JP5873790B2 - Sustained release particles and method for producing the same - Google Patents

Description

  The present invention relates to sustained-release particles and a method for producing the same, and more particularly to sustained-release particles for slowly releasing an antibiotic compound and a method for producing the same.

  In recent years, sustained-release particles containing antibiotic compounds such as bactericides, preservatives and fungicides have been proposed.

  As a method for producing such sustained release particles, the following methods have been proposed (see, for example, Patent Documents 1 and 2).

  That is, in Patent Document 1, first, a polymerizable vinyl monomer such as 3-iodo-2-propynylbutylcarbamate (IPBC, antifungal agent), methyl methacrylate and dilauroyl peroxide (polymerization initiator) are blended, While preparing a hydrophobic solution, water and polyvinyl alcohol (dispersant) are mix | blended and aqueous solution is prepared.

  Thereafter, a suspension of IPBC-containing sustained-release particles is prepared by blending a hydrophobic solution and an aqueous solution to prepare a suspension, and then raising the temperature while stirring to perform suspension polymerization. Have gained.

  In Patent Document 2, 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (an antifungal agent), a solvent and a polyisocyanate are blended to prepare a hydrophobic solution, and water is added. And an polyvinyl alcohol (dispersing agent) are mixed to prepare an aqueous solution.

  Thereafter, a hydrophobic solution and an aqueous solution are blended to prepare a suspension, and then polyamine is added with stirring, the temperature is raised, and interfacial polymerization is performed, whereby 4,5-dichloro-2-n Suspension of sustained release particles containing octyl-4-isothiazolin-3-one is obtained.

JP 2011-79816 A JP 2003-48802 A

  However, since the sustained release particles proposed in Patent Documents 1 and 2 are obtained by suspension polymerization and interfacial polymerization, respectively, the median diameter is as large as 1 μm or more. Therefore, the sustained release particles may settle in the suspension and cause caking.

  An object of the present invention is to provide sustained-release particles having excellent dispersibility as well as sustained-release properties, and a method for producing the same.

  The present inventors diligently studied the above-mentioned sustained release particles and the production method thereof, and prepared a hydrophobic solution by dissolving a hydrophobic antibiotic compound with a hydrophobic polymerizable vinyl monomer. , Water and emulsifier are mixed to prepare an emulsifier aqueous solution, the hydrophobic solution is emulsified in the emulsifier aqueous solution, and the polymerizable vinyl monomer in the emulsified hydrophobic solution is miniemulsion polymerized in the presence of a polymerization initiator. As a result, the inventors have found that sustained release particles having excellent dispersibility can be obtained as well as sustained release properties. As a result of further research, the present invention has been completed.

That is, the present invention
(1) A hydrophobic solution is prepared by dissolving a hydrophobic antibiotic compound with a hydrophobic polymerizable vinyl monomer, and an aqueous emulsifier solution is prepared by mixing water and an emulsifier. It is obtained by emulsifying in the aqueous emulsifier solution and subjecting the polymerizable vinyl monomer to miniemulsion polymerization in the presence of a polymerization initiator to produce a polymer having an average particle diameter of less than 1 μm and containing an antibiotic compound. Sustained release particles, characterized by
(2) a step of preparing a hydrophobic solution by dissolving a hydrophobic antibiotic compound with a hydrophobic polymerizable vinyl monomer, a step of preparing an aqueous emulsifier solution by blending water and an emulsifier, the hydrophobic A step of emulsifying the solution in the aqueous emulsifier solution, and an average particle containing the antibiotic compound by miniemulsion polymerization of the polymerizable vinyl monomer of the emulsified hydrophobic solution in the presence of a polymerization initiator A method for producing sustained-release particles, comprising a step of producing a polymer having a diameter of less than 1 μm.

  In the method for producing sustained-release particles of the present invention, the polymerizable vinyl monomer in an emulsified hydrophobic solution is subjected to miniemulsion polymerization in the presence of a polymerization initiator, and the average particle size containing an antibiotic compound is less than 1 μm. Since the sustained release particles of the present invention are obtained by producing the polymer, the sustained release particles are excellent in dispersibility.

  Therefore, the sustained release particles of the present invention can be used in various industrial products as sustained release particles having excellent dispersibility as well as excellent sustained release properties.

  In addition, since the hydrophobic antibiotic compound can also be used as a hydrophobe in the miniemulsion polymerization, the average particle size containing the antibiotic compound is simply less than 1 μm without adding a hydrophobe. A polymer can be produced.

FIG. 1 shows an image processing diagram of an SEM photograph of sustained-release particles of Example 2. FIG. 2 shows an image processing diagram of an SEM photograph of sustained-release particles of Example 2. FIG. 3 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 2. FIG. 4 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 2. FIG. 5 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 4. FIG. 6 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 4. FIG. 7 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 5. FIG. 8 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 5. FIG. 9 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 6. FIG. 10 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 6. FIG. 11 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 7. FIG. 12 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 7. FIG. 13 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 8. FIG. 14 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 8. FIG. 15 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 9. FIG. 16 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 9. FIG. 17 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 11. FIG. 18 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 11. FIG. 19 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 12. FIG. 20 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 12. FIG. 21 is a graph showing sustained release tests of Examples 1 and 2 and Comparative Examples 4 and 5. 22 shows a graph of sustained release test of Example 3. FIG. 23 shows a graph of sustained release test of Example 5. FIG. 24 shows a graph of sustained release test of Example 6. FIG. FIG. 25 shows a graph of sustained release test of Example 7. FIG. 26 shows a graph of sustained release test of Example 8. FIG. 27 shows a perspective view of the frame assembly used in the sustained release test of Example 10. FIG. FIG. 28 is a front sectional view of an insect cage used in the sustained release test of Example 10. FIG. 29 shows a graph of sustained release test of Example 11. FIG. 30 shows a graph of sustained release test of Example 12.

  The sustained-release particles of the present invention prepare a hydrophobic solution by dissolving a hydrophobic antibiotic compound with a hydrophobic polymerizable vinyl monomer, and separately add an aqueous emulsifier solution by blending water and an emulsifier. Preparing and subsequently emulsifying a hydrophobic solution in an aqueous emulsifier solution, and then polymerizing the polymerizable vinyl monomer in the presence of a polymerization initiator to form a polymer containing an antibiotic compound. Is obtained.

  Antibiotic active compounds act as hydrophobes (costabilizers) in miniemulsion polymerization, specifically to prevent Ostwald ripening by contributing to stabilization of the miniemulsion (described later) in miniemulsion polymerization, Prevents enlargement of miniemulsion particles (increase in particle size).

  The antibiotic compound has, for example, at least two functional moieties that can interact with the polymer of the polymerizable vinyl monomer.

  Examples of such functional moieties include polar functional groups such as carbonyl group, nitro group, amino group, cyano group, phosphate ester group, carboxyl group, such as carboxylate bond, phosphate bond, urea bond, carbon-halogen. Examples include a polar bond including a polar group, such as a bond, such as a benzene ring, and a conjugated cyclic moiety such as a conjugated heterocycle such as a triazine ring, an imidazole ring, and an isothiazoline ring.

  The molecular weight of the antibiotic compound is, for example, 150 to 600, preferably 180 to 500.

  If the molecular weight of the antibiotic compound exceeds the above range, the compatibility of the antibiotic compound with the polymer may be reduced. On the other hand, when the molecular weight of the antibiotic compound is less than the above range, the antibiotic compound is leaked into the aqueous phase during the miniemulsion polymerization, and the antibiotic compound is precipitated after the miniemulsion polymerization. Thus, another particle may be formed, or the emulsion may be aggregated or solidified.

  The melting point of the antibiotic compound is, for example, 100 ° C. or less, preferably 90 ° C. or less, and more preferably 80 ° C. or less. When the melting point of the antibiotic compound exceeds the above range, the antibiotic compound may be difficult to encapsulate in the sustained-release particles and may precipitate out of the sustained-release particles. Even when encapsulated in sustained-release particles, it may become a solid during miniemulsion polymerization and precipitate and phase-separate within the particles from the polymer, and the antibiotic compound may not be released outside the sustained-release particles.

  Specifically, the antibiotic compound is an antibacterial agent, antibacterial agent, antiseptic agent, antifungal agent, antifungal agent, herbicidal agent having antibacterial activity such as bactericidal, antibacterial, antiseptic, algae, fungicide, insecticide, etc. Selected from agents, insect repellents, insecticides, attractants, repellents and rodenticides. Examples of the compounds having antibiotic activity include bactericidal antiseptic and algal fungicides such as iodine compounds, triazole compounds, carbamoylimidazole compounds, dithiol compounds, isothiazoline compounds, nitroalcohol compounds, and paraoxybenzoic acid esters. Examples include insecticides and insecticides such as pyrethroid compounds, neonicotinoid compounds, organochlorine compounds, organophosphorus compounds, carbamate compounds, and oxadiazine compounds.

  Examples of iodine compounds include 3-iodo-2-propynylbutylcarbamate (IPBC), 1-[[(3-iodo-2-propynyl) oxy] methoxy] -4-methoxybenzene, 3-bromo-2, Examples include 3-diiodo-2-propenyl ethyl carbonate.

  Examples of the triazole compound include 1- [2- (2,4-dichlorophenyl) -4-n-propyl-1,3-dioxolan-2-ylmethyl] -1H-1,2,4-triazole (propico). Nazole), bis (4-fluorophenyl) methyl (1H-1,2,4-triazol-1-ylmethylsilane (also known as flusilazole, 1-[[bis (4-fluorophenyl) methylsilyl] methyl] -1H- 1,2,4-triazole) and the like.

  Examples of the carbamoylimidazole compound include N-propyl-N- [2- (2,4,6-trichloro-phenoxy) ethyl] imidazole-1-carboxamide (prochloraz).

  Examples of the dithiol-based compound include 4,5-dichloro-1,2-dithiol-3-one.

  Examples of the isothiazoline-based compound include 2-n-octyl-4-isothiazolin-3-one (OIT) and 5-chloro-2-methyl-4-isothiazolin-3-one (Cl-MIT).

  Examples of the nitroalcohol compound include 2,2-dibromo-2-nitro-1-ethanol (DBNE).

  Examples of the paraoxybenzoic acid ester include butyl paraoxybenzoate and propyl paraoxybenzoate.

  Examples of the pyrethroid compound include pyrethrin, cineline, jasmolin, and the like obtained from Shirovanamyoyokeiku, and arelesrin, bifenthrin, acrinathrin, permethrin (3-phenoxybenzyl (1RS, 3RS; 1RS, 3SR) -3 derived from these compounds. -(2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate), alpha cypermethrin, tralomethrin, cyfluthrin ((RS) -α-cyano-4-fluoro-3-phenoxybenzyl- (1RS, 3RS) )-(1RS, 3RS) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate, specifically, isomer I ((1R-3R-αR) + (1S-3S-αS) )) [Melting point: 57 ° C.], isomer II ((( R-3R-S) + (1S-3S-αR)) [melting point: 74 ° C.], isomer III ((1R-3S-αR) + (1S-3R-αS))) [melting point: 66 ° C.] Mixture), ciphenothrin, plaretrin, etofenprox (2- (4-ethoxyphenyl) -2-methylpropyl-3-phenoxybenzyl ether), silafluophene, fenvalerate and the like.

Examples of neonicotinoid compounds include (E) -N ¹ -[(6-chloro-3-pyridyl) methyl] -N ² -cyano-N ¹ -methylacetamidine (acetamipride).

  Examples of the organic chlorine compound include Kelsen.

  Examples of the organophosphorus compounds include phoxime, pyridafenthione, fenitrothion, tetrachlorvinphos, diclofenthione, propetanephos, and the like.

  Examples of carbamate compounds include fenocarb and propoxur.

  Examples of the oxadiazine compound include indoxacarb.

