JP2019206500A - Microneedle sheet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To effectively deliver C-glycoside such as C-xyloside under the stratum corneum of the skin, that is, in the epidermis and / or dermis of the skin, preferably to the dermal-epidermal junction of the skin. Provided is a microneedle sheet comprising a base sheet and a plurality of microneedles on the base sheet, wherein the microneedles are 50 to 1000 microns, preferably 100 to 300 microns. Preferably having a height of 150-250 microns, the microneedles comprise at least one water-soluble or water-dispersible polymer and the microneedles comprise at least one C-glycoside. According to the present invention, C-glycosides such as C-xyloside can be effectively delivered under the stratum corneum of the skin, i.e. in the epidermis and / or dermis of the skin, preferably at the dermal-epidermal junction of the skin. Is. [Selection diagram] None

Description

  The present invention relates to a microneedle sheet having a plurality of microneedles that can be used for cosmetic treatment of the skin.

  C-xyloside is a covalent product of proxylan and vanillin. Similar to proxylan, C-xyloside stimulates the synthesis of glucosaminoglycans and heparin sulfate proteoglycans occurring at the dermis-epidermal junction.

  The anti-aging and depigmentation efficacy of C-xyloside has been shown in several patent applications. WO2011 / 157746 and WO2010 / 067036 describe the cosmetic use of C-xyloside for treating keratin materials, and more particularly the use of this compound as an antioxidant. It has been demonstrated that this compound can be used in cosmetics to prevent and / or treat signs of skin aging. C-xyloside was prepared and tested as an anti-aging agent and showed its effect on glycosaminoglycan sulfate on fibroblasts and keratinocytes. Furthermore, WO 2014/096699 shows the use of this compound in cosmetics for depigmenting efficacy.

  WO2015 / 097029 discloses a topical cosmetic composition comprising an oil, a specific nonionic surfactant, C-glycoside and water.

  However, in passive diffusion with these conventional topical cosmetic formulations, C-xyloside does not soak deeply into the skin and builds up in the outermost layer of the skin, the stratum corneum, resulting in anti-aging efficacy. And depigmenting efficacy is difficult to expect. This is mainly due to the hydrophilic nature of C-xyloside.

WO2011 / 157746 WO2010 / 067036 WO2014 / 096699 WO2015 / 097029 U.S. Pat. Canadian Patent Application No. 2226718 U.S. Pat. No. 6,652,478 WO02 / 051828 EP2376510 French Patent No. 1262731

  The object of the present invention is to effectively deliver C-glycosides such as C-xyloside under the stratum corneum of the skin, i.e. within the epidermis and / or dermis of the skin, preferably the dermis-epidermal junction of the skin. is there.

The above object can be achieved by a microneedle sheet comprising a substrate sheet and a plurality of microneedles on the substrate sheet, wherein
The microneedle has a height of 50 to 1000 microns, preferably 100 to 300 microns, more preferably 150 to 250 microns;
The microneedles include at least one water-soluble or water-dispersible polymer, and the microneedles include at least one C-glycoside.

  In the microneedle sheet according to the present invention, more C-glycoside can be applied to the dermis and / or epidermis of the skin, preferably to the dermis-epidermal junction of the skin than in the stratum corneum of the skin.

  The microneedle of the microneedle sheet according to the present invention may have a conical shape.

  The bottom of the microneedle cone of the microneedle sheet according to the invention may have a diameter of 50 to 350 microns, preferably 100 to 300 microns, more preferably 150 to 250 microns.

  The ratio of (cone height) / (cone bottom diameter) of the microneedles of the microneedle sheet according to the present invention may be 1 or more.

  The microneedle sheet according to the present invention may have a Young's modulus of 50 N / mm or more, preferably 55 N / mm or more, more preferably 60 N / mm or more.

  The microneedles of the microneedle sheet according to the present invention can penetrate into the skin at a depth of 200 microns or less, preferably 190 microns or less, more preferably 180 microns or less.

  The water-soluble or water-dispersible polymer in the microneedle of the microneedle sheet according to the present invention includes hyaluronic acid, monosaccharide, disaccharide, oligosaccharide, polysaccharide, dextrin, dextran, polyethylene glycol, polyvinyl alcohol, poly (methyl vinyl ether / anhydrous Maleic acid), polyvinylpyrrolidone, poly (methyl / vinyl ether / maleic acid) (PMVE / MA) and their esters, poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH), and mixtures thereof .

  The water-soluble or water-dispersible polymer in the microneedles of the microneedle sheet according to the present invention has a molecular weight of 10,000 to 400,000 daltons, preferably 30000 to 300,000 daltons, more preferably 50000 to 200,000 daltons.

  The C-glycoside in the microneedle of the microneedle sheet according to the present invention may be selected from C-xyloside.

  The amount of C-glycoside in the microneedles of the microneedle sheet according to the present invention is 0.01 to 50% by mass, preferably 0.1 to 40% by mass, more preferably 1 to 30% by mass, based on the total mass of the microneedles. It may be a range.

  Another aspect of the present invention relates to a skin cosmetic method comprising the steps of applying the microneedle sheet according to the present invention onto the skin and inserting the microneedles of the microneedle sheet into the skin.

  The skin cosmetic method according to the present invention may be intended to prevent and / or treat skin aging, in particular skin aging induced by oxidative stress.

  The skin cosmetic method according to the present invention may be intended to deliver more C-glycosides than in the stratum corneum of the skin and into the dermis and / or epidermis of the skin, preferably the dermis-epidermal junction of the skin. Good.

  Another aspect according to the present invention is to provide a C-glycoside more than in the stratum corneum of the skin, and to the microdermis according to the present invention for delivering to the dermis and / or the epidermis of the skin, preferably the dermis-epidermal junction of the skin It relates to the cosmetic use of a needle seat.

  The cosmetic use according to the invention may be intended to prevent and / or treat skin aging, in particular skin aging induced by oxidative stress.

  As a result of intensive studies, the present inventors have used C-glycosides such as C-xyloside by using a microneedle sheet having specific microneedles under the stratum corneum of the skin, that is, the epidermis and / or the skin. It has been found that it can be effectively delivered intradermally, preferably at the dermal-epidermal junction of the skin.

Thus, the microneedle sheet according to the present invention includes a base sheet and a plurality of microneedles on the base sheet,
The microneedle has a height of 50 to 1000 microns, preferably 100 to 300 microns, more preferably 150 to 250 microns;
The microneedle includes at least one water-soluble or water-dispersible polymer,
The microneedle contains at least one C-glycoside.

  Since the microneedles of the microneedle sheet according to the present invention have a limited height aimed at the upper epidermis of the skin, the microneedles can penetrate deeply into the skin. Therefore, the microneedle sheet according to the present invention can deliver C-glycoside into the epidermis and / or dermis of the skin without pain.

  If the water-soluble or water-dispersible polymer is selected from hyaluronic acid, the mechanical strength of the microneedle sheet according to the present invention can be further enhanced.

  Furthermore, hyaluronic acid can reduce stacking interactions between the aromatic rings of C-glycosides, so that it can stabilize C-glycosides during storage and penetration through the skin. Therefore, the microneedle of the microneedle sheet according to the present invention can stably release C-glycoside even after long-term storage.

