Method for improving percutaneous administration efficiency of active component from microneedle patch, and manufacturing method of microneedle patch

Abstract

To perform percutaneous administration of an active component efficiently.SOLUTION: There is provided a method for improving percutaneous administration efficiency of an active component from a microneedle patch including a support body, an adhesive layer provided on a principal surface of the support body, and a microneedle array, at least part of which is positioned in the adhesive layer. The adhesive layer includes an active component, a water-soluble polymer, glycerine, and water. The water content is 45-70 mass% of a total mass of the adhesive layer. The microneedle array includes a substrate and at least one microneedle erected from the principal surface of the substrate. The adhesive layer includes a main part positioned on the microneedle array. The method includes a process for arranging the microneedle array on the adhesive layer so that the thickness of the main part is 0.9-1.3 times the length of the microneedle.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] One aspect of the present disclosure relates to a method for improving the efficiency of transdermal administration of an active ingredient from a microneedle patch, and a method for producing a microneedle patch. [Background technology]

[0002] Patent Document 1 describes a patch with microneedles. This patch is provided with one or more microneedle members inside an adhesive layer that can protrude from the adhesive layer to the adhesive surface side.

[0003] Patent Document 2 describes a patch comprising a support, an adhesive layer containing an active ingredient provided on one side of the support, and a microneedle array having microneedles provided on a substrate. After the microneedles are exposed from within the adhesive layer and pierce the skin, they move away from the skin due to their elasticity. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2007-1938 A [Patent Document 2] JP 2015-151380 A Summary of the Invention [Problem to be solved by the invention]

[0005] There is a need for an efficient method for transdermal administration of active ingredients. [Means for solving the problem]

[0006] A method according to one aspect of the present disclosure is a method for improving the efficiency of transdermal administration of an active ingredient from a microneedle patch comprising a support, an adhesive layer provided on a main surface of the support, and a microneedle array at least a portion of which is located within the adhesive layer, wherein the adhesive layer comprises an active ingredient, a water-soluble polymer, glycerin, and water, the water content being 45 to 70 mass% relative to the total mass of the adhesive layer, the microneedle array comprises a substrate and at least one microneedle rising from the main surface of the substrate, the adhesive layer comprises a main portion located on the microneedle array, and the method comprises the step of arranging the microneedle array on the adhesive layer such that the thickness of the main portion is 0.9 to 1.3 times the length of the microneedle.

[0007] A manufacturing method according to one aspect of the present disclosure is a method for manufacturing a microneedle patch comprising a support, an adhesive layer provided on a main surface of the support, and a microneedle array at least a portion of which is located within the adhesive layer, the method comprising the steps of: forming an adhesive layer containing a water-soluble polymer, glycerin, and water, the water content being 45 to 70 mass% relative to the total mass of the adhesive layer; and arranging a microneedle array comprising a substrate and at least one microneedle rising from the main surface of the substrate, on the formed adhesive layer such that the thickness of the main part of the adhesive layer located on the microneedle array is 0.9 to 1.3 times the length of the microneedle.

[0008] In this aspect, the water content and the ratio of the thickness of the adhesive layer and the length of the microneedle on the microneedle array are set within the above-mentioned corresponding numerical ranges.With this configuration, the adhesion of the microneedle patch to the skin is maintained, and the skin is stretched by the microneedles protruding from the adhesive layer.As a result, the contact area between the stretched skin and the adhesive layer increases, so that the transdermal administration of the active ingredient can be performed efficiently. Effect of the Invention

[0009] According to one aspect of the present disclosure, it is possible to efficiently administer an active ingredient transdermally. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 is a perspective view showing an example of a microneedle patch. [Diagram 2] FIG. 1 is an enlarged perspective view showing an example of a microneedle array. [Diagram 3] FIG. 2 is a schematic diagram showing a microneedle patch as viewed from the side. [Figure 4] FIG. 1 is a diagram showing a schematic diagram of the change in a microneedle patch before and after application to the skin. [Diagram 5] FIG. 1 is a schematic diagram showing application of a microneedle patch to the skin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Hereinafter, embodiments of the present disclosure will be described in detail with reference to the accompanying drawings. In the description of the drawings, the same or equivalent elements are designated by the same reference numerals, and duplicated explanations will be omitted.

[0012] [Composition of microneedle patch] 1 is a perspective view of a microneedle patch 10 according to one example. The microneedle patch 10 is a preparation used as a cataplasm, a tape, or the like. In one example, the microneedle patch 10 comprises a support 12, an adhesive layer 14 formed on substantially the entire main surface of the support 12, a release sheet 16 removably attached to the working surface of the adhesive layer 14, and a microneedle array 20 embedded in the adhesive layer 14. The working surface of the adhesive layer 14 refers to the surface that comes into contact with the user's skin when the microneedle patch 10 is used.

[0013] The area of ​​the microneedle patch 10 may be set according to the symptoms, age, weight, sex, etc. of the user. For example, the area of ​​the microneedle patch 10 may be set to 1 to 500 cm. 2 Or 10~400cm 2It is also acceptable to divide the area into 1 cm 2 By making the area 500 cm or more, it becomes easier to maintain sufficient skin permeability of the active ingredient. 2 By doing the following, the microneedle patch 10 can be easily handled.

[0014] The support 12 is a sheet-like member. The support 12 may be stretchable. The material of the support 12 may be selected in consideration of physical properties (thickness, elongation, tensile strength, ease of application, etc.), the feel when applied, the sealing ability of the skin, the migration of the active ingredient to the support 12, etc. For example, the material may be a woven fabric, a nonwoven fabric, a resin film, a foam sheet, or paper. An example of a woven fabric is a knitted fabric. When a woven fabric, a nonwoven fabric, or a resin film is used as the support 12, examples of the material include polyolefins such as polyethylene, polypropylene, and polybutylene, polyesters such as polyethylene terephthalate (PET), rayon, polyurethane, and cotton. These materials may be used alone or in combination of two or more. The support 12 may have a single layer structure or a multilayer structure. The support 12 may be a sheet-like porous material or a sheet-like foam.

[0015] Examples of the knitted fabric include knitted fabrics made of one or a combination of two or more materials such as polyester, nylon, polypropylene, rayon, etc. For example, knitted fabrics made of polyester polyethylene terephthalate, which has little interaction with the active ingredient, may be used.

[0016] When the backing 12 is a knitted or nonwoven fabric, if a water-containing adhesive composition is spread on the backing 12, the adhesive composition may seep out to the back side of the backing through the mesh of the backing 12. In consideration of this point, the basis weight of the knitted or nonwoven fabric is set to 50 to 150 g / m 2 But 75-125g / m 2By setting the basis weight in this range, the pressure-sensitive adhesive composition tends to be able to be spread without seeping through gaps in the support 12 to the back side of the support 12. In addition, the anchoring property between the support 12 and the pressure-sensitive adhesive layer 14 can be maintained.

[0017] Regarding the stretchability of the support 12, the 50% modulus (load at 50% elongation) may be 0.5 to 10 N / 50 mm in at least one of the longitudinal and transverse directions. Here, the "longitudinal direction" refers to the flow direction in the process of manufacturing the knitted fabric, and the "transverse direction" refers to the direction perpendicular to the longitudinal direction, i.e., the width direction. The method for measuring the modulus is based on JIS L 1018:1999.

[0018] The thickness of the support 12 may be set in the range of 5 to 1000 μm, for example. The reason for making the thickness 5 μm or more is to facilitate handling of the microneedle patch 10. The reason for making the thickness 1000 μm or less is to prevent the hardness of the support 12 from affecting the adhesiveness of the microneedle patch 10.

[0019] The adhesive layer 14 is a layer having adhesiveness capable of adhering to human skin. In one example, the adhesive layer 14 contains a water-soluble polymer and water. The adhesive layer 14 may further contain an active ingredient (biologically active substance). The phrase "the adhesive layer contains an active ingredient" is a concept that includes both an embodiment in which the active ingredient is present in the adhesive layer 14 and an embodiment in which the active ingredient is attached to the working surface of the adhesive layer 14.

[0020] The water-soluble polymer means a polymer having a hydrophilic group. Examples of the hydrophilic group include a hydroxyl group, a carboxyl group, and an amino group. When the adhesive layer 14 contains a water-soluble polymer, the moisture in the microneedle patch 10 can be retained for a longer period of time.

[0021] The water-soluble polymer may be a neutralized polyacrylic acid (sometimes referred to as a "water-soluble acrylic polymer"). By including a neutralized polyacrylic acid in the pressure-sensitive adhesive layer 14, it is possible to provide the pressure-sensitive adhesive layer 14 with excellent adhesiveness.

[0022] The water-soluble acrylic polymer is a polymer obtained by polymerizing an acryloyl group-containing compound having a functional group (hydrophilic group) that exhibits water solubility. The adhesive layer 14 exhibits adhesion by containing a water-soluble acrylic polymer together with water. The water-soluble acrylic polymer is, for example, a polymer obtained by polymerizing a compound having an acryloyl group, such as polyacrylic acid or its neutralized product, an acrylic acid ester having a hydrophilic group, or an acrylic acid amide having a hydrophilic group. The water-soluble acrylic polymer may be a homopolymer obtained from a compound having one type of acryloyl group, or a copolymer obtained from a compound having two or more types of acryloyl groups.

