JP2018196401A - Microneedle sheet - Google Patents

Abstract

To provide microneedles having sharp tips or pointed edges that are not broken or chipped.SOLUTION: A microneedle sheet 8 comprises a base material sheet and a plurality of microneedles on the base material sheet, and at least one of the microneedles comprises a plurality of portions including a distal end portion 4 and a proximal end portion 5, the distal end portion 4 comprising a first composition, the proximal end portion 5 comprising a second composition, the first composition being different from the second composition, and the first composition containing at least one alkaline earth metal salt. The present invention is capable of providing microneedles of an excellent shape and can homogenize the proximal end portion 5 and/or distort the microneedle sheet 8.SELECTED DRAWING: Figure 3

Description

  The present invention relates to a microneedle sheet including a plurality of microneedles that can be used in a skin cosmetic treatment method.

  The stratum corneum (SC) constitutes a major barrier to exogenous substances including low molecular weight materials. Substances that penetrate the skin must diffuse through the highly organized intercellular lipid bilayer of SC. This microcellular pathway that is lipophilic is the primary pathway through which exogenous substances cross the SC barrier by passive diffusion along a concentration gradient between the delivery vehicle and SC. The ideal properties of molecules capable of effective passive diffusion and thereby penetration of the SC barrier are known to have molecular weights below 600 Da.

  For high molecular weight molecules, techniques aimed at removing the SC barrier, such as tape stripping and aspiration, laser or thermal ablation, are impractical, while needle-free injection has hitherto been a traditional needle-based delivery method. I couldn't replace it.

  The idea of using a microstructure device consisting of multiple microprojections to break the stratum corneum barrier was first proposed in the 1970s. Various devices have been developed, including solid microprojections, to provide a system that punctures the stratum corneum, leaving a microscopic hole and allows subsequent drug delivery to the interior or transfer of interstitial fluid to the exterior It has been. The production of solid microprojections and microneedle arrays using, for example, silicon or polymers has been described in the art, see for example WO 2009040548 and US Patent Application Publication No. 2015/0141910.

  The use of such systems currently known in the art is associated with the problem that drug delivery is very small.

  WO 2016/076442 discloses a microneedle sheet in which the microneedle includes at least a distal end portion and a proximal end portion, the distal end portion and the proximal end portion being different or separate.

International Publication No. 2009040548 US Patent Application Publication No. 2015/0141910 International Publication No. 2016/076442 U.S. Patent No. 6,219,574 Canadian Patent Application No. 2,226,718 U.S. Patent No. 6,652,478

  When preparing microneedle sheets, especially so-called dual laminated microneedle sheets having a distal end portion and a proximal end portion, such as those disclosed in WO 2016/076442, typically, A distal end portion is first formed by the first composition by molding the first composition in a mold cavity, where the cavity has a microneedle negative shape and then proximal An end portion is formed by the second composition by molding the second composition in the same cavity, and the distal end portion and the proximal end portion are connected to form a microneedle.

  However, if the second composition is molded in a cavity where the distal end portion is already formed and present, the distal end portion tends to expand. As the distal end portion expands within the cavity, the distal end portion deforms and is pulled away from the cavity surface. When the distal end portion is pulled away from the mold cavity surface, the distal end portion may no longer form the shape of a microneedle. In addition, the components of the distal end portion may move from the distal end portion to the proximal end portion, and thus the proximal end portion may not be homogeneous and the microneedle sheet may be distorted. .

  An object of the present invention includes a plurality of microneedles, at least one of which is at least a distal end portion and a proximal end portion of a well-shaped microneedle, preferably a similarly homogeneous proximal end portion And / or providing a microneedle sheet having a flat shape.

The above object includes a base sheet and a plurality of microneedles on the base sheet,
At least one of the microneedles includes a plurality of portions including a distal end portion and a proximal end portion;
The distal end portion comprises a first composition comprising a first polymer;
The proximal end portion comprises a second composition comprising a second polymer;
The first composition and the second composition are different;
The first composition can be achieved by a microneedle sheet comprising at least one alkaline earth metal salt.

  The microneedle can consist of only a distal end portion and a proximal end portion.

  The alkaline earth metal salt can be a solid at atmospheric pressure and at room temperature.

