Micro-needle array with non-uniform needle density

Abstract

To provide a microneedle array wherein even microneedles positioned at the central section of the microneedle array are easily inserted into the skin.SOLUTION: This microneedle array comprises a substrate and a plurality of microneedles disposed vertically and horizontally on one surface of the substrate, wherein the inter-needle gaps and the needle density of the microneedles are different in the peripheral section and the central section of the substrate. The needle density of the microneedles is preferably sparse in the central section compared to that in the peripheral section of the substrate, and the inter-needle gaps of the microneedles are preferably greater in the central section than those in the peripheral section of the substrate.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] The present invention relates to the technology of a microneedle array with non-uniform needle density.

Background Art

[0002] As methods for administering drugs into the human body, oral administration and transdermal administration are often used. Injection is a typical transdermal administration method. However, injection requires the hands of professionals such as doctors and nurses, is accompanied by pain, and is a method that should not be welcomed by many people. On the other hand, recently, a painless transdermal administration method using a microneedle array has attracted attention (Non-Patent Document 1).

[0003] When a drug is administered transdermally, the stratum corneum of the skin acts as a barrier to drug permeation, and simply applying the drug to the skin surface does not necessarily provide sufficient permeability. In contrast, by using minute needles, that is, microneedles, to pierce the stratum corneum, the drug permeation efficiency can be significantly improved compared to the application method. An array in which a large number of such microneedles are integrated on a substrate is a microneedle array. Also, a microneedle patch is a product that is made easy to use by adding an adhesive sheet for attaching the microneedle array to the skin, a release sheet for protecting the adhesive surface, etc. to the microneedle array.

[0004] As materials for microneedles, metals and silicon were initially used, but later, various polymer materials have attracted attention from the viewpoint of processability. In particular, if microneedles are made using substances such as saccharides that disappear by metabolism in the body as materials, even if the needles break and remain in the skin, it will not cause an accident.

[0005] The microneedle patches known in patent documents and academic documents, etc., have a planar microneedle array substrate, on which fine needles of uniform length stand vertically at a uniform density. The microneedle patches fabricated by the present inventors up to now and for which patent applications have been filed also fall within that category (Patent Documents 1 and 2). The microneedles disclosed in Patent Documents 1 and 2 are (circular) conical, (circular) frustoconical, or conical type, and it is described that the pitch between microneedles is preferably 0.4 to 1.0 mm. Also, regarding microneedle preparations and their manufacturing methods for which patent applications have been filed in recent years, various improvements have been made for the purpose of ensuring puncture of the skin by microneedles (Patent Documents 3 and 4), the purpose of uniformly loading a drug onto microneedles (Patent Documents 5 and 6), etc.

[0006] In Patent Document 3, it is described that for a needle-like device (microneedle array), the protrusions have a pyramid shape, and the blades formed on two sides of the pyramid shape are arranged such that the tangential direction of a circle centered at a predetermined position on the substrate surface. In Patent Document 4, a dissolving microneedle preparation containing hyaluronic acid, etc., has a substantially equal distance between adjacent needle parts, and about 1 to 10 needles are arranged per 1 mm, and the density of the needle parts is preferably 100 to 10,000 needles per 1 cm 2 It is described that. The microneedle array manufactured by the manufacturing method of the microneedle array of Patent Document 5, from the viewpoint of being able to administer a predetermined drug without pain, the needle density is preferably 1 to 200 needles / cm 2 It is described that. The microneedle device manufactured by the manufacturing method of the microneedle device of Patent Document 6 is provided at intervals such that the density is about 1 to 10 needles per 1 mm for the horizontal rows of needles, and they are separated from each other by an equal distance with respect to the space between the needles in the horizontal row, and it is described that it has a needle density of 100 to 10,000 needles per 1 cm 2 It is described that.

[0007] As described above, the microneedles of Patent Documents 1, 2, and 4 to 6 are provided at equal intervals on a substrate, and the needle density per unit area is also constant. On the other hand, in Patent Document 3, the substrate of the needle-like device (microneedle array) is flat, the blades of the needle-like bodies are arranged in the tangential direction of a circle, and the arrangement patterns include radial (Fig. 3) from the center of the circle toward the outer periphery, spiral (Fig. 4) spreading from the center of the circle toward the outer periphery, linear (Fig. 5(a)) eccentric from the central axis, and a plurality of non-linearly symmetric linear patterns (Fig. 5(b)), etc. are disclosed. However, the blades adjacent in the tangential direction are at equal intervals and are arranged almost evenly and in a well-balanced manner over the entire substrate of the needle-like bodies.

