JP2022092861A - Ceramide-containing liposome - Google Patents

Abstract

To provide a new pharmaceutical technique that can improve the stability of liposome.SOLUTION: The liposome containing (A) ceramide and (B) N-acyl amino acid monoester has improved stability. Preferably, the liposome further contains (C) a liquid oil selected from the group consisting of a higher fatty acid and a higher alcohol and (D) a nonionic surfactant.SELECTED DRAWING: None

Description

The present invention relates to ceramide-containing liposomes that can be easily formed and have excellent stability. The present invention also relates to an external composition using the liposome.

Ceramide is an important component of the skin and is considered to have a function of protecting the inside of the skin from external stimuli. Therefore, ceramide is blended and used in an external composition for the purpose of protecting the skin. However, ceramide has poor compatibility with both water and oily components. Therefore, the external composition containing ceramide has a pharmaceutical problem such as formation of an insoluble matter by long-term storage. Therefore, for the purpose of stably blending ceramide, it has been blended in the external composition in the form of an emulsified composition.

On the other hand, with the recent development of liposome formation technology, a technique for encapsulating ceramide in liposomes (vesicles formed using phospholipids) has also been developed. For example, in Non-Patent Document 1, the diameter is increased by swelling only the hydrophilic portion in the lamellar structure sandwiching the ceramide lipid.
A technique for preparing a single membrane vesicle of 40 nm and thereby formulating a ceramide lipid in a transparent state up to a concentration of 1% is described. Further, Non-Patent Document 2 describes a technique using phospholipid sphingomyelin as a liposome material.

"Development of transparent lotion containing high concentration of ceramide that succeeded in enhancing the barrier function of the stratum corneum with lotion", [online], October 6, 2008, Patent Society, [November 3, 2008 Search], Internet <URL: http://www.pola-rm.co.jp/pdf/release_2008_7.pdf J Liposome Res. 2010 Mar; 20 (1): 49-54.

In the technique of Non-Patent Document 1, the stability of liposomes has not been sufficiently investigated, and the amount of ceramide that can be blended into a lotion by forming liposomes is at most 1%. In the technique of Non-Patent Document 2, the material is limited in that a special liposome material called sphingomyelin is required. However, liposome formation of ceramide is still under development, and it is often difficult to form liposomes other than the already developed liposome formation method, and even if liposomes are formed, they are stable in terms of stability. Often not enough.

Therefore, an object of the present invention is to provide a new pharmaceutical technique capable of improving the stability of liposomes.

As a result of diligent studies, the present inventor has found that liposomes with excellent stability can be obtained by using N-acylamino acid monoester for liposome formation of ceramide. The present invention has been completed by further studies based on this finding.

That is, the present invention provides the inventions of the following aspects.
Item 1. Liposomes containing (A) ceramide and (B) N-acylamino acid monoester.
Item 2. Item 2. The liposome according to Item 1, wherein the content of the component (B) per part by weight of the component (A) is 0.3 to 15 parts by weight.
Item 3. Item 2. The liposome according to Item 1 or 2, further comprising (C) a liquid oil selected from the group consisting of higher fatty acids and higher alcohols.
Item 4. Item 3. The liposome according to Item 3, wherein the component (C) is a higher fatty acid.
Item 5. Item 3. The liposome according to Item 3 or 4, wherein the content of the component (C) per part by weight of the component (A) is 0.4 to 22 parts by weight.
Item 6. Item 2. The liposome according to any one of Items 1 to 5, further comprising (D) a nonionic surfactant.
Item 7. Item 6. The liposome according to Item 6, wherein the component (D) is selected from the group in which the component (D) is composed of a polyglycerin fatty acid ester, a polyoxyethylene sterol ether, and a polyoxyethylene polyoxypropylene alkyl ether.
Item 8. Item 6. The liposome according to Item 6 or 7, wherein the HLB value of the component (D) is 10 or more.
Item 9. The composition for external use containing the liposome according to any one of Items 1 to 8.
Item 10. Item 9. The external composition according to Item 9, wherein the content of the component (A) is 1.5 to 8% by weight.
Item 11. Item 9. The external composition according to Item 9 or 10, wherein the content of the component (C) is 2 to 6% by weight.

