JP7828630B2 - Topical medications - Google Patents

Description

Applicable under Article 30, Paragraph 2 of the Patent Law. Website publication date: October 21, 2020. Website address: https://www.scconline.org/ifscc2020/

This invention relates to a topical preparation comprising a liquid crystal dispersion composition having permeability to the skin and other surfaces.

Generally, various microcapsules are produced to enhance the penetration of physiologically active ingredients into topical preparations into the skin and mucous membranes. This technology has been applied to microcapsules containing various cosmetic ingredients internally or within their membranes. Representative microcapsules include liposomes, BiCells, and gelatin microcapsules (Patent Document 1).

As schematically shown in Figure 2, when dispersed in an aqueous component W ₁ such as water, the liposome 10 becomes a spherical vesicle having a lipid bilayer structure in which the hydrophobic regions 12 of the phospholipid 11 face each other, and the inner region surrounded by the hydrophilic region 13 of the phospholipid becomes a microcapsule capable of holding the aqueous component W ₂ .

However, these microcapsules have a structure in which the hydrophilic region of the surfactant is oriented outward, making them incompatible with the hydrophobic stratum corneum, and thus their affinity for the skin is insufficient.

Furthermore, to disperse and retain oily bioactive ingredients in aqueous cosmetics such as lotions, a well-known technique involves dispersing fine particles in which oily bioactive ingredients are held within a non-bismolecular-weight liquid crystal, similar to a lipid dispersion system like liposomes.

For example, as shown in Figure 3, a microcapsule with a liquid crystal structure capable of holding an oily component O containing a physiologically active ingredient and an aqueous component W ₂ is known, in which a skin topical preparation is prepared by holding a skin-soothing agent such as ceramide, various vitamins, or an oily component O with moisturizing effects between hydrophobic regions 2 of an inverse hexagonal liquid crystal made of a specific amphiphilic compound 1, and dispersing such microcapsules in an aqueous component W ₁ (Patent Documents 2 and 3).

As dispersion stabilizers for the above-mentioned liquid crystal structure microcapsules, polyoxyethylene lauryl ether acetate (Patent Document 1 [0049]) and poloxamer 14 (a block copolymer consisting of a polyoxypropylene chain 15 and two polyoxyethylene chains 16 flanking it) (Patent Document 2 [0042]) are known.

Patent No. 4093480 Japanese Patent Publication No. 2012-17318 Patent No. 4817435

However, hexosomes, which are microcapsules with a liquid crystal structure, and cubosomes, which are in the reverse hexagonal liquid crystal phase, have a problem in that their capsule surfaces are hydrophobic, making them prone to re-aggregation even when finely dispersed in an aqueous system.

Furthermore, the aforementioned poloxamer (POE/POP/POE triblock copolymer) and polyoxyethylene lauryl ether acetate, used as dispersion stabilizers to prevent re-aggregation, possess micelle-forming properties. Therefore, they do not efficiently orient themselves on the hydrophobic capsule surface. Moreover, as petroleum-derived chemicals, they tend to produce a resinous odor upon decomposition over time, making their use in topical preparations unsuitable.

Therefore, the objective of this invention is to solve the above-mentioned problems and to provide a topical preparation, such as a skin preparation, that contains dispersed fine particles holding liquid crystals, which can quickly and sufficiently penetrate physiologically active ingredients into the skin, mucous membranes, etc. Furthermore, it is a liquid crystal dispersion composition that is resistant to re-aggregation over time and has excellent dispersion stability, and moreover, does not produce any unpleasant odors such as resinous odors.

To solve the above problems, this invention employs a method for creating a topical preparation comprising a composition in which liquid crystal structure fine particles are dispersed in an aqueous component (A), with at least one amphiphilic compound (C) represented by the formula shown in Chemical Formula 1 below and a dispersion stabilizer (D) containing inulin carbamate ester or inulin fatty acid ester as essential components.

