JP7733993B2 - External composition - Google Patents

Description

The present invention relates to a topical composition that contains 50% or more by weight of white petrolatum, improves the solubility of glycyrrhetinic acids, and further inhibits separation of the white petrolatum during storage.

White petrolatum has a moisturizing effect that prevents moisture from evaporating from the skin, and a barrier effect that protects against irritation by forming a film on the skin. Topical compositions containing white petrolatum as a base are widely used to prevent or improve dry skin, sensitive skin, contact skin inflammation, etc.

Various formulations of topical compositions containing white petrolatum have been reported in the past. For example, Patent Document 1 reports that an emulsion formulation for topical skin containing (A) ethanol, isopropanol, and/or diethylene glycol monoethyl ether, (B) white petrolatum, (C) carboxyvinyl polymer and/or alkyl-modified carboxyvinyl polymer, and (D) phospholipids has improved formulation stability and excellent intradermal retention of the active ingredient. However, the emulsion formulation for topical skin described in Patent Document 1 contains 0.1 to 20% by weight of white petrolatum, and is not formulated to fully exhibit the moisturizing and barrier effects of white petrolatum. To fully exhibit the moisturizing and barrier effects of white petrolatum, it is necessary to increase the amount of white petrolatum in the topical composition. However, topical compositions containing a higher amount of white petrolatum may result in reduced solubility of the active ingredient.

Glycyrrhetinic acids, such as glycyrrhetinic acid, its derivatives, and salts thereof, are known to have anti-inflammatory and anti-allergic effects, and topical compositions containing glycyrrhetinic acids have been developed. However, no sufficient research has been conducted into formulations that can stably incorporate glycyrrhetinic acids into topical compositions containing increased amounts of white petrolatum.

JP 2008-195712 A

The inventors conducted research to develop a topical composition containing glycyrrhetinic acids and a higher amount of white petrolatum. They discovered that in topical compositions containing 50% by weight or more of white petrolatum and glycyrrhetinic acids, the glycyrrhetinic acids do not dissolve sufficiently, making formulation difficult. Furthermore, white petrolatum is a mixture of paraffins with different molecular weights, and it is known that some of the white petrolatum may become liquid and separate during storage. They discovered that in topical compositions containing 50% by weight or more of white petrolatum and glycyrrhetinic acids, the white petrolatum is prone to separation during storage, resulting in reduced storage stability.

The object of the present invention is to provide a formulation technology that can improve the solubility of glycyrrhetinic acids in a topical composition containing 50% by weight or more of white petrolatum and glycyrrhetinic acids, and suppress separation of the white petrolatum during storage.

The inventors conducted extensive research to solve the above-mentioned problems and found that a topical composition containing 50% by weight or more of white petrolatum and glycyrrhetinic acids, along with a polyhydric alcohol, can improve the solubility of glycyrrhetinic acids and inhibit separation of the white petrolatum during storage. Furthermore, the inventors discovered that the inclusion of diphenhydramine and/or a salt thereof in the topical composition significantly improves the solubility of glycyrrhetinic acids and inhibits separation of the white petrolatum during storage. The present invention was completed through further research based on these findings.

That is, the present invention provides the following aspects.
Item 1. 50% by weight or more of white petrolatum;
At least one glycyrrhetinic acid selected from the group consisting of glycyrrhetinic acid, its derivatives, and salts thereof;
A polyhydric alcohol,
A topical composition containing
Item 2. The topical composition according to Item 1, further comprising ufenamate.
Item 3. The composition for external use according to Item 1 or 2, further comprising diphenhydramine and/or a salt thereof.
Item 4. The composition for external use according to any one of Items 1 to 3, wherein the polyhydric alcohol is a dihydric alcohol and/or a trihydric alcohol.
Item 5. The composition for external use according to any one of Items 1 to 4, which is an oleaginous ointment.

