JP6903410B2 - Oil-in-water emulsified composition - Google Patents

Description

The present invention relates to an oil-in-water emulsified composition. More specifically, the present invention relates to an oil-in-water emulsification composition in which emulsification is stabilized while containing a lower alcohol.

Conventionally, skin external preparations such as lotions, creams, and gels containing anti-inflammatory analgesics for treating or alleviating symptoms such as stiff shoulders, low back pain, myalgia, and arthralgia have been known. For example, Patent Document 1 discloses a liquid preparation in which a phenylacetic acid derivative is dissolved in a relatively large amount of ethanol. In addition to the anti-inflammatory and analgesic effect of the phenylacetic acid derivative, which is the active ingredient, this liquid is a highly pain-relieving and comfortable-to-use formulation because a large amount of ethanol is volatilized to give a cooling sensation to the affected area with heat. It has become.

Further, in order to treat or alleviate symptoms such as stiff shoulders, low back pain, myalgia, and arthralgia, it is also effective to promote blood circulation in the affected area. Vitamin E is mentioned as a blood circulation promoting component used for external preparations for skin. Since vitamin E is an oil-soluble component, when it is used as a skin external preparation, it is prepared as an emulsified skin external preparation such as a cream or ointment containing an oil-based component (Patent Document 2).

Here, if a volatile lower alcohol such as ethanol is blended with an emulsified skin external preparation as in Patent Document 2, excellent skin having both the effect of an oily active ingredient of vitamin E and the cooling effect of the lower alcohol. It is considered that an external preparation can be obtained.

However, since a lower alcohol such as ethanol has a property of dissolving in both water and oil, there is a problem that emulsification is not stable when the lower alcohol is mixed in the emulsion.

Japanese Unexamined Patent Publication No. 2003-286161 Japanese Unexamined Patent Publication No. 2000-256167

A main object of the present invention is to provide an oil-in-water emulsified composition which contains a lower alcohol but whose emulsification is stabilized. The present invention also provides an oil-in-water emulsified skin external preparation which contains a lower alcohol but whose emulsification is stabilized, particularly a skin external preparation having an anti-inflammatory and analgesic effect.

The present inventors can stabilize the emulsifying property of an oil-in-water emulsified composition in which emulsification becomes unstable by blending a lower alcohol by blending a monoterpen and a thickener, and the lower alcohol. It has been found that an oil-in-water emulsified composition in which separation is significantly suppressed is obtained by ensuring emulsification stability after long-term storage even when a relatively large amount of the above is blended.

The present invention has been completed based on such findings, and provides the following oil-in-water emulsification composition and a method for stabilizing the emulsification of the oil-in-water emulsification composition.

(1) Oil-in-water emulsified composition (1-1). An oil-in-water emulsified composition comprising a lower alcohol, a monoterpene and a thickener.
(1-2). The oil-in-water emulsified composition according to (1-1), which further contains diclofenac or a salt thereof.
(1-3). The oil-in-water emulsified composition according to (1-1) or (1-2), which further contains a polyhydric alcohol.
(1-4). The oil-in-water emulsified composition according to any one of (1-1) to (1-3), wherein the content of the lower alcohol is 3 to 30% by weight.
(1-5). The oil-in-water emulsified composition according to any one of (1-1) to (1-4), which is an external preparation for skin.

(2) Method for stabilizing emulsification of oil-in-water emulsification composition containing lower alcohol (2-1). A method for stabilizing the emulsification of an oil-in-water emulsification composition containing a lower alcohol, which comprises further adding a monoterpene and a thickener to the oil-in-water emulsification composition.
(2-2). The emulsion stabilization method according to (2-1), further comprising at least one selected from the group consisting of diclofenac or a salt thereof, and a polyhydric alcohol.
(2-3). The emulsion stabilization method according to (2-1) or (2-2), wherein the content of the lower alcohol is 3 to 30% by weight.
(2-4). The emulsification stabilization method according to any one of (2-1) to (2-3), wherein the oil-in-water emulsification composition is an external preparation for skin.

