Microneedle array

Abstract

A disadvantage of coated-type microneedles is that it is difficult to coat the microneedles with a large amount of a drug, thus limiting effective use of the drug. The present invention overcomes this disadvantage of coated-type microneedles.　Provided is a drug coated-type microneedle array characterized by comprising a substrate and a plurality of microneedles, wherein groups of three or more microneedles are formed to form spaces, and each space is disposed on the substrate so as to provide a drug-coated section.

Description

Microneedle Array

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

[0002] Currently, various dosage forms of microneedles with different shapes and materials are known, and their properties are known to be water-soluble and water-insoluble. Microneedles are being widely used in medicines, cosmetics, etc. Microneedles for pharmaceutical applications, particularly vaccine applications, are broadly divided into those in which the drug is encapsulated in the microneedle and those in which the drug is applied to the microneedle. These are called solid microneedles. Considering the efficient use of the drug and the efficiency of production, the application type is more desirable than the encapsulation type.

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

[0004] Japanese Patent Application Laid-Open No. 2008-029710 Japanese Patent Application Laid-Open No. 2007-521090 Japanese Patent Application Laid-Open No. 2008-520370 International Publication No. 2008 / 139648 Pamphlet

[0005] The method of immersing the tip of a microneedle in a drug solution and attaching the drug to the tip of the microneedle is simple and easy to put into practical use. However, it is extremely difficult to quantitatively and consistently apply a drug to the tip of a microneedle. Applying a drug solution to a microneedle made of a hydrophobic material is difficult, and simply immersing a microneedle made of a hydrophilic material in a drug solution causes the drug solution to easily rise up the needle to the bottom of the substrate due to capillary action. Therefore, although many attempts have been made to immerse a microneedle array to a certain depth in a drug solution and quantitatively apply a large amount of drug, it has been extremely difficult. It is also known that adding a water-soluble polymer to the drug solution to thicken it and make it easier to adhere to the needle, in order to apply a large amount of drug to the tip of the microneedle (e.g., JP 2017-137311 A). However, it has been pointed out that adding a water-soluble polymer can make administering a drug-coated microneedle array to the skin time-consuming because the drug-coated area is dissolved by the trace amounts of water present on the skin, resulting in excessively long administration times. Furthermore, by increasing the amount of additive, the drug-applied area tends to become thick and spherical (see Comparative Example 1 and Figure 9), which significantly reduces the puncture force into the skin and tends to reduce the bioavailability of the drug. In a microneedle array in which a drug is simply applied to the tip of the microneedle, the amount of drug is 1 mg / cm ２ When the applied pressure exceeds 1000 MPa, it is often impossible to obtain a high drug bioavailability of 80% or more. The disadvantage of application-type microneedles is that it is difficult to apply a large amount of drug to the microneedles, and therefore the drugs that can be effectively used are limited. The object of the present invention is to eliminate such disadvantages of application-type microneedles.

[0006] To solve the above problems, the inventors conducted detailed studies on a wide variety of drug-coated microneedles and conducted extensive research into the geometric shape of the needles. As a result, they discovered that a microneedle array with a specific shape could achieve the desired objective, leading to the completion of 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 so as to form groups of at least three microneedles to form spaces, and the spaces provide drug-coated areas. [2] The microneedle array according to [1], wherein the microneedles are grouped into two or more groups. [3] The microneedle array according to [1] or [2], wherein the microneedles are made of a thermoplastic polymer. [4] The microneedle array according to [3], wherein 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 any one of [1] to [4], characterized in that 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 any one of [1] to [5], characterized in that the distance between adjacent microneedles within the group is 0.05 to 1 mm. [7] The microneedle array according to any one of [1] to [6], characterized in that the groups of microneedles are independently arranged on bases standing on a substrate. [8] The microneedle array according to [7], characterized in that the bases are cylindrical or truncated cones, and have 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] The microneedle array according to any one of [1] to [8], characterized in that the plurality of microneedles are non-uniform in any one of the base diameter, tip diameter, or length.