[0008] Regarding the needle density of the microneedles and the skin permeability of the needles, it is described that a microneedle array having needles of 900 needles / cm 2 has worse skin permeability than a microneedle array having needles of 400 needles / cm 2 (Non-Patent Document 2).

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Non-Patent Documents

[0010]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0011] When administering a conventional microneedle patch to animal skin for testing, the microneedle patch is struck at high speed from behind by an applicator, and the energy generated by the impact is applied to the microneedle patch to achieve insertion of fine needles into the skin. The surface of the applicator that strikes the microneedle patch known to date is flat. In the process of administering to animals or humans using such a system, the present inventors noticed the following phenomena. 1. When the needle density is too high, it becomes difficult to insert into animal and human skin (Phenomenon 1). According to the findings of the present inventors, when the needle density exceeds 1500 needles / cm 2 it tends to become difficult for the needles to penetrate the skin. Of course, this figure depends on many factors such as the hardness of the skin, the fineness and strength of the needles, and the impact strength of the applicator, so it is only a guideline. In a microneedle system where it is important to impregnate (in the case of dissolving microneedles) or coat (in the case of coating microneedles) a larger amount of valuable substances in the microneedles to increase the drug content per unit area, the needle density that allows stable insertion is a very important structural factor of the microneedle array. Prior to the present inventors, Non-Patent Document 2 reported that at 900 needles / cm2 The microneedle array having needles of 2 is described as having poor skin permeability compared to a microneedle array having needles of 400 needles / cm. 2. When analyzing the above phenomenon 1 in detail, the central part of the microneedle array is more difficult to insert into the skin compared to the peripheral part (phenomenon 2). Regarding phenomenon 2, a literature survey was conducted, but no literature pointing out such a phenomenon was found. An object of the present invention is to solve the problem that the fine needles located in the central part of the microneedle array are difficult to insert into the skin.

Means for Solving the Problem

[0012] To solve the above problems, the present inventors conducted a model experiment regarding phenomenon 2 (difficulty in inserting fine needles into the skin at the central part) using parafilm instead of skin. Eight sheets of parafilm (thickness 140 μm) were stacked, and a microneedle patch having fine needles with different needle densities was placed on top thereof (area = 0.8 cm 2 ), and it was impacted by an applicator (International Publication No. 2018 / 124290, or Japanese Patent Application Laid-Open No. 2017-185162), and the insertion behavior into the parafilm was examined in detail. Analyzing the insertion behavior of microneedles using parafilm as a skin substitute is already known from the literature (Int. J. Pharmaceutics 480 (2015) 152-157), and there is a reliable correlation with the skin insertion behavior. As a result, by using a microneedle array in which the fine needles are arranged such that the needle density is smaller at the central part than at the peripheral part, the total number of needles is increased compared to a microneedle array having the same needle density throughout, and it has been found that 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, wherein the needle pitch and needle density of the microneedles are different between the peripheral part and the central part of the substrate. 〔2〕 The micro needle array according to 〔1〕, wherein the needle density of the micro needles is sparser in the central portion of the substrate than in the peripheral portion thereof. 〔3〕 The micro needle array according to 〔1〕 or 〔2〕, wherein the needle pitch of the micro needles is wider in the central portion of the substrate than in the peripheral portion thereof. 〔4〕 The needle density of the micro needles is 600 to 1500 needles / cm 2 in the peripheral portion of the substrate, and 100 to 800 needles / cm 2 in the central portion of the substrate, and the needle density in the central portion of the substrate is smaller than the needle density in the peripheral portion of the substrate. The micro needle array according to 〔2〕. 〔5〕 The needle density of the micro needles is 400 to 2000 needles / cm 2 in the peripheral portion of the substrate, and 0 to 99 needles / cm 2 in the central portion of the substrate. The micro needle array according to 〔2〕. 〔6〕 The needle density of the micro needles is 400 to 2000 needles / cm 2 in the peripheral portion of the substrate, the arrangement of the micro needles in the peripheral portion is at least two rows, and 0 needles / cm 2 in the central portion of the substrate. The micro needle array according to 〔2〕. 〔7〕 The surface of the substrate is circular or elliptical, the central portion of the substrate is inside the circumference with a radius of 9 / 10 or less from the center of the circle or the ellipse, and the peripheral portion of the substrate is outside the central portion. The micro needle array according to any one of 〔1〕 to 〔6〕. 〔8〕 The surface of the substrate is square, the central portion of the substrate is inside the four sides connecting four points at a location of 9 / 10 or less of the diagonal from the center of the square, and the peripheral portion of the substrate is outside the central portion. The micro needle array according to any one of 〔1〕 to 〔6〕. 〔9〕 A micro needle patch further having an adhesive sheet on the micro needle array according to any one of 〔1〕 to 〔8〕. 〔10〕 The micro needle patch according to 〔9〕, further having a release sheet attached to the adhesive surface of the adhesive sheet.

