Microneedle array with uneven needle density

Abstract

To solve a problem that a fine needle located at the center part of a microneedle array is hardly inserted into skin.SOLUTION: In a microneedle array including a substrate and a plurality of microneedles arranged vertically and horizontally on one surface of the substrate, needle intervals and needle densities of the microneedles are different between a peripheral part and a central part of the substrate in the microneedle array. The needle densities of the microneedles are preferable to be sparer at the central part than in the peripheral part of the substrate, and the needle intervals of the microneedles are preferable to wider at the central part than in the peripheral part of the substrate.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a technology for a microneedle array having a non-uniform needle density. [Background technology]

[0002] Oral and transdermal administration are commonly used methods for administering drugs into the human body. Injection is a typical transdermal administration method. However, injection requires the intervention of specialists such as doctors and nurses, and is painful, making it an unwelcome method for many people. In response to this, a painless transdermal administration method using microneedle arrays has recently attracted attention (Non-Patent Document 1).

[0003] During transdermal administration of drugs, the stratum corneum acts as a barrier to drug permeation, and simply applying a drug to the skin surface does not necessarily provide sufficient permeability. In contrast, by perforating the stratum corneum using tiny needles, i.e., microneedles, the drug permeation efficiency can be significantly improved compared to application methods. A microneedle array is a product in which many of these microneedles are integrated on a substrate. In addition, a product that is easy to use by adding an adhesive sheet for attaching the microneedle array to the skin and a release sheet for protecting the adhesive surface to the microneedle array is called a microneedle patch.

[0004] Metals and silicon were initially used as materials for microneedles, but later, various polymeric materials have attracted attention due to their workability. In particular, if microneedles are made from materials that are metabolized in the body, such as carbohydrates, there is no risk of an accident even if the needle breaks and remains in the skin.

[0005] In the microneedle patch known in patent documents and academic documents, the microneedle array substrate is flat, on which fine needles of uniform length stand vertically at a uniform density. The microneedle patches that the present inventors have produced and filed patent applications for up to now also fall into this category (Patent Documents 1 and 2). The microneedles disclosed in Patent Documents 1 and 2 are (circular) cone-shaped, (circular) frustum-shaped, or cone-shaped, and it is described that the pitch between the microneedles is preferably 0.4 to 1.0 mm. In addition, various improvements have been made to the microneedle preparations and their manufacturing methods for which patent applications have been filed in recent years, for the purpose of ensuring that the microneedles puncture the skin (Patent Documents 3 and 4) and for the purpose of uniformly carrying the drug on the microneedles (Patent Documents 5 and 6).

[0006] Patent Document 3 describes that a needle-shaped device (microneedle array) has a protrusion that is pyramidal in shape, and is arranged so that the blades formed by the two side surfaces of the pyramidal shape are tangent to a circle whose center is a predetermined position on the substrate surface. In Patent Document 4, a dissolving microneedle preparation containing hyaluronic acid or the like is described in which the distance between adjacent needles is substantially equal, about 1 to 10 needles are arranged per mm, and the density of the needles is about 1 cm 2 It is described that 100 to 10,000 pieces per unit is preferable. The microneedle array manufactured by the method for manufacturing a microneedle array of Patent Document 5 has a needle density of 1 to 200 needles / cm from the viewpoint of being able to administer a predetermined drug without causing pain. 2 is described as being preferred. The microneedle device manufactured by the method of manufacturing a microneedle device of Patent Document 6 has rows of needles spaced apart to give a density of about 1 to 10 needles per mm, spaced apart by equal distances relative to the spacing of the needles within the rows, and having a density of about 1 to 10 needles per mm. 2 It is described that the needle density is 100 to 10,000 per needle.

