Transdermal absorption preparation having improved drug skin permeability

Abstract

The present invention significantly improves transdermal drug skin permeability from a matrix-type transdermal absorption preparation by utilizing dermal pores punctured by using microneedles.　In a microneedle transdermal preparation of the present invention: a microneedle array comprises a substrate and microneedles erected on the substrate; a bottom surface drug-containing layer is provided above the substrate when the tips of the microneedles are directed upward; and the bottom surface drug-containing layer has recesses between the microneedles.

Description

Transdermal absorption preparations with improved drug skin permeability

[0001] The present invention relates to a transdermal absorption preparation, and more particularly to a preparation that utilizes microneedles to improve the transdermal drug absorption performance.

[0002] In matrix-type transdermal preparations, a drug is dissolved or dispersed in a base that may be adhesive and applied to the skin, allowing the drug to be absorbed transdermally. In this case, the use of absorption enhancers is known to promote transdermal drug absorption, but this can increase skin irritation.

[0003] Microneedle patches in which a drug is applied to the tip of a patch forested with microneedles, and microneedle preparations in which a drug is dissolved or dispersed in the microneedles themselves are known (Patent Documents 1 to 6). The former are non-dissolving microneedle arrays, and the latter are soluble microneedle arrays. A disadvantage of microneedle preparations, whether soluble or non-soluble, is that the amount of drug that can be held in the preparation is significantly smaller than that of matrix-type transdermal preparations. Patches that combine non-dissolving microneedle arrays and matrix-type transdermal preparations are also known (Patent Documents 7 and 8).

[0004] JP 2014-079557 A JP 2017-137311 A JP 2018-108375 A JP 2010-082401 A JP 2019-034151 A JP 2019-084352 A JP 2007-001938 A JP 2015-151380 A

[0005] The present invention has been made to broaden the scope of application of matrix-type transdermal absorption preparations consisting of a base and a drug, and aims to significantly improve the transdermal drug skin permeability from matrix-type transdermal absorption preparations by utilizing skin pores created by puncturing with microneedles.

[0006] The inventors discovered that applying a drug-containing base to the bottom surface of a non-dissolving microneedle array to form a transdermal absorption formulation significantly improves drug transdermal absorption, leading to the completion of the present invention. The concept of the present invention is shown in Figure 1. Figure 1B shows a microneedle formulation in which a drug-containing layer is applied to the needle tips of a non-dissolving microneedle array. Figure 1A shows a microneedle transdermal formulation (the present invention) in which a drug-containing layer is applied to the bottom surface of a non-dissolving microneedle array substrate. In Figure 1A, a thin drug-containing layer is also present at the needle tips and around the needles. A characteristic of the present invention is that the drug content of the formulation is primarily contained in the bottom surface of the substrate. While the needle tips and surrounding areas may contain drug, the amount of drug is less than the amount of drug in the bottom drug-containing layer at the bottom surface of the substrate. The needle tips have the puncture properties of a microneedle and are sharpened to penetrate the skin. This is a transdermal absorption formulation with a completely different concept from known coated microneedle formulations (e.g., Figure 1B). Also, Figure 1C shows a dissolving microneedle, in which a drug-containing base is formed into a microneedle array. This method is known and is unrelated to the present invention. Figure 1D shows a non-dissolving microneedle array with a high amount of drug-containing base applied, but even when this formulation is applied transdermally with an applicator, the microneedles do not penetrate the skin, so this is a completely different concept from the product of the present invention and is unrelated to the present invention.

