Field of the Invention
The present invention relates to transdermal administration devices and methods for producing transdermal administration devices.
Discussion of the Background
Intradermal sites which are located inside the skin have a high immune response in the body. Since intradermal drug administration is expected to reduce the drug dosage required to achieve an administration effect compared with hypodermic administration by which a drug is delivered to a site under the skin, technical development for intradermal drug administration has been conducted.
For example, intradermal drug administration includes a Mantoux method by which a drug is delivered into an upper site in the skin by using an injection needle, and iontophoresis by which an ionized drug is intradermally infiltrated by applying a weak electric current to the skin. Other examples include jet injection by which a drug is intradermally delivered by means of hydraulic pressure, and a drug delivery method by which a drug is intradermally delivered via a hole created by a microneedle having a fine needle.
In the Mantoux method, which uses an injection needle for drug administration, many patients feel fear of injection needles in addition to pain caused by piercing using an injection needle. Further, iontophoresis and jet injection, which do not involve pain or fear caused by injection needles, require a large device for drug administration.
On the other hand, a needle-shaped projection of a microneedle is so small that patients would not feel pain or fear, and a method using a microneedle can perform drug administration without using a large device (for example, see PTLs 1 to 3).
PTL 1: WO2008/013282
PTL 2: WO2008/004597
PTL 3: WO2008/020632
According to an aspect of the present invention, a transdermal administration device including an administering part including a substrate having a first surface, and at least one projection protruding from the first surface. The projection has a shape which extends along the first surface and includes one linear top edge which is located away from the first surface and has a first end and a second end, two primary lateral faces which share the one linear top edge and have lateral edges each individually connecting the first surface with the first end of the one linear top edge, and a secondary lateral face which has the lateral edges in common with the respective two primary lateral faces and forms one corner together with the two primary lateral faces. The projection is formed such that one of the lateral edge and the top edge on the primary lateral face form an obtuse angle, and that the two lateral edges on the secondary lateral face form an acute angle.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:
The embodiments will now be described with reference to the accompanying drawings, wherein like reference numerals designate corresponding or identical elements throughout the various drawings.
With reference to
With reference to
As shown in
The administering part 20 includes a plate-shaped substrate 21 and a plurality of projections 22 which protrude from the substrate 21. The substrate 21 has a first surface 21S on which the projections 22 are formed and a second surface 21T which is a surface opposite from the first surface 21S. The first surface 21S supports base ends of the projections 22.
The adhesive sheet 30 includes a base sheet 31 and an adhesive layer 32 which covers one of two surfaces of the base sheet 31. The second surface 21T of the substrate 21 is bonded to a portion of the adhesive surface of the adhesive layer 32.
With reference to
As shown in
The base 23C is a defined surface located inside the first surface 21S of the substrate 21. The base 23C is defined by four sides, of which two long sides 24a extend in a first direction and two short sides 24b, which are shorter than the long side 24a, extend in a second direction. The first direction and the second direction are directions parallel to the first surface 21S, and the first direction and the second direction are perpendicular to each other. Further, a direction perpendicular to the first surface 21S, that is, a direction perpendicular to the first direction and the second direction is a third direction.
The two primary lateral faces 23A have identical isosceles trapezoid shapes, and one of the two primary lateral faces 23A intersects the base 23C at a long side 24a, and the other of the two primary lateral faces 23A intersects the base 23C at the other long side 24a. The primary lateral faces 23A are each inclined relative to the third direction such that the two primary lateral faces 23A intersect each other at their top edges 24c, which are opposite sides parallel to the corresponding long sides 24a of the primary lateral faces 23A. That is, the two primary lateral faces 23A have the common top edge 24c and separate lateral edges 24d. The top edge 24c has two ends, one of which is referred to as a first end, and the other is referred to as a second end. Two lateral edges 24d extend from the first end of the top edge 24c, which are referred to as first lateral edges, and another two lateral edges 24d extend from the second end of the top edge 24c, which are referred to as second lateral edges.
The two secondary lateral faces 23B have the identical isosceles triangular shapes. One of the secondary lateral faces 23B, which is a first secondary lateral face, intersects the base 23C at its short side 24b, and the other of the secondary lateral faces 23B, which is a second secondary lateral face, intersects the base 23C at its short side 24b. The secondary lateral faces 23B are each inclined relative to the third direction. Each secondary lateral face 23B intersects one of the two primary lateral faces 23A at one of the two lateral edges 24d, which are equal sides of the isosceles triangle, and intersects the other of the two primary lateral faces 23A at the other of the two lateral edges 24d. That is, the secondary lateral face 23B and each of the two primary lateral faces 23A have the common lateral edges 24d. In other words, the first secondary lateral face and each of the two primary lateral faces 23A have the common first lateral edge, and the second secondary lateral face and each of the two primary lateral faces 23A have the common second lateral edge. Further, two primary lateral faces 23A and one secondary lateral face 23B interposed between the two primary lateral faces 23A form a corner. That is, the projection 22 has a corner formed by the two primary lateral faces 23A and the first secondary lateral face, and another corner formed by the two primary lateral faces 23A and the second secondary lateral face.
In the projection 22, the top edge 24c is a tip. That is, the tip of the projection 22 is formed in a linear shape extending along the first direction.
Thus, the projection 22 has a blade shape extending along the first direction.
The projection 22 has a height H which extends from the first surface 21S of the substrate 21 to the tip of the projection 22 in the third direction. The height H is preferably in the range of 10 μm or more and 1000 μm or less, and is determined within this range depending on the depth required for a hole to be created by the projection 22 into the administration target, that is, a passage through which a drug is administered into the skin.
When the administration target is the human skin and the depth of the hole is designed to be in the stratum corneum, the length H is preferably in the range of 10 μm or more and 300 μm or less, more preferably in the range of 30 μm or more and 200 μm or less. When the depth of the hole is designed to penetrate through the stratum corneum and not to reach the nerve, the height H is preferably in the range of 200 μm or more and 700 μm or less, more preferably in the range of 200 μm or more and 500 μm or less, and further more preferably in the range of 200 μm or more and 300 μm or less. When the depth of the hole is designed to reach the dermis, the height H is preferably in the range of 200 μm or more and 500 μm or less. When the depth of the hole is designed to reach the epidermis, the height H is preferably in the range of 200 μm or more and 300 μm or less.
The projection 22 has a width D1 in the first direction, which is a maximum length of the projection 22 in the first direction. Further, the projection 22 has a width D2 in the second direction, which is a maximum length of the projection 22 in the second direction. That is, the width D1 is a length of the long side 24a and the width D2 is a length of the short side 24b, and the width D1 is larger than the width D2. Specifically, the width D1 is preferably in the range of 200 μm or more and 2000 μm or less, and the width D2 is preferably in the range of 1 μm or more and 1000 μm or less.
The projection 22 has a length L of the tip, which is a length of a linear portion of the projection 22 farthest from the first surface 21S of the substrate 21, that is, a length of the top edge 24c. The length L of the tip is smaller than the width D1 and larger than the width D2. Specifically, the length L of the tip is preferably in the range of 100 μm or more and 1000 μm or less.
With reference to
As shown in
The primary lateral face 23A has a height Hs which is a height of the isosceles trapezoid, that is, a minimum length from the long side 24a to the top edge 24c. An aspect ratio As of the primary lateral face 23A is a ratio of the height Hs to the length of the long side 24a, that is, the width D1 of the projection 22 (As=Hs/D1). The aspect ratio As is preferably smaller than 1, more preferably in the range of 0.05 or more and 0.8 or less.
The secondary lateral face 23B has an angle θ2 of a secondary apex angle, which is an apex of the isosceles triangle, that is, an angle formed between the two lateral edges 24d. The angle θ2 is an acute angle which is smaller than 90 degrees. Specifically, the angle θ2 of the secondary apex angle is preferably in the range of 10 degrees or more and 60 degrees or less.