INDUSTRIAL APPLICABILITY According to the present invention, a new pharmaceutical technique capable of improving the stability of liposomes is provided.

1. 1. Liposomes The liposomes of the present invention contain (A) ceramide (hereinafter, also referred to as "(A) component") and (B) N-acylamino acid monoester (hereinafter, also referred to as "(B) component"). It is characterized by including. Hereinafter, the external composition of the present invention will be described in detail.

(A) Ceramide The liposome of the present invention contains ceramide as the component (A). Ceramide is a kind of sphingolipid, and is a known component as a general term for a group of compounds in which a long-chain fatty acid is amide-bonded to an amino group of sphingosine.

Ceramide has ceramide 1, ceramide 2, ceramide 3, ceramide 4, ceramide 5, ceramide 6I, ceramide 6II, ceramide 7, and ceramide due to differences in the structure of sphingosine (N? Acyl group structure, etc.) and the structure of long-chain fatty acids. 8, ceramide 9, ceramide 10, and the like can be mentioned. These ceramides may be used alone or in combination of two or more. Among these ceramides, a ceramide selected from the group consisting of ceramide 1, ceramide 2, ceramide 3, ceramide 6I, and ceramide 6II is preferably mentioned, and more preferably from the group consisting of ceramide 1, ceramide 2, and ceramide 3. Two or more kinds of ceramides to be selected are mentioned, and more preferably, a combination of ceramide 1, ceramide 2 and ceramide 3 is mentioned.

The origin of the ceramide used in the present invention is not particularly limited and may be appropriately set according to the type of ceramide and the like, for example, those extracted from animals and plants, those obtained by a microbial fermentation method, and chemically. It may be any of those synthesized.

(B) N-acylamino acid monoester The liposome of the present invention contains N-acylamino acid monoester as a component (B). By using N-acylamino acid monoester to form liposomes of ceramide, stable liposomes can be formed.

The N-acylamino acid monoester is not particularly limited as long as it is a compound in the form of a monoester of an N-acylated amino acid and an alcohol.

Examples of the acyl group of the N-acylated amino acid include a linear or branched acyl group having 6 to 22 carbon atoms, and specifically, a caproyl group, a lauroyl group, a myritoyl group, a palmitoyl group, a stearoyl group and a behenoyl group. Examples thereof include a group, a linoleic acid, a linoloyl group, an oleoyl group, an isostearoyl group, a 2-ethylhexanoyl group, a cocoyl group and the like. Examples of the amino acid of the N-acylated amino acid include neutral amino acids such as glycine, alanine, β-alanine, aminobutyric acid, aminopropionic acid, sarcosine, and N-methyl-β-alanine. Examples of the alcohol include linear or branched alcohols having 1 to 40 carbon atoms, preferably 2 to 8 carbon atoms, cyclic alcohols having 3 to 30 carbon atoms, sterol and the like, and more specifically, methanol, ethanol and propanol. , Isopropanol, butanol, t-butanol, isobutanol, 3-methyl-1-butanol, 2-methyl-1-butanol, pentanol, hexanol, cyclohexanol, octanol, 2-ethyl-hexanol, decanol; cyclopropanol, cyclo Butanol, cyclopentanol, cyclohexanol; cholesterol, dihydrocholesterol, phytosterol and the like can be mentioned.

As the N-acyl amino acid monoester, one kind may be used alone from the compound group consisting of the above-mentioned amino acid having the above-mentioned acyl group and the above-mentioned alcohol, or a plurality of kinds may be used in combination. good. Among these N-acylamino acid monoesters, monoesters of N-lauroyl sarcosine and 2 to 8 linear or branched chain alcohols are preferable from the viewpoint of further improving the stability of liposomes, and more preferably. Examples include N-lauroyl sarcosine isopropyl.