[10] A microneedle patch comprising the microneedle array according to any one of [1] to [9] and an adhesive tape backed on the substrate of the microneedle array.

[11] A drug application system for skin comprising the microneedle array according to any one of [1] to [9] and a drug application part provided in the space between the groups of the microneedle array.

[12] A drug application system for skin comprising the microneedle patch according to

[10] and a drug application part provided in the space between the groups of the microneedle array of the microneedle patch.

[13] The drug application system according to

[11] or

[12] , characterized in that the amount of plaster held in the space between one group is 10 μg or more.

[14] The drug application system according to any one of

[11] to

[13] , 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, antiepileptic drugs, psychotropic agents, skeletal muscle relaxants, autonomic nervous system agents, antiparkinsonian drugs, diuretics, vasoconstrictors, respiratory stimulants, narcotics, antigenic components of pathogens, and cosmetic raw materials.

[15] The drug application system according to any one of

[11] to

[14] , wherein the height of the drug application section exceeds the tip of the microneedle.

[16] The drug application system according to any one of

[11] to

[15] , wherein the difference between the tip of the drug application section and the tip of the microneedle is 0.1 mm to 2.0 mm.

[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.

[0008] FIG. 1 is a schematic diagram showing an example of a microneedle array of the present invention. Three groups of microneedles are arranged on a substrate. FIG. 2 is a schematic diagram showing another example of a microneedle array of the present invention. The three groups of microneedles are arranged on separate group stands formed on a substrate. FIG. 3 is a schematic diagram showing an example of a coating method when a drug is coated on a coatable microneedle array of the present invention. FIG. 4 is a schematic diagram showing a microneedle array coated with a drug according to the prior art. FIG. 5 is a micrograph showing the microneedle array of Example 1. FIG. 6 is a micrograph showing an enlarged view of the drug-coated portion when a drug is coated on the microneedle array of Example 1. No drug is coated on the needle tip. FIG. 7 is a micrograph showing the puncture state when the coatable microneedle array of Example 1 is administered to the upper arm, reproduced on parafilm. FIG. 8 is a micrograph showing an enlarged view of the drug-coated portion of the coatable microneedle array of Example 2. The drug is coated up to the needle tip. FIG. 9 is a micrograph showing a drug-coated microneedle array of Comparative Example 1. FIG. 10 is a schematic diagram of a microneedle array of the present invention viewed from above. FIG. 10A shows an embodiment in which the groups are uniformly distributed, FIG. 10B shows an embodiment in which there are no groups in the center of the substrate, and FIG. 10C shows an embodiment in which the groups are sparsely arranged in the center of the substrate and densely arranged in the periphery of the substrate. FIG. 11 shows a microneedle array (FIGS. 11A and 11B) having microneedles with uniform or non-uniform needle lengths within a group, and schematic diagrams (FIGS. 11C and 11D) after drug application. FIGS. 11A and 11C show examples of microneedles with uniform needle lengths, and FIGS. 11B and 11D show examples of microneedles with non-uniform needle lengths. FIG. 12 is a micrograph showing the microneedle array of Example 3. FIG. 13 is a micrograph showing an example of a drug application system including the microneedle array of Example 3 and a drug application portion with a sharp tip. FIG. 14 is a micrograph showing an example of a drug application system including the microneedle array of Example 3 and a drug application portion with a blunt tip. FIG. 15 is a schematic diagram showing the cross-sectional structure of the simulated skin overlaid with parafilm.

[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 drug-coated microneedle array. The microneedle array of the present invention comprises a substrate and a plurality of microneedles, the microneedles being arranged on the substrate in groups of at least three to form a space, the space providing a drug-coated area. The microneedles are arranged in groups of at least three to form a space. The microneedles are arranged on the substrate in groups of at least three to form a space.

