JP2013010713A - Inorganic-organic composite particle, and method for producing the same - Google Patents
Inorganic-organic composite particle, and method for producing the same Download PDFInfo
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- 239000011246 composite particle Substances 0.000 title claims abstract description 75
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
- 239000002245 particle Substances 0.000 claims abstract description 111
- 150000002894 organic compounds Chemical class 0.000 claims abstract description 84
- 239000011148 porous material Substances 0.000 claims abstract description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 64
- 239000003960 organic solvent Substances 0.000 claims abstract description 44
- 238000009826 distribution Methods 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 28
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 79
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 47
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 47
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 47
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 21
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 13
- 238000001704 evaporation Methods 0.000 claims description 12
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000377 silicon dioxide Substances 0.000 claims description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 239000000378 calcium silicate Substances 0.000 claims description 5
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 5
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 5
- 238000007561 laser diffraction method Methods 0.000 claims description 5
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- 239000000920 calcium hydroxide Substances 0.000 claims description 4
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 6
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 4
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229930003427 Vitamin E Natural products 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 3
- 239000011368 organic material Substances 0.000 description 3
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- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
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- 239000011324 bead Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
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- 238000001035 drying Methods 0.000 description 2
- 239000010436 fluorite Substances 0.000 description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 2
- 229960002390 flurbiprofen Drugs 0.000 description 2
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- 239000004615 ingredient Substances 0.000 description 2
- 239000000976 ink Substances 0.000 description 2
- 239000010954 inorganic particle Substances 0.000 description 2
- 239000002114 nanocomposite Substances 0.000 description 2
- 239000003973 paint Substances 0.000 description 2
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- 238000001238 wet grinding Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
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- 239000012298 atmosphere Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- VPKDCDLSJZCGKE-UHFFFAOYSA-N carbodiimide group Chemical group N=C=N VPKDCDLSJZCGKE-UHFFFAOYSA-N 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
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- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
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Landscapes
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- Silicates, Zeolites, And Molecular Sieves (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は無機有機複合粒子及びその製造方法に関するものである。 The present invention relates to inorganic-organic composite particles and a method for producing the same.
従来、機能性成分をほかの一種又は二種以上の物質と複合させることで得られた複合粒子は、その機能性成分の効能・効果を高めることや新しい機能を創出することができ、医薬、化粧品、粉末冶金、インク、塗料など幅広い分野において利用されている。例えば、核粒子（母粒子）の表面に多数の微粒子（子粒子）を付着させた複合粒子が多く提案されている。これらの複合粒子は、その材質を選択することにより、多様な特性を示し、触媒担体、顔料、医薬品、化粧品等、多岐の用途に利用することができる。 Conventionally, composite particles obtained by combining a functional ingredient with another kind or two or more substances can enhance the efficacy / effect of the functional ingredient and create a new function, It is used in a wide range of fields such as cosmetics, powder metallurgy, ink and paint. For example, many composite particles have been proposed in which a large number of fine particles (child particles) are attached to the surface of a core particle (mother particle). These composite particles exhibit various characteristics by selecting their materials, and can be used in various applications such as catalyst carriers, pigments, pharmaceuticals, and cosmetics.
例えば、特許文献１には核粒子の表面にシリコーンエラストマーを付着してなる複合粒子が提案されている。
特許文献２〜４には有機化合物と無機固体粒子とを含有して構成される複合粒子が提案されている。
特許文献５にはカルボジイミド基と反応可能な官能基を有する母粒子と、カルボジイミド樹脂からなる外殻層とを有する複合粒子が提案されている。
特許文献６には有効成分が担持された多孔質無機粒子の表面に平均粒子径０．１０μｍ以下の無機ナノ粒子が被覆された複合粒子が提案されている。
For example, Patent Document 1 proposes composite particles obtained by attaching a silicone elastomer to the surface of a core particle.
Patent Documents 2 to 4 propose composite particles composed of an organic compound and inorganic solid particles.
Patent Document 5 proposes composite particles having a base particle having a functional group capable of reacting with a carbodiimide group and an outer shell layer made of a carbodiimide resin.
Patent Document 6 proposes composite particles in which the surface of porous inorganic particles carrying an active ingredient is coated with inorganic nanoparticles having an average particle size of 0.10 μm or less.
本発明は、水難溶解性有機化合物を無機多孔質の細孔内に含有し、種々の分野で利用することができるナノレベルサイズの無機有機複合粒子及びその製造方法を提供することを目的とする。 An object of the present invention is to provide nano-sized inorganic-organic composite particles that contain a poorly water-soluble organic compound in inorganic porous pores and can be used in various fields, and a method for producing the same. .
上記目的を達成するため、以下の発明が提供される。
＜１＞ 無機多孔粒子と、該無機多孔粒子の細孔内に含まれる水難溶解性有機化合物とを有し、レーザー回折・散乱法によって求めた粒度分布における積算値５０％での粒径が１μｍ以下である無機有機複合粒子。
＜２＞ 前記無機多孔粒子が、メタケイ酸アルミン酸マグネシウム、ケイ酸カルシウム及びシリカからなる群から選ばれる少なくとも１種である＜１＞に記載の無機有機複合粒子。
＜３＞ 前記水難溶解性有機化合物が過酸化ベンゾイルを含む＜１＞又は＜２＞に記載の無機有機複合粒子。
＜４＞ 有機溶媒に水難溶解性有機化合物を溶解した水難溶解性有機化合物含有溶液を用意する工程と、前記水難溶解性有機化合物含有溶液を無機多孔体に吸収させる工程と、前記有機溶媒を蒸発させることにより前記水難溶解性有機化合物を前記無機多孔体の細孔内に残留させる工程と、前記水難溶解性有機化合物を前記細孔内に含む前記無機多孔体を、水を含む媒体を用いた湿式粉砕法により粉砕する工程と、を含む、＜１＞〜＜３＞のいずれかに記載の無機有機複合粒子を製造する無機有機複合粒子の製造方法。
＜５＞ 前記有機溶媒はアセトン又はアセトンを含む混合溶媒である＜４＞に記載の無機有機複合粒子の製造方法。
＜６＞ 前記無機多孔体はメタケイ酸アルミン酸マグネシウムであり、前記水を含む媒体はリン酸水溶液又はクエン酸水溶液である＜４＞又は＜５＞に記載の無機有機複合粒子の製造方法。
＜７＞ 前記無機多孔体はシリカであり、前記水を含む媒体は水酸化カルシウム懸濁液である＜４＞又は＜５＞に記載した無機有機複合粒子を製造する方法。
＜８＞ ＜１＞〜＜３＞のいずれかに記載の無機有機複合粒子と水とを含む組成物。
In order to achieve the above object, the following invention is provided.
<1> Having inorganic porous particles and a poorly water-soluble organic compound contained in the pores of the inorganic porous particles, and having a particle size distribution of 1 μm at an integrated value of 50% in a particle size distribution determined by a laser diffraction / scattering method Inorganic organic composite particles that are:
<2> The inorganic-organic composite particle according to <1>, wherein the inorganic porous particle is at least one selected from the group consisting of magnesium aluminate metasilicate, calcium silicate, and silica.
<3> The inorganic-organic composite particle according to <1> or <2>, wherein the poorly water-soluble organic compound contains benzoyl peroxide.
<4> A step of preparing a poorly water-soluble organic compound-containing solution obtained by dissolving a poorly water-soluble organic compound in an organic solvent, a step of absorbing the poorly water-soluble organic compound-containing solution in an inorganic porous body, and evaporating the organic solvent The step of allowing the hardly water-soluble organic compound to remain in the pores of the inorganic porous body by using the medium containing water, and the inorganic porous body containing the hardly water-soluble organic compound in the pores. A method of producing inorganic-organic composite particles according to any one of <1> to <3>, comprising a step of pulverizing by a wet pulverization method.
<5> The method for producing inorganic-organic composite particles according to <4>, wherein the organic solvent is acetone or a mixed solvent containing acetone.
<6> The method for producing inorganic-organic composite particles according to <4> or <5>, wherein the inorganic porous body is magnesium aluminate metasilicate, and the medium containing water is a phosphoric acid aqueous solution or a citric acid aqueous solution.
<7> The method for producing inorganic-organic composite particles according to <4> or <5>, wherein the inorganic porous material is silica, and the medium containing water is a calcium hydroxide suspension.
<8> A composition comprising the inorganic-organic composite particles according to any one of <1> to <3> and water.
本発明によれば、水難溶解性有機化合物を無機多孔質の細孔内に含有し、種々の分野で利用することができるナノレベルサイズの無機有機複合粒子及びその製造方法を提供することができる。 According to the present invention, it is possible to provide nano-sized inorganic / organic composite particles that contain a poorly water-soluble organic compound in inorganic porous pores and can be used in various fields, and a method for producing the same. .
以下、本発明の実施形態について詳細に説明する。
機能性成分（有効成分）が水に溶け難い有機化合物（水難溶解性有機化合物）である場合、その有機化合物を含む粒子の微細化（粒径１μｍ以下）によってその効能・効果を高めることが期待できるが、一部の水難溶解性有機化合物（例えば、過酸化ベンゾイル）は、粒子を１μｍ以下に微細化させることや水中で安定に分散させることが難しい。
Hereinafter, embodiments of the present invention will be described in detail.
When the functional component (active ingredient) is an organic compound that is difficult to dissolve in water (an organic compound that is poorly soluble in water), it is expected to increase its efficacy and effect by making the particles containing the organic compound finer (particle size of 1 μm or less). However, some of the poorly water-soluble organic compounds (for example, benzoyl peroxide) are difficult to make particles finer to 1 μm or less and to be stably dispersed in water.