  Examples of the herbicide include pyraclonyl, pendimethalin, indanophan and the like.

  Examples of the insecticide include pyriproxyfen.

  Examples of the repellent include diet (N, N-diethyl-m-toluamide).

  Antibiotic active compounds are substantially hydrophobic and have, for example, very little solubility in water at room temperature (20-30 ° C., more specifically 25 ° C.). The solubility is 1 part by mass / 100 parts by mass of water (10000 ppm) or less, preferably 0.5 parts by mass / 100 parts by mass of water (5000 ppm) or less, more preferably 0.1 parts by mass / 100 water. For example, 1 g / water 100 mL or less, preferably 0.5 g / water 100 mL or less, and more preferably 0.1 g / water 100 mL or less on a volume basis.

  If the solubility of the antibiotic compound in water exceeds the above range, it cannot play the role of a hydrophobe when minimizing the polymerizable vinyl monomer, so that the polymerizable vinyl monomer droplet (oil droplet) Therefore, it becomes difficult to maintain an average particle size during emulsification and to synthesize sustained release particles sufficiently containing an antibiotic compound.

  These antibiotic compounds can be used alone or in combination of two or more.

  The above-mentioned antibiotic compound may contain, for example, impurities having a melting point outside the above range in an appropriate ratio during the production process. Specifically, a mixture of isomer I (melting point: 57 ° C.), isomer II (melting point: 74 ° C.) and isomer III (melting point: 66 ° C.) of cyfluthrin is, for example, isomer IV (impurity) Melting point 102 ° C.).

  The polymerizable vinyl monomer is, for example, a polymerizable monomer having at least one polymerizable carbon-carbon double bond in the molecule.

  Specific examples of the polymerizable vinyl monomer include (meth) acrylic acid ester monomers, (meth) acrylic acid monomers, aromatic vinyl monomers, vinyl ester monomers, maleic acid ester monomers, and halogenated monomers. Examples thereof include vinyl, vinylidene halide, and nitrogen-containing vinyl monomer.

  Examples of (meth) acrylic acid ester monomers include methacrylic acid esters and // acrylic acid esters, and specifically include methyl (meth) acrylate, ethyl (meth) acrylate, and (meth) acrylic acid n. -C1-C1 of alkyl moieties such as -propyl, isopropyl (meth) acrylate, n-butyl (meth) acrylate, isobutyl (meth) acrylate, tert-butyl (meth) acrylate, cyclohexyl (meth) acrylate (Meth) acrylic acid alkyl esters having 20 alkyl moieties, (meth) acrylic acid alkoxyalkyl esters such as 2-methoxyethyl (meth) acrylate, for example (meth) acrylic acid hydroxyethyl (meth) ) Hydroxyalkyl acrylate and the like. Preferably, (meth) acrylic acid alkyl ester is mentioned.

  Examples of (meth) acrylic acid monomers include methacrylic acid and acrylic acid.

  Examples of the aromatic vinyl monomer include styrene, p-methylstyrene, o-methylstyrene, and α-methylstyrene.

  Examples of vinyl ester monomers include vinyl acetate and vinyl propionate.

  Examples of maleate monomers include dimethyl maleate, diethyl maleate, and dibutyl maleate.

  Examples of the vinyl halide include vinyl chloride and vinyl fluoride.

  Examples of the vinylidene halide include vinylidene chloride and vinylidene fluoride.

  Examples of the nitrogen-containing vinyl monomer include (meth) acrylonitrile, N-phenylmaleimide, vinylpyridine, and the like.

  The polymerizable vinyl monomer is substantially hydrophobic and has, for example, extremely low solubility in water at room temperature. Specifically, the solubility at room temperature is, for example, 10 parts by mass / 100 parts by mass or less of water, preferably 8 parts by mass / 100 parts by mass or less of water. When different types of polymerizable vinyl monomers are used in combination, the entire polymerizable vinyl monomer (that is, a mixture of different types of polymerizable vinyl monomers) is substantially hydrophobic.

  Among the above-described polymerizable vinyl monomers, for example, the above-mentioned antibiotic active compound compatible monomer (hereinafter simply referred to as “highly compatible (or good)” with respect to the antibiotic active compound) can dissolve the antibiotic active compound. Is sometimes referred to as a compatible monomer).

  The compatible monomer is preferably a (meth) acrylic acid ester monomer.

  These compatible monomers can be used alone or in combination of two or more.

  As the (meth) acrylic acid ester monomer, preferably, alkyl alkyl ester having 1 to 3 carbon atoms in the alkyl moiety, more preferably, methyl methacrylate (MMA) alone is used.

  Preferably, a methacrylic acid alkyl ester having 1 to 3 carbon atoms in the alkyl portion and a (meth) acrylic acid alkyl ester having 4 to 8 carbon atoms in the alkyl portion may be used, more preferably methacrylic acid. A combination of methyl acid and butyl (meth) acrylate, particularly preferably a combination of MMA and isobutyl methacrylate.

  Two types of (meth) acrylic acid ester monomers (specifically, alkyl methacrylate having 1 to 3 carbon atoms in the alkyl portion and alkyl methacrylate having 4 to 8 carbon atoms in the alkyl portion) And) are used in combination, the blending ratio of alkyl alkyl ester having 1 to 3 carbon atoms in the alkyl portion is based on 100 parts by weight of the total amount of (meth) acrylic acid ester monomer. For example, it is 50 parts by mass or more, preferably 60 parts by mass or more, more preferably 65 parts by mass or more, and for example, less than 100 parts by mass.

  The (meth) acrylic acid monomer has a function of improving the colloidal stability of the copolymer emulsion, and may be included as a part of the compatible monomer in order to obtain this effect. In this case, the blending ratio is, for example, 0.1 to 20 parts by mass, preferably 0.5 to 10 parts by mass, and more preferably 1 to 5 parts by mass with respect to 100 parts by mass of the polymerizable vinyl monomer. .

  The antibiotic active compound and the compatible monomer are selected such that the polymer of the polymerizable vinyl monomer and the antibiotic active compound are compatible at the polymerization temperature (heating temperature) described later.

  The polymerizable vinyl monomer can also contain a crosslinkable monomer as a compatible monomer.

  The crosslinkable monomer is blended as necessary in order to adjust the sustained release property of the sustained release particles. For example, mono- or polyethylene glycol di (meth) such as ethylene glycol di (meth) acrylate and diethylene glycol di (meth) acrylate. Acrylates, for example, alkanediol di (meth) acrylates such as 1,3-propanediol di (meth) acrylate, 1,4-butanediol di (meth) acrylate, 1,5-pentanediol di (meth) acrylate, for example Alkane polyol poly (meth) acrylates such as trimethylolpropane tri (meth) acrylate and pentaerythritol tetra (meth) acrylate, for example, allyl monomers such as allyl (meth) methacrylate and triallyl (iso) cyanurate, examples If, like divinyl monomer such as divinylbenzene.

  The crosslinkable monomer is preferably ethylene glycol di (meth) acrylate, and more preferably ethylene glycol dimethacrylate.

  The blending ratio of the crosslinkable monomer is, for example, 1 to 80 parts by mass, preferably 2 to 50 parts by mass, and more preferably 5 to 20 parts by mass with respect to 100 parts by mass of the polymerizable vinyl monomer (compatible monomer). It is.

Moreover, as an antibiotic compound and a polymerizable vinyl monomer, the dipole force term δ _{p, compound} of the solubility parameter δ is, for example, 2 to 8 [(J / cm ³ ) ^1/2 ], preferably 3 to 7 [(J / cm ³ ) ^1/2 ], and the hydrogen bond term δ _{h, compound of} the solubility parameter δ is, for example, 5.5 to 9.5 [(J / cm ³ ) ^1/2 ], Preferably, an antibiotic compound that is 5.8 to 9.5 [(J / cm ³ ) ^1/2 ] and a dipole force term δ _{p, polymer of} the solubility parameter δ is, for example, 5 to 7 [ (J / cm ³ ) ^1/2 ], preferably 5 to 6.5 [(J / cm ³ ) ^1/2 ], and the hydrogen bonding force term δ _{h, polymer of} the solubility parameter δ is, for example, 8 ^{~10 [(J / cm 3)} 1/2], preferably, 8. 10 combination of ^{[(J / cm 3) 1/2} ] a polymerizable vinyl monomer to produce a polymer which is selected.

The dipole force term δ _p and the hydrogen bond force term δ _h of the solubility parameter δ are defined by Hansen, calculated by the van K r evelen and Hoftyzer method, and specifically described in Japanese Patent Application Laid-Open No. 2011-79816. It is stated.

The subscript compound and polymer in each term δ (δ _p and δ _h ) indicate an antibiotic compound and a polymer, respectively.

If the dipole force term δ _{p, polymer} and / or the hydrogen bond force term δ _{h, polymer} of _{the polymer} is less than the above range _{, the polymer} is excessively hydrophobic and sufficient with the antibiotic compound. In some cases, the compatibility cannot be obtained. Even if the compatibility is obtained, the antibiotic compound is leaked out of the sustained-release particles during the miniemulsion polymerization, and the antibiotic compound is sufficiently contained. It may be difficult to synthesize sustained release particles.

On the other hand, when the polymer dipole force term δp _{, polymer} and / or the hydrogen bond force term δh _{, polymer} exceeds the above range _{, the polymer} becomes excessively hydrophilic, and the polymer has a sufficient affinity with the antibiotic compound. In some cases, even if compatibility can be obtained, the free energy of the interface with the aqueous phase in the miniemulsion polymerization becomes low, and the antibiotic compound is gradually added during the miniemulsion polymerization. It may be difficult to synthesize sustained release particles that leak out of the release particles and sufficiently contain the antibiotic compound.

On the other hand, if the interdipolar force term δ _{p, compound} and / or the hydrogen bond term δ _{h, compound} of the antibiotic _compound is not within the above range, the hydrophobic property of the antibiotic compound becomes excessively high, and the polymer In some cases, sufficient compatibility cannot be obtained.

On the other hand, when the dipole force term δ _{p, compound} and / or the hydrogen bond force term δ _{h, compound} of the antibiotic compound exceeds the above range, the hydrophilic property of the antibiotic compound becomes excessively high, and the antibiotic activity The compound tends to leak out of the sustained-release particles, and it may be difficult to synthesize sustained-release particles sufficiently containing the antibiotic compound.

Further, in the solubility parameter δ, a value obtained by subtracting the dipole force term δ _{p, compound} of the antibiotic compound from the dipole force term δ _{p, polymer of the polymer} Δδ _p (= δ _{p, polymer} −δ _{p, compound} ) is, for example, −1.1 to 2.8 [(J / cm ³ ) ^1/2 ].

The hydrogen bonding term polymer [delta] _h, the hydrogen bonding term of the antibiotic compound from _Polymer [delta] _h, a value obtained by subtracting the _{compound Δδ h (= δ h,} polymer -δ h, compound) is, for example, - 0.1 to 4.2 [(J / cm ³ ) ^1/2 ].

If within a range .DELTA..delta _p and .DELTA..delta _h is above, to ensure excellent compatibility antibiotic compound and polymers, it is possible to ensure an excellent sustained release.

The dipole force term δ _{p, compound} and hydrogen bond force term δ _{h, compound of the} antibiotic compound are within the above-mentioned range, and the dipole force term δ _{p, polymer} and hydrogen bond force term of the _polymer If δh _{, polymer} is in the above range, the antibiotic compound is defined as being compatible with the polymer without leaking from the sustained release particles during miniemulsion polymerization. That is, the antibiotic compound is contained in the polymer.

  Examples of the emulsifier include emulsifiers commonly used in miniemulsion polymerization, such as sodium dioctyl sulfosuccinate, sodium dodecylbenzene sulfonate, sodium lauryl sulfate, sodium dodecyl diphenyl ether disulfonate, sodium nonyl diphenyl ether sulfonate, naphthalene sulfonate formaldehyde condensate Anionic emulsifiers such as sodium salts are listed.