In the liposome of the present invention, the content of the component (B) per part by weight of the component (A) is not particularly limited, and examples thereof include 0.3 to 15 parts by weight. From the viewpoint of further improving the stability of the liposome, the content of the component (B) per 1 part by weight of the component (A) is preferably 0.3 to 5 parts by weight, more preferably 0.4 to 3. 1 part by weight, more preferably 0.5 to 2.6 parts by weight, still more preferably 0.6 to 2.1 parts by weight, still more preferably 0.65 to 1.6 parts by weight, 0.75 to 1. Examples thereof include 26 parts by weight or 0.8 to 1.1 parts by weight. Further, from the viewpoint of improving the permeability of the component (A) into the stratum corneum of living skin, the content of the component (B) per part by weight of the component (A) is preferably 0.3 to 5 weight by weight. Parts, more preferably 0.3 to 3.1 parts by weight, still more preferably 0.3 to 2.6 parts by weight, still more preferably 0.3 to 2.1 parts by weight, still more preferably 0.3 to 1 part. 6.6 parts by weight, particularly preferably 0.3 to 1.26 parts by weight, and most preferably 0.3 to 1.1 parts by weight.

(C) Predetermined liquid oil The liposome of the present invention is (from the viewpoint of diversifying the composition of other components, increasing the amount of ceramide, and / or further improving the stability of the liposome. C) The component preferably contains a liquid oil selected from the group consisting of higher fatty acids and higher alcohols. Examples of "higher" in higher fatty acids and higher alcohols include 16 to 24 carbon atoms. The liquid oil is an oil that maintains a liquid form at 25 ° C.

Examples of the liquid higher fatty acid include isostearic acid, oleic acid, linoleic acid, linolenic acid and the like. These liquid higher fatty acids may be used alone or in combination of two or more. Among these liquid higher fatty acids, isostearic acid and oleic acid are preferable.

Examples of the liquid higher alcohol include hexyldecanol, isostearyl alcohol, octyldodecanol, decyltetradecanol, oleyl alcohol and the like. These liquid higher alcohols may be used alone or in combination of two or more. Among these liquid higher alcohols, isostearyl alcohol is preferable.

In the present invention, only one of the higher fatty acid and the higher alcohol may be used, or both may be used in combination. From the viewpoint of further improving the stability of the liposome, higher fatty acid is preferable, isostearic acid and oleic acid are more preferable, and isostearic acid is more preferable.

In the liposome of the present invention, the content of the component (C) per part by weight of the component (A) is not particularly limited, and examples thereof include 0.4 to 22 parts by weight. From the viewpoint of further improving the stability of the liposome, the content of the component (C) per 1 part by weight of the component (A) is preferably 0.6 to 22 parts by weight, more preferably 0.68 to 22 parts by weight. Parts, more preferably 0.75 to 22 parts by weight, still more preferably 0.83 to 22 parts by weight, even more preferably 0.9 to 22 parts by weight, particularly preferably 0.97 to 22 parts by weight, 1 to 22 parts. Examples thereof include parts by weight, 1.1 to 22 parts by weight, or 1.2 to 22 parts by weight. Further, from the viewpoint of improving the permeability of the component (A) into the stratum corneum of living skin, the content of the component (C) per part by weight of the component (A) is per part by weight of the component (A). The content of the component (C) is preferably 0.4 to 15 parts by weight, more preferably 0.4 to 10.5 parts by weight, still more preferably 0.4 to 7.5 parts by weight, still more preferably. 0.4 to 4.5 parts by weight, even more preferably 0.4 to 2.3 parts by weight, particularly preferably 0.4 to 2.0 parts by weight, 0.4 to 1.8 parts by weight, or 0. 4 to 1.7 parts by weight can be mentioned.

(D) Nonionic Surfactant The liposome of the present invention preferably contains a nonionic surfactant as the component (D) from the viewpoint of further improving the stability of the liposome.

The nonionic surfactant is not particularly limited. Specific examples of the nonionic surfactant include glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, and polyoxyethylene. Lanolin / lanolin alcohol / honey wax derivative, polyoxyethylene castor oil / hardened castor oil, polyoxyethylene sterol ether, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene fatty acid ester, monostearate polyoxy Ethylene glycerin, polyoxyethylene cetyl ether stearate, polyoxyethylene stearyl ether stearate, polyoxyethylene lauryl ether stearate, polyoxyethylene lauryl ether isostearate, polyoxyethylene hydrogenated castor oil fatty acid ester, polyoxyethylene trimethylol propane Examples thereof include fatty acid esters and sucrose fatty acid esters. These nonionic surfactants may be used alone or in combination of two or more.

