Topical medications

Abstract

To provide an external preparation in which fine particles having a liquid crystal structure capable of quickly and sufficiently penetrating a physiologically active component into the skin or the like are dispersed, which comprises a composition having excellent dispersion stability of fine particles having the liquid crystal structure and does not generate a nasty smell such as a resin smell.SOLUTION: There is provided an external preparation which contains an aqueous component (A), at least one amphiphilic compound (C) represented by the following formula and a dispersion stabilizer (D) containing an inulin carbamic acid ester or an inulin fatty acid ester as essential components and comprises a liquid crystal dispersion composition in which fine particles having a liquid crystal structure having an average particle diameter of 350 nm or less such as reverse hexagonal liquid crystals retaining an oily physiologically active component (B) are dispersed in the aqueous component (A) and can be applied to the skin or the like. (R is a residue obtained by removing one hydroxyl group from any one selected from the group consisting of glycerol, diglycerol, triglycerol, glucose, trehalose, galactose or the like.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an external preparation comprising a liquid crystal dispersion composition having permeability to the skin and the like. [Background technology]

[0002] Generally, various techniques for producing microcapsules are known for incorporating physiologically active ingredients into topical preparations and enhancing their permeability into the skin or mucous membranes, and microcapsules that incorporate various cosmetic ingredients into their interiors or membranes using these techniques. Typical microcapsules include liposomes, bicelles, and gelatin microcapsules (Patent Document 1).

[0003] As shown schematically in Figure 2, when dispersed in an aqueous component W1 such as water, liposomes 10 become spherical vesicles having a lipid bilayer structure in which the hydrophobic regions 12 of phospholipids 11 face each other, and the inner region surrounded by the hydrophilic regions 13 of the phospholipids becomes a microcapsule capable of holding an aqueous component W2.

[0004] However, such microcapsules have a structure in which the hydrophilic regions of the surfactant are oriented outward, making them less compatible with the hydrophobic stratum corneum and less compatible with the skin.

[0005] Furthermore, in order to disperse and retain oily physiologically active ingredients in aqueous cosmetics such as lotions, a technique is known in which the oily physiologically active ingredients are dispersed as fine particles retained in a liquid crystal non-bilayer membrane phase, which is a lipid dispersion system similar to liposomes.

[0006] For example, as shown in Figure 3, a known example of a microcapsule with a liquid crystal structure capable of holding an oily component O containing a physiologically active ingredient or an aqueous component W2 is a topical skin preparation in which a rough skin prevention agent such as ceramide, various vitamins, or an oily component O with a moisturizing effect is held between hydrophobic regions 2 of an inverted hexagonal liquid crystal made of a specific amphiphilic compound 1, and such microcapsules are dispersed in an aqueous component W1 (Patent Documents 2 and 3).

[0007] Known dispersion stabilizers for the above-mentioned liquid crystal structure microcapsules include polyoxyethylene lauryl ether acetic acid (Patent Document 1,

[0049] ) and poloxamer 14 (a block copolymer consisting of a polyoxypropylene chain 15 sandwiched between two polyoxyethylene chains 16) (Patent Document 2,

[0042] ). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 4093480 [Patent Document 2] Japanese Patent Application Laid-Open No. 2012-17318 [Patent Document 3] Patent No. 4817435 Summary of the Invention [Problem to be solved by the invention]

[0009] However, the hydrophobic capsule surfaces of hexosomes, which are microcapsules with a liquid crystal structure, and cubosomes, which are bicontinuous cubic liquid crystal phases, have the problem that they tend to re-aggregate even when finely dispersed in an aqueous system.

[0010] Furthermore, the aforementioned poloxamer (POE / POP / POE triblock copolymer) and polyoxyethylene lauryl ether acetic acid, which are dispersion stabilizers that prevent re-aggregation, have micelle-forming ability and therefore are not efficiently oriented on the surface of the hydrophobic capsules. In addition, since these are petroleum-derived chemical substances that tend to produce a resinous odor when decomposed over time, they are not suitable for use in topical preparations.

