External components

Abstract

The object of this disclosure is to provide a topical composition containing ceramide 2 and a heparin-like substance that can suppress insolubilization during manufacturing and creaming during storage. [Solution] The topical composition containing (A) ceramide 2, (B) heparin-like substance, and (C) petrolatum has been designed to suppress insolubilization during manufacturing and creaming during storage.

Description

Technical Field

[0001] The present disclosure relates to an external composition containing ceramide 2 and a heparin analogue, which has improved raw material solubility during production and can suppress creaming.

Background Art

[0002] The stratum corneum is mainly composed of stratum corneum cells and intercellular lipids that form a lamellar structure. The lamellar structure of the intercellular lipids in the stratum corneum plays an important role in the barrier function and moisturizing function. Also, about 50% of the intercellular lipids in the stratum corneum are composed of ceramides, and it is known that when the ceramide content in the stratum corneum decreases, the barrier function and moisturizing function decrease.

[0003] Therefore, conventionally, external compositions containing ceramides have been developed for the purpose of maintaining the function of the stratum corneum by supplementing ceramides in the stratum corneum. For example, Patent Document 1 reports that an emulsified composition containing ceramide, a specific monoalkyl glyceryl ether or monoalkenyl glyceryl ether, a higher fatty acid, and a polyhydric alcohol has high stability and excellent usability.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] Ceramides are broadly classified into human-type ceramides, animal-derived ceramides, plant-derived ceramides, and pseudo-ceramides. Of these, human-type ceramides have the same structure as ceramides found in human skin and have excellent affinity with the skin. Among human-type ceramides, ceramide 2 is the most abundant in human skin and plays a role in supporting moisturizing function. On the other hand, heparin-like substances have moisturizing and blood circulation promoting effects and are used in topical compositions to prevent skin aging and improve rough skin. The inventors of this invention proceeded with their research to develop a topical composition containing ceramide 2 and heparin-like substances, and encountered the problem that the solubility of the raw materials decreased during the manufacturing of the topical composition containing ceramide 2 and heparin-like substances, resulting in the retention of insoluble raw materials. Furthermore, the inventors also encountered the problem that creaming occurs when the topical composition containing ceramide 2 and heparin-like substances is stored.

[0006] Therefore, the object of this disclosure is to provide a topical composition containing ceramide 2 and a heparin-like substance that suppresses raw material insolubilization during manufacturing and suppresses creaming. [Means for solving the problem]

[0007] The inventors of the present invention conducted diligent research to solve the aforementioned problems and found that by preparing an external composition by combining ceramide 2, a heparin-like substance, and petrolatum, it is possible to suppress the insolubilization of raw materials during manufacturing and further suppress creaming during storage.

[0008] In other words, this disclosure provides external compositions in the following embodiments. Item 1. A topical composition containing (A) ceramide 2, (B) heparinoid, and (C) petrolatum. Item 2. The topical composition according to Item 1, wherein the content of component (A) is 0.001 to 10% by weight. Item 3. The topical composition according to item 1 or 2, wherein the content of component (B) per 1 part by weight of component (A) is 0.001 to 50 parts by weight. Item 4. The external composition according to any one of items 1 to 3, wherein the content of component (C) per 1 part by weight of component (A) is 0.1 to 500 parts by weight. Item 5. An emulsified composition, which is an external composition according to any one of items 1 to 4. Item 6. The topical composition described in Item 5, which is an oil-in-water type. [Effects of the Invention]

[0009] The topical composition disclosed herein contains ceramide 2 and a heparin-like substance, yet it can suppress the insolubilization of the raw materials during manufacturing. Furthermore, the topical composition disclosed herein can suppress creaming during storage. [Modes for carrying out the invention]