The topical composition of the present invention can improve the solubility of glycyrrhetinic acids while containing 50% or more by weight of white petrolatum, thereby effectively achieving the moisturizing and barrier effects of white petrolatum while also achieving the medicinal benefits of glycyrrhetinic acids. Furthermore, the topical composition of the present invention can inhibit separation of white petrolatum during storage, thereby providing excellent storage stability.

1. Topical Composition The topical composition of the present invention is characterized by containing 50% by weight or more of white petrolatum, at least one glycyrrhetinic acid selected from the group consisting of glycyrrhetinic acid, its derivatives, and salts thereof, and a polyhydric alcohol. The topical composition of the present invention will be described in detail below.

[White petrolatum]
The topical composition of the present invention contains 50% by weight or more of white petrolatum as a base. By including such a high content of white petrolatum, the moisturizing effect and barrier effect of white petrolatum can be effectively exhibited.

The content of white petrolatum in the topical composition of the present invention may be 50% by weight or more, but specifically, it can be 50 to 99% by weight, preferably 55 to 99% by weight, and more preferably 55 to 95% by weight.

[Glycyrrhetinic acid]
The topical composition of the present invention contains at least one glycyrrhetinic acid selected from the group consisting of glycyrrhetinic acid, its derivatives, and salts thereof. Glycyrrhetinic acids are known to have anti-inflammatory and anti-allergic effects.

Glycyrrhetinic acid derivatives are not particularly limited as long as they are pharmaceutically acceptable, but examples include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, and glycyrrhetinic acid monoglucuronide.

Salts of glycyrrhetinic acid and/or its derivatives are not particularly limited as long as they are pharmaceutically acceptable, but specific examples include alkali metal salts such as sodium salts and potassium salts, and ammonium salts.

The topical composition of the present invention may use one or more glycyrrhetinic acids selected from glycyrrhetinic acid, glycyrrhetinic acid derivatives, and salts thereof, as the glycyrrhetinic acid compound.

Of these glycyrrhetinic acids, glycyrrhetinic acid is preferred.

The content of glycyrrhetinic acids in the topical composition of the present invention may be set appropriately depending on the level of medicinal effect that the topical composition is to have, but examples include a total amount of glycyrrhetinic acids of 0.005 to 5% by weight, preferably 0.01 to 2% by weight, more preferably 0.01 to 0.3% by weight, and even more preferably 0.1 to 0.3% by weight.

[Polyhydric alcohol]
The topical composition of the present invention contains a polyhydric alcohol in addition to the above-mentioned components. By including a polyhydric alcohol together with glycyrrhetinic acids in a topical composition containing 50% by weight or more of white petrolatum, it is possible to improve the solubility of glycyrrhetinic acids while suppressing separation of the white petrolatum during storage.

Polyhydric alcohols are not particularly limited as long as they are pharmaceutically acceptable, but examples include dihydric alcohols such as propylene glycol, 1,3-butylene glycol, dipropylene glycol, and polypropylene glycol; and trihydric alcohols such as glycerin.

Among these polyhydric alcohols, dihydric alcohols are preferred, and propylene glycol and glycerin are more preferred.

These polyhydric alcohols may be used alone or in combination of two or more.

A suitable example of a combination of two or more polyhydric alcohols is a combination of propylene glycol and glycerin. Using a combination of propylene glycol and glycerin can more significantly improve the solubility of glycyrrhetinic acids and inhibit separation of white petrolatum during storage. When using a combination of propylene glycol and glycerin, there are no particular restrictions on the ratio between them, but examples include 0.001 to 500 parts by weight, preferably 0.1 to 50 parts by weight, and more preferably 0.5 to 20 parts by weight of glycerin per 1 part by weight of propylene glycol.

The content of polyhydric alcohol in the topical composition of the present invention is, for example, 0.01 to 40% by weight of the total amount of polyhydric alcohol, preferably 0.5 to 25% by weight, more preferably 1 to 15% by weight, from the viewpoint of achieving a more pronounced effect of improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum.

