WO2008015782A1

WO2008015782A1 - Microneedle patch and process for producing the same

Info

Publication number: WO2008015782A1
Application number: PCT/JP2007/000811
Authority: WO
Inventors: Masahiro Takigawa; Kazushi Kawatsu; Tatsuya Harikou
Original assignee: Hamamatsu Foundation For Science And Technology Promotion; Shizuoka Prefectural Government
Priority date: 2006-07-31
Filing date: 2007-07-30
Publication date: 2008-02-07
Also published as: JP2008029710A

Abstract

[PROBLEMS] To provide a microneedle patch that without reaching of the distal end of needles to the dermis, can attain puncturing so as to allow administration of medicine, such as a vaccine material, through the puncture, and provide a process for producing the same. [MEANS FOR SOLVING PROBLEMS] There is provided a microneedle patch comprising sheet patch part (1) and, integrally superimposed on the rear surface thereof, multiple microprotrusion needles (2), so that while sticking the rear surface of the patch part (1) to the skin of a patient, there can be attained puncturing of the skin with needles (2), wherein the needles (2) have a dimension of length (t) from its proximal end to distal end ranging from about 50 to 100 μm.

Description

Specification

Microneedle type patch and manufacturing method thereof

Technical field

In the present invention, a plurality of microprojection needles are integrally formed on the back surface of a sheet-like patch portion, and the needle is punctured into the skin while the back surface of the patch portion is in contact with the patient's skin. The present invention relates to a microneedle type / switch obtained and a manufacturing method thereof. Background art

[0002] Human skin is roughly divided into three layers from the surface: epidermis, dermis and subcutaneous fat. Of these, the epidermis is the stratum corneum, granule layer, spiny layer and dermis as the outermost layer in contact with the outside world. It consists of a basal layer in contact with. The epidermis has an average thickness of about 100 m, excluding palms and wrinkles, and has 500 to 600 Langerhans cells per square millimeter. Such Langerhans cells take up and activate antigens that are present or invaded in the skin, move to the regional lymph nodes, stimulate T cells to differentiate into cytotoxic T cells, and B cells through T cells Antibody is produced by stimulating. Because of this action, Langerhans cells are known to protect living organisms from infection and cancer.

[0003] As described above, as a means for reaching the Langerhans cells of the epidermis to protect the infection and cancer, vaccine material is widely administered with an injection needle. There was a problem that the material reached the dermis beyond the epidermis, and the uptake by Langerhans cells was not performed reliably. In addition, administration with an injection needle is painful for the patient, and there are risks of bleeding and secondary infection.

[0004] On the other hand, a device having a needle-like structure capable of administering a drug such as a vaccine material into a living body has been conventionally proposed (for example, see Patent Document 1). According to such a device (micro two-dollar type patch), a thin film film through which the needle part can penetrate is interposed between a needle-like structure having a needle part and a living body, and the needle part is punctured into the skin. Drugs in the thin film can be administered. This needle is The length is 2 3 0; U m, and it is a silicon needle structure with 50 lines arranged on the support.

Patent Document 1: Japanese Patent Laid-Open No. 2 0 00 _ 6 5 7 7 5

Disclosure of the invention

Problems to be solved by the invention

[0005] However, in the conventional microneedle type patch, since the length of the needle portion is 2 3 O m, when the patient's skin is punctured, the tip reaches the dermis like the injection needle. Therefore, even if a drug such as a vaccine material was administered from there, there was a problem that the uptake by Langerhans cells was not reliably performed. In addition, since the needle reaches the dermis, there is a problem that the patient is painful and there is a risk of bleeding and secondary infection.

[0006] The present invention has been made in view of such circumstances, and can be punctured without the tip of the needle reaching the dermis, from which a microphone mouth needle type capable of administering a drug such as a vaccine material is provided. It is to provide a patch and its manufacturing method.

Means for solving the problem

[0007] In the invention of claim 1, a plurality of micro-projection needles are integrally formed on the back surface of the sheet-like patch portion, and the needle is used while the back surface of the patch portion is in close contact with the patient's skin. In the microneedle type patch that can be pierced into the skin, the needle is characterized in that the length dimension from the proximal end to the distal end is approximately 50 to 10 O ^ m.

[0008] The invention according to claim 2 is the microneedle type patch according to claim 1, wherein the lengths of the needles are different, and the heights of the needles from the back surface of the patch part are non-uniform. It is characterized by.

[0009] The invention according to claim 3 is the microphone mouth needle type patch according to claim 1 or 2, characterized in that the needle is made of a biodegradable resin that can be decomposed in vivo. [0010] The invention according to claim 4 is the micro nidle type patch according to any one of claims 1 to 3, wherein the needle has a proximal end diameter of approximately 1 OO m or less. It has a conical shape.

