Microneedle array

Abstract

To address a disadvantage of coated-type microneedles in which it is difficult to coat the microneedles with a large amount of a drug, thus limiting the drug for effective use.SOLUTION: A drug coated-type microneedle array comprises a substrate and a plurality of microneedles, wherein the microneedles form groups of at least three to form spaces, and the spaces are disposed on the substrate so as to provide drug-coated sections.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a microneedle array having a special structure and arrangement. Furthermore, the present invention relates to a microneedle patch with an adhesive tape attached to the microneedle array.

Background Art

[0002] Currently, various dosage forms of microneedles with different shapes and materials are known, and their properties are also known to be water-soluble and water-insoluble. The applications of microneedles are also being widely developed in pharmaceuticals, cosmetics, and the like. Regarding the application of microneedles to pharmaceuticals, particularly vaccines, it is roughly classified into an encapsulation type of drug in microneedles and a coating type of drug on microneedles. These are called solid microneedles. There are also other hollow microneedles, but the present invention relates to solid microneedles. Considering the efficient use of drugs and production efficiency, the coating type is more desirable than the encapsulation type.

[0003] A technique of immersing the tip of a microneedle in a drug solution to attach the drug to the tip of the microneedle is known (Patent Documents 1-4).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0005] The method of immersing the micro-needle tip in a drug solution to attach the drug to the micro-needle tip is simple, so it is easy to put into practical use. However, it is very difficult to apply the drug quantitatively and with little variation to the micro-needle tip. In the case of micro-needles made of hydrophobic materials, it is difficult to apply the drug from an aqueous solution. When a micro-needle made of a hydrophilic material is simply immersed in an aqueous drug solution, due to capillary action, the aqueous drug solution easily rises along the needle to the bottom surface of the substrate. Therefore, although many attempts have been made to immerse the micro-needle array in an aqueous drug solution to a certain depth and apply a large amount of the drug quantitatively, it is extremely difficult. In order to apply a large amount of the drug to the tip of the micro-needle, it is also known to add a water-soluble polymer to the aqueous drug solution to thicken it and make it easier to adhere to the needle part (for example, Japanese Patent Laid-Open No. 2017-137311). However, it has also been pointed out that by adding a water-soluble polymer, when the drug-coated micro-needle array is administered to the skin, it takes time to dissolve the drug-coated part with a small amount of moisture present in the skin, and the administration time is too long. In addition, by increasing the amount of the additive, the drug-coated part tends to become thick and spherical (see Comparative Example 1 and FIG. 9), the piercing force into the skin is significantly reduced, and the bioavailability of the drug tends to be low. A simple tip-coated type micro-needle array often cannot obtain a high drug bioavailability of 80% or more when the drug amount exceeds 1 mg / cm 2 There are many cases. The drawback of the coated micro-needle is that it is difficult to apply a large amount of the drug to the micro-needle, and thus the drugs available for effective use are limited. The problem of the present invention is to solve such drawbacks of the coated micro-needle.

Means for Solving the Problem

[0006] To solve the above problems, the present inventors conducted a detailed study on various micro-needles coated with drugs and intensively studied the geometric shape of the needles. As a result, they found that a micro-needle array with a specific shape can achieve the intended purpose, and thus completed the present invention. The present invention is as follows. [1] A drug-coated microneedle array comprising a substrate and a plurality of microneedles, the microneedles being arranged on the substrate in groups of at least three to form spaces, and the spaces providing drug-coated areas. [2] The microneedle array according to [1], wherein the number of groups of microneedles is two or more. [3] The microneedle array according to [1], wherein the microneedles are made of a thermoplastic polymer. [4] The microneedle array according to [3], characterized in that the thermoplastic polymer is nylon, polycarbonate, polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyglycolic acid, polyethylene terephthalate, cyclic olefin polymer, or a mixture thereof. [5] The microneedle array according to [1], wherein the microneedles have a base diameter of 0.03 to 1 mm, a tip diameter of 0.02 to 0.2 mm, and a length of 0.2 to 3 mm. [6] The microneedle array according to [1], wherein the distance between adjacent microneedles within the group is 0.05 to 1 mm. [7] The microneedle array according to [1], wherein each group of microneedles is independently arranged on a base that stands on a substrate. [8] The microneedle array according to [7], wherein the base is cylindrical or truncated cone-shaped, and has a base diameter of 0.1 to 30 mm, a tip diameter of 0.04 to 30 mm, and a height of 0.2 to 10 mm. [9] A microneedle patch comprising the microneedle array according to any one of [1] to [8] and an adhesive tape backed on the substrate of the microneedle array.