  Examples of the emulsifier include nonionic emulsifiers such as polyoxyalkylene alkyl ether, polyoxyalkylene alkyl aryl ether, polyoxyalkylene aralkyl aryl ether, polyoxyalkylene block copolymer, and polyoxyalkylene aryl ether.

  Examples of the polyoxyalkylene alkyl ether include polyoxyethylene alkyl ether.

  Examples of the polyoxyalkylene alkyl aryl ether include polyoxyethylene nonyl phenyl ether and polyoxyethylene octyl phenyl ether.

  Examples of the polyoxyalkylene aralkyl aryl ether include polyoxyethylene styrenated phenyl ether (for example, Neugen EA-177 (Daiichi Kogyo Seiyaku Co., Ltd.)).

  Examples of the polyoxyalkylene block copolymer include a polyoxyethylene-polyoxypropylene block copolymer.

  Examples of the polyoxyalkylene aryl ether include polyoxyethylene aryl ether.

  HLB of a nonionic emulsifier is 11-20, for example, Preferably, it is 12-19, More preferably, it is 13-18.

  The HLB is calculated by the Griffin equation shown by the following equation (1).

HLB = 20 × (sum of formula weight of hydrophilic part / molecular weight) (1)
As a nonionic emulsifier, Preferably, a polyoxyalkylene aralkyl aryl ether is mentioned.

  The emulsifiers can be used alone or in combination of two or more. Preferably, an anionic emulsifier and a nonionic emulsifier are used in combination, and more preferably, a dioctyl sodium sulfosuccinate and a polyoxyalkylene aralkyl aryl ether are used in combination.

  When an anionic emulsifier and a nonionic emulsifier are used in combination, the blending ratio of the anionic emulsifier is, for example, 10 to 60% by mass, preferably 15 to 50% by mass with respect to the emulsifier. Is, for example, 40 to 90 mass%, preferably 50 to 85 mass% with respect to the emulsifier.

  In addition, an emulsifier can also be previously mixed and dissolved in water at an appropriate ratio to prepare an emulsifier-containing aqueous solution. The mixture ratio of the emulsifier in the emulsifier-containing aqueous solution is, for example, 10 to 90% by mass, preferably 20 to 80% by mass.

  Examples of the polymerization initiator include polymerization initiators usually used in miniemulsion polymerization, and examples include oil-soluble polymerization initiators and water-soluble polymerization initiators.

  Examples of the oil-soluble polymerization initiator include dilauroyl peroxide, 1,1,3,3-tetramethylbutylperoxy-2-ethylhexanoate, t-hexylperoxy-2-ethylhexanoate, and diisopropyl. Oil-soluble organic peroxides such as peroxydicarbonate and benzoyl peroxide, such as 2,2′-azobisisobutyronitrile, 2,2′-azobis (2,4-dimethylvaleronitrile), 2,2 Examples thereof include oil-soluble azo compounds such as' -azobis (2-methylbutyronitrile).

  Examples of the water-soluble polymerization initiator include 2,2′-azobis (2-methylpropionamidine) disulfate, 2,2′-azobis (2-methylpropionamidine) dihydrochloride, and 2,2′-azobis. (2-amidinopropane) dihydrochloride, 2,2′-azobis [N- (2-carboxyethyl) -2-methylpropionamidine] hydrate, 2,2′-azobis (N, N′-dimethylene) Isobutylamidine), 2,2′-azobis {2- [1- (2-hydroxyethyl) -2-imidazolin-2-yl] propane} dihydrochloride, 2,2′-azobis (1-imino-1- Pyrrolidino-2-methylpropane) dihydrochloride, 2,2′-azobis {2-methyl-N- [1,1-bis (hydroxymethyl) -2-hydroxyethyl] propionamide}, 2,2′-azo [2-methyl-N- (2-hydroxyethyl) propionamide], 2,2′-azobis [2- (2-imidazolin-2-yl) propane], 2,2′-azobis [2- (2 -Imidazolin-2-yl) propane] dihydrochloride, 2,2′-azobis [2- (2-imidazolin-2-yl) propane] disulfate dihydrate, such as peroxy Persulfate compounds such as potassium sulfate, sodium persulfate and ammonium persulfate, for example, water-soluble inorganic peroxides such as hydrogen peroxide, water-soluble organic peroxides such as tert-butyl peroxide and cumene peroxide, etc. Is mentioned. Further, as a water-soluble polymerization initiator, for example, a water-soluble polymerization initiator excluding a water-soluble azo compound, ascorbic acid, sodium bisulfite, sodium hyposulfite, sodium bisulfite, sodium sulfite, sodium bisulfite, hydroxymethanesulfine Examples also include redox-based water-soluble polymerization initiators in combination with water-soluble reducing agents such as sodium acid (Longalite), thiourea dioxide, sodium thiosulfate, divalent iron salt, monovalent copper salt, and amines.

  The polymerization initiators can be used alone or in combination of two or more.

  Preferably, an oil-soluble polymerization initiator is used, and more preferably, an oil-soluble organic peroxide is used.

  And in the manufacturing method of the sustained release particle | grains of this invention, a hydrophobic solution is first prepared by melt | dissolving a hydrophobic antibiotic compound with a hydrophobic polymerizable vinyl monomer.

  That is, a hydrophobic solution is obtained by blending an antibiotic compound and a polymerizable vinyl monomer and stirring them uniformly.

  The hydrophobic solution contains, for example, a solvent of an antibiotic compound (hydrophobic organic solvent such as hexane, toluene and ethyl acetate) and / or a hydrophobe (costabilizer such as hexadecane and cetyl alcohol). Without being prepared. Thereby, environmental load can be reduced.

  The blending ratio of the antibiotic compound to the polymerizable vinyl monomer is, for example, 0.01 to 4.0, preferably 0.01 to 4.0 on a mass basis (that is, the mass part of the antibiotic compound / the polymerizable vinyl monomer). 0.05-3.0.

  The hydrophobic solution may be prepared, for example, at room temperature, or in order to increase the dissolution rate of the antibiotic compound in the polymerizable vinyl monomer, and further, when the solubility of the antibiotic compound is not sufficient at room temperature. In addition, heating can be carried out to increase the solubility.

  The heating temperature is, for example, 30 to 100 ° C, preferably 40 to 80 ° C.

  In the preparation of the hydrophobic solution, when an oil-soluble polymerization initiator is used as the polymerization initiator, an oil-soluble polymerization initiator is blended together with the antibiotic compound and the polymerizable vinyl monomer. The blending of the oil-soluble polymerization initiator is preferably carried out at room temperature. When an antibiotic compound and a polymerizable vinyl monomer are blended and heated to dissolve the antibiotic compound in the polymerizable vinyl monomer, the dissolved solution is cooled to room temperature or dissolved. Then, the mixture is cooled to a temperature higher than the temperature at which the active antibiotic compound does not precipitate, and then an oil-soluble polymerization initiator is blended.

  The blending ratio of the oil-soluble polymerization initiator is, for example, 0.01 parts by mass or more, preferably 0.1 parts by mass or more, for example, 5 parts by mass or less, preferably 100 parts by mass of the polymerizable vinyl monomer. Is also 3 parts by mass or less.

  When the blending ratio of the oil-soluble polymerization initiator exceeds the above upper limit, the molecular weight of the polymer may be excessively decreased, and when it does not satisfy the above lower limit, the conversion rate is not sufficiently improved and unreacted. Of the polymerizable vinyl monomer may remain.

  Moreover, in the manufacturing method of the sustained release particle | grains of this invention, water and an emulsifier are mix | blended separately and an emulsifier aqueous solution is prepared.

  Specifically, an aqueous emulsifier solution is obtained by blending water and an emulsifier and stirring them uniformly.

  The amount of emulsifier is sufficient to allow the emulsifier to be adsorbed on the entire surface of the hydrophobic solution emulsified droplets, and the emulsion polymerized particles of a new polymerizable vinyl monomer that does not contain antibiotic active compounds due to the presence of excess emulsifier Is selected depending on the type of emulsifier, but for example, the effective amount of the emulsifier is 0.1 to 20% by mass, preferably 0.2 to 10% by mass.

  Preparation of the emulsifier aqueous solution may be performed, for example, at room temperature, or may be performed by heating as necessary.

  The heating temperature is, for example, 30 to 100 ° C, preferably 40 to 80 ° C.

  In the preparation of the aqueous emulsifier solution, when a water-soluble polymerization initiator is used as the polymerization initiator, a water-soluble polymerization initiator is blended together with water and the emulsifier. The blending of the water-soluble polymerization initiator is preferably carried out at room temperature. When water and an emulsifier are blended and heated to dissolve the emulsifier in water, the aqueous solution is cooled to room temperature, and then a water-soluble polymerization initiator is blended.

  The mixing ratio of the water-soluble polymerization initiator is, for example, 0.01 parts by mass or more, preferably 0.1 parts by mass or more, for example, 5 parts by mass or less, preferably 3 parts with respect to 100 parts by mass of water. It is also below mass parts.

  When the blending ratio of the water-soluble polymerization initiator exceeds the above upper limit, the molecular weight of the polymer may be excessively reduced. When the blending ratio is less than the above lower limit, the conversion rate is not sufficiently improved and unreacted. Of the polymerizable vinyl monomer may remain.

  Further, polyvinyl alcohol (hereinafter abbreviated as “PVA”) can be blended in the aqueous emulsifier solution.

  PVA is a dispersant blended in an aqueous phase to form a protective colloid of a mini-emulsion, for example, a polyvinyl acetate system obtained by polymerizing a vinyl monomer containing vinyl acetate as a main component by an appropriate method. It can be obtained by saponifying the polymer.

  By blending PVA into the emulsifier aqueous solution, a stable hydrated layer is formed by the protective colloid of PVA, and aggregation due to collision between particles is less likely to occur. As a result, for example, even in a formulation with a small amount of emulsifier, due to a polymerization initiator (including a reducing agent) added at the end of the polymerization in order to reduce the amount of aggregates during miniemulsion polymerization or to reduce the amount of residual monomer, Polymerization stability can be improved, for example, destabilization of miniemulsion polymerized particles can be prevented. In addition, when sustained release particles are prevented from agglomerating and caking during long-term storage, or when the sustained release particles are used as a wood treatment agent, they are diluted with water and passed through a high shear force pump or nozzle. In addition, the colloidal stability can be improved, for example, the aggregation of the sustained release particles can be prevented.

  The degree of saponification of PVA is, for example, 70% or more, preferably 80% or more, and for example, 99% or less, preferably 90% or less.

  The average degree of polymerization of PVA is, for example, 300 or more, preferably 500 or more, and for example, 4000 or less, preferably 2500 or less.

  PVA has a 4% aqueous solution having a viscosity at 20 ° C. of, for example, 3 mPa · sec or more, preferably 5 mPa · sec or more, and for example, 100 mPa · sec or less, preferably 50 mPa · sec or less.

  The viscosity of PVA can be measured using a B-type viscometer with a 4% aqueous solution at 20 ° C.

  When blending PVA, the blending ratio is selected in an amount sufficient for PVA to be adsorbed on the entire surface of the hydrophobic solution emulsified droplets, and varies depending on the type of PVA. The active ingredient amount of PVA is, for example, 0.5 to 10% by mass, preferably 1 to 8% by mass.

  For the preparation of the PVA aqueous solution, for example, PVA is added to and dispersed in cold water at 25 ° C. or lower with stirring, and the temperature is raised to 60 to 90 ° C. and dissolved. After confirming that PVA is completely dissolved in water, it can be carried out by cooling to room temperature.

  The emulsifier aqueous solution can also contain a dispersant other than PVA.

  Examples of the dispersant include condensates of aromatic sulfonic acid and formaldehyde, polycarboxylic acid type oligomers, and preferably condensates of aromatic sulfonic acid and formaldehyde.

