JP6114879B2 - 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.

  Conventionally, sustained-release particles have been used as particles that can exhibit sustained-release efficacy over a long period of time.

  For example, a microcapsule containing an antiseptic and fungicidal agent has been proposed (for example, see Patent Document 1 below). The microcapsules described in Patent Document 1 are excellent in sustained release properties (residual effect or water-release resistance). However, the microcapsules described in Patent Document 1 have a problem that they are settled in an aqueous dispersion and have insufficient redispersibility (water dispersion stability).

  Therefore, as a sustained release particle that does not settle in an aqueous dispersion and has excellent aqueous dispersion stability, it contains a homogeneous phase in which an antibiotic compound is compatible with a polymer obtained by polymerization of a polymerizable vinyl monomer. Sustained release particles having an average particle diameter of less than 1 μm have been proposed (for example, see Patent Document 2 below).

Japanese Patent Laid-Open No. 2006-001188 International Publication No. 2013/100102

  In recent years, sustained-release particles have been required to have excellent ultraviolet resistance and further excellent sustained-release properties.

  However, the sustained-release particles proposed in Patent Document 2 have a problem that the above-described ultraviolet resistance and sustained-release properties cannot be sufficiently satisfied.

  An object of the present invention is to provide sustained release particles having excellent ultraviolet resistance as well as excellent sustained release properties and water dispersion stability, and a method for producing the same.

  The present invention (1) is a core obtained by miniemulsion polymerization of a core raw material component containing a hydrophobic antibiotic compound and a hydrophobic first polymerizable vinyl monomer, the first polymerizable vinyl A core containing a homogeneous phase in which the antibiotic compound is compatible with a first polymer obtained by polymerization of a monomer, a shell raw material component containing a hydrophobic second polymerizable vinyl monomer, A shell obtained by seed emulsion polymerization using a seed, comprising sustained release particles provided with the shell covering the core.

  This invention (2) contains the sustained release particle | grains as described in (1) in which the said shell raw material component does not contain the said antibiotic active compound substantially.

According to the present invention (3), the antibiotic compound is defined by Hansen and the dipole force term δ _{p, compound of the} solubility parameter δ calculated by the van Krevelen and Hoftyzer method is 2.0 [(J / cm ³ ) ^1/2 ] to 8.0 [(J / cm ³ ) ^1/2 ], and the hydrogen bond term δ _{h, compound of the} solubility parameter δ is 5.5 [(J / cm ³ ) ^1/2 ] or more and 9.5 [(J / cm ³ ) ^1/2 ] or less, and the second polymer obtained by polymerization of the second polymerizable vinyl monomer is a bipolar of the solubility parameter δ. The inter-child force term δ _{p, 2nd polymer} is less than 5.0 [(J / cm ³ ) ^1/2 ], and the hydrogen bonding force term δ _{h, 2nd polymer of} the solubility parameter δ is 8.0 [(J / cm ³ It is less than ^1/2, including controlled release particles according to (1) or (2).

  In the present invention (4), the content of the second polymerizable vinyl monomer with respect to 100 parts by mass of the total amount of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer is 25 parts by mass or more. The sustained release particles according to any one of to (3) are included.

  This invention (5) contains the sustained release particle | grains in any one of (1)-(4) in which the said antibiotic active compound contains an isothiazoline type compound.

  This invention (6) contains the sustained release particle | grains as described in (5) whose said isothiazoline type compound is 5, 6- dichloro- 2-n-octyl-4- isothiazolin-3-one.

  In the present invention (7), at least one polymerizable vinyl monomer selected from the group consisting of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer contains a polymerization-reactive ultraviolet absorber, (1) The sustained release particles according to any one of to (6) are included.

  The present invention (8) contains a homogeneous phase in which a hydrophobic antibiotic compound is compatible with a first polymer obtained by polymerization of a hydrophobic first polymerizable vinyl monomer, and has an average particle diameter of 1 μm. A shell that is less than the core and a second polymer obtained by polymerization of a hydrophobic second polymerizable vinyl monomer, and is substantially free of the antibiotic compound, the shell covering the core And sustained release particles.

According to the present invention (9), the antibiotic compound is defined by Hansen and the dipole force term δ _{p, compound of the} solubility parameter δ calculated by the van Krevelen and Hoftyzer method is 2.0 [(J / cm ³ ) ^1/2 ] to 8.0 [(J / cm ³ ) ^1/2 ], and the hydrogen bond term δ _{h, compound of the} solubility parameter δ is 5.5 [(J / cm ³ ) ^1/2 ] or more and 9.5 [(J / cm ³ ) ^1/2 ] or less, and the second polymer obtained by polymerization of the second polymerizable vinyl monomer is a bipolar of the solubility parameter δ. The inter-child force term δ _{p, 2nd polymer} is less than 5.0 [(J / cm ³ ) ^1/2 ], and the hydrogen bonding force term δ _{h, 2nd polymer of} the solubility parameter δ is 8.0 [(J / cm ³ Is less than ^1/2, including controlled release particles according to (8).

  In the present invention (10), the content of the second polymerizable vinyl monomer with respect to 100 parts by mass of the total amount of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer is 25 parts by mass or more, (8) Or the sustained release particle | grains as described in (9) are included.

  This invention (11) contains the sustained release particle | grains as described in any one of (8)-(10) in which the said antibiotic active compound contains an isothiazoline type compound.

  This invention (12) contains the sustained release particle | grains as described in (11) whose said isothiazoline type compound is 5, 6- dichloro- 2-n-octyl-4- isothiazolin-3-one.

  According to the present invention (13), at least one polymerizable vinyl monomer selected from the group consisting of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer contains a polymerization-reactive UV absorber, (8) The sustained release particles according to any one of to (12) are included.

  According to the present invention (14), a core raw material component containing a hydrophobic antibiotic compound and a hydrophobic first polymerizable vinyl monomer is miniemulsion polymerized and obtained by polymerization of the first polymerizable vinyl monomer. A core preparation step of preparing a core containing a homogeneous phase in which the antibiotic compound is compatible with one polymer, and a shell raw material component containing a hydrophobic second polymerizable vinyl monomer; A shell obtained by seed emulsion polymerization using a seed, comprising a shell preparation step of preparing the shell covering the core, and a method for producing sustained-release particles.

  The present invention (15) includes the method for producing sustained-release particles according to (14), wherein the shell raw material component does not substantially contain the antibiotic compound.

According to the present invention (16), the antibiotic compound is defined by Hansen, and the dipole force term δ _{p, compound of the} solubility parameter δ calculated by the van Krevelen and Hoftyzer method is 2.0 [(J / cm ³ ) ^1/2 ] to 8.0 [(J / cm ³ ) ^1/2 ], and the hydrogen bond term δ _{h, compound of the} solubility parameter δ is 5.5 [(J / cm ³ ) ^1/2 ] or more and 9.5 [(J / cm ³ ) ^1/2 ] or less, and the second polymer obtained by polymerization of the second polymerizable vinyl monomer is a bipolar of the solubility parameter δ. The inter-child force term δ _{p, 2nd polymer} is less than 5.0 [(J / cm ³ ) ^1/2 ], and the hydrogen bonding force term δ _{h, 2nd polymer of} the solubility parameter δ is 8.0 [(J / cm ) Is less than ^1/2, including a process for producing a sustained-release particles according to (14) or (15).

  In the present invention (17), the content ratio of the second polymerizable vinyl monomer to the total amount of 100 parts by mass of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer is 25 parts by mass or more. The manufacturing method of the sustained release particle | grains as described in any one of-(16) is included.

  The present invention (18) includes the method for producing sustained-release particles according to any one of (14) to (17), wherein the antibiotic compound comprises an isothiazoline-based compound.

  The present invention (19) includes the method for producing sustained-release particles according to (18), wherein the isothiazoline-based compound is 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one. .

  The present invention (20) starts supplying the shell raw material component to the emulsion containing the core when the conversion rate of the miniemulsion polymerization is 95% or more. (14) to (19) The manufacturing method of the sustained release particle | grains as described in any one of these.

  In the present invention (21), at least one polymerizable vinyl monomer selected from the group consisting of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer contains a polymerization-reactive UV absorber, (14) -The manufacturing method of the sustained release particle | grains as described in any one of (20) is included.

  The sustained release particles obtained by the method for producing sustained release particles of the present invention have a core in which the antibiotic compound is compatible with the first polymer and a shell covering the core, and thus have excellent ultraviolet resistance. .

  Moreover, the sustained release particles obtained by the method for producing sustained release particles of the present invention have a homogeneous phase in which an antibiotic compound is compatible with the first polymer obtained by polymerization of the first polymerizable vinyl monomer. Since the core is contained, the sustained release property is excellent.

  Furthermore, since the above-mentioned sustained release particles are obtained by miniemulsion polymerization and seed emulsion polymerization, they are excellent in water dispersion stability.

FIG. 1 shows a schematic cross-sectional view of one embodiment of the sustained-release particles of the present invention. FIG. 2 shows a graph of sustained release tests of Examples 11-14. FIG. 3 shows graphs of sustained release tests of Examples 15-18. FIG. 4 shows a graph of sustained release tests of Examples 19 and 20. FIG. 5 shows a graph of sustained release tests of Examples 21 and 22. FIG. 6 shows a graph of the sustained release test of Examples 23 and 24. FIG. 7 shows a graph of sustained release tests of Examples 25 and 26. FIG. 8 shows a graph of the sustained release test of Examples 27 and 28. FIG. 9 shows a graph of sustained release test of Examples 29 and 30. FIG. 10 shows a perspective view of the frame assembly used in the sustained release test of Examples 31 and 32. FIG. FIG. 11 is a front sectional view of an insect cage used in the sustained release test of Examples 31 and 32. FIG. 12 shows a graph of the sustained release test of Examples 33 and 34. FIG. 13 shows a graph of sustained release tests of Examples 35 and 36.

1. Sustained-release particles The sustained-release particles of the present invention comprise a core obtained by miniemulsion polymerization of a core raw material component containing a hydrophobic antibiotic compound and a hydrophobic first polymerizable vinyl monomer, And a shell obtained by subjecting a shell raw material component containing the second polymerizable vinyl monomer to seed emulsion polymerization using a core as a seed.

  Hereinafter, the antibiotic compound, the first polymerizable vinyl monomer, and the second polymerizable vinyl monomer will be sequentially described.

1.1. Antibiotic active compounds Antibiotic active compounds act as hydrophobes (costabilizers) in miniemulsion polymerization, and specifically prevent Ostwald ripening by contributing to stabilization of the miniemulsion in miniemulsion polymerization. , Suppresses enlargement of the core (increase in particle diameter).

  Antibacterial active compounds have antibacterial, antibacterial, antiseptic, algae, fungicidal, fungicidal and other antibiotic activities, fungicides, antibacterial agents, antiseptics, algae control agents, fungicides, herbicides, insecticides, Selected from attractants, repellents and rodenticides. Examples of these antibiotic-active compounds include organic iodine compounds, triazole compounds, carbamoylimidazole compounds, dithiol compounds, isothiazoline compounds, nitroalcohol compounds, paraoxybenzoic acid esters, and the like. Fungicides (including antiseptic fungicides), for example, pyrethroid compounds, neonicotinoid compounds, organochlorine compounds, organophosphorus compounds, carbamate compounds, oxadiazine compounds, anticides (anticides) Etc.

  Examples of the organic iodo compound include 3-iodo-2-propynylbutylcarbamate (IPBC), 1-[[(3-iodo-2-propynyl) oxy] methoxy] -4-methoxybenzene, and 3-bromo-2. , 3-diiodo-2-propenyl ethyl carbonate and the like.

  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 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT). It is done.

