Manufacturing method of microneedle array

Abstract

To provide a manufacturing method of a microneedle array capable of suppressing formation of a cavity of a microneedle without using a facility for ultrasonic vibration.SOLUTION: A manufacturing method of microneedle array for manufacturing a microneedle array where a plurality of microneedles are formed, by using a mold 15 where recesses 14 having a plurality of fine holes 13 corresponding to the plurality of microneedles are formed, has: a step A for putting liquid 16 in the recesses 14 and filling the respective fine holes 13 with the liquid 16; a step B for removing air bubbles 17 adhering to inner surfaces of the respective fine holes 13 and air bubbles present in the liquid 16 from the respective fine holes 13 by decompression treatment; a step C for adding to the recesses 14 gel-like compositions 18 constituting the microneedle array; and a step D for evaporating solvent of the gel-like compositions 18 and the liquid 16 by drying treatment, and molding the microneedle array.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to a method for producing a microneedle array that can be used in place of syringes used in, for example, the medical and cosmetic fields. [Background technology]

[0002] Injecting medicines, cosmetic ingredients, etc. into the body using a syringe (hereinafter, collectively referred to as "medication") has the advantage of being able to administer medicine directly under the skin or into blood vessels, but it also has the disadvantages of causing pain and swelling, and of leaving marks on the skin as a result of repeated injections. Furthermore, in most cases, injections are administered by medical professionals, so patients who require regular injections have had to frequently visit medical institutions, etc. To overcome these disadvantages of injections, a large number of microneedles (e.g., 0.3 to 0.5 mm in diameter) are placed on a flat plate (e.g., 1 cm 2 One idea is to use a resin microneedle array with 30 to 300 needles per needle instead of an injection (see Patent Document 1).

[0003] If the microneedles are long enough to reach the subcutaneous painless point, the pain caused by the microneedle array during administration can be suppressed. In addition, since administration can be performed by attaching the microneedle array to the epidermis, the user can easily administer the medication at home, eliminating the burden of visiting a designated institution. Furthermore, since dissolving microneedles containing drugs and the like dissolve in the skin, the process from puncture to administration can be completed simply by attaching the microneedle array to the skin. Therefore, simple administration is possible, and individual differences in administration are unlikely to occur.

[0004] A specific example of a method for producing such a microneedle array is described in Patent Document 1. In the production method described in Patent Document 1, after filling the concave portions of a mold with a liquid composition, ultrasonic vibration is applied to the liquid composition in the concave portions to remove air bubbles from the liquid composition, thereby suppressing the formation of cavities caused by air bubbles in the formed microneedles. This makes it possible to produce microneedles with high transferability. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2022-157925 Summary of the Invention [Problem to be solved by the invention]

[0006] However, this manufacturing method has a problem in that it requires equipment for ultrasonic vibration. The present invention has been made in consideration of the above circumstances, and aims to provide a method for manufacturing a microneedle array that can suppress the formation of cavities in the microneedles without using equipment for ultrasonic vibration. [Means for solving the problem]

[0007] A manufacturing method for a microneedle array according to the present invention that meets the above-mentioned objective, in which a microneedle array having a plurality of microneedles formed therein is manufactured using a mold in which a recess is formed with a plurality of microholes each corresponding to the plurality of microneedles, comprises the steps of: step A of pouring liquid α into the recess to fill each of the microholes with the liquid α; step B of removing air bubbles adhering to the inner surface of each of the microholes and air bubbles present in the liquid α from each of the microholes by a decompression treatment; step C of adding a gel composition that constitutes the microneedle array to the recess; and step D of evaporating the solvent of the gel composition and the liquid α by a drying treatment to form the microneedle array. Effect of the Invention

[0008] The method for manufacturing a microneedle array according to the present invention includes step A of pouring liquid α into recesses in a mold to fill each microhole with liquid α, step B of removing air bubbles adhering to the inner surface of each microhole and air bubbles present in the liquid α from each microhole by decompression treatment, step C of adding a gel composition that constitutes the microneedle array to the recesses, and step D of evaporating the solvent of the gel composition and the liquid α by drying treatment to form a microneedle array, so that it is possible to suppress the formation of cavities in the microneedles without using equipment for ultrasonic vibration. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 is an explanatory diagram of a microneedle array manufactured by a method for manufacturing a microneedle array according to an embodiment of the present invention. [Diagram 2] FIG. 13 is an explanatory diagram of a microneedle according to a modified example. [Diagram 3] 1A, 1B, and 1C are explanatory diagrams showing the process of producing a microneedle array. [Figure 4] 1A, 1B, and 1C are explanatory diagrams showing the process of producing a microneedle array. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Next, with reference to the attached drawings, an embodiment of the present invention will be described for better understanding of the present invention. As shown in FIG. 1, a microneedle array 10 manufactured by a microneedle array manufacturing method according to one embodiment of the present invention comprises a plate-shaped base 11 and multiple (multiple) microneedles 12 formed on one side of the base 11.