(In the formula, X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer from 0 to 2, and m represents 1 or 2.)
(where R represents a single or double bond, and R is a residue obtained by removing one hydroxyl group from any one of the following groups: glycerol, diglycerol, triglycerol, glucose, trehalose, galactose, xylitol, erythritol, pentaerythritol, sorbitol, xylose, and ascorbic acid.)

Furthermore, when X and Y together in formula 1 represent an oxygen atom, it indicates that a carbonyl group has been formed, and the notation in the same formula is:
This means that the amphiphilic compound (C) represented by formula 1 is either the geometric isomer E (cis) or Z (trans) isomer, or a mixture thereof.

The amphiphilic compound (C) represented by the above-described predetermined chemical formula constitutes, for example, fine particles with a liquid crystal structure that hold an oily physiologically active component (B). One or more fine particles are surrounded by a dispersion stabilizer (D), which maintains the structure of the fine particles and stabilizes their dispersion state.

In this case, it is presumed that the dispersion stabilizer (D) surrounds the liquid crystal microparticles by inserting multiple branched hydrophobic carbamic acid ester chains or fatty acid ester chains from the main chain's inulin chain into the lipophilic region of the amphiphilic compound (C) inside the surface of the liquid crystal microparticles, while positioning the main chain's inulin chain outside the microparticles.

In this way, the surface of the liquid crystal microparticles is covered with inulin chains of water-soluble polysaccharides, forming a three-dimensional hydrophilic barrier on the surface of the microparticles, which can hold a relatively large amount of the oily physiologically active component (B) that is added as needed. When such microparticles are finely dispersed in an aqueous system, a liquid crystal dispersion composition is obtained that is less prone to re-aggregation over time and has excellent dispersion stability.
When used as a topical preparation, the bioactive components held within the fine liquid crystal structure, freed from the hydrophilic barrier, can be quickly and thoroughly penetrated into the skin, mucous membranes, etc.

The liquid crystal structure on which the dispersion stabilizer (D) acts sufficiently is preferably a non-lamellar liquid crystal structure, and is preferably a liquid crystal structure that includes at least one of, for example, an inverse hexagonal liquid crystal, an inverse cubic liquid crystal, or a sponge phase ( _L3 phase).
Furthermore, as long as the dispersion stability of the fine particles is good, there is no particular need to restrict the particle size of the fine particles. However, as can be seen from the results of the examples described later, an average particle size of 350 nm or less or 300 nm or less is a preferred particle size for topical use.

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

The topical preparation of this invention can selectively contain active ingredients such as physiologically active components as needed, and can be transported into the human body from outside the body through biological membrane structures such as mucous membranes and skin, thereby allowing it to act effectively.
When the topical preparation of this invention is an external preparation applied to the skin, it is preferable to use, for example, ceramide as the oily physiologically active component (B) to be retained in the liquid crystal structure, as this component can be expected to improve rough skin and restore the skin barrier function.
Furthermore, aqueous physiologically active components can be included in the aqueous component (A) in which the liquid crystal structure microparticles are dispersed.

This invention features a dispersion stabilizer that surrounds fine particles with a predetermined liquid crystal structure with a dispersion stabilizer that has very low micelle-forming ability, thereby efficiently stabilizing the dispersion state. This results in a liquid crystal structure that is less prone to re-aggregation over time, possessing excellent dispersion stability. Furthermore, it allows for rapid and sufficient penetration of physiologically active ingredients into the skin and mucous membranes, and has the advantage of producing a topical preparation without the generation of unpleasant odors such as resinous odors.

A schematic diagram showing fine particles dispersed in the inverse hexagonal liquid crystal phase of the embodiment. A schematic diagram showing liposomes dispersed in a conventional aqueous component. A schematic diagram showing fine particles dispersed in a conventional inverse hexagonal liquid crystal phase. Figures (a), (b), and (c) show, in this order, the measurement results of the liquid crystal structures of Examples 1, 2, and 3 by small-angle X-ray scattering (SAXS), and are diagrams showing the relationship between the scattering vector ratio q and the diffraction intensity. These are transmission electron microscope images of the liquid crystal structure microparticles of Example 1, where (a) is at a magnification of 30,000x, (b) is at a magnification of 120,000x, and (c) shows the Fourier transform pattern. The results of the skin penetration tests for Example 1 and Comparative Example 1 are shown in the chart, which illustrates the relationship with the total amount of ceramide NG recovered from each stratum corneum group and layers 2-7. This chart shows the relationship between time and transepidermal water evaporation when Example 1 and Comparative Example 1 were continuously applied to the skin of subjects who experienced skin irritation due to SDS treatment.