  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 compounds include pyrethroid insecticides such as pyrethrin, cineline, and jasmolin obtained from Shirovanamushiyogiku, and arelesulin, bifenthrin, acrinathrin, alpha cypermethrin, tralomethrin, and cifluthrin ((RS)-) derived therefrom. α-Cyano-4-fluoro-3-phenoxybenzyl- (1RS, 3RS)-(1RS, 3RS) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate. Form I ((1R-3R-αR) + (1S-3S-αS)) [melting point: 57 ° C.], isomer II ((1R-3R-S) + (1S-3S-αR)) [melting point: 74 ° C], isomer III ((1R-3S-αR) + (1S-3R-αS))) [melting point: 66 ° C] Mixture), ciphenothrin, praretrin, etofenprox (2- (4-ethoxyphenyl) -2-methylpropyl = 3-phenoxybenzyl = ether), silafluophene, fenvalerate, permethrin (3-phenoxybenzyl (1RS, 3RS; And pyrethroid insecticides such as 1RS, 3SR) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate).

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.

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

  Preferred examples of the antibiotic compound include organic iodine compounds, triazole compounds, carbamoylimidazole compounds, isothiazoline compounds, pyrethroid compounds, and repellents, and more preferably IPBC, propiconazole, flusilazole, prochloraz. , OIT, DCOIT, cyfluthrin, permethrin, and diet, and more preferably DCOIT.

  Antibiotic active compounds are, for example, substantially hydrophobic and specifically have, for example, extremely low solubility in water at room temperature (20-30 ° C., more specifically 25 ° C.). Specifically, for example, the solubility at room temperature is 1.5 parts by mass / 100 parts by volume of water (15 g / L) or less, preferably 0.5 parts by mass / 100 parts by volume of water (5 g / L) or less. Is 0.1 parts by mass / 100 parts by volume of water (1 g / L) or less.

  When the solubility of the antibiotic compound in water exceeds the above range, the antibiotic compound is removed from the core (that is, the aqueous phase) when mini-emulsion polymerization of the core raw material component containing the first polymerizable vinyl monomer is performed. ), And after the polymerization, the antibiotic compound dissolved in the aqueous phase is precipitated, so that it may be difficult to form a core containing the antibiotic compound.

The antibiotic compound has a dipole force term δ _{p, compound} with a solubility parameter δ of, for example, 2.0 [(J / cm ³ ) ^1/2 ] or more, preferably 3.0 [(J / cm ³ ) ^1/2 ] or more, for example, 8.0 [(J / cm ³ ) ^1/2 ] or less, preferably 7.0 [(J / cm ³ ) ^1/2 ] or less, and the solubility parameter δ Of the hydrogen bonding term δ _{h, compound} of, for example, 5.5 [(J / cm ³ ) ^1/2 ] or more, preferably 5.8 [(J / cm ³ ) ^1/2 ] or more, for example, It is 9.5 [(J / cm ³ ) ^1/2 ] or less. 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 Krevelen and Hoftyzer method, and specifically described in Japanese Patent Application Laid-Open No. 2011-79816. ing. Further, the solubility parameter δ of the first polymer and the second polymer, which will be described later, is also calculated by the same method as described above.

If the dipolar force term δ _{p, compound} and / or the hydrogen bond force 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 first polymer In some cases, sufficient compatibility with (described later) 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 core, and it may be difficult to prepare a core sufficiently containing an antibiotic compound.

On the other hand, the dipole force term δ _{p, compound} and the hydrogen bond force term δ _{h, compound of} the antibiotic _compound are within the above-mentioned range, and the dipole force term δ _{p of} the first polymer (described later). _{, 1st polymer} and hydrogen bonding term δ _{h, 1st polymer} are within the ranges described below, the antibiotic compound is compatible with the first polymer (described later) without leaking from the core during miniemulsion polymerization. Is defined as That is, the antibiotic compound is contained in the first polymer.

  The molecular weight of the antibiotic compound is, for example, 180 or more, preferably 200 or more, and for example, 600 or less, preferably 500 or less.

  The melting point of the antibiotic compound is, for example, 100 ° C. or lower, preferably 90 ° C. or lower, more preferably 80 ° C. or lower. 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.).

1.2. First polymerizable vinyl monomer The first polymerizable vinyl monomer has, for example, at least one polymerizable carbon-carbon double bond (specifically, a vinyl group or the like) in the molecule.

  Examples of the first polymerizable vinyl monomer include, for example, a first monomer containing one polymerizable carbon-carbon double bond in the molecule, for example, two or more polymerizable carbon-carbon double bonds in the molecule. Examples thereof include a second monomer containing, for example, a third monomer further containing a functional group.

1.2.1. First monomer The first monomer is a main monomer contained as a main component in the first polymerizable vinyl monomer. Examples of the first monomer include (meth) acrylic acid ester monomers, aromatic vinyl monomers, vinyl ester monomers, maleic acid ester monomers, vinyl halides, vinylidene halides, nitrogen-containing vinyl monomers, and the like.

  The (meth) acrylic acid ester monomer is a methacrylic acid ester and / an acrylic acid ester, and specifically, methyl (meth) acrylate (MMA / MA), ethyl (meth) acrylate, (meth) acrylic. N-propyl acid, iso-propyl (meth) acrylate, n-butyl (meth) acrylate, iso-butyl (meth) acrylate (i-BMA / i-BA), tert-butyl (meth) acrylate, N-pentyl (meth) acrylate, n-hexyl (meth) acrylate, n-heptyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, n-octyl (meth) acrylate, (meth) acrylic acid iso-nonyl, (meth) acrylate n-dodecyl (lauryl), (meth) acrylate n-octadecyl (stearyl), (meth) ) Alkyl moiety is a straight chain, such as cyclohexyl acrylate, etc. branched or having alkyl portions of 1 to 20 carbon atoms cyclic (meth) acrylic acid alkyl ester. Preferably, the (meth) acrylic-acid alkylester which has a C1-C4 alkyl part is mentioned. More preferably, methyl methacrylate (MMA) and iso-butyl methacrylate (i-BMA) are mentioned.

  Examples of the aromatic vinyl monomer include styrene (SM), p-methylstyrene, o-methylstyrene, α-methylstyrene, and the like. Preferably, styrene (SM) is used.

  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.

  Preferred examples of the first monomer include (meth) acrylic acid ester monomers and aromatic vinyl monomers.

  The first monomer can be used alone or in combination of two or more. Preferably, a single use of a (meth) acrylic acid ester monomer, a combination of a (meth) acrylic acid ester monomer and an aromatic vinyl monomer is used.

  The blending ratio of the first monomer is, for example, 50% by mass or more, preferably 55% by mass or more, more preferably 60% by mass or more, and 100% by mass or less with respect to the first polymerizable vinyl monomer. It is.

  When the first monomer is a combination of a (meth) acrylic acid ester monomer and an aromatic vinyl monomer, the total amount of the (meth) acrylic acid ester monomer and the aromatic vinyl monomer in the (meth) acrylic acid ester monomer The blending ratio with respect to is, for example, 50% by mass or more, preferably 75% by mass or more, and for example, less than 100% by mass, preferably 95% by mass or less.

1.2.2. Second monomer The second monomer is a submonomer optionally used in combination with the first polymerizable vinyl monomer, and is a crosslinkable monomer copolymerizable with the first monomer. Examples of the crosslinkable monomer include mono- or polyethylene glycol di (meth) acrylates such as ethylene glycol di (meth) acrylate (EGDA / EGDMA) and diethylene glycol di (meth) acrylate, such as 1,3-propanediol di (meth) ) Acrylates, 1,4-butanediol di (meth) acrylates, alkanediol di (meth) acrylates such as 1,5-pentanediol di (meth) acrylates, for example, trimethylolpropane tri (meth) acrylate, pentaerythritol tetra Alkane polyols such as (meth) acrylates Poly (meth) acrylates, for example, allyl monomers such as allyl (meth) methacrylate (ALMA), triallyl (iso) cyanurate, for example, divini Such as divinyl monomer such as benzene. In particular, ALMA plays a role as a grafting agent that chemically bonds the core and the shell using two types of carbon-carbon double bonds having different reactivities.

  The second monomer is preferably mono- or polyethylene glycol di (meth) acrylate, more preferably ethylene glycol di (meth) acrylate.

  The second monomer can be used alone or in combination of two or more.

  The blending ratio of the second monomer is, for example, 1% by mass or more, preferably 5% by mass or more, for example, 20% by mass or less, preferably 10% by mass with respect to the first polymerizable vinyl monomer. % Or less. Further, the blending ratio of the second monomer is, for example, 1 part by mass or more, preferably 5 parts by mass or more, and for example, 30 parts by mass or less, preferably 20 parts with respect to 100 parts by mass of the first monomer. It is below mass parts.

1.2.3. Third monomer The third monomer is a submonomer optionally used in combination with the first polymerizable vinyl monomer, and is a functional group-containing vinyl monomer copolymerizable with the first monomer. Examples of the functional group-containing vinyl monomer include (meth) acrylic acid monomers, hydroxyalkyl (meth) acrylates, epoxy group-containing (meth) acrylic esters, polymerization-reactive emulsifiers, polymerization-reactive UV absorbers, and the like. It is done.

  Examples of the (meth) acrylic acid monomer include acrylic acid, methacrylic acid (MAA), itaconic acid, and the like.

  Examples of the hydroxyalkyl (meth) acrylate include hydroxymethyl (meth) acrylate, hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, and the like.

  Examples of the epoxy group-containing (meth) acrylic acid ester include glycidyl (meth) acrylate.

The polymerization reactive emulsifier is an emulsifier having a polymerizable carbon-carbon double bond in the molecule, and is an emulsifier and a polymerizable monomer. The polymerization-reactive emulsifier has a hydrophilic group that exhibits an emulsifying function in the molecule, and examples of such a hydrophilic group include anionic hydrophilic groups such as a sulfonate group, a sulfate group, and a carboxylate group. Examples thereof include nonionic hydrophilic groups such as polyoxyethylene groups. Preferred examples of the polymerization-reactive emulsifier include those containing both an anionic hydrophilic group and a nonionic hydrophilic group, those containing only an anionic hydrophilic group, and those containing only a nonionic hydrophilic group. Particularly preferable examples include those containing both an anionic hydrophilic group and a nonionic hydrophilic group. As those containing both such an anionic hydrophilic group and a nonionic hydrophilic group, specifically, _{CH 2 = C (CH 3)} -COO (AO) n SO 3 Na ( wherein AO represents ethylene oxide, an alkylene oxide such as propylene _{oxide.), CH 3 -CH = CH} -C 6 H 4 (C n _{H 2n + 1) -. (} AO) m SO 3 NH 4 ( wherein AO is showing ethylene oxide, an alkylene oxide such as propylene oxide), _CH 2 = _{H-CH 2 -O-CH 2} CH (R) -O- (AO) n-SO 3 NH 4 ( wherein AO is ethylene oxide, an alkylene oxide such as propylene oxide, R represents an alkyl group.) And Can be mentioned. Further, as having only a nonionic hydrophilic group, specifically, CH ₂ ═C (CH ₃ ) —COO (AO) _n R (where AO is an alkylene oxide such as ethylene oxide or propylene oxide, R Represents an alkyl group.) Or CH ₃ —CH═CH—C ₆ H ₄ (C _n H _{2n + 1} ) —O— (AO) _m H (where AO represents an alkylene oxide such as ethylene oxide or propylene oxide). Etc.).

  The polymerization-reactive UV absorber is a UV absorber and a polymerizable monomer. Specifically, the polymerization-reactive ultraviolet absorber is a monomer having an ultraviolet absorbing group and a polymerizable carbon-carbon double bond in the molecule. Examples of the ultraviolet absorbing group include ultraviolet absorbing groups such as benzotriazole ring and phenol. Examples of the polymerization reactive ultraviolet absorber include 2- [3- (2H-benzotriazol-2-yl) -4-hydroxyphenyl] ethyl (meth) acrylate. As the polymerization-reactive ultraviolet absorber, for example, a commercially available product can be used. For example, RUVA series (manufactured by Otsuka Chemical Co., Ltd.) is used.

  Preferred examples of the third monomer include (meth) acrylic acid monomers and polymerization-reactive UV absorbers, and more preferred are MAA and (meth) acrylic acid 2- [3- (2H-benzotriazole-2- Yl) -4-hydroxyphenyl] ethyl.

  If the (meth) acrylic acid-based monomer is contained in the third monomer, it serves to increase the colloidal stability of the emulsion formed by the copolymer with the first monomer, and as necessary to obtain this effect. Blended.