本発明者は、検討を重ねた結果、粉砕し難い水難溶解性有機結晶物を有機溶媒に溶解させた溶液とし、この溶液を粉砕し易い無機多孔体に吸収させた後、有機溶媒を蒸発させることにより水難溶解性有機物を無機多孔体の細孔内に析出又は細孔内壁に付着させ、次いで、その無機多孔体を水中での湿式粉砕により微粉砕することにより、無機多孔粒子の細孔内に水難溶解性有機化合物を含み、粒径が１μｍ以下の無機有機複合粒子が得られることを見出した。 As a result of repeated studies, the inventor made a solution obtained by dissolving a hardly water-soluble organic crystal substance that is difficult to pulverize in an organic solvent, and this solution was absorbed in an easily pulverized inorganic porous body, and then the organic solvent was evaporated. By depositing poorly water-soluble organic matter in the pores of the inorganic porous body or adhering to the inner wall of the pores, and then finely pulverizing the inorganic porous body by wet pulverization in water, It was found that inorganic organic composite particles having a particle size of 1 μm or less can be obtained.
（１）無機有機複合粒子
本発明に係る無機有機複合粒子（以下、適宜「複合粒子」と記す。）は、無機多孔粒子と、該無機多孔粒子の細孔内に含まれる水難溶解性有機化合物とを有し、レーザー回折・散乱法によって求めた粒度分布における積算値５０％での粒径が１μｍ以下である。
(1) Inorganic organic composite particles The inorganic organic composite particles according to the present invention (hereinafter referred to as “composite particles” as appropriate) are inorganic porous particles and a poorly water-soluble organic compound contained in the pores of the inorganic porous particles. The particle size at an integrated value of 50% in the particle size distribution determined by the laser diffraction / scattering method is 1 μm or less.
［無機多孔粒子］
本発明の複合粒子を構成する無機多孔粒子は多孔性構造を有し、水及び特定の有機溶媒に対して難溶解性のものであれば限定されないが、比表面積及び嵩密度が大きく、自重より多くの液体を吸収する多孔質の無機粒子であることが好ましい。
[Inorganic porous particles]
The inorganic porous particles constituting the composite particles of the present invention are not limited as long as they have a porous structure and are hardly soluble in water and a specific organic solvent. A porous inorganic particle that absorbs many liquids is preferable.
無機多孔粒子の形状は特に限定されず、その幾何学的態様が、球状、多面体状、不定形等、いずれの形状でもよいが、流動性のよい球状体であることが望ましい。
無機多孔粒子の大きさは１μｍ以下であり、１μｍ〜０．０５μｍであることが好ましく、０．６μｍ〜０．１μｍであることがさらに好ましい。
また、無機多孔粒子の細孔径の大きさは、水難溶解性有機化合物を有機溶媒に溶かした溶液が細孔内に入り込む大きさであれば特に限定されないが、孔径が小さ過ぎると溶液が細孔内に入り込み難く、孔径が大き過ぎると後述する複合粒子を製造する際の粉砕工程において水難溶解性有機化合物が孔から排出され易い。このような観点から、無機多孔粒子の細孔径の大きさは、２００ｎｍ〜１ｎｍであることが好ましく、５０ｎｍ〜１ｎｍであることがさらに好ましい。また、細孔の形状は特に限定されない。また、規則的な細孔が無機多孔粒子全体にわたって均一に分布していることが望ましいが、細孔径にバラツキがあって、個別に大きな細孔径が存在してもよい。また、大きな細孔の内壁に小さな細孔が分布している構造（例えば、メソ細孔をミクロ細孔で連結している構造）を有する無機多孔粒子も好適である。
The shape of the inorganic porous particles is not particularly limited, and the geometric aspect may be any shape such as a spherical shape, a polyhedral shape, and an indeterminate shape, but a spherical shape with good fluidity is desirable.
The size of the inorganic porous particles is 1 μm or less, preferably 1 μm to 0.05 μm, and more preferably 0.6 μm to 0.1 μm.
In addition, the pore size of the inorganic porous particles is not particularly limited as long as a solution in which a poorly water-soluble organic compound is dissolved in an organic solvent enters the pores. If the pore diameter is too large, it is difficult for the organic compound to be hardly soluble to be discharged from the pores in the pulverization step when producing composite particles described later. From such a viewpoint, the size of the pore diameter of the inorganic porous particles is preferably 200 nm to 1 nm, and more preferably 50 nm to 1 nm. Moreover, the shape of the pore is not particularly limited. In addition, it is desirable that the regular pores are uniformly distributed over the entire inorganic porous particle, but there may be variations in the pore diameter, and there may be large pore diameters individually. Inorganic porous particles having a structure in which small pores are distributed on the inner walls of the large pores (for example, a structure in which mesopores are connected by micropores) are also suitable.
本発明の複合粒子を得るためにふさわしい無機多孔材料としては、化粧品、医薬品、食品などの分野で、流動性促進剤、流体の固定化剤、又は賦形剤として使用している無機孔質粉体を用いることができ、例えば、メタケイ酸アルミン酸マグネシウム、ケイ酸カルシウム、シリカが挙げられる。
無機多孔粒子は１種単独で又は２種以上を適宜組み合わせて用いることができる。
Examples of the inorganic porous material suitable for obtaining the composite particles of the present invention include inorganic porous powders used as fluidity promoters, fluid fixing agents, or excipients in the fields of cosmetics, pharmaceuticals, foods and the like. The body can be used, and examples thereof include magnesium aluminate metasilicate, calcium silicate, and silica.
An inorganic porous particle can be used individually by 1 type or in combination of 2 or more types as appropriate.
具体的には、「ノイシリン（登録商標）」（富士化学工業（株）製）として市販されているメタケイ酸アルミン酸マグネシウムを好適に用いることができる。ノイシリン（登録商標）は、極めて多孔性の非晶質構造を有し、比表面積が非常に大きく、高い吸油、吸着能を持つ白色粉末である。ノイシリン（登録商標）は、溶媒中での分散性が優れているため、賦形剤、結合剤、崩壊助剤、固結防止剤、流動性改善剤、粉末吸着化剤として、医薬品、化粧品、化成品などの品質改善に広く使われている。種々のノイシリン（登録商標）製品の中でもノイシリンＵＳ２は流動性がよく、特に好適である。 Specifically, magnesium metasilicate magnesium aluminate commercially available as “Neusilin (registered trademark)” (manufactured by Fuji Chemical Industry Co., Ltd.) can be suitably used. Neusilin (registered trademark) is a white powder having an extremely porous amorphous structure, a very large specific surface area, and high oil absorption and adsorption ability. Neusilin (registered trademark) is excellent in dispersibility in a solvent. Therefore, as an excipient, a binder, a disintegration aid, an anti-caking agent, a fluidity improver, and a powder adsorbent, pharmaceuticals, cosmetics, Widely used for quality improvement of chemical products. Among various Neusilin® products, Neusilin US 2 has good fluidity and is particularly suitable.
また、ケイ酸カルシウムである市販のフローライト（登録商標）ＲＥ（エーザイフードケミカル（株）製）も好適である。フローライト（登録商標）ＲＥはビタミンＥなどの脂溶性薬物の固形製剤用吸着剤として、液状物質の固形化担体として利用されている白色粉末である。 Further, commercially available Fluorite (registered trademark) RE (manufactured by Eisai Food Chemical Co., Ltd.), which is calcium silicate, is also suitable. Fluorite (registered trademark) RE is a white powder that is used as an adsorbent for solid preparations of fat-soluble drugs such as vitamin E as a solidified carrier for liquid substances.
また、シリカである市販のサイリシア（登録商標）（富士シリシア化学（株）製）も好適である。サイリシア（登録商標）はケイ酸のゲル化によりＳｉＯ２の多孔構造を形成させた、多孔性に富む内部比表面積の大きな白色粉末であり、その表面は多くの水酸基に覆われ、親水性を示す。使用目的に応じてこの三次元構造を調整することにより、塗料を始めインキ、プラスチックフィルム、接着剤などに幅広く利用されている。 Further, commercially available Silicia (registered trademark) (manufactured by Fuji Silysia Chemical Co., Ltd.), which is silica, is also suitable. Silicia (registered trademark) is a white powder having a large internal specific surface area rich in porosity, in which a porous structure of SiO 2 is formed by gelation of silicic acid, and its surface is covered with many hydroxyl groups and exhibits hydrophilicity. . By adjusting this three-dimensional structure according to the purpose of use, it is widely used for paints, inks, plastic films, adhesives and the like.
これらの無機多孔材料（無機多孔体）は平均粒子径が数十μｍ以上の粉体材料であり、数ｎｍの大きさの細孔が多数含まれており、自重の倍以上の有機溶媒を吸収することができる。従って、有機溶媒に溶解した水難溶解性有機物をこれらの無機多孔材料の細孔内に吸収させて有機溶媒を蒸発させた後、湿式粉砕することで粒径が１μｍ以下の無機有機複合粒子を得ることができる。
無機多孔材料は２種類以上を適宜に配合した混合粉体を用いることも可能である。これらの粉体を適宜配合することにより、水中で粉砕した水分散体の粘度を調整することができる。
These inorganic porous materials (inorganic porous materials) are powder materials having an average particle diameter of several tens of μm or more, and contain a large number of pores with a size of several nanometers, and absorb organic solvents more than double their own weight. can do. Accordingly, the poorly water-soluble organic substance dissolved in the organic solvent is absorbed into the pores of these inorganic porous materials to evaporate the organic solvent, and then wet pulverized to obtain inorganic-organic composite particles having a particle size of 1 μm or less. be able to.
It is also possible to use a mixed powder in which two or more kinds of inorganic porous materials are appropriately blended. By appropriately blending these powders, the viscosity of the aqueous dispersion pulverized in water can be adjusted.
