JP4669951B2 - Method for producing polymer-coated fine particles and polymer-coated fine particles - Google Patents

Description

  The present invention relates to a method for producing polymer-coated fine particles and polymer-coated fine particles, and more particularly to a method for producing polymer-coated fine particles having a stable coating, and a polymer-coated fine particle that is uniformly coated with a polymer and has a uniform particle size.

  Polymer fine particles and polymer-coated fine particles coated with various fine particles with polymers have not only been widely used in the industrial field, but in recent years their importance has increased in the fields of basic biology and medicine. For example, there is a growing interest in applications to affinity chromatography carriers, for example, in medical diagnosis and drug delivery systems (drug delivery systems, DDS).

  Among these applications, affinity chromatography supports are applied to polymer microparticles as carriers, ligands that are substances that specifically bind to biomolecules such as proteins are immobilized on these carriers, and the activity of these ligands is utilized. Specific biomolecules are separated and purified. The inventors of the present invention have provided styrene / glycidyl methacrylate (GMA) polymer particles, which are spherical polymer fine particle carriers, and polymer fine particles (microspheres) that are provided with spacers and can bind physiologically active substances via the spacers. , Patent Document 1: Japanese Patent Laid-Open No. 10-195099), and thereby greatly increasing the amount of ligand immobilized, and the problem of non-specific adsorption, which has been regarded as a problem of conventional affinity chromatography carriers Could be solved.

  When a magnetic substance is introduced into such polymer fine particles, it can be operated using magnetic force, and separation from the aqueous phase can be performed more simply and quickly than centrifugation. The present inventors have developed fine particles in which magnetic fine particles are combined with the polymer fine particles to form a composite (Patent Document 2: JP-A-2002-090366). In addition, the present inventors have developed a ferrite-bound organic substance that has been magnetized by directly bonding the organic substance and ferrite, and has many desirable properties in applications such as purification and identification of receptors for specific drugs. (Patent Document 3: WO 03/066644 A1). Many other research results on polymer fine particles into which a magnetic material has been introduced and their applications are described in Scientific and Clinical Application of Magnetic Carriers Plenum Press 1997 (Non-patent Document 1).

  Inorganic particles such as magnetic substances are coated with a polymer, a functional group capable of reacting with a biological molecule or a chemical molecule is introduced into the coating, and a biological molecule or a chemical molecule is bonded to the functional group, Utilization of specific interaction of the molecule for use in detection or separation / purification of a specific biological substance is also described in, for example, Japanese Patent Publication No. 2003-513093 (Patent Document 4).

  In addition to the above-mentioned affinity chromatography, in addition to the above-mentioned affinity chromatography, the application of polymer fine particles or polymer-coated fine particles in which various types of fine particles are coated with a polymer is applied to various labels such as gold labels and fluorescent labels. And application of magnetic resonance diagnosis (MRI) to sensitizers. In the case of a gold label or a fluorescent label, an appropriate polymer coating is desired to prevent nonspecific adsorption of biomolecules to the surface. Further, as a fluorescent label, in addition to a fluorescent label using a conventional fluorescent dye such as an organic substance, there is an increasing interest in the usefulness of a fluorescent label using a semiconductor nanocrystal particle (quantum dot). As described in, for example, Nano Lett., Vol. 2, 263-268 (2002) (Non-Patent Document 2), quantum dots have a sharp emission spectrum compared to conventional dye substances, and the wavelength depends on the particle size. It has many advantages such as being able to select.

In order to use quantum dots as fluorescent markers for diagnosis, etc., in addition to being protected and chemically stable, quantum dots have high affinity for water in the living body and nonspecific adsorption of biomolecules. And a functional group that can bind to a substance such as a biological substance to be detected. For this reason, it is desirable that an appropriate polymer coating be applied to the quantum dots. A water-soluble light-emitting quantum dot provided with a hydrophilic binding group is described in JP-T-2002-530630 (Patent Document 5).
Japanese Patent Laid-Open No. 10-195099 JP 2002-090366 A WO 03/066644 A1 publication Patent publication 2003-513093 Japanese translation of PCT publication No. 2002-530630 Scientific and Clinical Application of Magnetic Carriers Plenum Press 1997 Nano Lett., Vol.2, 263-268 (2002)

  The polymer coating on various fine particles such as magnetic materials, quantum dots, and gold fine particles is well coated without any coating leakage, and the coating is physically and chemically stable. It is desirable to be a thing. In the case where the polymer coating of the fine particles is uneven and the coating is leaked, there is a concern that the fine particles may aggregate or the fine particles may cause nonspecific adsorption of the biological material. If the coating is not stable, the polymer-coated fine particles may be damaged during use.

  The present invention relates to a method for producing polymer-coated fine particles capable of obtaining a uniform and stable polymer coating on the fine particles, and polymer-coated fine particles whose coating is made uniform and stable by the polymer and does not cause the above-mentioned concerns. The purpose is to provide.

  The present invention has been made based on the following research results. That is, as a result of repeated studies on the polymer coating method for ferrite, which is a hydrophilic fine particle, the present inventors have found that uniform and stable polymer coating can be realized by using the following method.

  First, ferrite fine particles were precipitated from an aqueous solution containing divalent iron ions. Next, the surface of the hydrophilic fine particles was made hydrophobic by coating with 10-undecenoic acid. Here, 10-undecenoic acid is a fatty acid having a double bond at the end of a hydrophobic group. The ferrite fine particles hydrophobized by the coating of 10-undecenoic acid are dispersed in an organic solvent to form a suspension, and this suspension is mixed with water to which 10-undecenoic acid is added. An emulsified liquid having emulsified particles formed by surrounding fine droplets of the suspension was obtained. Subsequently, while maintaining the state of the fine emulsified particles, the organic solvent was removed from the emulsion by evaporating and leaving 10-undecenoic acid on the surface, thereby being double coated with 10-undecenoic acid and hydrophilized. Ferrite fine particles were obtained.

  Next, a hydrophobic monomer is added to the dispersion in which the ferrite fine particles are dispersed in water, and the monomer is absorbed into the hydrophobic layer between the 10-undecenoic acid double coating layers of the ferrite fine particles to form re-emulsified particles. By doing so, a re-emulsified liquid could be obtained. Subsequently, polymer-coated ferrite fine particles could be obtained by polymerizing the monomer of the re-emulsified particles of the re-emulsified liquid. This polymer coating was not only polymerized between monomers but also copolymerized with 10-undecenoic acid, and the polymer coating was highly stable. In addition, this polymer coating can use an emulsification process, and polymer-coated fine particles having a spherical shape and a uniform particle size can be obtained.

  As a result of further research, it was found that this polymer coating method can be applied not only to ferrite fine particles but also to various other hydrophilic fine particles, and also to hydrophobic fine particles. Further, it was found that the double coating formed on the surface of the fine particles can use various substances in addition to 10-undecenoic acid.