According to the present invention, it is possible to significantly suppress and improve the decrease in emulsification stability due to the addition of a lower alcohol in the oil-in-water emulsification composition. As a result, there is provided an oil-in-water emulsification composition in which lower alcohol is contained in a relatively large amount of 3% by weight or more, 5% by weight or more, particularly 10% by weight or more, yet the emulsification stability after long-term storage is ensured. can do. Further, by containing diclofenac or a salt thereof, the emulsion stability is further improved, and the oil-in-water emulsification with a high therapeutic effect and a feeling of use, which has both an anti-inflammatory analgesic effect of diclofenac or its salt and a cooling effect by volatilization of lower alcohol. A type of external preparation for skin can be provided.

(1) Oil-in-water emulsification composition The oil-in-water emulsification composition of the present invention will be described in detail below.

The oil-in-water emulsified composition of the present invention is an oil-in-water emulsified composition containing a lower alcohol, and is characterized by further containing a monoterpene and a thickener.

(Lower alcohol)
In the present invention, the "lower alcohol" means a monohydric alcohol having 1 to 4 carbon atoms. Specific examples include methanol, ethanol, propanol, isopropanol, and butanol. Ethanol and isopropanol are preferable, and ethanol is more preferable.

Although the content ratio (total amount) of the lower alcohol in the oil-in-water emulsified composition of the present invention is not limited, from the viewpoint of imparting a cooling effect by volatilization, and the decrease in emulsification stability due to the addition of the lower alcohol, diclofenacs and the increase thereof. From the viewpoint of stabilizing emulsification by blending a thickener, the lower limit value can be 3% by weight or more, preferably 5% by weight or more, and more preferably 10% by weight or more. More specifically, it is about 3 to 30% by weight, preferably about 5 to 25% by weight, and more preferably about 10 to 25% by weight.

The oil-in-water emulsified composition of the present invention contains water, an oily component, and a surfactant as basic constituents thereof in order to obtain an oil-in-water emulsified composition.

(water)
Examples of water that can be used in the present invention include, but are not limited to, purified water, distilled water, sterilized water, ion-exchanged water, and the like. Purified water is preferable.

The content ratio of water in the oil-in-water emulsified composition of the present invention is not limited, but is usually about 20 to 80% by weight, preferably about 30 to 70% by weight.

(Oil component)
In the present invention, the oily component (oil phase) is a component constituting the oil phase of the emulsified composition of the present invention. For example, oily components usually used in pharmaceuticals, quasi-drugs, cosmetics and the like can be widely used. Such oily components include, but are not limited to, vegetable oils such as olive oil, wheat germ oil, rice oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil; lard, fish oil, squalane, etc. Animal oils such as beeswax; mineral oils such as liquid paraffin, gelled hydrocarbons and vaseline; lecithin derivatives such as soybean lecithin; fatty acid esters such as isopropyl myristate, isopropyl palmitate, cetyl palmitate, diethyl sebacate and ethyl oleate Silicones such as dimethyl silicone and cyclic silicone; fatty acids such as oleic acid and linoleic acid; hormones such as ethynyl estradiol; essential oils such as sardine oil, butterfly oil, peppermint oil, eucalyptus oil and lemon oil; silicon oil; And waxes and the like.

Further, examples of other oily components include higher alcohols. Examples of higher alcohols include aliphatic alcohols having 6 or more carbon atoms. Specific examples thereof include cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, stearyl alcohol, hexadecyl alcohol, lanolin alcohol and the like.

The oily component may be used alone or in combination of two or more. The oily component is preferably liquid at room temperature (25 ° C.) from the viewpoint of ensuring the fluidity of the oil-in-water emulsified composition. Further, among the above oily components, vegetable oils, animal oils, mineral oils, and fatty acid esters are preferable, and animal oils and minerals are more preferable, from the viewpoint that an emulsified composition having excellent thermal stability and fluidity can be prepared. Oils and fatty acid esters. In particular, it is preferable to mix liquid paraffin as a mineral oil alone or in combination with other oily components (vegetable oil, animal oil, mineral oil, fatty acid ester). Further, it is preferable to add the above higher alcohol together with these oily components (vegetable oil, animal oil, mineral oil, fatty acid ester).

