Ceramide mixture for improving compatibility

Abstract

Disclosed herein is a ceramide mixture. In an aspect, the ceramide mixture of the present invention can effectively improve the compatibility and solubility of ceramide. In another aspect, the microparticles comprising the ceramide mixture of the present invention can have a skin barrier component composition having a structure closer to normal skin due to increased structural uniformity and increased long periodicity phase (LPP) and orthorhombic structure compared to the case of simply mixing skin barrier components, and allows for the minimal use of formulation raw materials that may cause side effects, such as solvents, surfactants, dissolution aids, and the like. Moreover, the skin barrier components within the particles are protected by a coating agent, reducing interactions with external components. In another aspect, when applied to an oil-in-water emulsion, the ceramide mixture composition helps the formation of liquid crystals compared to the use of ceramide alone, and thus it is expected to improve sensory properties and moisturizing effects, which are advantages due to the formation of liquid crystals.

Description

Ceramide mixture for improved compatibility

[0001] [Cross-reference to related applications]

[0002] This application claims the benefit and priority of Korean Patent Application No. 10-2023-0115811, filed August 31, 2023, entitled “Ceramide Mixture for Improving Compatibility” and Korean Patent Application No. 10-2024-0108872, filed August 14, 2024, entitled “Ceramide Mixture for Improving Compatibility”, the entire contents of all of which are incorporated herein by reference.

[0003]

[0004] Disclosed herein are ceramide mixtures having improved compatibility.

[0005] The skin barrier is one of the important organs of the human body that performs the skin's protective function. The skin barrier is composed of interstitial lipids, mainly composed of ceramides, cholesterol, and fatty acids, and keratinocytes, which are differentiated skin cells, and is explained by the "brick and mortar model" or the "sandwich model." This skin barrier (interstitial lipids) is known to act as a major barrier against harmful bacteria and substances entering from the outside. Among these, ceramides account for 30-50% by weight of interstitial lipids and play an important role in the skin barrier function, such as skin moisturization and protection.

[0006] It is known that various ceramides exist in the human body, and research results have reported 18 to 22 types. It is known that ceramides are a structure that combines a fatty acid moiety and a sphingoid base moiety, and that the carbon lengths of these moieties vary. In addition, the composition of ceramides varies depending on the skin area or health condition, and it has been found that ceramide composition changes in various skin diseases such as atopy, psoriasis, lamellar ichthyosis, Netherton syndrome, and Chanarin-Dorfman syndrome. Ceramide NP, also known as ceramide 3, makes up the highest proportion of 22.1% of ceramides in the human body, and it is known that ceramide NP is deficient in diseases such as atopy. Research has been conducted on its utilization, such as clinical trials to improve the human body's moisturizing power using ceramide NP.

[0007] However, the direct use of components with human-derived ceramide structures (natural ceramides) has problems such as high cost and low stability. To solve these problems, pseudo-ceramides were developed, and a representative example is PC-104 (Hydroxypropyl bispalmitamide MEA). PC-104 is a pseudo-ceramide developed around 1996. Its cytotoxicity and skin safety have been confirmed, and in various human moisturizing tests, it has been confirmed to be effective in improving atopic symptoms, moisturizing skin, and improving skin moisture condition. In a test comparing the moisturizing power of PC-104 and ceramide NP, it was reported that there was no difference between the two. In addition, it has been used in cosmetics for about 20 years since its development, and in 2006, it was also used as a ceramide ingredient in a medicated moisturizer approved by the USA FDA 510(k). Therefore, PC-104 is a raw material with similar usability and reliability to human-derived ceramide.

[0008] To date, there have been structural studies on skin barrier components containing ceramides, but structural studies on skin barrier mimics using ceramide-like molecules are scarce. Because the high-dimensional arrangement of lipid bilayers is also an important factor in the primary barrier function of ceramides, structural studies on lipid compositions, including ceramides, should also be conducted in advance. For example, transepidermal water loss (TEWL) has been reported to be related to the degree of orthorhombic packing in the stratum corneum of human skin. Furthermore, in diseases with skin barrier abnormalities such as atopy and psoriasis, the orthorhombic (ORT) structure decreases and the short periodicity phase (SPP) structure increases rather than the long periodicity phase (LPP) structure. Therefore, such structural studies are expected to help enhance the moisturizing properties of skin barrier components. Recently, studies using Fourier-transformed infrared spectroscopy (FTIR) have confirmed that mixed forms are more similar to the human body than ceramides alone. Similarly, if similar ceramides are mixed with ceramides of various structures, the structure can be examined to determine whether they are more suitable for the human body.

[0009] Meanwhile, ceramides are poorly soluble, which limits their use in various formulations or the creation of high-concentration products. Previous research on ceramide formulations or delivery systems typically involved the use of various surfactants or solubilizing agents, such as high-alcohols. Studies have utilized oil-in-water emulsions (O / W emulsions), microemulsions, vesicles using solubilizing agents, liposomes, nanoparticles, and microparticles. However, when utilizing ingredients that can disrupt the skin barrier, such as solubilizing agents or surfactants, the potential side effects of these agents must be considered, and the effects of surfactants on skin lipids can even lead to delipidation. Furthermore, clinical trials have shown that simply wiping the skin with a cotton pad soaked in a 4% SDS (Sodium dodecyl sulfate) solution can cause roughness, flaking, and dryness. This, in turn, alters the composition of ceramides, cholesterol, and fatty acids in the stratum corneum. Therefore, research into formulation methods that do not utilize these solubilizing agents is warranted.

[0010] Accordingly, the inventors of the present invention have endeavored to develop a method for implementing a more stable ceramide carrier while reducing the help of a solubilizing agent such as a surfactant through a study on the compatibility between ceramides, and as a result, confirmed the effect of improving the compatibility of a ceramide mixture, and completed the present invention by confirming the structural study of the ceramide carrier as a skin barrier and its effect on skin absorption.

