JP6074889B2 - Micro needle tip - Google Patents

Description

  The present invention relates to a microneedle chip and a manufacturing method thereof.

  The percutaneous absorption method in which a drug is permeated through the skin and then administered into the body allows the drug to be easily administered without causing pain to the human body. However, depending on the type of drug, there are drugs that are difficult to administer by the transdermal absorption method. As a method for efficiently absorbing these drugs into the body, a method of using a microneedle tip having a fine needle of the order of μm, puncturing the needle into the skin, and directly administering the drug into the skin has attracted attention.

  The needle of the microneedle tip punctures the epidermis having a barrier function (specifically, the stratum corneum formed in the outermost layer of the epidermis), and normal percutaneous absorption from the puncture part impedes the barrier function of the epidermis. Therefore, it is possible to absorb a drug that is difficult to administer into the body. According to this method, it is possible to easily administer a drug subcutaneously without using a special medication device (see Patent Document 1).

  The needle of the microneedle chip described in Patent Document 1 needs to have a sufficient fineness for puncturing the skin, a tip angle, and a sufficient length for allowing the drug solution to penetrate subcutaneously. Therefore, the diameter of the needle is several μm to several hundred μm, the length of the needle penetrates the stratum corneum, which is the outermost layer of the skin, and does not reach the nerve layer, for example, about several tens μm to several hundred μm, The tip angle of the needle is preferably an acute angle, for example, 30 ° or less.

  The fine needle is required to penetrate the stratum corneum, which is the outermost skin layer, for example. The thickness of the stratum corneum varies slightly depending on the part of the human body, but is about 20 μm on average. In addition, an epidermis having a thickness of about 200 μm to 350 μm exists under the stratum corneum, and further, a dermis layer in which capillaries are stretched exists under the epidermis. For this reason, in order to penetrate the stratum corneum and allow the chemical solution to penetrate, a needle having a length of at least 20 μm or more is required.

  However, even if the needle of the microneedle chip of Patent Document 1 is punctured into the skin by hand, there is a problem that the needle does not sufficiently reach the needle root and the performance cannot be fully utilized.

  For this reason, Patent Document 2 discloses a microneedle chip in which needles having different heights are mixed in a support portion. Patent Document 3 discloses a method of puncturing deeper into the skin using a microneedle chip equipped with a puncture assisting device.

Japanese Patent Application Laid-Open No. 6-192068 JP 2007-37707 A Special table 2008-543528

  However, since the microneedle tip described in Patent Document 2 has different needle heights within the same support portion, the needle tip must be focused to check the formability of the needle tip. Inspection of the tip takes time and productivity is reduced. Furthermore, when the drug is applied to the needle surface, the height of the needle is different, so that the application efficiency is greatly reduced.

  In addition, the microneedle chip described in Patent Document 3 must use an applicator, and the operation is complicated compared to direct puncturing by hand. Furthermore, since the microneedle tip has a planar shape, depending on the pressure applied during puncturing, the peripheral portion of the support portion of the microneedle tip bites into the skin and causes skin irritation.

  The present invention relates to a microneedle tip capable of deepening puncture depth and reducing skin irritation compared to a conventional microneedle tip even at the same puncture pressure, and a highly productive method for producing a microneedle tip. I will provide a.

  According to the first aspect of the present invention, there is provided a microneedle chip including a support portion and a needle array region formed by providing a plurality of needles on the surface of the support portion, and the support portion is formed from the back surface of the needle. A microneedle chip is provided that has a curved shape that is curved toward the surface on which the array region is formed.

According to the second aspect of the present invention, a step of preparing a planar microneedle chip comprising a support portion having a planar shape and a needle array region formed by providing a plurality of needles on the surface of the support portion;
Preparing a chip holding member having a through hole having an area smaller than the needle array region;
Placing the planar microneedle chip on the chip holding member by fitting the needle array region of the planar microneedle chip into the through hole of the chip holding member;
A step of pressurizing the support portion of the planar microneedle chip from the back surface thereof toward the surface on which the needle array region is formed, thereby forming the support portion into a curved surface. A method is provided.