[0010] The topical composition disclosed herein is characterized by containing (A) ceramide 2 (hereinafter also referred to as "component (A)"), (B) heparinoid (hereinafter also referred to as "component (B)"), and (C) petrolatum (hereinafter also referred to as "component (C)"). The topical composition disclosed herein has suppressed creaming during storage. In this disclosure, creaming refers to the phenomenon in which the dispersed phase is partially concentrated due to the floating (if the dispersed phase is the oil phase) or sedimentation (if the dispersed phase is the oil phase) of the continuous phase and dispersed phase. Furthermore, the topical composition disclosed herein also has suppressed insolubilization during manufacturing. Insolubilization during manufacturing refers to the insolubilization and precipitation of raw materials when the components of the topical composition are mixed and formulated. The topical composition disclosed herein will be described in detail below. In this disclosure, the numerical range "X~Y" refers to the range from X to Y.

[0011] [(A) Ceramide 2] The topical composition disclosed herein contains ceramide 2 as component (A). Conventionally, when ceramide 2 is incorporated into topical compositions together with either heparin-like substances or petrolatum, it causes insolubilization during manufacturing and creaming during storage. However, the topical composition disclosed herein suppresses insolubilization during manufacturing and creaming during storage. Furthermore, conventional topical compositions containing heparin-like substances and petrolatum experience insolubilization during manufacturing and creaming during storage. However, in the topical composition disclosed herein, by using ceramide 2 in combination with heparin-like substances and petrolatum, insolubilization during manufacturing and creaming during storage can be suppressed.

[0012] Ceramide 2 is N-stearoyldihydrosphingosine, a type of human-type ceramide.

[0013] The content of ceramide 2 in the topical composition of this disclosure is not particularly limited and can be set appropriately depending on the desired degree of insolubilization inhibition and / or creaming inhibition, the formulation form, etc., but for example, 0.001 to 10% by weight is possible. From the viewpoint of enhancing the effect of insolubilization inhibition and / or creaming inhibition, preferred content of component (A) is 0.01 to 10% by weight, more preferably 0.1 to 10% by weight, even more preferably 0.3 to 10% by weight, even more preferably 0.4 to 10% by weight, particularly preferably 0.45 to 10% by weight, 0.45 to 5% by weight, 0.45 to 3% by weight, or 0.45 to 2% by weight.

[0014] [(B) Heparin-like substances] The topical composition disclosed herein contains a heparin-like substance as component (B). Conventionally, when heparin-like substances are incorporated into topical compositions together with either ceramide 2 or petrolatum, they cause insolubilization during manufacturing and creaming during storage. However, the topical composition disclosed herein suppresses insolubilization during manufacturing and creaming during storage. Furthermore, conventional topical compositions containing ceramide 2 and petrolatum cause insolubilization during manufacturing and creaming during storage. However, in the topical composition disclosed herein, by using heparin-like substances in combination with ceramide 2 and petrolatum, insolubilization during manufacturing and creaming during storage can be suppressed.

[0015] Heparin-like substances are polysulfated mucopolysaccharides such as chondroitin polysulfate, and are known components that have moisturizing and blood circulation promoting effects. The origin of the heparin-like substances 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 of this disclosure, heparin-like substances listed in the Japanese Pharmacopoeia Standards for Non-Official Drugs are preferably used as the heparin-like substances.

[0016] The content of component (B) in the topical composition of this disclosure is not particularly limited and may be set appropriately depending on the desired degree of insolubilization inhibition and / or creaming inhibition, the formulation form, etc., but for example, 0.01 to 10% by weight is possible. From the viewpoint of enhancing the effect of insolubilization inhibition and / or creaming inhibition, a preferred content of component (B) is 0.01 to 1% by weight, more preferably 0.01 to 0.4% by weight, even more preferably 0.1 to 0.3% by weight, and even more preferably 0.2 to 0.3% by weight.

[0017] In the external composition of the present disclosure, the ratio of component (A) to component (B) is determined according to the content of each component described above. From the viewpoint of enhancing the effect of suppressing insolubilization and / or creaming, the content of component (B) per 1 part by weight of component (A) is preferably 0.001 to 50 parts by weight, more preferably 0.01 to 20 parts by weight, still more preferably 0.03 to 10 parts by weight, even more preferably 0.06 to 5 parts by weight, still even more preferably 0.1 to 3 parts by weight or 0.1 to 1 part by weight, and particularly preferably 0.3 to 0.7 parts by weight.

