WO2015147040A1

WO2015147040A1 - Microneedle staying in stratum corneum

Info

Publication number: WO2015147040A1
Application number: PCT/JP2015/059094
Authority: WO
Inventors: 英淑権; 文男神山
Original assignee: コスメディ製薬株式会社
Priority date: 2014-03-26
Filing date: 2015-03-25
Publication date: 2015-10-01
Also published as: JP2015192872A; JP2021087866A

Abstract

Under the provisions of Pharmaceutical Affairs Law, a microneedle as a cosmetic should not pierce through the stratum corneum and penetrate into the deep part of the skin. Provided is a microneedle staying in the stratum corneum when puncturing. The microneedle has such a structure as to be capable of breaking through the surface of the skin stratum corneum but scarcely capable of deeply puncturing. For this purpose, an appropriate structure of the microneedle is a stepped structure of, for example, a prismatoid or slider shape, provided with a sharp tip which is to be punctured alone, or a composite volcano-type structure provided with a non-sharp tip in which the thickness gradually increases from the tip.

Description

Microneedle stays in the stratum corneum

The present invention relates to a microneedle that remains in the skin stratum corneum even after insertion and a method for fastening the microneedle to the stratum corneum.

There are two methods for administering drugs to the human body: oral administration and transdermal administration. Injection is a typical transdermal administration method, but it is painful and should not be welcomed by many. On the other hand, a transdermal administration method using a microneedle and not causing pain has recently attracted attention (Patent Document 1).

The skin stratum corneum acts as a barrier for drug permeation, and simply applying the drug to the skin surface does not allow the drug to permeate sufficiently. On the other hand, by perforating the stratum corneum using a fine needle, that is, a microneedle, the drug permeation efficiency can be significantly improved as compared with the coating method. A microneedle array is a large number of microneedles integrated on a substrate. In addition, microneedles are made by adding an adhesive tape (adhesive film) for attaching the microneedle array to the skin and a cover sheet for maintaining aseptic conditions until use. This is called a patch.

If a microneedle is created using a substance that dissolves in the body and disappears due to metabolism, such as carbohydrates, and the drug is retained in the microneedle, the inserted microneedle is easily dissolved in the body. The drug can be administered intradermally or subcutaneously (Patent Document 2). In particular, when a microneedle made of a biosoluble polymer substance such as hyaluronic acid or collagen is inserted into the skin, moisture in the skin diffuses into the microneedle, and the needle portion inserted into the skin swells and then dissolves. As a result, hyaluronic acid and collagen diffuse into the skin, and drugs and valuable substances held by the microneedles diffuse into the skin (Patent Documents 3 and 4).

In order to manufacture and sell microneedle arrays for the administration of drugs and valuable substances as cosmetics, it is required by the Pharmaceutical Affairs Law that the inserted microneedle stays in the stratum corneum of the skin and does not enter further inside. Has been. If it is inserted inside the stratum corneum, it is interpreted as a pharmaceutical product and cannot be manufactured and sold as a cosmetic.

The stratum corneum of the skin is hard to some extent, but the inside is not so hard. Therefore, when a thin and long conical needle-like microneedle is inserted, it is known that the microneedle passes through the stratum corneum and enters the back of the skin. This is interpreted as a medicine and cannot be manufactured and sold as a cosmetic. The standards for manufacturing and selling pharmaceuticals are much stricter than cosmetics.

Special Table 2002-517300 JP 2003-238347 A JP 2009-238772 A JP 2010-029634 A

The problem to be solved by the present invention is to provide a microneedle that can penetrate the stratum corneum through the skin surface, but the tip stays in the stratum corneum and does not penetrate deeper than the stratum corneum. is there.

According to a wide aspect of the present invention, it comprises a tip and a tip lower part continuous with the tip, and the tip of the tip is sharp enough to penetrate the skin stratum corneum surface, but the tip lower part is more than the tip A microneedle is provided that is thick and stays in the stratum corneum when inserted.