  According to the present invention, a microneedle tip capable of deepening puncture depth and reducing skin irritation compared to a conventional microneedle tip even at the same puncture pressure, and a highly productive microneedle tip are provided. A manufacturing method can be provided.

It is a figure which shows the microneedle chip | tip which concerns on 1st Embodiment. It is a top view which shows the other form of the microneedle chip | tip which concerns on 1st Embodiment. It is sectional drawing which shows the other form of the microneedle chip | tip which concerns on 1st Embodiment. It is a figure which shows the manufacturing process of the microneedle chip concerning 2nd Embodiment. It is a figure which shows the manufacturing process of the microneedle chip concerning 2nd Embodiment. It is a figure which shows the manufacturing process of the microneedle chip concerning 2nd Embodiment. It is a figure which shows the manufacturing process of the microneedle chip concerning 2nd Embodiment. It is a figure which shows the other form of the chip | tip holding member used for the manufacturing process of the microneedle chip | tip which concerns on 2nd Embodiment. It is a figure which shows the other manufacturing process of the microneedle chip | tip which concerns on 2nd Embodiment. It is a figure which shows the other manufacturing process of the microneedle chip | tip which concerns on 2nd Embodiment.

  Hereinafter, a microneedle chip and a manufacturing method thereof according to an embodiment will be described with reference to the drawings.

(First embodiment)
FIG. 1A is a plan view showing the microneedle chip according to the first embodiment, and FIG. 1B is a cross-sectional view taken along the line bb of FIG.

  The microneedle chip 1 includes a support portion 2 and a needle array region 4 formed by providing a plurality of needles 3 on the surface of the support portion 2. The needle array region 4 is formed in the portion of the support portion 2 located inside from the outer edge of the support portion 2 with an interval of a width d. As shown in FIG. 1A, the support portion 2 has a curved surface shape curved from the back surface thereof toward the surface on which the needle array region 4 is formed.

  According to such a microneedle chip according to the first embodiment, when the support portion 2 is curved from the back surface toward the surface on which the needle array region 4 is formed, the skin is punctured. The needle 3 located near the center of the support portion 2 is preferentially punctured with respect to the skin surface, and then puncture is performed with the needle 3 near the periphery of the support portion 2. As a result, the percutaneous absorption can be further promoted because the depth of puncture into the skin can be increased as compared with a conventional microneedle chip in which the support portion has a planar shape, that is, a plurality of needle heights are all the same as the plane.

  In addition, according to the microneedle chip 1 according to the first embodiment, it is not necessary to use an instrument for increasing the puncture depth, and thus the puncture operation can be performed simply.

  Furthermore, since the support portion 2 is curved from the back surface toward the surface on which the needle array region 4 is formed, the peripheral portion of the support portion 2 is located away from the skin when puncturing the skin. Further, it is possible to prevent the skin from being damaged at the peripheral edge portion of the support portion 2. In addition, the needle 3 naturally floats from the peripheral edge of the support part 2 after puncturing, and the tip of the needle 3 at the peripheral edge of the support part 2 is easily detached from the skin, so that the tip of the needle 3 is removed when the needle 3 is extracted after puncturing. The risk of inadvertently damaging the skin or damaging the tip of the needle 3 and remaining in the body can be reduced.

  It is preferable that the material of the support part 2 has appropriate rigidity. The support part 2 is not deformed even when pressure is applied at room temperature during puncturing, and is deformed when it is pressurized for a long time in the curved surface forming process described later, and remains in a deformed state even when the pressure is released. It is preferable that the material has properties. Here, it is preferable that the pressure at the time of puncture is 10 to 500 kPa, and the pressure is 30 to 100 kPa.

  The support portion 2 and the needle 3 may be made of the same material or different materials.

  As the material of the support part 2 and the needle 3, any resin can be used. For example, polyethylene, polypropylene, polystyrene, polyethylene terephthalate, polycarbonate, polycaprolactone, polyethylene glycol, polyglycolic acid, polylactic acid, polybutylene succinate , Polyethylene succinate, polyhydroxybutyrate, polyvinyl alcohol, starch, gelatin, silicone resin, and the like, and a plurality of mixtures or copolymers selected from these are preferably used. In particular, biocompatible materials such as medical silicone resins, polyglycolic acid, polylactic acid, and chitosan are preferable.

