JPH10101524A - Emulsified composition containing fat-soluble vitamin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition capable of remarkably improving stability of a fat-soluble vitamin and forming a sufficiently stable emulsion without passing through a heating process, by adding the vitamin to an oil phase to be added. SOLUTION: This composition is obtained by a production method comprising a first process for (A) adding water to an aqueous solvent mixed with a hydrophilic nonionic surfactant and then (B) adding an oil phase containing a fat soluble vitamin except vitamin A palmitate, α-tocopherol and vitamin E acetate to prepare an oil-in-water-soluble solvent type emulsion and a second process for adding a water phase to the emulsion. Preferably, the component A is a nonionic surfactant having >=10.0 HLB, to be concrete, an adduct of 30-80mol ethylene oxide to a castor oil or a hardened castor oil.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention belongs to the technical field of an emulsion composition. More specifically, the present invention belongs to the technical field of an emulsified composition mainly composed of an oil-in-water-based emulsion having excellent stability over time of a fat-soluble vitamin contained therein.

[0002]

2. Description of the Related Art Conventionally, various vitamins have been used as active ingredients in skin external preparations. Among them, fat-soluble vitamins such as vitamin A, vitamin E, vitamin D, etc. are highly effective in improving skin. As a very effective ingredient. However, it is known that these fat-soluble vitamins are relatively stable when water is not present, but are very easily oxidized and unstable in the presence of water. Therefore, when it is intended to incorporate this fat-soluble vitamin in a skin external preparation where the active ingredient often comes into contact with water, it is important to keep the fat-soluble vitamin stable over time.

[0003] Conventionally, these fat-soluble vitamins have also been incorporated into emulsified skin external preparations, but they are extremely unstable due to the water present in the system and are rapidly oxidized over time. There is a strong tendency to lose much of its efficacy, and it is not easy to maintain fat-soluble vitamins stably in this system for a long time. Furthermore, in the usual emulsification step, a heating step is often performed for the main purpose of obtaining a stable emulsification system. As a result, fat-soluble vitamins such as vitamin A and vitamin D having high thermal decomposability are used. , The stability tends to be further reduced.

[0004] In order to stabilize the emulsification system of these fat-soluble vitamins, it has been proposed to use a combination preparation of vitamin A with various tocopherol antioxidants, edetates or specific ester oils. However, in this case, the effect of the blending of the ester oil on the feeling of use of the product becomes a problem, and it cannot be denied that this is not a radical solution.

[0005]

The problem to be solved by the present invention is to provide an emulsion which significantly improves the stability of fat-soluble vitamins incorporated as an active ingredient and which is sufficiently stable without a heating step. It is an object of the present invention to provide an emulsified composition capable of preventing the decomposition of fat-soluble vitamins having high thermal decomposability by heating.

[0006]

Means for Solving the Problems The present inventor has conducted intensive studies to solve the above-mentioned problems. As a result, a method for producing the above stable oil-in-water emulsion (Japanese Patent Laid-Open No. 57-292)
No. 13), when producing an oil-in-water emulsion, it was found that the above problem could be solved by adding a fat-soluble vitamin to the oil phase to be added, and completed the present invention.

That is, the present invention provides an emulsified composition containing a fat-soluble vitamin (excluding vitamin A palmitate, α-tocopherol and vitamin E acetate) produced by a production method comprising the following steps. 1. Water is contained in an aqueous solvent to which a hydrophilic nonionic surfactant has been added, and then an oil phase containing a fat-soluble vitamin excluding vitamin A palmitate, α-tocopherol and vitamin E acetate is added thereto. 1. a first step of preparing an oil-in-solvent emulsion; A second step of adding an aqueous phase to the above oil-in-water-soluble emulsion. An emulsified composition comprising a fat-soluble vitamin (excluding vitamin A palmitate, α-tocopherol and vitamin E acetate) produced by a production method comprising the following steps.

