JP7730636B2 - External emulsion composition - Google Patents

Description

The present invention relates to an emulsion composition containing tocopherol and/or its derivatives and having excellent emulsion stability.

Topical emulsion compositions can contain both aqueous and oily components, making them suitable for a variety of formulations. They also offer excellent compatibility with the skin, ease of application, and a pleasant feel when used, making them widely used in the field of topical preparations.

On the other hand, tocopherol and its derivatives have antioxidant, immunostimulating, and circulation-promoting effects, and are widely used in topical preparations. However, when tocopherol or its derivatives are incorporated into an emulsion composition, separation of the oil and water phases (phase separation) easily occurs during storage, making it difficult to maintain a stable emulsion state.

Therefore, various formulation technologies have been investigated to improve emulsion stability in emulsion compositions containing tocopherol and/or its derivatives. For example, Patent Document 1 describes that the emulsifying properties of emulsion compositions can be improved by using a tocopherol aminoalkyl carboxylic acid ester and/or a salt thereof having a substituent on the nitrogen atom as a tocopherol derivative. However, the technology in Patent Document 1 has the disadvantage that it can only be applied to specific tocopherol derivatives and cannot be applied to commonly used tocopherol derivatives such as tocopherol acetate.

Japanese Patent Application Laid-Open No. 2004-2278

The object of the present invention is to provide an emulsion composition for external use that contains tocopherol and/or its derivatives and has excellent emulsion stability.

The inventors conducted extensive research to solve the above-mentioned problems and discovered that an external emulsion composition can be endowed with excellent emulsion stability by incorporating ufenamate together with tocopherol and/or its derivatives, without including allantoin. The present invention was completed through further research based on this finding.

That is, the present invention provides the following aspects.
Item 1. An emulsion composition for external use containing (A) tocopherol and/or a derivative thereof, and (B) ufenamate, and not containing (C) allantoin.
Item 2. The emulsion composition for external use according to Item 1, further comprising (C) a monoterpene.

The topical emulsion composition of the present invention, while containing tocopherol and/or its derivatives, is able to suppress phase separation during storage and has excellent emulsion stability.

1. Topical Emulsion Composition The topical emulsion composition of the present invention is characterized by containing (A) tocopherol and/or a derivative thereof, and (B) ufenamate, but not containing (C) allantoin. The topical emulsion composition of the present invention is described in detail below.

[(A) Tocopherol and/or its derivative]
The emulsion composition for external use of the present invention contains tocopherol and/or a derivative thereof (sometimes referred to as component (A)).

Tocopherol is a well-known component known as vitamin E. Tocopherol derivatives are not particularly limited as long as they are pharmaceutically acceptable, but examples include esters with carboxylic acids such as acetic acid, nicotinic acid, and succinic acid, and diesters with phosphoric acid. Tocopherol derivatives may be in the d-, l-, or dl-form, with the dl-form being preferred. Tocopherol derivatives may be in the α-, β-, γ-, or δ-form, with the α-form being preferred.

In the topical emulsion composition of the present invention, one type of tocopherol and its derivatives may be selected and used alone as component (A), or two or more types may be used in combination.

Among component (A), tocopherol derivatives are preferred, tocopherol esters with carboxylic acids are more preferred, tocopherol acetate is even more preferred, and d-α-tocopherol acetate, l-α-tocopherol acetate, and dl-α-tocopherol acetate are particularly preferred.

The content of component (A) in the topical emulsion composition of the present invention is not particularly limited, but may be, for example, 0.01 to 15% by weight, preferably 0.01 to 10% by weight, more preferably 0.1 to 5% by weight, and even more preferably 1 to 5% by weight.

[(B) Ufenamart]
The topical emulsion composition of the present invention contains ufenamate (sometimes referred to as component (B)). By allowing tocopherol and/or a derivative thereof and ufenamate to coexist in the topical emulsion composition of the present invention, emulsion destabilization caused by tocopherol and/or a derivative thereof can be suppressed, thereby providing excellent emulsion stability.

