Collagen microneedle preparation

Abstract

Provided are: a high-quality microneedle preparation containing collagen as a main component; and a method for producing the microneedle preparation. A microneedle preparation containing collagen and one or more pH regulators as essential components; a microneedle preparation which further contains, as an essential component, one or more types of carboxyl group-containing water-soluble polymers; also provided is a method for producing a microneedle preparation, which comprises: a step for preparing an aqueous solution at 37 DEG C or less from a raw material that contains collagen and one or more pH regulators and, if necessary, one or more carboxyl group-containing water-soluble polymers, and preparing a microneedle raw material solution in which the content of collagen in the aqueous solution is 5 mass% or less; and a step for filling a mold with the microneedle starting material liquid and drying the microneedle starting material liquid.

Description

Technical Field

[0001] The present invention relates to novel cosmetics and cosmetics utilizing collagen. Background Art

[0002] Collagen is a type of protein that makes up the skin and bones of animals. There are several types of collagen, among which type I collagen forms the skin and bones of animals and is widely distributed. Type I collagen has a triple helical structure consisting of one α1 chain and two α2 chains. When this type I collagen aggregates, it becomes fibrous and is called collagen fiber.

[0003] Type I collagen is mostly contained in the dermis, maintaining its toughness and tension. Therefore, if type I collagen is insufficient, the skin will lose its tension. Therefore, supplementing type I collagen in the form of cosmetics is considered effective, and various skin care products are being developed.

[0004] Cosmetics containing collagen with a triple helix structure are generally liquid preparations such as essences, but since microorganisms easily reproduce in collagen, it is necessary to add preservatives, which is problematic as cosmetics. Microneedles containing collagen with a triple helix structure are also known (Patent Documents 1 to 3). Cosmetics in which collagen with a triple helix structure is formed into a film are also known (Patent Document 4). Microneedle arrays using low molecular collagen as the main material are also known (Patent Document 5).

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: Japanese Patent Application Publication No. 2005-272398

[0008] Patent Document 2: International Publication No. 2013 / 122160

[0009] Patent Document 3: International Publication No. 2017 / 002466

[0010] Patent Document 4: Japanese Patent Application Publication No. 2017-128566

[0011] Patent Document 5: Japanese Patent Application Publication No. 2009-273872 Summary of the invention

[0012] Problems to be solved by the invention

[0013] The collagen-containing microneedle products so far are products in which collagen is dispersed in a base that is soluble in the body. In addition, even when collagen is used as a base, the collagen-containing microneedle products so far are either made with low-molecular collagen as the main material, or are made by mixing with other bases that are soluble in the body, or the content of collagen in the microneedle products is less than 50% by mass in the base, and high-molecular collagen products with high content have not been achieved. The purpose of the present invention is to provide a high-quality microneedle preparation with collagen as the main component (high content) and a method for manufacturing the same.

[0014] Means for solving problems

[0015] The present inventors conducted intensive research on the method of producing a microneedle array with collagen as the main component in order to better exert the effectiveness of collagen as a cosmetic. As a result, they came up with a method completely different from the existing production method, thereby completing the present invention.

[0016] The present invention is as follows.

[0017] [1] A microneedle preparation comprising collagen and one or more pH adjusters as essential ingredients.

[0018] [2] A microneedle preparation comprising collagen, one or more pH adjusters, and one or more carboxyl group-containing water-soluble polymers as essential ingredients.

[0019] [3] The microneedle preparation according to [2], wherein the carboxyl group-containing water-soluble polymer is at least one selected from hyaluronic acid and its sodium salt and derivatives thereof, carboxymethyl cellulose and its sodium salt, chondroitin sulfate and its sodium salt, and polyacrylic acid and its sodium salt.

[0020] [4] The microneedle preparation according to [2] or [3], wherein the content of the carboxyl group-containing water-soluble polymer in the microneedle preparation is 1% by mass or more of the amount of collagen.

[0021] [5] The microneedle preparation according to any one of [1] to [4], wherein at least one of the pH adjusters is a pH adjuster containing a carboxyl group.

[0022] [6] The microneedle preparation according to any one of [1] to [5], wherein the microneedle preparation further contains a cosmetically valuable substance.

[0023] [7] The microneedle preparation according to any one of [1] to [6], wherein the microneedle has a needle length of 50 μm to 550 μm and is a microneedle preparation that is inserted into the stratum corneum or epidermis.

[0024] [8] The microneedle preparation according to any one of [1] to [6], wherein the microneedle has a needle length of 351 μm to 1000 μm and is a microneedle preparation that is inserted into the dermis.

[0025] [9] A microneedle preparation according to any one of [1] to [8], wherein the pH adjuster is at least one selected from an organic acid comprising acetic acid, oxalic acid, citric acid, malic acid, lactic acid, glycolic acid, succinic acid, tartaric acid, gluconic acid, fumaric acid, aspartic acid, glutamic acid, and ascorbic acid, and a mixture thereof.