  The alkaline earth metal can be selected from magnesium, calcium and mixtures thereof.

  The alkaline earth metal salt may be selected from alkaline earth metal halides, preferably alkaline earth metal chlorides, more preferably magnesium chloride, calcium chloride and mixtures thereof.

  The amount of alkaline earth metal salt in the first composition of the distal end portion is 0.01% to 20% by weight, preferably 0.05% to 15% by weight, more preferably relative to the total weight of the composition. It may be from 0.1% to 10% by weight.

  The distal end portion may be swellable, preferably water swellable, more preferably swellable within the skin.

  The first polymer is 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 crosslinked PMVE / MA, crosslinked polyvinylpyrrolidone, sodium starch glycolate, cellulose, natural and synthetic rubber, alginate, sodium polyacrylate, PEG crosslinked poly (methyl / vinyl ether / maleic acid) (PMVE / MA) and its esters , PEG cross-linked poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH) and its sells, and mixtures thereof.

  The first polymer can be a high molecular weight hyaluronic acid having a molecular weight greater than 500 kDa, preferably greater than 1000 kDa, more preferably greater than 2100 kDa.

  The proximal end portion may be soluble or dispersible, preferably water soluble or water dispersible, more preferably soluble or dispersible within the skin.

  The second polymer is low molecular weight hyaluronic acid, monosaccharide, disaccharide, oligosaccharide, dextrin, dextran, polyethylene glycol, polyvinyl alcohol, poly (methyvinylether / maleic anhydride), polyvinylpyrrolidone, poly (methyl / Vinyl ether / maleic acid) (PMVE / MA) and its esters, poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH), and mixtures thereof.

  The second polymer may be polyvinylpyrrolidone having a molecular weight between 1 kDa and 300 kDa, preferably between 5 kDa and 200 kDa, more preferably between 7 kDa and 100 kDa.

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

  The base sheet may contain the second composition.

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

  Another aspect of the invention also relates to the cosmetic use of the microneedle sheet described above for reducing skin wrinkles.

It is a figure which shows an example of the microneedle of the microneedle sheet | seat by this invention. It is a figure which shows another embodiment of the microneedle of the microneedle sheet | seat by this invention. It is a figure which shows one Embodiment of the microneedle sheet | seat by this invention. 2 is an enlarged photograph of two perspective views of a microneedle on a microneedle sheet according to Example 1. FIG. 3 is a view showing a photograph of a microneedle sheet according to Example 1. FIG. 6 is an enlarged photograph of two perspective views of a microneedle on a microneedle sheet according to Comparative Example 1. FIG. 6 is a view showing a photograph of a microneedle sheet according to Comparative Example 1. FIG. FIG. 3 is a graph showing changes in the cross-sectional area of the microneedle of the microneedle sheet according to Example 1.

  As a result of intensive studies, the present inventors provide a microneedle sheet that includes a plurality of microneedles, and at least one of the microneedles includes at least a distal end portion and a proximal end portion of a well-shaped microneedle. I found it possible to do.

Accordingly, the microneedle sheet according to the present invention includes a substrate sheet and a plurality of microneedles on the substrate sheet, wherein at least one of the microneedles includes a plurality of portions including a distal end portion and a proximal end portion. Including
The distal end portion includes a first composition that includes a first polymer;
The proximal end portion comprises a second composition comprising a second polymer;
The first composition and the second composition are different,
The first composition includes at least one alkaline earth metal salt.

  It is possible for the present invention to provide a microneedle having a good shape as a needle (eg, a sharp tip or pointed tip without breaking or chipping).

  Thus, in other words, an object of the present invention includes a substrate sheet and a plurality of microneedles on the substrate sheet, wherein at least one of the microneedles includes a plurality of portions including a distal end portion and a proximal end portion. In other words, providing a microneedle sheet, in particular, a double laminated microneedle sheet that has a well-shaped microneedle and can be easily prepared.

  It is also possible with the present invention to homogenize the proximal end portion and / or to flatten the microneedle sheet.

  The microneedle sheet according to the present invention can be used for skin cosmetic purposes or cosmetic treatment methods, preferably to reduce skin wrinkles, more preferably to reduce facial wrinkles.

