JP7499023B2 - External Composition - Google Patents

Description

The present invention relates to a composition for external use that contains ufenamate and vitamin A and has improved mixability between the aqueous phase and the oil phase.

Ufenamate is used as a medicinal nonsteroidal anti-inflammatory agent to treat skin diseases. Retinol and its derivatives (vitamins A) are used in topical compositions as skin activators. However, because both ufenamate and vitamins A are poorly water-soluble, it is difficult to stably incorporate these ingredients into formulations of topical medicines that contain water.

In response to this, a technique has been proposed for stably incorporating poorly water-soluble ingredients into a topical composition. For example, Patent Document 1 describes that an emulsion composition containing at least one functional oil component selected from the group consisting of glycyrrhetinic acid derivatives, fat-soluble vitamins other than vitamin E, and carotenoids, vitamin E, a specific acyl glutamic acid ester, and a polyhydric alcohol whose content relative to the total weight of the emulsion composition is 30% to 50% by weight has excellent emulsion stability.

Patent Document 2 also describes that an emulsion containing a fat-soluble functional component, which contains a fat-soluble functional component solution obtained by dissolving a fat-soluble functional component with a melting point of 20°C or higher in an emulsifier, enzymatically decomposed lecithin, a polyglycerol fatty acid ester, a polyol, and water, has excellent emulsion stability.

Patent Document 3 also describes that a medicinal emulsion preparation for topical skin application, which contains (a) ufenamate, (b) glycerin fatty acid monoester, and (c) polyoxyethylene (2-50 moles added) alkyl ether in a ratio of component (b)/component (c) = 0.1-1.3 (mass ratio), can stably incorporate ufenamate, and further describes that vitamin A oil and/or tocopherol acetate may be incorporated into this medicinal emulsion preparation for topical skin application.

JP 2017-105856 A JP 2019-180381 A JP 2011-219369 A

Although topical preparations containing poorly water-soluble ingredients to date have been advertised as having stabilizing effects, the aqueous and oil phases themselves are essentially immiscible, and so they have no choice but to rely on surfactants to create a dispersion system. In fact, if no surfactant is used, the aqueous and oil phases are very difficult to mix.

If a combination of water and oil phases that are easily mixed with each other can be found, not only can an excellent dispersion system be constructed without using a surfactant, but it is believed that even better emulsion stability can be obtained by using a surfactant as well.

The present invention aims to provide a composition for external use that contains ufenamate and vitamin A, while also containing a combination of an aqueous phase and an oil phase that are easily mixed with each other.

The inventors conducted extensive research into aqueous compositions for topical use that contain ufenamate and vitamin A and unexpectedly discovered that by incorporating isopropyl palmitate, an excellent dispersion system can be constructed without the use of a surfactant. The present invention was completed through further research based on this finding.

That is, the present invention provides the following aspects.
Item 1. A composition for external use comprising (A) ufenamate, (B) retinol and/or a retinol derivative, (C) isopropyl palmitate, and (D) water.
Item 2. The composition for external use according to Item 1, wherein the component (C) is contained in an amount of 0.1 part by weight or more per 1 part by weight of the component (A).
Item 3. The composition for external use according to item 1 or 2, wherein the component (C) is contained in an amount of 0.01 g or more per 10,000 I.U. of the component (B).
Item 4. The composition for external use according to any one of Items 1 to 3, wherein the content of the component (D) is 60% by weight or more.
Item 5. The composition for external use according to any one of Items 1 to 4, wherein the content of the surfactant is 0.1% by weight or less.
Item 6. A method for dispersing a composition for external use comprising (A) ufenamate, (B) retinol and/or a retinol derivative, and (D) water, comprising blending (C) isopropyl palmitate.

According to the present invention, it is possible to provide a combination of an aqueous phase and an oil phase that are easily mixed together, for use in a topical composition containing ufenamate and vitamin A. As a result, the aqueous phase and the oil phase of the topical composition of the present invention are easily mixed, and an excellent dispersion system can be constructed (hereinafter, such an effect is also referred to as a dispersion effect).

