JP2009084158A - Aqueous dispersion - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aqueous dispersion prepared by dispersing a hardly water-soluble active component having bactericidal or bacteriostatic activity by incorporating it in nano-sized fine particles as an O/W type, also expressing the bactericidal or bacteriostatic activity and maintaining preservation stability. <P>SOLUTION: This aqueous dispersion is prepared by dispersing liquid or solid particles containing (A) a hardly water-soluble actively acting substance and (B) a lipophilic matrix and having ≤200 nm mean particle diameter in water. The content of (A) the hardly water-soluble actively acting substance is 0.01 to 20 mass% based on the total liquid mass, also the content of (B) the lipophilic matrix is 0.2 to 20 mass% based on the total liquid mass and the contained mass of (A) the hardly water-soluble actively acting substance is ≥0.05 fold of the contained mass of (B) the lipophilic matrix. The aqueous dispersion contains (C) an anionic surfactant or (D) a cationic surfactant of 0.001 to 0.2 fold of the contained mass of the particles. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an aqueous dispersion and a method for producing the same.

  Since a poorly water-soluble active ingredient having bactericidal and bacteriostatic ability is difficult to dissolve in water, when it is blended in a liquid toiletry product, it is blended in advance with a solvent such as ethanol, or a large amount of interface For example, an activator is used that is solubilized and stabilized in water.

  However, when the poorly water-soluble active ingredient is dissolved in a solvent in advance, there is a drawback in that irritation occurs when touching the skin. In addition, when a poorly water-soluble active ingredient is solubilized in water using a large amount of a surfactant, the poorly water-soluble active ingredient solubilized in water by a large amount of the surfactant is not released from the micelles. There is a drawback that the bacteriostatic ability cannot be demonstrated.

  On the other hand, when a slightly water-soluble active ingredient is contained in fine particles and dispersed in an O / W type, effects such as enhanced and sustained bactericidal / bacteriostatic ability can be exhibited.

  However, when a slightly water-soluble active ingredient is contained in fine particles and dispersed in an O / W type, aggregation and coalescence are likely to proceed with a significant increase in the surface area, making it difficult to maintain the nano size of the particles. In addition, there is a problem in terms of storage stability of the aqueous dispersion in which crystals of the poorly water-soluble active ingredient are precipitated in the aqueous phase due to the crystal habit of the poorly water-soluble active ingredient.

In view of the above circumstances, studies have been made with the aim of maintaining the storage stability of aqueous dispersions by expressing sparingly water-soluble active ingredients in fine particles and dispersing them in an O / W type to achieve sterilization and bacteriostatic activity. Yes. For example, (i) an emulsion for injection of antibacterial amitiamycins (Patent Document 1), (b) an O / W type fat emulsion (Patent Document 2) containing imidazole, and (c) a bioactive agent In the particles and the production method thereof (Patent Document 3), a method of dispersing a poorly water-soluble active ingredient by using phospholipid or betaine is disclosed. (D) Bioadhesive nanoparticle compositions having a cationic surface stabilizer (Patent Document 4) and the like are known.
JP-A-9-124503 JP-A 63-48214 JP 2007-23051 A Special table 2003-511406 gazette

  It is an object of the present invention to disperse a slightly water-soluble active ingredient having bactericidal and bacteriostatic activity in nano-sized fine particles and to disperse it in an O / W type, and to maintain its storage stability.

In the aqueous dispersion of the present invention, liquid or solid particles having an average particle size of 200 nm or less, including a poorly water-soluble active substance (A) having a bactericidal / bacteriostatic ability and a lipophilic matrix (B), are dispersed in water. An aqueous dispersion,
The content of the poorly water-soluble active substance (A) is 0.01 to 20% by mass of the total liquid mass, and the content of the lipophilic matrix (B) is 0.2 to 20% by mass of the total liquid mass. And the content of the poorly water-soluble active substance (A) is 0.05 times or more of the content of the lipophilic matrix (B),
An anionic surfactant (C) or a cationic surfactant (D) is contained in an amount of 0.001 to 0.2 times the content of the particles.

The method for producing the aqueous dispersion of the present invention comprises:
Step 1 of preparing a first liquid by mixing a poorly water-soluble active agent (A) having a bactericidal and bacteriostatic ability and a lipophilic matrix (B) in a liquid state;
Step 2 of preparing the second liquid by mixing the anionic surfactant (C) or the cationic surfactant (D) and water;
Step 3 for preparing an O / W type aqueous dispersion in which liquid or solid particles having an average particle size of 200 nm or less are dispersed in water by mixing and stirring the first and second liquids prepared in Steps 1 and 2 above. When,
With
In the first liquid, the content of the poorly water-soluble active substance (A) is set to 0.01 to 20% by mass of the total mass of the aqueous dispersion, and the content of the lipophilic matrix (B). And 0.2 to 20% by mass of the total liquid mass, and the mass content of the poorly water-soluble active agent (A) is 0.05 times or more the mass content of the lipophilic matrix (B),
In the second liquid, the content of the anionic surfactant (C) or the cationic surfactant (D) is 0.001 to 0.2 times the mass of the first liquid.