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

[Microneedle sheet]
A microneedle sheet according to the present invention includes a substrate sheet and a plurality of microneedles on the substrate sheet, wherein at least one of the microneedles includes a plurality of portions including a distal end portion and a proximal end portion. ,
The distal end portion includes a first composition that includes a first polymer;
The proximal end portion comprises a second composition comprising a second polymer;
The first composition and the second composition are different,
The first composition includes at least one alkaline earth metal salt.

  According to the present invention, the alkaline earth metal salt in the first composition of the distal end portion functions to reduce or control the expansion of the distal end portion during manufacture of the microneedle sheet according to the present invention. can do. Therefore, it does not expand in the mold cavity during manufacture of the microneedle sheet so that the distal end portion is pulled away from the cavity surface and cannot deform. Therefore, the shape of the cavity is sufficiently transferred to the distal end portion, and the microneedle can have a good shape as a needle. Therefore, the microneedle sheet according to the present invention can be easily penetrated into the skin.

  In addition, due to the presence of the alkaline earth metal salt in the first composition, the transition of the component from the distal end portion to the proximal end portion is also reduced or controlled, so that the proximal end portion is homogeneous. Thus, the microneedle sheet according to the present invention can be flat or flat (without distortion).

  On the other hand, the alkaline earth metal salt in the first composition can be removed from the distal end portion when the microneedle penetrates the skin. Alkaline earth metal salts can be absorbed in the skin. Thus, the distal end portion can recover its swellability and provide a cosmetic effect due to the swelling properties of the microneedles, particularly the distal end portion of the microneedles.

  Thus, the microneedle sheet according to the present invention can provide cosmetic effects such as reduction of skin wrinkles, and at the same time, the microneedle of the microneedle sheet can have a good shape as a needle.

(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 base sheet.

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

  According to the present invention, at least one of the microneedles includes a plurality of portions including a distal end portion and a proximal end portion. The distal end portion is a portion including a distal end such as a tip. The proximal end portion is a portion including a proximal end such as a bottom portion. The proximal end can form the bottom of the microneedle and the distal end can form the tip of the microneedle.

  It is preferred that 50% or more of the microneedles, more preferably 70% or more, more preferably 90% or more, and even more preferably all include a plurality of portions (sections or compartments).

  There is no limit on the number of microneedle portions. There may be two or more, three or more, or four or more portions in the microneedle. This portion includes at least a distal end portion and a proximal end portion. The microneedle is preferably composed of only a distal end portion and a proximal end portion.

  This part may be separate from each other or different. The boundary between the parts can be clear. On the other hand, the boundary between parts may not be clear due to the gradual change of the composition surrounding the boundary between adjacent parts.

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

  The microneedles can be of any size and shape suitable for puncturing the stratum corneum. The microneedle is designed to penetrate and optionally pass through the stratum corneum. Suitably, the height of the microneedles may be modified to allow penetration into the upper epidermis or deep into the epidermis.

  The microneedles can be any size and shape suitable for use in a sheet for puncturing the stratum corneum. The microneedles on the sheet are designed to penetrate the stratum corneum and optionally pass through it. Suitably, the height of the microneedles may be modified to allow penetration into the upper epidermis or deep into the epidermis.

  The tip separation distance between each of the individual microneedles on the substrate sheet is modified to have a sufficiently short separation distance to ensure microneedle penetration into the skin and at the same time provide high transdermal transport rates Can be done.

  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.

  FIG. 1 shows one embodiment of a microneedle of a microneedle sheet according to the present invention. In this embodiment, the microneedle 1 is conical and consists of two parts: a distal end part 4 with a tip 2 and a proximal end part 5 with a bottom surface 3. In this embodiment, the bottom surface 3 is flat.

  FIG. 2 shows another embodiment of the microneedle of the microneedle sheet according to the present invention. In this embodiment, the microneedle 1 ′ is conical and consists of three parts: a distal end part 4 with a tip 2, an intermediate part 6 and a proximal end part 5 with a bottom surface 3. In this embodiment, the bottom surface 3 is flat.