  Examples of the condensate of aromatic sulfonic acid and formaldehyde include sodium salt of β-naphthalene sulfonic acid formaldehyde condensate.

  These dispersants can be used alone or in combination of two or more.

  The blending ratio of the dispersant is, for example, 0.001% by mass or more, preferably 0.01% by mass or more, for example, 0.5% by mass or less, preferably, with respect to the hydrophobic solution. 0.3 mass% or less, and more preferably 0.2 mass% or less.

  In the method for producing sustained-release particles of the present invention, the hydrophobic solution is then emulsified in an aqueous emulsifier solution.

  Specifically, a hydrophobic solution is blended in an emulsifier aqueous solution, and a high shear force is applied to them to emulsify the hydrophobic solution in the emulsifier aqueous solution to prepare a mini-emulsion.

  In emulsification of the hydrophobic solution, for example, an emulsifier such as a homomixer (homogenizer), an ultrasonic homogenizer, a pressure homogenizer, a milder, or a porous membrane press emulsifier is used, and preferably a homomixer is used.

  The stirring conditions are set as appropriate, and when a homomixer is used, the number of rotations is set to, for example, 6000 rpm or more, preferably 8000 rpm or more, more preferably 10,000 rpm or more, for example, 30000 rpm or less.

  If the rotational speed is less than the lower limit, miniemulsion particles having a particle diameter of less than 1 μm may not be formed.

  The stirring time is, for example, 1 minute or longer, preferably 2 minutes or longer, and 1 hour or shorter.

  The miniemulsion can be prepared, for example, at room temperature or by heating. Moreover, it can also heat at the time of emulsification. The heating temperature is, for example, not less than the heating temperature at the time of preparation of the above-described hydrophobic solution and / or emulsifier aqueous solution, and specifically, 30 to 100 ° C, preferably 40 to 80 ° C.

  The mixing ratio of the hydrophobic solution is, for example, 10 to 150 parts by mass, preferably 25 to 90 parts by mass with respect to 100 parts by mass of the aqueous emulsifier solution.

  A mini-emulsion of a hydrophobic solution is prepared by the method described above. In addition, in the hydrophobic emulsion mini-emulsion, the emulsifier is adsorbed on the mini-emulsion particles (hydrophobic solution emulsified droplets), and the hydrophobic emulsion mini-emulsion particles having an average particle diameter of less than 1 μm are formed in the aqueous medium. Has been.

  The average particle diameter (median diameter, described later) of the miniemulsion particles is, for example, less than 1 μm, preferably 750 nm or less, more preferably 500 nm or less, particularly preferably 400 nm or less, and most preferably 300 nm or less. For example, it is adjusted to 50 nm or more.

  Note that an emulsifier is adsorbed on the surface of the miniemulsion particles, thereby stabilizing the miniemulsion.

  Therefore, the miniemulsion prepared by stirring can be subjected to the next miniemulsion polymerization after being prepared and allowed to stand. In that case, the standing time may be 24 hours or longer, for example.

  The average particle size of the miniemulsion particles does not change substantially with time, or the rate of change is extremely small.

  Specifically, the ratio of the average particle size after the lapse of 24 hours (standing at room temperature) after the preparation to the average particle size after lapse of 20 minutes (standing at room temperature) from the preparation of the miniemulsion (from the preparation to 24 The average particle diameter after the lapse of time / the average particle diameter after the lapse of 20 minutes from the preparation) is, for example, 0.9 to 1.1, preferably 0.95 to 1.05.

  In the present invention, the polymerized vinyl monomer in the emulsified hydrophobic solution is then subjected to miniemulsion polymerization in the presence of a polymerization initiator to produce a polymer.

  This miniemulsion polymerization is an in situ polymerization because all of the polymerizable vinyl monomers as raw materials are only in the miniemulsion particles (hydrophobic liquid phase).

  That is, in the mini-emulsion polymerization, by heating the mini-emulsion while stirring, the polymerization vinyl monomer starts polymerization in the mini-emulsion particles as it is, and a polymer is generated.

  Agitation can be performed, for example, with a stirrer having a stirring blade, and stirring sufficient to control uniform heat conduction to the miniemulsion, sticking of the miniemulsion particles to the wall, and retention of the miniemulsion on the surface of the miniemulsion. As long as the effect can be realized, excessive stirring causes aggregation of the miniemulsion particles. As for the stirring speed, the peripheral speed of the stirring blade is, for example, 10 m / min or more, preferably 20 m / min or more, and 400 m / min or less, preferably 200 m / min or less.

  The heating conditions are appropriately selected depending on the type of the polymerization initiator and the antibiotic compound, and the heating temperature is, for example, not less than the melting point of the antibiotic compound, specifically 30 to 100 ° C., preferably 50 to The heating time is, for example, 2 to 24 hours, preferably 3 to 12 hours. Furthermore, after heating to a predetermined temperature, the temperature can be maintained for a predetermined time, and then heating and temperature maintenance can be repeated to heat in stages.

In order to reduce the remaining polymerizable vinyl monomer at the end of the polymerization, a water-soluble polymerization initiator can be added in order to polymerize the polymerizable vinyl monomer saturated and dissolved in the aqueous phase.

  Examples of the water-soluble polymerization initiator include the same water-soluble polymerization initiators as described above. When using a water-soluble initiator excluding a water-soluble azo compound, there are a case where only a water-soluble polymerization initiator is added and a case where a redox-based water-soluble polymerization initiator containing a water-soluble reducing agent is added. From the viewpoint of reducing residual monomers, a redox-based water-soluble polymerization initiator (the latter) is preferred.

  Examples of the water-soluble reducing agent include ascorbic acid, sodium hydrogen sulfite, sodium formaldehyde sulfoxylate, divalent iron salt, monovalent copper salt, amines and the like.

  The mixing ratio of the water-soluble polymerization initiator is, for example, 0.01 to 0.5 parts by mass with respect to 100 parts by mass of the polymerizable vinyl monomer, and when a redox water-soluble polymerization initiator is added. The mixing ratio of the water-soluble reducing agent is, for example, 0.01 to 0.5 parts by mass with respect to 100 parts by mass of the water-soluble polymerization initiator.

  Moreover, the pressure at the time of miniemulsion polymerization is not specifically limited, For example, it is a normal pressure.

  In the above description, the miniemulsion polymerization is carried out at normal pressure, but it can also be carried out under high pressure, for example. Thereby, the reaction system can be set to a temperature exceeding 100 ° C., and the antibiotic compound having a melting point of 80 to 100 ° C. can be easily made liquid.

  As described above, the miniemulsion polymerization is clearly different from emulsion polymerization in which the polymerization process is not in situ polymerization but polymerization is performed by mass transfer of a polymerizable vinyl monomer, in that the polymerization process is in situ polymerization. .

  Specifically, emulsion polymerization is carried out in the aqueous phase in the presence of an emulsifier, a polymerizable vinyl monomer, and a polymerization initiator (radical polymerization initiator), and is polymerized by radicals generated by decomposition of the radical polymerization initiator. To start. At this time, the polymerizable vinyl monomer exists in the following three states. That is, (1) a state solubilized in micelles of an emulsifier (state having an average particle diameter of less than several tens of nanometers), (2) a state dissolved in an aqueous phase, and (3) a state existing as oil droplets (particle diameter The polymerizable vinyl monomer exists in three states (several μm or more).

  The radicals generated by the decomposition of the radical polymerization initiator may collide and invade the three-state polymerizable vinyl monomer and add to the polymerizable vinyl monomer to start polymerization. 1) The micelle of the emulsifier solubilized with the polymerizable vinyl monomer has an overwhelmingly larger number of particles than the oil droplets of the above-described (3) polymerizable vinyl monomer, and therefore has a large surface area and a radical penetration probability. Since it is high, (1) Polymerization starts in the micelle of the emulsifier to form polymer particles. When a highly water-soluble polymerizable vinyl monomer is used as the polymerizable vinyl monomer, (2) radical addition to the vinyl monomer dissolved in the aqueous phase described above occurs, and the produced polymer enters the aqueous phase. When it cannot be dissolved and precipitates, it is stabilized by an emulsifier, and polymer particles are produced. Such an initiation reaction is also observed in the emulsion polymerization process.

  When the emulsion polymerization starts, (3) the polymerizable vinyl monomer is dissolved in the water phase from the oil droplets of the polymerizable vinyl monomer, and then the polymerizable vinyl monomer moves to the polymer particles and the polymerization proceeds. That is, the polymerization field is polymer particles, and the oil droplets of the polymerizable vinyl monomer only serve as a supply source of the polymerizable vinyl monomer, and polymerization, that is, in situ polymerization does not occur on the spot. .

  In contrast, miniemulsion polymerization is highly sheared into oil droplets of polymerizable vinyl monomers in the aqueous phase by the presence of emulsifiers and hydrophobes (costabilizers), using homomixers, homogenizers, and ultrasonic irradiation. When the particle size is reduced to less than 1 μm, preferably less than 0.5 μm by applying force, and the polymerization initiator (radical polymerization initiator) is oil-soluble, the minute and stable polymerizable vinyl monomer In the oil droplets, due to radicals generated by the decomposition of the polymerization initiator, or when the polymerization initiator is water-soluble, the radicals penetrate into the oil droplets, and polymerization starts by the penetrating radicals, This is a polymerization method in which radical polymerization proceeds.

  In detail, the oil droplets of a minute polymerizable vinyl monomer exist stably by adopting an anionic emulsifier as an emulsifier, for example. At the same time, oil droplets of small polymerizable vinyl monomers can be produced from oil droplets of smaller (fine) polymerizable vinyl monomers via the aqueous phase by using hydrophobes (costabilizers). It exists stably by controlling the enlargement (Ostwald ripening) due to the transfer of the polymerizable vinyl monomer to the oil droplets.

  On the other hand, in the present invention, miniemulsion polymerization in which a polymerizable vinyl monomer is polymerized (radical polymerization) proceeds in miniemulsion particles (fine oil droplets composed of an antibiotic compound and a polymerizable vinyl monomer). During miniemulsion polymerization, the polymer of polymerizable vinyl monomer is preferably compatible with the antibiotic compound. That is, the polymer is dissolved in the antibiotic compound to form an antibiotic compound solution of the polymer, and the antibiotic compound solution is emulsified in water.

  In addition, the polymerizable vinyl monomer is preferably a combination in which the polymer of the polymerizable vinyl monomer and the antibiotic compound are compatible as described above at the polymerization temperature (heating temperature) during the above-described miniemulsion polymerization. Therefore, it is possible to prevent phase separation during miniemulsion polymerization, so that the polymer (polymer in the middle of the reaction) is dissolved in the antibiotic compound or the polymer (heavy in the middle of the reaction). The reaction proceeds in a state in which the compound) is swollen with respect to the antibiotic compound, whereby sustained-release particles in which a uniform phase is formed can be obtained. If the antibiotic compound is liquid at room temperature, the state of the polymer antibiotic compound solution is maintained as it is at room temperature.

  On the other hand, since the average particle size of the miniemulsion particles is as small as less than 1 μm, the polymerizable vinyl monomer easily diffuses in the water phase. In the miniemulsion polymerization of the present invention, the antibiotic compound acts as a hydrophobe. Therefore, as a result of effectively preventing the molecular diffusion described above, Ostwald ripening can be prevented and enlargement of the miniemulsion particles (increase in particle diameter) can be suppressed.

  Thereafter, the emulsion after polymerization is cooled, for example, by standing to cool.

  The cooling temperature is, for example, room temperature (20 to 30 ° C., more specifically 25 ° C.).

  When the sustained-release particles are formulated as a powder (described later) or a granule (described later), preferably at a room temperature, the hard-release glass is used to prevent the sustained-release particles from fusing together. As such, a polymerizable vinyl monomer is selected.

