JP4800246B2 - emulsion - Google Patents

Description

  The present invention relates to an emulsion having improved storage stability.

  In recent years, in the cosmetics field, research has been conducted on the reduction of the amount of surfactants used as emulsifiers in emulsified preparations or the use of mild ones in terms of human safety. Improvements in the pharmacokinetics of active ingredients including intracellular enrichment have been sought. Recently, it has also been proposed to use amphiphilic drugs as emulsifiers. Among them, studies using the compound represented by the chemical formula (1) and / or a salt thereof as an emulsifier are disclosed in Patent Documents 1, 2, 3, and 4, and are examined from the viewpoint of an external preparation for skin.

Japanese Patent Laid-Open No. 11-199465 JP 2003-212751 A JP 2004-149445 A JP 2005-068026 A

  On the other hand, emulsions containing fat-soluble drugs are emulsions in which drugs are encapsulated at the oil-water interface together with the core or emulsion that is the oil part of the formulation particles. In order to easily dissolve drugs with various polarities, simple lipids are used. It is necessary to blend highly polar oils such as certain fats and oils into the emulsion. However, as described in Non-Patent Document 1, vegetable oils and fats are said to be difficult to emulsify compared to hydrocarbons and ester oils. Therefore, as described in Patent Document 5, an emulsion obtained by emulsifying soybean oil needs to be emulsified by applying a large energy using a homogenizer or the like.

Oil chemistry, 40 (11), 988 (1991) JP-A-5-9111

  In addition, salts, sugars, and the like, which are isotonic agents, are added to the emulsion to enhance percutaneous absorption, but generally the addition of salt destabilizes the emulsion. An object of the present invention is to solve such problems and to provide an emulsion having improved emulsion storage stability.

  As a result of studying means for solving these problems, the present inventors can easily emulsify vegetable oils and fats or synthetic triglycerides by chance using the compound represented by Chemical Formula 1 which is a drug as an emulsifier. Invented that the stability of the emulsion can be drastically increased by adding a salt of a monovalent cationic species in the range of 2 mM to 20 mM.

  That is, the present invention is as follows.

(1) An emulsion having emulsion grains comprising (A) and (B) and containing a salt concentration of 2 mM to 20 mM having sodium ions or potassium ions .
(A) 30 to 95% of vegetable oil or synthetic tri glycerides
(B) 5 to 70% of the compound represented by Chemical Formula 1

  (2) The emulsion according to (1), wherein among the compounds represented by Chemical Formula 1, R1 and R2 are selected from hydrogen and alkali metals, and at least one of them is one or more alkali metals.

  (3) R1 and R2 are chosen from hydrogen, sodium thru | or potassium among the compounds represented by Chemical formula 1, and at least one is 1 thru | or 2 types of sodium thru | or potassium, (1) description emulsion.

  (4) The emulsion according to (1), wherein among the compounds represented by Formula 1, R1 and R2 are selected from hydrogen and sodium, and at least one is sodium.

( 5 ) A skin external preparation containing the emulsion according to (1) to ( 4 ).

Emulsions according to the present invention, the stability in the ratio of the compound represented by Formula 1 is a drug against vegetable oil or synthetic tri glycerides by adding a salt having a sodium ion or potassium ion is improved Is characteristic.

  In order to stabilize the emulsion of the present invention, the content ratio of the compound represented by Chemical Formula 1 in the emulsion grains is preferably 5% or more and 70% or less. This is because the surface area of the emulsion increases due to the formation of fine particles, so that it is necessary to increase the amount of the compound represented by Chemical Formula 1 in order to cover and stabilize the emulsion grain surface. When the compound represented by the chemical formula 1 of less than 5% is used, mixing of particles having a diameter of several microns or more is unavoidable, and when the compound represented by the chemical formula 1 exceeding 70% is used, the chemical formula 1 Incorporation of aggregates of the represented compounds is inevitable.