[0011]

[0012] One object of the present invention is to provide a ceramide mixture with improved compatibility.

[0013]

[0014] To achieve the above object, the present invention provides a ceramide mixture comprising one or more ceramide NPs and PC-104 (Hydroxypropyl bispalmitamide MEA) in one aspect.

[0015]

[0016] In one aspect, the ceramide mixture of the present invention can effectively improve the compatibility and solubility of ceramide by including one or more ceramide NPs and PC-104 (Hydroxypropyl bispalmitamide MEA).

[0017] In another aspect, the microparticles including the ceramide mixture of the present invention have increased structural uniformity compared to a case where skin barrier components are simply mixed, and have increased long repetition periods and orthorhombic structures, so that they can have a skin barrier component composition with a structure closer to normal skin.

[0018] In another aspect, the microparticles including the ceramide mixture of the present invention can minimize the use of formulation raw materials that cause side effects, such as solvents, surfactants, and solubilizers, while the skin barrier components inside the particles can be protected by the coating agent, thereby minimizing interaction with components outside the particles, and have the advantage of being more stable in terms of dynamic equilibrium than carriers such as emulsions or liposomes.

[0019] In another aspect, the microparticles containing the ceramide mixture of the present invention can enhance liquid crystal formation. Specifically, the ceramide mixture, when applied to an oil-in-water emulsion, promotes liquid crystal formation compared to ceramide alone. Therefore, improved usability and moisturizing properties, which are benefits of liquid crystal formation, are also expected.

[0020] In another aspect, the composition of the present invention can be applied to sensitive skin or atopic skin without irritation by containing only a minimal amount of a large amount of surfactant or solubilizing agent.

[0021]

[0022] Figure 1 is about the total enthalpy of the ceramide mixture.

[0023] Figures 2a to 2f are about ceramide compatibility ratios (abbreviated as ratio): (a) 104 + NPM mixture (the lowest ratio is shown in the area around 104 : NPM = 9 : 1), (b) 104 + NPO (the lowest ratio is shown in the area around 104 : NPO = 9 : 1, similar to the 104 + NPM mixture), (c) 104 + NPS (the lowest ratio is shown in the area around 104 : NPS = 8 : 2), (d) NPS + NPM (poor compatibility, almost none below 1), (e) NPS + NPO (slightly better compatibility ratio is shown around NPS : NPO = 6 : 4, but worse than the mixture containing 104), (f) NPO + NPM (poor compatibility, almost none below 1). Since the enthalpy values ​​obtained through Differential Scanning Calorimetry (DSC) differ depending on the ceramide, a calculation method to compensate for this is necessary to compare the DSC values ​​of mixtures between different ceramides. Therefore, the measured DSC enthalpy value was divided by the theoretical enthalpy value calculated from the DSC enthalpy values ​​of the two unmixed ceramide raw materials, and this was defined as the ceramide compatibility ratio (or ratio) and used.

[0024] Figures 3A to 3D show small-angle X-ray scattering (SAXS) and X-ray diffraction (XRD) profiles of microparticles (MPs) and lipid films (LFs). All MPs were swollen with a 0.15% aqueous solution of polyacrylic acid. In Figures 3A to 3D, 1, 2: long periodicity phase (LPP), I: short periodicity phase (SPP), H: hexagonal, O: orthorhombic, and *: compatibility.

[0025] Figure 4 is about the effect of increasing liquid crystal by mixing ceramide.

[0026]

[0027] Hereinafter, the present invention will be described in detail.

[0028] In this specification, “ceramide” includes not only natural ceramides known to exist in the human body in the form of fatty acids bonded to amino groups of a sphingoid skeleton, but also pseudoceramides which are compounds having a similar chemical structure or function to natural ceramides.

[0029] In this specification, “ceramide NP” is a ceramide in which the sphingoid is phytosphingosine and the fatty acid is a non-hydroxy fatty acid.

[0030] There is a need for products that incorporate various raw materials and technologies to improve skin condition by supplying skin barrier components to the skin. The present inventors have developed a formulation technology that overcomes the poor solubility of ceramide, which was one of the existing problems, by examining the compatibility of pseudo-ceramide PC-104 and three types of ceramide NPs. As a result, they confirmed that the mixture of PC-104 and ceramide NPs had excellent compatibility. In addition, they prepared microparticles with a size of 380 μm or less by mixing mixed ceramide, stearic acid, and cholesterol, and through SAXS and WAXS analyses, they confirmed that the microparticles had more favorable conditions for forming a long periodicity phase (LPP) and an orthorhombic structure than ceramide alone or a combination of ceramide, stearic acid, and cholesterol.

[0031] Accordingly, the present invention relates to a ceramide mixture comprising, from one aspect, one or more ceramide NPs and PC-104 (Hydroxypropyl bispalmitamide MEA).

[0032] The present invention relates to a method for producing ceramides with improved compatibility, comprising a step of mixing at least one ceramide NP and PC-104 (Hydroxypropyl bispalmitamide MEA) from another aspect.

[0033] In an exemplary embodiment, the mixed ceramide may be manufactured by, but is not limited to, a method of simply mixing ceramides, a method of melting / cooling ceramides together, a method of mixing and dissolving ceramides with the help of a solvent and then removing the solvent, a method of milling and mixing in a milling machine, a neat grinding method, and a liquid-assisted grinding method.

[0034] In an exemplary embodiment, the ceramide NP may be characterized as being a ceramide NP to which a fatty acid having carbon atoms C10 to C24 is bound, but is not limited thereto.

[0035] In an exemplary embodiment, the fatty acid may include at least one selected from the group consisting of lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and oleic acid, and for example, may include lauric acid, myristic acid, palmitic acid, and stearic acid in combination thereof, and more specifically, may be a mixed form of 52-56 wt% of palmitic acid, 42-47 wt% of stearic acid, up to 2 wt% of myristic acid, and up to 1 wt% of lauric acid, but is not limited thereto.

