Microneedle array and method for producing same

Abstract

Provided are a microneedle array that can be produced more easily than in the past and can improve solubility, and a method for producing the microneedle array.　A microneedle array 1 has: a needle support 10 that is configured from one or more resins and / or one or more metals, the needle support 10 having a base substrate 11 on which two or more protrusions 12 are formed; and two or more microneedles 2 that are erected on each of the plurality of protrusions 12, the microneedles 2 including, as main materials, an active substance and a biosoluble substance that dissolves within 24 hours in vivo.

Description

Microneedle array and method for manufacturing the same

[0001] The present invention relates to a microneedle array and a method for producing the same.

[0002] Microneedles include single-type microneedles such as syringes, and array-type microneedles with multiple needles. Array-type microneedles include integrated types in which the needle substrate and the active substance (e.g., pharmaceutical composition, cosmetic drug) are integrated, and hollow types in which the active substance is contained within the hollow of the needle substrate. Typically, integrated and hollow needles penetrate the skin, remain there, and dissolve within the skin.

[0003] Patent Document 1 discloses a dissolvable microneedle patch that is attached to human skin, and Patent Document 2 discloses a microneedle having grooves formed on the side surface of the microneedle to reduce the contact area.

[0004] In general, conventional dissolvable microneedle arrays have a plurality of tapered needles arranged on a base portion, and for example, an adhesive layer is provided on the surface of the base portion, which is attached to the skin to pierce the needles and maintain the pierced state.

[0005] Many methods for manufacturing dissolvable microneedle arrays have also been proposed. Generally, a cavity mold (female mold) in the shape of the microneedle is used.

[0006] JP 2022-145122 A JP 2022-132921 A

[0007] The present disclosure provides a microneedle array that can be produced more easily than conventional methods and has improved solubility, and a method for producing the same.

[0008] The microneedle array (1) of the present disclosure is a microneedle array (1) for delivering one or more active substances selected from physiologically active substances, cosmetic preparations, and pharmaceutical preparations into the body through the skin, and comprises a needle support (10) having a base substrate (11) made of one or more types of resin and / or one or more types of metal and having two or more convex portions (12) formed thereon; and two or more microneedles (2) erected on each of the plurality of convex portions (12) and containing as main materials the active substance and a biologically (skin) soluble substance that dissolves in the living body (skin) within 24 hours.

[0009] It is preferable that the microneedle is pierced into the skin and the microneedle separated from the base substrate and the convex portion is left in the skin, and the left microneedle dissolves within 24 hours (preferably, the start and end times of dissolution can be controlled in minutes or hours), and the active substance is delivered to the body (including the skin).

[0010] Another disclosed method for manufacturing a microneedle array as described above includes a mold setting step of setting a base substrate (11) (needle support 10) in a cavity (C1) of a first mold (M1) for molding microneedles so that a convex portion (12) is inserted therein, and setting the second mold (M2) with the set base substrate (11) and the convex portion (12) positioned therebetween so that the positions of the convex portion (12) and a support through-hole (T10) penetrating the base substrate (11) correspond to the positions of the raw material feed through-hole (M211) of the second mold (M2) for feeding the raw material for the microneedles; and a mold embossing step of feeding the raw material for the microneedles from the raw material storage section (M21) of the second mold (M2) into the first mold (M1) through the raw material feed through-hole (M211) and the support through-hole (T10) of the second mold (M2), and hardening the raw material to form microneedles. The method may include a step of removing the second mold (M2); and a step of removing the first mold (M1) to obtain a microneedle array formed on the needle support (10).

[0011] (Effects) (1) Microneedle arrays can be manufactured more easily than before. (2) The microneedles can be placed in the skin, dissolve due to the skin temperature, and deliver active substances to the skin.

[0012] FIG. 1 is a diagram showing an example of a microneedle shape; FIG. 2 is a diagram showing an example of a microneedle array; FIG. 3 is a diagram showing an example of a microneedle manufacturing flow; FIG. 4 is a diagram showing an example of each means used in manufacturing; FIG. 5 is a diagram showing an example of an operation in the manufacturing process of a microneedle; FIG. 6 is a conceptual diagram showing how microneedles are delivered to the skin; FIG. 7 is an example of an enlarged image of a microneedle array; FIG. 8 is a diagram showing an experiment in which microneedles are dissolved; and FIG. 9 is an example of a microneedle array in which multiple microneedles are arranged radially.

[0013] Several embodiments of the present disclosure will be described below. The embodiments described below are examples of the present disclosure. The present disclosure is not limited to the following embodiments and includes various modified forms implemented within the scope of the present disclosure. Note that not all of the configurations described below are necessarily essential configurations of the present disclosure.