[0023] The hydrophilic group may be any of cationic hydrophilic groups, anionic hydrophilic groups, and nonionic hydrophilic groups. An example of the cationic hydrophilic group is a quaternary ammonium group. An example of the anionic hydrophilic group is a carboxy group, a sulfo group, and a phosphate group. An example of the nonionic hydrophilic group is a hydroxy group and an amino group.

[0024] The polyacrylic acid neutralizer may be a completely neutralized polyacrylic acid, a partially neutralized polyacrylic acid, or a mixture thereof. Polyacrylic acid may also be mixed. From the viewpoint of easily suppressing decomposition of the components contained in the adhesive layer by adjusting the pH of the adhesive layer, the polyacrylic acid neutralizer may be a mixture of a partially neutralized polyacrylic acid and polyacrylic acid. Examples of the completely neutralized polyacrylic acid and the partially neutralized polyacrylic acid include polyacrylic acid salts, and for example, sodium salts, potassium salts, calcium salts, and ammonium salts can be used. When the polyacrylic acid neutralizer is contained in the adhesive layer 14 as the water-soluble polymer, the content of the polyacrylic acid neutralizer may be adjusted to 1 to 15% by mass, 2 to 12% by mass, or 5 to 10% by mass with respect to the total mass of the adhesive layer 14. By making the content of the polyacrylic acid neutralizer 1% by mass or more, the adhesive force of the polyacrylic acid neutralizer can be sufficiently obtained. By setting the content of neutralized polyacrylic acid to 12% by mass or less, the moldability and shape retention of the pressure-sensitive adhesive layer 14 are improved.

[0025] As the neutralized polyacrylic acid, a partially neutralized polyacrylic acid that has high initial adhesion and adhesion over time may be used. The partially neutralized polyacrylic acid is a composition in which structural units derived from acrylic acid and structural units derived from acrylic acid salts are present in any ratio in one polymer chain. As the partially neutralized polyacrylic acid, one in which 20 to 80 mol % of the carboxyl groups in one polymer chain are neutralized may be used.

[0026] When at least one of a completely neutralized polyacrylic acid and a partially neutralized polyacrylic acid is contained in the pressure-sensitive adhesive layer 14 as the water-soluble polymer, the total content may be adjusted to 1 to 10 mass % or 2 to 9 mass % based on the total mass of the pressure-sensitive adhesive layer 14. By making the total content of at least one of a completely neutralized polyacrylic acid and a partially neutralized polyacrylic acid 1% or more by mass, the pressure-sensitive adhesive layer 14 can obtain sufficient adhesive force. By making the total content of at least one of a completely neutralized polyacrylic acid and a partially neutralized polyacrylic acid 9% or less by mass, the pressure-sensitive adhesive layer 14 can improve its moldability and shape retention.

[0027] When the adhesive layer 14 further contains polyacrylic acid as a water-soluble polymer, the content thereof may be adjusted to 0.1 to 5 mass%, 0.2 to 4 mass%, or 0.3 to 3 mass% relative to the total mass of the adhesive layer 14. By making the polyacrylic acid content 0.1 mass% or more, the moldability and shape retention of the adhesive layer 14 tend to be further improved. By making the polyacrylic acid content 5 mass% or less, the hardness of the adhesive layer 14 is less likely to increase, and the adhesive layer 14 tends to have higher adhesion to the skin.

[0028] In the acrylic ester having a hydrophilic group, the acrylic ester portion may be an alkyl acrylate. This alkyl portion may be an alkyl having 1 to 10 carbon atoms, or an alkyl having 1 to 8 carbon atoms. In the acrylic ester having a hydrophilic group, the hydrophilic group may be present in this alkyl portion.

[0029] The adhesive layer 14 may contain a component other than the water-soluble acrylic polymer as the water-soluble polymer. For example, the adhesive layer 14 may contain gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, sodium hyaluronate, hydroxypropyl cellulose, sodium carboxymethylcellulose (sodium carmellose), methylcellulose, carrageenan, glucomannan, agar, guar gum, xanthan gum, gellan gum, pectin, or locust bean gum. These may be used alone or in combination of two or more. For example, sodium carmellose, gelatin, or polyvinyl alcohol may be used. These components may be used in combination with a water-soluble acrylic polymer.

[0030] When the pressure-sensitive adhesive layer 14 contains a water-soluble polymer other than the water-soluble acrylic polymer, the content thereof may be adjusted to 0.1 to 30 mass%, 3 to 18 mass%, or 3 to 10 mass%, based on the total mass of the pressure-sensitive adhesive layer 14. When the content of the water-soluble polymer other than the water-soluble acrylic polymer is 3 mass% or more, the cohesive force of the pressure-sensitive adhesive layer 14 tends to be high. When the content is 10 mass% or less, the active ingredient contained in the pressure-sensitive adhesive layer 14 tends to be uniformly dispersed.

[0031] By including water in the adhesive layer 14, the skin permeability of the active ingredient is improved, and the action of the active ingredient is more effectively exerted. The water content may be 45 to 70 mass % based on the total mass of the adhesive layer 14. By setting the water content to 70 mass % or less, the formability and shape retention of the adhesive layer tend to be improved.

[0032] The adhesive layer 14 may contain a methyl acrylate-2-ethylhexyl acrylate copolymer resin. In conventional patches, when the mass of the adhesive layer 14 is small, the water content is likely to decrease and the adhesive strength is likely to decrease. By containing a methyl acrylate-2-ethylhexyl acrylate copolymer resin in the adhesive layer 14, sufficient adhesive strength tends to be maintained even after a long period of time, even when the mass of the adhesive layer 14 is relatively small.

[0033] The adhesive layer 14 may further contain other components such as a solubilizing agent, a crosslinking agent, a moisturizing agent, a cooling agent, a stabilizer, a filler, a preservative, a chelating agent, an inorganic powder, a coloring agent, a flavoring agent, or a pH adjuster.

[0034] The solubilizing agent is used to dissolve the active ingredient. Examples of the solubilizing agent include crotamiton, N-methylpyrrolidone, polyalkylene glycols such as polyethylene glycol (PEG) and polybutylene glycol, fatty acid esters such as isopropyl myristate and diethyl adipate, oxyalkylene fatty acid esters such as polyethylene glycol monostearate, fatty acid esters such as polyoxyalkylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and surfactants such as polysorbate 80. These solubilizing agents may be used alone or in combination of two or more. The content of the solubilizing agent may be adjusted to 0.1 to 10% by mass with respect to the total mass of the adhesive layer 14.

[0035] The crosslinking agent is used to strengthen the adhesive layer 14 and provide water retention. Examples of the crosslinking agent include thermosetting resins such as amino resins, phenolic resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, potassium aluminum sulfate (alum), aluminum silicate, magnesium sulfate, magnesium aluminometasilicate, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, and inorganic crosslinking agents such as metals or metal compounds. The content of the crosslinking agent may be 0.01 to 10 mass%, 0.01 to 6.5 mass%, 0.01 to 3 mass%, 0.05 to 2 mass%, or 0.1 to 1 mass% relative to the total mass of the adhesive layer 14.

[0036] The moisturizer is used to suppress evaporation of water from the adhesive layer 14 over time. Examples of the moisturizer include polyhydric alcohols such as glycerin, sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, 1,3-propanediol, and 1,4-butanediol, and also hyaluronic acid, collagen, ceramide, urea, and heparin. These moisturizers may be used alone or in combination of two or more. The content of the moisturizer may be adjusted to be 0.1 to 70% by mass, or 3 to 70% by mass, based on the total mass of the adhesive layer 14.

[0037] By including a polyhydric alcohol in the adhesive layer 14, the adhesive layer 14 becomes softer, and the adhesiveness of the microneedle patch 10 tends to be improved.

[0038] When glycerin is contained as the polyhydric alcohol in the adhesive layer 14, the content of glycerin may be 5 to 70 mass%, 10 to 50 mass%, or 15 to 45 mass% relative to the total mass of the adhesive layer 14. When the content of glycerin is 5 mass% or more, the drying of the adhesive layer 14 can be further delayed during use of the microneedle patch 10, and the adhesive force of the microneedle patch 10 can be easily maintained for a longer period of time. When the content of glycerin is 50 mass% or less, glycerin is less likely to separate from the adhesive layer 14, and the surface of the adhesive layer 14 becomes less sticky.

[0039] Examples of the refreshing agent include thymol, l-menthol, dl-menthol, l-isopulegol, and peppermint oil. L-menthol may be used as the refreshing agent. The content of the refreshing agent may be adjusted to 0.5 to 3 mass % with respect to the total mass of the adhesive layer 14.

[0040] Examples of the stabilizer include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, UV absorbers (e.g., dibenzoylmethane derivatives), etc. The content of the stabilizer may be adjusted to 0.01 to 3 mass % with respect to the total mass of the pressure-sensitive adhesive layer 14.

[0041] Examples of the filler include calcium carbonate, magnesium carbonate, silicates (e.g., aluminum silicate, magnesium silicate, etc.), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide, etc. The content of the filler may be 0.01 to 10 mass % or 3 to 9 mass % relative to the total mass of the pressure-sensitive adhesive layer 14.

