External components

Abstract

The object of this disclosure is to provide a topical composition comprising a heparin-like substance, allantoin, and vitamin A derivatives, which can suppress changes in appearance and properties due to storage under unsealed conditions. [Solution] A topical composition containing (A) a heparin-like substance, (B) allantoin, (C) vitamin A compounds, (D) glycyrrhizic acid, its derivatives, and salts thereof, and (E) ceramide 2.

Description

Technical Field

[0001] The present disclosure relates to an external composition containing a heparin analogue, allantoin, and vitamin A compounds, which can suppress changes in appearance properties due to storage under unsealed conditions.

Background Art

[0002] Heparin analogues are known to have functions such as a moisturizing effect and a blood circulation promoting effect. In addition, allantoin is known to have functions such as a tissue repair activating effect, an anti-inflammatory effect, and an antipruritic effect. In addition, vitamin A compounds are known to have functions such as promoting skin turnover, improving acne and wrinkles, and whitening effect.

[0003] In recent years, there has been a strong demand for improving the functionality of external compositions. Focusing on the functionality of heparin analogues, allantoin, and vitamin A compounds, external compositions that improve functionality by using these components in combination have also been proposed. For example, Patent Document 1 reports that a topical skin preparation containing a heparin analogue, allantoin, vitamin A compounds, allantoin, and diphenhydramine or diphenhydramine hydrochloride is effective in treating dry skin diseases accompanied by itching.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] For topical compositions to be put into practical use, it is necessary to give full consideration not only to their effectiveness but also to their formulation stability. The inventors of this invention have investigated topical compositions containing heparinoid, allantoin, and vitamin A derivatives from various perspectives and have found that there are problems with formulation stability. Specifically, they have found that when topical compositions containing heparinoid, allantoin, and vitamin A derivatives are stored under unsealed conditions, changes in appearance (separation of components and resulting changes in appearance) occur. Topical compositions are usually stored in a sealed state, but since users may forget to close the lid of the container, it is desirable that the appearance can be stably maintained even when stored under unsealed conditions.

[0006] Therefore, the object of this disclosure is to provide an external composition comprising a heparin-like substance, allantoin, and vitamin A derivatives that can suppress changes in appearance and properties due to storage under unsealed conditions. [Means for solving the problem]

[0007] The inventors of the present invention conducted diligent studies to solve the aforementioned problems and found that by including glycyrrhizic acid derivatives and ceramide 2 together with heparinoid, allantoin, and vitamin A derivatives in an external composition, changes in appearance and properties due to storage under unsealed conditions can be suppressed. This disclosure was completed by further studies based on these findings.

[0008] In other words, this disclosure provides external compositions in the following embodiments. Item 1. A topical composition containing (A) heparinoid, (B) allantoin, (C) vitamin A compounds, (D) glycyrrhizic acid, its derivatives, and salts thereof, and (E) ceramide 2. Item 2. The topical composition according to Item 1, wherein the vitamin A compounds are vitamin A1 and / or derivatives thereof. Item 3. An emulsified external composition as described in Item 1 or 2. Item 4. The topical composition described in Item 3, which is a cream. [Effects of the Invention]

[0009] According to this disclosure, a formulation is provided for a topical composition containing a heparin-like substance, allantoin, and vitamin A derivatives that can suppress changes in appearance and properties due to storage under unsealed conditions and provide excellent formulation stability. Topical compositions may be stored under unsealed conditions if the user carelessly forgets to close the container lid, but the topical composition of this disclosure can suppress changes in appearance and properties even when stored under unsealed conditions, thus preventing changes in appearance and properties even in such improper storage conditions. [Modes for carrying out the invention]

[0010] The topical compositions disclosed herein are characterized by containing (A) heparin-like substances, (B) allantoin, (C) vitamin A compounds, (D) glycyrrhizic acid, its derivatives, and salts thereof, and (E) ceramide 2. The topical compositions disclosed herein are described in detail below. In this disclosure, the numerical range "X~Y" refers to a range of X or more and Y or less.

