Linoleic acid-encapsulated liposome-containing composition

Abstract

To provide a linoleic acid-encapsulated liposome-containing composition that stably contains linoleic acid and liposomes. [Solution] The solution comprises liposomes and a liposome outer phase composition, wherein the liposome outer phase composition comprises (A) tocopherol, (B) a specific surfactant, and (C) a divalent or trivalent C2-C6 alkyl alcohol. Composition containing linoleic acid-encapsulated liposomes

Description

[Technical Field]

[0001] This disclosure relates to a composition containing liposomes encapsulating linoleic acid, and to a method for producing a composition containing liposomes encapsulating linoleic acid. [Background technology]

[0002] Linoleic acid is a polyunsaturated fatty acid with skin-whitening properties and is incorporated into topical compositions such as cosmetics, quasi-drugs, and topical pharmaceuticals. Generally, polyunsaturated fatty acids have poor stability, so technologies for stably incorporating them into compositions have been investigated. For example, Patent Document 1 describes a technology that improves the time-dependent stability of polyunsaturated fatty acids by incorporating a specific amount of vitamin E, etc., into an emulsion. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Special Publication No. 2010-502733 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Liposomes are artificial capsules composed of phospholipids and other materials that are major components of biological membranes. Phospholipids have an amphiphilic structure and form a lipid bilayer (in other words, a bilayer membrane). Because oil-soluble substances can be incorporated into the bilayer membrane, this property is utilized to encapsulate some oil-soluble substances in liposomes for purposes such as increasing their stability.

[0005] The inventors have considered improving a composition containing linoleic acid encapsulated in liposomes (i.e., linoleic acid-encapsulated liposomes) and further enhancing the stability of linoleic acid. This composition is expected to preferably exhibit effects such as a whitening effect when used particularly as an external composition (e.g., a cosmetic composition). In this external composition, since the stability is improved by encapsulating linoleic acid, an active ingredient, in liposomes, it is considered important that not only linoleic acid but also liposomes are stably contained, and measures to further improve these stabilities have been investigated. **Means for Solving the Problems**

[0006] This disclosure encompasses, for example, the subject matter described in the following items. Item 1. A liposome-containing composition containing liposomes and a liposome outer phase composition, where the liposomes are linoleic acid-encapsulated liposomes encapsulating linoleic acid, and the liposome outer phase composition (A) tocopherol, (B) polyethylene glycol (PEG)-n , , a , h , <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​(C) A divalent or trivalent C2-C6 alkyl alcohol, comprising a composition containing linoleic acid-encapsulated liposomes. Item 2. The composition according to Item 1, comprising 0.1 to 10 parts by mass of (A) with respect to 1 part by mass of linoleic acid. Item 3. The composition according to Item 1 or 2, comprising 0.1 to 10 parts by mass of (B) with respect to 1 part by mass of linoleic acid. Item 4. The composition according to any one of Items 1 to 3, comprising 10 to 500 parts by mass of (C) with respect to 1 part by mass of linoleic acid. Item 5. The composition according to Item 1, comprising 0.1 to 10 parts by mass of (A), 0.1 to 10 parts by mass of (B), and 10 to 500 parts by mass of (C) with respect to 1 part by mass of linoleic acid. Item 6. The composition according to any one of Items 1 to 5, wherein the Z-average particle size of the liposomes is 10 to 90 nm. Item 7. The composition according to any one of Items 1 to 6, which is a topical composition. Item 8. (C) is at least one selected from the group consisting of 1,3-butylene glycol and glycerin, and the composition according to any one of Items 1 to 7.

Advantages of the Invention

[0007] A composition containing linoleic acid-encapsulated liposomes is provided. The composition is one with improved stability of linoleic acid compared to the prior art. Further, the composition has high stability of the liposomes over time, and in particular, an increase in the particle size of the liposomes can be preferably suppressed. Generally, it is considered that the smaller the particle size of liposomes, the higher the skin permeability tends to be. Therefore, it is expected that the composition can also exhibit the effect of being less likely to reduce skin permeability due to the suppression of an increase in particle size. From the above, the composition can be suitably used as a topical composition (for example, a cosmetic composition).

Modes for Carrying Out the Invention

[0008] The embodiments included in this disclosure will be described in more detail below. This disclosure preferably includes, but is not limited to, compositions containing linoleic acid-encapsulating liposomes (linoleic acid-encapsulating liposomes) and methods for producing the same, and this disclosure includes everything disclosed herein and recognizable to those skilled in the art.

[0009] The linoleic acid-encapsulated liposome-containing compositions included in this disclosure are compositions in which the liposome outer phase composition comprises (A) tocopherol, (B) a specific surfactant, and (C) a divalent or trivalent C2-C6 alkyl alcohol. Such linoleic acid-encapsulated liposome-containing compositions may be referred to as the compositions of this disclosure.