As one embodiment of this invention, a topical preparation applied to the skin or the like is described, comprising a composition in which fine particles of a liquid crystal structure that hold an oily physiologically active component (B) with an aqueous component (A) as a dispersion medium are dispersed in the aqueous component ( _A ), wherein the liquid crystal structure includes at least one non-lamellar (non-layered) liquid crystal structure such as an inverse hexagonal liquid crystal, an inverse cubic liquid crystal, or a sponge phase (L3 phase), and the raw materials consist of the aqueous component (A), the oily physiologically active component (B), at least one amphiphilic compound (C) represented by the formula in Chemical Formula 1, and a dispersion stabilizer (D).

The aforementioned raw materials are mixed to form an inverse hexagonal liquid crystal phase, which holds one or more liquid crystal structures internally. The fine particles, which are encapsulated with a dispersion stabilizer consisting of hydrophobic modified inulin, such as inulin carbamate ester or inulin fatty acid ester, and whose dispersed state is stabilized, exhibit the following structure in an aqueous component _W1 such as water in the dispersion medium.

As shown in Figure 1, the amphiphilic compound 1, which has a hydrophobic region 2 and a hydrophilic region 3, encapsulates an aqueous component W ₂ such as water inside the hydrophilic region 3, while holding an oily component or an oily physiologically active component 4 near the outer hydrophobic region 2, forming an inverse hexagonal liquid crystal structure. This is surrounded by a dispersion stabilizer 6, which stabilizes the dispersion state while maintaining the structure of the fine particles 5.

At this time, it is presumed that the dispersion stabilizer 6 inserts multiple branched hydrophobic fatty acid ester chains or carbamic acid ester chains 8 from the main chain's inulin chain 7 into the hydrophobic regions 2 of the amphiphilic compound 1 on the surface or inside of the liquid crystal structure microparticles 5, while positioning the hydrophilic inulin chain 7 of the main chain on the outside of the microparticles 5, thus enclosing them in a capsule-like structure.

In this way, the surface of the microparticles 5 is covered with the inulin chain 7 of the water-soluble polysaccharide, forming a three-dimensional barrier on the surface of the microparticles 5. As a result, the microparticles 5, which retain the oily physiologically active component 4 internally, are less prone to re-aggregation over time even when finely dispersed in an aqueous system, resulting in a liquid crystal dispersion composition with excellent dispersion stability.

Furthermore, although the liquid crystal structure described above mainly refers to an inverse hexagonal liquid crystal phase, it may also refer to an inverse cubic liquid crystal phase or a sponge phase ( _L3 phase). In other words, the liquid crystal structure may be a non-lamellar liquid crystal structure that includes one or more selected from inverse hexagonal liquid crystal, inverse cubic liquid crystal, and sponge phase.

In either case, it is presumed that the added dispersion stabilizer is positioned on the outside of the microparticles, enclosing one or more liquid crystal structures in a capsule-like manner around the inulin chain, which consists of the water-soluble polysaccharide main chain. This allows the dispersion state of the microparticles, which hold such liquid crystal structures internally, to be stabilized in the aqueous component.
Incidentally, the sponge phase ( _L3 phase) is an isotropic phase in which two molecular films are randomly oriented, and is a type of non-lamellar liquid crystal phase. It can be emulsified and micronized without changing the liquid crystal structure.