[10] A system for applying a drug to the skin, comprising the microneedle array according to any one of [1] to [8] and a drug application portion provided in the space between the groups of the microneedle array.

[11] A system for applying a drug to the skin, comprising the microneedle patch according to [9] and a drug application portion provided in the space between the groups of microneedle arrays of the microneedle patch.

[12] The drug application system according to

[10] , wherein the amount of plaster held in the space of one group is 10 μg or more.

[13] The drug application system according to

[11] , wherein the amount of plaster held in the space of one group is 10 μg or more.

[14] The drug application system according to

[10] , 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, hormones, antihistamines, general anesthetics, hypnotic analgesics, antiepileptics, psychotropic agents, skeletal muscle relaxants, autonomic nervous system agents, antiparkinsonian agents, diuretics, vasoconstrictors, respiratory stimulants, narcotics, antigenic components of pathogens, and cosmetic raw materials.

[15] The drug application system according to

[11] , 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, hormones, antihistamines, general anesthetics, hypnotic analgesics, antiepileptics, psychotropic agents, skeletal muscle relaxants, autonomic nervous system agents, antiparkinsonian agents, diuretics, vasoconstrictors, respiratory stimulants, narcotics, antigenic components of pathogens, and cosmetic raw materials.

[16] The microneedle array according to [1], wherein the plurality of microneedles are non-uniform in any of the base diameter, tip diameter, or length.

[17] The drug application system according to

[10] , wherein the height of the drug application portion exceeds the tip of the microneedle.

[18] The drug application system described in

[11] , characterized in that the height of the drug application portion exceeds the tip of the microneedle.

[19] The drug application system according to

[17] , wherein the distance between the tip of the drug application part and the tip of the microneedle is 0.1 mm to 2.0 mm.

[20] The drug application system according to

[18] , wherein the distance between the tip of the drug application part and the tip of the microneedle is 0.1 mm to 2.0 mm. [Effects of the Invention]

[0007] The microneedle array and microneedle patch of the present invention can provide a drug application area as a predetermined space by specifying the arrangement of the microneedles, i.e., by grouping the microneedles arranged on the substrate. As a result, the amount of drug applied has been significantly increased compared to conventional microneedle arrays and microneedle patches. The microneedle array and microneedle patch of the present invention can be used as a transdermal absorption preparation that further increases the amount of drug delivered percutaneously. [Brief explanation of the drawings]

[0008]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

[0009] The microneedle array of the present invention is characterized by the fact that when the tips of the microneedles standing on the substrate surface are immersed in a drug solution, the surface tension of the drug solution covers the space between the needle tips, thereby significantly increasing the amount of drug applied compared to conventional microneedle arrays.

[0010] The microneedle array of the present invention is a solid drug-coated microneedle array. The microneedle array of the present invention includes a substrate and a plurality of microneedles. The microneedles form a group of at least three each to form a space, and the space is arranged on the substrate so as to provide a drug application part.

[0011] (Substrate) The shape of the substrate of the microneedle array of the present invention is preferably circular, but there is no particular limitation. In the case of a circular shape, the diameter of the substrate is preferably 1 mm to 30 mm. If the diameter is less than 1 mm, the number of microneedles standing on it is small and it is difficult to ensure a sufficient drug application amount. Considering the flatness of the human skin to be punctured, a diameter of 30 mm or less is desirable. The thickness of the substrate is 0.05 to 3.0 mm, preferably 0.1 to 2.0 mm, from the viewpoint of handling the microneedle array.

[0012] (Patch plate) The patch plate is under the substrate and supports the substrate. It is provided for the convenience of molding and storage, but it is not an essential part related to the performance of the microneedles. It has a larger area than the substrate and a thickness of 0.5 to 2.0 mm.