  Hereinafter, the microneedle sheet according to the present invention will be described in detail.

[Microneedle sheet]
The microneedle sheet according to the present invention comprises a base sheet and a plurality of microneedles on the base sheet, wherein
The microneedle has a height of 50 to 1000 microns, preferably 100 to 300 microns, more preferably 150 to 250 microns;
The microneedle includes at least one water-soluble or water-dispersible polymer,
The microneedle contains at least one C-glycoside.

(Microneedle)
The microneedle sheet according to the present invention includes a plurality of microneedles.

  The microneedles are present on the surface of the base sheet. The microneedles may be present in 50% or more, preferably 70% or more, more preferably 90% or more of the surface of the base sheet.

  The microneedles are preferably present on one of the surfaces of the base sheet.

  The microneedles in the microneedle sheet according to the invention are designed to penetrate or insert into the stratum corneum of the skin, in particular the face.

  The shape of the microneedle is not limited as long as the shape is a “needle”. It will be apparent to those skilled in the art that the microneedles of the present invention can take any reasonable shape including, but not limited to, conical, rod and / or columnar. Therefore, the microneedle may have a tip portion having the same diameter as the bottom portion, or the diameter may be tapered from the bottom portion toward the tip portion.

  For example, the shape of the microneedle may be a triangular pyramid, a quadrangular pyramid, or a pentagonal pyramid. Alternatively, the microneedle may preferably have a cylindrical shape having a tip portion, and can be formed by cutting the cylinder along a diagonal line.

  As described above, “microneedle” is referred to as a fine protrusion or a kind of fine protrusion to be used. It will be appreciated by those skilled in the art that in many cases the same inventive principles apply to the use of other microprojections or microprojections to penetrate the skin. Other microprojections or microprojections include, for example, the microblades described in US Pat. No. 6,219,574 and Canadian Patent Application No. 2226718, and the edged microneedles described in US Pat. No. 6,652,478.

  According to one embodiment of the invention, the microneedles are in the form of a cone.

  The cone may have a distal end such as a tip and a bottom. The shape of the bottom may be circular or elliptical.

  The microneedles can be of any size and shape suitable for puncturing the stratum corneum. Microneedles are designed to pass through the stratum corneum. Suitably, the height of the microneedles may be varied to allow penetration into the epidermis and / or dermis of the skin, preferably the upper dermis, more preferably the dermis.

  The tip separation distance between each of the individual microneedles on the substrate sheet is modified to have a separation distance short enough to ensure penetration into the skin by the microneedles and at the same time provide a high transdermal transport rate. sell.

  In one embodiment, the range of the tip separation distance between the microneedles can be in the range of 50-1000 μm, such as 100-400 μm or 200-300 μm. This allows a compromise to be achieved between the effective penetration of the stratum corneum by as many microneedles as possible and the room necessary for possible swelling of the microneedles when swollen. To do.

  The height or length of the microneedles of the microneedle sheet according to the present invention is 50 to 1000 microns, preferably 100 to 300 microns, more preferably 150 to 250 microns.

  The bottom of the microneedle cone of the microneedle sheet according to the present invention may have a diameter or width of 50 to 350 microns, preferably 100 to 300 microns, more preferably 150 to 250 microns. When the bottom of the microneedle cone of the microneedle sheet according to the present invention has an oval or oval shape, the length or width of the main axis of the oval is 50 to 350 microns, preferably 100 to 300 microns, More preferably, it may be 150 to 250 microns.

  The microneedles can have an aspect ratio (length / width at the bottom) of at least about 3: 1, at least about 2: 1, or at least about 1: 1. However, the ratio of (cone height) / (cone bottom diameter) of the microneedles is preferably 1 or more.

  When microneedles are used for transdermal delivery, in order to be used for transdermal delivery, it should be possible for the microneedles to create openings in the stratum corneum.

Preferably, the microneedle is less than 50.0N / cm ^2, for example 20.0N / cm less than ^2, for example, when the insertion pressure of less than ^2, such as 10 N / cm is applied along the length of the microneedle is disrupted by the force There is nothing.

  It is also preferred that the microneedle sheet according to the present invention, in particular the microneedles of the microneedle sheet, has a Young's modulus of 50 N / mm or more, preferably 55 N / mm or more, more preferably 60 N / mm or more.

  It is preferred that the microneedles can penetrate into the skin at a depth of 200 microns or less, preferably 190 microns or less, more preferably 180 microns or less.

  According to the present invention, the microneedle of the microneedle sheet according to the present invention comprises at least one water-soluble or water-dispersible polymer. Here, the terms “water-soluble” and “water-dispersible” mean soluble and dispersible, respectively, when in contact with water. A single water soluble or water dispersible polymer may be used. Two or more water-soluble or water-dispersible polymers can be used in combination.

  The water-soluble or water-dispersible polymer is preferably soluble or dispersible in the skin. Thus, in one embodiment of the invention, the water soluble or water dispersible polymer is soluble or dispersible after insertion into the skin. Due to the solubility and dispersibility of the polymer, the microneedle of the microneedle sheet according to the present invention can effectively release the cosmetic active ingredient in the microneedle, that is, C-glycoside. Optional external water combined with application of the microneedle sheet according to the present invention can be used to facilitate dissolution or dispersion of the microneedles.

  Water-soluble or water-dispersible polymers include hyaluronic acid (specifically low molecular weight hyaluronic acid), monosaccharides, disaccharides, oligosaccharides, polysaccharides (including derivatives thereof such as hydroxymethylcellulose), dextrin, dextran, polyethylene glycol, polyvinyl alcohol Poly (methyl vinyl ether / maleic anhydride), polyvinyl pyrrolidone, poly (methyl / vinyl ether / maleic acid) (PMVE / MA) and their esters, poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH), and These mixtures can be selected.

  The water-soluble or water-dispersible polymer may have a molecular weight of 10,000 to 400,000 daltons, preferably 30000 to 300,000 daltons, more preferably 50000 to 200,000 daltons.

  The low molecular weight hyaluronic acid may have a molecular weight of 100 kDa or less, preferably 50 kDa or less, more preferably 10 kDa or less.

  The polyvinylpyrrolidone may have a molecular weight between 1 kDa and 300 kDa, preferably between 5 kDa and 200 kDa, more preferably between 7 kDa and 100 kDa.

  Poly (methyl / vinyl ether / maleic acid) (PMVE / MA) and its esters, and poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH) are known as Gantrez type polymers.

  The amount of the water-soluble or water-dispersible polymer (solid base) in the microneedle of the microneedle sheet according to the present invention is 50% by mass or more, preferably 60% by mass or more, more preferably based on the total mass of the microneedle. It may be 70% by mass or more. The amount of the water-soluble or water-dispersible polymer (solid base) in the microneedle of the microneedle sheet according to the present invention is 100% by mass or less, preferably 90% by mass or less, more preferably based on the total mass of the microneedle. It may be 80% by mass or less. Thus, the amount of the water-soluble or water-dispersible polymer (solid base) in the microneedles of the microneedle sheet according to the present invention is 50% by mass to 100% by mass, preferably 60%, based on the total mass of the microneedles. It may be 70% to 80% by mass, more preferably 70% to 80% by mass.

