Microneedle device and method for manufacturing the same

Abstract

An object of the present invention is to provide a method for manufacturing a microneedle device, the microneedle device having a coating containing dexmedetomidine and isoproterenol, and having high stability of isoproterenol during and after the manufacturing process of the microneedle device. The method for manufacturing a microneedle device according to an embodiment of the present invention includes a step of applying a coating solution onto the microneedles to form a coating on the microneedles. The microneedle device includes a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles. The coating solution contains: dexmedetomidine or a pharmaceutically acceptable salt thereof, isoproterenol or a pharmaceutically acceptable salt thereof, ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, and a sulfated polysaccharide.

Description

Technical Field

[0001] The present invention relates to a microneedle device and a method for manufacturing the same. Background Art

[0002] Dexmedetomidine is a physiologically active substance that acts on the α2 - adrenergic receptor and exhibits a sedative effect. Conventionally, a microneedle device containing dexmedetomidine as an active ingredient has been known (for example, Patent Document 1). A microneedle device is a device that forms fine pores through which a medicament can pass by puncturing the stratum corneum of the skin with microneedles, thereby enabling transdermal administration of the medicament. A microneedle device generally includes a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles, and the coating contains a medicament.

[0003] The microneedle device of Patent Document 1 is characterized in that by containing both dexmedetomidine and isoproterenol in the coating, the concentration of dexmedetomidine in plasma after administration rises more rapidly.

[0004] Prior Art Documents

[0005] Patent Documents

[0006] Patent Document 1: WO 2018 / 123982 Summary of the Invention

[0007] Problems to be Solved by the Invention

[0008] The microneedle device of Patent Document 1 has a problem that isoproterenol decomposes during the manufacturing process or during storage after manufacturing depending on the circumstances. Therefore, an object of the present invention is to provide a method for manufacturing a microneedle device that has a coating containing dexmedetomidine and isoproterenol and is characterized in that isoproterenol has high stability during the manufacturing process and after manufacturing of the microneedle device. Another object of the present invention is to provide a microneedle device manufactured by this method.

[0009] Means for Solving the Problems

[0010] A method for manufacturing a microneedle device according to an embodiment of the present invention includes a step of applying a coating solution onto the microneedles to form a coating on the microneedles. The microneedle device includes a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles. The coating solution contains: dexmedetomidine or a pharmaceutically acceptable salt thereof, isoproterenol or a pharmaceutically acceptable salt thereof, ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, and a sulfated polysaccharide. The sulfated polysaccharide may be chondroitin sulfate or a pharmaceutically acceptable salt thereof. The mass ratio of ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof in the coating solution to isoproterenol or a pharmaceutically acceptable salt thereof may be 0.013 or more. The concentration of the sulfated polysaccharide in the coating solution may be 0.5% by mass or more.

[0011] A microneedle device according to an embodiment of the present invention includes a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles. The coating contains: dexmedetomidine or a pharmaceutically acceptable salt thereof, isoproterenol or a pharmaceutically acceptable salt thereof, ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, and a sulfated polysaccharide. The sulfated polysaccharide may be chondroitin sulfate or a pharmaceutically acceptable salt thereof. The mass ratio of ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof to isoproterenol or a pharmaceutically acceptable salt thereof may be 0.013 or more. The amount of the sulfated polysaccharide may be 0.5 parts by mass or more based on 100 parts by mass of the coating.

[0012] Advantages of the Invention

[0013] According to the method of the present invention, by using a coating solution containing ethylenediaminetetraacetic acid, the stability of isoproterenol during and after the manufacturing process of the microneedle device is improved.

[0014] In addition, according to the method of the present invention, by using a coating solution containing a sulfated polysaccharide, a microneedle device can be manufactured in which each microneedle loads more dexmedetomidine and isoproterenol. Thus, each microneedle can deliver more dexmedetomidine. Brief Description of the Drawings

[0015] Figure 1 It is a perspective view schematically showing an embodiment of the microneedle device.

[0016] Figure 2 It is a graph showing the relationship between the time required to manufacture the microneedle device and the production rate of an isoproterenol analogue. Detailed Description of the Embodiments

[0017] A method for manufacturing a microneedle device according to an embodiment of the present invention includes a step of applying a coating solution on the microneedles to form a coating on the microneedles (coating step). After the coating step, a step of drying the coating (drying step) may be performed. Here, the microneedle device is a device including a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles. The composition of the coating will be described later.

[0018] Figure 1 It shows an embodiment of the microneedle device of the present invention. The microneedle device 10 includes a substrate 2, a plurality of microneedles 4 disposed on the main surface of the substrate 2, and a coating 6 formed on the microneedles 4. In the present specification, a structure in which a plurality of microneedles 4 are disposed on the substrate 2 is referred to as a microneedle array.