[0036] In an exemplary embodiment, the ceramide NP may include, but is not limited to, one or more selected from the group consisting of a ceramide NP bound to stearic acid; a ceramide NP bound to oleic acid; and a mixed ceramide NP composed of a plurality of ceramide NPs bound to C14 to C24 fatty acids.

[0037] In an exemplary embodiment, the PC-104 and the ceramide NP may be included in a weight ratio of 9.99:0.01 to 1:9.

[0038] In an exemplary embodiment, the ceramide NP is a mixed ceramide NP composed of a plurality of ceramide NPs having C14 to C24 fatty acids bonded thereto, and may include the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 3:7, or 9.5:0.5 to 5:5. More specifically, in the above range, the PC-104 may be 9.99 or less, 9.95 or less, 9.9 or less, 9.85 or less, 9.8 or less, 9.75 or less, 9.7 or less, 9.65 or less, 9.6 or less, 9.55 or less, or 9.5 or less, or 3 or more, 3.25 or more, 3.5 or more, 3.75 or more, 4 or more, 4.25 or more, 4.5 or more, 4.75 or more, or 5 or more. Additionally, within the above range, the ceramide NP may be 0.01 or more, 0.05 or more, 0.1 or more, 0.15 or more, 0.2 or more, 0.25 or more, 0.3 or more, 0.35 or more, 0.4 or more, 0.45 or more, or 0.5 or more, or 7 or less, 6.75 or less, 6.5 or less, 6.25 or less, 6 or less, 5.75 or less, 5.5 or less, 5.25 or less, or 5 or less. For example, the weight ratio of the PC-104 and the ceramide NP may be about 9.5:0.5, about 9:1, or about 8.5:1.5. Within the above range, the compatibility of the ceramide mixture may be significantly improved.

[0039] In an exemplary embodiment, the ceramide NP is a ceramide NP bound with oleic acid, and may include the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 1:9, or 9.99:0.1 to 4:6. More specifically, in the above range, the PC-104 may be 9.99 or less, 9.95 or less, 9.9 or less, 9.85 or less, 9.8 or less, 9.75 or less, 9.7 or less, 9.65 or less, 9.6 or less, 9.55 or less, or 9.5 or less, or 1 or more, 1.25 or more, 1.5 or more, 1.75 or more, 2 or more, 2.25 or more, 2.5 or more, 2.75 or more, 3 or more, 3.25 or more, 3.5 or more, 3.75 or more, 4 or more. In addition, in the above range, the ceramide NP may be 0.01 or more, 0.05 or more, 0.1 or more, 0.15 or more, 0.2 or more, 0.25 or more, 0.3 or more, 0.35 or more, 0.4 or more, 0.45 or more, or 0.5 or more, or 9 or less, 9.75 or less, 9.5 or less, 9.25 or less, 8 or less, 8.75 or less, 8.5 or less, 8.25 or less, 8 or less, 7.75 or less, 7.5 or less, 7.25 or less, 7 or less, 6.75 or less, 6.5 or less, 6.25 or less, or 6 or less. For example, the weight ratio of the PC-104 and the ceramide NPs may be about 9:1. Within the above range, the compatibility of the ceramide mixture can be significantly improved.

[0040] In an exemplary embodiment, the ceramide NP is a ceramide NP bound with stearic acid, and may include the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 2:8, or 9.99:0.1 to 5:5. More specifically, in the above range, the PC-104 may be 9.99 or less, 9.95 or less, 9.9 or less, 9.85 or less, 9.8 or less, 9.75 or less, 9.7 or less, 9.65 or less, 9.6 or less, 9.55 or less, or 9.5 or less, or 2 or more, 2.25 or more, 2.5 or more, 2.75 or more, 3 or more, 3.25 or more, 3.5 or more, 3.75 or more, 4 or more, 4.25 or more, 4.5 or more, 4.75 or more, or 5 or more. Additionally, in the above range, the ceramide NP may be 0.01 or more, 0.05 or more, 0.1 or more, 0.15 or more, 0.2 or more, 0.25 or more, 0.3 or more, 0.35 or more, 0.4 or more, 0.45 or more, or 0.5 or more, or 8 or less, 7.75 or less, 7.5 or less, 7.25 or less, 7 or less, 6.75 or less, 6.5 or less, 6.25 or less, 6 or less, 5.75 or less, 5.5 or less, 5.25 or less, or 5 or less. For example, the weight ratio of the PC-104 and the ceramide NP may be about 8:2. Within the above range, the compatibility of the ceramide mixture may be significantly improved.

[0041] The present invention relates to a composition comprising the above ceramide mixture from another aspect.

[0042] In an exemplary embodiment, the composition may further comprise, but is not limited to, ethanol as a solvent.

[0043] In exemplary embodiments, the composition may further include, but is not limited to, fatty acids and / or cholesterol.

[0044] In an exemplary embodiment, the fatty acid may be a saturated fatty acid having 10 to 30 carbon atoms, and for example, the fatty acid may be at least one selected from the group consisting of, but not limited to, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, and behenic acid.

[0045] In an exemplary embodiment, the composition may be characterized as having a particle or film form, but is not limited thereto.

[0046] In an exemplary embodiment, the composition may be an emulsion formulation, and the emulsion formulation may be, but is not limited to, an oil-in-water emulsion (O / W emulsion) emulsion formulation.

[0047] In an exemplary embodiment, the emulsion formulation may be characterized by, but is not limited to, having a liquid crystal structure.

[0048] In an exemplary embodiment, the particles may be nanoparticles.

[0049] In an exemplary embodiment, the nanoparticles may further include various surfactants (e.g., lecithin, polysorbate, etc.) and may be manufactured through various manufacturing methods (e.g., high pressure emulsification, ultrasonic emulsification, chemical precipitation, spray drying, electrostatic spraying, mechanical milling, etc.).

