TW201632063A - Controlled release particles, method for manufacturing the same - Google Patents

Controlled release particles, method for manufacturing the same Download PDF

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TW201632063A
TW201632063A TW105104604A TW105104604A TW201632063A TW 201632063 A TW201632063 A TW 201632063A TW 105104604 A TW105104604 A TW 105104604A TW 105104604 A TW105104604 A TW 105104604A TW 201632063 A TW201632063 A TW 201632063A
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sustained release
core
monomer
compound
polymerization
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鳥巣修一
大島純治
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大阪瓦斯化學股份有限公司
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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
    • A01N25/02—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 containing liquids as carriers, diluents or solvents
    • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
    • 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
    • A01N25/08—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 containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • 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
    • 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
    • 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
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2

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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dentistry (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Agronomy & Crop Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Toxicology (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Polymerisation Methods In General (AREA)

Abstract

This invention controlled provides release particles 1 which include a core2 obtained by miniemulsion polymerization of a core ingredient component containing an antibiotic compound having hydrophobic and a fist polymerizable vinyl monmer having hydrophobic, and containing a homogeneous phase of a first polymer formed by a first polymerizable vinyl monomer and the antibiotic compound present in the first polymer that have compatibility with each other; and a shell 3 obtained by the core 2 is used as a seed in a seed micro-suspension polymerization of a shell ingredient component containing a second polymerizable vinyl monomer, and covering the core 2.

Description

持續釋放性粒子及其製造方法 Sustained release particle and method of producing the same

本發明係有關持續釋放性粒子及其製造方法。 The present invention relates to sustained release particles and a method of producing the same.

以往，持續釋放性粒子係可被使用來作為經過長時間可發揮持續釋放效力之粒子。 In the past, sustained release particle systems can be used as particles which exert a sustained release effect over a long period of time.

例如已提出將防腐防黴劑內包之微膠囊(例如參照下述專利文獻1)。專利文獻1所記載之微膠囊之持續釋放性(殘效性或耐水溶脫性)優越。惟，專利文獻1所記載之微膠囊係有在水分散液中沈降，再分散性(水分散安定性)不充分之不佳情形。 For example, microcapsules in which a preservative and antifungal agent are encapsulated have been proposed (for example, refer to Patent Document 1 below). The microcapsules described in Patent Document 1 are excellent in sustained release property (residuality or water repellency). However, the microcapsules described in Patent Document 1 are inferior in sedimentation in an aqueous dispersion, and the redispersibility (water dispersion stability) is insufficient.

此處，作為在水分散液中不會沈降而水分散安定性優越之持續釋放性粒子，已提出在藉由聚合性乙烯單體之聚合所獲得之聚合物中含有抗生物活性化合物為相溶之均一相，平均粒徑未達1μm之持續釋放性粒子(例如，參照下述專利文獻2)。 Here, as a sustained release particle which does not sediment in an aqueous dispersion and which is excellent in water dispersion stability, it has been proposed that a polymer obtained by polymerization of a polymerizable ethylene monomer contains an antibiotic compound as a compatible one. The uniform release particle having a uniform particle diameter of less than 1 μm (for example, refer to Patent Document 2 below).

[先前技術文獻] [Previous Technical Literature] [專利文獻] [Patent Literature]

專利文獻1：日本特開2006-001188號公報 Patent Document 1: Japanese Laid-Open Patent Publication No. 2006-001188

專利文獻2：國際公開2013//100102號 Patent Document 2: International Publication 2013//100102

近年來對於持續釋放性粒子係要求優越之抗紫外線性及更優越之持續釋放性。 In recent years, superior sustained-release particle systems have required superior UV resistance and superior sustained release properties.

惟，於專利文獻2所提出之持續釋放性粒子，不能充分滿足上述之抗紫外線性及持續釋放性之不佳情形。 However, the sustained-release particles proposed in Patent Document 2 cannot sufficiently satisfy the above-mentioned poor ultraviolet resistance and sustained release property.

本發明之目的為提供一種具有優越之持續釋放性及水分散安定性之外，尚具有優越之抗紫外線性之持續釋放性粒子及其製造方法。 SUMMARY OF THE INVENTION An object of the present invention is to provide a sustained release particle which has excellent ultraviolet repellency in addition to excellent sustained release property and water dispersion stability, and a method for producing the same.

本發明(1)為一種持續釋放性粒子，具備將含有疏水性抗生物活性化合物及疏水性第1聚合性乙烯單體之核芯原料成分藉由微乳化液聚合獲得之核芯，在藉由上述第1聚合性乙烯單體之聚合獲得之第1聚合物中含有抗生物活性化合物為相溶之均一相之核芯；及將含有疏水性第2聚合性乙烯單體之殼層原料成分藉由將上述核芯作為種子之種子乳化聚合獲得之殼層，將上述核芯包覆之殼層。 The present invention (1) is a sustained release particle comprising a core obtained by polymerizing a core material component containing a hydrophobic bioactive compound and a hydrophobic first polymerizable ethylene monomer by a microemulsion, The first polymer obtained by the polymerization of the first polymerizable ethylene monomer contains a core in which the bioactive compound is a compatible homogeneous phase; and the shell material component containing the hydrophobic second polymerizable ethylene monomer is borrowed The shell layer obtained by emulsion-polymerizing the above-mentioned core as a seed of the seed is coated with the core.

本發明(2)為如(1)所述之持續釋放性粒子，其中，上述殼層原料成分為實質上不含有上述抗生物活性化合物。 The present invention (2) is the sustained release particle according to (1), wherein the shell raw material component does not substantially contain the antibiotic active compound.

本發明(3)為如(1)或(2)所述之持續釋放性粒 子，其中，上述抗生物活性化合物以漢森(Hansen)定義，以Van Krevelen and Hoftyzer法所算出之溶解度參數δ之偶極力項δp,compound在2.0[(J/cm3)1/2]以上、8.0[(J/cm3)1/2]以下，上述溶解度參數δ之氫鍵力項δh,compound在5.5[(J/cm3)1/2]以上、9.5[(J/cm3)1/2]以下，藉由上述第2聚合性乙烯單體之聚合所獲得之第2聚合物，上述溶解度參數δ之偶極力項δp,2nd polymer未達5.0[(J/cm3)1/2]，溶解度參數δ之氫鍵力項δh,2nd polymer未達8.0[(J/cm3)1/2]。 The present invention (3) is the sustained release particle according to (1) or (2), wherein the above-mentioned antibiotic compound is defined by Hansen, and the solubility parameter δ calculated by the Van Krevelen and Hoftyzer method is The dipole force term δ p,compound is 2.0 [(J/cm 3 ) 1/2 ] or more, 8.0 [(J/cm 3 ) 1/2 ] or less, and the hydrogen bond force term δ h of the above solubility parameter δ is compound 5.5 [(J/cm 3 ) 1/2 ] or more, 9.5 [(J/cm 3 ) 1/2 ] or less, the second polymer obtained by polymerization of the second polymerizable ethylene monomer, the solubility The dipole force term δ p of the parameter δ , 2nd polymer is less than 5.0 [(J/cm 3 ) 1/2 ], the hydrogen bond force term δ h of the solubility parameter δ , 2nd polymer is less than 8.0 [(J/cm 3 ) 1 /2 ].

本發明(4)為如(1)至(3)中任一項所述之持續釋放性粒子，其中，上述第2聚合性乙烯單體對上述第1聚合性乙烯單體與上述第2聚合性乙烯單體之總量100質量份之含有率為25質量份以上。 The sustained release particles according to any one of the above aspects, wherein the second polymerizable ethylene monomer is the first polymerizable ethylene monomer and the second polymerization. The content of the total amount of the ethylene monomer in 100 parts by mass is 25 parts by mass or more.

本發明為(5)為如(1)至(4)中任一項所述之持續釋放性粒子，其中，上述抗生物活性化合物含有異噻唑啉系化合物。 The sustained-release particle according to any one of (1) to (4), wherein the anti-biologically active compound contains an isothiazoline-based compound.

本發明(6)為如(5)所述之持續釋放性粒子，其中，上述異噻唑啉系化合物為5,6-二氯-2-正辛基-4-異噻唑啉-3-酮。 The sustained release particle according to the above aspect (5), wherein the isothiazolin compound is 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one.

本發明(7)為如(1)至(6)中任一項所述之持續釋放性粒子，其中，選自由上述第1聚合性乙烯單體及上述第2聚合性乙烯單體所成群組之至少1種的聚合性乙烯單體含有聚合反應性紫外線吸收劑。 The sustained release particles according to any one of (1) to (6), wherein the particles are selected from the group consisting of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer. At least one of the polymerizable ethylene monomers of the group contains a polymerization-reactive ultraviolet absorber.

本發明(8)為一種持續釋放性粒子，具備：在藉由疏水性第1聚合性乙烯單體之聚合所獲得之第1聚合物 中含有疏水性抗生物活性化合物為相溶之均一相，平均粒徑未達1μm之核芯；及藉由疏水性第2聚合性乙烯單體之聚合所獲得之第2聚合物所組成，且實質上未含有上述抗生物活性化合物之殼層，並將上述核芯包覆之上述殼層。 The present invention (8) is a sustained release particle comprising: a first polymer obtained by polymerization of a hydrophobic first polymerizable ethylene monomer a core comprising a hydrophobic antibiotic-active compound which is a homogeneous phase, a core having an average particle diameter of less than 1 μm; and a second polymer obtained by polymerization of a hydrophobic second polymerizable ethylene monomer, and The shell layer of the above anti-biologically active compound is not substantially contained, and the shell layer is coated with the core.

本發明(9)為如(8)所述之持續釋放性粒子，其中，上述抗生物活性化合物以漢森定義，以Van Krevelen and Hoftyzer法算出之溶解度參數δ之偶極力項δp,compound在2.0[(J/cm3)1/2]以上、8.0[(J/cm3)1/2]以下，上述溶解度參數δ之氫鍵力項δh,compound在5.5[(J/cm3)1/2]以上、9.5[(J/cm3)1/2]以下，藉由上述第2聚合性乙烯單體之聚合所獲得之第2聚合物，上述溶解度參數δ之偶極力項δp,2nd polymer未達5.0[(J/cm3)1/2]，溶解度參數δ之氫鍵力項δh,2nd polymer未達8.0[(J/cm3)1/2]。 The present invention (9) is the sustained release particle according to (8), wherein 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 ] or more, 8.0 [(J/cm 3 ) 1/2 ] or less, the hydrogen bond force term δ h of the above solubility parameter δ , compound is 5.5 [(J/cm 3 ) 1/2 ] or more, 9.5 [(J/cm 3 ) 1/2 ] or less, the second polymer obtained by the polymerization of the second polymerizable ethylene monomer, the dipole force term δ p of the solubility parameter δ 2nd polymer is less than 5.0 [(J/cm 3 ) 1/2 ], the hydrogen bonding force term δ h of the solubility parameter δ , and the 2nd polymer is less than 8.0 [(J/cm 3 ) 1/2 ].

本發明(10)為如(8)或(9)所述之持續釋放性粒子，其中，上述第2聚合性乙烯單體對上述第1聚合性乙烯單體與上述第2聚合性乙烯單體之總量100質量份之含有率為25質量份以上。 The sustained release particle according to the above aspect (8), wherein the second polymerizable ethylene monomer is the first polymerizable ethylene monomer and the second polymerizable ethylene monomer. The content of the total amount of 100 parts by mass is 25 parts by mass or more.

本發明(11)為如(8)至(10)中任一項所述之持續釋放性粒子，其中，上述抗生物活性化合物含有異噻唑啉系化合物。 The sustained-release particle according to any one of (8) to (10), wherein the anti-biologically active compound contains an isothiazoline-based compound.

本發明(12)為如(11)所述之持續釋放性粒子，其中，上述異噻唑啉系化合物為5,6-二氯-2-正辛基-4-異噻唑啉-3-酮。 The sustained release particle according to the above aspect (11), wherein the isothiazolin compound is 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one.

本發明(13)為如(8)至(12)中任一項所述之持續 釋放性粒子，其中，選自由上述第1聚合性乙烯單體及上述第2聚合性乙烯單體所成群組之至少1種的聚合性乙烯單體含有聚合反應性紫外線吸收劑。 The invention (13) is the continuation as described in any one of (8) to (12) The polymerizable ethylene monomer which is at least one selected from the group consisting of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer contains a polymerizable reactive ultraviolet absorber.

本發明(14)為一種持續釋放性粒子之製造方法，具備核芯調製步驟，其係將含有疏水性抗生物活性化合物及疏水性第1聚合性乙烯單體之核芯原料成分進行微乳化液聚合，調製在藉由上述第1聚合性乙烯單體之聚合所獲得之第1聚合物中含有抗生物活性化合物為相溶之均一相之核芯；及殼層調製步驟，其係將含有疏水性第2聚合性乙烯單體之殼層原料成分藉由將上述核芯作為種子之種子乳化聚合所獲得之殼層，且調製將上述核芯包覆之上述殼層。 The invention (14) is a method for producing a sustained release particle, comprising a core preparation step of performing a microemulsion of a core material component containing a hydrophobic bioactive compound and a hydrophobic first polymerizable ethylene monomer; Polymerization, preparing a core in which the anti-biologically active compound is a homogeneous phase in which the first polymer obtained by polymerization of the first polymerizable ethylene monomer is contained; and a shell layer modulating step which is hydrophobic The shell raw material component of the second polymerizable ethylene monomer is obtained by emulsion-polymerizing the core as a seed of the seed, and the shell layer coated with the core is prepared.

本發明(15)為如(14)所述之持續釋放性粒子之製造方法，其中，上述殼層原料成分為實質上未含有上述抗生物活性化合物。 The method of producing a sustained release particle according to the above aspect (14), wherein the shell raw material component does not substantially contain the antibiotic active compound.

本發明(16)為如(14)或(15)所述之持續釋放性粒子之製造方法，其中，上述抗生物活性化合物以漢森定義，以van Krevelen and Hoftyzer法算出之溶解度參數δ之偶極力項δp,compound在2.0[(J/cm3)1/2]以上、8.0[(J/cm3)1/2]以下，上述溶解度參數δ之氫鍵力項δh,compound在5.5[(J/cm3)1/2]以上、9.5[(J/cm3)1/2]以下，藉由上述第2聚合性乙烯單體之聚合所獲得之第2聚合物，上述溶解度參數δ之偶極力項δp,2nd polymer未達5.0[(J/cm3)1/2]，溶解度參數δ之氫鍵力項δh,2nd polymer未達8.0[(J/cm3)1/2]。 (16) The method for producing a sustained release particle according to (14) or (15), wherein the antibiotic compound is defined by Hansen and the solubility parameter δ calculated by the van Krevelen and Hoftyzer method The force term δ p,compound is 2.0 [(J/cm 3 ) 1/2 ] or more, 8.0 [(J/cm 3 ) 1/2 ] or less, and the hydrogen bond force term δ h of the above solubility parameter δ , compound is 5.5. [(J/cm 3 ) 1/2 ] or more, 9.5 [(J/cm 3 ) 1/2 ] or less, the second polymer obtained by polymerization of the second polymerizable ethylene monomer, the solubility parameter The even force term δ p of δ , 2nd polymer is less than 5.0 [(J/cm 3 ) 1/2 ], the hydrogen bond force term δ h of the solubility parameter δ , 2nd polymer is less than 8.0 [(J/cm 3 ) 1/ 2 ].

本發明(17)為如(14)至(16)中任一項所述之持 續釋放性粒子之製造方法，其中，上述第2聚合性乙烯單體對上述第1聚合性乙烯單體與上述第2聚合性乙烯單體之總量100質量份之含有率為25質量份以上。 The invention (17) is the holding according to any one of (14) to (16) In the method of producing a continuous release particle, the content ratio of the second polymerizable ethylene monomer to 100 parts by mass of the total amount of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer is 25 parts by mass or more. .

本發明(18)為如(14)至(17)中任一項所述之持續釋放性粒子之製造方法，其中，上述抗生物活性化合物含有異噻唑啉系化合物。 The method for producing sustained-release particles according to any one of the aspects of the present invention, wherein the anti-biologically active compound contains an isothiazoline-based compound.

本發明(19)為如(18)所述之持續釋放性粒子之製造方法，其中，上述異噻唑啉系化合物為5,6-二氯-2-正辛基-4-異噻唑啉-3-酮。 (19) The method for producing a sustained release particle according to (18), wherein the isothiazolin compound is 5,6-dichloro-2-n-octyl-4-isothiazoline-3 -ketone.

本發明(20)為如(14)至(19)中任一項所述之持續釋放性粒子之製造方法，其中，上述微乳化液聚合之轉化率為95%以上時，開始將上述殼層原料成分供給於含有上述核芯之乳濁液。 The method for producing a sustained-release particle according to any one of the aspects of the present invention, wherein the above-mentioned shell layer is started when the conversion ratio of the microemulsion polymerization is 95% or more The raw material component is supplied to the emulsion containing the above-mentioned core.

本發明(21)為如(14)至(20)中任一項所述之持續釋放性粒子之製造方法，其中，選自由上述第1聚合性乙烯單體及上述第2聚合性乙烯單體所成群組之至少1種的聚合性乙烯單體含有聚合反應性紫外線吸收劑。 The method for producing sustained release particles according to any one of the aspects of the present invention, wherein the first polymerizable ethylene monomer and the second polymerizable ethylene monomer are selected from the group consisting of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer. At least one of the polymerizable ethylene monomers in the group contains a polymerization-reactive ultraviolet absorber.

藉由本發明之持續釋放性粒子之製造方法所獲得之持續釋放性粒子由於在第1聚合物具備抗生物活性化合物為相溶之核芯及將核芯包覆之殼層，故，抗紫外線性優越。 The sustained release particle obtained by the method for producing a sustained release particle of the present invention has a UV-resistant property because the first polymer has an antibiotic-active compound as a compatible core and a core coated with a core. superior.

藉由本發明之持續釋放性粒子之製造方法所獲得之持續釋放性粒子，由於在藉由第1聚合性乙烯單體 之聚合所獲得之第1聚合物中含有抗生物活性化合物為相溶之均一相之核芯，故，持續釋放性優越。 Sustained release particles obtained by the method for producing sustained release particles of the present invention, by the first polymerizable ethylene monomer The first polymer obtained by the polymerization contains an antibiotic-active compound which is a core of a homogeneous phase which is compatible, and therefore has excellent sustained release property.

另，上述之持續釋放性粒子由於係藉由微乳化液聚合及種子乳化聚合而獲得，故，水分散安定性優越。 Further, since the above sustained release particles are obtained by microemulsion polymerization and seed emulsion polymerization, water dispersion stability is excellent.

1‧‧‧持續釋放性粒子 1‧‧‧Continuous release particles

2‧‧‧核芯 2‧‧‧core

3‧‧‧殼層 3‧‧‧ shell

11‧‧‧框架 11‧‧‧Frame

12‧‧‧第1框架 12‧‧‧1st frame

13‧‧‧第2框架 13‧‧‧2nd frame

14‧‧‧連絡框架 14‧‧‧Contact Framework

15‧‧‧濾布 15‧‧‧ filter cloth

16‧‧‧第1空間 16‧‧‧1st space

17‧‧‧第2空間 17‧‧‧Second space

第1圖表示本發明之持續釋放性粒子的一實施形態之概略剖面圖。 Fig. 1 is a schematic cross-sectional view showing an embodiment of the sustained release particles of the present invention.

第2圖表示實施例11至14之持續釋放性試驗之曲線。 Fig. 2 is a graph showing the sustained release test of Examples 11 to 14.

第3圖表示實施例15至18之持續釋放性試驗之曲線。 Figure 3 is a graph showing the sustained release test of Examples 15 to 18.

第4圖表示實施例19及20之持續釋放性試驗之曲線。 Fig. 4 is a graph showing the sustained release test of Examples 19 and 20.

第5圖表示實施例21及22之持續釋放性試驗之曲線。 Fig. 5 is a graph showing the sustained release test of Examples 21 and 22.

第6圖表示實施例23及24之持續釋放性試驗之曲線。 Fig. 6 is a graph showing the sustained release test of Examples 23 and 24.

第7圖表示實施例25及26之持續釋放性試驗之曲線。 Fig. 7 is a graph showing the sustained release test of Examples 25 and 26.

第8圖表示實施例27及28之持續釋放性試驗之曲線。 Fig. 8 is a graph showing the sustained release test of Examples 27 and 28.

第9圖表示實施例29及30之持續釋放性試驗之曲線。 Fig. 9 is a graph showing the sustained release test of Examples 29 and 30.

第10圖表示於實施例31及32持續釋放性試驗中使用之框架結合體之立體圖。 Fig. 10 is a perspective view showing the frame combination used in the sustained release test of Examples 31 and 32.

第11圖表示實施例31及32之持續釋放性試驗中使用之蟲籠之正剖面圖。 Fig. 11 is a front sectional view showing the insect cage used in the sustained release test of Examples 31 and 32.

第12圖表示實施例33及34之持續釋放性試驗之曲線。 Fig. 12 is a graph showing the sustained release test of Examples 33 and 34.

第13圖表示實施例35及36之持續釋放性試驗之曲線。 Fig. 13 is a graph showing the sustained release test of Examples 35 and 36.

1.持續釋放性粒子 Sustained release particle

本發明之持續釋放性粒子具備將含有疏水性抗生物活性化合物及疏水性第1聚合性乙烯單體之核芯原料成分藉由微乳化液聚合所獲得之核芯；及將含有疏水性第2聚合性乙烯單體之殼層原料成分藉由將核芯作為種子之種子乳化聚合所獲得之殼層。 The sustained-release particle of the present invention comprises a core obtained by polymerizing a core material component containing a hydrophobic bioactive compound and a hydrophobic first polymerizable ethylene monomer by a microemulsion; and containing a hydrophobic second The shell material component of the polymerizable ethylene monomer is obtained by emulsion polymerization of a core as a seed seed.

以下，依序說明有關抗生物活性化合物、第1聚合性乙烯單體及第2聚合性乙烯單體。 Hereinafter, the antibiotic-active compound, the first polymerizable ethylene monomer, and the second polymerizable ethylene monomer will be described in order.

1.1.抗生物活性化合物 1.1. Antibiotic active compounds

抗生物活性化合物係作用為微乳化液聚合中之水電霍夫(hydrohove)(共穩定劑)，具體而言，藉由有助於微乳化液聚合中之微乳化液的安定化，防止奧斯瓦爾德熟化(Ostwald ripening)，抑制核芯之肥大化(粒徑増大)。 The anti-biologically active compound acts as a hydrohove (co-stabilizer) in the microemulsion polymerization, specifically, by preventing the stabilization of the microemulsion in the microemulsion polymerization, preventing Oss Ostwald ripening inhibits the enlargement of the core (large particle size).

抗生物活性化合物係具有殺菌、抗菌、防腐、防藻、防黴、殺蟲等抗生物活性，且選自殺菌劑、抗菌劑、防腐劑、防藻劑、防黴劑、除草劑、殺蟲劑、引誘劑、忌避劑及殺鼠劑等。具有該等抗生物活性之化合物可列舉例如有機碘系化合物、***系化合物、胺基甲醯基咪唑系化合物、二硫醇系化合物、異噻唑啉系化合物、硝基醇系化合物、對羥基苯甲酸酯等之殺菌防腐防藻防黴劑(包含防腐防黴劑)、例如合成除蟲菊酯類化合物、新煙鹼類系化合物、有機氯系化合物、有機磷系化合物、胺基甲酸酯系化合物、噁二嗪系化合物等防蟻劑(殺蟻劑)等。 The anti-bioactive compound has antibiotic activity such as sterilization, antibacterial, antiseptic, anti-algae, mildewproof, insecticidal, etc., and is selected from the group consisting of a bactericide, an antibacterial agent, a preservative, an anti-algae agent, an anti-fungal agent, a herbicide, and an insecticide. Agents, attractants, repellents and rodenticides. Examples of the compound having such an antibiotic activity include an organic iodine compound, a triazole compound, an aminomercaptoimidazole compound, a dithiol compound, an isothiazoline compound, a nitro alcohol compound, and a p-hydroxy group. A bactericidal, antiseptic, antibacterial and antifungal agent (including a preservative and antifungal agent) such as a benzoic acid ester, such as a pyrethroid compound, a neonicotinoid compound, an organochlorine compound, an organophosphorus compound, or an amine group An anti-termite agent (anticide) such as an acid ester compound or a oxadiazine compound.

有機碘系化合物可列舉例如3-碘-2-丙炔基胺基甲酸丁酯(IPBC)、1-[[(3-碘-2-丙炔基)氧基]甲氧基]-4-甲氧基苯、3-溴-2,3-二碘-2-丙烯基碳酸乙酯等。 The organic iodine compound may, for example, be butyl 3-iodo-2-propynylcarbamate (IPBC), 1-[[(3-iodo-2-propynyl)oxy]methoxy]-4- Methoxybenzene, 3-bromo-2,3-diiodo-2-propenylcarbonate, and the like.

***系化合物可列舉例如1-[2-(2,4-二氯苯基)-4-正丙基-1,3-二氧雜戊環-2-基甲基]-1H-1,2,4-***(丙環唑(propiconazole)、雙(4-氟苯基)甲基(1H-1,2,4-***-1-基甲基矽烷(別名：氟矽唑(flusilazole)、1-[[雙(4-氟苯基)甲基矽烷基]甲基]-1H-1,2,4-***)等。 The triazole-based compound may, for example, be 1-[2-(2,4-dichlorophenyl)-4-n-propyl-1,3-dioxolan-2-ylmethyl]-1H-1. 2,4-triazole (propiconazole, bis(4-fluorophenyl)methyl (1H-1,2,4-triazol-1-ylmethyldecane) (alias: flusilazole ), 1-[[bis(4-fluorophenyl)methyldecyl]methyl]-1H-1,2,4-triazole) and the like.

胺基甲醯基咪唑系化合物可列舉例如正丙基-N-[2-(2,4,6-三氯-苯氧基)乙基]咪唑-1-甲醯胺(撲克拉(Prochloraz))等。 The aminomethylimidazole-based compound may, for example, be n-propyl-N-[2-(2,4,6-trichloro-phenoxy)ethyl]imidazole-1-carboxamide (Prochloraz) )Wait.

二硫醇系化合物可列舉例如4,5-二氯-1,2-二硫醇-3-酮等。 Examples of the dithiol-based compound include 4,5-dichloro-1,2-dithiol-3-one.

