Microneedle array coated with a particle-containing composition

Abstract

The present invention provides a microneedle array wherein microneedles are coated with a composition that contains poorly water-soluble or water-insoluble particles having an average particle diameter of 1 μm or less, from 2% by weight to 20% by weight of a binder, and 60% by weight or more of water. This microneedle array is loaded with a uniform amount of poorly water-soluble or water-insoluble particles, while exhibiting good puncture properties.

Description

[Technical Field]

[0001] The present invention relates to a microneedle array coated with a particle-containing composition, and more particularly to a microneedle array in which a particle-containing composition is coated on microneedles. [Background technology]

[0002] In recent years, the use of microneedle arrays has been actively attempted as a method for transdermal drug administration. One method for loading a drug onto a microneedle array is to apply a drug-containing solution to the microneedles. The solution to be applied to the microneedle array must have fluidity that makes it easy to apply to the fine microneedles, and must also have appropriate viscosity and drying properties so that the solution can be fixed without flowing off the microneedles after application and have a tip shape that is easy to puncture after drying. Although additives can be added to give the coating solution for microneedles certain properties, the types of additives are limited considering compatibility with drugs and the need to ensure safety similar to that of injectable aqueous solution formulations. For example, Patent Document 1 reports that it is preferable to use a substance that is compatible (has the property of being uniformly mixed with) active ingredients such as follicle-stimulating hormone as a coating carrier for polylactic acid resin microneedle arrays.

[0003] However, microneedle arrays carrying particles of poorly water-soluble or water-insoluble drugs that do not mix uniformly with a solution have not yet been put to practical use. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Republished Publication No. 2010-074239 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a microneedle array that has a consistent amount of poorly water-soluble particles or water-insoluble particles loaded thereon and that has good puncture properties. [Means for solving the problem]

[0006] The present inventors have confirmed that applying a solution containing a poorly water-soluble drug to a microneedle results in a rough surface and a large variation in the amount of drug loaded. A rough surface can lead to poor puncture performance or the drug peeling off during puncture. Furthermore, methods that result in variation in the amount loaded are unsuitable for the manufacture of pharmaceutical preparations. Therefore, the inventors conducted extensive research and found that, even if particles of poorly water-soluble drugs or the like are used, if particles having a predetermined average particle size are used and the solution has a predetermined composition, microneedles with good reproducibility of particle loading, sharp tips, and smooth surfaces can be obtained, leading to the completion of the present invention.