[0010] The composition of this disclosure is a composition containing liposomes encapsulating linoleic acid, as described above. In other words, the composition of this disclosure may also be said to contain a liposome inner phase composition (which can also be said to be a composition encapsulated within the liposome), a liposome membrane (which can also be said to be a membrane separating the liposome inner phase composition from the liposome outer phase composition), and a liposome outer phase composition (which can also be said to be the composition of this disclosure other than the liposome). Note that a liposome may also be said to be a liposome inner phase composition enclosed by a liposome membrane. For this reason, the composition of this disclosure may also be said to contain liposomes and a liposome outer phase composition.

[0011] The liposomes contained in the compositions of this disclosure (sometimes referred to as the liposomes of this disclosure) are not particularly limited as long as they contain linoleic acid.

[0012] The linoleic acid content in the compositions of this disclosure is not particularly limited as long as the desired effect is obtained, but may be, for example, 0.0001 to 10% by mass relative to the total amount of the compositions of this disclosure. The upper or lower limits of the range may be, for example, 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by mass. The range is preferably, for example, 0.001 to 5% by mass, more preferably 0.01 to 1% by mass, and even more preferably 0.05 to 0.5% by mass.

[0013] In the composition of this disclosure, linoleic acid is encapsulated in liposomes. The linoleic acid content in the liposomes of this disclosure is preferably 0.05 to 5% by mass, more preferably 0.1 to 4% by mass, and even more preferably 0.5 to 2% by mass, relative to the liposomes of this disclosure.

[0014] Furthermore, linoleic acid may be encapsulated within liposomes, and linoleic acid may also be contained outside of liposomes. For example, linoleic acid may be encapsulated within liposomes, and linoleic acid may also be contained in the liposome outer phase composition. When linoleic acid is contained in the liposome outer phase composition, it is preferable that the sum of the amount of linoleic acid contained in the liposomes and the amount of linoleic acid contained in the liposome outer phase composition is within the range described above. Although not particularly limited, when linoleic acid is contained in the liposome outer phase composition, for example, the amount may be 0.01 to 1% by mass or 0.05 to 0.5% by mass relative to the composition of this disclosure. In this disclosure, unless otherwise specified, linoleic acid content refers to the total amount of linoleic acid contained in the composition of this disclosure.

[0015] In this disclosure, "liposome" refers to an artificial vesicle having at least one lipid bilayer membrane. Liposomes are classified into multilayer liposomes (MLVs) and monolayer liposomes based on the number of lipid bilayer membranes, and monolayer liposomes are further classified into SUVs (small unilamella vesicles), LUVs (large unilamella vesicles), GUVs (giant unilamella vesicles), etc., according to their size. The liposomes of this disclosure may have any of the above structures. In the case of multilayer liposomes, the total composition of all components other than the outermost lipid bilayer membrane is referred to in this disclosure as the liposome internal phase composition.

[0016] The liposomes of this disclosure contain phospholipids, which are amphiphilic substances. In particular, it is preferable that they are contained in the lipid bilayer membrane. The phospholipids have a structure in which fatty acids and phosphate are bonded to a central backbone of glycerol or sphingosine, and an alcohol is ester-bonded to the phosphate. The phospholipids contained in the liposomes of this disclosure may be glycerophospholipids with glycerol as the central backbone, or sphingophospholipids with sphingosine as the central backbone, but it is preferable that they contain at least glycerophospholipids.

[0017] Examples of phospholipids include phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, and sphingomyelin. Phospholipids are found in lecithin, for example. From the viewpoint of availability and economics, the liposomes of this disclosure preferably contain lecithin as a component (particularly as a membrane component).

[0018] Examples of lecithins include soy lecithin, egg yolk lecithin, hydrogenated soy lecithin, hydrogenated egg yolk lecithin, and synthetic lecithin. Among these, soy lecithin and / or egg yolk lecithin are particularly preferred. Purified lecithin with increased phospholipid purity is also preferably used. The liposomes of this disclosure may contain one or more phospholipids and / or lecithin.

[0019] If the composition of this disclosure contains lecithin, its content is not particularly limited as long as the desired effect is obtained, but may be, for example, 0.01 to 10% by mass relative to the total amount of the composition of this disclosure. The upper or lower limit of this range may be, for example, 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by mass. From the viewpoint of more stably encapsulating linoleic acid in liposomes, if the composition of this disclosure contains lecithin, its content is preferably 0.05 to 5% by mass, more preferably 0.1 to 1% by mass, and even more preferably 0.2 to 0.8% by mass relative to the total amount of the composition of this disclosure.

[0020] Furthermore, if the composition of this disclosure contains lecithin, it is preferable that it be contained in the lipid bilayer membrane of the liposome as described above. In this case, the amount of lecithin is preferably 1 to 10% by mass, more preferably 2 to 8% by mass, and even more preferably 3 to 5% by mass, relative to the liposome of this disclosure.