  In the method for producing polymer-coated fine particles of the present invention, the hydrophilic group of a hydrophobic substance having a hydrophilic group and a hydrophobic group is adsorbed on the surface of the hydrophilic fine particle to form a hydrophobic substance layer, and the hydrophobic group is present on the outer surface. Hydrophobizing step of hydrophobizing hydrophilic fine particles to obtain hydrophobic fine particles, a suspension step of suspending hydrophobic fine particles in an organic solvent to obtain a suspension, and a hydrophilizing substance having a hydrophobic group and a hydrophilic group This suspension is mixed with water containing water to give a mixture, and ultrasonic vibration is applied to the mixture to obtain an emulsion in which emulsified particles in which the hydrophilic substance surrounds the suspension are dispersed in water. Hydrophobic by forming a layer of hydrophilic particles by emulsifying and evaporating the organic solvent contained in the emulsified particles while applying ultrasonic vibration to the emulsified liquid and adsorbing the hydrophilic substance on the surface of the hydrophobic particles Hydrophobize the microparticles with the hydrophobic material layer. An organic solvent evaporating step for obtaining hydrophilized fine particles in which a hydrophobic layer is formed between the layer of the hydrophilizing substance adsorbed on the water, and suspending the hydrophilized fine particles in water and adding a monomer to the water, The monomer-absorbing and re-emulsifying step in which the monomer is absorbed and re-emulsified in the hydrophobic layer of the pulverized fine particles, and the monomer absorbed by the hydrophilized fine particles in the re-emulsified liquid is polymerized to form the polymer-coated fine particles. And a monomer polymerization step to be obtained.

  In the hydrophobizing step in the method for producing polymer-coated microparticles of the present invention, the hydrophobizing substance is adsorbed to the microparticles in the water in which the hydrophilic microparticles are suspended, and then the water is removed, thereby removing the water. The hydrophobic substance can be adsorbed evenly.

  In the method for producing polymer-coated microparticles of the present invention, as described above, the hydrophilic microparticles are adsorbed on the hydrophobic microparticles to obtain the hydrophilized microparticles. Use. According to these steps, the hydrophobic fine particles are dispersed and suspended in an organic solvent, and this is mixed with water having a hydrophilic substance and emulsified using ultrasonic vibration, whereby the suspension surrounded by the hydrophilic substance in water is obtained. As the emulsified particles, fine particles having a uniform particle size can be obtained. By applying ultrasonic vibration to the emulsified particles to maintain a fine and uniform particle size state, the organic solvent in the emulsified particles is evaporated to obtain fine and well-equipped hydrophilic particles. it can. During the evaporation of the organic solvent, it is desirable to reduce the disorder of the structure of the emulsified particles. For this reason, the evaporation is preferably allowed to proceed gradually over time.

  In the thus obtained hydrophilized fine particles, a hydrophobic layer is formed by the hydrophobic group of the hydrophobic substance adsorbed on the surface of the hydrophilic fine particles by the hydrophilic group and the hydrophobic group of the hydrophilic substance. This hydrophobic layer is an important layer for absorbing the hydrophobic monomer in the next step.

  In the method for producing polymer-coated fine particles of the present invention, as a step of obtaining polymer-coated fine particles by coating the hydrophilicized fine particles with a polymer, a monomer absorption / re-emulsification step in which monomers are absorbed into the hydrophilic fine particles to form re-emulsified particles; And an emulsion polymerization step of polymerizing the monomer of the re-emulsified particles. In the above-mentioned hydrophilic particles, a hydrophobic layer is formed by the hydrophobic substance and the hydrophobic group of the hydrophilic substance. When a hydrophobic monomer is introduced in the monomer absorption / re-emulsification process, the monomer is added to the hydrophobic layer. Affinity is selectively absorbed and penetrates well into this hydrophobic layer, so that the periphery of the fine particles can be covered well. Thus, each hydrophilized fine particle which absorbed the monomer is re-emulsified to become a re-emulsified particle. If the fine particles having the same particle diameter obtained by the above-described process are used as the hydrophilic fine particles at this time, it is possible to obtain spherical re-emulsified particles having the same particle diameter. Subsequently, the polymer of the re-emulsified particles is polymerized in the emulsion polymerization step to obtain spherical polymer-coated fine particles in which the fine particles are well coated with the polymer, and are fine and have a uniform particle size and no aggregation between the particles. Can do.

  Various monomers can be used as the monomer used here, and among them, various hydrophobic monomers that form polymers by addition polymerization are particularly suitable for adsorbing to the hydrophobic layer of fine particles. preferable.

  The above-mentioned hydrophobizing substance that hydrophobizes hydrophilic fine particles has hydrophilic properties such as sulfonic acid group, sulfuric acid group, phosphoric acid group, mercapto group, amino group and hydroxyl group as hydrophilic groups, and has a straight chain length as hydrophobic group. Various hydrophobic substances having a chain alkyl group (C8 to C20), a branched long chain alkyl group (C8 to C20), a long chain alkyl group (C8 to C15) and an alkylbenzene residue can be used.

Among them, those having a carboxyl group in the hydrophilic group are preferable because they have good adsorption to hydrophilic substances, and those having a vinyl group in the hydrophobic group as the hydrophobic substance are preferably used in the emulsion polymerization step. Are polymerized and integrated, so that a stable polymer coating can be formed, which is particularly preferable. Such hydrophobic materials, for example _CH 2 _{= CH (CH} 2) may be mentioned 10-undecenoic acid or a salt thereof represented by the rational formula of 8 -COOH.

  The method for producing polymer-coated fine particles of the present invention may start from hydrophobic fine particles instead of making hydrophilic fine particles hydrophobic. That is, a suspension step in which hydrophobic fine particles are suspended in an organic solvent to obtain a suspension, and the suspension and water containing the hydrophilic substance are mixed to form a mixed solution. An emulsification step of obtaining an emulsion in which the suspension is surrounded by the hydrophilizing substance by applying sonic vibration, and the hydrophilization by evaporating the organic solvent contained in the emulsified particles while applying ultrasonic vibration to the emulsion. An organic solvent evaporation step for obtaining hydrophobic fine particles hydrophilized by the adsorption of the substance, and adsorbing the hydrophobic group of the hydrophilic substance having a hydrophobic group and a hydrophilic group on the surface of the hydrophobic fine particle so that the hydrophilic group is present on the outer surface. The polymer is polymerized by monomer polymerization in a hydrophobic layer comprising a hydrophilic substance adsorption step for hydrophilizing hydrophobic fine particles, and a hydrophobic surface of the hydrophobic fine particles and a hydrophobic group of the hydrophilic substance adsorbed on the surface. Sparse by forming Sex particles may also be those having a polymer coated particle generating step of obtaining a coated with a polymer polymer-coated particles.

  Further, the method for producing polymer-coated fine particles of the present invention comprises adsorbing the hydrophobic group of a hydrophilizing substance having a hydrophobic group and a hydrophilic group on the surface of the hydrophobic fine particle and causing the hydrophilic group to exist on the outer surface. A hydrophilic substance adsorbing step for hydrophilizing, the hydrophilic fine particles are suspended in water, a monomer is contained in the water, and the hydrophobic fine particle surface of the hydrophilic fine particles and the hydrophobic group of the hydrophilic substance adsorbed on the surface And a monomer absorption step for absorbing the monomer in the hydrophobic layer containing the monomer, and a monomer polymerization step for obtaining the polymer-coated fine particles by polymerizing the monomer of the hydrophilic fine particles that have absorbed the monomer.