  It may be possible for the microneedles of the microneedle sheet according to the invention to comprise at least one material that is swellable, more preferably water-swellable, even more preferably swellable in the skin. The material may be a polymer that is swellable, more preferably water swellable, even more preferably swellable in the skin. Here, the term “water swellable” means swellable when in contact with water. Said swellable material or polymer is at least 10-fold, preferably at least 20-fold, more preferably 1-hour in 1-hour incubation in saline solution or phosphate-buffered saline in vitro. It may have high swellability such that it can swell at least 30 times in incubation, even more preferably at least 40 times in 1 hour incubation, most preferably about 45 to 55 times in 1 hour incubation.

  At least the distal end portion of the microneedle may swell at least twice upon insertion into the skin, more preferably within less than 1 hour after insertion into the skin, and even more preferably within 24 hours. It may be preferable.

The swellable material, preferably the swellable polymer, may have a high viscoelasticity so that a gel can be formed after in vitro incubation in saline solution or phosphate buffered saline. The gel was tested in a dynamic frequency sweep test using a rheometer, even at low frequencies (0.01 Hz), high modulus G ', high viscosity coefficient G'', tangent (δ) less than 1 (tangent (δ) = G''/G') and high consistency G * (G * ² = G ' ² + G'' ² ).

  In one embodiment, the swellable material, preferably a swellable polymer, is not water soluble or water dispersible.

  In another embodiment, the swellable material, preferably a swellable polymer, can be a hydrogel-forming polymer.

  The above swellable polymers include high molecular weight hyaluronic acid, crosslinked hyaluronic acid, crosslinked polyethylene glycol, polyethylene glycol crosslinked polylactic acid or polyglycolic acid or poly-lactic acid-co-glycolic acid or polydioxanone, poly (styrene) block poly (acrylic acid) ), Polyethylene glycol cross-linked PMVE / MA, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, cellulose, natural and synthetic rubber, alginate, sodium polyacrylate, PEG cross-linked poly (methyl / vinyl ether / maleic acid) (PMVE / MA) and its It may be selected from esters, PEG cross-linked poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH) and its swells, and mixtures thereof.

  The high molecular weight hyaluronic acid may have a molecular weight greater than 500 kDa, preferably greater than 1000 kDa, more preferably greater than 2100 kDa, preferably less than 10000 kDa.

  Unless otherwise defined, molecular weight herein refers to number average molecular weight.

  Poly (methyl / vinyl ether / maleic acid) (PMVE / MA) and its esters, and poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH) are known as Gantrez type polymers.

  The amount of swellable material (solid base) in the microneedles of the microneedle sheet according to the present invention is 1% by mass or more, preferably 5% by mass or more, more preferably 10% by mass or more, based on the total mass of the microneedles It may be. The amount of the swellable material (solid base) in the microneedles of the microneedle sheet according to the present invention is 30% by mass or less, preferably 25% by mass or less, more preferably 20% by mass or less, based on the total mass of the microneedles. It may be. Thus, the amount of the swellable material (solid base) in the microneedles of the microneedle sheet according to the present invention is 1% by mass to 30% by mass, preferably 5% by mass to 25%, based on the total mass of the microneedles. It may be 10% by mass, more preferably 10% by mass to 20% by mass.

  Decreasing the amount of matrix, such as the epidermis, in the skin tends to cause wrinkle formation, resulting in a decrease in skin thickness and skin elasticity.

  If the microneedles of the microneedle sheet according to the present invention comprise at least one swellable material, preferably at least one swellable polymer, the microneedle is a skin, by reducing the appearance of wrinkles In particular, it can be swellable so as to improve the aesthetic appearance of the face.

  In other words, if the microneedle is swellable, it can swell in the skin, further increasing the volume of the microneedle, for example with the absorption of moisture in the skin. Such volume expansion below the skin surface of the heel site effectively pushes the heel from within the skin, making the heel shallower and wider. In this way, wrinkles can be reduced or become less noticeable.

  Thus, swellable microneedles can increase the amount of matrix in the skin, causing increased skin elasticity and resulting in reduced skin wrinkles.

(C-glycoside)
The microneedle of the microneedle sheet according to the present invention contains at least one C-glycoside. A single type of C-glycoside may be used. Alternatively, two or more C-glycosides can be used in combination.

  C-glycosides are represented by the following general formula (I):

[Where
R is OH, COOH, Y and COOR '' ₂ (wherein, R '' ₂ is a saturated C ₁ -C ₄ alkyl group, Y is optionally with one to five (OR _a) group saturated may be optionally substituted with at least one group selected from a phenyl group or a heterocycle is substituted) or unsaturated C ₁ -C _10, in particular represents a C ₁ -C ₄ alkyl group,
S represents a L- and / or D-type pyranose and / or furanose form of a monosaccharide or a polysaccharide containing 20 or less saccharide units, particularly 6 or less saccharide units, and the monosaccharide or polysaccharide must be Can be substituted with a free hydroxyl group, and optionally with one or more optionally protected amine functions;
X is -CO-, -CH (OR ')-, -CH (NH ₂ )-, -CHNR _b R _c- , -CHNHOR _d , -C (OR')-, -C (NH ₂ )-, A group selected from -CNR _b R _c- , -CNHOR _d- , -CH (NHCH ₂ CH ₂ CH ₂ OH)-, -CH (NHPh)-and -CH (CH ₃ )-, particularly -CO-,- CH (OH)-or -CH (NH ₂ )-, and more particularly a -CH (OH)-group,
R 'is a hydrogen atom; a linear C ₁ -C ₁₈ alkyl groups, saturated, linear C ₂ -C ₁₈ unsaturated alkyl groups, saturated or branched C ₃ -C ₁₈ unsaturated alkyl group, saturated or unsaturated C ₅ or C ₆ cyclic group, a linear or branched, saturated or unsaturated C ₂ -C _18, or a saturated or unsaturated C ₅ or C ₆ cyclic acyl group,
R _a represents a hydrogen atom; a linear or branched C _{1 to} C ₄ alkyl group, or a linear or branched unsaturated C _{3 to} C ₄ hydrocarbon group; a linear or branched group C ₂ -C ₁₈ acyl, or a linear or branched C ₂ -C ₁₈ alkenylcarbonyl group,
R _b represents a hydrogen atom; a linear C _{2 to} C ₁₈ or branched C _{3 to} C ₁₈ alkyl group, or a linear or branched unsaturated C _{3 to} C ₄ hydrocarbon group, or — CH (Z ₁ ) -CO ₂ Z ₂ group, wherein Z ₁ is a hydrogen atom, or a linear or branched C _{1 to} C ₆ , or a saturated or unsaturated cyclic C ₃ to C ₃ indicates ₆ alkyl group, said _{group, -NH, -NH 2, -N (} T) 2, -O, -OH, -OT, -SH, -ST, -CO 2 T, phenyl, -OH or - Phenyl substituted with OT,

And / or -NH-, -N- (COT)-or -S- group (T is a linear or branched C ₁ -C), optionally substituted with at least one group selected from ₆ or shows a cyclic C ₃ -C ₆ alkyl group) and interrupted by at, Z ₂ represents a hydrogen atom, or a linear or branched C ₁ -C ₆ alkyl group,
R _c represents a hydrogen atom; a linear C _{1 to} C ₄ or branched C _{3 to} C ₄ alkyl group, or a linear or branched unsaturated C _{3 to} C ₄ hydrocarbon group; The group is optionally substituted with a phenyl group;
R _d represents a hydrogen atom; a linear C _{1 to} C ₁₈ or branched C _{3 to} C ₁₈ alkyl group, or a linear or branched unsaturated C _{3 to} C ₁₈ hydrocarbon group; The group is optionally substituted with a phenyl group;
And the bond S—CH ₂ —X represents a C-anomeric bond, which may be α or β]
Furthermore, cosmetically acceptable salts thereof, solvates thereof such as hydrates, and optical isomers and geometric isomers thereof.