Further, when a salt having sodium ions or potassium ions is added, it is preferably in the range of 2 mM to 20 mM in the emulsion. This is because it is added to change the surface charge of the emulsion grains, and the dispersibility of the emulsion grains is improved in this range. If it is less than 2 mM, the ionic strength is low and the aggregation of particles proceeds. If it exceeds 20 mM, the ionic strength is high, and particle aggregation and creaming occur.

It was first demonstrated by the present invention that a stable emulsion can be obtained by this component constitution, and this can be used as an extremely excellent emulsion. That is, the present invention emulsion material constituting the emulsion particles, (a) is a vegetable oil or synthetic tri-glycerides, their content ratio in the emulsion is from 0.1 to 30% by (b) Formula 1 (A) a salt having sodium ions or potassium ions to be blended in the emulsion in the range of 2 mM to 20 mM, wherein the content ratio in the emulsion is 0.1 to 5% (a) ), (B) and (c) at the same time, an emulsion which is stable over time can be obtained.

The compound represented by the chemical formula 1 used in the present invention is a compound in which R ₁ and R ₂ are selected from hydrogen and an alkali metal, and at least one is one or more alkali metals, more preferably R ₁ , R ₂ is selected from hydrogen and sodium or potassium, at least one is one or two compounds of sodium or potassium, more preferably R ₁ and R ₂ are selected from hydrogen and sodium, and at least one is sodium A compound.

Vegetable oil used in the present invention, purified soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, Safura oil, and the like olive oil, synthetic tri glyceride trioleate glyceryl, trilinolein glyceryl Glyceryl tripalmitate, glyceryl tristearate, glyceryl trimyristate, glyceryl triarachidonate, glyceryl trilaurate, glyceryl trioctanoate, glyceryl triisostearate, and the like.

Examples of the salt having sodium ion or potassium ion used in the present invention include lithium chloride, sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, phosphorus Examples include dipotassium oxyhydrogen, potassium phosphate, sodium citrate, potassium citrate, sodium malate, and potassium malate. The compounding concentration of the salt having sodium ions or potassium ions is in the range of 2 mM to 20 mM, more preferably 5 mM to 10 mM.

  Various drugs can be blended in the emulsion used in the present invention. For example, the drug is selected from the group consisting of steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antiallergic agents, antibiotics, antihistamines, antioxidants, radical scavengers, amino acids, vitamins, and essential herbal medicines. Is.

  Examples of these include, for example, steroidal agents (e.g. dexamethasone palmitate, hydrocortisone palmitate, prednisolone palmitate, dexamethasone stearate, methylprednisolone, parameterzone, fluocinolone acetonide, vector methasone propionate, Hydrocortisone fatty acid esters, aldosterone, spironolactone, etc.) and non-steroidal agents (eg, ibuprofen, flufenamic acid, ketoprofen, phenacetin, antipyrine, aminopyrine, phenylbutazone indole acetate, biphenylylpropionic acid derivatives, indomethacin, indomethacin ethoxycarbonylmethyl ester , Indomethacin stearyl ester, gold thiomalic acid Chiruesuteru, diclofenac, such as acetylsalicylic acid and its derivatives). Antiallergic agents such as tranilast, ketotifen and azelastine can also be used. Examples of antibiotics and chemotherapeutic agents include tetracyclines, erythromycin, midecamycin, amphotericin, nalidixic acid, griseofulvin, minocycline and the like. As examples of prostaglandin agents, PGE1, PGA1, PGA1 alkyl ester, PGE1 alkyl ester, PGE1 derivative, PGI2 derivative, PGD2 derivative, and the like can be used. Also included are antihistamines such as diphenhydramine, orphenadillin, chlorphenoxamine, chlorpheniramine, promethazine, meclizine, cyproheptadine, and loxatidine acetate. Also included are local anesthetics such as lidocaine, benzocaine, dantrolene, cocaine, tetracaine, piperocaine, mepyracaine and their derivatives. Antioxidants (for example, tocopherol, tocotrienol, oil-soluble vitamin C derivatives, flavone derivatives, gallic acid derivatives, caffeic acid derivatives, gossypol, sezamol, oxyfatty acids, camphene, cineol, rosmanol, eugenol, phyllozulcins, catechins, lignans Analogs, p-coumaric acid, sterols, terpenes, bromophenol, etc.). In addition, guaiazulene, oil-soluble licorice extract and essential herbal medicine (for example, Kyonin oil, fennel oil, thyme oil, turpentine oil, eucalyptus oil, palm oil, poppy oil, camellia oil, mint oil, clove oil, mint oil, sage oil And other spice herbal medicine ingredients).