[0011] [(A) Heparin-like substances] The topical compositions disclosed herein contain a heparin-like substance (sometimes referred to as component (A)). The heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known component known to have moisturizing and blood circulation promoting effects. The origin of the heparin-like substance used in this disclosure is not particularly limited, but examples include those obtained by polysulfating mucopolysaccharides, or those extracted from the tissues of edible animals (e.g., lungs including tracheal cartilage of cattle). In the topical compositions disclosed herein, heparin-like substances listed in the Japanese Pharmacopoeia are preferably used as the heparin-like substance.

[0012] The content of component (A) in the topical composition of this disclosure may be set appropriately depending on the use of the topical composition, the formulation form, etc., but for example, it may be 0.001 to 5% by weight, preferably 0.01 to 1% by weight, more preferably 0.01 to 0.3% by weight, and even more preferably 0.1 to 0.3% by weight.

[0013] [(B) Allantoin] The topical composition disclosed herein contains allantoin (sometimes referred to as component (B)). Allantoin is a compound also known as 5-ureidohydantoin and is a known component that is known to have tissue repair activating effects, anti-inflammatory effects, antipruritic effects, etc.

[0014] The content of component (B) in the topical composition of this disclosure may be set appropriately depending on the use of the topical composition, the formulation form, etc., but for example, it may be 0.01 to 10% by weight, preferably 0.01 to 8% by weight, more preferably 0.01 to 1% by weight, and even more preferably 0.05 to 0.5% by weight.

[0015] [(C) Vitamin A] The topical compositions disclosed herein contain vitamin A derivatives (sometimes referred to as component (C)). Vitamin A compounds refer to vitamin A1 (retinol, retinal, retinoic acid), vitamin A2 (3-dehydroretinol, 3-dehydroretinal, 3-dehydroretinoic acid), and their derivatives. Specific examples of vitamin A1 derivatives include retinol acetate (vitamin A acetate), retinol propionate, retinyl palmitate, retinyl linoleate, retinyl octoate, retinyl lauryl, retinyl oleate, and retinyl linolenic acid, among other retinol organic acid esters.

[0016] In addition, vitamin A compounds may be used in a state dissolved in oils such as vegetable oils. Those obtained by dissolving vitamin A compounds in oils are known as "vitamin A oil". Vitamin A oil can be produced, for example, according to the method described in the Japanese Pharmacopoeia. As vitamin A oil, those having a vitamin A compound content of usually 100,000 to 2,000,000 IU / g, 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" of the content of vitamin A compounds indicates the international unit.

[0017] In the external composition of the present disclosure, as the component (C), one type of vitamin A compound may be used alone, or two or more types of vitamin A compounds may be used in combination.

[0018] Among these components (C), preferably vitamin A1 and its derivatives, and more preferably retinol and retinol organic acid esters can be mentioned.

[0019] The content of the component (C) in the external composition of the present disclosure may be appropriately set according to the use of the external composition, the dosage form, etc. For example, 1 to 12,500 IU / g, preferably 10 to 1,000 IU / g, more preferably 50 to 500 IU / g, still more preferably 80 to 300 IU / g, and even more preferably 100 to 250 IU / g can be mentioned. The unit "IU" of vitamin A compounds is the international unit.

[0020] [(D) Glycyrrhizic acids] The external composition of the present disclosure contains at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, its derivatives, and their salts (sometimes referred to as component (D)). In the external composition of the present disclosure, glycyrrhizic acids exhibit an action of suppressing changes in appearance properties due to storage under non-sealed conditions of an external composition containing a heparin-like substance, allantoin, and vitamin A compounds by a synergistic effect with ceramide 2 described later.

