JP6315743B2 - Silica microcapsule of lipid component having lamellar structure and method for producing the same - Google Patents

Description

The present invention relates Shirikama microcapsules and a method of manufacturing the lipid components were coated with silica having a lamellar structure.

  The stratum corneum composed of corneocytes and stratum corneum lipids in the skin epidermis imparts the skin barrier function. This stratum corneum lipid is produced during the keratinocyte keratinization process, accumulates in the lamellar granules in the “granular layer”, and is secreted outside the cell when it moves into the stratum corneum. And changes to keratinocyte lipids. In addition to ceramide, keratin intercellular lipid is composed of free fat, cholesterol ester and cholesterol. In normal skin, stratum corneum lipids constitute a lamellar structure.

  The lamellar structure of stratum corneum lipid has a short period structure (interlayer distance d = 5.6 nm) and a long period structure (d = 12.8 nm), and the structure of stratum corneum lipids using X-ray diffraction. Analysis has been performed (see Non-Patent Documents 1 and 2). In addition, it is known that human interstitial lipids have the composition shown in Table 1 (A). Ceramide, which is a poorly soluble substance, has the composition shown in Table 1 (B) and occupies about 50% of the lipids between keratinocytes, and its metabolism is important for maintaining the skin barrier function and moisturizing function. (See Non-Patent Document 3). The structural formula of each ceramide is as shown in Chemical Formula 1 and Chemical Formula 2, where (1) is ceramide 1, (9) is ceramide 9, (4) is ceramide 4, (2) is ceramide 2, (3) is ceramide 3 , (5) is ceramide 5, (6) is ceramide 6, (7) is ceramide 7, and (8) is ceramide 8.

  Ceramide is produced in the process of keratinization of epidermal cells, but it is known that the production amount is reduced if normal keratinization is not performed as in atopic disease. In atopic dermatitis, the ceramide content of the skin decreases and the barrier function of the skin decreases, resulting in a strong allergic reaction against antigens and pathogens (such as Staphylococcus aureus). In addition, the amount of ceramide in the stratum corneum decreases with age, and skin dryness, wrinkles, tarmi, etc. are likely to occur. As described in Non-Patent Documents 4 and 5, a lipid component having a lamellar structure derived from interkeratinous lipid existing in the epidermis efficiently repairs damaged defective corneocyte lipid by percutaneous penetration and absorption. .

  Currently, products encapsulating lipid components are commercially available. For example, the trade name “Beepan Joa 311” ceramide capsule cream of Beepan Joa Co., Ltd. contains ceramide capsules, which are simply porous silica microparticles containing ceramide. The ceramide component contained in the particles did not have a lamellar structure.

  Although emulsified products containing lipid components have been proposed as therapeutic agents for healthy and repairing the barrier function of the skin epidermis (for example, Patent Documents 1 to 3), lipids having a lamellar structure can be stably stored in the air. No microencapsulated product has been obtained.

  Patent Document 4 proposes a microcapsule containing a ceramide composition containing a ceramide having a lamellar structure, a higher alcohol, a sterol and an oil. However, since this capsule does not contain a free fatty acid, it does not have a function of repairing defective keratinocyte lipids, and there is a problem that the capsule material is aqueous collagen and easily rots in the atmosphere. In addition, although silicone (organopolysiloxane) is mentioned as a capsule material, an Example is not shown, and since a silicone forms a film by van der Waals force, a strong film cannot be expected. Furthermore, although it is disclosed that the ceramide composition has been confirmed to have a lamellar liquid crystal structure, it is not shown that the ceramide composition retains the lamellar structure in a capsule state.

  On the other hand, Patent Document 5 proposes a multilayer lamella granule comprising a ceramide-containing pseudo-keratin lipid lamellar layer on a nucleating agent such as sugar granule and a polymer layer on the pseudo-keratin lipid lamellar layer. The X-ray diffraction results of the lamellar structure are shown for a composition having a weight ratio of acid to cholesterol of 0.4: 0.4: 0.2. According to this, peaks at 2θ = 22 ° and 2θ = 5 ° are detected in the wide angle region, and d = 0.154 nm from the equation d = λ / 2 sin θ (general X-ray source CuKα: λ = 0.154 nm). It is converted to 41 nm and d = 1.7 nm. This is because d = 5.6 nm (converted to the small angle region 2θ = 1.6 °) of the short period lamella structure or d = 12.8 nm (converted to the small angle region 2θ = 0.7 °) of the long period lamella structure. The peak at 2θ = 5 ° (converted to d = 0.41 nm) is rather the hexagonal lareral packing described in Non-Patent Document 5. It is considered to match the structure. Moreover, it is not shown that the lipid obtained by coating the obtained particles with a natural polymer has a lamellar structure.