[0008]

Embodiments of the present invention will be described below. A. Embodiment in First Step of Preparing Oil-in-Water-in-Water Emulsion: First, a hydrophilic nonionic surfactant described below is dissolved in a water-soluble solvent, and the low surface tension of the water-soluble solvent is used. Then, after the hydrophilic nonionic surfactant is efficiently oriented at the interface, water is gradually added, so that the water-soluble solvent plays the role of the aqueous phase.

The hydrophilic nonionic surfactant added to the water-soluble solvent is a nonionic surfactant obtained by addition polymerization of ethylene oxide in an amount of at least 15 mol, and these are generally nonionic surfactants having an HLB of 10 or more. It is an ionic surfactant.

More specifically, for example, POE-sorbitan monolaurate, POE-sorbitan monostearate,
POE sorbitan fatty acid esters such as POE-sorbitan monooleate and POE-sorbitan tetraoleate; POE-sorbit monolaurate, POE-sorbit monolaurate, POE-sorbit monooleate, POE-sorbit pentaoleate, POE
POE sorbitol fatty acid esters such as sorbit monostearate; POE-glycerin monostearate, POE-glycerin monoisostearate, POE
POE glycerin fatty acid esters such as glycerin triisostearate; POE-monooleate, POE
POE fatty acid esters such as distearate, POE-monodiolate, ethylene glycol stearate, etc .; POE-lauryl ether, POE-oleyl ether, POE-stearyl ether, POE-behenyl ether, POE2-octyldodecyl ether, POE
POE alkyl ethers such as E-cholestanol ether; POE alkyl phenyl ethers such as POE-octyl phenyl ether, POE-nonyl phenyl ether, POE-nonyl phenyl ether, POE-dinonyl phenyl ether; POE POP-cetyl ether, POE
POP2-decyltetradecyl ether; POE ・ PO
POEs such as P-monobutyl ether, POE / POP hydrogenated lanolin, POE / POP-glycerin ether;
POP alkyl ethers; Tetra P such as Tetronic
OE / tetra-POP ethylenediamine condensates: POE
POE castor oil such as castor oil, POE hardened castor oil, POE hardened castor oil monoisostearate, POE hardened castor oil triisostearate, POE hardened castor oil monopyroglutamic acid monoisostearate diester, POE hardened castor oil maleic acid or the like; Hydrogenated castor oil derivatives;
Bee wax lanolin derivatives such as POE sorbit beeswax; alkanolamides such as coconut oil fatty acid diethanolamide, lauric acid monoethanolamide, fatty acid isopropanolamide; POE propylene glycol fatty acid ester, POE alkylamine, POE fatty acid amide, sucrose fatty acid ester, POE nonyl. Phenylformaldehyde condensate, alkylethoxydimethylamine oxide, trioleyl phosphoric acid and the like can be mentioned. In addition, these can be added alone or in combination of two or more.

In the present invention, particularly preferred hydrophilic nonionic surfactants are selected from the reason that the oil phase and the water-soluble solvent to be added to the system can be selected in a wide range in the production process of the emulsion composition of the present invention. For example, 30-80 moles of ethylene oxide adduct of castor oil or hydrogenated castor oil, 20-100 moles of ethylene oxide of oleic acid monoglyceride or stearyl glyceryl ether, 15-6 ethylene oxide of lanolin or fatty acids or alcohols thereof
0 mole adducts and the like can be mentioned.

The amount of the hydrophilic nonionic surfactant in the emulsion composition of the present invention is preferably 0.1% by weight or more and 10% by weight or less, particularly preferably 0% by weight or less, based on the composition. 0.3% by weight or more and 5% by weight or less.
When the amount is less than 0.1% by weight of the composition, the stability over time of the emulsified composition tends to decrease, which is not preferable.
Conversely, if the content exceeds 10% by weight, the stability of the fat-soluble vitamin to be added tends to be impaired, which is not preferable.

[0013] The water-soluble solvent to which the hydrophilic nonionic surfactant is added includes hydrophilic solvents such as lower monohydric alcohols, lower polyhydric alcohols, ketones, aldehydes, ethers, amines and lower fatty acids. There is no particular limitation as long as it has the property of “dissolving a hydrophilic nonionic surfactant”.