  According to the present invention, a nano-sized fine particle containing a slightly water-soluble active ingredient (A) having bactericidal and bacteriostatic properties by containing a small amount of an anionic surfactant (C) or a cationic surfactant (D). In addition, it can be dispersed in the O / W type, and the storage stability of the aqueous dispersion can be maintained.

  Hereinafter, embodiments will be described in detail.

(Water dispersion)
In the aqueous dispersion according to the present embodiment, liquid or solid particles having an average particle size of 200 nm or less including a poorly water-soluble active substance (A) having a bactericidal / bacteriostatic ability and a lipophilic matrix (B) are in water. It is distributed. And while content of a slightly water-soluble active agent (A) is 0.01-20 mass% of the whole liquid mass, content of a lipophilic matrix (B) is 0.2-20 mass of the whole liquid mass. % And the content of the poorly water-soluble active substance (A) is 0.05 times or more of the content of the lipophilic matrix (B), and 0.001 to 0.2 of the content of the particles. Double anionic surfactant (C) or cationic surfactant (D).

  This aqueous dispersion contains a small amount of an anionic surfactant (C) or a cationic surfactant (D), so that a slightly water-soluble active ingredient (A) having bactericidal and bacteriostatic activity can be converted into nano-sized fine particles. In addition, it can be dispersed in the O / W type, and the storage stability of the aqueous dispersion can be maintained.

  This aqueous dispersion is a dispersion of liquid or solid particles in water.

  The particles are liquid or solid, but may be a mixture of liquid and solid.

  The average particle diameter of the particles is 200 nm or less, more preferably 150 nm or less, and further preferably 100 nm or less. Further, the average particle diameter of the particles is preferably 10 nm or more, more preferably 20 nm or more, and further preferably 30 nm or more. This average particle diameter can be measured using a dynamic scattering particle size distribution analyzer.

  The content of the particles in the aqueous dispersion is preferably 0.3% by mass or more, more preferably 1% by mass or more, and further preferably 3% by mass or more of the total mass of the liquid. Further, the content of the particles in the aqueous dispersion is preferably 60% by mass or less, more preferably 50% by mass or less, and further preferably 40% by mass or less of the total mass of the liquid.

  The particles contain a poorly water-soluble active agent (A) having bactericidal and bacteriostatic activity.

  In this application, “bactericidal / bacteriostatic ability” refers to the ability to kill or inhibit the growth of fungi and bacteria. Examples of fungi and bacteria include Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, White staphylococcus, Bacillus subtilis, Serratia and the like.

  In the present application, “slightly water-soluble” means that the solubility in water at 25 ° C. is less than 1% by mass.

  The hardly water-soluble active substance (A) is roughly classified into a phenolic substance (A1) and an alcoholic substance (A2).

  Examples of the phenolic substance (A1) include triclosan, triclocarbanilide, methyl paraben, ethyl paraben, propyl paraben, isopropyl methyl phenol, and the like.

  Examples of the alcohol-based substance (A2) include dodecyl alcohol, decyl alcohol, decane diol, and the like.

  The poorly water-soluble active substance (A) may be composed of a single substance, may be composed of a mixture of a plurality of phenolic substances (A1), or may be composed of a plurality of alcoholic substances. (A2) may be mixed and comprised, and also phenolic substance (A1) and alcoholic substance (A2) may be mixed and comprised.

  The content of the poorly water-soluble active substance (A) in the aqueous dispersion is 0.01% by mass or more, more preferably 0.2% by mass or more, and more preferably 1% by mass or more based on the total mass of the liquid. More preferably. Further, the content of the poorly water-soluble active substance (A) in the aqueous dispersion is 20% by mass or less, more preferably 15% by mass or less, and more preferably 10% by mass or less of the total mass of the liquid. Further preferred.

  The particles comprise a lipophilic matrix (B). The lipophilic matrix (B) stabilizes the poorly water-soluble active substance (A).

  Examples of the lipophilic matrix (B) include fats and oils, waxes, esters, hydrocarbons, lipophilic sorbitan fatty acid esters and the like.

  Examples of the fats and oils include soybean oil, rapeseed oil, nuka oil, avocado oil, almond oil, olive oil, cacao butter, sesame oil, persic oil, castor oil, coconut oil, mink oil, beef tallow, and pork fat; Hardened oil obtained by hydrogenation of natural fats and oils; synthetic triglycerides such as myristic acid glyceride and 2-ethylhexanoic acid glyceride.

  Examples of the waxes include carnauba wax, candelilla wax, whale wax, beeswax, lanolin and the like.

  Examples of the esters include stearyl stearate, cetyl octanoate, myristyl lactate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, isopropyl adipate, butyl stearate, decyl oleate, and isostearyl isostearate. It is done.