[0026]

[10] The microneedle preparation according to any one of [1] to [9], wherein the content of the pH adjuster in the microneedle preparation is 0.5% by mass to 40% by mass of the collagen.

[0027]

[11] A microneedle array comprising collagen, citric acid, and hyaluronic acid or its sodium salt or its derivatives, wherein the content of citric acid is 0.5% to 40% by weight of the collagen, and the content of hyaluronic acid or its sodium salt or its derivatives is 1% to 49% by weight of the collagen.

[0028]

[12] The microneedle array according to

[11] , wherein the molecular weight of the collagen is greater than 100,000.

[0029]

[13] The microneedle array according to

[11] or

[12] , wherein the collagen has a trihelix structure and a molecular weight of about 300,000.

[0030]

[14] The microneedle array according to any one of

[11] to

[13] , wherein the collagen is derived from tuna skin.

[0031]

[15] A method for producing a microneedle preparation, which is the method for producing a microneedle preparation described in [1], comprising the following steps: preparing a microneedle raw material liquid having a collagen content of 5% by mass or less in the aqueous solution by modulating a raw material containing collagen and one or more pH adjusters at a temperature below 37°C; and filling a casting mold with the microneedle raw material liquid and drying the mold.

[0032]

[16] A method for producing a microneedle preparation, which is the method for producing a microneedle preparation described in [2], comprising the following steps: preparing a microneedle raw material solution having a collagen content of 5% by mass or less in the aqueous solution by modulating a raw material containing collagen, one or more pH adjusters and one or more water-soluble polymers containing a carboxyl group into an aqueous solution at a temperature below 37°C; and filling a casting mold with the microneedle raw material solution and drying the solution.

[0033]

[17] A microneedle raw material solution used in the production method described in

[15] , wherein the pH is 3.0 to 9.0.

[0034]

[18] A microneedle raw material solution used in the production method described in

[16] , wherein the pH is 3.0 to 9.0.

[0035]

[19] The microneedle raw material solution according to

[17] , wherein the pH of the microneedle raw material solution is 3.0 to 7.0.

[0036]

[20] The microneedle raw material solution according to

[18] , wherein the pH of the microneedle raw material solution is 3.0 to 7.0.

[0037]

[21] The microneedle raw material solution according to

[17] , wherein the pH of the microneedle raw material solution is 4.0 to 6.0.

[0038]

[22] The microneedle raw material solution according to

[18] , wherein the pH of the microneedle raw material solution is 4.0 to 6.0.

[0039] Effects of the Invention

[0040] According to the present invention, collagen can improve the skin's tension and reduce wrinkles and sagging. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 A cross-sectional view showing an example of the production method of the present invention. DETAILED DESCRIPTION

[0042] The collagen in the present invention refers to: trihelical collagen and a single-chain collagen obtained by unwinding three chains of trihelical collagen (this substance is also called gelatin). The collagen may be of natural origin or synthetic collagen.

[0043] It is well known that the molecular weight of triple helical collagen is about 300,000, and the molecular weight of single chain collagen is about 100,000. If triple helical collagen is heated to above 50°C, the triple helices will unwind into a single helix (this is gelatin). Single helical collagen is a stable aqueous solution at high temperatures, but it will gel if left at room temperature for several hours.

[0044] It is known that ultraviolet rays have various negative effects on the skin. It is known that when the skin is irradiated with ultraviolet rays, matrix metalloproteinases, which are proteolytic enzymes in the skin, increase, and collagen and elastin present in the dermis that maintain the elasticity of the skin are decomposed, thereby causing a decrease in tension and the formation of wrinkles. It is generally believed that by inhibiting the decomposition of collagen, the tension and elasticity of the skin can be maintained. In order to maintain the collagen concentration in the skin, it is effective to apply collagen from the outside, and further, it is also important to inhibit the enzymatic decomposition of collagen introduced into the skin for the continued effect.

[0045] Microneedle preparations are effective for introducing collagen into the skin, but it is difficult to obtain stable collagen preparations for the above reasons. The present inventors have conducted in-depth research on stable collagen preparations and found the following, thereby completing the present invention: by using a pH-modulated raw material solution and allowing a negatively charged polymer (a water-soluble polymer containing a carboxyl group, preferably hyaluronic acid) to coexist with collagen, a stable collagen preparation is produced. It was also found that a stable collagen preparation is produced in the above manner and allowed to coexist with hyaluronic acid, thereby inhibiting the enzymatic decomposition of collagen in the skin.

[0046] The essence of the present invention is a microneedle array having a plurality of microneedles, wherein the microneedles contain collagen from a living body as a main component and a base, and the absorption of collagen, a high molecular weight substance, into the skin is significantly improved by microneedling. The present invention can achieve the beauty effect of collagen more quickly and significantly than that of liquid collagen.

