WO2016143792A1 - Process for producing sheet for percutaneous absorption - Google Patents

Process for producing sheet for percutaneous absorption Download PDF

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Publication number
WO2016143792A1
WO2016143792A1 PCT/JP2016/057197 JP2016057197W WO2016143792A1 WO 2016143792 A1 WO2016143792 A1 WO 2016143792A1 JP 2016057197 W JP2016057197 W JP 2016057197W WO 2016143792 A1 WO2016143792 A1 WO 2016143792A1
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WO
WIPO (PCT)
Prior art keywords
mold
polymer layer
needle
layer forming
forming liquid
Prior art date
Application number
PCT/JP2016/057197
Other languages
French (fr)
Japanese (ja)
Inventor
圭央 岡野
哲史 若松
片桐　良伸
Original Assignee
富士フイルム株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2016040831A external-priority patent/JP6411395B2/en
Application filed by 富士フイルム株式会社 filed Critical 富士フイルム株式会社
Priority to KR1020177025161A priority Critical patent/KR102053675B1/en
Priority to EP16761760.4A priority patent/EP3269416B1/en
Priority to CN201680013235.1A priority patent/CN107405478B/en
Publication of WO2016143792A1 publication Critical patent/WO2016143792A1/en
Priority to US15/695,720 priority patent/US11135413B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

Definitions

  • the present invention relates to a method for producing a transdermal absorption sheet, and more particularly to a method for producing a transdermal absorption sheet in which needle-like convex portions containing a drug are arranged on a sheet portion.
  • a percutaneous absorption sheet formed with a high aspect ratio needle-like convex part also referred to as a microneedle or microneedle
  • a method of injecting a medicine by inserting a microneedle into the skin is used.
  • it is necessary to mix a medicine but since many medicines are expensive, it is necessary to concentrate the medicine on a microneedle and to contain the medicine.
  • a method for producing a percutaneous absorption sheet there is known a method of transferring a shape by pouring a polymer solution or the like into a mold in which a needle-like concave portion which is an inverted shape of the needle-like convex portion is formed.
  • a microneedle sheet mold with a through-hole penetrating the base material at the bottom of the recess first apply the drug-diluted solution on the mold, and then use the squeegee to remove the excess solution
  • the needle raw material is applied after scraping off and drying the chemical solution.
  • Microneedles that are manufactured in a one-step process with high accuracy by filling a flexible substrate with a concentrated liquid consisting of an admixture of a target substance and a base using a centrifugal force while drying and curing. There is a method for producing a sheet in which a ridge-shaped projection preparation is accumulated.
  • Patent Document 1 the functionality of filling a concave array with a polymer resin solution by applying a polymer resin solution to a mold having a concave array and pressurizing with a pressurized fluid. A method for manufacturing the membrane is described.
  • Patent Document 2 also describes the use of a pressure filling device to fill the needle-shaped recess with the polymer solution.
  • the needle-shaped body forming liquid is supplied in a state where the intaglio is inclined, and the needle-shaped body forming liquid is moved downward from above to fill the concave portion with the needle-shaped body forming liquid.
  • the needle-shaped intaglio may be made of a material having a low surface tension or may be surface-treated in order to improve the releasability of the formed needle-shaped convex portion. Therefore, when the polymer solution is directly applied, there is a problem that the liquid contracts due to the difference in surface tension between the solid and the liquid and the poor wettability, repels the liquid and cannot form a film.
  • the surface tension can be suppressed and the shape can be maintained by the formwork, but a large-scale device including the entire device is required, and the equipment cost is increased. In addition, it could not be applied and dried more precisely in a static state.
  • An object of the present invention is to provide a method for producing a percutaneous absorption sheet that can be dried while being maintained in a solid form.
  • the present invention provides a chemical solution filling step of filling a needle solution in a mold having a needle recess with a chemical solution that is a polymer solution containing a drug, and drying the drug solution filled in the needle recess.
  • a chemical solution drying step for forming a drug layer containing a drug, and the mold includes a step portion higher than the region in which the needle-like recess is formed around the region in which the needle-like recess is formed.
  • the polymer layer forming liquid supplying step for supplying the polymer layer forming liquid to the range of the stepped part or more when viewed from the top, and the polymer layer forming liquid supplied to the mold, There is provided a method for producing a transdermal absorption sheet having a polymer layer forming liquid drying step for forming a polymer layer.
  • the polymer layer is formed so as to have a step portion higher than the region where the needle-like recess is formed around the region where the needle-like recess is formed in the mold where the needle-like recess is formed,
  • the polymer layer forming liquid is prevented from being repelled by the mold in the area where the needle-shaped recess is formed. can do. Therefore, the transdermal absorption sheet can be stably produced while maintaining the shape of the transdermal absorption sheet.
  • “Supply the polymer layer forming liquid to a height higher than the stepped portion” means to supply the polymer layer forming liquid to a height higher than the surface where the stepped portion around the region where the needle-like concave portion is formed is cut. To do.
  • the polymer layer forming liquid supply step supplies the polymer layer forming liquid to a range higher than the stepped portion and wider than the stepped portion as viewed from above, and then shrinks the polymer layer forming liquid. It is preferable to fix the contact position between the polymer layer forming liquid and the mold to the stepped portion.
  • the transdermal absorption sheet can be stably produced while maintaining the shape of the transdermal absorption sheet.
  • the “contact position between the polymer layer forming liquid and the mold” is the periphery of the droplet of the polymer layer forming liquid when the polymer layer forming liquid contracts to the region side where the needle-like recess is formed
  • “Fixing the contact position to the stepped portion” means that the periphery of the polymer layer forming liquid droplet is fixed above the stepped portion.
  • contraction of a polymer layer forming liquid is performed using surface tension.
  • the height of the step portion of the mold is preferably 10 ⁇ m or more and 5000 ⁇ m or less.
  • the height of the step portion of the mold is defined, and the amount of the polymer layer forming liquid to be supplied can be reduced by setting the height of the step portion in the above range.
  • the liquid drying process can be shortened and the production cost can be reduced.
  • the thickness of the polymer layer forming solution is preferably 5000 ⁇ m or less.