  The support part 2 preferably has a thickness of 0.1 mm or more and 10 mm or less. When the thickness of the support portion 2 is less than 0.1 mm, it is easily deformed during handling, and it becomes difficult to maintain a desired curved shape. On the other hand, if the thickness of the support portion 2 exceeds 10 mm, it may be difficult to make a curved surface.

  The radius of curvature of the central portion of the support portion 2 having a curved shape is preferably in the range of 10 mm to 100 mm, more preferably 20 mm to 60 mm. When the radius of curvature of the central portion of the support portion 2 is less than 10 mm, the number of needles 3 that puncture perpendicular to the skin among the needles 3 provided on the support portion 2 may be reduced. On the other hand, if the radius of curvature of the central portion of the support portion 2 exceeds 100 mm, the effect of making the support portion a curved surface may be reduced.

  The needle 3 may have a medicinal component or a cosmetic component applied to its surface. The needle may contain a medicinal component or a cosmetic component.

The needle array region 4 preferably has an area of 0.3 cm ² or more and 25 cm ² or less. When the area of the needle array region 4 is less than 0.3 cm ² , it is difficult to obtain a sufficient effect in the puncturing operation on the skin. On the other hand, when the area of the needle array region 4 exceeds 25 cm ² , it becomes difficult to puncture the needles 3 of the needle array region 4 uniformly into the skin.

  In addition to the quadrangle shown in FIG. 1, the shape of the support portion 2 and the needle array region 4 may be hexagonal only in the needle array region 4 as shown in FIG. 2. Further, the shapes of the support portion 2 and the needle array region 4 are arbitrary such as a polygon including a triangle in addition to a quadrangle and a hexagon, or a circle, an ellipse, a semicircle, and a star.

  In the microneedle chip 1 provided with the support part 2 having the curved surface shape according to the first embodiment, the support part 2 may be used with the back surface having a concave shape. For example, as shown in FIG. The recess 5 is filled with a resin to form a filler 5 having a flat surface, or the back recess is filled with a resin to form a convex filler 6 as shown in FIG. Alternatively, as shown in (c) of the figure, the concave portion on the back surface may be filled with resin to form the gripping portion 7 so that the skin can be easily punctured.

(Second Embodiment)
Next, the manufacturing method of the microneedle chip concerning 2nd Embodiment is demonstrated with reference to FIGS. 4A to 7A are plan views, and FIG. 4B to FIG. 7B are cross-sectional views taken along the line bb of FIG. 4A.

  First, as shown in FIGS. 4A and 4B, a planar microneedle chip 11 is prepared. The microneedle chip 11 includes, for example, a planar support portion 12 having a square shape and a needle array region 14 formed by providing a plurality of needles 13 on the surface of the support portion 12. Such a planar microneedle chip 11 can be manufactured by a method disclosed in, for example, Japanese Patent No. 4396676 or Japanese Patent No. 4265696.

  The support part 12 is formed from the same material as described in the first embodiment.

  The needle 13 is formed from the same material as described in the first embodiment.

  If the width between the peripheral edge of the support portion 12 and the needle array region 14 is d, d is preferably 30 μm or more. When d is less than 30 μm, when the planar microneedle chip 11 is placed on a chip holding member, which will be described later, in the step of forming the curved surface of the support section 12 of the planar microneedle chip 11, the support section 12 holds the chip. There is a risk that it may be difficult to hold the part.

  Further, as shown in FIGS. 5A and 5B, a chip holding member 21 is prepared. The chip holding member 21 includes a square holding portion main body 22 and a square through hole 23 that penetrates the main body 22 in the thickness direction.

  The material of the holding portion main body 22 can be selected from any rigid metal or resin. Examples of the metal include gold, silver, copper, iron, nickel, chromium, titanium, molybdenum, tungsten, or an alloy containing two or more kinds of metals in an arbitrary ratio. Examples of the resin include hard resins such as polystyrene, polycarbonate, and PEEK.