[0011] (Substrate) The microneedle array of the present invention comprises a substrate. The shape (shape in plan view) of the substrate is preferably circular, but is not particularly limited. When the substrate is circular, 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 thereon is small, making it difficult to ensure a sufficient amount of drug application. Considering the planarity of the human skin to be punctured, a diameter of 30 mm or less is desirable. From the viewpoint of handling the microneedle array, the thickness of the substrate is 0.05 mm to 3.0 mm, preferably 0.1 mm to 2.0 mm.

[0012] (Patch Plate) The microneedle array of the present invention may or may not include a patch plate on the surface of the substrate opposite to the microneedle side. The patch plate is located below the substrate and supports it. The patch plate is provided for ease of molding and storage, but is not an essential part related to the performance of the microneedles. The patch plate has a larger area than the substrate and a thickness of 0.5 mm to 2.0 mm.

[0013] (Grouped Microneedles) The microneedle array of the present invention comprises a plurality of microneedles. The present invention is characterized by the arrangement of the microneedles standing on the substrate of the microneedle array. The microneedles stand on the substrate in groups, with each group standing directly on the substrate (an example is shown in FIG. 1), or each group may form its own group base (an example is shown in FIG. 2). Each group has a shape such as a circle, square, or triangle, and the microneedles are arranged therein. In the case of a circle, the diameter is 0.1 mm to 30 mm. If the diameter is less than 0.1 mm, it is difficult to hold three microneedles therein. If the diameter exceeds 30 mm, one group becomes the size of the substrate. When the groups stand on the substrate as a base, 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 differ between groups. If the number of microneedles in one group is less than three, it is difficult to achieve the objective of the present invention, which is for the space between the microneedles to be filled with the coating solution, which then dries and retains the drug between the microneedles. If the number of microneedles exceeds 200, the needle density increases and skin puncture resistance decreases. The structure of the microneedle array is schematically shown in Figure 1. Although Figure 1 shows three groups of microneedles, 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 exceeds 1,000, the number of groups increases, resulting in increased needle density of the microneedles and decreased skin puncture resistance.

[0014] In the present invention, the groups of microneedles arranged on the substrate do not need to be uniformly arranged. Figure 10A shows an example in which the groups are uniformly arranged in an array. It is known that in microneedle arrays with a large number of microneedles, the puncture resistance tends to be inferior in the center of the substrate compared to the periphery of the substrate. In the present invention, rather than arranging the groups uniformly on the substrate, the density in the center of the substrate may be low (see Figure 10C) or zero (see Figure 10B). The number of groups in the schematic diagram shown in Figure 10 is much smaller than the number of groups shown in the photograph in Figure 5. In this way, reducing the number of groups is also possible depending on the purpose. The number of microneedles shown in Figure 10 is four per group, while the number of microneedles shown in Figure 5 is seven per group. The number of microneedles is related to the amount of drug applied or the strength of the coated microneedles, and it is desirable to change it as needed.

[0015] (Base) The microneedles stand on the substrate in groups, but a base may be formed on the substrate with the microneedles standing on top of it. That is, the microneedle array of the present invention may have a base between the substrate and the microneedles. A structure in which microneedles stand on a base for each group is schematically shown in Figure 2. In the case of a substrate on which a base is formed, the microneedles are arranged independently for each group on the base, and are not arranged directly on the substrate. The number of bases corresponds to the number of groups of microneedles, and is 1 to 1,000, with 2 to 500 being preferred.

[0016] The base maintains a certain space between the substrate of the microneedle array and the base of the microneedles, preventing the lower end of the drug-applied portion from reaching the substrate. Skin is elastic and has an uneven surface. The inventors have found that when administering a microneedle array using an applicator, the needles do not usually penetrate all the way to the base, but are often suspended approximately 200 μm above the base (see JP 2018-108375 A). In the present invention, too, it is desirable to set the lower end of the drug-applied portion at a height of 200 μm or more above the substrate of the microneedle array from the perspective of drug administration efficiency. In the case of a microneedle array having a base, the lower end of the drug-applied portion is prevented from reaching the substrate beyond the base, and the height of the base can define the lower limit of the lower end of the drug-applied portion. Therefore, the height of the base is preferably 0.2 mm to 10 mm.