Advantages of the Invention

[0013] By setting a density difference in the needle density of the microneedle array of the present invention, more needles can be reliably punctured into the skin compared to a microneedle array with uniform needle density. Thereby, the drug content per unit area can be increased, and the drug can be reliably transdermally delivered.

Brief Description of the Drawings

[0014]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7A

Figure 7B

Modes for Carrying Out the Invention

[0015] Substrate of the microneedle array The material, shape, and size of the substrate of the microneedle array are not particularly limited, and those conventionally used can be employed. Although it is basically assumed that the substrate and the base of the microneedle are the same, different bases may be used. Examples of the base material include silicon, silicon dioxide, ceramics, glass, metals (such as stainless steel, titanium, nickel, molybdenum, chromium, cobalt, etc.), and synthetic or natural resin materials. Examples of synthetic or natural resin materials include water-soluble or biodegradable polymers such as polylactic acid, polyglycolic acid, poly(lactic-glycolic acid) copolymer, caprolactone, polyurethane, polyvinylpyrrolidone, hydroxypropyl cellulose, and polyvinyl alcohol, or 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 material can be used by mixing one or more of these materials.

[0016] The shape of the substrate can be any shape. As an example, it may be based on a circle, ellipse, triangle, quadrilateral, polygon, etc., and may be further deformed according to the application site (skin). When the size of the substrate is represented by the diameter (major axis) or the length of one side (long side), it is usually 0.2 to 10 cm, preferably 0.5 to 5 cm.

[0017] The area of the substrate is usually 0.05 to 100 cm 2 From the perspective of ease of handling, it is preferably about 0.1 to 10 cm 2 and more preferably about 0.5 to 5 cm 2 is more preferred.

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

[0019] Shape of the microneedle 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 the 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] As 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 the stepped microneedle, the length of the tip portion 1 is preferably 50 to 500 μm, and the rest is the bottom (two-stage needle), or in the three-stage needle, the rest is the intermediate portion and the bottom. The size of the edge 2 of the step between the tip portion and the intermediate portion and between the intermediate portion and the bottom is preferably greater than 10 μm and less than 100 μm. More preferably, it is 14 to 50 μm.

[0023] Arrangement of the microneedles on the substrate The microneedle array of the present invention includes a plurality of microneedles arranged vertically and horizontally on one surface of a substrate, and the needle pitch and needle density of the microneedles are different between the peripheral portion and the central portion 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 central portion of the substrate than in the peripheral portion. Also, the needle pitch of the microneedles is preferably wider in the central portion of the substrate than in the peripheral portion.

[0025] As a preferred example, the needle density of the microneedles is 600 to 1500 needles / cm at the peripheral portion of the substrate 2 and 100 to 800 needles / cm at the central portion of the substrate. 2 More preferably, it is 700 to 1000 needles / cm at the peripheral portion of the substrate 2 and 300 to 800 needles / cm at the central portion of the substrate. 2 Here, a numerical value smaller than the needle density at the peripheral portion of the substrate is selected for the needle density at the central portion of the substrate. As another preferred example, the needle density at the central portion of the substrate is less than 100 needles / cm 2 Specifically, it may be 0 to 99 needles / cm. 2 In this case, it is 400 to 2000 needles / cm at the peripheral portion of the substrate 2 and more preferably 600 to 1500 needles / cm. 2 ​The needle pitch of the microneedles can be set to an appropriate interval 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 needle density of the microneedles.