[0011] Therefore, the object of the present invention is to solve the above-mentioned problems and to provide an external preparation such as an external preparation for skin containing dispersed fine particles holding liquid crystals that can quickly and sufficiently penetrate physiologically active ingredients, etc. into the skin, mucous membranes, etc., which is made of a liquid crystal dispersion composition that is resistant to re-aggregation over time and has excellent dispersion stability, and which does not produce an unpleasant odor such as a resinous odor. [Means for solving the problem]

[0012] In order to solve the above problems, the present invention employs a method of preparing an external preparation comprising a composition in which liquid crystal structured microparticles are dispersed in an aqueous component (A), the essential components of which are at least one amphiphilic compound (C) represented by the following formula 1 and a dispersion stabilizer (D) containing inulin carbamate ester or inulin fatty acid ester.

[0013] [ka] (In the formula, X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2, and m represents 1 or 2, TIFF0007828630000002.tif13129 represents a single bond or a double bond, and R represents a residue in which one hydroxyl group has been removed from any one selected from the group consisting of glycerol, diglycerol, triglycerol, glucose, trehalose, galactose, xylitol, erythritol, pentaerythritol, sorbitol, xylose, and ascorbic acid.

[0014] In addition, when X and Y in the formula 1 together represent an oxygen atom, a carbonyl group is formed, and the notation in the formula: TIFF0007828630000003.tif20129 means that the amphiphilic compound (C) represented by the formula 1 is a geometric isomer of E form (cis form) or Z form (trans form), or a mixture thereof.

[0015] The amphiphilic compound (C) represented by the above-mentioned specific chemical formula forms, for example, liquid crystal structured microparticles holding the oily physiologically active ingredient (B), and one or more microparticles are surrounded by a dispersion stabilizer (D) to maintain the structure of the microparticles and stabilize the dispersed state.

[0016] In this case, it is presumed that the dispersion stabilizer (D) surrounds the liquid crystal structure microparticles by positioning the main chain inulin chain on the outside of the microparticles, with multiple branched hydrophobic carbamate ester chains or fatty acid ester chains inserted from the main chain inulin chain into the lipophilic region of the amphiphilic compound (C) inside the surface of the liquid crystal structure microparticles.

[0017] In this way, the surface of the liquid crystal structured particles is covered with the inulin chains of the water-soluble polysaccharide, forming a three-dimensional hydrophilic barrier on the surface of the particles, which can hold a relatively large amount of the oily physiologically active ingredient (B) blended as needed. When such particles are finely dispersed in an aqueous system, they are less likely to re-aggregate over time, resulting in a liquid crystal dispersion composition with excellent dispersion stability. When used as an external preparation, the physiologically active ingredients held in the fine liquid crystal structure that is released from the hydrophilic barrier can be rapidly and sufficiently penetrated into the skin, mucous membranes, etc.

[0018] The liquid crystal structure in which the dispersion stabilizer (D) acts sufficiently is preferably a non-lamellar liquid crystal structure, and is preferably a liquid crystal structure containing at least one of a reverse hexagonal liquid crystal, a reverse cubic liquid crystal, or a sponge phase (L3 phase). Furthermore, as long as the dispersion stability of the microparticles is good, there is no need to particularly limit the particle size of the microparticles. However, for example, based on the results of the examples described below, an average particle size of 350 nm or less or 300 nm or less is a preferred particle size for external use.

[0019] Furthermore, in order to obtain a liquid crystal dispersion composition having excellent dispersion stability, the content ratio of the dispersion stabilizer (D) relative to 100 parts by mass of the amphiphilic compound (C) is preferably 5 to 100 parts by mass, more preferably 5 to 25 parts by mass, so as to maintain the dispersion stability of the fine particles in the liquid crystal dispersion composition and allow the fine particles to have the desired liquid crystal structure.

[0020] The topical preparation of the present invention can selectively contain active ingredients such as physiologically active ingredients as needed, and can be transported from outside the human body through biological membrane structures such as mucous membranes and skin to the inside of the body and act effectively. When the topical preparation of the present invention is an external preparation to be applied to the skin, it is preferable to use, for example, ceramide, which is expected to improve rough skin and restore skin barrier function, as the oily physiologically active ingredient (B) to be maintained in the liquid crystal structure. Furthermore, an aqueous physiologically active ingredient can be contained in the aqueous component (A) in which the fine particles having a liquid crystal structure are dispersed. [Effects of the Invention]