[0014] (Embodiment 1) The microneedle array 1 of Figure 2 is used to deliver one or more active substances selected from physiologically active substances, cosmetic preparations, and pharmaceutical preparations into the body through the skin. The needle support 10 has a base substrate 11 and a plurality of protrusions 12. The base substrate 11 is composed of one or more types of resin and / or one or more types of metal. Two or more protrusions 12 are formed on the base substrate 11 in accordance with the arrangement of the needles. A microneedle 2 is erected on each of the plurality of protrusions 12. The microneedles 2 contain, as main materials, an active substance and a biologically (skin) soluble substance that dissolves in the living body (skin) within 24 hours.

[0015] The biosoluble substance may contain one or more of glucose, maltose, water-soluble starch, and starch syrup.

[0016] FIG. 1 shows an example of the shape of a microneedle. The microneedle 2 may have a shape selected from, for example, a mushroom shape, a polygonal prism, a cylinder, a cone, a truncated cone, and a polygonal cone. The microneedle 2 may be configured as a combination of multiple shapes. FIG. 1( a) shows, for example, a microneedle having a pointed cone portion 21 and a truncated cone portion 22 having a planar tip that contacts the bottom surface of the cone portion 21, which are configured as an integral unit. FIG. 1( b) shows, for example, a microneedle having a pointed cone portion 21 and a cylindrical portion 23 that contacts the bottom surface of the cone portion 21, which are configured as an integral unit. FIG. 1( c) shows, for example, a microneedle having a conical shape. The maximum width (circular cross-sectional diameter of the cone base) of the microneedle 2 may be, for example, 0.5 mm or more and 0.9 mm or less. The maximum width (circular cross-sectional diameter of the cone base) of the pointed cone portion 21 may be, for example, 0.5 mm or more and 0.9 mm or less. The maximum height of the microneedle 2 may be 0.5 mm or more and 0.9 mm or less. The cross-sectional width of the tip of the microneedle (tip of the cone) may be 0.001 mm or more and 0.5 mm or less.

[0017] FIG. 2 shows an example of a conical microneedle array. The thickness of the main surface of the base substrate 11 may be 0.1 mm or more, preferably 0.2 mm or more, 0.3 mm or more, 0.4 mm or more, 0.5 mm or more, 0.6 mm or more, 0.7 mm or more, 0.8 mm or more, or 1.0 mm or less, 1.5 mm or less, 2.0 mm or less, 2.5 mm or less, or 3.0 mm or less. The base substrate 11 may have a rotating or swinging function as a mechanism to further relieve pain when the microneedles are inserted into the skin. Examples of this mechanism include a rotation mechanism that rotates the base substrate 11 and a swinging mechanism that swings the base substrate 11. These mechanisms can be realized by rotational motion of a gear mechanism, a motor, or the like, reciprocating motion of a linear actuator, or motion by a cam, etc. The maximum width of the cross section of the protrusion 12 may be 0.5 mm or more and 0.9 mm or less, and the height from the surface of the base substrate 11 may be 0.1 mm or more and 0.5 mm or less. The maximum width of the microneedles 2 may be 0.5 mm or more and 0.9 mm or less, and the height of the microneedles 2 may be 0.5 mm or more and 0.9 mm or less.

[0018] (Embodiment 2) Figure 8 shows an example of a microneedle array in which multiple microneedles are arranged radially. In the microneedle array 1 of Figures 8(a) and 8(b), multiple microneedles 2 are arranged at approximately uniform angles so as to be radial on a circular sheet-like base substrate 11. Note that descriptions similar to those described above may be omitted here.

[0019] As shown in FIG. 8( a), the microneedle array 1 can be a collection of rows of multiple microneedles 2, each extending along the radial direction of the sheet. Each row can consist of multiple microneedles 2 and multiple protrusions 12 supporting them. The multiple rows preferably extend radially from near the center of the sheet, allowing for easy folding and placement of the microneedles within the skin (body) during use. Note that the central portion of the sheet does not need to contain microneedles, as the microneedles simply rotate and do not break during use. The angle between two adjacent rows is not limited. For example, in FIG. 8( a), the rows are arranged approximately uniformly at approximately 45°, and in FIG. 8( b), the rows are arranged approximately 30°. However, the angle may be 10°, 15°, 30°, 45°, 60°, 90°, 120°, or 180°. Preferably, the rows are arranged at an angle between 15° and 60°. The angle may also be non-uniform. The shape of the array of microneedles is not limited to a straight line, but can be arbitrarily determined to be an arc or the like.