[0018] [(C) Petrolatum] The external composition of the present disclosure contains petrolatum in addition to the above components. Conventionally, external compositions containing ceramide 2 and heparin-like substances cause insolubilization during production and creaming during storage. However, in the external composition of the present disclosure, by using petrolatum in combination with ceramide 2 and heparin-like substances, insolubilization during production and creaming during storage can be suppressed. Further, conventionally, petrolatum is blended into an external composition together with either one of ceramide 2 and heparin-like substances, resulting in insolubilization during production and creaming during storage. However, the external composition of the present disclosure is suppressed in insolubilization and creaming during production and storage.

[0019] As the petrolatum, preferably white petrolatum is used. White petrolatum is a mixture of hydrocarbons obtained from petroleum, which is decolorized and purified and is an oily component.

[0020] The content of component (C) in the external composition of the present disclosure is not particularly limited and may be appropriately set according to the required degree of suppressing insolubilization and / or creaming, the dosage form, etc. For example, 0.1 to 20% by weight, preferably 0.5 to 15% by weight, more preferably 1 to 10% by weight, and still more preferably 2 to 7% by weight can be mentioned.

[0021] In the external composition of the present disclosure, the ratio of component (A) to component (C) is determined according to the content of each of the above components. From the viewpoint of enhancing the effect of insolubilization suppression and / or creaming suppression, the content of component (C) per 1 part by weight of component (A) is preferably 0.1 to 500 parts by weight, preferably 0.5 to 300 parts by weight, more preferably 1 to 100 parts by weight, still more preferably 3 to 50 parts by weight, even more preferably 5 to 20 parts by weight, and particularly preferably 5 to 10 parts by weight.

[0022] In the external composition of the present disclosure, the ratio of component (B) to component (C) is determined according to the content of each of the above components. From the viewpoint of enhancing the effect of insolubilization suppression and / or creaming suppression, the content of component (C) per 1 part by weight of component (B) is preferably 0.1 to 200 parts by weight, more preferably 1 to 100 parts by weight or 5 to 50 parts by weight, still more preferably 8 to 30 parts by weight, even more preferably 13 to 20 parts by weight.

[0023] [Water] The external composition of the present disclosure contains water in order to be prepared into a desired dosage form. The content of water in the external composition of the present disclosure may be appropriately set according to the dosage form and the like. For example, it may be 20 to 97% by weight, preferably 25 to 95% by weight, more preferably 30 to 90% by weight, still more preferably 35 to 80% by weight.

[0024] [Polyhydric alcohol] The external composition of the present disclosure may contain a polyhydric alcohol as needed. The type of polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable. For example, dihydric alcohols such as ethylene glycol, 1,3 - butylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, and polypropylene glycol; trihydric alcohols such as glycerin can be mentioned. Among these polyhydric alcohols, 1,3 - butylene glycol is preferably mentioned. These polyhydric alcohols may be used alone or in combination of two or more.

[0025] When a polyhydric alcohol is included in the topical composition of this disclosure, the amount is not particularly limited, but for example, it may be 1 to 20% by weight, preferably 4 to 15% by weight, and more preferably 6 to 10% by weight.

[0026] [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.

[0027] 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.

[0028] Among these nonionic surfactants, polyoxyethylene sorbitan fatty acid esters and glycerin fatty acid esters are preferred, and self-emulsifying glyceryl monostearate (glyceryl stearate (SE)) and polyoxyethylene sorbitan monostearate (polysorbate 60) are preferred.

[0029] These nonionic surfactants may be used individually or in combination of two or more.