[0021] In this invention, fine particles of a predetermined liquid crystal structure are surrounded by a dispersion stabilizer with very low micelle-forming ability, thereby efficiently stabilizing the dispersed state. As a result, the fine particles of the liquid crystal structure are less likely to re-aggregate over time, resulting in excellent dispersion stability, and the physiologically active ingredients, etc., contained as needed, can be quickly and sufficiently penetrated into the skin and mucous membranes, and the external preparation has the advantage of not producing any unpleasant odors, such as a resinous odor. [Brief explanation of the drawings]

[0022] [Figure 1] Schematic diagram showing fine particles dispersed in a reverse hexagonal liquid crystal phase according to an embodiment. [Figure 2] Schematic diagram showing liposomes dispersed in a conventional aqueous component [Figure 3] Schematic diagram showing particles dispersed in a conventional reverse hexagonal liquid crystal phase [Figure 4](a), (b), and (c) are graphs showing the results of small-angle X-ray scattering (SAXS) measurements of the liquid crystal structures of Examples 1, 2, and 3, respectively, and showing the relationship between the scattering vector ratio q and the diffraction intensity. [Figure 5] 1A and 1B are transmission electron microscope photographs of the liquid crystal structure particles of Example 1, where (a) is a 30,000x magnification, (b) is a 120,000x magnification, and (c) is a photograph showing the Fourier transform pattern. [Figure 6] 1 is a diagram showing the results of the skin penetration test of Example 1 and Comparative Example 1, and showing the relationship between the amount of ceramide NG recovered in each stratum corneum group and the total amount recovered in layers 2-7. [Figure 7] Graph showing the relationship between time and transepidermal water evaporation when Example 1 and Comparative Example 1 were continuously used on the skin of subjects whose skin had been roughened by SDS treatment. DETAILED DESCRIPTION OF THE INVENTION

[0023] As one embodiment of the present invention, an external preparation for application to the skin, etc., is described, which comprises a composition in which liquid crystal microparticles holding an oily physiologically active ingredient (B) are dispersed in an aqueous component (A) as a dispersion medium, the liquid crystal structure comprising at least one non-lamellar (non-layered) liquid crystal structure selected from reverse hexagonal liquid crystal, reverse cubic liquid crystal, and sponge phase (L3 phase), and the raw materials used are the aqueous component (A), the oily physiologically active ingredient (B), at least one amphiphilic compound (C) represented by the formula (1) above, and a dispersion stabilizer (D).

[0024] The raw materials are mixed to form an inverted hexagonal liquid crystal phase, and the microparticles, which retain one or more liquid crystal structures internally and are stabilized in their dispersed state by being wrapped in a dispersion stabilizer consisting of hydrophobically modified inulin, such as inulin carbamate ester or inulin fatty acid ester, exhibit the following structure in the aqueous component W1, such as water, which is the dispersion medium.

[0025] As shown in Figure 1, an amphiphilic compound 1 having a hydrophobic region 2 and a hydrophilic region 3 encapsulates an aqueous component W2 such as water inside the hydrophilic region 3, and forms an inverted hexagonal liquid crystal structure while retaining an oily component or an oily physiologically active component 4 near the outer hydrophobic region 2. This is surrounded by a dispersion stabilizer 6, which stabilizes the dispersion state while maintaining the structure of the microparticles 5.

[0026] At this time, it is presumed that the dispersion stabilizer 6 inserts multiple hydrophobic fatty acid ester chains or carbamate ester chains 8 branching from the main chain inulin chain 7 into the hydrophobic region 2 of the amphiphilic compound 1 on the surface or inside of the liquid crystal structure microparticle 5, and positions the main chain hydrophilic inulin chain 7 on the outside of the microparticle 5, surrounding it in a capsule-like manner.

[0027] In this way, when the surface of the microparticles 5 is covered with the inulin chains 7 of the water-soluble polysaccharide and a three-dimensional barrier is formed on the surface of the microparticles 5, the microparticles 5 that retain the oily physiologically active ingredient 4 inside are less likely to re-aggregate over time even when finely dispersed in an aqueous system, and become a liquid crystal dispersion composition with excellent dispersion stability.

[0028] Although the liquid crystal structure described above is mainly a reverse hexagonal liquid crystal phase, it may also be a reverse cubic liquid crystal phase or a sponge phase (L3 phase). That is, the liquid crystal structure may be a non-lamellar liquid crystal structure containing at least one selected from a reverse hexagonal liquid crystal, a reverse cubic liquid crystal, and a sponge phase.