[0007] The present invention is as follows: [1] A microneedle transdermal formulation, comprising a microneedle array consisting of a substrate and microneedles standing tall on the substrate, with a bottom drug-containing layer on the substrate when the tips of the microneedles are facing upward, the bottom drug-containing layer having depressions between the microneedles. [2] The microneedle transdermal formulation according to [1], wherein the minimum thickness of the bottom drug-containing layer at the depressions is 10 μm or more. [3] The microneedle transdermal formulation according to [1] or [2], wherein the minimum distance from the upper surface of the bottom drug-containing layer to the tips of the microneedles in the length direction is 50 μm or more. [4] The microneedle transdermal formulation according to any of [1] to [3], wherein the bottom drug-containing layer is a mixture of a drug and a base, and the main component of the base is a water-soluble component, an alcohol-soluble component, an acetone-soluble component, or an ethyl acetate-soluble component. [5] The microneedle transdermal formulation according to [4], wherein the base has adhesive properties. [6] The microneedle transdermal formulation according to [4] or [5], wherein the base contains a water-soluble polymer substance selected from the group consisting of sodium carboxymethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid and its salts, and chondroitin sulfate and its salts. [7] The microneedle transdermal formulation according to any of [4] to [6], wherein the drug is selected from the group consisting of antipyretic analgesic anti-inflammatory agents, steroidal anti-inflammatory agents, vasodilators, antiarrhythmic agents, antihypertensive agents, local anesthetics, hormones, antihistamines, general anesthetics, hypnotics, antiepileptics, psychotropic agents, skeletal muscle relaxants, autonomic nervous system agents, antiparkinsonian agents, diuretics, vasoconstrictors, respiratory stimulants, narcotics, and cosmetic raw materials. [8] The microneedle transdermal preparation according to any one of [4] to [7], wherein the molecular weight of the drug is 1000 or less. [9] The length of the microneedles is 50 μm to 2000 μm, and the needle density of the microneedles is 3 needles / cm ２ or more, and the area of ​​the substrate is 0.5 cm ２ ~50cm ２

[10] The microneedle transdermal preparation according to any one of [1] to [9], wherein the microneedles are made of a water-insoluble material.

[11] The microneedle transdermal preparation according to any one of [1] to

[10] , wherein the microneedles are made of a bioinsoluble material selected from the group consisting of polyglycolic acid, polylactic acid, polylactic acid-glycolic acid copolymer, polypropylene, polyethylene terephthalate, and cycloolefin polymer.

[0008] The present invention relates to a microneedle preparation in which a drug is loaded onto the bottom surface of a microneedle array substrate, specifically, the microneedles protrude from the base layer of a patch-type transdermal absorption preparation (for example, a matrix-type transdermal absorption preparation) toward the upper part (the side that is attached to the skin). Compared to conventional microneedle preparations in which the drug is loaded onto the tip of the needle, by loading a majority of the drug onto the substrate at the base of the needle, a larger amount of drug can be transdermally absorbed than with conventional microneedle preparations.

[0009] FIG. 1(A) is a schematic diagram showing an example of a microneedle transdermal formulation of the present invention, and FIG. 1(B) is a schematic diagram showing an example of a conventional application-type microneedle array formulation. FIG. 1(C) is a schematic diagram showing an example of a conventional dissolving-type microneedle array formulation. FIG. 1(D) shows a product with an extremely high drug loading, with the needle tips hidden, which is outside the concept of the present invention. FIG. 2 is a schematic diagram showing an appearance evaluation of the microneedle transdermal formulation of the present invention. FIG. 3 is a microscopic photograph of the microneedle transdermal formulation of the present invention. The formulation in the upper row of FIG. 3 has exposed microneedle tips, while the formulation in the lower row of FIG. 3 has microneedle tips that are not exposed but have not lost their sharp tips. The formulation in the lower row of FIG. 3 also belongs to the present invention. FIG. 4 is a graph showing the results of the first skin permeation test of the example products and the comparative example products. FIG. 5 is a graph showing the results of the second skin permeation test of the example products and the comparative example products.

[0010] The microneedle transdermal formulation of the present invention is characterized by a microneedle array comprising a substrate and microneedles standing on the substrate, with the tips of the microneedles facing upward, and a bottom drug-containing layer on the substrate. The microneedle transdermal formulation of the present invention is a microneedle transdermal absorption formulation. The microneedle transdermal formulation of the present invention comprises a microneedle array and a bottom drug-containing layer. The microneedle array comprises a substrate and microneedles standing on a first surface of the substrate. In this specification, the first surface of the substrate may be referred to as the bottom surface of the substrate. The bottom drug-containing layer is a drug-containing layer disposed on the first surface of the substrate (on the bottom surface of the substrate). The bottom drug-containing layer is in contact with both the first surface of the substrate (the bottom surface of the substrate) and the outer surfaces of the microneedles.

[0011] The bottom drug-containing layer has depressions between the microneedles. Therefore, the thickness of the bottom drug-containing layer is not constant. The thickness of the bottom drug-containing layer between the microneedles is smaller than the length of the microneedles. The bottom drug-containing layer between the microneedles forms depressions based on the height position of the microneedles.