異噻唑啉系化合物可列舉例如2-正辛基-4-異噻唑啉-3-酮(OIT)、5,6-二氯-2-正辛基-4-異噻唑啉-3-酮(DCOIT)等。 The isothiazoline-based compound may, for example, be 2-n-octyl-4-isothiazolin-3-one (OIT) or 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one ( DCOIT) and so on.

硝基醇系化合物可列舉例如2,2-二溴-2-硝基-1-乙醇(DBNE)等。 Examples of the nitroalcohol-based compound include 2,2-dibromo-2-nitro-1-ethanol (DBNE).

對羥基苯甲酸酯可列舉例如對羥基苯甲酸丁酯、對羥基苯甲酸丙酯等。 Examples of the p-hydroxybenzoic acid ester include butyl p-hydroxybenzoate and propyl p-hydroxybenzoate.

合成除蟲菊酯類系化合物可列舉例如從白花除蟲菊所獲得之除蟲菊酯(Pyrethrin)、瓜菊酯(Cinerin)、茉莉菊酯(Jasmolin)等合成除蟲菊酯類系殺蟲劑、從該等衍生之丙烯除蟲菊酯(allethrin)、聯苯菊酯(biphenthrin)、氟丙菊 酯(acrinathrin)、α-氯氰菊酯(alpha-Cypermethrin)、四溴菊酯(tralomethrin)、氟氯氰菊酯(cyfluthrin)((RS)-α-氰基-4-氟-3-苯氧基苯甲基-(1RS,3RS)-(1RS,3RS)-3-(2,2-二氯乙烯基)-2,2-二甲基環丙烷羧酸酯。詳言之，亦可列舉異構體I((1R-3R-α R)+(1S-3S-α S))[融點：57℃]、異構體II((1R-3R-S)+(1S-3S-α R))[融點：74℃]、異構體III((1R-3S-α R)+(1S-3R-α S)))[融點：66℃]之混合物)、苯醚氰菊酯(cyphenothrin)、炔丙菊酯(prallethrin)、醚菊酯(etofenprox)(2-(4-乙氧基苯基)-2-甲基丙基=3-苯氧基苯甲基=醚)、氟矽菊酯(silafluofen)、氰戊菊酯(fenvalerate)、氯菊酯(Permethrin)(3-苯氧基苯甲基(1RS,3RS；1RS,3SR)-3-(2,2-二氯乙烯基)-2,2-二甲基環丙烷羧酸酯)等合成除蟲菊酯類系殺蟲劑。 Examples of the pyrethroid-based compound include pyrethroid-based insecticides such as Pyrethrin, Cinerin, and Jasmolin obtained from Pyrethrum sinensis. Agent, pyrethroid (allethrin), biphenthrin, fluoroacetate derived from the same Acrylthrin, alpha-cypermethrin, tralmethrin, cyfluthrin ((RS)-α-cyano-4-fluoro-3-phenoxybenzyl- (1RS, 3RS)-(1RS, 3RS)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate. In particular, isomer I (also listed) (1R-3R-α R)+(1S-3S-α S)) [melting point: 57 ° C], isomer II ((1R-3R-S) + (1S-3S-α R)) Point: 74 ° C], isomer III ((1R-3S-α R) + (1S-3R-α S))) [melting point: 66 ° C] mixture), cyphenothrin, Prallethrin, etofenprox (2-(4-ethoxyphenyl)-2-methylpropyl=3-phenoxybenzyl-ether), flumethrin (silafluofen), fenvalerate, permethrin (3-phenoxybenzyl (1RS, 3RS; 1RS, 3SR)-3-(2,2-dichlorovinyl)- Pyrethroid-based insecticides such as 2,2-dimethylcyclopropanecarboxylate).

新煙鹼類系化合物可列舉例如(E)-N1-[(6-氯-3-吡啶基)甲基]-N2-氰基-N1-甲基乙脒(啶蟲脒(acetamiprid))等。 The neonicotinoid compound may, for example, be (E)-N 1 -[(6-chloro-3-pyridyl)methyl]-N 2 -cyano-N 1 -methylacetamidine (acetamiprid) ))Wait.

有機氯系化合物可列舉例如三氯殺蟎醇(kelthane)等。 Examples of the organic chlorine-based compound include kelphane and the like.

有機磷系化合物可列舉例如例如辛硫磷(phoxim)、噠嗪硫磷(pyridaphenthion)、殺螟硫磷(fenitrothion)、四氯烯磷(tetrachlorvinphos)、除線磷(dichlofenthion)、烯蟲磷(propetamphos)等。 Examples of the organophosphorus compound include, for example, phoxim, pyridaphenthion, fenitrothion, tetrachlorvinphos, dichlofenthion, and chlorpyrifos. Propetamphos) and so on.

胺基甲酸酯系化合物可列舉例如丁基滅必蝨(Fenobucarb)、殘殺威(propoxur)等。 Examples of the urethane-based compound include Fenobucarb, propoxur, and the like.

噁二嗪系化合物可列舉例如茚蟲威(indoxacarb)等。 Examples of the oxadiazine-based compound include indoxacarb and the like.

除草劑可列舉例如二唑草(pyraclonil)、胺硝草(pendimethalin)、茚草酮(indanofan)等。 Examples of the herbicide include pyralonil, pendimethalin, indanofan, and the like.

殺蟲劑可列舉例如吡丙醚(pyriproxyfen)等。 Examples of the insecticide include pyriproxyfen and the like.

忌避劑可列舉例如敵避(DEET)等。 Examples of the repellent include, for example, DEET.

該等抗生物活性化合物可單獨使用，亦可將2種以上併用。 These anti-biologically active compounds may be used singly or in combination of two or more.

抗生物活性化合物較佳可列舉有機碘系化合物、***系化合物、胺基甲醯基咪唑系化合物、異噻唑啉系化合物、合成除蟲菊酯類系化合物、忌避劑，更佳可列舉IPBC、丙環唑、氟矽唑、撲克拉、OIT、DCOIT、氟氯氰菊酯、氯菊酯、敵避，更佳可列舉DCOIT。 The antibiotic compound is preferably an organic iodine compound, a triazole compound, an aminopyridyl imidazole compound, an isothiazoline compound, a pyrethroid compound, or a repellent, and more preferably IPBC. , propiconazole, flucarbazole, poker, OIT, DCOIT, cyfluthrin, permethrin, enemies, and more preferably DCOIT.

抗生物活性化合物例如實質上為疏水性，具體而言，例如對於水之於室溫(20至30℃，更具體而言，為25℃)之溶解度極小，更具體而言，例如室溫之溶解度在1.5質量份/水100容量份(15g/L)以下，較佳為0.5質量份/水100容量份(5g/L)以下，更佳為0.1質量份/水100容量份(1g/L)以下。 The anti-biologically active compound is, for example, substantially hydrophobic, in particular, for example, the solubility of water at room temperature (20 to 30 ° C, more specifically 25 ° C) is extremely small, more specifically, for example, room temperature The solubility is 1.5 parts by mass/water 100 parts by volume (15 g/L) or less, preferably 0.5 parts by mass/water 100 parts by volume (5 g/L) or less, more preferably 0.1 part by mass/water 100 parts by volume (1 g/L). )the following.

抗生物活性化合物對於水之溶解度超過上述之範圍時，在將含有第1聚合性乙烯單體之核芯原料成分進行微乳化液聚合時，抗生物活性化合物容易漏出到核芯外(亦即，水相)，聚合後溶解於水相之抗生物活性化合物會析出，故有時難以形成含有抗生物活性化合物之核芯。 When the solubility of the bioactive compound in water exceeds the above range, when the core raw material component containing the first polymerizable ethylene monomer is subjected to microemulsion polymerization, the bioactive compound easily leaks out of the core (that is, The aqueous phase), after the polymerization, the anti-biologically active compound dissolved in the aqueous phase precipitates, so that it is sometimes difficult to form a core containing the anti-biologically active compound.

抗生物活性化合物為溶解度參數δ之偶極力項δp,compound例如在2.0[(J/cm3)1/2]以上，較佳為3.0[(J/cm3)1/2]以上，例如8.0[(J/cm3)1/2]以下，較佳為7.0[(J/cm3)1/2]以下，溶解度參數δ之氫鍵力項δh,compound例如為5.5[(J/cm3)1/2]以上，較佳為5.8[(J/cm3)1/2]以上，例如為9.5[(J/cm3)1/2]以下。溶解度參數δ之偶極力項δ p及氫鍵力項δ以漢森定義，以van Krevelen and Hoftyzer法算出，具體而言，詳述於日本特開2011-79816號公報。又，對於後述之第1聚合物及第2聚合物之溶解度參數δ亦藉由與上述相同之方法算出。 The antibiotic compound is a dipole force term δ p of the solubility parameter δ , and the compound is, 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, the hydrogen bond force term δ h of the solubility parameter δ , and the compound is, for example, 5.5 [(J/). Cm 3 ) 1/2 ] or more is preferably 5.8 [(J/cm 3 ) 1/2 ] or more, and is, for example, 9.5 [(J/cm 3 ) 1/2 ] or less. The dipole force term δ p and the hydrogen bond force term δ of the solubility parameter δ are defined by Hansen and calculated by the van Krevelen and Hoftyzer method. Specifically, it is described in detail in Japanese Laid-Open Patent Publication No. 2011-79816. Further, the solubility parameter δ of the first polymer and the second polymer to be described later is also calculated by the same method as described above.

抗生物活性化合物之偶極力項δp,compound及/或氫鍵力項δh,compound若未達上述範圍，則抗生物活性化合物之疏水性變過高，有時無法獲得與第1聚合物(後述)之充分相溶性。 The dipole force term δ p, compound and/or hydrogen bond force term δ h of the antibiotic compound becomes too high, and the hydrophobicity of the antibiotic compound becomes too high, and sometimes the first polymer is not obtained. Full compatibility (described later).

另一方面，抗生物活性化合物之偶極力項δp,compound及/或氫鍵力項δh,compound若超過上述範圍，則抗生物活性化合物之親水性變過高，有時抗生物活性化合物容易漏出到核芯外，難以調製使抗生物活性化合物充分內包之核芯。 On the other hand, if the dipole force term δ p, compound and/or the hydrogen bond force term δ h of the antibiotic compound exceeds the above range, the hydrophilicity of the antibiotic compound becomes too high, and sometimes the antibiotic compound It is easy to leak out of the core, and it is difficult to prepare a core in which the antibiotic compound is sufficiently encapsulated.

另一方面，抗生物活性化合物之偶極力項δp,compound及氫鍵力項δh,compound在上述範圍內且第1聚合物(後述)之偶極力項δp,1st polymer及氫鍵力項δh,1st polymer只要在後述之範圍內，則被定義為抗生物活性化合物在微乳化液聚合中不會從核芯漏出，而與第1聚合物(後述)相溶。 亦即，抗生物活性化合物係含於第1聚合物中。 On the other hand, the dipole force term δ p, compound and the hydrogen bond force term δ h of the antibiotic compound are in the above range and the dipole force term δ p, 1st polymer and hydrogen bonding force of the first polymer (described later). The term δ h,1st polymer is defined as an anti-biologically active compound which does not leak from the core in the microemulsion polymerization as long as it is within the range described later, and is compatible with the first polymer (described later). That is, the antibiotic compound is contained in the first polymer.

抗生物活性化合物之分子量在例如180以上，較佳為200以上，又，例如為600以下，較佳為500以下。 The molecular weight of the bioactive compound is, for example, 180 or more, preferably 200 or more, and is, for example, 600 or less, preferably 500 or less.

抗生物活性化合物之融點在例如100℃以下，較佳在90℃以下，更佳在80℃以下。又，上述之抗生物活性化合物例如在製造步驟中，可以適當之比率含有融點在上述範圍外之不純物。具體而言，氟氯氰菊酯之異構體I(融點：57℃)、異構體II(融點：74℃)及異構體III(融點：66℃)之混合物例如含有為不純物之異構體IV(融點：102℃)。 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. Further, the above-mentioned antibiotic-active compound may contain an impurity having a melting point outside the above range in an appropriate ratio, for example, in the production step. 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 contained, for example, as an impurity. Construct IV (melting point: 102 ° C).

1.2.第1聚合性乙烯單體 1.2. The first polymerizable ethylene monomer

第1聚合性乙烯單體為例如在分子內至少具有1個聚合性之碳-碳雙鍵(具體而言為乙烯基等)。 The first polymerizable ethylene monomer is, for example, a carbon-carbon double bond (specifically, a vinyl group or the like) having at least one polymerizable property in a molecule.

第1聚合性乙烯單體可列舉例如在分子內含有1個聚合性之碳-碳雙鍵之第1單體、例如在分子內含有2個以上聚合性之碳-碳雙鍵之第2單體、例如更含有官能基之第3單體等。 The first polymerizable ethylene monomer may, for example, be a first monomer containing one polymerizable carbon-carbon double bond in the molecule, for example, a second monomer containing two or more polymerizable carbon-carbon double bonds in the molecule. The body, for example, a third monomer further containing a functional group.

1.2.1.第1單體 1.2.1. The first monomer

第1單體為在第1聚合性乙烯單體中含有作為主成分之主單體。第1單體可列舉例如(甲基)丙烯酸酯系單體、芳族乙烯單體、乙烯酯系單體、馬來酸酯系單體、鹵化乙烯、鹵化亞乙烯、含氮之乙烯單體等。 The first monomer contains a main monomer as a main component in the first polymerizable ethylene monomer. Examples of the first monomer include a (meth) acrylate monomer, an aromatic vinyl monomer, a vinyl ester monomer, a maleate monomer, a halogenated ethylene, a vinylidene halide, and a nitrogen-containing ethylene monomer. Wait.

(甲基)丙烯酸酯系單體為甲基丙烯酸酯及/丙烯酸酯，具體而言，可列舉(甲基)丙烯酸甲酯(MMA/MA)、 (甲基)丙烯酸乙酯、(甲基)丙烯酸正丙酯、(甲基)丙烯酸異丙酯、(甲基)丙烯酸正丁酯、(甲基)丙烯酸異丁酯(i-BMA/i-BA)、(甲基)丙烯酸第三丁酯、(甲基)丙烯酸正戊酯、(甲基)丙烯酸正己酯、(甲基)丙烯酸正庚酯、(甲基)丙烯酸酸2-乙基己酯、(甲基)丙烯酸正辛酯、(甲基)丙烯酸異壬酯、(甲基)丙烯酸正十二烷酯(月桂酯)、(甲基)丙烯酸正十八烷酯(硬脂酯)、(甲基)丙烯酸環己酯等具有烷基部分為直鏈狀、支鏈狀或環狀之碳數1至20烷基部分之(甲基)丙烯酸烷基酯等。較佳可列舉具有碳數1至4烷基部分之(甲基)丙烯酸烷基酯。更佳可列舉甲基丙烯酸甲酯(MMA)、甲基丙烯酸異丁酯(i-BMA)。 The (meth)acrylate monomer is methacrylate and/or acrylate, and specific examples thereof include methyl (meth)acrylate (MMA/MA). Ethyl (meth)acrylate, n-propyl (meth)acrylate, isopropyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate (i-BMA/i- BA), tert-butyl (meth)acrylate, n-amyl (meth)acrylate, n-hexyl (meth)acrylate, n-heptyl (meth)acrylate, 2-ethylhexyl (meth)acrylate Ester, n-octyl (meth)acrylate, isodecyl (meth)acrylate, n-dodecyl (meth)acrylate (lauryl ester), n-octadecyl (meth)acrylate (stearyl ester) And a (meth)acrylic acid alkyl ester having a linear or branched or cyclic alkyl group having 1 to 20 alkyl groups, such as cyclohexyl (meth)acrylate. Preferred are alkyl (meth)acrylates having a C 1 to 4 alkyl moiety. More preferably, it is methyl methacrylate (MMA) and isobutyl methacrylate (i-BMA).

芳族系乙烯單體可列舉例如苯乙烯(SM)、對甲基苯乙烯、鄰-甲基苯乙烯、α-甲基苯乙烯等。較佳可列舉苯乙烯(SM)。 Examples of the aromatic vinyl monomer include styrene (SM), p-methylstyrene, o-methylstyrene, and α-methylstyrene. Preferably, styrene (SM) is mentioned.

乙烯酯系單體可列舉例如乙酸乙烯酯、丙酸乙烯酯等。 Examples of the vinyl ester monomer include vinyl acetate and vinyl propionate.

馬來酸酯系單體可列舉例如馬來酸二甲酯、馬來酸二乙酯、馬來酸二丁酯等。 Examples of the maleate-based monomer include dimethyl maleate, diethyl maleate, and dibutyl maleate.

鹵化乙烯可列舉例如氯化乙烯、氟化乙烯等。 Examples of the halogenated ethylene include vinyl chloride and ethylene fluoride.

鹵化亞乙烯可列舉例如氯化亞乙烯、氟化亞乙烯等。 Examples of the vinylidene halide include vinylidene chloride and vinylidene fluoride.

含氮之乙烯單體可列舉例如(甲基)丙烯腈、正苯基馬來醯亞胺、乙烯基吡啶等。 Examples of the nitrogen-containing ethylene monomer include (meth)acrylonitrile, n-phenylmaleimide, vinylpyridine, and the like.

第1單體較佳為(甲基)丙烯酸酯系單體、芳 族乙烯單體。 The first monomer is preferably a (meth) acrylate monomer or a aryl group. Family ethylene monomer.

第1單體可單獨使用或將2種以上併用。較佳可列舉(甲基)丙烯酸酯系單體之單獨使用、(甲基)丙烯酸酯系單體及芳族乙烯單體之組合。 The first monomer may be used singly or in combination of two or more. Preferably, a (meth)acrylate type monomer is used alone, and a combination of a (meth)acrylate type monomer and an aromatic vinyl monomer is mentioned.

第1單體之調配比率係相對於第1聚合性乙烯單體，例如在50質量%以上，較佳在55質量%以上，更佳在60質量%以上或在100質量%以下。 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, or 100% by mass or less based on the first polymerizable ethylene monomer.

第1單體為(甲基)丙烯酸酯系單體及芳族乙烯單體之組合時，(甲基)丙烯酸酯系單體對(甲基)丙烯酸酯系單體及芳族乙烯單體之總量之調配比率例如在50質量%以上，較佳在75質量%以上，又，例如未達100質量%，較佳在95質量%以下。 When the first monomer is a combination of a (meth) acrylate monomer and an aromatic vinyl monomer, the (meth) acrylate monomer pair (meth) acrylate monomer and the aromatic vinyl monomer The blending ratio of the total amount is, for example, 50% by mass or more, preferably 75% by mass or more, and further, for example, less than 100% by mass, preferably 95% by mass or less.

1.2.2.第2單體 1.2.2. The second monomer

第2單體為與第1聚合性乙烯單體任意併用之副單體，為可與第1單體共聚之交聯性單體。交聯性單體可列舉例如乙二醇二(甲基)丙烯酸酯(EGDA/EGDMA)、二乙二醇二(甲基)丙烯酸酯等單或聚乙二醇二(甲基)丙烯酸酯，例如1,3-丙二醇二(甲基)丙烯酸酯、1,4-丁二醇二(甲基)丙烯酸酯、1,5-戊二醇二(甲基)丙烯酸酯等烷基二醇二(甲基)丙烯酸酯，例如三羥基丙烷三(甲基)丙烯酸酯、新戊四醇四(甲基)丙烯酸酯等烷基多醇聚(甲基)丙烯酸酯，例如烯丙基(甲基)甲基丙烯酸酯(ALMA)、三烯丙基(異)三聚氰酸酯等烯丙基系單體，例如二乙烯基苯等二乙烯系單體等。尤其，ALMA利用反應性不同之2種碳-碳雙鍵，發揮作為使核芯 及殼層化學鍵結之接枝劑之腳色。 The second monomer is a secondary monomer which is used in combination with the first polymerizable ethylene monomer, and is a crosslinkable monomer copolymerizable with the first monomer. Examples of the crosslinkable monomer include mono or polyethylene glycol di(meth)acrylate such as ethylene glycol di(meth)acrylate (EGDA/EGDMA) or diethylene glycol di(meth)acrylate. For example, alkyl diols such as 1,3-propanediol di(meth)acrylate, 1,4-butanediol di(meth)acrylate, and 1,5-pentanediol di(meth)acrylate a methyl (meth) acrylate, such as an alkyl alcohol poly(meth) acrylate such as trihydroxypropane tri(meth) acrylate or neopentyl alcohol tetra (meth) acrylate, such as allyl (methyl) An allyl monomer such as methacrylate (ALMA) or triallyl (iso) cyanurate, for example, a divinyl monomer such as divinylbenzene. In particular, ALMA uses two kinds of carbon-carbon double bonds with different reactivity to function as a core. And the color of the grafting agent of the shell chemical bond.

第2單體較佳可列舉單或聚乙二醇二(甲基)丙烯酸酯，更佳可列舉乙二醇二(甲基)丙烯酸酯。 The second monomer is preferably a mono or polyethylene glycol di(meth)acrylate, and more preferably ethylene glycol di(meth)acrylate.

第2單體可單獨使用或將2種以上併用。 The second monomer may be used singly or in combination of two or more.

第2單體之調配比率相對於第1聚合性乙烯單體，例如在1質量%以上，較佳在5質量%以上，又，例如在20質量%以下，較佳在10質量%以下。又，第2單體之調配比率相對於第1單體100質量份，例如在1質量份以上，較佳在5質量份以上，又，例如在30質量份以下，較佳在20質量份以下。 The blending ratio of the second monomer is, for example, 1% by mass or more, preferably 5% by mass or more, and for example, 20% by mass or less, preferably 10% by mass or less, based on the first polymerizable ethylene monomer. In addition, the blending ratio of the second monomer is, for example, 1 part by mass or more, preferably 5 parts by mass or more, and further, for example, 30 parts by mass or less, preferably 20 parts by mass or less, based on 100 parts by mass of the first monomer. .

1.2.3.第3單體 1.2.3. Third monomer

第3單體為與第1聚合性乙烯單體任意併用之副單體，又，為可與第1單體共聚之含有官能基之乙烯單體。含有官能基之乙烯單體可列舉例如(甲基)丙烯酸系單體、(甲基)丙烯酸羥基烷酯、含有環氧基之(甲基)丙烯酸酯、聚合反應性乳化劑、聚合反應性紫外線吸收劑等。 The third monomer is a secondary monomer which is used in combination with the first polymerizable ethylene monomer, and is a functional group-containing ethylene monomer copolymerizable with the first monomer. Examples of the functional group-containing ethylene monomer include a (meth)acrylic monomer, a (meth)acrylic acid hydroxyalkyl ester, an epoxy group-containing (meth)acrylate, a polymerization reactive emulsifier, and a polymerization-reactive ultraviolet ray. Absorbent, etc.

(甲基)丙烯酸系單體可列舉例如丙烯酸、甲基丙烯酸(MAA)、衣康酸等。 Examples of the (meth)acrylic monomer include acrylic acid, methacrylic acid (MAA), itaconic acid, and the like.

(甲基)丙烯酸羥基烷酯可列舉例如(甲基)丙烯酸羥基甲酯、(甲基)丙烯酸羥基乙酯、(甲基)丙烯酸羥基丙酯等。 Examples of the hydroxyalkyl (meth)acrylate include hydroxymethyl (meth)acrylate, hydroxyethyl (meth)acrylate, and hydroxypropyl (meth)acrylate.

含有環氧基之(甲基)丙烯酸酯可列舉例如(甲基)丙烯酸縮水甘油酯等。 Examples of the epoxy group-containing (meth) acrylate include glycidyl (meth)acrylate.

聚合反應性乳化劑為在分子內具有聚合性碳- 碳雙鍵之乳化劑，為乳化劑之同時亦為聚合性單體。聚合反應性乳化劑係在分子內具有表現乳化機能之親水性基，該等親水性基可列舉例如磺酸酯基、硫酸酯基、羧酸酯基等陰離子性親水基，例如聚環氧乙烷基等非離子性親水基等。聚合反應性乳化劑較佳可列舉含有陰離子性親水基及非離子性親水基之兩者、只含有陰離子性親水基者、只含有非離子性親水基者，特佳可列舉含有陰離子性之親水基及非離子性之親水基之兩者，該等含有陰離子性之親水基及非離子性之親水基之兩者具體而言可列舉CH2=C(CH3)-COO(AO)nSO3Na(式中AO表示環氧乙烷、環氧丙烷等環氧烷等)、CH3-CH=CH-C6H4(CnH2n+1)-(AO)mSO3NH4(式中AO表示環氧乙烷、環氧丙烷等環氧烷)、CH2=CH-CH2-O-CH2CH(R)-O-(AO)n-SO3NH4(式中AO表示環氧乙烷、環氧丙烷等環氧烷，R表示烷基)等。又，只具有非離子性親水性基者具體而言可列舉CH2=C(CH3)-COO(AO)nR(式中AO表示環氧乙烷、環氧丙烷等環氧烷，R表示烷基)或CH3-CH=CH-C6H4(CnH2n+1)-O-(AO)mH(式中AO表示環氧乙烷、環氧丙烷等環氧烷)等。 The polymerization-reactive emulsifier is an emulsifier having a polymerizable carbon-carbon double bond in the molecule, and is also an emulsifier and a polymerizable monomer. The polymerization-reactive emulsifier has a hydrophilic group which exhibits an emulsification function in the molecule, and examples of the hydrophilic group include an anionic hydrophilic group such as a sulfonate group, a sulfate group or a carboxylate group, for example, a polyethylene oxide. A nonionic hydrophilic group such as an alkyl group. The polymerization-reactive emulsifier preferably includes both an anionic hydrophilic group and a nonionic hydrophilic group, an anionic hydrophilic group, and a nonionic hydrophilic group, and particularly preferably an anionic hydrophilic group. Both of the base group and the nonionic hydrophilic group, and the hydrophilic group having an anionic group and the nonionic hydrophilic group are specifically CH 2 =C(CH 3 )-COO(AO) n SO 3 Na (wherein AO represents an alkylene oxide such as ethylene oxide or propylene oxide, etc.), CH 3 -CH=CH-C 6 H 4 (C n H 2n+1 )-(AO) m SO 3 NH 4 (wherein AO represents an alkylene oxide such as ethylene oxide or propylene oxide), CH 2 =CH-CH 2 -O-CH 2 CH(R)-O-(AO) n -SO 3 NH 4 (wherein AO represents an alkylene oxide such as ethylene oxide or propylene oxide, and R represents an alkyl group. Further, specific examples of the nonionic hydrophilic group include CH 2 =C(CH 3 )-COO(AO) n R (wherein AO represents an alkylene oxide such as ethylene oxide or propylene oxide, R Represents alkyl) or CH 3 -CH=CH-C 6 H 4 (C n H 2n+1 )-O-(AO) m H (wherein AO represents an alkylene oxide such as ethylene oxide or propylene oxide) Wait.