[0029] In either case, the dispersion stabilizer added is presumed to be positioned on the outside of the microparticles, encapsulating one or more liquid crystal structures in the inulin chains, which are made up of a water-soluble polysaccharide main chain, and can stabilize the dispersion state of the microparticles that retain such liquid crystal structures inside in the aqueous component. Incidentally, the sponge phase (L3 phase) is an isotropic phase in which bilayer membranes are randomly oriented, and is a type of non-lamellar liquid crystal phase, which can be emulsified and microparticulated without changing the liquid crystal structure.

[0030] The aqueous component (A) used in this invention includes the dispersion medium of the particulate liquid crystal in the liquid crystal dispersion composition and the aqueous component W2 encapsulated in the crystalline structure, and may also contain other aqueous components such as glycerin (a moisturizer) that are preferably incorporated into topical preparations, as well as other well-known aqueous physiologically active components.

[0031] The oily physiologically active component (B) used in this invention is an oily physiologically active component for cosmetics that is expected to have physiologically active effects such as suppressing moisture evaporation from the skin to maintain moisture and keeping the skin soft, and specific examples include oil-soluble rough skin prevention agents, whitening agents, anti-aging agents, antioxidants, anti-inflammatory agents, various vitamins and their derivatives, hair growth agents, and various plant or animal extracts.

[0032] Specific examples include ceramides, glycyrrhizinic acid, amino acids, sugars, mucopolysaccharides, hydrolyzed proteins, sphingolipids, phospholipids, ascorbyl palmitate, ascorbyl stearate, ascorbyl tetraisopalmitate, 3-O-cetyl ascorbic acid, rucinol, retinol, vitamin A acid, alkyl glyceryl ethers, and ε-aminocaproic acid derivatives.

[0033] Furthermore, as an alternative to sebum, for example, hydrocarbon oils such as α-olefin oligomers and squalane, silicone oils such as dimethylpolysiloxane, and other well-known emollient oils can also be used.

[0034] The above-mentioned ceramide is a constituent of the stratum corneum that enhances the skin barrier function, and is particularly preferable as the oily physiologically active ingredient (B) used in the present invention.

[0035] In addition to the oily physiologically active ingredient (B) described above, the topical preparation of the present invention that can be applied to the skin, etc., can also contain an aqueous physiologically active ingredient in the aqueous ingredient (A).

[0036] Examples of aqueous physiologically active ingredients that can be incorporated into general cosmetics include water-soluble ingredients such as ascorbic acid and its derivatives and their water-soluble salts, other water-soluble vitamins, whitening agents such as arbutin, ellagic acid, and tranexamic acid, natural moisturizing factors (NMFs) such as amino acids, salts of glycyrrhizic acid, water-soluble collagen, elastin, zinc glycine complex, nicotinamide, and ε-aminocaproic acid, anti-aging agents and anti-inflammatory agents, various vitamins and their derivatives, and various plant extracts.

[0037] The amphiphilic compound (C) used in the present invention is at least one compound represented by the formula (1) above, in which the hydrophilic group R or R' is a residue obtained by removing one hydroxyl group from any one compound selected from the group consisting of glycerol, diglycerol, triglycerol, erythritol, pentaerythritol, sorbitol, xylose, and ascorbic acid, and is particularly preferably glycerol.

[0038] An example of the glycerol ester represented by the formula 1 is the glycerol ester (C 1 ) which is mono-O-(5,9,13-trimethyltetradec-4-enoyl)glycerol represented by the following formula 2. 17 Examples of such glycerol esters include diglycerol esters (DGPA) represented by the formula 3, and triglycerol esters (TGPA) represented by the formula 4. Alternatively, mono-O-(5,9,13,17-tetramethyloctadecanoyl)glycerol represented by the following Chemical Formula 5 may be used, and amphiphilic compounds having aliphatic chains with a wide range of carbon numbers and degrees of unsaturation represented by the above Chemical Formula 1 may be used.

[0039] [ka]

[0040] [ka]

[0041] [ka]

[0042] [ka]

[0043] The dispersion stabilizer (D) used in this invention may contain either an inulin carbamic acid ester or an inulin fatty acid ester, but both may be used if necessary. As the inulin fatty acid ester, inulin stearate, inulin palmitate, etc. can be suitably used.