  On the other hand, if the polymerization-reactive ultraviolet absorber is contained in the third monomer, the decomposition of the antibiotic compound by ultraviolet rays can be suppressed.

  The third monomer can be used alone or in combination of two or more. Preferably, a single use of a (meth) acrylic acid-based monomer, and a combination of a (meth) acrylic acid-based monomer and a polymerization-reactive UV absorber, more preferably a single use of a (meth) acrylic acid-based monomer Is mentioned.

  In addition, it is also preferable that a 3rd monomer does not contain a polymerization reactive ultraviolet absorber from a viewpoint of reducing manufacturing cost. That is, the polymerization-reactive ultraviolet absorber is preferably not contained in the third monomer. In that case, the manufacturing cost of sustained release particles can be reduced.

  The blending ratio of the third monomer is, for example, 0.5% by mass or more, preferably 1% by mass or more, and, for example, 45% by mass or less, preferably 40% with respect to the first polymerizable vinyl monomer. It is below mass%. The blending ratio of the third monomer is, for example, 0.5 parts by mass or more, preferably 1 part by mass or more, and for example, 80 parts by mass or less, preferably 100 parts by mass of the first monomer. , 60 parts by mass or less.

  The first polymerizable vinyl monomer can be used alone or in combination of two or more. Preferably, the combination of a 1st monomer, a 2nd monomer, and a 3rd monomer is mentioned, More preferably, a (meth) acrylic-ester type monomer (1st monomer) and mono or polyethyleneglycol di (meth) acrylate ( Combination of (second monomer) and (meth) acrylic acid monomer (third monomer), (meth) acrylic acid ester monomer and aromatic vinyl monomer (first monomer), and mono- or polyethylene glycol diester Combination of (meth) acrylate (second monomer) and (meth) acrylic acid monomer (third monomer), (meth) acrylic acid ester monomer (first monomer), mono or polyethylene glycol di ( (Meth) acrylate (second monomer), (meth) acrylic acid monomer and A combination with a polymerization-reactive UV absorber (third monomer), a (meth) acrylic acid ester monomer and an aromatic vinyl monomer (first monomer), and a mono or polyethylene glycol di (meth) acrylate (first monomer) 2 monomers), a (meth) acrylic acid monomer, and a polymerization-reactive ultraviolet absorber (third monomer). From the viewpoint of reducing the production cost of the sustained release particles, the combination of the first polymerizable vinyl monomer is more preferably a (meth) acrylic acid ester monomer and an aromatic vinyl monomer (first monomer), mono or A combination of polyethylene glycol di (meth) acrylate (second monomer) and (meth) acrylic acid monomer (third monomer) can be mentioned.

  In addition, from the viewpoint of reducing the manufacturing cost, it is also preferable that the first polymerizable vinyl monomer does not contain a polymerization reactive ultraviolet absorber.

  When the first polymerizable vinyl monomer is a combination of the first monomer, the second monomer, and the third monomer, the mixing ratio of the third monomer is, for example, 30 parts by mass with respect to 100 parts by mass of the second monomer. As mentioned above, Preferably, it is 50 mass parts or more, for example, 1000 mass parts or less, Preferably, it is 500 mass parts or less.

  The first polymerizable vinyl monomer described above 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 water. It is 5 parts by mass / 100 parts by volume of water (50 g / L) or less, more preferably 3 parts by mass / 100 parts by volume of water (30 g / L) or less. When the first polymerizable vinyl monomer is used in combination with different types (for example, when the first monomer, the second monomer, and the third monomer are used in combination), the entire first polymerizable vinyl monomer (that is, It is substantially hydrophobic as a mixture of different types of first polymerizable vinyl monomers).

In the first polymerizable vinyl monomer, the dipole force term δ _{p, 1st polymer} of the solubility parameter δ is, for example, 5.0 [(J / cm ³ ) ^1/2 ] or more, for example, 7.0 [(J / Cm ³ ) ^1/2 ] or less, preferably 6.5 [(J / cm ³ ) ^1/2 ] or less, and the hydrogen bonding force term δ _{h, 1st polymer of} the solubility parameter δ is, for example, 8 [ (J / cm ³ ) ^1/2 ] or more, preferably 8.5 [(J / cm ³ ) ^1/2 ] or more, for example, 10 [(J / cm ³ ) ^1/2 ] or less. A first polymerizable vinyl monomer that forms a polymer.

When the dipole force term δ _{p, 1st polymer} and / or the hydrogen bond force term δ _{h, 1st polymer of the first polymer} is less than the above range, the hydrophobicity of the first polymer becomes excessively high and antibiotics In some cases, sufficient compatibility with the active compound may not be obtained, and even if compatibility is obtained, the antibiotic compound may leak out of the core during miniemulsion polymerization and In some cases, it may be difficult to prepare a core that sufficiently encapsulates.

On the other hand, when the dipole force term δ _{p, 1st polymer} and / or the hydrogen bond force term δ _{h, 1st polymer of the first polymer} exceeds the above range, the hydrophilicity of the first polymer becomes excessively high, Sufficient compatibility with the biologically active compound may not be obtained, and even if compatibility can be obtained, the free energy of the interface with the aqueous phase in the miniemulsion polymerization is reduced, and the antibiotic compound is During the miniemulsion polymerization, it may leak out of the core, making it difficult to prepare a core sufficiently containing an antibiotic compound.

If the interpolar force term δ _{p, 1st polymer} and the hydrogen bond term δ _{h, 1st polymer of the first polymer} are within the above ranges, the antibiotic compound will be _released from the sustained release particles during miniemulsion polymerization. It is defined as being compatible with the first polymer without leakage. That is, the antibiotic compound is uniformly contained in the first polymer.

Furthermore, the solubility parameter [delta], the value obtained by subtracting the polar term [delta] _{p, Compound} of the antibiotic compound from polar term [delta] _{p, 1st Polymer} first polymer _{Δδ p (= δ p, 1st} polymer −δ _{p, compound} ) is, for example, −1.1 to 2.8 [(J / cm ³ ) ^1/2 ].

The first polymer of the hydrogen bonding term [delta] _h, the hydrogen bonding term from _{1st Polymer} antibiotic compound [delta] _h, a value obtained by subtracting the _{compound Δδ h (= δ h,} 1st 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 the first polymer, it is possible to ensure excellent sustained release.

1.3. Second polymerizable vinyl monomer Examples of the second polymerizable vinyl monomer include the same polymerizable vinyl monomer as the first polymerizable vinyl monomer exemplified above. Specifically, the second polymerizable vinyl monomer preferably includes a first monomer and a third monomer, and more preferably a first monomer.

  Specifically, the second polymerizable vinyl monomer is preferably a (meth) acrylic acid ester monomer, an aromatic vinyl monomer, or a (meth) acrylic acid monomer, more preferably (meth) acrylic acid. Examples include ester monomers and aromatic vinyl monomers. More specifically, as the second polymerizable vinyl monomer, MMA, SM, and MAA are preferable, and MMA and SM are more preferable.

  Further, at least one polymerizable vinyl monomer selected from the group consisting of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer preferably contains a polymerization reactive ultraviolet absorber. Thereby, the ultraviolet-ray resistance of the antibiotic compound in sustained release particles can be improved.

  Specifically, for example, the polymerization-reactive UV absorber is contained in the first polymerizable vinyl monomer, and the first embodiment not contained in the second polymerizable vinyl monomer, for example, the polymerization-reactive UV absorber is the first A second embodiment that is not contained in the first polymerizable vinyl monomer but is contained in the second polymerizable vinyl monomer, for example, a polymerization-reactive UV absorber is contained in the first polymerizable vinyl monomer, and the second polymerizable vinyl monomer is contained. The 3rd aspect contained also in a monomer is mentioned. From the viewpoint of further improving the ultraviolet resistance of the antibiotic compound in the sustained-release particles, the third embodiment is preferable.

  On the other hand, a fourth embodiment in which the polymerization-reactive ultraviolet absorber is not contained in the first polymerizable vinyl monomer and is not contained in the second polymerizable vinyl monomer is also preferable. If it is the 4th aspect, the manufacturing cost of sustained-release particle | grains can be reduced.

  When the second polymerizable vinyl monomer is a combination of a first monomer (preferably a (meth) acrylic acid ester monomer) and a third monomer (preferably a polymerization-reactive UV absorber), the second polymerizable property The blending ratio of the third monomer in the vinyl monomer is, for example, 0.1% by mass or more, preferably 0.5% by mass or more, more preferably 1% by mass or more, and for example, less than 50% by mass, Preferably, it is 25 mass% or less, More preferably, it is 20 mass% or less. When the second polymerizable vinyl monomer is a combination of a first monomer (preferably a (meth) acrylic acid ester monomer) and a third monomer (preferably a polymerization-reactive UV absorber), the first monomer 100 The mixing ratio of the third monomer with respect to part by mass is, for example, 1 part by mass or more, preferably 5 parts by mass or more, and for example, 40 parts by mass or less, preferably 20 parts by mass or less.

The second polymerizable vinyl monomer is preferably a monomer in which the second polymer obtained by polymerization of the second polymerizable vinyl monomer is incompatible with (ie, incompatible with) the antibiotic compound. Is selected. Specifically, as the second polymerizable vinyl monomer, the dipole force term δ _{p, 2nd polymer} of the solubility parameter δ of _{the second polymer} is, for example, 0.0 [(J / cm ³ ) ^1/2 ]. or more, preferably, 1.0 is the ^{[(J / cm 3) 1/2} ] or more, and is, for example, less than ^{5.0 [(J / cm 3)} 1/2], preferably, 4.9 [ (J / cm ³ ) ^1/2 ] or less, the hydrogen bonding term δ _{h, 2nd polymer of} the solubility parameter δ is, for example, 0.0 [(J / cm ³ ) ^1/2 ] or more, and For example, a monomer that is less than 8.0 [(J / cm ³ ) ^1/2 ], preferably 7.0 [(J / cm ³ ) ^1/2 ] or less is selected.

When the dipole force term δ _{p, 2nd polymer} and / or the hydrogen bond strength term δ _{h, 2nd polymer} of the solubility parameter δ of the second polymer exceeds the upper limit described above _{, the second polymer} is reduced _relative to the antibiotic compound. May be compatible. On the other hand, the dipole force term δ _{p, 2nd polymer} and / or the hydrogen bond force term δ _{h, 2nd polymer} of the solubility parameter δ of the _{second polymer} takes a value less than 0 in the definition of the Hansen solubility parameter δ. There is nothing. However, the closer the dipole force term δ _{p, 2nd polymer} and / or the hydrogen bond force term δ _{h, 2nd polymer} to 0, the easier the second polymerizable vinyl monomer penetrates into the core, so the shell raw material component (or The shell raw material emulsion (to be described later) is preferably fed (supplied) to the emulsion while paying attention not to retain the second polymerizable vinyl monomer.

The dipole force term δ _{p, 2nd polymer} and / or the hydrogen bond force term δ _{h, 2nd polymer of the second polymer} is within the above-described range (that is, the dipole force term δ _{p, 2nd polymer of the second polymer).} And at least one of the hydrogen bond term δ _{h, 2nd polymer} is within the above range) and both the dipole force term δ _{p, compound} and the hydrogen bond term δ _{h, compound} of the antibiotic _compound are Within the above range, even if the antibiotic compound contained in the core migrates into the shell, the antibiotic compound is not compatible with the second polymer, that is, they are Is defined as incompatible.

  When the second polymer is incompatible with the antibiotic compound, the second polymer is prevented from leaking out of the shell due to the compatibility of the antibiotic compound with the antibiotic compound. The rate at which the antibiotic compound is released out of the shell can be reduced. Therefore, the sustained release property of the sustained release particles can be further improved.

  As described above, the second polymerizable vinyl monomer for producing a second polymer that is incompatible with the antibiotic compound is preferably a first monomer, specifically, a plurality of types of second monomers. A combination of one monomer, more preferably a combination of a (meth) acrylic acid ester monomer and an aromatic vinyl monomer, more preferably a (meth) acrylic acid alkyl ester having an alkyl moiety having 1 to 4 carbon atoms, and A combination of aromatic vinyl monomers, particularly preferably a combination of MMA and SM is mentioned.