[0007] That is, the present invention provides the following aspects. (1) Water-insoluble or poorly water-soluble particles having an average particle size of 1 μm or less; 2% by weight to 20% by weight of a binder; 60% by weight or more of water; A microneedle array having a composition comprising the compound applied to the microneedles. (2) The microneedle array described in (1) above, wherein the binder is one or more selected from the group consisting of sugars or derivatives thereof, protein-based additives, polyvinyl alcohol-based compounds, polyacrylic acid-based compounds, polyglycolic acid-based compounds, polyamide-based compounds, polyester-based compounds, and polyvinylpyrrolidone. (3) The microneedle array according to (2) above, wherein the sugar or its derivative comprises one or more selected from the group consisting of hydroxypropyl cellulose, sodium carboxymethyl cellulose, trehalose, and sucrose. (4) The microneedle array according to any one of (1) to (3) above, wherein the poorly water-soluble or water-insoluble particles have an average particle size of 700 nm or less. (5) The microneedle array according to any one of (1) to (3) above, wherein the poorly water-soluble or water-insoluble particles have an average particle size of 500 nm or less. (6) The microneedle array according to any one of (1) to (5) above, wherein the poorly water-soluble or water-insoluble particles have an average particle size of 50 nm or more. (7) A microneedle array according to any one of (1) to (6) above, wherein the water-insoluble or poorly water-soluble particles are drugs selected from indomethacin, diclofenac, flurbiprofen, etodolac, fentanyl, lidocaine, apomorphine, donepezil, buprenorphine, naproxen, meloxicam, estradiol, progesterone, metaxalone, cyclosporine, celecoxib, cilostazol, ciprofloxacin, or salts thereof. (8) The microneedle array according to any one of (1) to (7) above, wherein the poorly water-soluble or water-insoluble particles have been previously pulverized. (9) A microneedle array according to any one of (1) to (8) above, wherein the weight of the poorly water-soluble or water-insoluble particles is 60% or more of the weight of the composition excluding water. (10) grinding the poorly water-soluble or water-insoluble substance until the average particle size is 1 μm or less; preparing a composition containing the pulverized water-insoluble or poorly water-soluble substance, 60% by weight or more of water, and 2% by weight to 20% by weight of a binder; and applying the composition to microneedles. (11) The method for producing a microneedle array according to (10) above, wherein the pulverization of the poorly water-soluble or water-insoluble substance is wet pulverization using at least one method selected from a jet mill method, a bead mill method, and a planetary mill method. (12) pouring a composition containing poorly water-soluble or water-insoluble particles having an average particle diameter of 1 μm or less, water, and a binder into a mold having recesses formed in the shape of microneedles; evaporating the water to form a microneedle array; removing the microneedle array from the mold; A method for manufacturing a microneedle array comprising: (13) The method for producing a microneedle array according to (12) above, wherein the composition contains 60% by weight or more of water and 2% by weight to 20% by weight of a binder. (14) A method for producing a microneedle array according to (12) or (13) above, which comprises, before the step of pouring into the mold, a step of pulverizing a poorly water-soluble or water-insoluble substance to obtain poorly water-soluble or water-insoluble particles having an average particle diameter of 1 μm or less. (15) The method for producing a microneedle array according to (14) above, wherein the pulverization of the poorly water-soluble or water-insoluble substance is wet pulverization using at least one method selected from a jet mill method, a bead mill method, and a planetary mill method. (16) A microneedle array manufactured by the method according to any one of (12) to (15) above. (17) A microneedle array in which water-insoluble or poorly water-soluble particles having an average particle diameter of 1 μm or less and a binder are encapsulated in microneedles. [Effects of the Invention]

[0008] The microneedle array of the present invention has little variation in the amount of particles loaded, a smooth surface and a sharp tip, even when the microneedles are coated with a composition containing poorly water-soluble or water-insoluble particles, making it suitable for pharmaceutical preparations and also excellent in puncture properties. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a graph showing the distribution of average particle size after indomethacin is pulverized by a planetary ball mill. [Figure 2]2A and 2B are magnified photographs (×600) of the tip of a microneedle coated with a composition containing crushed or uncrushed indomethacin. Figure 2A shows the tip of a microneedle coated with a composition containing crushed indomethacin, and Figure 2B shows the tip of a microneedle coated with a composition containing uncrushed indomethacin. [Figure 3] 1 is a graph showing the variation in the amount of indomethacin loaded onto a microneedle array, with crushed and uncrushed indomethacin. ● indicates the amount loaded for a composition containing uncrushed indomethacin, ○ indicates the amount loaded for crushed indomethacin, and ━ indicates the average amount loaded (left: uncrushed, right: crushed). DETAILED DESCRIPTION OF THE INVENTION

[0010] A first aspect of the present invention is a microneedle array in which a composition containing poorly water-soluble or water-insoluble particles having an average particle size of 1 μm or less, 60% by weight or more of water, and 5% by weight to 10% by weight of a binder is applied to microneedles.

[0011] In one embodiment, a "microneedle array" is a substrate having microneedles (microneedles) with a height of about 300 μm to about 1000 μm, arranged at about 50 to about 1000 per cm. 2 The microneedle array is a microneedle array in which a needle is placed. The material of the microneedle array can be made of resin, ceramic, metal, or the like. A thermoplastic resin may also be used, and a biodegradable thermoplastic resin is preferably used. This is because such a material can be easily mass-produced and is thought to further ensure safety during use. The shape of each microneedle is not particularly limited, and may be, for example, a polygonal pyramid (such as a triangular pyramid, a square pyramid, or a hexagonal pyramid) or a cone whose cross-sectional area decreases toward the tip. In this case, the cross-sectional area may be configured to decrease continuously toward the tip, or may be configured to decrease discontinuously at one or more locations. As disclosed in International Publication No. 2012 / 057345, a triangular, square, hexagonal, or conical tip may be disposed on a truncated pyramid such as a triangular, square, hexagonal, or conical truncated pyramid. Alternatively, as disclosed in International Publication No. 2013 / 162053, a microneedle may have a base such as a triangular, square, hexagonal, or conical truncated pyramid, and a shaft disposed on the base, with the area of ​​the top surface of the base being larger than the area of ​​the bottom surface of the shaft, resulting in a two-tiered shape.