[0011] In this embodiment, as shown in FIG. 1, each microneedle 12 is cone-shaped tapered toward the tip, and the base end (bottom surface) is connected to the pedestal 11 and is provided standing on the pedestal 11. Each microneedle 12 does not need to be cone-shaped, and may be elliptical cone-shaped or polygonal pyramid-shaped (triangular pyramid, quadrangular pyramid, etc.). Furthermore, it may be a shape other than a pyramid. For example, as shown in FIG. 2, a microneedle having a groove or depression at the tip side can be used so that a solid drug can be held at the tip side. The shape, size, etc. of each microneedle 12 may be the same or different.

[0012] In this embodiment, the microneedle array 10 is formed mainly with polyvinylpyrrolidone, which is an example of a resin. However, the present invention is not limited to this, and the microneedle array 10 can be formed mainly with resin, or with a combination of resin and a biomaterial, or with other components. In addition to polyvinylpyrrolidone, the resin can be one or a combination of two or more of polylactic acid, polycaprolactone, polyhydroxyalkanoate, polyglycolic acid, modified polyvinyl alcohol, casein, and modified starch.

[0013] As the biomaterial, for example, any one or a combination of two or more of hyaluronic acid, collagen, elastin, and cellulose can be used. The microneedle array 10 may also contain components other than the resin and the biomaterial, such as ceramics such as alumina and zirconia, or metals such as stainless steel, cobalt alloy, and titanium alloy. The shape of the base 11 is not particularly limited, and may be a square, rectangular, or circular shape. In this embodiment, the base 11 has a thickness of 1 cm. 2 10 to 1000 microneedles 12 are formed per one.

[0014] Next, a method for producing the microneedle array 10 will be described. 3(A), a plate-shaped mold 15 is used in which recesses 14 having a plurality of microholes 13 corresponding to the plurality of microneedles 12 are formed on one side. The microholes 13 corresponding to the microneedles 12 means that the size and shape of the microholes 13 are equal to the shape and size of the microneedles 12 to be formed, and one microneedle 12 is formed in one microhole 13 through the method for producing the microneedle array 10 described below. The mold 15 can be made of resin, metal, or ceramic.

[0015] First, as shown in FIG. 3(A), the mold 15 is supported by a member not shown in the figure in a state where it is horizontally arranged so that the recess 14 is located on the upper side, and a liquid 16 (liquid α) is poured into the recess 14 to fill each microhole 13 with the liquid 16 (step A). ​​When the liquid 16 is poured into the recess 14, air bubbles 17 are generated on the inner surface of the recess 14 (including the inner surface of each microhole 13). In this embodiment, distilled water, which is an example of pure water, is used as the liquid 16, but the liquid 16 may be any material that has a lower viscosity than the gel composition 18 (see FIG. 3(C)) that constitutes the microneedle array 10 (later becomes the microneedle array 10) that is later poured into the recess 14 and has a good affinity (affinity) with the gel composition 18. As the liquid 16, ultrapure water, desalted water or purified water, which is an example of pure water, or alcohol such as ethanol can be used. Furthermore, by using the same substance as the solvent for the gel composition 18 for the liquid 16, the affinity with the gel composition 18 is improved, and furthermore, the amount of material used in manufacturing the microneedle array 10 can be reduced.

[0016] In this embodiment, in consideration of the case where the mold 15 supported by a member not shown is arranged at an angle rather than horizontally, an amount of liquid 16 larger than the total volume of all the micro-holes 13 (spaces) is poured into the recess 14 in step A so that all the micro-holes 13 are stably filled with the liquid 16. As a result of various verifications regarding the amount of liquid 16 to be poured into the recess 14 in step A, since the liquid 16 overflowing outside the micro-holes 13 in the recess 14 is removed in step B-2 described later, pouring more liquid 16 than necessary is not preferable in terms of work efficiency when removing the liquid 16 overflowing outside the micro-holes 13 in the recess 14. Therefore, in this embodiment, the amount of liquid 16 to be poured into the recess 14 is adjusted by visual inspection.

