Method for producing lipid membrane structure-containing composition

Abstract

To provide means which can control the particle diameter of a lipid membrane structure by a simple technique in the production of the lipid membrane structure.SOLUTION: The present disclosure relates to a method for producing a composition containing a lipid membrane structure, in which the composition comprises (A) a hydrogenated phospholipid having an acid value of 5 mgKOH / g or more, (B) a compound represented by formula 1, and (C) water. The method includes a dispersion step for mixing the components (A), (B) and (C) together to produce a liquid dispersion in which a lipid membrane structure having a particle diameter of 10 nm to 200 nm inclusive is formed spontaneously, in which the dispersion step includes determining the concentration of the component (A) in the liquid dispersion in accordance with a desired particle diameter of the lipid membrane structure contained in the composition containing a lipid membrane structure.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for producing a lipid membrane structure-containing composition. [Background technology]

[0002] Lipid membrane structures such as liposomes and bicelles have skin care effects such as moisturizing, and can encapsulate active ingredients, making them useful in cosmetics and topical skin preparations. Phospholipids are primarily used as raw materials for lipid membrane structures in these applications because they are naturally derived and highly safe. Among these, hydrogenated phospholipids, in which hydrogen atoms are added to the unsaturated carbon bonds of phospholipids, are preferred because they are less susceptible to deterioration by oxidation.

[0003] Techniques for forming lipid membrane structures using hydrogenated phospholipids have been investigated. For example, Patent Document 1 describes that liposomes with high lipid membrane flexibility and storage stability can be obtained by preparing a composition by mixing hydrogenated phospholipids with ceramides, branched alcohols, etc., and dispersing the mixture in a large excess of water. Patent Document 2 describes that multilayer liposomes can be formed by mixing an oil-soluble composition containing hydrogenated phospholipids, a glycol compound, and a fat-soluble compound with a water-soluble composition, and then treating the mixture in a conversion process to obtain fine unilamellar liposomes. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-32230 [Patent Document 2] Special Publication No. 2012-504620 Summary of the Invention [Problem to be solved by the invention]

[0005] For cosmetic and topical skin applications, fine lipid membrane structures (e.g., particle diameter of 200 nm or less) are required from the viewpoints of skin penetration, the expression of the effects of the encapsulated active ingredients, and storage stability. However, hydrogenated phospholipids have a higher phase transition temperature than non-hydrogenated phospholipids, making it difficult to form fine lipid membrane structures. In fact, in the techniques for forming lipid membrane structures using hydrogenated phospholipids as described in Patent Documents 1 and 2, it was necessary to use a micronization means such as a microfluidizer in order to form fine lipid membrane structures (e.g., particle diameter of 200 nm or less).

[0006] Furthermore, it is preferable that the particle size of the lipid membrane structures be adjusted depending on their intended use. For example, the smaller the particle size, the lighter the feel of the lipid membrane structure-containing composition upon application, the greater the sense of penetration into the skin, and the closer to transparency the appearance. However, the larger the particle size, the heavier the feel of the lipid membrane structure-containing composition upon application, the gentler the sense of penetration into the skin, and the closer the appearance to translucent or opaque. Therefore, it is necessary to design the particle size according to the desired feel and appearance. Furthermore, when a translucent appearance is desired to impart a luxurious appearance, the degree of translucency varies depending on the particle size, so a technology that can appropriately adjust the particle size is also required from the perspective of quality control. With industrially used micronization methods such as microfluidizers, it is difficult to control the particle size, and excessive consideration of conditions such as pressure and number of passes is required. If the formulation composition and the device conditions are not appropriately combined, lipid membrane structures tend to be obtained with a wide distribution of particle sizes in terms of uniformity of dispersion. Furthermore, even with micronization methods used in small-scale production (e.g., ultrasonication and extrusion), it is difficult to control the particle size, or even if it is possible to control the particle size, the process is complicated. Therefore, it has been difficult to easily obtain liposomes with a specific particle size.

[0007] Therefore, an object of the present invention is to provide a means for controlling the particle size of lipid membrane structures by a simple method when producing the lipid membrane structures. [Means for solving the problem]

[0008] In view of the above problems, the present inventors have conducted extensive research. As a result, they have found that a hydrogenated phospholipid having an acid value of 5 mg KOH / g or more and a phospholipid having an acid value of 5 mg KOH / g or more are combined together to produce a phospholipid having an acid value of 5 mg KOH / g or more.

[0009] [ka]

[0010] (In the above formula 1, R is a substituted or unsubstituted alkyl group having 2 to 6 carbon atoms or a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, X is -O-, -C(=O)O-, or -OC(=O)-, and n is 0 or 1.) and (C) water, it has been found that the concentration of component (A) in a dispersion obtained by mixing these components shows a strong positive correlation with the particle size of the lipid membrane structures contained in the lipid membrane structure-containing composition produced by the production method (the particle size increases as the concentration increases) (hereinafter, this correlation will be referred to as the "relationship of the present invention"). Based on this finding, it has been found that the above problem can be solved by controlling the concentration of component (A) in the dispersion according to the target particle size of the lipid membrane structures when obtaining the dispersion, and the present invention has been completed.

[0011] That is, one aspect of the present invention is a method for producing a lipid membrane structure-containing composition comprising the component (A), the component (B), and the component (C), comprising a dispersion step of mixing the component (A), the component (B), and the component (C) to obtain a dispersion in which lipid membrane structures having particle diameters of 10 nm or more and 200 nm or less are spontaneously formed, wherein the dispersion step comprises determining the concentration of the component (A) relative to the dispersion in accordance with the target particle diameter of the lipid membrane structures contained in the lipid membrane structure-containing composition. [Effects of the Invention]

[0012] According to the present invention, when producing lipid membrane structures, it is possible to control the particle size of the lipid membrane structures by a simple method. [Brief explanation of the drawings]

[0013] [Figure 1] 1 shows an image of a lipid membrane structure of an example taken by cryo-electron microscopy (Cryo-TEM). DETAILED DESCRIPTION OF THE INVENTION

[0014] One aspect of the present invention is a method for producing a phospholipid comprising: (A) a hydrogenated phospholipid with an acid value of 5 mg KOH / g or more; and (B) a phospholipid having the following formula 1:

[0015] [ka]

[0016] (In the above formula 1, R is a substituted or unsubstituted alkyl group having 2 to 6 carbon atoms or a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, X is -O-, -C(=O)O-, or -OC(=O)-, and n is 0 or 1.) and (C) water, the method for producing a lipid membrane structure-containing composition comprising: a compound represented by the formula:

[0017] The lipid membrane structure-containing composition of the present invention makes it possible to form fine lipid membrane structures having a desired particle size (specifically, a particle size of 10 nm or more and 200 nm or less) without the need for a micronization means such as a microfluidizer.

[0018] As described above, lipid membrane structures such as liposomes and bicelles are useful in cosmetics and topical skin preparations. For these applications, fine lipid membrane structures (e.g., particle diameters of 200 nm or less) are required from the viewpoints of skin permeability, efficacy of encapsulated active ingredients, and storage stability. Furthermore, since the desired particle diameter of the lipid membrane structure varies depending on which of the above-mentioned aspects is being aimed at, there has been a demand for controlling the particle diameter depending on the application.

[0019] Phospholipids are primarily used as raw materials for lipid membrane structures for the above applications because they are naturally derived and highly safe. Among these, hydrogenated phospholipids are preferably used because they are less susceptible to deterioration due to oxidation. However, compared to non-hydrogenated phospholipids, hydrogenated phospholipids have a higher phase transition temperature, and the physical properties of the two are significantly different. For this reason, the techniques described in Patent Documents 1 and 2 make it difficult to easily form fine lipid membrane structures (e.g., particle diameters of 200 nm or less) using hydrogenated phospholipids with high phase transition temperatures, and therefore, it was not possible to obtain lipid membrane structures with the desired particle diameter.

[0020] Therefore, the present inventors have intensively investigated means for easily forming fine lipid membrane structures using hydrogenated phospholipids. Surprisingly, they have found that, in producing a lipid membrane structure-containing composition, when (A) a hydrogenated phospholipid having an acid value of 5 mg KOH / g or more, (B) a compound represented by the above formula 1 (hereinafter also referred to as a "polyol compound"), and (C) water are mixed to obtain a dispersion, the concentration of component (A) in the dispersion can be changed depending on the target particle size of the lipid membrane structures, thereby forming fine lipid membrane structures of the target particle size (specifically, a particle size of 10 nm to 200 nm) without the need for a micronization means (i.e., the relationship of the present invention exists). In the present invention, the target particle size of the lipid membrane structures is in the range of 10 nm to 200 nm.

[0021] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to only the following embodiments. In this specification, the range "x to y" includes x and y and means "x or more and y or less." Furthermore, unless otherwise specified, operations and measurements of physical properties, etc. are performed under conditions of room temperature (20°C or more and 25°C or less) and a relative humidity of 40% RH or more and 50% RH or less.

[0022] <Method of producing lipid membrane structure-containing composition> A method for producing a lipid membrane structure-containing composition according to one embodiment of the present invention comprises: (A) a hydrogenated phospholipid with an acid value of 5 mg KOH / g or more; and (B) a compound represented by the following formula 1:

[0023] [ka]

[0024] (In the above formula 1, R is a substituted or unsubstituted alkyl group having 2 to 6 carbon atoms or a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, X is -O-, -C(=O)O-, or -OC(=O)-, and n is 0 or 1.) and (C) water to obtain a dispersion in which lipid membrane structures having particle diameters of 10 nm or more and 200 nm or less are spontaneously formed, and the dispersion step further includes determining the concentration of component (A) relative to the dispersion in accordance with the target particle diameter of the lipid membrane structures contained in the lipid membrane structure-containing composition.

[0025] That is, in a method for producing a lipid membrane structure-containing composition according to one embodiment of the present invention, the desired particle size of the lipid membrane structures to be produced is determined, and the concentration of component (A) in the dispersion liquid prepared in the dispersion step is determined in light of the relationship of the present invention. The lipid membrane structures produced by the production method according to the present invention have a particle size of 10 nm or more and 200 nm or less.

[0026] Before describing the production method of the present invention, the lipid membrane structure will first be described below.

[0027] [Lipid membrane structure] The form of the lipid membrane structure is not particularly limited as long as it has a lamellar (lipid bilayer) structure in which lipid molecules are arranged with their hydrophilic groups facing outward and their hydrophobic groups facing inward, and examples include liposomes, bicelles, α-gels, etc. The lipid membrane structure may be a single-layer lamellar structure called a unilamellar or single lamellar structure, a multilayer lamellar structure with several layers (2 to 10 layers) called an oligolamellar structure, a multilayer lamellar structure with a larger number of layers, or a mixture of these.

[0028] Whether a lipid membrane structure is a unilamellar structure (hereinafter also referred to as "unilamellar") or a multilamellar structure (hereinafter also referred to as "multilayer") can be confirmed, for example, using cryo-electron microscopy (Cryo-TEM).

[0029] In one embodiment of the present invention, the lipid membrane structure is preferably a unilamellar liposome. Unilamellar liposomes are unilamellar structures that have a small particle size and a large internal aqueous phase volume, and therefore are excellent in encapsulation efficiency and permeability for water-soluble compounds. Therefore, they are useful in cosmetics and topical skin preparations that contain water-soluble cosmetic ingredients. Furthermore, in one embodiment of the present invention, the lipid membrane structure is preferably a bicelle. Bicelles are fine, disc-shaped unilamellar structures with a thickness of 3 to 10 nm and a diameter of 15 to 100 nm, and are excellent in encapsulation efficiency and permeability for fat-soluble ingredients. Therefore, they are useful in cosmetics and topical skin preparations that contain fat-soluble cosmetic ingredients.

[0030] In one embodiment of the present invention, the lipid membrane structure is preferably a multilamellar liposome. Multilamellar liposomes have a small particle size, a large lamellar volume, and can incorporate fat-soluble compounds into the lamellae, resulting in excellent encapsulation efficiency and penetration of fat-soluble compounds. Therefore, they are useful in cosmetics and topical skin preparations that incorporate fat-soluble cosmetic ingredients.

