WO2025022897A1 - Microneedle array and method for producing same - Google Patents

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 producing same

The present invention relates to a microneedle array and a method for manufacturing the same.

Microneedles come in two types: single-type, like a syringe, and array-type, in which multiple needles are arranged. Array-type microneedles include integrated types, in which the needle base is integrated with an active substance (e.g., pharmaceutical composition, cosmetic drug), and hollow types, in which the active substance is contained within the hollow space of the needle base. Typically, integrated and hollow needles remain after being inserted into the skin, and dissolve within the skin.

Patent Document 1 discloses a dissolvable microneedle patch that is attached to human skin. Patent Document 2 discloses a microneedle in which a groove is formed on the side of the microneedle to reduce the contact area.

　Generally, conventional dissolvable microneedle arrays have multiple tapered needles arranged on a base. In addition, for example, an adhesive layer is provided on the surface of the base, which is attached to the skin to insert the needles into the skin and maintain them inserted.

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

JP 2022-145122 A JP 2022-132921 A

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

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,
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 protrusions (12) formed thereon;
Two or more microneedles (2) are provided on each of the plurality of protrusions (12) and contain, as main materials, the effective substance and a substance soluble in the living body (skin) that dissolves within 24 hours in the living body (skin);
has.

The microneedle is inserted into the skin and the microneedle separated from the base material and the protruding 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 preferably delivered to the body (including the skin).

Another disclosed method for producing the above-described microneedle array includes the steps of:
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 support through-holes (T10) penetrating the convex portion (12) and the base substrate (11) correspond to the positions of the raw material feed through-holes (M211) of the second mold (M2) for feeding raw material for the microneedles;
a stamping step of feeding a raw material for the microneedle from the raw material storage section (M21) of the second mold (M2) to the first mold (M1) through the raw material feeding through hole (M211) and the support through hole (T10) of the second mold (M2) and hardening the raw material to form a microneedle;
removing the second mold (M2);
removing the first mold (M1) to obtain a microneedle array formed on a needle support (10);
may also include

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

FIG. 1 is a diagram showing an example of a shape of a microneedle. FIG. 1 is a diagram showing an example of a microneedle array. FIG. 1 is a diagram showing an example of a manufacturing flow of a microneedle. FIG. 2 is a diagram showing an example of each means used in manufacturing. FIG. 1 is a diagram showing an example of an operation of a manufacturing process of a microneedle. A conceptual diagram of microneedle delivery to the skin is shown. 1 is an example of a magnified image of a microneedle array. FIG. 1 shows a dissolution experiment of a microneedle. 1 shows an example of a microneedle array in which multiple microneedles are arranged radially.

Below, several embodiments of the present disclosure are described. 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 that are implemented within the scope that does not change the gist of the present disclosure. Note that not all of the configurations described below are necessarily essential configurations of the present disclosure.

(Embodiment 1)
The microneedle array 1 of FIG. 2 is used to deliver one or more active substances, including biologically active substances, cosmetic preparations, and pharmaceutical preparations, through the skin into the body.
The needle support 10 has a base substrate 11 and a plurality of protrusions 12. The base substrate 11 is made of one or more types of resin and/or one or more types of metal. The base substrate 11 has two or more protrusions 12 formed thereon in accordance with the arrangement of the needles.
The microneedles 2 are provided upright on each of the plurality of protrusions 12. The microneedles 2 contain, as main materials, an effective substance and a substance soluble in the living body (skin) that dissolves within 24 hours in the living body (skin).

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

An example of the shape of the microneedle is shown in Fig. 1. The microneedle 2 may have a shape selected from, for example, a mushroom shape, a polygonal prism, a cylinder, a cone, a pyramid, and a polygonal pyramid. The microneedle 2 may be configured with a combination of a plurality of shapes.
Fig. 1(a) shows, for example, a cone portion 21 having a pointed tip and a cone portion 22 having a planar tip side that contacts the bottom surface of the cone portion 21, which are configured as one unit. Fig. 1(b) shows, for example, a cone portion 21 having a pointed tip and a column portion 23 that contacts the bottom surface of the cone portion 21, which are configured as one unit. Fig. 1(c) shows, for example, a cone shape.
The maximum width (diameter of the circular cross section of the conical base) of the microneedle 2 may be, for example, 0.5 mm or more and 0.9 mm or less. The maximum width (diameter of the circular cross section of the conical base) of the pointed conical 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 (the tip of the cone) may be 0.001 mm or more and 0.5 mm or less.

