Topical compositions

Abstract

To provide a pharmaceutical technique that improves solubility of glycyrrhetinic acid and can suppress separation of white petrolatum during its storage in an external composition, which contains the glycyrrhetinic acid as well as the white petrolatum of 50 wt.% or more.SOLUTION: An external composition contains white petrolatum of 50 wt.% or more and glycyrrhetinic acid as well as a polyhydric alcohol. The external composition can improve solubility of glycyrrhetinic acid and can suppress separation of white petrolatum during its storage.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for external use that contains 50% by weight or more of white petrolatum, has improved solubility of glycyrrhetinic acids, and is capable of suppressing separation of the white petrolatum during storage. [Background technology]

[0002] White petrolatum has a moisturizing effect that prevents moisture from evaporating from the skin, and a barrier effect that protects the skin from irritation by forming a film on the skin, and external compositions containing white petrolatum as a base are widely used for preventing or improving dry skin, sensitive skin, contact skin inflammation, etc.

[0003] Various formulations of topical compositions containing white petrolatum have been reported. 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) a carboxyvinyl polymer and / or an alkyl-modified carboxyvinyl polymer, and (D) a phospholipid exhibits 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, which is not a formulation that can 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 increased amounts of white petrolatum may result in reduced solubility of the active ingredient.

[0004] On the other hand, 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 to date, but sufficient research has not been conducted into formulations that can stably incorporate glycyrrhetinic acids in topical compositions that contain a higher amount of white petrolatum. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2008-195712 Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have conducted research to develop an external composition containing glycyrrhetinic acids and an increased amount of white petrolatum, and have found that in an external composition containing 50% by weight or more of white petrolatum and glycyrrhetinic acids, the glycyrrhetinic acids are not sufficiently dissolved, making it difficult to formulate.Furthermore, white petrolatum is a mixture of paraffins with different molecular weights, and it is known that a portion of the white petrolatum may become liquid and separate during storage.However, the present inventors have found that in an external composition containing 50% by weight or more of white petrolatum and glycyrrhetinic acids, the white petrolatum is likely to separate during storage, resulting in a decrease in storage stability.

[0007] Therefore, the object of the present invention is to provide a formulation technology that can improve the solubility of glycyrrhetinic acids in an external composition containing 50% by weight or more of white petrolatum and glycyrrhetinic acids, and suppress separation of the white petrolatum during storage. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems and have found that a topical composition containing 50% by weight or more of white petrolatum and glycyrrhetinic acids, as well as a polyhydric alcohol, can improve the solubility of glycyrrhetinic acids and inhibit separation of the white petrolatum during storage.Furthermore, the present inventors have found that by further adding diphenhydramine and / or a salt thereof to the topical composition, the effect of improving the solubility of glycyrrhetinic acids and the effect of inhibiting separation of the white petrolatum during storage become significant.The present invention was completed based on these findings and through further research.

[0009] 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 oily ointment. [Effects of the Invention]

[0010] According to the topical composition of the present invention, even though it contains 50% by weight or more of white petrolatum, the solubility of glycyrrhetinic acids can be improved, so that the moisturizing effect and barrier effect of white petrolatum can be effectively exhibited while the medicinal effect of glycyrrhetinic acids can be exhibited. Furthermore, according to the topical composition of the present invention, separation of white petrolatum during storage can be suppressed, so that it can also have excellent storage stability. DETAILED DESCRIPTION OF THE INVENTION

[0011] 1. External 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.

[0012] [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 exerted.

[0013] The content of white petrolatum in the topical composition of the present invention may be 50% by weight or more, specifically 50 to 99% by weight, preferably 55 to 99% by weight, and more preferably 55 to 95% by weight.

[0014] [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.

[0015] The derivatives of glycyrrhetinic acid are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, and glycyrrhetinic acid monoglucuronide.

[0016] The salt of glycyrrhetinic acid and / or its derivative is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include alkali metal salts such as sodium salts and potassium salts, and ammonium salts.

[0017] In the topical composition of the present invention, one or more glycyrrhetinic acids selected from glycyrrhetinic acid, derivatives of glycyrrhetinic acid, and salts thereof may be used as the glycyrrhetinic acid compound, or a combination of two or more thereof may be used.

[0018] Among these glycyrrhetinic acids, glycyrrhetinic acid is preferred.

[0019] The content of glycyrrhetinic acids in the topical composition of the present invention may be appropriately determined depending on the degree of medicinal effect that the topical composition is to have, and may be, for example, 0.005 to 5 wt %, preferably 0.01 to 2 wt %, more preferably 0.01 to 0.3 wt %, and even more preferably 0.1 to 0.3 wt % in total of glycyrrhetinic acids.

[0020] [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.

[0021] The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include dihydric alcohols such as propylene glycol, 1,3-butylene glycol, dipropylene glycol, and polypropylene glycol; and trihydric alcohols such as glycerin.

[0022] Among these polyhydric alcohols, dihydric alcohols are preferred, and propylene glycol and glycerin are more preferred.

[0023] These polyhydric alcohols may be used alone or in combination of two or more.