JP 2012-001556 A Special table 2010-505886 JP 2010-018558 A JP 2010-047493 A Special table 2011-529043 gazette

Takako Obata et al., “Development of pharmaceuticals and cosmetics based on structural analysis of stratum corneum lipids using synchrotron radiation X-ray diffraction”, 2008 Spring-8 Priority Industrial Use Issue Results Report (2008A1784) Joke A. Bouwstra et al., “Phase Behavior of Stratum Corneum Lipid Mixtures Based on Human Ceramides: The Role of Natural and Synthetic Ceramide 1”. THE JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2002, 118 (4), pp 606-617. Philip W. Wertz, et al., "Composition and Morphology of Epidermal Cyst Lipid", THE JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1987, 89 (4), pp 419-425. Ichiro Hatta, et al., "X-Ray diffraction study on ordered, disordered and reconstituted intercellular Lipid lamellar structure in stratum", Biophysical Chemistry, 2001, 89, pp.239-242. Joke A. Bouwstra and Gert S. Gooris, "The Lipid Organization in Human Stratum Corneum and Model Systems", The Open Dermatology Journal, 2010, 4, pp.10-13.

The problem to be solved by the present invention is that a lipid having a lamellar structure derived from interkeratin lipid present in the epidermis, which can efficiently repair damaged and defective stratum corneum lipid by percutaneous penetration and absorption. the component is to provide a Shirikama microcapsules and a method of manufacturing the microencapsulated while holding the lamellar structure.

As a result of earnest studies to achieve the above object, the present inventor has coated a labile lipid component composed of ceramide, fatty acid, cholesterol and oil prepared with In Vitro with silica to maintain a lamellar structure. And found that it can be microencapsulated.
The present invention has been created based on such knowledge, and is as follows.
(1) A silica microcapsule in which a lipid component having a lamellar structure is coated with silica.
(2) The silica microcapsule according to (1), wherein the lipid component contains ceramides, free fatty acids, cholesterols, and oil.
(3) The silica microcapsule according to (2) above, wherein the ceramide is a mixture of at least two kinds selected from ceramides 1 to 9, a sphingosine derivative, and a phytosphingosine derivative.
(4) The silica microcapsule according to (2), wherein the free fatty acid is a mixture of at least two selected from oleic acid, palmitic acid, linoleic acid, stearic acid, myristic acid, and palmitoleic acid.
(5) The silica microcapsule according to (2) above, wherein the cholesterol is cholesterol alone or a mixture of cholesterol and cholesterol ester.
(6) The silica microcapsule according to (2), wherein the oil is higher alcohol or animal or vegetable oil.

(7) A method for producing silica microcapsules, comprising reacting a lipid component having a lamellar structure with an aqueous solution containing tetraethoxysilane and coating with silica.
(8) The method for producing silica microcapsules according to (7), wherein the lipid component contains ceramides, free fatty acids, cholesterols, and oils.
(9) The method for producing silica microcapsules according to (8), wherein the ceramides are a mixture of at least two kinds selected from ceramides 1 to 9, a sphingosine derivative, and a phytosphingosine derivative.
(10) The method for producing silica microcapsules according to (8) above, wherein the free fatty acid is a mixture of at least two kinds selected from oleic acid, palmitic acid, linoleic acid, stearic acid, myristic acid, and palmitoleic acid.
(11) The method for producing silica microcapsules according to (2), wherein the cholesterol is cholesterol alone or a mixture of cholesterol and cholesterol ester.
(12) The method for producing silica microcapsules according to (8) above, wherein the oil is higher alcohol or animal or vegetable oil.
(13) The tetraethoxysilane-containing aqueous solution contains tetraethoxysilane, a surfactant, and water, and the pH is adjusted to a range of 3 to 6, according to any one of the above (7) to (12). Process for producing silica microcapsules.
(14) The method for producing silica microcapsules according to (13) above, wherein the surfactant is a mixture containing sorbitan oleic acid monoester, polyoxyethylene sorbitan monooleate, and polyvinyl alcohol.