なお、これらの無機多孔材料（無機多孔体）は使用前に水中で微粉砕されると、賦形剤、結合剤、崩壊助剤、固結防止剤、流動性改善剤や粉末吸着化剤としてその性能が低下する可能性があり、従来の用途では、これらの粉末を水中で微粉砕する工程を経る必要は無かった。しかし、本発明者はこれらの無機多孔材料を水中で粉砕することにより平均粒子径を１μｍ以下に微細化することが可能であることを見出した。 In addition, when these inorganic porous materials (inorganic porous bodies) are pulverized in water before use, they can be used as excipients, binders, disintegration aids, anti-caking agents, fluidity improvers, and powder adsorbents. Its performance may be reduced, and in conventional applications, it was not necessary to go through a step of pulverizing these powders in water. However, the present inventors have found that the average particle size can be reduced to 1 μm or less by pulverizing these inorganic porous materials in water.
［水難溶解性有機化合物］
無機多孔粒子の細孔内に含まれる水難溶解性有機化合物は、水に溶け難く、特定の有機溶媒には溶け易く、かつ、該有機溶媒中で少なくとも一定期間（例えば７２時間）内に分解され難いものを用いる。
かかる水難溶解性有機化合物は製造する複合粒子の用途に応じて選択すればよいが、好ましくは２０℃の水に対する溶解度が０．５ｇ／１００ｇ以下であり、特定の有機溶媒（アセトン等）に溶解し、この溶液から有機溶媒を蒸発させた後、その性質又は結晶構造が変化せず、さらに、その粒子は水中で強く凝集し、単独では安定して分散しにくい物質群から選択されることが望ましい。
[Liquid-soluble organic compound]
The poorly water-soluble organic compound contained in the pores of the inorganic porous particles is hardly soluble in water, is easily soluble in a specific organic solvent, and is decomposed in the organic solvent within at least a certain period (for example, 72 hours). Use difficult things.
Such a poorly water-soluble organic compound may be selected according to the use of the composite particles to be produced, but preferably has a solubility in water at 20 ° C. of 0.5 g / 100 g or less and is soluble in a specific organic solvent (acetone or the like). In addition, after evaporating the organic solvent from the solution, its properties or crystal structure does not change, and the particles are selected from a group of substances that strongly aggregate in water and are difficult to disperse stably alone. desirable.
また、該水難溶解性有機化合物が溶媒の蒸発に伴い瞬時に粗大粒子に成長する性質を有する場合では、従来の製造方法（例えば、（i）噴霧乾燥法、すなわち、水難溶解性有機化合物とその他の物質を有機溶媒に溶解又は分散させた後、高温で噴霧して乾燥することにより複合粒子を製造する方法、（ii）溶媒法、すなわち、水難溶解性有機化合物とその他の物質を有機溶媒に溶解又は分散させた後、貧溶媒（例えば、水）の添加で沈殿物を生じさせる方法、（iii）混合法、すなわち、水難溶解性有機化合物を有機溶媒に溶解した後、さらにナノ粒子を添加して撹拌しながら有機溶媒を蒸発して複合粒子を生じさせる方法）によりナノレベル大きさの無機有機複合粒子を製造することが極めて困難であるが、本発明によればナノレベルの大きさの無機有機複合粒子を製造することが容易である。
すなわち、本発明は、このような性質を有する水難溶解性有機化合物を含むナノレベル大きさの複合粒子を低コストで製造することができ、大量生産に適する。
In the case where the poorly water-soluble organic compound has the property of instantly growing into coarse particles as the solvent evaporates, the conventional production method (for example, (i) spray drying, ie, the poorly water-soluble organic compound and other (Ii) Solvent method, that is, a poorly water-soluble organic compound and other substances in an organic solvent, after dissolving or dispersing the substance in an organic solvent and then spraying at high temperature and drying. A method in which a precipitate is formed by adding a poor solvent (for example, water) after dissolution or dispersion, (iii) a mixing method, that is, a slightly water-soluble organic compound is dissolved in an organic solvent, and then nanoparticles are added. It is extremely difficult to produce nano-level inorganic organic composite particles by a method of evaporating an organic solvent with stirring and producing composite particles). It is easy to manufacture the inorganic organic composite particles.
That is, the present invention can produce nano-sized composite particles containing a poorly water-soluble organic compound having such properties at low cost, and is suitable for mass production.
無機多孔粒子の細孔内の水難溶解性有機化合物の形態は特に限定されず、結晶質、非結晶質、分子或いは分子集合体などの形態で存在することが可能である。 The form of the poorly water-soluble organic compound in the pores of the inorganic porous particles is not particularly limited, and can exist in the form of crystalline, amorphous, molecules, molecular aggregates, or the like.
本発明で用いることができる水難溶解性有機化合物の具体例として、過酸化ベンゾイルがあげられる。過酸化ベンゾイルは白色粒状の無臭の固体であり、水にはほとんど溶けない（０．１ｇ／１００ｍｌ（２６℃））が、アセトン等の有機溶剤には溶ける。なお、過酸化ベンゾイルは、８０℃まで加熱すると発火、さらに１００℃を超えると白煙を発生して激しく分解するが、水中では化学的に安定で分解しにくいため、市販品は爆発防止のため２５％の水で湿らせて純度７５％としているものが一般的である。 Specific examples of the poorly water-soluble organic compound that can be used in the present invention include benzoyl peroxide. Benzoyl peroxide is a white granular odorless solid that is hardly soluble in water (0.1 g / 100 ml (26 ° C.)), but is soluble in organic solvents such as acetone. Benzoyl peroxide ignites when heated up to 80 ° C, and generates white smoke when heated above 100 ° C. However, it is chemically stable and difficult to decompose in water. It is common that the purity is 75% by moistening with 25% water.
過酸化ベンゾイルは、ニキビ治療薬の有効成分として知られているが、皮膚の乾燥や炎症など副作用が指摘されている。過酸化ベンゾイルの粒子径が小さければ小さいほど、副作用が少ないと考えられる。しかし、過酸化ベンゾイルは、粉砕の方法による微細な粒子を製造することが難しい。また、過酸化ベンゾイルは溶媒中から析出する際に、瞬時に結晶が成長して粒子径が数μｍ以上の大きさの粒子となるため、析出法による微細な粒子を製造することが難しい。また、水中では微細な過酸化ベンゾイル粒子は凝集しやすく、安定した水分散体を得ることが難しい。 Benzoyl peroxide is known as an active ingredient in acne treatment drugs, but side effects such as dry skin and inflammation have been pointed out. It is considered that the smaller the particle size of benzoyl peroxide, the fewer side effects. However, it is difficult for benzoyl peroxide to produce fine particles by a grinding method. Further, when benzoyl peroxide is precipitated from a solvent, crystals grow instantaneously and become particles having a particle size of several μm or more, and it is difficult to produce fine particles by a precipitation method. Further, in water, fine benzoyl peroxide particles tend to aggregate and it is difficult to obtain a stable aqueous dispersion.
このように粒径が１μｍ以下の過酸化ベンゾイル粒子を得ることは困難であるが、本発明によれば、不燃性の無機多孔粒子の細孔内に過酸化ベンゾイルを分散して包含し、さらに、大量の水を吸収した複合粒子とすることで、安定的な複合粒子とすることができる。
また、本発明の無機有機複合粒子は非常に安定で微細的な粒子であるため、皮膚の細孔に入りやすく皮膚細孔内のアクネ菌の増殖を抑えニキビに対する治療効果を高めることも期待される。
Thus, although it is difficult to obtain benzoyl peroxide particles having a particle size of 1 μm or less, according to the present invention, benzoyl peroxide is dispersed and included in the pores of nonflammable inorganic porous particles. By forming composite particles that have absorbed a large amount of water, stable composite particles can be obtained.
In addition, since the inorganic-organic composite particles of the present invention are very stable and fine particles, they can easily enter the pores of the skin and are expected to increase the therapeutic effect against acne by suppressing the growth of acne bacteria in the skin pores. The
ほかの水難溶解性有機化合物、例えば、ビタミンＥ類は水に難溶解であるが、オクタノールなどアルコール類に溶解しやすい。本発明により得られたビタミンＥを含有するナノレベルサイズの無機有機複合粒子は健康飲料に添加すれば沈殿しにくく摂取されやすいなど効果が期待できる。
また、内服用医薬品化合物の中に水難溶解性であるが有機溶剤には溶けやすい有機化合物が数多くあり、これらの物質群から本発明の水難溶解性有機化合物を選択することができる。本発明により得られたこれらの薬物を含有するナノレベルサイズの無機有機複合粒子を用いれば医薬品の安定性が改善され、摂取されやすくなるなどの効果が期待できる。
具体的な例をあげると、例えば、消炎鎮痛作用のフルルビプロフェン（化学式C15H13FO2）は白色の結晶性粉末で、弱い刺激臭があり、メタノール・エタノール・アセトン・ジエチルエーテルに易溶、アセトニトリルに可溶、水に難溶解であり、本発明の水難溶解性有機化合物として使うことができる。本発明により得られたフルルビプロフェンを含有するナノレベルサイズの無機有機複合粒子を用いれば、例えば、内服薬として配合すればナノサイズによる効能効果が期待できる。また、貼付薬に配合すれば、皮膚の細孔に入り込みやすくなり治療効果を高めることが期待できる。
ほかに、機能性材料分野においては、機能性有機材料の多くは水に溶けにくい、特定溶剤に溶けやすい性質があるため、これらの物質群から本発明の水難溶解性有機化合物を選択することができる。本発明により得られた機能性有機材料を含有するナノレベルサイズの無機有機複合粒子を用いれば、機能性有機材料の性能（例えば、耐熱性、耐久性、耐候性、水への分散性）を向上させると同時に、ナノサイズによる新しい効能効果の発見が期待できる。
Other poorly water-soluble organic compounds such as vitamin E are hardly soluble in water, but are easily soluble in alcohols such as octanol. Nano-sized inorganic / organic composite particles containing vitamin E obtained according to the present invention can be expected to have an effect of being difficult to precipitate and easily ingested when added to a health drink.