For example, alcohols such as methanol, ethanol, propanol, isopropanol and benzyl alcohol; glycols such as ethylene glycol, propylene glycol, 1,3-butylene glycol and dipropylene glycol; glycerin, polyglycerin (diglycerin, triglycerol) Glycerins such as glycerin and tetraglycerin); polyhydric alcohols such as reduced starch-alcohol; ketones such as acetone, acetonylacetone and diacetone alcohol; aldehydes such as formaldehyde and acetaldehyde; ethylene oxide, dioxane and ethylene glycol monomethyl. Ether, dimethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether Ethylene glycol monoisobutyl ether, ethylene glycol monopropyl ether (monoisopropyl ether), dimethylene glycol monoethyl ether, dimethylene glycol monomethyl ether, dimethylene glycol monobutyl ether, dimethylene glycol diethyl ether, ethoxytriglycol, monopropylene glycol methyl Ethers such as ether, ethylene glycol monomethyl ether acetate, diethylene glycol monomethyl ether acetate, diethylene glycol monomethyl ether acetate;
Monoethanolamine, diethanolamine, triethanolamine, n-butylamine, ethylenediamine,
Amines such as propylenediamine, ethylamine, pyridine, and cyclohexylamine; lower fatty acids such as formic acid, acetic acid, butyric acid, and lactic acid; and methoxyglycol acetate, methyl lactate, ethyl lactate, acetonitrile, tetrahydrofuran, and furfuryl alcohol. It is possible, but not limited to these. In addition, these water-soluble solvents can be used alone, and 2
By using a combination of more than one species, for example, it is possible to appropriately adjust the solubility of the above-mentioned hydrophilic nonionic surfactant.

In the present invention, particularly preferred water-soluble solvents include, for example, propylene glycol, 1,1, and the like, because it is easy to obtain very fine emulsified particles.
Examples thereof include 3-butylene glycol and dipropylene glycol.

The water-soluble solvent used in the present invention is:
Although water is gradually added as described above, it is preferable that the water is finally contained in an amount of 1% by weight or more and 30% by weight or less, more preferably 5% by weight or more. 15% by weight or less. If the content of this water is less than 1% by weight based on the water-soluble solvent, the viscosity tends to be considerably high as the above-mentioned hydrophilic nonionic surfactant is added to the water-soluble solvent. In a neutral solvent,
It becomes difficult to uniformly dissolve the added hydrophilic nonionic surfactant, which is not preferable.
If it exceeds 0% by weight, the emulsified particles tend to coalesce, and the stability of the emulsified composition over time tends to decrease, which is not preferable.

The water-soluble solvent containing water is incorporated into the emulsified composition of the present invention in a range of about 1% to 90% by weight of the composition.

Next, an oil phase containing a fat-soluble vitamin excluding vitamin A palmitate, α-tocopherol and vitamin E acetate is added to a water-soluble solvent in which the above-mentioned hydrophilic nonionic surfactant has been added and dissolved. Thus, an oil-in-water emulsion is prepared.

The fat-soluble vitamin to be added is not particularly limited as long as it is a fat-soluble vitamin other than vitamin A palmitate, α-tocopherol and vitamin E acetate.
Specifically, for example, vitamins A such as retinol, 3-hydroretinol, retinal, 3-hydroretinal, retinoic acid, 3-dehydroretinoic acid, and vitamin A acetate; α, β, γ-carotene, β-cryptoxanthin And provitamin A such as xanthophyll and carotenoids such as echinenone.

Further, vitamin D such as vitamin D ₂ to D _7; beta, gamma, .delta.-tocopherol, alpha, beta, gamma, .delta.
Tocotrienol, esters such as nicotinic acid vitamin E; vitamin K ₁ or K vitamin K such as ₃ can be mentioned. In addition, these fat-soluble vitamins can be added alone or in combination of two or more.

The amount of the fat-soluble vitamin to be added is appropriately selected according to the specific dosage form of the emulsion composition of the present invention, the function to be imparted, and the like, and is not particularly limited. Other oil phase components (pharmaceutical components and / or base components) can be added to the oil phase component containing the fat-soluble vitamin as long as the desired effect of the present invention is not impaired.