The secondary lateral face 23B has a height Hf which is a height of the isosceles triangle, that is, a minimum length from the short side 24b to the apex of the secondary lateral face 23B. An aspect ratio Af of the secondary lateral face 23B is a ratio of the height Hf to the length of the short side 24b which is a base side of the isosceles triangle, that is, the width D2 of the projection 22 (As=Hf/D2). The aspect ratio Af is preferably larger than 1, more preferably in the range of 1.2 or more and 4.6 or less.
Further, when the projection 22 having the above configuration is viewed in a direction along the second direction, an angle between the side that constitutes the tip of the projection 22 and the side that connects the tip of the projection 22 and the first surface 21S of the substrate 21 of the projection 22 is an obtuse angle larger than the angle θ1. In addition, when the projection 22 is viewed in a direction along the first direction, an angle between two sides that connect the tip of the projection 22 and the first surface 21S of the substrate 21 is preferably an acute angle larger than the angle θ2.
With reference to
As shown in
When viewed in the direction perpendicular to the first surface 21S of the substrate 21, the adhesive sheet 30 has an outer shape larger than the substrate 21 and having a longer dimension in the first direction than in the second direction substrate 21. For example, the adhesive sheet 30 has a rectangular shape or an ellipse shape which is similar to the shape of the substrate 21. When viewed in the direction perpendicular to the first surface 21S of the substrate 21, the adhesive sheet 30 extends outward from the substrate 21 such that the adhesive surface of the adhesive layer 32 is exposed.
In the above configuration, when viewed in the direction perpendicular to the first surface 21S of the substrate 21, an extending direction of the projection 22, an extending direction of the substrate 21, and an extending direction of the adhesive sheet 30 are aligned. In other words, when viewed in the direction perpendicular to the first surface 21S of the substrate 21, an extending direction of the tip of the projection 22, a longitudinal direction of the substrate 21 along which the long side or longer diameter of the substrate 21 extends, and a longitudinal direction of the adhesive sheet 30 along which the long side or longer diameter of the adhesive sheet 30 extends are aligned.
The number of projections 22 is not specifically limited, but is one or more. When the administering part 20 includes a plurality of projections 22, the plurality of projections 22 are arranged with the extending direction of the tips of the projections 22 being aligned as shown in
Forming materials of the transdermal administration device 10 in the first embodiment will be described.
The administering part 20 can be made of silicon, metal, ceramic, resin, or a material that dissolves in water contained in the skin. The forming material of the administering part 20 is preferably a biocompatible material. A metal material used as a forming material of the administering part 20 may be stainless steel, titanium, manganese or the like, and a ceramic material used as a forming material of the administering part 20 may be glass, alumina or the like. However, the forming material of the administering part 20 is not limited to these materials. A resin used for forming the administering part 20 may be a medical grade silicone resin, polylactic acid, polyglycolic acid, polycarbonate, polyethylene, polypropylene, epoxy resin, polyamide resin, phenolic resin, polystyrene resin, polycaprolactone, acrylic resin, urethane resin, aromatic polyether ketone, cyclic olefin copolymer or the like. However, the forming material of the administering part 20 is not limited to these materials.
In the configuration in which the administering part 20 is made of a material that dissolves in water contained in the skin, the projection 22 dissolves in the skin after it is pierced into the skin. Examples of a material that dissolves in water contained in the skin, that is, a water soluble material, include a water soluble polymer and disaccharide.
Examples of water soluble polymer include carboxymethyl cellulose (CMC), methylcellulose (MC), hydroxylpropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyacrylic acid polymer, polyacrylic amide (PAM), polyethylene oxide
(PEO), pullulan, alginate, pectin, chitosan, chitosan succinamide, and oligochitosan. Among these materials, chitosan, oligochitosan, chitosan succinamide, carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC) are particularly desirable as a material for the projection 22 since they have high biological safety. However, the forming material of the administering part 20 is not limited to these materials.
The disaccharide is preferably trehalose or maltose. In particular, when the projection 22 includes protein as a drug, trehalose serves to protect and stabilize the protein since trehalose, among others, has a crystal structure close to that of water. However, the forming material of the administering part 20 is not limited to these materials.
Further, the projection 22 may also include an additive such as stabilizer in addition to a water soluble polymer and disaccharide.
A drug administered by the administering part 20 may be any kind of drug as long as it works when administered into the skin. A drug may be applied on the surface of the projection 22 and delivered into the skin as the projection 22 creates a hole in the skin. Alternatively, when the projection 22 is made of a soluble material as described above, a drug may be contained inside the projection 22 and delivered into the skin as the projection 22 dissolves. Further, a liquid drug may be applied on the skin before or after the projection 22 is pierced into the skin so that the drug is delivered into the skin through a hole created by the projection 22. Moreover, a drug may be applied by combinations of these techniques. When the projection 22 is made of a soluble material, a water soluble polymer that constitutes the projection 22 may serve as a drug.
A drug may be, for example, various types of proteins, pharmacologically active agents, or cosmetic compositions, and is appropriately selected depending on the purpose.
Examples of a pharmacologically active agent include vaccines such as influenza vaccine, pain relievers for cancer patients, insulin, biologics, gene therapy agents, injections, oral agents, skin application preparations and the like. In transdermal administration using the administering part 20, a drug is administered into a hole created in the skin. Therefore, transdermal administration using the administering part 20 can be applied to not only administration of the pharmacologically active agents used in the conventional transdermal administration, but also administration of pharmacologically active agents that requires hypodermic injection. In particular, since transdermal administration using the administering part 20 does not cause pain by administration, it is suitable for administration of an injection drug such as vaccines for children. Further, since transdermal administration using the administering part 20 does not require oral administration of a drug, it is suitable for administration of an oral drug for children who have difficulty in taking an oral drug.
Cosmetic compositions are compositions for use as cosmetics or beauty products. Examples of a cosmetic composition include humectants, colorants, fragrance, and physiologically active agents exhibiting cosmetic effects such as improvement effect on wrinkles, acne, stretch marks or the like, and improvement effect on hair loss or the like. When an aromatic material is used as a cosmetic composition, a fragrance can be imparted to the administering part 20. Accordingly, the transdermal administration device 10 suitable for use as a beauty product can be obtained.
In addition, the substrate 21 and the projection 22 may be made of a material having the same composition, or materials having different compositions. In the configuration in which the substrate 21 and the projection 22 are made of a material having the same composition, the substrate 21 and the projection 22 can be easily integrally formed. Moreover, when the substrate 21 is made of a soluble material, a drug may also be contained in the substrate 21. As the substrate 21 dissolves in a surface layer of the skin, the drug contained in the substrate 21 is introduced into the surface layer of the skin.
Although materials for the adhesive sheet 30 are not specifically limited, the base sheet 31 is formed of, for example, a resin film made of polyethylene terephthalate or the like, and the adhesive layer 32 is formed of, for example, an epoxy or acrylic adhesive. An adhesive is preferably made of a material having properties suitable for a skin patch, and more preferably, a material that withstands a sterilization process.
With reference to
In use of the transdermal administration device 10, the projection 22 is oriented to the skin of administration target, the substrate 21 is pressed against the skin, and the adhesive sheet 30 exposed outside the substrate 21 is affixed to the skin.
Here, it is difficult to place the substrate 21 parallel to the skin surface and press the entire surface of the first surface 21S against the skin at a time, since the substrate 21 and the adhesive sheet 30 have a certain amount of surface area and the surface of the skin of administration target is not a completely flat surface. Usually, edges of the adhesive sheet 30 and the substrate 21 are first pressed against the skin.
As a result, as shown in
In the first embodiment, since the primary apex angle of the primary lateral face 23A is an obtuse angle, the corner G has a high strength compared with a case where the primary apex angle is a right angle or an acute angle. As a result, the corner G is prevented from being bent or collapsed.
On the other hand, since the secondary apex angle of the secondary lateral face 23B is an acute angle, the corner G has sharpness compared with a case where the secondary apex angle is a right angle or an acute angle. Accordingly, even if the primary apex angle is an obtuse angle, the sharpness of the corner G as a whole is prevented from being excessively reduced.
Further, as shown in
Further, as shown in
On the other hand, in piercing of the projection 22 into the skin, the projection 22 needs to be pressed against the skin along the direction in which the tip extends.