In the topical composition of the present invention, the ratio of polyhydric alcohol to glycyrrhetinic acids is, for example, 0.01 to 5,000 parts by weight of the total amount of polyhydric alcohol per 1 part by weight of the total amount of glycyrrhetinic acids. From the viewpoint of achieving a more pronounced effect of improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum, the ratio is preferably 0.1 to 500 parts by weight, and more preferably 1 to 50 parts by weight.

[Ufenamart]
The topical composition of the present invention may further contain ufenamate in addition to the above-mentioned components. By further containing ufenamate, it is possible to more significantly improve the solubility of glycyrrhetinic acids and inhibit the separation of white petrolatum during storage.

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

When ufenamate is contained in the topical composition of the present invention, the content may be, for example, 0.1 to 10% by weight, preferably 1 to 8% by weight, and more preferably 3 to 5% by weight, from the viewpoint of achieving a more pronounced effect of improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum.

When ufenamate is contained in the topical composition of the present invention, the ratio of ufenamate to glycyrrhetinic acids is, for example, 0.1 to 2000 parts by weight of ufenamate per 1 part by weight of the total amount of glycyrrhetinic acids, preferably 1 to 200 parts by weight, more preferably 5 to 50 parts by weight, from the viewpoint of achieving a more pronounced effect of improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum.

[Diphenhydramine and/or its salts]
The topical composition of the present invention may contain diphenhydramine and/or a salt thereof in addition to the above-mentioned components. By further containing diphenhydramine and/or a salt thereof, it is possible to more significantly improve the solubility of glycyrrhetinic acids and inhibit the separation of white petrolatum during storage.

Diphenhydramine is a known drug known to have antihistamine properties.

Diphenhydramine salts are not particularly limited as long as they are pharmaceutically acceptable, but examples include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate.

These diphenhydramines and their salts may be used singly or in combination of two or more.

Among diphenhydramine and its salts, diphenhydramine and diphenhydramine hydrochloride are preferred, and diphenhydramine is more preferred, from the viewpoint of improving the solubility of glycyrrhetinic acids and more significantly inhibiting the separation of white petrolatum during storage.

When diphenhydramine and/or a salt thereof is contained in the topical composition of the present invention, the content is not particularly limited, but may be, for example, 0.01 to 5% by weight in total of diphenhydramine and/or a salt thereof. From the viewpoint of achieving a more pronounced effect of improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum, the content is preferably 0.05 to 3% by weight, more preferably 0.01 to 1% by weight, and even more preferably 0.5 to 1% by weight.

When diphenhydramine and/or a salt thereof is contained in the topical composition of the present invention, the ratio of diphenhydramine and/or a salt thereof to glycyrrhetinic acids is not particularly limited, but for example, the total amount of diphenhydramine and/or a salt thereof is 0.01 to 1,000 parts by weight per 1 part by weight of the total amount of glycyrrhetinic acids. From the viewpoint of achieving a more significant effect of improving the solubility of glycyrrhetinic acids and inhibiting the separation of white petrolatum, the total amount is preferably 0.1 to 100 parts by weight, and more preferably 1 to 10 parts by weight.

[water]
The topical composition of the present invention may contain water as needed, as long as it can be prepared into a desired dosage form.When the topical composition of the present invention contains water, the content thereof is, for example, 5% by weight or less, preferably 4% by weight or less, more preferably 1% by weight or less.When the topical composition of the present invention contains water, the lower limit of the water content is not particularly limited, but may be, for example, 0.01% by weight or more or 0.1% by weight or more.

[Other ingredients]
In addition to the above-mentioned components, the topical composition of the present invention may contain other commonly used additives as needed.Such additives include, for example, surfactants, thickeners, vegetable oils, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, higher alcohols, pH adjusters, buffers, solubilizers, chelating agents, preservatives, preservatives, antioxidants, stabilizers, fragrances, etc.When these additives are contained in the topical composition of the present invention, the content thereof may be appropriately determined depending on the type of additive used, etc.