[0021] Glycyrrhizic acid is a well-known drug known to have anti-inflammatory and anti-allergic effects, etc. As derivatives of glycyrrhizic acid, there are no particular limitations as long as they are pharmaceutically acceptable. Specifically, methyl glycyrrhizinate, stearyl glycyrrhizinate, etc. can be mentioned. As salts of glycyrrhizic acid and its derivatives, there are no particular limitations as long as they are pharmaceutically acceptable. Specifically, alkali metal salts such as sodium salt and potassium salt; ammonium salts, etc. can be mentioned.

[0022] In the external composition of the present disclosure, as the component (D), one kind may be selected from glycyrrhizic acid, its derivatives, and their salts, or two or more kinds may be used in combination.

[0023] Among these component (C), from the viewpoint of more effectively suppressing the change in appearance properties due to storage under sealed conditions, preferably a salt of glycyrrhizic acid, more preferably dipotassium glycyrrhizinate can be mentioned.

[0024] In the external composition of the present disclosure, as the ratio of the component (A) and the component (D), for example, per 1 part by weight of the component (A), the component (D) is 0.01 to 100 parts by weight, preferably 0.05 to 50 parts by weight, more preferably 0.1 to 10 parts by weight, still more preferably 1 to 6 parts by weight.

[0025] The content of the component (D) in the external composition of the present disclosure may be appropriately set according to the use, dosage form, etc. of the external composition. For example, 0.01 to 10% by weight, preferably 0.01 to 2.5% by weight, more preferably 0.1 to 2.5% by weight, still more preferably 0.5 to 2% by weight can be mentioned.

[0026] [(E) Ceramide 2] The topical composition disclosed herein contains ceramide 2 (sometimes referred to as component (E)). In the topical composition disclosed herein, ceramide 2 exerts a synergistic effect with the glycyrrhizic acid derivatives to suppress changes in the appearance and properties of the topical composition containing heparinoid, allantoin, and vitamin A derivatives due to storage under unsealed conditions. Ceramide 2 is N-stearoyldihydrosphingosine, a type of human-type ceramide.

[0027] In the topical composition of the present disclosure, the ratio of component (A) to component (E) is, for example, 0.005 to 50 parts by weight, preferably 0.02 to 25 parts by weight, more preferably 0.05 to 5 parts by weight, even more preferably 0.5 to 4 parts by weight, and particularly preferably 1.3 to 4 parts by weight of component (E) per 1 part by weight of component (A).

[0028] The content of component (E) in the topical composition of this disclosure may be set appropriately depending on the use of the topical composition, the formulation form, etc., but for example, it can be 0.001 to 10% by weight, preferably 0.001 to 5% by weight, more preferably 0.05 to 3% by weight, even more preferably 0.1 to 1.5% by weight, even more preferably 0.3 to 1% by weight, and particularly preferably 0.5 to 1% by weight.

[0029] [water] The topical compositions disclosed herein contain water for preparation into a desired formulation. The water content in the topical compositions disclosed herein may be set appropriately depending on the formulation, etc., but examples include 20 to 97% by weight, preferably 25 to 95% by weight, more preferably 30 to 90% by weight, and even more preferably 35 to 80% by weight.

[0030] [Polyhydric alcohols] The topical compositions disclosed herein may optionally contain polyhydric alcohols. The type of polyhydric alcohol is not particularly limited, as long as it is pharmaceutically acceptable, but examples include dihydric alcohols such as ethylene glycol, 1,3-butylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, and polypropylene glycol; and trihydric alcohols such as glycerin. Among these polyhydric alcohols, propylene glycol and 1,3-butylene glycol are preferred. These polyhydric alcohols may be used individually or in combination of two or more.

[0031] When a polyhydric alcohol is included in the topical composition of this disclosure, there are no particular limitations on its content, but for example, it may be 0.1 to 25% by weight, preferably 1 to 20% by weight, and more preferably 2 to 15% by weight.