[0007] Thus, the microneedles in Patent Documents 1, 2, and 4 to 6 are provided at equal intervals on the substrate, and the needle density per unit area is also constant. On the other hand, Patent Document 3 discloses that the substrate of the needle-shaped device (microneedle array) is flat, the blades of the needle-shaped bodies are arranged in the tangential direction of a circle, and the arrangement patterns are radial from the center of the circle to the periphery (FIG. 3), spiral lines spreading from the center of the circle to the periphery (FIG. 4), lines eccentric from the central axis (FIG. 5(a)), and multiple lines asymmetrical (FIG. 5(b)). However, the blades adjacent in the tangential direction are at equal intervals, and are arranged almost evenly and in a balanced manner over the entire substrate of the needle-shaped bodies.

[0008] Regarding the needle density and skin permeability of the microneedles, the needle density was 900 needles / cm 2 The microneedle array has 400 needles / cm 2 However, it has been described that the skin permeability of such a microneedle array is poorer than that of a microneedle array having needles of the same type (Non-Patent Document 2). [Prior art documents] [Patent documents]

[0009] [Patent Document 1] JP 2009-273872 A [Patent Document 2] JP 2010-029634 A [Patent Document 3] JP 2017-074196 A [Patent Document 4] JP 2016-175853 A [Patent Document 5] JP 2015-109963 A [Patent Document 6] JP 2017-047075 A [Non-patent literature]

[0010] [Non-Patent Document 1] Kwon, Young-sook, and Kamiyama, Fumio, "The road to commercializing microneedles," Pharmacology, Japan Society of Pharmaceutical Sciences, September 2009, Vol. 69, No. 4, pp. 272-276. [Non-Patent Document 2] G.Ya, et al., Evaluation needle length and density of microneedle arrays in the pretreatment of skin for transdermal drug delivery, International Journal of Pharmaceutics 391 (2010) 7-12 Summary of the Invention [Problem to be solved by the invention]

[0011] When administering a conventional microneedle patch to animal skin for testing, an applicator strikes the microneedle patch from behind at high speed, imparting the energy of the impact to the microneedle patch and realizing the insertion of fine needles into the skin. The surface of the applicator known to date that strikes the microneedle patch is flat. In the process of administering to animals or humans using such a system, the present inventors have noticed the following phenomenon. 1. If the needle density is too high, it becomes difficult to insert the needle into animal and human skin (phenomenon 1). According to the findings of the present inventors, the needle density is 1500 / cm 2 If the diameter is larger, it tends to be difficult for the needle to penetrate the skin. Of course, this number is only a guideline, as it depends on many factors such as the hardness of the skin, the thinness and strength of the needle, and the impact strength of the applicator. In a microneedle system in which it is important to impregnate (in the case of dissolving type microneedles) or coat (in the case of coating type microneedles) a larger amount of valuable material into the microneedles to increase the drug content per unit area, the needle density that allows stable insertion is an extremely important structural factor of the microneedle array. Prior to the present inventors, Non-Patent Document 2 reported that2 The microneedle array has 400 needles / cm 2 However, it has been described that the skin permeability of this type of microneedle array is poorer than that of a microneedle array having needles of type 1. 2. A detailed analysis of the above phenomenon 1 reveals that the central part of the microneedle array is more difficult to insert into the skin than the peripheral parts (phenomenon 2). We investigated the literature regarding phenomenon 2, but could not find any literature pointing out such a phenomenon. An object of the present invention is to solve the problem that it is difficult to insert fine needles located in the center of a microneedle array into the skin. [Means for solving the problem]

