WO2012124598A1 - 徐放性粒子 - Google Patents

徐放性粒子 Download PDF

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WO2012124598A1
WO2012124598A1 PCT/JP2012/055968 JP2012055968W WO2012124598A1 WO 2012124598 A1 WO2012124598 A1 WO 2012124598A1 JP 2012055968 W JP2012055968 W JP 2012055968W WO 2012124598 A1 WO2012124598 A1 WO 2012124598A1
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Prior art keywords
suspension
polymer
vinyl monomer
polymerizable vinyl
meth
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French (fr)
Japanese (ja)
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大島　純治
杉山　孝之
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Japan Enviro Chemicals Ltd
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Japan Enviro Chemicals Ltd
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Priority to CN2012800126121A priority Critical patent/CN103415207A/zh
Priority to US14/003,271 priority patent/US9511030B2/en
Publication of WO2012124598A1 publication Critical patent/WO2012124598A1/ja
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
    • A01N25/28—Microcapsules or nanocapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to sustained-release particles, and more particularly to sustained-release particles for sustained release of an antibiotic compound.
  • antibiotic active compounds such as bactericides, preservatives, and fungicides are microencapsulated to gradually release the antibiotic active compounds to ensure sustained efficacy.
  • a microcapsule containing a microbial growth inhibitor obtained by blending and dispersing an oil phase containing a microbial growth inhibitor and a polyisocyanate component and an aqueous phase containing an active hydrogen group-containing component and interfacial polymerization has been proposed.
  • an oil phase containing a microbial growth inhibitor and a polyisocyanate component and an aqueous phase containing an active hydrogen group-containing component and interfacial polymerization has been proposed.
  • An object of the present invention is to provide sustained-release particles having excellent sustained-release properties.
  • the present inventors have provided a core containing an antibiotic compound present in the first polymer and a shell made of the second polymer. As a result of finding the knowledge that it is excellent in sustained release and further researching it, the present invention has been completed.
  • the present invention (1) formed by suspension polymerization of a core raw material component containing an antibiotic compound and a first polymerizable vinyl monomer, the first polymer of the first polymerizable vinyl monomer, and the first heavy Formed by suspension polymerization of a core containing an antibiotic compound present in the coalescence and a second polymerizable vinyl monomer having an affinity for water equal to or higher than that of the first polymerizable vinyl monomer, A sustained-release particle comprising a second polymer obtained from a second polymerizable vinyl monomer, and a shell covering the core.
  • FIG. 1 shows an image processing diagram of a TEM photograph of sustained-release particles of Example 4.
  • the sustained release particles (1) of the present invention include a core (2) and a shell (3) covering the core (2).
  • the core (2) has a substantially spherical shape and contains a first polymer and an antibiotic compound.
  • the shell (3) is formed in a film shape covering the surface of the core (2) and contains the second polymer.
  • the shell (3) is formed along the outer periphery of the core (2) and has a relatively smooth surface.
  • the core (2) is formed by suspension polymerization of a core raw material component containing an antibiotic compound and a first polymerizable vinyl monomer
  • the shell ( 3) is formed by suspension polymerization of the second polymerizable vinyl monomer.
  • the antibiotic compound has, for example, at least two functional moieties that can interact with the polymer of the first polymerizable vinyl monomer.
  • Examples of such a functional moiety include polar functional groups such as a carbonyl group, a nitro group, an amino group, a cyano group, a phosphate ester group, a carboxyl group, and an ether group, such as a carboxylate bond, a phosphate bond, a urea bond, Examples thereof include a polar bond containing a polar group such as a carbon-halogen bond, for example, a benzene ring, and a conjugated cyclic moiety such as a conjugated heterocycle such as a triazine ring, an imidazole ring, and an isothiazoline ring.
  • polar functional groups such as a carbonyl group, a nitro group, an amino group, a cyano group, a phosphate ester group, a carboxyl group, and an ether group, such as a carboxylate bond, a phosphate bond, a urea bond
  • Examples thereof include a polar bond
  • the molecular weight of the antibiotic compound is, for example, 200 to 600, preferably 200 to 500.
  • the compatibility of the antibiotic compound with the first polymer may decrease.
  • the molecular weight of the antibiotic compound is less than the above range, the antibiotic compound remains in the aqueous phase during suspension polymerization, and the antibiotic compound precipitates after suspension polymerization.
  • the first suspension may solidify.
  • the melting point of the antibiotic compound is, for example, 100 ° C. or less, preferably 90 ° C. or less, and more preferably 80 ° C. or less.
  • the antibiotic compound may not be encapsulated in the core and may be deposited outside the core, and even if the antibiotic compound is encapsulated in the core. However, the antibiotic compound may not be released slowly from the core.
  • the antibiotic compound is an antibacterial agent, antibacterial agent, antiseptic agent, antifungal agent, antifungal agent, insecticide having antibacterial activity such as antibacterial agent, antibacterial agent, antiseptic agent, antialgal agent, antifungal agent and insecticide. Selected from agents, herbicides, attractants, repellents and rodenticides.
  • the compounds having antibiotic activity include bactericidal antiseptic and algal fungicides such as iodine compounds, triazole compounds, carbamoylimidazole compounds, dithiol compounds, isothiazoline compounds, nitroalcohol compounds, and paraoxybenzoic acid esters.
  • anticides such as pyrethroid compounds, neonicotinoid compounds, organochlorine compounds, organophosphorus compounds, carbamate compounds, alkoxyamine compounds, oxadiazine compounds, etc. .
  • iodine compounds include 3-iodo-2-propynylbutylcarbamate (IPBC), 1-[[(3-iodo-2-propynyl) oxy] methoxy] -4-methoxybenzene, 3-bromo-2, And 3-diiodo-2-propenyl ethyl carbonate.
  • triazole compound examples 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.
  • carbamoylimidazole compound examples include N-propyl-N- [2- (2,4,6-trichloro-phenoxy) ethyl] imidazole-1-carboxamide (prochloraz).
  • dithiol-based compound examples include 4,5-dichloro-1,2-dithiol-3-one.
  • isothiazoline-based compound examples include 2-n-octyl-4-isothiazolin-3-one (OIT), 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT), 5- And chloro-2-methyl-4-isothiazolin-3-one (Cl-MIT).
  • OIT 2-n-octyl-4-isothiazolin-3-one
  • DCOIT 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one
  • Cl-MIT 5- And chloro-2-methyl-4-isothiazolin-3-one
  • nitroalcohol compound examples include 2,2-dibromo-2-nitro-1-ethanol (DBNE).
  • paraoxybenzoic acid ester examples include butyl paraoxybenzoate and propyl paraoxybenzoate.
  • pyrethroid compound examples include pyrethrin, cineline, jasmolin and the like obtained from Shirovanamushiyogiiku, and examples thereof include allethrin, bifenthrin, acrinathrin, alpha cypermethrin, tralomethrin, cyfluthrin ((RS) - ⁇ -cyano derived therefrom.
  • neonicotinoid compounds include (E) -N 1 -[(6-chloro-3-pyridyl) methyl] -N 2 -cyano-N 1 -methylacetamidine (acetamipride).
  • organochlorine compounds examples include Kelsen.
  • organophosphorus compounds examples include oxime, pyridafenthion, fenitrothion, tetrachlorbinphos, diclofenthion, propetanephos, and the like.