  The average particle size of the sustained-release particles (polymer) thus obtained is a median size of less than 1 μm, preferably 750 nm or less, more preferably 500 nm or less, particularly preferably 400 nm or less, most preferably , 300 nm or less, and for example, 10 nm or more, preferably 50 nm or more.

  Thereby, an emulsion in which sustained-release particles in which the antibiotic compound is uniformly present is finely dispersed can be obtained.

  In addition, known additives such as other dispersants, thickeners, antifreeze agents, preservatives, microbial growth inhibitors, specific gravity regulators, and the like are appropriately blended into the emulsion containing sustained release particles as necessary. .

  The thus obtained sustained-release particles may be used as they are (emulsion), that is, as an emulsion, or aggregated by spray drying, freezing / thawing, salting out, or the like. After that, solid-liquid separation is performed by centrifugation, washing, drying, and the like, and for example, it may be formulated into a known dosage form such as powder or granule.

  In the method for producing sustained-release particles of the present invention, the polymerized vinyl monomer in the emulsified hydrophobic solution is subjected to miniemulsion polymerization in the presence of a polymerization initiator to produce a polymer having an average particle size of less than 1 μm. By doing so, the sustained-release particles of the present invention are obtained, so that the sustained-release particles are excellent in dispersibility.

  Specifically, since the sustained release particles have an average particle diameter of less than 1 μm, sedimentation based on gravity is unlikely to occur, and the sustained release particles are uniformly dispersed in the emulsion due to Brownian motion of the sustained release particles, When this emulsion is added to various aqueous media, it can be uniformly dispersed in the liquid.

  Therefore, the sustained-release particles of the present invention are uniformly dispersed with an average particle diameter of less than 1 μm (submicron size) in the added medium, so that excellent sustained-release properties are superior to the original dispersion. As a sustained release particle having a property, it can be used for various applications.

  Specifically, the sustained-release particles can be applied to various industrial products, such as indoor and outdoor paints, rubber, fibers, resins, plastics, adhesives, joint agents, sealing agents, building materials, caulking agents. , Soil treatment agent, wood treatment agent, white water in papermaking process, pigment, printing plate treatment liquid, cooling water, ink, cutting oil, cosmetics, non-woven fabric, spinning oil, leather, etc. Can be added as In addition, the addition amount of the antibiotic compound in the sustained release particles for these industrial products is, for example, 10 mg / kg to 100 g / kg (product mass).

  Moreover, this sustained release particle | grain can be suitably mix | blended with the aqueous coating material in which the emulsifier common with the emulsifier mix | blended with the emulsifier aqueous solution is used. The water-based paint is a water-based paint used indoors and outdoors. Specifically, for example, acrylic, acrylic-styrene, styrene, vinyl acetate, vinyl acetate-acrylic, polyester, silicone, urethane Paints using vehicle, alkyd, and fluororesin emulsions or water-based resins and mixtures of these as vehicles. Among them, when blended with zero VOC paints, they are environmentally friendly and contain sustained release particles. The stability can be maintained well, and the durability of the effect can be further improved.

  In addition, since the hydrophobic antibiotic compound can also be used as a hydrophobe in miniemulsion polymerization, a sustained-release particle having an average particle diameter of less than 1 μm can be easily produced without separately adding a hydrophobe. be able to.

  Further, if the average particle diameter of the sustained-release particles is 750 nm or less and 100 nm or more, for example, when there is a difference of 0.2 or more between the refractive index of the sustained-release particles and the refractive index of the medium The reflection of light (visible light, wavelength 360 to 760 nm) is large at the interface between the sustained-release particles and the medium, and the sustained-release particles mixed in the medium appear white.

  Furthermore, if the average particle size of the sustained-release particles is less than 100 nm, the ratio of light (visible light, wavelength 360 to 760 nm) that permeates the sustained-release particles is high regardless of the medium, and the transparency is enhanced. .

  Therefore, the sustained-release particles of the present invention blended in an appropriate medium can be suitably used as an additive for paints since the discoloration can be suppressed visually even if the antibiotic compound is substantially discolored. it can.

  Moreover, this sustained release particle | grain can also be used as a wood processing agent. When using sustained-release particles as a wood treating agent, it is sufficient that the sustained-release particles are contained. For example, an emulsion (raw emulsion) containing the above-mentioned sustained-release particles and an emulsion Can be used as a wood treating agent.

  When the wood treatment agent is a raw emulsion, the content of the sustained release particles in the wood treatment agent is, for example, 10% by mass or more, preferably 30% by mass or more, and for example, 60% by mass. Hereinafter, preferably, it is also 50% by mass or less. On the other hand, when the wood treatment agent is a diluent, it is, for example, 0.2% by mass or more, preferably 0.5% by mass or more. It is also 10% by mass or less, preferably 5% by mass or less.

  In the case of the raw emulsion, the concentration of the antibiotic compound in the wood treatment agent is, for example, 2% by mass or more, preferably 5% by mass or more, and for example, 50% by mass or less, preferably 40%. On the other hand, in the case of a diluent, it is, for example, 0.03% by mass or more, preferably 0.1% by mass or more, and for example, 10% by mass or less, preferably 5% by mass. It is also below.

  For the wood treatment agent, for example, known additives such as dispersants, thickeners, antifreeze agents, preservatives, insecticides, insecticides, pest repellents, microbial growth inhibitors, specific gravity regulators and the like are appropriately blended. be able to.

  Details of the raw materials or measurement methods used in each example and each comparative example are described below.

IPBC: Trade name “Fangitrol 400”, 3-iodo-2-propynylbutylcarbamate, molecular weight 281, melting point: 60 ° C., solubility in water: 150 ppm, dipole force term δ _{p, compound of} solubility parameter δ: 3 .23 [(J / cm ³ ) ^1/2 ], hydrogen bonding force term δ _{h, compound of} solubility parameter δ: 7.83 [(J / cm ³ ) ^1/2 ], OIT manufactured by International Specialty Products : Trade name “Caisson 893T”, 2-n-octyl-4-isothiazolin-3-one, molecular weight 213, melting point less than 20 ° C., solubility in water 300 ppm, solubility parameter δ dipole force term δ _{p, compound} : ^{5.47 [(J / cm 3)} 1/2], hydrogen bonding term solubility parameter _δ δ _h, compoun ^{: 5.87 [(J / cm 3} ) 1/2], Dow Co. cyfluthrin: trade name "Prevention Torr HS12", (RS) -α- cyano-4-fluoro-3-phenoxy-benzyl - (1RS, 3RS )-(1RS, 3RS) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate, molecular weight 434, solubility in water: 1-2 ppb, isomer I (melting point 57 ° C.) Mixture of isomer II (melting point 74 ° C.), isomer III (melting point 66 ° C.) and isomer IV (melting point 102 ° C.), dipole force term δ _{p, compound of} solubility parameter δ: 3.46 [(J / Cm ³ ) ^1/2 ], hydrogen bonding term δ _{h, compound of} solubility parameter δ 6.09 [(J / cm ³ ) ^1/2 ], manufactured by LANXESS Propiconazole: 1- [2- ( 2 , 4-Dichlorophenyl) -4-n-propyl-1,3-dioxolan-2-ylmethyl] -1H-1,2,4-triazole, molecular weight 342, melting point less than 20 ° C., water solubility 110 ppm, solubility parameter δ The dipole force term δ _{p, compound of} 6.55 [(J / cm ³ ) ^1/2 ] and the hydrogen bond force term δ _{h, compound of} the solubility parameter δ 9.44 [(J / cm ³ ) ^{1 / 2} ], Yokotsu Trading Co., Ltd. Prochloraz: N-propyl-N- [2- (2,4,6-trichloro-phenoxy) ethyl] imidazole-1-carboxamide, molecular weight 375, melting point 45-52 ° C., to water solubility: 55 ppm, the solubility parameter polar term δ _p, compound of ^{δ: 7.07 [(J / cm} 3) 1/2], hydrogen bonding solubility parameter [delta] Term _{δ h, compound: 8.31 [(} J / cm 3) 1/2], Maruzen Pharmaceutical Co. flusilazole: bis (4-fluorophenyl) methyl (IH-1,2,4-triazol-1-ylmethyl Silane, molecular weight 315, melting point: 54 ° C., solubility in water: 45 ppm, dipole force term δ _{p, compound of} solubility parameter δ: 5.95 [(J / cm ³ ) ^1/2 ], solubility parameter δ Hydrogen bond strength term δ _{h, compound} : 6.85 [(J / cm ³ ) ^1/2 ], manufactured by Air Brown Co., Ltd. Diet: N, N-diethyl-m-toluamide, molecular weight 191, melting point: −45 ° C., water _{solubility: 990ppm, δ p, compound:} 5.42 [(J / cm 3) 1/2], δ h, compound: 5.83 [(J / cm 3) 1/2], E Reagents manufactured by Kasei Kogyo Co., Ltd. Permethrin: Trade name “Pliventol HS75”, 3-phenoxybenzyl (1RS, 3RS; 1RS, 3SR) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate, Molecular weight 391, melting point: 34-35 ° C., solubility in water: 6 ppb, δ _{p, compound} : 3.63 [(J / cm ³ ) ^1/2 ], δ _{h, compound} : 6.22 [(J / cm ³ ) ^1/2 ], etofenprox manufactured by LANXESS, Inc .: trade name “Trebone insecticide active ingredient”, 2- (4-ethoxyphenyl) -2-methylpropyl-3-phenoxybenzyl ether, molecular weight 377, melting point: 36 ~ 38 ° C, solubility in water: 22.5 ppb, δ _p , _compound : 2.27 [(J / cm ³ ) ^1/2 ], δ _h , ^{_{compound: 5.33 [(J / cm}} 3) 1/2], Mitsui Chemicals Agro, Inc. methacrylate: trade name "Accession Rie ester M", the solubility in water: 1.6 wt%, as a monomer unit Dipole force term of solubility parameter δ δ _{p, monomer unit} : 5.98 [(J / cm ³ ) ^1/2 ], hydrogen bonding force term of solubility parameter δ as a monomer unit δ _{h, monomer unit} : 9. 25 [(J / cm ³ ) ^1/2 ], manufactured by Mitsubishi Rayon Co., Ltd. Isobutyl methacrylate: water solubility: 0.06% by mass, dipole force term δ _p, monomer unit of solubility parameter δ as a monomer _unit : 3.75 [(J / cm ³ ) ^1/2 ], hydrogen bond term δ _h, monomer unit of solubility parameter δ as a monomer _unit : 7. 32 [(J / cm ³ ) ^1/2 ], manufactured by Nippon Shokubai Co., Ltd. Ethylene glycol dimethacrylate: trade name “Light Ester EG”, solubility in water: insoluble , dipole force term of solubility parameter δ as a monomer unit δ _{p, monomer unit} : 5.37 [(J / cm ³ ) ^1/2 ], hydrogen bond term of solubility parameter δ as a monomer unit δ _{h, monomer unit} : 10.42 [(J / cm ³ ) ^{1 / 2} ], Kyoeisha Chemical Co., Ltd. T-1890: trade name “VESTANAT T 1890/100”, isocyanurate of isophorone diisocyanate, Evonik Industries, Ltd. DETA: diethylenetriamine, Wako first grade reagent, Wako Pure Chemical Industries, Ltd. ATBC: Perbutyl acetyl citrate, solvent, Asahi Kasei Finechem L: Trade name (“Perroyl” is a registered trademark), dilauroyl peroxide, manufactured by NOF Corporation Neocol SW-C: trade name, 70% by weight isopropanol solution of sodium dioctylsulfosuccinate (anionic emulsifier), Daiichi Kogyo Seiyaku DBN: Brand name “Neopelex No. 6 powder ", sodium dodecylbenzenesulfonate, anionic emulsifier, manufactured by Kao Corporation Neugen EA-177: trade name, polyoxyethylene styrenated phenyl ether (nonionic emulsifier, HLB: 15.6), manufactured by Daiichi Kogyo Seiyaku Demol NL: Trade name, 41 mass% aqueous solution of β-naphthalenesulfonic acid formaldehyde condensate sodium salt, dispersant, manufactured by Kao Chemical Co., Ltd. PVA-217: Trade name “Kuraraypoval 217”, partially saponified polyvinyl alcohol, dispersant, saponification Degree 87-89%, degree of polymerization (average degree of polymerization) 1700, Kuraray Co., Ltd. average particle size: The following samples were evaluated by the following measuring methods.