  • This aspect defines the thickness of the polymer layer forming liquid in the polymer layer forming liquid supplying step.
  • the “thickness of the polymer layer forming liquid” is the thickness from the region where the needle-like recess is formed after the polymer layer forming liquid supplying step, and is the thickness of the thickest part of the polymer layer forming liquid.
  • the stepped portion is preferably a mold provided so as to be separable from the mold.
  • the chemical solution filling step and the chemical solution drying step can be performed with a flat mold, and each step can be performed efficiently.
  • a formwork can be installed according to the transdermal absorption sheet to manufacture.
  • the stepped portion preferably has a step in the mold itself.
  • the polymer layer forming liquid can be stably supplied.
  • the stepped portion is preferably tapered in a direction extending from the region side where the needle-like concave portion is formed toward the upper side in the vertical direction.
  • the stepped portion is tapered upward, there is an effect of defoaming bubbles mixed in the polymer layer forming liquid.
  • defoaming the bubbles mixed in the polymer layer forming liquid it is possible to prevent the needle-like projections from being lost in the peeling step and the needle-like projections from being damaged during puncturing.
  • the present invention provides a chemical solution filling step of filling a chemical solution, which is a polymer solution containing a drug, into a needle-shaped recess of a mold having a needle-shaped recess, and drying the chemical solution filled in the needle-shaped recess.
  • the chemical solution drying step for forming the drug layer containing the drug, and the mold includes a step portion lower than the area where the needle-shaped recess is formed around the area where the needle-shaped recess is formed.
  • a method for producing a percutaneous absorption sheet comprising: drying a polymer layer forming solution supplied to a mold to form a polymer layer.
  • the polymer layer is formed so as to have a step portion lower than the region where the needle-like recess is formed around the region where the needle-like recess is formed in the mold where the needle-like recess is formed.
  • the polymer layer forming liquid supply step supplies the polymer layer forming liquid for each needle-like concave portion provided with a stepped portion.
  • the supplied polymer layer forming liquid can be fixed at each stepped portion.
  • the thickness of the polymer layer forming solution is preferably 5000 ⁇ m or less.
  • the thickness of the polymer layer forming liquid in the polymer layer forming liquid supplying step is defined.
  • the amount of the polymer layer forming liquid to be supplied is reduced. Therefore, the polymer layer forming liquid drying step can be shortened, and the production cost can be reduced.
  • the stepped portion preferably has a step in the mold itself.
  • the polymer layer forming liquid can be stably supplied.
  • the shape formed by the stepped portion is a hexagonal or more polygon formed at all angles of 120 ° or more when the step is viewed from the top, a regular hexagon or more regular polygon, or More preferably, it is circular.
  • the shape formed by the stepped portion is a hexagon or more polygon, preferably a regular hexagon or more, with all angles formed at an angle of 120 ° or more.
  • the shrinkage of the polymer layer forming liquid proceeds at the corners of the polygon.
  • the polymer layer forming liquid is not fixed at the stepped portion, and it is possible to prevent the liquid droplets of the polymer layer forming liquid from dropping into the region where the needle-like recess is formed. If a droplet in the polymer layer forming region falls in the region where the needle-like recess is formed, the polymer layer forming liquid is repelled, and the shape of the transdermal absorption sheet is not stable, which is not preferable.
  • the liquid level can be stably maintained even with a thin film with a simple apparatus configuration.
  • the cost can be reduced with a simple configuration.
  • FIG. 1 is a perspective view of a transdermal absorption sheet having needle-like convex portions.
  • FIG. 2 is a perspective view of a transdermal absorption sheet having a needle-like convex portion having another shape.
  • FIG. 3 is a cross-sectional view of the needle-like convex portion of the transdermal absorption sheet shown in FIGS. 1 and 2.
  • FIG. 4 is a perspective view of a transdermal absorption sheet having a needle-like convex portion having another shape.
  • FIG. 5 is a perspective view of a transdermal absorption sheet having a needle-like convex portion having another shape.
  • FIG. 6 is a cross-sectional view of the needle-like convex portion of the transdermal absorption sheet shown in FIGS. 4 and 5.
  • FIG. 7A is a process diagram of a mold manufacturing method.
  • FIG. 7B is a process diagram of a mold manufacturing method.
  • FIG. 7C is a process diagram of a mold manufacturing method.
  • FIG. 8A is a process diagram of a method for producing another finely shaped mold.
  • FIG. 8B is a process diagram of a method for manufacturing another finely shaped mold.
  • FIG. 8C is a process diagram of a method for manufacturing another finely shaped mold.
  • FIG. 9A is a process diagram of a method for manufacturing a mold having another shape.
  • FIG. 9B is a process diagram of a method for manufacturing a mold having another shape.
  • FIG. 9C is a process diagram of a method for manufacturing a mold having another shape.
  • FIG. 9A is a process diagram of a method for manufacturing a mold having another shape.
  • FIG. 9B is a process diagram of a method for manufacturing a mold having another shape.
  • FIG. 9C is a process
  • FIG. 10 is a partially enlarged view of the mold.
  • FIG. 11 is a partially enlarged view of the mold.
  • FIG. 12 is a flowchart of a method for producing a transdermal absorption sheet.
  • FIG. 13A is a schematic diagram showing a process of filling a liquid medicine into a needle-like recess of a mold.
  • FIG. 13B is a schematic view showing a step of filling the needle-shaped concave portion of the mold with the chemical solution.
  • FIG. 13C is a schematic view showing a step of filling the needle-shaped concave portion of the mold with the chemical solution.
  • FIG. 14 is a perspective view showing the tip of the nozzle.
  • FIG. 15 is a perspective view showing the tip of another nozzle.
  • FIG. 16 is a partially enlarged view of the tip of the nozzle during filling and the mold.
  • FIG. 17 is a partially enlarged view of the nozzle tip and the mold during scanning.
  • FIG. 18 is a schematic configuration diagram of a chemical liquid filling apparatus.
  • FIG. 19 is an explanatory diagram showing the relationship between the fluid pressure in the nozzle and the supply of a solution containing a drug.
  • FIG. 20A is a schematic view showing a part of the production process of a transdermal absorption sheet.
  • FIG. 20B is a schematic diagram illustrating a part of the manufacturing process of the transdermal absorption sheet.