[0017] Next, after the mold 15 with the liquid 16 put in the recess 14 is placed in a decompression container, as shown in FIG. 3(B), the air bubbles 17 (air) adhering to the inner surface of each micro-hole 13 and the air bubbles (air) present in the liquid 16 are removed together with the air bubbles 17 adhering to the inner surface of the portion of the recess 14 other than the micro-hole 13 and the air dissolved in the liquid 16 by decompressing the inside of the decompression container (i.e., by decompression treatment) (up to this point, step B). In this embodiment, the air bubbles 17 adhering to the inner surface of each micro-hole 13 and the air dissolved in the liquid 16 are completely (substantially completely) removed by decompressing to -1.5 MPa or more and -0.8 MPa for 5 minutes or more (preferably 10 minutes or more, more preferably 15 minutes or more). After removing the air bubbles and dissolved air (after step B), the liquid 16 overflowing outside each micro-hole 13 in the recess 14 is removed (step B-2).

[0018] After step B-2, as shown in Figures 3(C) and 4(A), gel composition 18 is added to recess 14 at room temperature (15°C or higher and 30°C or lower) to create a state in which composition 19 (an example of composition β) consisting of liquid 16 and gel composition 18 enters recess 14 (step C). In this embodiment, gel composition 18 is a composition in which polyvinylpyrrolidone is added to distilled water, with a polyvinylpyrrolidone concentration of 10% by mass or higher and 30% by mass or lower, and has a viscosity of approximately 3 to 10 Pa s.

[0019] Thereafter, the mold 15 is removed from the reduced pressure container and placed in a desiccator or the like, and a drying process (including a heating process) is performed to evaporate part or substantially all of the solvent (water in this embodiment) from the composition 19 in the recesses 14 (i.e., the solvent of the gel composition 18 and the liquid 16 are evaporated) to solidify the composition, and the microneedle array 10 is molded in the mold 15 (recesses 14) as shown in Fig. 4(B) (Step D). The microneedle array 10 molded in the mold 15 is removed from the mold 15 as shown in Fig. 4(C).

[0020] In this embodiment, after step C and before step D, the composition 19 (liquid 16 and gel composition 18 placed in the recess 14 in step C) is degassed by reducing the pressure in a decompression container (step C-2). This degassing process causes air bubbles (foam) 20 to be generated (appear) in the upper part (surface layer) of the composition 19, as shown in FIG. 4(A). Here, in this embodiment, an amount of gel composition 18 that is surplus to the production of the microneedle array 10 is added to the recess 14 in step C, and the excess of composition 19 is removed from the upper part of the composition 19 in the recess 14, so that the air bubbles 20 in the upper part of the composition 19 are stably removed before the drying process (step C-3).

[0021] In this way, it has been confirmed through verification that by pouring a liquid 16 having a lower viscosity than the gel composition 18 into the recess 14 of the mold 15 and removing air bubbles 17 before pouring a gel composition 18 containing a component (resin in this embodiment) that will ultimately be the main component of the microneedle array 10 into the recess 14 of the mold 15, the occurrence of cavities in the microneedle array 10 (particularly the microneedles 12) can be reliably avoided. From the viewpoint of work efficiency, it is preferable to carry out all of the processes A, B, B-2, C and C-2 with the mold 15 placed in a reduced pressure container. EXAMPLES

[0022] Next, an experiment conducted to confirm the effects of the present invention will be described. In the experiment, microneedle arrays were manufactured by the method according to the example and the method according to the comparative example described below, and the height (length) of the microneedles was measured.

[0023] Working Example: Distilled water was poured into the recess of the mold and the pressure was reduced to -0.95 MPa for 10 minutes. The distilled water overflowing outside the fine holes was then removed, and a gel composition constituting the microneedle array (specifically, a polyvinylpyrrolidone solution of a predetermined concentration) was added. The pressure was reduced to -0.95 MPa for 20 minutes. The excess gel composition was then removed from the recess of the mold together with the distilled water, and the mixture was dried in a desiccator for 24 to 48 hours until the mass remained substantially unchanged, producing a microneedle array.