  Examples of the hydrocarbons include liquid paraffin, petrolatum, paraffin microcrystalline wax, ceresin, squalane and the like.

  Examples of the lipophilic sorbitan fatty acid ester include sorbitan trioleate and sorbitan tristearate.

  The lipophilic matrix (B) may be composed of a single species, or may be composed of a mixture of a plurality of species.

  The lipophilic matrix (B) is a storage stability when the poorly water-soluble active agent (A) is a phenolic substance (A1) in which coarse crystals tend to precipitate in combination with the poorly water-soluble active agent (A). From this point of view, it is preferably at least one selected from fats and oils, waxes, esters, and lipophilic sorbitan fatty acid esters. In addition, when the poorly water-soluble active substance (A) is an alcohol-based substance (A2) that tends to increase the particle size of the particles, the lipophilic matrix (B) is waxes, fats and oils from the viewpoint of storage stability. And at least one selected from hydrocarbons.

  The content of the lipophilic matrix (B) in the aqueous dispersion is 0.2% by mass or more, more preferably 1% by mass or more, and further preferably 2% by mass or more of the total mass of the liquid. Further, the content of the lipophilic matrix (B) in the aqueous dispersion is 20% by mass or less, more preferably 15% by mass or less, and further preferably 10% by mass or less of the total mass of the liquid.

  The content of the poorly water-soluble active substance (A) in the aqueous dispersion is 0.05 times or more, more preferably 0.1 or more, and more preferably 0.1 times or more of the content of the lipophilic matrix (B). More preferably, it is twice or more. In addition, the content of the poorly water-soluble active substance (A) in the aqueous dispersion is preferably 4.0 times or less, more preferably 2.0 times or less of the content of the lipophilic matrix (B). More preferably, it is more preferably 1.0 times or less.

  In addition, the particles may contain a fragrance, a colorant, inorganic fine particles, and the like.

  Examples of water include distilled water and ion exchange water.

  The aqueous dispersion according to this embodiment contains an anionic surfactant (C) or a cationic surfactant (D). This anionic surfactant (C) or cationic surfactant (D) stabilizes the aqueous dispersion as well as the finer particles.

Examples of the anionic surfactant (C) include C _{8 to} C ₂₀ sodium alkyl sulfate, polyoxyethylene alkyl ether sodium sulfate, alkyl sulfate triethanolamine, ammonium alkyl sulfate, sodium alkylbenzene sulfonate, sodium alkyl naphthalene sulfonate, Polyoxyethylene alkyl ether triethanolamine sulfate, sodium α-olefin sulfonate, sodium salt of β-naphthalene sulfonic acid formalin condensate, sodium salt of special aromatic sulfonic acid formalin condensate, fatty acid soap, monoalkyl phosphate, N-acyl glutamate, N-acyl methyl taurate, sulfosuccinic acid monoester salt, alkyl polyoxyethylene acetate and the like can be mentioned.

  Examples of the cationic surfactant (D) include cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, distearyldimethylammonium chloride, benzethonium chloride, alkylbenzyldimethylammonium chloride, stearylamine acetate and the like.

  The aqueous dispersion may contain only one of the anionic surfactant (C) and the cationic surfactant (D), or may contain both of them. Each of the anionic surfactant (C) and the cationic surfactant (D) may be composed of a single species or a mixture of plural species.

  The content of the anionic surfactant (C) or the cationic surfactant (D) in the aqueous dispersion is 0.001 times or more, more preferably 0.005 times or more of the contained mass of the particles, More preferably, it is 0.01 times or more. The content of the anionic surfactant (C) or the cationic surfactant (D) in the aqueous dispersion is not more than 0.2 times the content mass of the particles, and more preferably not more than 0.175 times. More preferably, it is 0.15 times or less.

  The aqueous dispersion according to this embodiment may contain an isotonic agent (E). The tonicity agent (E) functions as an emulsification aid for further atomizing the particles.

  Examples of the isotonic agent (E) include glycerin, sugar alcohol, monosaccharide, disaccharide, amino acid and the like.

  Examples of the sugar alcohol include sorbitol, xylitol, maltitol, mannitol and the like.

  Examples of monosaccharides include glucose and fructose.

  Examples of disaccharides include trehalose, sucrose (sugar), lactose, and maltose.

  The isotonic agent (E) may be composed of a single species or a mixture of a plurality of species.

  The content of the isotonic agent (E) in the aqueous dispersion is preferably 10% by mass or more, more preferably 20% by mass or more, and further preferably 30% by mass or more. The content of the isotonic agent (E) in the aqueous dispersion is preferably 70% by mass or less, more preferably 60% by mass or less, and further preferably 50% by mass or less.

  The aqueous dispersion according to this embodiment may contain other substances as necessary. Examples of such substances include fragrances, thickeners, preservatives, colorants, disintegration inhibitors, and antioxidants. Further, the aqueous dispersion according to the present embodiment may contain a nonionic surfactant to the extent that the antibacterial / bactericidal ability is not inhibited.