[0047] In the present invention, the collagen preferably has a molecular weight of 100,000 or more, and more preferably includes collagen having a triple helix structure (collagen having a molecular weight of about 300,000).

[0048] Since collagen is prone to molecular weight reduction, gelation, coloring, etc. in aqueous solution, it is important to prepare a stable microneedle raw material solution and perform microneedle molding while preventing these situations. As collagen, collagen from animals such as pigs and collagen from fish scales are often used, but collagen from tuna skin can be used in the present invention. Tuna skin collagen has a high content of hydroxyproline and proline, and has a characteristic that is closer to the composition of human collagen than collagen from the skin and scales of other fish such as salmon, so it is more preferred.

[0049] As a result of in-depth research by the inventors, the conditions under which the raw material solution can be maintained stably at room temperature (i.e., the collagen does not precipitate or gel) when making microneedles with collagen as the main body have been determined. As the first necessary condition, the pH when the collagen is dissolved in water is appropriately adjusted. As the second necessary condition, it is: the addition of an ionic polymer (preferably a water-soluble polymer with a negative charge) for long-term stabilization of the raw material solution and enhancement of the mechanical strength of the collagen microneedles and the amount of addition. Room temperature in the present invention refers to 15 to 30°C. By adjusting the pH of the raw material solution and adding ionic polymers in this way, collagen can be uniformly solubilized in an aqueous solution at a concentration of less than 20% by mass. A solution with a collagen concentration of 20% by mass is an extremely concentrated solution, 10% by mass is a concentrated solution, and 5% by mass is a highly fluid solution. A stable raw material solution can be produced at any concentration.

[0050] The present invention is based on the following basic conditions: the raw material solution for preparing collagen-based microneedles contains appropriate amounts of positive and negative ions, and furthermore, contains a negatively charged water-soluble polymer to maintain stability as a solution for a long time.

[0051] Collagen microneedle preparation (microneedle array)

[0052] The invention is a preparation of a microneedle array comprising conical volcano-shaped, pyramid-shaped, or needle-shaped microneedles with a height of 50 to 1000 μm standing on a substrate with a thickness of 10 to 200 μm.

[0053] When the microneedle preparation is inserted into the stratum corneum or epidermis, the needle length is preferably 50 to 550 μm, and more preferably 100 to 400 μm.

[0054] When the microneedle preparation is inserted into the dermis, the needle length is preferably 351 to 1000 μm, and more preferably 400 to 800 μm.

[0055] The essential components of the microneedle preparation of the present invention are collagen and one or more pH adjusters. The microneedle preparation of the present invention may further contain one or more negatively charged water-soluble polymers as essential components.

[0056] The pH adjuster in the present invention refers to an acidic substance (anion adjuster) or an alkaline substance (cation adjuster) added for the purpose of changing the pH in order to increase the stability of the collagen in an aqueous solution.

[0057] By adding an anion adjuster or a cation adjuster, the collagen aqueous solution is adjusted to pH 3.0-9.0, and a stable microneedle raw material solution can be obtained. Since the concentration of collagen in the aqueous solution is prone to gelation if it exceeds 20% by mass, the concentration in the raw material solution is preferably adjusted to 20% by mass or less. Furthermore, by adjusting the concentration in the raw material solution to 5% by mass or less, the fluidity of the raw material solution is excellent, so it is more preferred. As an anion adjuster, it can be an inorganic acid such as nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, and boric acid, and it can also be acetic acid, oxalic acid, citric acid, malic acid, lactic acid, glycolic acid, succinic acid, tartaric acid, gluconic acid, fumaric acid, aspartic acid, glutamic acid, ascorbic acid and organic acids and mixtures thereof. As a cation adjuster, use: ammonia water, sodium hydroxide aqueous solution, sodium bicarbonate, etc. It is preferred that at least one of the pH adjusters is a pH adjuster containing a carboxyl group. A preferred pH adjuster is at least one selected from the group consisting of acetic acid, oxalic acid, citric acid, malic acid, lactic acid, glycolic acid, succinic acid, tartaric acid, gluconic acid, fumaric acid, aspartic acid, glutamic acid, and ascorbic acid, and mixtures thereof.

[0058] When the commercialized collagen microneedle array is applied to the skin, it is preferably weakly acidic in consideration of skin irritation. If a polyacid such as citric acid or tartaric acid is used as an anion adjuster for pH adjustment to make the raw material solution weakly acidic, the stability of the solution is increased compared to the case where the pH is adjusted by a monoacid such as acetic acid or hydrochloric acid.

[0059] The content of the pH adjuster in the microneedle preparation is 0.5 to 40% by mass of the collagen, and preferably 1.0 to 20% by mass.