  The double-layer coated fine particle of the present invention forms a layer of the hydrophobic substance by adsorbing the hydrophilic group of the hydrophobic substance having a hydrophilic group and a hydrophobic group on the surface of the hydrophilic fine particle, thereby forming the hydrophobic substance of the hydrophobic substance. Hydrophobic fine particles with groups existing on the outer surface, the hydrophobic fine particles are suspended in an organic solvent to form a suspension, and this suspension is mixed with water containing a hydrophilizing substance having a hydrophobic group and a hydrophilic group The mixture liquid is subjected to ultrasonic vibration to give an emulsion liquid in which the emulsified particles in which the hydrophilic substance surrounds the suspension are dispersed in water, and the ultrasonic vibration is applied to the emulsion liquid. Formed by refining emulsified particles and applying ultrasonic vibrations to evaporate the organic solvent contained in the emulsified particles while keeping the emulsified particles finer, and then coat these hydrophobic fine particles with a layer of hydrophilic fine particles Hydrophobic material layer and hydrophilic The double layer of the layer of material, characterized in that the hydrophilic fine particles are coated. In addition, when both the hydrophobizing substance and the hydrophilizing substance have a vinyl group at the end of the hydrophobic group, this double-layer-coated fine particle can form a polymer coating by polymerizing the vinyl group in the double layer. Polymer coated fine particles can be obtained.

  The polymer-coated fine particles of the present invention comprise hydrophilic fine particles and a polymer coating that coats the fine particles. The polymer coating comprises a monomer having a vinyl group, a vinyl group in a hydrophobic group, and a hydrophilic group. It is characterized by forming a copolymer with a hydrophobizing substance adsorbed on hydrophilic fine particles.

  In the polymer-coated fine particle of the present invention, the polymer coating comprises a monomer having a vinyl group, a hydrophobic substance having a vinyl group in a hydrophobic group and a hydrophilic group adsorbed on the hydrophilic fine particle, and a vinyl group in the hydrophobic group. It may be one having a hydrophilic group present on the outer surface of the polymer coating and forming a copolymer with a hydrophilic substance that hydrophilizes the polymer coating.

  The polymer-coated fine particle of the present invention is formed by copolymerization of a monomer having a double bond and a hydrophobic substance having a vinyl group and adsorbed on the hydrophilic fine particle. The coating is characterized by a stable polymer coating.

  The polymer-coated fine particles used in the organic solvent of the present invention are composed of the above-mentioned polymer-coated magnetic fine particles, and have organic solvent resistance. Further, the magnetic solid phase carrier for combinatorial chemistry of the present invention, a magnetic solid phase carrier for affinity chromatography of at least one of the group of chemical substances consisting of proteins, peptides, nucleic acids and drugs, and a magnetic solid phase for chemical synthesis of peptides or nucleic acids The carrier is characterized in that polymer-coated fine particles used in an organic solvent using magnetic fine particles as hydrophilic fine particles are used as the carrier.

  The magnetic solid support for combinatorial chemistry, the magnetic support for affinity chromatography, and the magnetic solid support for chemical synthesis having such a structure are methanol, 1,4-dioxane, N, N′-dimethylformamide, dimethyl, while having a very small size. An organic solvent that does not dissolve the polymer coating layer in the organic solvent even when immersed in an organic solvent such as sulfoxide, acetone, diethyl ether, toluene, chloroform, or hexane, and does not desorb from the magnetic particles. And a remarkable property that the state of the polymer coating is kept stable. By having such organic solvent resistance and magnetism, there can be an advantage that magnetic separation in an organic solvent is possible. For this reason, separation operations can be performed stably and rapidly in combinatorial chemistry, affinity chromatography, chemical synthesis and the like using these carriers.

  According to the production method of the present invention, polymer-coated fine particles in which a good and stable polymer coating is formed on the fine particles can be obtained. In addition, the particle sizes of the polymer-coated fine particles can be well aligned, and the particle size can be easily controlled. In addition, the polymer-coated fine particles according to the present invention have a polymer coating formed by copolymerization of a monomer having a double bond and a hydrophobic substance having a vinyl group and adsorbed on the hydrophilic fine particles. It is characterized by high. For this reason, according to the present invention, a good and stable polymer coating for various fine particles such as magnetic materials and quantum dots can be obtained, so that various polymer-coated fine particles suitable for use in biological sciences and medical treatment can be provided.

(Embodiment 1) [Production process of polymer-coated fine particles]
Next, based on an embodiment of the present invention, the present invention will be described in more detail with reference to the drawings.

  FIG. 1 shows a flow chart of steps in one embodiment of the method for producing polymer-coated fine particles in the present invention. In FIG. 1, a hydrophobic fine particle 4 is obtained by a hydrophobizing step 3 in which a hydrophobic substance 2 is adsorbed on the hydrophilic fine particle 1 to make it hydrophobic. As the hydrophobizing step 3, a method of adsorbing the hydrophobizing substance 2 to the hydrophilic fine particles 1 in water in which the hydrophilic fine particles are suspended and removing water can be used.

  Next, a hydrophilic substance is obtained by adsorbing a hydrophilic substance to the hydrophobic fine particles 4. In FIG. 1, hydrophobic fine particles 4 are suspended in an organic solvent 6 in a suspension step 5 to obtain a suspension 7. Next, in the emulsification step 8, the suspension 7 is mixed with water 10 containing the hydrophilizing substance 9 and emulsified by applying ultrasonic vibrations 11 so that the particle size surrounded by the hydrophilizing substance 9 is improved. An emulsified liquid 12 in which uniform fine emulsified particles are dispersed in water is obtained.

  Subsequently, in the organic solvent evaporating step 13, the emulsified liquid 12 is subjected to ultrasonic vibration 14 to gradually evaporate the organic solvent while keeping the emulsion particles fine, thereby making the particle size well-equalized. Fine particles 15 are obtained.

  Next, in the suspension / monomer absorption / re-emulsification step 16 of FIG. 1, the hydrophilized fine particles 15 are suspended in the water 17 and the monomer 17 and the hydrophobic initiator 18 are contained in the water 17. The re-emulsified liquid 19 in which the re-emulsified particles 19A are re-emulsified is obtained by absorbing the hydrophilic initiator 18 in the hydrophobic layer of the hydrophilized fine particles 15. Here, the hydrophobic layer of the hydrophilic fine particles 15 is a layer between the surface of the hydrophobic fine particles 4 and the hydrophilic substance 9 adsorbed thereto. Subsequently, in the emulsion polymerization step 20, the re-emulsified liquid 19 contains a hydrophilic initiator 21 for addition polymerization reaction and is heated 22 to obtain polymer-coated fine particles 23 having a uniform particle size.

  FIG. 2 is a diagram schematically showing the state of fine particles at the main stage from the fine particles to the production of polymer-coated fine particles in the process of FIG. In the hydrophilic fine particles 1 schematically shown in FIG. 2A, the hydrophobic substance 2 is adsorbed and coated in the hydrophobizing step 3 to form the hydrophobic fine particles 4, which are dispersed in the organic solvent 6. Thus, the suspension 7 schematically shown in FIG. This suspension 7 is mixed with water 10 containing a hydrophilizing substance 9, and is subjected to ultrasonic vibration 11 to be finely emulsified, resulting in an emulsified liquid 12 schematically shown in FIG. The emulsified particles 12A of the emulsified liquid 12 are formed by covering the surface of the droplets of the suspension 7 in which the hydrophobic fine particles 4 are suspended in the organic solvent 6 with a hydrophilizing substance, and the particle size is fine. It is well aligned. The emulsified particles 12A may be made finer so as to contain each of the coarse particles 3 one by one, or the particle size is made relatively larger than the hydrophobic fine particles 3 and a plurality of hydrophobic fine particles 3 are contained. You may do it. In any case, it is possible to obtain the emulsified particles 12A which are fine and have a uniform particle size. The organic solvent 6 of the emulsified particles 12A is gradually evaporated and removed over a sufficient period of time, whereby the suspension of the hydrophilized fine particles 15 schematically shown in FIG. It becomes.