[0032] [Surfactants] The topical compositions disclosed herein may contain surfactants for preparation into desired formulations. The surfactant may be a nonionic surfactant, anionic surfactant, cationic surfactant, or amphoteric surfactant, but a nonionic surfactant is preferred.

[0033] The types of nonionic surfactants are not particularly limited, as long as they are pharmaceutically acceptable, but examples include polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyethylene glycol fatty acid esters, lecithin derivatives, etc. Among these, examples of preferred nonionic surfactants include polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and glycerin fatty acid esters. These nonionic surfactants may be used individually or in combination of two or more.

[0034] When a surfactant is included in the topical composition of this disclosure, the amount can be appropriately set depending on the formulation form, the type of surfactant used, etc., but for example, 0.1 to 20% by weight, preferably 0.5 to 10% by weight, and more preferably 1 to 5% by weight is used.

[0035] [Thickener] The topical compositions disclosed herein may contain thickeners as needed to impart viscosity, etc. The type of thickener is not particularly limited, as long as it is pharmaceutically acceptable, but examples include carboxyvinyl polymer, xanthan gum, guar gum, locust bean gum, carrageenan, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, alkyl acrylate methacrylate copolymer, sodium polyacrylate bentonite, dextrin fatty acid ester, pectin, and the like. Among these thickeners, carboxyvinyl polymer is preferred. These thickeners may be used individually or in combination of two or more.

[0036] When a thickening agent is included in the topical composition of this disclosure, there are no particular limitations on its content, but examples include 0.05 to 5% by weight, preferably 0.1 to 3% by weight, and more preferably 0.1 to 1% by weight.

[0037] [Chelating agent] The topical compositions disclosed herein may optionally contain chelating agents. The type of chelating agent is not particularly limited, as long as it is pharmaceutically acceptable, but examples include EDTA, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphate, metaphosphate, hexametaphosphate, and pharmaceutically acceptable salts thereof. Among these thickeners, EDTA and its salts are preferred, and sodium EDTA is more preferred. These chelating agents may be used individually or in combination of two or more.

[0038] When a chelating agent is included in the topical composition of this disclosure, there are no particular limitations on its content, but examples include 0.001 to 5% by weight, preferably 0.01 to 1% by weight, and more preferably 0.05 to 0.5% by weight.

[0039] [Oil content] The topical compositions disclosed herein may contain oils (oily bases) to prepare them into desired formulations. The type of oil is not particularly limited as long as it is pharmaceutically acceptable, but examples include higher monohydric alcohols, fatty acid alkyl esters, hydrocarbon oils, silicone oils, vegetable oils, animal oils, cholesterol, etc.

[0040] Among these oils, suitable examples include monohydric higher alcohols, fatty acid alkyl esters, hydrocarbon oils, and silicone oils. Examples of monohydric higher alcohols include monohydric alcohols with 12 to 34 carbon atoms, specifically myristyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, hexadecyl alcohol, and lanolin alcohol. Examples of fatty acid alkyl esters include esters of fatty acids with 6 to 30 carbon atoms and alcohols with 1 to 34 carbon atoms, specifically diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetyl palmitate, diethyl sebacate, and ethyl oleate. Examples of hydrocarbon oils include paraffin, hydrogenated polyisobutene, liquid paraffin, gelling hydrocarbons (such as Plastibase), ceresin, microcrystalline wax, white petrolatum, and squalane. Examples of silicone oils include methylpolysiloxane, dimethylpolysiloxane, cyclic silicones, alkyl-modified silicones, amino-modified silicones, polyether-modified silicones, polyglycerin-modified silicones, acrylic silicones, and phenyl-modified silicones.

[0041] These oils may be used individually or in combination of two or more types.

[0042] When the topical composition of this disclosure contains oil, the amount can be appropriately set depending on the formulation form, etc., but for example, 1 to 60% by weight, preferably 5 to 50% by weight, more preferably 5 to 40% by weight, and even more preferably 10 to 30% by weight.