In addition, there are many organic compounds that are poorly soluble in water but easy to dissolve in organic solvents, and the poorly soluble organic compound of the present invention can be selected from these substance groups. If nano-sized inorganic-organic composite particles containing these drugs obtained by the present invention are used, effects such as improved drug stability and ease of ingestion can be expected.
For example, flurbiprofen (chemical formula C 15 H 13 FO 2 ), which has anti-inflammatory analgesic action, is a white crystalline powder with a weak irritating odor, such as methanol, ethanol, acetone, and diethyl ether. It is easily soluble, soluble in acetonitrile, hardly soluble in water, and can be used as the hardly soluble organic compound of the present invention. If nano-sized inorganic / organic composite particles containing flurbiprofen obtained by the present invention are used, for example, if they are formulated as internal medicines, the effect of nano-size can be expected. Moreover, if it mix | blends with a patch, it will be easy to enter into the pore of skin, and it can be expected that the therapeutic effect is enhanced.
In addition, in the field of functional materials, many of the functional organic materials are difficult to dissolve in water and easily dissolve in a specific solvent. Therefore, it is possible to select the poorly water-soluble organic compound of the present invention from these substance groups. it can. If the inorganic organic composite particles of nano-size size containing the functional organic material obtained by the present invention are used, the performance of the functional organic material (for example, heat resistance, durability, weather resistance, dispersibility in water) will be improved. At the same time, it can be expected to discover new efficacy effects by nano-size.
複合粒子中の水難溶解性有機化合物の含有量は、無機多孔粒子の細孔内に収容可能な範囲内であれば特に限定されず、製造する複合粒子の用途に応じて選択すればよいが、水難溶解性有機化合物の含有比率が高くなるほど無機多孔粒子の細孔外に水難溶解性有機化合物が析出し易くなり、凝集が起こる可能性が高くなる。
複合粒子の用途にもよるが、通常、本発明に係る複合粒子中の水難溶解性有機化合物の含有量は、３０〜０．１質量％程度である。
例えば、ノイシリン（登録商標）（富士化学工業（株）製）の細孔内に過酸化ベンゾイルを含有させて本発明の複合粒子を得る場合は、ノイシリン（登録商標）に対して過酸化ベンゾイルの量が０．０１〜２０質量％の範囲内であることが好ましい。無機多孔粒子に対する過酸化ベンゾイルの配合量が０．０１質量％以上であれば機能性成分としての過酸化ベンゾイルの効果が確実に得られ、２０質量％以下であれば水中での凝集を抑制することができる。
The content of the poorly water-soluble organic compound in the composite particles is not particularly limited as long as it is within a range that can be accommodated in the pores of the inorganic porous particles, and may be selected according to the use of the composite particles to be manufactured. The higher the content ratio of the poorly water-soluble organic compound, the more easily the poorly water-soluble organic compound is precipitated out of the pores of the inorganic porous particles, and the possibility of aggregation is increased.
Although depending on the use of the composite particles, the content of the poorly water-soluble organic compound in the composite particles according to the present invention is usually about 30 to 0.1% by mass.
For example, when benzoyl peroxide is contained in the pores of Neusilin (registered trademark) (Fuji Chemical Industry Co., Ltd.) to obtain the composite particles of the present invention, the content of benzoyl peroxide relative to Neusilin (registered trademark) The amount is preferably in the range of 0.01 to 20% by mass. If the blending amount of benzoyl peroxide with respect to the inorganic porous particles is 0.01% by mass or more, the effect of benzoyl peroxide as a functional component is surely obtained, and if it is 20% by mass or less, aggregation in water is suppressed. be able to.
［平均粒子径の定義及び測定条件］
本発明の無機有機複合粒子は平均粒子径が１μｍ以下である。
粒子の平均粒子径測定法としては、一般的に、顕微鏡法、光散乱法、レーザー回折法、液相沈降法、電気抵抗法等があげられるが、本発明の複合粒子の平均粒子径は、レーザー回折・散乱法によって求めた粒度分布における積算値５０％（Ｄ５０径（メジアン径））であることを指す。
[Definition of average particle size and measurement conditions]
The inorganic-organic composite particles of the present invention have an average particle size of 1 μm or less.
Examples of the average particle size measurement method of the particles generally include microscopy, light scattering method, laser diffraction method, liquid phase precipitation method, electric resistance method, etc., but the average particle size of the composite particles of the present invention is: It means that the integrated value in the particle size distribution determined by the laser diffraction / scattering method is 50% (D50 diameter (median diameter)).
なお、本発明に係る粒子の粒径は以下の測定装置及び測定条件によって求めることができる。
−測定装置−
レーザ回折／散乱式粒子径分布測定装置ＬＡ−９５０Ｖ２（（株）堀場製作所）
−測定条件−
内蔵超音波照射時間：２分、照射強度：７
攪拌速度：３
循環速度：７
粒子径基準：体積
反復回数：１５
屈折率（Ｒ）：１．４５０−０．０００ｉ 水 １．３３３
屈折率（Ｂ）：１．４５０−０．０００ｉ 水 １．３３３
In addition, the particle size of the particle | grains based on this invention can be calculated | required with the following measuring apparatuses and measurement conditions.
-Measurement device-
Laser diffraction / scattering particle size distribution analyzer LA-950V2 (Horiba, Ltd.)
-Measurement conditions-
Built-in ultrasonic irradiation time: 2 minutes, irradiation intensity: 7
Stirring speed: 3
Circulation speed: 7
Particle diameter standard: volume Number of repetitions: 15
Refractive index (R): 1.450-0.000i Water 1.333
Refractive index (B): 1.450-0.000i Water 1.333
（１）無機有機複合粒子の製造方法
本発明の無機有機複合粒子を製造する方法は特に限定されないが、有機溶媒に水難溶解性有機化合物を溶解した水難溶解性有機化合物含有溶液を用意する工程と、前記水難溶解性有機化合物含有溶液を無機多孔体に吸収させる工程と、前記有機溶媒を蒸発させることにより前記水難溶解性有機化合物を前記無機多孔体の細孔内に残留させる工程と、前記水難溶解性有機化合物を前記細孔内に含む前記無機多孔体を、水を含む媒体を用いた湿式粉砕法により粉砕する工程と、を含む方法によって容易に製造することができる。図１は、本発明の無機有機複合粒子の製造工程を示している。
(1) Method for Producing Inorganic Organic Composite Particles The method for producing the inorganic organic composite particles of the present invention is not particularly limited, and a step of preparing a poorly water-soluble organic compound-containing solution in which a poorly water-soluble organic compound is dissolved in an organic solvent; Absorbing the poorly water-soluble organic compound-containing solution into the inorganic porous body; evaporating the organic solvent to leave the poorly water-soluble organic compound in the pores of the inorganic porous body; and The inorganic porous body containing the soluble organic compound in the pores can be easily produced by a method including a step of pulverizing by a wet pulverization method using a medium containing water. FIG. 1 shows a process for producing the inorganic-organic composite particles of the present invention.
（Ａ）溶解工程
まず、有機溶媒に水難溶解性有機化合物を溶解した水難溶解性有機化合物含有溶液を用意する。
有機溶媒としては、例えば、アセトン、アセトンを含む混合溶媒、エタノール、トルエン、ベンジン、シンナーなどが挙げられ、使用する無機多孔体を溶解せず、水難溶解性有機化合物を溶解し、この水難溶解性有機化合物を分解せずに蒸発させることができるものを選択すればよい。例えば、水難溶解性有機化合物として過酸化ベンゾイルを用いる場合は、アセトンを好適に用いることができる。
ここで水難溶解性有機化合物の量に対して有機溶媒の量が少な過ぎると水難溶解性有機化合物が十分溶解しない可能性があるため、溶液中の水難溶解性有機化合物の濃度は２５質量％以下となるように調製することが好ましい。
(A) Dissolution Step First, a hardly water-soluble organic compound-containing solution in which a poorly water-soluble organic compound is dissolved in an organic solvent is prepared.
Examples of the organic solvent include acetone, a mixed solvent containing acetone, ethanol, toluene, benzine, thinner, and the like. What is necessary is just to select what can evaporate without decomposing | disassembling an organic compound. For example, when benzoyl peroxide is used as the poorly water-soluble organic compound, acetone can be preferably used.
Here, if the amount of the organic solvent is too small relative to the amount of the poorly water-soluble organic compound, the poorly water-soluble organic compound may not be sufficiently dissolved. Therefore, the concentration of the hardly water-soluble organic compound in the solution is 25% by mass or less. It is preferable to prepare such that
溶解工程では、水難溶解性有機化合物のほかに、必要に応じて他の添加剤を有機溶媒に加えてもよい。そのような添加剤として、例えば、生分解性ポリマーなどが挙げられる。 In the dissolution step, in addition to the poorly water-soluble organic compound, other additives may be added to the organic solvent as necessary. Examples of such additives include biodegradable polymers.