  The holding part main body 22 preferably has a thickness of 1 mm or more, for example. If the thickness of the holding portion main body 22 is less than 1 mm, the tip of the needle 13 may protrude from the back surface of the through hole 23 and damage the needle in the step of curving the support portion 12 of the planar microneedle chip 11. is there. there is a possibility.

  The shape of the opening of the through hole 23 is preferably matched with the needle array region 14 of the planar microneedle chip 11, in addition to a square, a polygon such as a triangle, a circle, an ellipse, a semicircle, a star It can be made into a shape such as. The through hole 23 may have a tapered shape or a straight shape.

  The opening area of the through hole 23 is larger than the area of the needle array region 14 of the planar microneedle chip 11 and smaller than the area of the support portion 12 of the chip 11. When the planar microneedle chip 11 is installed in the through hole 23 by fitting the needle array region 14 of the chip 11 through the opening of the through hole 23 by setting the opening area as described above, It becomes possible to prevent the needle 13 from being damaged.

  Next, as shown in FIGS. 6A and 6B, the planar microneedle chip 11 is placed on the chip holding member 21 so that the needle array region 14 is fitted into the through hole 23 of the holding member 21. .

  In installing the planar microneedle chip 11 on the chip holding member 21, an adhesive is interposed between the holding part main body 22 of the chip holding member 21 and the support part 12 of the chip 11, or they are fixed. It may be fixed by using a fixture or the like from the back surface of the support portion 12 of the chip 11.

  Next, as shown in FIGS. 7A and 7B, the support portion 12 of the planar microneedle chip 11 is pressed from its back surface toward the surface on which the needle 13 is formed to deform the support portion. Thus, the support portion 2 having a curved shape is formed. Through this process, the microneedle chip 1 including the support portion 2 having the curved surface shape shown in FIGS. 1A and 1B of the first embodiment described above is manufactured.

Pressurization can be performed by pressing from the front surface side of the through hole 23 of the chip holding member 21, suction from the rear surface side of the through hole 23 of the chip holding member 21, or both pressing and suction. The pressing force or suction force is determined by the material and thickness of the support portion 12 of the microneedle chip 11. The pressing force or suction force with respect to the support portion 12 is preferably set to 30 to 100 kg / cm ² , for example.

  In the step of curving the support portion 12 of the chip 11, the chip holding member 21 may be heated to near the softening temperature of the support portion 12 of the chip 11.

  The chip holding member 21 is not limited to the structure shown in FIGS. 5A and 5B described above. For example, as shown in FIGS. 8A and 8B, a lid member 24 having a vent hole may be provided on the back surface of the through hole 22. The vent hole preferably has a diameter of 0.5 mm or more, and a plurality of vent holes are formed in the lid member 24. More preferably, the lid member 24 has a mesh structure. The material of the lid can be selected from any metal or resin, and may be formed integrally with the chip holding member 21.

  Next, another method for manufacturing the microneedle chip according to the second embodiment will be described in detail with reference to FIGS. 9 and 10A are plan views, and FIG. 9B and FIG. 10B are cross-sectional views taken along the line bb in FIG. 9A.

  After the planar microneedle chip 11 is installed on the chip holding member 21 so that the needle array region 14 is fitted in the through hole 23 of the holding member 21 as shown in FIGS. The microneedle chip 11 is housed in the film bag 25 together with the chip holding member 21 and packaged. Subsequently, as shown in FIGS. 10A and 10B, the inside of the film bag 25 is depressurized, and the needle 13 is formed from the back surface of the support portion 12 of the planar microneedle chip 11 by the film bag 25. The support portion is deformed into a curved surface by applying pressure toward the surface to form a support portion 2 having a curved shape. Through this process, the microneedle chip 1 including the support portion 2 having the curved surface shape shown in FIGS. 1A and 1B of the first embodiment described above is manufactured.

  As the film bag 25, any film bag that can be vacuum-packed can be selected. The film bag 25 can be formed from, for example, a flexible packaging film such as polyethylene, polypropylene, nylon, polyurethane, or a laminated film thereof. The film bag 25 may have a functional layer for maintaining the performance of the microneedle chip such as water vapor barrier performance, oxygen barrier performance, and light shielding performance.