[0013] (Grouped microneedles) The present invention is characterized by the arrangement of microneedles standing on a microneedle array substrate. The microneedles are arranged in groups on the substrate, and each group may stand directly on the substrate (an example is shown in Figure 1), or each group may form its own group base (an example is shown in Figure 2). Each group is circular, square, triangular, or other shape, and the microneedles are arranged within it. If the group is circular, the diameter is 0.1 to 30 mm. If the diameter is less than 0.1 mm, it is difficult to hold three microneedles within it. If the diameter exceeds 30 mm, one group becomes the size of the substrate. When the groups stand on the substrate as bases, the diameter of the base is the same as above, and the number of microneedles in each group is 3 to 200, preferably 3 to 150. The number of microneedles may vary between groups. If the number of microneedles in a group is less than three, it is difficult to achieve the feature of the present invention, in which the coating solution fills the spaces between the microneedles, dries, and holds the drug between the microneedles. If the number of microneedles exceeds 200, the needle density increases, resulting in a decrease in skin puncture resistance. The structure of a microneedle array is shown schematically in Figure 1. Although three groups of microneedles are shown in Figure 1, microneedles consisting of one group are also possible. Typically, the number of groups is 1 to 1,000, with 2 to 500 being preferred. If the number of groups exceeds 1,000, the needle density of the microneedles increases as the number of groups increases, resulting in a decrease in skin puncture resistance.

[0014] In the present invention, the groups arranged on the substrate of the microneedles do not necessarily have to be uniformly arranged. FIG. 10A shows an example in which the groups are uniformly arranged in an array. In a microneedle array in which a large number of microneedles stand, it is known that the puncture property is likely to be inferior in the central part of the substrate than in the peripheral part of the substrate. In the present invention, instead of arranging the groups uniformly on the substrate, the density in the central part of the substrate may be lowered (see FIG. 10C) or even set to 0 (see FIG. 10B). The number of groups in the schematic diagram shown in FIG. 10 is much smaller than the number of groups shown in the photograph of FIG. 5. Thus, it is also possible to reduce the number of groups according to the purpose. The number of microneedles shown in FIG. 10 is 4 needles / group, and the number of microneedles shown in FIG. 5 is 7 needles / group. The number of microneedles is related to the amount of drug applied or the strength of the microneedles containing the coating, and it is desirable to change it as necessary.

[0015] (Base) The microneedles stand on the substrate in groups, but a base may be formed on the substrate and the microneedles may stand thereon. A structure in which the microneedles stand on the base for each group is schematically shown in FIG. 2. In the case of a substrate on which a base is formed, the microneedles are arranged on the base independently for each group and are not directly arranged on the substrate. The number of bases coincides with the number of groups of microneedles and is from 1 to 1,000, preferably from 2 to 500.

[0016] The base keeps a certain space between the substrate of the micro-needle array and the base of the micro-needles, and serves to prevent the lower end of the drug application part from reaching the substrate. The skin has elasticity and unevenness on its surface. The inventors have found that when administering a micro-needle array using an applicator, it usually does not penetrate all the way to the base of the needles, but often floats about 200 μm from the base of the needles (see Japanese Patent Application Laid-Open No. 2018-108375). Also in the present invention, from the viewpoint of drug administration efficiency, it is desirable to set the lower end of the drug application part to a height of 200 μm or more from the substrate of the micro-needle array. In the case of a micro-needle array having a base, since it prevents the lower end of the drug application part from reaching the substrate beyond the base, the height of the base can define the lower limit value of the lower end of the drug application part. Therefore, the height of the base is preferably 0.2 to 10 mm.

[0017] The presence of the base has the effect of increasing the overall length of the needles and is also advantageous in terms of puncture performance. Examples of the shape of the base include a frustum of a cone, a cylinder, a frustum of a pyramid, etc., and a frustum of a cone and a cylinder are preferred. The upper area of the base needs to be an area sufficient to stably support the group of micro-needles standing thereon, and is appropriately determined according to the number of micro-needles on the group. It is desirable that the lower area of the base is equal to or larger than the upper area.

[0018] When the base is cylindrical or frustum-shaped, suitable sizes are such that the base diameter at the root is 0.1 to 30 mm and the tip diameter is 0.04 to 30 mm.