（Ｂ）吸収工程
有機溶媒に水難溶解性有機化合物を溶解した後、得られた水難溶解性有機化合物含有溶液を無機多孔体に吸収させる。
無機多孔体は、粉砕し易い材料が好ましく、粉砕後に無機有機複合粒子を構成する無機多孔粒子となる。無機多孔体は、前記した無機多孔粒子と同様、多孔性構造を有し、水及び有機溶媒に対して難溶解性のものであり、比表面積及び嵩密度が大きく、自重より多くの液体を吸収する多孔体であることが好ましい。例えば、メタケイ酸アルミン酸マグネシウム、ケイ酸カルシウム、シリカが挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。
(B) Absorption process After dissolving a poorly water-soluble organic compound in an organic solvent, the resulting poorly water-soluble organic compound-containing solution is absorbed into the inorganic porous body.
The inorganic porous material is preferably a material that is easily pulverized, and becomes an inorganic porous particle constituting the inorganic-organic composite particle after pulverization. The inorganic porous material, like the inorganic porous particles described above, has a porous structure, is hardly soluble in water and organic solvents, has a large specific surface area and bulk density, and absorbs more liquid than its own weight. It is preferable to be a porous body. Examples thereof include magnesium aluminate metasilicate, calcium silicate, and silica, and these can be used alone or in combination of two or more.
無機多孔体の形状は特に限定されないが、水難溶解性有機化合物含有溶液を吸収し易い観点から顆粒状又は粉末状であることが好ましい。また、吸収が均一且つ迅速に行うために、粉末を撹拌させながら吸収を行わせることが望ましい。なお、無機多孔体の粒径が大き過ぎると、撹拌されにくく、水難溶解性有機化合物含有溶液が中心部まで十分吸収され難く、粒径が小さ過ぎると流動性が悪くなり水難溶解性有機化合物含有溶液を吸収したときに凝集し易い。そのため、無機多孔体の粒径は、好ましくは１μｍ〜３０００μｍであり、より好ましくは１０μｍ〜１０００μｍである。 The shape of the inorganic porous material is not particularly limited, but is preferably granular or powdery from the viewpoint of easily absorbing the poorly water-soluble organic compound-containing solution. Moreover, in order to perform absorption uniformly and rapidly, it is desirable to perform absorption while stirring the powder. In addition, if the particle size of the inorganic porous material is too large, it is difficult to stir, the hardly water-soluble organic compound-containing solution is not sufficiently absorbed to the center, and if the particle size is too small, the fluidity becomes poor and the hardly water-soluble organic compound content is contained. Aggregates easily when the solution is absorbed. Therefore, the particle size of the inorganic porous body is preferably 1 μm to 3000 μm, more preferably 10 μm to 1000 μm.
例えば、水難溶解性有機化合物含有溶液を収容したガラス容器に無機多孔体粉末を加えて攪拌することで水難溶解性有機化合物含有溶液を無機多孔体に吸収させることができる。このとき、水難溶解性有機化合物含有溶液に対して無機多孔体の添加量が多過ぎると、無機多孔体の一部は水難溶解性有機化合物含有溶液をほとんど吸収せず、蒸発及び粉砕後に有機化合物を含まない粒子が生じる可能性があり、一方、無機多孔体の添加量が少な過ぎると、水難溶解性有機化合物含有溶液の一部が無機多孔体に吸収されず、蒸発及び粉砕後に有機化合物の粒子が析出したり、無機多孔粒子の表面に有機化合物が析出される可能性がある。そのため、無機多孔体の添加量は、無機多孔体全体で水難溶解性有機化合物含有溶液を吸収する量とすることが好ましい。
具体的には、無機多孔体の質量１に対して、溶液の質量が１〜３の割合とすることが好ましい。
For example, the inorganic porous material can absorb the hardly water-soluble organic compound-containing solution by adding the inorganic porous material powder to a glass container containing the poorly water-soluble organic compound-containing solution and stirring. At this time, if the amount of the inorganic porous material added is too large with respect to the hardly water-soluble organic compound-containing solution, a part of the inorganic porous material hardly absorbs the hardly water-soluble organic compound-containing solution, and the organic compound after evaporation and pulverization On the other hand, if the amount of the inorganic porous material added is too small, a part of the poorly water-soluble organic compound-containing solution is not absorbed by the inorganic porous material, and the organic compound is removed after evaporation and pulverization. There is a possibility that particles are deposited or an organic compound is deposited on the surface of the inorganic porous particles. Therefore, it is preferable that the addition amount of the inorganic porous material is an amount that absorbs the hardly water-soluble organic compound-containing solution in the entire inorganic porous material.
Specifically, the mass of the solution is preferably set to a ratio of 1 to 3 with respect to 1 of the inorganic porous body.
（Ｃ）蒸発工程
水難溶解性有機化合物含有溶液を無機多孔体に吸収させた後、有機溶媒を蒸発させることにより前記水難溶解性有機化合物を前記無機多孔体の細孔内に残留させる。
有機溶媒として例えばアセトンを用いた場合には、大気中に放置することで揮発させることができる。減圧乾燥、あるいは、加熱によって水難溶解性有機化合物が分解しない温度以下に加熱して有機溶媒の蒸発を促進してもよい。例えば、吸収工程後の有機溶媒を水難溶解性有機結晶物の分解温度以下の温度（例えば４０℃以下）で減圧方式により無機多孔体内から除去する。
なお、揮発した有機溶媒は公知公用の方法により回収して再利用することが好ましい。
(C) Evaporation step After the hardly water-soluble organic compound-containing solution is absorbed by the inorganic porous body, the hardly water-soluble organic compound is left in the pores of the inorganic porous body by evaporating the organic solvent.
For example, when acetone is used as the organic solvent, it can be volatilized by being left in the atmosphere. The evaporation of the organic solvent may be promoted by drying under reduced pressure or by heating to a temperature at which the poorly water-soluble organic compound is not decomposed by heating. For example, the organic solvent after the absorption step is removed from the inorganic porous body by a reduced pressure method at a temperature lower than the decomposition temperature of the poorly water-soluble organic crystal (for example, 40 ° C. or lower).
The volatilized organic solvent is preferably recovered and reused by a publicly known method.
水難溶解性有機化合物含有溶液は無機多孔体の細孔内に入り込んでいるため、水難溶解性有機化合物は有機溶媒の蒸発により無機多孔体の細孔内に残留する。なお、ここで有機溶媒を完全に蒸発させる必要はないが、９０質量％以上蒸発させることが好ましい。
例えば、揮発しやすいアセトンなど有機溶媒に粉砕されにくい過酸化ベンゾイルを溶解させ、次に、粉砕されやすいメタケイ酸アルミン酸マグネシウムなど無機多孔体に吸収させた後に有機溶媒を揮発させる。このようにして無機多孔体の細孔内に過酸化ベンゾイルを析出させることによりその結晶成長を抑えることができる。
Since the poorly water-soluble organic compound-containing solution has entered the pores of the inorganic porous body, the poorly water-soluble organic compound remains in the pores of the inorganic porous body due to evaporation of the organic solvent. In addition, although it is not necessary to evaporate an organic solvent completely here, it is preferable to evaporate 90 mass% or more.
For example, benzoyl peroxide which is difficult to be pulverized is dissolved in an organic solvent such as acetone which is easily volatilized, and then the organic solvent is volatilized after being absorbed in an inorganic porous material such as magnesium aluminate metasilicate which is easily pulverized. Thus, the crystal growth can be suppressed by precipitating benzoyl peroxide in the pores of the inorganic porous material.
（Ｄ）粉砕工程
水難溶解性有機化合物を前記細孔内に含む前記無機多孔体を、水を含む分散媒を用いた湿式粉砕法により粉砕する。
湿式粉砕法としては公知の方法を利用することができ、例えば、ジルコニアボールを用いた遊星型ボールミル粉砕機によって好適に微細化することができる。ほかに、公知の湿式粉砕法としては、粉砕媒体（メデイア）として、直径０．０３ｍｍ以上１ｍｍ以下のビーズを用いてビーズミル粉砕法があげられる。例えば、湿式微粉砕機「スターミル」（商品名、アシザワ・ファインテック（株）製）を用いて微細化することができる。また、近年、新しく開発された、粉砕媒体を要らない湿式粉砕法である湿式ジェトミル粉砕法も公知の湿式粉砕法である。例えば、湿式粉砕装置「スターバースト」（商品名、（株）スギノマシン製）を用いて微細化することができる。
湿式粉砕法に用いる分散媒としては、水のほか、水を溶媒とする水溶液や懸濁液などが挙げられ、無機多孔体及び水難溶解性有機化合物に応じて選択すればよい。無機多孔体の性質に応じて酸性或いはアルカリ性に調整することにより、より微細な複合粒子が得られるとともに、複合粒子の水分散体の粘度及び安定性を向上させることができる。
(D) Grinding step The inorganic porous material containing the poorly water-soluble organic compound in the pores is pulverized by a wet pulverization method using a dispersion medium containing water.
As the wet pulverization method, a known method can be used, and for example, it can be suitably miniaturized by a planetary ball mill pulverizer using zirconia balls. In addition, a known wet pulverization method includes a bead mill pulverization method using beads having a diameter of 0.03 mm to 1 mm as a pulverization medium (media). For example, it can be refined using a wet pulverizer “Star Mill” (trade name, manufactured by Ashizawa Finetech Co., Ltd.). In addition, a recently developed wet jet milling method, which is a wet grinding method that does not require a grinding medium, is a known wet grinding method. For example, it can be refined using a wet pulverizer “Starburst” (trade name, manufactured by Sugino Machine Co., Ltd.).
Examples of the dispersion medium used in the wet pulverization method include water and aqueous solutions and suspensions using water as a solvent, and may be selected according to the inorganic porous material and the poorly water-soluble organic compound. By adjusting the acidity or alkalinity according to the properties of the inorganic porous material, finer composite particles can be obtained, and the viscosity and stability of the aqueous dispersion of composite particles can be improved.