  The manufactured microneedle chip provided with a support portion having a curved surface shape may be housed and packaged in the film bag 25 until it is used, and keep the vacuum.

  Thus, when it accommodates in the film bag 25, packages, and hold | maintains a vacuum, when it makes the support part of a microneedle chip | tip curved into the curved-surface shape, it has the following effects. The user can use the microneedle chip immediately after breaking the film bag at the time of use. For this reason, even if a material having a certain degree of resilience is used as the material of the support part, it is possible to maintain the curved state of the support part when the microneedle chip is punctured into the skin.

  Since the film bag 25 can be used as a packaging material for a microneedle chip provided with a support portion having a curved shape, information such as a drug name may be printed on the surface thereof.

  As described above, according to the second embodiment, in order to prepare a planar microneedle chip and make the support part into a curved surface, it is complicated to make the support part into a curved surface in the manufacturing process of the microneedle chip. It is possible to provide a method capable of manufacturing a microneedle chip having a support portion having a curved surface shape with high productivity because no operation is required.

  In general, when a microneedle chip made of a thermoplastic resin is heated to deform its support portion to form a curved surface, not only the support portion but also the tip of the needle is deformed. According to the second embodiment, since the support portion can be curved in a normal temperature environment, the tip of the needle is prevented from being deformed by heat, and a microneedle chip having a plurality of needles having a predetermined shape is manufactured. be able to.

  Examples of the present invention will be described below.

Example 1
<Manufacture of a microneedle chip having a planar support part>
Based on Examples 3 and 5 of Japanese Patent No. 4396676, a polylactic acid microneedle chip having a support portion having a curved surface shape was manufactured.

That is, a single crystal silicon substrate having a thickness of 525 μm was prepared as the substrate. Subsequently, the silicon substrate was diced into a grid pattern using a dicing blade having an inclination of 170 ° between the side surface and the inclined surface. At this time, the upper plane of the island-shaped structure formed by processing was formed into a square shape with a side length of 100 μm. The processing depth was 250 μm. Next, isotropic etching was performed on the formed island-shaped structure. ICP-RIE was used as the isotropic etching, and SF ₆ gas was used as the reactive gas species. Etching was performed until the upper plane of the island-like structure became a dot.

  By such a method, a quadrangular pyramidal microneedle having a root diameter of 100 μm, a height of 250 μm, a tip angle of 20 °, and a tip diameter of 100 nm was produced.

  The obtained microneedle chip was used as a plate, and transfer processing was performed. First, nickel was formed on the microneedle tip as a filling layer by electroforming. A nickel sulfamate solution was used for the plating bath. A 60% sulfamic acid solution was used, the bath temperature was 45 ° C., and a filling layer was formed by plating for 5 hours. Subsequently, a micro-needle chip made of silicon, which is a plate type, was subjected to a dissolution treatment at 80 ° C. for 4 hours using a 25% KOH solution to prepare a duplicate plate. Next, a microneedle chip was produced on the duplicate plate using a hot press method. Polycarbonate was used as the microneedle material to be filled.

  The polylactic acid microneedle tip manufactured by such a method had a support portion of 1 cm square, a needle height of 500 μm, and a needle number of 625.

<Manufacture of a microneedle chip provided with a support portion having a curved surface shape>
After the obtained microneedle tip was fitted into an aluminum tray (thickness 1 cm) with a 0.8 cm square through hole opened, the microneedle tip was placed in a nylon film bag together with the aluminum tray. Stored inside and packaged. The inside of the film bag was vacuum-packed and vacuum-packed. The vacuum-packed state was kept at room temperature for 3 days, and then the microneedle chip was taken out. As a result, a microneedle chip provided with a support portion having a curved surface shape was obtained.

  About the obtained microneedle chip | tip, when the curvature radius near the center part of a support part was measured with the laser displacement meter, it turned out that the curvature radius of a support part center part is about 40 mm.