Among these nonionic surfactants, it is preferable to select from polyglycerin fatty acid ester, polyoxyethylene sterol ether, and polyoxyethylene polyoxypropylene alkyl ether from the viewpoint of further improving the stability of liposomes. ..

Examples of the polyglycerin fatty acid ester include polyglycerin fatty acid esters having 12 to 24 carbon atoms in the fatty acid, 1 to 5 additions of the fatty acid, and 2 to 12 mol of the addition number of the glycerin. The polyoxyethylene sterol ether is selected from the group consisting of 5 to 50 mol of ethylene oxide and phytosterol, cholesterol and their hydrogenated additives (that is, phytostanol and chorestanol). Ether is mentioned. As the polyoxyethylene polyoxypropylene alkyl ether, the polyoxyethylene polyoxypropylene alkyl ether having an addition number of ethylene oxide of 1 to 50 mol, an addition number of propylene oxide of 2 to 16 mol, and an alkyl carbon number of 12 to 24. Can be mentioned.

Among these nonionic surfactants, from the viewpoint of further improving the stability of the liposome, the HLB value is preferably 10 or more, more preferably 11 to 19.5, still more preferably 14 to 14. 19, more preferably 15 to 18.5, even more preferably 15.5 to 18, and particularly preferably 16 to 18. The HLB value (hydrophilic-lipophilic balance) indicates the molecular weight of the hydrophilic group portion in the total molecular weight of the surfactant, and is determined by the Griffin formula.

Specific examples of preferable nonionic surfactants include polyglyceryl monooleate-5 (HLB value 12.5) and polyglyceryl-6 monolaurate (HLB value 14.5) as polyglycerin fatty acid esters having an HLB value of 10 or more. , Polyglyceryl-6 monomyristate (HLB value 11.0), Polyglyceryl monolaurate-10 (HLB value 15.5), Polyglyceryl monomyristate-10 (HLB value 14.0), Polyglyceryl monostearate-10 (HLB). Value 12.0), polyglyceryl monoisostearate-10 (HLB value 12.0), polyglyceryl monooleate-10 (HLB value 12.0), polyglyceryl diisostearate-10 (HLB value 10.0) and the like. As polyoxyethylene sterol ethers having an HLB value of 10 or more, POE (10) phytosterol (HLB12.5), POE (20) phytosterol (HLB15.5), POE (30) phytosterol (HLB18.0), POE (25) Phytostanol (HLB14.5), POE (30) cholestanol (HLB17.0) and the like; as a polyoxyethylene polyoxypropylene alkyl ether having an HLB value of 10 or more, POE (10) POP (4) cetyl ether ( HLB value 10.5), POE (20) POP (4) cetyl ether (HLB value 16.5), POE (20) POP (8) cetyl ether (HLB value 12.5), POE (20) POP (6) ) Tetradecyl ether (HLB value 11.0), POE (30) POP (6) Tetradecyl ether (HLB value 12.0), POE (7) POP (2) Tetradecyl ether (HLB value 10.0), POE (10) POP (2) tetradecyl ether (HLB value 12.0), POE (12) POP (2) tetradecyl ether (HLB value 12.0), POE (15) POP (2) tetradecyl ether (2) HLB value 13.0), POE (20) POP (2) tetradecyl ether (HLB value 14.0), POE (30) POP (2) tetradecyl ether (HLB value 15.0) and the like can be mentioned.

In the liposome of the present invention, the content of the component (D) per 1 part by weight of the component (A) is not particularly limited, and examples thereof include 0.5 to 20 parts by weight. From the viewpoint of further improving the stability of the liposome, the content of the component (D) per 1 part by weight of the component (A) is preferably 1 to 10 parts by weight, more preferably 1.5 to 5 parts by weight. More preferably, 1.8 to 2.2 can be mentioned.

Other Membrane Constituents In addition to the above-mentioned components, the liposome of the present invention may contain other membrane constituents, if necessary, as long as it does not interfere with the effects of the present invention. Examples of such membrane constituents include phospholipids, phospholipid polymers, sterols, and charged substances other than the component (B).