FIG. 2 shows an example of a cone-shaped 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, and may be 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 function of rotating or swinging as a mechanism for further relieving pain when the microneedle is inserted into the skin. Examples of this mechanism include a rotation mechanism for rotating the base substrate 11 and a swing mechanism for swinging the base substrate 11. These mechanisms can be realized by a gear mechanism, a rotary motion of a motor, a reciprocating motion of a linear actuator, a motion by a cam, or the like.
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 microneedle 2 may be 0.5 mm or more and 0.9 mm or less, and the height of the microneedle 2 may be 0.5 mm or more and 0.9 mm or less.

(Embodiment 2)
An example of a microneedle array in which multiple microneedles are arranged radially is shown in Fig. 8. In the microneedle array 1 in Fig. 8(a) and Fig. 8(b), multiple microneedles 2 are arranged radially at a substantially uniform angle on a circular sheet-like base substrate 11. Note that the description here may be omitted for the same contents as those described above.

As shown in FIG. 8(a), the microneedle array 1 can be a collection of rows in which a plurality of microneedles 2 each extend along the radial direction of the sheet. Each row can be composed of a plurality of microneedles 2 and a plurality of protrusions 12 supporting the microneedles. It is preferable that the plurality of rows extend radially from near the center of the sheet from the viewpoint of easily folding during use to place the microneedles in one's own skin (body). It is not necessary to place the microneedles in the center part of the sheet, since the microneedles do not break when used because they simply rotate. The angle formed by two adjacent rows is not limited. For example, in FIG. 8(a), the microneedles are arranged almost uniformly at about 45°, and in FIG. 8(b), the angle is about 30°, but the angle may be 10°, 15°, 30°, 45°, 60°, 90°, 120°, or 180°, but it is preferable that the microneedles are arranged so as to be 15° or more and 60° or less. The angle may also be non-uniform. The shape of the microneedle row is not limited to a straight line, but can be any shape, such as an arc.

The needle density (the density at which the microneedles 2 are arranged on the base substrate 11) is expressed by the number of microneedles per unit area. From the viewpoint of introducing more active ingredients into the skin, the needle density may be, for example, 10 needles/cm ² or more, 50 needles/cm ² or more, or 100 needles/cm ² or more. From the viewpoint of reducing skin irritation, the needle density may be, for example, 850 needles/cm ² or less, 500 needles/cm ² or less, 200 needles/cm ² or less, or 160 needles/cm ² or less. The needle density is preferably, for example, 10 needles/cm ² or more and 850 needles/cm ² or less.

The shape of the base substrate 11 can be any shape to suit the application site (skin), but can also be a circular, elliptical, 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.

The user uses the microneedle array 1 with the side on which the microneedles 2 are erected (the surface of the microneedle array) facing the user's 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), and the active ingredient contained in the microneedle dissolves within 24 hours and can be administered within the user's skin (body).

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 one portion of the base substrate 11. It is preferable to design the microneedles to be dense in one 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, which increases the active ingredient content per unit area and ensures transdermal delivery of the active ingredient.

(Production method)
FIG. 3 shows an example of a manufacturing flow of a microneedle. FIG. 4B shows an example of the operation of the manufacturing process of the microneedle corresponding to the manufacturing flow of FIG. 3. FIG. 4A shows an example of each means used in the 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 a plurality of 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 a plurality of protrusions 12.

(Step S1)
The raw materials for the microneedles are prepared. Temperature and mixing conditions are set. Contains active substances and biosoluble substances.
(Step S2)
A microneedle support 10 is prepared. The base substrate 11 and the protrusion 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 on the first mold M1. The needle support 10 is set in the cavity C1 of the first mold M1 for molding the microneedle 2 so that the protrusion 12 is inserted.
(Step S4: Mold setting process)
The second mold M2 is set on the first mold M1 and the needle support 10. The 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 of the microneedle 2, and the second mold M2 is set.