  • carbamate compounds examples include fenocarb and propoxur.
  • alkoxyamine compound examples include 3-lauryloxypropylamine.
  • Examples of the oxadiazine compound include indoxacarb.
  • insecticide examples include pyriproxyfen.
  • herbicides examples include pyraclonyl, pendimethalin, indanophan and the like.
  • repellents examples include diet.
  • 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.).
  • the solubility at room temperature is 1 part by mass / 100 parts by mass of water (10000 ppm) or less, preferably 0.5 parts by mass / 100 parts by mass of water (5000 ppm) or less, more preferably 0.1 parts by mass / 100 parts by mass of water (1000 ppm) or less, and on a volume basis, for example, 1 g / 100 mL or less of water, preferably 0.5 g / 100 mL or less of water, more preferably 0.1 g / 100 mL of water. It is as follows.
  • the solubility of the antibiotic compound in water exceeds the above range, the suspension of the core raw material component containing the first polymerizable vinyl monomer causes the antibiotic compound to be out of the core (that is, in the aqueous phase). ), 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.
  • antibiotic compounds can be used alone or in combination of two or more.
  • the above-mentioned antibiotic compound may contain, for example, impurities having a melting point outside the above range at an appropriate ratio during the production process.
  • impurities having a melting point outside the above range at an appropriate ratio during the production process.
  • a mixture of isomer I (melting point: 57 ° C.), isomer II (melting point: 74 ° C.) and isomer III (melting point: 66 ° C.) of cyfluthrin is, for example, isomer IV (impurity) Melting point 102 ° C.).
  • the first polymerizable vinyl monomer is a monomer having at least one polymerizable carbon-carbon double bond in the molecule, for example.
  • the first polymerizable vinyl monomer for example, (meth) acrylic acid ester monomers, (meth) acrylic acid monomers, aromatic vinyl monomers, vinyl ester monomers, maleic acid ester monomers, Examples include vinyl halide monomers and nitrogen-containing vinyl monomers.
  • (meth) acrylic acid ester monomers include methacrylic acid esters and / or acrylic acid esters, and specifically include, for example, methyl (meth) acrylate, ethyl (meth) acrylate, and (meth) acrylic.
  • (Meth) acrylic acid alkyl ester which is a chain or branched aliphatic group
  • a (meth) acrylic acid cycloalkyl ester in which an alkyl moiety such as cyclopentyl (meth) acrylate, cyclohexyl (meth) acrylate, or cycloheptyl (meth) acrylate is a cyclic aliphatic group having 3 to 20 carbon atoms is used.
  • an alkyl moiety such as cyclopentyl (meth) acrylate, cyclohexyl (meth) acrylate, or cycloheptyl (meth) acrylate is a cyclic aliphatic group having 3 to 20 carbon atoms
  • (meth) acrylic acid alkyl ester in which the alkyl moiety is a linear or branched aliphatic group having 1 to 6 carbon atoms (preferably 1 to 3 carbon atoms or 4 to 6 carbon atoms) is mentioned.
  • a (meth) acrylic acid ester-based monomer a hydroxyl group-containing (meth) acrylic acid alkyl ester having a hydroxyalkyl moiety having 2 to 10 carbon atoms in which the hydrogen atom of the alkyl moiety is substituted with a hydroxyl group in the above-described monomer Specifically, for example, 2-hydroxyethyl (meth) acrylate, 3-hydroxypropyl (meth) acrylate, 4-hydroxybutyl (meth) acrylate, 6-hydroxyhexyl (meth) acrylate Etc.
  • a hydroxyl group-containing (meth) acrylic acid alkyl ester having a hydroxyalkyl moiety in which the acrylic moiety has 2 to 6 carbon atoms (preferably 2 to 3 carbon atoms) is used.
  • Examples of the (meth) acrylic acid monomer include methacrylic acid and acrylic acid.
  • aromatic vinyl monomer examples include styrene, 4-chlorostyrene, p-methylstyrene, o-methylstyrene, ⁇ -methylstyrene, and the like.
  • vinyl ester monomers examples include vinyl acetate and vinyl propionate.
  • maleate ester monomers examples include dimethyl maleate, diethyl maleate, and dibutyl maleate.
  • Examples of the vinyl halide monomer include vinyl chloride and vinyl fluoride.
  • Examples of the vinyl halide monomer include vinylidene halide monomers, and specific examples include vinylidene chloride and vinylidene fluoride.
  • nitrogen-containing vinyl monomer examples include (meth) acrylonitrile, N-phenylmaleimide, vinylpyridine, and the like.
  • the first polymerizable vinyl monomer is, for example, substantially hydrophobic and specifically has, for example, extremely low solubility in water at room temperature. More specifically, the solubility at room temperature is, for example, 10 masses. Parts / 100 parts by weight or less of water, preferably 8 parts by weight / 100 parts by weight or less of water.
  • an antibiotic compound compatible with an antibiotic compound having a strong compatibility with an antibiotic compound and capable of dissolving (compatible) the antibiotic compound (hereinafter simply referred to as “compatible”). May be referred to as a monomer).
  • These compatible monomers can be used alone or in combination of two or more.
  • the compatible monomer is preferably a combined use of a (meth) acrylic acid ester monomer and a (meth) acrylic acid monomer.
  • MMA methyl methacrylate
  • MA methacrylic acid
  • IBMA isobutyl methacrylate
  • MA methacrylic acid
  • the blending ratio of the (meth) acrylic acid monomer is, for example, 30 masses with respect to 100 parts by mass of the compatible monomer. Less than 20 parts by weight, preferably 20 parts by weight or less, for example 1 part by weight or more, preferably 3 parts by weight or more.
  • the antibiotic compound and the compatible monomer are preferably compatible with each other at the polymerization temperature (heating temperature) described later, and the first polymer which is a polymer of the first polymerizable vinyl monomer and the antibiotic compound. A combination is selected.
  • the first polymerizable vinyl monomer can also contain a crosslinkable monomer as a compatible monomer.
  • the crosslinkable monomer is blended as necessary in order to adjust the sustained release property of the sustained release particles.
  • mono- or polyethylene glycol di (meth) such as ethylene glycol di (meth) acrylate and diethylene glycol di (meth) acrylate.
  • Acrylates for example alkanediol di (meth) acrylates such as 1,3-propanediol di (meth) acrylate, 1,4-butanediol di (meth) acrylate, 1,5-pentanediol di (meth) acrylate, for example , Alkane polyol poly (meth) acrylates such as trimethylolpropane tri (meth) acrylate, pentaerythritol tetra (meth) acrylate, for example, allyl monomers such as allyl (meth) methacrylate, triallyl (iso) cyanurate, Eg to such divinyl monomers such as divinylbenzene.
  • mono or polyethylene glycol di (meth) acrylate is used.
  • the crosslinkable monomer has a molecular structure similar to the molecular structure of the compatible monomer excluding the crosslinkable monomer in order to ensure the compatibility between the monomer mixture containing the crosslinkable monomer (first polymerizable vinyl monomer) and the antibiotic compound.
  • the compatible monomer excluding the crosslinkable monomer contains a (meth) acrylic acid ester monomer, mono- or polyethylene glycol di (meth) acrylate as the crosslinkable monomer Is selected.