Ufenamate, also known as butyl flufenamate, is a known lipid-soluble nonsteroidal anti-inflammatory drug.

The content of component (B) in the topical emulsion composition of the present invention is, for example, 1 to 20% by weight, and from the viewpoint of further improving emulsion stability, it is preferably 2 to 10% by weight, and more preferably 3 to 7% by weight. From the viewpoint of further improving emulsion stability, the content of component (B) in the topical emulsion composition of the present invention is even more preferably 5 to 7% by weight, and particularly preferably 5% by weight.

In the topical emulsion composition of the present invention, the ratio of component (B) to component (A) is determined depending on the content of each of these components, but for example, the ratio of component (B) is 0.01 to 100 parts by weight, preferably 0.1 to 10 parts by weight, and more preferably 0.2 to 5 parts by weight per part by weight of component (A).

[(C) Allantoin]
The topical emulsion composition of the present invention does not contain allantoin (sometimes referred to as component (C)). The topical emulsion composition of the present invention can improve emulsion stability by containing tocopherol and/or a derivative thereof and ufenamate, but even if these components are contained, the emulsion stabilizing effect of the present invention is impaired when allantoin is contained.

[(D) Monoterpene]
The topical emulsion composition of the present invention may further contain a monoterpene (sometimes referred to as component (D)). When tocopherol and/or a derivative thereof coexists with a monoterpene in the absence of ufenamate, emulsion stability is significantly reduced. However, the topical emulsion composition of the present invention can maintain excellent emulsion stability even when it contains a monoterpene.

Monoterpenes are known compounds with a structure containing two isoprene units within the molecule, and have cooling and refreshing properties.

The type of monoterpene used in the present invention is not particularly limited, as long as it is pharmaceutically acceptable. Examples include alcohol-based monoterpenes such as menthol, thymol, geraniol, linalool, borneol, cineole, and terpineol; aldehyde-based monoterpenes such as citral, citronellal, perillaldehyde, and safranal; and ketone-based monoterpenes such as camphor, menthone, carbomenthone, and ionone. When optical isomers exist, these monoterpenes may be in the d-, l-, or dl-form. These monoterpenes may be used alone or in combination of two or more.

In addition, in the present invention, essential oils containing monoterpenes may be used as monoterpenes. Essential oils containing monoterpenes can be appropriately selected from known essential oils, but examples of essential oils containing menthol include peppermint oil, peppermint oil, and spearmint oil. Note that, when using essential oils containing monoterpenes, descriptions of the content and ratio of monoterpenes in this specification are values converted into the amount of monoterpenes contained in the essential oil.

Of these monoterpenes, menthol is preferred, and l-menthol is even more preferred, from the perspective of further improving emulsion stability.

When component (D) is contained in the topical emulsion composition of the present invention, its content is not particularly limited, but may be, for example, 0.01 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.1 to 5% by weight, and even more preferably 0.2 to 5% by weight, of the total amount of component (D).

When the topical emulsion composition of the present invention contains component (D), the ratio of component (D) to component (A) is determined depending on the respective contents of components (A) and (D), but may be, for example, 0.001 to 20 parts by weight, preferably 0.01 to 10 parts by weight, and more preferably 0.05 to 5 parts by weight of component (D) per 1 part by weight of component (A).

[Polyhydric alcohol]
The emulsion composition for external use of the present invention may contain a polyhydric alcohol, if necessary. The polyhydric alcohol used in the present invention is not particularly limited, as long as it is applicable to the skin, and examples thereof include 1,3-butylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, and glycerin.

Among polyhydric alcohols, 1,3-butylene glycol and glycerin are preferred. These polyhydric alcohols may be used alone or in combination of two or more.

When a polyhydric alcohol is contained in the emulsion composition for external use of the present invention, the content is not particularly limited, but may be, for example, 0.1 to 40% by weight, preferably 1 to 30% by weight, and more preferably 5 to 25% by weight, of the total amount of polyhydric alcohol.