[0012] In order to solve the above problem, the present inventors carried out a model experiment on phenomenon 2 (difficulty in inserting fine needles into the skin at the center) using parafilm instead of skin. Eight sheets of parafilm (thickness 140 μm) were layered, and microneedle patches (area = 0.8 cm2) with fine needles of different needle densities were placed on top of each other. 2 ) was placed on the skin and impacted with an applicator (International Publication No. 2018 / 124290, or Japanese Patent Application Publication No. 2017-185162), and the insertion behavior of the microneedle into the parafilm was examined in detail. Analysis of the insertion behavior of a microneedle using parafilm as a skin substitute has already been known in the literature (Int. J. Pharmaceutics 480 (2015) 152-157), and there is a reliable correlation with the skin insertion behavior. As a result, it was found that by using a microneedle array in which fine needles are arranged so that the needle density is smaller in the center than in the peripheral area, the total number of needles can be increased compared to a microneedle array in which the needle density is the same over the entire surface, and all needles can be stably inserted into the skin, leading to the completion of the present invention. The present invention is as follows. [1] A microneedle array comprising a substrate and a plurality of microneedles arranged vertically and horizontally on one surface of the substrate, characterized in that the needle spacing and needle density of the microneedles are different between the peripheral portion and the central portion of the substrate. [2] The microneedle array described in [1], wherein the needle density of the microneedles is sparse in the central part of the substrate compared to the peripheral part. [3] The microneedle array according to [1] or [2], wherein the needle spacing of the microneedles is wider in the central part of the substrate than in the peripheral part. [4] The needle density of the microneedles is 600 to 1500 needles / cm in the peripheral portion of the substrate. 2 and in the central portion of the substrate, the density is 100 to 800 lines / cm 2 The microneedle array described in [2], wherein the needle density at the center of the substrate is smaller than the needle density at the periphery of the substrate. [5] The needle density of the microneedles is 400 to 2000 needles / cm in the peripheral portion of the substrate. 2 and in the central portion of the substrate, the density is 0 to 99 lines / cm 2 The microneedle array according to [2], [6] The needle density of the microneedles is 400 to 2000 needles / cm in the peripheral portion of the substrate. 2 the microneedle arrangement in the peripheral portion is at least two rows, and the microneedle arrangement in the central portion of the substrate is 0 needles / cm 2 The microneedle array according to [2], [7] The microneedle array described in any of [1] to [6], wherein the surface of the substrate is a circle or an ellipse, the central part of the substrate is within a circumference that is 9 / 10 or less of the radius from the center of the circle or the ellipse, and the peripheral part of the substrate is outside the central part. [8] The microneedle array described in any of [1] to [6], wherein the surface of the substrate is rectangular, the central part of the substrate is inside the four sides connecting four points that are 9 / 10 or less of the diagonal from the center of the rectangle, and the peripheral part of the substrate is outside the central part. [9] A microneedle patch further comprising an adhesive sheet in addition to the microneedle array described in any one of [1] to [8].

[10] The microneedle patch described in [9], further comprising a release sheet attached to the adhesive surface of the adhesive sheet. Effect of the Invention

[0013] By setting a difference in needle density for the microneedles, the microneedle array of the present invention can reliably puncture the skin with a greater number of needles than a microneedle array with a uniform needle density, thereby enabling a greater drug content per unit area and reliable transdermal delivery of the drug. [Brief description of the drawings]

[0014] [Figure 1] Schematic diagram of a microneedle with a step [Diagram 2] FIG. 1 shows an embodiment of a microneedle patch having a release sheet. [Diagram 3] Photograph of the microneedle array produced in Example 1 [Figure 4] Enlarged photograph of the microneedle array produced in Example 1 [Diagram 5] Micrograph showing the shape of the needles of the microneedle array produced in Example 1 [Figure 6] Micrograph of the parafilm after the needles of the microneedle array produced in Example 1 were pierced. [Figure 7A] Enlarged photograph of the microneedle array produced in Comparative Example 3 [Figure 7B] Enlarged photograph of the microneedle array produced in Example 2 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Microneedle array substrate The material, shape and size of the substrate of the microneedle array are not particularly limited, and any conventionally used material can be used. Basically, the base material of the substrate and the microneedle is the same, but they may be different base materials. Examples of the base include silicon, silicon dioxide, ceramics, glass, metals (stainless steel, titanium, nickel, molybdenum, chromium, cobalt, etc.), and synthetic or natural resin materials. Examples of the synthetic or natural resin materials include water-soluble or biodegradable polymers such as polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid) copolymers, capronolactone, polyurethane, polyvinylpyrrolidone, hydroxypropyl cellulose, and polyvinyl alcohol, and non-biodegradable polymers such as nylon, polycarbonate, polymethacrylic acid, ethylene vinyl acetate, polytetrafluoroethylene, polyoxymethylene, polyethylene terephthalate, and COP (cyclic olefin polymer). Polysaccharides such as hyaluronic acid, sodium hyaluronate, hyaluronic acid derivatives, pullulan, dextran, dextrin, and chondroitin sulfate may also be used. The base may be one or more of these in combination.