[0019] The substrate 2 is a base for supporting the microneedles 4. The shape of the substrate 2 is not particularly limited. For example, it may be rectangular or circular, and the main surface may be flat or curved. The area of the substrate 2 may be, for example, 0.5 cm 2~10cm 2 , 0.5cm 2 ~5cm 2 , 1cm 2 ~5cm 2 , 0.5cm 2 ~3cm 2 or 1cm 2 ~3cm 2 The thickness of the substrate 2 may be, for example, 50 μm to 2000 μm, 300 μm to 1200 μm, or 500 μm to 1000 μm.

[0020] The microneedle 4 may be a needle-shaped convex structure. The shape of the microneedle 4 may be, for example, a quadrangular pyramid or a cone. The microneedle 4 is a tiny structure, and the length (height) of the microneedle 4 in the direction perpendicular to the main surface of the substrate 2 is H. M For example, it may be 50 μm to 600 μm, 100 μm to 500 μm or 300 μm to 500 μm.

[0021] The microneedles 4 may be arranged on the main surface of the substrate in, for example, a square lattice, a rectangular lattice, a rhombus lattice, a 45° staggered arrangement, or a 60° staggered arrangement.

[0022] The density (needle density) of the microneedles 4 arranged on the substrate 2 is represented by the number of microneedles 4 per unit area of ​​the region substantially provided with the microneedles 4. The region substantially provided with the microneedles 4 refers to a region formed by connecting the outermost microneedles 4 among the plurality of microneedles 4 arranged in the microneedle device 10. From the viewpoint of introducing more dexmedetomidine into the skin, the needle density may be, for example, 10 microneedles / cm 2 Above, 50 pieces / cm 2 Above, or 100 pieces / cm 2 From the perspective of reducing skin irritation, the needle density may be, for example, 2000 needles / cm 2 Below, 850 pieces / cm 2 Below, 500 pieces / cm 2 Below, 200 pieces / cm 2 Below, or 160 / cm 2 the following.

[0023] The materials of the substrate 2 and the microneedles 4 can be, for example, silicon, silicon dioxide, ceramics, metals, polysaccharides, or synthetic or natural resin materials. As polysaccharides, pullulan, chitin, and chitosan can be exemplified. The resin raw materials can be, for example, biodegradable polymers such as polylactic acid, polyglycolide, poly(lactide-co-glycolide), polycaprolactone, polyurethane, polyamino acids (e.g., poly-γ-aminobutyric acid), or non-degradable polymers such as polycarbonate, polymethacrylic acid, ethylene-vinyl acetate, polytetrafluoroethylene, polyoxymethylene, and cyclic olefin copolymer.

[0024] In the coating step in the method for manufacturing the microneedle device 10 according to an embodiment of the present invention, a coating solution is applied to the microneedles 4 to form a coating 6 on the microneedles 4. The coating solution contains: dexmedetomidine or a pharmaceutically acceptable salt thereof; isoproterenol or a pharmaceutically acceptable salt thereof; ethylenediaminetetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof; and sulfated polysaccharide. In the present specification, unless otherwise specified, "dexmedetomidine" means "dexmedetomidine or a pharmaceutically acceptable salt thereof", "isoproterenol" means "isoproterenol or a pharmaceutically acceptable salt thereof", and "ethylenediaminetetraacetic acid" means "ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof".

[0025] In the present invention, dexmedetomidine is the active ingredient, isoproterenol is the ingredient that causes the concentration of dexmedetomidine in the plasma to rise more rapidly, EDTA is the ingredient that improves the stability of isoproterenol, and sulfated polysaccharide is the ingredient that helps to load dexmedetomidine and isoproterenol on the microneedles 4.

[0026] Sulfated polysaccharide is a polysaccharide in which sulfuric acid is bonded to a hydroxyl group or an amino group. Sulfated polysaccharide can be, for example, one or more sulfated polysaccharides selected from chondroitin sulfate, carrageenan, fucoidan, ascophyllan, heparin, heparan sulfate, heparin analogs, keratan sulfate, funoran, porphyran, agaropectin, furselan, rhamnansulfate, sulfated glucuronic acid-xylose-rhamnose polysaccharide, sulfated xylose-arabinogalactan, sulfated glucuronic acid-xylose-rhamnose-galactan, arabinan sulfate, and arabinorhamnan sulfate, dextran sulfate, pentosan sulfate, curdlan sulfate, and cellulose sulfate, and salts thereof. Sulfated polysaccharide is preferably chondroitin sulfate or a pharmaceutically acceptable salt thereof, more preferably sodium chondroitin sulfate.