  When the second polymerizable vinyl monomer is a combination of a (meth) acrylic acid ester monomer and an aromatic vinyl monomer, the total amount of the (meth) acrylic acid ester monomer and the aromatic vinyl monomer is 100 parts by mass. On the other hand, the blending ratio of the aromatic vinyl monomer is, for example, 10 parts by mass or more, preferably 20 parts by mass or more, more preferably 25 parts by mass or more, and for example, 50 parts by mass or less, preferably , 40 parts by mass or less, more preferably 35 parts by mass or less. If the blending ratio of the aromatic vinyl monomer is equal to or more than the lower limit described above, the compatibility of the second polymer with the antibiotic compound can be reduced to make them incompatible. If the blending ratio of the aromatic vinyl monomer is equal to or less than the upper limit described above, the penetration of the second polymer into the core can be suppressed.

  The blending ratio of the (meth) acrylic acid ester monomer is the balance of the blending ratio of the aromatic vinyl monomer.

2. The method for producing sustained release particles The method for producing sustained release particles of the present invention comprises miniemulsion polymerization of a core raw material component containing a hydrophobic antibiotic compound and a hydrophobic first polymerizable vinyl monomer. A core preparation step for preparing the core, and a shell preparation step for preparing a shell covering the core by seed emulsion polymerization using the core raw material component containing the hydrophobic second polymerizable vinyl monomer as a seed. Prepare. Moreover, in a core preparation process, in order to produce a mini emulsion from a core raw material component, the 1st emulsifier aqueous solution is prepared separately.

2.1. Preparation of Core Raw Material Component, First Emulsifier Aqueous Solution, and Shell Raw Material Component First, preparation of the core raw material component, the first emulsifier aqueous solution, and the shell raw material component will be sequentially described.

2.1.1. Preparation of core raw material component To prepare the core raw material component, for example, an antibiotic compound and a first polymerizable vinyl monomer are blended. Preferably, the antibiotic compound is dissolved with the first polymerizable vinyl monomer. This prepares the core raw material component containing the antibiotic compound and the first polymerizable vinyl monomer.

  The core raw material component is a hydrophobic solution (oil phase component), for example, an antibiotic compound solvent (hydrophobic organic solvent such as hexane, toluene, ethyl acetate), and / or hydrophobe ( (Costabilizers such as hexadecane and cetyl alcohol) are prepared. Thereby, environmental load can be reduced.

  The blending ratio of the antibiotic compound to 100 parts by mass of the first polymerizable vinyl monomer is, for example, 1 part by mass or more, preferably 5 parts by mass or more, for example, 400 parts by mass or less, preferably 300 parts by mass. Or less.

  Preferably, an oil-soluble polymerization initiator is blended in the preparation of the core raw material component.

  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). The oil-soluble polymerization initiator is preferably an oil-soluble organic peroxide.

  Oil-soluble polymerization initiators can be used alone or in combination of two or more.

  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, with respect to 100 parts by mass of the first polymerizable vinyl monomer. The amount is preferably 3 parts by mass or less.

  Moreover, the core raw material component can also contain a ultraviolet absorber as an arbitrary component, for example.

  The ultraviolet absorber is an ultraviolet absorber excluding the above-described polymerization-reactive ultraviolet absorber. For example, the ultraviolet absorber has a UV-absorbing group in the molecule but does not have a polymerizable carbon-carbon double bond in the molecule. It is a polymerization reactive ultraviolet absorber. The ultraviolet absorber is, for example, hydrophobic.

  Specifically, examples of the ultraviolet absorber include benzophenone ultraviolet absorbers, benzotriazole ultraviolet absorbers, hydroxyphenyltriazine ultraviolet absorbers, and natural ultraviolet absorbers.

  Examples of the benzophenone ultraviolet absorber include 2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, and 2-hydroxy-4-n-octoxy. Benzophenone (Adekastab 1413, manufactured by ADEKA), 2-hydroxy-4-n-dodecyloxybenzophenone, bis (5-benzoyl-4-hydroxy-2-methoxyphenyl) methane (Adekastab LA-51, manufactured by ADEKA), 2 2,2'-dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, and the like.

  Examples of the benzotriazole ultraviolet absorber include TINUVIN 384-2 (5% 2-methoxy-1-methylethyl acetate, 95% benzenepropanoic acid, 3- (2H-benzotriazol-2-yl) -5- ( 1,1-dimethylethyl) -4-hydroxy, C7-9 side chain and linear alkyl ester, manufactured by Ciba Japan), TINUVIN PS (2- (2-hydroxy-5-t-butylphenyl) -2H- Benzotriazole, manufactured by Ciba Japan).

  Examples of the hydroxyphenyltriazine-based ultraviolet absorber include TINUVIN 400 (85% 2- (4,6-bis (2,4-dimethylphenyl) -1,3,5-triazin-2-yl) -5-hydroxy. Reaction product of phenyl and oxirane [(C10-C16 mainly C12-C13 alkyloxy) methyl] oxirane, 15% 1-methoxy-2-propanol, manufactured by Ciba Japan Ltd.), TINUVIN 460 (2,4-bis [2-hydroxy-4-butoxyphenyl] -6- (2,4-dibutoxyphenyl) -1,3-5-triazine, manufactured by Ciba Japan Ltd.).

  Examples of natural ultraviolet absorbers include yangonin.

  As the ultraviolet absorber, a benzotriazole-based ultraviolet absorber is preferably used.

  The ultraviolet absorber can be used alone or in combination.

  The ultraviolet absorber can be used in combination with a light stabilizer. Examples of the light stabilizer include polymerizable light stabilizers such as LA-82 and LA-87 (manufactured by ADEKA), and hindered amine light stabilizers such as TINUVIN 123, TINUVIN 144 and TINUVIN 292 (manufactured by Ciba Japan). Agents.

  The ultraviolet absorber is used in combination with, for example, a polymerization reactive ultraviolet absorber.

  When the ultraviolet absorbent is contained in the core raw material component, an embodiment in which the polymerization reactive ultraviolet absorbent is contained in the shell raw material component and / or the core raw material component can be mentioned. In such an embodiment, specifically, for example, the ultraviolet absorber is contained in the core raw material component, and the polymerization reactive ultraviolet absorber is not contained in the core raw material component but is contained in the shell raw material component. In the sixth embodiment, for example, the ultraviolet absorber is contained in the core raw material component, the polymerization reactive ultraviolet absorber is contained in the core raw material component, and not contained in the shell raw material component, for example, A seventh embodiment is included in which the polymerization-reactive ultraviolet absorber is contained in the core raw material component, the polymerization reactive ultraviolet absorber is contained in the core raw material component, and is also contained in the shell raw material component.

  On the other hand, it is also preferable to mix the ultraviolet absorber with the core raw material component without using it together with the polymerization-reactive ultraviolet absorber. That is, the eighth aspect is that the ultraviolet absorber is contained in the core raw material component, and the polymerization reactive ultraviolet absorber is not contained in the core raw material component and is not contained in the shell raw material component.

  The blending ratio of the ultraviolet absorber is, for example, 0.2 parts by mass or more, preferably 1 part by mass or more, for example, 30 parts by mass or less, preferably 100 parts by mass of the antibiotic compound. 20 parts by mass or less. The blending ratio of the ultraviolet absorber is, for example, 0.1 parts by mass or more, preferably 1 part by mass or more, for example, 20 parts by mass or less, preferably 100 parts by mass of the first polymerizable vinyl monomer. Is 10 parts by mass or less.

  When the ultraviolet absorber is used in combination with the polymerization reactive ultraviolet absorber, the blending ratio of the ultraviolet absorber (non-polymerization reactive ultraviolet absorber) is, for example, 10 masses per 100 mass parts of the polymerization reactive ultraviolet absorber. Part or more, preferably 50 parts by weight or more, and for example, 500 parts by weight or less, preferably 100 parts by weight or less.

  The ultraviolet absorber is blended with the antibiotic compound and the first polymerizable vinyl monomer. Preferably, the ultraviolet absorber is dissolved in the first polymerizable vinyl monomer together with the antibiotic compound. Thus, a first polymerizable vinyl monomer solution (that is, a core raw material component) containing an antibiotic compound and an ultraviolet absorber is prepared. Specifically, a core raw material component containing an antibiotic compound, a first polymerizable vinyl monomer, an oil-soluble polymerization initiator blended if necessary, and an ultraviolet absorber blended if necessary is prepared.

2.1.2. Preparation of 1st emulsifier aqueous solution In order to prepare 1st emulsifier aqueous solution, water and an emulsifier are mix | blended.

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

  Examples of the emulsifier include anionic emulsifiers such as sodium dioctyl sulfosuccinate, sodium dodecylbenzene sulfonate, sodium lauryl sulfate, sodium dodecyl diphenyl ether disulfonate, sodium nonyl diphenyl ether sulfonate.

  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.

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

  Examples of the polyoxyalkylene aryl ether include polyoxyethylene aryl ether.

  As the emulsifier, an anionic emulsifier is preferably used.

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

  The blending ratio of the emulsifier is set so as not to generate micelles when the core raw material component is emulsified in the first emulsifier aqueous solution described below. Specifically, the blending ratio of the emulsifier includes the amount of the emulsifier necessary for coating the miniemulsion particles calculated from the occupied area per unit mass specific to the emulsifier when the core raw material component is emulsified in the first emulsifier aqueous solution. It sets so that the sum with the amount of emulsifier used as the critical micelle concentration in 1 emulsifier aqueous solution may not be exceeded. The blending ratio of the emulsifier is, for example, 0.1% by mass or more, preferably 0.2% by mass or more, and, for example, 20% by mass or less as the active ingredient amount of the emulsifier with respect to the first emulsifier aqueous solution. Preferably, it is 10 mass% or less. Further, the blending ratio of the emulsifier is, for example, 0.1% by mass or more, preferably 0.2% by mass or more, and for example, 20% by mass as the active ingredient amount of the emulsifier to the core raw material component Hereinafter, it is preferably adjusted to 10% by mass or less. If the blending ratio of the emulsifier is less than the above-mentioned upper limit, generation of new particles based on the formation of micelles can be suppressed, and the polymerization proceeds with a constant number of particles, so that the antibiotic compound is surely included. Can do.

  The first aqueous emulsifier solution can also contain a dispersant.

  The dispersant is preferably used in combination with an emulsifier. Specifically, for example, polyvinyl alcohol (hereinafter abbreviated as “PVA”), a salt of a condensate of aromatic sulfonic acid and formaldehyde, polycarboxylic acid type Examples thereof include cellulose-based dispersants such as oligomers and hydroxycellulose, and preferred examples include salts of PVA and condensates of aromatic sulfonic acid and formaldehyde.

  PVA is a dispersant blended in the aqueous phase (first emulsifier aqueous solution) to form a protective colloid of the miniemulsion. For example, PVA is obtained by polymerizing a vinyl monomer mainly composed of vinyl acetate by an appropriate method. It can be obtained by saponifying the obtained polyvinyl acetate polymer.

  By adding PVA to the first emulsifier aqueous solution, a stable hydration 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, the polymerization stability can be improved, for example, the amount of aggregate during miniemulsion polymerization can be reduced.

  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.

  In order to make PVA contain in 1st emulsifier aqueous solution, PVA aqueous solution is prepared previously, water and an emulsifier are mix | blended with this, and they are stirred uniformly. 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.

  Examples of the aromatic sulfonic acid include benzene sulfonic acid, toluene sulfonic acid, cumene sulfonic acid, and naphthalene sulfonic acid. Preferably, naphthalenesulfonic acid such as α-naphthalenesulfonic acid and β-naphthalenesulfonic acid is used.

  Examples of the cation for forming the salt include monovalent alkali metal cations such as sodium cation and potassium cation, such as ammonium cation. Preferably, a monovalent alkali metal cation is used.