[0016] The shape of the substrate can be any shape. For example, it may be a circle, an ellipse, a triangle, a rectangle, a polygon, etc., which is further modified according to the application site (skin). The size of the substrate, expressed typically by the diameter (major axis) or the length of one side (long side), is usually 0.2 to 10 cm, and preferably 0.5 to 5 cm.

[0017] The area of ​​the substrate is usually 0.05 to 100 cm 2 From the viewpoint of ease of handling, the range is 0.1 to 10 cm. 2 Approximately 0.5 to 5 cm is preferable. 2 degree is more preferable.

[0018] The thickness of the substrate varies depending on the material of the base, but is usually 50 to 2000 μm, and preferably 100 to 1000 μm.

[0019] Microneedle shape The microneedles constituting the microneedle array have a needle length of 100 μm or more and 2,000 μm or less, preferably 200 to 1,000 μm, in order to ensure transdermal absorption of a drug. The size of the tip of the needle, expressed as a diameter, is 80 μm or less, preferably 30 μm or less, in order to facilitate insertion into the skin and reduce drug residue on the skin. Examples of individual microneedles include a cylindrical or conical shape with a circular base, an elliptical cylindrical or elliptical cone shape with an elliptical base, a triangular prism or triangular pyramid with a triangular base, a quadrangular prism or quadrangular pyramid with a square base, or a polygonal prism or polygonal pyramid with a polygonal base. In the case of an ellipse, the size of the base is expressed as the major axis as the diameter, and the minor axis is shorter than the major axis as long as an ellipse can be formed. In the case of a triangle or polygon, one side may be expressed as a representative, or a diagonal may be expressed as a representative. When the microneedle is conical, the diameter of the base is about 100 to 400 μm, preferably about 150 to 300 μm.

[0020] The microneedle of the present invention may have a step. Here, the step refers to a step in which the cross-sectional area of ​​the microneedle is discontinuously reduced from a certain point of the microneedle toward the tip, and the cross section has a step-like shape as shown in FIG. 1. The shape of the microneedle having a step will be described with reference to FIG. 1. In the stepped microneedle, the length of the tip 1 is preferably 50 to 500 μm, and the remainder is the bottom 3. The size of the edge 2 of the step between the tip and the bottom is preferably greater than 10 μm and smaller than 100 μm. It is more preferably 14 to 50 μm. 4 denotes a substrate of the microneedle array.

[0021] The edge 2 of the step is a surface perpendicular to the axis of the microneedle (a surface parallel to the substrate) within the range of machining accuracy. The size of the edge 2 of the step refers to the difference in radius between the tip and the bottom of the step. The tip and the bottom differ depending on the shape of the microneedle.

[0022] In a preferred embodiment, the shape of the microneedle of the present invention is conical. The total length (needle length) of the microneedle is preferably about 70 to 1000 μm. In a stepped microneedle, the length of the tip 1 is preferably 50 to 500 μm, and the remainder is the bottom (two-step needle), or in a three-step needle, the remainder is the middle and bottom. The size of the edge 2 of the step between the tip and middle, and between the middle and bottom is preferably greater than 10 μm and smaller than 100 μm. It is more preferably 14 to 50 μm.

[0023] Placement of microneedles on the substrate The microneedle array of the present invention comprises a plurality of microneedles arranged lengthwise and widthwise on one surface of a substrate, with the needle spacing and needle density of the microneedles differing between the periphery and the center of the substrate.