[0012] In one embodiment, the "poorly water-soluble or water-insoluble particles" contained in the composition applied to the microneedles are poorly water-soluble or water-insoluble drugs. "Poorly water-soluble" or "water-insoluble" is interpreted in its broadest sense, and is understood to mean, for example, the range defined in the 17th Edition of the Japanese Pharmacopoeia as "slightly soluble" to "practically insoluble," i.e., the amount of solvent required to dissolve 1 g of solute is 30 mL or more. The poorly water-soluble or water-insoluble drug can be selected from, for example, indomethacin, diclofenac, flurbiprofen, etodolac, fentanyl, lidocaine, apomorphine, donepezil, buprenorphine, naproxen, meloxicam, estradiol, progesterone, metaxalone, cyclosporine, celecoxib, cilostazol, ciprofloxacin, and salts thereof.

[0013] The "poorly water-soluble or water-insoluble particles" may be substances other than drugs. For example, fine particles of lipids, resins, metals, etc. may be used depending on the purpose.

[0014] In one embodiment, the "poorly water-soluble particles or water-insoluble particles" have an average particle diameter of approximately 1 μm or less. This range ensures sufficiently small variation in the amount of particles loaded onto the microneedle array. The variation in the amount of particles loaded among microneedle arrays can be evaluated, for example, by the coefficient of variation (CV). The CV is not particularly limited, but is preferably 10% or less, and more preferably 5% or less. Furthermore, by ensuring that the "poorly water-soluble particles or water-insoluble particles" have an average particle diameter of approximately 1 μm or less, a microneedle array with a smooth surface and sharp tips can be obtained after application of the composition. The average particle diameter is preferably approximately 700 nm or less, more preferably approximately 500 nm or less. The average particle diameter may be approximately 50 nm or more or approximately 100 nm or less. The average particle diameter can be measured by a known method or a method equivalent thereto. The present invention encompasses particles having an average particle diameter of 1 μm or less measured by any one of these methods.

[0015] When the average particle size of a poorly water-soluble or water-insoluble substance, such as a bulk powder of a poorly water-soluble or water-insoluble drug, exceeds 1 μm, it can be pre-milled to an average particle size of 1 μm or less. The milling method can be selected appropriately depending on the type of poorly water-soluble or water-insoluble substance, and can be dry or wet milling. The milling mechanism can be compression, impact, shear, friction, or a combination of two or more of these. Depending on the mechanism, mills such as jaw crushers, gyratory crushers, crushing rolls, hammer mills, roller mills, jet mills, ball mills, vibrating ball mills, planetary mills, and bead mills can be used. In particular, wet milling using jet mills, planetary mills, and bead mills can mill the target to nanometer size.

[0016] In one embodiment, the amount of "poorly water-soluble particles or water-insoluble particles" in the composition is not particularly limited, but can be, for example, 1% by weight to 30% by weight, preferably 5% by weight to 25% by weight.

