscope. Observation with a scanning electron microscope was performed in the same manner as in Example 1 except that the magnification was 500 times. As shown in FIG. 11, particles having various shapes including particles having a particle diameter of 46 μm were confirmed. This indicates that CaP composite fine particles having various shapes in which the surface of polylactic acid is uniformly coated with CaP were obtained.

[Example 10: Production of CaP hollow particles]
First, the CaP composite fine particles obtained in Example 8 were thinly coated on an evaporating dish and dried at 60 ° C. Thereafter, the temperature was raised to 1000 ° C. at a rate of 1 ° C./min in an electric furnace, and the CaP composite fine particles were fired by holding at 1000 ° C. for 1 hour to obtain CaP hollow particles. In addition, the polylactic acid in CaP composite fine particles is thermally decomposed by the said baking.

  The result of having observed the obtained CaP composite fine particle with the scanning electron microscope is shown in FIG. In FIG. 12, (a) shows the result observed at a magnification of 500 times, and (b) shows the result observed at a magnification of 5000 times. Observation with a scanning electron microscope was carried out in the same manner as in Example 1 except that the magnification was 500 times or 5000 times.

  As shown in FIG. 12, it was confirmed that CaP hollow particles were obtained.

[Example 11: Production 3 of CaP composite fine particles]
In a 50 ml capacity sample bottle, 2.5 g of dichloromethane containing 1% by mass of polylactic acid was added to 25 g of water containing 0.2% by mass of spherical CaP and stirred to prepare a dispersion. Polylactic acids having molecular weights of 5,000, 125,000 and 300,000 were used, respectively. Each obtained dispersion was allowed to stand at room temperature for 24 hours to evaporate dichloromethane to obtain CaP composite fine particles.

  Next, the obtained CaP composite fine particles were observed with a scanning electron microscope. The results are shown in FIG. FIG. 14 is a diagram showing the results obtained by observing the CaP composite fine particles obtained in this example with a scanning electron microscope. (A) and (a ′) show the results using polylactic acid having a molecular weight of 5,000. , (B) and (b ′) show results using polylactic acid having a molecular weight of 125,000, and (c) and (c ′) show results using polylactic acid having a molecular weight of 300,000.

  As shown in FIG. 14, it was confirmed that CaP composite fine particles having a surface uniformly coated with spherical CaP were obtained without being affected by the molecular weight of polylactic acid.

  FIG. 15 shows the relationship between the particle diameter of the CaP composite fine particles calculated based on FIG. 14 and the molecular weight of polylactic acid. FIG. 15 is a graph showing the relationship between the particle size of the CaP composite fine particles obtained in this example and the molecular weight of polylactic acid, the vertical axis shows the particle size, and the horizontal axis shows the molecular weight of polylactic acid. As shown in FIG. 15, in this example, CaP composite fine particles having a particle diameter of about 7 to 30 μm were obtained.

[Example 12: Preparation 4 of CaP composite fine particles]
In a sample bottle of 50 ml capacity, 2.5 g of dichloromethane containing polylactic acid (molecular weight 5,000) is added to 25 g of water containing 0.2% by mass of spherical CaP, and the dispersion is obtained by stirring the sample bottle. Produced. The concentration of polylactic acid in dichloromethane was 2.0% by mass, 4.8% by mass or 9.1% by mass. The obtained dispersion was allowed to stand at room temperature for 24 hours to evaporate dichloromethane to produce CaP composite fine particles.

  Next, the obtained CaP composite fine particles were observed with a scanning electron micrograph. The results are shown in FIG. FIG. 16 is a diagram showing the results of observation of the CaP composite fine particles obtained in this example with a scanning electron microscope. (A) and (a ′) are cases where the concentration of polylactic acid is 2.0% by mass. (B) and (b ′) show the results when the polylactic acid concentration is 4.8% by mass, and (c) and (c ′) show the polylactic acid concentration of 9.1 masses. The result when% is shown. In all cases, it was confirmed that CaP composite fine particles whose surface was uniformly coated with spherical CaP were obtained.