  • FIG. 20C is a schematic diagram illustrating a part of the manufacturing process of the transdermal absorption sheet.
  • FIG. 20A is a schematic view showing a part of the production process of a transdermal absorption sheet.
  • FIG. 20B is a schematic diagram illustrating a part of the manufacturing process of the transdermal absorption sheet.
  • FIG. 20C is
  • FIG. 20D is a schematic diagram illustrating a part of the manufacturing process of the transdermal absorption sheet.
  • FIG. 21A is a diagram illustrating a polymer layer forming liquid supply step of the first embodiment.
  • FIG. 21B is a diagram illustrating a polymer layer forming liquid supply step of the first embodiment.
  • FIG. 22A is a diagram for explaining an unfavorable example of the polymer layer forming liquid supply step.
  • FIG. 22B is a diagram for explaining an undesirable example of the polymer layer forming liquid supply step.
  • FIG. 23A is a diagram illustrating a method for applying a polymer layer forming liquid onto a mold.
  • FIG. 23B is a diagram illustrating a method for applying a polymer layer forming liquid onto a mold.
  • FIG. 24A is a diagram illustrating another application method of the polymer side forming liquid to the mold.
  • FIG. 24B is a diagram illustrating another application method of the polymer side forming liquid to the mold.
  • FIG. 24C is a diagram illustrating another method of applying the polymer side forming liquid to the mold.
  • FIG. 25A is a diagram for explaining the contraction of the polymer layer forming liquid due to the shape of the mold.
  • FIG. 25B is a diagram for explaining the contraction of the polymer layer forming liquid due to the shape of the mold.
  • FIG. 25C is a diagram for explaining the contraction of the polymer layer forming liquid due to the shape of the mold.
  • FIG. 26A is a diagram illustrating shrinkage due to the coating shape of the polymer layer forming liquid.
  • FIG. 26B is a diagram illustrating shrinkage due to the application shape of the polymer layer forming liquid.
  • FIG. 26C is a diagram illustrating shrinkage due to the application shape of the polymer layer forming liquid.
  • FIG. 27A is a diagram for explaining the contraction of the polymer layer forming liquid due to another shape of the mold.
  • FIG. 27B is a diagram for explaining the contraction of the polymer layer forming liquid due to another shape of the mold.
  • FIG. 27C is a diagram for explaining the contraction of the polymer layer forming liquid due to another shape of the mold.
  • FIG. 28A is a diagram for explaining a polymer layer forming liquid supply step using a mold having another shape.
  • FIG. 28B is a diagram illustrating a polymer layer forming liquid supply step using a mold having another shape.
  • FIG. 29A is a diagram illustrating a polymer layer forming liquid supply step according to a modification of the first embodiment.
  • FIG. 29B is a diagram illustrating a polymer layer forming liquid supply step according to a modification of the first embodiment.
  • FIG. 30A is a diagram illustrating a polymer layer forming liquid supply step of the second embodiment.
  • FIG. 30B is a diagram illustrating a polymer layer forming liquid supply step of the second embodiment.
  • FIG. 31A is a diagram illustrating an undesirable example of the polymer layer forming liquid supply step.
  • FIG. 31B is a diagram for explaining an undesirable example of the polymer layer forming liquid supply step.
  • FIG. 32A is a plan view of the original plate used in the examples.
  • FIG. 32B is a cross-sectional view of the original plate used in the examples.
  • ⁇ is used to mean that the numerical values described before and after it are included as a lower limit value and an upper limit value.
  • Transdermal absorption sheet The percutaneous absorption sheet manufactured by this Embodiment is demonstrated. 1 and 2 show a needle-like convex portion 110 (also referred to as a microneedle or a microneedle), which is a partially enlarged view of the transdermal absorption sheet 100.
  • a needle-like convex portion 110 also referred to as a microneedle or a microneedle
  • the transdermal absorption sheet 100 supplies the drug into the skin by being affixed to the skin.
  • a transdermal absorption sheet 100 includes a tapered needle portion 112, a frustum portion 114 connected to the needle portion 112, and a flat sheet portion 116 connected to the frustum portion 114. have.
  • the tapered needle part 112 and the frustum part 114 constitute the needle-like convex part 110.
  • a plurality of frustum portions 114 are formed on the surface of the sheet portion 116 (only one frustum portion 114 is shown in FIG. 1). Of the two end faces of the frustum part 114, an end face (lower base) having a large area is connected to the sheet part 116. Of the two end faces of the frustum part 114, the end face (upper bottom) having a small area is connected to the needle part 112. That is, the area of the end surface in the direction away from the sheet portion 116 of the two end surfaces of the frustum portion 114 is small. Since the surface of the needle portion 112 having a large area is connected to the end surface of the frustum portion 114 having a small area, the needle portion 112 is gradually tapered away from the frustum portion 114.
  • the frustum portion 114 has a truncated cone shape
  • the needle portion 112 has a cone shape.
  • the shape of the tip of the needle portion 112 can be appropriately changed to a curved surface with a radius of curvature of 0.01 ⁇ m or more and 50 ⁇ m or less, a flat surface, or the like.
  • FIG. 2 shows a needle-like convex part 110 having another shape.
  • the frustum portion 114 has a quadrangular frustum shape
  • the needle portion 112 has a quadrangular pyramid shape.
  • FIG. 3 is a cross-sectional view of the transdermal absorption sheet 100 shown in FIGS. 1 and 2.
  • the transdermal absorption sheet 100 includes a drug layer 120 containing a predetermined amount of drug and a polymer layer 122.
  • the phrase “containing a predetermined amount of drug” means including an amount of drug that exhibits a medicinal effect when puncturing the body surface.
  • the drug layer 120 containing a drug is formed at the tip of the needle-like convex part 110 (tip of the needle part 112). By forming the drug layer 120 at the tip of the needle-like convex part 110, the drug can be efficiently delivered into the skin.
  • “containing a predetermined amount of drug” is referred to as “containing a drug” as necessary.
  • a polymer layer 122 is formed on a portion of the needle portion 112 excluding the drug layer 120.
  • the frustum 114 is composed of a polymer layer 122.