聚合反應性紫外線吸收劑為紫外線吸收劑，亦同時為聚合性單體。具體而言，聚合反應性紫外線吸收劑為在分子內具有紫外線吸收基及聚合性碳-碳雙鍵之單體。紫外線吸收基可列舉例如苯并***環、苯酚等紫外線吸收基。聚合反應性紫外線吸收劑可列舉例如(甲基)丙烯酸2-[3-(2H-苯并***-2-基)-4-羥基苯基]乙酯等。聚合反 應性紫外線吸收劑亦可使用例如市售品，可使用例如RUVA系列(大塚化學公司製造)等。 The polymerization-reactive ultraviolet absorber is an ultraviolet absorber and is also 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 a benzotriazole ring and phenol. The polymerization-reactive ultraviolet absorber may, for example, be 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl (meth)acrylate or the like. Convergence For example, a commercially available product can be used as the ultraviolet ray absorbing agent, and for example, RUVA series (manufactured by Otsuka Chemical Co., Ltd.) or the like can be used.

第3單體較佳可列舉(甲基)丙烯酸系單體、聚合反應性紫外線吸收劑，更佳可列舉MAA、(甲基)丙烯酸2-[3-(2H-苯并***-2-基)-4-羥基苯基]乙酯。 The third monomer is preferably a (meth)acrylic monomer or a polymerization-reactive ultraviolet absorber. More preferably, it is MAA or 2-[2-(2H-benzotriazol-2-)(meth)acrylate. Base)-4-hydroxyphenyl]ethyl ester.

於第3單體若含有(甲基)丙烯酸系單體，則有可提高藉由與第1單體之共聚物形成之乳濁液之膠體之安定性的作用，為了獲得該效果，可依需要調配。 When the (meth)acrylic monomer is contained in the third monomer, the stability of the colloid of the emulsion formed by the copolymer with the first monomer can be enhanced, and in order to obtain the effect, the effect can be obtained. Need to be deployed.

另一方面，於第3單體若含有聚合反應性紫外線吸收劑，則可抑制抗生物活性化合物因紫外線引起之分解。 On the other hand, when the third monomer contains a polymerization-reactive ultraviolet absorber, decomposition of the bioactive compound due to ultraviolet rays can be suppressed.

第3單體可單獨使用或將2種以上併用。較佳可列舉單獨使用(甲基)丙烯酸系單體、(甲基)丙烯酸系單體與聚合反應性紫外線吸收劑之組合，更佳可列舉單獨使用(甲基)丙烯酸系單體。 The third monomer may be used singly or in combination of two or more. A combination of a (meth)acrylic monomer, a (meth)acrylic monomer, and a polymerization reactive ultraviolet absorber is preferably used, and a (meth)acrylic monomer is preferably used alone.

從降低製造成品之觀點而言，較佳係第3單體未含有聚合反應性紫外線吸收劑。亦即，較佳係於第3單體未含有聚合反應性紫外線吸收劑。於此情況，可降低持續釋放性粒子之製造成本。 From the viewpoint of lowering the finished product, it is preferred that the third monomer does not contain a polymerization-reactive ultraviolet absorber. That is, it is preferred that the third monomer does not contain a polymerization-reactive ultraviolet absorber. In this case, the manufacturing cost of the sustained release particles can be reduced.

第3單體之調配比率相對於第1聚合性乙烯單體，例如在0.5質量%以上，較佳在1質量%以上，又，例如在45質量%以下，較佳在40質量%以下。又，第3單體之調配比率相對於第1單體100質量份，例如在0.5質量份以上，較佳在1質量份以上，又，例如在80質量份以 下，較佳在60質量份以下。 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% by mass or less, based on the first polymerizable ethylene monomer. In addition, 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, based on 100 parts by mass of the first monomer. Next, it is preferably 60 parts by mass or less.

第1聚合性乙烯單體可單獨使用或將2種以上併用。較佳可列舉第1單體、第2單體與第3單體之組合，更佳可列舉(甲基)丙烯酸酯系單體(第1單體)、單或聚乙二醇二(甲基)丙烯酸酯(第2單體)與(甲基)丙烯酸系單體(第3單體)之組合，(甲基)丙烯酸酯系單體及芳族系乙烯單體(第1單體)、單或聚乙二醇丙烯酸酯(第2單體)與(甲基)丙烯酸系單體(第3單體)之組合，進一步，(甲基)丙烯酸酯系單體(第1單體)、單或聚乙二醇二(甲基)丙烯酸酯(第2單體)、(甲基)丙烯酸系單體及聚合反應性紫外線吸收劑(第3單體)之組合，進一步又，(甲基)丙烯酸酯系單體及芳族系乙烯單體(第1單體)、單或聚乙二醇二(甲基)丙烯酸酯(第2單體)、(甲基)丙烯酸系單體及聚合反應性紫外線吸收劑(第3單體)之組合。從降低持續釋放性粒子之製造成本之觀點而言，第1聚合性乙烯單體之組合更佳可列舉(甲基)丙烯酸酯系單體及芳族系乙烯單體(第1單體)、單或聚乙二醇二(甲基)丙烯酸酯(第2單體)與(甲基)丙烯酸系單體(第3單體)之組合。 The first polymerizable ethylene monomer may be used singly or in combination of two or more kinds. Preferably, a combination of a first monomer, a second monomer and a third monomer is preferred, and a (meth)acrylate monomer (first monomer), a single or polyethylene glycol di(a) is more preferred. a combination of a acrylate (second monomer) and a (meth)acrylic monomer (third monomer), a (meth) acrylate monomer and an aromatic vinyl monomer (first monomer) , a combination of a single or polyethylene glycol acrylate (second monomer) and a (meth)acrylic monomer (third monomer), and further, a (meth)acrylate monomer (first monomer) , a combination of a single or polyethylene glycol di(meth)acrylate (second monomer), a (meth)acrylic monomer, and a polymerization reactive ultraviolet absorber (third monomer), further Acrylate monomer and aromatic vinyl monomer (first monomer), mono or polyethylene glycol di(meth)acrylate (second monomer), (meth)acrylic monomer and A combination of a polymerization-reactive ultraviolet absorber (third monomer). The combination of the first polymerizable ethylene monomer is more preferably a (meth) acrylate monomer or an aromatic vinyl monomer (first monomer), from the viewpoint of reducing the production cost of the sustained release particles. A combination of a single or polyethylene glycol di(meth)acrylate (second monomer) and a (meth)acrylic monomer (third monomer).

從降低製造成本之觀點而言，第1聚合性乙烯單體較佳未含有聚合反應性紫外線吸收劑。 The first polymerizable ethylene monomer preferably does not contain a polymerization-reactive ultraviolet absorber from the viewpoint of reducing the production cost.

第1聚合性乙烯單體為第1單體、第2單體、第3單體之組合時，第3單體之調配比率相對於第2單體100質量份例如在30質量份以上，較佳在50質量份以上，又，例如在1000質量份以下，較佳在500質量份以下。 When the first polymerizable ethylene monomer is a combination of the first monomer, the second monomer, and the third monomer, the blending ratio of the third monomer is, for example, 30 parts by mass or more based on 100 parts by mass of the second monomer. It is preferably 50 parts by mass or more, and further, for example, 1000 parts by mass or less, preferably 500 parts by mass or less.

因此，上述之第1聚合性乙烯單體實質上為疏水性，例如對於水之室溫中的溶解度極小，具體而言，於室溫之溶解度為例如在10質量份/水100容量份(100g/L)以下，較佳在5質量份/水100容量份(50g/L)以下，更佳在3質量份/水100容量份(30g/L)以下。又，第1聚合性乙烯單體併用不同種類時(例如第1單體、第2單體、第3單體併用時)，第1聚合性乙烯單體全體(亦即，不同種類之第1聚合性乙烯單體之混合物)實質上為疏水性。 Therefore, the first polymerizable ethylene monomer described above is substantially hydrophobic, and for example, the solubility in water at room temperature is extremely small, and specifically, the solubility at room temperature is, for example, 10 parts by mass per 100 parts by volume of water (100 g). /L) Hereinafter, it is preferably 5 parts by mass/water 100 parts by volume (50 g/L) or less, more preferably 3 parts by mass/water 100 parts by volume (30 g/L) or less. When the first polymerizable ethylene monomer is used in a different type (for example, when the first monomer, the second monomer, and the third monomer are used in combination), the entire first polymerizable ethylene monomer (that is, the first type of the different type) The mixture of polymerizable ethylene monomers) is substantially hydrophobic.

第1聚合性乙烯單體為溶解度參數δ之偶極力項δp,1st polymer例如在5.0[(J/cm3)1/2]以上，例如在7.0[(J/cm3)1/2]以下，較佳在6.5[(J/cm3)1/2]以下，溶解度參數δ之氫鍵力項δh,1st polymer例如在8[(J/cm3)1/2]以上，較佳在8.5[(J/cm3)1/2]以上，例如在10[(J/cm3)1/2]以下之第1聚合物之第1聚合性乙烯單體。 The first polymerizable ethylene monomer is a dipole force term δ p of the solubility parameter δ , and the 1st polymer is, for example, 5.0 [(J/cm 3 ) 1/2 ] or more, for example, 7.0 [(J/cm 3 ) 1/2 ]. Hereinafter, it is preferably 6.5 [(J/cm 3 ) 1/2 ] or less, and the hydrogen bonding force term δ h of the solubility parameter δ , and 1st polymer is, for example, 8 [(J/cm 3 ) 1/2 ] or more, preferably. The first polymerizable ethylene monomer of the first polymer of 8.5 [(J/cm 3 ) 1/2 ] or more, for example, 10 [(J/cm 3 ) 1/2 ] or less.

第1聚合物之偶極力項δp,1st polymer及/或氫鍵力項δh,1st polymer若未達上述範圍，則第1聚合物之疏水性變過高，有時無法獲得與抗生物活性化合物之充分相溶性，即使可獲得相溶性時，抗生物活性化合物於微乳化液聚合中漏出到核芯外，有時難以調製使抗生物活性化合物充分內包之核芯。 When the first polymer has a dipole force term δ p, a 1st polymer and/or a hydrogen bond force term δ h, if the 1st polymer does not reach the above range, the hydrophobicity of the first polymer becomes too high, and the antibiotic may not be obtained. The sufficient compatibility of the active compound, even when compatibility is obtained, the anti-biologically active compound leaks out of the core in the microemulsion polymerization, and it is sometimes difficult to prepare a core in which the anti-biologically active compound is sufficiently encapsulated.

另一方面，第1聚合物之偶極力項δp,1st polymer及/或氫鍵力項δh,1st polymer若超過上述範圍，則第1聚合物之親水性變過高，有時無法獲得與抗生物活性化合物之充分相溶性，即使可獲得相溶性，與在微乳化液聚合中之水 相之界面自由能量變低，抗生物活性化合物在微乳化液聚合中漏出到核芯外，有時難以調製使抗生物活性化合物充分內包之核芯。 On the other hand, if the dipole force term δ p of the first polymer , the 1st polymer and/or the hydrogen bond force term δ h, and the 1st polymer exceed the above range, the hydrophilicity of the first polymer may become too high, and sometimes the film may not be obtained. Fully compatible with the anti-biologically active compound, even if the compatibility is obtained, the free energy at the interface with the aqueous phase in the microemulsion polymerization becomes low, and the anti-biologically active compound leaks out of the core in the microemulsion polymerization, It is difficult to prepare a core in which the antibiotic-active compound is sufficiently encapsulated.

第1聚合物之偶極力項δp,1st polymer及氫鍵力項δh,1st polymer只要在上述範圍內，則抗生物活性化合物被定義為在微乳化液聚合中不會從持續釋放性粒子漏出，而與第1聚合物相溶。亦即，抗生物活性化合物均一含於第1聚合物中。 The dipole force term δ p of the first polymer , 1st polymer and the hydrogen bond force term δ h, 1st polymer are within the above range, and the antibiotic compound is defined as not releasing the sustained release particles in the microemulsion polymerization. Leaks out and is compatible with the first polymer. That is, the antibiotic compound is uniformly contained in the first polymer.

更且，於溶解度參數δ，從第1聚合物之偶極力項δp,1st polymer扣除抗生物活性化合物之偶極力項δp,compound之值△δp(=δp,1st polymer-δp,compound)為例如-1.1至2.8[(J/cm3)1/2]。 Further, in the solubility parameter δ, the dipole force term δ p of the antibiotic compound is subtracted from the dipole force term δ p,1st polymer of the first polymer , and the value of the compound Δδ p (=δ p,1st polymer −δ p , compound ) is, for example, -1.1 to 2.8 [(J/cm 3 ) 1/2 ].

從第1聚合物之氫鍵力項δh,1st polymer扣除抗生物活性化合物之氫鍵力項δh,compound之值△δh(=δh,1st polymer-δh,compound)為例如-0.1至4.2[(J/cm3)1/2]。 The hydrogen bond force term δ h of the antibiotic compound is subtracted from the hydrogen bond force term δ h of the first polymer , and the value of the compound Δδ h (=δ h,1st polymer -δh ,compound ) is, for example, -0.1 To 4.2 [(J/cm 3 ) 1/2 ].

△δp及△δh只要在上述範圍內，則可確保抗生物活性化合物與第1聚合物之優越相溶性，可確保優越之持續釋放性。 When Δδ p and Δδ h are within the above range, excellent compatibility with the bioactive compound and the first polymer can be ensured, and excellent sustained release property can be ensured.

1.3.第2聚合性乙烯單體 1.3. 2nd polymerizable ethylene monomer

第2聚合性乙烯單體可列舉與上述例示之第1聚合性乙烯基單體為相同之聚合性乙烯單體。具體而言，第2聚合性乙烯單體較佳可列舉第1單體、第3單體，更佳可列舉第1單體。 The second polymerizable ethylene monomer is the same as the above-described first polymerizable vinyl monomer. Specifically, the second polymerizable ethylene monomer is preferably a first monomer or a third monomer, and more preferably a first monomer.

具體而言，第2聚合性乙烯單體較佳可列舉(甲 基)丙烯酸酯系單體、芳族乙烯單體、(甲基)丙烯酸系單體，更佳可列舉(甲基)丙烯酸酯系單體、芳族乙烯單體。更具體而言，第2聚合性乙烯單體較佳可列舉MMA、SM、MAA，更佳可列舉MMA、SM。 Specifically, the second polymerizable ethylene monomer is preferably exemplified (A The acrylate monomer, the aromatic vinyl monomer, and the (meth)acrylic monomer are more preferably a (meth) acrylate monomer or an aromatic vinyl monomer. More specifically, the second polymerizable ethylene monomer is preferably MMA, SM or MAA, and more preferably MMA or SM.

選自由第1聚合性乙烯單體及第2聚合性乙烯單體所成群組之至少一種的聚合性乙烯單體較佳含有聚合反應性紫外線吸收劑。藉由此，可提昇持續釋放性粒子中之抗生物活性化合物之抗紫外線性。 The polymerizable ethylene monomer which is at least one selected from the group consisting of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer preferably contains a polymerization-reactive ultraviolet absorber. Thereby, the ultraviolet resistance of the anti-biologically active compound in the sustained release particles can be enhanced.

具體而言，可列舉例如聚合反應性紫外線吸收劑含於第1聚合性乙烯單體、未含有於第2聚合性乙烯單體之第1態樣，例如聚合反應性紫外線吸收劑未含有於第1聚合性乙烯單體、含於第2聚合性乙烯單體之第2態樣，例如聚合反應性紫外線吸收劑含於第1聚合性乙烯單體、亦含於第2聚合性乙烯基單體之第3態樣。從更提昇持續釋放性粒子中之抗生物活性化合物之抗紫外線性之觀點而言，較佳可列舉第3態樣。 Specifically, for example, the polymerization-reactive ultraviolet absorber is contained in the first polymerizable ethylene monomer and the first aspect in which the second polymerizable ethylene monomer is not contained. For example, the polymerization-reactive ultraviolet absorber is not included in the first aspect. A polymerizable ethylene monomer and a second aspect of the second polymerizable ethylene monomer. For example, the polymerization-reactive ultraviolet absorber is contained in the first polymerizable ethylene monomer and also in the second polymerizable vinyl monomer. The third aspect. From the viewpoint of further enhancing the ultraviolet resistance of the bioactive compound in the sustained release particles, a third aspect is preferred.

另一方面，聚合反應性紫外線吸收劑未含有於第1聚合性乙烯單體，亦未含有於第2聚合性乙烯單體之第4態樣亦佳。只要是第4態樣，即可降低製造持續釋放性粒子之成本。 On the other hand, the polymerization-reactive ultraviolet absorber is not contained in the first polymerizable ethylene monomer, and is not contained in the fourth aspect of the second polymerizable ethylene monomer. As long as it is the fourth aspect, the cost of manufacturing sustained release particles can be reduced.

第2聚合性乙烯單體為第1單體(較佳為(甲基)丙烯酸酯系單體)及第3單體(較佳為聚合反應性紫外線吸收劑)之組合時，第2聚合性乙烯單體中之第3單體之調配比率例如在0.1質量%以上，較佳在0.5質量%以上，更 佳在1質量%以上，又，例如未達50質量%，較佳在25質量%以下，更佳在20質量%以下。第2聚合性乙烯單體為第1單體(較佳為(甲基)丙烯酸酯系單體)及第3單體(較佳為聚合反應性紫外線吸收劑)之組合時，第3單體對第1單體100質量份之調配比率例如在1質量份以上，較佳在5質量份以上，又，例如在40質量份以下，較佳在20質量份以下。 When the second polymerizable ethylene monomer is a combination of a first monomer (preferably a (meth) acrylate monomer) and a third monomer (preferably a polymerization reactive ultraviolet absorber), the second polymerizable property The blending ratio of the third monomer in the ethylene monomer is, for example, 0.1% by mass or more, preferably 0.5% by mass or more, more preferably It is preferably at least 1% by mass, and further, for example, less than 50% by mass, preferably 25% by mass or less, more preferably 20% by mass or less. When the second polymerizable ethylene monomer is a combination of a first monomer (preferably a (meth) acrylate monomer) and a third monomer (preferably a polymerization reactive ultraviolet absorber), the third monomer The blending ratio of 100 parts by mass of the first monomer 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.

作為第2聚合性乙烯單體，較佳係藉由第2聚合性乙烯基單體之聚合所獲得之第2聚合物選擇對於抗生物活性化合物為不相溶(亦即，為非相溶)之單體。具體而言，第2聚合性乙烯單體係第2聚合物之溶解度參數δ之偶極力項δp,2nd polymer例如在0.0[(J/cm3)1/2]以上，較佳在1.0[(J/cm3)1/2]以上，又，例如未達5.0[(J/cm3)1/2]，較佳在4.9[(J/cm3)1/2]以下，溶解度參數δ之氫鍵力項δh,2nd polymer例如在0.0[(J/cm3)1/2]以上，又，例如未達8.0[(J/cm3)1/2]，較佳在7.0[(J/cm3)1/2]以下之單體。 As the second polymerizable ethylene monomer, it is preferred that the second polymer obtained by polymerization of the second polymerizable vinyl monomer is incompatible with respect to the antibiotic compound (that is, is incompatible). Monomer. Specifically, the dipole force term δ p, 2nd polymer of the solubility parameter δ of the second polymer of the second polymerizable ethylene single system is , for example, 0.0 [(J/cm 3 ) 1/2 ] or more, preferably 1.0 [ (J/cm 3 ) 1/2 ] or more, for example, less than 5.0 [(J/cm 3 ) 1/2 ], preferably 4.9 [(J/cm 3 ) 1/2 ] or less, solubility parameter δ The hydrogen bonding force term δ h, 2nd polymer is, for example, 0.0 [(J/cm 3 ) 1/2 ] or more, and, for example, less than 8.0 [(J/cm 3 ) 1/2 ], preferably 7.0 [( J/cm 3 ) 1/2 ] or less of the monomer.

第2聚合物之溶解度參數δ之偶極力項δp,2nd polymer及/或氫鍵力項δh,2nd polymer若超過上述之上限，則有時第2聚合物對於抗生物活性化合物為相溶。另一方面，第2聚合物之溶解度參數δ之偶極力項δp,2nd polymer及/或氫鍵力項δh,2nd polymer在漢森之溶解度參數δ定義上無未達0之值。惟，由於偶極力項δp,2nd polymer及/或氫鍵力項δh,2nd polymer越接近0，則第2聚合性乙烯單體變得容易浸入核芯中，殼層原料成分(或後述之殼層原料乳化液)較佳係一邊 留意不使第2聚合性乙烯單體滯留，一邊供給至乳濁液(供給)。 If the solubility parameter δ of the second polymer has a dipole force term δ p, 2nd polymer and/or a hydrogen bond force term δ h, if the 2nd polymer exceeds the above upper limit, the second polymer may be compatible with the antibiotic compound. . On the other hand, the dipole force term δ p of the solubility parameter δ of the second polymer, 2nd polymer and/or the hydrogen bond force term δ h, 2nd polymer has no value of 0 in the definition of the solubility parameter δ of Hansen. However, due to the dipole force term δ p, the 2nd polymer and/or the hydrogen bond force term δ h, the closer the 2nd polymer is to 0, the second polymerizable ethylene monomer is easily immersed in the core, and the shell raw material component (or later) The shell layer raw material emulsion is preferably supplied to the emulsion (supply) while keeping the second polymerizable ethylene monomer stagnant.

第2聚合物之偶極力項δp,2nd polymer及/或氫鍵力項δh,2nd polymer在上述之範圍內(亦即，第2聚合物之偶極力項δp,2nd polymer及氫鍵力項δh,2nd polymer至少一方在上述之範圍內)且抗生物活性化合物之偶極力項δp,compound及氫鍵力項δh,compound雙方只要在上述之範圍內，即使核芯中含有之抗生物活性化合物在殼層中遷移(移動)，如此之抗生物活性化合物與第2聚合物不相溶，亦即，該等被定義為非相溶。 The dipole force term δ p of the second polymer, 2nd polymer and/or the hydrogen bond force term δ h, 2nd polymer is within the above range (that is, the dipole force term δ p, 2nd polymer and hydrogen bond of the second polymer) The force term δ h, at least one of the 2nd polymers is within the above range) and the dipole force term δ p, compound and hydrogen bond force term δ h of the antibiotic compound are within the above range, even if the core contains The anti-biologically active compound migrates (move) in the shell such that the anti-biologically active compound is immiscible with the second polymer, i.e., the ones are defined as being incompatible.

第2聚合物對於抗生物活性化合物為不相溶時，可抑制以第2聚合體與抗生物活性化合物相溶為基礎之抗生物活性化合物漏出到殼層外，降低抗生物活性化合物釋放到殼層外之速度。因此，可更提昇持續釋放性粒子之持續釋放性。 When the second polymer is incompatible with the anti-biologically active compound, the anti-biologically active compound based on the compatibility of the second polymer with the anti-biologically active compound can be prevented from leaking out of the shell layer, and the release of the anti-biologically active compound to the shell can be suppressed. The speed outside the layer. Therefore, the sustained release of the sustained release particles can be further enhanced.

如上所述，用以生成對於抗生物活性化合物為非相溶之第2聚合物之第2聚合性乙烯單體，較佳係第1單體，具體而言可列舉複數種第1單體之組合，更佳為(甲基)丙烯酸酯系單體及芳族系乙烯單體之組合，更佳為具有碳數1至4烷基部分之(甲基)丙烯酸烷基酯及芳族系乙烯單體之組合，最佳為MMA及SM之組合。 As described above, the second polymerizable ethylene monomer for producing the second polymer which is incompatible with the antibiotic compound is preferably a first monomer, and specific examples thereof include a plurality of first monomers. In combination, it is more preferably a combination of a (meth) acrylate monomer and an aromatic vinyl monomer, more preferably an alkyl (meth) acrylate having an alkyl 1 to 4 alkyl moiety and an aromatic vinyl group. The combination of monomers is preferably a combination of MMA and SM.

第2聚合性乙烯單體為(甲基)丙烯酸酯系單體及芳族系乙烯單體之組合時，芳族系乙烯單體對(甲基)丙烯酸酯系單體及芳族系乙烯單體之總量100質量份之調 配比率在例如10質量份以上，較佳在20質量份以上，更佳在25質量份以上，又，例如在50質量份以下，較佳在40質量份以下，更佳在35質量份以下。芳族系乙烯單體之調配比率只要在上述之下限以上，則可降低第2聚合物對於抗生物活性化合物之相溶性，可將該等設為非相溶。芳族系乙烯單體之調配比率只要在上述之上限以下，則可抑制第2聚合物侵入核芯。 When the second polymerizable ethylene monomer is a combination of a (meth) acrylate monomer and an aromatic vinyl monomer, the aromatic vinyl monomer pair (meth) acrylate monomer and the aromatic vinyl monomer The total amount of the body is 100 parts by mass The blending ratio 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 further, for example, 50 parts by mass or less, preferably 40 parts by mass or less, more preferably 35 parts by mass or less. When the blending ratio of the aromatic vinyl monomer is at least the above lower limit, the compatibility of the second polymer with respect to the bioactive compound can be lowered, and these can be made incompatible. When the blending ratio of the aromatic vinyl monomer is at most the above upper limit, the penetration of the second polymer into the core can be suppressed.

(甲基)丙烯酸酯系單體之調配比率為芳族系乙烯單體調配比率之殘餘部分。 The compounding ratio of the (meth) acrylate monomer is a residual portion of the aromatic vinyl monomer compounding ratio.