[0024] Comparative Example: A gel composition (polyvinylpyrrolidone solution of a given concentration) was added to the recesses of the mold, and the pressure was reduced to -0.95 MPa for 20 minutes. The excess gel composition was then removed from the recesses of the mold, and the mixture was dried in a desiccator for 24 to 48 hours until the mass remained substantially unchanged to produce a microneedle array.

[0025] Using the method of the embodiment and the method of the comparative example, a mold designed to form microneedles with a height of 1000 μm was used to manufacture two microneedle arrays each (four in total) using gel compositions with a concentration of 20% by mass and a concentration of 25% by mass. Each microneedle array had 52 microneedles, and the heights of eight randomly selected microneedles were measured. The experimental results are shown in Table 1 below.

[0026] [Table 1]

[0027] In Table 1, "20% PVP" and "25% PVP" refer to gel compositions with concentrations of 20% by mass and 25% by mass, respectively, and "with water" and "without water" represent examples and comparative examples, respectively. The experimental results showed that for all concentrations of gel composition, the average height of the eight microneedles in the Example was higher than in the Comparative Example, and the shape of the microneedles was closer to the design value (shape with pointed tips).

[0028] Although the embodiment of the present invention has been described above, the present invention is not limited to the above-mentioned embodiment, and all changes in conditions that do not depart from the gist of the present invention are within the scope of application of the present invention. For example, the step C-2 of degassing the gel composition in the cavity of the mold by reducing pressure can be omitted.

[0029] Here, it was confirmed that even when step C-2 was omitted, that is, when liquid α was put into the recess of the mold, reduced pressure treatment was performed, and then a gel composition was added and a drying treatment was performed without degassing treatment to produce a microneedle array, the shape of the microneedle was closer to the design value than when a gel composition was put into the recess of the mold (without putting liquid α in beforehand), degassed by reduced pressure, and then a drying treatment was performed to produce a microneedle array. It goes without saying that the shape of the microneedle is closer to the design value when step C-2 is performed than when step C-2 is omitted.

[0030] Furthermore, it is not necessary to add an amount of gel composition to the recess in step C such that composition β is in excess of the amount required for generating the microneedle array; it is possible to add an amount of gel composition to the recess in step C such that only the amount of composition β necessary for generating the microneedle array enters the recess. In step A, it is not necessary to pour an amount of liquid α greater than the total volume of all the fine holes in the mold into the recesses, and the amount of liquid α poured into the recesses may be equal to the total volume of all the fine holes in the mold. Furthermore, it is not necessary to add an amount of gel composition in step C that results in an excess of gel composition for the production of the microneedle array, and the amount of gel composition can be adjusted so that the gel composition corresponding to the production of the microneedle array is contained within the recesses of the mold. [Explanation of symbols]

[0031] 10: microneedle array, 11: base, 12: microneedle, 13: microhole, 14: recess, 15: mold, 16: liquid, 17: air bubbles, 18: gel composition, 19: composition, 20: air bubbles

Claims

1. A method for manufacturing a microneedle array, in which a microneedle array having a plurality of microneedles formed thereon is manufactured using a mold having a recess having a plurality of microholes respectively corresponding to the plurality of microneedles, A step A of injecting liquid α into the recessed portion so as to fill each of the microholes with the liquid α; a step B of removing air bubbles adhering to the inner surfaces of the microholes and air bubbles present in the liquid α from the microholes by a decompression treatment; A step C of adding a gel composition constituting the microneedle array to the recess; and D. evaporating the solvent of the gel composition and the liquid α by a drying treatment to form the microneedle array.

2. 2. The method for producing a microneedle array according to claim 1, further comprising, after step B, a step B-2 of removing the liquid α overflowing outside each of the microholes in the recess, before step C.

3. The method for producing a microneedle array according to claim 1, further comprising a step C-2, prior to step D, of degassing the gel composition placed in the recess in step C by reducing pressure.

4. 4. The method for producing a microneedle array according to claim 3, further comprising a step C-3, which is performed after step C-2 and before step D, of adding to the recess in step C an amount of composition β consisting of the gel composition and the liquid α such that the gel composition is in excess of the amount of composition β required for producing the microneedle array, and removing the excess of composition β from above the composition β in the recess.

5. 5. The method for manufacturing a microneedle array according to claim 1, wherein the liquid α has a lower viscosity than the gel composition and an affinity for the gel composition.

6. 5. The method for manufacturing a microneedle array according to claim 1, wherein the liquid α is either the same substance as the solvent of the gel composition, distilled water or ethanol.

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