[0021] If the composition of this disclosure contains lecithin, the mass ratio of the lecithin content to the linoleic acid content (lecithin content / linoleic acid content) may be, for example, 0.5 to 30. From the viewpoint of stably encapsulating linoleic acid in liposomes, the mass ratio of the lecithin content to the linoleic acid content is preferably 1 to 20, more preferably 2 to 10, and particularly preferably 2 to 6. The upper or lower limit of the above range may be 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0022] In this disclosure, "encapsulation" of linoleic acid in liposomes means that linoleic acid is contained within the structure of a lipid vesicle (liposome), which is mainly formed of a lipid bilayer. The linoleic acid encapsulated in liposomes in this disclosure is preferably contained within a space surrounded by the liposome membrane, which is a lipid bilayer, but may also be present with the components of the liposome membrane, may be present between the multiple membranes constituting a multilayer liposome, may be present in a form attached to or bound to the surface of the outermost membrane of the lipid bilayer constituting the liposome, or may be present in all or part of these forms.

[0023] The Z-average particle size of the liposomes in this disclosure is preferably 90 or 80 nm or less, more preferably 70 nm or less, even more preferably 60 nm or less, and particularly preferably 55 nm or less. The lower limit is not particularly limited, but may be, for example, 10 nm or more. The Z-average particle size of the liposomes in this disclosure may be, for example, 10 to 90 nm. From the viewpoint of the transparency of the composition, the stability of the liposomes over time, and the skin permeability of the liposomes, the Z-average particle size of the liposomes in this disclosure is preferably 15 to 80 nm, more preferably 20 to 70 nm, even more preferably 25 to 60 nm, and particularly preferably 30 to 55 nm. The upper or lower limits of the Z-average particle size range are 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 4 9, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 nm.

[0024] Generally, the Z-average particle size of liposomes can be adjusted by known methods or methods readily conceivable from known methods. For example, when a stirrer is used to prepare a liposome dispersion, the Z-average particle size tends to decrease as the stirrer's rotation speed increases and the stirring time increases. When a high-pressure wet atomizer is used to prepare a liposome dispersion, the Z-average particle size tends to decrease as the pressure increases and the number of times the material passes through the flow path increases.

[0025] Generally, the Z-mean particle size can be measured and calculated by known methods or methods readily conceivable from known methods, for example, by using a particle size measuring device that utilizes light scattering. In this disclosure, the Z-mean particle size is determined by the dynamic light scattering method. More specifically, it can be determined as the Z-mean value calculated from the particle size distribution measured using a particle size measuring device that utilizes light scattering. For this measurement and calculation, for example, the Zetasizer Nano ZS (Malvern) and its accompanying software can be used.

[0026] The pH of the composition of this disclosure (more specifically, the liposome outer phase composition of the composition of this disclosure) is not particularly limited, but is preferably 9 or lower from the viewpoint of skin irritation, etc. The pH of the composition of this disclosure is preferably 6.2 to 9, more preferably 6.4 to 8.5, and even more preferably 6.6 to 8. The upper or lower limit of the above range may be 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, or 9.5. The pH is measured with a pH meter at 25°C.

[0027] pH can be adjusted by known methods or by methods readily conceivable from known methods. For example, pH adjusting agents may be used, and examples of pH adjusting agents include citric acid, phosphoric acid, malic acid, pyrophosphate, lactic acid, tartaric acid, glycerophosphate, acetic acid, nitric acid, and chemically possible salts thereof (particularly alkali metal salts, especially sodium salts and potassium salts), as well as sodium hydroxide, potassium hydroxide, arginine, triethanolamine, etc. In the art of this disclosure, from the viewpoint of availability and economics, it is preferable to adjust the pH of the composition using at least one pH adjusting agent selected from the group consisting of citric acid and its salts, sodium hydroxide, and potassium hydroxide.

[0028] Furthermore, the liposome outer phase composition of the composition disclosed herein contains, as described above, (A) tocopherol, (B) a specific surfactant, and (C) a divalent or trivalent C2-C6 alkyl alcohol. These may be referred to as component (A), component (B), and component (C), respectively.

[0029] (A) Examples of tocopherols include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, etc., with δ-tocopherol being preferred. Tocopherol succinate or tocopherol acetate may also be used. Either the d-isomer or the l-isomer can be used, with the dl-isomer and d-isomer being preferred, and the dl-isomer being more preferred. In particular, dl-α-tocopherol, d-α-tocopherol, dl-δ-tocopherol, d-δ-tocopherol, etc. are preferred, with dl-δ-tocopherol being more preferred. (A) Tocopherols can be used individually or in combination of two or more.

[0030] Although component (A) is included in the liposome outer phase composition, this does not prevent component (A) from being included in the liposomes themselves.

[0031] (B) The specific surfactant used as component is PEG-n p Phytosterols, POE(n c ) Cholesteryl ether, PEG-nh Hydrogenated castor oil, POE(n a )C10-30 linear alkyl ethers, and PCA isostearate glycereth-n i It is at least one surfactant selected from the group consisting of the following: PEG represents polyethylene glycol, POE represents polyoxyethylene, and PCA represents pyrrolidone carboxylic acid.

[0032] PEG-n p Phytosterols are compounds that have a structure in which PEG (polyethylene glycol (PEG)) is bonded to a phytosterol (in other words, compounds that have a structure in which ethylene oxide is added polymerized to a phytosterol). PEG-n p In phytosterols, n p is the number of moles of ethylene oxide added, preferably 5 to 50, more preferably 10 to 40, and even more preferably 10 to 30. More specifically, PEG-10 phytosterol, PEG-20 phytosterol, PEG-30 phytosterol, etc., are preferred examples. PEG-n p Phytosterols can be used individually or in combination of two or more types.