  Specific examples of the salt of the condensate of aromatic sulfonic acid and formaldehyde include a salt of a condensate of naphthalene sulfonic acid and formaldehyde (a sodium salt of formaldehyde condensate of naphthalene sulfonic acid). A commercially available product can be used as the salt of the condensate of aromatic sulfonic acid and formaldehyde. Specifically, Demol NL (41% aqueous solution of sodium salt of β-naphthalenesulfonic acid formaldehyde condensate, manufactured by Kao Corporation) Etc.

  These dispersants can be used alone or in combination of two or more. As the dispersant, a combination of PVA and a salt of a condensate of aromatic sulfonic acid and formaldehyde is preferably used.

  When the dispersant is a combination of PVA and a salt of a condensate of aromatic sulfonic acid and formaldehyde, the blending ratio of PVA as an active ingredient amount is 100 parts by mass of the core raw material component, for example 0.5 parts by mass or more, preferably 1 part by mass or more, and for example, 20 parts by mass or less, preferably 10 parts by mass or less. The blending ratio of the salt of the condensate of aromatic sulfonic acid and formaldehyde is, for example, 0.01 parts by mass or more, preferably 0.1 parts by mass or more, with respect to 100 parts by mass of the core raw material component, as the amount of active ingredient Also, for example, adjustment is performed so that the amount is 10 parts by mass or less, preferably 1 part by mass or less.

2.1.3. Preparation of Shell Raw Material Component In order to prepare the shell raw material component, for example, a hydrophobic second polymerizable vinyl monomer is prepared as it is as the shell raw material component. Alternatively, a hydrophobic second polymerizable vinyl monomer is emulsified. Preferably, the hydrophobic second polymerizable vinyl monomer is emulsified. That is, a hydrophobic second polymerizable vinyl monomer is emulsified to prepare a shell raw material component as a shell raw material emulsion.

  The shell raw material component (shell raw material emulsion) preferably contains substantially no antibiotic compound. That is, the shell raw material component (shell raw material emulsion) preferably contains substantially no antibiotic compound. That is, the antibiotic compound is not substantially contained in the shell raw material component (shell raw material emulsion).

  In other words, the shell raw material component can tolerate the inclusion of antibiotic active compounds to the extent that the effects of the present invention are not impaired. Specifically, the content ratio of the antibiotic compound that is, for example, 1 part by mass or less and further 0.1 part by mass or less is permissible with respect to 100 parts by mass of the second polymerizable vinyl monomer.

  In addition, from a viewpoint of reducing manufacturing cost, the shell raw material component preferably does not contain an ultraviolet absorber. That is, the ultraviolet absorber is preferably not contained in the shell raw material component and is not contained in the core raw material component.

  In order to prepare the shell raw material emulsion, for example, the second polymerizable vinyl monomer is emulsified in water in the presence of an emulsifier. Preferably, first, an emulsifier is mixed with water to prepare a second emulsifier aqueous solution, and then the second polymerizable vinyl monomer is emulsified in the second emulsifier aqueous solution. Specifically, the second polymerizable vinyl monomer is blended in the second aqueous emulsifier solution and stirred.

  Examples of the emulsifier include the same as the above-mentioned emulsifier, and preferably an anionic emulsifier.

  The blending ratio of the emulsifier is set so that micelles are not generated when the second polymerizable vinyl monomer is emulsified in the second aqueous emulsifier solution. Specifically, the blending ratio of the emulsifier is, for example, 0.01% by mass or more, preferably 0.1% by mass or more, as the active ingredient amount of the emulsifier, with respect to the second aqueous emulsifier solution. It is 10 mass% or less, preferably 5 mass% or less.

  For emulsification of the second polymerizable vinyl monomer, the second polymerizable vinyl monomer may simply be dispersed in the second aqueous emulsifier solution, and the particle size of the second polymerizable vinyl monomer is arbitrary. The second polymerizable vinyl monomer is added to the second aqueous emulsifier solution, and then fed to the reaction liquid after miniemulsion polymerization while stirring with a stirrer equipped with a stirring blade, a magnetic stirrer, etc. A shell raw material emulsion emulsified with a disper or homomixer in advance may be prepared (prepared), and this may be fed (supplied) to the reaction liquid (emulsion) after miniemulsion polymerization.

  The blending ratio of the second polymerizable vinyl monomer is, for example, 10 parts by mass or more, preferably 50 parts by mass or more, and for example, 200 parts by mass or less, preferably 100 parts by mass of the second emulsifier aqueous solution. 150 parts by mass or less, more preferably 100 parts by mass or less, and still more preferably 80 parts by mass or less. Further, the mixing ratio of the second polymerizable vinyl monomer is, for example, 1 part by mass or more, preferably 10 parts by mass or more, and, for example, 1000 parts by mass or less, preferably 100 parts by mass of the core. It adjusts so that it may become 100 mass parts or less.

  The blending ratio of the second polymerizable vinyl monomer is, for example, 5 parts by mass or more, preferably 10 parts by mass or more, with respect to 100 parts by mass of the total amount of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer. More preferably, it is 20 parts by mass or more, further preferably 25 parts by mass or more, particularly preferably 30 parts by mass or more, and most preferably 40 parts by mass or more. If the blending ratio of the second polymerizable vinyl monomer is equal to or more than the lower limit described above, the shell thickness with respect to the core diameter (average particle diameter) can be increased, so that the antibiotic compound contained in the core is outside the shell. Can be effectively delayed to further improve the sustained-release properties of the sustained-release particles.

  On the other hand, the blending ratio of the second polymerizable vinyl monomer is 90 parts by mass or less, preferably 50 parts by mass or less with respect to 100 parts by mass of the total amount of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer. When the blending ratio of the second polymerizable vinyl monomer is equal to or less than the upper limit described above, sustained release of the antibiotic compound in the sustained release particles can be ensured.

  Preferably, an aqueous polymerization initiator solution is prepared separately from the preparation of the shell raw material emulsion.

  In order to prepare a polymerization initiator aqueous solution, a water-soluble polymerization initiator is dissolved in water.

  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 water-soluble polymerization initiators can be used alone or in combination of two or more.

  The water-soluble polymerization initiator is preferably a persulfate compound.

  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, 3 parts by mass or less, with respect to 100 parts by mass of the second polymerizable vinyl monomer. The amount is preferably 1 part by mass or less.

  Further, the blending ratio of the water-soluble polymerization initiator is appropriately set and is, for example, 0.1% by mass or more, preferably 1% by mass or more, and, for example, 20% by mass with respect to the polymerization initiator aqueous solution. Hereinafter, it is preferably 10% by mass or less.

2.2. Next, miniemulsion polymerization in the core preparation step and seed emulsion polymerization in the shell preparation step will be sequentially described.

2.2.1 Mini Emulsion Polymerization In the core preparation step, in order to mini-emulsion polymerize the core raw material component, first, the core raw material component is emulsified in the first emulsifier aqueous solution.

  Specifically, a core raw material component is blended in a first emulsifier aqueous solution, and a high shear force is applied to them to emulsify the core raw material component in the first emulsifier aqueous solution to prepare a mini-emulsion.

  In emulsification of the core raw material component, 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 blending ratio of the core raw material component is, for example, 10 parts by mass or more, preferably 25 parts by mass or more, and for example, 100 parts by mass or less, preferably 90 parts by mass with respect to 100 parts by mass of the first emulsifier aqueous solution. Or less.

  A mini-emulsion of core raw material components is prepared by the above method. In the core material component miniemulsion, the emulsifier is adsorbed on the miniemulsion particles (emulsion droplets of the core material component), and the core material component miniemulsion particles having an average particle diameter of less than 1 μm are contained in the aqueous medium. Is formed.

  The average particle size of the mini-emulsion particles is calculated as the median size, and is, for example, 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, For example, it is adjusted to 50 nm or more.

  In addition, since the antibiotic compound contained in the particles of the miniemulsion particles acts as a hydrophobe (costabilizer), prevents Ostwald ripening and suppresses the enlargement of the core (increase in particle diameter), The particle size when emulsified is maintained, and furthermore, the emulsifier is adsorbed on the surface of the miniemulsion particles, whereby the miniemulsion is dispersed and stabilized (that is, the water dispersion of the miniemulsion). Stability is ensured).

  Thereafter, the emulsified first polymerizable vinyl monomer is miniemulsion polymerized in the presence of an oil-soluble polymerization initiator to produce a core composed of the first polymer and the antibiotic compound. At this time, the mini-emulsion polymerization may be performed by adding the water-soluble polymerization initiator in combination with the oil-soluble polymerization initiator. Alternatively, miniemulsion polymerization can be performed only with a water-soluble polymerization initiator.

  This miniemulsion polymerization is an in situ polymerization because all the first polymerizable vinyl monomers as raw materials are only in the miniemulsion particles (hydrophobic liquid phase). That is, in the mini-emulsion polymerization, the mini-emulsion is heated while being stirred, whereby the first polymerizable vinyl monomer starts polymerization in the mini-emulsion particles as it is, and a first polymer is generated.

  The peripheral speed of the stirring blade in stirring the miniemulsion 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 oil-soluble polymerization initiator and the first polymerizable vinyl monomer, and the heating temperature is, for example, not less than the melting point of the antibiotic compound, specifically, for example, not less than 30 ° C., Preferably, it is 50 ° C. or higher, for example, 100 ° C. or lower, and the heating time is, for example, 2 hours or longer, preferably 3 hours or longer, and for example, 24 hours or shorter, preferably 12 Below time. 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.

  Miniemulsion polymerization yields an emulsion containing a core containing a first polymer and an antibiotic compound. In the emulsion, the core is dispersed.

  The core is a homogeneous phase in which the antibiotic compound is compatible with the first polymer obtained by polymerization of the first polymerizable vinyl monomer.

  Thereafter, the emulsion after the reaction is maintained at the polymerization temperature without cooling, and the seed emulsion polymerization is carried out continuously.

  Or you may cool an emulsion to room temperature (20-30 degreeC, more specifically 25 degreeC), for example.

  The average particle diameter of the core thus obtained is calculated as the median diameter, and is 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 10 nm or more, preferably 50 nm or more.

  Thereby, the emulsion with which the core was emulsified can be obtained.

2.2.2. Seed emulsion polymerization In the shell preparation step, in order to seed emulsion polymerization of the shell raw material component, for example, the shell raw material component is supplied to the emulsion containing the core. Alternatively, the shell raw material emulsion is supplied to the above-described emulsion. Alternatively, the shell raw material component and the shell raw material emulsifier aqueous solution are separately supplied to the above emulsion. Preferably, the shell raw material emulsion is supplied to the emulsion.

  In order to supply the shell raw material emulsion to the emulsion, for example, continuous supply, divided supply, and batch supply are adopted, and preferably, continuous supply is adopted. If it is continuous supply, supply (addition) shock at the time of divided supply or collective supply (specifically, the core becomes unstable in the emulsion and the core aggregates) can be reduced.

  In the continuous supply, the shell raw material emulsion is continuously supplied to the emulsion. Specifically, the shell raw material emulsion is, for example, 10 minutes or more, preferably 30 minutes or more, more preferably, Supply over 60 minutes or more, eg within 180 minutes.

  Moreover, in continuous supply, a shell raw material emulsion is supplied with respect to an emulsion using a tubing pump etc., for example.

  Specifically, the emulsion is heated in miniemulsion polymerization and supplied to an emulsion in which the temperature is maintained (that is, an emulsion that has been reacted but not cooled). When the emulsion is once cooled, the cooled emulsion is heated again to a predetermined temperature, and then the shell raw material emulsion is supplied to the emulsion.

  The mixing ratio of the shell raw material emulsion is, for example, 10 parts by mass or more, preferably 20 parts by mass or more, and, for example, 500 parts by mass or less, preferably 100 parts by mass of the core raw material component. 100 parts by mass or less. Moreover, the blending ratio of the shell raw material component is, for example, 5 parts by mass or more, preferably 10 parts by mass or more, and for example, 250 parts by mass or less, preferably 50 parts by mass with respect to 100 parts by mass of the core raw material component. It adjusts so that it may become below a mass part.

  Further, the blending ratio of the shell raw material emulsion is adjusted so that the blending ratio of the second polymerizable vinyl monomer to the first polymerizable vinyl monomer and the second polymerizable vinyl monomer is the above-described blending ratio.