[0017] In one embodiment, the term "binder" is used in its broadest sense, and can be, for example, one or a combination of two or more selected from the group consisting of sugars or derivatives thereof, protein-based additives, polyvinyl alcohol-based compounds, polyacrylic acid-based compounds, polyglycolic acid-based compounds, polyamide-based compounds, polyester-based compounds, and polyvinylpyrrolidone. Examples of "saccharides or derivatives thereof" that can be used include one or more selected from the group consisting of alginic acid, agar, starch, hydroxypropyl cellulose, sodium carboxymethylcellulose, hyaluronic acid, trehalose, lactose, sucrose, fructose, galactose, mannose, maltose, glucose, mannitol, pullulan, sorbitol, and dextran. Preferably, one or more selected from hydroxypropyl cellulose, sodium carboxymethylcellulose, trehalose, and sucrose are used. By adding saccharides or derivatives thereof, it is possible to attract surrounding moisture due to differences in osmotic pressure after puncturing the skin, thereby enhancing the release of drugs from the microneedle array. Examples of the "protein additive" that may be used include albumin, casein, gelatin, and collagen.

[0018] In one embodiment, the amount of "binder" in the composition is not particularly limited, but is, for example, about 2% by weight to about 20% by weight, preferably about 3% by weight to about 10% by weight. If the amount of binder in the composition is less than about 2% by weight, the composition tends to be difficult to support on the microneedles, and tends to be prone to cracking or falling off after being applied to the microneedles and dried. If the amount of binder in the composition is more than about 20% by weight, the viscosity tends to be too high to apply to the needles, and the proportion of particles in the composition tends to be unable to be sufficiently increased.

[0019] In one embodiment, the composition contains about 60% by weight or more of water. The amount of water in the composition is preferably about 70% by weight or more. The composition may contain solvents other than water as long as the object of the present invention is achieved. However, from the viewpoint of drying properties, it is preferable that the solvent is water alone. Examples of solvents other than water include water-soluble solvents such as alcohols, such as ethyl alcohol and isopropyl alcohol, and miscible amounts of organic solvents (ethers, such as tetrahydrofuran, esters, such as ethyl acetate). When a solvent other than water is contained, the proportion of water in the solvent is preferably 90% by weight or more, and more preferably 95% by weight or more.

[0020] In one embodiment, the composition may further contain additives such as a pH adjuster, an antioxidant, a preservative, etc. Commercially available reagents can be used as these additives depending on the purpose, as long as the effects of the present invention are not impaired.

[0021] Examples of pH adjusters include buffers made of organic acids such as citric acid, tartaric acid, lactic acid, fumaric acid, and malic acid and their alkali metal salts, and buffers made of inorganic acids such as phosphoric acid and their alkali metal salts.

[0022] Examples of antioxidants include ascorbic acid, dibutylhydroxytoluene (BHT), sodium hydrogen sulfite, sodium sulfite, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, tocopherol, sodium pyrosulfite, butylhydroxyanisole, and propyl gallate.

[0023] Examples of preservatives include benzoic acid, sodium benzoate, sorbic acid, sodium sorbate, sodium dehydroacetate, parahydroxybenzoic acid, sodium parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate (propylparaben), butyl parahydroxybenzoate, isopropyl parahydroxybenzoate, isobutyl parahydroxybenzoate, propionic acid, and sodium propionate.

[0024] In one embodiment, the composition containing poorly water-soluble or water-insoluble particles is preferably applied as close to the tip of the microneedle as possible so as not to impair the sharpness of the tip. To apply the composition in this state, for example, a method of immersing the microneedle array in a groove filled with a drug solution (International Publication No. 2010 / 122816) can be used. By adjusting the immersion depth (the distance to which the drug is applied to the microneedle array), the amount of drug carried and the application position can be appropriately adjusted. For example, it is preferable to apply the composition within a range of 400 μm from the tip of the microneedles of the microneedle array. When only a small amount of drug is required, application within a range of 100 μm from the tip is sufficient. The microneedle array of the present invention can be manufactured by applying known manufacturing methods. For example, it may be manufactured in accordance with WO 2012 / 057345 or WO 2013 / 162053. In the latter case, the microneedle has a base and a shaft disposed on the base, and the area of ​​the top surface of the base is larger than the area of ​​the bottom surface of the shaft, resulting in a two-tiered structure. This shape allows a larger amount of composition to be carried on the top of the base, while also ensuring good puncture properties.

[0025] In one embodiment, the microneedle array of the present invention can be used as a microneedle array preparation.