[0019] (Micro-needle) In each group, the arrangement of the micro-needles within the group is preferably an arrangement surrounded to hold the applied drug, such as circular, square, triangular, etc. When puncturing the skin, one group serves as one drug holder to achieve drug delivery to the skin.

[0020] The length of the microneedle is 0.2 mm to 3 mm from the substrate or base to the needle tip. If the length is less than 0.2 mm, the volume of the filling part that fills the space between the needles is too small, deviating from the object of the present invention. Considering the moldability of the microneedle and the puncturability to the skin, 3 mm or less is desirable.

[0021] Basically, the lengths of the microneedles are all the same, but this is not a necessary condition. The lengths of the microneedles within a group may be different. The lengths of multiple microneedles may be non-uniform. For example, by making the length of the needle at the center of the group the longest and shortening the needle length as going to the periphery, if the shape after drug application in the group becomes convex at the center in drug application, the puncturability of the needle can be improved. For example, in FIG. 11, FIG. 11A has uniform needle lengths, and FIG. 11B has needles that are longer at the center than at the peripheral part. When a drug is applied to such a microneedle array, the drug application systems shown in FIGS. 11C and D are obtained. The drug application system of FIG. 11D has a pointed tip of the drug application part, so the puncturability and the bioavailability of the drug are more improved than the drug application system of FIG. 11C.

[0022] The root diameter of the microneedle is at most 1 mm under the condition of filling the drug solution between the microneedles. The minimum is 0.03 mm, and if it is less than 0.03 mm, the mechanical strength of the microneedle is insufficient. The microneedle may have a step in the middle. The root diameters of multiple microneedles may be non-uniform. The tip diameter of the microneedle is 0.02 to 0.2 mm. If it is less than 0.03 mm, the mechanical strength of the needle becomes weak and a problem occurs in puncturability. If it exceeds 0.2 mm, the needle becomes thick and the skin puncturability deteriorates. The tip diameters of multiple microneedles may be non-uniform.

[0023] The distance between adjacent microneedles within each group (adjacent needle distance) is 0.05 to 1 mm. If the adjacent needle distance is less than 0.05 mm, it does not conform to the gist of the present invention in which a large amount of drug fills between the needles. When the adjacent needle distance is within 1 mm, it is easy to hold the drug solution by surface tension between the needles.

[0024] (Materials of Microneedles, Substrate, and Base) Examples of the material of the microneedles in the present invention include thermoplastic polymers that are easy to injection mold or press mold. Preferred thermoplastic polymers include nylon, polycarbonate, polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyglycolic acid, polyethylene terephthalate, cyclic olefin polymer, and mixtures thereof. The microneedles, substrate, and base are usually manufactured from the same material, but different materials may be selected.

[0025] (Drugs Applied to Microneedles) The drug is not particularly limited as long as it is a drug conventionally used as a transdermal absorption preparation and a raw material for cosmetics. Examples of the drug include antipyretic, analgesic, and anti-inflammatory agents, steroid anti-inflammatory agents, vasodilators, antiarrhythmic agents, antihypertensive agents, local anesthetics, hormonal agents, antihistamines, general anesthetics, sleep analgesics, antiepileptic agents, psychotropic agents, skeletal muscle relaxants, autonomic nerve agents, anti-Parkinson agents, diuretics, vasoconstrictors, respiratory stimulants, narcotics, and antigenic components of pathogens (e.g., vaccine antigen proteins), etc. The content of the drug can be appropriately set according to the characteristics of the components, administration purpose, administration target, administration frequency, etc.

[0026] Most drugs are low molecular weight compounds with a molecular weight of 600 or less, but high molecular weight drugs can also be used. Examples of preferred high molecular weight drugs include physiologically active peptides and their derivatives, nucleic acids, oligonucleotides, various antigen proteins, bacteria, virus fragments, etc.

[0027] Examples of the above-mentioned bioactive peptides and their derivatives include calcitonin, adrenocorticotropic hormone, epidermal growth factor (EGF), parathyroid hormone (PTH), hPTH(1→34), insulin, atrial natriuretic peptide, growth hormone, growth hormone-releasing hormone, endothelin, and salts thereof. These drugs can be administered not only to humans but also to animals. Examples of the antigen proteins include influenza antigen, Japanese encephalitis antigen, diphtheria, tetanus antigen, HBs surface antigen, HBe antigen, and the like.