[0050] In an exemplary embodiment, the nanoparticle diameter (size) may be, but is not limited to, 10 nm to 999 nm.

[0051] In an exemplary embodiment, the particles may be microparticles.

[0052] In an exemplary embodiment, the diameter (size) of the microparticles may be 400 μm or less, and more specifically, 1 μm or more, 10 μm or more, 20 μm or more, 30 μm or more, 40 μm or more, 50 μm or more, 60 μm or more, 70 μm or more, 80 μm or more, 90 μm or more, 100 μm or more, 110 μm or more, 120 μm or more, 130 μm or more, 140 μm or more, 150 μm or more, 160 μm or more, 170 μm or more, 180 μm or more, 190 μm or more, 200 μm or more, 210 μm or more, 220 μm or more, 230 μm or more, 240 μm or more, or 250 μm or more, or 400 μm or less, 395 μm or less, 390 μm or less, 385 μm or less, 380 μm Below, it can be 375 ㎛ or less, 370 ㎛ or less, 365 ㎛ or less, 360 ㎛ or less, or 355 ㎛ or less. For example, the diameter (size) of the microparticles can be 380 ㎛ or less, or 250 ㎛ to 355 ㎛, but is not limited thereto. Within the above range, the microparticles can effectively carry skin barrier components.

[0053] In an exemplary embodiment, the microparticles may be an emulsified formulation made by mixing two or more types of substances that do not mix with water, or two or more substances that do not mix with each other, and the particle size may be from 1 um or more to several hundred um, but is not limited thereto.

[0054] In an exemplary embodiment, the emulsifying formulation may be, but is not limited to, a mixture of water and vegetable oil, water and synthetic oil, water and silicone oil, or a mixture of silicone and an oil that is not miscible with silicone.

[0055] In another aspect, the present invention relates to a composition for moisturizing the skin; improving the skin moisture condition; or preventing, improving, or treating skin diseases, comprising the ceramide mixture.

[0056] In another aspect, the present invention relates to a cosmetic composition for moisturizing the skin; improving the skin moisture condition; or preventing or improving skin diseases, comprising the ceramide mixture.

[0057] In another aspect, the present invention relates to a food composition for moisturizing the skin, improving the skin moisture condition, or preventing or improving skin diseases, comprising the ceramide mixture.

[0058] From another perspective, the present invention relates to a pharmaceutical composition for preventing or improving skin diseases comprising the above ceramide mixture.

[0059] From another aspect, the present invention relates to a pharmaceutical composition for preventing or treating skin diseases comprising the above ceramide mixture.

[0060] The present invention relates to the use of the ceramide mixture for preparing a composition for moisturizing the skin; improving the skin moisture condition; or preventing, improving or treating skin diseases.

[0061] In another aspect, the present invention relates to the use of the ceramide mixture for moisturizing the skin; improving the moisture condition of the skin; or preventing, improving or treating skin diseases.

[0062] In one exemplary embodiment, the use is therapeutic or non-therapeutic.

[0063] In another aspect, the present invention relates to a method for moisturizing skin; improving skin moisture status; or preventing, improving, or treating a skin disease, comprising administering an effective amount of the ceramide mixture to a subject in need of moisturizing skin; improving skin moisture status; or preventing, improving, or treating a skin disease.

[0064] In an exemplary embodiment, the skin disease may be one or more selected from the group consisting of, but not limited to, atopy, psoriasis, lamellar ichthyosis, Netherton syndrome, and Chanarin-Dorfman syndrome.

[0065] In an exemplary embodiment, when a skin barrier component is applied, it can improve damaged skin barrier and increase skin hydration, and can also be used for the purpose of improving general skin hydration and skin moisture condition in addition to skin diseases.

[0066] In an exemplary embodiment, the composition may comprise 0.001 to 99.9 wt% of the active ingredient, for example, 0.01 to 20.0 wt% or 0.1 to 10.0 wt%, but is not limited thereto.

[0067] In an exemplary embodiment, the cosmetic composition can be prepared in the form of a general emulsified formulation and a solubilized formulation. The emulsified formulation includes a nourishing toner, a cream, an essence, etc., and the solubilized formulation includes a softening toner, etc. Suitable formulations are not limited thereto, but may be, for example, in the form of a solution, a gel, an anhydrous product in a solid or paste form, an emulsion obtained by dispersing an oil phase in an aqueous phase, a suspension, a microemulsion, a microcapsule, a microgranule, or an ionic (liposome) or nonionic vesicle dispersion, a cream, a skin, a lotion, a powder, an ointment, a spray, or a concealer stick. In addition, the cosmetic composition may be in the form of a foam or an aerosol composition further containing a compressed propellant.

[0068] In an exemplary embodiment, the cosmetic composition may additionally contain conventionally used adjuvants such as fatty substances, organic solvents, solubilizers, thickening and gelling agents, emollients, antioxidants, suspending agents, stabilizers, foaming agents, fragrances, surfactants, water, ionic or nonionic emulsifiers, fillers, sequestering agents, chelating agents, preservatives, vitamins, blocking agents, humectants, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles or any other ingredients conventionally used in cosmetic compositions.

[0069] In an exemplary embodiment, when the composition is used as an additive to a general food or health functional food, it can be added as is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method. The amount of active ingredients mixed can be appropriately determined depending on the intended use, such as prevention, health, or treatment. The food formulation can be in the form of powder, granules, pills, tablets, capsules, or any form of general food or beverage.

[0070] In an exemplary embodiment, there is no particular limitation on the type of the general food or health functional food, and examples of foods to which the composition can be added include dairy products including meat, confectionery, noodles, gum, ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and all foods in the conventional sense can be included.

[0071] In an exemplary embodiment, the beverage among the general foods or health functional foods may contain various flavoring agents or natural carbohydrates as additional ingredients, just like a regular beverage. The natural carbohydrates described above may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. As a sweetener, a natural sweetener such as thaumatin and stevia extract, or a synthetic sweetener such as saccharin and aspartame may be used. The proportion of the natural carbohydrate may be about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g, per 100 mL of the beverage according to the present invention, but is not limited thereto.