  • the blending ratio of the crosslinkable monomer is, for example, 1 to 100 parts by weight, preferably 5 to 90 parts by weight, and more preferably 10 to 80 parts by weight with respect to 100 parts by weight of the compatible monomer excluding the crosslinkable monomer. is there.
  • the dipole force term ⁇ p compound of the solubility parameter ⁇ defined by Hansen and calculated by the van Krevelen and Hoftyzer method is, for example, 2 To 8 [(J / cm 3 ) 1/2 ]
  • the hydrogen bonding term ⁇ h compound of the solubility parameter ⁇ is, for example, 5.0 to 9.5 [(J / cm 3 ) 1/2 ].
  • first polymer of the solubility parameter ⁇ is, for example, 4 to 7 [(J / cm 3 ) 1/2 ], and the hydrogen bond strength of the solubility parameter ⁇ term [delta] h, first polymer, for example, the first polymerizable Binirumo for generating a first polymer which is 8 ⁇ 10 [(J / cm 3) 1/2] The combination of the mer is selected.
  • the subscript compound, first polymer, and second polymer of each term ⁇ indicate an antibiotic compound, a first polymer, and a second polymer, respectively.
  • the dipole force term ⁇ p and the hydrogen bond force term ⁇ h of the solubility parameter ⁇ defined by Hansen and calculated by the van Krevelen and Hoftyzer method are the type and number of atomic groups (including chemical bonds or substituents). Specifically, it is represented by the following formulas (1) and (2), respectively.
  • F p is a dipole force element of intermolecular force (polar component of the molar attraction function), and V is a molar volume.)
  • the F p of the substituents> Si ⁇ , ⁇ N— and ⁇ C— is also calculated by the same calculation process as described above.
  • E h of the substituents —I,> Si ⁇ , ⁇ N—, and ⁇ C— are also calculated by performing the same calculation processing as described above.
  • the above calculation processing is recorded on a computer as a program and optimized.
  • n represents the degree of polymerization.
  • ⁇ p Dipole force term
  • PMMA In the monomer unit (—CH 2 —C (CH 3 ) COOCH 3 —) of the above formula (3), F p and V corresponding to each atomic group are described below.
  • the above-described monomer unit dipole force term ⁇ p, monomer unit is the polymethyl methacrylate dipole force term ⁇ p, PMMA which is a repeating structure of the monomer unit.
  • Hydrogen bond strength term ⁇ h, PMMA In the monomer unit (—CH 2 —C (CH 3 ) COOCH 3 —) of the above formula (3), E h corresponding to each atomic group is described below.
  • the hydrogen bond strength term ⁇ h, first polymer of the monomer unit described above is used as the hydrogen bond strength term ⁇ h, PMMA of polymethyl methacrylate which is a repeating structure of the monomer unit. 2.
  • Co-dipole force term ⁇ p and hydrogen bond force term ⁇ h of the copolymer Next, a dipole force term ⁇ p and a hydrogen bond force term ⁇ h of the copolymer are calculated.
  • the dipole force term ⁇ p, monomer unit of each monomer unit by the monomer mass ratio and adding them together the dipole force term ⁇ p, copolymer of the solubility parameter ⁇ of the copolymer is calculated.
  • the hydrogen bond strength term ⁇ h, copolymer of the solubility parameter ⁇ of the copolymer is calculated by multiplying the hydrogen bond strength term ⁇ h, monomer unit of each monomer unit by the monomer mass ratio and adding them together. To do.
  • the copolymer a copolymer of monomers containing methyl methacrylate, methacrylic acid and ethylene glycol dimethacrylate in a mass ratio of 75: 12.5: 12.5 (corresponding to the mass ratio of Example 1 described later).
  • the force term ⁇ h , PMMA-PMA-EGDMA is calculated.
  • Dipole force term ⁇ p, PMMA-PMA-EGDMA The dipole force term ⁇ p, MMA unit of the monomer unit of methyl methacrylate is 5.98 [(J / cm 3 ) 1/2 ] as calculated above.
  • the dipole force term ⁇ p, MA unit of the monomer unit of methacrylic acid is 7.36 [(J / cm 3 ) 1/2 ] by the same calculation as described above.
  • dipole force term ⁇ p, EDGMA of the monomer unit of ethylene glycol dimethacrylate is 5.37 [(J / cm 3 ) 1/2 ] by calculation in the same manner as described above.
  • the dipole force term ⁇ p, PMMA-PMA-EGDMA of this copolymer is calculated as in the following formula (6).
  • Hydrogen bond strength term ⁇ h, PMMA-PMA-EGDMA The hydrogen bond term ⁇ h, MMA unit of the monomer unit of methyl methacrylate is 9.25 [(J / cm 3 ) 1/2 ].
  • the hydrogen bond term ⁇ h, MA unit of the monomer unit of methacrylic acid is 10.25 [(J / cm 3 ) 1/2 ].
  • the hydrogen bond term ⁇ h, EGDMA of the monomer unit of ethylene glycol dimethacrylate is 10.42 [(J / cm 3 ) 1/2 ].
  • the hydrogen bonding force term ⁇ h, PMMA-PMA-EGDMA of this copolymer is calculated as in the following formula (7).
  • the dipole force term ⁇ p, first polymer of the solubility parameter ⁇ of the first polymer is preferably 4.25 to 6.5 [(J / cm 3 ) 1/2 ], and the first weight
  • the hydrogen bond strength term ⁇ h, first polymer of the solubility parameter ⁇ of the coalescence is preferably 8.25 to 10 [(J / cm 3 ) 1/2 ].
  • 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 will leak out of the core during suspension polymerization, and the antibiotic compound In some cases, it may be difficult to synthesize sustained-release particles sufficiently encapsulating.
  • first 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 the compatibility can be obtained, the free energy of the interface with the aqueous phase in suspension polymerization is reduced, and the antibiotic compound is During suspension polymerization, it may leak out of the core, making it difficult to synthesize a core sufficiently containing an antibiotic compound. 3.
  • Dipole force term ⁇ p, compound and hydrogen bond term ⁇ h, compound of solubility ⁇ of antibiotic compound The dipole force term ⁇ p, compound and the hydrogen bond term ⁇ h, compound of the solubility ⁇ of the antibiotic compound are also calculated in the same manner as the monomer unit described above.
  • the dipole force term ⁇ p, compound of the solubility parameter ⁇ of the antibiotic compound is preferably 3-7 [(J / cm 3 ) 1/2 ], and the hydrogen bond force term ⁇ h, compound is Preferably, it is 5.8 to 9.5 [(J / cm 3 ) 1/2 ].
  • the dipolar force term ⁇ p, compound and / or the hydrogen bond force term ⁇ 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 cannot be obtained.
  • the difference between the dipole force terms ⁇ p of the solubility parameter ( ⁇ p1 ) and the difference between the hydrogen bond force terms ⁇ h ( ⁇ h1 ) Further, the solubility parameter [delta], the value obtained by subtracting the polar term [delta] p, Compound of the antibiotic compound from polar term [delta] p, first Polymer first polymer ⁇ p1 ( ⁇ p, first polymer ⁇ p, compound ) is, for example, ⁇ 2.5 to 3.0 [(J / cm 3 ) 1/2 ], preferably ⁇ 1.1 to 2.7 [(J / cm 3 ) 1 / 2 ], more preferably 0 to 2.6 [(J / cm 3 ) 1/2 ].