[0020] The needle density (the density at which the microneedles 2 are arranged on the base substrate 11) is expressed as the number of microneedles per unit area. From the viewpoint of introducing a larger amount of active ingredient into the skin, the needle density is set to, for example, 10 needles / cm ２ More than 50 strands / cm ２ or more, or 100 strands / cm ２ From the viewpoint of reducing skin irritation, the needle density may be, for example, 850 needles / cm ２ Below, 500 pieces / cm ２ Below, 200 pieces / cm ２ or less, or 160 strands / cm ２The needle density may be, for example, 10 needles / cm or less. ２ Over 850 strands / cm ２ It is preferable that:

[0021] The shape of the base substrate 11 can be any shape to suit the application site (skin), but can also be a circular, oval, triangular, rectangular, polygonal, or other sheet shape, and can be further modified to suit the application site (skin). The thickness of the sheet can be the same as that of the base substrate. When the base substrate 11 is a circular sheet, for example, the lower limit of the sheet diameter can be any size to suit the dosage of the active ingredient, but can be 1 mm or 10 mm, and the upper limit of the sheet diameter can be any size to suit the application site (skin), but can be 600 mm, 500 mm, 300 mm, or 200 mm. For example, the sheet diameter is preferably 1 mm or more and 600 mm or less.

[0022] The user uses the microneedle array 1 with the surface on which the microneedles 2 are erected (the surface of the microneedle array) facing their skin. Specifically, the user presses the surface of the microneedle array toward the skin and rotates the microneedle array 1 clockwise or counterclockwise while holding down the back side, so that each microneedle 2 breaks and remains within the user's skin (body). By twisting the microneedle array 1 in this way, each microneedle 2 easily breaks within the user's skin (body), allowing the microneedles to be retained within the user's skin (body). The active ingredient contained in the microneedles dissolves within 24 hours and can be administered within the user's skin (body).

[0023] In addition, although not shown, it is possible to set a difference in needle density of the microneedles. For example, in the portion of FIG. 8(a) where no microneedles 2 are provided, a plurality of microneedles 2 can be provided, and the needle density can be set so that the microneedles 2 are densely packed in a portion of the base substrate 11. It is preferable to design it so that it is dense in a portion according to the application site (skin). Compared to a microneedle array with a uniform needle density, a larger number of needles can be reliably punctured into the skin, thereby increasing the active ingredient content per unit area and ensuring transdermal delivery of the active ingredient.

[0024] (Manufacturing method) Figure 3 shows an example of a manufacturing flow for microneedles. Figure 4B shows an example of the operation of the manufacturing process for microneedles corresponding to the manufacturing flow in Figure 3. Figure 4A shows an example of each means used in manufacturing. M1 is a first mold, M2 is a second mold, M23 is a pressing means, and 10 is a needle support. The first mold M1 has multiple cavities C1 that define the shape of the microneedle. The second mold M2 has a raw material storage section M21 and a raw material feed through hole M211. The needle support 10 has a base substrate 11 and multiple convex portions 12.

[0025] (Step S1) The raw materials for the microneedles are prepared. Temperature conditions and mixing conditions are set. The raw materials include an active substance and a biosoluble substance. (Step S2) The microneedle support 10 is prepared. The base substrate 11 and the convex portion 12 of the microneedle support 10 have a support through-hole T10 formed therein. (Step S3: Mold setting process) The micro support 10 is set in the first mold M1. The needle support 10 is set so that the convex portion 12 is inserted into the cavity C1 of the first mold M1 used to mold the microneedle 2. (Step S4: Mold setting process) The second mold M2 is set on top of the first mold M1 and the needle support 10. The set needle support 10 is positioned between them so that the position of the support through-hole T10 corresponds to the position of the raw material feed through-hole M211 of the second mold M2 for feeding the raw material for the microneedle 2, and the second mold M2 is set.

[0026] (Step S5) The needle raw material prepared in step S1 is loaded into the raw material storage section M21 of the second mold M2. (Step S6-1: Filling process of embossing process) The needle raw material is filled. Pressure is applied from above the needle raw material, and the needle raw material is sent from the raw material feed through hole M211 of the second mold M2 through the support through hole T10 of the needle support 10 to the cavity C1 of the first mold M. (Step S6-2: Hardening process of embossing process) The needle raw material is hardened to form a microneedle. With a predetermined pressure applied to the needle raw material, the temperature is lowered to the hardening temperature to harden the raw material.