[0017] The presence of a base has the effect of increasing the overall length of the needle and is also advantageous in terms of puncture performance. The shape of the base can be a truncated cone, a cylindrical shape, a polygonal truncated pyramid shape, etc., with a truncated cone and a cylindrical shape being preferred. The upper area of ​​the base must be large enough to stably support the group on which the microneedles stand, and is appropriately determined depending on the number of microneedles in the group. It is desirable that the lower area of ​​the base be equal to or larger than the upper area.

[0018] When the base is cylindrical or truncated cone, the base preferably has a base diameter of 0.1 mm to 30 mm and a tip diameter (top diameter of the base) of 0.04 mm to 30 mm.

[0019] (Microneedles) In each group, the microneedles are preferably arranged in a circular, square, triangular, or other shape to hold the applied drug. When puncturing the skin, one group acts as a drug holder to deliver the drug to the skin. The microneedles are preferably solid microneedles.

[0020] The length of the microneedle is 0.2 mm to 3 mm. The length of the microneedle is the length from the base of the needle to the tip of the needle. The base of the needle is located on the upper surface of the substrate or the upper surface of the base. If the length is less than 0.2 mm, the volume of the filling portion that fills the space between the needles is too small, which deviates from the purpose of the present invention. Considering the moldability of the microneedle and its ability to puncture the skin, a length of 3 mm or less is desirable.

[0021] Although it is basic that all microneedles have the same length, this is not a requirement. The lengths of the microneedles within a group may vary. The lengths of multiple microneedles may be uneven. For example, by making the needles in the center of the group the longest and shortening the needle lengths toward the periphery, the shape of the group after drug application can be made convex in the center, thereby improving needle penetration. For example, in FIG. 11, the needles in FIG. 11A have uniform lengths, while in FIG. 11B the needles in the center are longer than those in the periphery. When a drug is applied to such a microneedle array, the drug application system shown in FIGS. 11C and 11D is obtained. The drug application system in FIG. 11D has a sharp tip at the drug application portion, thereby improving penetration and drug bioavailability compared to the drug application system in FIG. 11C.

[0022] The base diameter of the microneedle is a maximum of 1 mm, provided that the drug solution is filled 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 along the way. The base diameter of multiple microneedles may be uneven. The tip diameter of the microneedle is 0.02 mm to 0.2 mm. If it is less than 0.02 mm, the mechanical strength of the needle will be weak, causing problems with puncture ability. If it exceeds 0.2 mm, the needle will be too thick and will have poor skin puncture ability. The tip diameter of multiple microneedles may be uneven.

[0023] The distance between adjacent microneedles in each group (adjacent needle distance) is 0.05 mm to 1 mm. If the adjacent needle distance is less than 0.05 mm, this does not meet the purpose of the present invention, which is to fill the gaps with a large amount of drug. If the adjacent needle distance is 1 mm or less, it is easy to retain the drug solution between the needles due to surface tension.

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

[0025] (Drugs to be applied to microneedles) The drugs are not particularly limited as long as they are drugs and cosmetic raw materials that have been conventionally used as transdermal absorption preparations. Examples of drugs include antipyretic analgesic anti-inflammatory drugs, steroidal anti-inflammatory drugs, vasodilators, antiarrhythmic drugs, antihypertensive drugs, local anesthetics, hormones, antihistamines, general anesthetics, hypnotics, antiepileptic drugs, psychotropic drugs, skeletal muscle relaxants, autonomic nervous system drugs, antiparkinsonian drugs, diuretics, vasoconstrictors, respiratory stimulants, narcotics, and antigenic components of pathogens (e.g., vaccine antigen proteins). The content of the drug can be appropriately set according to the characteristics of the component, the purpose of administration, the subject of administration, the number of administrations, etc.