The microneedle that stays in the stratum corneum according to the present invention made to solve the above problems is sharp enough that the tip can pierce the surface of the stratum corneum, but the bottom of the tip is thick, and when inserted, it enters the stratum corneum. It is characterized by staying.
Here, “lower” refers to the direction from the tip of the microneedle to the substrate, and “lower end” refers to a portion slightly closer to the substrate than the tip of the microneedle.

In order for the microneedle to penetrate the stratum corneum surface, the tip of the microneedle must be sharp to some extent. In order to stay in the stratum corneum and prevent deep penetration, it is preferable to make the diameter of the microneedle larger than the vicinity of the tip or make the tip not very sharp.

If the diameter of the microneedle is increased from the vicinity of the tip, it is not inserted deeply because the momentum of insertion is reduced. In particular, if a step is provided at the lower end of the tip, the step is caught in the hole created at the beginning of insertion and the microneedle does not penetrate deeper into the skin. Even if a step is not provided, if the cross-sectional area of the microneedle is increased from the tip toward the substrate, resistance to penetration can be obtained and the tip of the microneedle can be retained in the stratum corneum.

The tip of the microneedle can penetrate the stratum corneum surface, but in order not to penetrate the stratum corneum and penetrate further into the inside, it is more effective to make the tip slightly dull than to make the tip very sharp. is there.

∙ Do not allow the microneedle to penetrate deeply into the skin, because the skin has elasticity, and cannot be achieved simply by shortening the length of the microneedle. As shown in FIG. 1, when a conventional short microneedle is to be inserted, the skin 14 is bent due to elasticity and it is difficult to insert the skin into the skin. Here, the conventional microneedle includes a microneedle body 12 and a microneedle substrate 13. A microneedle is pressed against the skin surface 14. Since the skin has elasticity, the portion pressed against the microneedle body 12 is recessed, and the microneedle body 12 is in contact with the substrate 13 to prevent the microneedle body 12 from being inserted. Fastening the microneedles to the stratum corneum cannot be achieved simply by shortening the length of the microneedles, but only by selecting an appropriate microneedle shape.

The material of the microneedle of the present invention is not limited. It may be a metal, silicon, a resin insoluble in the living body, or a resin insoluble in the living body such as a polysaccharide.
When the microneedle is a material that is insoluble in the living body, drugs and valuables can be applied to the surface of the microneedle, and the microneedle can be held or allowed to flow by providing a vertical hole or a horizontal hole. When the material is soluble in the living body, it can be applied, retained, and flowed in, and can also be contained inside the microneedle.

Preferably, the material of the microneedle is water-soluble so that it quickly dissolves when inserted into the skin and does not penetrate the stratum corneum and enter the skin.

単に Simply elongate microneedles penetrate the stratum corneum as they penetrate the skin surface and enter the interior. If the lower part of the tip of the microneedle is made thicker, the momentum of insertion is reduced and the microneedle can be retained in the stratum corneum.

It is recognized that the microneedles that remain in the stratum corneum of the present invention do not penetrate the stratum corneum and enter the inside, and are legally manufactured and sold as cosmetics. This is because microneedles that pass through the stratum corneum and enter the inside are not recognized as cosmetics.
In any country, a product with a specific purpose must be designed in accordance with the country's laws regarding that product. It is recognized that the microneedles that remain in the stratum corneum of the present invention are legally manufactured and sold as cosmetics in Japan.

FIG. 1 is a schematic diagram showing a state in which a short conventional microneedle is pressed against the skin. FIGS. 2A to 2C are schematic front views showing the microneedles of the embodiments of the present invention. FIG. 3 is a photomicrograph of a skin site to which microneedles are applied. A indicates the stratum corneum, B indicates the living epidermal layer, and C indicates the dermal layer.

In order to prevent the microneedle from penetrating deeply through the stratum corneum, it is preferable to increase the cross-sectional area of the microneedle as it goes from the tip to the bottom of the tip and resist deep penetration. That is, the design of the shape of the microneedle is basically important in order to keep the microneedle in the stratum corneum when it is inserted.