(15) In (1) to (6) microswitch antiwrinkle for functional cosmetics containing capsule according to any one of.
(16) In (1) to transdermal therapeutic agents for atopic diseases comprising a microswitch capsule according to any one of (6).

Microcapsules of the present invention, because it is covered with silica, but stored in air, the lipid component having a lamellar structure derived from horny intercellular lipids are stably retained for a long time, Ma microcapsules By crushing the skin on the skin and uniformly applying the released lipid component, percutaneous permeation and absorption can be carried out to repair the damaged defective keratinocyte lipid. Therefore, the present invention can be used as a functional cosmetic for wrinkle improvement or a percutaneous absorption therapeutic for atopic diseases.

It is the schematic diagram of the lamellar structure of keratinocyte lipid, and its X-ray-diffraction pattern figure. It is an electron micrograph figure of the microcapsule obtained in the Example. It is an X-ray-diffraction pattern figure of the silica microcapsule which enclosed the lamella lipid. It is a photograph figure which shows the wrinkle improvement effect of a lamella lipid enclosure silica microcapsule. It is an X-ray-diffraction pattern figure which shows the repair function of damage-defective keratinocyte lipid. It is the schematic of a percutaneous absorption and permeation experiment apparatus Franz cell. It is a XPS spectrum figure of a Franz cell permeation liquid.

The lipid component coated on the silica microcapsules of the present invention has a lamellar structure as shown in FIG. 1, and this structure can be confirmed by an X-ray diffraction method. That is, the main peak is d = 5.6 nm (small angle region 2θ = 1.6 °) in the short-period lamella structure, and d = 12.8 (small angle region 2θ = 0.7 °) in the long-period lamella structure. Is recognized.
The lipid component having such a lamellar structure is preferably composed of ceramides / free fatty acids / cholesterol / oil, and the lipid component having a lamellar structure is reacted by adding the lipid component to an aqueous tetraethoxysilane (TEOS) solution. Coated silica microcapsules can be made.
The silica microcapsules of the present invention preferably have an average particle size of 0.1 to 2.0 μm, more preferably 0.3 to 1 for use as functional cosmetics or transdermal therapeutic agents. .2 μm.

  The ceramides in the present invention include ceramides 1 to 9 and derivatives thereof, which are contained in human keratinocyte lipids and have the chemical structures shown in Chemical Formula 1 and Chemical Formula 2, such as sphingosine, dihydrosphingosine, phytosphingosine, sphinga. Dienine, dehydrosphingosine, dehydrophytosphingosine, and derivatives thereof such as N-alkyl (for example, N-methyl) and acetylated compounds can be used. It is particularly preferable to use a mixture of two or more ceramides.

  As the free fatty acid, an unsaturated or saturated fatty acid having 12 to 30 carbon atoms, more preferably 18 to 26 carbon atoms is preferably used. For example, lauric acid, myristic acid, pentadecylic acid, palmitic acid, valmitoleic acid, margaric acid , Stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid, nonadecanoic acid, arachidic acid, arachidonic acid, bahenic acid, tetracosanoic acid, etc., especially oleic acid, palmitic acid, linoleic acid, stearic acid, myristic acid It is preferable to use a mixture of two or more selected from palmitoleic acid.

As cholesterols in the present invention, cholesterol, cholesterol esters, phytosterols and the like can be used, and it is particularly preferable to use a mixture of cholesterol and cholesterol ester oil.
Oils include higher alcohols such as octyldodecanol, natural animal and vegetable oils such as olive squalane, rose pip oil, tri (caprylic acid / capric acid) glyceryl, and semi-synthetic oils and hydrocarbons such as α-olefin oligomers. Oils, higher fatty acids, ester oils, silicone oils, animal and plant and synthetic essential oil components, fat-soluble vitamins, and the like can be used.

  Particularly preferred lipid component compositions are (1) a mixture of ceramide 3 and ceramide 6 with other ceramides or ceramide derivatives, (2) a mixture of oleic acid and palmitic acid with other fatty acids, (3) cholesterol, and (4) It consists of tri (caprylic acid / capric acid) glyceryl (hereinafter sometimes referred to as “CCT”).