1. Topical Composition The topical composition of the present invention is characterized by containing (A) ufenamate (hereinafter also referred to as "component (A)"), (B) retinol and/or a derivative of retinol (hereinafter also referred to as "component (B)"), (C) isopropyl palmitate (hereinafter also referred to as "component (C)"), and (D) water (hereinafter also referred to as "component (D)"). The topical composition of the present invention will be described in detail below.

(A) Ufenamate The topical composition of the present invention contains ufenamate as component (A). Ufenamate is also known as butyl flufenamate, and is a known component as a poorly water-soluble nonsteroidal anti-inflammatory drug. The aqueous phase and oil phase used in the topical composition containing ufenamate are very difficult to mix, but the aqueous phase and oil phase of the topical composition of the present invention are easily mixed, and an excellent dispersion system can be constructed.

The content of component (A) in the topical composition of the present invention is not particularly limited and is set appropriately depending on the efficacy to be imparted, but may be, for example, 1 to 20% by weight, preferably 2 to 10% by weight, and more preferably 3 to 7% by weight.

(B) Retinol and/or its derivatives The topical composition of the present invention contains retinol and/or its derivatives as component (B). Retinol and/or its derivatives are poorly soluble in water and are known as skin protection components, agents for improving or preventing wrinkles, and acne treatments. The aqueous phase and oil phase used in topical compositions containing retinol and/or its derivatives are very difficult to mix, but the aqueous phase and oil phase of the topical composition of the present invention are easily mixed, and an excellent dispersion system can be constructed.

Retinol is a type of vitamin A and is sometimes called vitamin A alcohol.

A retinol derivative is a component that has the same skeleton as retinol and is obtained by adding a substituent to retinol. There are no particular limitations on the type of retinol derivative, so long as it is pharmacologic acceptable, but examples include esters of retinol and fatty acids, esters of retinol and acetic acid (i.e., retinol acetate), oxides of retinol, and esters of the oxides.

Specific examples of esters of retinol and fatty acids include esters of retinol and fatty acids having 4 to 30 carbon atoms, preferably 10 to 18 carbon atoms. More specific examples of esters of retinol and fatty acids include retinol acetate, retinol propionate, retinol butyrate, retinol octylate, retinol laurate, retinol palmitate, retinol stearate, retinol myristicate, retinol oleate, retinol linolenate, retinol linoleate, and the like. These esters of retinol and fatty acids may be used alone or in combination of two or more.

Specific examples of retinol oxides include retinoic acid (sometimes called "tretinoin"), retinal, etc. These retinol oxides may be used alone or in combination of two or more.

Specific examples of retinol oxide esters include methyl retinoate, ethyl retinoate, retinol retinoate, and tocopherol retinoate (tocopherol may be any of α, β, γ, or δ). These retinol oxide esters may be used alone or in combination of two or more.

These retinols and/or derivatives are not particularly limited in terms of raw materials, manufacturing method, purification method, etc., and may be those isolated and purified from animals, etc., or commercially available products. Examples of commercially available retinol or its derivatives include products manufactured or sold by Riken Vitamin Co., Ltd., DSM Nutrition Japan, Inc., Xiaohua Pharmaceutical Co., Ltd., BASF Japan Ltd., etc.

In the emulsion composition of the present invention, one type of retinol or its derivatives may be selected and used, or two or more types may be used in combination.

Among retinol and its derivatives, preferred are retinol derivatives, more preferred are esters of retinol and fatty acids, and particularly preferred are retinol palmitate esters.

In the present invention, retinol and/or its derivatives may be used in a state dissolved in oil such as vegetable oil. Such a solution of retinol and/or its derivatives in oil is known as "vitamin A oil". Vitamin A oil can be produced, for example, according to the method described in the Japanese Pharmacopoeia. Vitamin A oil that generally contains 100,000 to 2,000,000 IU/g of retinol and/or its derivatives, preferably 500,000 to 1,700,000 IU/g, and more preferably 500,000 to 1,000,000 IU/g, can be used. In this specification, the unit "IU" for the content of retinol and/or its derivatives indicates the international unit.