  When the supply of the shell raw material emulsion to the emulsion is started, the above-described miniemulsion polymerization is preferably completed. Specifically, the conversion rate of the first polymerizable vinyl monomer in the miniemulsion polymerization is For example, at 75% or more, preferably 95% or more, and more preferably 99% or more, the shell raw material emulsion is supplied to the emulsion. The conversion rate of the first polymerizable vinyl monomer is the conversion rate of the first polymerizable vinyl monomer in the core, and is measured by HPLC. When the supply of the shell raw material emulsion to the emulsion is started, if the conversion rate of the first polymerizable vinyl monomer is not less than the above lower limit, it can have a core-shell structure.

  In addition to supplying the shell raw material emulsion to the emulsion, an aqueous polymerization initiator solution is supplied to the emulsion.

  In order to supply the polymerization initiator aqueous solution to the emulsion, for example, continuous supply, divided supply, and batch supply are adopted, and preferably, continuous supply is adopted. With continuous supply, supply (addition) shock (specifically, the core becomes unstable and aggregates in the emulsion) at the time of divided supply or collective supply can be reduced.

  In the continuous supply, the polymerization initiator aqueous solution is continuously supplied to the emulsion. Specifically, the time required for supplying the polymerization initiator aqueous solution to the emulsion of the shell raw material emulsion. More specifically, for example, 10 minutes or more, preferably 30 minutes or more, more preferably 60 minutes or more, and for example, within 180 minutes.

  In continuous supply, for example, an aqueous polymerization initiator solution is supplied to the emulsion using a tubing pump or the like.

  In this way, the seed emulsion polymerization is performed by supplying the shell raw material emulsion and the polymerization initiator aqueous solution, or the shell raw material component, the shell raw material emulsifier aqueous solution and the polymerization initiator aqueous solution to the heated emulsion after the mini-emulsion polymerization. Progresses.

  The heating temperature of seed emulsion polymerization is, for example, 30 ° C. or higher, preferably 50 ° C. or higher, and for example, 100 ° C. or lower. The heating time is, for example, 2 hours or more, preferably 3 hours or more, and for example, 24 hours or less, preferably 12 hours or less. 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.

  Then, with the core as a seed (seed particle), the second polymerizable vinyl monomer is seed-emulsified on the surface of the core, and a shell made of the second polymer that covers the core is generated.

  In seed emulsion polymerization, the core prepared by miniemulsion polymerization is used as a seed (seed particle), the shell raw material component is supplied to the core suspension, and seeded with a water-soluble polymerization initiator in a separately added polymerization initiator aqueous solution. This is a polymerization method. Therefore, the seed emulsion polymerization has an average particle size of less than 1 μm, and the sustained-release particles do not easily settle, and is excellent in water dispersion stability.

  On the other hand, in seed suspension polymerization, the core prepared by suspension polymerization is used as a seed (seed particle), the shell raw material component is supplied to the core suspension, and seed polymerization is performed with the oil-soluble polymerization initiator remaining in the core. Is the method. Therefore, seed suspension polymerization, unlike seed emulsion polymerization, has an average particle size of 1 μm or more, and sustained release particles easily settle, resulting in poor water dispersion stability. In order to ensure seed suspension polymerization of the shell raw material component, the core suspension is once cooled below the polymerization start temperature, the shell raw material component is supplied and stirred, and the core is swollen with the shell raw material component. After that, it is necessary to take a method such as raising the temperature above the polymerization initiation temperature.

  Also, the particle shell prepared by seed emulsion polymerization is preferably substantially free of antibiotic active compounds. In other words, the shell can tolerate the inclusion of antibiotic active compounds to the extent that they do not inhibit the effects of the present invention. Specifically, it is allowed that the antibiotic compound is migrated from the core to the shell and a trace amount of the antibiotic compound is present in the shell.

  The content rate of the antibiotic compound in a shell is 1 mass% or less, for example, Furthermore, it is 0.1 mass% or less.

  The maximum thickness of the shell is, for example, 1 nm or more, preferably 3 nm or more, more preferably 10 nm or more, still more preferably 30 nm or more, and for example, 200 nm or less, preferably 150 nm or less. It is.

  The percentage of the shell thickness to the core diameter (average particle diameter) (shell thickness / core diameter × 100) is, for example, 1% or more, preferably 3% or more, more preferably 5% or more, Preferably, it is 10% or more, for example, 50% or less.

  The average particle diameter of the sustained-release particles is calculated as a median diameter, and is less than 1 μm, preferably 750 nm or less, more preferably 500 nm or less, still more preferably 400 nm or less, particularly preferably 300 nm or less. It is 50 nm or more.

  The percentage of the shell thickness to the average particle diameter of the sustained release particles (shell thickness / average particle diameter of the sustained release particles × 100) is, for example, 1% or more, preferably 3% or more, more preferably, 5% or more, more preferably 10% or more, and for example, 50% or less.

  As shown in the cross-sectional view of FIG. 1, an emulsion containing sustained release particles 1 having a core 2 and a shell 3 covering the core 2 is obtained by such a manufacturing method.

  That is, the sustained release particles 1 are formed as spherical particles, and specifically include a core 2 and a shell 3 that covers the core 2.

  The core 2 is formed in a substantially spherical shape. The core 2 contains a homogeneous phase in which a hydrophobic antibiotic compound is compatible with the first polymer obtained by polymerization of the hydrophobic first polymerizable vinyl monomer.

  The shell 3 is formed on the surface of the core 2. Specifically, the shell 3 is formed in a film shape covering the surface of the core 2, for example. The shell 3 contains a second polymer obtained by polymerization of a hydrophobic second polymerizable vinyl monomer. The shell 3 is preferably substantially free of antibiotic active compounds. In other words, for example, 1% by mass or less, and further 0.1% by mass or less of the antibiotic compound is allowed with respect to the shell 3.

  Therefore, the sustained release particles 1 have a core-shell structure.

  Then, after the seed emulsion polymerization, the emulsion after polymerization is cooled by, for example, cooling, and filtered through a 100th filter cloth or the like, whereby an emulsion of the sustained release particles (aqueous dispersion). Get.

  Then, for example, known additives such as thickeners, antifreeze agents, preservatives, and microbial growth inhibitors can be appropriately blended in the emulsion containing sustained release particles.

  The sustained release particles thus obtained are used as they are (emulsion), that is, as an emulsion. The sustained-release particles can be used after being solid-liquid separated by spray drying, freeze-thawing / dehydration / drying, salting-out / dehydration / drying, etc., and then formulated into a known dosage form such as powder. Such a powder may be prepared, for example, as a powder in which sustained release particles are aggregated.

  Such emulsions or powders can be added to various industrial products. Specifically, an emulsion or powder is applied to, for example, exterior materials (particularly, housing exterior materials), interior materials (including wallpaper, etc.), ceiling materials, floor materials, etc., for example, paints, eg, adhesives. Agents such as inks such as sealing agents, caulking agents such as paper products such as binders such as resin emulsions such as pulps such as wood materials such as wood products such as plastic products such as films For example, it can be applied (or blended) to textile products, nonwoven fabrics, filters, and the like.

3. The sustained-release particles obtained by the above-described method for producing sustained-release particles are provided with a core in which the antibiotic compound is compatible with the first polymer and a shell that covers the core. Excellent.

  Specifically, in general, an antibiotic compound such as an isothiazoline-based compound may be decomposed when stored for a long time under exposure to ultraviolet rays. Therefore, the content of the antibiotic compound in the sustained release particles may decrease.

  However, since the above-mentioned sustained-release particles comprise a core in which the antibiotic compound is compatible with the first polymer and a shell covering the core, the above-described antibiotic compound resulting from exposure to ultraviolet rays as described above Can be suppressed, and the decrease in the content of the antibiotic compound in the sustained-release particles can be suppressed.

  Further, the sustained release particles obtained by the above-described method for producing sustained release particles contain a homogeneous phase in which an antibiotic compound is compatible with the first polymer obtained by polymerization of the first polymerizable vinyl monomer. Since it has a core to perform, it has excellent sustained release properties.

  Moreover, since this sustained release particle | grain is equipped with the core which an antibiotic compound is compatible with the 1st polymer, and the shell which coat | covers a core, it is excellent in sustained release property.

  In addition, since the antibiotic compound and the second polymer have the solubility parameter δ described above, the antibiotic compound and the second polymer are incompatible. Therefore, leakage of the antibiotic compound from the core to the outside of the shell can be suppressed. As a result, the sustained release properties of the sustained release particles can be improved.

  Furthermore, the shell raw material component is substantially free of antibiotic active compounds and is therefore substantially free of antibiotic active compounds. Therefore, the shell can suppress leakage of the antibiotic compound to the outside of the shell, so that the sustained release property of the sustained release particles can be further improved.

  Furthermore, since the above-mentioned sustained release particles are obtained by miniemulsion polymerization and subsequent seed emulsion polymerization, they are excellent in water dispersion stability.

  Further, if the blending ratio of the second polymerizable vinyl monomer to the total amount of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer is equal to or more than the above lower limit, the shell thickness with respect to the core diameter (average particle diameter) is set. Therefore, it is possible to effectively delay the release of the antibiotic compound contained in the core out of the shell, thereby further improving the sustained release properties of the sustained release particles.

  Specific numerical values such as blending ratio (content ratio), physical property values, and parameters used in the following description are described in the above-mentioned “Mode for Carrying Out the Invention”, and the corresponding blending ratio (content ratio) ), Physical property values, parameters, etc. may be replaced with the upper limit values (numerical values defined as “less than” or “less than”) or lower limit values (numbers defined as “greater than” or “exceeded”). it can.

  In the following description, “%” and “part” are based on mass unless otherwise specified.