[0030] A preferred example of a surfactant used in the topical composition of this disclosure is a combination of polyoxyethylene sorbitan fatty acid ester and glycerin fatty acid ester. When using a combination of polyoxyethylene sorbitan fatty acid ester and glycerin fatty acid ester, the ratio is not particularly limited, but for example, per 100 parts by weight of polyoxyethylene sorbitan fatty acid ester, the amount of glycerin fatty acid ester can be 1 to 1000 parts by weight, preferably 10 to 500 parts by weight, more preferably 20 to 200 parts by weight, even more preferably 30 to 100 parts by weight, even more preferably 40 to 80 parts by weight, and particularly preferably 45 to 65 parts by weight.

[0031] 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, the total amount of surfactant can be 0.1 to 20% by weight, preferably 0.5 to 15% by weight, more preferably 1 to 10% by weight, and even more preferably 2 to 7% by weight.

[0032] [Oily base] The topical compositions disclosed herein may contain oily bases (oils) other than component (C) in order to prepare them into a desired formulation. The type of oily base is not particularly limited as long as it is pharmaceutically acceptable, but examples include mineral oil (other than component (C)), higher monohydric alcohols, fatty acid alkyl esters, vegetable oils, animal oils, cholesterol, higher fatty acids having 12 to 34 carbon atoms, silicone oils, etc.

[0033] Among these oily bases, suitable examples include mineral oil (excluding component (C)) and higher monohydric alcohols. Specific examples of mineral oils include paraffin, hydrogenated polyisobutene, liquid paraffin, gelling hydrocarbons (such as Plastibase), ceresin, and microcrystalline wax. Higher monohydric alcohols are monohydric alcohols with 6 to 34 carbon atoms. Preferably, higher monohydric alcohols have 10 to 18 carbon atoms, and specific examples include octyl alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol, cetanol, stearyl alcohol, oleyl alcohol, and eicosanol.

[0034] These oily bases may be used individually or in combination of two or more.

[0035] A suitable example of an oily base used in the external composition of this disclosure is a combination of mineral oil (other than component (C)) and a higher monohydric alcohol. When using a combination of mineral oil (other than component (C)) and a higher monohydric alcohol, the ratio is not particularly limited, but for example, per 100 parts by weight of mineral oil (other than component (C)), the higher monohydric alcohol may be 0.1 to 1000 parts by weight, preferably 0.1 to 500 parts by weight, more preferably 1 to 200 parts by weight, even more preferably 5 to 100 parts by weight, even more preferably 10 to 50 parts by weight, and particularly preferably 20 to 40 parts by weight.

[0036] When an oily base (other than component (C)) is included in the topical composition of the present disclosure, the amount thereof can be appropriately set depending on the formulation form, etc., but for example, the total amount of the oily base (other than component (C)) can be 1 to 80% by weight, preferably 3 to 60% by weight, more preferably 5 to 40% by weight, even more preferably 10 to 20% by weight, and even more preferably 10 to 15% by weight.

[0037] [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 monohydric lower alcohols, pH adjusters, buffers, thickeners, 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.

[0038] 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.

[0039] Specific examples of the above-mentioned pharmacological components include hyaluronic acid, its derivatives (acetylated hyaluronic acid with acetylated hydroxyl groups, sulfated hyaluronic acid with sulfated hydroxyl groups, cationized hyaluronic acid, hydrophobized hydrolyzed hyaluronic acid (hydrolyzed alkyl (C12-13) glyceryl hyaluronate, etc.), cross-linked hyaluronic acid, carboxymethyl hyaluronic acid, alkylene glycol hyaluronate, silanol hyaluronate, etc.), and their salts; diphenhydramine and its salts; ascorbic acid and its salts, etc., but preferred embodiments of this disclosure do not include one or more of these specific components.

[0040] [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. In the prior art, when ceramide 2 and heparin-like substances are included in emulsified formulations (especially oil-in-water emulsions), insolubilization during manufacturing and creaming during storage tend to be significant. In contrast, the topical compositions disclosed herein can effectively suppress insolubilization during manufacturing and creaming during storage, 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.