The content of component (B) in the topical composition of the present invention is not particularly limited, but for example, the total amount of retinol and/or its derivatives per 100 g of the topical composition of the present invention is 1,000 to 10,000,000 IU, preferably 10,000 to 5,000,000 IU, more preferably 100,000 to 3,000,000 IU, even more preferably 300,000 to 1,000,000 IU, and particularly preferably 500,000 to 700,000 IU.

When vitamin A oil is used as component (B), the content of vitamin A oil in the topical composition of the present invention may be set so that the content of retinol and/or its derivatives in the topical composition of the present invention satisfies the above-mentioned content depending on the content of retinol and/or its derivatives in the vitamin A oil. Specifically, when vitamin A oil containing 1 million I.U./g of retinol and/or its derivatives is used, the content of vitamin A oil in the topical composition of the present invention may be set to 0.001 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.1 to 3% by weight, even more preferably 0.3 to 1% by weight, and particularly preferably 0.5 to 7% by weight.

In the topical composition of the present invention, the ratio of component (A) to component (B) is determined by the content of each of the above components, but preferably the total amount of retinol and/or its derivatives per 1 g of component (A) is 25,000 to 500,000 I.U., more preferably 50,000 to 250,000 I.U., even more preferably 70,000 to 170,000 I.U., and even more preferably 80,000 to 120,000 I.U.

When vitamin A oil is used as component (B), and the vitamin A oil contains 1,000,000 I.U./g of retinol and/or its derivatives, the content of vitamin A oil per part by weight of component (A) is 0.025 to 0.5 parts by weight, preferably 0.05 to 0.25 parts by weight, more preferably 0.07 to 0.17 parts by weight, and even more preferably 0.8 to 0.12 parts by weight.

(C) Isopropyl palmitate The topical composition of the present invention contains isopropyl palmitate as component (C). The aqueous phase and oil phase used in a topical composition containing ufenamate and retinol and/or its derivatives are very difficult to mix, but the topical composition of the present invention contains isopropyl palmitate, which makes the aqueous phase and oil phase more easily mixable, thereby enabling the construction of an excellent dispersion system.

The content of component (C) in the topical composition of the present invention is not particularly limited and is set appropriately depending on the dispersion effect to be imparted, and may be, for example, 0.1% by weight or more. From the viewpoint of obtaining a more preferable dispersion effect, it is preferably 0.5% by weight or more, more preferably 1% by weight or more, and even more preferably 5% by weight or more. The upper limit of the range of the content of component (C) is not particularly limited, and may be, for example, 10% by weight or less, preferably 8% by weight or less, and more preferably 6% by weight or less.

In the topical composition of the present invention, the ratio of the content of the (C) component to the content of the (A) component is determined by the content of each of the above components, but from the viewpoint of obtaining a more preferable dispersion effect, the content of the (C) component per 1 part by weight of the (A) component is 0.1 parts by weight or more, preferably 0.2 parts by weight or more, and more preferably 1 part by weight or more. The upper limit of the range of the content of the (C) component per 1 part by weight of the (A) component is not particularly limited, but examples thereof include 2 parts by weight or less, preferably 1.6 parts by weight or less, and more preferably 1.2 parts by weight or less.

In the topical composition of the present invention, the ratio of the content of the (C) component to the content of the (B) component is determined by the content of each of the above components, but from the viewpoint of obtaining a more favorable dispersion effect, the content of the (C) component per 10,000 I.U. of the (B) component is 0.01 g or more, preferably 0.02 g or more, and more preferably 0.1 g or more. The upper limit of the range of the content of the (C) component per 10,000 I.U. of the (B) component is not particularly limited, but examples thereof include 0.2 g or less, preferably 0.16 g or less, and more preferably 0.12 g or less.