[001 1] The invention according to claim 5 is the micro niddle type patch according to any one of claims 1 to 4, wherein the surface of the needle is provided with a fine uneven shape. It is characterized by that.

[0012] The invention according to claim 6 is the microneedle type patch according to any one of claims 1 to 5, wherein the patch portion is made of a flexible member, and the entire back surface of the patch is formed by the patient. It is characterized by being able to closely adhere to the shape of the skin.

[0013] The invention according to claim 7 is that a predetermined resin material having thermoplastic properties is melted in a mold having a plurality of conical holes each having a depth of approximately 50 to 10 Om. After the resin material is cooled and cured, it is released from the mold so that a plurality of micro-projections of needles following the hole shape are integrally formed on the back surface of the sheet-like patch. It is characterized by obtaining a 21 dollar type patch.

[0014] The invention described in claim 8 is the method of manufacturing a microneedle mold / touch according to claim 7, wherein the mold has a height dimension of approximately 50 to 100 by machining such as cutting. It is obtained by forming a master in which a plurality of conical micro-protrusion needles with U m are arranged side by side, and growing a Ni metal layer on the master containing the needles by electrical contact. It is characterized by.

[0015] The invention according to claim 9 is the method of manufacturing a microneedle type / touch according to claim 8, wherein the master forms a single block having the needle shape by lathe machining using a byte. It is obtained by arranging a plurality of such blocks in parallel.

The invention's effect

[0016] According to the invention of claim 1, since the length of the needle formed on the back surface of the patch portion from the proximal end to the distal end is approximately 50 to 10 Om, The tip can be punctured without reaching the dermis, and drugs such as acupuncture material can be administered from there. [001 7] According to the invention of claim 2, since the lengths of the needles are made different and the heights of the needles from the back surface of the patch portion are uneven, the back surface of the patch portion is kept in close contact with the patient's skin. When the urine is pressed, the puncture is performed by dispersing the urging force so that the needle can smoothly enter the patient's skin and the puncture can be performed satisfactorily.

[0018] According to the invention of claim 3, since the needle is made of a biodegradable resin that can be decomposed in a living body, for example, when the needle is punctured, it breaks and remains in the patient's body. However, there is no impact and safety, and even if the microneedle type patch is discarded, it can be easily disassembled, preventing problems such as environmental destruction.

[001 9] According to the invention of claim 4, since the needle has a conical shape with a proximal diameter of approximately 100 m or less, the pain is prevented from being given to the patient, Better puncture can be made possible.

[0020] According to the invention of claim 5, since the surface of the needle is provided with a fine uneven shape, when the drug is applied to the surface of the needle, the drug continues to be held in the uneven shape, The drug can be successfully administered from the puncture site.

[0021] According to the invention of claim 6, since the patch portion is made of a flexible member, and the entire back surface thereof can closely adhere to the shape of the patient's skin, the puncturing operation can be performed more reliably and satisfactorily. Can do.

[0022] According to the invention of claim 7, a predetermined resin material having thermoplastic properties is melted in a mold having a plurality of conical holes each having a depth of approximately 50 to 10 Om. By pouring in a state and transferring the shape of the hole to the resin material, a micro bi-dollar type patch can be obtained easily and easily.

[0023] According to the invention of claim 8, since the mold is obtained by growing the Ni metal layer on the master including the needle shape by electroplating, it is easy to change the needle length and the like. It is possible to obtain a micro two-dollar patch at a lower cost.

[0024] According to the invention of claim 9, the master 1 is obtained by forming a block having a single needle shape by lathe machining with a byte and arranging a plurality of the blocks in parallel. That you can get a micro two-dollar patch In addition, since the concave / convex shape is imparted to the surface of the master by the cutting trace by the byte, it is possible to easily obtain the micro two-dollar type patch in which the fine concave / convex shape is imparted to the surface of the needle.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, embodiments of the present invention will be specifically described with reference to the drawings.

The microneedle type patch according to the present embodiment punctures the skin of a patient with a microprojection needle and administers a drug (cancer peptide or the like) from there to activate Langerhans cells to infect the living body. It produces antibodies and cytotoxic T cells to protect against cancer and the like. As shown in FIG. 1, a sheet-like patch portion 1 is integrally formed with the patch portion 1, and the patch portion 1 Mainly composed of a plurality of micro-projection needles 2 formed on the back surface.