[0026] When the surface of the substrate is circular or elliptical, based on the result of observing the regions where it is difficult to insert the microneedle array into the skin, the central portion of the substrate is preferably inside the circumference that is 9 / 10 or 2 / 3 or less of the radius from the center of the circle or ellipse, and the peripheral portion of the substrate is outside the central portion. When the surface of the substrate is square, the central portion of the substrate is preferably inside the four sides connecting the four points that are 9 / 10 or 2 / 3 or less of the diagonal from the center of the square, and the peripheral portion of the substrate is outside the central portion. Also, it is preferable that the arrangement of the microneedles in the peripheral portion of the substrate has at least two rows.

[0027] Microneedle patch The microneedle patch of the present invention further has an adhesive sheet on the microneedle array. The adhesive sheet typically uses polyurethane, polyethylene, polyester, paper, etc. as the base material of the film, and an acrylic or rubber-based adhesive is applied to a film formed to a thickness of about 5 to 50 μm. The shape of the adhesive sheet is not particularly limited, but circular, elliptical, jade-shaped, etc. are preferable, 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 so as to protect the adhesive surface of the adhesive sheet and hold the flexible microneedle array for easy handling. Regarding the release sheet, the protective release sheet disclosed in Japanese Patent Application Laid-Open No. 2014-028108 can be used. A specific example of the microneedle patch having a release sheet is shown in FIG. 2.

[0029] Drug held by the microneedle In the case of the microneedle array of the present invention, when the base of the microneedle is a water-soluble polymer, it may contain a drug in the base. Alternatively, the microneedle array of the present invention may have a drug coating layer at the tip of the microneedle. Here, the drug includes all compounds that act on the skin, penetrate the skin, and produce some beneficial effects. Examples of drugs suitable for the purpose of the present invention include, for example, bioactive peptides and their derivatives, nucleic acids, oligonucleotides, various antigenic proteins, bacteria, fragments of viruses, etc. Examples of the bioactive peptides and their derivatives include, for example, 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 the antigenic proteins include influenza antigen, HBs surface antigen, HBe antigen, etc. The drug may be a cosmetic.

[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 at any height depending on the coating amount of the drug. Preferably, the upper end is the tip of the microneedle, but it is not necessarily applied up to 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 end and the upper end of the drug coating layer are the values obtained by measuring the lower end and the upper end of the microneedle coated with the drug in the vertical direction from the substrate of the microneedle array. The length of the drug coating layer is represented by the difference between the lower end and the upper end of the microneedle coated with the drug. On the other hand, the thickness of the drug coating layer varies depending on the drug coating solution and the number of coating times.

[0031] When immersing the tip of the microneedle in an aqueous drug solution to apply the drug to the tip of the microneedle, it is desirable that a substrate substance is dissolved in the aqueous drug solution and the drug is retained on the microneedle together with the substrate substance during drying after coating. The substrate substance needs to be a substance that does not impair the stability of the drug. Examples include high molecular 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 polyvinyl pyrrolidone and polyvinyl alcohol, etc., high molecular substances, low molecular saccharides such as glucose, sucrose, maltose, trehalose, etc., or mixtures thereof. The substrate substance and the aqueous drug solution added with a water-soluble salt are appropriate. Here, as the water-soluble salt, water-soluble salts such as sodium chloride and zinc chloride are suitable.

[0032] The concentration of the substrate substance in the aqueous drug solution is desirably from 2% by mass to 60% by mass. At a concentration lower than 2% by mass, the viscosity of the aqueous drug solution is small and the coating adhesion amount during immersion is small. Also, at 60% by mass or more, the concentration of the aqueous drug solution is too high and the drug coating is not stable. The ratio of the high molecular and low molecular saccharides in the substrate can be changed according to the properties of the drug. When the drug is a high molecular medicine, the base may be all low molecular saccharides. Antioxidants, surfactants, etc. may be added to the aqueous drug solution as necessary. Also, glycerin, ethylene glycol and its low molecular polymers may be added to further enhance the dissolution of the drug in the skin.

[0033] Manufacturing method of the microneedle array (1) Processing of the mold The mold used for 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 (such as electrical discharge machining, laser machining, hot embossing, injection molding, etc.), mechanical cutting, etc.