2 (a) to 2 (c) are schematic front views for explaining the shape of the microneedle according to the first to third embodiments of the present invention. A microneedle 1 shown in FIG. 2A has a microneedle body 2 and a substrate 3. One end of the microneedle body 2 is provided on the substrate 3. The microneedle main body 2 has a front end portion 7 and a lower end of the front end that is continuous with the front end portion and joined to the substrate 3. “Lower” means the substrate 3 side of the microneedle 1.

In the microneedle 1 of FIG. 2A, the tip 7 and the tip lower part 8 are continuously connected, and there is no step between them. Moreover, the front-end | tip part 7 is relatively thin, and the front-end | tip lower part 8 is relatively thick. The diameter increases gradually from the tip 7 toward the tip bottom 8. Therefore, as shown in FIG. 2A, the outer shape of the tip 7 and the tip lower part 8 has a shape like a ridgeline of a Conide volcano.

On the other hand, in the microneedle shown in FIG. 2 (b), a step X is provided between the tip lower portion 8 and the tip portion 7. The tip 7 of the tip side closer to the step X has a sharp tip. The relatively thick tip lower part 8 gradually increases in diameter from the step X toward the substrate 3. The outer shape of the tip lower end 8 is a quadratic curve projecting toward the tip 7 side.

In the microneedle shown in FIG. 2 (c), the tip lower end 8 has the same shape as the tip lower end 8 shown in FIG. 2 (a). But the front-end | tip lower part 8 and the front-end | tip part 7 are connected via the level | step difference X. FIG. The tip 7 has a sharp tip, similar to the tip 7 shown in FIG.

It should be noted that the microneedle of the present invention is not limited to the specific shape shown in FIGS. The tip is relatively thin so that it is sharp enough to penetrate the skin stratum corneum, and the tip bottom is relatively thicker than the tip. As long as can remain, there is no particular limitation.

Both the corner type (Fig. 2 (b)) and the slide type (Fig. 2 (c)) have a sharp tip, a step and a center. The two types differ in that the stepped portion is square or smooth. When the sharp tip is inserted into the skin, it is designed to prevent further insertion at the stepped portion, the tip remains in the stratum corneum, and the center is not inserted. That is, the tip portion is designed to have a length that can stay in the stratum corneum.

What is important here is the shape from the tip to the step, not the shape of the center. That is, the base part of the slide type in FIG. 2B may have a widened skirt as shown in FIG. 2C, and the central part of the corner type in FIG. 2C is perpendicular to the substrate as shown in FIG. You may be close to.
The cross-sectional shape of the tip portion and the central portion can take various shapes such as a circle, an ellipse, a triangle, and a quadrangle.

In order to prevent the microneedle from being deeply inserted beyond the stratum corneum by providing a step at the tip as shown in FIGS. 2B and 2C, it is important to set the size of the step and the length of the tip. .
If the step is too small, the step portion passes through a small hole whose tip is opened on the surface of the stratum corneum, and the entire microneedle is inserted. Then, it is thought that the tip passes through the stratum corneum and reaches deeper. On the other hand, if the level difference is too large, the phenomenon shown in FIG. 1 occurs due to the elasticity of the skin, and the sharp tip cannot break the stratum corneum surface.

If the tip is too short or too thin, a sufficient amount of drugs or valuables cannot be delivered into the stratum corneum. This is because drugs and valuables are held at the tip. If the tip is too long, naturally the tip will penetrate the stratum corneum even if the insertion is stopped by a step. This makes it impossible to manufacture and sell it as a cosmetic.

The width of the step of the microneedle staying on the horny stratum corneum is preferably 0.01 to 0.1 mm.
Here, the width of the step means the difference in radius between the tip and the center of the step when the microneedle has a circular cross section. Even if it is not circular, the width of the corresponding step can be assumed based on the cross-sectional view of the microneedle. If the width of the step is not uniform, an average value may be considered.