  FIG. 17 shows the relationship between the particle size of the CaP composite fine particles calculated based on FIG. 16 and the polylactic acid concentration. FIG. 17 is a graph showing the relationship between the particle size of the CaP composite fine particles obtained in this example and the polylactic acid concentration, where the vertical axis shows the particle size and the horizontal axis shows the polylactic acid concentration. As shown in FIG. 17, in this example, CaP composite fine particles having a particle diameter of about 7 to 20 μm were obtained.

[Example 13: Cell adhesion of CaP composite fine particles]
In this example, cell adhesion to the CaP composite fine particles obtained in Example 8 was confirmed. First, the CaP composite fine particles were placed on a polyethylene terephthalate (PET) film. For comparison, fine particles from which CaP was removed by dropping hydrochloric acid aqueous solution (pH 2) onto the CaP composite fine particles obtained in Example 8 (hereinafter referred to as “polylactic acid fine particles”) were placed on a PET film. .

Next, ethanol was dropped onto each PET film and sterilized for 5 minutes, and then the PET film was placed in a 24-well multiplate. Next, the cultured L929 fibroblasts (1.0 × 10 ⁵ cells) were seeded on each PET film and cultured for 24 hours under conditions of 37 ° C. and CO ₂ concentration of 5%. After the culture, the culture solution was removed, and the PET film was collected using tweezers. Next, the collected PET film was washed three times with a phosphate buffer at 37 ° C., and then fixed with a 5% glutaraldehyde solution for 20 minutes. Next, 30%, 50%, 70%, 90%, 95%, 99.5%, 100% ethanol and butanol were dehydrated in this order for 15 minutes, and then lyophilized. The PET film after lyophilization was observed with a scanning electron microscope. The results are shown in FIG. FIG. 18 is a diagram showing the results of observing cell adhesion to CaP composite particles, (a) shows the results when CaP composite particles are used, and (b) shows the results when polylactic acid particles are used. Show.

  As shown in FIG. 18, when polylactic acid microparticles were used, fibroblasts were hardly confirmed. This indicates that the adhesion of fibroblasts to the polylactic acid fine particles was extremely low. On the other hand, when CaP composite microparticles were used, it was observed that fibroblasts were adhered to CaP composite microparticles. From this, the excellent cell adhesiveness of the CaP composite fine particles whose surface was coated with CaP was shown.

[Example 14: Preparation of dispersion]
In this example, a dispersion was prepared in which the dispersion medium was oil (dichloromethane in which polylactic acid was dissolved), the dispersoid was water, and the dispersant was rod-shaped CaP prepared in Example 1. In this example, in order to produce the dispersion more efficiently, the rod-shaped CaP that is the dispersant was modified with polylactic acid. As a result, the dispersant is easily dispersed in the dispersion medium, and the dispersion can be more easily produced. Hereinafter, for convenience of description, rod-like CaP modified with polylactic acid is referred to as “polylactic acid-modified CaP”.

(14-1: Modification of rod-like CaP with polylactic acid)
First, a method of modifying rod-like CaP with polylactic acid will be described. The rod-shaped CaP prepared in Example 1 and dichloromethane were added to a 50 ml glass container. Next, dichloromethane in which polylactic acid (molecular weight 5,000) was dissolved was added. At this time, the mass ratio of rod-shaped CaP and polylactic acid was set to 0.3 / 1. Next, dichloromethane was evaporated at room temperature, and the remaining rod-like CaP and polylactic acid mixture was heat-treated under reduced pressure. The heat treatment temperature was 100 ° C., 150 ° C., or 200 ° C.

  Here, it was observed that polylactic acid-modified CaP (heat treated at 150 ° C.) was added to dichloromethane. The result is shown in FIG. FIG. 19 is a diagram showing the results of observation of adding polylactic acid-modified CaP to dichloromethane, (a) shows the results when polylactic acid-modified CaP is used, and (b) is a rod not modified with polylactic acid. The result in the case of using CaP is shown.