  • the sheet part 116 is constituted by a polymer layer 122. The distribution of the drug layer 120 and the polymer layer 122 constituting the needle part 112, the frustum part 114, and the sheet part 116 can be set as appropriate.
  • the thickness T of the sheet part 116 is in the range of 10 ⁇ m to 2000 ⁇ m, and preferably in the range of 10 ⁇ m to 1000 ⁇ m.
  • the width (W1) of the part (lower base) in contact with the frustum part 114 and the sheet part 116 is in the range of 100 ⁇ m to 1500 ⁇ m, preferably in the range of 100 ⁇ m to 1000 ⁇ m.
  • the width (W2) of the portion (upper base) where the frustum portion 114 and the needle portion 112 are in contact is in the range of 100 ⁇ m to 1500 ⁇ m, and preferably in the range of 100 ⁇ m to 1000 ⁇ m.
  • the width W1 and the width W2 satisfy W1> W2 within the above numerical range.
  • the height H of the needle-like convex part 110 is in the range of 100 ⁇ m to 2000 ⁇ m, and preferably in the range of 200 ⁇ m to 1500 ⁇ m. Further, regarding H1 / H2, which is the ratio of the height H1 of the needle portion 112 and the height H2 of the frustum portion 114, H1 / H2 is in the range of 1 to 10, preferably 1.5 to 8. It is a range. Further, the height H2 of the frustum portion 114 is preferably in the range of 10 ⁇ m or more and 1000 ⁇ m or less.
  • the angle ⁇ formed between the side surface of the frustum portion 114 and the plane parallel to the surface of the sheet portion 116 is in the range of 10 ° to 60 °, and preferably in the range of 20 ° to 50 °.
  • the angle ⁇ formed between the side surface of the needle portion 112 and the surface parallel to the upper base of the frustum portion 114 is in the range of 45 ° to 85 °, and preferably in the range of 60 ° to 80 °.
  • the angle ⁇ is preferably not less than the angle ⁇ . This is because it becomes easier to insert the needle-like convex portion 110 into the skin.
  • the percutaneous absorption sheet 100 shown in FIGS. 1 and 4 and the percutaneous absorption sheet 100 shown in FIGS. 2 and 5 have the same shape of the frustum portion 114 and different shapes of the needle portions 112. ing.
  • the needle part 112 shown in FIGS. 4 and 5 has a tapered needle-like part 112A and a cylindrical body part 112B. The bottom surface of the needle-like part 112A and the end face of the body part 112B are connected. Of the end surface of the body portion 112B, the end surface not connected to the needle-like portion 112A and the upper base of the frustum portion 114 are connected.
  • the needle-like portion 112A shown in FIG. 4 has a conical shape, and the body portion 112B has a cylindrical shape.
  • the needle-like portion 112A shown in FIG. 5 has a quadrangular pyramid shape, and the body portion 112B has a quadrangular prism shape.
  • the needle portion 112 Since the needle portion 112 has the body portion 112B, the needle portion 112 has a shape having a certain width in a direction away from the frustum portion 114.
  • the tapered needle part 112A of the needle part 112 has a gradually tapered shape in a direction away from the body part 112B.
  • the cylindrical body portion 112B has substantially the same area of two opposing end faces.
  • the needle part 112 has a tapered shape as a whole.
  • the shape of the tip of the needle portion 112 can be appropriately changed to a curved surface with a radius of curvature of 0.01 ⁇ m or more and 50 ⁇ m or less, a flat surface, or the like.
  • FIG. 6 is a cross-sectional view of the transdermal absorption sheet 100 shown in FIGS.
  • the transdermal absorption sheet 100 includes a drug layer 120 containing a drug and a polymer layer 122.
  • the drug layer 120 containing a drug is formed at the tip of the needle-like convex part 110 (tip of the needle part 112). By forming the drug layer 120 at the tip of the needle-like convex part 110, the drug can be efficiently supplied into the skin.
  • a polymer layer 122 is formed on a portion of the needle portion 112 excluding the drug layer 120.
  • the frustum 114 is composed of a polymer layer 122.
  • the sheet part 116 is constituted by a polymer layer 122. The distribution of the drug layer 120 and the polymer layer 122 constituting the needle part 112, the frustum part 114, and the sheet part 116 can be set as appropriate.
  • the length can be the same as that of the transdermal absorption sheet 100 shown in FIG.
  • the ratio H1 / H2, which is the ratio of the height H1 of the needle portion 112 and the height H2 of the frustum portion 114, can be set to the same ratio as that of the transdermal absorption sheet 100 shown in FIG.
  • H1B / H1A which is the ratio of the height H1A of the needle-like portion 112A and the height H1B of the body portion 112B
  • H1B / H1A is in the range of 0.1 to 4, preferably 0.3 to 2. It is.
  • the angle ⁇ formed between the side surface of the frustum portion 114 and the plane parallel to the surface of the sheet portion 116 is in the range of 10 ° to 60 °, and preferably in the range of 20 ° to 50 °. Further, the angle ⁇ formed between the side surface of the needle-like portion 112A and the surface parallel to the end face of the body portion 112B is in the range of 45 ° to 85 °, and preferably in the range of 60 ° to 80 °.
  • the angle ⁇ is preferably not less than the angle ⁇ . This is because it becomes easier to insert the needle-like convex portion 110 into the skin.
  • the percutaneous absorption sheet 100 having the needle portion 112 shown in FIGS. 1, 2, 4 and 5 is shown, but the percutaneous absorption sheet 100 is not limited to these shapes.
  • FIG. 7A to FIG. 7C are process diagrams for producing a mold.
  • an original plate for producing a mold for producing a transdermal absorption sheet is first produced.
  • the first method is to apply a photoresist on a Si substrate, and then perform exposure and development. Then, by performing etching by RIE (Reactive Ion Etching) or the like, a plurality of convex portions 12 having the same shape as the needle-like convex portions of the percutaneous absorption sheet are formed in an array on the surface of the original plate 11. Make it.
  • etching such as RIE is performed to form the convex portion 12 on the surface of the original plate 11, the convex portion 12 can be formed by performing etching from an oblique direction while rotating the Si substrate. It is.