The content of the oily component in the oil-in-water emulsified composition of the present invention is not limited, but is, for example, about 1 to 60 parts by weight, preferably 5 to 60 parts by weight, based on 100 parts by weight of water contained in the oil-in-water emulsified composition. About 50 parts by weight can be mentioned.

(Surfactant)
The surfactant is not particularly limited as long as it is usually used in pharmaceuticals, quasi-drugs, cosmetics, etc., but is preferably a nonionic surfactant from the viewpoint of thermal stability and fluidity. As the nonionic surfactant, a polyoxyethylene (hereinafter, POE) addition type surfactant is suitable, for example, POE (10 to 50 mol) phytosterol ether, POE (10 to 50 mol) dihydrocholesterol ether. , POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl ether, POE (10-50 mol) oleyl ether, POE (10-50 mol) behenyl ether, POE (10-10 mol) Poly such as 50 mol) cetyl ether, POE (5 to 30 mol) polyoxypropylene (5 to 30 mol) 2-decyltetradecyl ether, POE (10 to 50 mol) polyoxypropylene (2 to 30 mol) cetyl ether, etc. Oxyethylene alkyl ether; these phosphates and phosphates (POE cetyl ether sodium phosphate, etc.); POE (20-60 mol) sorbitan monoolate, POE (10-60 mol) sorbitan monoisostearate, POE (10) ~ 80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100) hardened castor oil, POE (20-100) POE / polyoxypropylene-modified silicone, POE / alkyl-modified Examples thereof include silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol dilysinoleate and the like. These surfactants may be used alone or in combination of two or more.

The content of the surfactant in the oil-in-water emulsified composition of the present invention is not limited, but is, for example, about 10 to 100 parts by weight, preferably about 10 to 100 parts by weight, based on 100 parts by weight of the oily component contained in the oil-in-water emulsified composition. About 20 to 70 parts by weight can be mentioned.

(Monotelpene)
The monoterpenes that can be used in the present invention are not particularly limited, but are monoterpene-based hydrocarbons such as limonene, pinen, and camphor; monoterpene-based alcohols such as citronellol, geraniol, linalol, menthol, terpineol, and borneol; Examples include monoterpene-based aldehydes such as citral and safranal; and monoterpene-based ketones such as menthone, carbomentone, and yonon. It is preferably a monoterpene alcohol, and more preferably menthol. These monoterpenes may be in any of d-, l-, and dl-forms. These may be used alone or in combination of two or more.

The content of the monoterpene in the oil-in-water emulsified composition of the present invention is not limited, but may be, for example, about 0.5 to 10% by weight, preferably about 1 to 6% by weight.

(Thickener)
The oil-in-water emulsified composition of the present invention is characterized by further containing a thickener in addition to the above-mentioned lower alcohol, water, oily component, surfactant, and monoterpene. The thickener that can be used in the present invention is not particularly limited, and examples thereof include hypromellose (HPMC), hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, methyl cellulose, carboxyvinyl polymer, xanthan gum and the like. Carboxyvinyl polymers, xanthan gum and hydroxypropyl cellulose are preferred, and carboxyvinyl polymers and xanthan gum are more preferred. These thickeners may be used alone or in combination of two or more.

The content ratio (total amount) of the thickener in the oil-in-water emulsified composition of the present invention is not limited, but is, for example, about 0.05 to 5% by weight, preferably about 0.1 to 3% by weight.

In addition to the above-mentioned lower alcohol, water, oily component, surfactant, monoterpene, and thickener, the oil-in-water emulsified composition of the present invention further comprises at least one of diclofenac or a salt thereof and a polyhydric alcohol. Can be blended.

(Diclofenac or its salt)
Diclofenac is an arylacetic acid-based, specifically phenylacetic acid-based, anti-inflammatory analgesic compound. Here, as the salt of diclofenac, preferably, a pharmaceutically acceptable salt can be mentioned. Pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium and potassium salts of diclofenac; or alkaline earth metal salts such as lithium salt, calcium salt and magnesium salt. It is preferably an alkali metal salt, more preferably a sodium salt.