[0042] Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate.

[0043] Examples of the chelating agent include ethylenediaminetetraacetate, pyrophosphate, hexametaphosphate, gluconic acid, etc. The content of the chelating agent may be 0.01 to 1 mass %, 0.05 to 0.5 mass %, or 0.1 to 0.3 mass % relative to the total mass of the pressure-sensitive adhesive layer 14.

[0044] Examples of the pH adjuster include organic acids such as acetic acid, lactic acid, oxalic acid, citric acid, and tartaric acid; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; and pharma- ceutically acceptable salts of the organic acids and inorganic acids. The content of the pH adjuster may be 0.01 to 1 mass%, 0.05 to 0.7 mass%, or 0.1 to 0.5 mass%, relative to the total mass of the adhesive layer 14.

[0045] As the inorganic powder, coloring agent, and flavoring agent, compositions generally used for the microneedle patch 10 can be used.

[0046] The active ingredient may be, for example, an antioxidant, a free radical scavenger, a moisturizer, a depigmenting agent, a fat regulating agent, an ultraviolet light reflecting agent, a humectant, an antibacterial agent, an antiallergy agent, an anti-acne agent, an anti-aging agent, an anti-wrinkle agent, a bactericide, an analgesic, a cough suppressant, an anti-itching agent, a local anesthetic, an anti-hair loss agent, a hair growth aid, a hair growth inhibitor, an antidandruff agent, an antihistamine, a keratolytic agent, an anti-inflammatory agent, a soft drink, a therapeutic agent, an anti-infective agent, an anti-inflammatory agent, an antiemetic agent, an anticholinergic agent, a vasoconstrictor, a vasodilator, an injury healing aid, a peptide, a polypeptide, a protein, an anti-odor agent, an antiperspirant, a skin softener, a skin moisturizer, a softener, a hair conditioner ... The active ingredient may be selected from the group consisting of conditioners, hair softeners, hair moisturizers, tanning agents, skin lightening agents, antifungal agents, hair removers, topical analgesics, counterirritants, hemorrhoid medications, insecticides, poison ivy treatments, poison sumac treatments, burn treatments, anti-diaper rash medications, heat rash medications, lotions, vitamins, amino acids, amino acid derivatives, herbal extracts, retinoids, flavonoids, sensory markers, skin conditioners, hair lighteners, chelating agents, cell turnover enhancers, colorants, sunscreens, anesthetics, immunostimulants, nourishing agents, moisture absorbents, sebum absorbents, skin beautifying ingredients, and mixtures thereof.

[0047] The active ingredient may comprise a plant preparation, such as an extract or tincture, for the treatment of local skin conditions. Examples of extracts or tinctures include oak bark extract, walnut extract, arnica tincture, witch hazel extract, plantain extract, pansy extract, thyme or sage extract; St. John's wort tincture, burdock extract, chamomile flower extract or calendula tincture; for the treatment of severely fatigued and damaged skin, such as birch leaf extract, nettle extract, cole's foot extract, comfrey tincture, horsetail extract or aloe extract; horse chestnut and burdock extract, arnica, calendula and capsicum extract.

[0048] As active ingredient, amino acid may include amino acid obtained from hydrolysis of various proteins, as well as its salt, ester or acyl derivative.Examples of such amino acid drugs include amphoteric amino acids such as alkylamidoalkylamines, glutamic acid stearyl acetyl, capryloyl silk amino acid, capryloyl collagen amino acid; capryloyl keratin amino acid; capryloyl pea amino acid; cocodimonium hydroxypropyl amino acid silk; corn gluten amino acid; cysteine; glutamic acid; glycine; hair keratin amino acid; hair amino acid such as aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, half cystine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, cysteic acid, lysine, histidine, arginine, cysteine, tryptophan, citrulline; lysine; silk amino acid; wheat amino acid; and mixtures thereof.

[0049] As active ingredients, peptides, polypeptides, and proteins include polymers with long chains, e.g., at least about 10 carbon atoms, and high molecular weights, e.g., at least 1000, formed by self-condensation of amino acids. Examples of such proteins include collagen; deoxyribonuclease; iodized corn protein; keratin; milk protein; protease; serum protein; silk; sweet almond protein; wheat germ protein; wheat protein; wheat protein, alpha and beta helices of keratin protein; hair proteins, e.g., intermediate filament proteins, high sulfur content proteins, very high sulfur content proteins, intermediate filament associated proteins, high tyrosine proteins, high glycine-tyrosine proteins, trichohyalin, and mixtures thereof.

[0050] Examples of anti-wrinkle ingredients include hyaluronic acid, sodium hyaluronate, retinol (vitamin A), silybin peptides (HTC collagen, palmitoyl penta, peptide 3, argirlin), amino acids, hydroxyproline, tocopheryl retinoate, ursolic acid, vitamin C derivatives, coenzyme Q10, astaxanthin, fullerene, polyphenols, alpha lipoic acid, soybean extract, pullulan, active isoflavones, sugars, polysaccharides, glycerin, glycerin derivatives, etc. The anti-wrinkle ingredient may be a mixture of at least two of these compositions.

[0051] Examples of vitamins include vitamin B complex; vitamins A, C, D, E, K and derivatives thereof, such as, for example, vitamin A palmitate, including thiamine, nicotinic acid, biotin, pantothenic acid, choline, riboflavin, vitamin B6, vitamin B12, pyridoxine, inositol, carnitine; and provitamins, such as, for example, panthenol (provitamin B5) and panthenol triacetate; and mixtures thereof.

[0052] Examples of antibacterial agents include bacitracin, erythromycin, neomycin, tetracycline, chlortetracycline, benzethonium chloride, phenol, and mixtures thereof.

[0053] Examples of emollients and skin moisturizers include mineral oil, lanolin, vegetable oil, isostearyl isostearate, glyceryl laurate, methyl gluceth-10, methyl gluceth-20, chitosan, and mixtures thereof.

[0054] Examples of hair conditioners include fat-soluble compounds such as cetyl alcohol, stearyl alcohol, hydrogenated polydecene, and mixtures thereof, as well as quaternary compounds such as behenamidopropyl PG-dimonium chloride, tricetylammonium chloride, hydrogenated tallowamidoethyl hydroxyethylmonium methosulfate, and mixtures thereof.

[0055] Examples of sunscreens include butyl methoxydibenzoylmethane, octyl methoxycinnamate, oxybenzone, octocrylene, octyl salicylate, phenylbenzimidazole sulfonic acid, ethyl hydroxypropyl aminobenzoate, menthyl anthranilate, aminobenzoic acid, cinoxate, diethanolamine methoxycinnamate, glyceryl aminobenzoate, titanium dioxide, zinc oxide, oxybenzone, padimate O, red petrolatum, and mixtures thereof. An example of a tanning agent is dihydroxyacetone.

[0056] Examples of skin lightening agents include hydroquinone and its derivatives, catechol and its derivatives, ascorbic acid and its derivatives, ellagic acid and its derivatives, kojic acid and its derivatives, tranexamic acid and its derivatives, resorcinol derivatives, placenta extract, arbutin, oil-soluble licorice extract, and mixtures thereof.

[0057] Examples of anti-inflammatory analgesics include acetaminophen, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac, fenclofenac, clidanac, flurbiprofen, fentiazac, bufexamac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, and tiaramide hydrochloride. Examples of steroidal anti-inflammatory analgesics that may be used with the microneedle patch 10 include hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumethasone, fluorometholone, and beclomethasone dipropionate.

[0058] Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorphenamine maleate, isothipendyl hydrochloride, tripeleramine hydrochloride, promethazine hydrochloride, and methdilazine hydrochloride. Examples of local anesthetics that may be used with the microneedle patch 10 include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, benzocaine, p-butylaminobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dyclonine, and dyclonine hydrochloride.

[0059] Examples of germicides and disinfectants include thimerosal, phenol, isopropylmethylphenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone-iodine, cetylpyridinium chloride, eugenol, and trimethylammonium bromide. Examples of vasoconstrictors that may be used with the microneedle patch 10 include naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, and tramazoline hydrochloride. Examples of hemostatic agents that may be used with the microneedle patch 10 include thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbazochrome sodium sulfonate, rutin, and hesperidin.

[0060] Examples of chemotherapeutic agents include sulfamine, sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazal, sulfisomidine, sulfamethizole, and nitrofurazone. Examples of antibiotics that may be used with the microneedle patch 10 include penicillin, methicillin, oxacillin, cephalothin, cephalosin, erythromycin, lincomycin, tetracycline, chlorotetracycline, oxytetracycline, methacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, and cycloserine.

[0061] Examples of antiviral agents include protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, constitutive protein synthesis inhibitors, attachment and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir.

[0062] Examples of hair growth or hair restoration drugs include minoxidil, carpronium chloride, pentadecanoic acid glyceride, tocopherol acetate, piroctone olamine, glycyrrhizic acid, hinokitiol, Swertia japonica extract, ceramides and precursors, nicotinamide, and capsicum tincture.