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

DCOIT: 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one, molecular weight 282.2, melting point: 42 ° C., solubility in water: 2 × 10 ⁻³ g / L (25 ° C.), Dipole force term δ _{p, compound of the} solubility parameter δ: 6.36 [(J / cm ³ ) ^1/2 ], hydrogen bond force term δ _{h, compound of} the solubility parameter δ: 6.05 [(J / cm ³ ) ^1/2 ], manufactured by Tokyo Chemical Industry Co., Ltd. OIT: trade name “Caisson 893T” (“Caisson” is a registered trademark), 2-n-octyl-4-isothiazolin-3-one, molecular weight 213, melting point: 20 ° C. Less than, solubility in water: 0.3 × 10 ⁻³ g / L (25 ° C.), dipole force term δ _{p, compound of} solubility parameter δ: 5.47 [(J / cm ³ ) ^1/2 ] , Hydrogenation of solubility parameter δ Force term _{δ h, compound: 5.87 [(} J / cm 3) 1/2], manufactured by Rohm and Haas Company IPBC: trade name "fan formate trawl 400", 3-iodo-2-propynyl butyl carbamate, molecular weight 281, melting point: 60 ° C., solubility in water: 0.15 × 10 ⁻³ g / L (25 ° C.), dipole force term δ _{p, compound of} solubility parameter δ: 3.23 [(J / cm ³ ) ^1/2 ], hydrogen bond strength term δ _{h, compound of} solubility parameter δ: 7.83 [(J / cm ³ ) ^1/2 ], Propiconazole manufactured by International Specialty Products: 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., solubility in water: 0.11 × 10 ⁻³ g / L (25 ° C.), dipole force term δ _{p, compound of} solubility parameter δ: 6.55 [(J / cm ³ ) ^{1 / 2} ], hydrogen bond term δ _{h, compound of} the solubility parameter δ: 9.44 [(J / cm ³ ) ^1/2 ], manufactured by Yakotsu 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., solubility in water: 0.055 × 10 ⁻³ g / L (25 ° C.), solubility parameter δ Dipole force term δ _{p, compound} : 7.07 [(J / cm ³ ) ^1/2 ], hydrogen bonding force term δ _{h, compound of} solubility parameter δ: 8.31 [(J / cm ³ ) ^{1 / 2],} Maruzen Pharmaceutical Co., Ltd. off Shirazoru: Bis (4-fluorophenyl) methyl (IH-1,2,4-triazol-1-yl methyl silane), molecular weight 315, melting point: 54 ° C., solubility in water: 0.0.045 × ^{10 -3} g / L (25 ° C.), Dipole force term δ _{p, compound of} solubility parameter δ: 5.95 [(J / cm ³ ) ^1/2 ], Hydrogen bond force term δ _{h, compound of} solubility parameter δ: 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., solubility in water: 0.99 × 10 ⁻³ g / L (25 ° C.), δ _{p, compound} : 5.42 [(J / cm ³ ) ^1/2 ], δ _{h, compound} : 5.83 [(J / cm ³ ) ^1/2 ], Reagent Perme from Tokyo Chemical Industry Co., Ltd. Phosphorus: 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 × 10 ⁻⁶ g / L (25 ° C.), δ _{p, compound} : 3.63 [(J / cm ³ ) ^1/2 ], δ _{h, compound} : 6. 22 [(J / cm ³ ) ^1/2 ], manufactured by LANXESS, Cyfluthrin: trade name “Priventol HS12” (“Priventol” is a registered trademark), (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 × 10 -6 g / L} (25 ℃) ~2 × 10 -6 g / L (25 ℃), isomer I (melting point: 57 ° C.) and isomer II (mp: 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 bond strength term δ _{h, compound of} solubility parameter δ: 6.09 [(J / cm ³ ) ^1/2 ], manufactured by LANXESS MMA: methyl methacrylate, trade name “light ester M”, water Solubility: 16 g / L (25 ° C.), Dipole force term δ _p, monomer unit of solubility parameter δ as monomer _unit : 5.98 [(J / cm ³ ) ^1/2 ], Solubility as monomer unit hydrogen bonding term parameters [delta] [delta] ^{_{, Monomer unit: 9.25 [(J}} / cm 3) 1/2], Kyoeisha Chemical Co. SM: Styrene, solubility in water: 0.3g / L (25 ℃) , bipolar solubility parameter δ as a monomer unit _{Intermolecular} force term δ _{p, monomer unit} : 1.27 [(J / cm ³ ) ^1/2 ], hydrogen bonding force term δ _h, monomer unit of solubility parameter δ as a monomer _unit : 0.00 [(J / cm ³ ) ^1/2 ], manufactured by Idemitsu Kosan Co., Ltd. EGDMA: Ethylene glycol dimethacrylate, trade name “light ester EG”, solubility in water: 0.58 g / L (25 ° C.), dipole force with solubility parameter δ term _{δ p, 1st monomer unit: 5.37} [(J / cm 3) 1/2], hydrogen bonding term solubility parameter _δ δ _{h, 1st} monomer ^{_{nit: 10.42 [(J / cm}} 3) 1/2], Kyoeisha Chemical Co., Ltd. MAA: methacrylic acid, solubility in water: 89g / L (25 ℃) , between dipole solubility parameter δ as a monomer unit Force term δ _{p, monomer unit} : 7.13 [(J / cm 3) 1/2], hydrogen bonding force term of solubility parameter δ as a monomer unit δ _{h, monomer unit} : 13.03 [(J / cm 3) 1 / 2], i-BMA manufactured by Mitsubishi Rayon Co., Ltd .: iso-butyl methacrylate, solubility in water: 0.5 g / L (25 ° C.), dipole force term δ _{p, monomer unit of} solubility parameter δ: 3.75 ^{[(J / cm 3) 1/2} ], hydrogen bonding term solubility parameter _{δ δ h, monomer unit: 7.32} [(J / cm 3) 1/2], manufactured by Nippon Shokubai Co., Ltd. R VA-93: trade name, 2- [3- (2H-benzotriazol-2-yl) -4-hydroxyphenyl] ethyl methacrylate, polymerization-reactive UV absorber, solubility in water: 0.1 g / L ( 25 ° C) and below, dipole force term δ _p , monomer unit of solubility parameter δ as a monomer _unit : 5.61 [(J / cm ³ ) ^1/2 ], hydrogen bond strength of solubility parameter δ as monomer unit Term δ _{h, monomer unit} : 13.07 [(J / cm ³ ) ^1/2 ], manufactured by Tokyo Chemical Industry Co., Ltd. Parroyl L: trade name _{, dilauroyl} peroxide, oil-soluble polymerization initiator, TINUVIN PS manufactured by NOF Corporation: Product name, (2- (2-hydroxy-5-t-butylphenyl) -2H-benzotriazole, non-polymerization reactive UV absorber, Neocor manufactured by Ciba Japan SW-C: Trade name, 70 mass% isopropanol solution of sodium dioctyl sulfosuccinate (anionic emulsifier), Dai-ichi Kogyo Seiyaku Co., Ltd. DEMAL NL: Trade name, 41 mass of sodium salt of β-naphthalenesulfonic acid formaldehyde condensate % Aqueous solution, anionic dispersant, manufactured by Kao Chemical Co., Ltd. PVA-205: trade name, polyvinyl alcohol, saponification degree: 87.0-89.0%, polymerization degree: 500, viscosity (4% aqueous solution, 20 ° C.): 5 0.0-6.0 mPa · sec, manufactured by Kuraray Co., Ltd., PRISURF A210G: trade name (“PRISURF” is a registered trademark), polyoxyethylene phosphate ammonium salt, manufactured by Daiichi Kogyo Seiyaku Co., Ltd. TCP-10U: trade name, Tricalcium phosphate, [Ca ₃ (PO ₄ ) ₂ ] · Ca (OH) ₂ 10% by mass suspension, dispersant, Made by Matsuo Pharmaceutical Co., Ltd.

Example 1
(After miniemulsion polymerization, seed emulsion polymerization)
A 200 mL beaker is charged with 20 parts of DCOIT, 44 parts of MMA, 8 parts of SM, 4 parts of EGDMA, 4 parts of MAA, and 0.40 part of Parroyl L, and stirred at room temperature to prepare a uniform core raw material component. did.

  Separately, in a 1000 mL beaker, charge 86.12 parts of deionized water, 40 parts of a 10% aqueous solution of PVA-205, 1.57 parts of Neocor SW-C, and 0.24 parts of Demol NL and stir at room temperature. Thus, a uniform first emulsifier aqueous solution was prepared.

  Next, the core raw material component was added to the first emulsifier aqueous solution in a 1000 mL beaker, and T.P. K. A mini-emulsion was prepared by stirring for 10 minutes at a rotational speed of 10,000 rpm with a homomixer MARK 2.5 (manufactured by PRIMIX). Thereafter, the prepared mini-emulsion was transferred to a 500 mL four-necked flask equipped with a stirrer, reflux condenser, thermometer and nitrogen introducing tube, and stirred at a rotation speed of 200 rpm with a 3 cm diameter stirring blade under a nitrogen stream. 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. Thereby, an emulsion containing the core was prepared.

  Separately, 0.87 part of a 10% aqueous solution of Neocor SW-C was charged into 20 parts of deionized water in a 200 mL beaker to prepare a second aqueous emulsifier solution. Next, 20 parts of MMA was added to a 200 mL beaker and stirred with a magnetic stirrer for 30 minutes to emulsify MMA in the second emulsifier aqueous solution to prepare a shell raw material emulsion.

  Separately from the preparation of the shell raw material emulsion, sodium persulfate (water-soluble polymerization initiator) was dissolved in water to prepare 0.80 part of a 5% aqueous solution of sodium persulfate (aqueous polymerization initiator solution).

  The dropping of each of the prepared shell raw material emulsion and the polymerization initiator aqueous solution is simultaneously started using a tubing pump (ATIST Perista Pump) to a 500 mL four-necked flask after miniemulsion polymerization. Initiated seed emulsion polymerization.

  The dropping time of the shell raw material emulsion and the polymerization initiator aqueous solution was both 60 minutes, and the polymerization time was 3 hours (2 hours at 70 ± 2 ° C., then heated to 1 hour at 80 ± 2 ° C. ( The temperature rise time was included)), and then the emulsion was cooled to 30 ° C. or lower to obtain an emulsion of sustained-release particles containing DCOIT.

  At the start of seed emulsion polymerization, the conversion rate of the first polymerizable vinyl monomer in miniemulsion polymerization was 99.3%. Further, at the end of the seed emulsion polymerization, the conversion rate of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer was 99.6%. The above conversion was calculated by HPLC. The results are listed in Table 1. The conversion rates of the following examples and comparative examples were also calculated by the above method.

  The obtained emulsion was filtered through a 100th filter cloth, and the median diameter of the sustained release particles in the filtrate was measured. The results are listed in Table 1. The same applies to the following examples and comparative examples.

Examples 2-8
(After miniemulsion polymerization, seed emulsion polymerization)
Polymerization was carried out in the same manner as in Example 1 except that the formulation was changed according to the descriptions in Tables 1 and 2, to obtain an emulsion of sustained-release particles.

Example 9
(After miniemulsion polymerization, seed emulsion polymerization)
Polymerization was carried out in the same manner as in Example 1 except that the conversion rate of the first polymerizable vinyl monomer in the miniemulsion polymerization at the start of seed emulsion polymerization was changed to 76.3%, and an emulsion of sustained release particles was obtained. Got.

  Specifically, the miniemulsion polymerization is started, and then at the time when 3 hours have passed at 60 ± 2 ° C., by simultaneously starting the supply of both the shell raw material emulsion and the polymerization initiator aqueous solution, the seed emulsion polymerization is performed. Started. The polymerization time of seed emulsion polymerization was set to 4 hours at 70 ± 2 ° C. and 1 hour at 80 ± 2 ° C. including the temperature rising time.

Example 10
(After miniemulsion polymerization, seed emulsion polymerization)
Polymerization was carried out in the same manner as in Example 2 except that the conversion rate of the first polymerizable vinyl monomer in the miniemulsion polymerization at the start of seed emulsion polymerization was changed to 75.2%, and an emulsion of sustained release particles was obtained. Got.

  Specifically, the miniemulsion polymerization is started, and then at the time when 3 hours have passed at 60 ± 2 ° C., by simultaneously starting the supply of both the shell raw material emulsion and the polymerization initiator aqueous solution, the seed emulsion polymerization is performed. Started. The polymerization time of seed emulsion polymerization was set to 4 hours at 70 ± 2 ° C. and 1 hour at 80 ± 2 ° C. including the temperature rising time.

Comparative Example 1
(Mini emulsion polymerization only)
Polymerization was carried out in the same manner as in Example 1 except that seed emulsion polymerization was not carried out to obtain an emulsion of sustained-release particles composed of core particles containing DCOIT.

Comparative Example 2
(After suspension polymerization, seed suspension polymerization)
A hydrophobic solution was prepared by charging 20 parts of DCOIT, 60 parts of MMA, 10 parts of SM, 5 parts of EGDMA, 5 parts of MAA, and 0.50 part of Parroyl L into a 200 mL beaker and stirring at room temperature.

  Separately, in a 1000 mL beaker, 120 parts of deionized water, 120 parts of TCP-10U and 1 part of 5% aqueous solution of Prisurf A210G were prepared and stirred at room temperature to prepare a uniform aqueous solution.

  The hydrophobic solution was then added to the 1000 mL beaker aqueous solution. K. A suspension was prepared by stirring for 5 minutes at a rotational speed of 5000 rpm with a homomixer MARK 2.5 (manufactured by PRIMIX). Thereafter, the prepared suspension was transferred to a 500 mL four-necked flask equipped with a stirrer, reflux condenser, thermometer and nitrogen introduction tube, and stirred at a rotation speed of 200 rpm with a 3 cm diameter stirring blade under a nitrogen stream. Suspension polymerization was carried out by raising the temperature of the 4-neck flask with a water bath.

  The suspension 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. The suspension was then cooled to room temperature.

  Separately, 17.2 parts of ion-exchanged water and 22.8 parts of 1% aqueous solution of Neocor SW-C were charged into a 200 mL beaker and stirred at room temperature to prepare a uniform aqueous solution. Next, 20.0 parts of MMA was charged into a 200 mL beaker (3). K. A shell raw material emulsion was prepared by emulsifying MMA by stirring with a homomixer MARK 2.5 type (manufactured by Primex) for 10 minutes at a rotational speed of 10,000 rpm. Next, while stirring the suspension cooled to room temperature after the reaction, the shell raw material emulsion was added to the suspension and stirred for 2 hours. Thereafter, the mixture was heated with stirring under a nitrogen stream to carry out seed suspension polymerization (second step). Seed suspension polymerization was initiated when the temperature of the suspension reached 65 ° C in the course of raising the temperature of the suspension, followed by maintaining the temperature of the suspension at 70 ° C for 3 hours.