In the first embodiment, the extending direction of the tip of the projection 22, the longitudinal direction of the substrate 21, and the longitudinal direction of the adhesive sheet 30 are aligned. Accordingly, the direction in which a user of the transdermal administration device 10 can easily press the substrate 21 against the skin matches the direction in which the projection 22 should be pressed against the skin. Therefore, the projection 22 can be easily pierced into the skin.
For example, in
In addition, compared with a needle-shaped projection of the conventional microneedles, the projection 22 of the first embodiment can ensure a large volume and a large surface area, and thus a large amount of drug capable of being contained in the projection 22 and a large amount of drug capable of being applied on the surface of the projection 22. Further, compared with the above projection of the conventional microneedles, the projection 22 of the first embodiment can ensure a large area of the base which is defined within the first surface 21S of the substrate 21. As a result, in a production process of the administering part in which an intaglio plate is filled with a material for the administering part, which will be described later, a recess that corresponds to an administering part can be easily filled with the material.
From these points of view, the projection 22 is preferably made of a water soluble material or made of both a water soluble material and a drug from among the above materials. In this configuration, deformation of the projection 22 can be prevented, and furthermore, at least one of the amount of a substance delivered into the skin by the projection 22, that is, the amount of a water soluble material and the amount of a drug can be increased. The conventional projection often has a cone or pyramid shape as described above, which is a conical shape elongated in a direction perpendicular to the first surface 21S of the substrate 21. Since a projection of a conical shape does not have sufficient volume, the amount of substance delivered into the skin by the conical shape projection may be insufficient. In contrast, the projection 22 of the transdermal administration device 10 according to the present embodiment has a large volume for the projection, compared with that of the conical shape projection. Accordingly, the amount of substance delivered into the skin can be increased by the projection.
Although the projection 22 is preferably made of a water soluble material or made of both a water soluble material and a drug, the projection 22 may also include an additive such as stabilizer in addition to these materials.
As described above, the transdermal administration device 10 of the first embodiment can reduce occurrence of pain or fear in a patient by using fine projections similar to the conventional microneedle, and can perform drug administration without using a large device. Furthermore, the projection 22 can be prevented from being deformed. The inventors of the present application have focused on the function of the projection 22 to form a passage for drug administration by piercing the skin, in particular, focused on at what orientation the projection 22 is inserted and advanced into the skin, and arrived at the idea of the shape of the projection 22 in the present embodiment.
As described above, according to the transdermal administration device of the first embodiment, the following effects can be obtained.
(1) Since the angle θ1 of the primary apex angle of the primary lateral face 23A is an obtuse angle and the angle θ2 of the secondary apex angle of the secondary lateral face 23B is an acute angle, the sharpness of the corner G formed by the primary lateral faces 23A and the secondary lateral face 23B viewed in the first direction is prevented from being excessively reduced and the strength of the corner G against an external force in the first direction can be enhanced. Therefore, deformation of the projection 22 can be reduced.
(2) Since the aspect ratio Af of the secondary lateral face 23B is larger than 1, the secondary lateral face 23B has a sharper shape than the secondary lateral face 23B with the aspect ratio Af of not more than 1. As a result, the corner G has higher sharpness, which facilitates piercing of the projection 22.
(3) Since the secondary lateral face 23B is a triangular flat surface having an apex made by an end of the top edge 24c, designing of an angle of the primary apex angle or the secondary apex angle is facilitated, and further, production of the projection 22 is also facilitated.
(4) Since the extending direction of the tip of the projection 22, the extending direction of the substrate 21, and the extending direction of the adhesive sheet 30 are aligned, the direction in which a user of the transdermal administration device 10 can easily press the substrate 21 against the skin matches the direction in which the projection 22 should be pressed against the skin. Therefore, the projection 22 can be easily pierced into the skin.
With reference to
As shown in
The two primary lateral faces 23D have the identical shape, and each primary lateral face 23D is surrounded by the long side 24a and the top edge 24c which are parallel to each other, and two curved lateral edges 24e which connect the long side 24a and the top edge 24c. The primary lateral faces 23D are each inclined relative to the third direction such that the two primary lateral faces 23D intersect each other at their top edges 24c. The top edge 24c constitutes the tip of the projection 25, and tip of the projection 25 is formed in a linear shape extending along the first direction. Further, each primary lateral face 23D has an axisymmetric shape to a perpendicular bisector of the long side 24a.
The two secondary lateral faces 23E have the identical shape, and each secondary lateral face 23E is a curved surface surrounded by the short side 24b and two lateral edges 24e and having a curvature which curves inward to the projection 25. The secondary lateral faces 23E are each inclined relative to the third direction. Each secondary lateral face 23E intersects one of the two primary lateral faces 23D at one of the two lateral edges 24e and intersects the other of the two primary lateral faces 23D at the other of the two lateral edges 24e.
That is, the lateral edge 24d of the projection 22 in the first embodiment has a linear shape, while the lateral edge 24e of the projection 25 in the second embodiment has a curved shape.
Here, one plane formed by connecting three apexes on the secondary lateral face 23E, that is, one plane having an apex P1 which is an intersection between two lateral edges 24e and the short side 24b is defined as a virtual plane N. A direction perpendicular to the virtual plane N is a normal direction M, which is indicated by the arrow in
The height H, the width D1 in the first direction, the width D2 in the second direction, and the length L of the tip of the projection 25 are preferably in the range described previously for the height H, the width D1 in the first direction, the width D2 in the second direction, and the length L of the tip of the projection 22 of the first embodiment.
With reference to
As shown in
The primary apex angle is an angle formed between a tangent Ta and the top edge 24c. The tangent Ta is a line extends from the apex P2, which is an intersection between the top edge 24c of the primary lateral face 23D and the lateral edge 24e, to be tangent to the lateral edge 24e.
The primary lateral face 23D has the height Hs which is a minimum length from the long side 24a to the top edge 24c. An aspect ratio As of the primary lateral face 23D is a ratio of the height Hs to the width D1 of the projection 22 (As=Hs/D1). The aspect ratio As is preferably smaller than 1, more preferably in the range of 0.05 or more and 0.8 or less.
The secondary lateral face 23E has an angle θ4 of a secondary apex angle, which is an angle formed between the two lateral edges 24e. The angle θ4 is an acute angle which is smaller than 90 degrees. Specifically, the angle θ4 of the secondary apex angle is preferably in the range of 10 degrees or more and 60 degrees or less.
When the secondary lateral face 23E is viewed in the normal direction M perpendicular to the virtual plane N, that is, when the secondary lateral face 23E is projected onto the virtual plane N, the secondary apex angle is an angle formed between each of the lateral edges 24e, that is, an angle formed between two tangents Tb which extend from the apex P1, which is an intersection between the two lateral edges 24e, to be tangent to each of the lateral edges 24e.
The secondary lateral face 23E has the height Hf which is a minimum length from the short side 24b when the secondary lateral face 23E is projected onto the virtual plane N to the apex P1 of the secondary lateral face 23E. An aspect ratio Af of the secondary lateral face 23E is a ratio of the height Hf to the width D2 of the projection 22 (Af=Hf/D2). The aspect ratio Af is preferably larger than 1, more preferably in the range of 1.2 or more and 4.6 or less.
When the projection 25 having the above configuration is viewed in a direction along the second direction, an angle between the side that constitutes the tip of the projection 25 and the side that connects the tip of the projection 25 and the first surface 21S of the substrate 21 of the projection 25 is an obtuse angle. Further, when the projection 25 is viewed in a direction along the first direction, an angle between two sides that connect the apex of the projection 25 and the first surface 21S of the substrate 21 is an acute angle.
As with the first embodiment, in the transdermal administration device of the second embodiment, the administering part 20 and the adhesive sheet 30 are disposed such that the extending direction of the projection 25, the extending direction of the substrate 21, and the extending direction of the adhesive sheet 30 are aligned when viewed in the direction perpendicular to the first surface 21S of the substrate 21. The transdermal administration device of the second embodiment is also made of a material described as an example of the forming material of the transdermal administration device in the first embodiment.