  The emulsion or skin external preparation of the present invention can be used in any of cosmetics, quasi-drugs, and pharmaceuticals. Examples of the dosage form include lotions, creams, emulsions, gels, aerosols, essences, Packs, cleaning agents, bath preparations, foundations, powders, lipsticks, ointments, poultices and the like can be mentioned.

  In the production of the emulsion of the present invention and a preparation using the same, various conventional emulsion production methods can be applied. For example, a mechanical emulsification method in which all components including a drug are sufficiently refined by a Manton-gaurine type homogenizer, a microfluidizer, an ultrasonic homogenizer, etc. Can be produced by a general emulsification method. At this time, a fatty acid or a derivative thereof can be added as an emulsification aid.

J. et al. Colloid Interface Sci. , 129, 491 (1989)

Emulsion of the present invention, the emulsion can be easily emulsified difficult vegetable oil or synthetic tri-glycerides, are excellent in that significantly improves the storage stability of the emulsion.

  The present invention will be described in more detail with reference to examples and comparative examples below, but the present invention is not limited to the following examples. In addition, content of each component in prescription shall be weight%. The storage stability of the emulsion was evaluated by visual observation and microscopic observation after storage for 2 weeks at 25 ° C. and 60% humidity. Further, the zeta potential as an index of emulsion stability is the same using a zeta potential measuring device (LEZA-600) manufactured by Otsuka Electronics Co., Ltd. so that the concentration of simple lipid becomes 1 / 10,000 at 25 ° C. It was diluted with a salt concentration aqueous solution and measured. The larger the absolute value of the zeta potential, the greater the repulsion between emulsion grains, indicating better dispersion stability.

Disperse the sodium salt of the compound represented by the chemical formula 1 at 70 ° C. in 6% glycerin, add 20% soybean oil and mix until uniform, and then refine at 22% at 70 ° C. Water was gradually added to make the mixture uniform and cooled to 30 ° C. to obtain a concentrated emulsion. Next, a 10 mM potassium chloride aqueous solution having the same volume as this concentrated emulsion was added and mixed to obtain an emulsion to which 5 mM potassium chloride was added (capacity 100 ml).
As a result, the emulsion was not visually creamed, and no increase or aggregation of grains was observed by microscopic observation.

Disperse the sodium salt of the compound represented by the chemical formula 1 at 70 ° C. in 3% glycerin, add 10% soybean oil and mix until uniform, then 36% purification at 70 ° C. Water was gradually added to make the mixture uniform and cooled to 30 ° C. to obtain a concentrated emulsion. Next, a 20 mM sodium chloride aqueous solution having the same volume as this concentrated emulsion was added and mixed to obtain an emulsion to which 10 mM sodium chloride was added (capacity 500 ml).
As a result, the emulsion was not visually creamed, and no increase or aggregation of grains was observed by microscopic observation.

After dispersing 2% of the sodium salt of the compound represented by Chemical Formula 1 at 70 ° C. in 3% glycerin, add 17% glyceryl trioctanoate and 1% oil-soluble licorice extract and mix until uniform. Thereafter, 25% purified water at 70 ° C. was gradually added to make it uniform and cooled to 30 ° C. to obtain a concentrated emulsion. Next, a 50% 6 mM potassium citrate aqueous solution of the same volume as this concentrated emulsion was added and mixed to obtain an emulsion to which 3 mM potassium citrate was added (volume 200 ml).
As a result, the emulsion was not visually creamed, and no increase or aggregation of grains was observed by microscopic observation.