[0060] As the water-soluble polymer with negative charge, a water-soluble polymer containing a carboxyl group can be used. As the water-soluble polymer containing a carboxyl group, it is preferably selected from at least one of hyaluronic acid and its sodium salt and derivatives thereof, carboxymethyl cellulose and its sodium salt, chondroitin sulfate and its sodium salt, and polyacrylic acid and its sodium salt.

[0061] The content of the carboxyl group-containing water-soluble polymer in the microneedle preparation is 1% by mass or more, and preferably 90% by mass or less, based on the amount of collagen.

[0062] A more preferred embodiment of the present invention is a microneedle array containing collagen, citric acid, and hyaluronic acid or its sodium salt or its derivatives. The content of citric acid is 0.5 to 40% by mass of the collagen, and the content of hyaluronic acid or its sodium salt or its derivatives is 5 to 80% by mass of the collagen, or 1 to 49% by mass.

[0063] The microneedle preparation of the present invention may contain cosmetic valuable substances. The content of the valuable substance relative to the total mass is preferably 0.001 mass % to 20 mass %. If the valuable substance is a water-soluble raw material, the valuable substance can be directly added to the raw material aqueous solution. If it is oil-soluble, it is dissolved or dispersed in an appropriate amount of ethanol, or it is made soluble using a surfactant and then added to the raw material aqueous solution.

[0064] Examples of the above-mentioned cosmetic valuable substances include anti-inflammatory agents, vitamins, amino acids or their derivatives, keratin softening ingredients, anti-aging ingredients, anti-glycation ingredients, blood circulation promoting ingredients, whitening ingredients, polyphenols, etc. It should be noted that in the above-mentioned various compositions and various preparations of the present invention, these ingredients can be used alone or in combination of two or more.

[0065] Examples of the anti-inflammatory agent include plant-derived components, allantoin and its derivatives, glycyrrhetinic acid and its derivatives, glycyrrhizic acid and its salts or derivatives, salicylic acid derivatives, aminocaproic acid, azulene and its derivatives, and the like.

[0066] As the above-mentioned vitamins, for example, the following can be cited: vitamin B6 such as pyridoxine, pyridoxal, pyridoxamine, pyridoxal 5'-phosphate, and their salts; pantothenic acid such as pantothenic acid, calcium pantothenate, panthenol, D-panthenol (Japanese: パンテサイン), D-pantethine, coenzyme A, panthenol ethyl ether, and their salts; niacin such as nicotinic acid, dl-α-tocopheryl nicotinate, nicotinamide, and their salts; vitamin B1 such as γ-oryzanol, thiamine, thiamine monophosphate, thiamine diphosphate, thiamine triphosphate, and their salts; vitamin B2 such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, and their salts; biotin such as biotin, biocytin, and their salts; folic acid such as folic acid, pteroylglutamic acid, and their salts; vitamin B12 such as cyanocobalamin, hydroxocobalamin, cobalamin coenzyme, and their salts; water-soluble vitamin C such as ascorbic acid, dehydroascorbic acid, ascorbic acid phosphate, ascorbic acid-2-glucoside, 3-O-ethyl ascorbic acid, glycerol ascorbate, diglycerol ascorbate, alkyl glycerol ascorbate and other ascorbic acid derivatives, and their salts; vitamin E such as d1-α-tocopherol, d1-α-tocopherol acetate, tocopherol, (ascorbic acid / tocopherol) potassium phosphate, etc.; oil-soluble vitamin C and its salts such as ascorbyl palmitate, L-ascorbyl dipalmitate, tetra-2-hexyldecanoic acid ascorbate, etc.; vitamin D such as ergocalciferol, cholecalciferol, etc.; vitamin K such as vitamin K1, vitamin K2, etc.; vitamin A such as retinol, retinal, retinoic acid, 3-dehydroretinol, 3-dehydroretinal, 3-dehydroretinoic acid, hydroretinol, etc. and vitamin A derivatives such as retinol palmitate, retinol linoleate, retinol acetate, etc. as its derivatives, provitamin A such as α-carotene, β-carotene, γ-carotene, cryptoxanthin, etc.; vitamin-like action factors such as ferulic acid, pyrroloquinoline quinone or its salt, hesperidin and glucosyl hesperidin, ubiquinone, glucuronolactone, glucuramide, orotic acid (Japanese: 才口チン酸), L-carnitine, α-lipoic acid, orotic acid (Japanese: 才口ッ卜酸), etc.

[0067] As the above-mentioned amino acids or their derivatives, for example, the following can be cited: betaine, proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cystine, methionine, leucine, isoleucine, valine, histidine, threonine, tyrosine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, creatinine, ε-aminohexanoic acid, tryptophan, ornithine, etc.