[0024] From the viewpoint of reliable skin puncture of the needles, the needle density of the microneedles is preferably sparser in the center of the substrate than in the peripheral area, and the needle spacing of the microneedles is preferably wider in the center of the substrate than in the peripheral area.

[0025] As a preferred example, the density of the microneedles is 600 to 1500 needles / cm at the periphery of the substrate. 2 At the center of the substrate, the density is 100 to 800 lines / cm 2 More preferably, the density is 700 to 1000 fibers / cm at the periphery of the substrate. 2 At the center of the substrate, the density is 300 to 800 lines / cm 2 Here, the needle density at the center of the substrate is selected to be smaller than the needle density at the periphery of the substrate. As another preferred example, the needle density in the center of the substrate is 100 needles / cm 2 Less than, specifically 0-99 strands / cm 2 In this case, the number of lines / cm may be 400 to 2000 in the peripheral portion of the substrate. 2 and more preferably 600 to 1500 fibers / cm 2 It is. The spacing between the microneedles can be appropriately set based on the ratio of the area of ​​the central portion to the area of ​​the peripheral portion of the substrate, as well as the density of the microneedles.

[0026] When the surface of the substrate is a circle or ellipse, based on the results of observing areas where it is difficult to insert a microneedle array into the skin, it is preferable that the central part of the substrate is within a circumference that is 9 / 10 or 2 / 3 or less of the radius from the center of the circle or ellipse, and that the peripheral part of the substrate is outside the central part. When the surface of the substrate is rectangular, the central part of the substrate is preferably within the four sides connecting four points that are 9 / 10 or 2 / 3 or less of the way along the diagonal from the center of the rectangle, and the peripheral part of the substrate is preferably outside the central part. Furthermore, the microneedles are preferably arranged in at least two rows on the periphery of the substrate.

[0027] Microneedle patch The microneedle patch of the present invention further comprises an adhesive sheet in addition to the microneedle array. The adhesive sheet is typically prepared by applying an acrylic or rubber adhesive to a thickness of about 5 to 50 μm on a film formed to a thickness of about 5 to 50 μm using polyurethane, polyethylene, polyester, paper, etc. as a film substrate. The shape of the adhesive sheet is not particularly limited, but is preferably circular, elliptical, or bead-shaped, similar to the shape of the microneedle array.

[0028] The microneedle patch of the present invention may further have a release sheet attached to the adhesive surface of the adhesive sheet to protect the adhesive surface of the adhesive sheet and to hold the flexible microneedle array for easy handling. The release sheet may be the protective release sheet disclosed in JP 2014-028108 A. A specific example of a microneedle patch having a release sheet is shown in FIG.

[0029] Drugs held in microneedles When the base of the microneedles of the present invention is a water-soluble polymer, the base may contain a drug. Alternatively, the microneedle array of the present invention may have a drug coating layer on the tip of the microneedle. The drug as used herein includes all compounds that act on or penetrate the skin and produce some beneficial effect. Examples of drugs suitable for the purpose of the present invention include, for example, physiologically active peptides and their derivatives, nucleic acids, oligonucleotides, various antigenic proteins, bacteria, virus fragments, etc. Examples of the physiologically active peptides and their derivatives include calcitonin, adrenocorticotropic hormone, parathyroid hormone (PTH), hPTH (1→34), insulin, exendin, 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 influenza antigen, HBs surface antigen, HBe antigen, etc. The drug may be a cosmetic product.

[0030] In the case of a microneedle array having a drug coating layer at the tip of the microneedle, the lower end of the drug coating layer is 50 μm or more from the base of the needle, and the upper end may be any height depending on the amount of drug applied.Preferably, the upper end is the tip of the microneedle, but it does not necessarily have to be coated to the edge of the tip.The length of the drug coating layer is typically 50 μm or more and 800 μm or less, and preferably 150 μm or more and 600 μm or less. The lower and upper ends of the drug-coated layer are values ​​obtained by measuring the lower and upper ends of the drug-coated microneedles in the vertical direction from the substrate of the microneedle array, respectively. The length of the drug-coated layer is represented by the difference between the lower and upper ends of the drug-coated microneedles. On the other hand, the drug coating layer varies in thickness depending on the drug coating solution and the number of applications.