[0031] The lipid membrane structure-containing composition of the present invention may contain only one of unilamellar liposomes, bicelles, or multilamellar liposomes, or may contain a mixture of two or more types selected from the group consisting of multilamellar liposomes, unilamellar liposomes, and bicelles.

[0032] In the present invention, the lipid membrane structures have a particle diameter of 10 nm or more and 200 nm or less. The particle diameter of the lipid membrane structures is preferably 20 nm or more and 190 nm or less, more preferably 30 nm or more and 180 nm or less, even more preferably 40 nm or more and 170 nm or less, particularly preferably 50 nm or more and 160 nm or less, and particularly preferably 50 nm or more and 150 nm or less. The upper limit of the particle diameter of the lipid membrane structures is not particularly limited in terms of dispersibility, storage stability, and skin permeability, but is, for example, 200 nm or less, 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 135 nm or less, or 130 nm or less. The lower limit of the particle diameter of the lipid membrane structures is not particularly limited, but is, for example, 10 nm or more, 20 nm or more, 30 nm or more, 40 nm or more, or 50 nm or more in terms of the efficiency of lipid membrane structure formation.

[0033] The upper limit of the polydispersity index (PDI) of the lipid membrane structures is not particularly limited in view of dispersibility, storage stability, and skin permeability, but is, for example, 0.80 or less, 0.70 or less, 0.60 or less, 0.50 or less, 0.40 or less, 0.30 or less, 0.25 or less, or 0.20 or less. The lower limit of the polydispersity index (PDI) of the lipid membrane structures is not particularly limited, but is, for example, 0.01 or more.

[0034] In this specification, the particle size of the lipid membrane structure refers to the average hydrodynamic diameter. The particle size (average hydrodynamic diameter) and polydispersity index (PDI) of the lipid membrane structure are measured using a dynamic light scattering measurement device (Malvern Instruments, Zetasizer Nano ZSP) and the harmonic mean diameter (Z-Average) and polydispersity index (PDI) based on scattered light intensity by cumulant analysis. The definitions of particle size and polydispersity index used here are as described in "JIS Z8828:2019 Particle Size Analysis - Dynamic Light Scattering Method."

[0035] The lipid membrane structure-containing composition of the present invention contains the above-mentioned lipid membrane structures. In this specification, if the particle size of the lipid membrane structure-containing composition can be measured using a dynamic light scattering measurement device, more specifically, a Zetasizer Nano ZSP (manufactured by Malvern Instruments), it is considered that lipid membrane structures have been formed.

[0036] The lipid membrane structures contained in the lipid membrane structure-containing composition of the present invention are formed by dispersing the components that form the lipid membrane structures in component (C) (water). In the present invention, the components that form the lipid membrane structures are dispersed in component (C) (water) in the dispersion step to form lipid membrane structures. Therefore, the dispersion obtained in the dispersion step is a solution in which lipid membrane structures are formed. Specifically, in the present invention, the dispersion obtained in the dispersion step is one in which lipid membrane structures with particle diameters of 10 nm or more and 200 nm or less are spontaneously formed.

[0037] Here, the lipid membrane structure-containing composition of the present invention includes (i) the state of a dispersion obtained by the dispersing step, and (ii) the state of the dispersion obtained by the dispersing step, the concentration of which is further adjusted with component (C). Thus, in case (i), the dispersion of the present invention becomes a lipid membrane structure-containing composition as it is. Furthermore, in case (ii), the dispersion of the present invention becomes a lipid membrane structure-containing composition by further adjusting the concentration with component (C). Thus, in case (i), a lipid membrane structure-containing composition is obtained by the dispersing step, and in case (ii), the dispersion is subjected to the concentration adjusting step described below to obtain a lipid membrane structure-containing composition. Note that component (C), in which the components forming the lipid membrane structures are dispersed, may contain components other than component (C). For example, it may be used together with components (D) to (F) described below or the components described in [Other Components] below, or a mixture thereof may be used in advance. Furthermore, component (C) in a system in which lipid membrane structures are present (i.e., components (C-2) and (C-3) described below) is sometimes referred to as the "aqueous phase." For example, the components (C-2) and (C-3) in which the components that form the lipid membrane structures are dispersed form an "aqueous phase" relative to the components that form the lipid membrane structures.

[0038] In the method for producing a lipid membrane structure-containing composition of the present invention, component (C) is used as an additive not only in the dispersion step but also in the mixing step and concentration adjustment step described below. Therefore, hereinafter, the mixing component (C) added in the mixing step will be referred to as "component (C-1)" or "water (for forming agent)," the dispersion component (C) added in the dispersion step will be referred to as "component (C-2)" or "water (for dispersion)," and the concentration adjustment component (C) added in the concentration adjustment step will be referred to as "component (C-3)" or "water (for concentration adjustment)." The amount of component (C) contained in the lipid membrane structure-containing composition is the total amount of the mixing component (C-1) added in the mixing step, the dispersion component (C-2) added in the dispersion step, and the concentration adjustment component (C-3) added in the concentration adjustment step described below. In the method for producing a lipid membrane structure-containing composition of the present invention, the mixing step and the concentration adjustment step are steps that are performed as needed.

[0039] A preferred embodiment of the manufacturing method according to one aspect of the present invention will be described below.

[0040] [Dispersion process] The dispersion step involves mixing components (A), (B), and (C-2) to obtain a dispersion in which lipid membrane structures with particle diameters of 10 nm to 200 nm are spontaneously formed. In this dispersion step, the concentration of component (A) in the dispersion is determined based on the relationship of the present invention and in accordance with the target particle diameter of the lipid membrane structures contained in the lipid membrane structure-containing composition. Specifically, to produce lipid membrane structures with a larger particle diameter, the concentration of component (A) in the dispersion can be increased. The production method according to this embodiment may further include determining the correlation (the relationship of the present invention) between the concentration of component (A) in the dispersion and the particle diameter of the lipid membrane structures contained in the lipid membrane structure-containing composition. This correlation can be determined using known regression analysis methods such as the method of least squares (OLS) by conducting preliminary experiments in which the concentration of component (A) in the dispersion is varied to obtain lipid membrane structure-containing compositions with various particle diameters for the desired lipid membrane structure-containing composition. Here, there are no particular limitations on the specific expression of the "relationship of the present invention" determined by a known regression analysis method. For example, it may be an approximate straight line (linear regression) or an approximate curve (polynomial approximation). Furthermore, there are no particular limitations on the degree of the approximate curve (polynomial approximation). It is preferably a second to fifth order, and more preferably a third to fourth order. These approximate straight lines and approximate curves can be obtained using the "linear approximation" or "polynomial approximation" function in the "formatting approximate curve" section of Microsoft Excel (manufactured by Microsoft Corporation). Furthermore, if a "relationship of the present invention" determined separately by such a method is available, it can also be used to carry out the production method of this embodiment. In this case, the production method of this embodiment does not involve determining the "relationship of the present invention." The target particle diameter of the lipid membrane structure can be appropriately set within the particle diameter range described in the "Lipid Membrane Structure" section. For example, the target particle diameter of the lipid membrane structure is 10 nm or more and 200 nm or less.

[0041] Once the target particle size of the lipid membrane structures is determined, the concentration of component (A) in the dispersion is determined according to that particle size (in light of the "relevance of the present invention"). The concentration of component (A) determined according to the target particle size of the lipid membrane structures is, for example, preferably 0.01 to 15% by mass, more preferably 0.05 to 15% by mass, even more preferably 0.1 to 12% by mass, even more preferably 0.2 to 10% by mass, particularly preferably 0.3 to 7.5% by mass, and most preferably 0.5 to 5% by mass, relative to the dispersion (total mass 100% by mass). The concentration of component (A), which is determined depending on the target particle size of the lipid membrane structures, is, for example, as a lower limit relative to the dispersion liquid (total mass 100% by mass), 0.01% by mass or more, 0.02% by mass or more, 0.1% by mass or more, 0.2% by mass or more, 0.3% by mass or more, 0.4% by mass or more, 0.5% by mass or more, 0.6% by mass or more, 0.7% by mass or more, 0.8% by mass or more, 0.9% by mass or more, 1.0% by mass or more, 1.1% by mass or more, 1.2% by mass or more, 1.3% by mass or more, 1.4% by mass or more, 1.5% by mass or more, 1.6% by mass or more, 1.7% by mass or more, 1.8% by mass or more, 1.9% by mass or more, or 2.0% by mass or more. In this case, the upper limit of the concentration of component (A) is 15% by mass or less, 14% by mass or less, 13% by mass or less, 12% by mass or less, 11% by mass or less, 10% by mass or less, 9.5% by mass or less, 9.0% by mass or less, 8.5% by mass or less, 8.0% by mass or less, 7.5% by mass or less, 7.0% by mass or less, 6.5% by mass or less, 6.0% by mass or less, 5.5% by mass or less, or 5.0% by mass or less. In one embodiment, the concentration of component (A), which is determined depending on the target particle size of the lipid membrane structures, is 0.05% by mass or more and less than 4.5% by mass of the dispersion. By setting the concentration of component (A) within the above range, the particle size of the obtained lipid membrane structures can be controlled. That is, the present invention was accomplished based on the discovery that the particle size of the lipid membrane structures contained in a lipid membrane structure-containing composition can be controlled by producing a lipid membrane structure-containing composition through a concentration of component (A) within the above range.

[0042] That is, in producing a lipid membrane structure-containing composition, the concentration of component (A) in the dispersion obtained in the dispersion step is changed depending on the target particle diameter of the lipid membrane structures (in light of the relationship of the present invention). As a result, lipid membrane structures of the target particle diameter are formed in the finally obtained lipid membrane structure-containing composition. This embodiment has the advantage that the particle diameter of the lipid membrane structures in the lipid membrane structure-containing composition can be controlled, and therefore the particle diameter can be set according to the purpose.

[0043] Here, the present inventors have found that the structure of the lipid membrane structures contained in the lipid membrane structure-containing composition can also be controlled by the production method according to one embodiment of the present invention. In the examples, when the concentration of component (A) in the dispersion step of the lipid membrane structure-containing composition was 2% by mass or less relative to the dispersion liquid (total mass 100% by mass), lipid membrane structures having a unilamellar liposome structure were confirmed (Examples 1-1, 1-2, etc.). In contrast, when the concentration of component (A) in the dispersion step of the lipid membrane structure-containing composition was 3% by mass or more relative to the dispersion liquid (total mass 100% by mass), unilamellar lipid membrane structures were obtained, and when the concentration of component (A) in the dispersion step of the lipid membrane structure-containing composition was 3% by mass or more relative to the dispersion liquid (total mass 100% by mass), lipid membrane structures having a multilamellar liposome structure were confirmed (Examples 1-3 to 1-5, etc.). That is, it has also been found that the production method according to the present invention allows the structure of the lipid membrane structures to be controlled by adjusting the concentration of component (A) in light of the relationship of the present invention.

[0044] Furthermore, in a production method according to one embodiment of the present invention, lipid membrane structures are preferably formed by forming lipid membrane structures at a concentration of component (A) higher than the concentration of component (A) in the target lipid membrane structure-containing composition, and then adding component (C-3) to obtain the target concentration of component (A). That is, one embodiment of the present invention may further include a concentration adjustment step of mixing the dispersion with component (C-3) (water) after the dispersion step. In this embodiment, lipid membrane structures are formed at a high concentration of component (A), and then the step of diluting the lipid membrane structures makes it possible to vary the particle size of the lipid membrane structures in the lipid membrane structure-containing composition even if the composition (content of each component, particularly the concentration of component (A)) in the lipid membrane structure-containing composition is the same. That is, since the particle size of lipid membrane structures can be controlled in lipid membrane structure-containing compositions of the same composition, there is the advantage that the particle size can be set according to the purpose.

[0045] The dispersion obtained by the dispersion step contains component (A), component (B), and component (C) (component (C-2)), and optionally contains components (D) to (F) and components described in [Other Components] below. These components that make up the dispersion are explained below. Note that even when the dispersion contains components other than components (A) to (C-2), the relationships of the present invention apply depending on the composition. Therefore, even in such cases, the production method of this embodiment can be carried out by utilizing the relationships of the present invention in the same manner as described above.