  • ⁇ p1 and ⁇ h1 are within the above-described ranges, excellent compatibility of the antibiotic compound and the first polymer can be ensured, and excellent sustained release can be ensured.
  • the dipole force term ⁇ p, compound and hydrogen bond force term ⁇ h, compound of the antibiotic compound are within the above ranges, and the dipole force term ⁇ p, first polymer and hydrogen of the first polymer If the binding force term ⁇ h, first polymer is within the above range, the antibiotic compound is defined as being compatible with the first polymer without leaking from the core during suspension polymerization.
  • the ratio of the antibiotic compound to the first polymerizable vinyl monomer is, for example, 10/90 to 90/10 on a mass basis (that is, the mass part of the antibiotic compound / the mass part of the first polymerizable vinyl monomer). That is, 0.11 to 9.0), and preferably 10/90 to 70/30 (that is, 0.11 to 2.33).
  • the second polymerizable vinyl monomer has a higher affinity for water (that is, hydrophilicity) than the first polymerizable vinyl monomer (specifically, compatible monomer), and specifically, the first polymerizable property described above.
  • Examples thereof include monomers similar to vinyl monomers and having a high affinity for water.
  • the second polymerizable vinyl monomer is preferably a (meth) acrylic acid ester monomer, and more preferably a hydroxyl group-containing (meth) acrylic acid alkyl ester or (meth) acrylic acid alkyl ester.
  • a hydroxyl group-containing (meth) acrylic acid alkyl ester specifically, a hydroxyl group-containing (meth) acrylate alkyl having a hydroxyalkyl moiety having 2 to 3 carbon atoms. Ester) alone, (meth) acrylic acid alkyl ester (specifically, (meth) acrylic acid alkyl ester having an alkyl moiety having 1 to 3 carbon atoms), or a combination of these two types. It is done.
  • the first polymerizable vinyl monomer may be, for example, A combination of 4 to 6 (meth) acrylic acid alkyl ester and (meth) acrylic acid-based monomer, preferably a combination of 4 (meth) acrylic acid alkyl ester and methacrylic acid is selected.
  • the first polymerizable vinyl monomer may be, for example, 4 to 4 carbon atoms.
  • a combination of 6 (meth) acrylic acid alkyl esters and (meth) acrylic acid monomers, preferably a combination of 4 (meth) acrylic acid alkyl esters and methacrylic acid is selected.
  • a hydroxyl group-containing (meth) acrylic acid alkyl ester having a hydroxyalkyl moiety having 2 to 3 carbon atoms and a (meth) acrylic acid alkyl ester having an alkyl moiety having 1 to 3 carbon atoms are provided.
  • the first polymerizable vinyl monomer for example, a combination of a (meth) acrylic acid alkyl ester having 4 to 6 carbon atoms and a (meth) acrylic acid ester monomer, A combination of a meth) acrylic acid alkyl ester and methacrylic acid is used in combination.
  • the dipole force term ⁇ p, second polymer of the second polymer that is a polymer of the second polymerizable vinyl monomer is, for example, 5.0 to 9.0 [(J / cm 3 ) 1/2 ]. Preferably, it is 6.5 to 8.0 [(J / cm 3 ) 1/2 ], and the hydrogen bond term ⁇ h, second polymer of the solubility parameter ⁇ of the second polymer is, for example, 8.0. To 20.0 [(J / cm 3 ) 1/2 ], preferably 12.0 to 18.0 [(J / cm 3 ) 1/2 ].
  • the hydrophilicity of the second polymer becomes excessively high and forms a shell. In some cases, the second polymer that swells due to water or water absorption cannot maintain the shape of the shell.
  • the dipole force term ⁇ p, second polymer and / or the hydrogen bond force term ⁇ h, second polymer of the second polymer is less than the above range, the hydrophilicity of the second polymer becomes insufficient, and the shell However, the effect of the barrier layer described later cannot be achieved, and the antibiotic active compound may leak out of the shell due to compatibility with the antibiotic active compound.
  • the second polymer has higher affinity (hydrophilicity) for water than the first polymer.
  • the second polymerizable vinyl monomer is defined as having higher affinity for water (hydrophilicity) than the first polymerizable vinyl monomer.
  • the core raw material component containing the antibiotic compound and the first polymerizable vinyl monomer is subjected to suspension polymerization.
  • the core raw material component is prepared as a hydrophobic solution containing an antibiotic compound and a first polymerizable vinyl monomer.
  • the antibiotic compound is dissolved in the first polymerizable vinyl monomer (or compatible with the first polymerizable vinyl monomer) in the absence of a solvent.
  • an initiator is preferably added to the hydrophobic solution.
  • the initiator is an oil-soluble radical polymerization initiator.
  • the radical polymerization initiator include dilauroyl peroxide (10 hour half-life temperature T 1/2 : 61.6 ° C.), 1,1,3, 3-tetramethylbutylperoxy-2-ethylhexanoate (10-hour half-temperature T 1/2 : 65.3 ° C.), t-hexylperoxy-2-ethylhexanoate (10-hour half-temperature T 1/2 2 : 69.4 ° C.), diisopropyl peroxydicarbonate (10-hour half-life temperature T 1/2 : 40.5 ° C.), benzoyl peroxide (10-hour half-life temperature T 1/2 : 73.6 ° C.), etc.
  • peroxides for example, 2,2'-azobisisobutyronitrile (10 hours half-life temperature T 1/2: 60 ° C.), 2,2'-azobis (2,4-dimethylvaleronitrile) (10 hours half Degrees T 1/2: 51 °C), 2,2'- azobis (2-methylbutyronitrile) (10 hours half-life temperature T 1/2: 67 ° C.), and the like azo compounds such as.
  • an organic peroxide is used.
  • the mixing ratio of the initiator is, for example, 0.01 parts by mass or more, preferably 0.1 parts by mass or more, more preferably 1 part by mass or more, particularly preferably 100 parts by mass of the first polymerizable vinyl monomer. Is 2.0 parts by mass or more, and usually, for example, 10 parts by mass or less.
  • the mixing ratio of the initiator is not less than the above lower limit value, the conversion rate of the second polymerizable vinyl monomer in the suspension polymerization described below can be increased.
  • the initiator is blended at the same time as or before or after the blending of the antibiotic compound and the first polymerizable vinyl monomer.
  • the initiator is dissolved simultaneously when the antibiotic compound is dissolved in the first polymerizable vinyl monomer.
  • the preparation of the hydrophobic solution may be performed at room temperature, for example, or may be performed by heating to 30 to 100 ° C. as necessary.
  • the hydrophobic solution is prepared at room temperature without heating.
  • hydrophobic solution is suspended (dispersed in water).
  • the hydrophobic solution and water are mixed, and the hydrophobic solution is suspended by stirring uniformly. As a result, a first suspension in which the hydrophobic solution is suspended is obtained.
  • the suspension conditions are not particularly limited, and may be carried out at room temperature, for example, or may be carried out by heating at 30 to 100 ° C., for example. Preferably, suspension is performed without heating from the viewpoint of suppressing thermal decomposition of the initiator.
  • the mixing ratio of water is, for example, 10 to 1000 parts by mass, preferably 50 to 500 parts by mass with respect to 100 parts by mass of the hydrophobic solution.