Phospholipids include natural phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lysophosphatidylcholine, sphingomyelin, egg yolk lecithin, soybean lecithin, synthetic phospholipids such as dioleoil phosphatidylcholine; extracted from microorganisms such as Escherichia coli. Phospholipids; Examples thereof include hydrogenated phospholipids in which the unsaturated carbon chains of these phospholipids are saturated with hydrogen. These phospholipids can be used alone or in combination of two or more.

Examples of the phospholipid polymer include polymethacrylicloyloxyethylphosphorylcholine, 2-methacrylicoyloxyethylphosphorylcholine / butylmethacrylate copolymer, 2-methacrylicoyloxyethylphosphorylcholine / butylmethacrylate / sodium methacrylate copolymer, and 2-methacrylic acid. Examples thereof include oxyethylphosphorylcholine / 2-hydroxy-3-methacrylicoyloxypropyltrimethylammonium chloride copolymer, 2-methacryloyloxyethylphosphorylcholine / stearylmethacrylate copolymer and the like. These phospholipid polymers may be used alone or in combination of two or more.

Examples of sterols include cholesterol, phytosterol, cholesteryl acetate, cholesteryl nonanoate, cholesteryl stearate, cholesteryl isostearate, cholesteryl oleate, phytosteryl isostearate, phytosteryl stearate, phytosteryl oleate, phytosteryl palmitole, and soft lanolin fatty acid cholesteryl. Examples thereof include hard lanolin fatty acid cholesteryl, long-chain branched fatty acid cholesteryl, long-chain α-hydroxy fatty acid cholesteryl, and 12-hydroxystearate cholesteryl. These sterols may be used alone or in combination of two or more.

Examples of the charged substance include fatty acids such as lauric acid, myristic acid, palmitic acid, ellagic acid and eleostearic acid; fatty acid salts such as these sodium salts, potassium salts, calcium salts and ammonium salts; phosphatidic acid and disetyl. Phosphate and the like can be mentioned. These charged substances may be used alone or in combination of two or more.

Among these other membrane constituents, phospholipids are preferable, and hydrogenated phospholipids are more preferable. The content of the phospholipid per 1 part by weight of the component (A) is, for example, 1 to 25 parts by weight, preferably 1.2 to 10 parts by weight, more preferably 1.4 to 5 parts by weight, still more preferable. Is 1.6 to 4 parts by weight, more preferably 2 to 3 parts by weight.

Other Ingredients The liposome of the present invention may contain an active ingredient exhibiting cosmetic or pharmacological activity, if necessary. Such active ingredients are not particularly limited, but are, for example, water-soluble vitamins and derivatives thereof, oil-soluble vitamins and derivatives thereof, glycyrrhizinic acid and derivatives thereof, glycyrrhetinic acid and derivatives thereof, astaxanthin, coenzyme Q10, α-. Glycosaminoglycans such as lipoic acid, ceramide or similar substances, linoleic acid, arbutin, tranexamic acid, kodiic acid, enzymes, peptides, hormones, various cytokines, hyaluronic acid, salts thereof, and salts thereof or derivatives thereof, hyaluron Acid hydrolyzate or its salt, collagen or its hydrolyzate, elastin or its hydrolyzate, physiologically active substances such as sugars, various animal and plant extracts, substances obtained by fermentation with microorganisms, steroids, antihistamine, local anesthesia Examples thereof include agents, anti-inflammatory agents, antibacterial agents, antibacterial agents, antipruritic agents, skin protective agents, blood circulation promoters, steroids and the like. These active ingredients may be used alone or in combination of two or more. These active components may be contained in any one of the inner aqueous phase (inner phase of liposome), the outer aqueous phase (outer phase of liposome), and the inside of the membrane (inside the liposome membrane).