[0063] Examples of cosmetic active ingredients include D-alpha-tocopherol, DL-alpha-tocopherol, D-alpha-tocopheryl acetate, DL-alpha-tocopheryl acetate, ascorbyl palmitate, vitamin D, vitamin D2, vitamin D3, retinol, retinol esters, retinyl palmitate, retinyl propionate, beta-carotene, coenzyme Q10, D-panthenol, farnesol, farnesyl acetate; jojoba oil and blackcurrant oil, which are rich in essential fatty acids; 5-n-octanoyl salicylic acid and its esters, salicylic acid and its esters; e.g. citric acid, lactic acid, glyceryl stearate ... alkyl esters of alpha-hydroxy acids such as licholic acid; asiatic acid, madecassic acid, asiaticoside, total extract of Centella asiatica, beta-glycyrrhetinic acid, alpha-bisabolol, ceramides such as 2-oleoylamino-1,3-octadecane; phytantriol, a phospholipid of marine origin rich in polyunsaturated essential fatty acids, ethoxyquin; rosemary extract, balm extract, quercetin, extract of dried microalgae, anti-inflammatory drugs such as steroidal anti-inflammatory drugs, and biochemical stimulants such as hormones or compounds resulting from fat and / or protein synthesis.

[0064] Vitamin C promotes collagen (connective tissue) synthesis, lipid (fat) and carbohydrate metabolism, and neurotransmitter synthesis. Vitamin C may also contribute to optimal maintenance of the immune system. Vitamin C is toxic to a wide range of cancer cells, especially melanoma. Tyrosine oxidase, which catalyzes the aerobic activity of tyrosine to melanin and other pigments, is also inhibited by the presence of vitamin C. Vitamin C has been found to be effective in catalyzing immune responses to many viral and bacterial infections. In addition to the many applications mentioned above, vitamin C is essential for collagen synthesis and wound healing. The microneedle patch 10 may include a combination of vitamin C, vitamin E, and other ingredients, such as moisturizers, collagen synthesis promoters, and facial scrubs.

[0065] Skin conditioner ingredients may include mineral oil, petrolatum, vegetable oils (such as soybean oil or maleated soybean oil), dimethicone, dimethicone copolyol, cationic monomers and polymers (such as guar hydroxypropyltrimonium chloride and distearyl dimethyl ammonium chloride), and mixtures thereof. The humectant may be a polyol, such as sorbitol, glycerin, propylene glycol, ethylene glycol, polyethylene glycol, polypropylene glycol, 1,3-butanediol, hexylene glycol, isoprene glycol, xylitol, fructose, and mixtures thereof.

[0066] The skin-beautifying ingredients may include tea extracts (e.g., karatsu tea extract, ureshino tea extract, Shizuoka tea extract, etc.), sake lees extracts (e.g., junmai daiginjo sake lees extract, daiginjo sake lees extract, junmai ginjo sake lees extract, ginjo sake lees extract, etc.), citrus extracts (e.g., genkou extract, sudachi extract, unshu mandarin orange extract, etc.), seaweed extracts (e.g., nori extract, etc.), and plant extracts (e.g., asparagus extract, etc.), as well as mixtures thereof.

[0067] These active ingredients may be used alone or in combination of two or more kinds. As long as the salt is pharma- ceutically acceptable, the active ingredient may be in the form of either an inorganic salt or an organic salt. The active ingredient may be applied directly to the skin, and then the microneedle array 20 described below may be applied to the same part of the skin. In this case, the effect of stretching the skin and the ODT (occlusive dressing therapy) effect on the skin can promote the penetration of the active ingredient into the skin.

[0068] The mass of the adhesive layer 14 is, for example, 100 g / m 2 More than 250g / m 2 The mass of the pressure-sensitive adhesive layer 14 may be, for example, 2000 g / m 2 or less, 1500g / m 2 The mass of the pressure-sensitive adhesive layer 14 may be 250 to 1500 g / m 2In this case, the fit is improved and the adhesiveness can be maintained for a longer period of time. By setting the mass of the adhesive layer 14 as described above, the overall thickness of the microneedle patch 10 can be reduced, and as a result, the microneedle patch 10 can easily conform to the skin and become less likely to peel off.

[0069] The release sheet 16 is a sheet-like member that protects the adhesive layer 14 before the microneedle patch 10 is used.

[0070] The release sheet 16 may have a weakened portion 16a formed over its entire length or width. The weakened portion 16a is provided to make the release sheet 16 easier to tear. In the example of FIG. 1, the weakened portion 16a is a linear perforation, but the form of the weakened portion 16a is not limited thereto. For example, the weakened portion 16a may be thin-walled, half-cut, or may have another form. The weakened portion 16a may have a corrugated or sawtooth shape, etc.

[0071] As the release sheet 16, a plastic film such as polypropylene (for example, unstretched polypropylene or stretched polypropylene), polyethylene terephthalate, polybutylene terephthalate, polyethylene, polyester, polyurethane, polyvinyl chloride, polystyrene, or the like may be used, or a silicone-processed paper obtained by processing a synthetic resin, synthetic paper, or synthetic fiber with silicone may be used, or a laminated paper obtained by laminating an aluminum foil or craft paper with polyethylene, or the like may be used. The release sheet 16 may be colorless, or at least a part of it may be colored.

[0072] The microneedle array 20 is an instrument for puncturing or pressing the skin. Although the example in Fig. 1 shows one microneedle array 20, multiple microneedle arrays 20 may be embedded in the adhesive layer 14. When multiple microneedle arrays 20 are used, the shapes and dimensions of the arrays may be uniform, or at least one of the shapes and dimensions may be different from each other.

[0073] In one example, at least a portion of the microneedle array 20 is embedded in the adhesive layer 14. That is, at least a portion of the microneedle array 20 is located within the adhesive layer 14. For example, at least a portion of each microneedle 22 may be located within the adhesive layer 14. Alternatively, the entire microneedle array 20 may be embedded in the adhesive layer 14, in which case the entirety of each microneedle 22 is located within the adhesive layer 14.

[0074] 2 is an enlarged perspective view showing an example of the microneedle array 20. In one example, the microneedle array 20 includes a substrate 21 and at least one microneedle 22 provided on the substrate 21.

[0075] As the material of the microneedle array 20 (substrate 21 and microneedles 22), for example, silicon, silicon dioxide, ceramic, metal (stainless steel, titanium, nickel, molybdenum, chromium, cobalt, etc.), synthetic or natural resin materials, etc. may be used. Alternatively, taking into consideration the antigenicity of the microneedles 22 and the unit price of the material, biodegradable polymers such as polylactic acid, polyglycolide, polylactic acid-co-polyglycolide, pullulan, caprolactone, polyurethane, polyanhydride, etc. may be used, or synthetic or natural resin materials such as non-degradable polymers such as polyethylene, polypropylene, polyamide, polyethylene terephthalate, cyclic olefin copolymer, polycarbonate, polymethacrylic acid, polymethyl methacrylate, rigid vinyl chloride, ethylene vinyl acetate, polytetrafluoroethylene, tetrafluoroethylene-ethylene copolymer, polyoxymethylene, acrylonitrile-butadiene-styrene copolymer, etc. may be used. Alternatively, polysaccharides such as hyaluronic acid, sodium hyaluronate, pullulan, dextran, dextrin or chondroitin sulfate, cellulose derivatives, etc. may be used. Considering the possibility that the microneedle 22 may break on the skin, a biodegradable resin may be adopted, for example, polylactic acid may be used. Polylactic acid includes polylactic acid homopolymers such as poly-L-lactic acid and poly-D-lactic acid, poly-L / D-lactic acid copolymers, and mixtures thereof, and any of these may be used. The greater the average molecular weight of polylactic acid, the stronger its strength becomes, and for example, polylactic acid with an average molecular weight of 40,000 to 100,000 may be used. The substrate 21 and the microneedle 22 may be made of the same material or different materials.

[0076] The substrate 21 is a base for supporting the microneedles 22. In the present disclosure, the surface from which the microneedles 22 stand is referred to as the main surface of the substrate 21, and the side opposite to the main surface is referred to as the back surface of the substrate 21. In the example of FIG. 1, the back surface of the substrate 21 contacts the main surface of the support 12. The dimensions of the substrate 21 may be determined taking into consideration the dimensions of the adhesive layer 14. In the example of FIG. 1, the area of ​​the substrate 21 is smaller than the area of ​​the adhesive layer 14. In another example, the areas of the substrate 21 and the adhesive layer 14 may be the same. Alternatively, the area of ​​the substrate 21 may be larger than the area of ​​the adhesive layer 14, in which case a part of the substrate 21 will be exposed. The area of ​​the substrate 21 is 0.5 cm 2 ~300cm 2 Or 1cm 2 ~100cm 2 Or 1cm 2 ~50cm 2 Alternatively, the area of ​​the substrate 21 may be 0.5 cm 2 ~10cm 2 , 0.5cm 2 ~5cm 2 , 1cm 2 ~5cm 2 , 0.5cm 2 ~3cm 2 , or 1 cm 2 ~3cm 2 A substrate of a desired size may be formed by joining several substrates 21. The lower limit of the thickness of substrate 21 may be 5 μm or 20 μm, and the upper limit of the thickness may be 1000 μm or 300 μm. The thickness of substrate 21 may be 0.5 to 2.5 times the length of microneedles 22 described later.