When diclofenac or a salt thereof is blended in the oil-in-water emulsified composition of the present invention, the blending ratio (total amount) is not limited, but is, for example, about 0.1 to 5% by weight, preferably 0.5 to 3% by weight. About 0.5 to 1.5% by weight, more preferably about 0.5 to 1.5% by weight.

(Multivalent alcohol)
The polyhydric alcohol that can be used in the present invention is not particularly limited, and for example, ethylene glycol, propylene glycol, 1,3-butylene glycol, diethylene glycol, dipropylene glycol, triethylene glycol, 1,3-butanediol, and the like. Examples thereof include isopropylene glycol, 1,2-pentanediol, 2-methyl-2,4-pentanediol, hexylene glycol, glycerin, sorbitol, xylitol and the like. From the viewpoint of solubility (compatibility) with diclofenac or a salt thereof, propylene glycol, 1,3-butylene glycol, glycerin and sorbitol are preferable. These may be used alone or in combination of two or more.

When the polyhydric alcohol is blended in the oil-in-water emulsified composition of the present invention, the blending ratio (total amount) is not limited, but is, for example, about 1 to 30% by weight, preferably about 2 to 25% by weight.

(Other ingredients)
In the oil-in-water emulsified composition of the present invention, other components may be appropriately selected and blended in combination of one or more as long as the effects of the present invention are not impaired. For example, various additives such as stabilizers, preservatives, buffers, pH adjusters, and fragrances that are generally used for the preparation of liquids and semi-solids can be mentioned, and specific examples are as follows. Can be mentioned.

Stabilizers: dibutylhydroxytoluene, sodium edetate, sodium sulfite, dry sodium sulfite, etc.

Preservatives: Butylparaben, methylparaben, propylparaben, ethylparaben, sodium benzoate, benzyl alcohol, etc.

Buffer: Borate buffer, phosphate buffer, carbonic acid buffer, citric acid buffer, acetate buffer, epsilon-aminocaproic acid, aspartic acid, aspartate, etc.

pH adjuster: Inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid; lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, Organic acids such as aspartic acid, epsilon-aminocaproic acid, glutamate, aminoethylsulfonic acid; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide; monoethanolamine, Organic salts such as triethanolamine, diisopropanolamine, triisopropanolamine, and lysine.

In addition, the oil-in-water emulsified composition of the present invention may contain other active ingredients as long as the effects of the present invention are not impaired. For example, anti-inflammatory analgesics other than diclofenacs (indole acetic acid such as indomethacin; phenylacetic acid such as ibfenac, arcphenac, metiazic acid, amphenac and 4-biphenylacetic acid; indenyl acetic acid such as slindac; pyrrole acetic acid such as tolmethin; And naphthylacetic acid such as nabmeton), tocopherol (α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol) or derivatives thereof (tocopherol acetate, tocopherol succinate, tocopherol nicotinate, tocopherol linolenate, etc. Tocopherol organic acid ester), steroids (dexamethasone, dexamethasone hydrochloride, dexamethasone acetate, hydrocortisone hydrochloride, prednisolone valerate, prednisolone acetate, etc.), antihistamines (diphenhydramine, diphenhydramine hydrochloride, chlorhexidine maleate, etc.), local anesthetics (lydocaine, Dibucaine, procaine, tetracaine, bupipacain, mepipacaine, chloroprocine, proparacaine, meprilcaine or salts thereof, alkyl benzoate (eg ethyl aminobenzoate, diethylaminoethyl parabutylaminobenzoate), orthokine, oxesazein, oxypolyentoxy Decane, funnel extract, percamine pase, tesitdecitin, etc.), anti-inflammatory agents (glycyrrhetinic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhetinate, allantin, salicylic acid, glycol salicylate, methyl salicylate, etc.), bactericides (benzalconium chloride, decalinium chloride, etc.) , Benzethonium chloride, cetylpyridinium chloride, inpropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfaziazine, lactic acid, phenol, etc.), antipruritic agent (crotamiton, thiantolu, etc.), skin protectant (corodione, castor oil, etc.) , Blood circulation promoting components (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, capsicum extract, etc.), vitamins (vitamins A, B, C, D, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, hyaluronic acid, etc.), etc. Can be mentioned.