2.持續釋放性粒子之製造方法 2. Method for producing sustained release particles

繼而，本發明持續釋放性粒子之製造方法具備將含有疏水性抗生物活性化合物及疏水性第1聚合性乙烯單體之核芯原料成分進行微乳化液聚合，調製核芯之核芯調製步驟；及將含有疏水性第2聚合性乙烯單體之殼層原料成分藉由將核芯作為種子之種子乳化聚合，調製將核芯包覆之殼層之殼層調製步驟。於核芯調製步驟中，為了從核芯原料成分製作微乳化液，以另一途徑調製第1乳化劑水溶液。 Then, the method for producing a sustained release particle of the present invention comprises a core preparation step of preparing a core by subjecting a core material component containing a hydrophobic antibiotic active compound and a hydrophobic first polymerizable ethylene monomer to a microemulsion polymerization; And a shell layer raw material component containing a hydrophobic second polymerizable ethylene monomer is subjected to emulsion polymerization of a seed having a core as a seed to prepare a shell layer modulating step of coating the core layer. In the core preparation step, in order to prepare a microemulsion from the core material component, the first emulsifier aqueous solution is prepared in another route.

2.1.核芯原料成分、第1乳化劑水溶液及殼層原料成分之調製 2.1. Modulation of core material components, first emulsifier aqueous solution and shell material components

首先，依序說明有關對於核芯原料成分、第1乳化劑水溶液及殼層原料成分之調製。 First, the preparation of the core raw material component, the first emulsifier aqueous solution, and the shell raw material component will be described in order.

2.1.1.核芯原料成分之調製 2.1.1. Modulation of core material components

於調製核芯原料成分，例如調配抗生物活性化合物及第1聚合性乙烯單體。較佳係將抗生物活性化合物以第1 聚合性乙烯單體溶解。經由此，調製含有抗生物活性化合物及第1聚合性乙烯單體之核芯原料成分。 For modulating the core material component, for example, an anti-biologically active compound and a first polymerizable ethylene monomer are formulated. Preferably, the antibiotic compound is the first The polymerizable ethylene monomer is dissolved. Thus, a core material component containing the antibiotic compound and the first polymerizable ethylene monomer is prepared.

又，核芯原料成分為疏水性溶液(油相成分)，例如不調配抗生物活性化合物之溶劑(己烷、甲苯、乙酸乙酯等疏水性有機溶劑)及/或水電霍夫(十六烷、十六烷醇等共穩定劑)，並被調製。藉由此，可降低環境負荷。 Further, the core material component is a hydrophobic solution (oil phase component), for example, a solvent (hydrophobic organic solvent such as hexane, toluene or ethyl acetate) which does not mix the antibiotic compound and/or hydroelectric Hoff (hexadecane) , a co-stabilizer such as cetyl alcohol), and is prepared. Thereby, the environmental load can be reduced.

抗生物活性化合物對於第1聚合性乙烯單體100質量份之調配比率例如在1質量份以上，較佳在5質量份以上，又，例如在400質量份以下，較佳在300質量份以下。 The blending ratio of the bioactive compound to 100 parts by mass of the first polymerizable ethylene monomer is, for example, 1 part by mass or more, preferably 5 parts by mass or more, and for example, 400 parts by mass or less, preferably 300 parts by mass or less.

在調製核芯原料成分，較佳係調配油溶性聚合引發劑。 In preparing the core material component, it is preferred to formulate an oil-soluble polymerization initiator.

油溶性聚合引發劑可列舉例如過氧化二月桂醯、1,1,3,3-四甲基丁基過氧化-2-乙基己酸酯、第三己基過氧化-2-乙基己酸酯、二異丙基過氧化二羧酸酯、苯醯基過氧化苯甲醯等油溶性有機過氧化物，例如2,2’-偶氮二異丁腈、2,2’-偶氮二(2,4-二甲基戊腈)、2,2’-偶氮雙(2-甲基丁腈)等油溶性偶氮化合物等。油溶性聚合引發劑較佳係可列舉油溶性有機過氧化物。 Examples of the oil-soluble polymerization initiator include dilaurin peroxide, 1,1,3,3-tetramethylbutylperoxy-2-ethylhexanoate, and third hexylperoxy-2-ethylhexanoic acid. Oil-soluble organic peroxides such as esters, diisopropyl peroxydicarboxylates, benzoquinone-based benzoyl peroxide, such as 2,2'-azobisisobutyronitrile, 2,2'-azo An oil-soluble azo compound such as (2,4-dimethylvaleronitrile) or 2,2'-azobis(2-methylbutyronitrile). The oil-soluble polymerization initiator is preferably an oil-soluble organic peroxide.

油溶性聚合引發劑可單獨使用或將2種以上併用。 The oil-soluble polymerization initiator may be used singly or in combination of two or more.

油溶性聚合引發劑之調配比率相對於第1聚合性乙烯單體100質量份，例如在0.01質量份以上，較佳在0.1質量份以上，例如在5質量份以下，較佳在3質量 份以下。 The blending ratio of the oil-soluble polymerization initiator is, for example, 0.01 parts by mass or more, preferably 0.1 parts by mass or more, for example, 5 parts by mass or less, preferably 3 parts by mass, per 100 parts by mass of the first polymerizable ethylene monomer. The following.

核芯原料成分例如可含有紫外線吸收劑作為任意成分。 The core material component may contain, for example, an ultraviolet absorber as an optional component.

紫外線吸收劑為除去上述聚合反應性紫外線吸收劑之紫外線吸收劑，例如雖然於分子內具有紫外線吸收基，但在分子內不具有聚合性碳-碳雙鍵之非聚合反應性紫外線吸收劑。又，紫外線吸收劑例如為疏水性。 The ultraviolet absorber is an ultraviolet absorber that removes the above-mentioned polymerization-reactive ultraviolet absorber. For example, a non-polymerizable ultraviolet absorber having no ultraviolet absorbing group in the molecule but having no polymerizable carbon-carbon double bond in the molecule. Further, the ultraviolet absorber is, for example, hydrophobic.

具體而言，紫外線吸收劑可列舉例如二苯甲酮系紫外線吸收劑、苯并***系紫外線吸收劑、羥基苯基三嗪系紫外線吸收劑、天然系紫外線吸收劑等。 Specifically, examples of the ultraviolet absorber include a benzophenone-based ultraviolet absorber, a benzotriazole-based ultraviolet absorber, a hydroxyphenyltriazine-based ultraviolet absorber, and a natural ultraviolet absorber.

二苯甲酮系紫外線吸收劑可列舉例如2,4-二羥基二苯甲酮、2-羥基-4-甲氧基二苯甲酮、2-羥基-4-甲氧基二苯甲酮-5-磺酸、2-羥基-4-正辛氧基二苯甲酮(ADK STAB1413，ADEKA公司製造)、2-羥基-4-正十二烷基氧基二苯甲酮、二(5-苯醯基-4-羥基-2-甲氧基苯基)甲烷(ADK STAB LA-51，ADEKA公司製造)、2,2’-二羥基-4-甲氧基二苯甲酮、2,2’-二羥基-4,4’-二甲氧基二苯甲酮等。 Examples of the benzophenone-based ultraviolet absorber include 2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, and 2-hydroxy-4-methoxybenzophenone- 5-sulfonic acid, 2-hydroxy-4-n-octyloxybenzophenone (ADK STAB1413, manufactured by ADEKA), 2-hydroxy-4-n-dodecyloxybenzophenone, di(5- Benzoyl-4-hydroxy-2-methoxyphenyl)methane (ADK STAB LA-51, manufactured by ADEKA), 2,2'-dihydroxy-4-methoxybenzophenone, 2,2 '-Dihydroxy-4,4'-dimethoxybenzophenone and the like.

苯并***系紫外線吸收劑可列舉例如TINUVIN 384-2(5% 2-甲氧基-1-甲基乙基乙酯、95%苯丙酸、3-(2H-苯并***-2-基)-5-(1,1-二甲基乙基)-4-羥基、C7-9側鏈及直鏈烷基酯，汽巴日本(Ciba Japan)公司製造)、TINUVIN PS(2-(2-羥基-5-第三丁基苯基)-2H-苯并***，汽巴．日本公司製造)等。 The benzotriazole-based ultraviolet absorber may, for example, be TINUVIN 384-2 (5% 2-methoxy-1-methylethylethyl ester, 95% phenylpropionic acid, 3-(2H-benzotriazole-2) -yl)-5-(1,1-dimethylethyl)-4-hydroxyl, C7-9 side chain and linear alkyl ester, Ciba Japan Co., Ltd., TINUVIN PS(2- (2-Hydroxy-5-t-butylphenyl)-2H-benzotriazole, Ciba. Manufactured by Japan Corporation, etc.

羥基苯基三嗪系紫外線吸收劑可列舉例如 TINUVIN 400(85% 2-(4,6-二(2,4-二甲基苯基)-1,3,5-三嗪-2-基)-5-羥基苯酯與環氧乙烷[(以C10-C16為主之C12-C13烷基氧基)甲基]環氧乙烷之反應生成物、15% 1-甲氧基-2-丙醇，汽巴日本公司製造)、TINUVIN 460(2,4-二[2-羥基-4-丁氧基苯基]-6-(2,4-二丁氧基苯基)-1,3-5-三嗪，汽巴日本公司製造)等。 The hydroxyphenyltriazine-based ultraviolet absorber can be exemplified by, for example TINUVIN 400 (85% 2-(4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl)-5-hydroxyphenyl ester with ethylene oxide [ (Reaction product of C12-C13 alkyloxy)methyl]oxirane based on C10-C16, 15% 1-methoxy-2-propanol, manufactured by Ciba Japan, TINUVIN 460 (2,4-bis[2-hydroxy-4-butoxyphenyl]-6-(2,4-dibutoxyphenyl)-1,3-5-triazine, manufactured by Ciba Japan) Wait.

天然系紫外線吸收劑可列舉例如卡法椒素(yangonin)等。 Examples of the natural ultraviolet absorber include yangonin and the like.

紫外線吸收劑較佳可列舉苯并***系紫外線吸收劑。 The ultraviolet absorber is preferably a benzotriazole-based ultraviolet absorber.

紫外線吸收劑可單獨使用或併用。 The ultraviolet absorbers may be used singly or in combination.

紫外線吸收劑可與光安定劑併用。光安定劑可列舉例如LA-82、LA-87(以上皆為ADEKA公司製造)等之聚合性光安定劑，例如TINUVIN123、TINUVIN144、TINUVIN292(以上皆為汽巴．日本公司製造)等之受阻胺系光安定劑。 The ultraviolet absorber can be used in combination with a light stabilizer. Examples of the light stabilizers include polymerizable photosensitizers such as LA-82 and LA-87 (all of which are manufactured by ADEKA Co., Ltd.), for example, hindered amines such as TINUVIN123, TINUVIN144, and TINUVIN292 (all of which are manufactured by Ciba. Japan). Light stabilizer.

紫外線吸收劑例如可與聚合反應性紫外線吸收劑併用。 The ultraviolet absorber can be used in combination with, for example, a polymerization-reactive ultraviolet absorber.

紫外線吸收劑含於核芯原料成分時，可列舉聚合反應性紫外線吸收劑含於殼層原料成分及/或核芯原料成分之態樣。於該等態樣，具體而言可列舉例如紫外線吸收劑含於核芯原料成分、聚合反應性紫外線吸收劑未含有於核芯原料成分而是含於殼層原料成分之第5態樣，例如紫外線吸收劑含於核芯原料成分、聚合反應性紫外線吸 收劑含於核芯原料成分未含有於殼層原料成分之第6態樣，例如紫外線吸收劑含於核芯原料成分、聚合反應性紫外線吸收劑含於核芯原料成分、亦含於殼層原料成分之第7態樣。 When the ultraviolet absorber is contained in the core raw material component, the polymerization reactive ultraviolet absorber is contained in the shell raw material component and/or the core raw material component. Specifically, for example, the fifth embodiment in which 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, for example, The ultraviolet absorber is contained in the core material component, and the polymerization is reactive with ultraviolet light. The charging agent is contained in the sixth aspect in which the core material component is not contained in the shell material component, for example, the ultraviolet absorber is contained in the core material component, the polymerization reactive ultraviolet absorber is contained in the core material component, and is also contained in the shell layer. The seventh aspect of the raw material composition.

另一方面，較佳紫外線吸收劑不與聚合反應性紫外線吸收劑併用，調配於核芯原料成分。亦即，紫外線吸收劑含於核芯原料成分，聚合反應性紫外線吸收劑不含於核芯原料成分，而亦不含於殼層原料成分之第8態樣。 On the other hand, it is preferred that the ultraviolet absorber is not used in combination with the polymerization-reactive ultraviolet absorber and is formulated in the core material component. That is, the ultraviolet absorber is contained in the core material component, and the polymerization reactive ultraviolet absorber is not contained in the core material component, and is not contained in the eighth aspect of the shell material component.

紫外線吸收劑之調配比率相對於抗生物活性化合物100質量份，例如在0.2質量份以上，較佳在1質量份以上，例如在30質量份以下，較佳在20質量份以下。又，紫外線吸收劑之調配比率相對於第1聚合性乙烯單體100質量份，例如在0.1質量份以上，較佳在1質量份以上，例如在20質量份以下，較佳在10質量份以下。 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 20 parts by mass or less, based on 100 parts by mass of the anti-biologically active compound. In addition, 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 10 parts by mass or less, based on 100 parts by mass of the first polymerizable ethylene monomer. .

紫外線吸收劑與聚合反應性紫外線吸收劑併用時，紫外線吸收劑(非聚合反應性紫外線吸收劑)之調配比率對於聚合反應性紫外線吸收劑100質量份例如在10質量份以上，較佳在50質量份以上，例如在500質量份以下，較佳在100質量份以下。 When the ultraviolet absorber is used in combination with the polymerization-reactive ultraviolet absorber, the blending ratio of the ultraviolet absorber (non-polymerizable ultraviolet absorber) is, for example, 10 parts by mass or more, preferably 50 mass, per 100 parts by mass of the polymerization-reactive ultraviolet absorber. The part or more is, for example, 500 parts by mass or less, preferably 100 parts by mass or less.

紫外線吸收劑調配於抗生物活性化合物及第1聚合性乙烯單體。較佳將紫外線吸收劑與抗生物活性化合物一起溶解於第1聚合性乙烯單體。藉由此，調製含有抗生物活性化合物及紫外線吸收劑之第1聚合性乙烯單體溶液(亦即，核芯原料成分)。詳言之，調製含有抗生物活 性化合物、第1聚合性乙烯單體、必要時所調配之油溶性聚合引發劑及必要時所調配之紫外線吸收劑之核芯原料成分。 The ultraviolet absorber is formulated with the antibiotic compound and the first polymerizable ethylene monomer. Preferably, the ultraviolet absorber is dissolved in the first polymerizable ethylene monomer together with the antibiotic compound. Thereby, the first polymerizable ethylene monomer solution (that is, the core material component) containing the antibiotic compound and the ultraviolet absorber is prepared. In detail, the modulation contains antibiotics. The core compound component of the compound, the first polymerizable ethylene monomer, the oil-soluble polymerization initiator which is blended if necessary, and the ultraviolet absorber which is optionally blended.

2.1.2.調製第1乳化劑水溶液 2.1.2. Preparation of the first emulsifier aqueous solution

於調製第1乳化劑水溶液，係將水及乳化劑調配。 In the preparation of the first aqueous emulsifier solution, water and an emulsifier are prepared.

具體而言，將水與乳化劑調配，將該等均一攪拌，獲得第1乳化劑水溶液。 Specifically, water and an emulsifier are blended, and these are uniformly stirred to obtain a first emulsifier aqueous solution.

乳化劑可列舉例如二辛基磺基琥珀酸鈉、十二烷基苯磺酸鈉、月桂基硫酸鈉、十二烷基二苯基醚二磺酸鈉、壬基二苯基醚磺酸鈉等陰離子系乳化劑。 Examples of the emulsifier include sodium dioctylsulfosuccinate, sodium dodecylbenzenesulfonate, sodium lauryl sulfate, sodium dodecyl diphenyl ether disulfonate, and sodium decyl diphenyl ether sulfate. An anionic emulsifier.

乳化劑可列舉例如聚氧伸烷基烷基醚、聚氧伸烷基烷基芳基醚、聚氧伸烷基芳烷基芳基醚、聚氧伸烷基嵌段共聚合物、聚氧伸烷基芳基醚等非離子系乳化劑。 The emulsifier may, for example, be a polyoxyalkylene alkyl ether, a polyoxyalkylene alkyl aryl ether, a polyoxyalkylene arylalkyl aryl ether, a polyoxyalkylene block copolymer, a polyoxygen. A nonionic emulsifier such as an alkyl aryl ether.

聚氧伸烷基烷基醚可列舉例如聚環氧乙烷烷基醚等。 The polyoxyalkylene alkyl ether may, for example, be a polyethylene oxide alkyl ether or the like.

聚氧伸烷基烷基芳基醚可列舉例如，聚環氧乙烷壬基苯基醚、聚環氧乙烷辛基苯基醚等。 The polyoxyalkylene alkyl aryl ether may, for example, be polyethylene oxide nonylphenyl ether or polyethylene oxide octylphenyl ether.

聚氧伸烷基芳烷基芳基醚可列舉例如聚環氧乙烷苯乙烯化苯基醚等。 The polyoxyalkylene aralkyl aryl ether may, for example, be a polyethylene oxide styrene phenyl ether or the like.

聚氧伸烷基嵌段共聚合物可列舉例如聚環氧乙烷-聚環氧丙烷嵌段共聚合物等。 The polyoxyalkylene block copolymer may, for example, be a polyethylene oxide-polypropylene oxide block copolymer or the like.

聚氧伸烷基芳基醚可列舉例如聚環氧乙烷芳基醚等。 The polyoxyalkylene aryl ether may, for example, be a polyethylene oxide aryl ether or the like.

乳化劑較佳可列舉陰離子系乳化劑。 An emulsifier is preferably an anionic emulsifier.

乳化劑可單獨使用或將2種以上併用。 The emulsifier may be used singly or in combination of two or more.

乳化劑之調配比率例如設定成在將核芯原料成分於以下說明之第1乳化劑水溶液中進行乳化時不會產生微胞。詳言之，乳化劑之調配比率設定成在將核芯原料成分於第1乳化劑水溶液進行乳化時，不超過將從乳化劑固有之每個單位質量之占有面積所算出之微乳化液粒子包覆時必需之乳化劑量、及在第1乳化劑水溶液中成為臨界微胞濃度之乳化劑量之總和。乳化劑之調配比率對於第1乳化劑水溶液，乳化劑之有效成分量例如在0.1質量%以上，較佳在0.2質量%以上，又，例如在20質量%以下，較佳在10質量%以下。將乳化劑之調配比率，相對於核芯原料成分，調整成使乳化劑之有效成分量例如在0.1質量%以上，較佳在0.2質量%以上，又，例如在20質量%以下，較佳在10質量%以下。乳化劑之調配比率只要在上述之上限以下，則可抑制於生成微胞之新粒子的發生，由於以固定之粒子數進行聚合，可確實地將抗生物活性化合物內包。 The blending ratio of the emulsifier is set, for example, so that the micelle does not generate when the core raw material component is emulsified in the first emulsifier aqueous solution described below. In particular, when the core material component is emulsified in the first emulsifier aqueous solution, the ratio of the emulsifier is not more than the microemulsion particle package calculated from the occupied area per unit mass of the emulsifier. The emulsifier dose necessary for the coating and the sum of the emulsifier doses which become the critical microcell concentration in the first emulsifier aqueous solution. The ratio of the emulsifier to the aqueous solution of the first 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, preferably 10% by mass or less. The blending ratio of the emulsifier is adjusted so that the amount of the active component of the emulsifier is, for example, 0.1% by mass or more, preferably 0.2% by mass or more, and further, for example, 20% by mass or less, preferably in the core raw material component. 10% by mass or less. When the ratio of the emulsifier is less than or equal to the above upper limit, the generation of new particles of the micelles can be suppressed, and the polymerization can be carried out by the number of fixed particles, whereby the antibiotic compound can be surely encapsulated.

第1乳化劑水溶液亦可含有分散劑。 The first aqueous emulsifier solution may also contain a dispersing agent.

分散劑較佳與乳化劑併用，具體而言，可列舉例如聚乙烯醇(以下，簡稱為「PVA」)、芳族磺酸與甲醛之縮合物之鹽、聚羧酸型低聚物、羥基纖維素等纖維素系分散劑等，較佳可列舉PVA、芳族磺酸與甲醛之縮合物之鹽。 The dispersing agent is preferably used in combination with an emulsifier. Specific examples thereof include polyvinyl alcohol (hereinafter abbreviated as "PVA"), a salt of a condensate of an aromatic sulfonic acid and formaldehyde, a polycarboxylic acid type oligomer, and a hydroxyl group. A cellulose-based dispersant such as cellulose is preferably a salt of a condensate of PVA or aromatic sulfonic acid and formaldehyde.

PVA為用以形成微乳化液之保護膠體，調配於水相(第1乳化劑水溶液)中之分散劑，可藉由例如將乙 酸乙烯作為主成分之乙烯單體，以適當之方法進行聚合獲得之聚乙酸乙烯系聚合體皂化而獲得。 PVA is a protective colloid for forming a microemulsion, and a dispersing agent formulated in an aqueous phase (a first emulsifier aqueous solution) can be, for example, B A vinyl monomer having a main component as the main component is obtained by saponifying a polyvinyl acetate-based polymer obtained by polymerization in an appropriate manner.

藉由將PVA調配於第1乳化劑水溶液，藉由PVA之保護膠體，形成安定之水合層，不容易因粒子間衝突引起凝集。其結果，即使例如於乳化劑量少之處方，亦可降低微乳化液聚合中之凝集物量等，可提昇聚合安定性。 By disposing the PVA in the first emulsifier aqueous solution, the P-protecting colloid forms a stable hydration layer, which is less likely to cause aggregation due to collision between particles. As a result, even if the amount of the emulsifier is small, for example, the amount of agglomerates in the polymerization of the microemulsion can be lowered, and the polymerization stability can be improved.

PVA之皂化度例如在70%以上，較佳在80%以上，又，例如在99%以下，較佳在90%以下。 The degree of saponification of PVA is, for example, 70% or more, preferably 80% or more, and further, for example, 99% or less, preferably 90% or less.

PVA之平均聚合度例如在300以上，較佳在500以上，又，例如在4000以下，較佳在2500以下。 The average degree of polymerization of the PVA is, for example, 300 or more, preferably 500 or more, and further, for example, 4,000 or less, preferably 2,500 or less.

PVA於20℃、4%水溶液之粘度例如在3mPa．sec以上，較佳在5mPa．sec以上，又，例如在100mPa．sec以下，較佳在50mPa．sec以下。PVA之粘度可使用B型粘度計，於20℃測定該4%水溶液。 The viscosity of PVA at 20 ° C, 4% aqueous solution, for example, at 3 mPa. Above sec, preferably at 5mPa. Above sec, again, for example at 100mPa. Below sec, preferably at 50 mPa. Sec below. The viscosity of PVA can be measured at 20 ° C using a Brookfield viscometer.

使PVA含於第1乳化劑水溶液係可預先調製PVA水溶液，於此調配水及乳化劑，將該等均一攪拌。PVA水溶液之調製可藉由例如在25℃以下之冷水，於攪拌下投入PVA使其分散，以原狀昇溫至60至90℃，使其溶解。確認PVA完全溶解於水後於室溫冷卻來實施。 The PVA is contained in the first emulsifier aqueous solution, and the PVA aqueous solution can be prepared in advance, and water and an emulsifier are prepared, and the mixture is uniformly stirred. The preparation of the PVA aqueous solution can be carried out by, for example, cooling water at 25 ° C or lower, PVA is added to the dispersion under stirring, and the temperature is raised to 60 to 90 ° C in the original state to be dissolved. It was confirmed that PVA was completely dissolved in water and then cooled at room temperature to carry out.

芳族磺酸可列舉例如苯磺酸、甲苯磺酸、枯烯磺酸、萘磺酸等。較佳可列舉α-萘磺酸、β-萘磺酸等萘磺酸。 Examples of the aromatic sulfonic acid include benzenesulfonic acid, toluenesulfonic acid, cumenesulfonic acid, naphthalenesulfonic acid and the like. Preferable examples thereof include naphthalenesulfonic acid such as α-naphthalenesulfonic acid and β-naphthalenesulfonic acid.

作為用以形成鹽之陽離子可列舉例如鈉陽離子、鉀陽離子等1價鹼金屬陽離子、例如銨陽離子等。較 佳可列舉1價之鹼金屬陽離子。 The cation for forming a salt may, for example, be a monovalent alkali metal cation such as a sodium cation or a potassium cation, for example, an ammonium cation. More A exemplified by a monovalent alkali metal cation.

作為芳族磺酸與甲醛之縮合物之鹽，具體而言，可列舉萘磺酸與甲醛之縮合物之鹽(萘磺酸甲醛縮合物鈉鹽)。作為芳族磺酸與甲醛之縮合物之鹽可使用市售品，具體而言，可列舉迪莫(Demol)NL(β-萘磺酸甲醛縮合物之鈉鹽之41%水溶液，花王公司製造)等。 Specific examples of the salt of the condensate of aromatic sulfonic acid and formaldehyde include a salt of a condensate of naphthalenesulfonic acid and formaldehyde (sodium salt of a naphthalenesulfonic acid formaldehyde condensate). A commercially available product can be used as a salt of a condensate of an aromatic sulfonic acid and formaldehyde, and specific examples thereof include Demol NL (41% aqueous solution of a sodium salt of a β-naphthalenesulfonic acid formaldehyde condensate, manufactured by Kao Corporation). )Wait.

該等分散劑可單獨使用或將2種以上併用。分散劑較佳可列舉PVA、芳族磺酸與甲醛之縮合物之鹽之組合。 These dispersing agents may be used singly or in combination of two or more. The dispersing agent is preferably a combination of a salt of PVA, a condensate of an aromatic sulfonic acid and formaldehyde.