The aqueous component (A) used in this invention includes the aqueous component _W2 contained within the dispersion medium and crystal structure of particulate liquid crystals in the liquid crystal dispersion composition, and may also contain other aqueous components such as glycerin (moisturizer), which is preferable to be incorporated into topical preparations, as well as other well-known aqueous physiologically active components.

The oily bioactive ingredient (B) used in this invention is an oily bioactive ingredient for cosmetics that is expected to have physiological active effects such as suppressing moisture evaporation from the skin to maintain moisture and keep the skin supple. Specific examples include oil-soluble anti-inflammatory agents, whitening agents, anti-aging agents, antioxidants, anti-inflammatory agents, various vitamins and their derivatives, hair growth agents, and various plant or animal extracts.

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

Furthermore, as substitutes for sebum, hydrocarbon oils such as α-olefin oligomers and squalane, silicone oils such as dimethylpolysiloxane, and other well-known emollient oils can also be used.

The above-mentioned ceramide is a component of the stratum corneum that enhances the skin barrier function, and is particularly preferred as the oily physiologically active ingredient (B) used in this invention.

Furthermore, in addition to the oily bioactive component (B) described above, the topical preparation applicable to the skin and other areas according to this invention may also contain an aqueous bioactive component in the aqueous component (A).

Commonly accepted aqueous physiologically active ingredients in cosmetics include 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 (NMF) such as amino acids, salts of glycyrrhizic acid, water-soluble collagen, elastin, zinc glycine complex, nicotinamide, anti-aging and anti-inflammatory agents such as ε-aminocaproic acid, various vitamins and their derivatives, and various plant extracts.

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

Examples of glycerol esters represented by formula 1 include mono-O-(5,9,13-trimethyltetradeca-4-enoyl)glycerol ester (also called _C17 glycerol ester or MGPA) shown in formula 2 below, diglycerol ester (DGPA) shown in formula 3, and triglycerol ester (TGPA) shown in formula 4.
Furthermore, mono-O-(5,9,13,17-tetramethyloctadecanoyl)glycerol, as shown in formula 5 below, may also be used, and amphiphilic compounds having a wide range of carbon numbers and degrees of unsaturation in fatty chains represented by formula 1 can be used.

The dispersion stabilizer (D) used in this invention may contain either inulin carbamate ester or inulin fatty acid ester, but both may be used if necessary.
Suitable inulin fatty acid esters include inulin stearate and inulin palmitate.

Incidentally, inulin, which constitutes the above-mentioned dispersion stabilizer (D), is a water-soluble polysaccharide produced in nature by various plants such as chicory, burdock, and onions. It consists of sucrose linked to fructose via β-2,1 bonds in a linear chain, with a maximum fatty acid substitution degree of 3. The average molecular weight of inulin is preferably in the range of 300 to 10,000. The fatty acids are preferably those with 8 to 32 carbon atoms, and the fatty acids may be saturated or unsaturated, and linear or branched.

Thus, the dispersion stabilizer (D) is made from inulin of biological origin and does not develop an odor like that of synthetic resins derived from chemical compounds over time.

Furthermore, the dispersion stabilizer (D) consists of hydrophobic modified inulin, which has a water-soluble polysaccharide inulin as its main chain and is grafted with hydrophobic fatty acids or alkylcarbamates. It has the characteristic of having lower micelle-forming ability than poloxamers. Therefore, a small amount of dispersion stabilizer (D) can efficiently orient itself onto the surface of the inverse hexagonal liquid crystal.

For example, while 1% by mass of poloxamer is required to stabilize 4% by mass of amphiphilic compound (C) fine particles, with dispersion stabilizer (D), long-term stabilization of the fine particles is possible even at 0.5% concentration, as shown in Example 1 described later.

The content ratio of the dispersion stabilizer (D) 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. The concentration of the dispersion stabilizer (D) is preferably above the lower limit of the predetermined range in order to ensure that the average particle size of the fine particles is 350 nm or less. Furthermore, if the concentration of the dispersion stabilizer (D) is increased beyond the predetermined range, although the particle size of the liquid crystal structure fine particles decreases and dispersion stability improves, the desired liquid crystal structure may not be obtained. Therefore, it is more preferable that the content ratio be less than 25 parts by mass.