Other oily components include, for example, linseed oil, camellia oil, macadamia nut oil, corn oil,
Liquids such as mink oil, olive oil, avocado oil, sasanqua oil, castor oil, safflower oil, jojoba oil, sunflower oil, rapeseed oil, sesame oil, soybean oil, peanut oil, triglycerin, glycerin trioctanoate, glycerin triisopalmitate. Oils and fats; solid oils such as cocoa butter, coconut oil, palm oil, palm kernel oil, hardened oil, hardened castor oil, mocro, shea butter; liquid paraffin, squalane, squalene, paraffin, isoparaffin, ceresin, petrolatum, microcrystalline wax, etc. Hydrocarbon oils; chain polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, and methylhydrogenpolysiloxane; cyclic polysiloxanes such as decamethylpolysiloxane, dodecamethylpolysiloxane, and tetramethyltetrahydrodienepolysiloxane Silicone oils such as Rokisan; three-dimensional network structure formed by that the silicone resin, and silicone oils such as silicone rubber.

Also, para-aminobenzoic acid-based ultraviolet absorbers such as para-aminobenzoic acid, anthranilic acid-based ultraviolet absorbers such as methyl anthranilate, salicylic acid-based ultraviolet absorbers such as octyl salicylate and phenyl salicylate, octyl paramethoxycinnamate, Cinnamic acid-based ultraviolet absorbers such as isopropyl paramethoxycinnamate and glyceryl mono-2-ethylhexanoate diparamethoxycinnamate;
4-dihydroxybenzophenone, 2-hydroxy-4
Benzophenone ultraviolet absorbers such as -methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, urocanic acid, 2- (2'-hydroxy-5'-methylphenyl) benzotriazole,
An ultraviolet absorber such as -tert-butyl-4'-methoxydibenzoylmethane can be blended.

In addition, various oil-soluble drugs such as bisabolol, thymol, pantothenyl ethyl ether, ethinyl estradiol, and the like; Rumex japonicus, Clara, Kouhone, Orange, Sage, Yarrow, Zeniaoi, Senkyu,
Assembly, thyme, touki, spruce, birch, horsetail,
Organic solvent extracts of plants such as loofah, horse chestnut, saxifrage, arnica, lily, mugwort, peonies, aloe, gardenia, sawara, izayoibara; fat-soluble preservatives such as ethylparaben, methylparaben; fat-soluble pigments, flavors, etc. The above oil phase component can be blended with the emulsion composition of the present invention.

Thus, a desired oil-in-water emulsion can be prepared by adding an oil phase containing a fat-soluble vitamin.

B. Embodiment in the step of adding the aqueous phase to the water-soluble oil-in-solvent emulsion to prepare the emulsion composition of the present invention: Then, further adding the aqueous phase to the water-soluble oil-in-solvent emulsion prepared in A above, An emulsion composition is prepared.

The aqueous phase component includes not only water but also vegetable polymers such as gum arabic, carrageenan, pectin, agar, quince seed (quince), starch, alge colloid (brown algae extract), dextran and pullulan. Microbial macromolecules, animal macromolecules such as collagen, casein, gelatin, etc., starch macromolecules such as carboxymethyl starch and methylhydroxypropyl starch, and cellulose macromolecules such as methylcellulose, nitrocellulose, ethylcellulose, methylhydroxypropylcellulose and hydroxyethylcellulose Polymers, alginic acid polymers such as sodium alginate, vinyl polymers such as carboxyvinyl polymers (such as CARBOPOL), polyoxyethylene polymers, and polyoxyethylene polyoxypropylene copolymers System polymer, sodium polyacrylate, acrylic acid-based polymers such as polyacrylamide, bentonite, aluminum magnesium silicate, a water-soluble polymer such as inorganic water-soluble polymers such as laponite; B vitamins (e.g., vitamin B ₁ , B ₂ , B ₆ , B ₁₂ ,
The B _15, etc.), vitamin C, pantothenic acid, pantethine,
Water-soluble vitamins such as folic acid; hinokitiol, inositol, saponins (saikosaponin, carrot saponin,
Various water-soluble drugs such as luffemasaponin, muclodisaponin), tranexamic acid, placenta extract, etc .; Rigid ginkgo, Clara, kuhon, orange, sage, yarrow, zenioi, senkyu, assembly, thyme, touki, spruce, birch, sugiina, hechima , Horseradish, saxifrage, arnica, lily, mugwort, peonies, aloe, gardenia, sourdough, izayoibara and other plant alcohols, polyhydric alcohols, water, aqueous solvent extracts such as aqueous alcohols, and the like. It is not limited.