[0072] In an exemplary embodiment, in addition to the above, the general food or health functional food according to the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, and carbonating agents used in carbonated beverages. In addition, the food according to the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients may be used independently or in mixtures. The ratio of these additives is not limited, but is generally selected in the range of 0.01 to 0.1 parts by weight relative to 100 parts by weight of the health functional food according to the present invention.

[0073] In an exemplary embodiment, when the composition is used as an over-the-counter drug additive, the composition may be added as is or used together with other over-the-counter drugs or over-the-counter drug ingredients, and may be used appropriately according to a conventional method. The amount of the active ingredient mixed may be appropriately determined depending on the intended use. The ingredients included in the over-the-counter drug composition may include, in addition to the active ingredient, ingredients commonly used in over-the-counter drug compositions, and may include, for example, an abrasive, a wetting agent, a binder, a foaming agent, a sweetener, a preservative, a medicinal ingredient, a flavoring agent, a pigment, a solvent, a whitening agent, a solubilizer, or a pH adjuster.

[0074] In an exemplary embodiment, the pharmaceutical composition may be provided in any dosage form suitable for topical application. For example, it may be administered orally, transdermally, intravenously, intramuscularly, or subcutaneously. For example, the pharmaceutical composition may be, but is not limited to, an injection, a topical solution for skin use, a suspension, an emulsion, a gel, a patch, or a spray. The dosage form may be readily prepared according to a method conventional in the art, and may appropriately use surfactants, excipients, wetting agents, emulsifying promoters, suspending agents, salts or buffers for osmotic pressure adjustment, coloring agents, flavoring agents, stabilizers, preservatives, preservatives, or other commonly used auxiliary agents.

[0075] In one exemplary embodiment, the active ingredient of the pharmaceutical composition will vary depending on the subject's age, sex, weight, pathological condition and its severity, the route of administration, and the prescriber's judgment. Determining the appropriate dosage based on these factors is within the skill of those skilled in the art.

[0076]

[0077] Hereinafter, the composition and effects of the present invention will be described in more detail with examples. However, the examples below are provided for illustrative purposes only to aid understanding of the present invention and are not intended to limit the scope and scope of the present invention.

[0078]

[0079] [Example]

[0080] [Example 1]

[0081] Evaluation of improved compatibility by mixing ceramides

[0082] The compatibility of ceramides was evaluated using differential scanning calorimetry (DSC). Although DSC measurement is known to be useful for studying ceramide compatibility when polythermal and isothermal methods cannot be used or when the slurry density of the solution is high, it has rarely been used in ceramide research. In predicting the solubility of indomethacin (IMC) in polymers such as hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), it was confirmed that the DSC method predicted the solubility better in the combination of IMC and HPMC. Since the compatibility between ceramides is a situation where the solubility is confirmed when two solid substances are mixed, it was determined that a DSC experiment is very suitable. Therefore, the inventors of the present invention measured the enthalpy of each ceramide, predicted the enthalpy of the binary mixture, and actually measured it to confirm the compatibility. The ceramides used are as shown in Table 1. A Thermal Analysis System (differential scanning calorimeter) such as the Discovery DSC 250 from TA Instruments was used for the DSC measurement. The melting enthalpy was measured by obtaining the peak area from the DSC graph, and the unit of the peak area was J / g. The compatibility ratio was calculated by comparing the peak area measurement result of the sample mixed with ceramides with the calculated theoretical value (calculated sum area). The compatibility ratio is a ratio that indicates the compatibility of two components when mixed, and can be used to evaluate whether the two components are stable when mixed and can maintain desired characteristics.The above ratio is the measured peak area / calculated theoretical value. If the value is 1, it indicates that the measured peak area is the same as the theoretical value, and if the ratio is 0.5, it indicates that the actual measured peak area is half the theoretical value, so the substance can be melted with half the calculated energy. In other words, the smaller the value is than 1, the smaller the measured peak area is compared to the theoretical value, which means that the substance can be melted with low energy, and indicates excellent compatibility.

[0083] Ceramides used Sample Ceramide Type PC-104 HYDROXYPROPYL BISPALMITAMIDE MEANPOCERAMIDE NP (Oleic Acid) NPSCERAMIDE NP (Stearic Acid) NPMCERAMIDE NP (C 14~24 fatty acid mixture)

[0084] Samples without mixing PC-104 and ceramide NP (CERAMIDE NP) alone (10:0 or 0:10) and samples mixed with PC-104 and ceramide NP in ratios ranging from 1:9 to 9.99:0.01 were prepared, and the DSC peak areas were measured, and the actual measured DSC peak areas and calculated theoretical values ​​according to the ratio of PC-104 and ceramide NP were compared. For the compatibility evaluation, the ceramide mixing ratio with a low mutual compatibility ratio was identified.

[0085] The melting enthalpy values ​​of each ceramide are shown in Table 2 below. PC-104 showed the highest value at 151.6 J / g, and ceramide NP showed high enthalpy values ​​in the order of NPS, NPO, and NPM. Ceramide is a structure in which a sphingoid skeleton and a fatty acid are combined, and NPS, which is combined with stearic acid as a fatty acid, showed a higher enthalpy than NPO, which is combined with oleic acid. NPM is a ceramide raw material made using a mixture of fatty acids with various lengths ranging from 14 to 24 carbon atoms, and is a raw material in which ceramides of various structures are complexed, rather than a ceramide composed of a single structure. NPM showed the lowest total enthalpy value among NPs.