However, even if part of the liquid crystal structure is destroyed, it is possible to maintain the dispersion stability of the fine particles. Furthermore, since the fine particles are capsule-shaped materials with the hydrophobic groups of the amphiphilic compound (C) facing outwards, as long as the structural characteristic of high affinity to biological surfaces is maintained, the amount of dispersion stabilizer (D) can be increased as much as possible. In such cases, it is preferable that the content ratio be 100 parts by mass or less to avoid stickiness caused by excessive dispersion stabilizer (D).

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

First, the amphiphilic compound (C), mono-O-(5,9,13-trimethyltetradeca-4-enoyl)glycerol, i.e., the _C17 glycerol ester shown in formula 2 above, was synthesized as follows.

Tetrahydronerolidol was reacted with trimethyl orthoacetate in the presence of an 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 1 M hydrochloric acid, extracted with ether, washed with aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified to obtain _C17 glycerol ester with a purity of 98.3%.

An inverse hexagonal liquid crystal containing ceramide NG was formed using the obtained amphiphilic compound (C), _C17 glycerol ester. This inverse hexagonal liquid crystal was dispersed in an aqueous component (A) containing a dispersion stabilizer (D), inulin laurylcarbamate. The liquid crystal was then finely dispersed using a high-pressure homogenizer to obtain a liquid crystal dispersion composition in which fine particles of the liquid crystal structure were dispersed in the aqueous component (A).

The particle size of the obtained fine particles was determined by measuring the particle size distribution using a laser diffraction/scattering particle size distribution analyzer (LA-960V2, Horiba). The average particle size, defined as the volume-based median diameter, was 185.5 ± 0.4 nm.

[Example 2]
A lotion (toner) made from the _liquid crystal dispersion composition of Example 2 was prepared in exactly the same manner as in Example 1, except that the ratio of the dispersion stabilizer (D), inulin laurylcarbamate, to the amphiphilic compound (C), C17 glycerol 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.

[Example 3]
A lotion (toner) made from the _liquid crystal dispersion composition of Example 2 was prepared in exactly the same manner as in Example 1, except that the ratio of the dispersant stabilizer (D), inulin laurylcarbamate, to the amphiphilic compound (C), C17 glycerol 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.

For Examples 1 to 3, small-angle X-ray scattering (SAXS) measurements were performed under the following measurement conditions to investigate whether the structure was an inverse hexagonal liquid crystal structure and the relationship between the liquid crystal structure and the ratio of the dispersion stabilizer (D) to the amphiphilic compound (C) _C17 glycerol ester.

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

These results are shown in Figure 4(a) Example 1, (b) Example 2, and (c) Example 3. Incidentally, for the diffraction pattern of the inverse hexagonal liquid crystal, the ratio q (nm ^{- 1} ) of the scattering vectors from the largest peak to the second and third peaks is 1:√3:√4.

The results shown in Figure 4 clearly indicate that (a) Example 1 and (b) Example 2 exhibit diffraction intensity (au) peaks for each of the scattering vector q (nm ^{- 1} ) ratios of 1:√3:√4, suggesting that they are inverse hexagonal liquid crystals.

However, the ratio of the scattering vector q( ^nm⁻¹ ) in Example (c) 3 differs slightly from that of the inverse hexagonal liquid crystal, and the presence of a sponge phase ( _L₃ ) is indicated by the appearance of a slightly gentler peak at q( ^nm⁻¹ ) 0.81.

Therefore, when the dispersion stabilizer (D) for the amphiphilic compound (C), _C17 glycerol ester, is present in excess, part or all of the liquid crystal structure changes into a sponge phase ( _L3 ). The liquid crystal structure can maintain the dispersion stability of non-lamellar microparticles, and the structural characteristic that such microparticles have high affinity for biological surfaces is also preserved.