[0027] The coating solution contains one or more solvents that dissolve the components in the coating solution (i.e., dexmedetomidine, isoproterenol, EDTA, and sulfated polysaccharide). As the solvent, for example, water, polyols, lower alcohols, and triacetin can be mentioned, and water is preferred.

[0028] As long as it does not damage the stability of isoproterenol, the coating solution may further contain other components (e.g., pH regulators, components that promote the migration of dexmedetomidine into the plasma, oils or inorganic substances) in addition to dexmedetomidine, isoproterenol, EDTA, sulfated polysaccharides, and solvents. However, the coating solution preferably does not contain surfactants, monosaccharides, and disaccharides. Surfactants, monosaccharides, and disaccharides may reduce the surface tension and viscosity of the coating solution and decrease the loading amount of the physiologically active substance in each microneedle 4. In addition, from the viewpoint of maintaining the stability of isoproterenol, the coating solution preferably does not contain ascorbic acid or its salts, α-thioglycerol, L-cysteine, and pyrosulfurous acid or its salts.

[0029] The concentration of dexmedetomidine in the coating solution may be, for example, 0.5% by mass or more, 20% by mass or more, 30% by mass or more, or 40% by mass or more, and may be 60% by mass or less or 50% by mass or less. From the viewpoint of sufficiently obtaining the therapeutic effect of dexmedetomidine, the concentration of dexmedetomidine in the coating solution is preferably 0.5% by mass to 60% by mass or 5% by mass to 50% by mass, more preferably 30% by mass to 50% by mass, and further preferably 40% by mass to 50% by mass.

[0030] The concentration of isoproterenol in the coating solution may be, for example, 0.01% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 0.2% by mass or more, 0.3% by mass or more, 1.0% by mass or more, or 1.5% by mass or more, and may be 10% by mass or less, 5% by mass or less, 2.5% by mass or less, or 1.5% by mass or less. From the viewpoint of more rapidly increasing the concentration of dexmedetomidine in the plasma, the concentration of isoproterenol in the coating solution is preferably 0.01% by mass to 10% by mass or 0.1% by mass to 5% by mass, more preferably 0.2% to 2.5% by mass, and further preferably 0.3% by mass to 1.5% by mass.

[0031] The concentration of EDTA in the coating solution may be, for example, 0.01% by mass or more, 0.02% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 1.0% by mass or more, or 1.5% by mass or more, and may be 10% by mass or less, 5% by mass or less, 2.5% by mass or less, or 1.5% by mass or less. From the viewpoint of improving the stability of isoproterenol, the concentration of EDTA in the coating solution is preferably 0.01% by mass to 10% by mass, 0.02% by mass to 5% by mass, or 0.05% by mass to 5% by mass, more preferably 0.1% by mass to 2.5% by mass, and further preferably 0.1% by mass to 1.5% by mass.

[0032] The concentration of the sulfated polysaccharide in the coating solution can be, for example, 0.5% by mass or more, 1% by mass or more, 2% by mass or more, 4% by mass or more, 6% by mass or more, 8% by mass or more, 10% by mass or more, or 12% by mass or more, and can be 16% by mass or less, 14% by mass or less, 12% by mass or less, 10% by mass or less, 8% by mass or less, 6% by mass or less, or 4% by mass or less. From the viewpoint of loading more dexmedetomidine and isoproterenol on each microneedle 4, the concentration of the sulfated polysaccharide in the coating solution is preferably 0.5% by mass to 16% by mass or 1% by mass to 16% by mass, more preferably 2% by mass to 16% by mass or 2% by mass to 14% by mass, and further preferably 4% by mass to 12% by mass.

[0033] The total concentration of other components in the coating solution except for dexmedetomidine, isoproterenol, EDTA, sulfated polysaccharide, and the solvent can be, for example, 80% by mass or less, 60% by mass or less, 30% by mass or less, or 20% by mass or less. The coating solution may also contain no components other than dexmedetomidine, isoproterenol, EDTA, sulfated polysaccharide, and the solvent.

[0034] The mass ratio of EDTA to isoproterenol in the coating solution can be, for example, 0.0067 or more, 0.013 or more, 0.033 or more, 0.067 or more, 0.33 or more, 0.67 or more, or 1 or more, and can be 5 or less, 3.3 or less, or 2 or less. From the viewpoint of improving the stability of isoproterenol, the mass ratio of EDTA to isoproterenol in the coating solution is preferably 0.013 or more or 0.033 or more, more preferably 0.067 or more or 1 or more, and further preferably 0.033 to 5, 0.033 to 1, or 0.067 to 1.