[0044] Incidentally, inulin, which constitutes the dispersion stabilizer (D), is a water-soluble polysaccharide naturally produced by various plants such as chicory, burdock, and onion, in which fructose is linked to sucrose in a linear chain via a β-2,1 bond, and the maximum degree of fatty acid substitution is 3. The average molecular weight of inulin is preferably in the range of 300 to 10,000. The fatty acid is preferably a fatty acid having 8 to 32 carbon atoms, and the fatty acid may be saturated or unsaturated, and may be linear or branched.

[0045] As described above, the dispersion stabilizer (D) is made from biologically derived inulin and does not generate an odor over time, unlike synthetic resins derived from chemically synthesized products.

[0046] Dispersion stabilizer (D) is a hydrophobically modified inulin in which hydrophobic fatty acids or alkyl carbamates are grafted onto the main chain of inulin, a water-soluble polysaccharide, and has the property of having a lower micelle-forming ability than poloxamer. Therefore, dispersion stabilizer (D) can be efficiently oriented on the surface of reversed hexagonal liquid crystals with a small amount.

[0047] For example, to stabilize microparticles of 4% by mass of amphiphilic compound (C), 1% by mass of poloxamer is required, whereas with dispersion stabilizer (D), long-term stabilization of microparticles is possible even with 0.5% as shown in Example 1 described below.

[0048] The content ratio of the dispersion stabilizer (D) relative to 100 parts by mass of the amphiphilic compound (C) in the liquid crystal dispersion composition is preferably within a predetermined range of 5 to 100 parts by mass, and the concentration of the dispersion stabilizer (D) is preferably equal to or greater than the lower limit of the predetermined range so that the average particle diameter of the fine particles is 350 nm or less. Furthermore, if the concentration of the dispersion stabilizer (D) is increased beyond the predetermined range, the particle diameter of the fine particles with a liquid crystal structure becomes smaller and dispersion stability is improved, but the desired liquid crystal structure may not be obtained, so the content ratio is more preferably less than 25 parts by mass.

[0049] However, it is possible to maintain the dispersion stability of the microparticles even if part of the liquid crystal structure is destroyed, and the microparticles are capsule-shaped materials in which the hydrophobic groups of the amphiphilic compound (C) face outward. Therefore, as long as the structural characteristic of high affinity for biological surfaces is maintained, the dispersion stabilizer (D) may be blended in as much as possible. In this case, the content ratio is preferably 100 parts by mass or less to prevent stickiness due to excess dispersion stabilizer (D). [Example]

[0050] [Example 1] As a lotion (skin lotion) consisting of a liquid crystal dispersion composition of an example of an external preparation, a liquid crystal dispersion composition (hexosome) in which reverse hexagonal liquid crystals containing ceramide, an oily physiologically active ingredient, were dispersed in water was prepared in the formulation shown in Table 1 as follows.

[0051] First, mono-O-(5,9,13-trimethyltetradec-4-enoyl)glycerol, which is an amphiphilic compound (C), i.e., C shown in Chemical Formula 2 above. 17 The glycerol ester was synthesized as follows.

[0052] Tetrahydronerolidol was reacted with trimethyl orthoacetate in the presence of acid, followed by simple distillation to obtain methyl 5,9,13-trimethyltetradec-4-enoate. Next, methyl 5,9,13-trimethyltetradec-4-enoate was reacted with glycerol in the presence of potassium carbonate in dimethylformamide (DMF). The reaction mixture was treated with 1M hydrochloric acid, extracted with ether, and the extract was washed with aqueous sodium bicarbonate and saturated brine, then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified to obtain C with a purity of 98.3%. 17 Glycerol ester was obtained.

[0053] The resulting amphiphilic compound (C) 17 Inverted hexagonal liquid crystals containing ceramide NG were formed using glycerin ester, and these were dispersed in an aqueous component (A) containing lauryl carbamate inulin, which is a dispersion stabilizer (D). The liquid crystals were then finely dispersed using a high-pressure homogenizer, yielding a liquid crystal dispersion composition in which fine particles with a liquid crystal structure were dispersed in the aqueous component (A).

[0054] The particle size distribution of the obtained microparticles was measured using a laser diffraction / scattering particle size distribution analyzer (LA-960V2, Horiba), and the volume-based median diameter was determined as the particle size. The average particle size was 185.5±0.4 nm.