  • the second method is a method in which a plurality of convex portions 12 are formed in an array on the surface of the original 11 by processing a metal substrate such as Ni using a cutting tool such as a diamond bite.
  • a mold 13 is produced using the original 11.
  • a method using Ni electroforming or the like is used for producing the normal mold 13. Since the original plate 11 has a convex portion 12 having a conical shape or a pyramid shape (for example, a quadrangular pyramid) with a sharp tip, the shape of the original plate 11 is accurately transferred to the mold 13, and the mold 13 is transferred from the original plate 11. Can be peeled off. Moreover, four methods that can manufacture the mold 13 at low cost are conceivable.
  • the first method is to pour PDMS (polydimethylsiloxane, for example, Sylgard (registered trademark) 184 manufactured by Dow Corning) into the original plate 11 and heat cure at 100 ° C. to cure. This is a method of peeling the mold 13 from the original plate 11 later.
  • the second method is a method in which a UV curable resin that is cured by irradiating ultraviolet rays is poured into the original 11, and after irradiating ultraviolet rays in a nitrogen atmosphere, the mold 13 is peeled off from the original 11.
  • the third method a plastic resin such as polystyrene or PMMA (polymethyl methacrylate) dissolved in an organic solvent is poured into the original plate 11 coated with a release agent, and dried to volatilize the organic solvent.
  • the mold 13 is peeled from the original plate 11 after being cured.
  • the fourth method is a method of creating a reverse product by Ni electroforming.
  • the mold 13 is produced in which the needle-like concave portions 15 which are the inverted shapes of the convex portions 12 of the original 11 are two-dimensionally arranged.
  • the mold 13 produced in this way is shown in FIG. 7C.
  • the mold 13 can be easily manufactured any number of times.
  • a mold having the inverted shape can be produced by providing the original plate with a stepped portion.
  • 8A to 8C are process diagrams for producing a mold 73 having a stepped portion 74 higher than the region where the needle-like recess 15 is formed around the region where the needle-like recess 15 is formed.
  • an original plate 71 for producing a mold 73 having a stepped portion 74 is produced.
  • the original plate 71 has a stepped portion 75 that is lower than the region where the convex portion 12 is formed.
  • the original plate can be produced by the same method as in FIG. 7A.
  • a mold 73 is produced using the original plate 71.
  • the mold 13 can also be produced by the same method as in FIG. 7B.
  • a mold 73 is produced in which the needle-like concave portions 15, which are the inverted shapes of the convex portions 12 and the step portions 75 of the original plate 71, are arranged two-dimensionally and have step portions 74 around the needle-like concave portions 15.
  • 9A to 9C are process diagrams for producing a mold 83 having a stepped portion 84 lower than the region where the needle-like recess 15 is formed around the region where the needle-like recess 15 is formed.
  • an original plate 81 for producing a mold 83 having a stepped portion 84 is produced.
  • the original plate 81 has a stepped portion 85 higher than the region where the convex portion 12 is formed.
  • a mold 83 is manufactured using the original plate 81.
  • a mold 83 is produced in which the needle-like concave portions 15, which are the inverted shapes of the convex portions 12 and the step portions 85 of the original plate 81, are arranged two-dimensionally and have the step portions 85 around the two.
  • the method for producing the original plate and the method for producing the mold can be performed in the same manner as in FIGS. 7A, 7B, 8A, and 8B.
  • FIG. 10 is a partial enlarged view of the needle-like recess 15 of the mold 13.
  • the needle-like recesses 15 of the molds 73 and 83 have the same configuration.
  • the needle-like recess 15 includes a tapered inlet portion 15A that narrows in the depth direction from the surface of the mold 13 and a tip recess 15B that tapers in the depth direction.
  • the taper angle ⁇ 1 of the inlet portion 15A basically matches the angle ⁇ formed by the side surface of the frustum portion of the percutaneous absorption sheet and the sheet portion.
  • the taper angle ⁇ 1 of the tip recess 15B basically matches the angle ⁇ formed by the side surface of the needle portion and the upper base of the frustum portion.
  • FIG. 11 shows a more preferable embodiment of the mold composite 18 in carrying out the method for producing a transdermal absorption sheet.
  • the mold composite 18 is bonded to the mold 13 having a through-hole 15C formed at the tip of the needle-like recess 15 and the through-hole 15C side of the mold 13 so that the gas can permeate but the liquid is And a gas permeable sheet 19 formed of a non-permeable material.
  • the tip of the needle-like recess 15 communicates with the atmosphere via the gas permeable sheet 19.
  • the tip of the needle-like recess 15 means the side tapered in the depth direction of the mold 13 and means the side opposite to the side filled with the chemical solution and the polymer layer forming solution.
  • the percutaneous absorption material solution filled in the needle-like recess 15 does not permeate, and only the air present in the needle-like recess 15 passes from the needle-like recess 15 to the through hole 15C. Can be pulled out. Transferability when transferring the shape of the needle-like concave portion 15 to the transdermal absorption material is improved, and a sharper needle-like convex portion can be formed.
  • the diameter D (diameter) of the through hole 15C is preferably in the range of 1 to 50 ⁇ m. By setting it within this range, air can be easily removed, and the tip of the needle-like convex portion of the transdermal absorption sheet can be made sharp.
  • the gas permeable sheet 19 formed of a material that allows gas to permeate but not liquid for example, Poeflon (trademark, Sumitomo Electric Industries, Ltd.) can be suitably used.
  • a resin material or a metal material can be used as a material used for the mold 13.
  • a resin-based material is preferable, and a material having high gas permeability is more preferable.
  • the oxygen permeability which is representative of gas permeability, is preferably greater than 1 ⁇ 10 ⁇ 12 (mL / s ⁇ m ⁇ Pa), and preferably greater than 1 ⁇ 10 ⁇ 10 (mL / s ⁇ m ⁇ Pa). Further preferred.
  • Examples of such materials include silicone resins, epoxy resins, PET (polyethylene terephthalate), PMMA (polymethyl methacrylate) PS (polystyrene: polystyrene), PE (polyethylene: polyethylene).
  • Common engineering plastics such as POM (polyacetal: polyoxymethylene), PTFE (polytetrafluoroethylene), UV (ultraviolet) curable resin, phenol resin, and urethane resin can be used.