[0012] The bottom drug-containing layer is a mixture of a drug and a base. The bottom drug-containing layer is a layer in which a drug is dissolved or dispersed in a base. The bottom drug-containing layer may also be a mixture of a drug, a base, and other components. The base serves to dissolve or disperse the drug and allow it to adhere to the microneedle array substrate. The base serves to fix most of the drug to the microneedle array substrate. A portion of the drug may be present at the tip of the needle and around the needle.

[0013] The base material may be a water-soluble or water-insoluble polymeric substance or a low-molecular-weight substance, or a mixture thereof. From the viewpoint of more effectively achieving the effects of the present invention, the main component of the base is preferably a water-soluble component, an alcohol-soluble component, an acetone-soluble component, or an ethyl acetate-soluble component, and more preferably a water-soluble polymeric substance. From the viewpoint of more effectively achieving the effects of the present invention, the base preferably contains a water-soluble polymeric substance selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid and its salts, and chondroitin sulfate and its salts. The base may have adhesive properties. Rubber-based adhesives, acrylic adhesives, silicone-based adhesives, etc. used in transdermal absorption preparations may be used as the base. Acrylic copolymers that are soluble in acetone and ethyl acetate are particularly preferred. If necessary, an absorption enhancer, stabilizer, oil, etc. may be added to the base to promote transdermal drug absorption, increase transdermal adhesion, and improve the drug's stability over time. When the base has adhesive properties, the microneedles themselves adhere to the skin, making formulation and use easy.

[0014] The base has a drug dissolved or dispersed therein. The drug is not particularly limited as long as it is a drug that has been conventionally used in transdermal absorption preparations, and examples thereof include those selected from the group consisting of antipyretic analgesic and anti-inflammatory agents, steroidal anti-inflammatory agents, vasodilators, antiarrhythmic agents, antihypertensive agents, local anesthetics, hormone agents, antihistamines, general anesthetics, hypnotic analgesics, antiepileptics, psychotropic agents, skeletal muscle relaxants, autonomic nervous agents, antiparkinsonian agents, diuretics, vasoconstrictors, respiratory stimulants, narcotics, and cosmetic raw materials.

[0015] Examples of the antipyretic, analgesic, and anti-inflammatory agents include ibuprofen, flurpiprofen, and ketoprofen, and examples of the steroid anti-inflammatory agents include hydrocortisone, triamcinolone, and prednisolone. Examples of the vasodilators include diltiazem hydrochloride and isosorbide dinitrate. Examples of the antiarrhythmic agents include procainamide hydrochloride and mexiletine hydrochloride.

[0016] Examples of the antihypertensive agents include clonidine hydrochloride, bunitrolol hydrochloride, captopril, etc. Examples of the local anesthetic agents include tetracaine hydrochloride, propitocaine hydrochloride, etc. Examples of the hormone agents include propylthiouracil, estradiol, estriol, progesterone, etc. Examples of the antihistamine agents include diphenhydramine hydrochloride, chlorpheniramine maleate, etc.

[0017] Examples of the general anesthetic include pentobarbital sodium and the like. Examples of the hypnotic analgesics include amobarbital, phenobarbital and the like. Examples of the antiepileptics include phenytoin sodium and the like. Examples of the psychoneurotic agents include etizolam, chlorpromazine hydrochloride, imipramine hydrochloride, chlordiazepoxide, diazepam and the like. Examples of the skeletal muscle relaxants include suxamethonium hydrochloride, eperisone hydrochloride and the like.

[0018] Examples of the autonomic nervous system agents include neostigmine bromide and bethanechol chloride. Examples of the anti-Parkinson's agents include amantadine hydrochloride. Examples of the diuretics include hydroflumethiazide, isosorbide, furosemide, etc. Examples of the vasoconstrictors include phenylephrine hydrochloride. Examples of the respiratory stimulants include lobeline hydrochloride, dimorpholamine, naloxone hydrochloride, etc. Examples of the narcotics include morphine hydrochloride, cocaine hydrochloride, pethidine hydrochloride, etc.