Furthermore, as shown in Example (c) 3, the particle size decreases as the concentration of the dispersion stabilizer (D) increases compared to Examples 2 and 1. However, the peak of the diffraction pattern characteristic of the inverse hexagonal liquid crystal structure becomes blunter, indicating that maintaining the inverse hexagonal liquid crystal structure becomes difficult when the concentration of the dispersion stabilizer (D) is excessively high.

Furthermore, in Example 2, the inverse hexagonal liquid crystal structure was confirmed using a transmission electron microscope (cryo-TEM), and the results are shown in Figure 5.

Observation of transmission electron microscope images of the electron-permeable ice-embedded sample prepared under cryogenic conditions as 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] confirmed the inverse hexagonal liquid crystal structure in Example 2, and the structural periodicity of the nanoparticles was confirmed from the Fourier transform pattern.

Next, the skin penetration tests described below were performed on Example 1 and Comparative Example 1 to investigate their ability to quickly and sufficiently penetrate the skin with the physiologically active ingredients. Comparative Example 1 employed a microparticle structure consisting of spherical capsules having a liposome lipid bilayer.

[Comparative Example 1]
A phospholipid containing ceramide NG was dissolved in chloroform, and a lipid film was formed at the bottom of the flask under rotating conditions while blowing nitrogen gas into a constant temperature bath. A liposome lipid dispersion was then prepared by adding a solvent of the same composition as in Example 1 (Bungham method).

[Skin Penetration Test]
Example 1 and Comparative Example 1 were coated on the inner side of the forearm of an adult subject (10 μL, 2 cm × 2 cm). Six hours later, stratum corneum samples were collected by tape stripping with adhesive tape. The stratum corneum samples were collected from the same area repeatedly with new tape to obtain samples from different depths.

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

As is clear from the results shown in Figure 6, the amount of ceramide NG recovered from the skin treated with the topical preparations of Example 1 and Comparative Example 1, while adhering to each tape, was 1.5 times higher from the skin coated with Example 1 than from the skin coated with Comparative Example 1, even though the particle size of the fine particles in Example 1 was larger than that of Comparative Example 1 (ceramide-containing liposomes), which had a particle size of 105.6 ± 0.5 nm. The amount of ceramide NG recovered from hexosomes in all tape release layers was greater than the amount recovered from liposomes.

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

[Measurement test of transepidermal water loss rate]
Transepidermal water loss was measured by applying Example 1 and Comparative Example 1 consecutively to three locations on the inner forearm of subjects whose skin had been chemically irritated to induce skin roughness (SDS treatment). SDS treatment of the subjects' test sites was performed by contacting cotton impregnated with 200 μL of 10% sodium lauryl sulfate (SDS) solution and sealing it for 3 hours.

On the day before and the day after the SDS treatment, transepidermal water loss (TEV) 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 the SDS treatment, each sample was used twice daily, and TEV was measured again after 1 to 4 weeks. TEV was measured using a VAPO SCAN AS-VT100RS (ASCH), and the results are shown in Figure 7.

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 suppressed compared to that of Comparative Example 1. Measurements were taken after cleaning the application area and acclimatizing it in a constant environment (temperature 22°C, humidity 50%). The reduction in epidermal water loss rate is considered to reflect an improvement in skin barrier function.

[Comparative Example 2-4]
In Example 1, a liquid crystal dispersion composition was prepared in which liquid crystal structure fine particles were dispersed in an aqueous component (A), except that, in addition to 0.5% by mass of laurylcarbamate inulin (D) as the dispersion stabilizer (D), 1.0% by mass of POE lauryl ether acetate (Comparative Example 2), 1.0% by mass of POE/POP block copolymer (Comparative Example 3), and 0.5% by mass of acrylic acid/alkyl methacrylate copolymer (Comparative Example 4), which are well known from Patent Document 1, etc., were used as the dispersion stabilizer.
Sensory evaluation tests were conducted on the liquid crystal dispersion compositions obtained in Comparative Examples 2-4 and Example 1 for their odor and feel, as well as for particle stability.