例えば、過酸化ベンゾイルを細孔内に含有したメタケイ酸アルミン酸マグネシウムの無機多孔体を水中で粉砕して平均粒子径１μｍ以下の複合粒子を得ることができる。また、前記水中での粉砕に無水リン酸又は無水クエン酸を添加した水（リン酸水溶液又はクエン酸水溶液）を用いることにより、より細かく、例えば平均粒子径０．３μｍ以下の複合粒子が得られる。
また、無機多孔粒子がシリカである場合は、水酸化カルシウム懸濁液を用いて湿式粉砕を行うことでより細かい微細化を行うことができる。
For example, an inorganic porous body of magnesium aluminate metasilicate containing benzoyl peroxide in pores can be pulverized in water to obtain composite particles having an average particle diameter of 1 μm or less. Further, by using water (phosphoric acid aqueous solution or citric acid aqueous solution) added with anhydrous phosphoric acid or anhydrous citric acid for pulverization in water, finer composite particles having an average particle diameter of 0.3 μm or less, for example, can be obtained. .
Further, when the inorganic porous particles are silica, finer refinement can be performed by performing wet pulverization using a calcium hydroxide suspension.
なお、粉砕工程を経て本発明の無機有機複合粒子と水を含む組成物が得られるが、分散媒の種類と量によって、粉末状、ゲル状、クリーム状、液状等に調整することができ、用途に応じて調整すればよい。
上記のような工程を経て、例えば、無機多孔粒子の細孔内に過酸化ベンゾイルを含有し、平均粒子径１μｍ以下の複合粒子と水を含む組成物を製造することができる。すなわち、本発明によれば、過酸化ベンゾイルを有機溶媒に溶かした後、多孔体細孔内の微細空間内での有機溶媒の蒸発に伴い過酸化ベンゾイル粒子を析出させることにより、過酸化ベンゾイルの結晶成長を抑制して平均粒子径１μｍ以下の過酸化ベンゾイル粒子を製造する方法が提供される。
本発明の製造方法によって得られた複合粒子は微細であり、しかも水中で安定的に分散されるため、皮膚治療薬として好適に使用することができる。
In addition, although the composition containing the inorganic-organic composite particles of the present invention and water is obtained through a pulverization step, it can be adjusted to powder, gel, cream, liquid, etc., depending on the type and amount of the dispersion medium, What is necessary is just to adjust according to a use.
Through the steps as described above, for example, a composition containing benzoyl peroxide in the pores of the inorganic porous particles and containing composite particles having an average particle diameter of 1 μm or less and water can be produced. That is, according to the present invention, after dissolving benzoyl peroxide in an organic solvent, benzoyl peroxide particles are precipitated along with evaporation of the organic solvent in the fine space in the porous pores. Provided is a method for producing benzoyl peroxide particles having an average particle size of 1 μm or less while suppressing crystal growth.
Since the composite particles obtained by the production method of the present invention are fine and are stably dispersed in water, they can be suitably used as a skin treatment drug.
以下に実施例を挙げて本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
＜実施例１＞
アセトン１２ｇを計量して５０ｍｌのガラス容器に入れ、次に過酸化ベンゾイル（２５％の水で湿らせた純度７５％品）１ｇを計量して前記ガラス容器に入れ、アセトンに溶かした。
次いで、ノイシリン（登録商標）（ＵＳ２タイプ、富士化学工業（株））粉末１０ｇを前記ガラス容器に投入し、前記過酸化ベンゾイルを含有するアセトン溶液が完全に吸収されるまで撹拌した。これにより、吸収前と外観的には変化のないアセトン及び過酸化ベンゾイルを含有するノイシリン（登録商標）粉末を得た。
次にこの粉末を室温で大気に曝露しアセトンを揮発させた。揮発前後に粉末の重量を量り、重量の減少からアセトンは約９０％が揮発したと推定される。
次に揮発後の粉末３ｇ、精製水２０ｇ及び直径３ｍｍのジルコニアボール５０ｇを容積４５ｍｌのジルコニア粉砕容器（ドイツ フリッチュ社製）に入れ、遊星型ボールミル粉砕機（Ｐ−７型、ドイツ フリッチュ社製）を用いて回転数８００ｒｐｍ、１時間で粉砕を行った。この粉砕したサンプルは安定したスラリー状組成物である。
レーザ回折／散乱式粒子径分布測定装置（Ｐａｒｔｉｃａ ＬＡ−９５０Ｖ２、（株）堀場製作所）を用いて測定した結果、図２に示す粒度分布図が得られ、前記粉砕したサンプルの平均粒子径（Ｄ５０径）は約３１０ｎｍである。
<Example 1>
12 g of acetone was weighed into a 50 ml glass container, and then 1 g of benzoyl peroxide (75% purity moistened with 25% water) was weighed into the glass container and dissolved in acetone.
Next, 10 g of Neusilin (registered trademark) (US 2 type, Fuji Chemical Industry Co., Ltd.) powder was put into the glass container and stirred until the acetone solution containing the benzoyl peroxide was completely absorbed. As a result, Neusilin (registered trademark) powder containing acetone and benzoyl peroxide having no change in appearance before absorption was obtained.
Next, this powder was exposed to air at room temperature to volatilize acetone. The powder was weighed before and after volatilization, and it was estimated that about 90% of the acetone was volatilized from the decrease in weight.
Next, 3 g of the powder after volatilization, 20 g of purified water and 50 g of zirconia balls having a diameter of 3 mm are put into a 45 ml zirconia crushing container (made by Frichtu, Germany), and a planetary ball mill crusher (P-7, made by Frichtu, Germany). Was pulverized at 800 rpm for 1 hour. This crushed sample is a stable slurry composition.
As a result of measurement using a laser diffraction / scattering particle size distribution measuring device (Partica LA-950V2, Horiba, Ltd.), the particle size distribution diagram shown in FIG. 2 was obtained, and the average particle size (D50) of the pulverized sample was obtained. (Diameter) is about 310 nm.
＜実施例２＞
実施例１において粉末の粉砕に用いた精製水２０ｇの代わりに、濃度２質量％のリン酸水溶液２０ｇを用いて、実施例１と同じ条件で粉砕を行った結果、図３に示す粒度分布図が得られ、平均粒子径（Ｄ５０径）が約２８０ｎｍの粉砕サンプルが得られた。
<Example 2>
As a result of grinding under the same conditions as in Example 1 using 20 g of phosphoric acid aqueous solution having a concentration of 2% by mass instead of 20 g of purified water used for grinding powder in Example 1, the particle size distribution diagram shown in FIG. And a pulverized sample having an average particle size (D50 size) of about 280 nm was obtained.
＜実施例３＞
アセトン１２ｇを計量して５０ｍｌのガラス容器に入れ、次に過酸化ベンゾイル（２５％の水で湿らせた純度７５％品）１ｇと生分解性ポリマー（ＰＬＡ−０００５、和光純薬工業）２ｇを計量して前記ガラス容器に入れ、これらの粉末をアセトンに完全に溶かした。
次いで、ノイシリン（登録商標）（ＵＳ２タイプ、富士化学工業（株））粉末１０ｇを前記ガラス容器に投入し、前記過酸化ベンゾイル及び前記生分解性ポリマーを含有するアセトン溶液が完全に吸収されるまで撹拌した。これにより、吸収前と外観的には変化のない粉末を得た。
次にこの粉末を室温で大気に曝露しアセトンを揮発させた。揮発前後に粉末の重量を量り、重量の減少からアセトンは約９０％が揮発したと推定される。
次に揮発後の粉末３ｇ、精製水２０ｇ及び直径３ｍｍのジルコニアボール５０ｇを容積４５ｍｌのジルコニア粉砕容器（ドイツ フリッチュ社製）に入れ、遊星型ボールミル粉砕機（Ｐ−７型、ドイツ フリッチュ社製）を用いて回転数８００ｒｐｍ、１時間で粉砕を行った。この粉砕したサンプルは安定したスラリー状組成物である。
レーザ回折／散乱式粒子径分布測定装置（Ｐａｒｔｉｃａ ＬＡ−９５０Ｖ２、（株）堀場製作所）を用いて測定した結果、図４に示す粒度分布図に示すように、前記粉砕したサンプルの平均粒子径（Ｄ５０径）は約２８４ｎｍである。
<Example 3>
Weigh 12 g of acetone into a 50 ml glass container, then add 1 g of benzoyl peroxide (75% pure product moistened with 25% water) and 2 g of biodegradable polymer (PLA-0005, Wako Pure Chemical Industries). These powders were weighed and placed in the glass container, and these powders were completely dissolved in acetone.
Next, 10 g of Neusilin (registered trademark) (US 2 type, Fuji Chemical Co., Ltd.) powder is put into the glass container, and the acetone solution containing the benzoyl peroxide and the biodegradable polymer is completely absorbed. Until stirred. As a result, a powder having no change in appearance before absorption was obtained.
Next, this powder was exposed to air at room temperature to volatilize acetone. The powder was weighed before and after volatilization, and it was estimated that about 90% of the acetone was volatilized from the decrease in weight.
Next, 3 g of the powder after volatilization, 20 g of purified water and 50 g of zirconia balls having a diameter of 3 mm are put into a 45 ml zirconia crushing container (made by Frichtu, Germany), and a planetary ball mill crusher (P-7, made by Frichtu, Germany). Was pulverized at 800 rpm for 1 hour. This crushed sample is a stable slurry composition.
As a result of measurement using a laser diffraction / scattering particle size distribution measuring apparatus (Partica LA-950V2, Horiba, Ltd.), as shown in the particle size distribution diagram shown in FIG. 4, the average particle size ( D50 diameter) is about 284 nm.