  When the monomer and the hydrophobic initiator 18 are added together with the water 17 in the suspension / monomer absorption / re-emulsification step 16, the hydrophilic substance-adsorbing fine particles 15 are mixed with the hydrophilic fine particles 15. The re-emulsified particles 19A are formed by being absorbed into the hydrophobic layer, and the re-emulsified liquid 19 schematically shown in FIG. The re-emulsified liquid 19 contains a hydrophilic initiator 21 and is heated 20 to polymerize the monomer. As shown schematically in FIG. 2 (f), the particles are fine and have a uniform particle size. The polymer-coated fine particles 23 in which the aggregation between them is avoided are obtained. In FIG. 2 (f), the hydrophilic substance 9 is removed by the cleaning process.

  FIG. 3 shows the surface of the fine particle without using the hydrophobic substance 2 and the hydrophilic substance 9 having a vinyl group as the hydrophobic group in FIG. 2, and the hydrophilic fine particles 15 do not absorb the monomer and the hydrophobic initiator 18. The polymer 24 is formed by polymerizing the vinyl group of the layer made of the hydrophobic substance 2 and the hydrophilic substance 9 to obtain the polymer-coated fine particles 23. That is, in FIG. 3, (a) to (d) are the same as in FIG. 2, and the hydrophilized fine particles 15 in FIG. 3 (d) do not absorb the monomer and polymerize the hydrophobized substance 2 and the hydrophilized substance 9. As a result, polymer-coated fine particles 23 schematically shown in FIG.

  4 starts with the hydrophobic fine particles 4 instead of hydrophobizing the hydrophilic fine particles 1 in FIG. 2, and obtains polymer-coated fine particles of hydrophobic fine particles through the same steps as in FIG. That is, the suspension 7 in which the hydrophobic fine particles 4 schematically shown in FIG. 4A are suspended in the organic solvent 6 is emulsified, and the emulsion 12 schematically shown in FIG. Then, the organic solvent 6 is gradually evaporated and removed over a sufficiently long time to obtain a suspension of the hydrophilized fine particles 15 schematically shown in FIG. Water 17, a monomer and a hydrophobic initiator 18 are added to the hydrophilic substance-adsorbing fine particles 15, and the monomer and the hydrophobic initiator 18 are absorbed in the hydrophobic layer of the hydrophilized fine particles 15 and re-emulsified. A re-emulsified liquid 19 schematically shown in d) is obtained. The re-emulsified liquid 19 contains a hydrophilic initiator 21 and is heated 20 to polymerize the monomer, whereby the polymer-coated fine particles 23 schematically shown in FIG. Get. Note that FIG. 2E also illustrates the case where the hydrophilic substance 9 is removed by the cleaning process.

(Embodiment 2) [Hydrophobic substance]
In the method for producing polymer-coated fine particles, the hydrophobizing substance 2 for hydrophobizing the hydrophilic fine particles 1 has a hydrophilic group and a hydrophobic group, and the hydrophilic group is adsorbed on the surface of the hydrophilic fine particles 1 while the hydrophobic group. A substance that is present on the outer surface and hydrophobizes the fine particles is used. As the hydrophilic group of the hydrophobizing substance 2, a carboxyl group is particularly preferable because of good adsorption to hydrophilic fine particles such as ferrite fine particles.

  As the hydrophilic group of the hydrophobizing substance 2, sulfonic acid group, sulfuric acid group, phosphoric acid group, and mercapto group are preferable because of their good adsorption to the surface of hydrophilic fine particles. It is preferable because it has hydrophilicity and adsorption of hydrophilic fine particles to the surface can be obtained.

  On the other hand, as the hydrophobic group of the hydrophobizing substance 2, a linear long chain alkyl group (C8 to C20), a branched long chain alkyl group (C8 to C20), a long chain alkyl group (C8 to C15) and an alkylbenzene residue The group is preferable because the hydrophilic fine particles can be hydrophobized.

  As the hydrophobizing substance 2, those having a vinyl group at the hydrophobic group, that is, those having a double bond of carbon atoms at the end of the hydrophobic group are preferable. Hydrophobized substance 2 having a vinyl group as a hydrophobic group is adsorbed to hydrophilic fine particles by a hydrophilic group, while the vinyl group of the hydrophobic group is subjected to addition polymerization in the emulsion polymerization step 20 with a monomer absorbed in the hydrophobic layer. And integrated with the polymer. As a result, the polymer coating formed by polymerization forms a stable coating on the hydrophilic fine particles.

  As such a hydrophobic substance having a vinyl group in the hydrophobic group, a fatty acid or a salt thereof that adsorbs to the hydrophilic fine particles and hydrophobizes the hydrophilic fine particles is preferable. In the case where such a fatty acid does not have a double bond in addition to the vinyl group, a carbon number in the range of 6 to 18 is preferable for easily hydrophobizing the hydrophilic fine particles. Is more preferably in the range of 8 to 15, more preferably in the range of 10 to 15 carbon atoms. On the other hand, when such a fatty acid has a double bond in addition to the vinyl group, the carbon number is preferably in the range of 6 to 20, more preferably in the range of 10 to 20, and the carbon number is A range of 12 to 18 is more preferred.

Among them _{CH 2 = CH (CH 2)} 8 -COOH can be particularly preferably used 10-undecenoic acid or a salt thereof represented by the rational formula of. By using such a fatty acid or a salt thereof, a stable polymer coating such as hydrophilic fine particles such as ferrite and semiconductor quantum dots can be formed.

As the hydrophobizing substance, various phospholipids, such as lecithin, which are lipids containing alcohol, fatty acid, and phosphate residue and which are physiologically important lipids, can be used. Similarly, various glycolipids can be used.

(Embodiment 3) [Hydrophilic substance]
As the hydrophilic substance 9, various substances having a hydrophilic group and a hydrophobic group and adsorbed on the hydrophobic fine particles 4 to hydrophilize the fine particles can be used. The hydrophilic group of the hydrophilic substance 9 is preferably a group such as a sulfonic acid group, a sulfuric acid group, a phosphoric acid group, a mercapto group, an amino group, a hydroxyl group and a polyoxyethylene chain in addition to a carboxyl group. On the other hand, the hydrophobic group of the hydrophilic substance includes a linear long chain alkyl group (C8 to C20), a branched long chain alkyl group (C8 to C20), a long chain alkyl group (C8 to C15), and an alkylbenzene residue. Groups are preferred.

  Further, as the hydrophilic substance, a surface active substance having a vinyl group in the hydrophobic group, that is, a substance having a carbon atom double bond at the end of the hydrophobic group can be used. When such a hydrophilic substance is used, the hydrophilic group is copolymerized with the monomer by the vinyl group of the hydrophilic substance and fixed integrally with the polymer, so that the hydrophilic group of the hydrophilic substance, for example, carboxyl By leaving the group on the surface of the polymer-coated fine particles, a biological substance having an amino group can be bound thereto. Moreover, deoxycholic acid which is a secondary bile acid can also be used as the hydrophilic substance.

  Further, the hydrophilizing substance on the surface of the polymer-coated fine particles that are not copolymerized with the polymer can be removed by washing.

(Embodiment 4) [Monomer]
The monomer 8 used for coating the fine particles with the polymer is not particularly limited as long as the fine particles are coated to form a polymer by polymerization. A hydrophobic monomer having a vinyl group and addition-polymerized by radical polymerization to form a polymer is preferred as a monomer used in the present invention because it is absorbed in the hydrophobic layer and covers fine particles well. Examples of such a monomer include monomers composed of a vinyl group and a hydrophobic group, such as styrene, glycidyl methacrylate, methyl methacrylate, benzyl methacrylate, n-butyl methacrylate, and acrylonitrile.