分散劑為PVA、芳族磺酸與甲醛之縮合物之鹽之組合時，作為有效成分量，相對於核芯原料成分100質量份，使PVA之調配比率調整成例如在0.5質量份以上，較佳在1質量份以上，又，例如在20質量份以下，較佳在10質量份以下。芳族磺酸與甲醛之縮合物之鹽之調配比率，作為有效成分量，相對於核芯原料成分100質量份調整成例如在0.01質量份以上，較佳在0.1質量份以上，又，例如在10質量份以下，較佳在1質量份以下。 When the dispersing agent is a combination of a salt of PVA or a condensate of aromatic sulfonic acid and formaldehyde, the blending ratio of the PVA is adjusted to, for example, 0.5 parts by mass or more based on 100 parts by mass of the core raw material component as the amount of the active ingredient. It is preferably 1 part by mass or more, and further, 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 the aromatic sulfonic acid and the formaldehyde is adjusted to, for example, 0.01 parts by mass or more, preferably 0.1 parts by mass or more, based on 100 parts by mass of the core raw material component, as in the amount of the active ingredient. 10 parts by mass or less, preferably 1 part by mass or less.

2.1.3.調製殼層原料成分 2.1.3. Modulation of shell material ingredients

為調製殼層原料成分例如準備疏水性第2聚合性乙烯單體直接作為殼層原料成分。或使疏水性第2聚合性乙烯單體乳化。較佳為使疏水性第2聚合性乙烯基單體乳化。亦即，使疏水性第2聚合性乙烯單體乳化，調製殼層原料成分作為殼層原料乳化液。 For example, a hydrophobic second polymerizable ethylene monomer is prepared as a shell material component in order to prepare a shell material component. Alternatively, the hydrophobic second polymerizable ethylene monomer is emulsified. It is preferred to emulsify the hydrophobic second polymerizable vinyl monomer. In other words, the hydrophobic second polymerizable ethylene monomer is emulsified to prepare a shell raw material component as a shell raw material emulsion.

殼層原料成分(殼層原料乳化液)較佳係實質 上不調配抗生物活性化合物。亦即，殼層原料成分(殼層原料乳化液)較佳係實質上不含有抗生物活性化合物。亦即，抗生物活性化合物實質上未含於殼層原料成分(殼層原料乳化液)。 The shell raw material component (shell material emulsion) is preferably the essence The anti-biologically active compound is not formulated. That is, the shell raw material component (shell material emulsion) preferably does not substantially contain an anti-bioactive compound. That is, the antibiotic compound is substantially not contained in the shell raw material component (shell material emulsion).

換言之，殼層原料成分可容許含有不阻礙本發明效果程度之抗生物活性化合物。具體而言，相對於第2聚合性乙烯基單體100質量份，可容許含有比率例如在1質量份以下，尤其是0.1質量份以下之抗生物活性化合物。 In other words, the shell raw material component can be allowed to contain an anti-biologically active compound which does not impair the effects of the present invention. Specifically, the content of the anti-biologically active compound is, for example, 1 part by mass or less, particularly 0.1 part by mass or less, based on 100 parts by mass of the second polymerizable vinyl monomer.

從降低製造成本之觀點而言，殼層原料成分較佳係不含有紫外線吸收劑。亦即，紫外線吸收劑較佳不含於殼層原料成分，亦不含於核芯原料成分。 From the viewpoint of reducing the production 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 material component.

為調製殼層原料乳化液係例如在乳化劑存在下，將第2聚合性乙烯單體於水中乳化。較佳，首先將乳化劑於水中調配，調製第2乳化劑水溶液，接著，將第2聚合性乙烯單體於第2乳化劑水溶液中乳化。具體而言，將第2聚合性乙烯單體於第2乳化劑水溶液中調配，將該等攪拌。 In order to prepare the shell raw material emulsion, for example, the second polymerizable ethylene monomer is emulsified in water in the presence of an emulsifier. Preferably, the emulsifier is first formulated in water to prepare a second emulsifier aqueous solution, and then the second polymerizable ethylene monomer is emulsified in the second emulsifier aqueous solution. Specifically, the second polymerizable ethylene monomer is blended in the second emulsifier aqueous solution, and the mixture is stirred.

乳化劑可列舉與上述之乳化劑相同者，較佳可列舉陰離子系乳化劑。 The emulsifier may be the same as the emulsifier described above, and an anionic emulsifier is preferred.

乳化劑之調配比率係設定成使第2聚合性乙烯單體於第2乳化劑水溶液中乳化時不生成微胞。乳化劑之調配比率具體而言，相對於第2乳化劑水溶液，乳化劑之有效成分量例如在0.01質量%以上，較佳在0.1質量%以上，又，例如在10質量%以下，較佳在5質量%以下。 The blending ratio of the emulsifier is set so that no micelle is formed when the second polymerizable ethylene monomer is emulsified in the second emulsifier aqueous solution. Specifically, the amount of the emulsifier is preferably 0.01% by mass or more, preferably 0.1% by mass or more, and further preferably 10% by mass or less, preferably in the second emulsifier aqueous solution. 5 mass% or less.

第2聚合性乙烯單體之乳化只要將第2聚合性乙烯單體分散於第2乳化劑水溶液中即可，第2聚合性乙烯單體之粒徑為任意，因此，例如將第2聚合性乙烯單體調配於容器中之第2乳化劑水溶液，之後藉由具備攪拌葉片之攪拌機、磁力攪拌器等，一邊攪拌一邊供給於微乳化液聚合後之反應液，例如預先調製(準備)藉由混合機、均混機乳化之殼層原料乳化液，將此供給於微乳化液聚合後之反應液(乳濁液)。 Emulsification of the second polymerizable ethylene monomer may be carried out by dispersing the second polymerizable ethylene monomer in the second emulsifier aqueous solution, and the particle diameter of the second polymerizable ethylene monomer is arbitrary. Therefore, for example, the second polymerizable property is used. The ethylene monomer is blended in the second emulsifier aqueous solution in the container, and then supplied to the reaction liquid after the polymerization of the microemulsion by stirring with a stirrer equipped with a stirring blade, a magnetic stirrer, or the like, for example, preliminarily prepared (prepared) by The mixture of the shell layer raw material emulsified by the mixer and the homomixer is supplied to the reaction liquid (emulsion) after the microemulsion polymerization.

第2聚合性乙烯單體之調配比率，相對於第2乳化劑水溶液100質量份例如在10質量份以上，較佳在50質量份以上，又，例如在200質量份以下，較佳在150質量份以下，更佳在100質量份以下，最佳在80質量份以下。將第2聚合性乙烯單體之調配比率調整使對於核芯100質量份例如在1質量份以上，較佳在10質量份以上，又，例如在1000質量份以下，較佳在100質量份以下。 The blending ratio of the second polymerizable ethylene monomer is, for example, 10 parts by mass or more, preferably 50 parts by mass or more, and more preferably 200 parts by mass or less, and more preferably 150 mass, per 100 parts by mass of the second emulsifier aqueous solution. The amount is preferably 100 parts by mass or less, more preferably 80 parts by mass or less. The blending ratio of the second polymerizable ethylene monomer is adjusted to, for example, 1 part by mass or more, preferably 10 parts by mass or more, and further, for example, 1000 parts by mass or less, preferably 100 parts by mass or less, based on 100 parts by mass of the core. .

第2聚合性乙烯單體之調配比率相對於第1聚合性乙烯單體及第2聚合性乙烯單體之總量100質量份，例如在5質量份以上，較佳在10質量份以上，更佳在20質量份以上，更佳在25質量份以上，特佳在30質量份以上，最佳在40質量份以上。第2聚合性乙烯單體之調配比率若在上述之下限以上，可使殼層對於核芯直徑(平均粒徑)之厚度增厚，可有效地延遲核芯含有之抗生物活性化合物釋放到殼層外，可更提昇持續釋放性粒子之釋放性。 The blending ratio of the second polymerizable ethylene monomer is, for example, 5 parts by mass or more, preferably 10 parts by mass or more, based on 100 parts by mass of the total of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer. It is preferably 20 parts by mass or more, more preferably 25 parts by mass or more, particularly preferably 30 parts by mass or more, and most preferably 40 parts by mass or more. When the ratio of the second polymerizable ethylene monomer is at least the above lower limit, the shell layer can be thickened to the core diameter (average particle diameter), and the core-containing antibiotic-active compound can be effectively delayed from being released to the shell. Outside the layer, the release of sustained release particles is enhanced.

另一方面，第2聚合性乙烯單體之調配比率， 對於第1聚合性乙烯單體及第2聚合性乙烯單體之總量100質量份在90質量份以下，較佳在50質量份以下。第2聚合性乙烯單體之調配比率若在上述之上限以下，即可確保持續釋放性粒子中之抗生物活性化合物之持續釋放性。 On the other hand, the ratio of the second polymerizable ethylene monomer, The total amount of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer is 90 parts by mass or less, preferably 50 parts by mass or less. When the ratio of the second polymerizable ethylene monomer is at most the above upper limit, the sustained release property of the antibiotic-active compound in the sustained release particles can be ensured.

又，殼層原料乳化液之調製較佳係另外調製聚合引發劑水溶液。 Further, the preparation of the shell raw material emulsion is preferably carried out by separately preparing a polymerization initiator aqueous solution.

為調製聚合引發劑水溶液，係將水溶性聚合引發劑溶解於水。 To prepare a polymerization initiator aqueous solution, a water-soluble polymerization initiator is dissolved in water.

水溶性聚合引發劑可列舉例如2,2’-偶氮雙(2-甲基丙脒)二硫酸鹽、2,2’-偶氮雙(2-甲基丙脒)二鹽酸鹽、2,2’-偶氮雙(2-脒基丙烷)二鹽酸鹽、2,2’-偶氮雙[N-(2-羧基乙基)-2-甲基丙脒]水合物、2,2’-偶氮雙(N,N’-二亞甲基異丁脒)、2,2’-偶氮雙{2-[1-(2-羥基乙基)-2-咪唑啉-2-基]丙烷}二鹽酸鹽、2,2’-偶氮雙(1-亞胺基-1-吡咯烷基-2-甲基丙烷)二鹽酸鹽、2,2’-偶氮雙{2-甲基-N-[1,1-二(羥基甲基)-2-羥基乙基]丙醯胺}、2,2’-偶氮雙[2-甲基-N-(2-羥基乙基)丙醯胺]、2,2’-偶氮雙[2-(2-咪唑啉-2-基)丙烷]、2,2’-偶氮雙[2-(2-咪唑啉-2-基)丙烷]二鹽酸鹽、2,2’-偶氮雙[2-(2-咪唑啉-2-基)丙烷]二硫酸鹽二水合物等水溶性偶氮化合物，例如過硫酸鉀、過硫酸鈉、過硫酸銨等過硫酸鹽化合物，例如過氧化氫等水溶性無機過氧化物，例如第三丁基過氧化物、枯烯過氧化物等水溶性有機過氧化物等。進一步，水溶性聚合引發劑可列舉例如將除去水溶性偶氮化合物之水溶性聚合引發劑、與抗壞血酸、 次亞硫酸氫鈉、次亞硫酸鈉、亞硫酸氫鈉、亞硫酸鈉、亞硫酸氫鈉、羥基甲烷亞磺酸鈉(吊白塊(Rongalite))、二氧化硫脲、硫代硫酸鈉、2價鐵鹽、1價銅鹽、胺類等水溶性還元劑組合之氧化還原(Redox)系水溶性聚合引發劑等。 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'-dimethylideneisobutane), 2,2'-azobis{2-[1-(2-hydroxyethyl)-2-imidazolin-2- Propane}dihydrochloride, 2,2'-azobis(1-imino-1-pyrrolidinyl-2-methylpropane) dihydrochloride, 2,2'-azo double { 2-methyl-N-[1,1-bis(hydroxymethyl)-2-hydroxyethyl]propanamine}, 2,2'-azobis[2-methyl-N-(2-hydroxyl) Ethyl)propanolamine, 2,2'-azobis[2-(2-imidazolin-2-yl)propane], 2,2'-azobis[2-(2-imidazoline-2) a water-soluble azo compound such as a propane]dihydrochloride or a 2,2'-azobis[2-(2-imidazolin-2-yl)propane]disulfate dihydrate, such as potassium persulfate a persulfate compound such as sodium persulfate or ammonium persulfate, for example, a water-soluble inorganic peroxide such as hydrogen peroxide, or a water-soluble organic peroxide such as a third butyl peroxide or a cumene peroxide.Further, examples of the water-soluble polymerization initiator include a water-soluble polymerization initiator which removes a water-soluble azo compound, and ascorbic acid. Sodium hyposulfite, sodium hyposulfite, sodium hydrogen sulfite, sodium sulfite, sodium hydrogen sulfite, sodium hydroxymethanesulfinate (Rongalite), thiourea dioxide, sodium thiosulfate, divalent iron salt, 1 A redox-based water-soluble polymerization initiator which is a combination of a water-soluble reductant such as a valence copper salt or an amine.

水溶性聚合引發劑可單獨使用或將2種以上併用。 The water-soluble polymerization initiator may be used singly or in combination of two or more.

水溶性聚合引發劑較佳可列舉過硫酸鹽化合物。 The water-soluble polymerization initiator is preferably a persulfate compound.

水溶性聚合引發劑之調配比率相對於第2聚合性乙烯單體100質量份例如在0.01質量份以上，較佳在0.1質量份以上，例如在3質量份以下，較佳在1質量份以下。 The blending 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, preferably 1 part by mass or less, per 100 parts by mass of the second polymerizable ethylene monomer.

水溶性聚合引發劑之調配比率對於聚合引發劑水溶液，可適當設定例如在0.1質量%以上，較佳在1質量%以上，又，例如在20質量%以下，較佳在10質量%以下。 The mixing ratio of the water-soluble polymerization initiator can be appropriately set to, for example, 0.1% by mass or more, preferably 1% by mass or more, and for example, 20% by mass or less, preferably 10% by mass or less.

2.2.微乳化液聚合及種子乳化聚合 2.2. Microemulsion polymerization and seed emulsion polymerization

接著，將核芯調製步驟中之微乳化液聚合及殼層調製步驟中之種子乳化聚合依序說明。 Next, the seed emulsion polymerization in the microemulsion polymerization and the shell layer preparation step in the core preparation step will be described in order.

2.2.1微乳化液聚合 2.2.1 Microemulsion polymerization

於核芯調製步驟，為將核芯原料成分進行微乳化液聚合，首先，將核芯原料成分在第1乳化劑水溶液中乳化。 In the core preparation step, in order to carry out microemulsion polymerization of the core material component, first, the core material component is emulsified in the first emulsifier aqueous solution.

具體而言，將核芯原料成分調配於第1乳化劑水溶液，於此等賦予高剪切力，藉此，將核芯原料成分 於第1乳化劑水溶液中乳化，調製微乳化液。 Specifically, the core raw material component is blended in the first emulsifier aqueous solution, and high shear force is imparted thereto, whereby the core raw material component is added. The emulsion was emulsified in the first emulsifier aqueous solution to prepare a microemulsion.

核芯原料成分之乳化例如使用均相混合機(homomixer)、超音波均質機、加壓式均質機、乳化分散機、多孔膜壓入乳化機等乳化機，較佳係使用均相混合機。 For the emulsification of the core material component, for example, an emulsifier such as a homomixer, an ultrasonic homogenizer, a pressurized homogenizer, an emulsification disperser, or a porous membrane press emulsifier is used, and a homomixer is preferably used.

攪拌條件可適當設定，於使用均相混合機時，其旋轉數設定於例如在6000rpm以上，較佳在8000rpm以上，更佳在10000rpm以上，例如在30000rpm以下。旋轉數未達上述下限時，有時不能形成粒徑未達1μm之微乳化液粒子。 The stirring condition can be appropriately set. When the 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, 30,000 rpm or less. When the number of rotations does not reach the above lower limit, microemulsion particles having a particle diameter of less than 1 μm may not be formed.

攪拌時間例如在1分鐘以上，較佳在2分鐘以上，又，在1小時以下。 The stirring time is, for example, 1 minute or longer, preferably 2 minutes or longer, and further, 1 hour or shorter.

核芯原料成分之調配比率相對於第1乳化劑水溶液100質量份，例如在10質量份以上，較佳在25質量份以上，又，例如在100質量份以下，較佳在90質量份以下。 The blending ratio of the core 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 or less, based on 100 parts by mass of the first emulsifier aqueous solution.

藉由上述方法調製核芯原料成分之微乳化液。又，核芯原料成分之微乳化液為乳化劑吸附於微乳化液粒子(核芯原料成分之乳化液滴)，在水介質中形成平均粒徑未達1μm之核芯原料成分之微乳化液粒子。 The microemulsion of the core material component is prepared by the above method. Further, the microemulsion of the core material component is an emulsifier adsorbed to the microemulsion particles (emulsified droplets of the core material component), and a microemulsion of a core material component having an average particle diameter of less than 1 μm is formed in an aqueous medium. particle.

微乳化液粒子之平均粒徑以中值徑算出，調整為例如未達1μm，較佳在750nm以下，更佳在500nm以下，更佳在400nm以下，最佳在300nm以下，又，例如在50nm以上。 The average particle diameter of the microemulsion particles is calculated as a median diameter, and is adjusted to, for example, less than 1 μm, preferably 750 nm or less, more preferably 500 nm or less, more preferably 400 nm or less, most preferably 300 nm or less, and further, for example, 50 nm. the above.

由於微乳化液粒子係在粒子中含有之抗生物 活性化合物作用為水電霍夫(共穩定劑)，防止奧斯瓦爾德熟化(ostwald ripening)，抑制核芯肥大化(粒徑之増大)，可維持乳化時之粒徑，另外，乳化劑吸附於該微乳化液粒子表面，經由此，可使微乳化液分散安定化(亦即，確保微乳化液之水分散安定性)。 Since the micro-emulsion particle system acts as a hydro-electrical compound (hydro-stabilizer) in the particles, it prevents Oswald ripening and inhibits core enlargement (larger particle size). The particle size at the time of emulsification is maintained, and the emulsifier is adsorbed on the surface of the microemulsion particle, whereby the microemulsion can be dispersed and stabilized (that is, the water dispersion stability of the microemulsion is ensured).

之後，將經乳化之第1聚合性乙烯單體在油溶性聚合引發劑存在下進行微乳化液聚合，生成由第1聚合物及抗生物活性化合物形成之核芯。又，此時，可併用油溶性聚合引發劑，添加上述之水溶性聚合引發劑而進行微乳化液聚合。又，亦可只以水溶性聚合引發劑進行微乳化液聚合。 Thereafter, the emulsified first polymerizable ethylene monomer is subjected to microemulsion polymerization in the presence of an oil-soluble polymerization initiator to form a core formed of the first polymer and the bioactive compound. Further, in this case, the oil-soluble polymerization initiator may be used in combination, and the above-described water-soluble polymerization initiator may be added to carry out microemulsion polymerization. Further, the microemulsion polymerization may be carried out only with a water-soluble polymerization initiator.

該微乳化液聚合，由於成為原料之第1聚合性乙烯單體全部只在於微乳化液粒子(疏水性液相)，為現場聚合(in-situ polymerization)。亦即，微乳化液聚合為藉由將微乳化液一邊攪拌一邊加熱，第1聚合性乙烯單體直接在微乳化液粒子中開始聚合，生成第1聚合物。 In the microemulsion polymerization, all of the first polymerizable ethylene monomers to be used as the raw materials are only in the microemulsion particles (hydrophobic liquid phase), and are in-situ polymerization. That is, the microemulsion is polymerized by heating the microemulsion while stirring, and the first polymerizable ethylene monomer is directly polymerized in the microemulsion particles to form a first polymer.

微乳化液之攪拌中攪拌葉片之周速度例如在10m/分鐘以上，較佳在20m/分鐘以上，又，在400m/分鐘以下，較佳在200m/分鐘以下。 The peripheral speed of the stirring blade during the stirring of the microemulsion is, for example, 10 m/min or more, preferably 20 m/min or more, and further 400 m/min or less, preferably 200 m/min or less.

加熱條件係可根據油溶性聚合引發劑或第1聚合性乙烯單體之種類而適當選擇，加熱溫度例如在抗生物活性化合物之融點以上，具體而言，例如在30℃以上，較佳在50℃以上，又，例如在100℃以下，加熱時間例如在2小時以上，較佳在3小時以上，又，例如在24小時以 下，較佳在12小時以下。另外，亦可於預定之溫度加熱後，將該溫度維持預定之時間，之後，可藉由反覆進行加熱及維持溫度，階段性加熱。 The heating condition can be appropriately selected depending on the type of the oil-soluble polymerization initiator or the first polymerizable ethylene monomer, and the heating temperature is, for example, at least the melting point of the anti-biologically active compound, specifically, for example, 30 ° C or higher, preferably 50 ° C or more, and, for example, below 100 ° C, the heating time is, for example, 2 hours or more, preferably 3 hours or more, and, for example, at 24 hours. Next, preferably less than 12 hours. Alternatively, the temperature may be maintained for a predetermined period of time after being heated at a predetermined temperature, and then the heating may be repeated and the temperature may be maintained by stepwise heating.

藉由微乳化液聚合，獲得含有含有第1聚合物及抗生物活性化合物之核芯之乳濁液。於乳濁液，核芯被分散著。 The emulsion containing the core of the first polymer and the antibiotic compound is obtained by polymerization in a microemulsion. In the emulsion, the core is dispersed.

核芯在藉由第1聚合性乙烯單體聚合所獲得之第1聚合體成為抗生物活性化合物相溶之均一相。 The first polymer obtained by polymerizing the first polymerizable ethylene monomer in the core becomes a homogeneous phase in which the bioactive compound is compatible.

之後，不將反應後之乳濁液冷卻，而維持於聚合溫度，繼續實施種子乳化聚合。 Thereafter, the emulsion after the reaction was not cooled, but maintained at the polymerization temperature, and the seed emulsion polymerization was continued.

或，亦可將乳濁液冷卻至例如室溫(20至30℃，更具體為25℃))。 Alternatively, the emulsion may be cooled to, for example, room temperature (20 to 30 ° C, more specifically 25 ° C)).

如此方式所獲得之核芯之平均粒徑，算出中值徑，為未達1μm，較佳在750nm以下，更佳在500nm以下，再更佳在400nm以下，最佳在300nm以下，又，例如在10nm以上，較佳在50nm以上。 The average particle diameter of the core obtained in this manner is calculated to be a median diameter of less than 1 μm, preferably 750 nm or less, more preferably 500 nm or less, still more preferably 400 nm or less, and most preferably 300 nm or less. It is 10 nm or more, preferably 50 nm or more.

藉由此，可獲得核芯經乳濁之乳濁液。 Thereby, an emulsion in which the core is opaque can be obtained.

2.2.2.種子乳化聚合 2.2.2. Seed emulsion polymerization

於殼層調製步驟中，為將殼層原料成分進行種子乳化聚合係例如對於含有核芯之乳濁液供給殼層原料成分。或，對於上述之乳濁液供給殼層原料乳化液。或，對於上述之乳濁液分別供給殼層原料成分及殼層原料乳化劑水溶液。較佳係對於乳濁液供給殼層原料乳化液。 In the shell layer preparation step, in order to subject the shell raw material component to seed emulsion polymerization, 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 emulsion. Alternatively, the shell raw material component and the shell raw material emulsifier aqueous solution are supplied to the above emulsion. It is preferred to supply the emulsion of the shell raw material to the emulsion.

為對於乳濁液供給殼層原料乳化液係可採用 例如連續供給、分開供給、整批供給，較佳係採用連續供給。只要為連續供給，即可減輕分開供給或整批供給時之供給(添加)衝擊(具體而言，核芯在乳濁液中變成不安定，核芯會凝集)。 It can be used to supply the shell raw material emulsion to the emulsion. For example, continuous supply, separate supply, and batch supply are preferably continuous supply. As long as it is continuously supplied, the supply (addition) impact at the time of separate supply or batch supply can be alleviated (specifically, the core becomes unstable in the emulsion, and the core agglomerates).

在連續供給係對於乳濁液連續供給殼層原料乳化液，具體而言，將殼層原料乳化液例如在10分鐘以上，較佳在30分鐘以上，更佳在60分鐘以上，又，例如在180分鐘以內供給。 In the continuous supply system, the shell raw material emulsion is continuously supplied to the emulsion, and specifically, the shell raw material emulsion is, for example, 10 minutes or longer, preferably 30 minutes or longer, more preferably 60 minutes or longer, and, for example, Available within 180 minutes.

於連續供給，係例如使用管式泵，對於乳濁液供給殼層原料乳化液。 For continuous supply, for example, a tubular pump is used, and a shell raw material emulsion is supplied to the emulsion.

具體而言，於微乳化液聚合中對於經加熱，並維持其溫度之狀態之乳濁液(亦即，為反應後而未經冷卻之乳濁液)進行供給。亦即，乳濁液經一次冷卻時，將經冷卻之乳濁液再度加熱至預定溫度後，對於乳濁液供給殼層原料乳化液。 Specifically, in the microemulsion polymerization, an emulsion (that is, an emulsion which is not cooled after the reaction) is supplied to the emulsion which is heated and maintained at the temperature. That is, 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.

殼層原料乳化液之調配比率相對於核芯原料成分100質量份，例如為10質量份以上，較佳為20質量份以上，又，例如為500質量份以下，較佳為100質量份以下。殼層原料成分之調配比率相對於核芯原料成分100質量份，調整成例如在5質量份以上，較佳在10質量份以上，又，例如在250質量份以下，較佳在50質量份以下。 The blending ratio of the shell raw material emulsion is, for example, 10 parts by mass or more, preferably 20 parts by mass or more, and further, for example, 500 parts by mass or less, preferably 100 parts by mass or less, based on 100 parts by mass of the core raw material component. The blending ratio of the shell raw material component is adjusted to, for example, 5 parts by mass or more, preferably 10 parts by mass or more, and further, for example, 250 parts by mass or less, preferably 50 parts by mass or less, based on 100 parts by mass of the core raw material component. .

殼層原料乳化液之調配比率係第2聚合性乙烯單體對於第1聚合性乙烯單體及第2聚合性乙烯單體之調配比率，調整成為上述之調配比率。 The blending ratio of the shell raw material emulsion is adjusted to the above blending ratio of the second polymerizable ethylene monomer to the first polymerizable ethylene monomer and the second polymerizable ethylene monomer.