＜実施例４＞
アセトン１２ｇを計量して５０ｍｌのガラス容器に入れ、次に過酸化ベンゾイル（２５％の水で湿らせた純度７５％品）１ｇを計量して前記ガラス容器に入れ、アセトンに完全に溶かした。
次いで、合成シリカ多孔体（サイリシア３５０、富士シリシア化学（株））粉末６ｇを前記ガラス容器に投入し、前記過酸化ベンゾイルを含有するアセトン溶液が完全に吸収されるまで撹拌した。これにより、吸収前と外観的には変化のないアセトン及び過酸化ベンゾイルを含有するサイリシア３５０粉末を得た。
次にこの粉末を室温で大気に曝露しアセトンを揮発させた。揮発前後に粉末の重量を量り、重量の減少からアセトンは約９０％が揮発したと推定される。
次に揮発後の粉末３ｇ、精製水２０ｇ及び直径３ｍｍのジルコニアボール５０ｇを容積４５ｍｌのジルコニア粉砕容器（ドイツ フリッチュ社製）に入れ、遊星型ボールミル粉砕機（Ｐ−７型、ドイツ フリッチュ社製）を用いて回転数８００ｒｐｍ、１時間で粉砕を行った。この粉砕したサンプルは安定したスラリー状組成物である。
レーザ回折／散乱式粒子径分布測定装置（Ｐａｒｔｉｃａ ＬＡ−９５０Ｖ２、（株）堀場製作所）を用いて測定した結果、図５に示す粒度分布図から、前記粉砕したサンプルの平均粒子径（Ｄ５０径）は約４１５ｎｍである。
<Example 4>
12 g of acetone was weighed into a 50 ml glass container, then 1 g of benzoyl peroxide (75% purity moistened with 25% water) was weighed into the glass container and completely dissolved in acetone.
Subsequently, 6 g of synthetic silica porous material (Silysia 350, Fuji Silysia Chemical Co., Ltd.) powder was put into the glass container and stirred until the acetone solution containing the benzoyl peroxide was completely absorbed. As a result, Silicia 350 powder containing acetone and benzoyl peroxide, which had no change in appearance before absorption, was obtained.
Next, this powder was exposed to air at room temperature to volatilize acetone. The powder was weighed before and after volatilization, and it was estimated that about 90% of the acetone was volatilized from the decrease in weight.
Next, 3 g of the powder after volatilization, 20 g of purified water and 50 g of zirconia balls having a diameter of 3 mm are put into a 45 ml zirconia crushing container (made by Frichtu, Germany), and a planetary ball mill crusher (P-7, made by Frichtu, Germany). Was pulverized at 800 rpm for 1 hour. This crushed sample is a stable slurry composition.
As a result of measurement using a laser diffraction / scattering particle size distribution measuring apparatus (Partica LA-950V2, Horiba, Ltd.), the average particle size (D50 diameter) of the pulverized sample was obtained from the particle size distribution diagram shown in FIG. Is about 415 nm.
＜実施例５＞
アセトン１２ｇを計量して５０ｍｌのガラス容器に入れ、次に過酸化ベンゾイル（２５％の水で湿らせた純度７５％品）１ｇを計量して前記ガラス容器に入れ、アセトンに完全に溶かした。
次いで、ノイシリン（登録商標）（ＵＳ２タイプ、富士化学工業（株））粉末１０ｇを前記ガラス容器に投入し、前記過酸化ベンゾイル含有するアセトン溶液が完全に吸収されるまで撹拌した。これにより、吸収前と外観的には変化のないアセトン及び過酸化ベンゾイルを含有するノイシリン（登録商標）粉末を得た。
次にこの粉末を室温で大気に曝露しアセトンを揮発させた。揮発前後に粉末の重量を量り、重量の減少からアセトンは約９０％が揮発したと推定される。
次に揮発後の粉末３ｇ、透明なコロイダルシリカ（スノーテックスＯＸＳ、日産化学工業（株））２０ｇ及び直径１ｍｍのジルコニアボール５０ｇを容積４５ｍｌのジルコニア粉砕容器（ドイツ フリッチュ社製）に入れ、遊星型ボールミル粉砕機（Ｐ−７型、ドイツ フリッチュ社製）を用いて回転数８００ｒｐｍ、１時間で粉砕を行った。この粉砕したサンプルは流動性のない白色のクリーム状組成物である。
レーザ回折／散乱式粒子径分布測定装置（Ｐａｒｔｉｃａ ＬＡ−９５０Ｖ２、（株）堀場製作所）を用いて測定した結果、図６に示す粒度分布図から、前記粉砕したサンプルの平均粒子径（Ｄ５０径）は約２６５ｎｍである。
<Example 5>
12 g of acetone was weighed into a 50 ml glass container, then 1 g of benzoyl peroxide (75% purity moistened with 25% water) was weighed into the glass container and completely dissolved in acetone.
Next, 10 g of Neusilin (registered trademark) (US 2 type, Fuji Chemical Industry Co., Ltd.) powder was put into the glass container and stirred until the acetone solution containing the benzoyl peroxide was completely absorbed. As a result, Neusilin (registered trademark) powder containing acetone and benzoyl peroxide having no change in appearance before absorption was obtained.
Next, this powder was exposed to air at room temperature to volatilize acetone. The powder was weighed before and after volatilization, and it was estimated that about 90% of the acetone was volatilized from the decrease in weight.
Next, 3 g of the powder after volatilization, 20 g of transparent colloidal silica (Snowtex OXS, Nissan Chemical Industries, Ltd.) and 50 g of zirconia balls having a diameter of 1 mm are placed in a 45 ml zirconia crushing container (manufactured by Frichtu, Germany), and planetary type Using a ball mill (P-7 type, manufactured by Frichtu, Germany), pulverization was performed at 800 rpm for 1 hour. This ground sample is a non-flowable white cream composition.
As a result of measurement using a laser diffraction / scattering type particle size distribution measuring apparatus (Partica LA-950V2, Horiba, Ltd.), the average particle size (D50 diameter) of the pulverized sample from the particle size distribution diagram shown in FIG. Is about 265 nm.
＜実施例６＞
アセトン１２ｇを計量して５０ｍｌのガラス容器に入れ、次に過酸化ベンゾイル（２５％の水で湿らせた純度７５％品）１ｇを計量して前記ガラス容器に入れ、アセトンに完全に溶かした。
次いで、合成シリカ多孔体（サイリシア３５０、富士シリシア化学（株））粉末６ｇを前記ガラス容器に投入し、前記過酸化ベンゾイルを含有するアセトン溶液が完全に吸収されるまで撹拌した。これにより、吸収前と外観的には変化のないアセトン及び過酸化ベンゾイルを含有するサイリシア３５０粉末を得た。
次にこの粉末を室温で大気に曝露しアセトンを揮発させた。揮発前後に粉末の重量を量り、重量の減少からアセトンは約９０％が揮発したと推定される。
次に揮発後の粉末３ｇ、水酸化カルシウム（特級、関東化学）０．２ｇ、精製水２０ｇ及び直径３ｍｍのジルコニアボール５０ｇを容積４５ｍｌのジルコニア粉砕容器（ドイツ フリッチュ社製）に入れ、遊星型ボールミル粉砕機（Ｐ−７型、ドイツ フリッチュ社製）を用いて回転数８００ｒｐｍ、１時間で粉砕を行った。この粉砕したサンプルは安定したスラリー状組成物である。
レーザ回折／散乱式粒子径分布測定装置（Ｐａｒｔｉｃａ ＬＡ−９５０Ｖ２、（株）堀場製作所）を用いて測定した結果、図７に示す粒度分布図から、前記粉砕したサンプルの平均粒子径（Ｄ５０径）は約５１５ｎｍである。
<Example 6>
12 g of acetone was weighed into a 50 ml glass container, then 1 g of benzoyl peroxide (75% purity moistened with 25% water) was weighed into the glass container and completely dissolved in acetone.
Subsequently, 6 g of synthetic silica porous material (Silysia 350, Fuji Silysia Chemical Co., Ltd.) powder was put into the glass container and stirred until the acetone solution containing the benzoyl peroxide was completely absorbed. As a result, Silicia 350 powder containing acetone and benzoyl peroxide, which had no change in appearance before absorption, was obtained.
Next, this powder was exposed to air at room temperature to volatilize acetone. The powder was weighed before and after volatilization, and it was estimated that about 90% of the acetone was volatilized from the decrease in weight.
Next, 3 g of the powder after volatilization, 0.2 g of calcium hydroxide (special grade, Kanto Chemical), 20 g of purified water and 50 g of zirconia balls having a diameter of 3 mm are placed in a 45 ml zirconia grinding container (manufactured by Frichtu, Germany), and a planetary ball mill The pulverization was performed using a pulverizer (P-7 type, manufactured by Friitch Germany) at 800 rpm for 1 hour. This crushed sample is a stable slurry composition.
As a result of measurement using a laser diffraction / scattering particle size distribution measuring apparatus (Partica LA-950V2, Horiba, Ltd.), the average particle size (D50 diameter) of the pulverized sample was determined from the particle size distribution diagram shown in FIG. Is about 515 nm.
＜比較例１＞
過酸化ベンゾイル（２５％の水で湿らせた純度７５％品）を用い、溶解、吸収、揮発の各工程を経ずに実施例１と同じ条件で以下の実験１〜３を行った結果、得られた粉砕物は水中では不安定であり、瞬時に凝集して水面上に浮上してしまう。乳化剤など添加することにより分散性がある程度改善できたが、放置すると２４時間以内に凝集により沈殿が見られた。
また、ほかの非多孔質無機ナノ粒子を添加して混合粉砕することにより微細化の促進効果が見られたが、放置すると２４時間以内に凝集により沈殿が見られた。
このような対照実験の結果、乳化剤・分散剤を添加しても安定した過酸化ベンゾイルを得ることが難しいことを分かった。
<Comparative Example 1>
As a result of performing the following Experiments 1 to 3 under the same conditions as in Example 1 without using the steps of dissolution, absorption, and volatilization using benzoyl peroxide (a 75% product moistened with 25% water), The obtained pulverized material is unstable in water, and aggregates instantly and floats on the water surface. Although the dispersibility could be improved to some extent by adding an emulsifier or the like, precipitation was observed due to aggregation within 24 hours when allowed to stand.