  Moreover, as a monomer used for polymer coating of fine particles, for example, styrene added with glycidyl methacrylate can be used. The polymer in which these are copolymerized coats the fine particles to form a stable coating layer, and the epoxy groups of glycidyl methacrylate are present on the surface of the polymer-coated fine particles, and biological molecules or chemical molecules are added to the epoxy groups. Can be combined.

  In addition, azobisisoptyronitrile (AIBN), which is a hydrophobic azo compound, as an initiator for addition polymerization of these monomers by radical polymerization to form a polymer, products of Wako Pure Chemical Industries, Ltd. Name VA-080 (2,2'-Azobis {2-methyl-N- [1,1-bis (hydroxymethyl) -2-hydroxyethyl] propionamide), VA-085 (2,2'-Azobis {2-methyl -N- [2- (1-hydroxybuthyl)]-propionamide}), VA-086 (2,2'-Azobis {2-methyl-N- (2-hydroxyethyl) -propionamide]), V-50 ( 2,2'-Azobis (2-methylpropionamidine) dihydrochloride, (2,2'-Azobis (2-amidinopropane) dihydrochloride)), VA-057 (2,2'-Azobis (N- (2-carboxyethyl) -2) -methyl-propionamidine, (2,2'-Azobis {2- [N- (2-carboxyethyl) amidino] propane}), V-501 (4,4'-Azobis (4-cyanovaleric acid), (4, 4'-Azobis (4-cyanopentanoic acid)), VPE-0201, and VPE-0601 And peroxides such as benzoyl peroxide, potassium peroxodisulfate (KPS), and ammonium peroxodisulfate (APS), and divinylbenzene, triallylamine, 1,3,5-trimethyl as a crosslinking agent. Each hydrophilic initiator such as acryloyl-hexahydro-s-triazine, triallyl trimesate, and ethylene glycol dimethacrylate can be used.

  The polymer coating can be provided with a monoethylene glycol diglycidyl ether or polyethylene glycol diglycidyl ether molecule as a spacer. Providing such a spacer facilitates the binding of biological or chemical molecules, so it can be used for detection and separation / purification of specific biological substances by specific molecular interactions such as affinity chromatography carriers. More convenient in application.

(Embodiment 5) [Hydrophilic fine particles]
According to the present invention, magnetic fine particles can be coated with a polymer. The polymer-coated fine particles coated with magnetic fine particles can be manipulated using magnetic force, and can be rapidly separated from the aqueous phase by magnetic separation or induced by magnetic force. Moreover, according to the present invention, the coating is good and stable. For this reason, the polymer-coated fine particles coated with magnetic fine particles can be widely used as a useful substance carrier in the fields of biology and medicine.

  The magnetic fine particles coated with the polymer in this way are metal or oxide magnetic fine particles, and among these magnetic fine particles, the iron oxide ferrite fine particles are chemically stable. Particularly preferred as magnetic fine particles. By adding elements such as Li, Mg, Fe, Mn, Co, Ni, Cu and Zn to the ferrite fine particles, the characteristics can be appropriately controlled depending on the purpose.

  The size of these magnetic fine particles coated with the polymer is preferably 3 nm or more in diameter for ensuring magnetism, and on the other hand, 100 nm or less for avoiding strong magnetic aggregation between the particles. Preferably, it is 50 nm or less.

  Further, according to the present invention, fine particles of semiconductor quantum dots used as an optical marker can be selected as the fine particles coated with the polymer. Fine particles of semiconductor quantum dots used as a light marker can determine the color of fluorescence as a light marker by selecting the particle size. In order to obtain a fluorescence wavelength suitable for detection, the diameter of the fine particles is 2 to 15 nm. It is preferred to choose a range value. Further, in order to obtain fluorescence suitable for detection, as a semiconductor used as a quantum dot, for example, a chalcogenide of Zn such as CdS, CdSe, ZnO, or ZnS can be selected.

(Embodiment 6) [Polymer-coated fine particles]
FIG. 5 is a diagram schematically showing an embodiment of the polymer-coated fine particles of the present invention. In FIG. 5, (a) shows a case where 10-undecenoic acid, which is a hydrophobizing substance adsorbed on ferrite fine particles 1 which are hydrophilic fine particles, is copolymerized with styrene to form polymer 24 and coat ferrite fine particles 1.

  FIG. 5 (b) shows the case where 10-undecenoic acid, which is a hydrophobic substance adsorbed on the ferrite fine particles 1 which are hydrophilic fine particles, is copolymerized with styrene and glycidyl methacrylate to form a polymer 20A and coat the ferrite fine particles 1. The epoxy group 31 is present on the surface. In addition, although many epoxy groups 31 exist on the particle | grain surface, in order to simplify description, only one piece is shown in this figure. (C) in the figure is obtained by treating the particles with ammonia and opening an epoxy group to form a hydroxyl group and an amino group 32. (D) of the figure forms a spacer 33 by binding a monoethylene glycol diglycidyl ether or polyethylene glycol diglycidyl ether molecule to this amino group. In this way, the epoxy group 31 is present at the tip of the spacer 33, and a substance such as a biological substance is bonded thereto, so that the bonded substance can be prevented from being sterically hindered by particles.

  Such polymer-coated fine particles can be used for various applications by setting the particle size to 10 to 300 nm. For example, when polymer-coated fine particles in which magnetic fine particles are coated with a polymer are used for magnetic separation of biological substances, the diameter of the polymer-coated fine particles is 50 to 300 nm, and the volume fraction of the magnetic fine particles is 10% or more. A large value of preferably 20% or more is preferable from the viewpoint of binding biological substances and ensuring a magnetic attractive force. For the same reason, when polymer-coated fine particles in which magnetic fine particles are coated with a polymer are used as a carrier for drugs or the like, the diameter of the polymer-coated fine particles is preferably 10 to 100 nm. Further, when the polymer-coated fine particles obtained by coating magnetic fine particles with a polymer are used as a magnetic marker using magnetic field detection, a contrast agent of a magnetic resonance diagnostic apparatus (MRI), or a marker for molecular imaging, the diameter of the polymer-coated fine particles is 10 nm. Preferably, it is 500 nm or less, and more preferably 100 nm or less.

  Although the polymer-coated fine particles of the present invention are fine particles, they are very excellent in organic solvent resistance, and it was found that the polymer coating does not dissolve even when immersed in an organic solvent, and its shape is maintained. . This solubility resistance is enhanced by crosslinking the coating polymer with a crosslinking agent. Further, it was found that the organic solvent resistance was further improved by providing a spacer such as EGDE as the surface modification of the polymer-coated magnetic fine particles.

  The polymer-coated fine particles having such a configuration can be used not only in an aqueous solution but also in various applications used in an organic solvent as polymer-coated fine particles that can be used in an organic solvent. For example, those using magnetic fine particles as hydrophilic fine particles are magnetic carriers for affinity chromatography of chemical substances such as proteins, peptides, nucleic acids and drugs, magnetic solid phase carriers for combinatorial chemistry, and chemical synthesis of nucleic acids or peptides. It can be used for many applications such as use as a magnetic solid phase carrier.