[0026] Most of the drugs are low molecular weight compounds with a molecular weight of 600 or less, but high molecular weight drugs can also be used. Preferred high molecular weight drugs include, for example, physiologically active peptides and their derivatives, nucleic acids, oligonucleotides, various antigenic proteins, bacterial and viral fragments, etc.

[0027] Examples of the physiologically active 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 to animals as well as humans. Examples of antigenic proteins include influenza antigen, Japanese encephalitis antigen, diphtheria antigen, tetanus antigen, HBs surface antigen, and HBe antigen.

[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 adhesive tape. When applying the microneedle array to the skin, the periphery of the substrate may be lined with adhesive tape to fix the array to the skin. Although adhesive tape is not essential, fixation with adhesive tape is preferred to stably fix the patch to the skin.

[0029] Adhesive tapes consist of an adhesive and a substrate, with the adhesive coated on the substrate. Adhesives such as rubber, silicone, acrylic, and urethane adhesives can be used. Hydrophilic adhesives are preferred for application to the oral mucosa. Examples of hydrophilic adhesives include hydrophilic acrylic adhesives, HiPAS10 (trade name) adhesive (an acrylic adhesive with methyl methacrylate as the main monomer, manufactured by Cosmedy Pharmaceuticals), and HiPAS-PU (trade name) (a urethane adhesive, manufactured by Cosmedy Pharmaceuticals).

[0030] A plasticizer may be added to the adhesive, and examples of the plasticizer that can be used include commonly used plasticizers such as isopropyl myristate, isopropyl palmitate, octyl myristate, and octyldodecyl lactate.

[0031] (Manufacturing of Microneedle Arrays) 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 JP 2003-238347 A,

[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 cm to form the shape of the microneedles. A microfabrication method 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) 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 that the immersion is limited to the needle part and does not reach the substrate part, and the application is carried out. 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, and the drug may be retained on the microneedle together with the coexisting substance upon drying after application. 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 mPa·S 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 is 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 a 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 may function as a single "needle" when puncturing 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 puncture power than conventional microneedles in which drug is coated onto the tip of the microneedle to form a large sphere. Figure 4 shows a schematic representation of a conventional drug-coated microneedle array. Conventional microneedle arrays have large spherical application areas, and the maximum application amount of the plaster is estimated to be approximately 1 μg per needle. Here, the plaster refers to the total applied solid, including the drug, base, plasticizer, etc. If the drug content is 50%, the maximum application amount of the drug is 0.5 μg per needle. The microneedle array of the present invention can increase the amount of plaster retained in the space between each group to 10 μg or more. The microneedle array and microneedle patch of the present invention coated with a drug are useful as a drug application system to the skin.

[0037] When a large amount of drug is held, the applied shape may be large enough to fill the microneedles enclosed within the largest group, in which case it may function as a single "needle" when puncturing the skin. For example, in the microneedle array shown in Figure 5, all of the formed groups can form drug-applied areas, and this state can be confirmed in the micrograph of Figure 6.

[0038] The drug-coated portion of each group shown in Figure 6 is located in the space between the microneedles of the group, and its height is equal to or lower than the tip of the microneedle. This is a characteristic of drug-coated microneedles obtained by conventional drug coating. However, the height of the drug-coated portion does not need to be equal to or lower than the tip of the needle. The height of the drug-coated portion can also be higher than the tip of the needle. By adjusting the concentration of the drug solution to increase viscosity, a drug-coated portion longer than the needle length can be formed. Sharpening the tip of the coated portion can improve the puncture ability of the microneedle itself. Another advantage is that making the coated portion higher and more pointed than the needle tip inevitably increases the volume of the drug-coated portion, i.e., allows for a larger amount of drug to be applied. Figure 13 shows an example of a drug-coated microneedle in which the drug-coated portion exceeds the tip of the microneedle. Details are described in Example 3. The difference between the tip of the drug-coated portion and the tip of the microneedle (the distance by which the drug-coated portion exceeds the tip of the microneedle) is preferably 0.1 mm to 2 mm.

