Topical composition

Abstract

[Problem] To provide a topical composition which contains ceramide 2 and a heparin analogue, and which can suppress insolubilization during production and creaming resulting from storage. [Solution] A topical composition containing (A) ceramide 2, (B) a heparin analogue, and (C) vaseline is such that insolubilization during production and creaming resulting from storage are suppressed.

Description

External composition 【0001】 The present disclosure relates to an external composition containing ceramide 2 and a heparin-like substance, which has improved solubility of raw materials during production and can suppress creaming. 【0002】 The stratum corneum is mainly composed of corneocytes 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. In addition, about 50% of the intercellular lipids in the stratum corneum are composed of ceramides. It is known that when the ceramide content in the stratum corneum decreases, the barrier function and moisturizing function also 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. 【0004】 Japanese Patent Application Laid-Open No. 2014-237595 【0005】 Ceramides are roughly classified into human ceramides, animal ceramides, plant ceramides, and pseudo-ceramides. Among these, human ceramides have the same structure as ceramides in human skin and have excellent affinity for the skin. In addition, among human ceramides, ceramide 2 is most abundantly contained in human skin and has a function of supporting the moisturizing function. On the other hand, heparin-like substances have functions such as a moisturizing effect and a blood circulation promoting effect, and are used in external compositions for preventing skin aging and improving rough skin. The present inventor has conducted studies to develop an external composition containing ceramide 2 and a heparin-like substance. As a result, when producing an external composition containing ceramide 2 and a heparin-like substance, the inventor faced the problem that the solubility of the compounded raw materials decreased and raw materials in an insoluble state remained. Furthermore, the present inventor also faced the problem that creaming occurred during storage in an external composition containing ceramide 2 and a heparin-like substance. 【0006】Therefore, the object of this disclosure is to provide an external composition containing ceramide 2 and a heparin-like substance, which suppresses raw material insolubilization during manufacturing and suppresses creaming. 【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】 That is, the present disclosure provides external compositions in the following embodiments: 1. An external composition containing (A) ceramide 2, (B) a heparin-like substance, and (C) petrolatum. 2. The external composition according to 1, wherein the content of component (A) is 0.001 to 10% by weight. 3. The external composition according to 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 any one of 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. 5. The external composition according to any one of 1 to 4, which is an emulsified composition. 6. The external composition according to 5, which is an oil-in-water type. 【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. 【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 to Y" refers to the range from X to Y. 【0011】 [(A) Ceramide 2] The topical composition of the present disclosure 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 of the present disclosure suppresses insolubilization during manufacturing and creaming during storage. Furthermore, conventional topical compositions containing heparin-like substances and petrolatum cause insolubilization during manufacturing and creaming during storage. However, in the topical composition of the present disclosure, 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 substance] The topical composition of this disclosure 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 of this disclosure 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 of this disclosure, 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 topical composition of the present disclosure, the ratio of component (A) to component (B) is determined according to the content of each component, but 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, even more preferably 0.03 to 10 parts by weight, even more preferably 0.06 to 5 parts by weight, 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) Vaseline] The topical composition of the present disclosure contains vaseline in addition to the above components. Conventionally, topical compositions containing ceramide 2 and heparin-like substances result in insolubilization during manufacturing and creaming during storage. However, in the topical composition of the present disclosure, by using vaseline in combination with ceramide 2 and heparin-like substances, insolubilization during manufacturing and creaming during storage can be suppressed. Furthermore, conventionally, when vaseline is incorporated into topical compositions together with either ceramide 2 or heparin-like substances, insolubilization during manufacturing and creaming during storage occur. However, in the topical composition of the present disclosure, insolubilization during manufacturing and creaming during storage are suppressed. 【0019】 White petrolatum is preferably used as the petrolatum. White petrolatum is an oily component obtained by decolorizing and refining a mixture of hydrocarbons derived from petroleum. 【0020】The content of component (C) 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, 0.1 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. 【0021】 In the topical composition of the present disclosure, the ratio of component (A) to component (C) is determined according to the content of each component, but from the viewpoint of enhancing the effect of suppressing insolubilization and / or creaming, 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, even 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 topical composition of this disclosure, the ratio of component (B) to component (C) is determined according to the content of each component, but from the viewpoint of enhancing the effect of suppressing insolubilization and / or creaming, 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, even more preferably 8 to 30 parts by weight, and even more preferably 13 to 20 parts by weight. 【0023】 [Water] The topical compositions of the present disclosure contain water in order to prepare them into a desired formulation. The water content in the topical compositions of the present disclosure may be set appropriately depending on the formulation, etc., but for example, it is 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. 