在對於乳濁液開始供給殼層原料乳化液時，較佳在上述之微乳化液聚合完成時，具體而言，於微乳化液聚合中之第1聚合性乙烯單體之轉化率例如在75%以上，較佳在95%以上，更佳在99%以上時，對於乳濁液供給殼層原料乳化液。第1聚合性乙烯單體之轉化率為在核芯中之第1聚合性乙烯單體之轉化率，且藉由HPLC測定。在對於乳濁液開始供給殼層原料乳化液時，第1聚合性乙烯單體之轉化率只要在上述下限以上，即可具有核芯殼層構造。 When the emulsion of the shell raw material is started to be supplied to the emulsion, it is preferred that, when the polymerization of the microemulsion described above is completed, specifically, the conversion ratio of the first polymerizable ethylene monomer in the microemulsion polymerization is, for example, 75. More than %, preferably 95% or more, more preferably 99% or more, the shell raw material emulsion is supplied to the emulsion. The conversion ratio of the first polymerizable ethylene monomer is the conversion ratio of the first polymerizable ethylene monomer in the core, and is measured by HPLC. When the emulsion of the shell raw material is supplied to the emulsion, the conversion ratio of the first polymerizable ethylene monomer may have a core-shell structure as long as it is at least the above lower limit.

在對於殼層原料乳化液之乳濁液的供給，同時對於乳濁液供給聚合引發劑水溶液。 The supply of the emulsion of the shell raw material emulsion and the aqueous solution of the polymerization initiator are supplied to the emulsion.

對於乳濁液供給聚合引發劑水溶液採用例如連續供給、分開供給、整批供給，較佳採用連續供給。只要為連續供給，即可減輕分開供給或整批供給時之供給(添加)衝擊(具體而言，核芯在乳濁液中變成不安定，且凝集)。 For the emulsion supply polymerization initiator aqueous solution, for example, continuous supply, separate supply, and batch supply are employed, and continuous supply is preferably employed. As long as it is continuously supplied, the supply (addition) impact at the time of separate supply or batch supply can be alleviated (specifically, the core becomes unstable in the emulsion and agglomerates).

於連續供給中，對於乳濁液連續供給聚合引發劑水溶液，具體而言，以與對於乳濁液供給殼層原料乳化液所需之時間相同的時間，詳言之，例如在10分鐘以上，較佳在30分鐘以上，更佳在60分鐘以上，又，例如在180分鐘以內供給聚合引發劑水溶液。 In the continuous supply, the aqueous solution of the polymerization initiator is continuously supplied to the emulsion, specifically, the same time as the time required to supply the emulsion of the shell raw material to the emulsion, in detail, for example, 10 minutes or longer. It is preferably 30 minutes or more, more preferably 60 minutes or more, and further, for example, an aqueous solution of a polymerization initiator is supplied within 180 minutes.

於連續供給中，例如使用管式泵等，對於乳濁液供給聚合引發劑水溶液。 In the continuous supply, for example, a tubular pump or the like is used, and an aqueous solution of a polymerization initiator is supplied to the emulsion.

經由如此操作，殼層原料乳化液及聚合引發劑水溶液或殼層原料成分、殼層原料乳化劑水溶液及聚合 引發劑水溶液，藉由對於經加熱之微乳化液聚合後之乳濁液的供給，而進行種子乳化聚合。 By doing so, 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 The aqueous initiator solution is subjected to seed emulsion polymerization by supplying the emulsion after polymerization of the heated microemulsion.

種子乳化聚合之加熱溫度例如在30℃以上，較佳在50℃以上，又，例如在100℃以下。加熱時間例如在2小時以上，較佳在3小時以上，又，例如在24小時以下，較佳在12小時以下。進而，加熱至預定溫度後，將其溫度維持預定時間，之後，藉由反覆加熱及維持溫度，亦可階段性加熱。 The heating temperature of the seed emulsion polymerization is, for example, 30 ° C or higher, preferably 50 ° C or higher, and further, for example, 100 ° C or lower. The heating time is, for example, 2 hours or longer, preferably 3 hours or longer, and further, for example, 24 hours or shorter, preferably 12 hours or shorter. Further, after heating to a predetermined temperature, the temperature is maintained for a predetermined period of time, and then, by repeatedly heating and maintaining the temperature, the heating may be performed stepwise.

繼而，將核芯作為種子(種粒子)，在核芯表面，第2聚合性乙烯單體進行種子乳化聚合，將核芯包覆，生成由第2聚合物所構成之殼層。 Then, the core is used as a seed (species particle), and the second polymerizable ethylene monomer is subjected to seed emulsion polymerization on the surface of the core, and the core is coated to form a shell layer composed of the second polymer.

種子乳化聚合係將藉由微乳化液聚合調製之核芯作為種子(種粒子)，在核芯懸濁液中供給殼層原料成分，另外，以所添加之聚合引發劑水溶液之水溶性聚合引發劑進行種子聚合之方法。因此，種子乳化聚合之平均粒徑未達1μm，持續釋放性粒子不容易沈降，而水分散安定性優越。 The seed emulsion polymerization system uses a core prepared by polymerization of a microemulsion as a seed (species particle), supplies a shell raw material component in a core suspension, and is caused by water-soluble polymerization of the added polymerization initiator aqueous solution. A method of seed polymerization. Therefore, the average particle diameter of the seed emulsion polymerization is less than 1 μm, and the sustained release particles are less likely to settle, and the water dispersion stability is superior.

種子懸濁聚合係將藉由懸濁聚合調製之核芯作為種子(種粒子)，在核芯懸濁液中供給殼層原料成分，以殘存於核芯之油溶性聚合引發劑進行種子聚合之方法。因此，種子懸濁聚合係與種子乳化聚合不同，平均粒徑在1μm以上，持續釋放性粒子容易沈降，水分散安定性差。又，為了使殼層原料成分確實地種子懸濁聚合係必須採取暫時將核芯懸濁液冷卻至聚合開始溫度以下，供給殼層原 料成分並攪拌之，使核芯以殼層原料成分膨潤後，昇溫至聚合引發溫度以上等之方法。 The seed suspension polymerization system uses a core prepared by suspension polymerization as a seed (species particle), supplies a shell raw material component in a core suspension, and performs seed polymerization by an oil-soluble polymerization initiator remaining in the core. method. Therefore, the seed suspension polymerization system is different from the seed emulsion polymerization, and the average particle diameter is 1 μm or more, and the sustained release particles are easily sedimented, and the water dispersion stability is poor. In addition, in order to make the shell raw material component reliably seed suspension polymerization system, it is necessary to temporarily cool the core suspension to a polymerization start temperature or lower, and supply the shell layer. After the components are stirred and the core is swollen by the shell raw material component, the temperature is raised to a polymerization initiation temperature or higher.

以種子乳化聚合所調製之粒子之殼層較佳係實質上不含有抗生物活性化合物。換言之，殼層可容許含有不阻礙本發明效果之程度之抗生物活性化合物。具體而言，抗生物活性化合物從核芯遷移到殼層(遷移)，容許微量之抗生物活性化合物存在於殼層中。 The shell layer of the particles prepared by emulsion polymerization of the seed is preferably substantially free of the anti-biologically active compound. In other words, the shell layer can tolerate an anti-biologically active compound to such an extent that it does not impair the effects of the present invention. In particular, the migration of the anti-biologically active compound from the core to the shell (migration) allows a small amount of the anti-biologically active compound to be present in the shell.

殼層中之抗生物活性化合物之含有比率例如在1質量%以下，進一步在0.1質量%以下 The content ratio of the anti-biologically active compound in the shell layer is, for example, 1% by mass or less, and further 0.1% by mass or less.

殼層之厚度係以最大厚度計，例如在1nm以上，較佳在3nm以上，更佳在10nm以上，最佳在30nm以上，又，例如在200nm以下，較佳在150nm以下。 The thickness of the shell layer is, for example, 1 nm or more, preferably 3 nm or more, more preferably 10 nm or more, more preferably 30 nm or more, and further, for example, 200 nm or less, preferably 150 nm or less.

殼層之厚度對核芯直徑(平均粒徑)之百分率(殼層之厚度/核芯之直徑×100)例如在1%以上，較佳在3%以上，更佳在5%以上，最佳在10%以上，又，例如在50%以下。 The thickness of the shell layer to the core diameter (average particle diameter) (thickness of the shell layer / diameter of the core x 100) is, for example, 1% or more, preferably 3% or more, more preferably 5% or more, and most preferably More than 10%, and, for example, 50% or less.

持續釋放性粒子之平均粒徑係算出中值徑，為未達1μm，較佳在750nm以下，更佳在500nm以下，更佳在400nm以下，尤佳在300nm以下，又，例如在50nm以上。 The average particle diameter of the sustained-release particles is calculated to be a median diameter of less than 1 μm, preferably 750 nm or less, more preferably 500 nm or less, still more preferably 400 nm or less, still more preferably 300 nm or less, and further, for example, 50 nm or more.

殼層之厚度對持續釋放性粒子之平均粒徑之百分率(殼層之厚度/持續釋放性粒子之平均粒徑×100)例如在1%以上，較佳在3%以上，更佳在5%以上，最佳在10%以上，又，例如在50%以下。 The percentage of the thickness of the shell layer to the average particle diameter of the sustained release particles (thickness of the shell layer / average particle diameter of the sustained release particles × 100) is, for example, 1% or more, preferably 3% or more, more preferably 5%. The above is preferably 10% or more, and further, for example, 50% or less.

藉由該等之製造方法，如第1圖之斷面圖所示，獲得含有具備核芯2、將核芯2包覆之殼層3之持續釋放性粒子1之乳濁液。 According to these manufacturing methods, as shown in the cross-sectional view of Fig. 1, an emulsion containing the sustained-release particles 1 having the core 2 and the shell layer 3 coated with the core 2 is obtained.

亦即，該持續釋放性粒子1係形成為球狀粒子，具體而言，含有核芯2、將核芯2包覆之殼層3。 That is, the sustained-release particles 1 are formed into spherical particles, specifically, a core 2 and a shell layer 3 in which the core 2 is coated.

核芯2係形成為略球狀。核芯2係含有在藉由上述疏水性第1聚合性乙烯單體之聚合獲得之第1聚合物中疏水性抗生物活性化合物為相溶之均一相。 The core 2 is formed into a slightly spherical shape. The core 2 contains a homogeneous phase in which the hydrophobic bioactive compound is compatible with the first polymer obtained by the polymerization of the hydrophobic first polymerizable ethylene monomer.

殼層3係形成於核芯2之表面。具體而言，殼層3係例如形成為將核芯2之表面包覆之膜狀。殼層3係含有藉由疏水性第2聚合性乙烯單體之聚合所獲得之第2聚合物。又，殼層3較佳實質上不含有抗生物活性化合物，換言之，對於殼層3，容許含有例如在1質量%以下，進而，在0.1質量%以下之抗生物活性化合物。 The shell layer 3 is formed on the surface of the core 2. Specifically, the shell layer 3 is formed, for example, in a film shape in which the surface of the core 2 is coated. The shell layer 3 contains a second polymer obtained by polymerization of a hydrophobic second polymerizable ethylene monomer. Further, the shell layer 3 preferably contains substantially no antibiotic compound, and in other words, the shell layer 3 is allowed to contain, for example, 1% by mass or less, and further preferably 0.1% by mass or less of the antibiotic compound.

因此，持續釋放性粒子1具有核芯殼層構造。 Therefore, the sustained release particles 1 have a core-shell structure.

接著，種子乳化聚合後，將聚合後之乳濁液例如藉由放冷等冷卻，藉由100網目之濾布等進行過濾，可獲得持續釋放性粒子之乳濁液(水分散液)。 Then, after the emulsion is polymerized and polymerized, the emulsion after the polymerization is cooled by, for example, cooling or the like, and filtered through a 100-mesh filter cloth or the like to obtain an emulsion (aqueous dispersion) of the sustained-release particles.

再者，於含有持續釋放性粒子之乳濁液中例如必要時可適當調配増粘劑、凍結防止劑、防腐劑、微生物増殖抑制劑等公知之添加劑。 Further, for example, a known additive such as a creping agent, a freeze preventing agent, a preservative, or a microbial colonization inhibitor may be appropriately added to the emulsion containing the sustained-release particles.

由此獲得之持續釋放性粒子可以原來狀態(乳濁液)，亦即使用作為乳濁劑。又，持續釋放性粒子藉由噴霧乾燥、凍結融解/脫水/乾燥、鹽析/脫水/乾燥等進行固液 分離後，例如製劑化為粉劑等公知之劑型而使用。該等粉劑例如可調製為持續釋放性粒子經凝集之粉劑。 The sustained release particles thus obtained can be used in the original state (emulsion), that is, as an opacifying agent. Further, the sustained release particles are subjected to solid-liquid drying by spray drying, freeze-thaw/dehydration/drying, salting out/dehydration/drying, and the like. After the separation, for example, it is used in a known dosage form such as a powder. Such powders may, for example, be prepared as a powder in which the sustained release particles are agglomerated.

可將該等乳濁劑或粉劑添加於種種工業製品。具體而言，可將乳濁劑或粉劑適用(或調配)於例如外部裝飾材料(尤其是住宅外部裝飾材料)、內部裝飾材料(包含壁紙等)、天花板材料、地板材料等建材，例如塗料，例如粘著劑，例如墨水，例如密封劑、嵌縫劑，例如紙製品，例如膠粘劑，例如樹脂乳液，例如紙漿、例如木質材料，例如木質製品，例如塑膠製品，例如薄膜，例如纖維製品、不織布、過濾器等。 These opacifiers or powders can be added to various industrial products. Specifically, the opacifier or powder may be applied (or formulated) to, for example, exterior decorative materials (especially residential exterior decorative materials), interior decorative materials (including wallpapers, etc.), ceiling materials, flooring materials, and the like, such as paints, For example, an adhesive, such as an ink, such as a sealant, a caulk, such as a paper product, such as an adhesive, such as a resin emulsion, such as a pulp, such as a wood material, such as a wood product, such as a plastic article, such as a film, such as a fiber product, a non-woven fabric. , filters, etc.

3.效果 3. Effect

因此，藉由上述持續釋放性粒子之製造方法所獲得之持續釋放性粒子由於在第1聚合物中具備抗生物活性化合物為相溶之核芯及將核芯包覆之殼層，因此，抗紫外線性優越。 Therefore, the sustained release particles obtained by the above method for producing a sustained release particle have a core which is compatible with the bioactive compound in the first polymer and a shell layer which coats the core, and therefore Excellent ultraviolet light.

具體而言，通常，異噻唑啉系化合物等抗生物活性化合物若長時間保存於紫外線曝露下，則有時進行分解。因此，有時持續釋放性粒子中之抗生物活性化合物之含量減少。 Specifically, in general, an anti-biologically active compound such as an isothiazoline-based compound may be decomposed if it is stored under ultraviolet light for a long period of time. Therefore, sometimes the content of the anti-biologically active compound in the sustained release particles is reduced.

但，由於上述之持續釋放性粒子在第1聚合物中具備抗生物活性化合物為相溶之核芯及將核芯包覆之殼層，故可抑制起因於曝露於上述紫外線之上述抗生物活性化合物之分解，可抑制持續釋放性粒子中之抗生物活性化合物之含量會減少。 However, since the above-mentioned sustained-release particles have the anti-biologically active compound in the first polymer as a compatible core and a core layer coated with the core, the above-mentioned antibiotic activity caused by exposure to the above ultraviolet rays can be suppressed. The decomposition of the compound inhibits the reduction of the content of the anti-biologically active compound in the sustained release particles.

又，藉由上述持續釋放性粒子之製造方法所獲得之持續釋放性粒子，由於在藉由第1聚合性乙烯單體之聚合所獲得之第1聚合物中具備含有抗生物活性化合物為相溶之均一相之核芯，因此，持續釋放性優越。 Further, the sustained release particles obtained by the method for producing a sustained release particle are provided to contain a bioactive compound in the first polymer obtained by polymerization of the first polymerizable ethylene monomer. The core of the uniform phase is therefore excellent in sustained release.

該持續釋放性粒子由於在第1聚合物中具備抗生物活性化合物為相溶之核芯及將核芯包覆之殼層，故持續釋放性優越。 Since the sustained-release particles have a core which is compatible with the bioactive compound in the first polymer and a shell layer which coats the core, the sustained release property is excellent.

抗生物活性化合物及第2聚合物由於具有上述之溶解度參數δ，因此，抗生物活性化合物及第2聚合物成為非相溶。因此，可抑制抗生物活性化合物從核芯漏出到殼層外。該結果可提昇持續釋放性粒子之持續釋放性。 Since the bioactive compound and the second polymer have the solubility parameter δ described above, the antibiotic compound and the second polymer become incompatible. Therefore, it is possible to inhibit the leakage of the antibiotic-active compound from the core to the outside of the shell. This result enhances the sustained release of sustained release particles.

再者，殼層原料成分實質上不含有抗生物活性化合物，因此，實質上不含有抗生物活性化合物。因此，殼層可抑制抗生物活性化合物漏出到殼層外，可更提昇持續釋放性粒子之持續釋放性。 Further, since the shell raw material component does not substantially contain the anti-biologically active compound, it does not substantially contain the anti-biologically active compound. Therefore, the shell layer can inhibit the leakage of the anti-biologically active compound out of the shell layer, and the sustained release property of the sustained-release particles can be further enhanced.

接著，上述之持續釋放性粒子由於可藉由微乳化液聚合及繼續之種子乳化聚合獲得，因此，水分散安定性優越。 Then, since the above-mentioned sustained release particles are obtained by microemulsion polymerization and continued seed emulsion polymerization, the water dispersion stability is excellent.

對於第1聚合性乙烯單體及第2聚合性乙烯單體之總量，第2聚合性乙烯單體之調配比率只要在上述之下限以上，可增厚殼層對核芯直徑(平均粒徑)之厚度，因此，可有效地延遲核芯含有之抗生物活性化合物釋放到殼層外，可更提昇持續釋放性粒子之釋放性。 In the total amount of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer, the blending ratio of the second polymerizable ethylene monomer may be increased to a core diameter (average particle diameter) as long as it is at least the above lower limit The thickness of the sustained-release particles can be further improved by delaying the release of the anti-biologically active compound contained in the core to the outside of the shell.

實施例 Example

以下之記載中所使用之調配比率(含有比率)、物性值、參數等之具體數值可代替成於上述「用以實施發明之形態」中所記載，且對應於該等之調配比率(含有比率)、物性值、參數等該記載之上限值(以「以下」、「未達」定義之數值)或下限值(以「以上」、「超過」定義之數值)。 The specific values of the blending ratio (content ratio), the physical property value, and the parameters used in the following descriptions may be substituted for the above-described "forms for carrying out the invention" and correspond to the blending ratios (content ratios) ), physical property values, parameters, etc., the upper limit (the value defined by "below", "not reached") or the lower limit (the value defined by "above" or "exceed").

於以下之記載中，「%」及「份」若無特別說明，為質量基準。 In the following descriptions, "%" and "parts" are quality standards unless otherwise stated.

將各實施例及各比較例中使用之原料詳細記載於下。 The raw materials used in the respective examples and comparative examples are described in detail below.

DCOIT：5,6-二氯-2-正辛基-4-異噻唑啉-3-酮，分子量282.2、融點：42℃、在水中之溶解度：2×10-3g/L(25℃)、溶解度參數δ之偶極力項δp,compound：6.36[(J/cm3)1/2]、溶解度參數δ之氫鍵力項δh,compound：6.05[(J/cm3)1/2]，東京化成化學公司製造 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 ), the dipole force term δ p of the solubility parameter δ , compound : 6.36 [(J/cm 3 ) 1/2 ], the hydrogen bond force term δ h of the solubility parameter δ , compound : 6.05 [(J/cm 3 ) 1/ 2 ], manufactured by Tokyo Chemical Industry Co., Ltd.

OIT：商品名「卡松(Kathon)893T」(「卡松」為註冊商標)，2-正辛基-4-異噻唑啉-3-酮、分子量213、融點：未達20℃、在水中之溶解度：0.3×10-3g/L(25℃)、溶解度參數δ之偶極力項δp,compound：5.47[(J/cm3)1/2]、溶解度參數δ之氫鍵力項δh,compound：5.87[(J/cm3)1/2]，羅姆&哈斯(Rohm and Haas)公司製造 OIT: trade name "Kathon 893T"("Kasong" is a registered trademark), 2-n-octyl-4-isothiazolin-3-one, molecular weight 213, melting point: less than 20 ° C, at Solubility in water: 0.3×10 -3 g/L (25°C), the dipole force term δ p of the solubility parameter δ , compound :5.47[(J/cm 3 ) 1/2 ], the hydrogen bond force term of the solubility parameter δ δ h,compound :5.87[(J/cm 3 ) 1/2 ], manufactured by Rohm and Haas

IPBC：商品名「芳集妥(Fungitrol)400」，3-碘-2-丙炔基胺基甲酸丁酯，分子量281、融點：60℃、在水中之溶解度：0.15×10-3g/L(25℃)、溶解度參數δ之偶極力項δp, compoumd：3.23[(J/cm3)1/2]、溶解度參數δ之氫鍵力項δh,compound：7.83[(J/cm3)1/2]，國際特殊製品(International Specialty Product)公司製造 IPBC: trade name "Fungitrol 400", butyl 3-iodo-2-propynylcarbamate, molecular weight 281, melting point: 60 ° C, solubility in water: 0.15 × 10 -3 g / L (25 ° C), the dipole force term δ p of the solubility parameter δ , compoumd : 3.23 [(J/cm 3 ) 1/2 ], the hydrogen bond force term δ h of the solubility parameter δ , compound : 7.83 [(J/cm 3 ) 1/2 ], manufactured by International Specialty Product

丙環唑：1-[2-(2,4-二氯苯基)-4-正丙基-1,3-二氧雜戊環-2-基甲基]-1H-1,2,4-***，分子量342、融點：未達20℃、在水中之溶解度：0.11×10-3g/L(25℃)、溶解度參數δ之偶極力項δp,compound：6.55[(J/cm3)1/2]、溶解度參數δ之氫鍵力項δh,compound：9.44[(J/cm3)1/2]，八幸通商公司製造 Propiconazole: 1-[2-(2,4-dichlorophenyl)-4-n-propyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4 - Triazole, molecular weight 342, melting point: less than 20 ° C, solubility in water: 0.11 × 10 -3 g / L (25 ° C), solubility parameter δ dipole force term δ p, compound : 6.55 [(J / Cm 3 ) 1/2 ], the hydrogen bond force term δ h of the solubility parameter δ , compound : 9.44 [(J/cm 3 ) 1/2 ], manufactured by Yasuke Trading Co., Ltd.

撲克拉：正丙基-N-[2-(2,4,6-三氯-苯氧基)乙基]咪唑-1-甲醯胺，分子量375、融點：45至52℃、在水中之溶解度：0.055×10-3g/L(25℃)、溶解度參數δ之偶極力項δp,compound：7.07[(J/cm3)1/2]、溶解度參數δ之氫鍵力項δh,compound：8.31[(J/cm3)1/2]，丸善藥品公司製造 Poker pull: n-propyl-N-[2-(2,4,6-trichloro-phenoxy)ethyl]imidazole-1-carboxamide, molecular weight 375, melting point: 45 to 52 ° C, in water Solubility: 0.055×10 -3 g/L (25°C), the dipole force term δ p of the solubility parameter δ , compound :7.07[(J/cm 3 ) 1/2 ], the hydrogen bond force term δ of the solubility parameter δ h,compound :8.31[(J/cm 3 ) 1/2 ], manufactured by Maruzen Pharmaceutical Co., Ltd.

氟矽唑：二(4-氟苯基)甲基(1H-1,2,4-***-1-基甲基矽烷)，分子量315、融點：54℃、在水中之溶解度：0.0.045×10-3g/L(25℃)、溶解度參數δ之偶極力項δp,compound：5.95[(J/cm3)1/2]、溶解度參數δ之氫鍵力項δh,compound：6.85[(J/cm3)1/2]，AR Brown公司製造 Fluconazole: bis(4-fluorophenyl)methyl (1H-1,2,4-triazol-1-ylmethylnonane), molecular weight 315, melting point: 54 ° C, solubility in water: 0.0. 045×10 -3 g/L (25°C), the dipole force term δ p of the solubility parameter δ , compound :5.95[(J/cm 3 ) 1/2 ], the hydrogen bond force term δ h of the solubility parameter δ , compound : 6.85 [(J/cm 3 ) 1/2 ], manufactured by AR Brown

敵避：N,N-二乙基-間-甲苯醯胺，分子量191、融點：-45℃、在水中之溶解度：0.99×10-3g/L(25℃)、δp,compound：5.42[(J/cm3)1/2]、δh,compound：5.83[(J/cm3)1/2]，東京化成工業公司製造試藥 Enemy avoidance: N,N-diethyl-m-toluidine, 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 ], manufactured by Tokyo Chemical Industry Co., Ltd.