  • a dispersant is blended in the suspension of the hydrophobic solution.
  • dispersant examples include polyvinyl alcohol (PVA, including partially saponified polyvinyl alcohol), polyvinyl pyrrolidone, gelatin, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cationized starch, polyacrylic acid and salts thereof.
  • PVA polyvinyl alcohol
  • polyvinyl pyrrolidone polyvinyl pyrrolidone
  • gelatin gum arabic
  • hydroxyethyl cellulose hydroxypropyl cellulose
  • carboxymethyl cellulose cationized starch
  • polyacrylic acid and salts thereof examples include polyacrylic acid and salts thereof.
  • water-soluble polymers such as styrene-maleic acid copolymers and salts thereof, for example, inorganic dispersants such as tricalcium phosphate, colloidal silica, montmorillonite, magnesium carbonate, aluminum hydroxide and zinc white.
  • inorganic dispersants are preferable, and tricalcium phosphate is more preferable. If it is tricalcium phosphate, when the obtained sustained release particles are formulated as a powder (described later) or granules (described later), the redispersibility of the powder or granules is improved, Occurrence of caking can be prevented.
  • the blending ratio of the dispersing agent is, for example, 0.1 to 20 parts by mass, preferably 0.1 to 15 parts by mass with respect to 100 parts by mass of the hydrophobic solution.
  • a surfactant when suspending the hydrophobic solution, a surfactant can be used in combination with the above-described dispersant.
  • Surfactant is blended in order to effectively prevent core aggregation during suspension polymerization.
  • examples of the surfactant include sodium dodecylbenzene sulfonate (DBN), sodium lauryl sulfate, sodium di-2-ethylhexyl sulfosuccinate, sodium dodecyl diphenyl ether disulfonate, sodium nonyl diphenyl ether sulfonate, sodium polyoxyethylene alkyl ether sulfate.
  • DBN sodium dodecylbenzene sulfonate
  • sodium lauryl sulfate sodium di-2-ethylhexyl sulfosuccinate
  • sodium dodecyl diphenyl ether disulfonate sodium nonyl diphenyl ether sulfonate
  • sodium polyoxyethylene alkyl ether sulfate sodium polyoxyethylene alkyl ether sulfate.
  • Anionic surfactants such as polyoxyethylene alkyl ether ammonium phosphate, sodium naphthalene sulfonic acid formaldehyde condensate sodium salt, sodium dialkyl sulfosuccinate, such as polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene mono Stearate, polyoxyethylene sorbitan monooleate, polyoxyethylene poly Carboxymethyl propylene block copolymers, and nonionic surfactants such as polyoxyethylene phosphoric acid ester.
  • a nonionic surfactant is used.
  • the blending ratio of the surfactant is, for example, 0.0001 to 1.0 part by mass, preferably 0.001 to 0.1 part by mass with respect to 100 parts by mass of the hydrophobic solution.
  • the dispersant and the surfactant can be blended, for example, before or after blending the hydrophobic solution and water.
  • the dispersant and surfactant are preferably blended in the water prior to blending with the hydrophobic solution. Thereby, an aqueous solution of the dispersant and the surfactant is prepared.
  • a homogenizer for example, a homogenizer, a disper, an ultrasonic homogenizer, a pressure type homogenizer, a milder, or a porous membrane press-in disperser is used for suspending the hydrophobic solution.
  • a homomixer is used, and its rotation speed is, for example, 200 to 20000 rpm, preferably 1500 to 15000 rpm.
  • the suspension time (stirring time) of the first suspension is, for example, 20 minutes or less, preferably 3 to 10 minutes.
  • the core raw material component is subjected to suspension polymerization by raising the temperature of the first suspension (first step).
  • the first polymerizable vinyl monomer reacts (specifically, vinyl polymerization) while stirring the first suspension so that the suspension state of the first suspension is maintained.
  • a polymer of the first polymerizable vinyl monomer (first polymer) is produced.
  • the 1st polymeric vinyl monomer used as a raw material exists in a hydrophobic phase (oil phase), it is set as in situ polymerization.
  • the first suspension is heated to a temperature that is higher than 0 ° C. and lower than 30 ° C., preferably 5 to 20 ° C., than the 10-hour half-life temperature T 1/2 of the initiator. Raise the temperature to a higher temperature.
  • the first suspension can also be heated to the same temperature as the 10 hour half-life temperature T 1/2 of the initiator.
  • suspension polymerization starts when the initiator is thermally decomposed at a predetermined temperature in an inert gas atmosphere such as nitrogen.
  • the polymerization temperature in the first step is, for example, 30 to 100 ° C., preferably 40 to 80 ° C., and more preferably 50 to 75 ° C.
  • the pressure during suspension polymerization is not particularly limited and is normal pressure. Alternatively, for example, it can be carried out under high pressure. Preferably, it is carried out at normal pressure.
  • the polymerization time in the first step is, for example, 1 hour or more, preferably 3 hours or more, more preferably 4 hours or more, and usually 10 hours or less.
  • the antibiotic compound is present in the matrix made of the first polymer.
  • the second polymerizable vinyl monomer is subjected to suspension polymerization.
  • the suspension after the reaction is cooled, for example, by cooling or water cooling.
  • the cooling temperature of the first suspension is a temperature at which thermal decomposition of the initiator remaining in the core can be suppressed, and specifically, for example, 50 ° C. or less, preferably 40 ° C. or less, more preferably Is below normal temperature and usually above 5 ° C.
  • the first suspension after the reaction can be subjected to the subsequent suspension polymerization of the second polymerizable vinyl monomer without cooling, for example.
  • the second polymerizable vinyl monomer is blended into the first suspension and reacted.
  • the second polymerizable vinyl monomer is prepared as an emulsion containing the second polymerizable vinyl monomer.
  • the emulsion is prepared by emulsifying the second polymerizable vinyl monomer in water in the presence of an emulsifier.
  • emulsifier examples include the same surfactants as described above, and preferably an anionic surfactant.
  • the blending ratio of the emulsifier is, for example, 0.0001 to 1.0 part by mass, preferably 0.001 to 0.1 part by mass with respect to 100 parts by mass of the emulsion.
  • the emulsifier can be blended, for example, before or after blending the second polymerizable vinyl monomer and water.
  • the emulsifier is preferably blended in water before blending with the second polymerizable vinyl monomer. Thereby, an aqueous solution of the emulsifier is prepared.
  • the blending ratio of the second polymerizable vinyl monomer is, for example, 10 to 1000 parts by mass, preferably 50 to 500 parts by mass with respect to 100 parts by mass of water.
  • the above-described disperser is used for emulsification of the second polymerizable vinyl monomer.
  • a homomixer is used, and the rotation speed thereof is higher than the rotation speed in suspension of the first suspension, and specifically, for example, 200 to 20000 rpm, preferably 1500 to 15000 rpm.
  • a silane coupling agent can be added to the emulsion.
  • a silane coupling agent can also be blended.
  • the silane coupling agent is, for example, an alkoxysilyl compound having at least a vinyl group or a (meth) acryloyl group.
  • a vinyl group-containing alkoxysilyl compound such as vinyltrimethoxysilane or vinyltriethoxysilane.
  • acryloyl group-containing alkoxysilyl compounds are examples of alkoxysilyl compounds.