(Step S5)
The needle raw material prepared in step S1 is charged into the raw material storage section M21 of the second mold M2.
(Step S6-1: Filling process in embossing process)
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 treatment of the 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 a hardening temperature to harden the raw material.

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

The first mold M1 may be, for example, a metal mold or a resin mold, and the second mold M2 may be, for example, a metal mold or a resin mold.
In the embossing process, for example, the temperature condition of the needle raw material (e.g., 50° C. or higher) and the pressure condition to be applied to the needle raw material when the needle raw material is sent from the second mold M2 to the first mold M1 may be set. Also, the hardening temperature condition (e.g., 0° C. to 10° C., etc.) and the hardening process time for hardening the needle raw material may be set. Instead of applying pressure to the needle raw material of the second mold M2, a negative pressure may be set on the first mold M1 to draw in the needle raw material.
The pressure means for applying pressure to the needle raw material may be a pressing means M23 for applying 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 ½ to ⅔ of the cross-sectional diameter (circular cross-sectional diameter) of the protrusion 12.

The concept of delivering a microneedle to the skin is shown in Figure 5. The microneedle 2 is pierced into the skin, and the microneedle 2 separated from the base substrate 11 and the protrusion 12 is left in the skin. As a result, the left microneedle 2 dissolves within 24 hours, and the active substance is delivered into the body (including the skin).
It is preferable to control the solubility by selecting a substance that dissolves in the living body (skin) and setting the shape of the microneedle. For example, it is preferable that the start and end times of dissolution be controllable in minutes or hours.

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

FIG. 7 shows a dissolution experiment of the microneedle.
The compounding ratio of the needle raw materials is shown below.
Glucose: 60 wt %,
Starch syrup: 25 wt%
Food coloring: Trace amount Water: Remainder The above raw materials were weighed into a container and heated to melt at 155°C. After that, when it was cooled naturally and reached an appropriate viscosity, the mixture was pulled into a thread shape with a glass rod and cooled and hardened in that state to form a needle. One needle was used for the dissolution experiment. Blue food coloring was mixed in to make it easy to check the dissolution status. It was pierced into pork with skin as shown in the photo and left to stand. After 30 minutes, the coloring began to bleed, so it was confirmed that it had dissolved in the pork.

Description of symbols in the drawings

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 portion M211 Raw material feed through hole T10 Support through hole C1 Cavity

Claims (4)

A microneedle array for delivering one or more active substances selected from the group consisting of a physiologically active substance, a cosmetic preparation, and a pharmaceutical preparation through the skin into the body, comprising:
a needle support having a base material made of one or more resins and/or one or more metals and having two or more protrusions formed thereon;
Two or more microneedles are provided on each of the plurality of protrusions and contain, as main materials, the effective substance and a biosoluble substance that dissolves in a living body within 24 hours;
having
Microneedle array. The microneedle is pierced into the skin, and the microneedle separated from the base substrate and the convex portion is left in the skin, whereby the left microneedle dissolves within 24 hours and the active substance is delivered into the body.
The microneedle array according to claim 1 . The thickness of the main surface of the base material is 0.1 mm or more,
The maximum width of the cross section of the protrusion is 0.5 mm or more and 0.9 mm or less, and the height from the surface of the base material is 0.1 mm or more and 0.5 mm or less,
The maximum width of the microneedle is 0.5 mm or more and 0.9 mm or less, and the height of the microneedle is 0.5 mm or more and 0.9 mm or less.
The microneedle array according to claim 1 . a mold setting step of setting a needle support in a cavity of a first mold for molding microneedles so that a convex portion is inserted into the cavity, and the second mold is set by positioning the set needle support between the support through-hole penetrating the convex portion and the base substrate so that the position of the support through-hole corresponds to the position of the raw material feed through-hole of a second mold for feeding raw material for the microneedle;
a stamping step of feeding a raw material for the microneedle from a raw material storage section of the second mold to the first mold through the raw material feed through hole and the support through hole of the second mold, and hardening the raw material to form a microneedle;
removing the second mold;
removing the first mold to obtain a microneedle array formed on the needle support;
Including,
A method for manufacturing a microneedle array.

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