[0077] The microneedle 22 is a minute structure rising from the main surface of the substrate 21. The microneedle 22 has a tapered shape that narrows from the bottom connected to the substrate 21 toward the tip. In this specification, the term "microneedle" is a concept that includes not only a needle-shaped structure in a broad sense and a structure including a needle shape, but also a shape without a pointed tip.

[0078] The lower limit of the density of the microneedles 22 is, for example, 0.05 needles / cm 2 , 1 piece / cm2 , 50 pieces / cm 2 , 75 pieces / cm 2 , 100 pieces / cm 2 , 150 pieces / cm 2 , 200 pieces / cm 2 , 300 pieces / cm 2 , 340 pieces / cm 2 , or 400 pieces / cm 2 On the other hand, the upper limit of the density is, for example, 10,000 fibers / cm 2 , 5000 pieces / cm 2 , 2000 pieces / cm 2 , 1200 pieces / cm 2 , 700 pieces / cm 2 , 640 pieces / cm 2 , or 340 strands / cm 2 The lower limit of the density is a value calculated from the number of microneedles capable of administering 1 mg of active ingredient and the required area. The upper limit of the density is a limit value taking into consideration the shape of the microneedle. In one example, the lower limit and the upper limit of the density of the microneedle 22 are set in consideration of stretching the skin by the microneedle 22 to increase the area of ​​the adhesive layer 14 in contact with the skin.

[0079] The length of the microneedle 22 may be 150 to 1200 μm, 200 to 1000 μm, or 300 to 900 μm. The length of the microneedle 22 is the distance from the bottom connected to the substrate 21 to the tip. The reason why the length of the microneedle 22 is set to 300 μm or more is to ensure the percutaneous absorption of the active ingredient. By setting the length of the microneedle 22 to 900 μm or less, the microneedle 22 can be prevented from contacting the nerve, reducing the possibility of pain and avoiding the possibility of bleeding. When the length of the microneedle is 500 μm or less, the amount of active ingredient to be introduced into the skin can be efficiently administered, and for example, it is possible to administer the active ingredient without perforating the basement membrane. In one example, the length of the microneedle 22 is selected so as not to penetrate the stratum corneum of the skin in normal use, but some of the microneedles 22 may penetrate the stratum corneum. That is, the epidermis is stretched and thinned by the microneedles 22, and the active ingredient penetrates into the epidermis which is now more easily permeable, but it is possible that some of the active ingredient may penetrate into the skin through holes formed in the stratum corneum.

[0080] In the example of FIG. 2, the microneedle 22 has a three-dimensional shape. For example, the microneedle 22 may be a cone or any other pyramid such as a square pyramid. The microneedle 22 does not have to be a cone, and may have, for example, a flat or rounded tip. A flat or rounded tip may be obtained by intentional processing or may be obtained as a result without such processing. When the tip is flat, the area of ​​the flat part is 20 to 600 μm 2 or 50 to 250 μm 2 When the tip is rounded, the radius of curvature of the tip may be 2 to 100 μm, or 5 to 30 μm.

[0081] Examples of methods for manufacturing the microneedle array 20 having the three-dimensional microneedles 22 include wet etching or dry etching using a silicon substrate, precision machining using metal or resin (electric discharge machining, laser machining, dicing, hot embossing, injection molding, etc.), and mechanical cutting. By these machining methods, the substrate 21 and the microneedles 22 are integrally molded. Examples of methods for making the microneedles 22 hollow include a method in which the microneedles 22 are fabricated and then secondary processed by laser machining or the like.

[0082] The microneedles 22 may contain an active ingredient or a coating containing the active ingredient may be formed on the surface of the microneedles 22 .

[0083] The microneedles 22 may be planar. For example, the microneedles 22 may be triangular or may be other shapes such as diamonds. The planar microneedles 22 are formed by punching the substrate 21 to form the microneedles 22, and then raising the microneedles 22 from the substrate 21. Therefore, the substrate 21 and the microneedles 22 have the same thickness. If the substrate 21 is metal, a number of microneedles 22 can be formed by punching the sheet with a chemical solution, and the microneedles 22 can be raised to form the microneedle array 20. If the substrate 21 is nonmetallic, a number of microneedles 22 can be formed by punching the substrate 21 with a laser, and the microneedles 22 can be raised in the same manner as in the case of a metal sheet. When etching is used in this way, voids are generated around each microneedle 22.

[0084] Regardless of whether the microneedle 22 has a three-dimensional or planar shape, the direction in which the tip of the microneedle 22 faces (the tip direction of the microneedle 22) may be perpendicular to the main surface of the substrate 21 or may be at an acute angle to the main surface (i.e., the inclination angle of the microneedle 22 is greater than 0 degrees and less than 90 degrees).

[0085] In the microneedle patch 10 before it is applied to the skin, the microneedles 22 may be entirely embedded in the adhesive layer 14, or the tips of the microneedles 22 may protrude from the adhesive layer 14. The relationship between the adhesive layer 14 and the microneedles 22 will be described with reference to Fig. 3. Fig. 3 is a schematic diagram of the microneedle patch 10 as viewed from the side.

[0086] The adhesive layer 14 includes a main portion 14a which is a region located on the microneedle array 20. When the microneedle array 20 is disposed on a part of the main surface of the support 12, the adhesive layer 14 further includes a peripheral portion 14b which is a region located outside the microneedle array 20 in addition to the main portion 14a. The peripheral portion 14b can also be said to be a region where the microneedle array 20 is not present. The adhesive layer 14 shown in FIG. 1 and FIG. 3 includes a main portion 14a and a peripheral portion 14b. When a plurality of microneedle arrays 20 are disposed apart from each other on the support 12, at least a part of the peripheral portion 14b may be located inside the microneedle patch 10. In the example of FIG. 3, the working surface of the peripheral portion 14b is recessed from the working surface of the main portion 14a, but the working surface of the adhesive layer 14 may be flat or approximately flat overall.

[0087] The relationship between the adhesive layer 14 and the microneedles 22 may be represented by the thickness of the adhesive layer 14 and the length of the microneedles 22. The thickness of the adhesive layer 14 refers to the length of the adhesive layer 14 along the direction from the main surface of the support 12 toward the working surface of the adhesive layer 14. The thickness of the adhesive layer 14 may be the thickness of the main portion 14a or the peripheral portion 14b. The thickness of the main portion 14a may be the distance from the main surface of the substrate 21 to the working surface of the adhesive layer 14. The thickness of the peripheral portion 14b may be the distance from the main surface of the support 12 to the working surface of the adhesive layer 14. In one example, the thickness of the main portion 14a (peripheral portion 14b) may be calculated as a statistical value of the thickness at each of a plurality of measurement points in the main portion 14a (peripheral portion 14b). The statistical value may be an average value.

[0088] Before the microneedle patch 10 is applied to the skin, the thickness Da of the main portion 14a may be 0.9 to 1.3 times, or may be 0.9 to 1.2 times, the length Ln of the microneedle 22. When this ratio is less than 1.0, it means that the tip of the microneedle 22 protrudes from the adhesive layer 14. When this ratio is greater than 1.0, it means that the entire microneedle 22 is embedded in the adhesive layer 14.

[0089] In one example, the thickness Db of the peripheral portion 14b may be smaller than the thickness Dm of the microneedle array 20. The thickness of the microneedle array 20 refers to the distance from the rear surface of the substrate 21 to the tip of the microneedle 22.

[0090] [Methods relating to microneedle patches] An example of a method for producing the microneedle patch 10 will be described. In the formation step, for example, an adhesive composition is spread on a release sheet 16 to form an adhesive layer 14. The configuration of this adhesive layer 14 may be selected from various configurations in the present disclosure. As described above, the adhesive layer 14 formed contains a water-soluble polymer, glycerin, and water, and the water content may be 45 to 70 mass% with respect to the total mass of the adhesive layer 14. The adhesive layer 14 formed may further contain an active ingredient.

[0091] In the preparation step, the microneedle array 20 is prepared. The configuration of the microneedle array 20 may be selected from various configurations in the present disclosure. As described above, the length of the microneedles 22 may be 300 to 900 μm.

[0092] In the arranging step, the microneedle array 20 is arranged on the adhesive layer 14 such that the thickness of the main portion 14a of the adhesive layer 14 is 0.9 to 1.3 times the length of the microneedles 22. In one example, the microneedle array 20 is arranged on the adhesive layer 14 such that at least a portion of each microneedle 22 is embedded in the adhesive layer 14. The microneedle array 20 may be arranged on the adhesive layer 14 such that a peripheral portion 14b is formed in the adhesive layer 14. The microneedle array 20 may be arranged on the adhesive layer 14 such that the thickness of the peripheral portion 14b is smaller than the thickness of the microneedle array 20.

[0093] In the placing step, the support 12 is placed on the adhesive layer 14 and the microneedle array 20 so that the main surface of the support 12 contacts the back surface of the substrate 21. As a result, the adhesive layer 14 and the microneedles 22 are sandwiched between the support 12 and the release sheet 16.