[0046] [Component (A)] The dispersion according to the present invention contains, as component (A), a hydrogenated phospholipid having an acid value of 5 mgKOH / g or more. Component (A) may be one or more hydrogenated phospholipids having an acid value of 5 mgKOH / g or more, or may be a combination of one or more hydrogenated phospholipids having an acid value of less than 5 mgKOH / g and one or more hydrogenated phospholipids having an acid value of 5 mgKOH / g or more, with an acid value of 5 mgKOH / g or more being adjusted to have an acid value of 5 mgKOH / g or more.

[0047] Hydrogenated phospholipids can be obtained by adding hydrogen atoms to the unsaturated carbon bonds of phospholipids using conventionally known methods. The origin of the phospholipid is not particularly limited, but lecithin is particularly preferred because it is naturally derived and can be suitably used in cosmetics and topical skin preparations. Therefore, in one embodiment of the present invention, component (A) is hydrogenated lecithin. Lecithin may be derived from soybeans, egg yolk, rapeseed, sunflower, corn, or the like, but is preferably derived from plants such as soybeans, rapeseed, sunflower, or corn, and is more preferably derived from soybeans due to its ease of availability and stable quality.

[0048] The acid value of component (A) is 5 mgKOH / g or more. When a hydrogenated phospholipid with an acid value of less than 5 mgKOH / g is used, fine lipid membrane structures cannot be formed even when combined with component (B). From the viewpoint of obtaining finer lipid membrane structures, the acid value of component (A) is preferably 12 mgKOH / g or more, more preferably 15 mgKOH / g or more, even more preferably 17 mgKOH / g or more, still more preferably 20 mgKOH / g or more, and particularly preferably 22 mgKOH / g or more. The acid value of component (A) is, for example, 6 mgKOH / g or more, 7 mgKOH / g or more, 8 mgKOH / g or more, 9 mgKOH / g or more, 10 mgKOH / g or more, 11 mgKOH / g or more, 12 mgKOH / g or more, 13 mgKOH / g or more, 14 mgKOH / g or more, 15 mgKOH / g or more, 16 mgKOH / g or more, 17 mgKOH / g or more, 18 mgKOH / g or more, 19 mgKOH / g or more, 20 mgKOH / g or more, 21 mgKOH / g or more, 22 mgKOH / g or more, 23 mgKOH / g or more, 24 mgKOH / g or more, 25 mgKOH / g or more, 26 mgKOH / g or more, or 27 mgKOH / g or more. Although not particularly limited, the acid value of component (A) is, for example, 70 mg KOH / g or less, 60 mg KOH / g or less, 50 mg KOH / g or less, or 40 mg KOH / g or less. By appropriately selecting the type of phospholipid, a hydrogenated phospholipid with the desired acid value can be obtained. The acid value of component (A) is measured in accordance with "Standards for Quasi-drug Ingredients 2021, General Test Method, 28. Acid Value Measurement Method."

[0049] The component (A) may be either a synthetic product or a commercially available product. Examples of commercially available products include EMALEX (registered trademark) SLP manufactured by Nippon Emulsion Co., Ltd. and SLP-White H manufactured by Tsuji Oil Mills Co., Ltd. These may be used alone or in combination of two or more.

[0050] The content of the component (A) in the dispersion according to the present invention is the above-mentioned "concentration of the component (A) determined according to the target particle diameter of the lipid membrane structures." Therefore, the concentration of the component (A) determined according to the above-mentioned target particle diameter of the lipid membrane structures is applied.

[0051] [(B) Component] The dispersion according to the present invention contains, as component (B), a compound represented by the following formula 1. The component (B) may be one type or two or more types.

[0052] [ka]

[0053] In the above formula 1, R is a substituted or unsubstituted alkyl group having 2 to 6 carbon atoms or a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms.

[0054] The alkyl group having 2 to 6 carbon atoms may be either linear or branched. Examples of the alkyl group having 2 to 6 carbon atoms include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-amyl, tert-pentyl, neopentyl, n-hexyl, 3-methylpentan-2-yl, 3-methylpentan-3-yl, 4-methylpentyl, 4-methylpentan-2-yl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, and 3,3-dimethylbutan-2-yl. The alkyl group having 2 to 6 carbon atoms is preferably linear. That is, the alkyl group having 2 to 6 carbon atoms is preferably a group selected from the group consisting of ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl.

[0055] Examples of the cycloalkyl group having 3 to 6 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and preferably a cyclohexyl group.

[0056] There are no particular limitations on the substituents that may be present on the alkyl group having 2 to 6 carbon atoms and the cycloalkyl group having 3 to 6 carbon atoms, as long as the effects of the present invention are achieved. Examples of the substituents include halogen atoms, acyl groups, alkyl groups, aryl groups, alkoxyl groups, nitro groups, amino groups, and cyano groups. However, the alkyl group having 2 to 6 carbon atoms is not substituted with an alkyl group.

[0057] In the above formula 1, X is -O-, -C(=O)O-, or -OC(=O)-, and is preferably -O-. Furthermore, in the above formula 1, n is 0 or 1. In the above formula 1, when X is -O- and n is 1, the number of carbon atoms in the alkyl group represented by R is preferably 4 or more.

[0058] The component (B) is preferably at least one selected from the group consisting of, for example, 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, 1,2-octanediol, cyclohexylglycerin, and hexylglycerin.

[0059] In particular, when 1,2-hexanediol, 1,2-heptanediol, or hexylglycerin is used as component (B), extremely fine lipid membrane structures can be formed. In this case, the lipid membrane structures are thought to form bicelles. Because bicelles are disc-shaped single-layer lamellar structures, they have superior permeability to the stratum corneum compared to liposomes of comparable particle size. Therefore, from the perspective of obtaining lipid membrane structures with high permeability for lipid-soluble components, it is preferable to use at least one selected from the group consisting of 1,2-hexanediol, 1,2-heptanediol, and hexylglycerin as component (B).

[0060] Component (B) may be either a synthetic product or a commercially available product.

[0061] The content of component (B) in the dispersion according to the present invention is preferably more than 0.01% by mass and not more than 24% by mass, more preferably from 0.02% to 23% by mass, even more preferably from 0.05% to 20% by mass, particularly preferably from 0.1% to 18% by mass, and most preferably from 0.2% to 15% by mass. The content of component (B) in the dispersion is preferably, for example, more than 0.01% by mass as a lower limit. The content of component (B) in the dispersion is, as a lower limit, 0.011% by mass or more, 0.02% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 0.2% by mass or more, 0.3% by mass or more, 0.4% by mass or more, 0.5% by mass or more, 0.6% by mass or more, 0.7% by mass or more, 0.8% by mass or more, 0.9% by mass or more, 1.0% by mass or more, 1.1% by mass or more, 1.2% by mass or more, 1.3% by mass or more, 1.4% by mass or more, 1.5% by mass or more, 1.6% by mass or more, 1.7% by mass or more, 1.8% by mass or more, 1.9% by mass or more, or 2.0% by mass or more. The content of component (B) in the dispersion is preferably, as an upper limit, 24% by mass or less. The upper limit of the content of component (B) in the dispersion is 23% by mass or less, 22% by mass or less, 21% by mass or less, 20% by mass or less, 19% by mass or less, 18% by mass or less, 17% by mass or less, 16% by mass or less, 15% by mass or less, 14% by mass or less, 13% by mass or less, 12% by mass or less, 11% by mass or less, 10% by mass or less, 9.5% by mass or less, 9.0% by mass or less, 8.5% by mass or less, 8.0% by mass or less, 7.5% by mass or less, 7.0% by mass or less, 6.5% by mass or less, 6.0% by mass or less, 5.5% by mass or less, 5.0% by mass or less, or 4.5% by mass or less.

[0062] In the dispersion of the present invention, the content of component (B) relative to 100 parts by mass of component (A) is preferably more than 100 parts by mass, more preferably from 110 to 2000 parts by mass, even more preferably from 120 to 1800 parts by mass, still more preferably from 130 to 1500 parts by mass, particularly preferably from 140 to 1200 parts by mass, and most preferably from 150 to 1000 parts by mass. When the content of component (B) is within the above range, component (A) can more efficiently form lipid membrane structures in the dispersion, and lipid membrane structures with excellent dispersibility can be formed. Furthermore, from the viewpoint of obtaining finer lipid membrane structures, the content of component (B) is, for example, 160 parts by mass or more, 170 parts by mass or more, 180 parts by mass or more, 190 parts by mass or more, 200 parts by mass or more, 210 parts by mass or more, 220 parts by mass or more, 230 parts by mass or more, 240 parts by mass or more, 250 parts by mass or more, 260 parts by mass or more, 270 parts by mass or more, 280 parts by mass or more, 290 parts by mass or more, 300 parts by mass or more, 310 parts by mass or more, 320 parts by mass or more, 330 parts by mass or more, 340 parts by mass or more, 350 parts by mass or more, 360 parts by mass or more, 370 parts by mass or more, 380 parts by mass or more, 390 parts by mass or more, or 400 parts by mass or more per 100 parts by mass of component (A). On the other hand, there is no particular upper limit for the content of component (B) per 100 parts by mass of component (A), but exceeding 2000 parts by mass does not affect the solubility or dispersibility of component (A) in the dispersion and is simply uneconomical. Therefore, the content of component (B) per 100 parts by mass of component (A) is, for example, 2000 parts by mass or less, 1900 parts by mass or less, 1800 parts by mass or less, 1700 parts by mass or less, 1600 parts by mass or less, 1500 parts by mass or less, 1400 parts by mass or less, 1300 parts by mass or less, 1200 parts by mass or less, 1100 parts by mass or less, 1000 parts by mass or less, 900 parts by mass or less, 800 parts by mass or less, 700 parts by mass or less, 600 parts by mass or less, or 500 parts by mass or less. Therefore, according to a preferred embodiment of the present invention, the amount of component (B) is preferably 110 parts by mass or more and 2000 parts by mass or less per 100 parts by mass of component (A).

[0063] [(C-2) component)] The dispersion of the present invention contains water as component (C-2). Component (C-2) serves as a medium for dispersing the components that form lipid membrane structures and is the main component that forms the aqueous phase in the dispersion. Component (C-2) also serves to facilitate the incorporation of component (D) (a basic compound) and component (E) (an acidic compound) into the dispersion. Specifically, component (D) and / or component (E) can be easily incorporated into the dispersion by dissolving component (D) and / or component (E) in component (C-2) beforehand and then mixing with component (A) and component (B).

[0064] As the component (C-2), water with few impurities is preferred, and for example, purified water, such as water purified from tap water using a system that employs ion exchange, distillation, reverse osmosis, or ultrafiltration, either alone or in combination, is preferred.

[0065] The content of component (C-2) in the dispersion of the present invention is preferably 50% by mass or more and 99.97% by mass or less, more preferably 60% by mass or more and 99.9% by mass or less, even more preferably 60% by mass or more and 99.8% by mass or less, particularly preferably 65% ​​by mass or more and 99.7% by mass or less, and most preferably 70% by mass or more and 99.6% by mass or less. The content of component (C-2) in the dispersion of the present invention is, for example, as a lower limit, 50% by mass or more, 55% by mass or more, 60% by mass or more, 65% by mass or more, 70% by mass or more, 75% by mass or more, 80% by mass or more, 85% by mass or more, or 90% by mass or more. The content of component (C-2) in the dispersion of the present invention is, for example, as an upper limit, 99.97% by mass or less, 99.9% by mass or less, 99.8% by mass or less, 99.7% by mass or less, or 99.6% by mass or less.

[0066] In the dispersion according to the present invention, the mass ratio of component (B) to component (C-2) ("component (B) : component (C-2)") preferably exceeds 0.01:99.99 as a lower limit, and is 0.1:99.9 or more, 1:99 or more, 2:98 or more, or 3:97 or more. In the dispersion, the mass ratio of component (B) to component (C-2) preferably has an upper limit of less than 25:75, and is 24:76 or less, 20:80 or less, 16:84 or less, 12.5:87.5 or less, or 10:90 or less.