[0026] The present microneedle type patch is obtained by forming a biodegradable resin that can be decomposed in a living body and integrating the patch portion 1 and the needle 2 together. As an applicable biodegradable resin, Examples thereof include polylactic acid (PLA), aliphatic copolymer polyester, and polyhydroxybutyrate (PHB). Thus, for example, even when the needle 2 is punctured and remains in the patient's body, the needle 2 is made of a biodegradable resin, so that the living body is not affected and is safe. At the same time, even if the microneedle type patch is discarded, it can be easily disassembled, preventing problems such as environmental destruction.

[0027] It should be noted that, instead of the above biodegradable resin, other resin materials having thermoplastic properties may be used. For example, polyvinyl chloride, polypropylene, polystyrene, poly force-ponate, polyethylene, polymethyl methacrylate , Hydroxyethyl methacrylate, polyvinyl alcohol, Teflon (registered trademark), polymer plastics such as polysulfone, or metals other than resin materials such as titanium, titanium alloy, stainless steel, and silicon.

[0028] In addition, the patch portion 1 is a flexible member formed by forming the biodegradable resin into a thin film, and the entire back surface (surface on which the needle 2 is formed) It is configured to be able to closely adhere to the shape of the patient's skin. This will cause needle 2 to When the patch part 1 is pressed against the patient's skin to puncture the patient, the patch part 1 bends along the site, so that the patient can adhere well, and the puncture operation can be performed more reliably and satisfactorily.

[0029] The needle 2 has a conical shape with a proximal end (patch 1 side end) diameter of approximately 1 OO m or less, and pain is imparted to the patient when the needle 2 is punctured into the skin. In addition to suppressing this, it is possible to achieve better puncture. It should be noted that the needle 2 may have another shape (such as a quadrangular pyramid or a cylinder) as long as the patient's skin can be punctured satisfactorily.

[0030] Further, as shown in FIG. 2, the surface of the needle 2 is provided with a fine uneven shape (in this embodiment, a spiral shape), and the surface of the needle 2 was coated with a drug. At this time, the drug is continuously held in the uneven shape (spiral shape), and the drug can be successfully administered from the puncture site. The uneven shape on the surface of the needle 2 is not limited to a spiral shape, but is a shape in which a plurality of recesses or grooves are formed at an arbitrary site, or a streak-like vertical stripe from the tip to the base, and corrugated in the circumferential direction of the cone surface It is good also as what formed the groove | channel of this uneven | corrugated.

[0031] Here, the needle 2 according to the present embodiment has a length dimension t from the proximal end to the distal end of approximately 50 to 1 O O m. Thus, as shown in FIG. 3, if the back surface of the patch part 1 is brought into close contact with the surface of the skin, the needle 2 is punctured into the body, and the tip does not reach the dermis, from which the drug is administered. be able to. In addition, if the stratum corneum is peeled off and removed in advance before the microneedle type patch is brought into close contact, the needle 2 can be punctured better and more reliably.

[0032] Further, the lengths of the respective needles 2 are different, and the heights of the needles 2 from the back surface of the patch portion 1 are non-uniform. However, the length of each needle 2 is varied within a range of about 50 to 100 m. For example, needles having large lengths and needles having small lengths may be alternately formed, or may be formed by mixing at regular intervals or irregularly. In this way, by making the length of the needle 2 different and making the height non-uniform, when the patch part 1 is pressed while closely contacting the back of the patient's skin, the pressing force is dispersed and punctured Makes needle 2 smooth on the patient's skin It can penetrate and make puncture well.

[0033] Next, a manufacturing method of the microneedle type patch as described above will be described. First, a metal cylindrical member (round bar) is set on a lathe machine, and its end face is cut by a byte. As shown in FIG. 4, a cylindrical block 3 in which a single micro-projection shape (needle shape 3 a) having a height dimension t of about 50 to 10 Om is formed in the approximate center of the end face. Get. Since the needle shape 3 a is formed by cutting with a lathe of a lathe, a cutting mark (feed mark) by the byte is formed in a spiral shape.

[0034] A plurality of blocks 3 having the needle shape 3a with different height dimensions as described above are prepared, and the blocks 3 are passed through the holes 4a of the structure 4 as shown in FIG. . The hole 4 a has an inner diameter substantially equal to the outer diameter of the block 3, and faces the needle shape 3 a from the opening of each hole 4 a. As a result, a plurality of needle shapes 3 a can be arranged side by side, and a master composed of the structure 4 facing the needle shapes 3 a can be obtained.