[0094] The manufacturing method may include a storage step. In this storage step, the microneedle patch 10 may be stored inside a packaging bag. An example of the material of the packaging bag is aluminum. This storage method can suppress the decrease in the water content of the adhesive layer 14 and reduce the adhesion of dirt and the like to the adhesive layer 14. The microneedle patch 10 may be stored in the packaging bag in a state where it is folded multiple times. In this case, the space required for storing the microneedle patch 10 is saved, and therefore the material used for the packaging bag can be reduced.

[0095] At least a part of the manufacturing method may be a method for improving the transdermal administration efficiency of an active ingredient from the microneedle patch 10. That is, the method for improving the transdermal administration efficiency includes at least one of a forming step, a preparing step, a placing step, a mounting step, and a storing step. For example, the method for improving the transdermal administration efficiency includes at least a placing step.

[0096] [Application of microneedle patches] FIG. 4 is a diagram showing a schematic diagram of the change in the microneedle patch 10 before and after application to the skin. Note that in this diagram, the microneedle patch 10 "considered" to have been applied to the skin is shown as the microneedle patch 10 applied to the skin. After the microneedle patch 10 is applied to the skin, the moisture in the adhesive layer 14 evaporates and the adhesive layer 14 gradually thins, so that the tips of the microneedles 22 protrude from the adhesive layer 14, or protrude further if they protruded before application. In the present disclosure, the length Lp of the part of the microneedle 22 protruding from the adhesive layer 14 is also referred to as the "protruding length". This protruding length is greater after a predetermined time has elapsed since the microneedle patch 10 was applied to the skin than before the microneedle patch 10 was applied to the skin. In one example, the predetermined time may be a time selected from between 1 minute and 8 hours, and may be, for example, 2 hours, 4 hours, 6 hours, or 8 hours. For example, the protrusion length 8 hours after microneedle patch 10 is applied to the skin may be 10 μm or more greater, 20 μm or more greater, or 28 μm or more greater than the protrusion length before microneedle patch 10 is applied to the skin.

[0097] FIG. 5 is a schematic diagram showing application of the microneedle patch 10 to the skin S. As described above, after the microneedle patch 10 is applied to the skin S, the tip of the microneedle 22 protrudes from the adhesive layer 14, or if it protrudes before application, it protrudes further. The protruding microneedles 22 stretch the skin S, and the adhesive layer 14 penetrates into the stretched portion, so that the contact area between the skin S and the adhesive layer 14 increases. As a result, the permeability of the active ingredient through the skin S can be improved. In addition, since the microneedles 22 do not protrude too much from the adhesive layer 14, that is, the protruding length is suppressed, sufficient adhesion of the adhesive layer 14 to the skin S can be maintained.

[0098] In order to realize application of the microneedle patch 10 as shown in Figures 4 and 5, the above-mentioned manufacturing method (method for improving transdermal administration efficiency) may be used. In one example, in the arranging step, the microneedle array 20 is arranged on the formed adhesive layer 14 so that the protruding length is greater after a predetermined time has elapsed since the microneedle patch 10 is applied to the skin S than before the microneedle patch 10 is applied to the skin S. The microneedle array 20 may be arranged on the adhesive layer 14 so that the protruding length 8 hours after the microneedle patch 10 is applied to the skin S is 10 μm or more greater than the protruding length before the microneedle patch 10 is applied to the skin S.

[0099] The present disclosure has been described in detail above based on the embodiments. However, the present disclosure is not limited to the above examples. Various modifications are possible without departing from the gist of the present disclosure.

[0100] In the above example, the microneedle patch 10 is approximately rectangular, but the microneedle patch may have other shapes. For example, the microneedle patch may be any shape, such as a square, a circle, an ellipse, a crescent, a magatama, or other polygonal shape. In the above example, the microneedle array 20 is approximately rectangular in shape, but the microneedle array may be any shape. For example, the microneedle array may be any shape, such as a square, a circle, an ellipse, a crescent, or other polygonal shape. The shape of the microneedle array may be the same as or different from the shape of the microneedle patch.

[0101] [Note] As can be seen from the various examples above, the present disclosure includes the following aspects. (Appendix 1) A method for improving the transdermal administration efficiency of an active ingredient from a microneedle patch comprising a support, an adhesive layer provided on a main surface of the support, and a microneedle array at least a portion of which is located within the adhesive layer, comprising: the pressure-sensitive adhesive layer comprises the active ingredient, a water-soluble polymer, glycerin, and water, the content of the water is 45 to 70% by mass relative to the total mass of the pressure-sensitive adhesive layer, The microneedle array comprises a substrate and at least one microneedle extending from a main surface of the substrate; the pressure-sensitive adhesive layer includes a main portion located on the microneedle array, The method includes a step of arranging the microneedle array on the adhesive layer so that the thickness of the main portion is 0.9 to 1.3 times the length of the microneedles. method. (Appendix 2) The length of the microneedle is 300 to 900 μm. The method described in Appendix 1. (Appendix 3) In the step of placing the microneedle array, the microneedle array is placed on the adhesive layer such that a peripheral portion located on the outer side of the microneedle array is formed on the adhesive layer. 3. The method according to claim 1 or 2. (Appendix 4) The thickness of the periphery is smaller than the thickness of the microneedle array. The method described in Appendix 3. (Appendix 5) a protrusion length, which is the length of the portion of the microneedle protruding from the adhesive layer, is greater after a predetermined time has elapsed since the microneedle patch was applied to the skin than before the microneedle patch was applied to the skin; The method according to any one of claims 1 to 4. (Appendix 6) The protrusion length 8 hours after the microneedle patch is applied to the skin is 10 μm or more greater than the protrusion length before the microneedle patch is applied to the skin. The method described in Appendix 5. (Appendix 7) A method for producing a microneedle patch comprising: a support; an adhesive layer provided on a main surface of the support; and a microneedle array at least a portion of which is located within the adhesive layer, forming a pressure-sensitive adhesive layer containing a water-soluble polymer, glycerin, and water, the water content being 45 to 70% by mass based on the total mass of the pressure-sensitive adhesive layer; a step of arranging the microneedle array, which comprises a substrate and at least one microneedle rising from a main surface of the substrate, on the formed adhesive layer such that the thickness of a main portion of the adhesive layer located on the microneedle array is 0.9 to 1.3 times the length of the microneedle; A manufacturing method comprising: (Appendix 8) The length of the microneedle is 300 to 900 μm. The manufacturing method described in Appendix 7. (Appendix 9) In the step of arranging the microneedle array, the microneedle array is arranged on the formed adhesive layer such that a peripheral portion located on the outer side of the microneedle array is formed on the adhesive layer. The method for producing the method according to claim 7 or 8. (Appendix 10) In the step of arranging the microneedle array, the microneedle array is arranged on the formed adhesive layer such that the thickness of the peripheral portion is smaller than the thickness of the microneedle array. The manufacturing method described in Appendix 9. (Appendix 11) In the step of arranging the microneedle array, the microneedle array is arranged on the formed adhesive layer such that a protrusion length, which is a length of a portion of the microneedles protruding from the adhesive layer, is greater after a predetermined time has elapsed since the microneedle patch was applied to the skin than before the microneedle patch was applied to the skin. The method for producing the same according to any one of claims 7 to 10. (Appendix 12) In the step of arranging the microneedle array, the microneedle array is arranged on the formed adhesive layer such that the protrusion length 8 hours after the microneedle patch is applied to the skin is 10 μm or more greater than the protrusion length before the microneedle patch is applied to the skin. The manufacturing method described in Appendix 11.

[0102] According to Supplementary Note 1 and 7, the water content and the ratio of the thickness of the adhesive layer and the length of the microneedles on the microneedle array are set within the corresponding numerical ranges. With this configuration, the skin is stretched by the microneedles protruding from the adhesive layer while maintaining the adhesion of the microneedle patch to the skin. As a result, the contact area between the stretched skin and the adhesive layer increases, so that the transdermal administration of the active ingredient can be performed efficiently. In another aspect, the adhesion of the microneedle patch to the skin during application can be improved by the contact of the microneedles protruding from the adhesive layer with the skin.

[0103] According to appendix 2 and 8, the length of the microneedle is set within the above-mentioned numerical range. With this configuration, the adhesion of the microneedle patch to the skin is more reliably maintained, and the skin is stretched by the microneedle protruding from the adhesive layer. As a result, the contact area between the stretched skin and the adhesive layer increases, so that the active ingredient can be efficiently administered transdermally.

[0104] According to Supplementary Note 3 and 9, since the adhesive layer is also located on the outside of the microneedle array, the degree of reduction in the adhesive layer after the microneedle patch is applied to the skin can be more easily controlled. For example, the phenomenon in which the microneedles protrude too much from the adhesive layer can be more reliably suppressed, and sufficient adhesion of the adhesive layer to the skin can be maintained.

[0105] According to Appendices 4 and 10, the thickness of the adhesive layer located on the outside of the microneedle array is limited, so that the microneedles can be more reliably protruded from the adhesive layer and the skin can be more reliably stretched by the microneedles.