  The length of the microneedle, such as the height of microneedle 1 or 1 ′, is at least about 100 μm, at least about 150 μm, at least about 200 μm, at least about 250 μm, or at least about 300 μm, and is about 1 mm or less, about 900 μm or less, about 800 μm Below, about 700 μm or less, about 600 μm or less, or about 500 μm or less, for example, about 100 to about 1000 μm, preferably about 150 to about 900 μm, more preferably about 200 to about 800 μm, more preferably about 250 to about 700 μm, more Preferably it may be about 300 to about 600 μm, even more preferably about 300 to about 500 μm.

  The width of the bottom of the microneedle 1 or 1 ′, such as the diameter of the bottom surface 3, can be about 1 to about 500 μm, preferably about 50 to about 400 μm, more preferably about 100 to about 300 μm. In another embodiment, the microneedles can have a bottom width in the range of about 1 to about 50 μm, such as in the range of about 20 to about 50 μm.

  The microneedles can have an aspect ratio (bottom length / width) of at least about 3: 1, at least about 2: 1, or at least about 1: 1.

  FIG. 3 shows one embodiment of a microneedle sheet according to the present invention. In this embodiment, the microneedle sheet 8 has a plurality of microneedles on the surface of the base sheet 7. In this embodiment, the microneedles are each conical and consist of a distal end portion 4 and a proximal end portion 5.

  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. As described above, 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 microprotrusions or microprojections include, for example, the microblades described in US Pat. No. 6,219,574 and Canadian Patent Application 2,226,718, and the edged microneedles described in US Pat. No. 6,652,478. Can be included.

  When microneedles are used for transdermal delivery, the microneedles should be capable of creating openings in the stratum corneum in order to be used for transdermal delivery.

Preferably, the microneedle is less than 50.0N / cm ^2, for example, when the insertion pressure of less than 20.0N / cm ² of less than ^2, such as 10 N / cm is applied along the length of the microneedles is not disrupted by the force.

(Distal end)
According to the present invention, the distal end portion includes a first composition that includes a first polymer.

  The distal end portion is preferably swellable, more preferably water swellable, and even more preferably swellable within the skin. Accordingly, the first polymer is preferably swellable, more preferably water swellable, and even more preferably swellable within the skin. Here, the term “water swellable” means swellable when contacted with water.

  The first polymer is at least 10-fold in 1 hour in vitro incubation in saline or phosphate buffered saline, preferably at least 20 times in 1 hour incubation, more preferably at least 30 in 1 hour incubation. It may be highly swellable so that it can swell at least 40 times in an incubation for 1 hour, even more preferably about 45 to 55 times in an incubation for 1 hour, most preferably about 45 to 55 times.

  The distal end portion preferably swells at least twice when inserted into the skin, more preferably within less than 1 hour, and even more preferably within 24 hours after insertion into the skin.

The first polymer can have high viscoelasticity so that a gel can be formed after in vitro incubation in saline or phosphate buffered saline. In a dynamic frequency sweep test using a rheometer, the gel has a high elastic modulus G ′, a high viscosity coefficient G ″, a tangent (δ) of less than 1 (tangent (δ) = even at low frequencies (0.01 Hz). G ″ / G ′) and high consistency G * (G * ² = G ′ ² + G ″ ² ).

  In one embodiment, the first polymer can be a hydrogel-forming polymer.

  The first polymer is 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 crosslinked PMVE / MA, crosslinked polyvinylpyrrolidone, sodium starch glycolate, cellulose, natural and synthetic rubber, alginate, sodium polyacrylate, PEG crosslinked poly (methyl / vinyl ether / maleic acid) (PMVE / MA) and its esters , PEG cross-linked poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH) and its sells, and mixtures thereof.

  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 means 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 the first polymer in the first composition of the distal end portion may be 10% by mass or more, preferably 20% by mass or more, more preferably 25% by mass or more, based on the total mass of the composition. . The amount of the first polymer in the first composition of the distal end portion may be 90% by weight or less, preferably 70% by weight or less, more preferably 50% by weight or less, based on the total weight of the composition. . Thus, the amount of the first polymer in the first composition of the distal end portion is 10% to 90% by weight, preferably 20% to 70% by weight, based on the total weight of the composition, More preferably, it may be 25% by mass to 50% by mass.

  In one embodiment, the first composition can also include at least one second polymer and is described below. The first polymer and the second polymer are different.