[0035] The mass ratio of the sulfated polysaccharide to dexmedetomidine in the coating solution can be, for example, 0.01 or more, 0.02 or more, 0.04 or more, 0.09 or more, 0.13 or more, 0.18 or more, 0.22 or more, or 0.27 or more, and can be 0.36 or less, 0.31 or less, 0.27 or less, 0.22 or less, 0.18 or less, 0.13 or less, or 0.09 or less. From the viewpoint of loading more dexmedetomidine on each microneedle 4, the mass ratio of the sulfated polysaccharide to dexmedetomidine in the coating solution is preferably 0.01 to 0.36 or 0.02 to 0.36, more preferably 0.04 to 0.36 or 0.04 to 0.31, and further preferably 0.09 to 0.27.

[0036] The mass ratio of the sulfated polysaccharide to isoproterenol in the coating solution can be, for example, 0.3 or more, 0.7 or more, 1 or more, 3 or more, 4 or more, 5 or more, 7 or more, or 8 or more, and can be 40 or less, 27 or less, 16 or less, 11 or less, 9 or less, 8 or less, 7 or less, 5 or less, 4 or less, or 3 or less. From the viewpoint of loading more isoproterenol on each microneedle 4, the mass ratio of the sulfated polysaccharide to isoproterenol in the coating solution is preferably 0.3 to 11 or 0.7 to 11, more preferably 1 to 11 or 1 to 9, and further preferably 3 to 8.

[0037] From the viewpoint of increasing the rising rate of the dexmedetomidine concentration in plasma, the mass ratio of isoproterenol to dexmedetomidine in the coating solution can be 0.003 or more, 0.008 or more, 0.01 or more, 0.03 or more, or 0.07 or more. The mass ratio of isoproterenol to dexmedetomidine in the coating solution can be 0.18 or less, 0.09 or less, 0.08 or less, 0.07 or less, or 0.03 or less, or 0.003 to 0.18 or 0.008 to 0.09. The mass ratio of isoproterenol to dexmedetomidine is preferably 0.008 to 0.03.

[0038] The concentration of each component contained in the coating solution can be measured, for example, by liquid chromatography.

[0039] From the viewpoints of applying more coating solution on the microneedle 4 and forming a coating 6 at the tip portion of the microneedle 4, the viscosity of the coating solution at 25 °C is preferably 500 mPa·s to 30,000 mPa·s, more preferably 1,000 mPa·s to 10,000 mPa·s. From the same viewpoints, the surface tension of the coating solution is preferably 10 mN / m to 100 mN / m, more preferably 20 mN / m to 80 mN / m.

[0040] The coating solution can be prepared by mixing the above components. That is, in one embodiment, the method of the present invention may include the following steps before the coating step: mixing dexmedetomidine, isoproterenol, EDTA, and sulfated polysaccharide to prepare the coating solution. The order of mixing the components is not particularly limited. For example, dexmedetomidine, isoproterenol, EDTA, sulfated polysaccharide, and a solvent can be mixed simultaneously. Or dexmedetomidine, EDTA, and sulfated polysaccharide can be first mixed with the solvent, and then isoproterenol can be added to the mixed solution. Before applying the coating solution to the microneedle 4, for example, a spatula can be used for mixing or stirring. The spatula is not particularly limited. For example, a spatula for screen printing such as a squeegee or a scraper can be used.

[0041] The method of applying the coating liquid onto the microneedles 4 is not particularly limited. For example, the coating liquid can be applied by inkjet coating or dip coating. Among them, dip coating is preferred. In dip coating, the microneedles 4 are immersed in a reservoir storing the coating liquid to a certain depth, and then the microneedles 4 are lifted from the reservoir, thereby applying the coating liquid onto the microneedles 4. According to the method of this embodiment using a coating liquid containing EDTA, even if it takes time from the preparation of the coating liquid to its application onto the microneedles, the decomposition of isoproterenol in the coating liquid in the reservoir can be inhibited. That is, the isoproterenol can be stabilized during the manufacturing process of the microneedle device.

[0042] As an example, the amount of the coating liquid applied onto the microneedles 4 can be adjusted by the depth of immersion of the microneedles 4 in the case of dip coating. Here, the depth of immersion of the microneedles 4 represents the distance from the tip of the immersed microneedles 4 to the surface of the coating liquid. The depth of immersion depends on the length H of the microneedles 4 M , and can be, for example, H M or less, or H M / 2 or less. However, among the components contained in the coating 6, the components contained in the part formed at the base portion of the microneedles 4 are more difficult to penetrate into the skin compared to the components contained in the part formed at the tip portion of the microneedles 4. Therefore, it is preferable to mainly apply more coating liquid onto the tip portion of the microneedles 4. Here, as described later, the tip portion of the microneedles 4 refers to the portion having a length, measured in the vertical direction with respect to the main surface of the substrate 2 (i.e., the base portion), from the tip of the microneedles 4, for example, within 50% of the length of the microneedles 4 M H.