[0019] Examples of the cosmetic raw materials include whitening ingredients such as ascorbyl palmitate, kojic acid, rucinol, tranexamic acid, oil-soluble licorice extract, and vitamin A derivatives; anti-wrinkle ingredients such as retinol, retinoic acid, retinol acetate, and retinol palmitate; blood circulation promoting ingredients such as tocopherol acetate, capsaicin, and vanillylamide norilate; diet ingredients such as raspberry ketone, evening primrose extract, and seaweed extract; antibacterial ingredients such as isopropyl methylphenol, photosensitizers, and zinc oxide; and vitamins such as vitamin D2, vitamin D3, and vitamin K.

[0020] The drugs are all low molecular weight compounds with a molecular weight of 1000 or less, or 600 or less, but may also be high molecular weight medicinal ingredients. Preferred high molecular weight medicinal ingredients include, for example, physiologically active peptides and their derivatives, nucleic acids, oligonucleotides, various antigenic proteins, bacterial and viral fragments, etc.

[0021] Examples of the physiologically active peptides and derivatives thereof include calcitonin, adrenocorticotropic hormone, parathyroid hormone (PTH), hPTH (1→34), insulin, secretin, oxytocin, angiotensin, β-endorphin, glucagon, vasopressin, somatostatin, gastrin, luteinizing hormone-releasing hormone, enkephalin, neurotensin, atrial natriuretic peptide, growth hormone, growth hormone-releasing hormone, bradykinin, substance P, dynorphin, thyroid-stimulating hormone, prolactin, interferon, interleukin, G-CSF, glutathione peroxidase, superoxide dismutase, desmopressin, somatomedin, endothelin, and salts thereof. Examples of antigenic proteins include HBs surface antigen and HBe antigen.

[0022] The drug is dissolved or dispersed in a suitable solvent, mixed homogeneously with a base component also dissolved in a solvent, and then coated on the substrate of the microneedle array and dried to form a bottom drug-containing layer. In this case, the coated surface of the substrate is the upper surface of the substrate when the side with the microneedles standing up is facing up.

[0023] The thickness of the bottom drug-containing layer is usually up to the height of the needle (needle length of the microneedle). The maximum thickness of the bottom drug-containing layer is usually equal to or less than the length of the microneedle. The upper part of Figure 3 shows a micrograph of a microneedle transdermal formulation in which the maximum thickness of the bottom drug-containing layer is less than the length of the microneedle. The lower part of Figure 3 shows a micrograph of a microneedle transdermal formulation in which the maximum thickness of the bottom drug-containing layer is approximately the same as the length of the microneedle. In the lower part of Figure 3, the maximum thickness of the bottom drug-containing layer is approximately the same as the length of the microneedle, but the bottom drug-containing layer has a depression with its apex at the tip of the microneedle. Having such an apex improves the skin permeability of the drug. If the thickness of the bottom drug-containing layer exceeds the length of the microneedle and no depression is formed in the bottom drug-containing layer, it is excluded from the present invention (see Figure 1D).

[0024] From the viewpoints of drug retention and release / penetration into the skin, the minimum thickness of the bottom drug-containing layer in the depression portion is preferably 10 μm or more, more preferably 50 μm or more, even more preferably 100 μm or more, and preferably 1,000 μm or less. The minimum thickness of the bottom drug-containing layer in the depression portion is usually the distance from the first surface of the substrate to the maximum depth position of the depression in the bottom drug-containing layer.

[0025] When the thickness of the bottom drug-containing layer is within the above range, the relationship between the thickness and the needle length of the microneedle preferably satisfies the following relationship: That is, in the length direction of the microneedle, the maximum distance from the upper surface of the bottom drug-containing layer in the recessed portion to the height position of the tip of the microneedle is preferably 20 μm or more, more preferably 50 μm or more, even more preferably 100 μm or more, particularly preferably 200 μm or more, preferably 2,500 μm or less, more preferably 2,000 μm or less, even more preferably 1,000 μm or less, and particularly preferably 500 μm or less. In this case, even greater amounts of drug can be absorbed transdermally. The maximum distance is the length represented by c in Figure 2. In the examples described below, the maximum distance is referred to as the "valley depth."

[0026] In the length direction of the microneedle, the minimum distance from the upper surface of the bottom drug-containing layer to the tip of the microneedle is preferably 20 μm or more, more preferably 50 μm or more, even more preferably 100 μm or more, particularly preferably 200 μm or more, preferably 2,500 μm or less, more preferably 2,000 μm or less, even more preferably 1,000 μm or less, even more preferably 500 μm or less, and particularly preferably 250 μm or less. In this case, a larger amount of drug can be absorbed transdermally. The minimum distance is the length represented by d in Figure 2, and is usually the exposed length of the microneedle from the bottom drug-containing layer. In the examples described below, the minimum distance is referred to as the "tip exposed length."