  The aqueous dispersion according to the present embodiment described above can obtain bactericidal and bacteriostatic activity by allowing the undiluted solution to act on the fungus as it is or as a diluted solution. In addition, since this aqueous dispersion is very stable, it is highly compatible with diversification of product forms. For example, hand soap, kitchen liquid detergent, toilet liquid detergent, shampoo, rinse, clothing liquid detergent, It can be applied to softeners, deodorant sprays, mouth washes, dentifrices and the like. In this case, the content of the aqueous dispersion in the product may be set to such an extent that the poorly water-soluble active agent (A) exhibits the bactericidal / bacteriostatic ability.

(Method for producing aqueous dispersion)
Next, a method for producing an aqueous dispersion according to this embodiment will be described.

  First, in step 1, a poorly water-soluble active agent (A) and a lipophilic matrix (B) are mixed at a predetermined ratio in a liquid state to prepare a first liquid.

  At this time, the content of the poorly water-soluble active substance (A) is set to 0.01 to 20% by mass of the total mass of the aqueous dispersion to be produced, and the content of the lipophilic matrix (B) is set to the total mass of the liquid. 0.2 to 20% by mass, and the content of the poorly water-soluble active substance (A) is 0.05 times or more of the content of the lipophilic matrix (B). In addition, when at least one of the poorly water-soluble active substance (A) and the lipophilic matrix (B) is solid, they are mixed while being heated and melted.

  In step 2, the second liquid is prepared by mixing the anionic surfactant (C) or the cationic surfactant (D) and water at a predetermined ratio.

  At this time, the content of the anionic surfactant (C) or the cationic surfactant (D) is set to 0.001 to 0.2 times the mass of the first liquid. Moreover, an isotonic agent (E) is mixed as needed. In addition, it is preferable to adjust the temperature of the second liquid to the same temperature as the first liquid.

  Either of these steps 1 and 2 may be performed first or may be performed simultaneously.

  In step 3, the first and second liquids prepared in steps 1 and 2 are mixed and stirred at a predetermined ratio to prepare an O / W type aqueous dispersion in which liquid or solid particles are dispersed in water.

  At this time, first, pre-emulsification treatment is performed on the mixed liquid of the first and second liquids prepared in Steps 1 and 2 by using a stirring type emulsifier such as a static emulsification / dispersing machine, a general stirrer, or a homomixer. After that, it is preferable to form fine particles by applying a high-pressure emulsification treatment using a high-pressure emulsification device such as a nanomizer, a homogenizer, or a microfil diizer. Moreover, it is preferable to mix the first and second liquids at the same temperature.

  In step 4, the aqueous dispersion prepared in step 3 is cooled.

  At this time, it is preferable to quench the aqueous dispersion to room temperature using a double-tube countercurrent cooling device or the like. Moreover, you may cool by what is called cooling.

  In addition, when the substance contains an easily oxidizable substance, it is preferable to carry out the operations in the above steps 1 to 4 in an atmosphere in which an inert gas such as nitrogen is passed.

(Preparation of aqueous dispersion)
<Example 1>
In a container, 25 g of triclosan (manufactured by Ciba Specialty Chemicals Inc., the same shall apply hereinafter) as a phenolic substance (A1) (2.5% by mass of the total mass of the liquid) and stearyl stearate (Kao Corporation) Product name: EXCEPARL SS, 75% (7.5% by mass of the total mass of the liquid) is charged, and it is heated to 80 ° C. to melt and mixed to prepare a first liquid in the oil phase ( Content mass of phenolic substance (A1) / content mass of lipophilic matrix (B) = 0.33).

  Put 885 g of ion-exchanged water in a separate container, add 15 g of sodium lauryl sulfate (trade name: EMAL 10PT, manufactured by Kao Corporation) as an anionic surfactant (C), and heat it to 80 ° C. And dispersed / dissolved to prepare a second liquid in the aqueous phase (mass content of anionic surfactant (C) / mass of first liquid = 0.15).

  After adding the first liquid to the second liquid, by using a homomixer (product name: TK homomixer manufactured by Primics Co., Ltd., the same shall apply hereinafter) for 3 minutes at a rotational speed of 7500 r / min. A pre-emulsification treatment was performed to obtain an O / W type aqueous dispersion (80 ° C.).

  The obtained aqueous dispersion was O / W atomized by high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer (trade name: Nanomizer, manufactured by Yoshida Kikai Kogyo Co., Ltd.). A mold aqueous dispersion was obtained.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The average particle size of the particles contained in the aqueous dispersion was 127 nm. In addition, about an average particle diameter, what diluted the obtained aqueous dispersion 10 times was used as a sample, and the dynamic scattering type particle size distribution measuring apparatus (Otsuka Electronics Co., Ltd. brand name: DLS-Z2) was used. Measured (hereinafter the same).