Hydrophobic solution-dispersed particles and sustained-release particles of Examples 1-12 and hydrophobic solution-dispersed particles of Comparative Examples 1-3:
Particle size analyzer (FPAR-1000, measurable average particle size of 3 nm to 7 μm, but in the region where the particle size exceeds several μm and the influence of gravity on the Brownian motion is greatly reduced, the measurement accuracy decreases significantly, Otsuka Electronics Co., Ltd.) Measured as volume-based median diameter by dynamic light scattering method using.

        For hydrophobic solution-dispersed particles, measure the miniemulsion after 20 minutes from the preparation.

        For sustained-release particles, the filtrate filtered through a 100th filter cloth was measured.

Sustained release particles of Comparative Examples 4 and 5:
Laser diffraction scattering type particle size distribution measuring device LA-920 (measurable average particle size of 20 nm to 2000 μm, however, if the particle size is 1 μm or less, mu scattering is not angularly dependent and the measurement accuracy is significantly reduced. ), And the filtrate filtered through a 100th filter cloth is measured as a volume-based median diameter.

Example 1
(Manufacture of sustained release particles containing IPBC by miniemulsion polymerization)
In a 200 mL container, 25 g of IPBC, 75 g of methyl methacrylate and 0.5 g of Parroyl L were charged and stirred at room temperature to prepare a uniform hydrophobic solution.

  Separately, 125.5 g of deionized water, 4.0 g of Neocor SW-C, and 20 g of a 25% by weight aqueous solution of Neugen EA-177 were placed in a 500 mL beaker and stirred at room temperature to prepare a uniform aqueous emulsifier solution.

  Next, the hydrophobic solution was added to the emulsifier aqueous solution of the 500 mL beaker. K. By stirring for 5 minutes at a rotational speed of 12000 rpm with a homomixer MARK 2.5 type (manufactured by Primix), the hydrophobic solution was emulsified in an aqueous emulsifier solution to prepare a mini-emulsion.

  Thereafter, the prepared mini-emulsion was transferred to a 300 mL four-necked flask equipped with a stirrer, a reflux condenser, a thermometer, and a nitrogen introduction tube, and the rotation speed was 125 rpm (circumferential speed 23. While stirring at 6 m / min), the temperature of the four-necked flask was raised with a water bath to carry out miniemulsion polymerization.

  The mini-emulsion polymerization was started at the time when the temperature reached 55 ° C., and then continuously carried out at 60 ± 2 ° C. for 1 hour and at 70 ± 2 ° C. for 3.5 hours.

  Subsequently, the temperature of the water bath was raised, the temperature of the reaction solution was raised to 80 ° C. ± 2 ° C., and aging was carried out at that temperature for 2.5 hours.

  Thereafter, the reaction solution was cooled to 30 ° C. or lower to obtain an emulsion of sustained-release particles containing IPBC.

  Then, after filtering an emulsion with the filter cloth of 100th, when the median diameter of the sustained release particle | grains in a filtrate was measured, the result was 201 nm.

  This emulsion was a stable colloidal dispersion similar to ordinary polymer latex, and no tendency of sedimentation of sustained release particles or phase separation was observed during storage at room temperature.

Example 2
(Manufacture of sustained release particles containing IPBC by miniemulsion polymerization)
In a 200 mL container, 25 g of IPBC, 70.5 g of methyl methacrylate, 4.5 g of ethylene glycol dimethacrylate, and 0.5 g of Parroyl L were charged and stirred at room temperature to prepare a uniform hydrophobic solution.

  Separately, 125.5 g of deionized water, 4.0 g of Neocor SW-C, and 20 g of a 25% by weight aqueous solution of Neugen EA-177 were placed in a 500 mL beaker and stirred at room temperature to prepare a uniform aqueous emulsifier solution.

  Next, the hydrophobic solution was added to the emulsifier aqueous solution of the 500 mL beaker. K. By stirring for 5 minutes at a rotational speed of 12000 rpm with a homomixer MARK 2.5 type (manufactured by Primix), the hydrophobic solution was emulsified in an aqueous emulsifier solution to prepare a mini-emulsion.

  Thereafter, the prepared miniemulsion was transferred to a 300 mL four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a nitrogen introduction tube, and miniemulsion polymerization was carried out according to the same procedure as in Example 1.

  Thereafter, the reaction solution was cooled to 30 ° C. or lower to obtain an emulsion of sustained-release particles containing IPBC. The emulsion was filtered through a 100th filter cloth, and the median diameter of the sustained-release particles in the filtrate was measured. The result was 230 nm.

  This emulsion was a stable colloidal dispersion similar to ordinary polymer latex, and no tendency for particle settling or phase separation during storage at room temperature was observed.

Example 3
(Manufacture of sustained release particles containing OIT by miniemulsion polymerization)
A 200 mL container was charged with 25 g of OIT, 48 g of methyl methacrylate, 22.5 g of isobutyl methacrylate, 4.5 g of ethylene glycol dimethacrylate and 0.5 g of Parroyl L, and stirred at room temperature to prepare a uniform hydrophobic solution. .

  Separately, 125.5 g of deionized water, 4.0 g of Neocol SW-C and 20 g of a 25% by weight aqueous solution of Neugen EA-177 were charged into a 500 mL beaker and stirred at room temperature to prepare a uniform aqueous emulsifier solution.

  Next, the hydrophobic solution was added to the emulsifier aqueous solution of the 500 mL beaker. K. By stirring for 5 minutes at a rotational speed of 12000 rpm with a homomixer MARK 2.5 type (manufactured by Primix), the hydrophobic solution was emulsified in an aqueous emulsifier solution to prepare a mini-emulsion.

  Thereafter, the prepared mini-emulsion was transferred to a 300 mL four-necked flask equipped with a stirrer, reflux condenser, thermometer and nitrogen introduction tube, and the four-necked flask was stirred with a stirrer at a rotation speed of 125 rpm under a nitrogen stream. The mixture was heated with a water bath to carry out miniemulsion polymerization.

  The mini-emulsion polymerization was started at the time when the temperature reached 55 ° C., and then continuously carried out at 60 ± 2 ° C. for 1 hour and at 70 ± 2 ° C. for 3.5 hours.

  Subsequently, the temperature of the water bath was raised, the temperature of the reaction solution was raised to 80 ° C. ± 2 ° C., and aging was carried out at that temperature for 2.5 hours.

  Thereafter, the reaction liquid was cooled to 30 ° C. or lower to obtain an emulsion of sustained-release particles containing OIT.

  The emulsion was filtered through a 100th filter cloth, and the median diameter of the sustained-release particles in the filtrate was measured. The result was 198 nm.

  This emulsion was a stable colloidal dispersion similar to ordinary polymer latex, and no tendency for particle settling or phase separation during storage at room temperature was observed.

Example 4
(Manufacture of sustained release particles containing OIT by miniemulsion polymerization)
A uniform hydrophobic solution was prepared by charging 30 g of OIT, 65.8 g of MMA, 4.2 g of EGDMA, and 0.5 g of parroyl L in a 200 mL container and stirring at room temperature.

  Separately, in a 500 mL beaker, 157.26 g of deionized water, 2.0 g of Neocol SW-C, 40 g of PVA217 (10% by mass) aqueous solution and 0.24 g of Demol NL are stirred and stirred at room temperature to obtain a uniform aqueous emulsifier solution. Prepared.

  Next, the hydrophobic solution was added to the emulsifier aqueous solution of the 500 mL beaker. K. A hydrophobic emulsion was emulsified in an emulsifier aqueous solution by stirring with a homomixer MARK 2.5 type (manufactured by Primix) at a rotational speed of 14,000 rpm for 10 minutes to prepare a mini-emulsion.

  Thereafter, the prepared mini-emulsion was transferred to a 300 mL four-necked flask equipped with a stirrer, a reflux condenser, a thermometer, and a nitrogen introduction tube, and a rotation speed of 200 rpm (peripheral speed: 37. While stirring at 7 m / min), the temperature of the four-necked flask was raised with a water bath to carry out miniemulsion polymerization.

  The mini-emulsion polymerization was started at the time when the temperature reached 55 ° C., and then continuously carried out at 60 ± 2 ° C. for 3 hours and at 70 ± 2 ° C. for 2 hours.

  Subsequently, the temperature of the water bath was raised, and the temperature of the reaction solution was raised to 80 ± 2 ° C. and aged for 2 hours.

  Thereafter, the reaction liquid was cooled to 30 ° C. or lower to obtain an emulsion of sustained-release particles containing OIT.

  The emulsion was filtered through a 100th filter cloth, and the median diameter of the sustained-release particles in the filtrate was measured. The result was 166 nm.

  This emulsion was a stable colloidal dispersion similar to ordinary polymer latex, and no tendency for particle settling or phase separation during storage at room temperature was observed.

Example 5
(Manufacture of sustained-release particles containing cyfluthrin by miniemulsion polymerization)
Based on the formulation and reaction conditions shown in Table 2 using cyfluthrin as the antibiotic compound, treatment was carried out in the same manner as in Example 4 to obtain an emulsion of sustained-release particles.

  Table 2 shows the results of measuring the median diameter of the sustained-release particles in the filtrate after filtering the emulsion with a 100th filter cloth.

Example 6
(Manufacture of sustained-release particles containing propiconazole by miniemulsion polymerization)
Propiconazole was used as the antibiotic compound and the same treatment as in Example 4 was performed based on the formulation and reaction conditions shown in Table 2 to obtain an emulsion of sustained release particles.

  Table 2 shows the results of measuring the median diameter of the sustained-release particles in the filtrate after filtering the emulsion with a 100th filter cloth.

Example 7
(Manufacture of sustained release particles containing prochloraz by miniemulsion polymerization)
Prochloraz was used as an antibiotic compound and treated in the same manner as in Example 4 based on the formulation and reaction conditions shown in Table 2 to obtain an emulsion of sustained release particles.

  Table 2 shows the results of measuring the median diameter of the sustained-release particles in the filtrate after filtering the emulsion with a 100th filter cloth.

Example 8
(Manufacture of sustained release particles containing flusilazole by miniemulsion polymerization)
Based on the formulation and reaction conditions shown in Table 2 using flusilazole as the antibiotic compound, the same treatment as in Example 4 was performed to obtain an emulsion of sustained-release particles.

  Table 2 shows the results of measuring the median diameter of the sustained-release particles in the filtrate after filtering the emulsion with a 100th filter cloth.

Examples 9 and 10
(Manufacture of sustained release particles containing diet by miniemulsion polymerization)
Based on the formulation and reaction conditions listed in Table 3, using Diet as an antibiotic compound, an emulsion of sustained release particles was obtained in the same manner as in Example 4.

  Table 3 shows the results of measuring the median diameter of the sustained-release particles in the filtrate after filtering the emulsion with a 100th filter cloth.

Example 11
(Manufacture of sustained-release particles containing permethrin by miniemulsion polymerization)
Based on the formulation and reaction conditions shown in Table 3, using permethrin as the antibiotic compound, an emulsion of sustained release particles was obtained in the same manner as in Example 4.

  Table 3 shows the results of measuring the median diameter of the sustained-release particles in the filtrate after filtering the emulsion with a 100th filter cloth.