(Preparation of hydrophilic fine particles)
200 mL of 1 M NaOH aqueous solution is maintained at 50 ° C., and a mixed aqueous solution of ferrous chloride and ferric chloride with Fe ² + / Fe ³ + = 1/2 and concentration of 1 M is added to this solution. The temperature was kept constant for 5 minutes to precipitate hydrophilic ferrite fine particles having an average particle diameter (average value of particle diameter in weight conversion distribution, the same as the average particle diameter described below) of about 8 nm. In addition, the transmission electron microscope (TEM) was used for the measurement of particle size.

(Hydrophobic substance adsorption, hydrophobization)
7.0 mL of 10-undecenoic acid was added to the liquid in which the ferrite fine particles were deposited, and the temperature was kept constant for 5 minutes.

  Next, 100 mL of 1M HCl was added to this solution, and 10-undecenoic acid was adsorbed on the surface of the ferrite fine particles, whereby the surface of the ferrite fine particles was coated with 10-undecenoic acid to be hydrophobized.

(Hydrophilic material adsorption, double layer film formation)
The ferrite fine particles coated with 10-undecenoic acid thus made hydrophobic were washed with water, and then water was separated. The ferrite fine particles coated with 10-undecenoic acid were immersed in 50 mL of ether to form a suspension and kept at a constant temperature for 30 minutes.

  Next, 7.0 mL of 10-undecenoic acid, 1M NaOH and 53 mL of water are added to this suspension to emulsify, and ultrasonic treatment is applied to refine the emulsion particles for 6 hours. The ether of the emulsified particles was gradually evaporated over a period of time to obtain ferrite fine particles double-coated with 10-undecenoic acid. FIG. 6 shows the result of measuring the particle size distribution of the ferrite fine particles double-coated with 10-undecenoic acid thus obtained. It was found that the ferrite fine particles doubly coated with 10-undecenoic acid had an average diameter of 25.0 nm and a standard deviation of 5.2 nm, and were fine and well-aligned.

(Polymer coating)
Next, 0.04 g of divinylbenzene (DVB), 1.2 g of styrene (St), and 1.8 g of glycidyl methacrylate (GMA) as monomers, and hydrophobic 2,2′-azobisisobutyronitrile (initiator) AIBN) was added with 10 g of ferrite fine particles double-coated with 10-undecenoic acid, and 110 g of water was added thereto.

  While this liquid was stirred at 70 ° C. at 350 rpm for 10 hours, polymer-coated ferrite fine particles were obtained. The conversion rate of the monomer at this time was 71.8%. A TEM photograph of the polymer coated ferrite fine particles obtained is shown in FIG. As shown in the TEM photograph of FIG. 7, it was found that the obtained polymer-coated ferrite fine particles were spherical fine particles having a uniform size, and were well coated with the polymer one by one.

  FIG. 8 is a diagram showing the results of measuring the particle size distribution of the polymer-coated ferrite fine particles. The average particle diameter was 77.8 nm, and the standard deviation was 13.5 nm, confirming that the particle diameters were well aligned. In this way, spherical fine particles that are well-sized and well-coated with polymer one by one are realized only by absorbing and polymerizing the ferrite fine particles doubly coated with 10-undecenoic acid. It was made.

  In the same process as in Example 1, monodisperse ferrite fine particles in which each of the ferrite fine particles was coated with a double layer of 10-undecenoic acid were prepared. FIG. 9A shows the particle size distribution of the ferrite fine particles coated with the 10-undecenoic acid double layer. The double layer-coated fine particles had an average particle size of 14.4 nm and a standard deviation of 3.3.

  The ferrite fine particles coated with the double layer of 10-undecenoic acid are immersed in 110 g of water, 0.6 g of styrene, 0.9 g of GMA, 0.02 g of divinylbenzene (DVB) are added thereto, and AIBN is further added. 0.015 g and 0.015 g of V-50 were added, mixed and stirred to re-emulsify, and polymerized ferrite fine particles were obtained by emulsion polymerization while maintaining the temperature at 70 ° C. for 24 hours while stirring at 200 rpm. It was.

  FIG. 9B is a diagram showing the particle size distribution of the polymer-coated ferrite fine particles thus obtained. The polymer-coated ferrite fine particles had an average particle size of 120.1 nm and a standard deviation of 40.8. As a result of observing the polymer-coated ferrite fine particles thus obtained with a transmission electron microscope, it was confirmed that monodisperse polymer-coated ferrite fine particles in which each ferrite fine particle was coated with a polymer were formed. It was.

  In the same process as in Example 1, monodisperse ferrite fine particles in which ferrite fine particles were coated one by one with a double layer of 10-undecenoic acid and SDS (Sodium Dodecyl Sulfate, sodium lauryl sulfate) were produced. This double layer coating is first made hydrophobic by adsorbing 10-undecenoic acid to ferrite fine particles, and adsorbing SDS to the hydrophobized fine particles by the same method as in Example 1 to thereby form 10-undecenoic acid layer and SDS. Ferrite fine particles coated with a double layer with a layer are obtained. FIG. 10 (a) is a graph showing the particle size distribution of ferrite fine particles having a double-layer coating of 10-undecenoic acid and SDS thus obtained. The double layer-coated fine particles had an average particle size of 9.4 nm and a standard deviation of 1.3.

  Ferrite fine particles having a double layer coating of 10-undecenoic acid and SDS are immersed in 110 g of water, 2.7 g of styrene, 0.3 g of GMA, 0.04 g of divinylbenzene (DVB), and 0.05 g of AIBN. Was added, mixed and stirred to emulsify, and while stirring (350 rpm), the temperature was maintained at 70 ° C. for 24 hours to carry out emulsion polymerization to obtain polymer-coated ferrite fine particles.

  FIG. 10B is a diagram showing the particle size distribution of the polymer-coated ferrite fine particles thus obtained. The polymer-coated ferrite fine particles had an average particle size of 49.0 nm and a standard deviation of 10.4. Observation of the polymer-coated ferrite fine particles thus obtained with a transmission electron microscope revealed that it was confirmed that monodisperse polymer-coated ferrite fine particles in which the ferrite fine particles were coated one by one with the polymer were formed. did it.

  As shown in Examples 2 and 3, the hydrophilic fine particles are dispersed and each of the fine particles is made hydrophobic by adsorbing the hydrophobizing substance, and the hydrophilic substance is further adsorbed on the fine particles to coat the single layer coated with the double layer. If dispersed fine particles are prepared, a monomer is absorbed in the hydrophobic layer of each fine particle, and a monomer polymerization reaction is performed, polymer-coated fine particles in which hydrophilic fine particles are coated with a polymer one by one can be obtained.

  In the same process as in Example 1, oleic acid was adsorbed on ferrite to be hydrophobized, and oleylamine was adsorbed thereon, and monodisperse in which ferrite fine particles were coated one by one with a double layer of an oleic acid layer and an oleylamine layer Ferrite fine particles were prepared. FIG. 11 shows the particle size distribution of ferrite fine particles coated with the 10-undecenoic acid double layer. The double layer-coated fine particles had an average particle size of 23.8 nm and a standard deviation of 9.2 nm.

  In the same process as in Example 1, fine particles in which ferrite fine particles having an average particle size of about 30 nm and a relatively large particle size were coated with a double layer of 10-undecenoic acid and SDS were produced. The fine particle double layer coating was formed by first adsorbing 10-undecenoic acid to ferrite fine particles to make them hydrophobic, and adsorbing 10-undecenoic acid to the hydrophobized fine particles using the same method as in Example 1. . FIG. 12 (a) shows the particle size distribution of ferrite fine particles coated with a double layer of 10-undecenoic acid and SDS thus obtained. The double layer-coated fine particles had an average particle size of 62.8 nm and a standard deviation of 32.8 nm.