<Comparative Example 1>
A container was charged with 25 g of triclosan (2.5% by mass of the total mass of the liquid) as a phenolic substance (A1), heated to 80 ° C. to melt and mixed to prepare a first liquid in the oil phase.

  Add 960 g of ion-exchanged water to another container, add 15 g of sodium lauryl sulfate as anionic surfactant (C), heat it to 80 ° C. and disperse / dissolve it to prepare the second liquid of the aqueous phase. (The mass of the anionic surfactant (C) / the mass of the first liquid = 0.60).

  After the first liquid was added to the second liquid, a pre-emulsification process was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (80 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer to obtain an O / W-type aqueous dispersion.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The obtained aqueous dispersion immediately started to aggregate and was unstable.

<Comparative example 2>
The container is charged with 25 g of triclosan (2.5% by mass of the total liquid mass) as the phenolic substance (A1) and 75 g of stearyl stearate (7.5% by mass of the total liquid mass) as the lipophilic matrix (B), It was heated to 80 ° C. to melt and mixed to prepare a first liquid in the oil phase (the content of phenolic substance (A1) / the content of lipophilic matrix (B) = 0.33).

  Put 885 g of ion-exchanged water in another container, add 15 g of sodium lauryl sulfate as an anionic surfactant (C), heat it to 80 ° C. and disperse / dissolve it to prepare the second liquid of the aqueous phase. (The content of the anionic surfactant (C) / the mass of the first liquid = 0.15).

  After the first liquid was added to the second liquid, an emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (80 ° C. ).

  The average particle size of the particles contained in the aqueous dispersion was 2500 nm (2.5 μm).

<Comparative Example 3>
The container is charged with 25 g of triclosan (2.5% by mass of the total liquid mass) as the phenolic substance (A1) and 75 g of stearyl stearate (7.5% by mass of the total liquid mass) as the lipophilic matrix (B), It was heated to 80 ° C. to melt and mixed to prepare a first liquid in the oil phase (the content of phenolic substance (A1) / the content of lipophilic matrix (B) = 0.33).

  Put 850 g of ion-exchanged water in a separate container, add 50 g of sodium lauryl sulfate as an anionic surfactant (C), heat it to 80 ° C. and disperse / dissolve it to prepare the second liquid of the aqueous phase. (The mass of the anionic surfactant (C) / the mass of the first liquid = 0.50).

  After the first liquid was added to the second liquid, a pre-emulsification process was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (80 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer to obtain an O / W-type aqueous dispersion.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The average particle size of the particles contained in the aqueous dispersion was 110 nm.

<Example 2>
In a container, 25 g (2.5% by mass of the total liquid mass) of decyl alcohol (trade name: Calcoal 1098, manufactured by Kao Corporation) as the alcohol-based substance (A2) and squalane (B) as the lipophilic matrix (B) 25 g (2.5% by mass of the total mass of the liquid) manufactured by Nikko Chemicals Co., Ltd. was charged, heated to 30 ° C. to melt and mixed to prepare a first liquid in the oil phase (alcohol Content mass of system substance (A2) / content mass of lipophilic matrix (B) = 1.00).

  Put 949 g of ion-exchanged water in a separate container, add 1 g of sodium lauryl sulfate as an anionic surfactant (C), heat it to 30 ° C. and disperse / dissolve to prepare a second liquid of the aqueous phase. (The mass of the anionic surfactant (C) / the mass of the first liquid = 0.02).

  After the first liquid was added to the second liquid, a pre-emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (30 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer to obtain an O / W-type aqueous dispersion.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The average particle size of the particles contained in the aqueous dispersion was 120 nm.

<Comparative example 4>
A container was charged with 50 g of decyl alcohol (5.0 mass% of the total mass of the liquid) as the alcohol-based substance (A2), and heated to 30 ° C. to prepare a first liquid in the oil phase.

  Put 949 g of ion-exchanged water in a separate container, add 1 g of sodium lauryl sulfate as an anionic surfactant (C), heat it to 30 ° C. and disperse / dissolve to prepare a second liquid of the aqueous phase. (The mass of the anionic surfactant (C) / the mass of the first liquid = 0.02).

  After the first liquid was added to the second liquid, a pre-emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (30 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer to obtain an O / W-type aqueous dispersion.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The obtained aqueous dispersion immediately started to aggregate and was unstable.

<Comparative Example 5>
A container is charged with 25 g of decyl alcohol (2.5% by mass of the total liquid mass) as the alcoholic substance (A2) and 25 g of squalane (2.5% by mass of the total liquid mass) as the lipophilic matrix (B). Was heated to 30 ° C. and melted and mixed to prepare a first liquid of the oil phase (content of alcohol-based substance (A2) / content of lipophilic matrix (B) = 1.00).