  As shown in FIG. 19, polylactic acid-modified CaP was uniformly dispersed in dichloromethane, but when rod-like CaP not modified with polylactic acid was used, precipitation of the rod-like CaP was confirmed. From this result, it was confirmed that the dispersibility in dichloromethane is improved by modifying CaP with polylactic acid.

(14-2: Production of dispersion using polylactic acid-modified CaP as a dispersant)
Next, a dispersion was prepared using the polylactic acid-modified CaP obtained in 14-1 above (heat treated at 150 ° C.) as a dispersant. Specifically, it is as follows. First, polylactic acid (molecular weight 5,000) and polylactic acid-modified CaP were added to dichloromethane so as to obtain a solid content concentration of CaP of 0.66% by mass and polylactic acid of 2% by mass to obtain a suspension. . After measuring 25 ml of the obtained suspension in a sample bottle (50 ml), 5 mg of water was added to the sample bottle. Next, it was emulsified by stirring for 5 minutes at 38 kHz, 120 W and room temperature using an ultrasonic bath (model name: US-2, manufactured by SND Corporation). The obtained dispersion was observed using an optical microscope (James Switch MP3502, Prior Scientific Instruments Ltd.) equipped with a digital camera (Nikon Coolpix 4500). The result is shown in FIG. FIG. 20 is a diagram showing the results of observing the dispersion obtained in this example. As shown in FIG. 20, in this example, a dispersion in which droplets having a diameter of about 50 μm were dispersed was obtained.

  Further, the conductivity of the dispersion obtained in this example was measured using a conductivity meter (D-24 manufactured by HORIBA). As a result, it was 1 mS / cm or less. From this result, it was confirmed that the dispersion obtained in this example was a water-in-oil type dispersion.

  In addition, a water-in-oil type dispersion was obtained even when polylactic acid-modified CaP produced at a heat treatment temperature of 200 ° C. was used. When polylactic acid-modified CaP produced at a heat treatment temperature of 100 ° C. was used, an oil-in-water dispersion was obtained. This is considered because polylactic acid peeled from CaP. Moreover, even when the rod-shaped CaP produced in Example 1 was used as it was, an oil-in-water dispersion was obtained. Thus, in this example, it was confirmed that the water-in-oil dispersion and the oil-in-water dispersion could be selectively produced depending on the properties of the dispersant.

[Example 15: Aggregation of dispersoids by pH operation]
In this example, dispersoids were assembled by adding acid to the dispersion obtained in Example 14 (using polylactic acid-modified CaP prepared as a dispersant at a heat treatment temperature of 150 ° C.).

  Specifically, nitric acid was mixed with the dispersion (15 mL) to adjust the pH to 3.0 or less. Next, an aqueous potassium hydroxide solution was mixed to adjust the pH to 5 or more, and the mixture was stirred with a homogenizer. The result is shown in FIG. FIG. 21 shows a study of reducing the pH of the solvent of the dispersion obtained in Example 14 to collect the dispersoid, and further increasing the pH to redisperse the liquid after the dispersoid has collected. It is a figure which shows a result, (a) before adding an acid, (b) after adding an acid, (c) shows the result of having observed the external appearance of the sample bottle after adding an alkali.

  Within several tens of seconds after mixing the nitric acid, as shown in FIG. 21 (b), droplets gathered to separate the aqueous phase and the oil phase. Further, when alkali (potassium hydroxide solution) was mixed, it was redispersed as shown in FIG.

[Example 16: Preparation of dispersion]
In this example, a dispersion (W / O / W type dispersion) in which oil droplets were dispersed using water as a dispersion medium and water droplets were dispersed in the oil droplets was prepared.

  First, the dispersion obtained in Example 14 (using polylactic acid-modified CaP prepared with a heat treatment temperature of 150 ° C. as a dispersant) (2.5 ml) was weighed into a sample bottle (50 ml), and the sample bottle was used. Was added with water (25 ml) containing 0.1 g of spherical CaP prepared in Example 1. Next, the W / O / W type dispersion was obtained by stirring the sample bottle.