[0039] The present invention will be described in more detail below with reference to the following examples. These examples are merely examples for specifically explaining the present invention, and the scope of the present invention is not limited to these examples.

[0040] Example 1 Microneedle Array Before Drug Application The characteristics of the microneedle array used in Example 1 will be explained with reference to FIG.

[0041] The microneedle array shown in Figure 5 has a circular substrate 1 with a diameter of 10 mm and a thickness of 1.5 mm on an oval patch plate (substrate 2: major axis 1.8 cm, minor axis 1.4 cm, thickness 1 mm), on which 109 bases stand. Seven microneedles stood on each base, resulting in a microneedle array with 109 bases and 763 microneedles. One of the seven microneedles was positioned at the center of the base, and the remaining six were positioned around the periphery of the base. The microneedle array was made of polyglycolic acid and manufactured by injection molding. Each base was a truncated cone with a tip diameter of 0.55 mm, a base diameter of 0.6 mm, and a height of 0.3 mm. The distance between the bases was 0.8 mm from center to center. Each microneedle had a tip diameter of 0.03 mm, a base diameter of 0.11 mm, a length of 0.6 mm, and a step along the middle. One microneedle was placed at the center of the base and six others were placed around the periphery of the base, with the needles being equally spaced apart with a center-to-center distance of 0.2 mm.

[0042] Microneedle Array with Drug-Coated Portion The microneedle array produced in Example 1 was evaluated as follows. A trace amount of red pigment (New Coccine) was added to an aqueous solution containing 20% ​​by weight of hyaluronic acid to prepare a test solution. A wide-mouthed container was filled with the test solution, and the microneedle array was immersed to a depth of 0.3 mm from the needle tip, then lifted out and dried with warm air. This immersion process was repeated twice. Figure 6 shows a micrograph of the tip needle after drying. The inner space of the six microneedles arranged around the base is filled with the coating material. The weight of the coating material after drying was calculated by subtracting the weight of the blank microneedle array from the weight of the coated microneedle array, resulting in 5.0 mg. This example is a model experiment, and the weight of the coating material is the weight of the plaster. When the drug is contained at 50%, the drug content is calculated as 2.5 mg. A microneedle array with a drug application area was administered to the upper arm of a human volunteer using an applicator, and after 24 hours it was removed, dried, and weighed. It was found that more than 90% of the applied substance (paste) had been transferred to the skin.

[0043] Prior to administering the microneedle array of Example 1 to the upper arm of a human volunteer using an applicator, parafilm (thickness 140 μm) was placed on the upper arm, and the microneedle array was then administered separately from the parafilm. A micrograph of the parafilm is shown in Figure 7. Traces of all microneedle insertions were confirmed on the parafilm.

[0044] Example 2 A microneedle array similar to that used in Example 1 was immersed a total of four times in the same test solution as in Example 1 to produce a microneedle array having a drug-coated portion. The weight of the coated material (plaster) after drying was 12.0 mg. A micrograph of the tip needle after drying is shown in Figure 8.

[0045] Comparative Example 1 A microneedle array made of polyglycolic acid, in which 745 microneedles of the same type as the needles of the microneedle array produced in Example 1 stood on a substrate with a diameter of 10 mm, was immersed in the test solution and dried twice under the same conditions as in Example 1. The weight of the coated product after drying was measured and found to be 0.45 mg. A micrograph of the microneedles after coating is shown in Figure 9.

[0046] Examples 3 and 4: A portion of the microneedle array similar to that used in Example 1 was removed by laser cutting, and a microarray consisting of 9 groups and 63 microneedles as shown in FIG. 12 was prepared. Using this array, the needle surface was facing downward, and a 20% by weight Metolose (registered trademark, manufactured by Shin-Etsu Chemical Co., Ltd.) aqueous solution was used as the coating solution, and the array was pulled up and dried at a pulling speed of 1 mm / min. This operation was repeated three times to prepare a microneedle array (without sharpened tips) (Example 4). After that, the fourth application was stopped when the needle tip rose 1 mm above the coating solution surface, and air-dried for 30 seconds to prepare a microneedle array (with sharpened tips) (Example 3). Micrographs of both the arrays after drying are shown in FIG. 13 (Example 3) and FIG. 14 (Example 4). The physical properties are also summarized in Table 1.