[0026] A second aspect of the present invention is a method for producing a microneedle array, in which a composition containing poorly water-soluble or water-insoluble particles having an average particle diameter of 1 μm or less, 60% by weight or more of water, and 2% by weight to 20% by weight of a binder is applied to microneedles.

[0027] In one embodiment, a method for producing a microneedle array coated with a composition includes the steps of: pulverizing a poorly water-soluble or water-insoluble substance until the average particle size is 1 μm or less; preparing a composition containing the pulverized particles, 60% by weight or more of water, and 2% by weight to 20% by weight of a binder; and applying the composition to microneedles.

[0028] The poorly water-soluble or water-insoluble substance can be pulverized by a known method or a method equivalent thereto, for example, dry or wet pulverization using the above-mentioned pulverization mechanism.

[0029] A third aspect of the present invention is a method for producing a microneedle array, comprising the steps of pouring a composition containing poorly water-soluble or water-insoluble particles having an average particle size of 1 μm or less, water, and a binder into a mold having recesses formed in the shape of microneedles, evaporating the water to form a microneedle array, and removing the formed microneedle array from the mold. This production method makes it possible to obtain a microneedle array containing poorly water-soluble or water-insoluble particles having an average particle size of 1 μm or less and a binder.

[0030] When manufacturing microneedles using a mold, the recesses of the mold are very small, so if large particles are present, the composition does not reach every corner of the mold, and when dried, a microneedle array with a smooth surface and sharp tips cannot be obtained, or the amount of particles contained in the microneedles may vary. However, by using particles with an average particle diameter of 1 μm or less, a microneedle array with a smooth surface, sharp tips, and no variation in the amount of particles loaded can be obtained.

[0031] In one embodiment, the composition contains 60% by weight or more of water and 2% by weight to 20% by weight of a binder. The amount of the binder is preferably 3% by weight to 10% by weight. The binder may be the same as that used in the first aspect of the present invention, but hyaluronic acid is preferred.

[0032] A fourth aspect of the present invention is a microneedle array in which water-insoluble or poorly water-soluble particles having an average particle diameter of 1 μm or less and a binder are encapsulated in microneedles. The microneedles may further contain various additives. Such a microneedle array can be produced, for example, by the method according to the third aspect of the present invention.

[0033] The terms used in the first and second aspects, such as microneedle array, poorly water-soluble or water-insoluble particles, binder, additive, etc., are interpreted in the same manner in the third and fourth aspects as in the first and second aspects.

[0034] The poorly water-soluble or water-insoluble particles may be obtained by previously pulverizing a poorly water-soluble or water-insoluble substance to an average particle size of 1 μm or less in the same manner as in the first embodiment.

[0035] The step of pouring the composition into a mold, the step of heating to evaporate the water, and the step of removing the formed microneedle array from the mold can all be carried out by a known method or a method similar thereto. [Example]

[0036] Examples are given below to help better understand the present invention, but they are not intended to limit the scope of the present invention.

[0037] 1. Preparation of drug crushing solution and measurement of drug particle size Indomethacin was used as a poorly water-soluble drug. Measurements of the bulk powder at 20 points within the same field of view under a microscope revealed a mean particle size of 15 μm with a large variation of 16 μm. The smallest particle was 2 μm in diameter, and the largest was 68 μm in diameter. This bulk powder was pulverized using a planetary ball mill (Thinky Corporation, NP-100). The initial charge composition per batch was 1.0 g of indomethacin, 4.0 g of 1.25% hydroxypropyl cellulose (HPC-H), and 5.0 g of zirconia beads (0.1 φ mm). These were weighed and added to a zirconia container, and pulverized three times at 1700 rpm, -20 ° C, and 2 minutes. The contents were then transferred to a media separation container and centrifuged once at 2000 rpm, -20 ° C, and 1 minute to remove the zirconia beads, yielding a drug pulverization solution. After grinding, the drug grinding solution was diluted appropriately, and the average particle size was measured using a Zetasizer Nano ZS ZEN3600 (Malvern Instruments). Figure 1 shows the particle size distribution. The average particle size was 448 nm.