[0043] In any drying process after the coating process, the coating 6 is dried. Here, drying the coating 6 means volatilizing part or all of the solvent contained in the coating 6. For example, the microneedle device 10 can be sealed in a moisture-absorbing aluminum laminated packaging material, or the coating 6 can be dried by methods such as air drying, vacuum drying, freeze drying, or a combination thereof. The preferred drying method is air drying.

[0044] Here, the coating liquid of the present invention containing sulfated polysaccharide has high viscosity and surface tension, so that the downward flow of the coating 6 due to gravity can be further reduced before or during the drying of the coating 6. Therefore, even when the microneedle array is arranged with the microneedles 4 facing upward to dry the coating 6, the coating 6 can be mainly retained at the tip portion of the microneedles 4.

[0045] The coating process and the drying process can be repeated. By repeating these processes, the amount of the formed coating 6 can be further increased.

[0046] The microneedle device 10 according to an embodiment of the present invention manufactured by the above method has a coating 6 on the microneedles 4, and the coating 6 contains dexmedetomidine, isoproterenol, EDTA, and sulfated polysaccharide.

[0047] Details of the microneedle array, dexmedetomidine, isoproterenol, EDTA, and sulfated polysaccharide constituting the microneedle device 10 are as described above. The above coating solution and the coating 6 have the same components except for the solvent. However, the coating 6 may also contain the above solvent.

[0048] The amount of dexmedetomidine, relative to 100 parts by mass of the coating 6, can be, for example, 10 parts by mass or more, 40 parts by mass or more, 45 parts by mass or more, or 60 parts by mass or more, and can be 90 parts by mass or less or 85 parts by mass or less. From the viewpoint of sufficiently obtaining the therapeutic effect of dexmedetomidine, the amount of dexmedetomidine, relative to 100 parts by mass of the coating 6, is preferably 10 parts by mass to 90 parts by mass or 40 parts by mass to 85 parts by mass, more preferably 45 parts by mass to 85 parts by mass, and further preferably 60 parts by mass to 85 parts by mass.

[0049] The amount of isoproterenol, relative to 100 parts by mass of the coating 6, can be, for example, 0.2 parts by mass or more, 0.6 parts by mass or more, 0.8 parts by mass or more, 1.5 parts by mass or more, 2.4 parts by mass or more, or 4.8 parts by mass or more, and can be 12 parts by mass or less, 9 parts by mass or less, 5.5 parts by mass or less, 5.0 parts by mass or less, 4.8 parts by mass or less, or 2.7 parts by mass or less. From the viewpoint of making the dexmedetomidine in plasma rise more rapidly, the amount of isoproterenol, relative to 100 parts by mass of the coating 6, is preferably 0.2 parts by mass to 12 parts by mass or 0.6 parts by mass to 9 parts by mass, more preferably 0.6 parts by mass to 5 parts by mass, and further preferably 0.6 to 2.7 parts by mass.

[0050] The amount of EDTA, relative to 100 parts by mass of the coating 6, can be, for example, 0.02 parts by mass or more, 0.04 parts by mass or more, 0.09 parts by mass or more, 0.2 parts by mass or more, 0.9 parts by mass or more, 1.8 parts by mass or more, or 2.7 parts by mass or more, and can be 10 parts by mass or less, 6 parts by mass or less, 4 parts by mass or less, or 2.7 parts by mass or less. From the viewpoint of improving the stability of isoproterenol, the amount of EDTA, relative to 100 parts by mass of the coating 6, is preferably 0.01 parts by mass to 10 parts by mass, 0.02 parts by mass to 6 parts by mass, or 0.04 parts by mass to 6 parts by mass, more preferably 0.2 parts by mass to 4 parts by mass, and further preferably 0.2 parts by mass to 2.7 parts by mass.

[0051] The amount of the sulfated polysaccharide can be, for example, 1 part by mass or more, 2 parts by mass or more, 4 parts by mass or more, 8 parts by mass or more, 11 parts by mass or more, 15 parts by mass or more, 18 parts by mass or more, or 20 parts by mass or more, relative to 100 parts by mass of the coating 6, and can be 25 parts by mass or less, 23 parts by mass or less, 20 parts by mass or less, 18 parts by mass or less, 15 parts by mass or less, 11 parts by mass or less, or 8 parts by mass or less. From the viewpoint of loading more dexmedetomidine and isoproterenol on each microneedle 4, the amount of the sulfated polysaccharide can be, for example, 1 part by mass to 25 parts by mass, 2 parts by mass to 25 parts by mass, 4 parts by mass to 25 parts by mass, 4 parts by mass to 23 parts by mass, or 8 parts by mass to 20 parts by mass, relative to 100 parts by mass of the coating 6.