The mixing ratio of this aqueous phase and the above-mentioned oil-in-water-soluble emulsion is 95: 5 to 5 depending on the specific dosage form.
It can be selected widely in the range of 5:95. In the conventional emulsification method, it was difficult to prepare a stable oil-in-water emulsion having an aqueous phase of 10% or less. Can also be manufactured stably.

The emulsion composition of the present invention can be prepared by adding the aqueous phase component as described above to the oil-in-water emulsion prepared in the above A. The form and dosage form of the emulsified composition of the present invention are not particularly limited as long as they are in the form and dosage form of an emulsified form such as cream or emulsion.

The emulsified composition of the present invention is excellent in emulsification stability irrespective of the addition amount of a small amount of a surfactant, and is also very excellent in stability of a fat-soluble vitamin contained therein. Specific formulations of the emulsified composition of the present invention will be specifically described in Examples described later.

[0031]

EXAMPLES The present invention will now be described in detail with reference to Examples, which should not be construed as limiting the technical scope of the present invention. In addition, in this Example, the compounding amount represents weight%. Before referring to specific formulations of the emulsified composition of the present invention, means for examining the intended effects of the present invention will be described.

Storage stability test The emulsion composition was allowed to stand in a constant temperature bath at 50 ° C., and the state after one month was observed. Evaluation criteria of “stability” ：: There is no change in any of color tone, smell, and appearance properties. X: Change was seen in any of color tone, smell, and appearance properties.

Drug stability test After leaving the emulsified composition in a thermostat at 50 ° C. for one month, the drug concentration in each emulsified composition was quantified by the HPLC method, and the residual ratio of each fat-soluble vitamin to the initial compounding amount was determined. (%) Was calculated.

Example 1, Comparative Examples 1 to 3 Emulsion compositions having the formulations shown in Table 1 below were produced according to the following production methods, and these emulsion compositions were evaluated based on the above criteria. The results are also shown in Table 1.

[0035]

[Table 1]

<Production Method> Example 1 and Comparative Example 2 First, regarding part (A), POE was added to propylene glycol.
After dissolving the hardened castor oil, ion-exchanged water was gradually added, and the oil phase (B) was added thereto, emulsified, and emulsified by homomixer treatment.

Next, the aqueous phase (C) was added to this emulsion and stirred to prepare an emulsion composition. The size of the emulsified particles in these compositions is uniform and the particle size is
It was very fine, 1-2 μm.

Comparative Examples 1 and 3 First, regarding part (A), propylene glycol was added to POE.
After dissolving the hardened castor oil, ion-exchanged water is gradually added, and this is dissolved in the aqueous phase (C) and heated to 70 ° C.
The oil phase (B) was added to this to emulsify, and a homomixer treatment was performed to prepare an emulsified composition. The size of the emulsified particles in this composition is uniform and the particle size is 5 to 15 μm.
Met.

Table 1 shows that the emulsified composition of the present invention of Example 1 is excellent in both storage stability and stability of fat-soluble vitamin. On the other hand, Comparative Example 2
In Comparative Example 2, which was different in the production method from Example 1, even if the composition was the same, separation over time was observed because of the large amount of surfactant added.

From the above, it has been clarified that not only the prescription but also the production method are important factors to obtain the desired effect. In comparison between Example 1 and Comparative Examples 1 and 3, it was found that increasing the amount of added surfactant had little effect on storage stability, but greatly reduced drug stability. In particular, since Comparative Example 3 involved a heating step in the preparation of the composition, the decomposition of heat-labile fat-soluble vitamins progressed, and the drug stability further decreased.