Effects of the transdermal administration device of the second embodiment will be described.
As with the first embodiment, the transdermal administration device of the second embodiment also has the primary apex angle of the primary lateral face 23D which is an obtuse angle, and the secondary apex angle of the secondary lateral face 23E which is an acute angle. Accordingly, the sharpness of the corner formed by two primary lateral faces 23D and one secondary lateral face 23E is prevented from being excessively reduced and the strength of the corner can be enhanced. Therefore, deformation of the projection 22 can be reduced.
Further, in the second embodiment, the secondary lateral face 23E is a curved surface. As previously shown in
As described above, according to the transdermal administration device of the second embodiment, the following effects can be obtained in addition to the effect (1), (2), and (4) of the first embodiment.
(5) Since the secondary lateral face 23E is a curved surface having a curvature that curves inward to the projection 25, the projection 25 can be further easily pierced into the skin.
The first and second embodiments can be implemented with modifications as described below.
In the first and second embodiments, the primary lateral faces 23A, 23D, and the secondary lateral faces 23B, 23E may have a ridge, groove, or hole. A hole may penetrate through or may not penetrate through the projection 22, 25 and the substrate 21 in the third direction. Further, a groove or hole may be filled with a drug.
The primary lateral faces 23A and 23D may be curved surfaces, and the base 23C may not be a rectangular shape. In other words, the shape of each face is not specifically limited as far as the projection has a shape extending along one direction parallel to the first surface 21S, the primary apex angle of each of the two primary lateral faces that have the common top edge in the form of a linear tip is an obtuse angle, and the secondary apex angle of the secondary lateral face that is connected to each of the primary lateral faces is an acute angle.
Further, when the primary lateral face is a curved surface, virtual planes including both ends of the top edge and both ends of the lateral edges are each defined as a projection surface, and the primary apex angle is defined on the basis of an image of the primary lateral face projected on the projection surface in the normal direction to the projection surface.
In addition, when the short side has a curved shape, the virtual plane N which includes both ends of the two lateral edges is defined as a projection surface as with the second embodiment, the secondary apex angle is defined on the basis of an image of the secondary lateral face projected on the projection surface in the normal direction to the projection surface. Further, the aspect ratio Af may be determined by a ratio of the height of the secondary lateral face to the length between both ends of the short side of the secondary lateral face projected onto the virtual plane N.
In the above embodiments, the primary lateral faces 23A and 23D are described as being axisymmetric to the perpendicular bisector of the long side 24a. However, the primary lateral faces 23A and 23D may not necessarily have an axisymmetric shape. That is, in each of the two primary lateral faces, an angle formed between the top edge and one of the two lateral edges and an angle formed between the top edge and the other of the two lateral edges may be different from each other. The only requirement for the two primary lateral faces is that at least one of the angles formed between the top edge and each of the two lateral edges serves as the primary apex angle which is an obtuse angle, and the lateral edge which forms the primary apex angle of an obtuse angle on one primary lateral face and the lateral edge which forms the primary apex angle of an obtuse angle on the other primary lateral face forms the secondary lateral face, forming the secondary apex angle which is an acute angle. That is, the angle formed between the first lateral edge and the top edge on each primary lateral face is required to be an obtuse angle, and the angle formed between the two first lateral edges on the first secondary lateral face is required to be an acute angle.
According to this configuration, the effect of the above (1) is achieved by the projection 22, 25 which pierces the skin with the corner formed of the primary apex angle which is an obtuse angle and the secondary apex angle which is an acute angle. When one of the angles formed by the top edge and each of the two lateral edges on each of the primary lateral faces is an acute angle, instructions for the pressing direction of the substrate 21 should be presented to a user, for example by printing on the adhesive sheet 30, so that the user can pierce the projection 22, 25 into the skin with the corner formed of the primary apex angle which is an obtuse angle and the secondary apex angle which is an acute angle.
As long as the projection has a shape extending along the first surface 21S of the substrate 21, that is, a shape longer in the first direction than in the third direction, the top edge may extend along a direction other than the first direction. For example, as shown in
In this case, as shown in
In other words, the extending direction of the top edge is not necessarily the first direction, and may be any direction different from the third direction. The top edge is required only to be a side having a linear shape and located away from the first surface 21S.
The projection does not necessarily include the second secondary lateral face as long as it has two primary lateral faces having the common top edge which is a linear-shaped tip and the separate first lateral edges, and the first secondary lateral face having the first lateral edges in common with the respective primary lateral faces and forming one corner together with the two primary lateral faces. Further, the angle formed between the first lateral edge and the top edge on each primary lateral face is required to be an obtuse angle, and the angle formed between the two first lateral edges on the first secondary lateral face is required to be an acute angle.
For example, as shown in
The primary lateral face 23H has a shape made up of trapezoids and triangles connected to the top of the trapezoids, and an inclined angle of the triangular portion in the third direction is larger than an inclined angle of the trapezoidal portion in the third direction. The primary apex angle formed by the top edge 24h and the lateral edge 24i on the primary lateral face 23H is an obtuse angle. The secondary lateral face 23I also has a shape made up of trapezoids and triangles connected to the top of the trapezoids, and an inclined angle of the triangular portion in the third direction is larger than an inclined angle of the trapezoidal portion in the third direction. A secondary apex angle of the secondary lateral face 23I, which is an angle formed between the two lateral edges 24i is an acute angle.
The lateral edge 24i is the first lateral edge that connects the first end of the top edge 24h and the first surface 21S of the substrate 21, and is a polygonal line. The second end of the top edge 24h and the first surface 21S of the substrate 21 are connected to each other by a lateral edge 24j which is one of the second lateral edges. That is, the two primary lateral faces 23H have the common lateral edge 24j. Further, a base 23J of the projection 27 has a triangular shape.
In this configuration as well, the effect of the above (1) is achieved by the projection 27 which pierces the skin with the corner formed by the primary apex angle which is an obtuse angle and the secondary apex angle which is an acute angle. When the transdermal administration device includes the projection 27, instructions for the pressing direction of the substrate 21 should be presented to a user, for example by printing on the adhesive sheet 30, so that the user can pierce the projection 27 into the skin with the above corner.
The extending direction of the tip of the projection 22, 25 is not necessarily aligned with the longitudinal direction of the substrate 21. Even if the extending direction of the tip of the projection 22, 25 is not aligned with the longitudinal direction of the substrate 21, the direction in which the user of the transdermal administration device can easily press the adhesive sheet 30 against the skin matches the direction in which the projection 22 should be pressed against the skin as long as the extending direction of the tip of the projection 22, 25 is aligned with the longitudinal direction of the adhesive sheet 30. Since the substrate 21 is pressed against the skin along the adhesive sheet 30, the effect similar to the above (4) is achieved.
The extending direction of the tip of the projection 22, 25 is not necessarily aligned with the longitudinal direction of the adhesive sheet 30. For example, a configuration is also possible in which the extending direction of the tip of the projection 22, 25 is not aligned with the longitudinal direction of the adhesive sheet 30, and the extending direction of the tip of the projection 22, 25 is aligned with the longitudinal direction of the substrate 21. In this configuration as well, in a portion of the adhesive sheet 30 to which the substrate 21 is attached, the user of the transdermal administration device can easily press the substrate 21 against the skin in a direction in which the projection 22 should be pressed against the skin. Accordingly, the effect similar to the above (4) is also achieved.
Further, the extending direction of the tip of the projection 22, 25 is not necessarily aligned with either of the longitudinal direction of the substrate 21 and the longitudinal direction of the adhesive sheet 30. In this configuration, for example, instructions for the pressing direction of the substrate 21 should be presented to a user, for example by printing on the adhesive sheet 30, so that the user can pierce the projection 22, 25 into the skin with the corner formed of the primary apex angle which is an obtuse angle and the secondary apex angle which is an acute angle.
The transdermal administration device 10 is only required to include at least the administering part 20, and does not necessarily include the adhesive sheet 30.