It is desirable that the length of the tip portion of the square or slide type is 0.01 to 0.1 mm. This is so that as many drugs or valuables as possible can be retained without penetrating from the stratum corneum.

The Conide type means a shape like a volcanic mountain as shown in FIG. The tip is slightly flat, gradually getting thicker from the tip, preventing deep penetration.
The tip of the Conide type should be slightly flat rather than sharp. This is to counter the momentum of insertion and to keep as many drugs and valuables as possible. The width of the tip is preferably 0.005 to 0.04 mm (25 × 10 ⁻⁶ to 16 × 10 ⁻⁴ mm ² ), assuming a circular shape. Even if it is not circular, it is desirable to have the same area as a circle having this diameter.

¡The tip of the coneide type and the stepped part of the slide type or the corner type are preferably close to a plane, but need not be strictly a plane.

A circular microneedle array (diameter 1 cm) having a coneide type microneedle was manufactured using hyaluronic acid (FCH-SU manufactured by Kikkoman Biochemical Co., Ltd.) as a material. The height of the microneedles was 200 μm, the tip diameter was 20 μm, the bottom diameter was 300 μm, and the spacing between the microneedles was 600 μm. A circular microneedle patch was prototyped using this microneedle array. A microneedle patch having a 2.5 cm diameter adhesive tape lined on the microneedle array was used for the subsequent experiments.

Human skin (obtained from IIAM, USA) was cut into a circle of 700 μm in diameter and used as test skin. The microneedle patch was administered to the test skin with a piston type applicator and fixed to the skin with an adhesive tape. Five minutes after administration, the microneedle patch was peeled from the skin, and the microneedle patch administration portion of the test skin was cut. Cut the cut skin. C. It was embedded in T compound and cooled with cold acetone for 10 minutes. The cooled skin was sliced to prepare a frozen section for microscopic observation, which was stained with HE to obtain a skin piece for observation.

When the part where the microneedle entered the skin was observed under the microscope, it was observed that the tip of the microneedle remained in the stratum corneum in all parts. An example of the observed photograph is shown in FIG. Here, A indicates the stratum corneum, B indicates the living epidermal layer, and C indicates the dermal layer.

Even though the height of the microneedle is 200 μm, it may remain in the stratum corneum because hyaluronic acid has a high hygroscopic property, and when it reaches the stratum corneum, it immediately becomes soft due to moisture from the skin.

Claims

The tip has a tip and a tip lower part connected to the tip, and the tip of the tip is sharp enough to penetrate the skin stratum corneum surface, but the tip lower part is thicker than the tip, and when inserted, Microneedle that stays.
The microneedle staying in the stratum corneum according to claim 1, wherein there is a step between the tip portion and the lower portion of the tip, and the step contacts the skin surface and prevents further puncture.
The microneedle staying in the stratum corneum according to claim 2, wherein the step has a width of 0.01 to 0.1 mm.
3. The microneedle staying in the stratum corneum according to claim 2, wherein a distance from the tip to the step is 0.01 to 0.1 mm.
The microneedle staying in the stratum corneum according to claim 2, wherein the shoulder of the step is angular.
The microneedle staying in the stratum corneum according to claim 2, wherein the shoulder of the step is a smooth curve.
The microneedle which stays in the stratum corneum according to claim 1, wherein the tip is thin enough to penetrate the skin stratum corneum surface, but is thick enough to cause penetration resistance, and the lower part of the tip is gradually thickened.
8. The microneedle staying in the stratum corneum according to claim 7, wherein the tip is substantially flat and has a size of 25 × 10 −6 to 16 × 10 −4 mm 2 .
The microneedle staying in the stratum corneum according to claim 7, wherein the length from the substrate to the tip is 0.1 to 0.8 mm.
The microneedle staying in the stratum corneum according to claim 1, wherein the material of the microneedle is water-soluble so that it quickly dissolves when inserted into the skin and does not penetrate the stratum corneum and enter the skin.