The method for producing the oil-in-water emulsified composition of the present invention is not particularly limited, and for example, it can be produced as follows. Aqueous phase (aqueous component: water, thickener, if necessary mixed with other water-soluble components [for example, lower alcohol, polyhydric alcohol, etc.]) and oil phase (oil-based component: surfactant, monoterpene, required (Mix other oil-soluble components according to the above) while heating and mixing using a mixer such as a homogenizer to prepare an emulsion, and then adding diclofenac or a lower alcohol in which a salt thereof is dissolved, if necessary. The oil-in-water emulsified composition of the present invention can be prepared. Although the heating temperature is not limited, it can be usually 50 to 90 ° C, preferably 65 to 85 ° C.

Further, the pH of the oil-in-water emulsified composition of the present invention can be adjusted in the manufacturing process thereof, if necessary. The pH is not particularly limited, but can usually be adjusted to be in the range of pH 4.5 to 10. The pH is preferably 5 to 9.5, more preferably pH 5.5 to 9.0. The pH is usually adjusted using a pH adjuster.

The oil-in-water emulsified composition of the present invention can be suitably used as a skin external preparation having the form of a liquid to semi-solid oil-in-water emulsified lotion, cream, or emulsion. In particular, when the oil-in-water emulsified composition of the present invention contains diclofenac or a salt thereof, it is possible to loosen or heal muscles by applying it as an anti-inflammatory and analgesic external preparation to the affected area of stiff shoulders and muscle fatigue. Become.

(2) Method for Stabilizing Emulsification of Oil-in-Water Emulsification Composition Containing Lower Alcohol The present invention improves the emulsification stability of an oil-in-water emulsification composition whose emulsification stability is reduced by blending a lower alcohol. And provide a way to improve.

The method can be carried out by further adding a monoterpene and a thickener to the oil-in-water emulsified composition containing a lower alcohol.

The composition of the oil-in-water emulsified composition targeted here, and the type and blending ratio of the lower alcohol blended therein are as described in (1) above, and can be incorporated herein by reference. Further, the types of monoterpenes and thickeners to be blended therein, and the blending ratio thereof with respect to the oil-in-water emulsified composition are also as described in (1) above, and can be incorporated herein by reference.

Further, for the emulsion stability of the oil-in-water emulsified composition containing a lower alcohol, at least one selected from the group consisting of diclofenac or a salt thereof and a polyhydric alcohol is blended in addition to the blending of monoterpenes and thickeners. It will be improved by doing. In particular, by blending diclofenac or a salt thereof and both a polyhydric alcohol, the emulsification stability of the oil-in-water emulsified composition containing a lower alcohol is further improved, and the emulsion stability is further improved even when stored under relatively harsh conditions for a long period of time. Separation can be suppressed. The types of diclofenac or its salt and polyhydric alcohol used here, and the blending ratio thereof with respect to the oil-in-water emulsified composition are also as described in (1) above, and can be incorporated herein by reference.

Hereinafter, the present invention will be described based on Experimental Examples and Examples. However, the experimental examples and examples are examples of the present invention, and the present invention is not limited to these experimental examples and examples.

Experimental Example 1
Liquid to semi-solid oil-in-water emulsified creams having the formulations shown in Table 1 (Reference Example 1, Examples 1 to 13, Comparative Examples 1 to 6) were prepared. Specifically, an oil phase and an aqueous phase (excluding diclofenac sodium and absolute ethanol) were prepared according to the formulations shown in Table 1, and these were mixed at 80 ° C. to prepare an oil-in-water emulsion. .. Then, Examples 4 and 6 to 13 and Comparative Example 5 were prepared by gradually adding diclofenac sodium dissolved in absolute ethanol and mixing them completely and uniformly. 18 ml of the obtained liquid to semi-solid emulsion was filled in a screw tube with a lid (screw tube No. 5 (27 x 55 mm), manufactured by Maruemu Corporation) having a capacity of about 20 ml, and in a constant temperature bath at 50 ° C. (dark). Place) and in a constant temperature bath (dark place) at 60 ° C., and stored for 1 week.