[0043] [Other ingredients] In addition to the components described above, the topical compositions of this disclosure may contain other commonly used additives as needed. Examples of such additives include preservatives, monohydric lower alcohols, pH adjusters, buffers, solubilizers, antioxidants, stabilizers, fragrances, colorants, and the like. When these additives are included in the topical compositions of this disclosure, their content may be appropriately determined depending on the type of additive used.

[0044] Furthermore, the topical compositions disclosed herein may contain pharmacological components in addition to the components described above. Examples of such pharmacological components include antihistamines, local anesthetics, moisturizers, bactericides, antibacterial agents, antipruritics, skin protectants, blood circulation promoting components, vitamins, and the like. These pharmacological components may be used individually or in combination of two or more. When these pharmacological components are included in the topical compositions disclosed herein, their concentrations may be appropriately set according to the type of pharmacological component used, the desired effect, etc.

[0045] [Formulation form / dosage type] The topical compositions disclosed herein may be emulsified formulations such as oil-in-water emulsions and water-in-oil emulsions, or non-emulsified formulations such as solubilized formulations and aqueous ointments. While heparin-like substances, allantoin, and vitamin A derivatives are typically present in emulsified formulations (especially oil-in-water emulsions), changes in appearance (separation of components and resulting changes in appearance) due to storage under unsealed conditions tend to be significant, the topical compositions disclosed herein effectively suppress changes in appearance due to storage under unsealed conditions, even in emulsified formulations. In view of these effects, emulsified formulations, and more preferably oil-in-water emulsions, are preferred as topical compositions of the disclosure.

[0046] The dosage form of the topical composition disclosed herein is not particularly limited as long as it is applicable transdermally, and may be liquid, semi-solid (cream, gel, ointment, paste), solid, etc., but liquid or semi-solid is preferred.

[0047] Furthermore, the topical compositions disclosed herein are used as topical skin pharmaceuticals (including quasi-drugs) or cosmetics. Specific formulations of the topical compositions of the present invention include creams, lotions, gels, emulsions, liquids, poultices, patches, liniments, aerosols, aqueous ointments, packs, and the like. Among these, creams are preferred.

[0048] [Manufacturing method] The topical compositions disclosed herein can be manufactured according to known formulation methods corresponding to their formulation form. For example, if the topical composition disclosed herein is an emulsified formulation, it can be prepared by separating the components to be contained into water-soluble components and oily components, preparing an aqueous phase containing the water-soluble components and an oil phase containing the oily components, and emulsifying these according to known methods. [Examples]

[0049] The present disclosure will be explained in more detail below with reference to examples, but the present disclosure is not limited to these examples.

[0050] Test example Topical compositions (cream-type oil-in-water emulsions) with the compositions shown in Tables 1 and 2 were prepared. Specifically, the oil phase composition was prepared by mixing predetermined amounts of vitamin A oil or retinol acetate (vitamin A acetate), ceramide 2, stearyl alcohol, cetanol, isopropyl myristate, white petrolatum, liquid paraffin, squalane, dimethylpolysiloxane, propyl parahydroxybenzoate, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, and self-emulsifying glyceryl monostearate, and heating and dissolving them at 75-85°C. Separately, the aqueous phase composition was prepared by mixing predetermined amounts of heparinoid, allantoin, dipotassium glycyrrhizate, propylene glycol, 1,3-butylene glycol, sodium edetate hydrate, carboxyvinyl polymer, pH adjuster, methyl parahydroxybenzoate, and purified water. Next, the aqueous phase composition, heated to 80°C, was gradually added to the oil phase composition, also heated to 80°C, and mixed to perform an emulsification operation, thereby obtaining an external composition (a creamy oil-in-water emulsion). Immediately after preparation, the external composition was white and in an emulsified state without separation.