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

[Dosage form/preparation form]
The formulation of the topical composition of the present invention is not particularly limited as long as it is applicable transdermally, and may be any of an oily ointment, a water-in-oil cream, etc., with an oily ointment being preferred.

Furthermore, the topical composition of the present invention may be in any formulation, such as a topical skin drug (including quasi-drugs) or a cosmetic, as long as it is applied to the skin.

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

Test Example : An oleaginous ointment was prepared having the composition shown in Table 1. Specifically, the oily bases shown in Tables 1 and 2 were heated to 80°C and mixed, and then the other ingredients were added in predetermined amounts and thoroughly mixed to prepare an oleaginous ointment.

Immediately after preparation, the oily ointment was left to stand at room temperature for 30 minutes, after which the appearance was observed and the solubility of glycyrrhetinic acid was graded on a 10-point scale from 1 to 10, with 10 points indicating "completely dissolved glycyrrhetinic acid powder," 5 points indicating "some residual glycyrrhetinic acid powder is visible, but within the acceptable range for commercialization," and 1 point indicating "significant residual glycyrrhetinic acid powder remains."

In addition, the appearance of the oily ointment was observed immediately after preparation after storing it at 50°C for two weeks, and the degree of separation of the white petrolatum was evaluated on a 10-point scale, with 10 points indicating "no separation of the white petrolatum at all"; 5 points indicating "some separation of the white petrolatum was observed, but it became uniform when shaken and the separation disappeared, and was within the acceptable range from a commercial standpoint"; and 1 point indicating "significant separation of the white petrolatum was observed and it did not become uniform even when shaken."

The results are shown in Tables 1 and 2. In oleaginous ointments containing 50% or more by weight of white petrolatum and glycyrrhetinic acid without a polyhydric alcohol, glycyrrhetinic acid did not dissolve, leaving significant residue, and significant separation of the white petrolatum after storage was also observed (Comparative Examples 1 and 2). In contrast, in oleaginous ointments containing 50% or more by weight of white petrolatum and glycyrrhetinic acid and a polyhydric alcohol, the solubility of glycyrrhetinic acid was improved, and separation of the white petrolatum during storage was also suppressed (Examples 1 to 15). In particular, when ufenamate and/or diphenhydramine was added to 50% or more by weight of white petrolatum and glycyrrhetinic acid, the solubility of glycyrrhetinic acid was significantly improved, and separation of the white petrolatum during storage was significantly suppressed (Examples 3 to 8, 10, 13, and 15). Furthermore, in the oil-based ointments of Examples 2, 7, and 10, in which propylene glycol was replaced with 1,3-butylene glycol, the solubility of glycyrrhetinic acid was improved to the same extent as in Examples 2, 7, and 10, and separation of white petrolatum during storage was also suppressed.

Oleaginous ointments having the compositions shown in Production Example Table 3 were prepared, and the solubility of glycyrrhetinic acid and the separation of white petrolatum during storage were evaluated in the same manner as in the above-mentioned Test Example. As a result, in all of the oleaginous ointments of Production Examples 1 to 8, the solubility of glycyrrhetinic acid was remarkably improved, and the separation of white petrolatum during storage was remarkably suppressed.

Claims (4)

50% by weight or more of white petrolatum;
at least one glycyrrhetinic acid selected from the group consisting of glycyrrhetinic acid, pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinic acid monoglucuronide , and salts thereof;
A polyhydric alcohol,
The topical composition is an oleaginous ointment . The topical composition according to claim 1, further containing ufenamate. The topical composition according to claim 1 or 2, further comprising diphenhydramine and/or a salt thereof. The composition for external use according to any one of claims 1 to 3, wherein the polyhydric alcohol is a dihydric alcohol and/or a trihydric alcohol.