With reference to
As shown in
On the surface of substrate of the transdermal administration device 10 opposite from the tip of the projection, that is, on the second surface 21T of the substrate 21 in the configuration in which the transdermal administration device 10 only includes the administering part 20, an adhesive holder 130 is disposed to support the substrate 21. The transdermal administration device 10 is temporarily fixed to the protective film 140 via the adhesive holder 130 attached on the protective film 140. In addition, the transdermal administration device 10 may be temporarily fixed to the support casing 120 instead of the protective film 140.
According to this transdermal administration device package, the transdermal administration device 10 is prevented from being impacted by other objects or being directly touched by the user's hand since the transdermal administration device 10 is packaged. As a result, deformation of the transdermal administration device 10 is prevented.
With reference to
In the fourth embodiment, an example of a production method of the transdermal administration device 10 according to any one of the first embodiment, the second embodiment, and modifications thereof will be described.
A method for producing the transdermal administration device 10 includes the steps of forming a molded product by filling a recess of an intaglio plate with a forming material of the administering part 20, and removing the molded product from the intaglio plate. The forming material of the administering part 20 may be provided to the intaglio plate singularly or in the form of liquid having the forming material dissolved or dispersed therein.
With reference to
The intaglio plate for use in production of the transdermal administration device includes a recess having a shape in conformity with the shape of the projection of the transdermal administration device 10. The recess is formed to have the longitudinal direction which is an extending direction of the recess when viewed in the direction perpendicular to the surface of the intaglio plate corresponds to a removal proceeding direction, which is a direction in which the molded product made of the forming material of the administering part 20 is removed from the intaglio plate.
As shown in
The above arrangement of the recesses 51 facilitates removal of the molded product from the intaglio plate 50. Accordingly, the precision of shape-transfer from the intaglio plate 50 to the forming material of the administering part 20 is improved.
In addition, the intaglio plate may have a plate-shape as long as the recesses are arranged such that the plan shape of the recesses viewed in the direction perpendicular to the surface of the intaglio plate extends in the removal proceeding direction.
As an example of the production method of the above intaglio plate, description will be provided below for the production method of an intaglio plate using a projection having substantially the same shape as that of the projection of the transdermal administration device 10 and a substrate that supports the projection.
A step of fabricating an original plate is a step of preparing a forming material of the original plate and fabricating an original plate by using a micromachining technique.
The forming material of the original plate is not specifically limited, and is preferably selected considering processing suitability or availability of the material. Examples of the forming material of the original plate include metal materials such as stainless steel (SUS), aluminum and titanium, ceramics such as alumina, aluminum nitride, and machinable ceramics, hard brittle materials such as silicon and glass, and organic materials such as acryl and polyacetal.
The fabrication method of the original plate is not specifically limited, and a known method may be used depending on the shape of the original plate to be fabricated. For example, the original plate may be fabricated by using a micromachining technique or a machine processing technique used for production of semiconductor devices. Specifically, micromachining technique used for fabrication of original plate includes, for example, lithography, wet etching, dry etching, sand blasting, laser processing, and micromachining.
In order to improve the mold releasability of the intaglio plate from the original plate, a surface shape processing or chemical surface modification may be applied on the original plate. Specifically, grinding, boring, or grooving by machine processing, surface treatment and surface modification by using an etching process, or application of a mold release agent may be advantageously used.
The original plate thus obtained is used as a plate for fabrication of the intaglio plate.
In production of the intaglio plate, a forming material of the intaglio plate is supplied onto the surface of the original plate. After curing of the forming material of the intaglio plate, the original plate is separated from the forming material to fabricate the intaglio plate having a shape of the original plate reproduced as a recessed shape. The intaglio plate thus fabricated allows for production of a large number of transdermal administration devices 10 from the same intaglio plate. Accordingly, the production cost of the transdermal administration device 10 can be reduced, thereby improving the productivity.
Examples of the forming material of the intaglio plate include inorganic materials such as nickel, silicon, silicon carbide, tantalum, glassy carbon, quartz, and silica, and resin compositions such as silicone resin, urethane rubber, norbornene resin, polycarbonate, polyethylene terephthalate, polystyrene, polymethacrylic acid methyl, acryl, and liquid crystal polymer. Of these materials, considering high formability, conformity with the microshapes, and mold releasability, the forming material is preferably silicone resin, nickel, silicon, silicon carbide, tantalum, glassy carbon, quartz and silica, more preferably silicone resin, and particularly preferably silicone resin containing polydimethyl siloxane. For example, silicone resin containing polydimethyl siloxane with a hardener added thereto can be used. Use of the silicone resin having high mold releasability improves the releasability of cured forming material of the intaglio plate, thereby preventing deformation of the intaglio plate when being removed from the mold.
Further, the production method of the intaglio plate is not limited to the above-mentioned methods, and the intaglio plate can be produced by a known shape-transfer technique. For example, an intaglio plate made of nickel may be produced by nickel electroforming.
The production method of the intaglio plate in the above description includes producing an original plate, and producing an intaglio plate from the original plate. However, the intaglio plate may also be produced by directly processing the forming material of the intaglio plate.
With reference to
When the forming material of the administering part 20 is a thermoplastic resin, the administering part 20 is produced as a molded product by molding the thermally melted forming material by using an intaglio plate. For transfer forming from the intaglio plate to the forming material, a known technique may be used.
When the forming material of the administering part 20 is a material that dissolves in water contained in the skin, such as a water soluble polymer or disaccharide, a liquid material having the forming material dissolved or dispersed in a solvent such as water is first prepared. Then, the liquid material is introduced into the recess of the intaglio plate, and is dried to remove the solvent in the liquid material to thereby form a molded product, which is the administering part 20. For transfer forming from the intaglio plate to the forming material, a known technique may be used.
In the following description, examples of the production method of the transdermal administration device will be described for each of the case which uses a thermoplastic resin and the case which uses a water soluble material as a forming material of the administering part 20.
The production method of the transdermal administration device is only required to include the steps of forming a molded product by filling the recess of the intaglio plate with the forming material of the administering part 20 and removing the molded product from the intaglio plate so that removal is carried out in the extending direction of the recess when viewed in the direction perpendicular to the surface of the intaglio plate, and the details of these steps may be different from the description below.
With reference to
As shown in
As shown in
As shown in
As shown in
As shown in
In addition, when a resin is used for the forming material of the administering part 20, the administering part 20 may be produced not only by thermal compression molding as described in
The obtained administering part 20 is provided as the transdermal administration device 10 by itself or together with other member bonded thereto such as the adhesive sheet 30. The administering part 20 and the adhesive sheet 30 can be bonded to each other by a conventional technique. Further, the molded product 71 and the adhesive sheet 30 may be bonded after the molded product 71 is formed on the intaglio plate 60, and then removed from the intaglio plate 60 to obtain a structure made up of the administering part 20 and the adhesive sheet 30. Moreover, the outer shape of the molded product 71 or the combination of the molded product 71 and the adhesive sheet 30 or the like may be adjusted as necessary by cutting the outer portion of the substrate 21 by punching or the like using a Thomson blade or the like.
With reference to
As shown in
As shown in
Further, in the case where the compositions of the projection and the substrate are different from each other or the compositions of the tip and the base of the projection are different from each other in the administering part 20 which is the production target, liquid materials which contain forming materials of different compositions may be sequentially filled into the recesses 63 and 64.
As shown in
As shown in
As shown in
The obtained administering part 20 is provided as the transdermal administration device 10 by itself or together with other member bonded thereto such as the adhesive sheet 30. The administering part 20 and the adhesive sheet 30 can be bonded to each other by a conventional technique. Further, the molded product 72 and the adhesive sheet 30 may be bonded after the molded product 72 is formed on the intaglio plate 62, and then removed from the intaglio plate 62 to obtain a structure made up of the administering part 20 and the adhesive sheet 30. Moreover, the outer shape of the molded product 72 or the combination of the molded product 72 and the adhesive sheet 30 or the like may be adjusted as necessary by cutting the outer portion of the substrate 21 by punching or the like using a Thomson blade or the like.
The molded product of the administering part 20 may also be formed by applying pressure onto a sheet made of the forming material of the substrate 21 which is placed on the forming material of the projection filled in the recess 63 of the intaglio plate 62.