  The obtained W / O / W type dispersion was observed with an optical microscope. The result is shown in FIG. FIG. 22 is a diagram showing the results of observing the dispersion obtained in this example. As shown in FIG. 22, the W / O / W type dispersion obtained in this example was stable, and it was confirmed that water was dispersed in oil droplets dispersed in water. The size of the oil droplets was about 60 μm.

[Example 17: Set 2 of dispersoids by pH operation]
In this example, the dispersoid was assembled by adding an acid to the W / O / W type dispersion obtained in Example 16.

  Specifically, nitric acid was mixed with the dispersion (15 mL) to adjust the pH to 3.0 or less. Next, an aqueous potassium hydroxide solution was mixed to adjust the pH to 5 or more, and the mixture was stirred with a homogenizer. The result is shown in FIG. FIG. 23 shows a study of lowering the pH of the solvent of the dispersion obtained in Example 16 to collect the dispersoid, and further increasing the pH to redisperse the liquid after the dispersoid has gathered. It is a figure which shows a result, (a) before adding an acid, (b) after adding an acid, (c) shows the result of having observed the external appearance of the sample bottle after adding an alkali.

  Within tens of seconds after the nitric acid was mixed, as shown in FIG. 23 (b), droplets gathered to separate the water phase and the oil phase. Further, when alkali (potassium hydroxide solution) was mixed, it was redispersed as shown in FIG.

[Example 18: Preparation 5 of CaP composite fine particles]
The W / O / W dispersion obtained in Example 16 was allowed to stand at room temperature for 24 hours to evaporate dichloromethane. Next, water was evaporated by drying at 60 ° C. for 24 hours. Thereby, CaP composite fine particles were obtained.

  The obtained CaP composite fine particles were further dried at 60 ° C., put in a polyethylene capsule, and then embedded in an epoxy resin made by Agar SCIENTIFIC LTD. Next, using an ultramicrotome diamond knife (manufactured by Sumitomo Electric, product number: SK3045), the epoxy resin was cut into a thickness of 100 nm to prepare a slice. The section was observed using a transmission electron microscope (manufactured by PHILIPS, product number: CM120). The results are shown in FIG. FIG. 24 is a diagram showing a result of observing a cross section of the CaP composite fine particles obtained in this example using a transmission electron microscope. In FIG. 24, (a) shows the entire CaP composite fine particle, and (b) shows the wall surface of the space formed in the CaP composite fine particle. This space originates from the water droplets dispersed in the oil droplets in the W / O / W type dispersion state before obtaining the CaP composite fine particles.

  As shown in FIG. 24, CaP composite fine particles in which spherical CaP uniformly coats the outer surface and rod-like CaP uniformly coats the inner surface, and polylactic acid is included as an arbitrary substance are obtained. I was able to confirm. The particle diameter of the composite particles was about 10 μm.

[Example 19: Preparation 6 of CaP composite fine particles]
In this example, CaP composite fine particles having a surface coated with CaP and having CaP dispersed therein were produced.

  First, polylactic acid (molecular weight 5,000) and polylactic acid-modified CaP obtained in Example 14 were added to dichloromethane so that the solid concentration was 0.66% by weight of CaP and 2% by weight of polylactic acid. A suspension was obtained. 2.5 ml of the obtained suspension was weighed into a sample bottle (50 ml), and water (25 ml) containing 0.1 g of spherical CaP obtained in Example 1 was added to the sample bottle. Next, the sample bottle was stirred. This gave a dispersion.

  Next, the obtained dispersion was allowed to stand at room temperature for 24 hours to evaporate dichloromethane. Next, water was evaporated by drying at 60 ° C. for 24 hours. Thereby, CaP composite fine particles were obtained.