[0052] The total amount of other components other than dexmedetomidine, isoproterenol, EDTA, sulfated polysaccharide, and the solvent can be, for example, 95 parts by mass or less, 75 parts by mass or less, 50 parts by mass or less, or 30 parts by mass or less, relative to 100 parts by mass of the coating 6. The coating 6 may also contain no components other than dexmedetomidine, isoproterenol, EDTA, sulfated polysaccharide, and the solvent.

[0053] The mass ratio of EDTA to isoproterenol, the mass ratio of sulfated polysaccharide to dexmedetomidine, the mass ratio of sulfated polysaccharide to isoproterenol, and the mass ratio of isoproterenol to dexmedetomidine are as described above. That is, these mass ratios can be the same as those in the coating solution.

[0054] The loading amount of the coating 6 on each microneedle 4 can be, for example, 10 ng to 10,000 ng, 490 ng to 700 ng, 516 ng to 642 ng, 456 ng to 836 ng, or 819 ng to 836 ng. From the viewpoint of exerting sufficient drug efficacy, the loading amount of dexmedetomidine on each microneedle 4 can be 390 ng or more, 451 ng or more, or 670 ng or more. The upper limit of the loading amount of dexmedetomidine on each microneedle 4 is not particularly limited and can be, for example, 2 μg or less, 1 μg or less, 755 ng or less, 545 ng or less, or 500 ng or less. The loading amount of isoproterenol on each microneedle 4 can be, for example, 0.1 ng to 100 ng, 0.6 ng to 25 ng, or 0.4 ng to 25 ng.

[0055] The amount of each component contained in the coating 6 can be measured, for example, by liquid chromatography.

[0056] In the case where there are multiple microneedles 4, the coating 6 can be formed on all of the microneedles 4 or only on a part of the microneedles 4. The coating 6 can be formed only on a part of the microneedles 4 or can be formed to cover the entirety of the microneedles 4. The coating 6 is preferably formed on the tip portion of the microneedles 4. Here, the tip portion of the microneedles 4 refers to the portion having a length that is within 50%, within 40%, within 30%, or within 20% of the length H of the microneedles 4 measured in the vertical direction from the apex of the microneedles 4 with respect to the main surface of the substrate 2 (i.e., the base portion). The average thickness of the coating 6 can be less than 100 μm, less than 50 μm, or 1 μm to 30 μm. M

[0057] Example

[0058] <Test Example 1-1> Stability of Isoproterenol in a Microneedle Device

[0059] As described below, microneedle devices were manufactured using different stabilizers, and the stability of isoproterenol hydrochloride after 1 month was evaluated.

[0060] A coating solution having the composition shown in Table 1 was prepared, filled into a reservoir, and mixed with a spatula for 60 minutes. Microneedles were provided at a density of 156 needles / cm in a 1 cm 2 area. The shape of each microneedle was a quadrangular pyramid with a height of 500 μm. A microneedle array of polylactic acid was prepared, and the tips of the microneedles were immersed in the coating solution in the reservoir. 2

[0061] After lifting the microneedles from the coating solution, the microneedle device was sealed in a moisture-absorbing aluminum laminate packaging material and stored under the conditions of 50 °C and 75% RH. After storing for 1 month, the coating on the microneedles was extracted, and isoproterenol hydrochloride and isoproterenol analogs in the extract were quantified by high performance liquid chromatography (HPLC).

[0062] The conditions for HPLC were as follows:

[0063] Column: ODS 80Ts QA 5 μm (4.6 mm I.D. × 150 mm)

[0064] Flow rate: 0.5 mL / min

[0065] Detection wavelength: 280 nm

[0066] Calculate the amount (%) of isoproterenol hydrochloride in the coating represented by Formula 1 below, and the production rate (%) of isoproterenol analogs represented by Formula 2 below. Based on these results, evaluate the stability of isoproterenol hydrochloride in the coating. The results are shown in Table 1. Note that the "peak area" in Formula 2 refers to the peak area in the HPLC results after 1 month of storage. The relative retention time (RRT) of isoproterenol analogs relative to isoproterenol hydrochloride is around 1.05.