[0038] 2. Preparation of drug composition and application to microneedles To the pulverized drug solution obtained in 1. above, HPC-H, sucrose, and water (MilliQ) were added in the following proportions to prepare a drug composition for application to microneedles (Example). As a comparative example, a similar composition was prepared using unpulverized indomethacin instead of pulverized indomethacin. [Table 1]

[0039] The drug composition was applied to the microneedles by filling the grooves with a composition prepared according to the method described in WO 2010 / 122816 and immersing the microneedle array in the composition. Figure 2 shows a magnified photograph (×600) of the microneedles after application. Figure 2A shows a microneedle applied with a composition containing pulverized indomethacin (Example), and Figure 2B shows a microneedle applied with a composition containing unpulverized indomethacin (Comparative Example). The microneedles coated with a composition containing crushed indomethacin had a smooth surface, a sharp tip, and were expected to have excellent puncture properties, whereas the microneedles coated with a composition containing uncrushed indomethacin had a rough surface, were expected to have poor puncture properties, and the drug would peel off when punctured.

[0040] Next, the amount of indomethacin loaded on the microneedle array was measured by HPLC using a conventional method. The results of measuring five examples each of the Examples and Comparative Examples are shown in Tables 2 and 3 and Figure 3. As shown in the results, the microneedle arrays coated with a composition containing pulverized indomethacin showed good reproducibility in the amount of drug loaded. On the other hand, the microneedle arrays coated with a composition containing unpulverized indomethacin showed large variations in the amount of drug loaded, and are considered unsuitable for pharmaceutical preparations. [Table 2]

[0041] [Table 3] [Industrial Applicability]

[0042] According to the present invention, even when a composition containing poorly water-soluble or water-insoluble particles is applied to the microneedles, it is possible to provide a microneedle array that has little variation in the amount of particles loaded, has a smooth surface, and a sharp tip, is suitable for pharmaceutical preparations, and has excellent puncture properties.

Claims

1. A step of pulverizing a poorly water-soluble or water-insoluble substance until the average particle size is 1 μm or less; preparing a composition containing the pulverized water-insoluble or poorly water-soluble substance, 60% by weight or more of water, and 2% by weight to 20% by weight of a binder; applying the composition to microneedles; and evaporating the water content of the microneedles to form a microneedle array.

2. The method for manufacturing a microneedle array according to claim 1, wherein the binder is one or more selected from the group consisting of sugars or derivatives thereof, protein-based additives, polyvinyl alcohol-based compounds, polyacrylic acid-based compounds, polyglycolic acid-based compounds, polyamide-based compounds, polyester-based compounds, and polyvinylpyrrolidone.

3. The method for producing a microneedle array according to claim 2 , wherein the sugar or a derivative thereof comprises one or more selected from the group consisting of hydroxypropyl cellulose, sodium carboxymethyl cellulose, trehalose, and sucrose.

4. The method for producing a microneedle array according to claim 1 , wherein the poorly water-soluble or water-insoluble particles have an average particle size of 700 nm or less.

5. The method for producing a microneedle array according to claim 1 , wherein the poorly water-soluble or water-insoluble particles have an average particle size of 500 nm or less.

6. The method for producing a microneedle array according to claim 1 , wherein the poorly water-soluble or water-insoluble particles have an average particle size of 50 nm or more.

7. The method for producing a microneedle array according to any one of claims 1 to 6, wherein the poorly water-soluble or water-insoluble particles are drugs selected from indomethacin, diclofenac, flurbiprofen, etodolac, fentanyl, lidocaine, apomorphine, donepezil, buprenorphine, naproxen, meloxicam, estradiol, progesterone, metaxalone, cyclosporine, celecoxib, cilostazol, ciprofloxacin, or salts thereof.

8. The method for producing a microneedle array according to claim 1 , wherein the poorly water-soluble or water-insoluble particles have been previously pulverized.

9. The method for producing a microneedle array according to claim 8, wherein the pulverization of the poorly water-soluble or water-insoluble substance is wet pulverization using at least one method selected from a jet mill method, a bead mill method, and a planetary mill method.

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