<Microneedle puncture test>
An LLDPE film (thickness: 40 μm) was placed on a silicone rubber (thickness: 1 cm) having a rubber hardness of 10, and the film was fixed while being pulled. The microneedle tip (Example 1) produced by the above method was placed on a film, and puncture was performed by applying a load of 5 kg to the microneedle tip at a speed of 1 cm / min with a load tester (Tensilon).

  In addition, the microneedle tip (Comparative Example 1) provided with a support portion having a planar shape obtained by the above method was similarly installed on the film, and the load was tested (tensilon) on the microneedle tip at 1 cm / min. The puncture was performed by applying a load of 5 kg at a speed.

  After puncturing, the microneedle tips of Example 1 and Comparative Example 1 were extracted from the film. As a result, the microneedle chip of Example 1 provided with a support portion having a curved surface shape was easily peeled from the film. In contrast, in the microneedle chip of Comparative Example 1 provided with a support portion having a planar shape, the tip of the needle was caught on the film. Further, indentation traces by the surface near the periphery of the microneedle tip were compared in Example 1 and Comparative Example 1. As a result, the indentation trace was clearly observed in the microneedle chip of Comparative Example 1 provided with a support portion having a planar shape.

  Further, the puncture mark of the film subjected to the puncture test was observed with a microscope, and the puncture depth was calculated. As a result, the microneedle tip of Example 1 provided with a support portion having a curved shape is punctured to about 10% deeper than the microneedle tip of Comparative Example 1 provided with a support portion having a planar shape. I was able to confirm that.

  Such a microneedle chip and a method for producing the same according to the present invention are useful as a transfer plate and transfer method for a microneedle chip used for medical instruments, foods, cosmetics, and the like.

  DESCRIPTION OF SYMBOLS 1 ... Microneedle chip | tip provided with the support part which has a curved surface shape, 2,12 ... Support part, 3,13 ... Needle, 4,14 ... Needle array area | region, 11 ... Microneedle chip | tip provided with the support part which has a planar shape , 21 ... chip holding part, 22 ... holding part body, 23 ... through hole, 25 ... film bag.

Claims (6)

A microneedle chip comprising a support part and a needle array region formed by providing a plurality of needles on the surface of the support part,
The support part has a curved surface shape curved from the back surface toward the surface on which the needle array region is formed, and
The support is within a thickness range of 0.1 mm to 10 mm, and
The support portion has a radius of curvature of 10 mm or more and 100 mm or less, and
The needle array region is within a range of 0.3 cm ² or more and 25 cm ² or less, and the plurality of needles have a drug applied to the surface , and
A microneedle chip , wherein a filling material is filled in a concave shape opposite to the needle array region of the support portion, and the surface is flat .   The microneedle chip according to claim 1, wherein a width d between a peripheral edge of the support portion and the needle array region is 30 µm or more. A microneedle chip comprising a support part and a needle array region formed by providing a plurality of needles on the surface of the support part,
The support part has a curved surface shape curved from the back surface toward the surface on which the needle array region is formed, and
The support is within a thickness range of 0.1 mm to 10 mm, and
The support portion has a radius of curvature of 10 mm or more and 100 mm or less, and
The needle array region is within a range of 0.3 cm ² or more and 25 cm ² or less, and the plurality of needles have a drug applied to the surface , and
A microneedle chip , wherein a filling material is filled in a concave shape opposite to the needle array region of the support portion, and the surface has a convex shape . The microneedle chip according to claim 3, wherein a width d between a peripheral edge of the support portion and the needle array region is 30 µm or more. A microneedle chip comprising a support part and a needle array region formed by providing a plurality of needles on the surface of the support part,
The support part has a curved surface shape curved from the back surface toward the surface on which the needle array region is formed, and
The support is within a thickness range of 0.1 mm to 10 mm, and
The support portion has a radius of curvature of 10 mm or more and 100 mm or less, and
The needle array region is within a range of 0.3 cm ² or more and 25 cm ² or less, and the plurality of needles have a drug applied to the surface , and
A microneedle chip , wherein a filling material is filled in a concave shape opposite to the needle array region of the support portion, and a gripping portion is provided . 6. The microneedle chip according to claim 5, wherein a width d between a peripheral edge of the support portion and the needle array region is 30 μm or more.

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