However, as shown in FIG. 6, when a Ni metal layer is grown on the master including the needle shape 3 a by electrical fitting and the Ni metal layer is removed from the master, as shown in FIG. It is possible to obtain a mold 5 having a plurality of holes 5 a having a shape opposite to the needle shape 3 a (manufacture of a mold by an electroplating method). Since the hole 5 a of the mold 5 is formed by transferring the surface shape of the needle shape 3 a, the depth (height) dimension t is approximately 50 to 1 like the needle shape 3 a. Although it is set to OO m, the dimension t is varied to be non-uniform.

Thereafter, as shown in FIG. 8, a mold 5 and another mold 6 are arranged to face each other to form a cavity C therein, and a resin material having thermoplastic properties in the cavity C. (In this embodiment, biodegradable resin) is poured in a molten state, and after releasing the cooling effect of the resin material, a microneedle type having a patch portion 1 and a needle 2 as shown in FIG. You can get a patch. Of course, since the shape of the hole 5 is transferred and imitated, the needle 2 has a length dimension t of approximately 5 0 to 1 0 0 m.

[0037] According to this embodiment, the mold 5 (cavity C) having a plurality of conical holes 5a having a depth of approximately 50 to 100; um had thermoplastic properties. By pouring a predetermined resin material in a molten state while applying a predetermined pressure, and transferring the shape of the hole 5a to the resin material, it is possible to easily and easily obtain a two-dollar microphone patch. (Molding by injection molding method). The spiral cutting trace on the surface of the master needle 3a is transferred to the hole 5a, and the cutting trace is transferred to the needle 2. Therefore, the hole 2a is transferred to the surface of the needle 2. In addition to being provided with a spiral uneven shape, the needles 2 are of uneven height with different length dimensions.

[0038] In addition, since a die (electron type) is obtained by growing a Ni metal layer on a master including a needle shape by electroplating (electroplating method), it is easy to change the length of needle 2, etc. It is possible to obtain a micro two-dollar type patch at a lower cost. That is, for example, various blocks 3 each having a needle shape 3 a having an arbitrary height are formed on the end face, and the block 3 passing through the hole 4 a of the structure 4 can be arbitrarily selected and changed. For example, the length dimension of the needle 2 can be easily changed to a desired one.

[0039] Furthermore, the master 1 is obtained by forming a block 3 having a single needle shape 3a by lathe machining with a byte and arranging a plurality of the blocks 3 in parallel with the structure 4. A micro two-dollar patch can be obtained at a lower cost, and a concave / convex shape (spiral shape) is imparted to the master surface due to the cutting trace by the byte, so that a fine concave / convex shape is imparted to the surface of the needle 2. It is possible to easily obtain a micro two-dollar patch. If the block 3 and the structure 4 are made of non-ferrous stainless steel or the like, the master can be made difficult.

[0040] By the way, instead of manufacturing the mold by the above-described electroplating method, the following method can be used. A mold made of, for example, a titanium alloy sintered body can be obtained by metal powder injection molding using the master. According to such a mold, since titanium has good releasability from resin, it can be used when forming microneedle type patches. Thus, a release agent or the like can be dispensed with. In addition, due to the fine pores generated in the process of metal powder injection molding, a concavo-convex shape is formed on the surface of the mold, and the concavo-convex shape is transferred to the surface of the needle when the micro two-dollar type patch is formed.

[0041] Alternatively, the mold may be manufactured by laser processing a titanium alloy material (femtosecond laser). Specifically, a die is obtained by irradiating the surface of the titanium alloy material with a laser to form a plurality of conical holes having a depth of about 50 to 10 Om. In this case, laser processing traces (a plurality of stripe-like vertical stripes extending substantially linearly from the periphery of the hole to the top thereof, and a wavy uneven groove shape in the circumferential direction of the surface of the conical hole) are formed in the hole. Therefore, when forming a microneedle type patch, the streaks are transferred to the surface of the needle to give an uneven shape.

[0042] —On the other hand, in order to mold the microneedle type patch using the mold as described above, instead of the injection molding method, a semi-molten resin such as nanoimprint (hot press) is pressed against the mold cavity. It may be a molding method using a molding method or a coater (means for pouring molten resin into the mold cavity using a centrifugal force).

[0043] According to the micro two-dollar type patch obtained by the manufacturing method as described above, after the drug is applied to the surface of the needle 2, the back surface of the patch 1 is applied to the patient's skin (for example, the skin of the arm or The needle 2 punctures the skin, and the drug applied to the needle 2 is administered into the body by bringing it into close contact with the skin (chest, back, stomach, etc.). Also, without applying the drug to the surface of the needle 2, the back surface of the patch part 1 is in close contact with the skin and the needle 2 is punctured, then the microneedle patch is removed from the skin and the drug is administered from the puncture mark. It may be.