【0024】[Polyhydric Alcohols] The topical compositions of this disclosure may contain polyhydric alcohols as needed. 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, 1,3-butylene glycol is preferred. These polyhydric alcohols may be used individually 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 of this disclosure may contain surfactants to prepare them into a desired formulation. 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 compositions of this disclosure is a combination of polyoxyethylene sorbitan fatty acid ester and glycerin fatty acid ester. When polyoxyethylene sorbitan fatty acid ester and glycerin fatty acid ester are used in combination, 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 1,000 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 of this disclosure may contain an oily base (oil) 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 having 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 types. 【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 ingredients 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, etc. 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, and so on. 【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 salts thereof; 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 - Dosage Form] The topical composition of the present disclosure may be an emulsion formulation such as an oil - in - water emulsion formulation or a water - in - oil emulsion formulation, or may also be a non - emulsion formulation such as a solubilized formulation or an aqueous ointment. In the prior art, when ceramide 2 and heparin - like substances are contained in an emulsion formulation (especially an oil - in - water emulsion formulation), insolubilization during production and creaming due to storage tend to be remarkable. In contrast, in the topical composition of the present disclosure, even if it is an emulsion formulation, insolubilization during production and creaming due to storage can be effectively suppressed. In view of such an effect, as the topical composition of the present disclosure, preferably an emulsion formulation, more preferably an oil - in - water emulsion formulation, can be mentioned. 【0041】 Also, the topical composition of the present disclosure is used as a topical pharmaceutical for the skin or a quasi - drug for topical use on the skin, and is preferably used as a topical pharmaceutical for the skin. As the dosage form of the topical composition of the present invention, specifically, cream agents, lotion agents, gel agents, emulsion agents, liquid agents, patch agents, sticking agents, liniment agents, aerosol agents, aqueous ointment agents, pack agents, etc. can be mentioned. Among these, preferably cream agents and emulsion agents, more preferably cream agents, can be mentioned. 【0042】 [Manufacturing Method] The topical composition of the present disclosure can be manufactured according to known pharmaceutical formulation techniques according to its dosage form. For example, when the topical composition of the present disclosure is an emulsion formulation, the components to be contained are divided into water - soluble components and oil - based components, an aqueous phase containing water - soluble components and an oil phase containing oil - based components are prepared, and these are emulsified according to known techniques to be prepared. 【0043】 The following examples are shown to more specifically explain the present disclosure, but the present disclosure is not limited thereto. 【0044】 A topical composition (oil - in - water emulsion composition, cream agent) shown in Test Example Table 3 was prepared. Specifically, an oil - phase composition composed of the components of [1] and an aqueous - phase composition composed of the components of [2] and [3] were each dissolved at 80°C. Both the oil - phase composition and the aqueous - phase composition were in a state where the compounding components were dissolved. The oil - phase composition and the aqueous - phase composition were mixed at 80°C, stirred, and cooled to room temperature to prepare the topical composition. 【0045】<Evaluation of Suppression of Insolubilization>One drop of the topical composition immediately after preparation was placed on a slide glass and observed at 100-fold magnification with a polarizing microscope. The degree of insolubilization was evaluated on a 10-point scale where the case where no insoluble matter was observed was scored as "1", and the case where a large amount of insoluble matter was observed was scored as "10". More specifically, the degree of insolubilization was scored according to the degree of the amount of precipitated insoluble matter. Representative examples of the microscopic images in the case where the degree of suppression of insolubilization was score 1 or 10 are shown in Table 1. In Table 1, the length of the scale bar indicates 100 μm. The results are shown in Table 3. 【0046】 【0047】 <Evaluation of Suppression of Creaming>The prepared topical composition was filled into a vial and stored at 60 °C for 1 week. From the appearance after storage, the degree of creaming was evaluated on a 10-point scale where the case where no creaming was observed was scored as "1", and the case where significant creaming was observed was scored as "10". More specifically, the degree of creaming was evaluated according to the degree of the ratio of the thickness of the creaming phase (the concentrated region of the dispersed phase (oil phase) due to creaming) (the length from the lower end surface of the concentrated region to the upper surface of the topical composition) to the height of the topical composition in the vial. Representative examples of the appearance in the case where the degree of creaming was score 1 or 10 are shown in Table 2. In Table 2, the arrow indicates the position of the lower end surface of the concentrated region of the dispersed phase (oil phase) due to creaming, and the lower the position, the greater the degree of creaming. The results are shown in Table 3. 【0048】 【0049】 【0050】 As shown in Table 3, insolubilization did not occur in the topical composition not containing components (A) to (C) (reference example), but significant insolubilization was observed in the topical composition containing component (A) and component (B) (comparative example 1), the topical composition containing component (A) and component (C) (comparative example 2), and the topical composition containing component (B) and component (C) (comparative example 3). In contrast, in the topical compositions containing all of components (A) to (C) (Examples 1 and 2), insolubilization was significantly suppressed at each stage, and thus excellent production suitability was obtained at each stage. 【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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