[0047]

[0048] (Evaluation of Puncture Ability of Parafilm) Puncture ability was evaluated using the microneedle array of Example 3 (sharp tip) and the microneedle array of Example 4 (non-sharp tip).

[0049] For the puncture resistance test, eight sheets of parafilm (PF) were stacked to form simulated skin, and a polystyrene foam sheet, a silicone sheet, and eight sheets of PF (approximately 130 μm thick per sheet) were stacked from the bottom as shown in Figure 15. The silicone sheet and polystyrene foam were used to provide cushioning similar to that of skin. A microneedle array was struck on the surface of the first (top) sheet of PF using an in-house applicator, and the number of PFs through which the microneedles penetrated was evaluated. After application of the microneedle array, the PFs were removed, and each PF was observed under a microscope to measure the area penetrated by the needles. As a result, the number of PFs through which the needles penetrated was up to the fifth sheet (650 μm) from the top in the microneedle array (sharp tip) of Example 3, and up to the third sheet (390 μm) in the microneedle array (non-sharp tip) of Example 4.

[0050] Discussion The microneedle array of Example 1 and the microneedle array of Comparative Example 1 have approximately the same number of microneedles, but the drug application amount is 5.0 mg versus 0.45 mg, which is approximately 10 times different. A large amount of the applied substance was efficiently absorbed transdermally in the drug application area formed on the microneedle array of Example 1, demonstrating the superiority of the microneedle array of the present invention. It is believed that having three or more microneedles in one group allows for greater skin puncture power. In Comparative Example 1, a drug application area with a diameter exceeding 90 μm at the tip of one microneedle (Figure 9) is believed to have low transdermal absorption efficiency. Microneedles with uniform needle length but drug application height exceeding the needle tip were confirmed to have superior puncture performance.

[0051] REFERENCE SIGNS LIST 1 Substrate 2 Microneedle 3 Group of microneedles 4 Group diameter 5 Base 6 Drug application portion 7 Substrate 1 8 Substrate 2 (patch plate) 9 Group 10 Top surface of microneedle array

Claims

1. An array of drug - applying micro - needles, comprising a substrate and a plurality of micro - needles, wherein at least three micro - needles form a group 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 or 2, 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 any one of claims 1 to 4, 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 any one of claims 1 to 5, wherein the distance between adjacent micro - needles in the group is 0.05 - 1 mm.

7. The micro - needle array according to any one of claims 1 to 6, wherein each group of the micro - needles is 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. The micro - needle array according to any one of claims 1 to 8, wherein the plurality of micro - needles are non - uniform in any one of the root diameter, tip diameter, or length.

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

11. A drug - application system to the skin, comprising the micro - needle array according to any one of claims 1 to 9 and a drug - applying part provided in the space of the group of the micro - needle array.

12. A drug application system for the skin, comprising the micro-needle patch according to claim 10 and a drug application part provided in the space of the group of the micro-needle arrays of the micro-needle patch.

13. The drug application system according to claim 11 or 12, characterized in that the paste holding amount in one group of spaces is 10 μg or more.

14. The drug according to any one of claims 11 to 13, 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, anti-Parkinson agents, diuretics, vasoconstrictors, respiratory stimulants, narcotics, antigen components of pathogens, and cosmetic raw materials. Drug application system.

15. The drug application system according to any one of claims 11 to 14, characterized in that the height of the drug application part exceeds the tip of the micro-needle.

16. The drug application system according to any one of claims 11 to 15, characterized in that the difference between the drug application part and the tip of the micro-needle is 0.1 mm to 2.0 mm.

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