Example 12
(Manufacture of sustained-release particles containing etofenprox by miniemulsion polymerization)
Using etofenprox as an antibiotic compound, treatment was carried out in the same manner as in Example 4 based on the formulation and reaction conditions shown in Table 3, to obtain an emulsion of sustained-release particles.

  Table 3 shows the results of measuring the median diameter of the sustained-release particles in the filtrate after filtering the emulsion with a 100th filter cloth.

Comparative Example 1
(Preparation of aqueous dispersion without emulsifier)
In the preparation of the aqueous emulsifier solution, an aqueous dispersion of a hydrophobic solution was prepared in the same manner as in Example 1 except that the aqueous solution of neocol SW-C and Neugen EA-177 (above, the emulsifier) was not blended. .

  However, oil droplets made of a hydrophobic solution were not formed as miniemulsion particles, and therefore, miniemulsion polymerization could not be performed.

Comparative Example 2
(Preparation of water dispersion without IPBC)
In the preparation of the hydrophobic solution, an aqueous dispersion of the hydrophobic solution was prepared in the same manner as in Example 1 except that 25 g of IPBC and 75 g of methyl methacrylate were replaced with 100 g of methyl methacrylate.

  However, oil droplets made of a hydrophobic solution were not formed into miniemulsion particles having an average particle size of less than 1 μm, and therefore miniemulsion polymerization could not be carried out.

Comparative Example 3
(Preparation of water dispersion without OIT)
In the preparation of the hydrophobic solution, except that 25 g OIT, 48 g methyl methacrylate, 22.5 g isobutyl methacrylate and 4.5 g ethylene glycol dimethacrylate were replaced with 64 g methyl methacrylate, 30 g isobutyl methacrylate and 6 g ethylene glycol dimethacrylate, A mini-emulsion of a hydrophobic solution was prepared in the same manner as in Example 3.

  However, when this miniemulsion was allowed to stand at room temperature, the miniemulsion particles were enlarged over time (that is, the average particle size was increased, which will be described later), and it was judged that in-situ miniemulsion polymerization could not be carried out.

Comparative Example 4
(Production of sustained-release particles containing IPBC by suspension polymerization)
In a 200 mL container, 25 g of IPBC, 52.5 g of methyl methacrylate, 22.5 g of ethylene glycol dimethacrylate and 0.5 g of Parroyl L were charged and stirred at room temperature to prepare a uniform hydrophobic solution.

  Separately, 109.3 g of deionized water, 40 g of a 10% by weight aqueous solution of PVA-217, and 200 mg of a 5% aqueous solution of DBN were placed in a 500 mL beaker and stirred at room temperature to prepare a uniform aqueous solution.

  The hydrophobic solution was then added to the 500 mL beaker. K. The suspension was prepared by dispersing the hydrophobic solution in the aqueous solution by stirring for 10 minutes at a rotational speed of 3000 rpm with a homomixer (manufactured by Primix).

  Thereafter, the suspension was transferred to a 300 mL four-necked flask equipped with a stirrer, reflux condenser, thermometer, and nitrogen introduction tube, and the four-necked flask was water bathed while stirring at 125 rpm with a stirrer under a nitrogen stream. Then, the temperature was raised and suspension polymerization was carried out.

  The suspension polymerization was initiated at the time when it reached 55 ° C., and then reacted continuously at 60 ± 2 ° C. for 1 hour, 70 ± 2 ° C. for 3 hours, and 80 ± 2 ° C. for 2 hours.

  Thereafter, the suspension after the reaction was cooled to 30 ° C. or lower to obtain a suspension of sustained-release particles containing IPBC.

  The obtained suspension was transferred from a four-necked flask to a translucent polyethylene container, and the state of the sustained-release particles when allowed to stand at room temperature for several hours was observed. Separation was confirmed.

  Subsequently, after 3 days at room temperature, a hard cake was formed in which the sedimented lower layer could not be redispersed even if shaken strongly.

Comparative Example 5
(Manufacture of sustained release particles containing IPBC by interfacial polymerization)
A uniform hydrophobic solution was prepared by charging 25 g of IPBC, 64 g of ATBC and 10 g of T-1890 in a 200 mL container and stirring at room temperature.

  Separately, 97.8 g of deionized water, 40 g of a 10% by weight aqueous solution of PVA-217 and 200 mg of a 5% aqueous solution of DBN were placed in a 500 mL beaker and stirred at room temperature to prepare a uniform aqueous solution.

  The hydrophobic solution was then added to the 500 mL beaker. K. The suspension was prepared by dispersing the hydrophobic solution in the aqueous solution by stirring for 10 minutes at a rotation speed of 5000 rpm with a homomixer (manufactured by Primix).

  Thereafter, the suspension was transferred to a 300 mL four-necked flask equipped with a stirrer, a reflux condenser, and a thermometer, and 13 g of a 10% by mass aqueous solution of DETA was added while stirring at a rotation speed of 125 rpm. Next, the temperature of the four-necked flask was raised with a water bath, and interfacial polymerization was carried out at 75 ± 2 ° C. for 4 hours.

  Thereafter, the suspension after the reaction was cooled to 30 ° C. or lower to obtain a suspension of sustained release particles containing IPBC having a median diameter of 10 μm.

  The obtained suspension was transferred from a four-necked flask to a translucent polyethylene container, and the state of the sustained-release particles when allowed to stand at room temperature for several hours was observed. Separation was confirmed.

  Subsequently, after 3 days at room temperature, a hard cake was formed in which the sedimented lower layer could not be redispersed even if shaken strongly.

(Combination prescription)
Tables 1 to 5 show the compounding prescriptions in Examples and Comparative Examples.

  In the table, the numerical values in the compounding recipe column of raw materials indicate the number of blends g unless otherwise specified.

(Evaluation)
1. Stability of miniemulsion (1) Examples 1-12
When the miniemulsions of Examples 1 to 12 were allowed to stand at room temperature for a predetermined time, the median diameter of the hydrophobic solution dispersed particles (miniemulsion particles) was measured. The results are shown below.
(1-1) Example 1
194 nm after 20 minutes from preparation
195 nm after 5 hours from preparation
192 nm after 24 hours from preparation
(1-2) Example 2
223 nm after 20 minutes from preparation
220 nm after 16 hours from preparation
(1-3) Example 3
199 nm after 20 minutes from preparation
203 nm after 5 hours from preparation
201 nm after 24 hours from preparation
(1-4) Example 4
175 nm after 20 minutes from preparation
173 nm after 5 hours from preparation
171 nm after 24 hours from preparation
(1-5) Example 5
379 nm after 20 minutes from preparation
382 nm after 5 hours from preparation
380 nm after 24 hours from preparation
(1-6) Example 6
300 nm after 20 minutes from preparation
305 nm after 5 hours from preparation
301 nm after 24 hours from preparation
(1-7) Example 7
289 nm after 20 minutes from preparation
294 nm after 5 hours from preparation
287 nm after 24 hours from preparation
(1-8) Example 8
295 nm after 20 minutes from preparation
297 nm after 5 hours from preparation
24 hours after preparation 299 nm
(1-9) Example 9
320 nm after 20 minutes from preparation
315 nm after 5 hours from preparation
317 nm after 24 hours from preparation
(1-10) Example 10
261 nm after 20 minutes from preparation
265 nm after 5 hours from preparation
257 nm after 24 hours from preparation
(1-11) Example 11
372 nm after 20 minutes from preparation
375 nm after 5 hours from preparation
379 nm after 24 hours from preparation
(1-12) Example 12
366 nm after 20 minutes from preparation
370 nm after 5 hours from preparation
372 nm after 24 hours from preparation
(2) Comparative Examples 1-3
When the aqueous dispersions of Comparative Examples 1 to 3 were allowed to stand at room temperature for a predetermined time, the state of the hydrophobic solution dispersion particles (oil droplets) was observed, or the median diameter was measured. The results are shown below.
(2-1) Comparative Example 1
1 hour after preparation Enlargement of oil droplets (ie coalescence of oil droplets, phase separation)
(2-2) Comparative Example 2
20 minutes after preparation 2.06 μm
2.54 μm after 5 hours of preparation
24 hours after preparation 3.31 μm
(2-3) Comparative Example 3
504 nm after 20 minutes from preparation
679 nm after 5 hours from preparation
914 nm after 24 hours from preparation
2. SEM (Scanning Electron Microscope) Observation The emulsion obtained in Example 2 was naturally dried, and further metal-coated (conductive treatment) to prepare a sample. The prepared sample was observed by SEM with a scanning electron microscope (model number “S-4800”, manufactured by Hitachi High-Technologies Corporation).

  Image processing diagrams of the SEM photograph of Example 2 are shown in FIGS.

It can be confirmed that the sustained-release particles are particles corresponding to a measured median diameter of 230 nm.
3. TEM (Transmission Electron Microscope) Observation The emulsions of Examples 2, 4-9, 11 and 12 were air dried, dispersed in bisphenol liquid epoxy resin and cured with amine. A cross section was obtained by cutting this with an ultramicrotome, stained with ruthenium tetroxide, and cut into ultrathin sections with an ultramicrotome to prepare a sample. The prepared sample was observed with a transmission electron microscope (model number “H-7100”, manufactured by Hitachi, Ltd.) by TEM.

  Image processing diagrams of the TEM photograph of Example 2 are shown in FIGS. Image processing diagrams of the TEM photograph of Example 4 are shown in FIGS. Image processing diagrams of the TEM photograph of Example 5 are shown in FIGS. Image processing diagrams of the TEM photograph of Example 6 are shown in FIG. 9 and FIG. Image processing diagrams of the TEM photograph of Example 7 are shown in FIGS. Image processing diagrams of the TEM photograph of Example 8 are shown in FIGS. Image processing diagrams of the TEM photograph of Example 9 are shown in FIGS. Image processing diagrams of the TEM photograph of Example 11 are shown in FIGS. Image processing diagrams of the TEM photograph of Example 12 are shown in FIGS. 19 and 20.

The outer layer (surface) of the sustained-release particles is covered with an extremely thin emulsifier layer dyed with ruthenium tetroxide, and the inner layer (inner) of the sustained-release particles has a uniform structure without phase separation I understand.
4). Sustained release test of sustained release particles containing IPBC (Examples 1 and 2 and Comparative Examples 4 and 5) Sustained release properties of Examples 1 and 2 and Comparative Examples 4 and 5 containing IPBC according to the following procedure The particles were subjected to an IPBC sustained release test.

  That is, first, the emulsions of Examples 1 and 2 and the suspensions of Comparative Examples 4 and 5 (all IPBC concentrations of 10% by mass) and the IPBC suspension in which IPBC was suspended in water as a control. (IPBC concentration of 30% by mass) were prepared as samples for sustained release tests. A control sample was referred to as Comparative Example 6.

  Next, the prepared samples were put into 5 polypropylene centrifuge tubes of 50 mL each in an amount of 20 mg as IPBC mass, and then an IPBC-containing liquid having an IPBC concentration of 0.05 mass% with deionized water to make a total amount of 40 g. Prepared.

  Next, the five centrifuge tubes were shaken 140 times / minute on a shaker (TAITEC RECIPRO SHAKER SR-1 manufactured by Taitec Corporation), and the centrifuge tube was centrifuged after stopping shaking at predetermined intervals. Solid-liquid separation was performed at 15000 rpm for 5 minutes by using a machine (microcooled centrifuge 3740, manufactured by Kubota Seisakusho).

  The solid part was added with deionized water to a total amount of 40 g, re-dispersed with microspatel, and then shaken again with a shaker.

  On the other hand, the liquid part quantified IPBC using Shimadzu HPLC, and calculated the sustained release rate.

  The sustained release rate at each shaking time was calculated as an integrated value (that is, total sustained release rate).

  The result is shown in FIG.