[Thickener]
The topical emulsion composition of the present invention may contain a thickener as needed. The thickener used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include cellulose-based thickeners, polyvinyl-based thickeners, thickening polysaccharides, and acrylic acid-based thickeners. These thickeners may be used alone or in combination of two or more. Among these thickeners, polyvinyl-based thickeners are preferred.

Specific examples of polyvinyl thickeners include carboxyvinyl polymer, polyvinylpyrrolidone, and polyvinyl alcohol. Of these thickeners, polyvinyl alcohol is preferred, and carboxyvinyl polymer is more preferred.

When a thickener is contained in the emulsion composition for external use of the present invention, the content thereof is not particularly limited, but may be, for example, 0.0001 to 5% by weight, preferably 0.001 to 2% by weight, and more preferably 0.01 to 1% by weight, in terms of the total amount of thickener.

[Oil base]
The emulsion composition for external use of the present invention contains an oily base as a base component forming an oil phase. The oily base used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include hydrocarbon oils, vegetable oils, animal oils, cholesterol, fatty acid alkyl esters, fatty acids, higher alcohols, silicone oils, etc.

These oily bases may be used alone or in combination of two or more. Of these oily bases, hydrocarbon oils are preferred.

Hydrocarbon oils are not particularly limited as long as they are pharmaceutically acceptable, but examples include liquid paraffin, α-olefin oligomers, and petrolatum. Of these hydrocarbon oils, liquid paraffin is preferred.

The content of the oily base in the topical emulsion composition of the present invention may be set appropriately depending on the emulsion type, formulation form, etc., but may be, for example, 1 to 80% by weight, preferably 2 to 65% by weight, and more preferably 5 to 25% by weight, of the total amount of oily base.

[Aqueous base]
The emulsified composition for external use of the present invention contains water as a base component that forms an aqueous phase. The content of water in the emulsified composition for external use of the present invention may be appropriately determined depending on the emulsion type, formulation form, etc., and may be, for example, 20 to 97% by weight, preferably 35 to 90% by weight, and more preferably 40 to 80% by weight.

[Surfactant]
The emulsified composition for external use of the present invention preferably contains a surfactant to prepare it into an emulsified form. The type of surfactant used in the present invention may be appropriately selected depending on the type of emulsion, but a nonionic surfactant is preferred.

The nonionic surfactant used in the present invention may be selected appropriately depending on the emulsification type, but polyoxyethylene sorbitan fatty acid esters are preferred. Specific examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tristearate, and polyoxyethylene sorbitan monolaurate. Of these nonionic surfactants, polyoxyethylene sorbitan monooleate is preferred. These nonionic surfactants may be used alone or in combination of two or more.

The content of surfactant in the topical emulsion composition of the present invention may be set appropriately depending on the emulsion type, the type of surfactant used, etc., but may be, for example, 0.1 to 20% by weight, preferably 1 to 15% by weight, and more preferably 1 to 10% by weight.

[Other ingredients]
In addition to the above-mentioned components, the emulsion composition for external use of the present invention may contain other commonly used additives as needed. Examples of such additives include pH adjusters, buffers, solubilizers, antiseptics, preservatives, antioxidants, stabilizers, fragrances, colorants, etc. When these additives are contained in the emulsion composition for external use of the present invention, the content thereof may be appropriately determined depending on the type of additive used, etc.

The topical emulsion composition of the present invention may contain pharmacological ingredients in addition to the ingredients described above. Examples of such pharmacological ingredients include antihistamines, local anesthetics, anti-inflammatory agents (other than component (B)), moisturizers, disinfectants, antibacterial agents, antipruritics, skin protectants, blood circulation promoters, and vitamins (other than component (A)). These pharmacological ingredients may be used alone or in combination of two or more. Furthermore, when these pharmacological ingredients are contained in the topical emulsion composition of the present invention, their concentrations may be appropriately determined depending on the type of pharmacological ingredient used, the desired effect, etc.

[Emulsion type/formulation]
The emulsion type of the external emulsified composition of the present invention may be either an oil-in-water type or a water-in-oil type, but is preferably an oil-in-water type.