  Into another container, 949 g of ion-exchanged water is added, and 1 g of polyoxyethylene lauryl ether (trade name: Emulgen 120, manufactured by Kao Corporation), which is a nonionic surfactant, is added thereto, heated to 30 ° C. and dispersed / A second liquid in the aqueous phase was prepared by dissolving (nonionic surfactant content mass / first liquid mass = 0.02).

  After the first liquid was added to the second liquid, a pre-emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (30 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer to obtain an O / W-type aqueous dispersion.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The obtained aqueous dispersion immediately started to aggregate and was unstable.

<Example 3>
In a container, 25 g of triclosan as a phenolic substance (A1) (2.5% by mass of the total liquid mass) and sorbitan tristearate as a lipophilic matrix (B) (trade name: Leodol SP-S30V, manufactured by Kao Corporation) The same applies hereinafter) 75 g (7.5% by mass of the total mass of the liquid) was prepared, heated to 70 ° C. to melt and mixed to prepare the first liquid of the oil phase (containing phenolic substance (A1)) Mass / mass content of lipophilic matrix (B) = 0.33).

  Put 897 g of ion-exchanged water in a separate container, and add 3 g of N-lauroylmethyl taurine sodium (trade name: NIKKOL LMT, manufactured by Nikko Chemicals Co., Ltd.) as an anionic surfactant (C). The mixture was heated to 70 ° C. and dispersed / dissolved to prepare a second liquid in the aqueous phase (content of anionic surfactant (C) / mass of first liquid = 0.03).

  After the first liquid was added to the second liquid, a pre-emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (70 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer to obtain an O / W-type aqueous dispersion.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The average particle size of the particles contained in the aqueous dispersion was 145 nm.

<Example 4>
The container is charged with 25 g of triclosan (2.5% by mass of the total liquid mass) as the phenolic substance (A1) and 75 g of sorbitan tristearate (7.5% by mass of the total liquid mass) as the lipophilic matrix (B). Then, it was heated to 70 ° C. and melted and mixed to prepare a first liquid in the oil phase (the content of phenolic substance (A1) / the content of lipophilic matrix (B) = 0.33).

  In another container, 889.3 g of ion-exchanged water is added, and 10.7 g of Cotamin 86W manufactured by Kao Co., Ltd. containing 28% by mass of stearyltrimethylammonium chloride as the cationic surfactant (D) is added. Then, it was heated to 70 ° C. and dispersed / dissolved to prepare an aqueous phase second liquid (mass content of cationic surfactant (D) / mass of first liquid = 0.03).

  After the first liquid was added to the second liquid, a pre-emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (70 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer to obtain an O / W-type aqueous dispersion.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The average particle size of the particles contained in the aqueous dispersion was 146 nm.

<Example 5>
In a container, 25 g of triclosan as a phenolic substance (A1) (2.5% by mass of the total liquid mass) and sorbitan trioleate as a lipophilic matrix (B) (trade name: Leodol SP-O30V, hereinafter) Similarly, 75 g (7.5% by mass of the total mass of the liquid) was charged, and heated to 60 ° C. to melt and mixed to prepare a first liquid of the oil phase (content of phenolic substance (A1)) / Content mass of lipophilic matrix (B) = 0.33).

  In a separate container, 897 g of ion-exchanged water is added, and 3 g of sodium N-lauroylmethyltaurine as an anionic surfactant (C) is added thereto, heated to 60 ° C. and dispersed / dissolved to add a second aqueous phase. A liquid was prepared (the mass of the anionic surfactant (C) / the mass of the first liquid = 0.03).

  After the first liquid was added to the second liquid, a pre-emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (60 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer to obtain an O / W-type aqueous dispersion.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The average particle size of the particles contained in the aqueous dispersion was 140 nm.

<Example 6>
A container is charged with 25 g of triclosan as a phenolic substance (A1) (2.5% by mass of the total mass of the liquid) and 75 g of sorbitan trioleate as a lipophilic matrix (B) (7.5% by mass of the total mass of the liquid). It was heated to 60 ° C. and melted and mixed to prepare a first liquid in the oil phase (content of phenolic substance (A1) / content of lipophilic matrix (B) = 0.33).

  In another container, 448.5 g of ion-exchanged water was added, and 3 g of sodium N-lauroylmethyltaurine as an anionic surfactant (C) and D-sorbitol as an isotonic agent (E) (Towa Kasei Kogyo Co., Ltd.) Product name: 448.5 g of Sorbit D-powder (the same applies hereinafter) was added, heated to 60 ° C. and dispersed / dissolved to prepare a second liquid in the aqueous phase (of the anionic surfactant (C)) Content mass / mass of first liquid = 0.03).

  After the first liquid was added to the second liquid, a pre-emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (60 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification twice at 75 MPa with a desktop micro-treatment wet medialess atomizer to obtain an O / W-type aqueous dispersion.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The average particle size of the particles contained in the aqueous dispersion was 105 nm.