Further, by adding other non-porous inorganic nanoparticles and mixing and pulverizing them, the effect of promoting the miniaturization was observed, but when left untreated, precipitation was observed within 24 hours.
As a result of such a control experiment, it was found that it was difficult to obtain a stable benzoyl peroxide even when an emulsifier / dispersant was added.
（実験１）
過酸化ベンゾイル（２５％の水で湿らせた純度７５％品）１ｇ、乳化剤（エマゾール Ｌ−１２０Ｖ、花王ケミカル製）の２．５質量％水溶液２０ｇ及び直径３ｍｍのジルコニアボール５０ｇを容積４５ｍｌのジルコニア粉砕容器（ドイツ フリッチュ社製）に入れ、遊星型ボールミル粉砕機（Ｐ−７型、ドイツ フリッチュ社製）を用いて回転数８００ｒｐｍ、１時間で粉砕を行った。
粉砕したサンプルをレーザ回折／散乱式粒子径分布測定装置（Ｐａｒｔｉｃａ ＬＡ−９５０Ｖ２、（株）堀場製作所）を用いて測定した結果、平均粒子径（Ｄ５０径）は１６００ｎｍである。
(Experiment 1)
1 g of benzoyl peroxide (75% pure product moistened with 25% water), 20 g of a 2.5 mass% aqueous solution of emulsifier (Emazole L-120V, manufactured by Kao Chemical Co., Ltd.) and 50 g of zirconia balls having a diameter of 3 mm, zirconia having a volume of 45 ml. It grind | pulverized in rotation speed 800rpm and 1 hour using the planetary-type ball mill grinder (P-7 type, product made in Germany Frichue) using the grinding | pulverization container (product made from Germany Frichue).
As a result of measuring the pulverized sample using a laser diffraction / scattering particle size distribution analyzer (Partica LA-950V2, Horiba, Ltd.), the average particle size (D50 size) is 1600 nm.
（実験２）
過酸化ベンゾイル（２５％の水で湿らせた純度７５％品）１ｇ、無水クエン酸（特級、関東化学（株））０．４ｇ、精製水２０ｇ及び直径３ｍｍのジルコニアボール５０ｇを容積４５ｍｌのジルコニア粉砕容器（ドイツ フリッチュ社製）に入れ、遊星型ボールミル粉砕機（Ｐ−７型、ドイツ フリッチュ社製）を用いて回転数８００ｒｐｍ、１時間で粉砕を行った。
粉砕したサンプルをレーザ回折／散乱式粒子径分布測定装置（Ｐａｒｔｉｃａ ＬＡ−９５０Ｖ２、（株）堀場製作所）を用いて測定した結果、平均粒子径（Ｄ５０径）は５７００ｎｍである。
(Experiment 2)
1 g of benzoyl peroxide (75% pure product moistened with 25% water), 0.4 g of anhydrous citric acid (special grade, Kanto Chemical Co., Ltd.), 20 g of purified water and 50 g of zirconia balls having a diameter of 3 mm, zirconia having a volume of 45 ml It grind | pulverized in rotation speed 800rpm and 1 hour using the planetary-type ball mill grinder (P-7 type, product made in Germany Frichue) using the grinding | pulverization container (product made from Germany Frichue).
As a result of measuring the pulverized sample using a laser diffraction / scattering particle size distribution analyzer (Partica LA-950V2, Horiba, Ltd.), the average particle size (D50 size) is 5700 nm.
（実験３）
過酸化ベンゾイル（２５％の水で湿らせた純度７５％品）１ｇ、平均粒子径１３０ｎｍのヒドロキシアパタイト（ＨＡＰ）粒子の水分散液２０ｇ（ＨＡＰの濃度４質量％）及び直径３ｍｍのジルコニアボール５０ｇを容積４５ｍｌのジルコニア粉砕容器（ドイツ フリッチュ社製）に入れ、遊星型ボールミル粉砕機（Ｐ−７型、ドイツ フリッチュ社製）を用いて回転数８００ｒｐｍ、１時間で粉砕を行った。
粉砕したサンプルをレーザ回折／散乱式粒子径分布測定装置（Ｐａｒｔｉｃａ ＬＡ−９５０Ｖ２、（株）堀場製作所）を用いて測定した結果、平均粒子径（Ｄ５０径）は４１０ｎｍである。しかし、本実験で得られた粉砕物は、過酸化ベンゾイルと無機ナノ粒子（ＨＡＰ）との混合組成物であり、複合粒子ではなかった。
(Experiment 3)
1 g of benzoyl peroxide (75% pure product moistened with 25% water), 20 g of an aqueous dispersion of hydroxyapatite (HAP) particles having an average particle diameter of 130 nm (concentration of 4% by mass of HAP) and 50 g of zirconia balls having a diameter of 3 mm Was placed in a 45 ml zirconia grinding container (manufactured by Friitch Germany) and ground using a planetary ball mill grinder (P-7, manufactured by Friitch Germany) at a rotation speed of 800 rpm for 1 hour.
As a result of measuring the pulverized sample using a laser diffraction / scattering particle size distribution measuring apparatus (Partica LA-950V2, HORIBA, Ltd.), the average particle size (D50 size) is 410 nm. However, the pulverized product obtained in this experiment was a mixed composition of benzoyl peroxide and inorganic nanoparticles (HAP), and was not a composite particle.
例えば、メタケイ酸アルミン酸マグネシウムなど無機多孔体にその細孔径より小さいナノ過酸化ベンゾイルを含有させ、その複合粒子の平均粒子径を１μｍ以下に粉砕することにより製造した無機有機ナノ複合粒子は水中では凝集しにくく、安定的である。
本発明の無機有機複合粒子は、例えば、含水系化粧料又は皮膚治療薬に好適に用いることができる。また、本発明の無機有機複合粒子は微細であり、ほかの物質とよく分散・混合できるため、例えば、バイオ材料、ナノ複合材料、歯科材料、抗菌材料の反応開始剤、反応促進剤或いは添加剤としても利用することができる。
For example, inorganic organic nanocomposite particles produced by containing nanoporous benzoyl peroxide smaller than the pore diameter in an inorganic porous material such as magnesium aluminate metasilicate and pulverizing the composite particles to an average particle diameter of 1 μm or less It is difficult to agglomerate and is stable.
The inorganic-organic composite particles of the present invention can be suitably used for, for example, a water-containing cosmetic or a skin treatment. In addition, since the inorganic-organic composite particles of the present invention are fine and can be well dispersed and mixed with other substances, for example, biomaterials, nanocomposites, dental materials, reaction initiators, reaction accelerators or additives for antibacterial materials Can also be used.
以上、本発明について説明したが、本発明は実施形態及び実施例に限定されない。例えば、実施形態及び実施例では、水難溶解性有機化合物として過酸化ベンゾイルを用いる場合について主に説明したが、これに限定されず、水難溶解性有機化合物及び無機多孔体は製造すべき複合粒子の用途に応じて選択すればよい。 As mentioned above, although this invention was demonstrated, this invention is not limited to embodiment and an Example. For example, in the embodiments and examples, the case where benzoyl peroxide is used as the poorly water-soluble organic compound has been mainly described, but the present invention is not limited to this, and the poorly water-soluble organic compound and the inorganic porous material are the composite particles to be produced. What is necessary is just to select according to a use.
Claims (8)
前記水難溶解性有機化合物含有溶液を無機多孔体に吸収させる工程と、
前記有機溶媒を蒸発させることにより前記水難溶解性有機化合物を前記無機多孔体の細孔内に残留させる工程と、
前記水難溶解性有機化合物を前記細孔内に含む前記無機多孔体を、水を含む媒体を用いた湿式粉砕法により粉砕する工程と、
を含む、請求項１〜請求項３のいずれか１項に記載の無機有機複合粒子を製造する無機有機複合粒子の製造方法。 Preparing a hardly water-soluble organic compound-containing solution obtained by dissolving a poorly water-soluble organic compound in an organic solvent;
Absorbing the poorly water-soluble organic compound-containing solution into the inorganic porous body;
Leaving the poorly water-soluble organic compound in the pores of the inorganic porous body by evaporating the organic solvent;
Crushing the inorganic porous body containing the poorly water-soluble organic compound in the pores by a wet crushing method using a medium containing water;
The manufacturing method of the inorganic organic composite particle which manufactures the inorganic organic composite particle of any one of Claims 1-3 containing this.
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| US9701898B2 (en) | 2013-08-08 | 2017-07-11 | Samsung Electronics Co., Ltd. | Methods of grinding semiconductor nanocrystal polymer composite particles |
| JP2017217454A (en) * | 2016-06-07 | 2017-12-14 | ヘレウス メディカル ゲーエムベーハー | Pasty two component polymethacrylate bone cement |
| US10808169B2 (en) | 2013-08-08 | 2020-10-20 | Samsung Electronics Co., Ltd. | Methods of grinding semiconductor nanocrystal polymer composite particles |
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| JP2017217454A (en) * | 2016-06-07 | 2017-12-14 | ヘレウス メディカル ゲーエムベーハー | Pasty two component polymethacrylate bone cement |
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| JP5901156B2 (en) | 2016-04-06 |
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