Disperse the potassium salt of the compound represented by Chemical Formula 1 at 70 ° C. in 3% glycerin, add 18% glyceryl trioctanoate and 1% oil-soluble licorice extract, and mix until uniform. Thereafter, 26% purified water at 70 ° C. was gradually added to make it uniform and cooled to 30 ° C. to obtain a concentrated emulsion. Next, a 50% 20 mM potassium phosphate aqueous solution having the same volume as this concentrated emulsion was added and mixed to obtain an emulsion to which 10 mM potassium phosphate was added (volume: 100 ml).
As a result, the emulsion was not visually creamed, and no increase or aggregation of grains was observed by microscopic observation.

Add 2% sodium salt of the compound represented by Formula 1 at 70 ° C., 10% soybean oil and 0.1% indomethacin, 87.9% 2 mM potassium phosphate aqueous solution, and homogenizer (Silverson) Stir to give a crude dispersion (500 g). This dispersion was emulsified with a microfluidizer (Microfluidics) at a processing pressure of 15,000 psi for 10 minutes to obtain an emulsion.
As a result, the emulsion was not visually creamed, and no increase or aggregation of grains was observed by microscopic observation.

Sodium salt of the compound represented by Formula 1 at 70 ° C., 1.6% soybean oil, 0.1% sodium ascorbyl-2-phosphate-6-palmitate, 94.9% 10 mM aqueous potassium chloride solution was added and stirred with a homogenizer (Silverson) to give a crude dispersion (500 g). This dispersion was emulsified with a microfluidizer (Microfluidics) at a processing pressure of 15,000 psi for 5 minutes to obtain an emulsion.
As a result, the emulsion was not visually creamed, and no increase or aggregation of grains was observed by microscopic observation.

At 70 ° C., 0.5% of the sodium salt of the compound represented by Formula 1 is dispersed in 1.5% glycerin, and then 8% glyceryl triisostearate and 1% tocotrienol are added and mixed until uniform. Then, 28% purified water at 70 ° C. was gradually added to make it uniform and cooled to 30 ° C. to obtain a concentrated emulsion. Next, 50% 30 mM sodium phosphate aqueous solution of the same volume as this concentrated emulsion was added and mixed to obtain an emulsion added with 15 mM sodium phosphate (capacity 300 ml).
As a result, the emulsion was not visually creamed, and no increase or aggregation of grains was observed by microscopic observation.

(Comparative Example 1)
In the same manner as in Example 1, after dispersing 2% of the sodium salt of the compound represented by Chemical Formula 1 at 70 ° C. in 6% glycerin, 20% soybean oil was added and mixed until uniform. 72% purified water at 70 ° C. was gradually added to make it uniform, and cooled to 30 ° C. to obtain an emulsion (salt concentration 0 mM).
As a result, the emulsion was visually creamed.

(Comparative Example 2)
In the same manner as in Example 1, 2% of the sodium salt of the compound represented by Formula 1 was dispersed in 6% glycerin at 70 ° C., and then 20% soybean oil was added and mixed until uniform. 22% purified water at 70 ° C. was gradually added to make it uniform, and cooled to 30 ° C. to obtain a concentrated emulsion. Next, a 0.2 mM potassium chloride aqueous solution having the same volume as this concentrated emulsion was added and mixed to obtain an emulsion to which 0.1 mM potassium chloride was added.
As a result, the emulsion showed agglomeration of grains as observed under a microscope.

(Comparative Example 3)
In the same manner as in Example 1, 2% of the sodium salt of the compound represented by Formula 1 was dispersed in 6% glycerin at 70 ° C., and then 20% soybean oil was added and mixed until uniform. 22% purified water at 70 ° C. was gradually added to make it uniform, and cooled to 30 ° C. to obtain a concentrated emulsion. Next, a 2 mM potassium chloride aqueous solution having the same volume as this concentrated emulsion was added and mixed to obtain an emulsion to which 1 mM potassium chloride was added.
As a result, the emulsion showed agglomeration of grains as observed under a microscope.