<Example 7>
A container is charged with 25 g of triclosan as a phenolic substance (A1) (2.5% by mass of the total mass of the liquid) and 75 g of sorbitan trioleate as a lipophilic matrix (B) (7.5% by mass of the total mass of the liquid). It was heated to 60 ° C. and melted and mixed to prepare a first liquid in the oil phase (content of phenolic substance (A1) / content of lipophilic matrix (B) = 0.33).

  In a separate container, 448.5 g of ion-exchanged water is added, and 3 g of sodium N-lauroylmethyltaurine as an anionic surfactant (C) and 448.5 g of D-sorbitol as an isotonic agent (E) are added thereto. The mixture was heated to 60 ° C. and dispersed / dissolved to prepare a second liquid in the aqueous phase (content of anionic surfactant (C) / mass of first liquid = 0.03).

  After the first liquid was added to the second liquid, a pre-emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (60 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification treatment twice at 75 MPa with a desktop micro-treatment wet medialess atomizer, and then further subjected to high-pressure emulsification treatment four times at 100 MPa with a desktop micro-treatment wet medialess atomizer. A finely divided O / W aqueous dispersion was obtained.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The average particle size of the particles contained in the aqueous dispersion was 85 nm.

<Example 8>
A container is charged with 25 g of triclosan as a phenolic substance (A1) (2.5% by mass of the total mass of the liquid) and 75 g of sorbitan trioleate as a lipophilic matrix (B) (7.5% by mass of the total mass of the liquid). It was heated to 60 ° C. and melted and mixed to prepare a first liquid in the oil phase (content of phenolic substance (A1) / content of lipophilic matrix (B) = 0.33).

  In a separate container, 442.5 g of ion-exchanged water is added, and 15 g of sodium N-lauroylmethyltaurine as an anionic surfactant (C) and 442.5 g of D-sorbitol as an isotonic agent (E) are added thereto, It was heated to 60 ° C. and dispersed / dissolved to prepare an aqueous second liquid (mass content of anionic surfactant (C) / mass of first liquid = 0.15).

  After the first liquid was added to the second liquid, a pre-emulsification treatment was performed by a stirring operation for 3 minutes at a rotational speed of 7500 r / min using a homomixer to obtain an O / W type aqueous dispersion (60 ° C).

  The obtained aqueous dispersion was subjected to high-pressure emulsification treatment twice at 75 MPa with a desktop micro-treatment wet medialess atomizer, and then further subjected to high-pressure emulsification treatment four times at 100 MPa with a desktop micro-treatment wet medialess atomizer. A finely divided O / W aqueous dispersion was obtained.

  The obtained aqueous dispersion was rapidly cooled to room temperature with cooling water using a double pipe countercurrent cooling device.

  The average particle size of the particles contained in the aqueous dispersion was 53 nm.

(Test evaluation and results)
For each of the aqueous dispersions obtained in Examples 1 to 8 and Comparative Examples 1 to 5, three water dispersions in a glass bottle were prepared, and each temperature atmosphere at 5 ° C., room temperature, and 50 ° C. Then, the particles were allowed to stand for 30 days, and then the average particle size of the aqueous dispersion that was allowed to stand under each temperature atmosphere was measured. Moreover, visual observation was also performed using the optical microscope (2000 times). And it evaluated by the following references | standards.
○: The dispersion state of the particles is very good, there is almost no change in the average particle diameter, and no aggregates or coarse crystals are observed even by visual observation with a microscope.
X: Change in average particle diameter is remarkable, and coarse crystals having a size of 100 μm are observed by visual observation with a microscope.

  The test evaluation results are shown in Table 1.

  According to Table 1, when Example 1 including the lipophilic matrix (B) is compared with Comparative Example 1 not including the lipophilic matrix (B), the lipophilic matrix (B) is necessary for stabilizing the aqueous dispersion. I understand that there is.

  Comparing Example 1 with the atomization treatment with Comparative Example 2 without it, it can be seen that the aqueous dispersion needs to be atomized to a nano size in order to stabilize the aqueous dispersion. .

  Comparing Example 1 containing 0.15 times the content of the anionic surfactant (C) with Comparative Example 3 containing 0.50 times the content of the particles, the storage stability is remarkably low when there is too much surfactant. I understand that

  When Example 2 including the lipophilic matrix (B) is compared with Comparative Example 4 not including the lipophilic matrix (B), it can be seen that the lipophilic matrix (B) is necessary for stabilizing the aqueous dispersion.

  Comparing Example 2 containing an anionic surfactant (C) with Comparative Example 5 containing a nonionic surfactant instead, the anionic surfactant (C) can stabilize the aqueous dispersion in a small amount. On the other hand, it can be seen that the nonionic surfactant cannot stabilize the aqueous dispersion with a small amount.

  Comparing Example 3 containing the anionic surfactant (C) with Example 4 containing the cationic surfactant (D) instead, the cationic surfactant (D) was also different from the anionic surfactant (C). Similarly, it can be seen that the aqueous dispersion can be stabilized with a small amount.