  • the blending ratio of the silane coupling agent is, for example, 0.01 to 10 parts by mass, preferably 0.1 to 1 part by mass with respect to 100 parts by mass of the second polymerizable vinyl monomer.
  • the preparation of the emulsion may be carried out, for example, at room temperature, or may be carried out, for example, by heating to 30 to 100 ° C. as necessary.
  • the emulsion is prepared at room temperature without heating.
  • the emulsification time is, for example, 20 minutes or less, preferably 3 to 20 minutes.
  • the prepared emulsion is blended with the first suspension, and they are agitated to prepare a second suspension.
  • the above-mentioned disperser is used for the preparation of the second suspension described above.
  • a homomixer is used, and the number of revolutions thereof is, for example, 200 to 20000 rpm, preferably 1500 to 15000 rpm.
  • the suspension time (stirring time) of the second suspension is, for example, 0.1 hour or more, preferably 1 hour or more, from the viewpoint of sufficiently adsorbing the second polymerizable vinyl monomer to the surface of the core. More preferably, it is 2 hours or more, and usually 10 hours or less.
  • the second polymerizable vinyl monomer in the emulsion is attached (absorbed) to the core made of the first polymer.
  • the second polymerizable vinyl monomer is subjected to suspension polymerization by raising the temperature of the second suspension (second step).
  • the second suspension is at a temperature higher than the 10 hour half-temperature T 1/2 of the initiator, for example, more than 0 ° C. and not more than 30 ° C., preferably, The temperature is raised to a temperature 5 to 20 ° C higher.
  • the second suspension can also be heated to the same temperature as the 10 hour half-life temperature T 1/2 of the initiator.
  • suspension polymerization starts when the remaining initiator is thermally decomposed at a predetermined temperature, for example, in an inert gas atmosphere such as nitrogen.
  • the polymerization temperature in the second step is the same as the polymerization temperature in the first step.
  • the pressure during suspension polymerization of the second suspension is not particularly limited and is normal pressure. Alternatively, for example, it can be carried out under high pressure. Preferably, it is carried out at normal pressure.
  • the polymerization time in the second step is, for example, 0.1 hour or more, preferably 1 hour or more, more preferably 2 hours or more, and usually 10 hours or less.
  • the second polymerizable vinyl monomer reacts with stirring the second suspension so that the suspension state of the second suspension is maintained, and the second polymerizable vinyl monomer is reacted.
  • a coalescence (second polymer) is produced.
  • the core is covered by suspension polymerization of the second polymerizable vinyl monomer to form a shell made of the second polymer.
  • the second suspension is cooled, for example, by cooling or water cooling.
  • the cooling temperature is, for example, room temperature (20 to 30 ° C., more specifically 25 ° C.).
  • the antibiotic compound is present in the first polymer in the core.
  • the compatible state is frozen in the matrix composed of the first polymer in the core, and the uniform state is maintained.
  • the antibiotic compound is liquid at room temperature, it is compatible with the first polymer in the core (2), as shown in FIG.
  • a suspension containing sustained release particles (1) having a core (2) and a shell (3) can be obtained.
  • the particle diameter of the sustained-release particles is not particularly limited, and is an average particle diameter (median diameter), for example, 1 ⁇ m to 1 mm, preferably 2 ⁇ m to 100 ⁇ m.
  • the particle diameter of the core is an average particle diameter (median diameter), for example, 1 to 1000 ⁇ m, preferably 2 to 50 ⁇ m.
  • the thickness of the shell is a maximum thickness, for example, 0.01 to 500 ⁇ m, preferably 0.05 to 50 ⁇ m.
  • the particle diameter of the core and the thickness of the shell are calculated from a TEM photograph of the obtained sustained release particles.
  • the particle diameter of a core can also be measured by taking out the particle
  • sustained-release particles comprising a core containing an antibiotic compound and a shell covering the core are suspended.
  • the sustained-release particles thus obtained may be used as they are (suspension), that is, as a suspending agent, and after solid-liquid separation by filtration and / or centrifugation, for example, Alternatively, it may be formulated into a known dosage form such as powder or granule. Further, if necessary, water washing and / or acid washing can be performed. Furthermore, the suspension can be spray-dried or air-dried as it is to form a dosage form such as a powder or granule.
  • the solid concentration (sustained release particle concentration) in the suspension is, for example, 1 to 50% by mass, and preferably 5 to 40% by mass.
  • the concentration of the antibiotic compound in the suspension is, for example, 0.5 to 40% by mass, preferably 1 to 25% by mass.
  • the powder is excellent in fluidity especially when tribasic calcium phosphate is used as a dispersant. Moreover, an aqueous dispersion or suspension can be re-prepared by dispersing or suspending the powder again in water. Therefore, such a powder is excellent in re-water dispersibility or re-suspension.
  • sustained-release particles as a powder at the time of transportation, and preparing (re-formulation, regeneration) as an aqueous dispersion or suspension at the time of use. Can be enlarged.
  • the antibiotic active compound comprises a core present in the first polymer obtained from the first polymerizable vinyl monomer, and the second polymer, Since it is provided with a shell formed so as to be coated, by suppressing the release rate of the antibiotic compound, it has an excellent sustained release property and can exhibit an excellent effect sustaining effect.
  • the sustained release property is a property capable of slowly releasing the encapsulated compound.
  • the emulsion contains a silane coupling agent
  • a silanol group derived from the silane coupling agent is present in the shell, and the silanol group is an inorganic substance (specifically, a metal , Metal oxides and the like) and organic substances (specifically, cellulose and the like forming paper and wood). Therefore, when the sustained-release particles are used after being added (blended) to paints, sealants, adhesives, etc., the sustained-release particles can be chemically bonded to the above-mentioned base material, and antibiotics for a long time The activity can be maintained.
  • the second polymerizable vinyl monomer has been described as having a higher affinity for water than the first polymerizable vinyl monomer.
  • the second polymerizable vinyl monomer has an affinity for water.
  • the properties may be substantially the same as the first polymerizable vinyl monomer.
  • the affinity of the second polymerizable vinyl monomer for water is substantially the same as the affinity of the first polymerizable vinyl monomer for water.
  • a second polymerizable vinyl monomer is: It is hydrophobic.
  • Examples of such second polymerizable vinyl monomer include (meth) acrylic acid alkyl esters, and preferably (meth) acrylic acid alkyl esters having an alkyl moiety having 1 to 3 carbon atoms, which are used alone.
  • the first polymerizable vinyl monomer is, for example, a combination of a (meth) acrylic acid alkyl ester having 1 to 3 carbon atoms and a (meth) acrylic acid monomer, preferably a (meth) acrylic having 1 carbon atom.
  • a combination of an acid alkyl ester (specifically methyl (meth) acrylate) and methacrylic acid is selected.
  • the dipole force term ⁇ p, second polymer of the second polymer which is such a polymer of the second polymerizable vinyl monomer is, for example, 5.0 or more and 6.5 [(J / cm 3 ) 1/2. ], Preferably 5.5 to 6.5 [(J / cm 3 ) 1/2 ], and the hydrogen bond strength term ⁇ h of the second polymer, which is a polymer of the second polymerizable vinyl monomer ,
  • the second polymer is, for example, 8.0 [(J / cm 3 ) 1/2 ] or more and less than 13.0 [(J / cm 3 ) 1/2 ], preferably 9.0 to 11.0 [(J / Cm 3 ) 1/2 ].