In any case, according to the microneedle type patch as in the present embodiment, the tip of the needle 2 can be prevented from reaching the patient's dermis at the time of puncturing. The drug can be administered without pain and avoiding the risk of bleeding and secondary infection. In addition, if the vaccine material is administered as a drug, uptake by Langerhans cells is ensured, and the living body is infected. Antibodies and cytotoxic T cells can be produced to protect against cancer and cancer.

[0045] While the microneedle type patch according to the present embodiment has been described above, the present invention is not limited to this, and in particular, in the case of administering a drug from the puncture mark after puncture with a needle. The surface of the needle may not be provided with an uneven shape (such as a spiral shape). Also, when molding the needle with a resin material, etc., foreign matters such as salt (magnesium chloride, etc., which is the main component of Nigari) are included, and the foreign matter is removed after molding (in the case of salt, it is dissolved with hot water, etc.) By doing so, an uneven shape may be imparted to the surface of the needle.

[0046] Further, the manufacturing method of the microneedle type patch is not limited to the one in the present embodiment, and the surface of the plate-like member (metal plate or the like) is directly machined or laser processed, and the needle as in the present embodiment. A micro two-dollar type patch having the above may be formed. Further, by applying an adhesive to the back surface of the patch part 1 and allowing it to adhere to the skin with the adhesive, the micro two-dollar patch can be kept in close contact for a long time.

Industrial applicability

[0047] A microneedle type patch having needles with a length from the proximal end to the distal end of approximately 50 to 10 O ^ m and a method for manufacturing the microneedles, or having a different appearance or other functions It can also be applied to those that have been made.

Brief Description of Drawings

[0048] FIG. 1 is a schematic diagram showing a microneedle patch according to an embodiment of the present invention.

[Fig.2] Enlarged view of the needle in the micro $ 21 patch

FIG. 3 is a schematic diagram showing a state where the needle is punctured with the micro-bi dollar patch in close contact with the patient's skin.

[Fig. 4] Schematic diagram showing the blocks that make up the master for manufacturing the micro $ 2 patch.

FIG. 5 is a schematic diagram showing a master for manufacturing the micro two-dollar patch. FIG. 6 is a master for manufacturing the micro two-dollar patch and the master one. Schematic showing the mold obtained in

[Fig. 7] Schematic diagram showing the mold for manufacturing the same micro two-dollar patch

[Fig. 8] Schematic diagram showing a mold for manufacturing the micro two-dollar patch and a micro one-dollar patch obtained from the mold.

Explanation of symbols

1 Patch section

2 needles

3 blocks

3 a Needle shape (Master-)

4 Structure (Master-)

Type 5

5 a hole

6 Different mold

C cavityity

Claims

The scope of the claims

[1] A plurality of micro-projection needles are integrally formed on the back surface of a sheet-like patch portion, and the needle can be punctured into the skin while the back surface of the patch portion is in close contact with the patient's skin. In the dollar patch,

The micro two-dollar type patch characterized in that the length of the needle from its proximal end to the distal end is approximately 50 to 1 O O m.

[2] The micro two-dollar patch according to claim 1, wherein the length of the needle is made different so that the height of the needle from the back surface of the patch portion is non-uniform.

3. The microphone mouth needle type patch according to claim 1 or 2, wherein the needle is made of a biodegradable resin that can be decomposed in a living body.

[4] The microneedle type patch according to any one of claims 1 to 3, wherein the needle has a conical shape having a proximal end diameter of approximately 1 OO m or less. .

[5] The surface of the needle is provided with a fine uneven shape.

The micro two-dollar type patch according to any one of claims 1 to 4.

[6] The patch section according to any one of claims 1 to 5, wherein the patch portion is made of a flexible member, and the entire back surface thereof can be closely adhered following the shape of the patient's skin. A micro two-dollar patch.

[7] A predetermined resin material having thermoplastic properties is poured in a molten state into a mold having a plurality of conical holes with a depth of approximately 50 to 1 OO m, and the resin material After cooling and hardening, a microneedle-type patch is obtained in which a plurality of micro-projection needles that conform to the hole shape are integrally formed on the back surface of the sheet-like patch portion. A manufacturing method of a micro two-dollar type patch.

[8] The mold forms a master in which a plurality of conical micro-protrusions having a height of approximately 50 to 1 OO m by machining such as cutting are arranged side by side. 8. The method for producing a micro two-dollar type patch according to claim 7, wherein the micro two-dollar type patch is obtained by growing a Ni metal layer on a master including the needle shape by electroplating. The microphone mouth needle type patch according to claim 8, wherein the master is obtained by forming a single block having the needle shape by lathe processing using a byte, and arranging a plurality of the blocks in parallel. Manufacturing method.