[0068] Examples of the keratin-softening component include lactic acid, salicylic acid, gluconic acid, glycolic acid, citric acid, malic acid, fruit acid, phytic acid, urea, and sulfur.

[0069] Examples of the anti-aging ingredients include hydrolyzed soy protein, retinoids (retinol and its derivatives, retinoic acid, retinal, etc.), kinetin, adenosine, NMN (nicotinamide mononucleotide), AMP (adenosine monophosphate), ADP (adenosine diphosphate), ATP (adenosine triphosphate), ursolic acid, turmeric extract, sphingosine derivatives, and mevalonate.

[0070] Examples of the anti-glycation component include plant extracts such as Buddleja leaf extract, evening primrose oil, emblica fruit, fruit juice or an extract thereof, L-arginine, L-lysine, hydrolyzed casein, hydrolyzable tannin, carnosine and the like.

[0071] Examples of the blood circulation promoting ingredient include: plant-derived ingredients such as ginseng, ashitaba, arnica, ginkgo, fennel, safflower, Dutch oak, chamomile, Roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake mushroom, ginger, hawthorn, juniper, chuanxiong, Japanese swertia, thyme, clove, tangerine peel, pepper, angelica sinensis, peach kernel, spruce, carrot, garlic, broom, grape, peony, horse chestnut, lemon balm, grapefruit, coix seed, green tea, rosemary, rose hip, tangerine peel, angelica sinensis, spruce, peach, apricot, walnut, corn, golden chamomile, ichthyol, blister beetle tincture, and cephalothin; and γ-oryzanol, tocopheryl nicotinate, and glucosyl hesperidin.

[0072] Examples of the whitening ingredients include tranexamic acid, ascorbic acid and its salts, vitamin C such as ascorbic acid derivatives (sodium ascorbyl phosphate, magnesium ascorbyl phosphate, tetrakis 2-hexyldecanoate ascorbate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, ascorbyl glucoside, etc.), arbutin, kojic acid, placenta, ellagic acid, niacinamide, hydroquinone, linoleic acid and its derivatives, etc.

[0073] Examples of the polyphenols include flavonoid polyphenols such as curcumin, flavanones, stilbenes, polymethoxyflavonoids, flavonols, xanthones, chalcones, lignans, flavanols, and isoflavones.

[0074] Method for manufacturing collagen microneedle preparation (microneedle array)

[0075] As a production method, when forming microneedles, a collagen aqueous solution is filled into a mold, and after drying, the mold is taken out to form a microneedle array. Collagen maintains stability as an aqueous solution, and a microneedle raw material solution that does not gel or precipitate is prepared and used.

[0076] The first embodiment of the manufacturing method includes the following steps: a step of modulating a raw material containing collagen and one or more pH adjusters into an aqueous solution at below 37°C to prepare a microneedle raw material solution in which the content of collagen in the aqueous solution is less than 20 mass %; and a step of filling the above-mentioned microneedle raw material solution into a casting mold and drying it.

[0077] The second embodiment of the manufacturing method includes the following steps: a step of modulating a raw material containing collagen, one or more pH adjusters and one or more carboxyl-containing water-soluble polymers into an aqueous solution at below 37°C, and preparing a microneedle raw material solution in which the collagen content in the aqueous solution is less than 20 mass %; and a step of filling the above-mentioned microneedle raw material solution into a casting mold and drying it.

[0078] After the drying step, the microneedle array is peeled off and can be cut into a patch shape and used after being backed with an adhesive support.

[0079] In order to make a stable aqueous solution without heating collagen, pH adjustment is very important. If the pH exceeds 9.0, collagen gels and phase separates in the aqueous solution, and cannot become a stable aqueous solution. Although microneedle molding can be performed using an aqueous solution with a pH of less than 3.0, it is not preferred considering the stimulation of the produced microneedles to the skin. By adding an anion adjuster or a cation adjuster, the collagen aqueous solution is adjusted to pH 3.0-9.0, and a stable microneedle raw material solution can be made. Of course, if it is assumed that the microneedles made using these stable microneedle raw material solutions will be dissolved in the skin, then in the case of dissolving the microneedles of the present invention in the aqueous solution, the pH is also preferably 3.0-9.0. Considering the effect on the skin, the pH of the raw material solution and the solution in which the microneedles are dissolved is more preferably pH 3.0-7.0, and more preferably pH 4.0-6.0 as a weak acid. If the concentration of collagen in the raw material solution exceeds 20% by mass, gelation is likely to occur. Therefore, the concentration of collagen in the raw material solution is preferably adjusted to 20% by mass or less.