[0067] In the present invention, the mixture of components (A), (B), and (C-2) (i.e., component (C)) in which lipid membrane structures with particle diameters of 10 to 200 nm are spontaneously formed is referred to as a "dispersion," and the process of mixing components (A), (B), and (C-2) in which lipid membrane structures with particle diameters of 10 to 200 nm are spontaneously formed is referred to as a "dispersion process." Thus, for example, in the mixing process described below, components (A), (B), and (C-1) (i.e., component (C)) may be mixed, but even if component (C-1) (i.e., component (C)) is present, this mixing process does not "spontaneously form lipid membrane structures with particle diameters of 10 to 200 nm." The lipid membrane-forming agent obtained in the mixing process does not have lipid membrane structures with particle diameters of 10 to 200 nm. That is, to distinguish whether a dispersion according to the present invention is present or not (for example, whether it is a dispersion or a lipid membrane forming agent), the particle diameter can be measured and it can be confirmed whether "lipid membrane structures with particle diameters of 10 nm or more and 200 nm or less" are formed.

[0068] For example, one method for controlling the "spontaneous formation of lipid membrane structures with particle diameters of 10 nm to 200 nm" is to adjust the ratio of component (B) to component (C-2) in the dispersion to a predetermined ratio. Specifically, when the mass ratio of component (B) to component (C-2) in the dispersion ("component (B):component (C-2)") is greater than 0.01:99.98 and less than 25:75, mixing component (A), component (B), and component (C-2) results in the spontaneous formation of lipid membrane structures with particle diameters of 10 nm to 200 nm, thereby obtaining a dispersion.

[0069] [(D) component] The dispersion liquid of the present invention may further contain a basic compound as component (D) in addition to the above-mentioned components (A), (B), and (C-2). When component (A) with a high acid value is used, adding component (D) makes it possible to obtain a dispersion liquid with better dispersibility of lipid membrane structures. Component (D) may be one type or two or more types.

[0070] Examples of component (D) include inorganic bases such as sodium hydroxide, potassium hydroxide, and ammonia; basic amino acids such as arginine, lysine, and histidine; and amine compounds such as ethanolamine, diethanolamine, triethanolamine, 2-amino-2-methyl-1,3-propanediol (AMPD), and 2-amino-2-hydroxymethyl-1,3-propanediol (tromethamine). Among these, arginine is preferred.

[0071] The component (D) may be either a synthetic product or a commercially available product.

[0072] The content of component (D) in the dispersion of the present invention is preferably 0.000005 to 1.5% by mass, more preferably 0.00001 to 1.5% by mass, even more preferably 0.0001 to 1.0% by mass, particularly preferably 0.001 to 1.0% by mass, and most preferably 0.01 to 1.0% by mass. The content of component (D) in the dispersion is, as a lower limit, 0.000005% by mass or more, 0.00001% by mass or more, 0.0001% by mass or more, 0.001% by mass or more, 0.01% by mass or more, or 0.02% by mass or more. The content of component (D) in the dispersion is, as an upper limit, preferably 1.5% by mass or less, and more preferably 1.0% by mass or less.

[0073] In the dispersion according to the present invention, the content of component (D) is preferably at least 0.05 parts by mass, more preferably at least 0.1 parts by mass, relative to 100 parts by mass of component (A), and is preferably at most 10 parts by mass, more preferably at most 5 parts by mass.

[0074] [(E) component] The dispersion liquid of the present invention may contain, in addition to the above-mentioned components (A), (B), and (C-2), an acidic compound as component (E). The inclusion of component (E) can enhance the dispersibility of lipid membrane structures in the aqueous phase. Component (E) may be one type or two or more types.

[0075] Examples of component (E) include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid, and organic acids such as acetic acid, formic acid, propionic acid, butyric acid, citric acid, lactic acid, succinic acid, malic acid, tartaric acid, pyrrolidonecarboxylic acid (PCA), gluconic acid, benzoic acid, ethylenediaminetetraacetic acid (EDTA), etidronic acid, pentetic acid, and phytic acid. Of these, organic acids are preferred from the viewpoint of obtaining a dispersion liquid with excellent dispersibility of lipid membrane structures.

[0076] In particular, from the viewpoint of facilitating the efficient formation of lipid membrane structures, obtaining a dispersion with excellent dispersibility, and improving the storage stability of the dispersion and a lipid membrane structure-containing composition using the dispersion, component (E) is preferably an organic acid with chelating activity. Component (A), a major component forming lipid membrane structures, may have the property of easily binding to metal ions. In this case, adding an organic acid with chelating activity as component (E) captures metal ions in the dispersion, facilitating the efficient formation of lipid membrane structures, thereby obtaining a dispersion with excellent dispersibility of lipid membrane structures and improving the storage stability of the dispersion and the lipid membrane structure-containing composition using the dispersion. That is, it is presumed that the dispersion can form lipid membrane structures with excellent dispersibility in the aqueous phase and excellent storage stability. Examples of organic acids with chelating activity include citric acid, ethylenediaminetetraacetic acid (EDTA), etidronic acid, and pentetic acid, with ethylenediaminetetraacetic acid (EDTA) being more preferred.

[0077] The component (E) may be either a synthetic product or a commercially available product.

[0078] In the dispersion according to the present invention, the content of component (E) (calculated as free acid) is preferably at least 0.00001 mass%, at least 0.0001 mass%, at least 0.001 mass%, at least 0.01 mass%, at least 0.02 mass%, or at least 0.04 mass%, and preferably at most 3.0 mass%, at most 2.5 mass%, at most 2.0 mass%, at most 1.5 mass%, or at most 1.0 mass%.

[0079] In the dispersion according to the present invention, the content of component (E) (calculated as free acid) per 100 parts by mass of component (A) is preferably at least 0.1 parts by mass, more preferably at least 0.2 parts by mass, and the content of component (E) (calculated as free acid) per 100 parts by mass of component (A) is preferably at most 20 parts by mass, more preferably at most 10 parts by mass.

[0080] From the viewpoint of increasing the solubility of both components (D) and (E) in the dispersion and controlling the pH of the dispersion within a predetermined range, the dispersion of the present invention preferably contains both components (D) and (E). Such a dispersion may be obtained by adding components (D) and (E) separately, or by adding salts of components (D) and (E).

[0081] The salts of component (D) and component (E) are not particularly limited, but examples include lysine hydrochloride; sodium citrate salts such as trisodium citrate; sodium phosphate salts such as disodium hydrogen phosphate; sodium benzoate; sodium ethylenediaminetetraacetic acid salts such as trisodium ethylenediaminetetraacetic acid (EDTA-3Na); and sodium diethylenetriaminepentaacetic acid salts such as pentasodium diethylenetriaminepentaacetic acid (pentasodium pentetate).

[0082] When the dispersion contains the components (D) and (E), the mass ratio (D) / (E) of the components (D) and (E) is 0.2 to 10. The lower limit of the range of the mass ratio (D) / (E) may be 0.3, 0.4, or 0.5. The upper limit of the range of the mass ratio (D) / (E) may be 10, 9, 8, 7, 6, or 5. The range of the mass ratio (D) / (E) is preferably 0.5 to 5, for example.

[0083] In the dispersion of the present invention, the total content of components (D) and (E) is preferably at least 0.05% by mass, more preferably at least 0.1% by mass, and the total content of components (D) and (E) is preferably at most 4.5% by mass, more preferably at most 2% by mass.

[0084] [Component (F)] The dispersion liquid of the present invention may further contain a fat-soluble compound as component (F) in addition to the above-mentioned components (A), (B), and (C-2). When component (A) with a high acid value is used, the combined use of components (B) and (F) facilitates the formation of lipid membrane structures in which components (A) and (F) are oriented, allowing the formation of lipid membrane structures with high storage stability. Furthermore, the combined use of component (F) with component (D) and / or component (E) allows the formation of finer lipid membrane structures. The component (F) may be one type or two or more types.

[0085] Examples of component (F) include sterols such as phytosterols, cholesterol, di(phytosteryl / octyldodecyl) lauroyl glutamate, phytosteryl oleate, and phytosteryl glucoside; triterpenes such as γ-oryzanol, glycyrrhizic acid, ursolic acid, and Centella asiatica extract (a mixture of asiatic acid, madecassic acid, and asiaticoside); fat-soluble vitamins such as retinol, hydrogenated retinol, cholecalciferol, tocopherol, and ascorbic acid esters; and astaxanthin. carotenoids such as β-carotene; coenzymes such as ubiquinone; hydrocarbons such as limonene, petrolatum, and squalane; ceramides such as ceramide EOS, ceramide NG (ceramide 2), ceramide NP (ceramide 3), ceramide AP (ceramide 6II), ceramide EOP (ceramide 1), dihydroxylignoceroylphytosphingosine, cerebrosides, glycosphingolipids, and cetyl PG hydroxyethyl palmitamide; and polyphenols such as tetrahydrodiferuloylmethane and pterostilbene. Among these, from the viewpoint that combining component (F) with components (A) and (B) makes it easier to form lipid membrane structures in which components (A) and (F) are oriented, thereby enabling the production of a dispersion with good storage stability, and from the viewpoint of improving the storage stability of a lipid membrane structure-containing composition using such a dispersion, component (F) is preferably at least one selected from the group consisting of phytosterols, cholesterol, γ-oryzanol, glycyrrhizinic acid, ursolic acid, Centella asiatica extract (a mixture of asiatic acid, madecassic acid, and asiaticoside), hydrogenated retinol, tocopherol, astaxanthin, ubiquinone, ceramide NG, ceramide NP, ceramide AP, ceramide EOP, tetrahydrodiferuloylmethane, and pterostilbene.

[0086] Component (F) may be either a synthetic product or a commercially available product, such as Phytosterol-SKP (manufactured by Tama Biochemical Co., Ltd.), TECA (manufactured by Bayer), dl-α-tocopherol (manufactured by DSM K.K.), NIKKOL® Retinol H10, NIKKOL® VC-IP, and squalane (manufactured by Nikko Chemicals Co., Ltd.), astaxanthin-20C and γ-oryzanol (manufactured by Oryza Oil & Fat Chemical Co., Ltd.), Kaneka Coenzyme Q10 (manufactured by Kaneka Corporation), CERAMIDE2 (manufactured by Croda Japan Co., Ltd.), and ursolic acid 90%, Sabi White, and Ptero White (manufactured by Sabinsa Japan Corporation).

[0087] The content of component (F) in the dispersion according to the present invention is, for example, at least 0.0000005% by mass, at least 0.000001% by mass, at least 0.00001% by mass, at least 0.0001% by mass, at least 0.001% by mass, at least 0.01% by mass, or at least 0.1% by mass, and at most 9% by mass, at most 8% by mass, at most 7% by mass, at most 6% by mass, at most 5% by mass, at most 4% by mass, at most 3% by mass, at most 2% by mass, or at most 1% by mass.

[0088] In the dispersion of the present invention, the content of component (F) is preferably at least 0.005 parts by mass, more preferably at least 0.05 parts by mass, even more preferably at least 0.5 parts by mass, and particularly preferably at least 5 parts by mass, relative to 100 parts by mass of component (A).The upper limit is preferably at most 60 parts by mass, more preferably at most 50 parts by mass, even more preferably at most 40 parts by mass, and particularly preferably at most 30 parts by mass.

[0089] [Other ingredients] The dispersion according to the present invention may further contain components (other components) other than the components (A) to (F). The other components are not particularly limited and include polyol compounds other than component (B), oils, surfactants, moisturizers, whitening agents, colorants, alcohols, amino acids, sugars, vitamins, viscosity modifiers, polymers, colorants, powders, UV absorbers, preservatives, antibacterial agents, antioxidants, fragrances, cosmetic ingredients, electrolytes, fibers, plant extracts, and the like. These may be used alone or in combination of two or more. For example, by blending cosmetic ingredients such as moisturizers and whitening agents into the dispersion, lipid membrane structures encapsulating the cosmetic ingredients can be formed. When forming lipid membrane structures encapsulating the cosmetic ingredients, the timing of blending the cosmetic ingredients is not particularly limited. The particle size and structure (single layer or multilayer) of the lipid membrane structures change until the concentration of component (A) in the dispersion, which is determined according to the target particle size, is reached. This means that the lipid membrane structures are in a state where they can be reconstructed, and at this time, the cosmetic ingredients present in the dispersion are incorporated and encapsulated in the reconstructed lipid membrane structures. Therefore, by appropriately designing the concentration of component (A) in the dispersion, cosmetic ingredients for which a sense of penetration is desired to be enhanced and cosmetic ingredients for which a sense of penetration is desired to be suppressed and sustained release is desired to be enhanced can be encapsulated in lipid membrane structures that are optimal for each, in terms of the particle size and structure (single layer or multilayer) of the lipid membrane structures. In this way, it becomes possible to easily create a wide variety of lipid membrane structures designed to provide optimal penetration and sustained release for each cosmetic ingredient, and by combining these, it becomes possible to easily create a range of highly functional products that meet diverse consumer needs.