  Ferrite fine particles coated with a double layer of 10-undecenoic acid and SDS are immersed in 110 g of water, 2.7 g of styrene, 0.3 g of GMA, and 0.05 g of AIBN are added, mixed and stirred to emulsify, While stirring (350 rpm), the temperature was maintained at 70 ° C. for 18 hours to carry out emulsion polymerization to obtain polymer-coated ferrite fine particles.

  FIG. 12B is a diagram showing the particle size distribution of the obtained polymer-coated ferrite fine particles. The polymer-coated ferrite fine particles had an average particle size of 108.5 nm and a standard deviation of 21.0. Thus, it was confirmed that relatively large polymer-coated ferrite fine particles could be produced.

  The polymer-coated ferrite particles produced under the conditions described in Example 1 were tested for organic solvent resistance. Specifically, the state of the particles after being immersed in each organic solvent and subjected to vibration treatment for 16 hours with a mixer was examined using a transmission electron microscope and a particle size distribution meter using laser light scattering. As a result, the polymer coating is maintained even when immersed in any organic solvent such as methanol, 1,4-dioxane, N, N′-dimethylformamide, dimethyl sulfoxide, acetone, diethyl ether, toluene, chloroform and hexane. It was found that these organic solvents have resistance to organic solvents.

  According to the present invention, it is possible to obtain polymer-coated fine particles having sufficiently good coating with a polymer and stable coating, and obtaining polymer-coated fine particles which are uniformly coated with a polymer and have a uniform particle size. be able to. For this reason, it is promising as a carrier particle for biological and medical use as fine polymer-coated magnetic fine particles with good coating. Polymer-coated phosphors and quantum dots are expected to be used as new markers in living organisms.

It is the figure which showed the flowchart of the process in one Embodiment of the manufacturing method of the polymer coating fine particle of this invention. It is the figure which showed typically the relationship between the hydrophilic microparticle and the hydrophobization substance, the hydrophilization substance, the organic solvent, the monomer, and the polymer in the process from the generation of the hydrophilic microparticle to the polymer-coated microparticle. In FIG. 2, without making the hydrophilic particles finely absorb the monomer, a hydrophobic substance and a hydrophilic substance 9 having a vinyl group as a hydrophobic group are used to polymerize these double layers on the fine particle surface to form a polymer. It is the figure which showed typically a mode that the polymer coating fine particle was obtained. FIG. 3 is a diagram schematically showing how polymer coated fine particles of hydrophobic fine particles are obtained through the same steps as in FIG. 2 starting from hydrophobic fine particles 4 instead of hydrophobizing hydrophilic fine particles 1 in FIG. 2. It is the figure typically shown about embodiment of the polymer coating fine particle of this invention. 4 is a graph showing the measurement results of the particle size distribution of ferrite fine particles that are doubly coated with 10-undecenoic acid in Example 1. FIG. 2 is a TEM photograph of polymer-coated ferrite fine particles in Example 1. FIG. FIG. 4 is a diagram showing the measurement result of the particle size distribution of polymer-coated ferrite fine particles in Example 1. (A) is a figure which shows the particle size distribution of the ferrite fine particle coat | covered with the double layer of 10-undecenoic acid in Example 2, (b) is a figure which shows the particle size distribution of the polymer coating ferrite fine particle in this Example. It is. (A) is a figure which shows the particle size distribution of the ferrite fine particle coat | covered with the double layer of 10-undecenoic acid in Example 3, (b) is a figure which shows the particle size distribution of the polymer coating ferrite fine particle in this Example. It is. 6 is a graph showing the particle size distribution of ferrite fine particles coated with a double layer of 10-undecenoic acid in Example 4. FIG. (A) is a figure which shows the particle size distribution of the ferrite fine particle coat | covered with the double layer of 10-undecenoic acid in Example 5, (b) is a figure which shows the particle size distribution of the polymer coating ferrite fine particle in this Example. It is.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 1 ... Hydrophilic fine particle, 2 ... Hydrophobization substance, 3 ... Hydrophobization process, 4 ... Hydrophobic fine particle, 5 ... Suspension process, 6 ... Organic solvent, 7 ... Suspension, 8 ... Emulsification process, 9 ... Hydrophilization Substances: 10 ... Water, 11 ... Ultrasonic vibration, 12 ... Emulsified liquid, 12A ... Emulsified particles, 13 ... Organic solvent evaporation process, 14 ... Ultrasonic vibration, 15 ... Hydrophilized fine particles, 16 ... Suspension / monomer absorption / regeneration Emulsifying step, 17 ... water, 18 ... monomer and hydrophobic initiator, 19 ... re-emulsified liquid, 19A ... re-emulsified particles, 20 ... emulsion polymerization step, 21 ... hydrophilic initiator, 22 ... heating, 23 ... polymer-coated fine particles 24 ... polymer, 31 ... epoxy group, 32 ... amino group, 33 ... ethylene glycol diglycidyl ether (EGDE).

Claims (29)