[0080] After adding a water-soluble polymer containing a carboxyl group to the microneedle raw material liquid whose pH is adjusted as described above and making a uniform solution, microneedling is performed, thereby improving the mechanical strength of the prepared microneedle. As a water-soluble polymer containing a carboxyl group, it is preferably selected from at least one of hyaluronic acid and its sodium salt and its derivatives, carboxymethyl cellulose and its sodium salt, chondroitin sulfate and its sodium salt, and polyacrylic acid and its sodium salt, more preferably hyaluronic acid and its sodium salt and its derivatives, carboxymethyl cellulose and its sodium salt carboxymethyl cellulose.

[0081] The amount of the water-soluble polymer containing a carboxyl group added to the collagen is preferably 1% by mass or more. If it is 1% by mass or more, the effect of addition is easily manifested. In order to give full play to the characteristics of the product, i.e., the collagen microneedle, the amount of the carboxyl-containing polymer added to the collagen is preferably lower than the amount of the collagen, so that the amount added to the collagen is 90% by mass or less.

[0082] Microneedle patch

[0083] The size of the patch containing the microneedle array (microneedle patch) is 0.5 to 300 square centimeters. If it is less than 0.5 square centimeters, the effect is limited and it is difficult to be effective. If it exceeds 300 square em, there will be problems with adhesion when covering the body surface. When covering a larger body surface, multiple microneedle patches of less than 300 square em can be used. The needle length is 50 to 1000μm. Microneedles of 50 to 350μm act on the epidermis. Microneedles longer than this also act on the dermis.

[0084] In order to stably apply the microneedle patch to the skin and keep it on the skin, it is not necessary but more preferred to have an adhesive support on the back of the patch. Here, "back side" refers to the side opposite to the side where the microneedles are lined up. The adhesive support is a support film with an adhesive layer on one side.

[0085] As the adhesive layer in the present invention, an adhesive sheet containing a commercially available adhesive can be used. Although rubber-based adhesives, silicone-based adhesives, synthetic rubber-based (SIS-based) adhesives, etc. can be used, considering that the needle is rapidly dissolved by moisture in the skin by utilizing the closeness to the skin and the ODT (occlusive dressing technique, closed dressing technology) effect, SIS-based adhesives, hydrophilic colloid materials, acrylic adhesives, etc. are preferred. As SIS-based adhesives, it is well known that there are combinations of styrene-isoprene block copolymers, tackifying resins, and paraffin. Hydrophilic colloids are skin adhesive substrates containing a combination of hydrophilic polymers and hydrophobic elastomers. Acrylic adhesives are copolymers of alkyl acrylates and copolymers of acrylic acid, acrylamide, vinyl acetate, etc. based on alkyl acrylates. In these adhesives, in order to improve skin adhesion, a plasticizer such as isopropyl myristate or isopropyl palmitate can be added. The thickness of the adhesive layer is preferably more than 10 μm to 300 μm. Specifically, HiPAS (registered trademark) adhesive (acrylate, manufactured by Cosmed Pharmaceutical Co., Ltd.) and MASCOS10 (trade name) adhesive (acrylate, manufactured by Cosmed Pharmaceutical Co., Ltd.) can be preferably used.

[0086] The microneedle preparation, microneedle array and microneedle patch of the present invention are suitable for use on the face as well as areas where wrinkles, sagging and other skin aging are a concern. The applicable area is the entire skin, and there is no particular restriction on this. The application time for one application is about 0.25 to 24 hours. In the case of multiple applications, it is effective to apply at intervals of 0 to 7 days. It is also effective to promote the skin's absorption of valuable substances by instantly dissolving the front end of the microneedles in the skin by supplying water from the back of the array immediately after the microneedle array is applied to the skin. Such application is an effective application method, especially in the fields of beauty.

[0087] Example

[0088] The present invention will be described in more detail below by the following examples. These examples are only for the purpose of illustrating the present invention, and the scope of the present invention is not limited to these examples.

[0089] Example 1

[0090] Fabrication of microneedle arrays

[0091] Figure 1 The cross-sectional view is a diagram showing an example of a method for manufacturing a microneedle array of the present invention. In the figure, 1 is a casting mold, and after a conical volcano-shaped microneedle pattern is formed by photolithography using a light-irradiated photosensitive resin, an electroforming process is performed to form a conical volcano-shaped microneedle forming recess 11 to which the conical volcano-shaped microneedle pattern is transferred. In the figure, 2 is a microneedle raw material liquid cast onto the microneedle forming recess 11. The microneedle forming recess 11 is a conical volcano-shaped recess with a root diameter of 0.6 mm, a front end diameter of 0.02 mm, and a depth of 0.2 mm, and is arranged in a grid at intervals of 0.8 mm.

[0092] 4 parts by mass of natural collagen from tuna and 0.28 parts by mass of citric acid were added to 100 parts by mass of water at room temperature and stirred to form a uniform aqueous solution. The pH was 6.3. The aqueous solution (microneedle raw material solution of Example 1) was cast on the mold 1, and after the water in the aqueous solution was evaporated, it was peeled off from the mold 1 and punched into an elliptical shape (10×50 mm, short diameter×long diameter).