[0090] [Dispersion method in the dispersion process] As long as the dispersion liquid spontaneously forms lipid membrane structures of 10 to 200 nm in size in the dispersion step, the mixing form of component (A), component (B), and component (C-2) is not particularly limited. For example, in the dispersion step, the components may be mixed all at once or sequentially. When the components are mixed sequentially, the order is not particularly limited. For example, component (A) and component (B) may be mixed, and then component (C-2) may be added and mixed; component (A) and component (C-2) may be mixed, and then component (B) may be added and mixed; or component (B) and component (C) may be added simultaneously to component (A) and then mixed (e.g., a mixed solvent of component (B) and component (C-2) may be added). Furthermore, for example, when a dispersion liquid is produced using component (D) and / or component (E) in addition to component (A), component (B), and component (C-2), component (D) and / or component (E) may be added separately, or they may be mixed in advance and then the mixture added. Furthermore, for example, when a dispersion is prepared using the above-mentioned components (A), (B), (C-2), and (F) in addition to the component (D) and / or (E), the order of addition of the component (F) is not particularly limited. For example, after mixing the components (A), (B), (C-2), and (F), the component (C-2), the component (D), and / or the component (E) may be added simultaneously or sequentially. Alternatively, in addition to the components (A), (B), and (C-2), the component (D) and / or the component (E) may be mixed simultaneously or sequentially, and then the component (F) may be added last. Furthermore, when a dispersion is prepared using the components described above in [Other Components], the order of addition of the components described above in [Other Components] is not particularly limited and can be selected appropriately depending on, for example, the solubility. For example, if the component (F) is fat-soluble, it may be added together with the component (F) or last. Alternatively, if it is water-soluble, it may be added when component (D) and / or component (E) are added, or may be added last.

[0091] In the dispersion step, it is preferable to mix component (A), component (B), and component (C-2) at a temperature equal to or higher than the phase transition temperature of component (A). In this case, the formation efficiency of lipid membrane structures is further improved, resulting in a dispersion with even more excellent dispersion stability. The upper limit of the mixing temperature in the dispersion step is, for example, 120°C or lower, 110°C or lower, 100°C or lower, 95°C or lower, or 90°C or lower, and the lower limit is 40°C or higher, 45°C or higher, 50°C or higher, 55°C or higher, 60°C or higher, 65°C or higher, 70°C or higher, 75°C or higher, 80°C or higher, or 85°C or higher. The mixing temperature in the dispersion step is, for example, 40 to 120°C, preferably 40 to 100°C, and more preferably 60 to 90°C. When mixing water-soluble components such as component (D), component (E), and / or other cosmetic ingredients, these water-soluble components may be uniformly dissolved in component (C-2) before mixing. The dissolution temperature of the water-soluble components is not limited to the above-mentioned mixing temperature, and they may be heated and dissolved at any temperature suitable for dissolving the water-soluble components. When the water-soluble components are uniformly dissolved in component (C-2) and then mixed, they may be mixed at any timing and temperature. For example, when mixing all the components in one container, the water-soluble components may first be heated and dissolved in component (C-2), and then components (A) and (B) may be added and mixed. Alternatively, the water-soluble components may be heated and dissolved in component (C-2) in a separate container, and then mixed with components (A) and (B). Mixing may be performed at any timing and temperature. The mixing time is also not particularly limited, but is preferably 10 to 180 minutes.

[0092] The dispersion obtained by mixing components (A), (B), and (C-2) spontaneously forms fine lipid membrane structures even without substantial mechanical shearing force. Therefore, stirring is sufficient to uniformly mix these components. Specifically, the mixture obtained by mixing components (A) and (B) can be added to component (C-2) without stirring, followed by mixing with a stirring force sufficient to uniformly mix these components. Alternatively, component (C-2) can be added while stirring. The stirring conditions are not particularly limited, but for example, it can be carried out using a known stirring means at a rotation speed of 10 to 300 rpm. The mixture of components (A) and (B) can be added all at once, in portions, or sequentially at any desired rate using a known dropwise addition means. The stirring method is not particularly limited, but since it does not require high mechanical shearing force, it can be carried out using known stirring means such as a magnetic stirrer (e.g., a hot stirrer), a paddle mixer, a propeller mixer, or a planetary mixer.

[0093] In one embodiment of the present invention, the dispersion step may be a step of obtaining a dispersion by heating a mixture obtained by mixing component (A) and component (B) to a temperature above the phase transition temperature of component (A) (e.g., 80°C) (however, in this case, the mixture does not correspond to a lipid membrane-forming agent), and mixing it with component (C-2) that has been heated to a temperature above the phase transition temperature of component (A) (e.g., 80°C). In another embodiment, the dispersion step may be a step of obtaining a dispersion by mixing component (A), component (B), and component (C-2) while heating to a temperature above the phase transition temperature of component (A) (e.g., 80°C).

[0094] Here, the particle size of the lipid membrane structures in the dispersion obtained by the dispersion step is the same as that of the lipid membrane structure-containing composition described above, because in the present invention, the particle size of the lipid membrane structures contained in the dispersion is determined in the dispersion step.

[0095] From the viewpoint of obtaining finer lipid membrane structures, the pH of the dispersion is preferably 4.0 or higher, more preferably 5.0 or higher, even more preferably 7.0 or higher, and even more preferably 8.0 or higher. On the other hand, from the viewpoint of obtaining lipid membrane structures with a uniform particle size (i.e., a highly uniform dispersion), the pH of the dispersion is preferably 10.0 or lower, more preferably 9.5 or lower, and even more preferably 9.0 or lower. Therefore, the pH of the dispersion according to a preferred embodiment of the present invention is 4.0 to 10.0. Here, the "pH of the dispersion" refers to the pH of the dispersion measured at 25°C using a pH meter (HM-25R, manufactured by DKK-TOA Corporation) using the glass electrode method.

[0096] [Mixing process] In the method for producing a lipid membrane structure-containing composition of the present invention, a mixing step is optionally performed before the dispersing step. That is, in one embodiment, the method for producing a lipid membrane structure-containing composition of the present invention includes a mixing step. The mixing step is a step of heating and uniformly mixing component (A) and component (B) to obtain a lipid membrane-forming agent before the dispersing step. That is, the mixing step involves preheating and uniformly mixing the components that form lipid membrane structures to obtain a lipid membrane-forming agent in a mixed state in which each component is uniformly mixed. Here, the difference between the mixing step in the dispersing step and the mixing step can be distinguished by whether a uniform mixture is achieved before the inclusion of component (C-2). For example, a lipid membrane-forming agent that has undergone the mixing step exhibits a uniform, transparent liquid state when heated and dissolved at a temperature above the phase transition temperature of component (A) (e.g., above 80°C), and maintains this uniform state even after standing or cooling, without precipitation, separation, or sedimentation of some of the components contained therein. For example, even if component (A) and component (B) are heated to a temperature equal to or higher than the phase transition temperature of component (A) (e.g., 80°C) in the dispersion step, if there are undissolved components or the mixture is not homogeneous but cloudy, then when the mixture is left to stand or cooled, some of the contained components will precipitate, separate, or precipitate, which can be distinguished from the above.

[0097] Therefore, the lipid membrane-forming agent obtained by the mixing step becomes a homogeneous, transparent solution when the temperature reaches or exceeds the phase transition temperature of component (A). When a solution containing component (A) and component (B) or a solution containing component (A), component (B), and component (C-1) (i.e., component (C)) goes through a transparent, homogeneous solution, the solution is a lipid membrane-forming agent, and the step of obtaining the solution is considered a "mixing step."

[0098] In embodiments that include a mixing step, the dispersing step is a step of mixing the lipid membrane-forming agent obtained in the mixing step with component (C-2) to obtain a dispersion in which lipid membrane structures having particle diameters of 10 nm to 200 nm are spontaneously formed. That is, the dispersing step in this case is a step of mixing the lipid membrane-forming agent containing components (A) and (B) with component (C-2) to obtain a dispersion in which lipid membrane structures having particle diameters of 10 nm to 200 nm are spontaneously formed.

[0099] The lipid membrane-forming agent obtained in the blending step may contain, in addition to component (A) and component (B), component (C-1), components (D) to (F), and the components described in the section "Other Components" as necessary. The preferred content of each component in the lipid membrane-forming agent will be described below, but the preferred aspects of each component other than the content are as described above. In one embodiment, the blending step is a step of blending component (A), component (B), and, as necessary, one or more components selected from the group consisting of component (C-1), component (D), component (E), and component (F) to obtain a lipid membrane-forming agent.

[0100] The content of component (A) in the lipid film forming agent according to the present invention is not particularly limited, but may be, for example, at least 5% by mass, at least 6% by mass, at least 7% by mass, at least 8% by mass, at least 9% by mass, at least 10% by mass, at least 11% by mass, at least 12% by mass, at least 13% by mass, at least 14% by mass, at least 15% by mass, at least 16% by mass, at least 17% by mass, at least 18% by mass, or at least 19% by mass. The content of component (A) in the lipid film forming agent may be at most 40% by mass, at most 35% by mass, at most 30% by mass, at most 25% by mass, or at most 20% by mass. The content of component (A) in the lipid film forming agent is preferably 5 to 40% by mass, more preferably 10 to 20% by mass.

[0101] The content of component (B) in the lipid film forming agent according to the present invention is not particularly limited, but may be, for example, at least 15% by mass, at least 20% by mass, at least 25% by mass, at least 30% by mass, at least 35% by mass, at least 40% by mass, at least 45% by mass, or at least 50% by mass. The content of component (B) in the lipid film forming agent may be at most 95% by mass, at most 90% by mass, at most 85% by mass, at most 80% by mass, at most 75% by mass, at most 70% by mass, at most 65% by mass, at most 60% by mass, or at most 55% by mass. The content of component (B) in the lipid film forming agent is preferably 30 to 90% by mass, more preferably 40 to 80% by mass, and even more preferably 50 to 70% by mass.

[0102] In the lipid membrane forming agent of the present invention, the content of component (B) exceeds 100 parts by mass per 100 parts by mass of component (A). If the content of component (B) is 100 parts by mass or less per 100 parts by mass of component (A), fine lipid membrane structures cannot be formed. Furthermore, the content of component (B) is 110 parts by mass or more, 120 parts by mass or more, 130 parts by mass or more, 140 parts by mass or more, or 150 parts by mass or more per 100 parts by mass of component (A). If the content is 150 parts by mass or more, component (A) is more easily mixed homogeneously in the lipid membrane forming agent. By using this lipid membrane forming agent, lipid membrane structures with excellent dispersibility in an aqueous phase can be formed. Furthermore, from the viewpoint of obtaining finer lipid membrane structures, the content of component (B) is, for example, 160 parts by mass or more, 170 parts by mass or more, 180 parts by mass or more, 190 parts by mass or more, 200 parts by mass or more, 210 parts by mass or more, 220 parts by mass or more, 230 parts by mass or more, 240 parts by mass or more, 250 parts by mass or more, 260 parts by mass or more, 270 parts by mass or more, 280 parts by mass or more, 290 parts by mass or more, 300 parts by mass or more, 310 parts by mass or more, 320 parts by mass or more, 330 parts by mass or more, 340 parts by mass or more, 350 parts by mass or more, 360 parts by mass or more, 370 parts by mass or more, 380 parts by mass or more, 390 parts by mass or more, or 400 parts by mass or more per 100 parts by mass of component (A). On the other hand, the upper limit of the content of component (B) per 100 parts by weight of component (A) is not particularly limited, but exceeding 2000 parts by weight does not affect the solubility or dispersibility of component (A) in the lipid membrane-forming agent and is simply uneconomical. Therefore, the content of component (B) per 100 parts by weight of component (A) is, for example, 2000 parts by weight or less, 1900 parts by weight or less, 1800 parts by weight or less, 1700 parts by weight or less, 1600 parts by weight or less, 1500 parts by weight or less, 1400 parts by weight or less, 1300 parts by weight or less, 1200 parts by weight or less, 1100 parts by weight or less, 1000 parts by weight or less, 900 parts by weight or less, 800 parts by weight or less, 700 parts by weight or less, 600 parts by weight or less, or 500 parts by weight or less. Therefore, according to a preferred embodiment of the present invention, the content of component (B) per 100 parts by weight of component (A) is preferably 110 to 2000 parts by weight.