Further, the liposome of the present invention contains, in addition to the water forming the internal aqueous phase and the external aqueous phase, an additive to be added to the external composition for skin, if necessary, as long as the effect of the present invention is not impaired. It may be. Examples of such additives include lower monohydric alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol and butylene glycol; oils such as squalane and vaseline; antioxidants such as dibutylhydroxytoluene and sulfite. Agents; preservatives such as phenokiethanol, octoxyglycerin, parabens; pigments, pearling agents, thickeners, surfactants, stabilizers, chelating agents, coloring agents, fragrances, buffers, pH adjusters, etc. Be done. These additives may be contained in any of the inner aqueous phase (inner phase of the liposome), the outer aqueous phase (outer phase of the liposome), and the inside of the membrane (inside the liposome membrane) in the liposome of the present invention.

Production Method / Form The method for producing a liposome of the present invention is not particularly limited, and examples thereof include the following production methods. In a dispersion medium such as polyhydric alcohol, hydrogenated lecithin, the above-mentioned component (B), or any of the above-mentioned (C) components and / or any of the above-mentioned other membrane constituent components (other than a surfactant), and the above-mentioned (A). ) Is dissolved, water is added, and if necessary, other than the above-mentioned component (D) and / or any above-mentioned surfactant is added, and stirring (for example, homomixer treatment, etc.) is performed. It can be prepared as a liposome solution.

The liposome of the present invention may be used in the form of a liposome solution obtained by the above-mentioned production method, or may be used in the form of a powdered liposome obtained by subjecting it to a known powdering treatment.

2. 2. External composition The above-mentioned liposome of the present invention can be used as a raw material to be added to an external composition such as cosmetics and external pharmaceuticals. Therefore, the present invention also provides an external composition containing the above-mentioned liposomes.

In the external composition of the present invention, the content of the component (A) constituting the liposome in the external composition is, for example, 0.01 to 8% by weight. Since the above-mentioned liposome of the present invention is excellent in stability, excellent stability can be maintained even if the amount of the component (A) in the external composition is large. From this point of view, a preferred example of the component (A) in the external composition is preferably 1 to 8% by weight, more preferably 1.5 to 8% by weight, still more preferably 1.8 to 8% by weight. %, More preferably 2 to 6% by weight. Further, from the viewpoint of further improving the stability of the liposome, preferably 0.01 to 5% by weight, more preferably 0.01 to 4.5% by weight, still more preferably 0.01 to 4% by weight, still more preferable. Is 0.01 to 3.5% by weight, more preferably 0.01 to 3.2% by weight.

When the liposome in the external composition of the present invention contains the component (C), the content of the component (C) constituting the liposome in the external composition is, for example, 0.5 to 6% by weight. Can be mentioned. Since the above-mentioned liposome of the present invention is excellent in stability, excellent stability can be maintained even if the amount of the component (C) in the external composition which is a liquid oil is large. From this point of view, a preferred example of the component (C) in the external composition is preferably 2 to 6% by weight, more preferably 2.5 to 6% by weight, still more preferably 2.8 to 6% by weight. %. Further, from the viewpoint of further improving the stability of the liposome, preferably 0.5 to 4.5% by weight, more preferably 0.5 to 3.5% by weight, still more preferably 0.5 to 3.2% by weight. %.

The dosage form of the external composition according to the present invention may be liquid, solid, cream, gel or the like.

As the formulation form of the external composition of the present invention, for example, cosmetics such as creams, lotions, beauty liquids, milky lotions, gels, lipsticks, foundations; liquids (including lotions, sprays, aerosols, and milky lotions). , Foams, ointments, creams, gels, patches and the like for external use.

Further, even if the external composition of the present invention contains an active ingredient exhibiting cosmetic activity or pharmacological activity, an additive for preparing into a predetermined formulation form, water, etc., depending on the formulation form thereof. good. The types of such active ingredients and additives are the same as those exemplified as the above-mentioned components that can be contained in the inner aqueous phase, the outer aqueous phase, or the inside of the membrane of the liposome of the present invention.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Test Examples The external compositions shown in Tables 1 and 2 were prepared. Specifically, hydrogenated lecithin is dissolved by heating (80 ° C.) with 1,3-butylene glycol (BG), and the component (B) or the component (b), the component (C), and the component (A) are added in this order. It was added and heated (80 ° C.) to dissolve. Further, heated (80 ° C.) water was slowly added dropwise, the heated component (D) was added, and then the mixture was stirred with a homomixer and emulsified. The composition was filtered through a membrane filter and cooled to obtain an external composition in which liposomes were dispersed. The obtained external composition was evaluated as follows. The results are shown in Tables 1 and 2.