[0034] (2) Forming process of microneedle array A microneedle array made of a water-soluble polymer can be mass-produced using a mold. For example, a method of casting an aqueous solution containing a water-soluble polymer, a drug and other components as necessary, drying and then peeling it off can be mentioned (Japanese Patent Application Laid-Open No. 2009-273872

[0031] -

[0033] ). A microneedle made of a polymer capable of injection molding as a material may be manufactured by injection molding the material using a mold (Japanese Patent Application Laid-Open No. 2003-238347

[0017] ,

[0018] ). For the injection mold, stainless steel, heat-resistant steel, superalloy, etc. can be used. The mold has recesses corresponding to 100 to 1500 microneedles per square centimeter to form the shape of the microneedles. To form the recesses, fine processing means such as a laser and electrical discharge machining can be used.

[0035] As one aspect of the manufacturing method of a microneedle array made of a polymer capable of injection molding (for example, a thermoplastic resin) as a material, pellets made of a thermoplastic resin material are supplied to an injection molding machine equipped with a microneedle injection mold, and injection molding is performed at a cylinder temperature of 230 to 280°C, a mold 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 a copolymer thereof can be used alone or as a mixture. Furthermore, within a range that does not inhibit the object of the present invention, a composition containing an inorganic filler, another thermoplastic resin, etc. can be used. As a preferred specific example, a composition (compound) in which 0 to 20 parts by mass of an inorganic filler, 0 to 30 parts by mass of another thermoplastic resin, etc. are blended with respect to 100 parts by mass of polyglycolic acid can be used. If the inorganic filler or another thermoplastic resin exceeds 20 parts by mass, the impact strength and toughness of the resulting injection molded product may be insufficient, and the melt processability may decrease. Examples of the inorganic filler include silica, titanium oxide, calcium carbonate, calcium silicate, etc. These can 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 resin is usually used in a proportion of 0 to 30 parts by mass with respect to 100 parts by mass of polyglycolic acid.

[0036] The micro needle array obtained by injection molding is taken out of the mold after cooling.

Examples

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

[0038] Example 1 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, an injection pressure of 1350 kPa, and a mold temperature of 120 ° C, and a milky white micro needle array with a diameter of 10 mm was taken out (Figure 3). The enlarged view is shown in Figure 4. The needle density was different between the central part and the peripheral part of the substrate. The circular part with a diameter of about 5 mm in the central part had a needle density of 750 needles / cm 2 and had a total of 169 two-stage micro needles. The peripheral part (the part from 5 mm from the center to the outer diameter (10 mm)) had a needle density of 960 needles / cm 2 and had a total of 576 two-stage micro needles. A micrograph showing the shape of the needle is shown in Figure 5. It was a two-stage needle with a tip length of 30 μm.

[0039] This micro-needle array was attached to a spring-type applicator. The spring constant of the applicator was 0.516 N / mm 2 Paraffin film (manufactured by LMS, thickness: 170 μm) was stacked in five layers on a silicon plate with a thickness of 1 cm to serve as a skin model, and the micro-needle array was impact-administered from above using the applicator. The micro-needle array was peeled off from the paraffin film, and the penetration status of the second needle from the surface was observed with a microscope. The fact that the second needle penetrated is predictive of the needle reaching a depth of approximately 350 μm from the skin. The results are shown in Fig. 6. From Fig. 6, it was found that all the needles had penetrated.

[0040] Comparative Examples 1 and 2 In Example 1, a mold different from that of Example 1 (in the case of Comparative Example 1, the needle density was uniform at 750 needles / cm 2 and in the case of Comparative Example 2, the needle density was uniform at 960 needles / cm 2 was used) to manufacture a micro-needle array in the same manner as in Example 1 except for this. Using the obtained micro-needle array, a paraffin film penetration test was conducted 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

[0042] Comparative Examples 1 and 2 are micro-needle arrays with no density difference. The diameter of the array was 10 mm in both cases. By setting a density difference in the needle density of the micro-needles as in Example 1, results were obtained predicting that a larger number of needles would surely pierce the skin.