When vitamin A oil is used as component (B), the ratio of the content of component (C) to the content of component (B) is determined by the content of each of the above components, but from the viewpoint of obtaining a more favorable dispersion effect, the content of component (C) per part by weight of component (B) is 1 part by weight or more, preferably 2 parts by weight or more, and more preferably 10 parts by weight or more. There is no particular upper limit to the range of the content of component (C) per part by weight of component (B), but examples include 20 parts by weight or less, preferably 16 parts by weight or less, and more preferably 12 parts by weight or less.

The topical composition of the present invention contains water as component (D). The aqueous phase used in topical compositions containing ufenamate and retinol and/or a retinol derivative is very poorly mixed with the oil phase, but the aqueous phase of the topical composition of the present invention is easily mixed with the oil phase, making it possible to form an excellent dispersion system.

The content of component (D) in the topical composition of the present invention is not particularly limited and is set appropriately depending on the formulation form, etc., but can be, for example, 60% by weight or more. Since the topical composition of the present invention has an excellent dispersion effect, even if the content of component (D) is large, the dispersion effect can be effectively obtained. From this perspective, suitable examples of the content of component (D) are preferably 65% by weight or more, more preferably 70% by weight or more, even more preferably 75% by weight or more, even more preferably 80% by weight or more, and particularly preferably 85% by weight or more.

The upper limit of the range of the content of component (D) is not particularly limited, but from the viewpoint of obtaining an even more excellent dispersion effect, it is 96% by weight or less, preferably 94% by weight or less, and more preferably 90% by weight or less.

In the topical composition of the present invention, the ratio of the content of the (D) component to the content of the (C) component is determined by the content of each of the above components, but for example, the content of the (D) component per 1 part by weight of the (C) component may be, for example, 10 parts by weight or more. Since the topical composition of the present invention has an excellent dispersion effect, even if the content ratio of the (D) component is high, the dispersion effect can be effectively obtained. From this perspective, a suitable example of the content of the (D) component per 1 part by weight of the (C) component is preferably 12 parts by weight or more, more preferably 14 parts by weight or more, and even more preferably 17 parts by weight or more.

The upper limit of the range of the content of component (D) per part by weight of component (C) is not particularly limited, but from the viewpoint of obtaining an even more excellent dispersion effect, the content is 190 parts by weight or less, preferably 95 parts by weight or less, and more preferably 18 parts by weight or less.

In the topical composition of the present invention, the ratio of the content of the (D) component to the total amount of the oily base is determined by the content of each of the above components, but for example, the content of the (D) component to 1 part by weight of the total amount of the oily base can be, for example, 10 parts by weight or more. Since the topical composition of the present invention has an excellent dispersion effect, even if the content ratio of the (D) component is high, the dispersion effect can be effectively obtained. From this perspective, suitable examples of the content of the (D) component to 1 part by weight of the total amount of the oily base include preferably 12 parts by weight or more, more preferably 14 parts by weight or more, and even more preferably 17 parts by weight or more.

The upper limit of the range of the content of component (D) per 1 part by weight of the total amount of the oil base is not particularly limited, but from the viewpoint of obtaining an even more excellent dispersion effect, it is preferably 190 parts by weight or less, preferably 95 parts by weight or less, and more preferably 18 parts by weight or less.

Other components In addition to the above-mentioned components, the composition for external use of the present invention may contain other additives that are commonly used as necessary. Such additives include, for example, oil bases other than component (C) (hereinafter also referred to as other oil bases), surfactants, polyhydric alcohols, thickeners, pH regulators, buffers, solubilizers, chelating agents, preservatives, preservatives, antioxidants, stabilizers, fragrances, colorants, etc.

Other oily bases are not particularly limited as long as they are pharma- ceutically or cosmetically acceptable, but examples include liquid oils other than component (C) (oils that are liquid at 25°C), solid oils (oils that are liquid at 25°C), higher alcohols, etc. These oils may be used alone or in combination of two or more.