[0033] POE(n c Cholesteryl ethers are compounds that have a structure in which ethylene oxide is added to cholesterol through polymerization. (POE stands for polyoxyethylene.) c is the number of moles of ethylene oxide added, preferably 5 to 50, more preferably 10 to 40, and even more preferably 10 to 30. Note that POE(n c ) Cholesteryl ether is Choleth-n c (For example, Choleth-10, Choleth-20, Choleth-24, Choleth-30, etc.) are commercially available. More specifically, POE(10) cholesteryl ether (Choleth-10), POE(20) cholesteryl ether (Choleth-20), POE(30) cholesteryl ether (Choleth-30), etc. are preferred examples. c Cholesteryl ethers can be used individually or in combination of two or more types.

[0034] PEG-n h Hydrogenated castor oil is a compound having a structure in which PEG (polyethylene glycol (PEG)) is bonded to hydrogenated castor oil. (In other words, it is a compound having a structure in which ethylene oxide is added polymerized to hydrogenated castor oil.) h is the number of moles of ethylene oxide added, and is 80 or more, preferably 80 to 150, more preferably 80 to 120, and even more preferably 90 to 110. More specifically, PEG-80 hydrogenated castor oil, PEG-100 hydrogenated castor oil, PEG-120 hydrogenated castor oil, PEG-150 hydrogenated castor oil, etc. are preferably exemplified. h Hydrogenated castor oil can be used alone or in combination of two or more types.

[0035] POE(n a C10-30 linear alkyl ethers are compounds having a structure in which ethylene oxide is added polymerized (ether bonded) to a linear alkyl alcohol with 10-30 carbon atoms. (POE stands for polyoxyethylene.) a is the number of moles of ethylene oxide added, preferably 10 to 50, more preferably 10 to 40, and even more preferably 10 to 30. The number of C10 to 30 alkyl groups is preferably C15 to 30, and more preferably C20 to 30. These POE(n) structures are obtained by arbitrarily combining the number of moles of ethylene oxide added and the number of C10 to 30 alkyl groups. a )C10-30 linear alkyl ethers can preferably be used. POE(n a )C10~30 linear alkyl ethers, more specifically, POE(n a )C22 linear alkyl ether (beheneth-n a ), POE(n a )C12 linear alkyl ether (laureth-n a ), POE(n a )C16 linear alkyl ether (ceteth-n a ), POE(n a )C18 linear alkyl ether (steareth-n aExamples include POE(n a C10-30 linear alkyl ethers can be used individually or in combination of two or more.

[0036] PCA isostearate glycereth-n i This is an ester of a mixture of isostearic acid and pyrrolidone carboxylic acid (PCA) with glycerin obtained by addition polymerization of ethylene oxide. i is the average number of moles of ethylene oxide added, preferably 20 to 30, more preferably 22 to 28, and particularly preferably 25.

[0037] (B) Component can be used alone or in combination of two or more components.

[0038] Component (C), as described above, is a divalent or trivalent alkyl alcohol having 2 to 6 carbon atoms, with divalent or trivalent alkyl alcohol having 2 to 4 carbon atoms being more preferred. More specifically, examples include ethylene glycol, propylene glycol, 1,3-butylene glycol, isoprene glycol, and glycerin, among which are preferred.

[0039] (C) Component can be used alone or in combination of two or more types.

[0040] Although component (C) is included in the liposome outer phase composition, this does not prevent component (C) from being included in the liposome.

[0041] In the compositions of this disclosure, component (A) is preferably present in an amount of 0.01 to 1% by mass, more preferably 0.05 to 0.5% by mass, and even more preferably 0.05 to 0.2% by mass.

[0042] Furthermore, in the composition of this disclosure, component (A) is preferably present in an amount of 0.1 to 10 parts by mass per 1 part by mass of linoleic acid. The upper or lower limit of this range (0.1 to 10 parts by mass) may be, for example, 0.2, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, or 9 parts by mass. This range may be, for example, 0.2 to 5 parts by mass or 0.5 to 3 parts by mass.

[0043] If component (A) is also contained in the liposomes, the above-mentioned content and content ratio refer to the total amount of component (A) contained in the composition of this disclosure (i.e., the sum of the amount contained in the liposomes and the amount contained in the liposome outer phase composition). In this case, the amount of component (A) contained in the liposomes is preferably about 0.05 to 0.5 parts by mass, and more preferably about 0.07 to 0.2 parts by mass, per 1 part by mass of linoleic acid.

[0044] Furthermore, in the composition of this disclosure, component (B) is preferably present in an amount of 0.01 to 1% by mass, more preferably in an amount of 0.05 to 0.5% by mass, and even more preferably in an amount of 0.1 to 0.3% by mass.