[0067] (Formula 1):

[0068] Amount (%) of isoproterenol hydrochloride in the coating = Amount of isoproterenol hydrochloride in the coating after 1 month of storage / Amount of isoproterenol hydrochloride in the coating before 1 month of storage × 100

[0069] (Formula 2):

[0070] Production rate (%) of isoproterenol analogs = Peak area of isoproterenol analogs / Peak area of isoproterenol hydrochloride × 100

[0071] [Table 1]

[0072] Comparative Example 1 Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Dexmedetomidine Hydrochloride 45 45 45 45 45 45 IP Hydrochloride 1.5 1.5 1.5 1.5 1.5 1.5 Sodium Chondroitin Sulfate 8 8 8 8 8 8 Water for Injection 45.5 45 45 45 45 45 EDTA·2Na - 0.5 - - - - L-Cysteamine - - 0.5 - - - Ascorbic Acid - - - 0.5 - - Sodium Pyrosulfite - - - - 0.5 - α-Thioglycerol - - - - - 0.5 Total (mass%) 100 100 100 100 100 100 Amount of IP Hydrochloride in the Coating (%) 92.8 95.4 94.7 94.2 95.2 91.5 Formation Rate of IP Analogue (%) 3.5 2.1 2.2 1.3 4.1 10.5 Stability of IP Hydrochloride (after manufacture) B A A A B B

[0073] In the tables in this specification, "IP" represents isoproterenol, "chondroitin sulfate Na" represents sodium chondroitin sulfate, and "EDTA·2Na" represents disodium ethylenediaminetetraacetate. In Table 1, the microneedle devices with high stability of isoproterenol hydrochloride are evaluated as A, and the microneedle devices with insufficient stability of isoproterenol hydrochloride are evaluated as B. As shown in Table 1, in the microneedle devices containing disodium ethylenediaminetetraacetate, L-cysteine, or ascorbic acid in the coating, the stability of isoproterenol salts after manufacturing is high.

[0074] <Test Example 1-2> Stability of Isoproterenol during Preparation

[0075] As described below, microneedle devices were manufactured using different stabilizers, and the stability of isoproterenol hydrochloride during the manufacturing process (1 to about 24 hours) was evaluated. This test was conducted under the conditions of a temperature of 19 to 23°C and a humidity of 79 to 83% RH. In addition, the microneedle array used in this test was the same as the microneedle array used in Test Example 1-1.

[0076] Prepare a coating solution with the composition shown in Table 2, fill the coating solution in a reservoir, and mix it with a spatula for 60 minutes. After 60 minutes, immerse the tips of the microneedles of the microneedle array in the coating solution in the reservoir and then lift them to coat the microneedles with the coating solution. Quantify isoproterenol hydrochloride and isoproterenol analogs in the coating of the obtained microneedle device.

[0077] Furthermore, 75 minutes later (i.e., 135 minutes after the preparation of the coating solution), the tips of the microneedles of the new microneedle array were immersed in the coating solution in the reservoir and then lifted, and isoproterenol hydrochloride and isoproterenol analogs in the coating of the obtained microneedle device were quantified. In the same manner, microneedles were fabricated and evaluated every 75 minutes.

[0078] For each fabricated microneedle device, the production rate (%) of isoproterenol analogs represented by the following formula 3 was calculated. The curve showing the production rate of isoproterenol analogs representing the time from the preparation of the coating solution until before coating on the microneedles (i.e., the manufacturing time) is shown in Figure 2 . In addition, based on the production rate (%) of isoproterenol analogs and the appearance of the coating in the microneedle device coated with the coating solution approximately 24 hours after the preparation of the coating solution (i.e., the manufacturing time is approximately 24 hours), the stability of isoproterenol hydrochloride during the manufacturing process was evaluated. The results are shown in Table 2. It should be noted that the "peak area" in formula 3 refers to the peak area in the HPLC results of each microneedle device. The relative retention time (RRT) of isoproterenol analogs with respect to isoproterenol hydrochloride is around 1.05.

[0079] (Formula 3):

[0080] Production rate of isoproterenol analogs (%) = Peak area of isoproterenol analogs / Peak area of isoproterenol hydrochloride × 100

[0081] [Table 2]

[0082] Example 2 Comparative Example 6 Comparative Example 7 Dexmedetomidine Hydrochloride 45 45 45 IP Hydrochloride 1.5 1.5 1.5 Sodium Chondroitin Sulfate 8 8 8 Water for Injection 44.5 40.5 44.5 EDTA·2Na 1 - - L-Cysteamine - 5 - Ascorbic Acid - - 1 Total (mass%) 100 100 100 Formation Rate of IP Analogue (%) 0.13 1.2 0.9 Appearance of the Coating Transparent Transparent Brown Stability of IP Hydrochloride (during manufacture) A B B