  The obtained CaP composite fine particles were dried at 60 ° C., put in a polyethylene capsule, and then embedded in an epoxy resin made by Agar SCIENTIFIC LTD. Next, using an ultramicrotome diamond knife (manufactured by Sumitomo Electric, product number: SK3045), the epoxy resin was cut into a thickness of 100 nm to prepare a slice. The section was observed using a transmission electron microscope (manufactured by PHILIPS, product number: CM120). The result is shown in FIG. FIG. 25 is a diagram showing a result of observing a cross section of the CaP composite fine particles obtained in this example using a transmission electron microscope. It was confirmed that the CaP composite fine particles obtained in this example were uniformly coated with spherical CaP on the outer surface and rod-like CaP was dispersed inside. The particle size of the CaP composite fine particles was about 10 μm.

[Example 20: Preparation of dispersion 2 using oil for which a stable dispersion was not obtained in Example 2]
This example is a dispersion obtained by mixing polyethylene terephthalate, polymethyl methacrylate, and polyvinyl acetate, which are polymer compounds having a carbonyl group, with dichloromethane, which is an oil for which a stable dispersion was not obtained in Example 2. Tried to form. For comparison, the same study was performed using polystyrene, which is a polymer having no carbonyl group.

  First, each polymer was dissolved in dichloromethane at a concentration of 1% by mass with respect to dichloromethane. In addition, except having used the spherical CaP obtained in Example 1 as a dispersing agent, and using the dichloromethane which melt | dissolved the said high molecular compound as oil, preparation of the dispersion was performed by performing the same operation as Example 2. FIG. The result is shown in FIG. FIG. 26 is a diagram showing the results of observing the dispersion obtained in this example. (A) shows the results when polyethylene terephthalate is used, and (b) shows the results when polymethyl methacrylate is used. (C) shows the results when using polyvinyl acetate, and (d) shows the results when using polystyrene.

  As shown in FIG. 26, when polystyrene, which is a polymer having no carbonyl group, was used, coarse droplets were observed, and a stable dispersion could not be obtained. On the other hand, a stable dispersion was obtained by using polyethylene terephthalate, polymethyl methacrylate, and polyvinyl acetate, which are polymers having a carbonyl group.

  The dispersion according to the present invention uses only CaP having high biocompatibility as a dispersant, and further does not contain a surfactant other than CaP. Moreover, the CaP hollow particle, the CaPCaP porous body, and the composite fine particles according to the present invention have high biocompatibility. Therefore, it can be suitably used as a biomaterial such as a drug carrier, cell culture material, medical material, and dental material.