[0045] Furthermore, in the composition of this disclosure, component (B) is preferably present in an amount of 0.1 to 10 parts by mass per 1 part by mass of linoleic acid. The upper or lower limit of this range (0.1 to 10 parts by mass) may be, for example, 0.2, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, or 9 parts by mass. This range may be, for example, 0.2 to 5 parts by mass or 0.5 to 4 parts by mass.

[0046] Furthermore, in the compositions of this disclosure, component (C) is preferably present in an amount of 2 to 20% by mass, more preferably 5 to 15% by mass, and even more preferably 7 to 13% by mass. In particular, when component (C) includes 1,3-butylene glycol and glycerin, the mass ratio of these components is preferably 1:2 to 2:1.

[0047] Furthermore, in the composition of this disclosure, component (C) is preferably present in an amount of 10 to 500 parts by mass per 1 part by mass of linoleic acid. The upper or lower limit of this range (10 to 500 parts by mass) may be, for example, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, or 450 parts by mass. This range may be, for example, 20 to 400 parts by mass or 50 to 200 parts by mass.

[0048] If component (C) is also contained in the liposomes, the above-mentioned content and content ratio refer to the total amount of component (C) contained in the composition of this disclosure (i.e., the sum of the amount contained in the liposomes and the amount contained in the liposome outer phase composition). In this case, the amount of component (C) contained in the liposomes is preferably about 5 to 30 parts by mass, and more preferably about 10 to 20 parts by mass, per 1 part by mass of linoleic acid. Furthermore, if component (C) is also contained in the liposomes, the component (C) contained in the liposomes is preferably 1,3-butylene glycol.

[0049] For example, the composition of this disclosure can be prepared by a method that includes mixing a dispersion of liposomes containing linoleic acid with a composition containing water or other components. In this disclosure, when preparing the composition of this disclosure in this manner, the composition mixed with the dispersion of liposomes containing linoleic acid may be referred to as an intermediate composition. In other words, in this disclosure, an intermediate composition means a composition that can be used to prepare the composition of this disclosure by mixing it with a dispersion of liposomes containing linoleic acid. When preparing the composition of this disclosure using an intermediate composition, the liposome outer phase composition of the composition of this disclosure can be said to be a composition obtained by mixing the portion of the liposome dispersion other than the liposomes with the intermediate composition.

[0050] It is also possible to prepare the intermediate composition in multiple parts. For example, it is possible to prepare intermediate composition precursor composition I and intermediate composition precursor composition II, mix intermediate composition precursor composition I with a dispersion of liposomes containing linoleic acid, and then further mix in intermediate composition precursor composition II. In this case, the combined intermediate composition precursor compositions I and II can be called the intermediate composition.

[0051] When preparing the composition of this disclosure by the said method, it is preferable to use an intermediate composition containing component (A), component (B), and component (C).

[0052] By adding an alkali such as potassium hydroxide to the intermediate composition and adjusting the pH of the final composition to a specific range (specifically, pH 6.2 to 9.5), the Z-average particle size of the liposomes containing linoleic acid in the final composition can be adjusted.

[0053] The compositions of this disclosure may further contain known components that can be included in topical compositions, to the extent that they do not impair the effects of this disclosure. Examples of such known components include water, humectants, oils other than linoleic acid, surfactants other than component (B), thickeners, film-forming agents, preservatives, chelating agents, antioxidants, colorants, fragrances, cooling agents, UV absorbers, various powders, and known functional components other than linoleic acid used in topical compositions. The compositions of this disclosure may optionally contain one or more of these known components.

[0054] Furthermore, whether these known components are included in the liposomes or in the liposome outer phase composition can be appropriately determined as long as the effects of the composition disclosed herein are not impaired.

[0055] Examples of humectants include sugars such as trehalose, lactulose, and maltitol; sugar alcohols such as sorbitol, mannitol, and maltitol; and polyhydric alcohols such as diethylene glycol, polyethylene glycol, and diglycerin. Humectants can be used individually or in combination of two or more.

[0056] Examples of oils other than linoleic acid include vegetable oils, triglycerides, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, and silicone oils. These oils can be used individually or in combination of two or more.

[0057] (B) Other surfactants include, for example, anionic surfactants such as polyoxyethylene alkyl ether sulfate, alkyl sulfate ester, alkyl amide ether sulfate, polyoxyethylene alkyl amide ether sulfate, α-olefin sulfonate, alkyl sulfosuccinate, polyoxyethylene alkyl ether acetate, alkyl phosphate, polyoxyethylene alkyl ether phosphate, higher fatty acid salt, N-acyl amino acid salt, N-acyl isethionate, and N-acyl methyl taurate; Cationic surfactants such as quaternary ammonium salts; Amphoteric surfactants such as amidopropyl betaine type, amidoamine oxide type, sulfobetaine type, imidazoline type, and alkylbetaine type: Examples of nonionic surfactants include polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbitan fatty acid esters, polyoxyalkylene sorbitan fatty acid esters, polyoxyalkylene glycerin fatty acid esters, polyoxyalkylene fatty acid amides, polyoxyalkylene glycol fatty acid esters, polyoxyalkylene castor oil derivatives, polyoxyalkylene hydrogenated castor oil derivatives, polyglycerin fatty acid esters, sorbitan fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, alkyl glycol fatty acid esters, alkyl polyglycosides, fatty acid alkanolamides, and the like.