  • the metal materials include Ni, Cu, Cr, Mo, W, Ir, Tr, Fe, Co, MgO, Ti, Zr, Hf, V, Nb, Ta, ⁇ -aluminum oxide, stainless steel and alloys thereof. Can be mentioned.
  • the mold 13 since the mold 13 needs to fix the polymer layer forming liquid at the step portion in the polymer layer forming liquid supply step, it is preferable to use a material whose water repellency and wettability are controlled.
  • the contact angle between the mold and the polymer layer forming liquid is preferably more than 90 ° and close to 90 °.
  • Polymer solution A polymer solution that is a polymer resin solution used in the present embodiment will be described.
  • a polymer solution containing a predetermined amount of drug is referred to as a polymer solution containing a drug or a solution containing a drug as necessary.
  • a polymer solution containing a predetermined amount of drug is called a drug solution.
  • Whether or not a predetermined amount of drug is contained is determined by whether or not the drug effect can be exhibited when the body surface is punctured. Therefore, the phrase “containing a predetermined amount of drug” means including an amount of drug that exhibits a medicinal effect when puncturing the body surface.
  • the material of the resin polymer used for the polymer solution it is preferable to use a biocompatible resin.
  • resins include glucose, maltose, pullulan, chondroitin sulfate, sodium hyaluronate, hydroxyethyl starch and other sugars, gelatin and other proteins, polylactic acid, and lactic acid / glycolic acid copolymers. It is preferable to do.
  • gelatin-based materials have adhesive properties with many substrates, and have strong gel strength as a material to be gelled. Since a polymer sheet can be peeled off using a material, it can be suitably used.
  • the concentration varies depending on the material, but it is preferable that the concentration is such that 10 to 50 mass% of the resin polymer is contained in the polymer solution forming the polymer layer 122.
  • the solvent used for dissolution may be volatile even if it is other than warm water, and methyl ethyl ketone (MEK), alcohol, or the like can be used.
  • MEK methyl ethyl ketone
  • the polymer concentration of the polymer solution containing the drug that forms the drug layer 120 is preferably 0 to 30% by mass.
  • a water-soluble polymer such as gelatin
  • a water-soluble powder may be dissolved in water, and a drug may be added after the dissolution.
  • a water-soluble polymer powder may be added and dissolved.
  • the polymer resin is difficult to dissolve in water, it may be dissolved by heating.
  • the temperature can be appropriately selected depending on the type of the polymer material, but it is preferable to heat at a temperature of about 60 ° C. or lower.
  • the viscosity of the polymer resin solution is preferably 100 Pa ⁇ s or less, and more preferably 10 Pa ⁇ s or less, in the solution containing the drug forming the drug layer 120.
  • the pressure is preferably 2000 Pa ⁇ s or less, and more preferably 1000 Pa ⁇ s or less.
  • the viscosity of the polymer resin solution can be measured with a capillary tube viscometer, falling ball viscometer, rotary viscometer or vibration viscometer.
  • the drug contained in the polymer solution is not limited as long as it has a function as a drug.
  • the method for producing a transdermal absorption sheet of the present embodiment includes a chemical solution filling step, a chemical solution drying step, a polymer layer forming solution supplying step, a polymer layer forming solution drying step, and a peeling step. These steps are provided in this order.
  • a mold 13 having needle-like recesses 15 arranged two-dimensionally is disposed on a base 20.
  • the mold 13 is formed with two sets of a plurality of needle-like recesses 15 that are two-dimensionally arranged in a 5 ⁇ 5 manner.
  • a liquid supply having a liquid feed tank 30 that stores a chemical liquid 22 that is a polymer solution containing a predetermined amount of drug, a pipe 32 connected to the liquid feed tank 30, and a nozzle 34 connected to the tip of the pipe 32.
  • a device 36 is prepared. The chemical liquid 22 is discharged from the tip of the nozzle 34.
  • FIG. 14 shows a schematic perspective view of the tip of the nozzle.
  • the nozzle 34 has a lip portion 34A that is a flat surface on the tip side, a slit-shaped opening portion 34B, and two inclined surfaces 34C that extend in a direction away from the opening portion 34B along the lip portion 34A.
  • the slit-shaped opening 34B for example, the plurality of needle-like recesses 15 constituting one row can be filled simultaneously with the chemical solution 22.
  • the size (length and width) of the opening 34B is appropriately selected according to the number of needle-like recesses 15 to be filled at a time.
  • FIG. 15 shows a schematic perspective view of the tip of another nozzle.
  • the nozzle 34 has a lip portion 34A that is a flat surface on the tip side, two slit-shaped openings 34B, and two slopes that extend along the lip portion 34A away from the openings 34B. 34C.
  • the two openings 34B for example, the plurality of needle-like recesses 15 constituting two rows can be simultaneously filled with the drug solution 22 containing the drug.
  • an elastic material or a metal material can be used as the material used for the nozzle 34.
  • examples thereof include Teflon (registered trademark), stainless steel (SUS), and titanium.
  • the filling process will be described with reference to FIG. 13B.
  • the position of the opening 34 ⁇ / b> B of the nozzle 34 is adjusted on the needle-like recess 15.
  • a nozzle 34 for discharging the chemical liquid 22 is pressed against the mold 13, and the lip portion 34 ⁇ / b> A of the nozzle 34 and the surface of the mold 13 are in contact with each other.
  • the chemical liquid 22 is supplied from the liquid supply device 36 to the mold 13, and the chemical liquid 22 is filled into the needle-shaped recess 15 from the opening 34 ⁇ / b> B of the nozzle 34.
  • a plurality of needle-like recesses 15 constituting one row are filled with the chemical liquid 22 at the same time.
  • medical solution 22 can be filled into the needle-shaped recessed part 15 one by one. Moreover, the chemical
  • the chemical liquid 22 can be sucked by sucking from the back surface of the mold 13 and the filling of the chemical liquid 22 into the needle-shaped recess 15 can be promoted.
  • the liquid supply device 36 is perpendicular to the length direction of the opening 34 ⁇ / b> B while contacting the lip 34 ⁇ / b> A of the nozzle 34 and the surface of the mold 13. Are relatively scanned.