氯菊酯：商品名「雙氯酚(Preventol)HS75」，3-苯氧基苯甲基(1RS,3RS；1RS,3SR)-3-(2,2-二氯乙烯基)-2,2-二甲基 環丙烷羧酸酯，分子量391、融點：34至35℃、在水中之溶解度：6×10-6g/L(25℃)、δp,compound：3.63[(J/cm3)1/2]、δh,compound：6.22[(J/cm3)1/2]，朗盛(Lanxess)公司製造 Permethrin: trade name "Preventol HS75", 3-phenoxybenzyl (1RS, 3RS; 1RS, 3SR)-3-(2,2-dichlorovinyl)-2,2 - dimethylcyclopropanecarboxylate, molecular weight 391, melting point: 34 to 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

氟氯氰菊酯(Cyfluthrin)：商品名「雙氯酚HS12」(「雙氯酚」為註冊商標)，(RS)-α-氰基-4-氟-3-苯氧基苯甲基-(1RS,3RS)-(1RS,3RS)-3-(2,2-二氯乙烯基)-2,2-二甲基環丙烷接酸酯，分子量434、在水中之溶解度：1×10-6g/L(25℃)至2×10-6g/L(25℃)，異構體I(融點：57℃)、異構體II(融點：74℃)、異構體Ⅲ(融點：66℃)及異構體IV(融點：102℃)之混合物、溶解度參數δ之偶極力項δp,compound：3.46[(J/cm3)1/2]、溶解度參數δ之氫鍵力項δh,compound：6.09[(J/cm3)1/2]，朗盛公司製造 Cyfluthrin: trade name "dichlorophenol HS12"("dichlorophenol" is a registered trademark), (RS)-α-cyano-4-fluoro-3-phenoxybenzyl-(1RS, 3RS)-(1RS,3RS)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanoate, molecular weight 434, solubility in water: 1 × 10 -6 g / L (25 ° C) to 2 × 10 -6 g / L (25 ° C), isomer I (melting point: 57 ° C), isomer II (melting point: 74 ° C), isomer III (melting point : 66 ° C) and isomer IV (melting point: 102 ° C) mixture, solubility parameter δ dipole force term δ p, compound : 3.46 [(J / cm 3 ) 1/2 ], solubility parameter δ hydrogen bond Force term δ h,compound :6.09[(J/cm 3 ) 1/2 ], manufactured by LANXESS

MMA：甲基丙烯酸甲酯，商品名「輕酯(Light Ester)M」，在水中之溶解度：16g/L(25℃)、作為單體單位之溶解度參數δ之偶極力項δp,monomer unit：5.98[(J/cm3)1/2]、作為單體單位之溶解度參數δ之氫鍵力項δh,monomer unit：9.25[(J/cm3)1/2]、共榮社化學公司製造 MMA: methyl methacrylate, trade name "Light Ester M", solubility in water: 16g / L (25 ° C), as a monomer unit solubility parameter δ dipole force δ p, monomer unit : 5.98 [(J/cm 3 ) 1/2 ], the hydrogen bond force term δ h of the solubility parameter δ as a monomer unit , monomer unit : 9.25 [(J/cm 3 ) 1/2 ], Kyoeisha Chemical Company manufacturing

SM：苯乙烯，在水中之溶解度：0.3g/L(25℃)、作為單體單位之溶解度參數δ之偶極力項δp,monomer unit：1.27[(J/cm3)1/2]、作為單體單位之溶解度參數δ之氫鍵力項δh,monomer unit：0.00[(J/cm3)1/2]，出光興產公司製造 SM: styrene, solubility in water: 0.3 g / L (25 ° C), as the monomer unit solubility parameter δ dipole force term δ p, monomer unit : 1.27 [(J/cm 3 ) 1/2 ], The hydrogen bond force term δ h of the solubility parameter δ as a monomer unit , monomer unit : 0.00 [(J/cm 3 ) 1/2 ], manufactured by Idemitsu Kosan Co., Ltd.

EGDMA：乙二醇二甲基丙烯酸酯，商品名「輕酯EG」，在水中之溶解度：0.58g/L(25℃)、溶解度參數δ之偶極力項δp,1st monomer unit：5.37[(J/cm3)1/2]、溶解度參數δ之氫鍵力 項δh,1st monomer unit：10.42[(J/cm3)1/2]，共榮社化學公司製造 EGDMA: ethylene glycol dimethacrylate, trade name "light ester EG", solubility in water: 0.58g / L (25 ° C), solubility parameter δ dipole force term δ p, 1st monomer unit : 5.37 [( J/cm 3 ) 1/2 ], the hydrogen bond force term δ h of the solubility parameter δ , 1st monomer unit : 10.42 [(J/cm 3 ) 1/2 ], manufactured by Kyoeisha Chemical Co., Ltd.

MAA：甲基丙烯酸，在水中之溶解度：89g/L(25℃)、作為單體單位之溶解度參數δ之偶極力項δp,monomer unit：7.13[(J/cm3)1/2]、作為單體單位之溶解度參數δ之氫鍵力項δh,monomer unit：13.03[(J/cm3)1/2]、三菱嫘縈(Mitsubishi Rayon)公司製造 MAA: methacrylic acid, solubility in water: 89 g / L (25 ° C), as the monomer unit solubility parameter δ dipole force term δ p, monomer unit : 7.13 [(J / cm 3 ) 1/2 ], The hydrogen bond force term δ h of the solubility parameter δ as a monomer unit , monomer unit : 13.03 [(J/cm 3 ) 1/2 ], manufactured by Mitsubishi Rayon Co., Ltd.

i-BMA：異丁基甲基丙烯酸酯，在水中之溶解度：0.5g/L(25℃)、溶解度參數δ之偶極力項δp,monomer unit：3.75[(J/cm3)1/2]、溶解度參數δ之氫鍵力項δh,monomer unit：7.32[(J/cm3)1/2]，日本觸媒公司製造 i-BMA: isobutyl methacrylate, solubility in water: 0.5 g / L (25 ° C), solubility parameter δ dipole force term δ p, monomer unit : 3.75 [(J / cm 3 ) 1/2 ], The hydrogen bonding force term δ h of the solubility parameter δ , monomer unit :7.32[(J/cm 3 ) 1/2 ], manufactured by Nippon Shokubai Co., Ltd.

RUVA-93：商品名，甲基丙烯酸2-[3-(2H-苯并***-2-基)-4-羥基苯基]乙酯，聚合反應性紫外線吸收劑，在水中之溶解度：0.1g/L(25℃)以下，作為單體單位之溶解度參數δ之偶極力項δp,monomer unit：5.61[(J/cm3)1/2]、作為單體單位之溶解度參數δ之氫鍵力項δh,monomer unit：13.07[(J/cm3)1/2]，東京化成公司製造 RUVA-93: trade name, 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate, polymerizable reactive UV absorber, solubility in water: 0.1 Below g/L (25 ° C), the dipole force term δ p of the solubility parameter δ as a monomer unit , the monomer unit : 5.61 [(J/cm 3 ) 1/2 ], the hydrogen as the solubility parameter δ of the monomer unit Bond force term δ h,monomer unit :13.07[(J/cm 3 ) 1/2 ], manufactured by Tokyo Chemical Industry Co., Ltd.

葩洛(Peroyl)L：商品名，過氧化二月桂醯，油溶性聚合引發劑，日油公司製造TINUVIN PS：商品名，(2-(2-羥基-5-第三丁基苯基)-2H-苯并***，非聚合反應性紫外線吸收劑，汽巴．日本公司製造 Peroyl L: trade name, dilaurin peroxide, oil-soluble polymerization initiator, manufactured by Nippon Oil Co., Ltd. TINUVIN PS: trade name, (2-(2-hydroxy-5-t-butylphenyl)- 2H-benzotriazole, non-polymerizable UV absorber, Ciba. Made by Japan

新可魯(Neo Coal)SW-C：商品名，二辛基磺基琥珀酸鈉(陰離子系乳化劑)之70質量%異丙醇溶液，第一工業製藥公司製造 Neo Coal SW-C: 70% by mass isopropanol solution of the trade name, sodium dioctylsulfosuccinate (anionic emulsifier), manufactured by First Industrial Pharmaceutical Co., Ltd.

迪莫NL：商品名，β-萘磺酸甲醛縮合物之鈉鹽之41 質量%水溶液、陰離子系分散劑，花王化學公司製造 Dimo NL: trade name, sodium salt of β-naphthalenesulfonic acid formaldehyde condensate 41 Mass % aqueous solution, anionic dispersant, manufactured by Kao Chemical Co., Ltd.

PVA-205：商品名，聚乙烯醇，皂化度：87.0至89.0%、聚合度：500、粘度(4%水溶液、20℃)：5.0至6.0mPa．sec，庫拉雷(Kuraray)公司製造 PVA-205: trade name, polyvinyl alcohol, saponification degree: 87.0 to 89.0%, degree of polymerization: 500, viscosity (4% aqueous solution, 20 ° C): 5.0 to 6.0 mPa. Sec, manufactured by Kuraray

普萊賽(Plysurf)A210G：商品名(「普萊賽」為註冊商標)，聚環氧乙烷磷酸酸酯銨鹽，第一工業製藥公司製造 Plysurf A210G: trade name ("Pleasant" is a registered trademark), polyethylene oxide phosphate ammonium salt, manufactured by the first industrial pharmaceutical company

TCP-10U：商品名，第三磷酸鈣、[Ca3(PO4)2]．Ca(OH)2之10質量%懸濁液，分散劑，松尾藥品產業公司製造 TCP-10U: trade name, calcium phosphate, [Ca 3 (PO 4 ) 2 ]. 10% by mass suspension of Ca(OH) 2 , dispersant, manufactured by Matsuo Pharmaceutical Co., Ltd.

實施例1 Example 1

(微乳化液聚合後，種子乳化聚合) (emulsion polymerization after seeding of microemulsion)

於200mL燒杯中放入DCOIT 20份、MMA 44份、SM 8份、EGDMA 4份、MAA 4份及葩洛L 0.40份，於室溫攪拌，調製均一之核芯原料成分。 20 parts of DCOIT, 44 parts of MMA, 8 parts of SM, 4 parts of EGDMA, 4 parts of MAA, and 0.40 parts of yello L were placed in a 200 mL beaker, and stirred at room temperature to prepare a uniform core material component.

另外，於1000mL燒杯中，放入去離子水86.12份、PVA-205之10%水溶液40份、新可魯SW-C 1.57份及迪莫NL 0.24份，於室溫攪拌，調製均一之第1乳化劑水溶液。 In addition, 86.12 parts of deionized water, 40 parts of 10% aqueous solution of PVA-205, 1.57 parts of Xinkelu SW-C and 0.24 parts of dimo NL were placed in a 1000 mL beaker, and stirred at room temperature to prepare a uniform first. An aqueous emulsifier.

接著，於1000mL燒杯之第1乳化劑水溶液中加入核芯原料成分，藉由T.K均相混合機MARK2.5型(普莱密克司(Primix)公司製造)，以旋轉數10000rpm攪拌10分鐘，調製微乳化液。之後，將調製之微乳化液移到裝備有攪拌器、回流冷卻器、溫度計及氮氣導入管之500mL之4口燒瓶中，於氮氣大氣下，藉由3cm徑之攪拌葉片，以旋轉數200rpm一邊攪拌一邊將4口燒瓶藉由水浴昇溫，實 施微乳化液聚合。 Next, the core raw material component was added to the first emulsifier aqueous solution of a 1000 mL beaker, and the mixture was stirred by a TK homomixer MARK2.5 type (manufactured by Primix) at a rotation number of 10,000 rpm for 10 minutes. Microemulsion. Thereafter, the prepared microemulsion was transferred to a 500-mL four-necked flask equipped with a stirrer, a reflux condenser, a thermometer, and a nitrogen introduction tube, and rotated at a number of 200 rpm by a stirring blade of 3 cm in a nitrogen atmosphere. The 4-necked flask was heated by a water bath while stirring. Application of microemulsion polymerization.

微乳化液聚合係以到達55℃之時間點作為開始聚合，之後，於60±2℃ 3小時、70±2℃ 2小時，連續實施。藉此，調製含有核芯之乳濁液。 The microemulsion polymerization was started at a time point of reaching 55 ° C, and then continuously carried out at 60 ± 2 ° C for 3 hours and 70 ± 2 ° C for 2 hours. Thereby, the emulsion containing the core is prepared.

另外，在200mL燒杯中，在去離子水20份中放入新可魯SW-C之10%水溶液0.87份，調製第2乳化劑水溶液。接著，於200mL燒杯中加入MMA 20份，以磁力攪拌器攪拌30分鐘，將MMA在第2乳化劑水溶液中乳化，調製殼層原料乳化液。 Separately, 0.87 parts of a 10% aqueous solution of Xinkelu SW-C was placed in 20 parts of deionized water in a 200 mL beaker to prepare a second aqueous emulsifier solution. Next, 20 parts of MMA was placed in a 200 mL beaker, and the mixture was stirred for 30 minutes with a magnetic stirrer, and MMA was emulsified in the second emulsifier aqueous solution to prepare a shell layer raw material emulsion.

與殼層原料乳化液之調製為另外的方法，將過硫酸鈉(水溶性聚合引發劑)溶解於水，調製過硫酸鈉之5%水溶液(聚合引發劑水溶液)0.80份。 In a separate method from the preparation of the shell raw material emulsion, sodium persulfate (water-soluble polymerization initiator) was dissolved in water to prepare 0.80 parts of a 5% aqueous solution (polymerization initiator aqueous solution) of sodium persulfate.

將已預先調製之殼層原料乳化液及聚合引發劑水溶液分別使用管式泵(ATTO公司製造蠕動泵(Peristaltic Pump))，對於微乳化液聚合後之500mL之4口燒瓶，同時開始滴入，開始進行種子乳化聚合。 The pre-prepared shell layer raw material emulsion and the polymerization initiator aqueous solution were each subjected to a tube pump (Peristaltic Pump manufactured by ATTO Co., Ltd.), and a 500-mL four-necked flask after microemulsion polymerization was simultaneously introduced. The seed emulsion polymerization was started.

殼層原料乳化液及聚合引發劑水溶液之滴入時間都為60分鐘，聚合時間為3小時(於70±2℃ 2小時，之後，昇溫，於80±2℃為1小時(包含昇溫時間))，之後，將乳濁液冷卻至30℃以下，獲得含有DCOIT之持續釋放性粒子之乳濁液。 The instillation time of the shell raw material emulsion and the polymerization initiator aqueous solution was 60 minutes, and the polymerization time was 3 hours (2 hours at 70±2° C., then, the temperature was raised, and the temperature was raised at 80±2° C. for 1 hour (including the heating time). After that, the emulsion was cooled to 30 ° C or lower to obtain an emulsion containing sustained release particles of DCOIT.

於種子乳化聚合開始時，微乳化液聚合中之第1聚合性乙烯單體之轉化率為99.3%。又，於種子乳化聚合完成時，第1聚合性乙烯單體及第2聚合性乙烯基單 體之轉化率為99.6%。上述之轉化率藉由HPLC算出。將其結果記載於表1。以下之實施例及比較例之轉化率亦藉由上述之方法算出。 At the start of the seed emulsion polymerization, the conversion ratio of the first polymerizable ethylene monomer in the microemulsion polymerization was 99.3%. Further, when the seed emulsion polymerization is completed, the first polymerizable ethylene monomer and the second polymerizable vinyl monomer The conversion rate of the body was 99.6%. The above conversion rate was calculated by HPLC. The results are shown in Table 1. The conversion ratios of the following examples and comparative examples were also calculated by the above methods.

將所獲得之乳濁液以100網目之濾布過濾後測定濾液中持續釋放性粒子之中值徑。其結果記載於表1。以下之實施例及比較例亦相同。 The obtained emulsion was filtered through a 100-mesh filter cloth, and the median diameter of the sustained-release particles in the filtrate was measured. The results are shown in Table 1. The following examples and comparative examples are also the same.

實施例2至8 Examples 2 to 8

(微乳化液聚合後，種子乳化聚合) (emulsion polymerization after seeding of microemulsion)

除了將調配處方依照表1及表2之記載變更以外，與實施例1相同，實施聚合，獲得持續釋放性粒子之乳濁液。 In the same manner as in Example 1, except that the formulation was changed in accordance with the description of Tables 1 and 2, polymerization was carried out to obtain an emulsion of sustained release particles.

實施例9 Example 9

(微乳化液聚合後，種子乳化聚合) (emulsion polymerization after seeding of microemulsion)

除了將於種子乳化聚合開始之時間點中的微乳化液聚合之第1聚合性乙烯單體轉化率變更為76.3%以外，與實施例1相同，實施聚合、獲得持續釋放性粒子之乳濁液。 In the same manner as in Example 1, except that the conversion rate of the first polymerizable ethylene monomer in the microemulsion polymerization at the time of starting the seed emulsion polymerization was changed to 76.3%, the polymerization was carried out to obtain an emulsion of sustained release particles. .

具體而言，開始微乳化液聚合，之後，藉由在於60±2℃經過3小時之時間點，同時開始供給殼層原料乳化液及聚合引發劑水溶液之兩者，開始種子乳化聚合。種子乳化聚合之聚合時間包含昇溫時間，於70±2℃為4小時，於80±2℃為1小時。 Specifically, the microemulsion polymerization was started, and then the seed emulsion polymerization was started by simultaneously supplying both the shell raw material emulsion and the polymerization initiator aqueous solution at a time point of 60 ± 2 ° C for 3 hours. The polymerization time of the seed emulsion polymerization includes a heating time of 4 hours at 70 ± 2 ° C and 1 hour at 80 ± 2 ° C.

實施例10 Example 10

(微乳化液聚合後，種子乳化聚合) (emulsion polymerization after seeding of microemulsion)

除了將於種子乳化聚合開始之時間點中之微乳化液聚合之第1聚合性乙烯單體轉化率變更為75.2%以外，與 實施例2相同，實施聚合、獲得持續釋放性粒子之乳濁液。 In addition to the change of the first polymerizable ethylene monomer conversion rate of the microemulsion polymerization at the time point from the start of the seed emulsion polymerization to 75.2%, In the same manner as in Example 2, polymerization was carried out to obtain an emulsion of sustained release particles.

具體而言，開始微乳化液聚合，之後，藉由在於60±2℃經過3小時之時間點，同時開始供給殼層原料乳化液及聚合引發劑水溶液之兩者，開始種子乳化聚合。種子乳化聚合之聚合時間包含昇溫時間，於70±2℃為4小時，於80±2℃為1小時。 Specifically, the microemulsion polymerization was started, and then the seed emulsion polymerization was started by simultaneously supplying both the shell raw material emulsion and the polymerization initiator aqueous solution at a time point of 60 ± 2 ° C for 3 hours. The polymerization time of the seed emulsion polymerization includes a heating time of 4 hours at 70 ± 2 ° C and 1 hour at 80 ± 2 ° C.

比較例1 Comparative example 1

(只有微乳化液聚合) (only microemulsion polymerization)

除了未實施種子乳化聚合以外，與實施例1相同，實施聚合，獲得由含有DCOIT之核芯粒子所構成之持續釋放性粒子之乳濁液。 In the same manner as in Example 1, except that the seed emulsion polymerization was not carried out, polymerization was carried out to obtain an emulsion of sustained release particles composed of core particles containing DCOIT.

比較例2 Comparative example 2

(懸濁聚合後，種子懸濁聚合) (suspension polymerization after seed suspension polymerization)

於200mL燒杯中放入DCOIT 20份、MMA 60份、SM 10份、EGDMA 5份、MAA 5份及葩洛L 0.50份，於室溫攪拌，調製疏水性溶液。 20 parts of DCOIT, 60 parts of MMA, 10 parts of SM, 5 parts of EGDMA, 5 parts of MAA, and 0.50 parts of lycol L were placed in a 200 mL beaker, and stirred at room temperature to prepare a hydrophobic solution.

另外，於1000mL之燒杯中放入去離子水120份、TCP-10U 120份及普萊賽A 210G之5%水溶液1份，於室溫攪拌，調製均一水溶液。 Separately, 120 parts of deionized water, 120 parts of TCP-10U, and 1 part of a 5% aqueous solution of Pryseau A 210G were placed in a 1000 mL beaker, and stirred at room temperature to prepare a uniform aqueous solution.

接著，於1000mL燒杯之水溶液中加入疏水性溶液，藉由T.K.均相混合機MARK 2.5型(譜莱密克司公司製造)，以旋轉數5000rpm攪拌5分鐘，調製懸濁液。之後，將調製之懸濁液移到裝備有攪拌器、回流冷卻器、溫度計及氮氣導入管之500mL之4口燒瓶，於氮氣氣流下， 藉由3cm徑之攪拌葉片，以旋轉數200rpm一邊攪拌一邊將4口燒瓶藉由水浴昇溫，實施懸濁聚合。 Next, a hydrophobic solution was added to an aqueous solution of a 1000 mL beaker, and the suspension was stirred by a T.K. homomixer MARK 2.5 type (manufactured by Spectrum Co., Ltd.) at a number of revolutions of 5000 rpm for 5 minutes. Thereafter, the prepared suspension was transferred to a 500 mL 4-neck flask equipped with a stirrer, a reflux condenser, a thermometer, and a nitrogen introduction tube under a nitrogen gas stream. The four-necked flask was heated by a water bath while stirring at a number of rotations of 200 rpm by a stirring blade having a diameter of 3 cm to carry out suspension polymerization.

懸濁聚合為以到達55℃之時間點作為開始聚合，之後，於60±2℃進行3小時、70±2℃進行2小時，連續實施。之後，將懸濁液冷卻至室溫。 The suspension polymerization was started at a time point of reaching 55 ° C, and then it was continuously carried out at 60 ± 2 ° C for 3 hours and 70 ± 2 ° C for 2 hours. After that, the suspension was cooled to room temperature.

另外，於200mL之燒杯中放入離子交換水17.2份及新可魯SW-C之1%水溶液22.8份，於室溫攪拌，調製均一之水溶液。接著，於200mL之燒杯(3)放入MMA 20.0份，藉由T.K.均相混合機MARK 2.5型(譜莱密克司公司製造)，以旋轉數10000rpm攪拌10分鐘，將MMA乳化，調製殼層原料乳化液。接著，將於反應後冷卻至室溫之懸濁液一邊攪拌一邊在如此之懸濁液中加入殼層原料乳化液，攪拌2小時。之後，於氮氣氣流下一邊攪拌一邊昇溫，進行種子懸濁聚合(第2步驟)。種子懸濁聚合為將懸濁液在昇溫途中，於懸濁液之溫度達到65℃之時開始，接著，將懸濁液之溫度於70℃維持3小時。 Separately, 17.2 parts of ion-exchanged water and 22.8 parts of a 1% aqueous solution of Xinkelu SW-C were placed in a 200 mL beaker, and stirred at room temperature to prepare a uniform aqueous solution. Next, 20.0 parts of MMA was placed in a 200 mL beaker (3), and the mixture was stirred by a TK homomixer MARK 2.5 (manufactured by Spectrum Microsystems) at a rotation number of 10,000 rpm for 10 minutes to emulsifie MMA to prepare a shell material. Emulsion. Next, the suspension of the shell raw material was added to the suspension as it was stirred after cooling to room temperature after the reaction, and the mixture was stirred for 2 hours. Thereafter, the mixture was heated while stirring under a nitrogen gas stream to carry out seed suspension polymerization (second step). The seed suspension polymerization was started while the suspension was warmed up, and the temperature of the suspension reached 65 ° C. Then, the temperature of the suspension was maintained at 70 ° C for 3 hours.

之後，將懸濁液冷卻至室溫。 After that, the suspension was cooled to room temperature.

藉此，獲得將含有DCOIT之核芯作為種子而調製成之持續釋放性粒子之懸濁液(懸濁劑)。 Thereby, a suspension (suspension) of sustained release particles prepared by using a core containing DCOIT as a seed was obtained.

實施例11至36 Examples 11 to 36

(微乳化液聚合後種子乳化聚合) (Emulsified polymerization of seed after microemulsion polymerization)

除了將調配處方依照表5至表10之記載變更以外，與實施例1相同，實施聚合，獲得持續釋放性粒子之乳濁液。 In the same manner as in Example 1, except that the formulation was changed in accordance with the description of Tables 5 to 10, polymerization was carried out to obtain an emulsion of sustained release particles.

比較例3至10 Comparative Examples 3 to 10

(僅微乳化液聚合) (microemulsion polymerization only)

除了將調配處方依照表7至表10之記載變更以外，與比較例1相同，實施聚合，獲得由核芯粒子所形成之持續釋放性粒子之乳濁液。 In the same manner as in Comparative Example 1, polymerization was carried out to obtain an emulsion of sustained release particles formed of core particles, except that the formulation was changed in accordance with the description of Tables 7 to 10.

(評估) (assessment)

<水分散安定性(貯存安定性)> <Water dispersion stability (storage stability)>

將實施例1至36及比較例1、3至10之乳濁液及比較例2之懸濁液分別於60℃靜置2星期。其後，以目視確認有無持續釋放性粒子之沈降。沈降以下述之基準評估。經由此，評估持續性粒子之水分散安定性。 The emulsions of Examples 1 to 36 and Comparative Examples 1, 3 to 10 and the suspension of Comparative Example 2 were each allowed to stand at 60 ° C for 2 weeks. Thereafter, the presence or absence of sedimentation of the sustained release particles was visually confirmed. Settling was evaluated on the basis of the following. From this, the water dispersion stability of the continuous particles was evaluated.

○：未確認出持續釋放性粒子之沈降。 ○: The sedimentation of the sustained release particles was not confirmed.

X：確認出持續釋放性粒子之沈降。 X: The sedimentation of the sustained release particles was confirmed.

該結果表示於表1至表10。 The results are shown in Tables 1 to 10.

<流水浸漬試驗後之持續釋放性(DCOIT殘存率(持續釋放性))A> <Continuous release after running water immersion test (DCOIT residual rate (sustained release)) A>

將實施例1至10及比較例1之乳濁液及比較例2之懸濁液分別添加於丙烯酸苯乙烯乳液(商品名：烏拉唑C-63愛卡(Aica)工業公司製造)，以使乳液中之DCOIT濃度成為0.01%。之後，以均相分散機2.5型(譜莱密克司公司製造)，以旋轉數600至800rpm攪拌1小時。攪拌後，使用薄塗器，在150×150×0.3(mm)之鋁板上塗佈，使塗布厚為250μm，乾燥一晚，調製塗膜。之後，將塗膜及鋁板配置於200×500×150(mm)大小之大缸中，從鋁板的上面供給自來水1.5L/分鐘，將塗膜浸漬於水中。又，將自來水以常從大缸 中溢出之方式供給至大缸。以HPLC測定從將塗膜浸漬於水起經過2星期後之塗膜中的DCOIT之殘存量。具體而言，塗膜切割成30×30(mm)，以甲醇萃取，測定塗膜中DCOIT之殘存量。 The emulsions of Examples 1 to 10 and Comparative Example 1 and the suspension of Comparative Example 2 were each added to an acrylic styrene emulsion (trade name: urethane C-63 Aica Industrial Co., Ltd.) so that The DCOIT concentration in the emulsion was 0.01%. Thereafter, the mixture was stirred for 1 hour at a number of revolutions of 600 to 800 rpm in a homodisperser type 2.5 (manufactured by Spectrum Microsystems). After stirring, the film was coated on a 150 × 150 × 0.3 (mm) aluminum plate using a thin coater to a coating thickness of 250 μm, and dried overnight to prepare a coating film. Thereafter, the coating film and the aluminum plate were placed in a large cylinder of 200 × 500 × 150 (mm), and tap water was supplied from the upper surface of the aluminum plate at 1.5 L/min, and the coating film was immersed in water. Also, tap water from the big tank The medium overflow is supplied to the large tank. The residual amount of DCOIT in the coating film after 2 weeks from the immersion of the coating film on water was measured by HPLC. Specifically, the coating film was cut into 30 × 30 (mm), extracted with methanol, and the residual amount of DCOIT in the coating film was measured.