A double bond at the terminal and a hydrophilic group selected from a carboxyl group, sulfonic acid group, sulfuric acid group, phosphoric acid group, mercapto group, amino group, hydroxyl group and polyoxyethylene chain (hereinafter referred to as “hydrophilic group A”) A long-chain alkyl group having 8 to 20 carbon atoms, a long-chain alkyl group having 8 to 15 carbon atoms and a hydrophobic group selected from alkylbenzene residues (hereinafter referred to as “hydrophobic group B”). hydrophobic and hydrophobic to the hydrophilic group a diameter 100nm or less hydrophilic fine particles surface by adsorption of a layer of a hydrophobic material wherein the hydrophobic group of the hydrophilic fine particles be present in the outer surface of B hydrophobic substance having Hydrophobization step to obtain conductive fine particles,
A suspension step of suspending the hydrophobic fine particles in an organic solvent to obtain a suspension;
The hydrophobic group B and the suspension and mixed to the water containing the hydrophilic substance having a hydrophilic group A was mixed solution by applying ultrasonic vibration to the mixture, the hydrophilic substance is the An emulsification step of obtaining an emulsified liquid in which emulsified particles surrounding the suspension are dispersed in water;
The hydrophobic solvent is formed by evaporating the organic solvent contained in the emulsified particles while applying ultrasonic vibration to the emulsified liquid, and adsorbing the hydrophilic substance on the surface of the hydrophobic fine particles to form the hydrophilic substance layer. An organic solvent evaporation step of hydrophilizing the fine particles to obtain hydrophilized fine particles in which a hydrophobic layer is formed between the hydrophobic substance layer and the hydrophilic substance layer adsorbed thereto;
Monomer absorption / re-emulsification step of suspending the hydrophilized fine particles in water and containing a monomer in the water, and absorbing and re-emulsifying the monomer in the hydrophobic layer of the hydrophilized fine particles to obtain a re-emulsified liquid;
And a monomer polymerization step for obtaining polymer-coated fine particles by polymerizing the monomer absorbed by the hydrophilic fine particles of the re-emulsified liquid. The method for producing polymer-coated fine particles according to claim 1, wherein the hydrophobic fine particles are washed with water after the hydrophobizing step and before the suspending step. The monomer, method for producing a polymer-coated particles according to claim 1 or 2, wherein the monomers that form polymerized polymer by addition polymerization. The method for producing polymer-coated fine particles according to any one of claims 1 to 3, wherein the hydrophobic substance has a vinyl group in the hydrophobic group B. The hydrophobic material The method for manufacturing a polymer-coated particles according to claim 4, wherein the hydrophilic fine particles adsorbed on the fatty acid or salt thereof to hydrophobizing the hydrophilic fine particles. The fatty _{acid, CH 2 = CH (CH 2} ) method for producing a polymer-coated particles according to claim 5, characterized in that the 8 -COOH 10- undecenoic acid or a salt thereof represented by the rational formula of. A suspension step of suspending hydrophobic fine particles having a diameter of 100 nm or less in an organic solvent to obtain a suspension;
The hydrophobic group B and the suspension and mixed to the water containing the hydrophilic substance having a hydrophilic group A was mixed solution by applying ultrasonic vibration to the mixture, the hydrophilic substance is the An emulsification step of obtaining an emulsified liquid in which emulsified particles surrounding the suspension are dispersed in water;
The hydrophobic solvent is formed by evaporating the organic solvent contained in the emulsified particles while applying ultrasonic vibration to the emulsified liquid, and adsorbing the hydrophilic substance on the surface of the hydrophobic fine particles to form the hydrophilic substance layer. An organic solvent evaporation step of hydrophilizing the fine particles to obtain hydrophilic fine particles in which a hydrophobic layer is formed between the surface of the hydrophobic fine particles and the layer of the hydrophilic substance adsorbed on the surface;
Monomer absorption / re-emulsification step of suspending the hydrophilic microparticles in water and containing a monomer in the water, absorbing the monomer in the hydrophobic layer of the hydrophilized microparticles, and re-emulsifying to obtain a re-emulsified liquid;
And a monomer polymerization step for obtaining polymer-coated fine particles by polymerizing the monomer absorbed by the hydrophilic fine particles of the re-emulsified liquid. The hydrophilic group A is a layer on the hydrophobic group B and the hydrophilic groups of the hydrophobic material and a layer of hydrophobic material is formed by adsorption to the surface of the hydrophobic substance having said hydrophobic group B and the hydrophilic group A the hydrophilic to hydrophilic material having an a has a hydrophobic layer between the layer of the layer and the hydrophilic material of the hydrophobic substance having a double layer with a layer of hydrophilic material formed by adsorption A monomer absorption step of suspending the fine particles in water and containing the monomer in the water, and absorbing the monomer in the hydrophobic layer;
The polymer-coated fine particles according to any one of claims 1 to 7, further comprising a monomer polymerization step of obtaining polymer-coated fine particles by polymerizing the monomer of the hydrophilized fine particles that have absorbed the monomer. Method. A polymer-coated fine particle produced by the production method according to any one of claims 1 to 8. The hydrophobic group of the hydrophobic material to form a layer of the hydrophobic substance by adsorbing the hydrophilic group A hydrophobic substance having said hydrophobic group B and the hydrophilic group A on the surface of the hydrophilic fine particles B is a hydrophobic fine particles present in the outer surface, the hydrophobic microparticles are suspended in an organic solvent and suspension, containing a hydrophilizing agent having the suspension and the hydrophobic group B and the hydrophilic group a The mixture is mixed with water to give a mixture, and the mixture is subjected to ultrasonic vibration to form an emulsion in which the emulsified particles in which the hydrophilic substance surrounds the suspension are dispersed in water. Applying vibration to refine the emulsified particles, and applying ultrasonic vibration to evaporate the organic solvent contained in the emulsified particles while maintaining the refined state of the emulsified particles, the hydrophobic fine particles are made into a layer of a hydrophilic substance . Formed by coating with sparse Double layer coated microparticles according to claim 9, wherein said hydrophilic particles by double layer between the layer of the layer and hydrophilic substance product quality is characterized in that it is coated. The hydrophilic fine particles are coated with bilayer with a layer of hydrophilic material having a vinyl group at an end of the layer and the hydrophobic group B of hydrophobic substances having a vinyl group on the end of the hydrophobic group B, the two The polymer-coated fine particles according to claim 9 or 10, wherein a polymer coating is formed by a polymerization reaction of these vinyl groups in the multilayer. The hydrophilic fine particles;
A polymer coating for coating the hydrophilic fine particles,
The polymer coating, features and monomers having a vinyl group, said hydrophilic group A having a vinyl group to the hydrophobic group B forms a copolymer with the adsorbed hydrophobic material on the hydrophilic fine particles The polymer-coated fine particles according to claim 11 . The polymer coating comprises a monomer having a vinyl group, wherein the hydrophobic group hydrophobing substance the hydrophilic group A has a vinyl group is adsorbed on the hydrophilic fine particles B, the vinyl group to the hydrophobic group B 13. The polymer-coated fine particles according to claim 12, wherein the hydrophilic group A is present on the outer surface of the polymer coating and forms a copolymer with a hydrophilic substance that hydrophilizes the polymer coating. Said hydrophobic material, said any one of claims polymer coated microparticles of claims 11 to 13, characterized in that it comprises a carboxyl group as a hydrophilic group A. The polymer-coated fine particles according to any one of claims 11 to 14, wherein the hydrophobizing substance constituting the polymer is a fatty acid. The fatty _{acid, CH 2 = CH (CH 2} ) 8 -COOH claim 15 polymer-coated microparticles, wherein it is a 10-undecenoic acid represented by the rational formula of. The polymer-coated fine particles according to any one of claims 12 to 16, wherein the polymer is a copolymer of styrene or glycidyl methacrylate and the hydrophobic substance. The polymer-coated fine particles according to any one of claims 12 to 17, wherein the polymer is a copolymer of styrene, glycidyl methacrylate, and the hydrophobic substance. 19. The polymer-coated fine particles according to claim 18, comprising monoethylene glycol diglycidyl ether or polyethylene glycol diglycidyl ether as a spacer. The polymer-coated fine particles according to claim 11, wherein the hydrophilic fine particles are magnetic fine particles. 21. The polymer according to claim 20, wherein the magnetic fine particles are ferrite fine particles containing at least one element selected from the group consisting of Li, Mg, Fe, Mn, Co, Ni, Cu and Zn. Coated fine particles. The polymer-coated fine particles according to claim 11, wherein the fine particles are phosphors or quantum dots. A polymer-coated fine particle used in an organic solvent, comprising the polymer-coated fine particle according to any one of claims 11 to 22, and having organic solvent resistance. 24. Polymer-coated fine particles used in an organic solvent according to claim 23, wherein the organic solvent resistance is improved by crosslinking. The polymer-coated fine particles used in an organic solvent according to claim 23 or 24, wherein the organic solvent resistance is improved by having the spacer . As the organic solvent, at least one selected from the group consisting of methanol, 1,4-dioxane, N, N′-dimethylformamide, dimethyl sulfoxide, acetone, diethyl ether, toluene, chloroform and hexane is used. Polymer-coated fine particles used in an organic solvent according to any one of claims 23 to 25. 27. The polymer-coated fine particles used in an organic solvent according to any one of claims 23 to 26, wherein the hydrophilic fine particles are at least one of the group consisting of magnetic fine particles, phosphors and quantum dots. Solid phase support for affinity chromatography. 27. Polymer-coated fine particles used in the organic solvent according to claim 23, wherein the hydrophilic fine particles are at least one of the group consisting of magnetic fine particles, phosphors and quantum dots. A solid phase carrier for combinatorial chemistry that is characterized. 27. Polymer-coated fine particles used in the organic solvent according to claim 23, wherein the hydrophilic fine particles are at least one of the group consisting of magnetic fine particles, phosphors and quantum dots. A solid phase carrier for chemical synthesis of a featured peptide or nucleic acid.