[0027] (Step S7) The second mold M2 is removed. (Step S8) The first mold M1 is removed. The microarray 2 and the protrusions 12 are separated from the cavity C1 to obtain the microneedle array 1 formed on the needle support 10.

[0028] The first mold M1 may be, for example, a metal mold or a resin mold. The second mold M2 may be, for example, a metal mold or a resin mold. In the stamping process, for example, the temperature conditions (e.g., 50°C or higher) of the needle raw material when feeding the needle raw material from the second mold M2 to the first mold M1 and the pressure conditions to be applied to the needle raw material may be set. Furthermore, the hardening temperature conditions (e.g., 0°C to 10°C) and the hardening treatment time for hardening the needle raw material may be set. Instead of applying pressure to the needle raw material in the second mold M2, a negative pressure may be set in the first mold M1 to draw in the needle raw material. The pressure means to be applied to the needle raw material may be a pressing means M23 that applies pressure to the raw material in the raw material storage section M21 of the second mold M2. The cross-sectional diameter (circular cross-sectional diameter) of the support through hole T10 may be set in the range of 1 / 2 to 2 / 3 of the cross-sectional diameter (circular cross-sectional diameter) of the convex portion 12.

[0029] Figure 5 shows the concept of delivering microneedles to the skin. The microneedles 2 are pierced into the skin, and the microneedles 2 separated from the base substrate 11 and the protrusions 12 are left in the skin. As a result, the left microneedles 2 dissolve within 24 hours, and the active substance is delivered into the body (including the skin). It is preferable to control the solubility of the substance by selecting a substance that dissolves in the body (skin) and by setting the shape of the microneedle. For example, it is preferable to configure the microneedle so that the start and end times of dissolution can be controlled in minutes or hours.

[0030] (Example) A needle raw material consisting of glucose, water-soluble starch, and water was pressed into a first mold, hardened, and then removed from the first mold to obtain a microneedle array. Figure 6 shows an enlarged image of an example of a microneedle array.

[0031] Figure 7 shows a microneedle dissolution experiment. The compounding ratio of the needle raw materials is as follows: Glucose: 60 wt%, Starch syrup: 25 wt%, Food coloring: Trace amount, Water: Rest. The above raw materials were weighed into a container and heated to 155°C for melting. After that, when the appropriate viscosity was reached by natural cooling, the mixture was pulled into a thread shape with a glass rod and cooled and hardened in that state to form a single needle. One needle was used for the dissolution experiment. Blue food coloring was mixed in to make it easy to check the dissolution status. Pork with skin was pierced as shown in the photo and left to stand. After 30 minutes, the dye began to bleed, and when checked, it was confirmed to have dissolved within the pork. Description of symbols in the drawings

[0032] REFERENCE SIGNS LIST 1 Microneedle array 2 Microneedle 10 Needle support 11 Base substrate 12 Convex portion M1 First mold M2 Second mold M21 Raw material storage section M211 Raw material feed through hole T10 Support through hole C1 Cavity

Claims

1. A microneedle array for delivering one or more active substances from among physiologically active substances, cosmetic preparations, and pharmaceutical preparations into the body through the skin, comprising: a needle support having a base substrate made of one or more types of resin and / or one or more types of metal, on which two or more protrusions are formed; and two or more microneedles erected on each of the multiple protrusions, the microneedles comprising as their main material the active substance and a biosoluble substance that dissolves in the body within 24 hours.

2. The microneedle array according to claim 1, wherein the microneedles are inserted into the skin and the microneedles separated from the base material and the convex portions are left in the skin, whereby the left microneedles dissolve within 24 hours and the active substance is delivered into the body.

3. The microneedle array according to claim 1, wherein the thickness of the main surface of the base substrate is 0.1 mm or more, the maximum width of the cross section of the convex portion is 0.5 mm or more and 0.9 mm or less, the height from the surface of the base substrate is 0.1 mm or more and 0.5 mm or less, the maximum width of the microneedles is 0.5 mm or more and 0.9 mm or less, and the height of the microneedles is 0.5 mm or more and 0.9 mm or less.

4. A method for manufacturing a microneedle array, comprising: a mold setting step of setting a needle support in a cavity of a first mold used for molding microneedles so that a convex portion is inserted, and positioning the set needle support between a support through hole that penetrates the convex portion and a base substrate so that the position of the support through hole corresponds to the position of a material feed through hole of a second mold for feeding material for the microneedle; a mold pressing step of feeding material for the microneedle from a material storage section of the second mold to the first mold through the material feed through hole and the support through hole of the second mold and hardening the material to form a microneedle; a step of removing the second mold; and a step of removing the first mold to obtain a microneedle array formed on the needle support.

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