另一方面，將未浸漬於水之塗膜之DCOIT量藉由與上述相同之方法，以HPLC測定。將該DCOIT量作為「初期含有量」。 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 above. This DCOIT amount is referred to as "initial content".

因此，將流水浸漬試驗後之殘存率A從下述式算出。 Therefore, the residual ratio A after the running water immersion test was calculated from the following formula.

殘存率A(%)=[殘存量/初期含有量]×100 Residual rate A (%) = [residual amount / initial content] × 100

其結果表示於表1至表4。 The results are shown in Tables 1 to 4.

<UV照射試驗後之DCOIT殘存率B> <DCOIT residual rate after UV irradiation test B>

將實施例1至10及比較例1之乳濁液及比較例2之懸濁液分別添加於丙烯酸苯乙烯乳液(商品名：烏拉唑C-63，愛卡工業公司製造)，使乳液中之DCOIT濃度成為0.01%。之後，以均相分散機2.5型(譜莱密克司公司製造)，以旋轉數600至800rpm攪拌1小時。攪拌後，使用薄塗器，在150×150×0.3(mm)之鋁板上塗佈，使塗布厚為250μm，乾燥一晚，調製塗膜。之後，於塗膜藉由黑光燈，照射強度25至35μw/cm2之UV，測定經過2星期後之DCOIT殘存量。 The emulsions of Examples 1 to 10 and Comparative Example 1 and the suspension of Comparative Example 2 were each added to an acrylic styrene emulsion (trade name: urethane C-63, manufactured by Aika Industrial Co., Ltd.) to make it in an emulsion. The DCOIT concentration became 0.01%. Thereafter, the mixture was stirred for 1 hour at a number of revolutions of 600 to 800 rpm in a homodisperser type 2.5 (manufactured by Spectrum Microsystems). After stirring, the film was coated on a 150 × 150 × 0.3 (mm) aluminum plate using a thin coater to a coating thickness of 250 μm, and dried overnight to prepare a coating film. Thereafter, the coating film was irradiated with UV of 25 to 35 μw/cm 2 by a black light lamp, and the amount of DCOIT remaining after 2 weeks was measured.

另一方面，以HPLC測定未照射UV之塗膜之DCOIT量。以該DCOIT量作為「初期含量」。 On the other hand, the amount of DCOIT of the coating film which was not irradiated with UV was measured by HPLC. The amount of DCOIT is used as the "initial content".

從下述式算出UV照射試驗後之殘存率B。 The residual ratio B after the UV irradiation test was calculated from the following formula.

殘存率B(%)=[初期值含量/殘存量]×100 Residual rate B (%) = [initial value / residual amount] × 100

其結果表示於表1至表4。 The results are shown in Tables 1 to 4.

<持續釋放性粒子之DCOIT持續釋放性試驗C> <DCOIT sustained release test for sustained release particles C>

首先，分別準備比較例1及實施例11至20之乳濁液作為持續釋放性試驗C之試樣。又，調製甲醇60%之水溶液作為溶出液。 First, the emulsions of Comparative Example 1 and Examples 11 to 20 were prepared as samples of the sustained release test C, respectively. Further, an aqueous solution of 60% methanol was prepared as an eluent.

接著，在5支聚丙烯製之50mL離心管中投入作為DCOIT質量之預先準備之試樣，使各個成為20mg量，接著，以溶出液調製DCOIT濃度0.05質量%之DCOIT含有液，將總量作成40g。 Then, a sample prepared in advance as a DCOIT quality was placed in a 50 mL centrifuge tube made of polypropylene, and each was made into a 20 mg amount, and then a DCOIT-containing solution having a DCOIT concentration of 0.05% by mass was prepared as an eluate to prepare a total amount. 40g.

接著，將該5支離心管掛在振動機(汰德公司(Taitec Corporation)製造TAITEC RECIPRO SHAKER SR-1)，實施140次/分鐘之振動，於每預定時間停止振動，將離心管掛在遠心分離機(微冷卻離心機3740，久保田製作所公司製造)，以15000rpm進行固液分離5分鐘。 Next, the five centrifuge tubes were hung on a vibrating machine (TAITEC RECIPRO SHAKER SR-1 manufactured by Taitec Corporation), and the vibration was performed 140 times/min. The vibration was stopped every predetermined time, and the centrifuge tube was hung in the telecentricity. Separator (micro-cooling centrifuge 3740, manufactured by Kubota Seisakusho Co., Ltd.) was subjected to solid-liquid separation at 15,000 rpm for 5 minutes.

固體部分為添加去離子水，而作成總量40g，以微量刮勺再分散後，再次掛在振動機，繼續振動。 The solid portion was added with deionized water, and a total amount of 40 g was prepared. After dispersing with a small amount of spatula, it was hung again on the vibrating machine to continue the vibration.

另一方面，液體部分為使用島津製作所製造之HPLC，將IPBC定量，算出持續釋放率。 On the other hand, the liquid portion was subjected to HPLC manufactured by Shimadzu Corporation, and IPBC was quantified to calculate a sustained release rate.

算出各振動時間之持續釋放率作為累積值(亦即，總持續釋放率)。 The sustained release rate of each vibration time was calculated as a cumulative value (that is, a total sustained release rate).

該結果表示於第2圖至第4圖。 The results are shown in Figures 2 through 4.

<含有OIT之持續釋放性粒子之持續釋放性 試驗> <sustained release of sustained release particles containing OIT Test>

首先，準備在比較例3及實施例21、22之乳濁液中添加去離子水，以OIT濃度6質量%之乳濁液作為持續釋放性試驗之試樣。 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 mass% was used as a sample for the sustained release test.

接著，相對於丙烯酸苯乙烯系水性塗料(烏拉唑A-20 base、氧化鈦濃度20質量%、固體濃度50質量%，愛卡工業公司製造)之固體分量，作為OIT質量，添加各個試樣，攪拌以成為1000ppm質量，調製各個評估用塗料。 Next, each sample was added as an OIT mass to the solid component of the acrylic styrene-based aqueous coating material (Uraazole A-20 base, titanium oxide concentration: 20% by mass, solid concentration: 50% by mass, manufactured by Aika Industrial Co., Ltd.). The mixture was mixed to have a mass of 1000 ppm, and each evaluation coating was prepared.

接著，使用# 75塗佈棒，將評估用塗料塗佈於鋁板上，於40℃加熱16小時，乾燥，形成塗膜。 Next, the coating material for evaluation was applied onto an aluminum plate using a #75 coating bar, heated at 40 ° C for 16 hours, and dried to form a coating film.

接著，將鋁板切成70mm×150mm之大小，製作切割板，將切割板安裝於舒卡試驗機公司(Suga Test Instruments Co.,Ltd)製造之雙面板老化計(只設定降雨)，曝露於降雨環境7日。 Next, the aluminum plate was cut into a size of 70 mm × 150 mm to prepare a cutting plate, and the cutting plate was attached to a double-faced aging meter manufactured by Suga Test Instruments Co., Ltd. (only rainfall was set), and exposed to rain. Environment 7th.

將降雨曝露後之切割板切斷成25mm×25mm之大小，製作試驗片，將試驗片放入玻璃瓶中，加入甲醇10mL，以超音波萃取10分鐘，萃取試驗片之塗膜中之OIT。 The cutting plate after the rain exposure was cut into a size of 25 mm × 25 mm, and a test piece was prepared. The test piece was placed in a glass bottle, 10 mL of methanol was added, and ultrasonic extraction was performed for 10 minutes to extract the OIT in the coating film of the test piece.

將萃取有OIT之甲醇萃取液以島津製作所製造之HPLC分析，算出塗膜中OIT之殘存率。 The methanol extract extracted with OIT was analyzed by HPLC manufactured by Shimadzu Corporation, and the residual ratio of OIT in the coating film was calculated.

其結果表示於第5圖。 The result is shown in Fig. 5.

<含有IPBC之持續釋放性粒子之持續釋放性試驗> <Continuous release test of sustained release particles containing IPBC>

除了將溶出液從甲醇水溶液變更為去離子水以外，進行與上述「<持續釋放性粒子之DCOIT持續釋放性試驗C >」相同之操作，實施實施例23、24之乳濁液之IPBC持續釋放性試驗。其結果表示於第6圖。 In addition to changing the eluate from aqueous methanol to deionized water, the DCOIT sustained release test C of the above-mentioned "sustained release particles" was carried out. The same procedure was followed for the IPBC sustained release test of the emulsions of Examples 23 and 24. The result is shown in Fig. 6.

<含有丙環唑之持續釋放性粒子之持續釋放性試驗> <Successive release test of sustained release particles containing propiconazole>

首先，將比較例5及實施例25、26之乳濁液以去離子水稀釋，調製丙環唑6質量%之乳濁液。 First, the emulsions of Comparative Example 5 and Examples 25 and 26 were diluted with deionized water to prepare an emulsion of 6% by mass of propiconazole.

接著，將2張圓形濾紙(相當於5種東洋濾紙No.5C、JIS P 3801)重疊細褶。 Next, two circular filter papers (corresponding to five types of Toyo filter paper No. 5C and JIS P 3801) were superposed on each other.

接著，在該濾紙上慢慢地添加準備之各個乳濁液、懸濁液1.0mL後風乾。 Next, 1.0 mL of each of the prepared emulsion and suspension was slowly added to the filter paper, followed by air drying.

於該濾紙使用定量泵，以流速20mL/小時通水1000mL，以HPLC測定獲得之濾液之丙環唑量及殘存於濾紙之丙環唑量，算出丙環唑之持續釋放率。又，於各通水量之持續釋放率算出為累積值(亦即，總持續釋放率)。 A quantitative pump was used for the filter paper, and 1000 mL of water was passed at a flow rate of 20 mL/hour. The amount of propiconazole of the filtrate obtained by HPLC and the amount of propiconazole remaining on the filter paper were measured to calculate the sustained release rate of propiconazole. Further, the sustained release rate of each water amount is calculated as a cumulative value (that is, a total sustained release rate).

其結果表示於第7圖。 The result is shown in Fig. 7.

<含有撲克拉之持續釋放性粒子之持續釋放性試驗> <Continuous release test of sustained release particles containing poker pull>

將實施例27及28之持續釋放性粒子之撲克拉持續釋放性試驗依據上述之「<含有丙環唑之持續釋放性粒子之持續釋放性試驗>」而實施。 The poker pull sustained release test of the sustained release particles of Examples 27 and 28 was carried out in accordance with the above-mentioned "suspension test of sustained release particles containing propiconazole".

其結果表示於第8圖。 The result is shown in Fig. 8.

<含有氟矽唑之持續釋放性粒子之持續釋放性試驗> <Continuous release test of sustained release particles containing flucarbazole>

將實施例29、30之持續釋放性粒子之氟矽唑持續釋放 性試驗依據上述「<含有丙環唑之持續釋放性粒子之持續釋放性試驗>」而實施。 Continuous release of flucarbazole from the sustained release particles of Examples 29 and 30 The test was carried out in accordance with the above "Sustained release test of sustained release particles containing propiconazole".

其結果表示於9圖。 The result is shown in Figure 9.

<含有敵避之持續釋放性粒子之持續釋放性試驗> <Continuous release test of sustained release particles containing enemies>

(1)製作蟲籠 (1) Making insect cages

使用42mm平方之乾燥杉角材，製作第10圖表示之框架11。 The frame 11 shown in Fig. 10 was produced using a 42 mm square dried cedar.

亦即，框架11具備向左右方向延長，於左右方向間隔隔開，而對向配置之第1框架12及第2框架13及連結該等之連絡框架14。 In other words, the frame 11 is provided with the first frame 12 and the second frame 13 which are extended in the left-right direction and are spaced apart from each other in the left-right direction, and the connection frame 14 is connected.

第1框架12及第2框架13具有長方體框架狀。連絡框架14係連絡第1框架12及第2框架13各個之上側部分。第1框架12及第2框架13各個之尺寸係左右方向之長為300mm，前後方向之長(深度)為210mm，上下方向之長(高度)為210mm，連絡框架14之尺寸係左右方向之長度為210mm，前後方向之長度為210mm，上下方向之長度為70mm。 The first frame 12 and the second frame 13 have a rectangular parallelepiped frame shape. The contact frame 14 connects the upper side portions of the first frame 12 and the second frame 13. Each of the first frame 12 and the second frame 13 has a length of 300 mm in the left-right direction, a length (depth) of 210 mm in the front-rear direction, and a length (height) of 210 mm in the vertical direction, and the size of the contact frame 14 is the length in the left-right direction. It is 210 mm, the length in the front-rear direction is 210 mm, and the length in the up-and-down direction is 70 mm.

之後，如第11圖所示，於第10圖表示之框架11，於外側面各配置40網目之濾布15，將該等之周端部以圖釘固定於第1框架12、第2框架13及連絡框架14，以製作蟲籠20。 Thereafter, as shown in Fig. 11, in the frame 11 shown in Fig. 10, a filter cloth 15 of 40 mesh is placed on the outer side surface, and the peripheral end portions are fixed to the first frame 12 and the second frame 13 by push pins. And contacting the frame 14 to make the cage 20.

亦即，於蟲籠20形成藉由第1框架12及濾布15隔開之第1空間16、藉由第2框架13及濾布15隔 開之第2空間17、藉由連結框架14及濾布15隔開之連結空間18。第1空間16與第2空間17藉由連結空間18接通。 That is, the first cage 16 separated by the first frame 12 and the filter cloth 15 is formed in the cage 20, and separated by the second frame 13 and the filter cloth 15. The second space 17 opened is connected to the space 18 by the connection frame 14 and the filter cloth 15. The first space 16 and the second space 17 are connected by the connection space 18.

經由此，濾布15對於各框架為可裝缷，空氣可自由流通。放入蟲籠20之小昆蟲在第1空間16及第2空間17可藉由連結空間18自由來往，但不能出去到蟲籠20外。 Thereby, the filter cloth 15 is mountable for each frame, and air can flow freely. The small insects placed in the worm cage 20 can freely pass through the joint space 18 in the first space 16 and the second space 17, but cannot go out to the worm cage 20.

(2)含有敵避之持續釋放性粒子 (2) Sustained release particles containing enemy

將角濾紙切成120×200mm，將比較例8及實施例31、32之乳濁液以離子交換水稀釋為1.67倍，調製含有10質量%敵避之持續釋放性粒子乳濁液，將此以噴霧器散布於方濾紙上，使敵避附著200mg。將該方濾紙載置於靜置於夏季(2014年8月)屋外陰涼處(大阪市此花區)之蟲籠20之第1空間16底部濾布15之上面。 The angle filter paper was cut into 120 × 200 mm, and the emulsion of Comparative Example 8 and Examples 31 and 32 was diluted to 1.67 times with ion-exchanged water to prepare a sustained-release particle emulsion containing 10% by mass of the enemy. Disperse on the square filter paper with a sprayer to prevent the enemy from attaching 200mg. The filter paper was placed on top of the filter cloth 15 at the bottom of the first space 16 of the insect cage 20 which was placed in a cool place outside the summer (August 2014).

將蘋果切片(後述家蚊之飼料)載置於蟲籠20之第2空間17底部之濾布15上面。 An apple slice (a feed of a house mosquito described later) is placed on top of the filter cloth 15 at the bottom of the second space 17 of the insect cage 20.

接著，於試驗當日羽化之家蚊20隻放入蟲籠20之第2空間17內。放蟲後，經過24小時後，家蚊20隻沒有從第2空間17移動至第1空間16。惟，放蟲後，經過48小時後，下述之家蚊數量從第2空間17移動至第1空間16。 Next, on the day of the test, 20 mosquitoes of the house were placed in the second space 17 of the insect cage 20. After the insects were released, 20 mosquitoes did not move from the second space 17 to the first space 16 after 24 hours. However, after 48 hours of worming, the number of mosquitoes to be moved from the second space 17 to the first space 16 after 48 hours passed.

比較例8 9隻 Comparative Example 8 9

實施例31 5隻 Example 31 5

實施例32 0隻 Example 32 0

<含有氯菊酯之持續釋放性粒子之持續釋放性試驗> <Continuous release test of sustained release particles containing permethrin>

將比較例9及實施例33、34之乳濁液以去離子水稀釋，調製氯菊酯濃度6%之乳濁液。 The emulsions of Comparative Example 9 and Examples 33 and 34 were diluted with deionized water to prepare an emulsion having a chlorhexate concentration of 6%.

接著，將2張圓形濾紙(相當於5種C東洋濾紙No.5C，JIS P 3801)重疊褶疊。接著，在該濾紙上慢慢添加預先準備之氯菊酯濃度6%之各乳濁液溶液1.0mL後風乾。 Next, two circular filter papers (corresponding to five types of C Toyo filter paper No. 5C, JIS P 3801) were stacked and folded. Next, 1.0 mL of each emulsion solution having a pretreatment-prepared permethrin concentration of 6% was slowly added to the filter paper, followed by air drying.

之後，將濾紙放入玻璃瓶中，加入離子交換水/甲醇(=50/50(容量比))混合液180mL，於室溫靜置浸漬20小時。接著，採取離子交換水/甲醇混合液，加入新的離子交換水/甲醇混合液180mL，於室溫靜置浸漬20小時後，反覆操作上述離子交換水/甲醇混合液之交換操作2次。 Thereafter, the filter paper was placed in a glass bottle, and 180 mL of a mixed solution of ion-exchanged water/methanol (=50/50 (capacity ratio)) was added, and the mixture was allowed to stand at room temperature for 20 hours. Next, an ion-exchanged water/methanol mixture was added, and 180 mL of a new ion-exchanged water/methanol mixture was added thereto, and the mixture was allowed to stand at room temperature for 20 hours, and then the exchange operation of the above-mentioned ion-exchanged water/methanol mixture was repeated twice.

使用LC/TOF-MS，從上述所採取之各次之離子交換水/甲醇混合液測定氯菊酯之持續釋放量。又，將各次數之持續釋放量以累積值(亦即，總持續釋放量)算出。該等之結果表示於第12圖。 The sustained release amount of permethrin was determined from each of the ion exchange water/methanol mixtures taken as described above using LC/TOF-MS. Further, the sustained release amount of each order is calculated as an accumulated value (that is, a total sustained release amount). The results of these are shown in Figure 12.

<含有氟氯氰菊酯之持續釋放性粒子之持續釋放性試驗> <Continuous release test of sustained-release particles containing cyfluthrin>

依據上述「<含有氯菊酯之持續釋放性粒子之持續釋放性試驗>」，實施實施例35、36之氟氯氰菊酯持續釋放性試驗。其結果表示於第13圖。 The cyfluthrin sustained release test of Examples 35 and 36 was carried out in accordance with the above "<sustained release test of sustained release particles containing permethrin>". The result is shown in Fig. 13.

[產業上之利用可能性] [Industry use possibility]

從持續釋放性粒子製劑化之乳濁液或粉劑可適用(或調配)於例如外部裝飾材料、內部裝飾材料、天花板材料、地板材料等建材，例如塗料，例如粘著劑，例如墨水，例如密封劑、嵌縫劑，例如紙製品，例如膠粘劑，例如樹脂乳液，例如紙漿、例如木質材料，例如木質製品，例如塑膠製品，例如薄膜，例如纖維製品、不織布、過濾器等。 The emulsion or powder formulated from the sustained release particles can be applied (or formulated) to building materials such as exterior decorative materials, interior materials, ceiling materials, flooring materials, such as coatings, such as adhesives, such as inks, such as seals. Agents, caulks, such as paper products, such as adhesives, such as resin emulsions, such as pulp, such as wood materials, such as wood products, such as plastic articles, such as films, such as fibrous articles, nonwovens, filters, and the like.

1‧‧‧持續釋放性粒子 1‧‧‧Continuous release particles

2‧‧‧核芯 2‧‧‧core

3‧‧‧殼層 3‧‧‧ shell

Claims (15)

一種持續釋放性粒子，其係具備：將含有疏水性抗生物活性化合物及疏水性第1聚合性乙烯單體之核芯原料成分藉由微乳化液聚合所獲得者，且在藉由上述第1聚合性乙烯單體之聚合所獲得之第1聚合物中含有上述抗生物活性化合物為相溶之均一相之核芯；及將含有疏水性第2聚合性乙烯單體之殼層原料成分藉由以上述核芯作為種子之種子乳化聚合所獲得者，且將上述核芯包覆之殼層。 A sustained release particle obtained by polymerizing a core material component containing a hydrophobic bioactive compound and a hydrophobic first polymerizable ethylene monomer by a microemulsion, and by the first The first polymer obtained by polymerization of the polymerizable ethylene monomer contains the core of the homogeneous phase in which the antibiotic compound is compatible; and the shell material component containing the hydrophobic second polymerizable ethylene monomer is used The above core is used as a seed seed emulsion polymerization obtained, and the core is coated with a shell layer. 如申請專利範圍第1項所述之持續釋放性粒子，其中，上述殼層原料成分為實質上未含有上述抗生物活性化合物。 The sustained release particles according to claim 1, wherein the shell raw material component does not substantially contain the antibiotic active compound. 如申請專利範圍第1項所述之持續釋放性粒子，其中，上述抗生物活性化合物含有異噻唑啉系化合物。 The sustained release particle according to the above aspect of the invention, wherein the antibiotic compound contains an isothiazoline compound. 如申請專利範圍第3項所述之持續釋放性粒子，其中，上述異噻唑啉系化合物為5,6-二氯-2-正辛基-4-異噻唑啉-3-酮。 The sustained release particle according to the third aspect of the invention, wherein the isothiazolin compound is 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one. 如申請專利範圍第1項所述之持續釋放性粒子，其中，選自由上述第1聚合性乙烯單體及上述第2聚合性乙烯單體所成群組之至少1種的聚合性乙烯單體係含有聚合反應性紫外線吸收劑。 The sustained release particles according to the first aspect of the invention, wherein the polymerizable ethylene monomer is at least one selected from the group consisting of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer. Contains a polymeric reactive UV absorber. 一種持續釋放性粒子，為具備：在藉由疏水性第1聚合性乙烯單體之聚合所獲得之第1聚合物中含有疏水性抗生物活性化合物為相溶之均一相，平均粒徑未達1μ m之核芯；及藉由疏水性第2聚合性乙烯單體之聚合所獲得之第2聚合物組成，實質上未含有上述抗生物活性化合物之殼層，並將上述核芯包覆之上述殼層。 The sustained release particle is characterized in that the first polymer obtained by polymerization of the hydrophobic first polymerizable ethylene monomer contains a hydrophobic antibiotic active compound as a homogeneous phase, and the average particle diameter is less than 1μ a core of m; and a second polymer composition obtained by polymerization of a hydrophobic second polymerizable ethylene monomer, substantially not containing the shell layer of the antibiotic compound, and coating the core Shell layer. 如申請專利範圍第6項所述之持續釋放性粒子，其中，上述抗生物活性化合物含有異噻唑啉系化合物。 The sustained release particle according to claim 6, wherein the antibiotic compound contains an isothiazoline compound. 如申請專利範圍第7項所述之持續釋放性粒子，其中，上述異噻唑啉系化合物為5,6-二氯-2-正辛基-4-異噻唑啉-3-酮。 The sustained release particle according to claim 7, wherein the isothiazolin compound is 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one. 如申請專利範圍第6項所述之持續釋放性粒子，其中，選自由上述第1聚合性乙烯單體及上述第2聚合性乙烯單體所成群組之至少1種的聚合性乙烯單體含有聚合反應性紫外線吸收劑。 The sustained release particles according to claim 6, wherein the polymerizable ethylene monomer selected from the group consisting of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer is at least one selected from the group consisting of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer. Contains a polymeric reactive UV absorber. 一種持續釋放性粒子之製造方法，為具備：核芯調製步驟，係將含有疏水性抗生物活性化合物及疏水性第1聚合性乙烯單體之核芯原料成分進行微乳化液聚合，調製在藉由上述第1聚合性乙烯單體之聚合所獲得之第1聚合物中含有該抗生物活性化合物為相溶之均一相的核芯；及殼層調製步驟，係將含有疏水性第2聚合性乙烯單體之殼層原料成分藉由以上述核芯作為種子之種子乳化聚合所獲得者，並調製將上述核芯包覆之上述殼層。 A method for producing a sustained release particle, comprising: a core preparation step of performing a microemulsion polymerization of a core material component containing a hydrophobic bioactive compound and a hydrophobic first polymerizable ethylene monomer; The first polymer obtained by the polymerization of the first polymerizable ethylene monomer contains a core in which the antibiotic compound is a homogeneous phase; and the shell layer preparation step contains a hydrophobic second polymerizable property. The shell material component of the ethylene monomer is obtained by emulsion polymerization of the seed having the core as the seed, and the shell layer coated with the core is prepared. 如申請專利範圍第10項所述之持續釋放性粒子之製造方法，其中，上述殼層原料成分為實質上未含有上述抗 生物活性化合物。 The method for producing sustained release particles according to claim 10, wherein the shell raw material component is substantially free of the above-mentioned anti- Biologically active compound. 如申請專利範圍第10項所述之持續釋放性粒子之製造方法，其中，上述抗生物活性化合物含有異噻唑啉系化合物。 The method for producing sustained release particles according to claim 10, wherein the antibiotic compound contains an isothiazoline compound. 如申請專利範圍第12項所述之持續釋放性粒子之製造方法，其中，上述異噻唑啉系化合物為5,6-二氯-2-正辛基-4-異噻唑啉-3-酮。 The method for producing sustained release particles according to claim 12, wherein the isothiazoline compound is 5,6-dichloro-2-n-octyl-4-isothiazolin-3-one. 如申請專利範圍第10項所述之持續釋放性粒子之製造方法，其中，上述微乳化液聚合之轉化率在95%以上時，開始將上述殼層原料成分供給至含有上述核芯之乳濁液。 The method for producing a sustained release particle according to claim 10, wherein when the conversion ratio of the microemulsion polymerization is 95% or more, the shell raw material component is supplied to the emulsification containing the core. liquid. 如申請專利範圍第10項所述之持續釋放性粒子之製造方法，其中，選自由上述第1聚合性乙烯單體及上述第2聚合性乙烯單體所成群組之至少1種的聚合性乙烯單體含有聚合反應性紫外線吸收劑。 The method for producing a sustained release particle according to the above aspect of the invention, wherein the polymerizable property is at least one selected from the group consisting of the first polymerizable ethylene monomer and the second polymerizable ethylene monomer. The ethylene monomer contains a polymerization-reactive ultraviolet absorber.
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