  The suspension was then cooled to room temperature.

  Thereby, a suspension (suspension agent) of sustained release particles prepared using a core containing DCOIT as a seed was obtained.

Examples 11-36
(After miniemulsion polymerization, seed emulsion polymerization)
Polymerization was carried out in the same manner as in Example 1 except that the formulation was changed in accordance with the description in Tables 5 to 10, to obtain an emulsion of sustained release particles.

Comparative Examples 3-10
(Mini emulsion polymerization only)
Polymerization was carried out in the same manner as in Comparative Example 1 except that the formulation was changed according to the descriptions in Tables 7 to 10, to obtain an emulsion of sustained release particles composed of core particles.

(Evaluation)
<Water dispersion stability (storage stability)>
Each of the emulsions of Examples 1 to 36 and Comparative Examples 1 and 3 to 10 and the suspension of Comparative Example 2 were allowed to stand at 60 ° C. for 2 weeks. Thereafter, the presence or absence of sedimentation of the sustained release particles was visually confirmed. Sedimentation was evaluated according to the following criteria. Thus, the water dispersion stability of the sustained release particles was evaluated.
○: No settling of sustained release particles was confirmed.
X: Sedimentation of sustained release particles was confirmed.

  The results are shown in Tables 1-10.

<Slow release after running water immersion test (DCOIT residual rate (sustained release)) A>
Each of the emulsions of Examples 1 to 10 and Comparative Example 1 and the suspension of Comparative Example 2 was made into an acrylic styrene emulsion (trade name Ultrasol C-63 Aika Kogyo Co., Ltd.), and the DCOIT concentration in the emulsion was It added so that it might become 0.01%. Thereafter, the mixture was stirred for 1 hour at a rotational speed of 600 to 800 rpm with a homodisper 2.5 type (manufactured by Primex). After stirring, it was coated on a 150 × 150 × 0.3 (mm) aluminum plate with an application thickness of 250 μm using an applicator and dried overnight to prepare a coating film. Thereafter, the coating film and the aluminum plate are placed in a 200 × 500 × 150 (mm) vat, and the coating film is immersed in water by supplying 1.5 L / min of tap water from the top of the aluminum plate. did. The tap water was supplied to the bat so that it always overflowed from the bat. Then, the residual amount of DCOIT in the coating film after two weeks from the immersion of the coating film in water was measured by HPLC. Specifically, the DCOIT residual amount in the coating film was measured by cutting the coating film into 30 × 30 (mm) and extracting with methanol.

  On the other hand, the amount of DCOIT of the coating film not immersed in water was measured by HPLC in the same manner as described above. This DCOIT amount was defined as “initial content”.

And the residual rate A after a flowing water immersion test was computed from the following formula.
Residual rate A (%) = [residual amount / initial content] × 100
The results are shown in Tables 1 to 4.

<DCOIT residual ratio B after UV irradiation test>
Each of the emulsions of Examples 1 to 10 and Comparative Example 1 and the suspension of Comparative Example 2 was made into an acrylic styrene emulsion (trade name Ultrasol C-63 Aika Kogyo Co., Ltd.), and the DCOIT concentration in the emulsion was It added so that it might become 0.01%. Thereafter, the mixture was stirred for 1 hour at a rotational speed of 600 to 800 rpm with a homodisper 2.5 type (manufactured by Primex). After stirring, it was coated on a 150 × 150 × 0.3 (mm) aluminum plate with an application thickness of 250 μm using an applicator and dried overnight to prepare a coating film. Thereafter, the coating film was irradiated with UV with black light at an intensity of 25 to 35 μw / cm ² , and the residual amount of DCOIT after two weeks was measured.

  On the other hand, the DCOIT amount of the coating film not irradiated with UV was measured by HPLC. This DCOIT amount was defined as “initial content”.

And the residual rate B after a UV irradiation test was computed from the following formula.
Residual rate B (%) = [initial value content / residual amount] × 100
The results are shown in Tables 1 to 4.

<DCOIT Sustained Release Test C for Sustained Release Particles>
First, the emulsions of Comparative Example 1 and Examples 11 to 20 were prepared as samples for the sustained release test C, respectively. Further, an aqueous solution of 60% methanol was prepared as an eluent.

  Next, the prepared sample is put in 5 polypropylene centrifuge tubes made of polypropylene in an amount of 20 mg each as DCOIT mass, and then a DCOIT-containing solution having a DCOIT concentration of 0.05 mass% is prepared with an eluate as a total amount of 40 g. did.

  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 results are shown in FIGS.

<Sustained release test of sustained release particles containing OIT>
First, deionized water was added to the emulsions of Comparative Example 3 and Examples 21 and 22, and an emulsion having an OIT concentration of 6% by mass was prepared as a sample for the 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 Aika Kogyo Co., Ltd.), the OIT mass is 1000 ppm. Each sample was added and stirred to prepare a paint for evaluation.

  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.

<Sustained release test of sustained release particles containing IPBC>
Except that the eluent was changed from methanol aqueous solution to deionized water, the same procedure as the above-mentioned “<DCOIT sustained release test C for sustained release particles>” was performed, and the IPBC slowdown of the emulsions of Examples 23 and 24 was performed. A release test was performed. The result is shown in FIG.

<Sustained release test of sustained release particles containing propiconazole>
First, the emulsions of Comparative Example 5 and Examples 25 and 26 were diluted with deionized water to prepare an emulsion containing 6% by mass of propiconazole.

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

  Next, 1.0 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.

<Sustained release test of sustained release particles containing prochloraz>
The prochloraz sustained release test of the sustained release particles of Examples 27 and 28 was carried out according to the above-mentioned “<Sustained release test of sustained release particles containing propiconazole>”.

  The result is shown in FIG.

<Sustained release test of sustained release particles containing flusilazole>
The flusilazole sustained-release test of the sustained-release particles of Examples 29 and 30 was performed according to the above-mentioned “<Sustained-release test of sustained-release particles containing propiconazole>”.

  The result is shown in FIG.

    <Sustained release test of sustained release particles containing diet>

(1) Production of insect cage A frame 11 shown in FIG. 10 was produced using 42 mm square dried cedar timber.

  That is, the frame 11 includes a first frame 12 and a second frame 13 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 14 that connects them.

  The first frame 12 and the second frame 13 have a rectangular parallelepiped frame shape. The communication frame 14 communicates the upper portions of the first frame 12 and the second frame 13. Each of the first frame 12 and the second frame 13 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.

  Thereafter, as shown in FIG. 11, 40th filter cloths 15 are arranged as outer surfaces on the frame 11 shown in FIG. 10, and the first frame 12, the second frame 13, The insect cage 20 was produced by fixing to the communication frame 14.

  That is, the insect cage 20 is partitioned by the first space 12 partitioned by the first frame 12 and the filter cloth 15, the second space 17 partitioned by the second frame 13 and the filter cloth 15, and the connection frame 14 and the filter cloth 15. Connected space 18 to be formed. The first space 16 and the second space 17 communicate with each other through a connection space 18.

  Thereby, the filter cloth 15 can be attached to and detached from each frame, and air can freely flow. In addition, small insects placed in the insect cage 20 can freely pass through the first space 16, the second space 17, and the connection space 18, but cannot go out of the insect cage 20.

(2) Sustained-release particles containing diet The square filter paper is cut into 120 × 200 mm, and the emulsions of Comparative Example 8 and Examples 31 and 32 are diluted 1.67 times with ion-exchanged water to obtain 10 mass of diet. % Sustained-release particle emulsion was prepared and sprayed with a sprayer so as to adhere 200 mg as a diet on a square filter paper. This square filter paper was placed on the upper surface of the filter cloth 15 at the bottom of the first space 16 of the insect cage 20 placed in the outdoor shade (Konohana Ward, Osaka City) in the summer (August 2014).

  In addition, an apple slice (Akaeka feed described later) was placed on the upper surface of the filter cloth 15 on the bottom surface of the second space 17 of the insect cage 20.

Subsequently, 20 squids that emerged on the test day were released into the second space 17 of the insect cage 20. Twenty-four hours after the release, 20 squids did not move from the second space 17 to the first space 16. However, after 48 hours from the release, the following number of squids moved from the second space 17 to the first space 16.
Comparative Example 8 9 animals Example 31 5 animals Example 32 0 animals <Sustained release test of sustained release particles containing permethrin>
The emulsions of Comparative Example 9 and Examples 33 and 34 were diluted with deionized water to prepare emulsions having a permethrin concentration of 6%.

  Next, two circular filter papers (Toyo filter paper No. 5C, equivalent to 5 types C in JIS P 3801) were stacked and folded. Next, 1.0 mL of each prepared emulsion of permethrin having a concentration of 6% was 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 permethrin 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.

<Sustained release test of sustained release particles containing cyfluthrin>
The cyfluthrin sustained release test of Examples 35 and 36 was performed in accordance with the above-described “<Sustained release test of sustained-release particles containing permethrin>”. The result is shown in FIG.

  Emulsions or powders formulated from sustained-release particles can be used for building materials such as exterior materials, interior materials, ceiling materials, floor materials, for example, paints, for example, adhesives, for example, inks, for example, sealing agents. Caulking agents such as paper products such as binders such as resin emulsions such as pulp such as wood materials such as wood products such as plastic products such as films such as textiles, non-wovens, filters Can be applied (or blended).

1 Sustained release particles 2 Core 3 Shell

Claims (12)

A core obtained by miniemulsion polymerization of a core raw material component containing a hydrophobic antibiotic compound and a hydrophobic first polymerizable vinyl monomer, the core obtained by polymerization of the first polymerizable vinyl monomer A core containing a homogeneous phase in which the antibiotic compound is compatible with one polymer;
A shell obtained by continuously supplying a shell raw material component containing a hydrophobic second polymerizable vinyl monomer, supplying an aqueous polymerization initiator solution, and performing seed emulsion polymerization using the core as a seed, the core Sustained-release particles comprising: the shell covering the surface.   The sustained-release particles according to claim 1, wherein the shell raw material component does not substantially contain the antibiotic compound.   The sustained-release particle according to claim 1, wherein the antibiotic compound contains an isothiazoline-based compound.   The sustained-release particle according to claim 3, wherein the isothiazoline-based compound is 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one.   The at least one polymerizable vinyl monomer selected from the group consisting of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer contains a polymerization-reactive ultraviolet absorber. Sustained release particles. The average particle size of the core is less than 1 μm;
The sustained release particles according to claim 1, wherein the shell is substantially free of the antibiotic compound. A core raw material component containing a hydrophobic antibiotic compound and a hydrophobic first polymerizable vinyl monomer is subjected to miniemulsion polymerization, and the first polymer obtained by polymerization of the first polymerizable vinyl monomer is converted into the antibiotic. A core preparation step for preparing a core containing a homogeneous phase in which the active compound is compatible; and
A shell obtained by seed emulsion polymerization using a core as a seed by continuously supplying a shell raw material component containing a hydrophobic second polymerizable vinyl monomer, supplying an aqueous polymerization initiator solution, and covering the core A method for producing sustained-release particles, comprising a shell preparation step of preparing the shell.   The method for producing sustained-release particles according to claim 7, wherein the shell raw material component does not substantially contain the antibiotic compound.   The method for producing sustained-release particles according to claim 7, wherein the antibiotic compound contains an isothiazoline-based compound.   The method for producing sustained-release particles according to claim 9, wherein the isothiazoline-based compound is 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one.   The sustained-release property according to claim 7, wherein the supply of the shell raw material component to the emulsion containing the core is started when the conversion rate of the miniemulsion polymerization is 95% or more. Particle production method.   The at least one polymerizable vinyl monomer selected from the group consisting of the first polymerizable vinyl monomer and the second polymerizable vinyl monomer contains a polymerization-reactive ultraviolet absorber. A method for producing sustained-release particles.

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