(Comparative Example 4)
In the same manner as in Example 1, 2% of the sodium salt of the compound represented by Formula 1 was dispersed in 6% glycerin at 70 ° C., and then 20% soybean oil was added and mixed until uniform. 22% purified water at 70 ° C. was gradually added to make it uniform, and cooled to 30 ° C. to obtain a concentrated emulsion. Next, a 20 mM magnesium chloride aqueous solution having the same volume as this concentrated emulsion was added and mixed to obtain an emulsion to which 10 mM magnesium chloride was added.
As a result, the emulsion was visually creamed.

(Test Example 1)
The photomicrographs of the emulsified particles after 2 weeks of the emulsions prepared in Example 1 and Comparative Examples 1, 2, and 3 are shown in FIGS. While FIG. 1 was uniformly dispersed without aggregation of emulsion grains, it was observed that FIGS. 2 and 3 were aggregation of emulsion grains, and that aggregation and emulsion grains were broken in FIG.

(Test Example 2)
As in Example 2, 1% of the sodium salt of the compound represented by Chemical Formula 1 was dispersed in 3% glycerin at 70 ° C., 10% soybean oil was added and mixed until uniform, and then 70%. C. 36% purified water at 0.degree. C. was gradually added to make it uniform and cooled to 30.degree. C. to obtain a concentrated emulsion. Next, 0.1, 0.2, 1.0, 2.0, 10, 20, 100 mM sodium chloride aqueous solution of the same volume as this concentrated emulsion was added and mixed, and 0.05, 0.1, An emulsion to which 0.5, 1, 5, 10, 50 mM sodium chloride was added was obtained. The zeta potential of each emulsion was measured, and the relationship between sodium chloride and zeta potential is shown in FIG. The horizontal axis represents sodium chloride concentration (mM), and the vertical axis represents zeta potential (mV).

  5 to 5 and 10 mM show that the absolute value of the zeta potential is larger than other concentrations. The larger the absolute value of the zeta potential, the greater the repulsion between the emulsion grains, and the emulsion aggregation is suppressed and the emulsion grains are dispersed and stabilized. In general, in the case of a colloidal dispersion system, repulsion between particles is weakened by adding a salt, and the value of the zeta potential approaches zero, resulting in aggregation of particles. However, in the present invention, there was a concentration that showed the maximum absolute value of the zeta potential by adding salt. This result also shows that the emulsion of the present invention has improved storage stability.

Next, the formulation example of the external preparation for skin of this invention is shown.

Toner lotion Ingredients Amount (% by weight)
(1) Emulsion of Example 5 5.0
(2) 1,3 butylene glycol 5.0
(3) Ethanol 5.0
(4) Preservative appropriate amount (5) Perfume appropriate amount (6) Total amount with purified water 100.0
[Production Method] (1) to (6) are mixed.

Latex Blending ingredients Blending amount (wt%)
(1) Emulsion of Example 4 2.0
(2) POE monostearate (5) Glyceryl 1.0
(3) Lipophilic glyceryl monostearate 1.0
(4) Squalane 10.0
(5) Neopentyl glycol dicaprate 5.0
(6) Cetyl palmitate 2.0
(7) Behenyl alcohol 0.4
(8) Glycerin 5.0
(9) 1,3-butylene glycol 8.0
(10) Xanthan gum 0.1
(11) Preservative appropriate amount (12) Total amount with purified water 100.0
(13) Carboxyvinyl polymer 0.2
(14) Purified water 20.0
(15) Potassium hydroxide [Production method] (13) is dispersed well in (12), and (14), (15) and then (8) to (11) are added thereto to obtain an aqueous phase. (2)-(7) The oil phase raw material and the water phase part are heated to 75 ° C. and completely dissolved. And cool to room temperature.