[0106] According to Supplementary Note 5 and 11, the protruding length of the microneedles gradually increases as the microneedle patch is applied to the skin. Therefore, the contact area between the skin and the adhesive layer can be increased while gradually stretching the skin.

[0107] According to Supplementary Note 6 and 12, the length of the protruding microneedles gradually increases over 8 hours as the microneedle patch is applied to the skin. Therefore, during the application time, the contact area between the skin and the adhesive layer can be increased while gradually stretching the skin. EXAMPLES

[0108] Examples will be specifically described below, but the present disclosure is not limited thereto.

[0109] [Adhesive layer thickness (1)] An adhesive composition for the microneedle patch according to Example 1 was prepared according to the composition (unit: mass%) shown in Table 1. Using this adhesive composition, one microneedle patch was produced by the above-mentioned manufacturing method. The microneedle array had a thickness of 700 μm and an area of ​​1 cm. 2 On a roughly circular substrate, 156 microneedles with a length of 475 μm were placed per cm. 2 The density was set at 1.

[0110] [Table 1]

[0111] The protrusion length of the microneedles was then calculated for each of the time points: 0 hours, 2 hours, 4 hours, 6 hours, and 8 hours, as shown below. (1) In the first step, the prepared microneedle patch was cut using a CO2 laser marker LP-420, a laser cutter manufactured by Panasonic Devices SUNX Co., Ltd., along the thickness direction of the microneedle array so as to form a cross section of the microneedle array. (2) In the second step, a cross-sectional image of the cut surface was obtained at a magnification of 100 times using a microscope VHX-2000 manufactured by Keyence Corporation. Then, based on the cross-sectional image, the thickness was measured at nine points in the main part of the adhesive layer, and the average of the measured thicknesses was calculated as the thickness of the main part at time 0. This thickness can be said to be the thickness before the microneedle patch was applied to the skin. (3) In the third step, the microneedle patch having the cut surface was left in a stationary state for 2 hours in a space with an environmental temperature of 24±3° C. and a relative humidity of 50±10% RH. (4) In the fourth step, a laser cutter was used to cut the microneedle patch in the area where the microneedle array was present, parallel to the cut surface in the first step. (5) In the fifth step, similarly to the second step, the thickness of the main part of the adhesive layer at the two-hour time point was calculated based on the cross-sectional image of the new cut surface. This thickness can be said to be the thickness after the microneedle patch was applied to the skin. (6) In the sixth step, the protrusion length at 2 hours was calculated by subtracting the thickness obtained in the fifth step from the length of the microneedle. In addition, the ratio of the thickness of the main part of the adhesive layer to the length of the microneedle was calculated. (7) In the seventh step, steps 3 to 6 were carried out at 4 hours, 6 hours, and 8 hours, respectively, to determine the protrusion length and ratio at each time point.

[0112] Table 2 shows the results obtained by the above treatment. "Thickness of adhesive layer" is the thickness of the main part of the adhesive layer. "Thickness / length ratio" is the ratio of the thickness of the main part of the adhesive layer to the length of the microneedle. At time 0, the thickness of the adhesive layer is greater than the length of the microneedle, so the protrusion length is 0 μm and the thickness / length ratio is greater than 1. Two hours after the start of application of the microneedle patch, the microneedles protrude from the adhesive layer and the thickness / length ratio is less than 1. It was also found that the thickness of the adhesive layer tends to decrease linearly. The coefficient of determination in linear regression, R 2 was 0.9521.

[0113] [Table 2]

[0114] [Adhesive layer thickness (2)] According to the composition (unit: mass %) shown in Table 3, adhesive compositions for the microneedle patches according to Examples 2 to 12 and Comparative Examples 1 to 3 were prepared. Using these adhesive compositions, three microneedle patches were produced for each Example and Comparative Example by the manufacturing method exemplified above. The microneedle arrays had a thickness of 700 μm and an area of ​​1 cm. 2 The microneedles of a selected length were provided on a substantially circular substrate having a density of 1180 needles / cm in Example 5. 2 In Examples 7 and 8, the density was 316 fibers / cm 2 and 156 fibers / cm in other examples and comparative examples. 2 It was.

[0115] [Table 3]

[0116] Furthermore, adhesive compositions for the microneedle patches of Examples 12A, 12B, 12C, and 12D were prepared according to the compositions (unit: mass%) shown in Table 4. Using these adhesive compositions, three microneedle patches were produced for each of these four Examples by the manufacturing method exemplified above. The microneedle arrays had a thickness of 700 μm and an area of ​​1 cm. 2 In these four examples, the density of the microneedles was 156 needles / cm. 2 It was.

[0117] [Table 4]

[0118] Thereafter, for each of the Examples and Comparative Examples shown in Tables 3 and 4, the protrusion length was calculated at 0 hours and 8 hours, as shown below. (1) In the first step, using the above-mentioned laser cutter, each of the three microneedle patches was cut along the thickness direction of the microneedle array so as to form a cross section of the microneedle array. (2) In the second step, the above-mentioned microscope was used to obtain cross-sectional images of the cut surfaces of each of the three microneedle patches at a magnification of 100 times. Next, for each microneedle patch, the thickness was measured at nine points in the main part of the adhesive layer based on the cross-sectional images. Then, the average value of the measured thicknesses of the three microneedle patches was calculated as the thickness of the main part at time 0, i.e., the thickness before application. In addition, the thickness was used to calculate the thickness / length ratio. Furthermore, for each microneedle patch, the thickness was measured at nine points in the peripheral part of the adhesive layer based on the cross-sectional images. Then, the average value of the measured thicknesses of the three microneedle patches was calculated as the thickness of the peripheral part at time 0. (3) In the third step, the microneedle patch having the cut surface was left in a stationary state for 8 hours in a space with an environmental temperature of 24±3° C. and a relative humidity of 50±10% RH. (4) In the fourth step, a laser cutter was used to cut each of the three microneedle patches in the area where the microneedle array was present, parallel to the cut surface in the first step. (5) In the fifth step, the thickness of the main part of the adhesive layer at 8 hours was calculated based on the cross-sectional image of the new cut surface, similarly to the second step. This thickness can be said to be the thickness after the microneedle patch was applied to the skin. (6) In the sixth step, the thickness of the adhesive layer was subtracted from the length of the microneedle for each of the three microneedle patches to calculate the protrusion length at 8 hours. The thickness of the adhesive layer used in this calculation was not the average value obtained in the fifth step as in the second step, but the average value of the nine measured thicknesses in one microneedle patch for which the protrusion length was to be calculated. The average value of the three obtained protrusion lengths was then calculated as the protrusion length at 8 hours. In addition, for each of the second and fifth steps, the thickness / length ratio was calculated from the thickness of the main part of the adhesive layer and the length of the microneedle obtained in the second and fifth steps.

[0119] Table 5 shows the results obtained by the above treatment for Comparative Example 1 and Examples 2 to 4. The meanings of "thickness of adhesive layer" and "thickness / length ratio" are the same as in Table 2. When the water content was 45 to 70 mass%, the microneedles protruded from the adhesive layer when the microneedle patch was applied.

[0120] [Table 5]

[0121] Table 6 shows the results of Examples 5 to 8 obtained by the above treatment. The meanings of "thickness of adhesive layer" and "thickness / length ratio" are the same as in Table 2. When the length of the microneedles was 300 to 900 μm, the microneedles protruded from the adhesive layer or the protruding length increased when the microneedle patch was applied. [Table 6]

[0122] Table 7 shows the results of Examples 3, 6, 9-12, 12A, 12B, 12C, and 12D, and Comparative Examples 2 and 3, obtained by the above treatment. In this table, the thickness of the adhesive layer is shown for each of the main part and the peripheral part. The meaning of "thickness / length ratio" is the same as in Table 2. When the thickness of the main part of the adhesive layer was 0.9 to 1.3 times the length of the microneedles, the microneedles protruded from the adhesive layer or the protruding length increased when the microneedle patch was applied.

[0123] [Table 7]

[0124] [Probe tack test] According to the composition (unit: mass%) shown in Table 8, adhesive compositions for the microneedle patches according to Examples 13 and 14 and Comparative Examples 4 and 5 were prepared. Using these adhesive compositions, three microneedle patches were produced for each Example and Comparative Example by the manufacturing method exemplified above. The microneedle arrays had a thickness of 700 μm and an area of ​​1 cm. 2 On a roughly circular substrate, 156 microneedles with a length of 475 μm were placed per cm. 2 The density of the adhesive layer was set at 100 nm. In Example 14 and Comparative Examples 4 and 5, the product was left at room temperature to evaporate the water in the adhesive layer, thereby thinning the adhesive layer, thereby obtaining microneedle patches according to Example 14 and Comparative Examples 4 and 5. The composition of the adhesive layer during the manufacturing process was adjusted so that the composition of the adhesive layer during the probe tack test was the same between Examples 13 and 14 and Comparative Examples 4 and 5.

[0125] The meanings of "adhesive layer thickness" and "thickness / length ratio" in Table 8 are the same as those in Table 2. [Table 8]

[0126] Furthermore, an adhesive composition for the microneedle patch according to Example 13A was prepared according to the composition (unit: mass%) shown in Table 9. Using this adhesive composition, three microneedle patches were also produced in Example 13A by the manufacturing method exemplified above. The microneedle array had a thickness of 700 μm and an area of ​​1 cm. 2 On a roughly circular substrate, 156 microneedles with a length of 475 μm were placed per cm. 2 The density was set at 1.