After 1 week, the temperature was returned to room temperature, the properties of the emulsion were visually confirmed, and the storage stability (storage at 50 ° C. for 1 week, storage at 60 ° C. for 1 week) was evaluated based on the following criteria.

[Evaluation criteria]
⊚: No separation is observed ○: Almost no separation is observed Δ: Slight separation is observed ×: Clear separation (aqueous phase is 1/4 or more of the whole) is observed.

The results are shown in Table 1 along with the formulation.

The ethanol-free emulsion (Reference Example 1) did not separate and was stable under any storage conditions, but it was confirmed that the addition of ethanol to the emulsion made the emulsification unstable and separated it (Reference Example 1). Comparative example 3). The emulsification instability due to the ethanol blending is based on the formulation of Comparative Example 3, removal of monoterpenes and polyhydric alcohols (Comparative Example 1), removal of monoterpenes (Comparative Example 2), removal of monoterpenes, and ethanol blending amount. (Comparative Example 4), and the removal of monoterpenes and the formulation of diclofenac Na (Comparative Example 5) did not improve the situation. Further, when the monoterpene and the polyhydric alcohol were removed and a thickener was added instead, a slight improvement was observed, but it was not sufficient (Comparative Example 6). On the other hand, it was confirmed that by blending the thickener and the monoterpene, the emulsification was stabilized without separation under any storage conditions (Examples 1 to 3). In addition to the thickener and monoterpene, polyhydric alcohol and / or diclofenac Na is blended, and especially by blending both polyhydric alcohol and diclofenac Na, emulsification is further stabilized and relatively severe. It was confirmed that the separation was suppressed even when stored under the conditions (Examples 4 to 13, especially Examples 6 to 13). From these facts, the liquid to semi-solid oil-in-water emulsified cream agent (Examples 1 to 13) containing a lower alcohol such as ethanol is stabilized in emulsification by blending a thickener and a monoterpene. It was confirmed that it did not separate even after long-term storage. In addition, when an oil-in-water emulsified cream containing diclofenac Na was applied to the shoulders, it was confirmed that both had a cool feeling and a pain-relieving effect on stiff shoulders (anti-inflammatory and analgesic effect).

Experimental Example 2
Oil-in-water emulsified creams (Examples 14 to 24) having the formulations shown in Table 2 were prepared. Specifically, an aqueous phase and an oil phase are prepared respectively, and these are mixed at 80 ° C. to obtain an oil-in-water emulsion, and then a lower alcohol (absolute ethanol or isopropanol) in which felbinac or diclofenac sodium is dissolved is added. Gradually added and mixed completely uniformly. An appropriate amount of potassium hydroxide solution was added to the obtained emulsion to adjust the pH to 7 to 8, and then purified water was added to finally make the total amount 100% by weight. The obtained liquid to semi-solid oil-in-water emulsified cream was filled in a polyethylene container having a capacity of 50 ml and stored in a constant temperature bath (dark place) at 4 ° C.

The above cream was stable in emulsification without separation even after storage for 1 month (evaluation: ⊚). Moreover, when it was applied to the shoulder, it was confirmed that it had a cool feeling and a pain-relieving effect of stiff shoulder (anti-inflammatory and analgesic effect).

Claims (3)

Oil-in-water emulsified compositions in the form of lotions, creams, or emulsions containing 3-30% by weight of lower alcohols, monoterpenes , thickeners , and polyhydric alcohols (excluding the following compositions:
A skin external preparation containing a xanthine derivative and one or more oils selected from the group consisting of isostearyl alcohol, diisopropyl sebacate and alkylene polyglycol dineopenate ;
Dichloride Fe diclofenac sodium, ethanol, menthol, polysorbate 80, glycerol, soybean oil, nanogel compositions containing methyl salicylate, water, and carbomer; and
Nanoemulsion composition containing diclofenac sodium, ethanol, menthol, polysorbate 80, glycerol, soybean oil, methyl salicylate, and water ). The oil-in-water emulsified composition according to claim 1, further containing diclofenac or a salt thereof. The oil-in-water emulsified composition according to claim 1 or 2 , which is an oil-in-water emulsified skin external preparation.