[0083] In Table 2, a case where the stability of isoproterenol hydrochloride during the manufacturing process of the microneedle device is high was evaluated as A, and a case where the stability of isoproterenol hydrochloride during the manufacturing process of the microneedle device is insufficient was evaluated as B. As shown in Table 2, in Example 2 where disodium ethylenediaminetetraacetate was added to the coating solution, even when about 24 hours elapsed from the preparation of the coating solution until before coating on the microneedles, the decomposition of isoproterenol hydrochloride could be suppressed. On the other hand, in Comparative Example 6 where L-cysteine was added to the coating solution, the production rate of isoproterenol analogs was high, indicating the decomposition of isoproterenol hydrochloride. In Comparative Example 7 where ascorbic acid was added to the coating solution, not only was the production rate of isoproterenol analogs high, but the coating also turned brown, indicating that isoproterenol hydrochloride decomposed into multiple analogs.

[0084] <Test Examples 1 - 3> Stability of Isoproterenol in Microneedle Devices

[0085] As described below, microneedle devices were fabricated using different concentrations of disodium ethylenediaminetetraacetate and isoproterenol hydrochloride, and the stability of isoproterenol hydrochloride after 1 to 2 months was evaluated.

[0086] The composition of the coating solution was changed to the compositions shown in Tables 3 and 4. Otherwise, the same operations as in Test Example 1-1 were performed to fabricate microneedle devices, and the production rate (%) of the isoproterenol analog after 1 month of storage was calculated. In addition, the storage period of the microneedle devices was extended to 2 months, and the same test was conducted. The results are shown together in Tables 3 and 4.

[0087] [Table 3]

[0088]

[0089] [Table 4]

[0090]

[0091] [Test Example 1 - Results]

[0092] From the results of Test Examples 1-1 to 1-3, it was found that when microneedle devices were fabricated using a coating solution containing disodium ethylenediaminetetraacetate, the stability of isoproterenol hydrochloride during the manufacturing process and after manufacturing was high. On the other hand, when microneedle devices were fabricated using a coating solution containing a stabilizer other than EDTA, insufficient stability of isoproterenol hydrochloride during the manufacturing process or after manufacturing was shown. In addition, as shown by the results of Test Example 1-3, when the ratio of disodium ethylenediaminetetraacetate to isoproterenol hydrochloride was above a certain level, the stability of isoproterenol hydrochloride after manufacturing was further improved.

[0093] [Test Example 2] Loading amounts of dexmedetomidine and isoproterenol

[0094] A coating solution having the composition shown in Table 5 was prepared, filled into a reservoir, and mixed with a spatula for 60 minutes. A microneedle array identical to the one used in Test Example 1 was prepared, and the tips of the microneedles were immersed in the coating solution in the reservoir to a depth of about 140 μm. After lifting the microneedles from the coating solution, the coatings on the microneedles were dried.

[0095] The amounts of dexmedetomidine hydrochloride and isoproterenol hydrochloride in the coatings formed on the microneedles were quantified by HPLC, and the amounts of dexmedetomidine hydrochloride and isoproterenol hydrochloride per microneedle were calculated therefrom. The results are shown in Table 5.

[0096] [Table 5]

[0097]

[0098] As shown in Table 5, by adding a specific amount of sodium chondroitin sulfate to the coating solution, each microneedle can carry more dexmedetomidine hydrochloride.

[0099] Description of reference numerals

[0100] 2... Substrate, 4... Microneedle, 6... Coating, 10... Microneedle device.

Claims

1. A method for manufacturing a microneedle device, wherein, The microneedle device includes a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles. The method includes a step of applying a coating solution onto the microneedles to form a coating on the microneedles. The coating solution contains: Dexmedetomidine or a pharmaceutically acceptable salt thereof, Isoproterenol or a pharmaceutically acceptable salt thereof, Ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, and Chondroitin sulfate or a pharmaceutically acceptable salt thereof. The mass ratio of ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof in the coating solution to isoproterenol or a pharmaceutically acceptable salt thereof is 0.013 or more. The concentration of chondroitin sulfate or a pharmaceutically acceptable salt thereof in the coating solution is 0.5% by mass or more.

2. A microneedle device comprising a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles, The coating contains: Dexmedetomidine or a pharmaceutically acceptable salt thereof, Isoproterenol or a pharmaceutically acceptable salt thereof, Ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, and Chondroitin sulfate or a pharmaceutically acceptable salt thereof, The mass ratio of ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof to isoproterenol or a pharmaceutically acceptable salt thereof is 0.013 or more, The amount of chondroitin sulfate or a pharmaceutically acceptable salt thereof is 0.5 parts by mass or more based on 100 parts by mass of the coating.

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