  The content of the lipid component is 2 to 12% by weight of ceramides, more preferably 3 to 9% by weight, and 5 to 28% by weight of free fatty acid, more preferably 10 to 20% by weight based on the total amount of lipid components. %, Cholesterol is 0.7 to 4% by weight, more preferably 1 to 3% by weight, and the oil content is 60 to 90% by weight, more preferably 70 to 85% by weight. Outside this range, it becomes difficult to have a lamellar structure.

The silica microcapsule in which the lipid component having a lamellar structure of the present invention is coated with silica can be obtained by reacting the lipid component with an aqueous solution containing tetraethoxysilane (TEOS). The concentration of TEOS in this aqueous solution is preferably 4 to 14% by weight, and more preferably 6 to 10% by weight. Outside this range, it becomes difficult to obtain robust silica microcapsules.
Moreover, it is preferable to include a surfactant in the TEOS-containing aqueous solution. The amount of the surfactant added is preferably 1 to 5% by weight, and more preferably 2 to 4% by weight.
There are no particular limitations on the surfactant that can be used, and various types can be used. However, vegetable surfactants are preferred, and sorbitan oleic acid monoester, polyoxyethylene sorbitan monooleate, and A mixture of polyvinyl alcohol (Poval) is preferred. In addition, it is preferable that this aqueous solution is acidified (pH 3 to 6) with an acid such as acetic acid.

The reaction between the lipid component and the TEOS-containing aqueous solution can be performed by mixing and stirring the lipid component: TEOS-containing aqueous solution in a weight ratio of 1:20 to 2:10. The reaction conditions in this case are normal temperature and normal pressure, but can be carried out in the range of 20 to 70 ° C. and 0.8 to 1.2 kg / cm ² . After the reaction, the silica microcapsule of the present invention is obtained by filtration and drying.

The silica microcapsules of the present invention can be used in combination with functional cosmetics for improving wrinkles and transdermal therapeutic agents for atopic diseases.
In the functional cosmetics for improving wrinkles and the transdermal therapeutic agents for atopic diseases of the present invention, together with the silica microcapsules, they are usually used in ordinary cosmetics and transdermal therapeutic agents as long as the effects of the present invention are not impaired. Ingredients can be included.
The content of the silica microcapsules of the present invention in these cosmetics and transdermal absorption therapeutic agents is not particularly limited and can be appropriately selected according to the dosage form, etc., preferably 1 to 40% by weight, more preferably, 5 to 25% by weight.

  Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.

The lipid component shown in Table 2 and TEOS aqueous solution were mixed at a 1 to 10 weight ratio, adjusted to pH 4.5 with acetic acid, stirred for 6 hours, filtered and dried, and the lipid component was coated with silica. microcapsules were obtained.

An electron micrograph of the microcapsules obtained by the above method is shown in FIG.
FIG. 2A shows one capsule primary particle, and FIG. 2B shows an aggregate of 3 to 4 capsule primary particles. The average particle size of the primary particles was 0.3 μm.

Moreover, the X-ray-diffraction result of the microcapsule obtained by the said method was shown in FIG. As this result shows, the lipid contained in the silica microcapsule retains the lamellar structure. Peak ^* 1 is the scattering spectrum absolute value S ^{* 1} = 0.17 nm ⁻¹ (d = 5.8 nm), and peak ^* 2 is S ^{* 2} = 0.34 nm ⁻¹ = 2S ^{* 1} . This is consistent with the short-period lamella structure (d = 5.6 nm) derived from the keratinocyte lipid shown in Non-Patent Document 2.

  FIG. 4 shows a series of states when the microcapsules obtained above were crushed on the right hand skin and the released lipid was uniformly applied to the skin. In FIG. 4, A is a state before application of the microcapsule, B is a state in which the microcapsule is placed on the skin, C is a state in which the lipid released by crushing the microcapsule is uniformly applied to the skin, and D is immediately after application. It can be clearly seen that the skin wrinkles were improved by percutaneous penetration of the released lipid component.