[0027] Another component of the present invention, the microneedle array, is a bioinsoluble microneedle array. The microneedle array comprises a substrate and microneedles. The substrate and the microneedles may be made of water-insoluble materials such as metals, silica, titanium, and synthetic polymers. From the standpoints of ease of manufacture and biosafety, the substrate is preferably made of a bioinsoluble material selected from the group consisting of polylactic acid, polylactic acid-glycolic acid copolymer, polypropylene, polyethylene terephthalate, and cycloolefin polymers, but is not limited thereto. From the standpoints of ease of manufacture and biosafety, the microneedles are preferably made of a bioinsoluble material selected from the group consisting of polylactic acid, polylactic acid-glycolic acid copolymer, polypropylene, polyethylene terephthalate, and cycloolefin polymers, but is not limited thereto.

[0028] The tip of the microneedle is usually sharp and has the ability to pierce the skin.

[0029] The length of the microneedle is 20 μm to 3000 μm, preferably 50 μm to 2000 μm, and more preferably 100 μm to 1500 μm. If the length is shorter than 20 μm, the needle tip is less likely to be exposed from the upper surface of the bottom drug-containing layer. If the length is longer than 3000 μm, the exposed portion of the needle is also long, which may cause pain or bleeding. The length of the microneedle is usually the distance from the base of the microneedle (the first surface of the substrate) to the tip of the microneedle.

[0030] The needle density of the microneedles is 3 needles / cm ２ ~2,000 pieces / cm ２ The needle density is preferably 3 needles / cm ２ If the needle density is smaller than 2,000 needles / cm, there may be fewer holes punctured in the skin by the microneedles, resulting in a small amount of drug permeating from the bottom drug-containing layer. ２ If it is larger, the ability of the microneedle to pierce the skin may decrease.

[0031] The area of ​​the substrate is 0.5 cm to ensure the area of ​​the bottom drug-containing layer and to maintain the adhesion of the formulation to the skin. ２ ~50cm ２ The area of ​​the substrate is typically the area of ​​the first surface of the substrate.

[0032] To fabricate a microneedle array, a titanium plate is laser-cut into a V-shape, then bent 90 degrees and pulled up to form a microneedle. The number of microneedles is increased to create an array. Injection molding is convenient for bioinsoluble polyglycolic acid and polylactic acid, while press molding is convenient for polypropylene, polyethylene terephthalate, and cycloolefin polymer. To actually fabricate a microneedle transdermal formulation containing a bottom drug-containing layer, a drug-containing base is dissolved or suspended in an appropriate solvent. A predetermined amount of this solution (enough to form the desired drug layer but not to reach the tip of the upper needle) is dripped onto the top of the microneedle array, and the solvent is allowed to dry to form the bottom drug-containing layer (see Figure 1(A)). In Figure 1(A), the drug layer covers the needles, but the upper needles are extremely thin, so it does not affect the needle's puncture ability. Similar fabrication methods are possible using either water or an organic solvent.

[0033] The microneedle transdermal formulation of the present invention is preferably, but not necessarily, applied to the skin using an applicator. The microneedle tip is pressed against the skin so that it penetrates into the epidermal layer. The drug is absorbed transdermally by diffusion from the stratum corneum, where the bottom drug-containing layer is in contact. The drug is then absorbed transdermally through the pores in the skin created by the microneedles.

[0034] The present invention will be described in more detail below with reference to the following examples. These examples are merely examples for specifically explaining the present invention, and the scope of the present invention is not limited to these examples.