  • a value ⁇ p2 obtained by subtracting the dipole force term ⁇ p, first polymer of the first polymer from the dipole force term ⁇ p, second polymer of the second polymer is, for example, ⁇ 0.5 [(J / Cm 3 ) 1/2 ] or more, less than 2.0 [(J / cm 3 ) 1/2 ], -0.2 to 1.0 [(J / cm 3 ) 1/2 ], and also , ⁇ 0.1 to 0.0 [(J / cm 3 ) 1/2 ].
  • a value ⁇ h2 obtained by subtracting the hydrogen bond strength term ⁇ h, first polymer of the first polymer from the hydrogen bond strength term ⁇ h, second polymer of the second polymer is, for example, ⁇ 2.0 [(J / cm 3 ) 1/2 ] or more and less than 2.0 [(J / cm 3 ) 1/2 ], further ⁇ 0.5 to 1.0 [(J / cm 3 ) 1/2 ], or 0.3 to 0.0 [(J / cm 3 ) 1/2 ].
  • the affinity of the second polymer for water is defined as substantially the same as the affinity of the first polymer for water.
  • the hydrophobicity of the second polymerizable vinyl monomer is substantially the same as the hydrophobicity of the first polymerizable vinyl monomer.
  • the affinity of the second polymerizable vinyl monomer to water is higher than that of the first polymerizable vinyl monomer, it is preferable to use an antibiotic compound that is incompatible with the shell. That is, the second polymer that forms the shell is preferably one that is incompatible with the antibiotic compound.
  • the shell (3) is a polymer of a second polysynthetic vinyl monomer having a higher affinity for water than for the first polymerizable vinyl monomer ( Second polymer). Therefore, the shell (3) acts as a barrier layer that prevents the antibiotic compound present in the core (2) from leaking out of the sustained release particles (1).
  • the sustained release property of the sustained release particles (1) can be improved, and an even better efficacy sustaining effect can be expressed.
  • the hydrophobic solution was added to a 1000 mL beaker (2).
  • K The suspension was prepared by suspending the hydrophobic solution by stirring for 5 minutes at a rotational speed of 5000 rpm with a homomixer MARK 2.5 (manufactured by PRIMIX).
  • Suspension polymerization was started when the temperature of the suspension reached 65 ° C. during the temperature increase of the suspension, and then the temperature of the suspension was maintained at 70 ° C. for 2 hours.
  • Suspension polymerization was started when the temperature of the suspension reached 65 ° C. during the temperature increase of the suspension, and then the temperature of the suspension was maintained at 70 ° C. for 3 hours.
  • Example 2 (Formulation of suspension containing OIT-containing sustained release particles) (First step: suspension polymerization, second step: suspension polymerization) Except that 30.0 g of methyl methacrylate in the hydrophobic solution was changed to 30.0 g of isobutyl methacrylate, it was treated in the same manner as in Example 1 to provide a sustained release comprising a core containing OIT and a shell covering it. A suspension of suspension particles was obtained.
  • Example 3 (Formulation of suspension containing OIT-containing sustained release particles) (First step: suspension polymerization, second step: suspension polymerization) 30.0 g of methyl methacrylate in the hydrophobic solution was changed to 30.0 g of isobutyl methacrylate, and instead of 40.0 g of methyl methacrylate emulsified in a 200 mL beaker (3), 20.0 g of methyl methacrylate and 2 of methacrylic acid 2 -Suspension of sustained release particles (suspension) comprising a core containing OIT and a shell covering the same, treated in the same manner as in Example 1 except that 20.0 g of hydroxyethyl was charged.
  • First step: suspension polymerization, second step: suspension polymerization 30.0 g of methyl methacrylate in the hydrophobic solution was changed to 30.0 g of isobutyl methacrylate, and instead of 40.0 g of methyl methacrylate emulsified in a 200
  • Example 4 (Formulation of suspension containing OIT-containing sustained release particles) (First step: suspension polymerization, second step: suspension polymerization) 30.0 g of methyl methacrylate in the hydrophobic solution was changed to 30.0 g of isobutyl methacrylate, and instead of 40.0 g of methyl methacrylate emulsified in a 200 mL beaker (3), 40.0 g of 2-hydroxyethyl methacrylate was used. Except for charging, the same treatment as in Example 1 was performed to obtain a suspension (suspension) of sustained-release particles including a core containing OIT and a shell covering the core.
  • Example 5 (Formulation of suspension containing IPBC-containing sustained release particles) (First step: suspension polymerization, second step: suspension polymerization) A core containing IPBC was treated in the same manner as in Example 1 except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of IPBC and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. A suspension (suspension agent) of sustained-release particles comprising a shell covering the same was obtained.
  • Example 6 (Formulation of suspension containing IPBC-containing sustained release particles) (First step: suspension polymerization, second step: suspension polymerization) OIT 60.0 g in the hydrophobic solution was changed to IPBC 25.0 g, methyl methacrylate 30.0 g was changed to isobutyl methacrylate 65.0 g, and replaced with 40.0 g of methyl methacrylate to be emulsified in a 200 mL beaker (3). A suspension of sustained release particles comprising a core containing IPBC and a shell covering the same, treated in the same manner as in Example 1 except that 40.0 g of 2-hydroxyethyl methacrylate was charged. Suspension) was obtained.
  • Example 7 (Formulation of suspension containing propiconazole-containing sustained-release particles) (First step: suspension polymerization, second step: suspension polymerization) Propiconazole was treated in the same manner as in Example 1 except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of propiconazole and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. Suspension (suspension agent) of sustained-release particles comprising a core containing, and a shell covering the core was obtained.
  • Example 8 (Formulation of suspension containing propiconazole-containing sustained-release particles) (First step: suspension polymerization, second step: suspension polymerization) 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of propiconazole, 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate, and 40.0 g of methyl methacrylate to be emulsified in a 200 mL beaker (3) Instead of 40.0 g of 2-hydroxyethyl methacrylate, a sustained-release particle comprising a core containing propiconazole and a shell covering the same, treated in the same manner as in Example 1 A suspension (suspension agent) was obtained.
  • Example 9 (Formulation of suspension containing flusilazole-containing sustained-release particles) (First step: suspension polymerization, second step: suspension polymerization) A core containing flusilazole was treated in the same manner as in Example 1 except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of flusilazole and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. And a suspension (suspension agent) of sustained-release particles comprising a shell covering the same.
  • Example 10 (Formulation of suspension containing flusilazole-containing sustained-release particles) (First step: suspension polymerization, second step: suspension polymerization) Change 60.0 g of OIT in the hydrophobic solution to 25.0 g of flusilazole, change 30.0 g of methyl methacrylate to 65.0 g of isobutyl methacrylate, and replace with 40.0 g of methyl methacrylate emulsified in a 200 mL beaker (3). A suspension of sustained-release particles comprising a core containing flusilazole and a shell covering the same, except that 40.0 g of 2-hydroxyethyl methacrylate was charged. (Suspending agent) was obtained.
  • Example 11 (Formulation of suspension containing prochloraz-containing sustained-release particles) (First step: suspension polymerization, second step: suspension polymerization) A core containing prochloraz treated in the same manner as in Example 1 except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of prochloraz and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. And a suspension (suspension agent) of sustained-release particles comprising a shell covering the same.