Advantageous effects of the production method of the transdermal administration device of the present embodiment will be described.
The conventional production methods of a microneedle which has been proposed include fabricating an original plate of a projection by cutting work, producing an intaglio plate having an inverted pattern of bumps and dents of the original plate, and manufacturing an administering part having a projection made of resin by transfer molding using the intaglio plate. However, these production methods may have a phenomenon, so-called torare in Japanese, that the resin is adhered to the intaglio plate during removal of the molded product from the intaglio plate. If this phenomenon occurs, the precision of shape-transfer from the intaglio plate to the removed molded product is reduced.
Moreover, even if a material other than a thermoplastic resin is used as a forming material of the administering part 20, the forming material may be partially adhered to the intaglio plate during removal of the molded product from the intaglio plate, which may decrease the precision of shape-transfer from the intaglio plate to the removed molded product.
In contrast, according to the production method of the transdermal administration device of the present embodiment, the projection which is the production target has a shape extending along the first surface 21S of the substrate 21, and thus the recess of the intaglio plate for producing the projection has a shape extending in one direction when viewed in the direction perpendicular to the surface of the intaglio plate. Since the molded product is removed from the intaglio plate in the extending direction of the recess when viewed in the direction perpendicular to the surface of the intaglio plate, the molded product is easily removed from the intaglio plate compared with the case where the molded product is removed from the intaglio plate in the direction different from the extending direction of the recess such as that extending perpendicular to the extending direction of the recess. As a result, the forming material is prevented from being partially adhered to the intaglio plate during removal of the molded product. Accordingly, the precision of shape-transfer from the intaglio plate to the removed molded product is improved.
Next, as an example of the production method of the transdermal administration device package of the third embodiment, a production method of the transdermal administration device package having a configuration in which the transdermal administration device 10 is temporarily fixed to the protective film 140 will be described.
This production method of the transdermal administration device package includes the above steps of fabricating the transdermal administration device 10, and the steps of bonding a protective sheet having easy adhesiveness to a surface of the substrate of the transdermal administration device 10 opposite from the tip of the projection via a detachable adhesive material, bonding a casing sheet to the protective sheet so as to cover the tip of the projection on the transdermal administration device 10 and house the transdermal administration device 10, and cutting the protective sheet and the casing sheet bonded to each other.
In a feeding-out process shown in
In the feeding-out process shown in
The transdermal administration device package thus produced includes, as shown in
Detailed configuration of the members of the transdermal administration device package will be described.
The adhesive holder 130 is made of a material having adhesiveness at least capable of holding the transdermal administration device 10, and may be designed as appropriate depending on the specification of the transdermal administration device 10. For example, the adhesive holder 130 may be formed by a resin having viscoelasticity, an adhesive or the like.
Further, the adhesive holder 130 is preferably detachable to an adhesion target, and is preferably made of a gel polymer. The adhesive holder 130 made of a gel polymer has high adhesiveness, and can be repeatedly attached and removed from the adhesion target. Moreover, the adhesive holder 130 made of a gel polymer can be repeatedly used since the adhesiveness can be restored by cleansing with distilled water, purified water, ethyl alcohol or the like. Specifically, examples of gel polymer include silicone gel, urethane gel and the like.
The support casing 120 can be formed by thermal pressing. For example, as described above, a number of recesses, each having a size capable of housing the transdermal administration device 10, are formed by vacuum molding, vacuum pressure molding or the like so as to be arrayed in a matrix on a sheet material having an elongated strip shape. For example, as shown in
The shape of the recess can be designed as appropriate depending on the shape of the transdermal administration device 10, and may be, for example, a circle, ellipse, oblong circle, or a rectangle in plan view. Further, the number of recesses included in one support casing 120 may be arbitrarily determined depending on the number of the transdermal administration devices 10 housed in the support casing 120.
The sheet material used for formation of the support casing 120 may be a sheet material made of a known synthesized resin material such as polyvinyl chloride, polyethylene terephthalate, polypropylene, polyethylene, nylon, or ethylene-vinyl alcohol copolymer resin. Further, the sheet material is preferably a transparent synthesized resin material since it has high gas barrier properties and transparency which allows for visual inspection of the transdermal administration device 10 from the outside of the support casing 120 to easily check a foreign substance in the recess. Specifically, the forming material of the sheet material is preferably an ethylene-vinyl alcohol copolymer.
The transdermal administration device 10 is fixed to the protective film 140 by positioning the adhesive holder 130 on one surface of the protective film 140 so that the adhesive holder 130 holds the transdermal administration device 10. Since the transdermal administration device 10 is prevented from being moved in the recess of the support casing 120 during transportation of the transdermal administration device package or the like, the transdermal administration device 10 can be advantageously stored or transported. In particular, when the plurality of transdermal administration devices 10 are housed in one support casing 120, collision between each of the transdermal administration devices 10 can be reduced.
The support casing 120 can be sealed with the protective film 140 by using a heat sealer. That is, the protective sheet which is the protective film 140 is disposed to cover the opening of the support casing 120, and is thermally shrunk by applying heat to the protective sheet to thereby seal the recess in which the transdermal administration device 10 is housed. Sealing of the recess can prevent degeneration of the transdermal administration device 10 due to environmental change.
The protective film 140 is preferably a resin film that has strong adhesiveness to the support casing 120 when being bonded to the support casing 120, and easy openness when being peeled from the support casing 120 to open the transdermal administration device package.
In use of the transdermal administration device package, the user peels the protective film 140 from the support casing 120 and takes out the transdermal administration device 10 which is detachably attached to the protective film 140. Then, the user pierces the projection of the transdermal administration device 10 into the skin. Since the transdermal administration device 10 is packaged, it is prevented from being impacted by other objects or being directly touched by the user's hand. As a result, deformation of the transdermal administration device 10 is prevented.
Further, the transdermal administration device 10 housed in the transdermal administration device package is preferably sterilized. For example, the transdermal administration device 10 can be sterilized by dried heated air, hydrogen peroxide gas, ethylene oxide gas, electron beam radiation, or γ beam radiation. Of these techniques, use of low energy electron beam is widely adopted since the method can be conducted at low temperature and does not leave a residue in the sterilized object, and the handling is safe and easy. When the drug is applied on the transdermal administration device 10, high temperature processing cannot be performed. In addition, especially when the drug is filled in the groove or hole formed on the projection, sterilization must be performed not only on the outer surface of the projection but also on the inner area where the drug is filled. Accordingly, sterilization by γ beam radiation is preferably performed. As described above, sterilization performed on the transdermal administration device 10 can maintain the inside of the support casing 120 of the transdermal administration device package to have an aseptic state over a long period of time.
The fourth embodiment can be implemented with modifications as described below.
The transdermal administration device 10 included in the transdermal administration device package may not necessarily be the transdermal administration device 10 produced by the production method of the transdermal administration device according to the fourth embodiment, but may be the transdermal administration device 10 according to any one of the first embodiment, the second embodiment, and modifications thereof. Since the transdermal administration device 10 is packaged as the transdermal administration device package, the transdermal administration device 10 is prevented from being in contact with water, oxygen, carbon dioxide, odors or the like. Accordingly, the transdermal administration device 10 storing a drug which should not be in contact with these gases can be advantageously stored.
The transdermal administration device 10 according to any one of the first embodiment, the second embodiment, and modifications thereof may be produced by a method different from that of the fourth embodiment. For example, when the molded product is removed from the intaglio plate, the molded product may be removed in the direction different from the extending direction of the recess.
Moreover, the administering part 20 can be produced by various known techniques depending on the forming material of the administering part 20. The administering part 20 may also be produced without using the intaglio plate. For example, when the administering part 20 is made of resin, the administering part 20 can be produced by molding techniques such as injection molding, extrusion molding, imprinting, hot embossing, and casting. Further, the administering part 20 can also be produced by micromachining techniques such as lithography, wet etching, dry etching, sand blasting, and laser processing. In addition, the original plate may be produced by these techniques.
The above transdermal administration device will be described by using specific examples.