It is a figure which shows the result of having observed CaP obtained in Example 1 with the scanning electron microscope. It is a figure which shows the result of having observed the dispersion obtained in Example 3. FIG. It is a figure which shows the result of having observed the dispersion obtained in Example 4 with the optical microscope. It is a figure which shows the result of having measured the oil droplet size distribution of the dispersion obtained in Example 4. FIG. It is a figure which shows the result of having observed the dispersion obtained in Example 5 24 hours after preparation. It is a figure which shows the result of having observed the dispersion obtained in Example 5 with the optical microscope 24 hours after preparation. In Example 6, it is a figure which shows the result of having investigated the redispersion of the liquid after lowering | hanging the pH of the solvent of a dispersion | distribution, collecting a dispersoid, and raising the pH further, and the said dispersoid collected. . It is a figure which shows the result of having observed the CaP porous body obtained in Example 7 with the scanning electron microscope. It is a figure which shows the result of having observed the dispersion obtained in Example 8 with the optical microscope. It is a figure which shows the result of having observed the CaP composite fine particle obtained in Example 8 with the scanning electron microscope. It is a figure which shows the result of having observed the CaP composite fine particle obtained in Example 9 with the scanning electron microscope. It is a figure which shows the result of having observed the CaP composite fine particle obtained in Example 10 with the scanning electron microscope. It is a figure which shows the result of having observed the cross section of the CaP composite fine particle obtained in Example 8 using the transmission electron microscope. It is a figure which shows the result of having observed the CaP composite fine particle obtained in Example 11 with the scanning electron microscope. It is a figure which shows the relationship between the particle diameter of the CaP composite fine particle obtained in Example 11, and the molecular weight of polylactic acid. It is a figure which shows the result of having observed the CaP composite fine particle obtained in Example 12 with the scanning electron microscope. It is a figure which shows the relationship between the particle diameter of the CaP composite fine particle obtained in Example 12, and a polylactic acid density | concentration. It is a figure which shows the result of having observed the cell adhesiveness with respect to CaP composite fine particle. It is a figure which shows the result of having observed a mode that polylactic acid modification CaP was added to the dichloromethane. It is a figure which shows the result of having observed the dispersion obtained in Example 14. FIG. The figure which shows the result of having examined the redispersion of the liquid after lowering the pH of the solvent of the dispersion obtained in Example 14 to aggregate the dispersoid, and further raising the pH to collect the dispersoid. It is. It is a figure which shows the result of having observed the dispersion obtained in Example 16. FIG. The figure which shows the result of having investigated the redispersion of the liquid after lowering | hanging the pH of the solvent of the dispersion obtained in Example 16, and collecting a dispersoid, and also raising the pH and the said dispersoid collected. It is. It is a figure which shows the result of having observed the cross section of the CaP composite fine particle obtained in Example 18 using the transmission electron microscope. It is a figure which shows the result of having observed the cross section of the CaP composite fine particle obtained in Example 19 using the transmission electron microscope. It is a figure which shows the result of having observed the dispersion obtained in Example 20. FIG.

Claims (20)