[0041] Furthermore, the topical compositions of this disclosure are used as topical dermatological pharmaceuticals or quasi-drugs, and are preferably used as topical dermatological pharmaceuticals. 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 and emulsions are preferred, and creams are more preferred.

[0042] [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]

[0043] The present disclosure will be explained in more detail below with reference to examples, but the present disclosure is not limited to these examples.

[0044] Test example Topical compositions (oil-in-water emulsion compositions, creams) shown in Table 3 were prepared. Specifically, an oil-phase composition consisting of component [1] and an aqueous-phase composition consisting of components [2] and [3] were each dissolved at 80°C. Both the oil-phase and aqueous-phase compositions were in a dissolved state. The oil-phase and aqueous-phase compositions were mixed at 80°C, stirred, and cooled to room temperature to prepare the topical compositions.

[0045] <Evaluation of insolubilization suppression> One drop of the immediately prepared topical composition was placed on a glass slide using a dropper and observed under a polarizing microscope at 100x magnification. The degree of insolubilization was evaluated on a 10-point scale, with a score of "1" indicating no insolubilization and a score of "10" indicating a large amount of insolubilization. More specifically, the degree of insolubilization was scored according to the amount of precipitated insolubilization. Representative examples of microscopic images when the degree of insolubilization suppression was score 1 or 10 are shown in Table 1. In Table 1, the scale bar length represents 100 μm. The results are shown in Table 3.

[0046] [Table 1]

[0047] <Evaluation of creaming suppression> The prepared topical compositions were filled into vials and stored at 60°C for one week. The degree of creaming was evaluated based on the appearance after storage, on a 10-point scale, with a score of "1" indicating no creaming and a score of "10" indicating significant creaming. More specifically, the degree of creaming was evaluated according to the ratio of the thickness of the creaming phase (the region where the dispersed phase (oil phase) is concentrated due to creaming) to the height of the topical composition in the vial (the length from the lower end of the concentrated region to the upper surface of the topical composition). Table 2 shows representative examples of the appearance when the degree of creaming is a score of 1 or 10. In Table 2, the arrows indicate the position of the lower end of the region where the dispersed phase (oil phase) is concentrated due to creaming; the lower the relative position, the greater the degree of creaming. The results are shown in Table 3.

[0048] [Table 2]

[0049] [Table 3]

[0050] As shown in Table 3, no insolubilization occurred in topical compositions that did not contain components (A) to (C) (Reference Example). However, significant insolubilization was observed in topical compositions containing components (A) and (B) (Comparative Example 1), topical compositions containing components (A) and (C) (Comparative Example 2), and topical compositions containing components (B) and (C) (Comparative Example 3). In contrast, in topical compositions containing all of components (A) to (C) (Examples 1 and 2) showed significantly reduced insolubilization, resulting in significantly superior manufacturing suitability.

[0051] Furthermore, while no creaming occurred in topical compositions that did not contain components (A) to (C) (Reference Example), significant creaming was observed in topical compositions containing components (A) and (B) (Comparative Example 1), topical compositions containing components (A) and (C) (Comparative Example 2), and topical compositions containing components (B) and (C) (Comparative Example 3). In contrast, creaming was suppressed in topical compositions containing all of components (A) to (C) (Examples 1 and 2), thereby improving storage stability. In particular, creaming was significantly suppressed in the topical composition with the composition of Example 1, resulting in a significantly improved storage stability.

Claims

1. A topical composition containing (A) ceramide 2, (B) heparin-like substance, and (C) petrolatum.

2. The topical composition according to claim 1, wherein the content of component (A) is 0.001 to 10% by weight.

3. The external composition according to claim 1 or 2, wherein the content of component (B) per 1 part by weight of component (A) is 0.001 to 50 parts by weight.

4. The external composition according to claim 1 or 2, wherein the content of component (C) per 1 part by weight of component (A) is 0.1 to 500 parts by weight.

5. The external composition according to claim 1 or 2, which is an emulsified composition.

6. The topical composition according to claim 5, wherein it is an oil-in-water type.

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