[0035] Manufacturing Example 1: Method for manufacturing non-dissolving microneedle transdermal formulation 1) Polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC, low molecular weight: HPC-L, medium molecular weight: HPC-M), and sodium hyaluronate (HA) were each dissolved in water to prepare an aqueous solution. 2) The aqueous solutions were mixed so that the solid mass ratio of PVP and HPC-L was 10:3 to obtain a base aqueous solution (1). 3) The aqueous solutions were mixed so that the solid mass ratio of HPC-L, HPC-M, and HA was 2:2:1 to obtain a base aqueous solution (2). 4) Etizolam was used as the drug and dissolved in acetic acid to a concentration of 20% by mass. 5) The solid concentration of etizolam was adjusted, and the etizolam acetic acid solution was mixed with the base aqueous solution (1) or the base aqueous solution (2) to obtain a coating solution. 6) A polyglycolic acid (PGA) microneedle array (substrate diameter: 1 cm, needle length: 0.9 mm, number of needles: 193) was formed by injection molding. With the tips of the microneedles of the array facing upward, an appropriate amount of coating solution was placed on the center of the top surface of the substrate. 7) After the coating solution had spread over the entire needle portion of the substrate, it was placed in a desiccator and the water content of the coating solution was evaporated to dryness.

[0036] Comparative Production Example 1: Production method of application-type microneedle preparation 1) Using the base aqueous solution (2) in Production Examples 1 and 5) as the application liquid, the polyglycolic acid microneedle array in Production Examples 1 and 6) was immersed 0.5 mm into the application liquid with the needle tip facing downward, then pulled out and the solvent was dried. 2) The above operation 1) was repeated three times.

[0037] Comparative Preparation Example 2: Method for preparing a dissolving microneedle preparation 1) HPC-L, HPC-M, and HA were mixed in aqueous solutions so that the solid content mass ratio was 2:2:1 to prepare a base aqueous solution. 2) Etizolam was dissolved in acetic acid to a concentration of 20% by mass. 3) The solid content concentration of etizolam was adjusted, and the etizolam acetic acid solution and the base aqueous solution were mixed to prepare a filling solution. 4) The filling solution was cast into a mold, dried, and removed from the mold. The prepared microneedle array had a substrate diameter of 1 cm, needle length of 0.3 mm, and needle number of 500.

[0038] Comparative Preparation Example 3: Method for producing an etizolam adhesive preparation (patch) 1) Styrene-isoprene-styrene copolymer, polybutene, rosin, liquid paraffin, and dibutylhydroxytoluene were dissolved in toluene to prepare a base solution. 2) Etizolam and a solubilizer were added to the uniformly dissolved base solution and mixed until uniform, resulting in a plaster base. 3) The plaster base was coated onto a liner to a uniform thickness, and the solvent was dried at 80°C for 10 minutes. 4) The solvent-dried plaster base was laminated with a support. 5) 4) was punched into a circle with a diameter of 1.3 cm to prepare a patch preparation.

[0039] Test Example 1: Appearance Evaluation of Non-Dissolving Microneedle Transdermal Formulation (Non-Dissolving Microneedles) Non-dissolving microneedles were observed using a stereomicroscope (Leica M205C), and the length from the needle tip to the deepest part between the needles (c: valley depth) and the length of the exposed needle (d: tip exposed length) were measured (Figure 2). The measurement results are summarized in Tables 2 to 4. Figure 3 shows a micrograph of the needle portion of a non-dissolving microneedle. The top row of Figure 3 shows the product of Example 1, in which the microneedle tip is exposed from the bottom drug-containing layer, while the bottom row of Figure 3 shows the product in which the microneedle tip is not exposed from the bottom drug-containing layer but has a valley depth (c). Both satisfy the concept of the present invention.

[0040] Test Example 2: Skin permeation test method The non-dissolving microneedle preparations and dissolving microneedle preparations prepared in the above manufacturing examples were applied to the stratum corneum side of excised rat or human skin using dedicated applicators. The adhesive preparations prepared in the above manufacturing examples were directly applied to the stratum corneum side of excised human skin. Then, a Franz diffusion cell (receptor solution 5.7 ml, opening area = 2.27 cm) for transdermal permeation experiments was used. ２ The receptor side was filled with phosphate buffer (pH 7.4) as a receptor solution, and a skin permeation test was conducted at 32°C for 24 hours. After 3, 6, 12, 18, and 24 hours, 500 μL of the receptor solution was sampled, and the same amount of receptor solution was added. The amount of drug permeated into the receptor solution was measured by HPLC.

[0041] Results Three skin permeation tests were conducted. The objectives of the first to third skin permeation tests are shown in Table 1.

[0042]

[0043] Results of the first skin permeation test The test results are shown in Table 2 and Figure 4. This test was carried out using excised rat skin.