  Next, the keratinocyte lipid was removed from the hairless mouse skin using methanol, and the microcapsules obtained above were crushed and applied on the degreased skin. The mouse skin was analyzed for the structure of stratum corneum lipids by X-ray diffraction. The results are shown in FIG. (A) in FIG. 5 is an X-ray diffraction pattern of the skin of a hairless mouse after defatting, (B) is an X-ray diffraction pattern after the microcapsule is crushed and applied, and (B) is derived from the skin. A peak corresponding to the short-period lamella structure derived from the stratum corneum lipid appeared in the shoulder of the peak, and the effect of repairing the stratum corneum lipid in which the lipid released from the microcapsule was damaged was observed.

Further, in massaging collapsed lipid inclusions Shirikama microcapsule skin, silica debris through the stratum corneum of the epidermis, it penetrates into the dermis, subcutaneous tissue, and verify whether the problem unknown side effects caused.
The above microcapsules are crushed on the hairless mouse skin, and the crushed surface is mounted on a Franz cell as shown in FIG. From above. The permeate was collected with a stainless steel petri dish, dried, and moisture removed, and the residue was measured by XPS (X-ray photoelectron spectroscopy).

  As a result, as shown in FIG. 7 and Table 3, peaks of sodium Na, oxygen O, nitrogen N, carbon C, chlorine Cl and the like derived from skin, lipid components and physiological saline are detected in the permeate residue. However, no silicon Si peak was detected, confirming that the silica debris did not penetrate the stratum corneum of the skin epidermis. In FIG. 7, (A) is the control, (B) is the permeate after 8 hours of immersion, (C) is the permeate after 12 hours of immersion, and (D) is the XPS spectrum of the permeate after 24 hours of immersion. It is.

In the silica microcapsule of the present invention, the encapsulated lipid component stably retains the lamella structure derived from the interkeratinocyte lipid even when stored in the air. Crushed dispute between microcapsules to the skin, by applying a release lipid component, the percutaneous penetration absorption, since damage defective horny intercellular lipid is repaired, the present invention silica microcapsules, for antiwrinkle cosmetic Or, it can be used as a therapeutic agent for transdermal absorption for atopic diseases.

Claims (14)

Silica microcapsules lipid component have a lamellar structure consisting of the following composition range, were coated with silica. Here, the composition of the lipid component consists of ceramides: 2 to 12% by weight, free fatty acids: 5 to 28% by weight, cholesterols: 0.7 to 4% by weight, and oils: 60 to 90% by weight. Ceramides, ceramide 1-9, sphingosine derivatives, and silica microcapsule according to claim 1 is at least two mixtures selected from phytosphingosine derivative. The silica microcapsule according to claim 1 , wherein the free fatty acid is a mixture of at least two kinds selected from oleic acid, palmitic acid, linoleic acid, stearic acid, myristic acid, and palmitoleic acid. Cholesterols is silica microcapsule according to claim 1 is cholesterol alone, or cholesterol and cholesterol ester mixture. Oil content, silica microcapsule according to claim 1 is a higher alcohol or animal or vegetable oil. The lipid components having a lamellar structure composed composition of claim 1, is reacted with tetraethoxysilane containing aqueous solution, the method for producing a silica microcapsule characterized by coating with silica. The method for producing silica microcapsules according to claim 6 , wherein the ceramides are at least two kinds of mixtures selected from ceramides 1 to 9, sphingosine derivatives, and phytosphingosine derivatives. The method for producing silica microcapsules according to claim 6 , wherein the free fatty acid is a mixture of at least two selected from oleic acid, palmitic acid, linoleic acid, stearic acid, myristic acid, and palmitoleic acid. The method for producing silica microcapsules according to claim 6 , wherein the cholesterol is cholesterol alone or a mixture of cholesterol and cholesterol ester. The method for producing silica microcapsules according to claim 6 , wherein the oil is higher alcohol or animal or vegetable oil. The silica microcapsule production according to any one of claims 6 to 10 , wherein the tetraethoxysilane-containing aqueous solution contains tetraethoxysilane, a surfactant, and water, and the pH is adjusted to a range of 3 to 6. Method. The method for producing silica microcapsules according to claim 11 , wherein the surfactant is a mixture containing sorbitan oleic acid monoester, polyoxyethylene sorbitan monooleate, and polyvinyl alcohol. The functional cosmetics for wrinkle improvement containing the macrocapsule in any one of Claims 1-5 . A transdermal absorption therapeutic agent for atopic disease containing the macrocapsule according to any one of claims 1 to 5 . "