[0103] In the lipid film forming agent according to the present invention, the (C-1) component is added as needed, and there is no particular lower limit to the amount thereof. However, the amount of the (C-1) component in the lipid film forming agent may be, for example, at least 0.5% by mass, 1% by mass, 2% by mass, 3% by mass, 4% by mass, 5% by mass, 6% by mass, 7% by mass, 8% by mass, 9% by mass, 10% by mass, 11% by mass, 12% by mass, 13% by mass, 14% by mass, 15% by mass, 16% by mass, 17% by mass, 18% by mass, 19% by mass, 20% by mass, 21% by mass, 22% by mass, 23% by mass, 24% by mass, or 25% by mass. The upper limit of the content of component (C-1) in the lipid film forming agent is 75% by mass or less, 70% by mass or less, 65% by mass or less, 60% by mass or less, 55% by mass or less, 50% by mass or less, 45% by mass or less, 40% by mass or less, 35% by mass or less, or 30% by mass or less. The content of component (C-1) in the lipid film forming agent is preferably 0.5 to 70% by mass, more preferably 5 to 60% by mass, even more preferably 15 to 50% by mass, and particularly preferably 20 to 40% by mass.

[0104] In the lipid film forming agent according to the present invention, the mass ratio of the (B) component to the (C-1) component ("(B) component:(C-1) component") is, for example, at least 25:75, at least 30:70, at least 35:65, at least 40:60, at least 45:55, or at least 50:50. In the lipid film forming agent, the (C-1) component is added as needed, and there is no particular lower limit to its content. Therefore, there is no particular upper limit to the mass ratio of the (B) component to the (C-1) component ("(B) component:(C-1) component"), but the mass ratio of the (B) component to the (C-1) component is, for example, at most 99:1, at most 90:10, or at most 80:20. The mass ratio of the component (B) to the component (C-1) is preferably 25:75 or more and 99:1 or less, more preferably 30:70 or more and 90:10 or less, and even more preferably 35:65 or more and 80:20 or less.

[0105] In the lipid film forming agent of the present invention, component (D) is added as needed, and although there is no particular lower limit for its content, the content of component (D) in the lipid film forming agent is, for example, at least 0.01% by mass or at least 0.02% by mass as a lower limit and at most 2% by mass or at most 1% by mass as an upper limit. The content of component (D) in the lipid film forming agent is preferably 0.01 to 2% by mass, more preferably 0.02 to 1% by mass.

[0106] In the lipid film forming agent of the present invention, component (D) is added as needed, and there is no particular lower limit to its content, but the content of component (D) in the lipid film forming agent, per 100 parts by mass of component (A), is, for example, at least 0.05 parts by mass or at least 0.1 parts by mass as a lower limit, and at most 10%, 9%, 8%, 7%, 6%, or 5 parts by mass as an upper limit. In the lipid film forming agent, the content of component (D) is preferably 0.05 to 10 parts by mass, more preferably 0.1 to 5 parts by mass, per 100 parts by mass of component (A).

[0107] In the lipid film forming agent of the present invention, component (E) is added as needed, and although there is no particular lower limit for its content, the content of component (E) in the lipid film forming agent (calculated as free acid) is, for example, at least 0.02% by mass or at least 0.04% by mass as a lower limit, and at most 4%, at most 3%, or at most 2% by mass as an upper limit. In the lipid film forming agent, the content of component (E) (calculated as free acid) is preferably 0.02 to 4% by mass, more preferably 0.04 to 2% by mass.

[0108] In the lipid film forming agent of the present invention, component (E) is added as needed, and there is no particular lower limit to its content, but the content of component (E) (free acid equivalent) in the lipid film forming agent, per 100 parts by weight of component (A), is, for example, a lower limit of 0.1 parts by weight or more or 0.2 parts by weight or more, and an upper limit of 20 parts by weight or less, 19 parts by weight or less, 18 parts by weight or less, 17 parts by weight or less, 16 parts by weight or less, 15 parts by weight or less, 14 parts by weight or less, 13 parts by weight or less, 12 parts by weight or less, 11 parts by weight or less, or 10 parts by weight or less. In the lipid film forming agent, the content of component (E) (free acid equivalent) per 100 parts by weight of component (A) is preferably 0.1 to 20 parts by weight, more preferably 0.2 to 10 parts by weight.

[0109] When the lipid film-forming agent according to the present invention contains the components (D) and (E), the mass ratio (D) / (E) of the components (D) and (E) can be, for example, 0.2 to 10. The lower limit of the range of the mass ratio (D) / (E) is, for example, 0.2, 0.3, 0.4, or 0.5, and the upper limit is 10, 9, 8, 7, 6, or 5. The range of the mass ratio (D) / (E) is preferably, for example, 0.5 to 5.

[0110] When the lipid film forming agent of the present invention contains components (D) and (E), the total content of components (D) and (E) is, for example, at least 0.05% by mass or at least 0.1% by mass as a lower limit, and at most 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, or 2% by mass as an upper limit. In the lipid film forming agent, the total content of components (D) and (E) is preferably 0.05 to 4% by mass, more preferably 0.1 to 2% by mass.

[0111] In the lipid film forming agent of the present invention, component (F) is added as needed, and there is no particular lower limit to its content, but the content of component (F) in the lipid film forming agent is, for example, at least 0.00025% by mass, at least 0.001% by mass, at least 0.01% by mass, at least 0.1% by mass, or at least 1% by mass, and at most 12% by mass, at most 11% by mass, at most 10% by mass, at most 9% by mass, at most 8% by mass, at most 7% by mass, or at most 6% by mass. The content of component (F) in the lipid film forming agent is preferably 0.001 to 12% by mass, more preferably 0.01 to 10% by mass, even more preferably 0.1 to 8% by mass, and particularly preferably 1 to 6% by mass.

[0112] Furthermore, in the lipid film forming agent of the present invention, component (F) is added as needed, and there is no particular lower limit to its content, but the content of component (F) in the lipid film forming agent, per 100 parts by mass of component (A), is, for example, a lower limit of 0.005 parts by mass or more, 0.05 parts by mass or more, 0.5 parts by mass or more, or 5 parts by mass or more, and an upper limit of 60 parts by mass or less, 50 parts by mass or less, 40 parts by mass or less, or 30 parts by mass or less. In the lipid film forming agent, the content of component (F) per 100 parts by mass of component (A) is preferably 0.005 to 60 parts by mass, more preferably 0.05 to 50 parts by mass, even more preferably 0.5 to 40 parts by mass, and particularly preferably 5 to 30 parts by mass.

[0113] In the mixing step, the components may be mixed together or sequentially. When the components are mixed sequentially, the order is not particularly limited. For example, after mixing the components (A) and (B), the component (C-1) may be added and mixed; after mixing the components (A) and (C-1), the component (B) may be added and mixed; or the components (B) and (C-1) may be added simultaneously to the component (A) (e.g., a mixture of the components (B) and (C-1) may be added). Furthermore, for example, when a lipid membrane-forming agent is produced using the components (A), (B), and (C-1) in addition to the components (D) and / or (E), the components (D) and / or (E) may be added separately, or may be mixed with the component (C-1) in advance, and the resulting mixture may then be added to the mixture of the components (A) and (B). Furthermore, for example, when a lipid membrane-forming agent is prepared using component (A), component (B), component (C-1), and component (F) in addition to component (D) and / or component (E), the order of addition of component (F) is not particularly limited. For example, after component (A), component (B), and component (F) are mixed, component (C-1), component (D), and / or component (E) may be added simultaneously or sequentially. Alternatively, component (A) and component (B) may be mixed simultaneously or sequentially with component (C-1), component (D), and / or component (E) added last, and then component (F) may be added. Furthermore, when a lipid membrane-forming agent is prepared using the components described above in [Other Components], the order of addition of the components described above in [Other Components] is not particularly limited and can be selected appropriately depending on, for example, solubility. For example, if the component is lipid-soluble, it may be added together with component (F) or last. Alternatively, if it is water-soluble, it may be added when component (C-1), component (D) and / or component (E) are added, or may be added last.

[0114] In the mixing step, the mixing temperature is not particularly limited, but it is preferable to mix component (A) and component (B) at a temperature equal to or higher than the phase transition temperature of component (A). In this case, the miscibility of component (A) with component (B) is improved, resulting in a lipid membrane-forming agent with excellent dispersibility in component (C-2), which forms the aqueous phase. For example, the upper limit can be 120°C or lower, 110°C or lower, 100°C or lower, 95°C or lower, or 90°C or lower, while the lower limit can be 40°C or higher, 45°C or higher, 50°C or higher, 55°C or higher, 60°C or higher, 65°C or higher, 70°C or higher, 75°C or higher, 80°C or higher, or 85°C or higher. The temperature is preferably 25 to 120°C, more preferably 40 to 100°C, and even more preferably 60 to 90°C. The mixing time is also not particularly limited, but is preferably 10 to 180 minutes. The mixing method is not particularly limited, but since it does not require a high level of mechanical shearing force, it can be carried out using known mixing means such as a magnetic stirrer (e.g., a hot stirrer), a paddle mixer, a propeller mixer, or a planetary mixer.

[0115] [Concentration adjustment process] The method for producing a lipid membrane structure-containing composition of the present invention may include, in addition to the dispersion step, a step of further mixing the dispersion with component (C-3) to adjust the concentration (hereinafter referred to as the "concentration adjustment step"). When the concentration adjustment step is included in the production method of the present invention, the lipid membrane structure-containing composition is obtained through the concentration adjustment step.

[0116] In the method for producing a lipid membrane structure-containing composition of the present invention, a concentration adjustment step is carried out after the dispersion step, if necessary. That is, in one embodiment, the method for producing a lipid membrane structure-containing composition of the present invention includes a concentration adjustment step. The concentration adjustment step is a step of adding component (C-3) to the dispersion obtained in the dispersion step after the dispersion step so as to achieve the desired concentration of component (A) contained in the lipid membrane structure-containing composition. That is, the concentration adjustment step is a step of mixing the dispersion obtained in the dispersion step with an amount of component (C-3) necessary to achieve the desired concentration of component (A) contained in the lipid membrane structure-containing composition, thereby obtaining a lipid membrane structure-containing composition.

[0117] The amount of component (C-3) mixed with the dispersion in the concentration adjustment step is the amount of component (C) contained in the desired lipid membrane structure-containing composition minus the amount of component (C-2) used in the dispersion step when the mixing step is not performed. When the mixing step is performed, the amount of component (C-3) is the amount of component (C) contained in the desired lipid membrane structure-containing composition minus the amount of component (C-1) used in the mixing step and the amount of component (C-2) used in the dispersion step. Alternatively, the amount of component (C-3) required to dilute the dispersion to the desired concentration of component (A) in the desired lipid membrane structure-containing composition may be calculated.

[0118] The method for mixing the dispersion liquid and component (C-3) in the concentration adjustment step is not particularly limited, and may involve adding component (C-3) to the dispersion liquid, or adding the above-mentioned dispersion liquid to component (C-3). From the viewpoint of improving the dispersibility of lipid membrane structures, the latter method is preferred. Therefore, a method for producing a lipid membrane structure-containing composition according to one embodiment of the present invention comprises adding the above-mentioned dispersion liquid to component (C-3).

[0119] Considering that the concentration adjustment step may not be performed in some cases, the upper limits of the contents (concentrations) of the components (A) to (C) in the lipid membrane structure-containing composition are the same as the contents of each component in the dispersion liquid described above, and therefore will not be specified here. The lower limits of the components (A) and (B) are not particularly limited because the dispersion liquid is diluted in the concentration adjustment step, but can be calculated as values ​​diluted in accordance with the concentration adjustment step based on the contents of each component in the dispersion liquid described above.