The topical composition of the present invention has an excellent dispersing effect, and therefore, even without a surfactant, the composition can effectively obtain the dispersing effect. In a preferred embodiment, the composition does not contain a surfactant. However, the topical composition of the present invention may further contain a surfactant. By including a surfactant, the dispersed state can be further stabilized.

The surfactant is not particularly limited as long as it is pharma- ceutically or cosmetically acceptable, but examples thereof include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. These surfactants may be used alone or in combination of two or more.

The content of the surfactant in the topical composition of the present invention is not particularly limited, and may be in an amount similar to that contained in a typical ufenamate topical composition. On the other hand, since the topical composition of the present invention has an excellent dispersing effect, it is possible to effectively obtain the dispersing effect without containing a surfactant, and therefore the amount of the surfactant can be reduced compared to the amount contained in a typical ufenamate topical composition. From this perspective, suitable examples of the surfactant content include preferably 0.1% by weight or less, more preferably 0.01% by weight or less, even more preferably 0.001% by weight or less, and even more preferably 0.0005% by weight or less.

Furthermore, in addition to the above-mentioned components, the topical composition of the present invention may contain, as necessary, medicinal ingredients capable of exerting pharmaceutical or cosmetic physiological functions. Examples of such medicinal ingredients include steroids (dexamethasone, dexamethasone hydrochloride, dexamethasone acetate, hydrocortisone hydrochloride, prednisolone valerate, prednisolone acetate, etc.), antihistamines (diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), local anesthetics (lidocaine, dibucaine, procaine, tetracaine, bupivacaine, mepivacaine, chloroprocaine, proparacaine, meprylcaine, or salts thereof), alkyl benzoates (e.g., ethyl aminobenzoate, diethylaminoethyl p-butylaminobenzoate hydrochloride), orthocaine, oxethazaine, oxypolyethyleneoxydecane, scolymus extract, percaminpase, tesit decitin, etc.), anti-inflammatory agents (allantoin, salicylic acid, benzoic ... citric acid, glycol salicylate, methyl salicylate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), bactericides (isopropylmethylphenol, benzalkonium chloride, dequalinium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents (crotamiton, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting components (vanillylamide nonylate, benzyl nicotinate, capsaicin, chili pepper extract, etc.), vitamins (vitamins B, C, D, E, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, hyaluronic acid, etc.), etc. These medicinal components may be used alone or in combination of two or more. Furthermore, when these medicinal ingredients are contained in the topical composition of the present invention, the content may be appropriately set depending on the type of medicinal ingredient used, the desired effect, etc.

Formulation form and use The formulation form that the topical composition of the present invention can take is not particularly limited as long as it contains an aqueous phase and an oil phase, and examples thereof include oil-in-water dispersion type (not emulsion type), water-in-oil dispersion type (not emulsion type), oil-in-water emulsion type, and water-in-oil emulsion type. The topical composition of the present invention has excellent dispersion effect, so that even if the formulation contains a large amount of water, the dispersion effect can be effectively obtained. From this point of view, preferred examples of the formulation form that the topical composition of the present invention can take include oil-in-water dispersion type (not emulsion type) and oil-in-water emulsion type. Furthermore, since the topical composition of the present invention has excellent dispersion effect, the dispersion effect can be effectively obtained even without containing a surfactant. From this point of view, preferred examples of the formulation form that the topical composition of the present invention can take include oil-in-water dispersion type (not emulsion type).

The topical composition of the present invention can be used as a topical agent such as a cosmetic, topical quasi-drug, or topical medicine. The product form of the topical composition of the present invention is not particularly limited, but examples include lotions, creams, ointments, emulsions, gels, oils, liniments, and aerosols.

The external composition of the present invention can be manufactured according to the known method of formulation of external compositions according to the preparation form.For example, the method of manufacturing the external composition of the present invention includes the method of dividing the components to be contained into water-soluble components and oily components, preparing the aqueous phase containing the water-soluble components and the oily phase containing the oily components, and formulating them by known dispersion method.