C-glycosides of the formula (I) useful in the practice of the invention are in particular R linear saturated C ₁ -C ₆ , especially C ₁ -C ₄ , preferentially C ₁ -C, _{2 represents} an alkyl group, more preferably a methyl group. Among the alkyl groups suitable for use in the present invention, in particular, methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, n-hexyl, cyclopropyl, cyclopentyl and cyclohexyl These groups can be mentioned.

  According to one embodiment of the present invention, the C-glycoside compound represents that S represents a monosaccharide or a polysaccharide comprising 6 or less sugar units in the L and / or D form of pyranose and / or furanose form. Wherein the monosaccharide or polysaccharide contains at least one necessarily free hydroxyl function and / or optionally one or more necessarily protected amine functions, and other moieties X and R can be used according to formula (I), maintaining all the definitions given earlier. Advantageously, the monosaccharide of the present invention comprises D-glucose, D-galactose, D-mannose, D-xylose, D-lyxose, L-fucose, L-arabinose, L-rhamnose, D-gluconic acid, D- May be selected from galacturonic acid, D-iduronic acid, N-acetyl-D-glucosamine and N-acetyl-D-galactosamine, advantageously D-glucose, D-xylose, N-acetyl-D-glucosamine or L-fucose, specifically D-xylose.

  More particularly, the polysaccharide of the present invention containing 6 or fewer sugar units is selected from D-maltose, D-lactose, D-cellobiose, D-maltotriose; D-iduronic acid and D-gluconic acid Disaccharide in which uronic acid is combined with hexosamine selected from D-galactosamine, D-glucosamine, N-acetyl-D-galactosamine and N-acetyl-D-glucosamine; xylobiose, methyl-β-xylobioside, xylotriose, xylotetra May be selected from oligosaccharides containing at least one xylose which may advantageously be selected from aose, xylopentaose and xylohexaose, in particular xylobiose consisting of two xylose molecules linked via a 1-4 bond .

  More specifically, S can represent a monosaccharide selected from D-glucose, D-xylose, L-fucose, D-galactose and D-maltose, in particular D-xylose.

  Acceptable salts for the compounds described in this invention include conventional non-toxic salts of said compounds, such as those formed from organic acids or mineral acids. Examples include salts of mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid or boric acid. Mention may also be made of salts of organic acids which may contain one or more carboxylic acid groups, sulfonic acid groups or phosphoric acid groups. These may be linear, branched or cyclic aliphatic acids, or aromatic acids. These acids may also contain one or more heteroatoms selected from O and N, for example in the form of hydroxyl groups. Mention may be made especially of propionic acid, acetic acid, terephthalic acid, citric acid and tartaric acid.

When the compounds of formula (I) contains an acidic group, neutralized acidic groups, LiOH, NaOH, KOH, Ca (OH) 2, NH 4OH, Mg (OH) 2 or Zn (OH) ₂ such as inorganic It may be carried out with a base or with an organic base such as a primary, secondary or tertiary alkylamine, for example triethylamine or butylamine. The primary, secondary, or tertiary alkyl amine may contain one or more nitrogen and / or oxygen atoms, and thus may contain, for example, one or more alcohol functional groups, in particular, Mention may be made of 2-amino-2-methylpropanol, triethanolamine, 2-dimethylaminopropanol and 2-amino-2- (hydroxymethyl) -1,3-propanediol. Mention may also be made of lysine or 3- (dimethylamino) propylamine.

  Solvates acceptable for the compounds described in this invention include conventional solvates, such as those formed during the final steps of preparation of the compounds due to the presence of solvents. By way of example, mention may be made of solvates due to the presence of water or the presence of linear or branched alcohols such as ethanol or isopropanol.

According to the first embodiment, preferentially, the formula (I)
[Where
R is unsubstituted, straight C ₁ -C ₄ alkyl group, in particular C ₁ -C _2, when specifying a methyl,
S represents a monosaccharide as described above, specifically selected from D-glucose, D-xylose, N-acetyl-D-glucosamine and L-fucose, specifically selected from D-xylose;
X represents a group selected from —CO—, —CH (OH) — and —CH (NH ₂ ) —, and preferably represents a —CH (OH) — group]
C-glycoside derivatives are used.

As a non-limiting illustration of a C-glycoside compound that is more particularly suitable for use in the present invention, in particular,
C-β-D-xylopyranoside-n-propan-2-one,
C-α-D-xylopyranoside-n-propan-2-one,
C-β-D-xylopyranoside-2-hydroxypropane,
C-α-D-xylopyranoside-2-hydroxypropane,
1- (C-β-D-fucopyranoside) propan-2-one,
1- (C-α-D-fucopyranoside) propan-2-one,
1- (C-β-L-fucopyranoside) propan-2-one,
1- (C-α-L-fucopyranoside) propan-2-one,
1- (C-β-D-fucopyranoside) -2-hydroxypropane,
1- (C-α-D-fucopyranoside) -2-hydroxypropane,
1- (C-β-3-L-fucopyranoside) -2-hydroxypropane,
1- (C-α-L-fucopyranoside) -2-hydroxypropane,
1- (C-β-D-glucopyranosyl) -2-hydroxypropane,
1- (C-α-D-glucopyranosyl) -2-hydroxypropane,
1- (C-β-D-galactopyranosyl) -2-hydroxypropane,
1- (C-α-D-galactopyranosyl) -2-hydroxypropane,
1- (C-β-D-fucofuranosyl) propan-2-one,
1- (C-α-D-fucofuranosyl) propan-2-one,
1- (C-β-L-fucofuranosyl) propan-2-one,
1- (C-α-L-fucofuranosyl) propan-2-one,
C-β-D-maltopyranoside-n-propan-2-one,
C-α-D-maltopyranoside-n-propan-2-one,
C-β-D-maltopyranoside-2-hydroxypropane,
Mention may be made of compounds of C-α-D-maltopyranoside-2-hydroxypropane, and their isomers and mixtures thereof.

  According to one embodiment, C-β-D-xylopyranoside-2-hydroxypropane or C-α-D-xylopyranoside-2-hydroxypropane, preferably C-β-D-xylopyranoside-2-hydroxypropane, is It is advantageously used for the preparation of a composition according to the invention.