  Comparing Example 3 containing a lipophilic matrix (B) that is solid at room temperature and Example 5 containing a lipophilic matrix (B) that is liquid at room temperature instead, the lipophilic matrix (B) is liquid at room temperature. It can be seen that the aqueous dispersion can be stabilized regardless of whether it is solid or solid.

  When Example 5 containing no tonicity agent (E) is compared with Example 6 containing it, it can be seen that the average particle size becomes finer by adding the tonicity agent (E).

  Example 6 in which high-pressure emulsification treatment was performed twice at 75 MPa with a desktop micro-treatment wet medialess atomizer, and in addition, high-pressure emulsification treatment was performed four times at 100 MPa in a desktop micro-treatment wet medialess atomizer. Comparing with Example 7, it can be seen that the average particle size is further reduced by repeating the refinement treatment.

  Comparing Example 7 containing 0.03 times the content mass of the anionic surfactant (C) with Example 8 containing 0.15 times that of the particles, the average particle size was further increased by the appropriate increase in the amount of surfactant. It turns out that it becomes fine.

  According to the result of the above Examples 1-8, while containing a small amount of anionic surfactant (C) or a cationic surfactant (D), and making a particle | grain atomize to nanosize, it is in storage stability. It can be seen that an excellent aqueous dispersion can be obtained.

  The present invention is useful for an aqueous dispersion and a method for producing the same.

Claims (11)

An aqueous dispersion in which liquid or solid particles having an average particle size of 200 nm or less containing a poorly water-soluble active substance (A) having a bactericidal and bacteriostatic ability and a lipophilic matrix (B) are dispersed in water,
The content of the poorly water-soluble active agent (A) is 0.01 to 20% by mass of the total mass of the liquid, and the content of the lipophilic matrix (B) is 0.2 to 20% by mass of the total liquid. And the content of the poorly water-soluble active substance (A) is 0.05 times or more of the content of the lipophilic matrix (B),
An aqueous dispersion containing an anionic surfactant (C) or a cationic surfactant (D) 0.001 to 0.2 times the content of the particles.   The aqueous dispersion according to claim 1, wherein the poorly water-soluble active substance (A) is a phenolic substance (A1) or an alcoholic substance (A2).   The aqueous dispersion according to claim 2, wherein the phenolic substance (A1) is at least one selected from triclosan, trichlorocarbanilide, methylparaben, ethylparaben, propylparaben, and isopropylmethylphenol.   The aqueous dispersion according to claim 2, wherein the alcoholic substance (A2) is at least one selected from dodecyl alcohol, decyl alcohol, and decanediol.   The water dispersion according to any one of claims 1 to 4, wherein the lipophilic matrix (B) is at least one selected from fats and oils, waxes, esters, hydrocarbons, and lipophilic sorbitan fatty acid esters. liquid.   The poorly water-soluble active substance (A) is a phenolic substance (A1), and the lipophilic matrix (B) is at least one selected from fats and oils, waxes, esters, and lipophilic sorbitan fatty acid esters. The aqueous dispersion according to claim 2 or 3.   3. The poorly water-soluble active substance (A) is an alcoholic substance (A2), and the lipophilic matrix (B) is at least one selected from waxes, fats and oils, and hydrocarbons. Or the aqueous dispersion described in 4.   The aqueous dispersion according to any one of claims 1 to 7, further comprising at least one isotonic agent (E) selected from glycerin, sugar alcohol, monosaccharide, disaccharide, and amino acid. Step 1 of preparing a first liquid by mixing a poorly water-soluble active agent (A) having a bactericidal and bacteriostatic ability and a lipophilic matrix (B) in a liquid state;
Step 2 of preparing the second liquid by mixing the anionic surfactant (C) or the cationic surfactant (D) and water;
Step 3 for preparing an O / W type aqueous dispersion in which liquid or solid particles having an average particle size of 200 nm or less are dispersed in water by mixing and stirring the first and second liquids prepared in Steps 1 and 2 above. When,
With
In the first liquid, the content of the poorly water-soluble active substance (A) is set to 0.01 to 20% by mass of the total mass of the aqueous dispersion, and the content of the lipophilic matrix (B). And 0.2 to 20% by mass of the total liquid mass, and the mass content of the poorly water-soluble active agent (A) is 0.05 times or more the mass content of the lipophilic matrix (B),
The method for producing an aqueous dispersion in which the content of the anionic surfactant (C) or the cationic surfactant (D) in the second liquid is 0.001 to 0.2 times the mass of the first liquid.   The method for producing an aqueous dispersion according to claim 9, wherein in the step 2, an isotonic agent (E) is further mixed.   In the above step 3, the O / W type aqueous dispersion is prepared by subjecting the mixed liquid of the first and second liquids prepared in the above steps 1 and 2 to a preliminary emulsification treatment and then a high pressure emulsification treatment. The method for producing an aqueous dispersion according to claim 9 or 10.