The original plate of the administering part was produced from an acrylic plate by micromachining. The projection had the same shape as that of the projection 22 of the first embodiment, and the secondary lateral face is a flat surface. The height H of the projection was approximately 500 μm, the width D1 of the projection was approximately 770 μm, and the width D2 of the projection was approximately 280 μm, the length L of the tip was approximately 500 μm, the height Hs of the primary lateral face was approximately 520 μm, the height Hf of the secondary lateral face was approximately 520 μm, the angle θ1 of the primary apex angle was approximately 105 degrees, and the angle θ2 of the secondary apex angle was approximately 30 degrees. The 36 projections were arrayed on the substrate in a matrix of six rows and six columns with a pitch of 1 mm.
Then, a thermosetting silicone resin was applied on the surface of the projection of the original plate formed of an acrylic plate, and was removed after being thermally cured to obtain the intaglio plate made of silicone. The recesses which correspond to the 36 projections were formed on the intaglio plate.
The liquid material containing the forming material of the administering part, which was 0.1% Evans Blue/5% chitosan succinamide aqueous solution, was filled into the intaglio plate. The intaglio plate was heated at 90° C. for 10 minutes so as to dry and solidify the liquid material. The solidified molded product was punched into a circle shape, and removed from the intaglio plate to obtain the administering part.
An adhesive surface of an adhesive sheet which is larger than the substrate was bonded to the second surface of the substrate of the obtained administering part to obtain the transdermal administration device of Example 1.
The original plate of the administering part was produced from an aluminum plate by micromachining. The projection had the same shape as that of the projection 25 of the second embodiment, and the secondary lateral face is a curved surface. The height H of the projection was approximately 500 μm, the width D1 of the projection was approximately 1500 μm, and the width D2 of the projection was approximately 340 μm, the length L of the tip was approximately 500 μm, the height Hs of the primary lateral face was approximately 530 μm, the height Hf of the secondary lateral face was approximately 707 μm, the angle θ3 of the primary apex angle was approximately 135 degrees, and the angle θ4 of the secondary apex angle was approximately 27 degrees. The 36 projections were arrayed on the substrate in a matrix of six rows and six columns with a pitch of 1 mm.
Subsequently, the intaglio plate was fabricated by the same procedure as that of Example 1, the liquid material was filled into the intaglio plate to fabricate the administering part, and the adhesive sheet was bonded to the administering part to obtain the transdermal administration device of Example 2.
The liquid material containing the forming material of the administering part, which was 2% dextran/10% glycine/10% trehalose aqueous solution, was filled into the intaglio plate obtained in Example 2 by an ink jet method. The liquid material of 100 nl was filled into the respective recesses which correspond to the projections, and then, chitosan succinamide 5% aqueous solution was further filled into the recesses. The dextran was fluorescent-labeled dextran. Thereafter, the intaglio plate was heated at 90° C. for 10 minutes so as to dry and solidify the liquid material. The solidified molded product was punched into a circle shape, and removed from the intaglio plate to obtain the administering part having the fluorescent substance concentrated at the tip end of the projection.
The adhesive sheet was bonded to the obtained administering part by the same procedure as that of Example 1 to obtain the transdermal administration device of Example 3.
The transdermal administration device of Examples 1 to 3 was observed by using a stereoscopic microscope. As a result of observation, it was found that the formation rate of the projections, that is, the rate of the projections of the same shape as those of the original plate were formed on the administering part to the total number of the projections on the original plate was 100% for each of Examples 1 to 3.
The transdermal administration device of Examples 1 to 3 was applied to a mouse. In Example 3, a skin slice sample of the mouse to which the transdermal administration device was applied was prepared, and was observed by using a fluorescence microscope.
The transdermal administration device was applied to the mouse by pressing the projection against the skin along the extending direction of the projection.
In the skin of mouse, blue coloring was observed at a position where the transdermal administration device of Examples 1 and 2 was applied. Further, fluorescence emission was observed from the skin slice of the mouse to which the transdermal administration device of Example 3 was applied. The fluorescence emission was observed at a position in the epidermis or deeper than that. Accordingly, it was found that the drug can be transdermally absorbed by using the transdermal administration device.
The original plate of the administering part was produced from an aluminum plate by micromachining. The projection had the same shape as that of the projection 25 of the second embodiment, and the secondary lateral face is a curved surface. The height H of the projection was approximately 470 μm, the width D1 of the projection was approximately 770 μm, the length L of the tip was approximately 500 μm, the height Hs of the primary lateral face was approximately 500 μm, the angle θ3 of the primary apex angle was approximately 105 degrees, and an angle θ4 of the secondary apex angle was approximately 60 degrees. The 36 projections were arrayed on the substrate in a matrix of six rows and six columns with a pitch of 1 mm.
Then, the intaglio plate was fabricated in the same procedure as that of Example 1. The liquid material containing the forming material of the administering part, which was hydroxypropyl cellulose aqueous solution, was filled into the intaglio plate. The intaglio plate was then heated at 90° C. for 10 minutes so as to dry and solidify the liquid material. Subsequently, the solidified molded product was removed from the intaglio plate. Here, the direction in which the molded product is removed from the intaglio plate corresponded to the extending direction of the recess viewed in the direction perpendicular to the intaglio plate.
Thus, the transdermal administration device of Example 4 formed of the administering part was obtained.
The transdermal administration device of Example 4 was observed by using a scanning electron microscope. The result was that the height H of the projection was 471 μm, the width D1 of the projection was 769 μm, and the angle θ4 of the secondary apex angle was 59 degrees.
The liquid material containing the forming material of the administering part, which was 0.1% Evans Blue/5% chitosan succinamide aqueous solution, was filled into the recess having a shape in conformity with the shape of the projection of the intaglio plate obtained in Example 4. Then, the intaglio plate was heated at 90° C. for 10 minutes so as to dry and solidify the liquid material. Then, the liquid material containing the forming material of the administering part, which was 30% hydroxypropyl cellulose aqueous solution, was filled on the liquid material filled and solidified in the intaglio plate. The intaglio plate was heated at 90° C. for 20 minutes so as to dry and solidify the liquid material. Subsequently, the solidified molded product was removed from the intaglio plate. Here, the direction in which the molded product is removed from the intaglio plate corresponded to the extending direction of the recess viewed in the direction perpendicular to the intaglio plate.
Thus, the transdermal administration device of Example 5 formed of the administering part was obtained. In the administering part, an upper layer, that is, the projection is made of chitosan succinamide and Evans Blue, and a lower layer, that is, substrate is made of hydroxypropyl cellulose.
The transdermal administration device of Example 5 was observed by using an optical microscope. It was confirmed that the projection was blue and the substrate was transparent. That is, it was confirmed that the transdermal administration device of Example 5 had a two-layered structure in which the projection was formed of chitosan succinamide and Evans Blue, and the substrate was formed of hydroxypropyl cellulose.
The original plate which included the projection having the width D1 of approximately 800 μm, the width D2 of approximately 400 μm, and the height H of approximately 700 μm was fabricated, and a roll-shaped intaglio plate was fabricated by inverting the bumps and dents of the original plate. The recess which extends in the circumferential direction of the intaglio plate was formed on the intaglio plate. In other words, when viewed in the direction perpendicular to the surface of the intaglio plate, the long side of the recess, that is, the side having the length of 800 μm which corresponds to the above width D1 extends in the circumferential direction of the intaglio plate, and the short side of the recess, that is, the side having the length of 400 μm which corresponds to the above width D2 extends in the width direction of the intaglio plate.
Polyglycolic acid was used as the forming material of the administering part, and the bumps and dents of the intaglio plate were inverted by thermal compression molding to thereby fabricate the transdermal administration device. As a result, the plurality of projections were formed on the transdermal administration device, and 95% or more of the projections were formed without being bent.
From the above results, it was found that the precision of shape-transfer from the intaglio plate to the molded product was improved when the molded product, which is formed as the administering part, was removed from the intaglio plate so that removal is carried out in the extending direction of the recess when viewed in the direction perpendicular to the surface of the intaglio plate.