  • Example 12 (Formulation of suspension containing prochloraz-containing sustained-release particles) (First step: suspension polymerization, second step: suspension polymerization) 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of prochloraz, 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate, and replaced with 40.0 g of methyl methacrylate emulsified in a 200 mL beaker (3). A suspension of sustained-release particles comprising a core containing prochloraz and a shell covering the same, except that 40.0 g of 2-hydroxyethyl methacrylate was charged. (Suspending agent) was obtained.
  • Example 13 (Formulation of suspension containing cyfluthrin-containing sustained release particles) (First step: suspension polymerization, second step: suspension polymerization) A core containing cyfluthrin was treated in the same manner as in Example 1 except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of cyfluthrin and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. And a suspension (suspension agent) of sustained-release particles comprising a shell covering the same.
  • Example 14 (Formulation of suspension containing cyfluthrin-containing sustained release particles) (First step: suspension polymerization, second step: suspension polymerization) 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of prochloraz, 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate, and replaced with 40.0 g of methyl methacrylate emulsified in a 200 mL beaker (3). A suspension of sustained-release particles comprising a core containing cyfluthrin and a shell covering the same, except that 40.0 g of 2-hydroxyethyl methacrylate was charged. (Suspending agent) was obtained.
  • Comparative Example 1 (Formulation of suspension containing OIT-containing sustained release particles) (First step: Suspension polymerization) A 200 mL beaker (1) was charged with 60.0 g of OIT, 30.0 g of methyl methacrylate, 5 g of methacrylic acid, 5.0 g of ethylene glycol dimethacrylate and 1.9 g of dilauroyl peroxide and stirred uniformly at room temperature. A hydrophobic solution was prepared.
  • the hydrophobic solution was added to a 1000 mL beaker (2).
  • K The suspension was prepared by dispersing the hydrophobic solution by stirring for 5 minutes at a rotation speed of 5000 rpm with a homomixer MARK 2.5 (manufactured by PRIMIX).
  • Suspension polymerization was started when the temperature of the suspension reached 65 ° C. during the temperature increase of the suspension, and then the temperature of the suspension was maintained at 70 ° C. for 2 hours.
  • Comparative Example 2 (Formulation of suspension containing OIT-containing sustained release particles) (First step: Suspension polymerization) A suspension (suspension) of sustained-release particles containing OIT, which was treated in the same manner as in Comparative Example 1 except that 30.0 g of methyl methacrylate in the hydrophobic solution was changed to 30.0 g of isobutyl methacrylate. Got.
  • Comparative Example 3 (Formulation of suspension containing IPBC-containing sustained release particles) (First step: Suspension polymerization) The controlled release containing IPBC was carried out in the same manner as in Comparative Example 1 except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of IPBC and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. A suspension of suspension particles was obtained.
  • Comparative Example 4 (Formulation of suspension containing propiconazole-containing sustained-release particles) (First step: Suspension polymerization) Propiconazole was treated in the same manner as in Comparative Example 1 except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of propiconazole and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. Suspension (suspension agent) of sustained release particles containing
  • Comparative Example 5 (Formulation of suspension containing flusilazole-containing sustained-release particles) (First step: Suspension polymerization) The same procedure as in Comparative Example 1 was conducted except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of flusilazole and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. A suspension of suspension particles was obtained.
  • Comparative Example 6 (Formulation of suspension containing prochloraz-containing sustained-release particles) (First step: Suspension polymerization) The same procedure as in Comparative Example 1 was carried out except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of prochloraz and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. A suspension of suspension particles was obtained.
  • Comparative Example 7 (Formulation of suspension containing cyfluthrin-containing sustained release particles) (First step: Suspension polymerization) The same procedure as in Comparative Example 1 was carried out except that 60.0 g of OIT in the hydrophobic solution was changed to 25.0 g of cyfluthrin and 30.0 g of methyl methacrylate was changed to 65.0 g of isobutyl methacrylate. A suspension of suspension particles was obtained.
  • Tables 2 to 4 show the prescription of each component in each Example and each Comparative Example.
  • the numerical value of a compounding prescription shows g number in a table
  • Example 4 The suspension (suspension) of Example 4 was freeze-dried, dispersed in a bisphenol-type liquid epoxy resin, and cured with an amine. This was cut with an ultramicrotome to obtain a cross section, stained with osmium tetroxide, and if necessary, stained again with ruthenium tetroxide, and cut into ultrathin sections with an ultramicrotome to prepare a sample. The prepared sample was observed with a transmission electron microscope (model number “H-7100”, manufactured by Hitachi, Ltd.) by TEM.
  • Example 4 An image processing diagram of the TEM photograph of Example 4 is shown in FIG. 2.
  • Sustained release test (1) Sustained release test of OIT-containing sustained release particles (Examples 1 to 4 and Comparative Example 2) According to the following operation, the sustained release test was performed on the OIT-containing sustained release particles of Examples 1 to 4 and Comparative Example 2.
  • the suspension (suspension agent) of the sustained release particles obtained in Examples 1 to 4 and Comparative Example 2 was stirred into a commercially available acrylic styrene emulsion, and the OIT concentration was 0.15% by mass. And continued stirring for 1 hour.
  • the film is dried at 40 ° C. for 24 hours to produce a sustained-release particle-containing film, and then the sustained-release particle-containing film is cut into 7 cm ⁇ 15 cm to produce a test piece. Attached to a weather meter and exposed to continuous rain for 2 weeks.
  • the exposed test piece was cut into 2.5 cm ⁇ 2.5 cm, 10 mL of methanol was added, and OIT was extracted for 30 minutes using an ultrasonic cleaner.
  • the amount of OIT extracted as described above was measured using HPLC, and the residual rate of OIT of the sustained release particles in the sustained release particle-containing film was calculated from the unexposed test piece and the exposed test piece.
  • each prepared suspension was slowly added to the filter paper, and then air-dried.
  • the sustained release rate of cyfluthrin was calculated using GC from the third ion exchange water / methanol mixture collected as described above. The results are shown in Tables 3 and 4.
  • the sustained-release particles of the present invention are used in various industrial products such as indoor and outdoor paints, rubbers, fibers, resins, plastics, adhesives, jointing agents, sealing agents, building materials, caulking agents, soil treatment agents, wood, papermaking. Can be applied (or formulated) to white water, pigments, printing plate treatment liquid, cooling water, ink, cutting oil, cosmetics, nonwoven fabric, spinning oil, leather, etc. Thus, the efficacy of such an antibiotic compound can be continuously expressed.

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PCT/JP2012/055968 2011-03-11 2012-03-08 徐放性粒子 Ceased WO2012124598A1 (ja)

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JP2016523833A (ja) * 2013-05-17 2016-08-12 スリーエム イノベイティブ プロパティズ カンパニー 重合体複合粒子からの生物活性剤の放出
JP2019059719A (ja) * 2017-09-22 2019-04-18 新中村化学工業株式会社 コアシェル型農薬粒剤組成物及びその製造方法

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CN105085778B (zh) * 2014-04-22 2018-11-16 广东华润涂料有限公司 用于缓释功能成分的涂料组合物用水性胶乳、其制备方法以及应用
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