  • the nozzle 34 is scanned over the mold 13, and the nozzle 34 is moved to the needle-like recess 15 that is not filled with the chemical liquid 22.
  • the position of the opening 34 ⁇ / b> B of the nozzle 34 is adjusted on the needle-like recess 15.
  • the example in which the nozzle 34 is scanned has been described, but the mold 13 may be scanned.
  • the nozzle 34 Since the nozzle 34 is scanned over the mold 13 while the lip portion 34A of the nozzle 34 and the surface of the mold 13 are in contact with each other, the nozzle 34 scrapes off the chemical liquid 22 remaining on the surface other than the needle-like recess 15 of the mold 13. be able to. It is possible to prevent the chemical solution 22 containing the drug from remaining other than the needle-like recess 15 of the mold 13.
  • the inclined surface 34 ⁇ / b> C of the nozzle 34 is disposed so as to be orthogonal to the scanning direction indicated by the arrow. Therefore, the nozzle 34 can smoothly scan the mold 13.
  • the degree of pressing of the nozzle 34 is controlled. For example, it is preferable to control the pressing force of the nozzle 34 to the mold 13 and the pressing distance of the nozzle 34 to the mold 13. Further, in order to prevent the chemical liquid 22 from remaining other than the needle-like recess 15 of the mold 13, it is desirable that at least one of the mold 13 or the nozzle 34 is a flexible elastically deformable material.
  • the medicinal solution 22 is filled into the 5 ⁇ 5 two-dimensionally arranged needle-like recesses 15.
  • the liquid supply device 36 is moved to the adjacent 5 ⁇ 5 two-dimensionally arranged needle-like recesses 15, as shown in FIG. 13B.
  • the filling process and the scanning process shown in FIG. 13C are repeated. Adjacent 5 ⁇ 5 two-dimensionally arranged needle-like recesses 15 are also filled with the chemical solution 22.
  • the liquid medicine 22 may be filled into the needle-like recess 15 while scanning the nozzle 34, or (2) the nozzle on the needle-like recess 15 during the scanning of the nozzle 34.
  • the liquid 34 may be temporarily stopped, the chemical liquid 22 is filled, and the nozzle 34 is scanned again after filling.
  • the lip portion 34 ⁇ / b> A of the nozzle 34 is pressed against the surface of the mold 13 during the filling process and the scanning process.
  • the amount of the chemical liquid 22 discharged from the liquid supply device 36 is preferably equal to the total volume of the plurality of needle-like recesses 15 of the mold 13 to be filled. It is possible to prevent the chemical liquid 22 from remaining on the surface of the mold 13 other than the needle-like concave portion 15 and reduce the waste of the chemical.
  • FIG. 16 is a partially enlarged view of the tip of the nozzle 34 and the mold 13 during filling of the chemical liquid 22 into the needle-like recess 15.
  • the pressurizing force P ⁇ b> 1 in the nozzle 34 it is possible to facilitate filling the medicinal liquid 22 into the needle-like recess 15.
  • the pressing force P ⁇ b> 2 for bringing the nozzle 34 into contact with the surface of the mold 13 is equal to or greater than the pressure P ⁇ b> 1 in the nozzle 34.
  • the pressing force P2 ⁇ the applied pressure P1 it is possible to suppress the chemical liquid 22 from leaking from the needle-like recess 15 to the surface of the mold 13.
  • FIG. 17 is a partial enlarged view of the tip of the nozzle 34 and the mold 13 during the movement of the nozzle 34.
  • the pressing force P ⁇ b> 3 for bringing the nozzle 34 into contact with the surface of the mold 13 is made smaller than the pressing force P ⁇ b> 2 for bringing the nozzle 34 being filled into contact with the surface of the mold 13. Is preferred. This is for reducing damage to the mold 13 and suppressing deformation due to compression of the mold 13.
  • the lip portion 34A of the nozzle 34 is preferably parallel to the surface of the mold 13.
  • the posture of the nozzle 34 may be controlled by providing a joint drive mechanism at the attachment portion of the nozzle 34.
  • FIG. 18 is a schematic configuration diagram of a chemical liquid filling device 48 that can control the pressing force and / or the pressing distance.
  • the chemical solution filling device 48 includes a liquid supply device 36 having a liquid supply tank 30 for storing a chemical solution and a nozzle 34 attached to the liquid supply tank 30, and a Z for driving the liquid supply tank 30 and the nozzle 34 in the Z-axis direction.
  • An axis driving unit 50, a suction table 52 for placing the mold 13, an X-axis driving unit 54 for driving the suction table 52 in the X-axis direction, a gantry 56 for supporting the device, a control system 58, have.
  • the nozzle 34 is brought close to the mold 13 by the Z-axis drive unit 50 up to the Z coordinate that provides a desired pressing force. While the nozzle 34 in contact with the mold 13 is scanned using the X-axis drive unit 54, the chemical solution 22 is discharged while controlling the Z-axis coordinates so that the pressing force is constant.
  • the method for measuring the contact pressure is not particularly limited.
  • various load cells can be used, for example, under the suction table 52 or in place of the suction table 52.
  • the load cell means a measuring instrument capable of measuring a force compressing in the thickness direction.
  • the pressing force is preferably controllable to an arbitrary pressure within a range of 1 to 1000 kPa with respect to the mold 13.
  • the pushing distance is controlled to be constant.
  • the surface shape of the mold 13 is measured in advance. While scanning the nozzle 34 in contact with the mold 13 using the X-axis drive unit 54, the control system 58 sets a value obtained by offsetting the Z-axis coordinate so as to obtain a desired pushing distance with respect to the surface shape of the mold 13. Feedback is made to the shaft drive unit 50. In parallel with the feedback, the chemical liquid 22 is discharged.
  • the method of shape measurement is not particularly limited, and for example, an optical measuring instrument such as a non-contact type laser displacement meter 60, a contact type stylus type step gauge, or the like can be used.
  • the posture of the nozzle 34 in the slit direction may be controlled in accordance with the surface shape of the mold 13.
  • the indentation distance is preferably controlled in the range of 1 to 15% with respect to the thickness of the mold 13.
  • FIG. 19 is an explanatory diagram showing the relationship between the fluid pressure in the nozzle and the supply of the solution containing the drug.