  When the first composition comprises a second polymer, the amount of the second polymer in the first composition at the distal end portion is 30% by weight or more, preferably 40%, based on the total weight of the composition. It may be at least 50% by mass, more preferably at least 50% by mass. The amount of the second polymer in the first composition at the distal end portion may be 90% by weight or less, preferably 80% by weight or less, more preferably 70% by weight or less, based on the total weight of the composition. . Thus, the amount of the second polymer in the first composition of the distal end portion is 30% to 90% by weight, preferably 40% to 80% by weight, based on the total weight of the composition, More preferably, it may be 50% by mass to 70% by mass.

In a preferred embodiment of the present invention, the first composition can comprise at least one pore former such as sodium carbonate (Na ₂ CO ₃ ). According to the present invention, the pore former is an agent capable of ionizing the free acid groups of the first polymer, thereby retreating adjacent groups and opening the structure even further.

  According to the present invention, the first composition comprises at least one alkaline earth metal salt. Two or more alkaline earth metal salts can be used in combination.

  The alkaline earth metal salt is preferably solid at atmospheric pressure (eg, 1 atm) and room temperature (eg, 25 ° C.).

  The alkaline earth metal can be selected from magnesium, calcium and mixtures thereof.

  The alkaline earth metal salt may be selected from alkaline earth metal halides, preferably alkaline earth metal chlorides, more preferably magnesium chloride, calcium chloride and mixtures thereof.

  The amount of the alkaline earth metal salt in the first composition at the distal end portion is 0.01% by mass or more, preferably 0.05% by mass or more, more preferably 0.1% by mass or more with respect to the total mass of the composition. sell. The amount of the alkaline earth metal salt in the first composition of the distal end portion is 20% by mass or less, preferably 15% by mass or less, more preferably 10% by mass or less, with respect to the total mass of the composition. sell. Thus, the amount of alkaline earth metal salt in the first composition of the distal end portion is 0.01% to 20% by weight, preferably 0.05% to 15% by weight, based on the total weight of the composition. More preferably, it may be 0.1% by mass to 10% by mass.

(Proximal end part)
According to the present invention, the proximal end portion comprises a second composition comprising a second polymer. The first polymer and the second polymer are different.

  The proximal end portion is preferably soluble or dispersible, preferably water soluble or water dispersible, more preferably soluble or dispersible within the skin. Accordingly, the second polymer is preferably soluble or dispersible, preferably water-soluble or water-dispersible, more preferably soluble or dispersible in the skin. Here, the terms “water-soluble” and “water-dispersible” mean soluble and dispersible when contacted with water, respectively.

  In one embodiment, the second polymer may dissolve after being inserted into the skin. Due to the solubility of the proximal end portion, the distal end portion separates from the proximal end portion and remains in the skin. If the distal end portion is swellable, separation of the distal end portion from the proximal end portion can be facilitated by volume expansion of the distal end portion. Optional external water can be used in combination with the application of the microneedle sheet according to the present invention to accelerate dissolution of the proximal end portion.

  It is preferred in the present invention that at least the proximal end portion decomposes more rapidly than the distal end portion.

  The second polymer is low molecular weight hyaluronic acid, monosaccharide, disaccharide, oligosaccharide, dextrin, dextran, polyethylene glycol, polyvinyl alcohol, poly (methyl vinyl ether / maleic anhydride), polyvinyl pyrrolidone, poly (methyl / vinyl ether / maleic) Acid) (PMVE / MA) and its esters, poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH), and mixtures thereof.

  The polyvinylpyrrolidone can 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.

  The low molecular weight hyaluronic acid may have a molecular weight of less than 100 kDa, preferably less than 50 kDa, more preferably less than 10 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 second polymer in the second composition of the proximal end portion can be 50% by weight or more, preferably 60% by weight or more, more preferably 70% by weight or more based on the total weight of the composition. . The amount of the second polymer in the second composition of the proximal end portion may be 100% by mass or less, preferably 90% by mass or less, more preferably 80% by mass or less, based on the total mass of the composition. . Thus, the amount of the second polymer in the second composition of the proximal end portion is 50 wt% to 100 wt%, preferably 60 wt% to 90 wt%, relative to the total weight of the composition, More preferably, it may be 70% by mass to 80% by mass.