[0044]

[0045] As shown in Table 2 and Figure 4, the 24-hour permeation amount of Example 1 (tip-exposed non-dissolving etizolam microneedles) was 3.6 times that of Comparative Example 3 (etizolam adhesive preparation) and 6.5 times that of Example 2 (tip-unexposed non-dissolving etizolam microneedles). The effect of the tip-exposed non-dissolving microneedles in promoting transdermal drug absorption was confirmed. Furthermore, the permeation amount of the dissolving microneedles was low because the needles dissolved and blocked the puncture hole even after puncture.

[0046] Results of the Second Skin Permeation Test The test results are shown in Table 3 and Figure 5. This test was carried out using excised human skin.

[0047]

[0048] 5, the non-dissolving microneedles had the highest 24-hour permeation amount in the order of Example 3 > Example 4 > Example 5. The particularly low permeation amount in Example 5 is thought to be due to the valley depth and exposed tip length being significantly smaller than those in Examples 3 and 4. The results indicated that the exposed tip length is preferably 50 μm or more.

[0049] Results of the Third Skin Permeation Test The test results are shown in Table 4. In Example 5, an absorption enhancer, natural moisturizing factor (NMF), was added in an amount of 5% by mass to the composition of Example 4. This test was carried out using excised human skin.

[0050]

[0051] The effect of increasing the drug concentration in the microneedle formulation on enhancing transdermal drug absorption and the effect of adding an absorption enhancer were confirmed.

[0052] 1 Bottom drug-containing layer 2 Bottom portion 3 Drug-containing layer 4 Microneedle tip portion 5 Drug-applied portion 6 Dissolving microneedle array 7 Microneedle tip portion 8 Bottom portion 9 Drug-containing base applied portion

Claims

1. A microneedle transdermal formulation comprising a microneedle array consisting of a substrate and microneedles standing tall on the substrate, wherein the substrate has a bottom drug-containing layer when the tips of the microneedles are facing upward, and the bottom drug-containing layer has depressions between the microneedles.

2. The microneedle transdermal formulation according to claim 1, wherein the minimum thickness of the bottom drug-containing layer in the recessed portion is 10 μm or more.

3. The microneedle transdermal formulation according to claim 1 or 2, wherein the minimum distance from the upper surface of the bottom drug-containing layer to the tip of the microneedle in the length direction of the microneedle is 50 μm or more.

4. The microneedle transdermal formulation according to any one of claims 1 to 3, wherein the bottom drug-containing layer is a mixture of a drug and a base, and the main component of the base is a water-soluble component, an alcohol-soluble component, an acetone-soluble component, or an ethyl acetate-soluble component.

5. The microneedle transdermal preparation according to claim 4, wherein the base has adhesive properties.

6. The microneedle transdermal formulation according to claim 4 or 5, wherein the base contains a water-soluble polymeric substance selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid and its salts, and chondroitin sulfate and its salts.

7. The microneedle transdermal formulation according to any one of claims 4 to 6, wherein the drug is selected from the group consisting of antipyretic analgesic and anti-inflammatory agents, steroidal anti-inflammatory agents, vasodilators, antiarrhythmic agents, antihypertensive agents, local anesthetics, hormone agents, antihistamines, general anesthetics, hypnotic analgesics, antiepileptic drugs, psychotropic agents, skeletal muscle relaxants, autonomic nervous system agents, antiparkinsonian drugs, diuretics, vasoconstrictors, respiratory stimulants, narcotics, and cosmetic raw materials.

8. The microneedle transdermal preparation according to any one of claims 4 to 7, wherein the molecular weight of the drug is 1,000 or less.

9. The length of the microneedles is 50 μm to 2000 μm, and the needle density of the microneedles is 3 needles / cm ２ or more, and the area of ​​the substrate is 0.5 cm ２ ~50cm ２ The microneedle transdermal preparation according to any one of claims 1 to 8, wherein 10. The microneedle transdermal preparation according to any one of claims 1 to 9, wherein the microneedles are made of a water-insoluble material.

11. The microneedle transdermal preparation according to any one of claims 1 to 10, wherein the microneedles are made of a non-biologically soluble material selected from the group consisting of polyglycolic acid, polylactic acid, polylactic acid-glycolic acid copolymer, polypropylene, polyethylene terephthalate, and cycloolefin polymer.

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