2. Dispersion Method As described above, isopropyl palmitate disperses a topical composition having ufenamate, retinol and/or a derivative of retinol, and water. Therefore, the present invention further provides a method for dispersing a topical composition having (A) ufenamate, (B) retinol and/or a derivative of retinol, and (D) water, by blending (C) isopropyl palmitate.

In the dispersion method of the present invention, dispersion refers to the fact that the aqueous phase and oil phase used in the topical composition are stirred under conditions in which no surfactant is added, and that the dispersed state is maintained even after standing. Dispersed state means that at least most (meaning slight separation is allowed) is dispersed, preferably means a state in which no separation is observed and visible droplets (diameter 0.1 to 1.0 mm) are dispersed, and more preferably means a state in which no separation is observed and tiny droplets (diameter less than 0.1 mm) that cannot be seen with the naked eye are dispersed.

In the dispersion method of the present invention, the type and content of each component used, the type and content of components blended in the topical composition, and the formulation form are the same as those in "1. Topical composition" above.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these.

Test Example : Prepare the external use composition (oil-in-water dispersion) shown in Tables 2 and 3. Specifically, mix ufenamate and vitamin A oil until uniform to obtain oily liquid, add other components to oily liquid and mix until uniform, add purified water to total 100% by weight, and stir until uniform.In the following criteria, separation refers to the phenomenon that at least a part of the dispersed droplets (oil droplets) cannot be dispersed and sink to the bottom, and among them, the phenomenon that all droplets (oil droplets) sink to the bottom is called the completely separated state.In addition, the representative photographs of each evaluation criteria are shown in Table 1, and the evaluation results are shown in Tables 2 and 3.

The prepared topical compositions were left to stand at room temperature for 10 minutes, after which the dispersion state was evaluated based on the following criteria.

⊚: No separation was observed, and minute droplets (oil droplets) that cannot be seen with the naked eye were dispersed.
○: No separation was observed, and visible droplets (oil droplets) were dispersed.
Δ: Only slight separation occurred, and the dispersed state of the droplets (oil droplets) was maintained.
×: The degree of separation is large, and the dispersion state of the droplets (oil droplets) is hardly maintained.
XX: Completely separated.

As shown in Comparative Example 1, in the topical composition containing ufenamate and vitamin A oil, the oil phase consisting of ufenamate and vitamin A oil does not mix with the aqueous phase. In contrast, as shown in Examples 1 to 4, excellent dispersibility was obtained by adding isopropyl palmitate. In addition, as shown in Comparative Examples 2 to 6, when isopropyl adipate, diethyl sebacate, glyceryl tri-2-ethylhexanoate, isopropyl myristate, and cetyl ethylhexanoate, which are polar oils similar to isopropyl palmitate, were used, no dispersing effect was obtained. Furthermore, as shown in Comparative Examples 7 and 8, when only one of ufenamate and vitamin A oil was included, no dispersing effect was obtained even when isopropyl palmitate was used. In other words, it was found that the dispersing effect observed in Examples 1 to 4 is a unique effect of the combination of ufenamate and vitamin A oil with isopropyl palmitate.

Claims (7)

A topical composition comprising (A) ufenamate, (B) an ester of retinol and a fatty acid , (C) isopropyl palmitate, and (D) water. The topical composition according to claim 1, wherein the (C) component is contained in an amount of 0.1 part by weight or more per 1 part by weight of the (A) component. The topical composition according to claim 1 or 2, wherein the component (C) is contained in an amount of 0.01 g or more per 10,000 I.U. of the component (B). The composition for external use according to any one of claims 1 to 3, wherein the content of component (D) is 60% by weight or more. The composition for external use according to any one of claims 1 to 4, wherein the surfactant content is 0.1% by weight or less. The composition for external use according to any one of claims 1 to 5, wherein the component (B) is at least one selected from the group consisting of retinol palmitate and retinol acetate. A method for dispersing an external composition comprising (A) ufenamate, (B) an ester of retinol and a fatty acid , and (D) water, comprising blending (C) isopropyl palmitate therein.