[0120] Here, the particle size of the lipid membrane structures in the lipid membrane structure-containing composition obtained by the concentration adjustment step is the same as the particle size of the lipid membrane structures in the dispersion liquid described above. This is because, in the present invention, the particle size of the lipid membrane structures contained in the dispersion liquid is determined in the dispersion step, and the particle size is maintained even when the lipid membrane structures are subsequently diluted in the concentration adjustment step.

[0121] In the concentration adjusting step, the mixing temperature is not particularly limited, and the step may be performed at or above the phase transition temperature of component (A), or below the phase transition temperature of component (A). In the former case, the lower limit is, for example, 40°C or higher, 45°C or higher, 50°C or higher, 55°C or higher, 60°C or higher, or 65°C or higher, and the upper limit is 100°C or lower, 95°C or lower, or 90°C or lower. In the latter case, the upper limit is, for example, less than 40°C and 35°C or lower, 30°C or lower, 25°C or lower, 20°C or lower, 15°C or lower, or 10°C or lower, and the lower limit is -10°C or higher, -5°C or higher, 0°C or higher, or 5°C or higher. The mixing time is also not particularly limited, and may be, for example, 10 to 60 minutes.

[0122] The dispersion and component (C-3) may be mixed without stirring the aqueous phase (the dispersion may be added to the component (C-3)), or the component (C-3) may be stirred, or the component (C-3) may be added to the dispersion. The stirring conditions for the component (C-3) and / or the dispersion are not particularly limited, but may be, for example, performed using a known stirring means at a rotation speed of 10 to 300 rpm. The dispersion and / or component (C-3) may be added all at once, in portions, or sequentially at any desired rate using a known dropwise addition means.

[0123] In the concentration adjustment step, the temperatures of the dispersion and component (C-3) are not particularly limited and may be equal to or higher than the phase transition temperature of component (A) or lower than the phase transition temperature of component (A). In the former case, the lower limit is, for example, 40°C or higher, 45°C or higher, 50°C or higher, 55°C or higher, 60°C or higher, or 65°C or higher, and the upper limit is 100°C or lower, 95°C or lower, or 90°C or lower. In the latter case, the upper limit is, for example, less than 40°C and 35°C or lower, 30°C or lower, 25°C or lower, 20°C or lower, 15°C or lower, or 10°C or lower, and the lower limit is -10°C or higher, -5°C or higher, 0°C or higher, or 5°C or higher. Furthermore, the temperatures of both may be the same or different. For example, the dispersion or component (C-3) may be equal to or higher than the phase transition temperature of component (A), while the other component (C-3) or dispersion may be lower than the phase transition temperature of component (A).

[0124] Here, in the concentration adjustment step, in addition to component (C-3), component (D), component (E), and / or component (F) may be mixed with the dispersion. In this case, component (D), component (E), and / or component (F) may be added separately, or they may be mixed in advance and then the mixture added. Furthermore, when the lipid membrane structure-containing composition is produced using the components described in the above [Other Components], the order of addition of the components described in the above [Other Components] is not particularly limited and can be selected appropriately depending on, for example, solubility. For example, if the component is fat-soluble, it may be added together with component (F) or may be added last. Alternatively, if the component is water-soluble, it may be added together with component (D) and / or component (E) or may be added last. Considering that the concentration adjustment step may not be performed in some cases, the upper limit of the content of these components (D) to (F) and the components described in the above [Other Components] section is the same as the content of each component in the dispersion. The lower limit is not particularly limited because the dispersion is diluted by the concentration adjustment step, but can be calculated as a diluted value according to the concentration adjustment step based on the content of each component in the dispersion described above.

[0125] Here, other components may be added in the concentration adjustment step as long as the formation of lipid membrane structures is possible. Examples of such components include polyol compounds other than component (B), oils, surfactants, moisturizers, whitening agents, colorants, alcohols, amino acids, sugars, vitamins, viscosity modifiers, polymers, colorants, powders, UV absorbers, preservatives, antibacterial agents, antioxidants, fragrances, cosmetic ingredients, electrolytes, fibers, and plant extracts. The order of addition of these other components is not particularly limited and can be appropriately selected depending on, for example, solubility. The particle size of the resulting lipid membrane structures is determined by the concentration of component (A) in the dispersion obtained in the dispersion step. Therefore, even if other components are mixed in addition to component (C-3) in the concentration adjustment step as described above, the particle size of the lipid membrane structures is not affected by the addition of other components in the concentration adjustment step.

[0126] In the method for producing a lipid membrane structure-containing composition according to the present invention, in addition to the above-mentioned dispersing step, mixing step and concentration adjusting step, other steps such as purification (for example, filtration), cooling, storage and the like may be further carried out.

[0127] <Uses of the lipid membrane structure-containing composition> The lipid membrane structure-containing composition of the present invention can be used as is, or the lipid membrane structure-containing composition of the present invention can be further dispersed in a dispersion medium before use. In this case, the dispersion medium is not particularly limited, but examples thereof include water, a polyol compound, or a mixture thereof. Examples of the polyol compound may include a polyol compound represented by formula (1), such as 1,3-butylene glycol, dipropylene glycol, tripropylene glycol, glycerin, diglycerin, propylene glycol, and 1,2-pentanediol.

[0128] The lipid membrane structure-containing composition according to the present invention can spontaneously form fine lipid membrane structures without substantial mechanical shearing force, and can encapsulate water-soluble or fat-soluble components during the formation of the lipid membrane structures. This not only reduces production costs at the manufacturing plant, but also enables a system for preparing cosmetics or topical skin preparations containing lipid membrane structure-containing compositions encapsulating any water-soluble or fat-soluble cosmetic component based on consultation at stores such as cosmetic specialty stores, and is expected to enable a wide range of uses for lipid membrane structures.

[0129] The lipid membrane structure-containing composition of the present invention can be used as a cosmetic or topical skin preparation, and can also impart skin care effects such as moisturizing by incorporating the lipid membrane structure-containing composition into a cosmetic or topical skin preparation. Therefore, one embodiment of the present invention is a cosmetic containing the lipid membrane structure-containing composition. Another embodiment of the present invention is a topical skin preparation containing the lipid membrane structure-containing composition. Therefore, according to the present invention, there is provided a method for producing a cosmetic, which comprises producing a lipid membrane structure-containing composition by the above-described production method. Furthermore, according to the present invention, there is provided a method for producing a topical skin preparation, which comprises producing a lipid membrane structure-containing composition by the above-described production method.

[0130] The form of the cosmetic or topical skin preparation of the present invention is not particularly limited as long as the lipid membrane structures can be stably incorporated, and examples thereof include lotion, gel, emulsion, cream, shampoo, facial cleanser, etc. From the viewpoint of taking advantage of the transparent appearance, penetration upon application, and high stability that are achieved by containing the fine lipid membrane structures of the present invention (for example, particle diameter of 200 nm or less), preferred examples include incorporation into low-viscosity lotions, which are difficult to incorporate lipid membrane structures into.

[0131] In addition to the lipid membrane structure-containing composition, the cosmetic or topical skin preparation of the present invention may further contain ingredients commonly used in cosmetic or topical skin preparations, provided that the effects of the present invention are not impaired. Examples of such ingredients include, but are not limited to, polyol compounds other than component (B), oils, surfactants, moisturizers, whitening agents, coloring materials, alcohols, amino acids, vitamins, viscosity modifiers, polymers, colorants, powders, UV absorbers, preservatives, antibacterial agents, antioxidants, fragrances, cosmetic ingredients, electrolytes, pH adjusters, fibers, water, and plant extracts.

[0132] The concentration of lipid membrane structures in cosmetics and topical skin preparations containing the lipid membrane structure-containing composition of the present invention is preferably 0.0001% by mass or more, more preferably 0.01% by mass or more, and even more preferably 1% by mass or more, from the viewpoint of obtaining the skin care effect of the lipid membrane structures. On the other hand, the upper limit of the concentration is not particularly limited, but is, for example, less than 5% by mass.

[0133] Although the embodiments of the present invention have been described in detail, it is clear that this is by way of illustration and example only and not of limitation, and that the scope of the present invention should be interpreted by the appended claims.

[0134] The present invention encompasses the following aspects and configurations.

[0135] [1] (A) a hydrogenated phospholipid with an acid value of 5 mg KOH / g or more, and (B) a compound represented by the following formula 1:

[0136] [ka]

[0137] In the above formula 1, R is a substituted or unsubstituted alkyl group having 2 to 6 carbon atoms or a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms; X is -O-, -C(=O)O- or -OC(=O)-; n is 0 or 1; and (C) water, a dispersion step of mixing the component (A), the component (B), and the component (C) to obtain a dispersion in which lipid membrane structures having particle diameters of 10 nm or more and 200 nm or less are spontaneously formed, A method for producing a lipid membrane structure-containing composition, comprising determining the concentration of the component (A) in the dispersion liquid according to the target particle diameter of the lipid membrane structures contained in the lipid membrane structure-containing composition.

[0138] [2] The method for producing a lipid membrane structure-containing composition according to the above [1], wherein the content of the component (B) exceeds 100 parts by mass per 100 parts by mass of the component (A).

[0139] [3] The method for producing a lipid membrane structure-containing composition according to the above [1] or [2], wherein the concentration of the component (A) in the dispersion is 0.01 to 15% by mass.

[0140] [4] The method for producing a lipid membrane structure-containing composition according to any one of [1] to [3] above, further comprising a concentration adjustment step of mixing the dispersion liquid with the component (C) to obtain the lipid membrane structure-containing composition.

[0141] [5] The method for producing a lipid membrane structure-containing composition according to any one of [1] to [4] above, wherein in the dispersing step, mixing is carried out at a temperature equal to or higher than the phase transition temperature of component (A).

[0142] [6] A method for producing a cosmetic, comprising producing a lipid membrane structure-containing composition by the production method according to any one of [1] to [5] above.

[0143] [7] A method for producing an external preparation for skin, comprising producing a lipid membrane structure-containing composition by the production method according to any one of [1] to [5] above. [Example]

[0144] The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, unless otherwise specified, operations were performed at room temperature (20 to 25°C). Furthermore, unless otherwise specified, "%" and "parts" mean "% by mass" and "parts by mass", respectively.

[0145] <Preparation of lipid membrane structure-containing composition> A lipid membrane structure-containing composition was prepared by the following method. The hydrogenated lecithin was prepared by purchasing several commercially available soybean-derived hydrogenated lecithins with different acid values ​​(acid value 0.3 to 30.8 mg KOH / g) and mixing them in a ratio to obtain the desired acid value. The phase transition temperature of the hydrogenated lecithin of component (A) or component (A') used in the examples and comparative examples was 40 to 50°C.

[0146] [Examples 1-0 and 1-1, Examples 2-0 and 2-1, and Comparative Examples 1-0 and 1-1, and Comparative Examples 2-0 and 2-1] A 100 mL beaker was charged with 0.1 or 1 part by weight of (A) component: hydrogenated lecithin (acid value 6.1 mg KOH / g, 13.9 mg KOH / g, or 17.3 mg KOH / g) or (A') component: hydrogenated lecithin (acid value 0.3 mg KOH / g), and 0.4 or 4 parts by weight of (B) component: 1,2-pentanediol (listed as "Pentanediol" in Tables 1 and 2) or (B') component: propylene glycol. The resulting mixture was stirred at 80 °C for 20 minutes using a hot stirrer to prepare a lipid film-forming agent. Next, a 200 mL beaker was charged with 99.5 mL or 95 mL of (C-2) component: purified water (listed as "Water (for dispersion)" in Tables 1 and 2) to prepare an aqueous phase. The aqueous phase was heated to 80 °C, and the lipid film-forming agent prepared above was added while stirring at 100 rpm. After the addition was completed, the mixture was stirred at 80° C. for 2 minutes to prepare a dispersion liquid. The dispersion liquid was used as a lipid membrane structure-containing composition in Examples 1-0 and 1-1, Examples 2-0 and 2-1, Comparative Examples 1-0 and 1-1, and Comparative Examples 2-0 and 2-1.