[0028] (Microneedle patch) The microneedle array of the present invention can be provided as a microneedle patch by lining the substrate of the microneedle array with an adhesive tape. To apply the microneedle array to the skin, the array may be used with an adhesive tape lining the periphery of the substrate to fix the array to the skin. The adhesive tape is not essential, but fixation with an adhesive tape is preferred to stably fix the patch to the skin.

[0029] The adhesive tape consists of an adhesive and a base material, and is obtained by applying the adhesive on the base material. As the adhesive, a rubber-based, silicone-based, acrylic-based, urethane-based adhesive, etc. can be used. When applying to the oral mucosa, a hydrophilic adhesive is preferred. Examples of the hydrophilic adhesive include, for example, hydrophilic acrylic adhesive, HiPAS10 (trade name) adhesive (acrylic adhesive having methyl methacrylate as the main monomer, manufactured by Cosmed Pharmaceutical), HiPAS-PU (trade name) (urethane-based adhesive, manufactured by Cosmed Pharmaceutical).

[0030] A plasticizer may be added to the adhesive. As the plasticizer, commonly used plasticizers, for example, isopropyl myristate, isopropyl palmitate, octyl myristate, octyldodecyl lactate, etc. can be used.

[0031] (Manufacture of microneedle array) Microneedle arrays can be mass-produced using a mold (metal mold). Microneedle arrays made of injection-moldable thermoplastic polymers can be manufactured by injection molding the material using a mold (for example, the method described in Japanese Patent Application Laid-Open No. 2003-238347,

[0017] and

[0018] ). Stainless steel, heat-resistant steel, superalloys, etc. can be used for the injection molding mold. A typical mold has recesses corresponding to 100 to 1000 microneedles per square centimeter to form the microneedle shape. Microfabrication means such as a grinder can be used to form the recesses. Alternatively, the microneedle mold can be formed by molding using photolithography.

[0032] (drug application) The drug application to the microneedle is carried out by immersing the tip of the microneedle in a drug solution to hold the drug at the tip of the microneedle. It is desirable to apply the drug so that the immersion is limited to the needle part and does not reach the substrate part. The drug solution is typically an aqueous solution, but may contain a solvent other than water to dissolve the drug. In addition, the drug may be completely dissolved or dispersed in the solvent.

[0033] The drug solution may contain a coexisting substance dissolved therein, so that the drug and the coexisting substance are retained on the microneedle after application and drying. The coexisting substance must not impair the stability of the drug. Suitable examples include water-soluble polymers such as hyaluronic acid, collagen, dextrin, dextran, sodium chondroitin sulfate, hydroxypropyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, and alginic acid, as well as low-molecular-weight sugars such as glucose, sucrose, maltose, and trehalose, or mixtures thereof. The viscosity of the drug solution (coating solution) is preferably 50 to 2000 mPa·S. If the viscosity is too low, the amount of drug applied to the microneedle tends to be small. However, if no water-soluble polymer is added, a high-content low-molecular-weight sugar solution can be used to facilitate application. If the viscosity is too high, the application itself becomes difficult due to reduced fluidity caused by the high viscosity.

[0034] The drug application may be performed by other methods than immersing the tips of the microneedles in the drug solution. For example, a highly viscous drug solution may be dropped from above onto a group of upwardly facing microneedle arrays, and the liquid may be rapidly evaporated by ventilation or heating, thereby retaining the drug and coexisting substances between the needles. Alternatively, the drug solution may be formed into droplets of appropriate size, which may be sprayed and dried by a jet printer in groups to form a coating of the drug and coexisting substances.

[0035] (Drug Application System) When the microneedle tips of the microneedle array of the present invention are immersed in a drug solution, the drug solution is retained in the space surrounded by the multiple microneedles that form the group, and when the drug solution is dried, a drug-applied portion is formed in the space, resulting in a drug-applied microneedle array that differs from conventional microneedles. The drug application system of the present invention comprises the microneedle array or microneedle patch of the present invention and a drug-applied portion.