  According to a particular embodiment, the C-glycoside compound is C-β-D-, which is in the form of a solution containing 30% by weight of active material in a water / propylene glycol mixture (60% by weight / 40% by weight). It may be xylopyranoside-2-hydroxypropane (or hydroxypropyltetrahydropyrantriol).

  C-glycoside derivatives suitable for use in the present invention can be obtained in particular via the synthesis method described in document WO02 / 051828.

  According to a second embodiment, the C-glycoside is selected from C-xyloside.

Therefore, the C-glycoside is preferably represented by the general formula (I) [wherein S is xylose, R represents a saturated or unsaturated C2 alkyl group substituted with a Y group, and the Y group is A phenyl group or a heterocycle optionally substituted with 1 to 5 (OR _a ) groups]], selected from C-glycosides of the following formula (II):

[Where
The compound of formula (I) is a xylose derivative,
Y represents a phenyl group or a heterocycle optionally substituted with 1 to 5 (OR _a ) groups;
W is -OR ', (-O), NR _b R _c , NHOR _d ,
R 'is a hydrogen atom; unsaturated linear C ₂ -C ₁₈ alkyl group; branched C ₃ -C ₁₈ saturated or unsaturated alkyl group, a linear C ₁ -C ₁₈ alkyl group, saturated saturated or unsaturated C ₅ or C ₆ cyclic group; a linear or branched, indicates a saturated or unsaturated C ₂ -C _18, or a saturated or unsaturated C ₅ or C ₆ cyclic acyl group,
R _a represents a hydrogen atom; a linear or branched C _{1 to} C ₄ alkyl group, or a linear or branched unsaturated C _{3 to} C ₄ hydrocarbon group; a linear or branched group C ₂ -C ₁₈ acyl, or a linear or branched C ₂ -C ₁₈ alkylcarbonyl group,
When Y represents a phenyl group or a heterocyclic ring substituted with 2 to 5 (OR _a ) groups, two adjacent OR _a groups together form a divalent —O—CH ₂ —O— group. Provided that when W = OH, the compound does not contain an ethylenic double bond of α to the carbon holding the OH;
R _b represents a hydrogen atom; a linear C _{2 to} C ₁₈ or branched C _{3 to} C ₁₈ alkyl group, or a linear or branched unsaturated C _{3 to} C ₄ hydrocarbon group, or — CH (Z ₁ ) —CO ₂ Z ₂ represents a group, wherein Z ₁ is a hydrogen atom, or a linear or branched C _{1 to} C ₆ , or saturated or unsaturated C _{3 to} C ₆ cyclic Represents an alkyl group, and the group is --NH, --NH ₂ , --N (T) ₂ , --O, --OH, --OT, --SH, --ST, --CO ₂ T, phenyl, --OH or --OT Phenyl substituted with

And / or -NH-, -N- (COT)-or -S- group (T is a linear or branched C ₁ -C), optionally substituted with at least one group selected from ₆ or an annular C ₃ -C ₆ alkyl group) and interrupted by at, Z ₂ represents a hydrogen atom, or a linear or branched C ₁ -C ₆ alkyl group,
R _c represents a hydrogen atom; a linear C _{1 to} C ₄ or branched C _{3 to} C ₄ alkyl group, or a linear or branched unsaturated C _{3 to} C ₄ hydrocarbon group; The group is optionally substituted with a phenyl group;
R _d represents a hydrogen atom; a linear C _{1 to} C ₁₈ or branched C _{3 to} C ₁₈ alkyl group, or a linear or branched unsaturated C _{3 to} C ₁₈ hydrocarbon group; The group is optionally substituted with a phenyl group]
Furthermore, the salts, solvates thereof, such as hydrates, and stereoisomers thereof, which are cosmetically acceptable.

  For the purposes of the present invention, the term “heterocycle” is a saturated or unsaturated 5- to 10-membered cyclic hydrocarbon containing at least one heteroatom selected from O, S and N and containing an aromatic group. Indicates a system group. Preferably, the heterocycle represents a pyridine, pyrimidine or indole group, more preferentially pyridine or indole.

Preferred compounds of formula (II) are
The compound of formula (II) is a xylose derivative,
Y represents a phenyl group or a heterocycle optionally substituted with 1 to 5 (OR _a ) groups;
W is -OR ', (-O), NR _b R _c , NHOR _d ,
R ′ represents a hydrogen atom; linear or branched, saturated or unsaturated C _{1 to} C ₁₂ , or saturated cyclic C ₅ or C ₆ alkyl group; linear or branched, saturated or unsaturated saturated C ₁ -C _6, or cyclic C ₅ or C ₆ acyl group saturated,
R _a represents a hydrogen atom; a linear or branched C ₁ -C ₄ alkyl group, a linear or branched C ₁ -C ₆ acyl group, and Y is an (OR _a ) group having 2 to 5 When a phenyl group or a heterocycle substituted with is present, two adjacent OR _a groups can be taken together to form a divalent —O—CH ₂ —O— group, provided that W═OH Where the compound does not contain an α ethylenic double bond to the carbon bearing this OH,
R _b represents a hydrogen atom; a linear C ₂ -C ₁₂ or branched C ₃ -C ₁₂ alkyl group, or a —CH (Z ₁ ) —CO ₂ Z ₂ group, wherein Z ₁ is , A hydrogen atom, or a linear or branched C _{1 to} C ₆ , or a saturated or unsaturated cyclic C _{3 to} C ₆ alkyl group, the group being —NH, —NH ₂ , —N (T ) ₂ , -O, -OH, -OT, -SH, -ST, -CO ₂ T, phenyl substituted by phenyl, -OH or -OT,

It is optionally substituted with at least one group selected from, and / or -NH -, - N- (COT) - or -S- group (T is a linear C ₁ -C ₆ or cyclic C ₅ are interrupted by -C showing a ₆ alkyl group), Z ₂ represents a hydrogen atom, or linear C ₁ -C ₆ alkyl group,
R _c represents a hydrogen atom; a linear C _{1 to} C ₄ or branched C _{3 to} C ₄ alkyl group, or a linear or branched unsaturated C _{3 to} C ₄ hydrocarbon group; The group is optionally substituted with a phenyl group;
R _d represents a hydrogen atom; a linear C ₁ -C ₁₂ or branched C ₃ -C ₁₂ alkyl group, which group is optionally substituted with a phenyl group;
Furthermore, cosmetically acceptable salts thereof, solvates thereof, such as hydrates, and stereoisomers thereof.

  For the purposes of the present invention, the term “heterocycle” is a saturated or unsaturated 5- to 10-membered cyclic hydrocarbon containing at least one heteroatom selected from O, S and N and containing an aromatic group. Indicates a system group. Preferably, the heterocycle represents a pyridine, pyrimidine or indole group, more preferentially pyridine or indole.