[0043] Examples 2, 3, 4, Comparative Examples 3, 4 The mold was attached to an injection molding machine (Fanuc Corporation), and polyglycolic acid was melted for injection molding. Injection molding was carried out at a cylinder temperature of 235°C, an injection pressure of 1350 kPa, and a mold temperature of 120°C, and four types of milky white micro-needle arrays with a diameter of 10 mm were manufactured. The total length of the needles was all 600 μm. Magnified micrographs are shown in FIGS. 7A and 7B. No. 1 is a micro-needle array with a needle spacing of 650 μm and a uniform needle arrangement throughout (Comparative Example 3, FIG. 7A). No. 2 is a micro-needle array with a needle spacing of 400 μm and a needle arrangement concentrated on the outer periphery (Example 2, FIG. 7B). The number of needles in No. 1 and No. 2 was unified to 193. No. 3 is a micro-needle array with a needle spacing of 400 μm and a uniform needle arrangement throughout (Comparative Example 4). No. 4 is a micro-needle array with a needle spacing of 350 μm and a needle arrangement concentrated on the outer periphery (Example 3). The number of needles in No. 3 and No. 4 was unified to 489. No. 5 is a micro-needle array with a needle spacing of 400 μm and a needle arrangement concentrated in two rows on the outer periphery (Example 4). The number of needles is 110, and it was manufactured and evaluated in consideration of the need for a micro-needle array with a small number of needles depending on the application.

[0044] This micro-needle array was attached to a spring-type applicator. The spring constant of the applicator was 0.516 N / mm 2 Paraffin film (manufactured by LMS, thickness: 130 μm) was stacked in five layers on a 1 cm thick silicon plate to form a skin model, and the micro-needle array was impact-administered from above by the applicator. The micro-needle array was peeled off from the paraffin film, and the penetration status of the needles from the first to the fourth from the surface was observed with a microscope. Penetrating through the third one is expected to indicate that the needles reach a depth of approximately 390 μm from the skin. The results are shown in Table 2.

[0045]

Table 2

[0046] In Example 2 and Comparative Example 3, the number of needles in the microneedle array is the same. In Comparative Example 3 where the needle arrangement is uniform, all the needles penetrated up to the third paraffin film, but in Example 2 where the needle arrangement is concentrated on the outer periphery, all the needles penetrated up to the fourth paraffin film, and a result was obtained predicting that skin puncture would be surely achieved by setting the needle density at the center to 0. Similarly, in Example 3 and Comparative Example 4, the number of needles in the microneedle array is also the same, but the needle density is higher than that in Example 2 and Comparative Example 3. In Comparative Example 4 where the needle arrangement is uniform, the number of needles that penetrated the third paraffin film decreased to 1 / 4 of the whole, but in Example 3 where the needle arrangement is concentrated on the outer periphery, the number of needles that penetrated the third paraffin film was about 3 / 4 of the whole. Even in a microneedle array with a high needle density, a result was obtained predicting that more needles would surely be skin-pierced by concentrating the needle arrangement on the outer periphery. In Example 4, the needle pitch and needle density are the same as those in Example 2, but the number of needles is set to be small and concentrated on the outer two rows. Similar to Example 2, all the needles penetrated up to the fourth paraffin film, and a result was obtained predicting that skin puncture would be surely achieved by setting the needle density at the center to 0.

Explanation of Signs

[0047] 1 Tip 2 Edge of step 3 Bottom 4 Substrate of microneedle array 11 Microneedle array 12 Release sheet 13 Adhesive sheet 14 Hole 15 Cutting line 16 Gap

Claims

1. A micro-needle array comprising a substrate and a plurality of micro-needles arranged vertically and horizontally on one surface of the substrate (excluding hollow micro-needles), wherein the needle pitch and needle density of the micro-needles are different between the peripheral portion and the central portion of the substrate, The needle density of the microneedles is 600 to 1000 needles / cm at the peripheral portion of the substrate ２ and the microneedle arrangement in the peripheral portion is at least two rows, and it is 0 needles / cm at the central portion of the substrate ２ and the surface of the substrate is circular, elliptical, or square, when the surface of the substrate is circular or elliptical, the central portion of the substrate is inside the circumference with a radius of 9 / 10 to 2 / 3 from the center of the circle or the ellipse, and the peripheral portion of the substrate is outside the central portion, when the surface of the substrate is square, the central portion of the substrate is inside the four sides connecting the four points at 9 / 10 to 2 / 3 of the diagonal from the center of the square, and the peripheral portion of the substrate is outside the central portion, a micro-needle array.

2. A micro-needle patch further having an adhesive sheet on the micro-needle array according to Claim 1.

3. The micro-needle patch according to Claim 2, further having a release sheet attached to the adhesive surface of the adhesive sheet.

Images