  The sustained release particles of Examples 1 and 2 obtained by miniemulsion polymerization are more slowly compared to the sustained release particles of Comparative Example 5 obtained by interfacial polymerization and the IPBC particles prepared in Comparative Example 6 which is a control. While the release rate was slow, the sustained release rate was faster than the sustained release particles prepared in Comparative Example 4 obtained by suspension polymerization.

In consideration of the above, since the sustained-release particles of Examples 1 and 2 have an average particle diameter of 201 nm and 230 nm, respectively, the surface-release particles of Comparative Examples 4 and 5 having an average particle diameter of 10 μm Considering that the surface area is about 40 times wider than the surface area, the sustained release per unit surface area of the sustained release particles is superior to the sustained release particles of Comparative Examples 4 and 5.
5). Sustained release test of sustained release particles containing OIT (Example 3) According to the following procedure, the sustained release test of OIT was performed on the sustained release particles of Example 3 containing OIT.

  First, the emulsion of Example 3 (OIT concentration 10% by mass) and, as a control, an OIT (Caisson 893T) suspension (OIT concentration 10% by mass) in which OIT is suspended in water, Prepared as a sample for sustained release test.

  Next, with respect to the solid content of the acrylic styrene-based water-based paint (Ultrasol A-20 base, titanium oxide concentration 20% by mass, solid content concentration 50% by mass, manufactured by Ganz Kasei Co., Ltd.), the OIT mass is 1000 ppm. Each sample was added and stirred to prepare a paint for evaluation. A control sample was referred to as Comparative Example 7.

  Next, a coating film was formed by applying the coating material for evaluation on an aluminum plate using a # 75 bar coater, heating at 40 ° C. for 16 hours, and drying.

  Subsequently, an aluminum plate is cut into a size of 70 mm × 150 mm to produce a cut plate, and the cut plate is attached to a dew panel weather meter (set only for rainfall) manufactured by Suga Test Instruments Co., Ltd. Exposed.

  Cut the cut plate after exposure to rain to a size of 25 mm × 25 mm to prepare a test piece, put the test piece in a glass bottle, add 10 ml of methanol, and ultrasonically extract for 10 minutes. OIT was extracted.

  The methanol extract from which OIT was extracted was analyzed by HPLC manufactured by Shimadzu Corporation to calculate the residual rate of OIT in the coating film.

  The result is shown in FIG.

It can be seen that the coating film to which the sustained release particles of Example 3 were added had a higher residual ratio of OIT in the coating film than that of Comparative Example 7.
6). Sustained release test of sustained release particles containing cyfluthrin (Example 5)
According to the following operation, the sustained release test was conducted on the sustained release particles containing cyfluthrin of Example 5.

  That is, an emulsion (emulsifier) of sustained release particles of Example 5 (cyfluthrin concentration 10% by mass) and a 10% by mass acetonitrile solution in which cyfluthrin was dissolved as a control were prepared.

  Next, two circular filter papers (Toyo filter paper No. 5C, equivalent to 5 types C in JIS P 3801) were stacked and folded.

  Next, 0.5 mL of the prepared emulsion of Example 5 and 0.5 mL of cyfluthrin in acetonitrile were slowly added to the filter paper, and then air-dried.

  Thereafter, the filter paper was put into a glass bottle, 180 mL of a mixed solution of ion-exchanged water / methanol (= 50/50 (volume ratio)) was added, and the mixture was allowed to stand still at room temperature for 20 hours. Subsequently, an ion-exchanged water / methanol mixed solution was collected, 180 mL of a new ion-exchanged water / methanol mixed solution was added, and the solution was immersed at room temperature for 20 hours. Thereafter, the above-described exchange operation of the ion exchange water / methanol mixture was repeated twice.

  Based on the above, the sustained release amount of cyfluthrin was measured using each collected ion exchange water / methanol mixture or LC / TOF-MS. In addition, the sustained release amount in each number of times was calculated as an integrated value (that is, total sustained release amount).

The results are shown in FIG.
7). Controlled release test of controlled release particles containing propiconazole (Example 6)
According to the following operation, the sustained release test was performed on the sustained release particles containing propiconazole of Example 6.

  That is, first, an emulsion of sustained-release particles of Example 6 (propiconazole concentration 10% by mass) and propiconazole suspension (propiconazole concentration 10 mass) in which propiconazole was dispersed. %).

  Next, two circular filter papers (corresponding to five types of Toyo filter paper No. 5C and JIS P 3801) were stacked and folded.

  Next, 0.5 mL of the prepared emulsion and suspension was slowly added to the filter paper, and then air-dried.

  Using a metering pump, 1000 mL of water was passed through the filter paper at a flow rate of 20 mL / hr. The amount of propiconazole in the obtained filtrate and the amount of propiconazole remaining on the filter paper were measured by HPLC, and controlled release of propiconazole. The rate was calculated. In addition, the sustained release rate in each water flow amount was calculated as an integrated value (that is, total sustained release rate).

The result is shown in FIG.
8). Sustained release test of sustained release particles containing prochloraz (Example 7)
Based on the operation of “7. Sustained release particles containing propiconazole” described above, the sustained release test of the sustained release particles containing prochloraz in Example 7 was performed.

The result is shown in FIG.
9. Sustained release test of sustained release particles containing flusilazole (Example 8)
Based on the operation of “7. Sustained-release particles containing propiconazole” described above, the sustained-release test of the sustained-release particles containing flusilazole of Example 8 was performed.

The result is shown in FIG.
10. Sustained release test of sustained release particles containing diet (Example 10)
(1) Manufacture of insect cage Using a 42 mm square dried cedar timber, a frame assembly 1 shown in FIG. 27 was prepared.

  That is, the frame combination 1 includes a first frame 2 and a second frame 3 that extend in the left-right direction and are opposed to each other with an interval in the left-right direction, and a communication frame 4 that connects them.

  The first frame 2 and the second frame 3 are formed in a rectangular parallelepiped frame shape. The communication frame 4 is formed so as to connect the upper portions of the first frame 2 and the second frame 3. Each of the first frame 2 and the second frame 3 has a horizontal length of 300 mm, a longitudinal length (depth) of 210 mm, and a vertical length (height) of 210 mm. The horizontal length is 210 mm, the front-rear direction length is 210 mm, and the vertical direction length is 70 mm.

  Then, as shown in FIG. 28, 40th filter cloths 5 are arranged as outer surfaces on the frame combined body 1 shown in FIG. The insect cage 10 was produced by fixing to 3 and the communication frame 4.

  That is, the insect cage 10 is partitioned by the first space 2 partitioned by the first frame 2 and the filter cloth 5, the second space 7 partitioned by the second frame 3 and the filter cloth 5, and the connection frame 4 and the filter cloth 5. Connected space 8 to be formed. The first space 6 and the second space 7 communicate with each other through a connection space 8.

Thereby, the filter cloth 5 can be attached to and detached from each frame, and air can freely flow. In addition, small insects placed in the insect cage 10 can freely come and go through the first space 6, the second space 7, and the connection space 8, but cannot go out of the insect cage 10.
(2) Sustained release particles containing the diet of Example 10 The square filter paper is cut into 120 × 200 mm, and the emulsion of Example 10 is diluted 1.67 times with ion-exchanged water to contain 10% by mass of diet. Sustained release particle emulsion was prepared, and this was sprayed with a sprayer so that 200 mg was deposited as a diet on square filter paper. This square filter paper was placed on the upper surface of the filter cloth 5 on the bottom surface of the first space 6 of the insect cage 10 placed in the outdoor shade (Konohana Ward, Osaka City) in the summer (August 2012).

  In addition, apple slices (feeding of Stingrays described later) were placed on the upper surface of the filter cloth 5 on the bottom surface of the second space 7 of the insect cage 10.

Subsequently, 20 squids that emerged on the test day were released into the second space 7 of the insect cage 10. Even after 8 hours and even after 24 hours, 20 squids did not move from the second space 7 to the first space 6.
(3) Controlled release test for control with respect to Example 10 The square filter paper was cut into 120 × 200 mm, and a 10% by weight ethyl alcohol solution of Diet was sprayed with a sprayer so as to adhere to 200 mg on the filter paper. . This was placed on the upper surface of the filter cloth 5 on the bottom surface of the first space 6 of the insect cage 10 placed in the outdoor shade (Konohana Ward, Osaka City) in the summer (August 2012).

  In addition, apple slices (feeding of Stingrays described later) were placed on the upper surface of the filter cloth 5 on the bottom surface of the second space 7 of the insect cage 10.

  Subsequently, 20 squids that emerged on the test day were released into the second space 7 of the insect cage 10. Up to 8 hours after the release, 20 squids did not move from the second space 7 to the first space 6.

However, it was confirmed that seven squids move from the second space 7 to the first space 6 24 hours after the release.
11. Controlled Release Test of Controlled Release Particles Containing Permethrin (Example 11)
Based on the operation of “6. Sustained release particles containing cyfluthrin” described above, the sustained release particles containing permethrin of Example 11 were subjected to a sustained release test.

The result is shown in FIG.
12 Sustained release test of sustained release particles containing etofenprox (Example 12)
Based on the operation of “6. Sustained release particles containing cyfluthrin” described above, the sustained release particles containing etofenprox of Example 12 were subjected to a sustained release test.

  The result is shown in FIG.

  The sustained-release particles of the present invention can be applied to various industrial products, such as indoor and outdoor paints, rubber, fibers, resins, plastics, adhesives, joint agents, sealing agents, building materials, caulking agents, soils. Add to processing agent, wood treating agent, white water in paper making process, pigment, printing plate treatment liquid, cooling water, ink, cutting oil, cosmetics, non-woven fabric, spinning oil, leather, etc. as an additive to develop antibiotic activity can do.

Claims (2)

A hydrophobic solution is prepared by dissolving a hydrophobic antibiotic compound with a hydrophobic polymerizable vinyl monomer, and an aqueous emulsifier solution is prepared by mixing water and an emulsifier, and the hydrophobic solution is used as the emulsifier aqueous solution. It is obtained by emulsifying in, and polymerizing the polymerizable vinyl monomer in the presence of a polymerization initiator in a mini-emulsion to produce a polymer having an average particle diameter of 302 nm or more and 400 nm or less containing an antibiotic compound. ,
The antibiotic compound is at least one compound selected from the group consisting of IPBC, OIT, cyfluthrin, propiconazole, prochloraz, flusilazole, diet, permethrin, and etofenprox.
The polymer is defined by Hansen, and the dipole force term δ _{p, polymer of the} solubility parameter δ calculated by the van Krevelen and Hoftyzer method is 5 to 7 [(J / cm ³ ) ^1/2 ]. The sustained-release particles are characterized in that the hydrogen bonding term δ _{h, polymer of the} solubility parameter δ is 8 to 10 [(J / cm ³ ) ^1/2 ] . Preparing a hydrophobic solution by dissolving a hydrophobic antibiotic compound with a hydrophobic polymerizable vinyl monomer;
A step of blending water and an emulsifier to prepare an aqueous emulsifier solution;
Emulsifying the hydrophobic solution in the aqueous emulsifier solution; and
The emulsified polymerizable vinyl monomer is subjected to miniemulsion polymerization in the presence of a polymerization initiator to produce a polymer having an average particle diameter of 302 nm or more and 400 nm or less containing an antibiotic compound ,
The antibiotic compound is at least one compound selected from the group consisting of IPBC, OIT, cyfluthrin, propiconazole, prochloraz, flusilazole, diet, permethrin, and etofenprox.
The polymer is defined by Hansen, and the dipole force term δ _{p, polymer of the} solubility parameter δ calculated by the van Krevelen and Hoftyzer method is 5 to 7 [(J / cm ³ ) ^1/2 ]. The method for producing sustained-release particles , wherein the hydrogen bonding force term δ _{h, polymer of the} solubility parameter δ is 8 to 10 [(J / cm ³ ) ^1/2 ] .