[0055] [Table 1]

[0056] [Example 2] In Example 1, the amphiphilic compound (C) 17 A lotion (skin lotion) made of the liquid crystal dispersion composition of Example 2 was prepared in exactly the same manner, except that the blending ratio of the dispersion stabilizer (D) lauryl carbamate inulin to the glycerin ester was 1:0.05. The particle size of the obtained fine particles was measured in the same manner as in Example 1, and the average particle size was 296.3±0.1 nm.

[0057] [Example 3] In Example 1, the amphiphilic compound (C) 17 A lotion (skin lotion) made of the liquid crystal dispersion composition of Example 2 was prepared in exactly the same manner, except that the blending ratio of the dispersion stabilizer (D) lauryl carbamate inulin to the glycerin ester was 1:0.25. The particle size of the obtained fine particles was measured in the same manner as in Example 1, and the average particle size was 100.3±0.2 nm.

[0058] For Examples 1 to 3, a small angle X-ray scattering (SAXS) measurement test was carried out under the following measurement conditions, and it was confirmed that the liquid crystal structure had an inverted hexagonal liquid crystal structure, and that the liquid crystal structure and the amphiphilic compound (C) were C 17 The relationship between the blending ratio of the dispersion stabilizer (D) to the glycerin ester was investigated.

[0059] [Small-angle X-ray scattering (SAXS) measurement test] The liquid crystal structure of the examples was analyzed by small-angle X-ray scattering (SAXS) using an X-ray structure analysis system (Rigaku). The analysis conditions were wavelength λ = 0.1542 nm (Cu-Kα), 40 kV, 50 mA, and 25°C. Diffraction analysis was performed using a vacuum-resistant glass capillary cell. The obtained SAXS pattern was plotted as a function of the scattering vector coefficient q = (4π / λ) sin(θ / 2), where θ is the scattering angle.

[0060] These results are shown in Figure 4 (a) Example 1, (b) Example 2, and (c) Example 3. Incidentally, the diffraction pattern of the reverse hexagonal liquid crystal is a ratio q (nm -1 ) is 1:√3:√4.

[0061] From the results shown in FIG. 4, (a) Example 1 and (b) Example 2 have scattering vectors q (nm -1 ) ratio of 1:√3:√4, the diffraction intensity (au) peaks are clearly recognized, indicating that it is an inverted hexagonal liquid crystal.

[0062] However, (c) the scattering vector q (nm -1 ) ratio is slightly different from that of the reverse hexagonal liquid crystal, and q(nm -1 The appearance of a slightly gentle peak at 0.81 indicates the presence of a sponge phase (L3).

[0063] From this, it is clear that the amphiphilic compound (C) 17 When the dispersion stabilizer (D) is in excess relative to the glycerol ester, the liquid crystal structure partially or entirely changes to a sponge phase (L3). The liquid crystal structure can maintain the dispersion stability of non-lamellar microparticles, and the structural characteristics that give such microparticles a high affinity for biological surfaces are also maintained.

[0064] Furthermore, (c) as in Example 3, the higher the concentration of the dispersion stabilizer (D), the smaller the particle diameter becomes compared to Examples 2 and 1, but the peak of the diffraction pattern specific to the inverse hexagonal liquid crystal structure becomes duller, and it can be seen that if the concentration of the dispersion stabilizer (D) becomes excessively high, it becomes difficult to maintain the inverse hexagonal liquid crystal structure.

[0065] Furthermore, for Example 2, the inverted hexagonal liquid crystal structure was confirmed using a transmission electron microscope (Cryo-TEM), and the results are shown in FIG.

[0066] When observing the transmission electron microscope images of the electron-transparent ice-embedded sample prepared at cryogenic temperatures shown in Figure 5 [Cryo-TEM (A) magnification ×30,000, scale bar: 200 nm, (B) magnification ×120,000, scale bar: 50 nm, (C) Fourier transform pattern], the inverted hexagonal liquid crystal structure of Example 2 was confirmed, and the structural periodicity of the nanoparticles was confirmed from the Fourier transform pattern.

[0067] Next, the following skin penetration test was conducted to examine the properties of Example 1 and Comparative Example 1, allowing the physiologically active ingredient to penetrate the skin quickly and sufficiently. Comparative Example 1 employed a microparticle structure consisting of spherical capsules with a liposome lipid bilayer.