[0147] [Examples 3-0 and 3-1] A 100 mL beaker was charged with 0.1 or 1 part by mass of (A) component hydrogenated lecithin (acid value 23.1 mg KOH / g), 0.4 or 4 parts by mass of (B) component 1,2-pentanediol, and 0.013 or 0.13 parts by mass of (F) component phytosterols, and the mixture was stirred at 80°C for 20 minutes using a hot stirrer. Then, 0.15 or 1.49 parts by mass of (C-1) component purified water (labeled "Water (for former)" in Table 1), 0.003 or 0.03 parts by mass of (D) component arginine, and 0.001 or 0.01 parts by mass of (E) component citric acid were added and stirred at 80°C for 5 minutes using a hot stirrer to prepare a lipid membrane former. Next, component (C-2): 99.33 mL or 93.34 mL of purified water (labeled "Water (for dispersion)" in Table 1) was added to a 200 mL beaker to prepare an aqueous phase. The aqueous phase was heated to 80°C, and the lipid membrane-forming agent prepared above at 80°C was added while stirring at 100 rpm. After the addition was complete, the mixture was stirred at 80°C for 2 minutes to prepare a dispersion. This dispersion was used as a lipid membrane structure-containing composition in Examples 3-0 and 3-1.

[0148] [Comparative Examples 3-0 and 3-1] A 100 mL beaker was charged with 0.1 or 1 part by mass of hydrogenated lecithin (acid value 13.9 mg KOH / g) as component (A), 0.45 or 4.5 parts by mass of propylene glycol as component (B'), and 0.45 or 4.5 parts by mass of glycerin as component (B'), followed by stirring at 80°C for 20 minutes using a hot stirrer to prepare a lipid membrane-forming agent. Next, a 200 mL beaker was charged with 99 mL or 90 mL of purified water as component (C-2) (labeled "Water (for dispersion)" in Table 2) to prepare an aqueous phase. The aqueous phase was heated to 80°C, and the lipid membrane-forming agent prepared above at 80°C was added while stirring at 100 rpm. After the addition was complete, the mixture was stirred at 80°C for 2 minutes to prepare a dispersion. This dispersion was used as a lipid membrane structure-containing composition in Comparative Examples 3-0 and 3-1.

[0149] [Examples 1-2 to 1-5 and Examples 2-2 to 2-5 and Comparative Examples 1-2 to 1-5 and Comparative Examples 2-2 to 2-5] A lipid film-forming agent was prepared by adding 1 part by weight of (A) component: hydrogenated lecithin or (A') component: hydrogenated lecithin having an acid value (unit: mgKOH / g) listed in Table 1 or Table 2, and 4 parts by weight of (B) component: 1,2-pentanediol or (B') component: propylene glycol to a 100 mL beaker and stirring for 20 minutes at 80 °C using a hot stirrer. Next, purified water (C-2) component (amount listed as "Water (for dispersion)" in Table 1 or Table 2) heated to 80 °C was added to the lipid film-forming agent and stirred for 5 minutes at 80 °C using a hot stirrer to prepare a dispersion. Subsequently, purified water (C-3) component (amount listed as "Water (for concentration adjustment)" in Table 1 or Table 2) was added to a 200 mL beaker to prepare an aqueous phase. The aqueous phase was heated to 80 °C, and the 80 °C dispersion prepared above was added while stirring at 100 rpm. After the addition was completed, the mixture was stirred at 80°C for 2 minutes to prepare a lipid membrane structure-containing composition.

[0150] [Examples 3-2 to 3-5] In a 100 mL beaker, 1 part by weight of (A) component: hydrogenated lecithin, 4 parts by weight of (B) component: 1,2-pentanediol, and 0.13 parts by weight of (F) component: phytosterols, having an acid value (unit: mgKOH / g) as shown in Table 1, were added and stirred at 80 ° C for 20 minutes using a hot stirrer. Then, 1.49 parts by weight of (C-1) component: purified water (listed as "Water (for forming agent)" in Table 1), 0.03 parts by weight of (D) component: arginine, and 0.01 parts by weight of (E) component: citric acid were added and stirred at 80 ° C for 5 minutes using a hot stirrer to prepare a lipid membrane former. Next, 80 ° C-2 component: purified water (the amount listed as "Water (for dispersion)" in Table 1) was added and stirred at 80 ° C for 5 minutes using a hot stirrer to prepare a lipid membrane former. Next, component (C-3): purified water (the amount indicated as "Water (for concentration adjustment)" in Table 1) was added to a 200 mL beaker to prepare an aqueous phase. The aqueous phase was heated to 80°C, and the above-prepared 80°C dispersion was added while stirring at 100 rpm. After the addition was completed, the mixture was stirred at 80°C for 2 minutes to prepare a lipid membrane structure-containing composition.

[0151] [Comparative Examples 3-2 to 3-5] A 100 mL beaker was charged with 1 part by weight of hydrogenated lecithin (acid value 13.9 mg KOH / g), 4.5 parts by weight of propylene glycol (B'), and 4.5 parts by weight of glycerin (B') and stirred at 80°C for 20 minutes using a hot stirrer to prepare a lipid film-forming agent. Next, a 200 mL beaker was charged with purified water (C-2) (the amount indicated as "Water (for dispersion)" in Table 2) to prepare an aqueous phase. The aqueous phase was heated to 80°C, and the lipid film-forming agent prepared above at 80°C was added while stirring at 100 rpm. After the addition was complete, the mixture was stirred at 80°C for 2 minutes to prepare a dispersion. Next, a 200 mL beaker was charged with purified water (C-3) (the amount indicated as "Water (for concentration adjustment)" in Table 2) to prepare an aqueous phase. The aqueous phase was heated to 80° C., and the dispersion liquid prepared above at 80° C. was added while stirring at 100 rpm. After the addition was completed, the mixture was stirred at 80° C. for 2 minutes to prepare a lipid membrane structure-containing composition.

[0152] <Evaluation method> [Particle size / polydispersity index] The particle size (based on scattered light intensity) and polydispersity index (PDI) of the lipid membrane structures of the lipid membrane structure-containing composition prepared above were measured by cumulant analysis using a dynamic light scattering measurement device (Zetasizer Nano ZSP, manufactured by Malvern Instruments). The measurement results of the particle size and polydispersity index of the lipid membrane structure-containing composition are shown in Tables 1 and 2. In the lipid membrane structure-containing composition having a concentration adjustment step, the particle size of the lipid membrane structures in the dispersion obtained by the dispersion step was measured, and it was confirmed that the particle size and polydispersity index of the lipid membrane structures in the dispersion were similar to the particle size and polydispersity index of the lipid membrane structures in the lipid membrane structure-containing composition after the concentration adjustment step.

[0153] [Cryo-TEM observation] The lipid membrane structure-containing compositions prepared in Examples 1-0 to 1-5, 2-0 to 2-5, and 3-0 to 3-5 were subjected to cryo-TEM observation using a transmission electron microscope (Hitachi High-Technologies Corporation, H-7650). The lipid membrane structure-containing compositions prepared in Examples 3-1 and 3-3 were subjected to cryo-TEM observation, and photographs obtained as a result of the observation are shown in Figures 1(a) and 1(b). In the photograph shown in Figure 1(a), the ring-shaped image indicates a unilamellar liposome structure, and the rod-shaped image indicates a bicelle structure, confirming the formation of a lipid membrane structure with a unilamellar structure. In the photograph shown in Figure 1(b), the multilayered ring-shaped image indicates a multilamellar liposome structure, confirming the formation of a lipid membrane structure with a multilamellar structure.

[0154] The particle size, polydispersity index, and results of Cryo-TEM observation of the lipid membrane structures are shown in Tables 1 and 2 below. Note that the particle size of the lipid membrane structure-containing compositions of Comparative Examples 1-0 to 1-5 could not be measured due to poor dispersion. In addition, in the column "membrane structure of lipid membrane structures" in Table 1, the results of Cryo-TEM observation are shown as "single layer" when a single lamellar structure was confirmed, and as "multilayer" when a multilamellar structure was confirmed. Note that Cryo-TEM observation was not performed on the lipid membrane structure-containing compositions prepared in Comparative Examples because the particle size exceeded 200 nm.

[0155] [Table 1]

[0156] [Table 2]

[0157] As shown in Table 1, it was found that the particle size of the obtained lipid membrane structures increases by increasing the concentration of component (A) in the dispersion liquid in the dispersion step according to the target particle size of the lipid membrane structures contained in the lipid membrane structure-containing composition. On the other hand, as shown in Table 2, it was found that when the acid value of the hydrogenated phospholipid in the lipid membrane structure-containing composition is less than 5 mg KOH / g, or when propylene glycol or glycerin is contained instead of component (B), even if the concentration of the dispersion liquid in the dispersion step is changed, the particle size of the obtained lipid membrane structures is not consistent with the relationship of the present invention, or a dispersion cannot be prepared (poor dispersion and aggregation occurs).

[0158] For each series of Examples 1-0 to 1-5, 2-0 to 2-5, and 3-0 to 3-5, the concentration [%] of component (A) in the dispersion liquid obtained in the dispersion step was used as the explanatory variable (x), and the particle size [nm] of the lipid membrane structures contained in the finally obtained lipid membrane structure-containing composition was used as the dependent variable (y). The approximate curve (cubic polynomial) and its coefficient of determination (R 2 ) values ​​are shown in Table 3 below.

[0159] [Table 3]

[0160] From the above, it was found that the particle size of the obtained lipid membrane structures can be controlled by combining a hydrogenated phospholipid with an acid value of 5 mg KOH / g or more with a polyol compound having a specific structure, and determining the concentration of component (A) in the dispersion liquid in the dispersion step according to the target particle size of the lipid membrane structures contained in the lipid membrane structure-containing composition.

Claims

1. (A) hydrogenated lecithin with an acid value of 5 mg KOH / g or more, and (B) a lecithin having the following formula 1: 【Chemistry 1】 In the above formula 1, R is an alkyl group having 2 to 6 carbon atoms, n is 0; and (C) water, a dispersion step of mixing the component (A), the component (B), and the component (C) to obtain a dispersion in which lipid membrane structures having particle diameters of 10 nm or more and 200 nm or less are spontaneously formed, The dispersion step determining the correlation between the concentration of the component (A) in the dispersion and the particle size of the lipid membrane structures contained in the lipid membrane structure-containing composition; determining the concentration of the component (A) in the dispersion liquid based on the correlation and in accordance with the target particle diameter of the lipid membrane structures contained in the lipid membrane structure-containing composition; Including, the concentration of the component (A), which is determined depending on the target particle size of the lipid membrane structures, is 0.01% by mass or more and 10% by mass or less with respect to the total mass of the dispersion; A method for producing a lipid membrane structure-containing composition, wherein the content of the component (B) is 110 parts by mass or more and 2000 parts by mass or less per 100 parts by mass of the component (A).

2. The method for producing a lipid membrane structure-containing composition according to claim 1, wherein the component (B) is at least one selected from the group consisting of 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, and 1,2-octanediol.

3. The method for producing a lipid membrane structure-containing composition according to claim 1, wherein the component (B) is 1,2-pentanediol.

4. 3. The method for producing a lipid membrane structure-containing composition according to claim 1, wherein the content of the component (B) in the dispersion is 150 parts by mass or more and 1,000 parts by mass or less per 100 parts by mass of the component (A).

5. A method for producing a lipid membrane structure-containing composition according to claim 1 or 2, wherein the concentration of component (A), which is determined according to the target particle diameter of the lipid membrane structure, is 0.1 mass % or more and 5 mass % or less relative to the total mass of the dispersion liquid.

6. The method for producing a lipid membrane structure-containing composition according to claim 1 or 2, further comprising a concentration adjustment step of mixing the dispersion liquid with the component (C) to obtain the lipid membrane structure-containing composition.

7. 3. The method for producing a lipid membrane structure-containing composition according to claim 1, wherein in the dispersion step, the component (A), the component (B), and the component (C) are mixed at a temperature equal to or higher than the phase transition temperature of the component (A).

8. A method for producing a cosmetic, comprising producing a lipid membrane structure-containing composition by the method according to claim 1 or 2.

9. A method for producing an external preparation for skin, comprising producing a lipid membrane structure-containing composition by the method according to claim 1 or 2.

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