Particularly preferred compounds of the formula (II) are
The compound of formula (II) is a xylose derivative,
Y represents a phenyl group or a heterocycle optionally substituted with 1 to 3 (OR _a ) groups;
W is -OR ', (-O), NR _b R _c , NHOR _d ,
R ′ represents a hydrogen atom, a linear or branched, saturated or unsaturated C ₁ -C ₄ alkyl group, a linear or branched C ₁ -C ₆ acyl group,
R _a represents a hydrogen atom; a linear or branched C _{1 to} C ₄ alkyl group, a linear or branched C _{1 to} C ₆ acyl group, and Y is a 2 or 3 (OR _a ) group. Two adjacent OR _a groups together can form a divalent -O-CH ₂ -O- group when a phenyl group or heterocycle substituted with
However, when W = OH, the compound does not contain an α-ethylenic double bond with respect to the carbon holding this OH,
R _b represents a hydrogen atom; a linear C _{2 to} C ₈ or branched C _{3 to} C ₈ alkyl group, or a —CH (Z ₁ ) —CO ₂ Z ₂ group, wherein Z ₁ is , A hydrogen atom, or a linear or branched C _{1 to} C ₆ , or a saturated or unsaturated cyclic C _{3 to} C ₆ alkyl group, the group being —NH, —NH ₂ , —N (T ) ₂ , -O, -OH, -OT, -SH, -ST, -CO ₂ T, phenyl substituted with phenyl, -OH or -OT

It is optionally substituted with at least one group selected from, and / or -NH -, - N- (COT) - or -S- group (T is a linear C ₁ -C ₆ or cyclic C ₅ are interrupted by -C showing a ₆ alkyl group), Z ₂ represents a hydrogen atom, or linear C ₁ -C ₆ alkyl group,
R _c represents a hydrogen atom; a linear C ₁ -C ₄ or branched C ₃ -C ₄ alkyl group, which group is optionally substituted with a phenyl group;
R _d represents a hydrogen atom; a linear C ₁ -C ₄ or branched C ₃ -C ₄ alkyl group, which group is optionally substituted with a phenyl group;
Furthermore, cosmetically acceptable salts thereof, solvates thereof, such as hydrates, and stereoisomers thereof.

  For the purposes of the present invention, the term “heterocycle” is a saturated or unsaturated 5- to 10-membered cyclic hydrocarbon containing at least one heteroatom selected from O, S and N and containing an aromatic group. Indicates a system group.

  Preferably, the heterocycle represents a pyridine, pyrimidine or indole group, more preferentially pyridine or indole.

More particularly preferred compounds of formula (II) are:
Compound 1: (3R, 4S, 5R) -2- [2-hydroxy-4- (4-hydroxy-3-methoxyphenyl) butyl] tetrahydro-2H-pyran-3,4,5-triol

Compound 2: 4- (4-hydroxy-3-methoxyphenyl) -1-[(3R, 4S, 5R) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl] butan-2-one

Compound 3: (3R, 4S, 5R) -2- [2-hydroxy-4- (4-hydroxyphenyl) butyl] tetrahydro-2H-pyran-3,4, -5-triol

Compound 4: 4- (4-hydroxyphenyl) -1-[(3R, 4S, 5R) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl] butan-2-one

Compound 5: (3R, 4S, 5R) -2- [2- (benzylamino) -4- (4-hydroxy-3-methoxyphenyl) butyl] tetrahydro-2H-pyran-3,4,5-triol

Compound 6: ethyl {[3- (4-hydroxy-3-methoxyphenyl) -1-{[(3R, 4S, 5R) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl] methyl } Propyl] amino} (phenyl) acetate

Compound 7: (3E) -4-phenyl-1-[(3R, 4S, 5R) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl] but-3-en-2-one

Compound 8: (3E) -4- (4-hydroxy-3,5-dimethoxyphenyl) -1-[(3R, 4S, 5R) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl ] But-3-en-2-one

Compound 9: (3R, 4S, 5R) -2- [2-hydroxy-4- (2-hydroxyphenyl) butyl] tetrahydro-2H-pyran-3,4,5-triol

Compound 10: (3R, 4S, 5R) -2- [2-hydroxy-4- (3-hydroxy-4-methoxyphenyl) butyl] tetrahydro-2H-pyran-3,4,5-triol

Compound 11: (3R, 4S, 5R) -2- [2-hydroxy-4- (2,4-di-hydroxyphenyl) butyl] tetrahydro-2H-pyran-3,4,5-triol

Compound 12: (3R, 4S, 5R) -2- [2-hydroxy-4- (3-ethoxy-4-hydroxyphenyl) butyl] tetrahydro-2H-pyran-3,4,5-triol

Compound 13: 5,9-anhydro-1,2,4-trideoxy-1-pyridin-3-yl-D-xylononitol

Compound 14: (3R, 4S, 5R) -2-[(2E) -2- (methoxyimino) -4-phenylbutyl] tetrahydro-2H-pyran-3,4,5-triol

Compound 15: 5,9-anhydro-1,2,4-trideoxy-7-O-pentanoyl-1-phenyl-D-xylonone-3-urose

Compound 16: 5,9-anhydro-1,2,4-trideoxy-1- (3,4,5-trimethoxyphenyl) -D-xylononitol

  The C-xyloside of formula (II) is preferably selected from compounds (1) and (11).

  According to the present invention, the C-xyloside is preferably C-β-D-xylopyranoside-2-hydroxypropane, C-α-D-xylopyranoside-2-hydroxypropane, compounds (1) and (11), More specifically, it is selected from C-β-D-xylopyranoside-2-hydroxypropane and Compound 1.

  Compounds of formula (I) and / or (II) may be synthesized according to the general procedure described in patent application EP2376510 or according to patent application FR 1 2631331.

  Needless to say, according to the present invention, the C-glycoside derivatives corresponding to formulas (I) and / or (II) may be used alone or in a mixture in any ratio with other C-glycoside derivatives. May be used as

  The amount of C-glycoside (solid base) in the microneedles of the microneedle sheet according to the present invention is 0.01% by mass or more, preferably 0.1% by mass or more, more preferably 1% by mass or more, based on the total mass of the microneedles. It may be. The amount of C-glycoside (solid base) in the microneedles of the microneedle sheet according to the present invention is 50% by mass or less, preferably 40% by mass or less, more preferably 30% by mass or less, based on the total mass of the microneedles. It may be. Thus, the amount of C-glycoside (solid basis) in the microneedles of the microneedle sheet according to the present invention is 0.01% by mass to 50% by mass, preferably 0.1% by mass to 40%, based on the total mass of the microneedles. It may be 1% by mass, more preferably 1% by mass to 30% by mass.

(Beauty active ingredient)
According to one embodiment, the microneedle of the microneedle sheet according to the present invention may further comprise at least one additional cosmetic active ingredient. A single additional cosmetic active ingredient may be used. Two or more additional cosmetic active ingredients can be used in combination.

  The kind of additional beauty active ingredient is not limited. For example, anti-aging agents other than C-glycosides may be used as additional cosmetic active ingredients.

  Examples of anti-aging agents include antioxidants other than C-glycosides, moisturizers, free radical scavengers, keratolytic agents, vitamins, anti-elastase agents and anti-collagenase agents, protides, fatty acid derivatives, steroids, trace elements, bleaching agents And algal and plankton extracts, enzymes and coenzymes, flavonoids and ceramides, and mixtures thereof.