<Dispensability>
The formability of liposomes was evaluated according to the following criteria.
◯: No separation was observed during dispensing, and filtration was possible without difficulty.
Δ: A little undesired separation was observed during dispensing, but filtration was possible for the time being.
X: Filtration could not be performed due to solid-liquid separation or viscous liquid separation during dispensing.
Of these evaluations, only the evaluation of ○ was judged to have formed liposomes well.

<Stability>
The external composition evaluated as ◯ in the above-mentioned dispensing property test was scored according to the following criteria in terms of appearance and particle size. The room temperature is 25 ° C.
6: Stable at room temperature for at least 18 months 5: Stable at room temperature for at least 2 months 4: Stable at room temperature for at least 1 month 3: Stable at room temperature for at least 2 weeks 2: Stable at room temperature for at least 1 week 1: Stable at room temperature for at least 3 days Stable

<Permeability>
(1) Preparation of sample solution for test The external composition evaluated as ◯ in the above dispensing property test was prepared so that the ceramide content was 1% by weight immediately after the preparation. The obtained 1% by weight ceramide solution was used as a test sample solution.

(2) Equipment used In vivo confocal Raman spectroscope gen2-SCA (RiverD International BV) was used. This device can measure the amount of substance at each depth of the stratum corneum non-invasively, such as with a living human arm.

(3) Application conditions Cotton (1 layer out of 4 layers is divided and used) containing the test sample solution inside the upper arm of a living human (9 healthy men and women, 9 arbitrary arms), and 6 It was used in equal sizes.) Was pasted and left for 30 minutes. After that, the skin surface was wiped off and left to stand for 10 minutes.

(4) Evaluation method The amount of ceramide in the skin depth direction of 2 μm to 20 μm was measured at the unapplied site and the site where the test sample solution was applied. Five points were measured for each part, and the average value was taken as the value at the depth. Furthermore, the results with 9 arms were averaged. The relative value (%) of the average value in the coated portion was calculated when the average value in the non-coated portion was 100%, and the evaluation was made based on the following criteria.
⊚: 112% or more ◯: 108% or more and less than 112% Δ: 100% or more and less than 108% The larger the relative value, the larger the amount of permeation of living skin into the stratum corneum.

As shown in Comparative Examples 1 to 5, liposomes containing ceramide could not be formed when the component b was used, but when lauroyl sarcosine isopropyl was used as shown in Examples 1 to 15 (Example 1). Liposomes containing ceramide could be formed in ~ 15). Above all, as shown in the comparison between Examples 1 to 4 and 11 and Example 12. When fatty acid was used as the C component, the stability was further improved. Further, as shown in the comparison between Examples 1 to 4, 13 and Examples 14, 15, and 10, the stability is also obtained when a predetermined high HLB value specific ionic surfactant is used as the D component. It has improved even more.

Claims (11)

Liposomes containing (A) ceramide and (B) N-acylamino acid monoester. The liposome according to claim 1, wherein the content of the component (B) per part by weight of the component (A) is 0.3 to 15 parts by weight. The liposome according to claim 1 or 2, further comprising (C) a liquid oil selected from the group consisting of higher fatty acids and higher alcohols. The liposome according to claim 3, wherein the component (C) is a higher fatty acid. The liposome according to claim 3 or 4, wherein the content of the component (C) per part by weight of the component (A) is 0.4 to 22 parts by weight. The liposome according to any one of claims 1 to 5, further comprising (D) a nonionic surfactant. The liposome according to claim 6, wherein the component (D) is selected from the group consisting of a polyglycerin fatty acid ester, a polyoxyethylene sterol ether, and a polyoxyethylene polyoxypropylene alkyl ether. The liposome according to claim 6 or 7, wherein the HLB value of the component (D) is 10 or more. An external composition comprising the liposome according to any one of claims 1 to 8. The external composition according to claim 9, wherein the content of the component (A) is 1.5 to 8% by weight. The external composition according to claim 9 or 10, wherein the content of the component (C) is 2 to 6% by weight.