[0058] As mentioned above, the specific surfactant used as component (B) is PEG-n h Hydrogenated castor oil (n h Where n is the number of moles of ethylene oxide added (which is 80 or more), h PEG-n with a value of less than 80 (preferably 70 or less, more preferably 20 to 70, even more preferably 30 to 60) h Hydrogenated castor oil can be preferably used as a surfactant other than component (B). When a surfactant other than component (B) is used, PEG-n h Hydrogenated castor oil (n h (where represents less than 80) is preferable.

[0059] If a surfactant other than component (B) is used, it is preferable that the surfactant other than component (B) is included in the liposome outer phase composition of the composition of this disclosure. Furthermore, it is preferable that the surfactant other than component (B) is included in the composition of this disclosure in an amount of 0.05 to 2% by mass, more preferably 0.1 to 1% by mass, even more preferably 0.2 to 0.8% by mass, and still more preferably 0.3 to 0.7% by mass.

[0060] Examples of thickening agents include synthetic polymers such as carboxyvinyl polymer (carbomer), acrylic acid / alkyl methacrylate copolymer, and sodium polyacrylate; semi-synthetic polymers such as hydroxyethylcellulose; and natural polymers such as xanthan gum and guar gum.

[0061] Examples of preservatives include parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, as well as benzoic acid, sodium benzoate, phenoxyethanol, and alkyldiaminoethylglycine hydrochloride.

[0062] Examples of chelating agents include edetic acid, pentetic acid, metaphosphoric acid, gluconic acid, etidronic acid, or chemically possible salts thereof.

[0063] Examples of coloring agents include legally approved pigments such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3.

[0064] Examples of fragrances include menthol, anethole, carvone, eugenol, limonene, wintergreen, cineole, clove oil, rosemary oil, lemon oil, orange oil, ocimene oil, citronellol, and methyl eugenol.

[0065] Examples of cooling agents include menthol, spearmint oil, camphor, thymol, and methyl salicylate.

[0066] Examples of functional ingredients other than linoleic acid include collagen, sodium chondroitin sulfate, tocopherol, tranexamic acid, ascorbic acid and its derivatives, kojic acid, ellagic acid, arbutin, vitamins A, glycyrrhetinic acid, glycyrrhizic acid and its salts, allantoin, isopropylmethylphenol, elastin, and niacinamide.

[0067] The compositions of this disclosure can preferably be used as topical preparations, and more specifically, they may be, for example, pharmaceutical topical compositions, quasi-drug topical compositions, or cosmetic compositions. For example, they may be skin care agents, hair care agents, bath additives, etc. More specifically, they may be lotions, serums, emulsions, creams, ointments, pastes, gels, packs, sprays, shampoos, conditioners, hair growth agents, scalp lotions, etc.

[0068] The form of the composition of this disclosure is not particularly limited, but may be, for example, liquid, cream, gel, paste, etc.

[0069] The subjects to whom the compositions disclosed herein are applied are not particularly limited, but are preferably people who desire skin whitening, people who want to improve the transparency of their skin, etc.

[0070] This disclosure also includes methods for manufacturing the compositions of this disclosure. Such manufacturing methods may be referred to as the “manufacturing methods of this disclosure.” Any information relating to the compositions and liposomes of this disclosure will be incorporated by reference to the manufacturing methods of this disclosure.

[0071] The manufacturing method disclosed herein is, for example, (α) Step: A step to prepare a liposome dispersion containing linoleic acid. (β) Step: A step of preparing one or more compositions (intermediate compositions) comprising at least one selected from the group consisting of component (A), component (B), and component (C), and (γ) step: This step includes mixing the liposome dispersion containing linoleic acid prepared in step (α) with the composition prepared in step (β).

[0072] Step (α) is a step of preparing a liposome dispersion containing linoleic acid. The "liposome dispersion" is preferably a liquid in which liposomes are dispersed and has a lower water content than the composition obtained through step (γ). The water content in the liposome dispersion is not particularly limited, but may be 1 to 50% by mass of the total liposome dispersion, preferably 3 to 30% by mass, and more preferably 5 to 20% by mass. The upper or lower limit of the range may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50% by mass.

[0073] A dispersion of liposomes containing linoleic acid can be prepared by known liposome preparation methods or by methods readily conceivable from known liposome preparation methods. Specifically, for example, a method of mixing linoleic acid, phospholipids, water, and other components using a stirrer such as a disperser mixer or homomixer can be used. Alternatively, a method of appropriately mixing linoleic acid, phospholipids, water, and other components and then processing them using a high-pressure wet atomizer can be used. The rotational speed, rotational speed (rpm), and stirring time of the stirrer, as well as the pressure and number of passes through the flow path of the high-pressure wet atomizer, can be appropriately adjusted based on ordinary knowledge in the art.