[0036] Figure 3 shows a schematic representation of a drug-coated microneedle array. The drug is embedded between the microneedles that form a group, and each group can function as a single "needle" when piercing the skin. The microneedle array and microneedle patch of the present invention, which have three or more microneedles in a group, can exert greater skin piercing power than conventional microneedles, which are coated with drug at the tip to form a large sphere. Figure 4 shows a schematic representation of a conventional drug-coated microneedle array. The conventional microneedle array has a large spherical application area, and the maximum application amount of the plaster is calculated to be approximately 1 μg / needle. Here, the plaster refers to the total applied solid material, including the drug, base, plasticizer, etc. If the drug content is 50%, the maximum application amount of the drug is 0.5 μg / needle. In the microneedle array of the present invention, the amount of paste retained in one group of spaces can be increased to 10 μg or more. The microneedle array and microneedle patch of the present invention to which a drug is applied are useful as a drug application system to the skin.

[0037] When retaining a large amount of drug, it is also possible to fill the microneedles whose application shape is surrounded within the maximum group, and in that case, it is also conceivable to function as one "needle" when puncturing the skin. For example, in the microneedle array shown in FIG. 5, all the formed groups can form a drug application part, and that state can be confirmed by the micrograph of FIG. 6.

[0038] The drug application part for each group shown in FIG. 6 is in the space sandwiched by the microneedles of the group, and moreover, its height is equal to or lower than the tip of the microneedle. This is a characteristic of the drug application microneedle obtained by normal drug application. However, the height of the drug application part does not necessarily have to be equal to or lower than the tip of the needle. The height of the drug application part can also be made higher than the tip of the needle. By adjusting the concentration of the drug solution to increase the viscosity, a drug application part longer than the needle length can be formed. By making the tip of the application part pointed, the puncturability of the microneedle itself can be improved. Another merit is that making the shape of the application part higher and pointed than the needle tip necessarily increases the volume of the drug application part, that is, enables an increase in the amount of drug applied. An example of a drug application microneedle in which the drug application part exceeds the tip of the microneedle is shown in FIG. 13. Its details are described in Example 3. The difference between the tip of the drug application part and the tip of the microneedle (the distance by which the drug application part exceeds the tip of the microneedle) is preferably 0.1 mm to 2 mm.

Example

[0039] Hereinafter, the present invention will be described in more detail with 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.

[0040] Example 1 Micro-needle array before drug application The characteristics of the micro-needle array used in Example 1 will be described with reference to FIG. 5.

[0041] The micro-needle array shown in FIG. 5 has a circular substrate 1 with a diameter of 10 mm and a thickness of 1.5 mm on an elliptical patch board (substrate 2: major axis 1.8 cm, minor axis 1.4 cm, thickness 1 mm), and 109 pedestals stand on it. Since there are 7 micro-needles standing on each pedestal, this micro-needle array has 109 pedestals and 763 micro-needles. One of the 7 micro-needles is arranged at the center of the pedestal, and the remaining 6 are arranged around the pedestal. The material of this micro-needle array is polyglycolic acid and it was manufactured by injection molding. One pedestal is a frustum of a cone with a tip diameter of 0.55 mm, a root diameter of 0.6 mm, and a height of 0.3 mm. The distance between the pedestals is such that the center-to-center distance of the pedestals is 0.8 mm. One micro-needle has a tip diameter of 0.03 mm, a root diameter of 0.11 mm, and a length of 0.6 mm, and has a step in the middle. The micro-needles are arranged such that 1 is at the center of the pedestal and 6 surround it around the pedestal, with an equal-spacing arrangement where the center-to-center distance of the needles is 0.2 mm.