  According to the invention, the first composition and the second composition are different. The first composition preferably includes at least one alkaline earth metal salt, but the second composition preferably does not include any alkaline earth metal salt.

(Beauty active ingredient)
According to one embodiment, the first and second compositions, preferably the first composition, can further comprise at least one cosmetically active ingredient. Two or more cosmetic active ingredients can be used in combination. The second composition can be free of any cosmetic active ingredients.

  The type of cosmetic active ingredient is not limited. For example, an anti-aging agent can be used as a cosmetic active ingredient.

  Examples of anti-aging agents are moisturizers, free radical scavengers, keratolytic agents, vitamins, anti-elastase and anti-collagenase agents, protides, fatty acid derivatives, steroids, trace elements, bleach, algae and plankton extracts, enzymes And coenzymes, flavonoids and ceramides, and mixtures thereof.

  The amount of the cosmetic active ingredient in the composition is not limited, and is 0.01% by mass to 20% by mass, preferably 0.05% by mass to 15% by mass, more preferably 0.1% by mass to 10% by mass with respect to the total mass of the composition. It can be.

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

  The base sheet may contain the second composition. In this case, the base sheet and the proximal end portion of the microneedle can be integral. In other words, the base sheet and the proximal end portion of the microneedle can be a single element comprising the second composition. Preferably, a single element can be prepared from the second composition.

  On the other hand, the substrate sheet may be different from or separate from the proximal end portion of the microneedle. 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 less than the dimension of the plane in which they are defined.

  The substrate sheet may be cut to form a disk, mask, towel, glove, precut roll or any other form suitable for cosmetic use.

[Preparation]
There is no restriction on how to prepare the microneedle sheet according to the present invention. The microneedle sheet according to the present invention can be prepared based on a conventional technique for preparing a so-called double laminated microneedle sheet.

  The microneedle sheet according to the present invention includes, for example, a step of forming the first composition described above into a distal end portion and a step of forming the second composition described above into a proximal end portion. It can be prepared by the method.

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 the cavity with the first composition;
(c) forming the distal end portion of the microneedle sheet by drying and solidifying the first composition, for example, at room temperature (optionally heated) for a predetermined time, such as several hours Process,
(d) filling the cavity with the second composition and casting in the cavity;
(e) the proximal end portion of the microneedle sheet and the substrate by drying and solidifying the second composition, for example, at room temperature (optionally heated) for a predetermined time, such as several hours Forming a sheet;
(f) It can be prepared by a method including a step of removing the microneedle sheet from the mold.

  In the above embodiment, the base sheet and the proximal end portion of the microneedle are integrated into a single element of the microneedle sheet. In other words, the base sheet and the proximal end portion are made of the same material, ie the second composition.

In another 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 the cavity with the first composition;
(c) forming the distal end portion by drying and solidifying the first composition, for example, at room temperature (optionally heated) for a predetermined time, such as several hours;
(d ′) filling the cavity with the second composition;
(e ′) forming the proximal end portion by drying and solidifying the second composition, for example, at room temperature (optionally heated) for a predetermined time, such as several hours;
(f ') removing the microneedle from the mold;
(g) a step of preparing a base sheet;
(h) It can be prepared by a method including a step of attaching a microneedle on a substrate sheet.

  If necessary, at least one step of filling the cavity with an additional composition comprising at least one additional polymer and solidifying the additional composition, e.g., forming an intermediate portion, can be performed as described in step (c) above. And step (d) or (d ′) above.

  In the above embodiments, the base sheet and the proximal end portion of the microneedle are independent or separate. In other words, the base sheet and the proximal end portion are made from different materials. The step (h) of attaching the microneedles to the base material sheet can be performed by a conventional method such as an adhesive.

  At least one evaporable liquid component can be added to the first and / or second composition, if desired, to enhance the fluidity of the first and / or second 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 is 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 first or second composition. It can be. The amount of the evaporable liquid component is 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 first or second composition. It can be. Thus, the amount of the evaporable liquid component is 10% by mass to 90% by mass, preferably 20% by mass to 80% by mass with respect to the total mass of the mixture of the evaporable liquid component and the first or second composition. It may be 30% by mass, more preferably 30% by mass to 70% by mass.