[0031] When applying a drug to the tip of a microneedle by immersing the tip of the microneedle in a drug aqueous solution, it is desirable to dissolve a base material in the drug aqueous solution, and when the drug is applied and dried, the drug is retained on the microneedle together with the base material. The base material must be a material that does not impair the stability of the drug, and examples of the base material include polymeric polysaccharides such as hyaluronic acid, dextrin, dextran, chondroitin sulfate Na, hydroxypropyl cellulose, ethyl cellulose, carboxymethyl cellulose Na salt, etc., proteins such as collagen, water-soluble synthetic polymers such as polyvinylpyrrolidone and polyvinyl alcohol, and low molecular weight sugars such as glucose, sucrose, maltose, trehalose, etc., or mixtures thereof. The drug aqueous solution to which the base material and water-soluble salt are added is suitable. Here, the water-soluble salt is preferably a water-soluble salt such as sodium chloride or zinc chloride.

[0032] The concentration of the substrate material in the aqueous drug solution is preferably 2% to 60% by mass. At a concentration lower than 2% by mass, the viscosity of the aqueous drug solution is low and the amount of drug applied during immersion is small. At a concentration of 60% by mass or more, the concentration of the aqueous drug solution is too high and the drug application is not stable. The ratio of polymers and low molecular weight sugars in the substrate can be changed depending on the properties of the drug. When the drug is a high molecular weight drug, the base material may be all low molecular weight sugars. If necessary, an antioxidant, a surfactant, etc. may be added to the aqueous drug solution. Glycerin, ethylene glycol, and low molecular weight polymers thereof may also be added to further enhance the dissolution of the drug in the skin.

[0033] Method for manufacturing a microneedle array (1) Mold processing The mold used in manufacturing the microneedle array of the present invention can be manufactured by wet etching or dry etching using a silicon substrate, precision machining using metal or resin (electrical discharge machining, laser machining, hot embossing, injection molding, etc.), mechanical cutting, etc.

[0034] (2) Microneedle array molding process Microneedle arrays made of water-soluble polymers can be mass-produced using a mold (metal mold). For example, a method can be used in which an aqueous solution containing a water-soluble polymer, a drug and other components as necessary is cast, dried, and then peeled off (JP Patent Publication 2009-273872,

[0031] to

[0033] ). Microneedles made of injection-moldable polymers can be manufactured by injection molding the material using a mold (JP Patent Publication 2003-238347

[0017] ,

[0018] ). Stainless steel, heat-resistant steel, superalloys, etc. can be used for the injection molding mold. The mold has recesses corresponding to 100 to 1500 microneedles per square centimeter to form the shape of the microneedles. Micromachining means such as laser and electric discharge machining can be used to form the recesses.

[0035] One embodiment of a method for producing a microneedle array made from an injection-moldable polymer (e.g., thermoplastic resin) is to supply pellets made of a thermoplastic resin material to an injection molding machine equipped with a microneedle injection molding die, and perform injection molding at a cylinder temperature of 230 to 280°C, a die temperature of 60 to 130°C, and an injection pressure of 1000 to 1500 KPa. As the thermoplastic resin material, polyglycolic acid, polylactic acid, or copolymers thereof can be used alone or as a mixture. Furthermore, compositions containing inorganic fillers, other thermoplastic resins, etc. can be used within the scope of not impairing the object of the present invention. As a specific preferred example, a composition (compound) can be used in which 100 parts by mass of polyglycolic acid is blended with 0 to 20 parts by mass of inorganic filler, 0 to 30 parts by mass of other thermoplastic resin, etc. If the amount of inorganic filler or other thermoplastic resin exceeds 20 parts by mass, the impact strength and toughness of the obtained injection molded product may be insufficient, and melt processability may also be reduced. Examples of inorganic fillers include silica, titanium oxide, calcium carbonate, calcium silicate, etc. These may be used alone or in combination of two or more. Examples of the other thermoplastic resin include homopolymers and copolymers of ε-caprolactone, TPX, etc. These thermoplastic resins can be used alone or in combination of two or more. The other thermoplastic resins are usually used in a ratio of 0 to 30 parts by mass, for example, per 100 parts by mass of polyglycolic acid.