[0042] Micro-needle array having a drug application part The evaluation of the micro-needle array manufactured in Example 1 was carried out as follows. A trace amount of a red dye (New Coccine) was added to an aqueous solution containing 20% by mass of hyaluronic acid to obtain a test solution. The test solution was filled in a wide-mouth container, immersed from the tip end of the micro-needle array to a depth of 0.3 mm, and then pulled out and dried with warm air. The immersion operation was repeated twice. A micrograph of the dried tip needles is shown in FIG. 6. The inner space of the 6 micro-needles arranged around the pedestal is filled with the coating. When the weight of the dried coating was obtained by subtracting the weight of the blank micro-needle array from the weight of the coated micro-needle array, it was 5.0 mg. This example is a model experiment, and the coating weight is the paste weight. When the drug content is 50%, the drug content is calculated to be 2.5 mg. A micro-needle array having a drug application part was administered to the upper arm of a volunteer human by an applicator, taken out 24 hours later, and the micro-needle array was dried and weighed. It was found that more than 90% of the applied substance (paste) had migrated to the skin.

[0043] Prior to administering the micro-needle array of Example 1 to the upper arm of a volunteer human by an applicator, a parafilm (thickness 140 μm) was placed on the upper arm, and a micrograph of the parafilm when the micro-needle array was separately administered from above is shown in FIG. 7. Insertion traces of all the micro-needles were confirmed on the parafilm.

[0044] Example 2 A micro-needle array similar to that used in Example 1 was immersed in the same test solution as in Example 1 four times to produce a micro-needle array having a drug application part. The weight of the applied substance (paste) after drying was 12.0 mg. A micrograph of the dried tip needles is shown in FIG. 8.

[0045] Comparative Example 1 An operation of immersing 745 micro-needles of the same type as the needles of the micro-needle array manufactured in Example 1, which are micro-needle arrays made of polyglycolic acid standing on a substrate with a diameter of 10 mm, in a test solution and drying them was repeated twice under the same conditions as in Example 1. When the weight of the applied substance after drying was measured, it was 0.45 mg. A micrograph of the micro-needles after application is shown in FIG. 9.

[0046] Examples 3, 4 A part of the micro-needle array similar to that used in Example 1 was removed by laser cutting to fabricate a micro-array consisting of 63 micro-needles in 9 groups as shown in Fig. 12. Using this array with the needle surface facing downward, an aqueous solution of 20% by mass of Metrose (registered trademark, manufactured by Shin-Etsu Chemical Co., Ltd.) was used as the coating solution, and it was pulled up and dried at a pulling-up speed of 1 mm / min. This operation was repeated 3 times to fabricate a micro-needle array (without sharp tips) (Example 4). Then, for the fourth coating, when the tip of the needle rose 1 mm above the coating liquid surface, it was stopped and air-dried for 30 seconds to fabricate a micro-needle array (with sharp tips) (Example 3). Microscopic photographs of both after drying are shown in Fig. 13 (Example 3) and Fig. 14 (Example 4). Also, the physical properties are summarized in Table 1.

[0047]

Table 1

[0048] (Paraffin film puncture property evaluation) Puncture property evaluation was performed using the micro-needle array (with sharp tips) of Example 3 and the micro-needle array (without sharp tips) of Example 4.

[0049] For the puncture test, 8 paraffin films (PF) were stacked as a simulated skin, and as shown in Fig. 15, a styrofoam sheet, a silicon sheet, and 8 PF (thickness of about 130 μm per sheet) were stacked in order from the bottom. The silicon sheet and the styrofoam were used to provide cushioning similar to that of the skin. The micro-needle array was stamped on the surface of the first PF (the topmost) with the company's applicator, and it was evaluated how many PFs the micro-needles penetrated. After applying the micro-needle array, it was removed from the PF, and each PF was observed under a microscope to measure the area penetrated by the needles. As a result, the PFs that were all penetrated by the needles were up to the 5th sheet (650 μm) from the top for the micro-needle array (with sharp tips) of Example 3 and up to the 3rd sheet (390 μm) for the micro-needle array (without sharp tips) of Example 4.

[0050] Examination The micro-needle array of Example 1 and the micro-needle array of Comparative Example 1 have approximately the same number of micro-needles, but the drug coating amount is about 10 times different, being 0.45 mg for 5.0 mg. In the drug coating part formed on the micro-needle array of Example 1, a large amount of the coating is efficiently transdermally absorbed, indicating the superiority of the micro-needle array of the present invention. It is considered that having 3 or more micro-needles in one group can greatly exert the skin puncture force. In Comparative Example 1, since the tip of one micro-needle has a drug coating part with a diameter exceeding 90 μm (Fig. 9), the transdermal absorption efficiency is considered to be low. Although the needle length is uniform, the micro-needles having a drug coating above the tip of the needle were confirmed to have superiority in puncture performance.