[Cosmetics and use]
The microneedle sheet according to the present invention may be a cosmetic device, preferably a cosmetic device for skin, more preferably a cosmetic device for reducing skin, especially facial wrinkles.

  The microneedle sheet according to the present invention can be used in a cosmetic treatment method, preferably a skin cosmetic treatment method, more preferably a cosmetic treatment method for reducing wrinkles on the skin, particularly on the face.

  The microneedle sheet according to the invention can be used to deliver microneedles, preferably swellable, into the skin in order to improve the aesthetic appearance of the skin, especially the face, by reducing the appearance of wrinkles .

  Reduction of the amount of matrix, such as the epidermis, in the skin tends to cause wrinkle formation, resulting in a decrease in skin thickness and deterioration of skin elasticity. Microneedles increase the amount of matrix in the skin, increase skin elasticity, and reduce skin wrinkles.

  If the microneedle, especially the distal end portion, 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 fold shallower and wider. In this way, wrinkles can be reduced or become less noticeable.

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

  The invention also relates to the cosmetic use of the microneedle sheet according to the invention for reducing skin wrinkles, in particular facial wrinkles.

  In certain embodiments, the microneedles of the present invention can be used to apply a semi-permanent or permanent cosmetic treatment to the skin.

  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.

(Example 1 and Comparative Example 1)
[Preparation]
Using the SpeedMixer ™ (SpeedMixer ™ DAC 150.1 FVZ-K, Synergy Devices Limited, High Wycombe, Bucks, UK), each component of Example 1 and Comparative Example 1 shown in Table 1. Mixed. Immediately after mixing, the mixture was used to prepare a microneedle sheet as follows.
a. Approximately 0.05 g of the first mixture for the distal end portion (first layer) was poured into a silicone mold cavity corresponding to the microneedle.
b. The silicone mold was centrifuged at 5,000 rpm for 5 minutes to force the first mixture into the cavity.
c. The first mixture was dried at room temperature for several hours.
d. A second layer was prepared by pouring 0.1 g of the second mixture for the proximal end portion (second layer) behind the first layer in the mold cavity.
e. The silicone mold was centrifuged at 5,000 rpm for 1 minute to ensure that the second mixture completely covered the cavity and mold surface.
f. The second mixture was left to dry at room temperature for 48 hours.
g. Upon drying, the microneedle sheet was released and observed using an optical microscope (VHX-700F Digital microscope, Keyence, Milton Keynes, UK) to determine if microneedles were formed.

[result]
(Example 1)
It was observed that microneedles corresponding to all silicone-type microneedle cavities were formed on the resulting microneedle sheet. The microneedle had a good shape such as a sharp tip or pointed tip without breaking or chipping, and was reproducible with microneedles of uniform dimensions (FIG. 4). Furthermore, the microneedle sheet is in the form of a flat sheet and is homogeneous, indicating that the preparation of the double laminated microneedle sheet was successful (FIG. 5).

(Comparative Example 1)
It was observed that some microneedles were not formed on the resulting microneedle sheet. The microneedles had a good shape, such as a sharp tip or pointed tip, and were not reproducible with microneedles of uniform dimensions. The microneedle had many breaks or chips (FIG. 6). Furthermore, the microneedle sheet is not in the form of a flat sheet and is inhomogeneous, indicating that the preparation of the double laminated microneedle sheet was not successful (FIG. 7).

[Swelling characteristics in skin of Example 1]
Full thickness excised porcine skin was placed on a gel wound dressing and pre-equilibrated in phosphate buffered saline (PBS) for 24 hours to mimic the underflow of interstitial fluid. The pig skin was shaved by the use of a razor, then stretched tightly and tightened with a metal pin to Suprasorb® to mimic the in vivo situation.

The microneedle sheet according to Example 1 was applied for 30 seconds with thumb pressure (approximately 20 N / cm ² ). A transparent adhesive tape was used to hold in place.

  Optical coherence tomography (OCT) images were taken at predetermined time points to determine the microneedle cross-sectional area and to calculate the volume change. FIG. 8 shows the change in the area of the bottom of the microneedle.