[0086] Total melting enthalpy of the ceramide used Product Name Melting Enthalpy (J / g) PC-104 151.6 NPS 114.6 NPO 89.0 NPM 45.3

[0087] As shown in Table 3, it was confirmed that the ratio was 0.5 or less in the range of 9.99:0.01 to 3:7 for PC-104:NPM, and in particular, it was confirmed that the ratio was 0.2 or less in the range of 9.5:0.5 to 5:5. That is, it was confirmed that the compatibility was significantly improved because the energy required for melting was reduced to less than 1 / 2 by mixing the two ceramides in the range of 9.99:0.01 to 3:7 for PC-104:NPM. In particular, when the weight ratio of PC-104:NPM was 9.5:0.5, 9:1, and 8.5:1.5, the ratio was similar at 0.1 or less. Including PC-104 and NPM can improve the ethanol solubility by 1.67 times compared to the theoretical value, and can improve it by 25 times compared to its use alone.

[0088] DSC analysis results according to the mixing ratio of PC-104 and NPMPC-104NPM peak area (J / g) calculated sum area (J / g) Ratio 100 151.6 151.6 1.00 9.99 0.01 65.4 151.50 43 9.50 53.9 146.30 039 14.9 141.00 038.51.57 2135.70 058 215.01 30.40 127 313.6 119.70 116 416.6 109.10 15 55 19.09 8.50 194 6 20.48 7.80 23 37 32.07 7.20 41 28 36.86 6.60 55 1944.05 5.90 79 010 45.3 45.31 00

[0089] Furthermore, as shown in Table 4, in the case of ceramide PC-104 and NPO, it was confirmed that the weight ratio of PC-104 and NPO was lower than 0.5 in the range of 9.99:0.01 to 1:9, and in particular, it was confirmed that the ratio was 0.2 or less in the range of 9.99:0.01 to 4:6.

[0090] DSC analysis results according to the mixing ratio of ceramide PC-104 and NPO 104NPO Peak area (J / g) Ratio 100 151.6 1.00 9.99 0.0 16.7 0.0 49.5 0.5 7.10.0 59 13.3 0.0 28.5 1.5 5.10.0 48 26.2 0.0 47 39.4 0.0 76 414.9 0.1 25 5 11.8 0.1 04 6 18.2 0.1 6 37 39.4 0.3 7 28 48.8 0.4 8 19 44.9 0.4 7 0 10 8 9.0 1 00

[0091] In addition, as shown in Table 5, in the case of PC-104 and NPS, it was confirmed that the weight ratio of PC-104 and NPS was 0.5 or less in the range of 9.99:0.01 to 2:8, and in particular, it was confirmed that the ratio was 0.2 or less in the range of 9.99:0.01 to 7:3 or 5:5.

[0092] DSC analysis results according to the mixing ratio of ceramide PC-104 and NPS104NPS Peak area (J / g) Ratio 100 151.6 1.00 9.99 0.01 14.00.09 9.50.5 15.50.109 120.90.14 8.51.5 14.40.108 25.00.04 73 26.10.19 64 30.70.22 55 17.40.13 464 2.70.33 37 60.30.48 28 60.10.49 198 2.70.70 010 114.61.00

[0093] When a binary mixture was prepared, PC-104 showed good compatibility overall. In the compatibility between PC-104 and NPS, NPO, and NPM, the compatibility ratios were very low, at 0.04 to 0.7, 0.02 to 0.48, and 0.03 to 0.79, respectively. In the mixture between NPS and NPO, the compatibility ratio was less than 1, confirming an improvement in compatibility, but the lowest value was 0.65, which was higher than when PC-104 was included. As shown in Fig. 2, the compatibility ratios between NPM and NPO were 0.97 to 1.49, and those between NPM and NPS were 1.05 to 1.27. Therefore, it was confirmed that in the mixture between ceramides, including PC-104 was more advantageous than not including it in terms of improving the enthalpy measured through DSC. Meanwhile, as shown in Fig. 1, the mixture between PC-104 and ceramide showed the lowest values ​​not only in the compatibility ratio but also in the enthalpy value. Specifically, the enthalpy value was 67.7 J / g for the mixture of NPS and NPO, 45.3 J / g for the mixture of NPS-NPM and NPO-NPM, 3.9 J / g for the mixture of PC-104 and NPM, 3.3 J / g for the mixture of PC-104 and NPO, and 5.0 J / g for the mixture of PC-104 and NPS (Tables 6 and 7). This dramatic improvement in the enthalpy of PC-104 confirmed the possibility of improving the solubility of the PC-104 mixture.

[0094] Total melting enthalpy of mixed ceramides obtained from DSC tests enthalpy (J / g)104RatioNPMNPONPS100.0151.6151.6151.699.965.46.714.095.03.97.115.590.04.93.320.985.07.25.114.480.015.06.25.070.013.69.426.160.016.614.930.750.019.011.817.440.020.418.242.730.032.039.460.320.036.848.860.110.044.044.982.70.045.389.0114.6

[0095] Final summary of the compatibility ratio obtained from the total melting enthalpy of mixed ceramides obtained from DSC tests. Interoperability Ratio 104 Ratio 104+NPM 104+NPO 104+NPS 100.01.001.001.0099.90.430.040.0995.00.030.050.1090.00.030.020.1485.00.050.040.1080.00.120.040 .0470.00.110.070.1960.00.150.120.2250.00.190.100.1340.00.230.160.3330.00.410.370.4820.00.550.480.4910.00.790.470.700.01.001.001.00

[0096]

[0097] [Example 2]

[0098] Evaluation of improved solubility by mixing ceramides

[0099] In Example 1, the compatibility improvement effect of ceramide blending was confirmed through DSC measurements. Furthermore, the solubility improvement effect was further confirmed. Specifically, solubility was assessed by measuring how well the ceramide or ceramide blend dissolved in pure ethanol (94.5% or higher).

[0100] As a result, as shown in Table 8, the solubility of ceramide PC-104 alone was measured to be approximately 0.04636 mg / uL, and the solubility of NPM was measured to be approximately 0.00275 mg / uL. When the ethanol solubility according to the mixture of ceramide PC-104 and NPM was confirmed, it was confirmed that the ethanol solubility increased as the DSC enthanolpy value decreased. Through this experiment, it was confirmed that the optimal mixture composition measured by DSC was also excellent in terms of ethanol solubility.