[0093] Fabrication of microneedle arrays with protective adhesive tape

[0094] An elliptical microneedle array (10×50 mm, short diameter×long diameter) was mounted in the center of a rectangular (16×60 mm) adhesive tape with a support having rounded corners to obtain a microneedle array with a protective adhesive tape of the present invention.

[0095] Example 2

[0096] 1.0 parts by mass of hyaluronic acid FCH-SU (Kikkoman Biochemifa, molecular weight 50,000-110,000) was added to the microneedle raw material solution of Example 1, and stirred to form a stable aqueous solution, which was used as the microneedle raw material solution of Example 2. The subsequent manufacturing sequence was the same as that of Example 1, and the protective adhesive tape was added to obtain a microneedle patch.

[0097] In order to study the effects of the amount of collagen and the content of the pH adjuster in the microneedle preparation on the formability of the microneedle, the experiment shown in Table 1 was performed.

[0098] Additives in the amounts (parts by mass) listed in Table 1 were added to 100 parts by mass of purified water at room temperature, and the mixture was stirred at 400 rpm for 10 minutes using a stirrer to prepare a microneedle raw material solution.

[0099] In addition, the microneedle raw material liquids of Comparative Examples 1 to 2 and Examples 3 to 8 after stirring for 1 hour were cast on the same mold 1 as Example 1, and the water in the raw material liquid was evaporated, and then peeled from the mold 1 and punched into an elliptical shape (10×50 mm, short diameter×long diameter) to obtain a microneedle patch. The microscopic observation results of these microneedle patches are recorded in the "Formability" column of Table 1.

[0100] ◎: Good microneedle formability

[0101] ○: Microneedles can be formed, but not sufficiently

[0102] ×: The needle is incomplete and the formability is poor.

[0103] [Table 1]

[0104]

[0105] As shown in Table 1, when the content of the pH adjuster was 5-30% by mass relative to the amount of collagen, the microneedle had good formability. In addition, although it was possible to form at 3% and 40% by mass, it was not sufficient. When no pH adjuster was added and when the content was 50% by mass or more, the microneedle had poor formability.

[0106] [Table 2]

[0107]

[0108] Table 2 shows the results of the following study: the effect of carboxyl-containing water-soluble polymers on the formability of microneedles relative to the amount of collagen in the microneedles. Hyaluronic acid was used as the carboxyl-containing water-soluble polymer. When the pH adjuster was added at 20% by mass of the amount of collagen, good formability was shown when the ratio of hyaluronic acid / collagen was 5-48%.

[0109] [Table 3]

[0110]

[0111] In order to confirm the inhibition of collagen degradation by hyaluronic acid, a solution was prepared by dissolving collagen and hyaluronic acid in the amounts shown in Table 3 in 100 g of purified water.

[0112] Using a 10% aqueous solution of ZYMO ACID (H. Holstein) as a proteolytic enzyme, 0.18 mL of a 10% aqueous solution of ZYMO ACID was added to 0.9 g of a mixed solution of collagen and hyaluronic acid shown in Table 3, and the mixture was reacted at 35°C for 10 minutes to decompose the collagen. The decomposition of collagen was performed according to the "Anson method". The results show that as shown in Table 3, the degradation of collagen is suppressed as the content of hyaluronic acid increases, and the degradation of collagen is suppressed to 42% by the presence of 20% hyaluronic acid. In addition, the degradation of collagen is suppressed to 30% by the presence of 40% hyaluronic acid. It is clear that the degradation of collagen is significantly suppressed by the coexistence of hyaluronic acid.

[0113] Embodiment 17

[0114] The solution of Example 10 and 0.01 parts by mass of magnesium ascorbyl phosphate were added to the microneedle raw material solution of Example 11 and stirred. The subsequent manufacturing sequence was the same as that of Example 1, and a protective adhesive tape was added to obtain a microneedle patch for anti-wrinkle and whitening purposes.

[0115] Test Example 1 In vivo test

[0116] Before going to bed, the microneedle patch prepared in Example 2 was applied under the right eyelid of an adult male volunteer and removed the next morning. The area ratio and depth of wrinkles under the eyelid before and after the test are shown in Table 4.

[0117] Primos lite (GFM) was used to measure the wrinkle area ratio and depth. This device measures the wrinkle area ratio and wrinkle depth by a three-dimensional measurement method based on the grid pattern projection method in vivo, takes a photo of the subject's face, and quantifies the wrinkle area ratio and wrinkle depth. The wrinkle reduction effect can be confirmed in one application of the microneedle patch.