[Example 2]% by weight (A) Ethanol 5.0 POE-glyceryl isostearate 0.7 Deionized water 0.5 (B) Dimethylpolysiloxane 4.0 Tri-2-ethylhexanepentaerythritol 0 β-carotene 0.5 Preservative qs perfume qs (C) Carboxyvinyl polymer 0.4 potassium hydroxide 0.13 ion-exchanged water balance

<Manufacturing Method> This is the same as the manufacturing method of the first embodiment. The emulsified composition of Example 2 had very fine emulsified particles, and had very excellent stability over time and drug stability.

Example 3 Weight% (A) 1,3-butylene glycol 4.0 dihydrocholesterol derivative 4.0 ion-exchanged water 0.8 (B) pentaerythritol tetra-2-ethylhexanate 2.0 Cetyl octanoate 4.5 Squalane 6.0 γ-Tocopherol 0.8 (C) Magnesium phosphate ascorbate 1.0 Placenta extract 0.5 Deionized water balance

<Manufacturing Method> This is the same as the manufacturing method of the first embodiment. The emulsified composition of Example 3 had very fine emulsified particles, and had excellent temporal stability and drug stability.

Example 4% by weight (A) Dipropylene glycol 10.0 POP / POP cetyl alcohol ether 0.5 POE stearyl ether 2.0 Deionized water 1.5 (B) Squalane 5.0 Dimethylpolysiloxane 5.0 Olive oil 1.0 Isopropyl isostearate 5.0 Vitamin A acetate 0.3 (C) Trisodium edetate 0.1 Arbutin 2.0 Deionized water balance

<Manufacturing Method> This is the same as the manufacturing method of the first embodiment. The emulsified composition of Example 4 had very fine emulsified particles, and had very excellent stability over time and drug stability.

[0047]

According to the present invention, there is provided an emulsified composition having a fine emulsified particle diameter and excellent in stability over time and drug stability.

Claims (7)

[Claims] An emulsion composition comprising a fat-soluble vitamin (excluding vitamin A palmitate, α-tocopherol and vitamin E acetate) produced by a production method comprising the following steps: Water is contained in an aqueous solvent to which a hydrophilic nonionic surfactant has been added, and then an oil phase containing a fat-soluble vitamin excluding vitamin A palmitate, α-tocopherol and vitamin E acetate is added thereto. 1. a first step of preparing an oil-in-solvent emulsion; A second step of adding an aqueous phase to the above oil-in-water-soluble emulsion. 2. The emulsified composition according to claim 1, wherein
An emulsified composition wherein the hydrophilic nonionic surfactant added to the aqueous solvent in the step is a nonionic surfactant of HLB of 10.0 or more. 3. The emulsion composition according to claim 1, wherein
The hydrophilic nonionic surfactant to be added to the aqueous solvent in the step is an ethylene oxide of castor oil or hydrogenated castor oil of 30 to
Hydrophilic nonionic surfactants of the group consisting of 80 mol adducts, 20-100 mol ethylene oxide adducts of oleic acid monoglyceride or stearyl glyceryl ether and 15-60 mol ethylene oxide adducts of lanolin or its fatty acids or alcohols An emulsified composition which is one or two or more hydrophilic nonionic surfactants selected from agents. 4. The emulsion composition according to claim 1, wherein the content of water in the aqueous solvent in the first step is 1% by weight or more based on the aqueous solvent. An emulsified composition of not more than 30% by weight. 5. The emulsion composition according to claim 1, wherein the content of water in the aqueous solvent in the first step is 5% by weight or more based on the aqueous solvent. An emulsified composition that is 15% by weight or less. 6. The emulsified composition according to any one of claims 1 to 5, wherein the amount of the hydrophilic nonionic surfactant added to the aqueous solvent in the first step is the same as that of the composition. An emulsion composition having a content of 0.1% by weight or more and 10% by weight or less. 7. The emulsified composition according to any one of claims 1 to 5, wherein the amount of the hydrophilic nonionic surfactant added to the aqueous solvent in the first step is the same as that of the composition. An emulsion composition having a content of 0.3% by weight or more and 5% by weight or less.