[0127] The meanings of "adhesive layer thickness" and "thickness / length ratio" in Table 9 are the same as those in Table 2. [Table 9]

[0128] The adhesive strength of each of Examples 13, 13A, and 14 and Comparative Examples 4 and 5 was measured using a texture analyzer, TA.XT plus, manufactured by Stable Micro System, as follows. (1) In the first step, human skin was excised with a dermatome to a thickness of about 500 μm and cut into a circle with a diameter of 10 mm, and the cut piece was fixed to the tip of a circular probe with a diameter of 10 mm so that the epidermis side was on the surface. This procedure was carried out for each of the three samples. (2) In the second step, the microneedle patch was fixed to the stage of the texture analyzer so that the adhesive layer was on top. The position of the microneedle patch on the stage was adjusted so that the human excised skin fixed to the probe was in contact with the main part of the adhesive layer. This operation was performed for each of the three samples. (3) In the third step, the probe was lowered at a speed of 0.2 mm / sec to bring the human skin into contact with the microneedle patch, and a load of 5 g was applied for 1 second. The probe was then raised at a speed of 10 mm / sec, and the adhesive strength (unit: g·sec) was measured by integrating the load from the start of the raising process until the probe left the adhesive layer. This measured value can be said to be the adhesive strength of the main part of the adhesive layer. This measurement was performed for each of the three samples, and the average adhesive strength was calculated.

[0129] The average adhesive strength values ​​are as follows, and Examples 13, 13A, and 14 were superior to Comparative Examples 4 and 5 in adhesiveness. ·Comparative example 4: 0.250g·sec Comparative Example 5: 0.492g sec Example 13: 0.987g sec Example 13A: 1.214 g sec Example 14: 0.975g sec

[0130] [Microneedle Density] The adhesive composition for the microneedle patch according to each of Examples 15 to 17 was prepared with the same composition as in Examples 3, and 5 to 12. Using this adhesive composition, one microneedle patch was produced in each of the Examples by the manufacturing method exemplified above. The microneedle array had a thickness of 700 μm and an area of ​​1 cm. 2 On a roughly circular substrate of 0.1 mm in length, microneedles having a length of 475 μm were provided at a selected density.

[0131] Thereafter, for each Example, the protrusion length was calculated at 0 hours and 8 hours, in the same manner as in Examples 3 and 5 to 12.

[0132] Table 10 shows the results of Examples 3, and 15 to 17. The meanings of "thickness of adhesive layer" and "thickness / length ratio" are the same as in Table 2. In all cases, the microneedles protruded from the adhesive layer when the microneedle patch was applied. [Table 10]

[0133] [Skin stretching with microneedles] According to the composition shown in Table 11 (unit: mass %), an adhesive composition for the microneedle patch of Example 18 was prepared.

[0134] [Table 11]

[0135] Thereafter, as shown below, a microneedle patch according to Example 18 was prepared, and the length of the skin surface in contact with the adhesive layer was calculated for each of the time points 0 hour and 8 hours. (1) In the first step, the surface of the microneedle array was gold-coated using an IB-3 ion coater manufactured by Eiko Co., Ltd., for imaging by X-ray CT. The microneedle array had a thickness of 700 μm and an area of ​​1 cm. 2 On a roughly circular substrate, 156 microneedles with a length of 475 μm were placed per cm. 2 The density was set at 1. (2) In the second step, a microneedle patch was prepared using the above adhesive composition containing zirconium oxide as a contrast agent for X-ray CT imaging. The thickness of the main part of the adhesive layer before application was 439 μm, and therefore the thickness / length ratio was 0.92. (3) In the third step, polystyrene foam and human excised skin were prepared, each with dimensions of 20 mm x 20 mm. (4) In the fourth step, a microneedle patch was applied to the epidermis side of excised human skin to prepare a sample. (5) In the fifth step, the sample was placed on polystyrene foam with the opposite side of the epidermis of the excised human skin facing down, and the sample was fixed to the polystyrene foam using tape. The sample was then measured using a TDM1000H-II (2K) X-ray CT scanner manufactured by Yamato Scientific Co., Ltd. The measurement results were obtained as the results at time 0. (6) In the sixth step, another sample obtained in the fourth step was placed in a static state for eight hours in a space with an environmental temperature of 24±3°C and a relative humidity of 50±10%RH. Measurements were also performed on this material in the same manner as in the fifth step, and the measurement results were obtained as the results at the eight-hour point. (7) The length of the skin surface in a 7 mm linear distance section was analyzed from the measurement results for each of the 0 hour and 8 hour time points. For each sample, the length of the skin surface was measured in each of four different sections, and the average of the measurements was obtained as the final length.

[0136] Furthermore, the same adhesive composition as in Example 18, that is, the adhesive composition shown in Table 11, was prepared for Examples 18A, 18B, and 18C. Then, the microneedle patches according to Examples 18A, 18B, and 18C were prepared by the same manufacturing method as in Example 18. The parameters that differ between Examples 18, 18A, 18B, and 18C were the density of the microneedles, the thickness of the main part of the adhesive layer before application, and the thickness / length ratio. As in Example 18, the length of the skin surface in contact with the adhesive layer was calculated for each of Examples 18A, 18B, and 18C at 0 hours and 8 hours.

[0137] Table 12 shows the results of Examples 18, 18A, 18B, and 18C. The results show that application of the microneedle patch to the skin stretched the skin, increasing the area of ​​the adhesive layer in contact with the skin.

[0138] [Table 12] [Explanation of symbols]

[0139] Reference Signs List 10: microneedle patch, 12: support, 14: adhesive layer, 14a: main portion of adhesive layer, 14b: peripheral portion of adhesive layer, 16: release sheet, 16a: weakened portion, 20: microneedle array, 21: substrate, 22: microneedle.

Claims

1. A method for improving the transdermal administration efficiency of an active ingredient from a microneedle patch comprising a support, an adhesive layer provided on a main surface of the support, and a microneedle array at least a portion of which is located within the adhesive layer, comprising: the pressure-sensitive adhesive layer comprises the active ingredient, a water-soluble polymer, glycerin, and water, the water content is 45 to 70% by mass relative to the total mass of the pressure-sensitive adhesive layer, The microneedle array comprises a substrate and at least one microneedle extending from a main surface of the substrate; the pressure-sensitive adhesive layer includes a main portion located on the microneedle array, The method includes a step of arranging the microneedle array on the adhesive layer such that the thickness of the main portion is 0.9 to 1.3 times the length of the microneedles. method.

2. The length of the microneedle is 300 to 900 μm. The method of claim 1.

3. In the step of placing the microneedle array, the microneedle array is placed on the adhesive layer such that a peripheral portion located on the outer side of the microneedle array is formed on the adhesive layer. The method according to claim 1 or 2.

4. The thickness of the periphery is smaller than the thickness of the microneedle array. The method according to claim 3.

5. a protrusion length, which is the length of the portion of the microneedle protruding from the adhesive layer, is greater after a predetermined time has elapsed since the microneedle patch was applied to the skin than before the microneedle patch was applied to the skin; The method according to claim 1 or 2.

6. The protrusion length 8 hours after the microneedle patch is applied to the skin is 10 μm or more larger than the protrusion length before the microneedle patch is applied to the skin. The method according to claim 5.

7. A method for producing a microneedle patch comprising: a support; an adhesive layer provided on a main surface of the support; and a microneedle array at least a portion of which is located within the adhesive layer, forming a pressure-sensitive adhesive layer containing a water-soluble polymer, glycerin, and water, the water content being 45 to 70% by mass based on the total mass of the pressure-sensitive adhesive layer; a step of arranging the microneedle array, which comprises a substrate and at least one microneedle rising from a main surface of the substrate, on the formed adhesive layer such that the thickness of a main portion of the adhesive layer located on the microneedle array is 0.9 to 1.3 times the length of the microneedle; A manufacturing method comprising:

8. The length of the microneedle is 300 to 900 μm. The method of claim 7.

9. In the step of arranging the microneedle array, the microneedle array is arranged on the formed adhesive layer such that a peripheral portion located on the outer side of the microneedle array is formed on the adhesive layer. The method according to claim 7 or 8.

10. In the step of arranging the microneedle array, the microneedle array is arranged on the formed adhesive layer such that the thickness of the peripheral portion is smaller than the thickness of the microneedle array. The method of claim 9.

11. In the step of arranging the microneedle array, the microneedle array is arranged on the formed adhesive layer such that a protrusion length, which is a length of a portion of the microneedles protruding from the adhesive layer, is greater after a predetermined time has elapsed since the microneedle patch was applied to the skin than before the microneedle patch was applied to the skin. The method according to claim 7 or 8.

12. In the step of arranging the microneedle array, the microneedle array is arranged on the formed adhesive layer such that the protrusion length 8 hours after the microneedle patch is applied to the skin is 10 μm or more greater than the protrusion length before the microneedle patch is applied to the skin. The method of claim 11.

Images