[0036] The microneedle array obtained by injection molding is removed from the mold after cooling. EXAMPLES

[0037] Examples of the present invention are shown below, but the present invention is not limited to these examples.

[0038] Example 1 The mold was attached to an injection molding machine (FANUC Corporation), and polyglycolic acid was melted and injection molded. After injection molding at a cylinder temperature of 235°C, injection pressure of 1350 kPa, and mold temperature of 120°C, a milky white microneedle array with a diameter of 10 mm was taken out (Figure 3). An enlarged view is shown in Figure 4. The needle density was different between the center and the periphery of the substrate. The central circular area with a diameter of about 5 mm had a needle density of 750 needles / cm 2 The needle density in the peripheral area (5 mm to the outer diameter (10 mm) from the center) was 960 needles / cm 2 The needles had a total of 576 two-stage microneedles. A micrograph showing the shape of the needles is shown in Figure 5. The needles were two-stage needles with a tip length of 30 μm.

[0039] The microneedle array was attached to a spring-loaded applicator. The spring constant of the applicator was 0.516 N / mm 2 Five sheets of Parafilm (manufactured by LMS, thickness: 170 μm) were layered on a 1 cm thick silicon plate to form a skin model, and the microneedle array was impact-administered from above using an applicator. The microneedle array was peeled off from the Parafilm, and the state of penetration of the second sheet of needle from the surface was observed under a microscope. The fact that the needle had penetrated the second sheet predicted that the needle would reach a depth of approximately 350 μm from the skin. The results are shown in Figure 6. Figure 6 shows that all of the needles had penetrated.

[0040] Comparative Examples 1 and 2 In Example 1, a mold different from that in Example 1 (in the case of Comparative Example 1, the needle density is 750 pieces / cm 2 In the case of Comparative Example 2, the needle density was 960 / cm 2 A microneedle array was produced in the same manner as in Example 1, except that a 100% cellulose acetate solution (100% cellulose acetate and 100% cellulose acetate) was used. Using the obtained microneedle array, a parafilm penetration test was carried out in the same manner as in Example 1. The results of Example 1 and Comparative Examples 1 and 2 are shown in Table 1.

[0041] [Table 1] O: All needles penetrated two layers of Parafilm. ×: Some needles did not penetrate the two sheets of Parafilm.

[0042] Comparative Examples 1 and 2 are microneedle arrays without density difference. The diameter of each array was 10 mm. As in Example 1, by setting a density difference in the needle density of the microneedles, a result was obtained that predicted that a larger number of needles would reliably puncture the skin.

[0043] Examples 2, 3, and 4, Comparative Examples 3 and 4 The mold was attached to an injection molding machine (FANUC Corporation), and polyglycolic acid was melted and injection molded. Injection molding was performed at a cylinder temperature of 235°C, injection pressure of 1350 kPa, and mold temperature of 120°C to produce four types of milky white microneedle arrays with a diameter of 10 mm. The total length of the needles was all 600 μm. Enlarged microscope photographs are shown in Figures 7A and 7B. No. 1 is a microneedle array with a needle spacing of 650 μm and uniform needle arrangement (Comparative Example 3, FIG. 7A). No. 2 is a microneedle array with a needle spacing of 400 μm and needles concentrated on the periphery (Example 2, FIG. 7B). The number of needles in No. 1 and No. 2 was unified to 193. No. 3 is a microneedle array with a needle spacing of 400 μm and uniform needle arrangement overall (Comparative Example 4). No. 4 is a microneedle array with a needle spacing of 350 μm and needle arrangement concentrated on the periphery (Example 3). The number of needles in No. 3 and No. 4 was unified to 489. No. 5 is a microneedle array in which the needle spacing is 400 μm and the needles are concentrated in two rows on the periphery (Example 4). The number of needles is 110, and it was produced and evaluated in consideration of the need for a microneedle array with a smaller number of needles depending on the application.