[0024] A suitable example of a combination of two or more polyhydric alcohols is a combination of propylene glycol and glycerin. By adopting a combination of propylene glycol and glycerin, it is possible to more significantly improve the solubility of glycyrrhetinic acids and inhibit the separation of white petrolatum during storage. When propylene glycol and glycerin are used in combination, the ratio between them is not particularly limited, but for example, 0.001 to 500 parts by weight, preferably 0.1 to 50 parts by weight, more preferably 0.5 to 20 parts by weight of glycerin per part by weight of propylene glycol.

[0025] The content of polyhydric alcohol in the topical composition of the present invention is, for example, 0.01 to 40% by weight in total of polyhydric alcohol, preferably 0.5 to 25% by weight, more preferably 1 to 15% by weight, from the viewpoint of more significantly improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum.

[0026] In the topical composition of the present invention, the ratio of polyhydric alcohol to glycyrrhetinic acids is, for example, 0.01 to 5000 parts by weight of the total amount of polyhydric alcohol per 1 part by weight of the total amount of glycyrrhetinic acids, and from the viewpoint of more significantly improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum, preferably 0.1 to 500 parts by weight, more preferably 1 to 50 parts by weight.

[0027] [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.

[0028] Ufenamate, also known as butyl flufenamate, is a known lipid-soluble nonsteroidal anti-inflammatory drug.

[0029] 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 more significantly improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum.

[0030] 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 more significantly improving the solubility of glycyrrhetinic acids and inhibiting the separation of white petrolatum.

[0031] [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.

[0032] Diphenhydramine is a known drug known to have antihistamine properties.

[0033] The salt of diphenhydramine is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate.

[0034] These diphenhydramines and salts thereof may be used singly or in combination of two or more.

[0035] Among diphenhydramine and its salts, from the viewpoint of more significantly improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum during storage, preferred are diphenhydramine and diphenhydramine hydrochloride, and more preferred is diphenhydramine.

[0036] When diphenhydramine and / or a salt thereof is contained in the topical composition of the present invention, the content is not particularly limited, but for example, the total amount of diphenhydramine and / or a salt thereof is 0.01 to 5 wt %, and from the viewpoint of more significantly improving the solubility of glycyrrhetinic acids and suppressing the separation of white petrolatum, the content is preferably 0.05 to 3 wt %, more preferably 0.01 to 1 wt %, and even more preferably 0.5 to 1 wt %.

[0037] 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 1000 parts by weight per 1 part by weight of the total amount of glycyrrhetinic acids, and from the viewpoint of more significantly improving the solubility of glycyrrhetinic acids and inhibiting the separation of white petrolatum, the ratio is preferably 0.1 to 100 parts by weight, and more preferably 1 to 10 parts by weight.

[0038] [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.

[0039] [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 can be appropriately determined depending on the type of additive used, etc.

[0040] The topical composition of the present invention may contain pharmacological ingredients in addition to the above-mentioned ingredients. Examples of such pharmacological ingredients include steroids, antihistamines, local anesthetics, anti-inflammatory agents, moisturizers, disinfectants, antibacterial agents, antipruritics, skin protectants, blood circulation promoters, vitamins, mucopolysaccharides, etc. 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 concentration may be appropriately determined depending on the type of pharmacological ingredient used, the desired effect, etc.

[0041] [Dosage form / preparation type] 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.

[0042] Furthermore, the topical composition of the present invention may be in any formulation such as a topical drug for skin application (including quasi-drugs) or a cosmetic, as long as it is applied to the skin. [Example]

[0043] The present invention will be explained in more detail below by showing examples, but the present invention is not limited to these examples.

[0044] Test Example An oleaginous ointment was prepared with the composition shown in Table 1. Specifically, the oleaginous 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 the oleaginous ointment.

[0045] Immediately after preparation, the oily ointment was left to stand at room temperature for 30 minutes, and then its appearance was observed. The solubility of glycyrrhetinic acid was graded on a 10-point scale from 1 to 10, with 10 points indicating that "glycyrrhetinic acid powder is completely dissolved," 5 points indicating that "a small amount of undissolved glycyrrhetinic acid powder is found, but this is within the acceptable range from the viewpoint of commercialization," and 1 point indicating that "glycyrrhetinic acid powder has not dissolved and significant undissolved glycyrrhetinic acid remains."

[0046] 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 from 1 to 10, with 10 points indicating "no separation of the white petrolatum at all"; 5 points indicating "some separation of the white petrolatum is observed, but it becomes uniform when shaken and the separation disappears, so it is within the acceptable range from the viewpoint of commercialization"; and 1 point indicating "significant separation of the white petrolatum is observed and it does not become uniform even when shaken."

[0047] The results are shown in Tables 1 and 2. When no polyhydric alcohol was added, in oleaginous ointments containing 50% by weight or more of white petrolatum and glycyrrhetinic acid, glycyrrhetinic acid did not dissolve, significant undissolved residue was observed, and significant separation of the white petrolatum was also observed after storage (Comparative Examples 1 and 2). In contrast, in oleaginous ointments containing 50% by weight or more 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 together with 50% by weight or more 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 each of the oily ointments in 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.

[0048] [Table 1]

[0049] [Table 2]

[0050] Manufacturing example Oily ointments having the compositions shown in 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 test examples. As a result, in all of the oily 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.

[0051] [Table 3]

Claims

1. 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.

2. The topical composition according to claim 1, further comprising ufenamate.

3. The topical composition according to claim 1 or 2, further comprising diphenhydramine and / or a salt thereof.

4. 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.

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