  The amount of the additional cosmetic active ingredient in the microneedle of the microneedle sheet according to the present invention is not limited, and is 0.01% by mass to 10% by mass, preferably 0.05% by mass to 5% by mass, based on the total mass of the composition. More preferably, it may be 0.1% by mass to 1% by mass.

(Base sheet)
The microneedle sheet according to the present invention includes a substrate sheet on which microneedles are present or placed.

  The substrate sheet may include at least one water-soluble or water-dispersible polymer. In this case, the base sheet and the microneedle can be integrated. In other words, the substrate sheet and the microneedles can be a single component that includes a water-soluble or water-dispersible polymer. Preferably, this single component can be prepared using a water soluble or water dispersible polymer.

  On the other hand, the substrate sheet may be different from or separate from the microneedles. In this case, the substrate sheet may be selected from, for example, masks, wipes, patches and generally all types of porous substrate sheets. Preferably, these substrate sheets have an oval structure, i.e. have a thickness smaller than the dimension of the plane in which they are defined.

  The substrate sheet may be cut to be in the form of a disc, mask, towel, glove, pre-cut roll, or any other form suitable for cosmetic use.

[Preparation]
There is no restriction as to how the microneedle sheet according to the present invention is prepared. The microneedle sheet according to the present invention can be prepared based on conventional techniques such as molding or 3D printing.

  The microneedle sheet according to the present invention can be prepared, for example, by a method including a step of molding a composition comprising at least one water-soluble or water-dispersible polymer described above and at least one C-glycoside. it can.

In one embodiment, the microneedle sheet according to the present invention comprises:
(a) preparing a mold having a cavity corresponding to the negative of the microneedle;
(b) filling a composition comprising at least one water-soluble or water-dispersible polymer as described above and at least one C-glycoside;
(c) solidifying the composition by drying, for example, at room temperature (optionally heated) for a period of several hours, etc. to form microneedles;
(d) It can be prepared by a method including a step of removing the microneedle sheet from the mold.

  If necessary, the composition may comprise at least one additional polymer, such as the swellable polymers described above, and / or at least one additional cosmetic active ingredient.

  At least one evaporable liquid component can be added to the above composition, if necessary, to enhance the flowability of the composition. Examples of the evaporating liquid component are not limited, but are preferably water and alcohols such as ethanol.

  The amount of the evaporable liquid component may be 10% by mass or more, preferably 20% by mass or more, more preferably 30% by mass or more based on the total mass of the mixture of the evaporable liquid component and the composition. The amount of the evaporable liquid component may be 90% by mass or less, preferably 80% by mass or less, more preferably 70% by mass or less, based on the total mass of the mixture of the evaporable liquid component and the composition. Thus, the amount of the evaporable liquid component is 10% by mass to 90% by mass, preferably 20% by mass to 80% by mass, more preferably the total mass of the mixture of the evaporable liquid component and the composition. It may be 30% by mass to 70% by mass.

[Cosmetics and cosmetic use]
The microneedle sheet according to the present invention may be a cosmetic device, preferably a cosmetic device for skin, more preferably C-glycoside, skin, in particular facial stratum corneum. There may be more cosmetic devices for delivery to the dermis and / or epidermis of the skin, preferably into the dermis-epidermal junction of the skin.

  The microneedle sheet according to the invention is used for (non-therapeutic) cosmetic treatment, preferably for skin cosmetic treatment, more preferably for skin aging, in particular for oxidative stress-induced skin aging. Can be used for cosmetic procedures to prevent and / or treat.

  Therefore, the cosmetic method according to the present invention can include a step of applying the microneedle sheet according to the present invention onto the skin and inserting the microneedle of the microneedle sheet into the skin.

  The skin cosmetic method according to the present invention may be intended to prevent and / or treat skin aging, in particular skin aging induced by oxidative stress.

  Another embodiment according to the present invention is that the microneedle sheet according to the present invention is applied on the skin so that more C-glycosides are present than in the stratum corneum of the skin, within the dermis and / or epidermis of the skin, preferably the dermis of the skin. -It relates to a skin cosmetic method comprising the step of delivering to the epidermis junction.

  The invention also provides for the delivery of C-glycosides of the microneedle sheet according to the invention more than in the stratum corneum of the skin, into the dermis and / or the epidermis of the skin, preferably the dermis-epidermal junction of the skin. Concerning cosmetic use.

  The cosmetic use according to the invention may be intended to prevent and / or treat skin aging, in particular skin aging induced by oxidative stress.

  The invention is explained in more detail by means of examples. However, these examples should not be construed as limiting the scope of the invention. The following examples are presented as non-limiting illustrations in the field of the invention.

(Examples 1 and 2)
[Preparation]
The ingredients for each of Examples 1 and 2 shown in Table 1 were mixed with water to obtain a mixture. Immediately after mixing, the mixture was injected into a mold cavity corresponding to the shape of the microneedles. After drying at room temperature to remove water, the microneedles in the cavity were removed from the mold as a microneedle sheet having a plurality of microneedles.

  Each shape of the microneedle is a cone, and the dimensions of the cone are shown in Table 2.

  The pitch between the two cones on the microneedle sheet was 600 μm.

The microneedle sheet has a plurality of microneedles having a conical shape at a density of 324 needles / cm ² .

[Evaluation]
(Stability)
After storing for 2 months at 4 ° C and 40 ° C at 75% humidity respectively, the microneedle sheet was sonicated for 10 minutes and shaken for 10 minutes, 5 mL (for Example 1) or 15 mL (for Example 2) C-xyloside was extracted from the microneedle sheet according to Example 1 or Example 2. After centrifuging at 12000 rpm for 3 minutes, C-xyloside in the solution was measured by HPLC. The content of C-xyloside in mass percentage was calculated as a measured value divided by the mass of the microneedle sheet.

  The results are shown in Table 3.

  As shown in Table 3, the microneedle sheets according to Examples 1 and 2 release almost the entire amount of C-xyloside from the microneedle sheet even after 2 months storage at 4 ° C and 40 ° C at 75% humidity, respectively. It was very stable.

(Mechanical strength)
The compression test on the microneedle sheets according to Examples 1 and 2 was performed with Tensile Testing Machine EZ-SX (Shimadzu Corporation) as described below.

  Each of the microneedle sheets according to Examples 1 and 2 was compressed at a compression rate of 1.0 mm / min using two stainless steel flat plates to obtain a stress-tensile curve (S-S curve). The slope of the tensile S-S curve between 0.0 and 0.1 mm was considered as Young's modulus (n = 3). The Young's modulus is considered to reflect the mechanical strength or rigidity of the needle of the microneedle sheet.

  The results are shown in Table 4.

  As shown in Table 4, it was found that the microneedles on the microneedle sheets according to Examples 1 and 2 had a mechanical strength exceeding 50 N / mm, sufficient for insertion into the skin.

(Penetration depth)
The penetration depth of the microneedles according to Examples 1 and 2 was determined using optical coherence tomography described below.

  Pig skin was excised and trimmed to a thickness of 500.0 μm using an electrical dermatome (Integra Life Sciences ™, Padgett Instruments, Plainsboro, NJ, USA). To ensure the use of uniform thickness skin in each study, two cuts of 500 μm thick skin are brought together, with the dermis sides facing each other so that the stratum corneum faces are exposed to each other side. Placed in contact. This resulted in a total skin thickness of 1000 μm, which was then used for OCT analysis of microneedle penetration.