[0051] Approximately 1 g of each topical composition immediately after manufacturing was placed on a flat surface without being placed in a container and left to stand at room temperature for 4 days. The appearance of each topical composition after storage was visually observed, and the formulation stability was evaluated according to the following criteria. <Criteria for determining formulation stability> AA: Maintains a white appearance, no separation of components is observed, and there is no difference in appearance or properties compared to immediately after preparation. A: It maintains a white appearance, and although slight separation of components is observed, there is almost no difference in appearance compared to immediately after preparation. B: The appearance has changed to a slightly translucent state, and slight separation of components is also observed, indicating a change in appearance compared to immediately after preparation. C: The appearance has changed to a translucent state, and separation of components is also observed, indicating a significant change in appearance compared to immediately after preparation.

[0052] The results are shown in Tables 1 and 2. In topical compositions containing heparinoid, allantoin, and vitamin A oil, the appearance and properties changed significantly after storage under unsealed conditions (Comparative Example 1). In addition, in topical compositions containing either dipotassium glycyrrhizate or ceramide 2 in addition to heparinoid, allantoin, and vitamin A oil, the appearance and properties also changed significantly after storage under unsealed conditions (Comparative Examples 2 and 3). Furthermore, in topical compositions containing the four components heparinoid, vitamin A oil, dipotassium glycyrrhizate, and ceramide 2, or a combination of the four components allantoin, vitamin A oil, dipotassium glycyrrhizate, and ceramide 2, changes in appearance and properties were observed after storage under unsealed conditions (Comparative Examples 4 and 5). In contrast, when a combination of heparinoid, allantoin, vitamin A oil or retinol acetate, dipotassium glycyrrhizate, and ceramide 2 was included, changes in appearance and properties were suppressed even after storage under unsealed conditions, demonstrating excellent formulation stability (Examples 1-5). In particular, topical compositions containing heparinoid, allantoin, vitamin A oil or retinol acetate, dipotassium glycyrrhizate, and 0.5% by weight or more of ceramide 2 showed remarkably suppressed changes in appearance and properties even after storage under unsealed conditions, demonstrating remarkably excellent formulation stability (Examples 2-5). It was also confirmed that the topical compositions of Examples 1-5 showed significantly better suppression of changes in appearance and properties even after storage under unsealed conditions than the topical compositions of Examples 1-5 without vitamin A oil or retinol acetate, respectively.

[0053] [Table 1]

[0054] [Table 2]

[0055] Prescription Example 1 Topical compositions with the compositions shown in Tables 3-10 (cream-type oil-in-water emulsion formulations; Formulation Examples 1-36 and Comparative Formulation Examples 1-36) were prepared in the same manner as in the test examples. The formulation stability of each obtained topical composition was evaluated in the same manner as in the test examples. The topical compositions of Formulation Examples 1-36 showed excellent formulation stability, as changes in appearance and properties were suppressed even after storage under unsealed conditions.

[0056] [Table 3]

[0057] [Table 4]

[0058] [Table 5]

[0059] [Table 6]

[0060] [Table 7]

[0061] [Table 8]

[0062] [Table 9]

[0063] [Table 10]

[0064] Prescription Example 2 This disclosure provides, as yet another embodiment, topical compositions (cream-type oil-in-water emulsion formulations) shown in Tables 11 and 12. Each of the topical compositions shown in Tables 11 and 12 may have a preventive or ameliorative effect on skin diseases.

[0065] [Table 11]

[0066] [Table 12]

Claims

1. A topical composition containing (A) heparinoid, (B) allantoin, (C) vitamin A compounds, (D) glycyrrhizic acid, its derivatives, and salts thereof, and (E) ceramide 2.

2. The aforementioned vitamin A compounds are vitamin A 1 The topical composition according to claim 1, which is and / or a derivative thereof.

3. The topical composition according to claim 1 or 2, which is an emulsified preparation.

4. The topical composition according to claim 3, which is a cream.

Images