[0101] Ceramide PC-104 and NPM Solubility analysis results according to mixing ratio PC-104NPMEtOHSolubility (mg / uL)DSC Enthalpy (J / g) of the corresponding composition 100Approximately 0.04636151.691Approximately 0.070004.928Approximately 0.0432036.819Approximately 0.0166744.0010Approximately 0.0027545.3

[0102] The actual ethanol solubility by the PC-104:NPM = 0:10 mixing ratio (NPM alone) is approximately 0.00275 mg / uL, so the actual ethanol solubility by the PC-104:NPM = 9:1 mixing ratio shows a 25.5-fold improvement in solubility compared to the actual ethanol solubility by using NPM alone.

[0103]

[0104] [Example 3]

[0105] Preparation of microparticles and lipid film samples

[0106] Lipid microparticles were manufactured by mixing ceramide with the optimal combination of PC-104 and NPM derived through a ceramide compatibility study, and mixing stearic acid and cholesterol. The particles were manufactured using a fluidized bed granulator (GPCG-1, Glatt, Germany). The particles were manufactured by dissolving ceramide in a mixture of PC-104 and NPM at a ratio of 85 wt%:15 wt%, mixed stearic acid (raw materials in the form of a mixture of up to 2 wt% myristic acid, 52-56 wt% palmitic acid, 42-47 wt% stearic acid, and up to 1 wt% lauric acid), and cholesterol in a solvent such as ethanol and spraying them. The microparticles (104NP-MP) mixed with PC-104 and NPM were confirmed to have a size of less than 380 μm. It was confirmed that 104-MP made with only PC-104 as ceramide and the same ratio of mixed stearic acid and cholesterol had similar sizes. A mixture was prepared by dispersing the particles in 0.15 wt% polyacrylic acid (Goldschmidt, Germany). The lipid membrane was prepared by mixing 49.37 wt% of ceramide (85 wt% PC-104: 15 wt% NPM was considered as ceramide), 49.37 wt% of stearic acid, and 1.26 wt% of cholesterol, dissolving them by heating, and then pouring the dissolved solution into a mold so that it became a plate having a thickness of 2 mm or more, and then cooling it.

[0107]

[0108] [Example 4]

[0109] Small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS) analysis

[0110] To confirm the structural changes that occur when PC-104 and NPM are mixed, SAXS (Small-Angle X-ray Scattering) and WAXS (Wide-Angle X-ray Scattering) measurements were performed. SAXS allowed for the analysis of the lamellar structure of lipids, and WAXS allowed for the analysis of the packing structure between lipids. Meanwhile, through comparison between samples, it was confirmed that the lipid membrane (LF) was composed of only ceramide, fatty acid, and cholesterol, which is a structure that lipid compositions inherently prefer, and the internal structure of microparticles (MP) could be confirmed in a state suitable for skin application (Fig. 3). First, analysis using SAXS confirmed that a short periodicity phase (SPP) structure could exist in the lipid membrane (104-LF) containing PC-104 as ceramide, the lipid membrane (104NP-LF) containing PC-104 and NPM as ceramide, and the microparticle (104-MP) containing PC-104 through the I peak (4.73 nm). On the other hand, peaks 1 and 2 (9.99, 4.96 nm), which are presumed to be long periodicity phase (LPP), were confirmed only in the microparticle mixed with PC-104 and NPM (104NP-MP). In other words, this indicates that the LPP structure can be formed in MP only when ceramide is a mixture of 104 + NPM. In addition, 104LF showed two peaks of * (5.20 nm, 4.07 nm), whereas only the * peak (5.04 nm) was observed in 104NP-LF, indicating that 104NP-LF has a more uniform structure (Fig. 3C). Similarly to LF, 104-MP showed three peaks of * (6.1 nm, 4.96 nm, 3.99 nm), whereas 104NP-MP showed two peaks of * (4.96 nm, 3.99 nm), confirming that the structural uniformity was further increased (Fig. 3A).

[0111] WAXS measurements confirmed H and O peaks (0.42 nm, 0.38 nm), which may indicate hexagonal and orthorhombic structures, in all four samples. However, in the case of 104NP, the O peak (0.36 nm or 0.37 nm) was weakly confirmed in LF, but the O peak (0.38 nm) was stronger in MP. This meant that the orthorhombic structure may be stronger in MP. At the normal temperature of human skin (30 to 32°C), orthorhombic packing is dominant, but there is a study that observed a transition from orthorhombic to hexagonal lateral packing when the temperature of the stratum corneum is increased (30 to 40°C) (J. Bouwstra et al., The lipid organization of the skin barrier: liquid and crystalline domains coexist in lamellar phases. Volume 28, pages 211-223, (2002)). Therefore, the above results suggest that lipid components can be absorbed into the skin in a structural form closer to normal skin when MP is applied rather than LF.

[0112]

[0113] [Example 5]

[0114] Confirmation of the effect of increasing liquid crystallinity by mixing ceramides in an oil-in-water emulsion.

[0115] As shown in Table 9, emulsions were prepared according to the comparative example (PC-104 alone) and the example (PC-104 and NPM mixed at 85 wt%:15 wt%), and the liquid crystal formation was compared using a polarizing microscope.

[0116] Comparison of liquid crystal formation according to ceramide mixingComparative Example Example 5 Squalane 10 10 ARACHIDYL ALCOHOL * BEHENYL ALCOHOL * ARACHIDYL GLUCOSIDE * GLUCOSE * WATER 2 2 PC-10 4 1.5 1.5 NPM-0.28 Water 8 3.85 8 3.57 HYDROXYETHYL ACRYLATE / SODIUM ACRYLOYLDIMETHYL TAURATE COPOLYMER * SORBITAN ISOSTEARATE * POLYSORBATE 6 0 0.5 0.5 Mixture of 3 skin conditioning agents 2.15 2.15

[0117] As a result, it was confirmed that liquid crystal formation increased in the example as shown in Fig. 4. Since liquid crystal formation in emulsions is known to have various positive effects, such as improved moisturizing properties, the advantages of using a mixture of PC-104 and NPM compared to using PC-104 alone were also confirmed in oil-in-water emulsions.