[0074] While not particularly limited, in the technology disclosed herein, it is especially preferable that the dispersion of liposomes containing linoleic acid be prepared using a high-pressure wet atomizer. Specific examples of high-pressure wet atomizers include STAR BURST (Sugino Machine Co., Ltd.).

[0075] Step (β) is a step of preparing one or more compositions (intermediate compositions) comprising at least one selected from the group consisting of component (A), component (B), and component (C). The method of preparing the intermediate composition in step (β) is not particularly limited and can be prepared by mixing components (A) to (C), water, and other components.

[0076] It is also possible for the intermediate composition to contain all of components (A) to (C). Alternatively, as described above, it is possible to prepare the intermediate composition in multiple parts. In this case, it is sufficient that all of components (A) to (C) are contained when all of the multiple intermediate composition precursors are mixed together. For example, it is also possible to prepare intermediate composition precursor I and intermediate composition precursor II. In this case, in step (γ) below, it is also possible to mix a dispersion of liposomes containing linoleic acid with intermediate composition precursor I, and then further mix in intermediate composition precursor II. It is sufficient that all of components (A) to (C) are contained when intermediate composition precursors I and II are combined.

[0077] Step (γ) is a step of mixing the liposome dispersion containing linoleic acid prepared in step (α) with the composition prepared in step (β). The mixing method is not particularly limited, and known mixing methods can be used.

[0078] The information relating to the compositions of this disclosure may be incorporated into the manufacturing methods of this disclosure. Furthermore, heating may be performed at any appropriate time in the manufacturing methods of this disclosure. In addition, a step to adjust the pH of the composition may be performed after step (γ).

[0079] In this specification, the term "comprising" includes both "consisting essentially of" and "consisting of." Furthermore, this disclosure encompasses all combinations of the constituent elements described herein.

[0080] Furthermore, the various characteristics (properties, structure, function, etc.) described in each embodiment of this disclosure above may be combined in any way to identify the subject matter covered by this disclosure. In other words, this disclosure covers all subject matter consisting of any combination of the combinable characteristics described herein. [Examples]

[0081] The embodiments of this disclosure will be described in more detail below with examples, but the embodiments of this disclosure are not limited to the examples below.

[0082] Preparation of a linoleic acid-encapsulated liposome dispersion A linoleic acid-encapsulated liposome dispersion was prepared according to the composition shown in the table below. The values ​​for each component in the table are in grams (g). Commercially available products corresponding to soybean phospholipid as described in the 2018 Japanese Standards for Pharmaceutical Additives or lecithin as defined in the Japanese Food Additives Standards were purchased and used.

[0083] [Table 1]

[0084] More specifically, Phase 1 of the components listed in the table above was added to a beaker and stirred until homogeneous, then subjected to high-pressure treatment at 100 MPa using a high-pressure wet atomizer (STAR ​​BURST: Sugino Machine Co., Ltd.). Xanthan gum, 1,3-butylene glycol, and purified water (Phase 2) were added to a separate beaker and stirred until homogeneous. The high-pressure treated Phase 1 and Phase 2 were mixed until homogeneous to prepare a linoleic acid-encapsulated liposome dispersion.

[0085] Preparation of a composition containing linoleic acid-encapsulated liposomes Linoleic acid-encapsulated liposome-containing compositions (each example and comparative example) were prepared according to the compositions listed in Table 2. Note that the values ​​for each component in the table represent grams (g). More specifically, the preparations were carried out as follows.

[0086] Each component listed in A1 was sequentially added to a beaker and stirred to obtain the A1 mixture. Next, each component listed in A2 was dissolved in a beaker and stirred, and this mixture was added to the A1 mixture and stirred to obtain composition A.

[0087] Separately, a solution of each component described in B1 dissolved in 1,3-butylene glycol (B2) was added to purified water (B3) and stirred to obtain composition B.

[0088] Composition B was added to a pre-prepared linoleic acid-encapsulated liposome dispersion and stirred. The resulting mixture was added to composition A and stirred to prepare a linoleic acid-encapsulated liposome-containing composition.

[0089] Furthermore, linoleic acid-encapsulated liposome-containing compositions (each example) were prepared according to the description in Table 3. Note that the values ​​for each ingredient in the table represent grams (g). More specifically, the preparations were carried out as follows.

[0090] Each component listed in A1 was sequentially added to a beaker and stirred to obtain the A1 mixture. Next, each component listed in A2 was dissolved in a beaker and stirred, and this mixture was added to the A1 mixture and stirred to obtain composition A.

[0091] A linoleic acid-encapsulated liposome-containing composition was prepared by adding composition A to a pre-prepared linoleic acid-encapsulated liposome dispersion and stirring.

[0092] In Tables 2 and 3, an appropriate amount of potassium hydroxide was used. Potassium hydroxide was used as a pH adjuster to adjust the pH of the resulting linoleic acid-encapsulated liposome-containing composition to around neutral (pH 7), and was added in an amount of approximately 0.001 to 0.1 g. The pH was measured using a pH meter at 25°C.