  The skin was then placed on a sheet of dental wax for support. The microneedle on the microneedle sheet according to Example 1 was inserted into the skin with gentle hand pressure or with a given force and immediately observed using an EX1301 OCT Microscope (Michelson Diagnostics Ltd, Kent, UK) did. The sweep source Fourier domain OCT system has a laser center wavelength of 1305.0 ± 15.0 nm and facilitates real-time high resolution imaging (horizontal resolution 7.5 μm and vertical resolution 10.0 μm) of the upper skin layer. The skin was scanned at a frame rate of 15 B scans per second (2D cross-section scan) (scan width = 2.0 mm) to obtain a 2D (two-dimensional) image. The 2D images were analyzed using the image software ImageJ® (National Institute of Health, USA). The scale of the resulting image file is 1.0 pixel = 4.2 μm, which allows accurate measurement of the microneedle penetration depth. To allow differentiation between microneedles and skin, false colors were applied using Ability Photopaint® Version 4.14 (Ability Plus Software Ltd, Crawley, UK). The above measurement was repeated 10 times.

  The penetration depth is 117.89 ± 12.67 μm, which corresponds to the skin layer above the epidermis in vivo.

(Ex vivo)
Twelve Franz diffusion cells with an effective diffusion area of 3.14 cm ² were used for the ex vivo penetration study described below.

  Human dermatome skin with filter paper was placed between the receptor chamber of the cell and the donor chamber, with the stratum corneum of the skin facing the donor chamber.

  The receptor chamber was filled with 2.4 ml of saline solution, the receptor solution, and the temperature was maintained at 32 ° C. during the 24 hour penetration study. The receptor solution (500 ml) was automatically withdrawn at a fixed time and replaced with a new receptor solution of the same volume.

Twelve pieces of human skin were divided into four groups, and each group consisted of three pieces of human skin. For the two groups of skin pieces, the microneedle sheets according to Examples 1 and 2 were applied, respectively (the average mass of the microneedle sheets was 5.5 mg), and for the other two groups of skin pieces, 10 masses respectively. % And 30% by weight aqueous solution of C-xyloside (each dosed 5.5 mg / 0.785 cm ² solution, which means 22 mg / cell (area 3.14 cm ² ), which is a microneedle sheet Equivalent to the amount of

  The amount of C-xyloside that penetrated into the stratum corneum (S.C.) was determined after penetration of the microneedle sheet applied above. The microneedle sheet remaining on the skin surface was carefully wiped off with cotton. Subsequently, S.C. was peeled off by peeling 20 times using an adhesive tape. C-xyloside was extracted from these exfoliated S.C. with methanol. After filtration, the amount of C-xyloside in the supernatant liquid was analyzed by LC / MS / MS.

  The amount of C-xyloside penetrating into the epidermis and dermis was also determined. After stripping the tape, the skin pieces were cut into smaller pieces and homogenized for 20 minutes in 4 ml of distilled water. Subsequently, ethanol was added to the skin homogenate and shaken for 16 hours. The suspended solution was centrifuged. After filtration, the amount of C-xyloside in the supernatant liquid was analyzed by LC / MS / MS.

  The results are shown in Table 5.

  As shown in Table 5, when applying an aqueous solution containing C-xyloside, which is a topical formulation, C-xyloside is primarily applied into the outermost layer of the skin, while applying it, Only low levels of C-xyloside are applied into the deeper layers of the skin. However, both the microneedle sheet according to Example 1 and the microneedle sheet according to Example 2 modify the skin distribution profile of C-xyloside well, and the active ingredient is much more abundant into deeper layers of the skin. Allows you to soak in. Thus, it has been demonstrated that the microneedle sheets according to Examples 1 and 2 can effectively impart C-xyloside to deeper levels in the skin.

Claims (15)

A microneedle sheet comprising a substrate sheet and a plurality of microneedles on the substrate sheet,
The microneedles have a height of 50 to 1000 microns, preferably 100 to 300 microns, more preferably 150 to 250 microns;
The microneedle comprises at least one water-soluble or water-dispersible polymer;
The microneedle comprises at least one C-glycoside,
Microneedle sheet.   2. The microneedle according to claim 1, wherein the microneedles can impart more C-glycosides to the dermis and / or epidermis of the skin, preferably the dermis-epidermal junction of the skin, than in the stratum corneum of the skin. Microneedle sheet.   The microneedle sheet according to claim 1 or 2, wherein the microneedle has a conical shape.   4. The microneedle sheet according to claim 3, wherein the bottom of the cone of the microneedle has a diameter of 50 to 350 microns, preferably 100 to 300 microns, more preferably 150 to 250 microns.   5. The microneedle sheet according to claim 4, wherein a ratio of (cone height) / (cone bottom diameter) of the microneedles is 1 or more.   6. The microneedle sheet according to claim 1, which has a Young's modulus of 50 N / mm or more, preferably 55 N / mm or more, more preferably 60 N / mm or more.   The microneedle sheet according to any one of claims 1 to 6, wherein the microneedles can penetrate into the skin at a depth of 200 microns or less, preferably 190 microns or less, more preferably 180 microns or less. .   The water-soluble or water-dispersible polymer is hyaluronic acid, monosaccharide, disaccharide, oligosaccharide, polysaccharide, dextrin, dextran, polyethylene glycol, polyvinyl alcohol, poly (methyl vinyl ether / maleic anhydride), polyvinyl pyrrolidone, poly (methyl / Vinyl ether / maleic acid) (PMVE / MA) and esters thereof, poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH), and mixtures thereof. The microneedle sheet according to 1.   The microneedle sheet according to any one of claims 1 to 8, wherein the water-soluble or water-dispersible polymer has a molecular weight of 10,000 to 400,000 daltons, preferably 30,000 to 300,000 daltons, more preferably 50,000 to 200,000 daltons. .   10. The microneedle sheet according to any one of claims 1 to 9, wherein the C-glycoside is selected from C-xyloside.   The amount of the C-glycoside ranges from 0.01 to 50% by mass, preferably from 0.1 to 40% by mass, more preferably from 1 to 30% by mass, based on the total mass of the microneedles. The microneedle sheet according to any one of the above.   12.C-glycoside more than in the stratum corneum of the skin, to deliver to the dermis and / or epidermis of the skin, preferably the dermis-epidermal junction of the skin. A skin cosmetic method comprising the step of applying the microneedle sheet of claim 1 onto the skin.   12. The microneedle sheet according to any one of claims 1 to 11 is applied on the skin in order to prevent and / or treat skin aging, in particular skin aging induced by oxidative stress. A skin cosmetic method comprising a step.   The C-glycoside of the microneedle sheet according to any one of claims 1 to 11, more than in the stratum corneum of the skin, preferably in the dermis and / or epidermis of the skin, preferably the dermis-epidermal junction of the skin Cosmetic use for delivery to.   The cosmetic use according to claim 14, which is intended to prevent and / or treat skin aging, in particular skin aging induced by oxidative stress.