[0118]

[0119] The present disclosure is further illustrated by the following non-limiting implementation examples.

[0120] Embodiment 1. A ceramide mixture comprising one or more ceramide NPs; and PC-104 (Hydroxypropyl bispalmitamide MEA).

[0121] Embodiment 2. A ceramide mixture according to Embodiment 1, wherein the ceramide NP is a ceramide NP to which a fatty acid having C14 to C24 carbon atoms is bound.

[0122] Embodiment 3. A ceramide mixture according to any one of Embodiments 1 to 2, wherein the fatty acid comprises at least one selected from the group consisting of palmitic acid, stearic acid, and oleic acid.

[0123] Embodiment 4. A ceramide mixture according to any one of Embodiments 1 to 3, wherein the ceramide NP comprises at least one selected from the group consisting of a ceramide NP to which stearic acid is bound; a ceramide NP to which oleic acid is bound; and a mixed ceramide NP composed of a plurality of ceramide NPs to which C14 to C24 fatty acids are bound.

[0124] Embodiment 5. A ceramide mixture according to any of Embodiments 1 to 4, comprising the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 1:9.

[0125] Embodiment 6. A ceramide mixture of any of Embodiments 1 to 5, wherein the ceramide NP is a mixed ceramide NP composed of a plurality of ceramide NPs having C14 to C24 fatty acids bonded thereto, and wherein the ceramide mixture comprises the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 3:7.

[0126] Embodiment 7. A ceramide mixture according to any one of Embodiments 1 to 6, wherein the ceramide NP is a ceramide NP to which oleic acid is bound, and the ceramide mixture comprises the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 1:9.

[0127] Embodiment 8. A ceramide mixture according to any one of Embodiments 1 to 7, wherein the ceramide NP is a ceramide NP bound to stearic acid, and the ceramide mixture comprises the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 2:8.

[0128] Embodiment 9. A composition comprising any of the ceramide mixtures of Embodiments 1 to 8.

[0129] Embodiment 10. A composition according to Embodiment 9, further comprising ethanol as a solvent.

[0130] Embodiment 11. A composition according to any of Embodiments 9 to 10, further comprising a fatty acid and / or cholesterol.

[0131] Embodiment 12. A composition according to any of Embodiments 9 to 11, wherein the fatty acid is a saturated fatty acid having 10 to 30 carbon atoms.

[0132] Embodiment 13. A composition according to any of Embodiments 9 to 12, wherein the composition has a particle or film form.

[0133] Embodiment 14. A composition according to any of Embodiments 9 to 13, wherein the composition is an emulsion formulation.

[0134] Embodiment 15. A composition according to any of Embodiments 9 to 14, wherein the emulsion formulation is an oil-in-water emulsion (O / W emulsion) emulsion formulation.

[0135] Embodiment 16. A composition according to any of Embodiments 9 to 15, wherein the emulsion formulation has a liquid crystal structure.

[0136] Embodiment 17. A composition according to any one of Embodiments 9 to 16, wherein the composition is a composition for moisturizing skin; improving skin moisture status; or preventing, improving, or treating skin diseases.

Claims

1. A ceramide mixture comprising 1.1 or more types of ceramide NPs; and PC-104 (Hydroxypropyl bispalmitamide MEA).

2. In paragraph 1, The above ceramide NP is a ceramide mixture, which is a ceramide NP to which a fatty acid having a carbon number of C14 to C24 is bound.

3. In paragraph 2, A ceramide mixture, wherein the fatty acid comprises at least one selected from the group consisting of palmitic acid, stearic acid, and oleic acid.

4. In paragraph 2, A ceramide mixture comprising at least one selected from the group consisting of a ceramide NP having stearic acid bound thereto; a ceramide NP having oleic acid bound thereto; and a mixed ceramide NP composed of a plurality of ceramide NPs having C14 to C24 fatty acids bound thereto.

5. In paragraph 1, A ceramide mixture comprising the above PC-104 and the above ceramide NP in a weight ratio of 9.99:0.01 to 1:

9.

6. In paragraph 5, The above ceramide NP is a mixed ceramide NP composed of a plurality of ceramide NPs having C14 to C24 fatty acids bonded thereto, and a ceramide mixture comprising the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 3:

7.

7. In paragraph 5, The above ceramide NP is a ceramide NP combined with oleic acid, and is a ceramide mixture comprising the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 1:

9.

8. In paragraph 5, The above ceramide NP is a ceramide NP bound to stearic acid, and is a ceramide mixture comprising the PC-104 and the ceramide NP in a weight ratio of 9.99:0.01 to 2:

8.

9. A composition comprising a ceramide mixture according to any one of claims 1 to 8.

10. In paragraph 9, A composition further comprising ethanol as a solvent.

11. In paragraph 10, A composition further comprising fatty acids and / or cholesterol.

12. In paragraph 11, A composition wherein the fatty acid is a saturated fatty acid having 10 to 30 carbon atoms.

13. In paragraph 9, The composition above is a composition having the form of particles or a film.

14. In paragraph 9, The above composition is a composition in the form of an emulsion.

15. In paragraph 14, The above emulsion formulation is a composition that is an oil-in-water emulsion (O / W emulsion) emulsion formulation.

16. In paragraph 14, The above emulsion formulation is a composition having a liquid crystal structure.

17. In paragraph 16, The composition is a composition for moisturizing the skin; improving the moisture condition of the skin; or preventing, improving, or treating a skin disease.

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