[0068] [Comparative Example 1] A phospholipid containing ceramide NG was dissolved in chloroform, and a lipid film was formed on the bottom of the flask under rotating conditions while nitrogen gas was blown into a thermostatic bath. A solvent with the same composition as in Example 1 was then added to prepare a liposomal lipid dispersion (Bangham method).

[0069] [Skin penetration test] Example 1 and Comparative Example 1 were coated onto the inside of the forearm of an adult subject (10 μL, 2 cm × 2 cm), and 6 hours later, stratum corneum samples were collected by tape stripping with adhesive tape. The stratum corneum samples were collected from different depths by repeatedly stripping the same area with new tape.

[0070] The stripped stratum corneum samples (layers 2-7) were divided into three groups: layers 2, 3, and layers 4-7. The amount of ceramide NG recovered from each group was quantified using a liquid chromatography-mass spectrometer (LC / MS). The results are shown in Figure 6. The total amount (layers 2-7) for the three groups is also shown in the figure.

[0071] As is clear from the results shown in Figure 6, the amount of ceramide NG recovered from the skin coated with the topical preparations of Example 1 and Comparative Example 1 in a state where it was attached to each tape was 1.5 times higher than the amount recovered from the skin coated with Example 1 compared to Comparative Example 1 (ceramide-containing liposomes), even though the particle size of the microparticles in Example 1 was larger than that of Comparative Example 1 (ceramide-containing liposomes), which was 105.6 ± 0.5 nm. The amount of ceramide NG recovered from the hexosomes in all tape release layers was greater than the amount recovered from the liposomes.

[0072] For further reference, 10 μL of each of the topical preparations from Example 1 and Comparative Example 1 was dropped onto the inside of the forearm of an adult subject (liposomes were dropped first), and the samples were fitted to the skin with a rubber gloved finger. The penetration speed of each sample was compared using video recording, and it was confirmed that Example 1 was absorbed into the skin significantly more quickly than Comparative Example 1.

[0073] [Transepidermal water loss measurement test] The skin of a subject was chemically irritated to induce rough skin (SDS treatment), and then the test was conducted by continuously using Example 1 and Comparative Example 1 on three sites on the inner forearm, and the amount of transepidermal water loss was measured. The SDS treatment of the test sites was carried out by contacting the sites with cotton soaked in 200 μL of 10% sodium lauryl sulfate (SDS) solution and sealing them for 3 hours.

[0074] The day before and the day after the SDS treatment, transepidermal water loss was measured for the treated and untreated areas of Example 1 and Comparative Example 1 in a measurement environment of 22°C and 50% humidity. After SDS treatment, each sample was used twice daily, and transepidermal water loss was measured 1 to 4 weeks later. Transepidermal water loss was measured using a VAPO SCAN AS-VT100RS (manufactured by ASCH), and the results are shown in Figure 7.

[0075] As is clear from the results shown in Figure 7, the transepidermal water loss rate after 3 weeks of continuous use in Example 1 was significantly reduced compared to that in Comparative Example 1. Measurements were performed after the application site was washed and acclimatized to a constant environment (temperature 22°C, humidity 50%), and the decrease in epidermal water loss rate was considered to reflect an improvement in the skin barrier function.

[0076] [Comparative Example 2-4] A liquid crystal dispersion composition in which fine particles having a liquid crystal structure were dispersed in an aqueous component (A) was prepared in exactly the same manner as in Example 1, except that in Example 1, 0.5 mass% of lauryl carbamate inulin as the dispersion stabilizer (D) was replaced by 1.0 mass% of POE lauryl ether acetate (Comparative Example 2), 1.0 mass% of POE / POP block copolymer (Comparative Example 3), or 0.5 mass% of acrylic acid / alkyl methacrylate copolymer (Comparative Example 4), all of which are well known in Patent Document 1, etc., as dispersion stabilizers. The obtained topical preparations of the liquid crystal dispersion compositions of Comparative Examples 2-4 and Example 1 were subjected to a sensory evaluation test for the presence or absence of odor and the feeling when used, and also to an evaluation test for particle stability.