The formulation of the topical emulsion composition of the present invention is not particularly limited, but examples include topical pharmaceuticals such as creams, emulsions, lotions, liniments, and aerosols. Of these, creams are preferred.

[Manufacturing method]
The emulsion composition for external use of the present invention can be produced according to a known formulation method for emulsion preparations depending on the emulsion type. For example, a method for producing the emulsion composition for external use of the present invention includes separating the components to be contained into water-soluble components and oily components, preparing an aqueous phase containing the water-soluble components and an oily phase containing the oily components, and emulsifying them according to a known method.

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

Test Example 1
An external emulsion composition (oil-in-water cream) having the composition shown in Table 1 was prepared by the following method. Specifically, first, predetermined amounts of the oil phase components, l-menthol, ufenamate, and dl-α-tocopherol acetate shown in Table 1 were mixed and dissolved at a temperature of 70 to 80°C to prepare an oil phase composition. Separately, predetermined amounts of the aqueous phase components and allantoin shown in Table 1 were mixed to prepare an aqueous phase composition. Next, the oil phase composition heated to 70 to 80°C was mixed with the aqueous phase composition heated to 70 to 80°C to emulsify, thereby preparing an external emulsion composition (oil-in-water cream).

None of the obtained topical emulsion compositions showed phase separation immediately after preparation. Immediately after preparation, 45 g of each topical emulsion composition was filled into a glass bottle and stored at 50°C for two days in the dark. After two days of storage, each topical emulsion composition was centrifuged (3,000 rpm, 10 minutes). The emulsified state after centrifugation was observed and the emulsion stability was scored on a 10-point scale from 1 to 10 according to the level of emulsification (clarity of the boundary between the oil and aqueous phases), with 1 point representing "significant phase separation observed, with a clear boundary between the oil and aqueous phases" and 10 points representing "no phase separation observed at all." Note that a score of 8 or higher indicates that phase separation was sufficiently suppressed and is deemed to pose no problems for practical use.

The results are shown in Table 1. In topical emulsion compositions that did not contain dl-α-tocopherol acetate, no phase separation was observed even after storage, and the emulsified state was stably maintained (Reference Example 1). On the other hand, in topical emulsion compositions that did not contain ufenamate, when dl-α-tocopherol acetate was included, phase separation was observed after storage (Comparative Examples 1 to 4). When dl-α-tocopherol acetate and l-menthol were also included, phase separation became more pronounced after storage, further reducing emulsion stability (Comparative Examples 3 and 4). Furthermore, in topical emulsion compositions that contained dl-α-tocopherol acetate and allantoin, phase separation was pronounced after storage, regardless of the presence or absence of ufenamate (Comparative Examples 5 and 6). In contrast, in topical emulsion compositions that contained dl-α-tocopherol acetate and ufenamate, phase separation was suppressed after storage, and the emulsified state was stably maintained (Examples 1 to 4). Furthermore, even in the case of the topical emulsion composition in Example 3, in which the amount of l-menthol was changed to 5% by weight, phase separation after storage was suppressed and the emulsified state was stably maintained. Furthermore, even in the case of the topical emulsion composition in Example 3, in which the amount of dl-α-tocopherol acetate was changed to 5% by weight, phase separation after storage was suppressed and the emulsified state was stably maintained.

Topical emulsion compositions having the compositions shown in Formulation Examples Tables 2 and 3 were prepared, and emulsion stability after storage was evaluated in the same manner as in Test Example 1. Phase separation after storage was suppressed in all of the topical emulsion compositions of Formulation Examples 1 to 6, and the emulsified state was stably maintained. Note that, in the topical emulsion compositions of Formulation Examples 1 to 6 in which ufenamate was not blended, phase separation was observed after storage.

Claims (2)

An oil-in-water emulsion composition for external use, which contains (A) an ester of tocopherol and a carboxylic acid, ( B) ufenamate , and (D) a monoterpene , and does not contain (C) allantoin. 2. The emulsion composition for external use according to claim 1, comprising 0.01 to 15% by weight of component (A) and 1 to 20% by weight of component (B) .