A dispersion comprising a hydrophilic liquid, a hydrophobic material, and calcium phosphate,
Dispersion characterized in that the hydrophobic substance is methyl myristate . The dispersion according to claim 1, wherein the calcium phosphate is calcium phosphate having an average particle diameter of 1 nm to 1000 nm. The dispersion according to claim 1, wherein the calcium phosphate is hydroxyapatite. The dispersion according to claim 1, wherein the calcium phosphate is a sintered body of hydroxyapatite. A dispersion comprising a hydrophilic liquid, a hydrophobic material, and calcium phosphate,
The hydrophobic substance is a substance containing at least one compound selected from a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane.
A dispersion containing the first liquid droplet and the second liquid droplet in the dispersion medium, using the hydrophilic liquid or the hydrophobic substance as a dispersion medium,
The first droplet is formed by coating the calcium phosphate with the hydrophilic liquid and the hydrophobic substance which is not the dispersion medium, and is dispersed in the dispersion medium.
The second droplet is formed by coating the hydrophilic liquid when the dispersion medium is the hydrophilic liquid, and covering the hydrophobic substance when the dispersion medium is the hydrophobic substance with the calcium phosphate. A dispersion, wherein the dispersion is dispersed in the first droplet. A method for producing a dispersion comprising a hydrophilic liquid, a hydrophobic substance, and calcium phosphate,
Mixing a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a hydrophobic substance containing at least one compound selected from a cyclic olefin having a carbonyl group and an alkane, a hydrophilic liquid, and calcium phosphate Including steps,
The dispersion disperses a hydrophobic substance containing at least one compound selected from a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane, or a hydrophilic liquid. As a medium, a dispersion in which the first droplet is dispersed in the dispersion medium, and the second droplet is dispersed in the first droplet,
By mixing the hydrophobic substance, the hydrophilic liquid, and the calcium phosphate to make the dispersion medium the hydrophilic liquid, the hydrophilic liquid is used, and the dispersion medium is the hydrophobic substance. The first dispersion in which the second droplet formed by coating the hydrophobic substance with the calcium phosphate is dispersed in the hydrophilic liquid and the hydrophobic substance that is not the dispersion medium. A first mixing step for producing
By mixing the first dispersion, the dispersion medium, and the calcium phosphate, the first droplet formed by coating the first dispersion with calcium phosphate is dispersed in the dispersion medium. And a second mixing step for producing the dispersion. The method for producing a dispersion according to claim 6, wherein a hydrophobic substance in which a saturated organic compound having a carbonyl group is mixed in advance is used. A hydrophilic liquid, a hydrophobic substance, and calcium phosphate, wherein the hydrophobic substance is methyl myristate, and one of the hydrophilic liquid and the hydrophobic substance is used as a dispersion medium, and the other is a dispersoid. And a dispersoid assembly method comprising mixing an acidic compound with a dispersion containing calcium phosphate as a dispersant. A hydrophilic liquid, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a hydrophobic substance containing at least one compound selected from a cyclic olefin having a carbonyl group and an alkane, and calcium phosphate, By mixing one of the hydrophilic liquid and the hydrophobic substance as a dispersion medium, the other as a dispersoid, and a dispersion containing calcium phosphate as a dispersant, the dispersoid is collected. A method for redispersing a dispersoid, wherein an alkaline compound is mixed with a liquid. Including the following steps (i) and (ii):
(i) a step of producing a dispersion by mixing a hydrophilic liquid, a hydrophobic substance, and calcium phosphate;
(ii) a step of firing the dispersion;
The method for producing hollow calcium phosphate particles, wherein the hydrophobic substance is a saturated fatty acid ester. Before the step (ii) above,
(iii) drying the dispersion
The manufacturing method of the calcium-phosphate hollow particle of Claim 10 characterized by the above-mentioned. Including the following steps (iv) to (vi):
(iv) a step of producing a dispersion by mixing a hydrophilic liquid, a hydrophobic substance, and calcium phosphate;
(v) concentrating droplets dispersed in the dispersion;
(vi) firing the dense droplets;
The method for producing a porous calcium phosphate, wherein the hydrophobic substance is a saturated fatty acid ester. Before step (vi) above,
(vii) drying the dispersion
The manufacturing method of the calcium-phosphate porous body of Claim 12 characterized by the above-mentioned. A method for producing calcium phosphate composite fine particles in which an arbitrary substance is coated with calcium phosphate, comprising the following steps (viii) and (ix):
(Viii) a hydrophobic liquid containing at least one compound selected from a hydrophilic liquid, a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane, and calcium phosphate And a step of producing a dispersion by mixing with
(Ix) drying the dispersion;
A method for producing calcium phosphate composite fine particles, wherein in the step (viii), the arbitrary substance is mixed in advance with the hydrophilic liquid or the hydrophobic substance. The dispersion produced in the step (viii) comprises a hydrophobic compound containing at least one compound selected from a saturated organic compound having a carbonyl group, a vinylene compound having a carbonyl group, a cyclic olefin having a carbonyl group, and an alkane. A dispersion in which the first droplet is dispersed in the dispersion medium, and the second droplet is dispersed in the first droplet, using the active substance or the hydrophilic liquid as a dispersion medium,
The step (viii)
By mixing the hydrophobic substance, the hydrophilic liquid, and the calcium phosphate to make the dispersion medium the hydrophilic liquid, the hydrophilic liquid is used, and the dispersion medium is the hydrophobic substance. Forms the first dispersion in which the second droplet formed by coating the hydrophobic substance with the calcium phosphate is dispersed in the hydrophilic liquid and the hydrophobic substance that is not the dispersion medium. A first mixing step;
By mixing the first dispersion, the dispersion medium, and the calcium phosphate, the first droplet formed by coating the first dispersion with calcium phosphate is dispersed in the dispersion medium. A second mixing step to form a dispersion of
A process including
The method for producing calcium phosphate composite fine particles according to claim 14, wherein, in the first mixing step, at least one of the hydrophilic liquid and the hydrophobic substance is mixed in advance with the arbitrary substance. A biomaterial comprising the dispersion according to any one of claims 1 to 5. A drug carrier comprising the biomaterial according to claim 16. A cell culture material comprising the biomaterial according to claim 16. A medical material comprising the biomaterial according to claim 16. A dental material comprising the biomaterial according to claim 16.