[0044] The microneedle array was attached to a spring-loaded applicator. The spring constant of the applicator was 0.516 N / mm 2 The skin model was created by stacking five sheets of Parafilm (manufactured by LMS, thickness: 130 μm) on a 1 cm thick silicon plate, and the microneedle array was impact-administered from above using an applicator. The microneedle array was peeled off from the Parafilm, and the penetration state of the needles from the surface to the first to fourth sheets was observed under a microscope. The fact that the needles had penetrated the third sheet predicted that the needles would reach a depth of approximately 390 μm from the skin. The results are shown in Table 2.

[0045] [Table 2]

[0046] The number of needles in the microneedle array is the same in Example 2 and Comparative Example 3. In Comparative Example 3, where the needles were uniformly arranged, all the needles penetrated up to the third sheet of parafilm, but in Example 2, where the needles were concentrated on the periphery, all the needles penetrated up to the fourth sheet of parafilm, and the results suggest that the skin can be reliably punctured by setting the needle density in the center to 0. Similarly, Example 3 and Comparative Example 4 have the same number of needles in the microneedle array, but the needle density is higher than that of Example 2 and Comparative Example 3. In Comparative Example 4, where the needle arrangement is uniform, the number of needles that penetrated the third sheet of parafilm was reduced to 1 / 4 of the total, while in Example 3, where the needle arrangement was concentrated on the periphery, the number of needles that penetrated the third sheet of parafilm was about 3 / 4 of the total. Even in a microneedle array with a high needle density, the results showed that more needles would reliably puncture the skin by concentrating the needle arrangement on the periphery. In Example 4, the needle spacing and density are the same as in Example 2, but the number of needles is set to be small and concentrated in two rows on the periphery. As in Example 2, all needles penetrated up to the fourth sheet of parafilm, and the results suggest that the skin will be punctured reliably by setting the needle density in the center to 0. [Explanation of symbols]

[0047] 1 Tip 2. Edge of step 3 bottom 4. Microneedle array substrate 11 Microneedle Array 12 Release sheet 13 Adhesive sheet 14 holes 15 Cutting line 16 Gap

Claims

1. A microneedle array comprising a substrate and a plurality of microneedles (excluding hollow microneedles) arranged lengthwise and widthwise on one surface of the substrate, wherein the needle spacing and needle density of the microneedles are different between the peripheral part and the central part of the substrate, The needle density of the microneedles is 400 to 1000 needles / cm at the periphery of the substrate. ２ The microneedle arrangement in the peripheral portion is at least two rows, and the microneedle arrangement in the central portion of the substrate is 0 to 99 needles / cm ２ and the surface of the substrate is circular, elliptical, or rectangular; When the surface of the substrate is a circle or an ellipse, the central part of the substrate is within a circumference that is 9 / 10 to 2 / 3 of the radius from the center of the circle or the ellipse, and the peripheral part of the substrate is outside the central part; When the surface of the substrate is square, the central part of the substrate is inside the four sides connecting four points 9 / 10 to 2 / 3 of the way down the diagonal from the center of the square, and the peripheral part of the substrate is outside the central part, a microneedle array.

2. A microneedle patch comprising the microneedle array according to claim 1 and an adhesive sheet.

3. The microneedle patch according to claim 2 , further comprising a release sheet attached to the adhesive surface of the adhesive sheet.

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