Since a needle-shaped projection of a microneedle has an elongated shape extending from a surface of a plate-shaped substrate, it does not have a sufficient strength against a force in the lateral direction which is parallel to the surface of the substrate. When the projection pierces the skin, force in the lateral direction is inevitably applied to the projection since the surface of the skin is not flat. Accordingly, if lateral force is excessively applied to the projection, the projection is bent or collapsed, leading to decrease in piercing properties of the projection.
Therefore, in transdermal administration devices such as microneedles having a fine projection to create a passage for intradermal drug administration, there is a need for a device having a projection which is not easily deformed compared with that of the microneedle.
The present invention has an aspect of providing a transdermal administration device that reduces deformation of a projection and a method for producing the transdermal administration device.
A transdermal administration device that solves the above problem includes an administering part including a substrate having a first surface and a second surface which is a surface opposite from the first surface, and a projection which protrudes from the first surface, wherein the projection has a shape extending along the first surface, and includes: one linear top edge which is located away from the first surface, the top edge having a first end and a second end; two primary lateral faces which have the top edge in common with each other, the two primary lateral faces having lateral edges, each lateral edge individually connecting the first end of the top edge and the first surface; and a secondary lateral face which has the lateral edges in common with the respective primary lateral faces and forms one corner together with the two primary lateral faces, an angle made between the lateral edge and the top edge on the primary lateral face is an obtuse angle, and an angle made between the two lateral edges on the secondary lateral face is an acute angle.
According to the above configuration, in piercing of the projection into the target, a corner of the projection formed by the two primary lateral faces and the secondary lateral face is first pierced into the target. At this time, the corner is subject to an external force having a large component directed in the first direction, which is an extending direction of the projection. Since an angle formed between the top edge and the lateral edge on the primary lateral face is an obtuse angle, the corner has high strength against the external force acting on the corner, compared with a case where the angle is a right angle or an acute angle. On the other hand, since the angle made between the two lateral edges on the secondary lateral face is an acute angle, the corner has a sharp shape when viewed in the first direction compared with a case where the angle is a right angle or an acute angle. As a result, since the sharpness of the corner viewed in the first direction is prevented from being excessively reduced and the strength of the corner against the external force in the first direction can be enhanced, deformation of the projection can be reduced.
In the above transdermal administration device, the secondary lateral face may include a base side located within the first surface, and an aspect ratio which is a ratio of a height of the secondary lateral face to a length between both ends of the base side may be larger than 1.
According to the above configuration, the aspect ratio of the secondary lateral face is larger than 1. Accordingly, the secondary lateral face has a sharp shape compared with a case where the aspect ratio of the secondary lateral face is not more than 1. As a result, the corner has higher sharpness, which facilitates piercing of the projection.
In the above transdermal administration device, the secondary lateral face may be a triangular flat surface having an apex made by the first end of the top edge.
According to the above configuration, the secondary lateral face is a triangular flat surface, and accordingly, designing of an angle made between the top edge and the lateral edge and designing of an angle of the corner viewed in the first direction are facilitated.
In the above transdermal administration device, the secondary lateral face may be a curved surface which curves inward to the projection.
According to the above configuration, the secondary lateral face which constitutes the corner is pierced into the target by digging into the target. Accordingly, the projection can be easily pierced into the skin compared with a case where the secondary lateral face is a flat surface.
In the above transdermal administration device, the secondary lateral face may be a first secondary lateral face, the lateral edge may be a first lateral edge, the two primary lateral faces may have lateral edges, each lateral edge individually connecting the second end of the top edge and the first surface, and the transdermal administration device may further includes a second secondary lateral face which has the second lateral edges in common with the respective primary lateral faces and forms one corner together with the two primary lateral faces.
In the above transdermal administration device, a direction along which the projection extends may be a first direction, the top edge may extend along the first direction, the substrate may have a shape extending along the first direction when viewed in a direction perpendicular to the first surface, the transdermal administration device may include a plurality of the projections, and the plurality of projections may include the plurality of the projections disposed at different positions in the first direction on the first surface.
According to the above configuration, the direction in which a user of the transdermal administration device can easily press the substrate against the target matches the direction in which the projection should be pressed against the target. Therefore, the projection can be easily pierced into the target.
In the above transdermal administration device, a direction along which the projection extends may be the first direction, the top edge may extend along the first direction, the transdermal administration device may include the plurality of the projections, the plurality of projections may include the plurality of the projections disposed at different positions in the first direction on the first surface, the transdermal administration device may further include an adhesive sheet having an adhesive surface, the adhesive surface may be bonded to the second surface, and the adhesive surface may have a shape extending along the first direction when viewed in the direction perpendicular to the first surface and protrude outward from the substrate.
According to the above configuration, the direction in which a user of the transdermal administration device can easily press the adhesive surface against the target matches the direction in which the projection of the administering part bonded to the adhesive surface should be pressed against the skin. Therefore, the projection can be easily pierced into the target.
In the above transdermal administration device, the substrate may have a shape extending along the first direction when viewed in the direction perpendicular to the first surface.
According to the above configuration, both the direction in which a user of the transdermal administration device can easily press the substrate against the target and the direction in which a user can easily press the adhesive surface against the target match the direction in which the projection should be pressed against the target. Therefore, the projection can be easily pierced into the target.
A method of producing a transdermal administration device that solves the above problem includes the steps of: forming a molded product by filling a recess of an intaglio plate with a forming material of the administering part, the recess being formed to conform with a shape of the projection; and removing the molded product from the intaglio plate so that removal is carried out in an extending direction of the recess when viewed in a direction perpendicular to a surface of the intaglio plate.
According to the above method, the above transdermal administration device can be produced. This transdermal administration device can reduce deformation of the projection as described above.
Further, methods for producing a microneedle have been proposed in which an administering part is produced by transfer molding using an intaglio plate. For example, the intaglio plate is filled with thermoplastic resin to produce a molded product, and the molded product is removed from the intaglio plate to form an administering part. However, these production methods may have a phenomenon that the resin is adhered to the intaglio plate during removal of the molded product from the intaglio plate. If this phenomenon occurs, the precision of shape-transfer from the intaglio plate to the removed molded product is reduced. Moreover, even if a material other than a thermoplastic resin is used as a forming material of the administering part, the forming material may be partially adhered to the intaglio plate during removal of the molded product from the intaglio plate, which may decrease the precision of shape-transfer from the intaglio plate to the removed molded product.
On the other hand, according to the above method for producing a transdermal administration device, the molded product is easily removed from the intaglio plate since the molded product is removed from the intaglio plate in the extending direction of the recess when viewed in the direction perpendicular to the surface of the intaglio plate. As a result, the forming material is prevented from being partially adhered to the intaglio plate. Accordingly, the precision of shape-transfer from the intaglio plate to the removed molded product is improved. Also, deformation of the projection can be reduced.
10 . . . transdermal administration device, 20 . . . administering part, 21 . . . substrate, 21S . . . first surface, 21T . . . second surface, 22,25,26,27 . . . projection, 23A,23D,23F,23H . . . primary lateral face, 23B,23E,23G,23I . . . secondary lateral face, 23C,23J . . . base, 24a . . . long side, 24b . . . short side, 24c,24f,24h . . . top edge, 24d,24e,24g,24i,24j . . . lateral edge, 30 . . . adhesive sheet, 31 . . . base sheet, 32 . . . adhesive layer, 50,60,62 . . . intaglio plate, 51,61,63 . . . recess, 120 . . . support casing, 130 . . . adhesive holder, 140 . . . protective film
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
Number | Date | Country | Kind |
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2014-226366 | Nov 2014 | JP | national |
2015-004382 | Jan 2015 | JP | national |
The present application is a continuation of International Application No. PCT/JP2015/081320, filed Nov. 6, 2015, which is based upon and claims the benefits of priority to Japanese Application No. 2014-226366, filed Nov. 6, 2014, and claims the benefits of priority to Japanese Application No. 2015-004382, filed Jan. 13, 2015. The entire contents of all of the above applications are incorporated herein by reference.
Number | Date | Country | |
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Parent | PCT/JP2015/081320 | Nov 2015 | US |
Child | 15589453 | US |