  From the analysis of the area of the bottom of the microneedle, it was found that the microneedle increased significantly up to + 173% 48 hours after penetrating the skin, increasing the size of the microneedle in the skin. (Figure 8).

During the production of the microneedle sheet according to Example 1, the incorporation of CaCl ₂ contributes to preventing the immediate swelling of the mixture for the first layer, but the microneedles still have good swelling in the skin. The characteristics are shown. This is thought to be due to the diffusion of small solids of CaCl ₂ diluted by the interstitial fluid of the skin, which makes the first layer, especially hyaluronic acid therein, again swellable in the skin .

1 Microneedle
2 Tip
3 Bottom
4 Distal end
5 Proximal end part
6 Middle part
7 Base sheet
8 Microneedle seat

Claims (15)

Comprising a substrate sheet and a plurality of microneedles on the substrate sheet,
At least one of the microneedles includes a plurality of portions including a distal end portion and a proximal end portion;
The distal end portion comprises a first composition comprising a first polymer;
The proximal end portion comprises a second composition comprising a second polymer;
The first composition and the second composition are different;
The first composition comprises at least one alkaline earth metal salt;
Microneedle sheet.   2. The microneedle sheet according to claim 1, comprising only the distal end portion and the proximal end portion.   3. The microneedle sheet according to claim 1, wherein the alkaline earth metal salt is a solid at atmospheric pressure and at room temperature.   4. The microneedle sheet according to any one of claims 1 to 3, wherein the alkaline earth metal is selected from magnesium, calcium, and a mixture thereof.   5. The alkaline earth metal salt according to claim 1, wherein the alkaline earth metal salt is selected from alkaline earth metal halides, preferably alkaline earth metal chlorides, more preferably magnesium chloride, calcium chloride and mixtures thereof. The microneedle sheet according to one item.   The amount of the alkaline earth metal salt in the first composition at the distal end portion is 0.01% by mass to 20% by mass, preferably 0.05% by mass to 15% by mass, based on the total mass of the composition. The microneedle sheet according to any one of claims 1 to 5, more preferably 0.1 mass% to 10 mass%.   7. The microneedle according to any one of claims 1 to 6, wherein the distal end portion is swellable, preferably water swellable, more preferably swellable in the skin.   Said first polymer is 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 crosslinked PMVE / MA, crosslinked polyvinylpyrrolidone, sodium starch glycolate, cellulose, natural and synthetic rubber, alginate, sodium polyacrylate, PEG crosslinked poly (methyl / vinyl ether / maleic acid) (PMVE / MA) and its 8. The microneedle according to any one of claims 1 to 7, selected from esters, PEG-crosslinked poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH) and esters thereof, and mixtures thereof.   9. The microneedle according to any one of claims 1 to 8, wherein the first polymer is a high molecular weight hyaluronic acid having a molecular weight of more than 500 kDa, preferably more than 1000 kDa, more preferably more than 2100 kDa.   10. The microneedle according to any one of claims 1 to 9, wherein the proximal end portion is soluble or dispersible, preferably water soluble or water dispersible, more preferably soluble or dispersible in the skin.   The second polymer is low molecular weight hyaluronic acid, monosaccharide, disaccharide, oligosaccharide, dextrin, dextran, polyethylene glycol, polyvinyl alcohol, poly (methyl vinyl ether / maleic anhydride), polyvinyl pyrrolidone, poly (methyl / vinyl ether / The maleic acid) (PMVE / MA) and esters thereof, poly (methyl / vinyl ether / maleic anhydride) (PMVE / MAH), and mixtures thereof, according to any one of claims 1 to 10. Microneedle.   12.The second polymer is polyvinyl pyrrolidone having a molecular weight between 1 kDa and 300 kDa, preferably between 5 kDa and 200 kDa, more preferably between 7 kDa and 100 kDa. Microneedle.   13. The microneedle according to any one of claims 1 to 12, wherein the base sheet contains a second composition. Skin beauty method,
A method comprising applying the microneedle sheet according to any one of claims 1 to 13 to the skin, and inserting the microneedle of the microneedle sheet into the skin.   The cosmetic use of the microneedle sheet according to any one of claims 1 to 13, for reducing skin wrinkles.