Cream Ingredient Ingredient Amount (wt%)
(1) Emulsion of Example 3 3.0
(2) POE monostearate (5) Glyceryl 2.0
(3) Glyceryl monostearate 2.0
(4) Cetanol 3.0
(5) Squalane 10.0
(6) Liquid paraffin 5.0
(7) Perfume appropriate amount (8) Glycerin 5.0
(9) 1,3-butylene glycol 5.0
(10) Xanthan gum 0.2
(11) Preservative appropriate amount (12) Total amount with purified water 100.0
[Production Method] The raw materials for the oil phase part (2) to (7) and the raw material for the water phase part (8) to (12) are heated to 75 ° C. and completely dissolved. Mix and emulsify, add (1) at 40 ° C. and cool to room temperature.

Foundation Ingredient Ingredient Amount (% by weight)
(1) Emulsion of Example 6 0.5
(2) POE monostearate (20) sorbitan 1.0
(3) POE (20) cetyl ether 2.0
(4) Cetanol 1.0
(5) Liquid lanolin 2.0
(6) Liquid paraffin 3.0
(7) Isopropyl myristate 6.5
(8) Butyl paraoxybenzoate 0.1
(9) Carboxymethylcellulose sodium 0.1
(10) Bentonite 0.5
(11) Propylene glycol 4.0
(12) Triethanolamine 1.1
(13) Methyl paraoxybenzoate 0.2
(14) Titanium dioxide 8.0
(15) Talc 4.0
(16) Bengala 1.0
(17) Yellow iron oxide 2.0
(18) Fragrance 0.1
(19) Total amount with purified water 100.0
[Production Method] Components (2) to (8) are dissolved by heating and kept at 80 ° C. to obtain an oil phase. The component (9) is well swollen with the component (19), and then the components (10) to (13) are added and mixed uniformly. Components (14) to (17) pulverized and mixed with a pulverizer are added thereto, and the mixture is stirred with a homomixer and kept at 75 ° C. to obtain an aqueous phase. The oil phase is added to the aqueous phase with stirring, cooled, component (18) is added at 45 ° C., and the product is cooled to 30 ° C. with stirring to give a product.

  The emulsion of the present invention can easily emulsify simple lipids that are difficult to emulsify using the compound represented by Chemical Formula 1 as an emulsifier, and can significantly improve the storage stability of the emulsion. It can be used for cosmetics, quasi-drugs, pharmaceuticals, etc.

It is a microscope picture of the emulsion which added 10 mM potassium chloride. (Example 1) It is a microscope picture of the emulsion which added 0 mM potassium chloride. (Comparative Example 1) It is a microscope picture of the emulsion which added 0.1 mM potassium chloride. (Comparative Example 2) It is a microscope picture of the emulsion which added 1 mM potassium chloride. (Comparative Example 3) It is the graph which showed the relationship between the sodium chloride density | concentration of an emulsion, and zeta potential. (Test Example 2)

Claims (5)

An emulsion having emulsion grains comprising (A) and (B) and containing a salt concentration of 2 mM to 20 mM having sodium ions or potassium ions .
(A) 30 to 95% of a vegetable oil or synthetic tri glycerides in the emulsion particles
(B) 5 to 70% of the compound represented by Chemical Formula 1 in the emulsion grains
_2. The emulsion according to claim ₁ , wherein among the compounds represented by Formula 1, R ₁ and R ₂ are selected from hydrogen and alkali metals, and at least one of them is one or more alkali metals. 2. The emulsion according to claim ₁ , wherein among the compounds represented by Chemical Formula 1, R ₁ and R ₂ are selected from hydrogen and sodium to potassium, and at least one of them is one or two of sodium to potassium. . _2. The emulsion according to claim ₁ , wherein among the compounds represented by the chemical formula 1, R ₁ and R ₂ are selected from hydrogen and sodium, and at least one is sodium. A skin external preparation containing the emulsion according to any one of claims 1 to 4.