[Evaluation test of odor and usability]
Ten adults (five men and five women) were used as monitors for a questionnaire survey on odor. After applying the substance to their forearms, they evaluated whether they detected any odor from chemicals, etc., on a three-point scale: no odor detected (○), slight odor detected (△), and odor detected (×). The most frequent evaluation is shown in Table 2 with a corresponding symbol.

Furthermore, in the above tests, the user experience was also evaluated, using a three-tiered system: good absorption into the skin (○), slightly difficult absorption (△), and poor absorption (×). The most frequent evaluation was indicated by a symbol in Table 2.

[Particle stability evaluation test]
The topical preparations from Comparative Examples 2-4 and Example 1 were sealed in transparent glass bottles and subjected to accelerated temperature testing. The particle stability after 6 months at 40°C was visually examined and evaluated in three stages: stable with no re-aggregation (○), slight re-aggregation observed (△), and re-aggregation observed (×). The results are indicated in Table 2 using symbols.

As is clear from the results shown in Table 2, the topical preparations in Comparative Example 2-4, which used conventional dispersion stabilizers other than the specified dispersion stabilizer, had some kind of off-odor, specifically a smell of some chemical substance such as petroleum or resin. In addition, re-aggregation was observed in the topical preparations in Comparative Example 2-4 depending on the type of dispersion stabilizer used.
In contrast, no particular odor was detected in the topical preparation of Example 1, and all monitors reported it to be odorless. Furthermore, it was found to be well absorbed by the skin and exhibited good particle stability over a long period.

Thus, these microparticles are capsule-like materials in which the hydrophobic groups (amphiphilic compounds) that hold the oily bioactive component ceramide face outward, forming an inverse hexagonal liquid crystal structure. This structure is surrounded by a predetermined dispersion stabilizer, maintaining the microparticle structure and stabilizing the dispersion state. Therefore, they have high affinity for the skin. Due to these structural characteristics, these liquid crystal microparticles exhibit a higher skin penetration effect than ceramide-containing liposomes, and also demonstrate improved barrier function by retaining moisture in the epidermis.

The following are examples of formulations for the topical preparation of this invention.
[Essence (Beauty Serum)]

[Gel (Skincare)]

1. Amphiphilic compounds 2, 12. Hydrophobic regions 3, 13. Hydrophilic regions 4. Oily physiologically active components 5. Microparticles 6. Dispersion stabilizers 7. Inulin chains 8. Fatty acid ester chains or carbamic acid ester chains 10. Liposomes 11. Phospholipids 14. Poloxamer 15. Polyoxypropylene chains 16. Polyoxyethylene chains

Claims (8)

A topical preparation comprising, as essential components, at least one amphiphilic compound (C) represented by the formula shown in Chemical Formula 1 below, and a dispersion stabilizer (D) containing inulin carbamate ester or inulin fatty acid ester, wherein fine particles with an inverse hexagonal liquid crystal structure are dispersed in an aqueous component (A).
(In the formula, X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer from 0 to 2, and m represents 1 or 2.)
(where R represents a single or double bond, and R is a residue obtained by removing one hydroxyl group from any one of the following groups: glycerol, diglycerol, triglycerol, glucose, trehalose, galactose, xylitol, erythritol, pentaerythritol, sorbitol, xylose, and ascorbic acid.) The topical preparation according to claim 1, wherein the particle size of the fine particles is 350 nm or less in average particle diameter. The topical preparation according to claim 1 or 2 , wherein the content ratio of the dispersion stabilizer (D) to 100 parts by mass of the amphiphilic compound (C) is 5 to 100 parts by mass. The topical preparation according to any one of claims 1 to 3 , wherein the dispersion stabilizer (D) is inulin laurylcarbamate. The topical preparation according to any one of claims 1 to 4 , further comprising an oily physiologically active ingredient (B). The topical preparation according to claim 5 , wherein the oily physiologically active component (B) is ceramide. 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 component. The topical preparation according to any one of claims 1 to 7 , wherein the topical preparation is a topical preparation for the skin.