[0093] Evaluation of linoleic acid-encapsulated liposome-containing compositions [Linoleic acid quantitative analysis] A composition containing linoleic acid-encapsulated liposomes was sealed in a glass container and left in the dark at 50°C for one month. After standing, the linoleic acid content was quantified using high-performance liquid chromatography (HPLC) according to a standard method. The peak area of ​​the peak corresponding to linoleic acid in the obtained chromatogram was determined, and the linoleic acid content of the composition containing linoleic acid-encapsulated liposomes was calculated using Sunstar's peak area as a reference. In addition, the percentage of linoleic acid content after standing at 50°C for one month was calculated using the linoleic acid content measured by the same method before standing as a reference. The above measurement results are shown in Table 2 or Table 3.

[0094] In this percentage, a smaller decrease from 100% indicates that the decrease in linoleic acid content was suppressed. Tables 2 and 3 also show the evaluations: ○ for examples where the percentage is 95% or higher, and × for examples where it is less than 95%.

[0095] [Z average particle size measurement] A composition containing linoleic acid-encapsulated liposomes was sealed in a glass container and left in the dark at 40°C for two months. After standing, it was diluted 100-fold with purified water to prepare the measurement sample. The particle size distribution of the liposomes in the measurement sample was measured using a Zetasizer Nano ZS (Malvern). From the measured particle size distribution, the Z-mean particle size was determined using the analysis software "Zetasizer software (Malvern)".

[0096] The percentage of the average Z particle size after 2 months of storage at 40°C was calculated, using the average Z particle size measured using the same method before storage as a baseline. The measurement results are shown in Table 2 or Table 3.

[0097] In this percentage, the smaller the increase from 100%, the more the increase in the average Z particle size is suppressed, and therefore the suppression of liposome particle size. Tables 2 and 3 also show the evaluations: ○ for examples where the percentage is 110% or less, and × for examples where it exceeds 110%.

[0098] [Table 2]

[0099] [Table 3]

[0100] From each example and comparative example, it was found that when a specific surfactant is included in the liposome outer phase composition in combination with tocopherol, a linoleic acid-encapsulated liposome-containing composition is obtained in which the time-dependent stability of linoleic acid is significantly increased, and the time-dependent stability of the liposomes is also good.

[0101] Furthermore, comparing Comparative Example 1 and Comparative Example 2, tocopherol improved both the time-dependent stability of linoleic acid and the time-dependent stability of liposomes. Comparing Comparative Example 2 and Example 1, it might appear at first glance that Example 1 shows only a slight improvement compared to Comparative Example 2. However, because tocopherol is excellent at improving the time-dependent stability of linoleic acid, further improving this effect is not easy. In other words, obtaining a linoleic acid-encapsulated liposome-containing composition that achieves a remarkably high percentage of linoleic acid content (%) of 95% or more is not easy. The linoleic acid content percentage of Comparative Example 2 is 93.1%, while the linoleic acid content percentage of Example 1 is 96.7%. Although this change represents an improvement of 3.6%, it can be considered a significant improvement.

[0102] Furthermore, considering the various reference examples, it was found that simply incorporating tocopherol into the liposome outer phase composition does not provide a high linoleic acid time-dependent stability effect. However, it was also found that combining tocopherol with divalent or higher alkyl alcohols such as glycerin or 1,3-butylene glycol, and further combining it with specific surfactants, can provide a remarkably high linoleic acid time-dependent stability effect.

Claims

1. A liposome-containing composition comprising liposomes and a liposome outer phase composition, The liposome is a linoleic acid-encapsulating liposome that contains linoleic acid. The liposome outer phase composition is (A) Tocopherol, (B) Polyethylene glycol (PEG)-n ｐ Phytosterol (n ｐ (This indicates 5 to 50), Polyoxyethylene (POE) (n ｃ ) Cholesteryl ether (n ｃ (This indicates 5 to 50), Polyethylene glycol (PEG)-n ｈ Hydrogenated castor oil (n ｈ (This indicates 80-150), Polyoxyethylene (POE) (n ａ ) C10-30 linear alkyl ethers (n ａ (wherein it represents 10 to 50), and Pyrrolidone carboxylic acid (PCA) glyceryl isostearate - n ｉ (n ｉ represents 20 to 30) At least one surfactant selected from the group consisting of, and (C) Divalent or trivalent alkyl alcohol having 2 to 6 carbon atoms, including, Composition containing linoleic acid-encapsulated liposomes

2. The composition according to claim 1, comprising 0.1 to 10 parts by mass of (A) per 1 part by mass of linoleic acid.

3. The composition according to claim 1, comprising 0.1 to 10 parts by mass of (B) per 1 part by mass of linoleic acid.

4. The composition according to claim 1, comprising 10 to 500 parts by mass of (C) per 1 part by mass of linoleic acid.

5. The composition according to claim 1, comprising 0.1 to 10 parts by mass of (A), 0.1 to 10 parts by mass of (B), and 10 to 500 parts by mass of (C) per 1 part by mass of linoleic acid.

6. The composition according to any one of claims 1 to 5, wherein the Z-average particle size of the liposomes is 10 to 90 nm.

7. A composition for external use, as described in any one of claims 1 to 5.

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