[0118] [Table 4]

[0119] Wrinkle area ratio Wrinkle Depth Before use 100 100 After use 50.7 85.7

[0120] Test Example 2 Microneedle Strength Test

[0121] The microneedle patch prepared by Examples 1 and 2 was placed with the needle side facing down on a sheet obtained by overlapping 15 sealing films (thickness 120 μm, with strength similar to that of the skin, and can be used for skin puncture evaluation), and then the microneedle was punctured into the sealing film using a special spring-type applicator. Take it out after 1 minute and observe the bending and breaking of the needle. In the microneedle patch of Example 1, 20% of the needles were defective and bent, while in the patch of Example 2, it was less than 5%.

[0122] Description of Reference Numerals

[0123] 1. Casting

[0124] 2Microneedle raw material liquid

[0125] 11Concave portion for forming microneedles

Claims

1. A microneedle preparation comprising collagen and one or more pH adjusters as essential components.

2. A microneedle preparation comprising collagen, one or more pH adjusters and one or more carboxyl group-containing water-soluble polymers as essential ingredients.

3. The microneedle preparation according to claim 2, wherein The carboxyl group-containing water-soluble polymer is at least one selected from hyaluronic acid and its sodium salt and derivatives thereof, carboxymethyl cellulose and its sodium salt, chondroitin sulfate and its sodium salt, and polyacrylic acid and its sodium salt.

4. The microneedle preparation according to claim 2 or 3, wherein The content of the carboxyl group-containing water-soluble polymer in the microneedle preparation is 1% by mass or more of the amount of collagen.

5. The microneedle preparation according to any one of claims 1 to 4, wherein At least one of the pH adjusters is a pH adjuster containing a carboxyl group.

6. The microneedle preparation according to any one of claims 1 to 5, wherein Microneedle preparations also contain cosmetically valuable substances.

7. The microneedle preparation according to any one of claims 1 to 6, wherein The microneedle has a needle length of 50 μm to 550 μm, and is a microneedle preparation that is inserted into the stratum corneum or epidermis.

8. The microneedle preparation according to any one of claims 1 to 6, wherein The microneedle has a needle length of 351 μm to 1000 μm, and is a microneedle preparation that is inserted into the dermis.

9. The microneedle preparation according to any one of claims 1 to 8, wherein The pH adjuster is at least one selected from organic acids including acetic acid, oxalic acid, citric acid, malic acid, lactic acid, glycolic acid, succinic acid, tartaric acid, gluconic acid, fumaric acid, aspartic acid, glutamic acid and ascorbic acid, and mixtures thereof.

10. The microneedle preparation according to any one of claims 1 to 9, wherein The content of the pH adjuster in the microneedle preparation is 0.5% by mass to 40% by mass of the collagen.

11. A microneedle array comprising collagen, citric acid and hyaluronic acid or its sodium salt or a derivative thereof, The content of citric acid is 0.5% to 40% by mass of the collagen. The content of hyaluronic acid, its sodium salt or its derivative is 1% by mass to 49% by mass of the collagen.

12. The microneedle array according to claim 11, wherein The molecular weight of collagen is over 100,000.

13. The microneedle array according to claim 11 or 12, wherein: Collagen has a triple helical structure and a molecular weight of approximately 300,000.

14. The microneedle array according to any one of claims 11 to 13, wherein The collagen comes from the skin of tuna.

15. A method for producing a microneedle preparation, which is the method for producing the microneedle preparation according to claim 1, comprising the following steps: A step of preparing a microneedle raw material solution in which the collagen content in the aqueous solution is 5% by mass or less by preparing a raw material containing collagen and one or more pH adjusters at 37° C. or less; and A step of filling the microneedle raw material liquid into a mold and drying the mold.

16. A method for producing a microneedle preparation, which is the method for producing a microneedle preparation according to claim 2, comprising the following steps: A step of preparing a microneedle raw material solution in which the collagen content in the aqueous solution is 5% by mass or less by preparing a raw material containing collagen, one or more pH adjusters, and one or more carboxyl-containing water-soluble polymers at a temperature below 37° C.; and A step of filling the microneedle raw material liquid into a mold and drying the mold.

17. A microneedle raw material liquid, which is a microneedle raw material liquid used in the manufacturing method according to claim 15, The pH of the microneedle raw material solution is 3.0-9.

0.

18. A microneedle raw material liquid, which is a microneedle raw material liquid used in the manufacturing method according to claim 16, The pH of the microneedle raw material solution is 3.0-9.

0.

19. The microneedle raw material solution according to claim 17, wherein: The pH of the microneedle raw material solution is 3.0-7.

0.

20. The microneedle raw material solution according to claim 18, wherein The pH of the microneedle raw material solution is 3.0-7.

0.

21. The microneedle raw material solution according to claim 17, wherein: The pH of the microneedle raw material solution is 4.0-6.

0.

22. The microneedle raw material solution according to claim 18, wherein The pH of the microneedle raw material solution is 4.0-6.0.

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