Explanation of Signs

[0051] 1 Substrate 2 Micro-needle 3 Group of micro-needles 4 Group diameter 5 Base 6 Drug coating part 7 Substrate 1 8 Substrate 2 (patch board) 9 Group 10 Upper surface of the micro-needle array

Claims

1. A drug - applying type micro - needle array comprising a substrate and a plurality of micro - needles, wherein the micro - needles form groups of at least three each to form a space, and the space is arranged on the substrate so as to provide a drug - applying part.

2. The micro - needle array according to Claim 1, wherein there are two or more groups of the micro - needles.

3. The micro - needle array according to Claim 1, wherein the micro - needles are made of a thermoplastic polymer.

4. The micro - needle array according to Claim 3, wherein the thermoplastic polymer is nylon, polycarbonate, polylactic acid, poly (lactic - glycolic acid) copolymer, polyglycolic acid, polyethylene terephthalate, cyclic olefin polymer, and mixtures thereof.

5. The micro - needle array according to Claim 1, wherein the root diameter of the micro - needles is 0.03 - 1 mm, the tip diameter is 0.02 - 0.2 mm, and the length is 0.2 - 3 mm.

6. The micro - needle array according to Claim 1, wherein the distance between adjacent micro - needles within the group is 0.05 - 1 mm.

7. The micro - needle array according to Claim 1, wherein the groups of the micro - needles are independently arranged on a base standing on the substrate.

8. The micro - needle array according to Claim 7, wherein the base is cylindrical or frustum - shaped, the root diameter of the base is 0.1 - 30 mm, the tip diameter is 0.04 - 30 mm, and the height is 0.2 - 10 mm.

9. A micro - needle patch comprising the micro - needle array according to any one of Claims 1 to 8 and an adhesive tape laminated on the substrate of the micro - needle array.

10. A drug - applying system to the skin, comprising the micro - needle array according to any one of Claims 1 to 8 and a drug - applying part provided in the space of the group of the micro - needle array.

11. A drug - applying system to the skin, comprising the micro - needle patch according to Claim 9 and a drug - applying part provided in the space of the group of the micro - needle array of the micro - needle patch.

12. The drug application system according to claim 10, characterized in that the paste retention amount in the space of one group is 10 μg or more.

13. The drug application system according to claim 11, characterized in that the paste retention amount in the space of one group is 10 μg or more.

14. The drug application system according to claim 10, wherein the drug is selected from the group consisting of antipyretics, anti-inflammatory steroids, vasodilators, antiarrhythmic agents, antihypertensive agents, local anesthetics, hormones, antihistamines, general anesthetics, sleep analgesics, antiepileptic agents, psychotropic agents, skeletal muscle relaxants, autonomic nerve agents, antiparkinson agents, diuretics, vasoconstrictors, respiratory stimulants, narcotics, antigenic components of pathogens, and cosmetic raw materials.

15. The drug application system according to claim 11, wherein the drug is selected from the group consisting of antipyretics, anti-inflammatory steroids, vasodilators, antiarrhythmic agents, antihypertensive agents, local anesthetics, hormones, antihistamines, general anesthetics, sleep analgesics, antiepileptic agents, psychotropic agents, skeletal muscle relaxants, autonomic nerve agents, antiparkinson agents, diuretics, vasoconstrictors, respiratory stimulants, narcotics, antigenic components of pathogens, and cosmetic raw materials.

16. The microneedle array according to claim 1, characterized in that the plurality of microneedles are non-uniform in any of the root diameter, tip diameter or length.

17. The drug application system according to claim 10, characterized in that the height of the drug application part exceeds the tip of the microneedle.

18. The drug application system according to claim 11, characterized in that the height of the drug application part exceeds the tip of the microneedle.

19. The drug application system according to claim 17, characterized in that the difference between the drug application part and the tip of the microneedle is 0.1 m to 2.0 mm.

20. The drug application system according to claim 18, characterized in that the difference between the drug application part and the tip of the microneedle is 0.1 m to 2.0 mm.

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