[0077] [Odor and usability evaluation test] A questionnaire survey on odor was conducted on 10 adults (5 men and 5 women) as monitors. When the product was applied to the subjects' forearms, they rated the odor of chemical substances or other substances on a three-point scale: no odor (◯), slightly detectable (△), or detectable (×). The most common rating is shown by a symbol in Table 2.

[0078] In addition, in the above test, the feeling of use was also evaluated, and rated on a three-point scale: good compatibility with the skin (◯), slightly poor compatibility (△), and poor compatibility (×). The most common evaluation is also shown in Table 2.

[0079] [Particle stability evaluation test] The topical preparations of Comparative Examples 2-4 and Example 1 were used as test samples and sealed in transparent glass bottles, and a temperature acceleration test was carried out. The particle stability after 6 months at 40°C was visually examined and rated on a three-point scale: stable with no reagglomeration (◯), slight reagglomeration observed (△), and reagglomeration observed (×), and the results are shown by symbols in Table 2.

[0080] [Table 2]

[0081] As is clear from the results shown in Table 2, the topical preparation of Comparative Example 2-4, which used a conventional dispersion stabilizer other than the specified dispersion stabilizer, had some kind of strange odor, specifically, some kind of chemical odor such as petroleum odor, resin odor, etc. Furthermore, the topical preparation of Comparative Example 2-4 was observed to re-aggregate depending on the type of dispersion stabilizer. In contrast, the topical preparation of Example 1 had no particular unpleasant odor, and all monitors reported that it was odorless. It was also confirmed to be well absorbed into the skin and to have good long-term particle stability.

[0082] In this way, the microparticles are capsule-like materials in which the hydrophobic groups (amphiphilic compounds) holding the oily physiologically active ceramides face outward, forming an inverted hexagonal liquid crystal structure, which is surrounded by a specific dispersion stabilizer to maintain the microparticle structure and stabilize the dispersion state, resulting in high affinity for the skin.Due to this structural feature, the microparticles with the liquid crystal structure have a higher skin penetration effect than ceramide-containing liposomes, and have also been shown to retain moisture in the epidermis and improve barrier function.

[0083] Examples of formulations for the topical preparation of the present invention are given below. [Essence (beauty serum)]

[0084] [Table 3]

[0085] [Gel (skin care)]

[0086] [Table 4] [Explanation of symbols]

[0087] 1. Amphiphilic compounds 2, 12 Hydrophobic region 3, 13 Hydrophilic region 4 Oil-based physiologically active ingredients 5 Fine particles 6. Dispersion stabilizer 7 Inulin Chain 8. Fatty acid ester chain or carbamate ester chain 10 Liposomes 11 Phospholipids 14 Poloxamer 15 Polyoxypropylene chain 16 Polyoxyethylene chain

Claims

1. The topical preparation comprises, as essential components, at least one amphiphilic compound (C) represented by the following formula 1 and a dispersion stabilizer (D) containing an inulin carbamate ester or an inulin fatty acid ester, and is composed of a composition in which microparticles having an inverted hexagonal liquid crystal structure are dispersed in an aqueous component (A). 【Chemistry 1】 (In the formula, X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2, and m represents 1 or 2, 【change】 represents a single bond or a double bond, and R represents a residue in which one hydroxyl group has been removed from any one selected from the group consisting of glycerol, diglycerol, triglycerol, glucose, trehalose, galactose, xylitol, erythritol, pentaerythritol, sorbitol, xylose, and ascorbic acid.

2. 2. The topical preparation according to claim 1, wherein the particle diameter of the microparticles is an average particle diameter of 350 nm or less.

3. 3. The topical preparation according to claim 1, wherein the content ratio of the dispersion stabilizer (D) relative to 100 parts by mass of the amphiphilic compound (C) is 5 to 100 parts by mass.

4. 4. The topical preparation according to claim 1, wherein the dispersion stabilizer (D) is inulin lauryl carbamate.

5. The topical preparation according to any one of claims 1 to 4, further comprising an oily physiologically active ingredient (B).

6. 6. The topical preparation according to claim 5, wherein the oily physiologically active ingredient (B) is a ceramide.

7. The topical preparation according to any one of claims 1 to 6, wherein the aqueous component (A) is an aqueous component (A) containing an aqueous physiologically active ingredient.

8. The external preparation according to any one of claims 1 to 7, which is an external preparation for application to the skin.

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