  • the supply of the chemical liquid 22 is started before the nozzle 34 is positioned on the needle-like recess 15. This is because the medical solution 22 is surely filled into the needle-like recess 15.
  • the chemical liquid 22 is continuously supplied to the mold 13 until the filling of the plurality of needle-like concave portions 15 configured by 5 ⁇ 5 is completed.
  • the supply of the chemical liquid 22 to the mold 13 is stopped before the nozzles 34 are positioned on the needle-like recesses 15 in the fifth row.
  • the chemical liquid 22 can be prevented from overflowing from the needle-like recess 15.
  • the liquid pressure in the nozzle 34 when the supply of the chemical liquid 22 is started, it becomes higher in a region where the nozzle 34 is not located in the needle-like recess 15. On the other hand, when the nozzle 34 is positioned on the needle-like recess 15, the chemical liquid 22 is filled in the needle-like recess 15, and the hydraulic pressure in the nozzle 34 is lowered. Such fluid pressure fluctuations are repeated.
  • the nozzle 34 is moved to the plurality of needle-shaped recesses 15 configured by adjacent 5 ⁇ 5.
  • the chemical liquid 22 When the chemical liquid 22 is filled, it is preferable to use after cleaning the tip of the nozzle 34. This is because if there is a deposit on the surface of the lip portion 34A of the nozzle 34 before filling, the accuracy of the filling amount of the chemical liquid 22 is lowered.
  • a wipe with a nonwoven fabric is generally used. When wiping, the nonwoven fabric can be effectively cleaned by infiltrating it with water or a solvent.
  • the chemical liquid 22 may remain on the surface of the mold 13.
  • the sucking back control for sucking the chemical liquid 22 from the opening 34B of the nozzle 34 is performed, so that the excessive liquid chemical 22 is sucked up and the liquid remaining on the surface of the mold 13 is reduced.
  • the chemical solution 22 can be filled into the needle-shaped recess 15 by using the mold complex 18 shown in FIG.
  • the process proceeds to the chemical liquid drying process, the polymer layer forming liquid supply process, the polymer layer forming liquid drying process, and the peeling process.
  • the chemical liquid 22 is filled into the needle-like concave portion 15 of the mold 13 from the nozzle 34 in the chemical liquid filling step.
  • the chemical solution filling step is performed by the method described above.
  • the chemical solution drying step is a step of drying the chemical solution 22 filled in the needle-like recess 15 of the mold 13 and localizing it at the tip of the needle-like recess 15. It is preferable to perform a chemical
  • a windshield In order to achieve drying in a windless state, for example, it is preferable to install a windshield.
  • the windshield is installed so that the wind does not directly hit the mold 13.
  • a method of installing a physical obstacle such as a lid, a fence, a screen, or an enclosure is preferable because it is simple.
  • it is preferable to secure a vent etc. so that the installation space of the mold 13 may not be sealed. If it is in a sealed state, the water vapor in the sealed space is saturated and there is a possibility that the drying of the chemical liquid 22 will not proceed.
  • the vent is preferable if the vapor can enter and exit, and in order to stabilize the airflow in the windshield, it is more preferable to cover the vent with a water vapor permeable film or the like.
  • the drying time is appropriately adjusted in consideration of the shape of the needle-like recess 15, the arrangement and number of the needle-like recess 15, the type of medicine, the filling amount and concentration of the drug solution 22, and the like.
  • No wind refers to a case where the wind speed is 0.5 m / s or less in addition to a state where there is no wind. This is because within this range, drying unevenness hardly occurs.
  • the chemical solution 22 is solidified by drying, and is smaller than the state when the chemical solution 22 is filled. Thereby, in the peeling step, the drug layer 120 can be easily peeled from the needle-like recess 15 of the mold 13.
  • a polymer layer forming solution 24 which is a polymer solution for forming the polymer layer 122, is supplied onto the drug layer 120 containing a predetermined amount of drug, and the polymer layer forming solution 24 is needle-shaped.
  • the recess 15 is filled.
  • the supply of the polymer layer forming liquid can be applied by a dispenser, bar coating, spin coating, spraying, or the like, but is not limited thereto.
  • a mode in which the polymer layer forming liquid 24 is supplied to the mold 13 by coating will be described. Since the drug layer 120 containing the drug is solidified by drying, the drug contained in the drug layer 120 can be prevented from diffusing into the polymer layer forming liquid 24.
  • 21A and 21B are diagrams for explaining the polymer layer forming liquid supply step.
  • the mold 14 is installed around the region 16 where the needle-like recess 15 is formed, and the mold has a step portion higher than the region 16 where the needle-like recess 15 is formed. 13 is coated with a polymer layer forming liquid 24.
  • the mold 14 can be installed so as to be separable from the mold 13.
  • the polymer layer forming liquid supply step has a height higher than the stepped portion formed by the mold 14 installed around the needle-like recess 15 and is higher than the stepped portion when viewed from above.
  • the polymer layer forming liquid 24 is applied by the applying means 92.
  • the application of the polymer layer forming liquid to a height higher than the mold 14 means that the height of the polymer layer forming liquid 24 at the portion where the polymer layer forming liquid 24 and the mold 14 are in contact is higher than the mold 14. Is to be.
  • the mold 14 is formed of a material that makes it easy to play the polymer layer forming liquid.
  • the polymer layer forming liquid 24 is 14 and is shrunk by surface tension. As shown in FIG. 21B, the contracted polymer layer forming liquid 24 is fixed at the stepped portion of the mold 14 at the contact position with the mold 13.
  • the shape of the polymer layer 122 of the percutaneous absorption sheet (the shape of the sheet portion 116) can be stably formed by drying the polymer layer forming liquid in a state of being fixed by the mold 14.
  • FIG. 22A and 22B are diagrams for explaining an unfavorable example of the polymer layer forming liquid supply step.
  • the polymer layer forming liquid 24 is applied in the mold 14 at a height lower than that of the mold 14.
  • the polymer layer forming liquid 24 contracts in the region 16 where the needle-like recess 15 is formed due to the surface tension.
  • FIG. 22B shows a portion where the sheet portion 116 of the percutaneous absorption sheet is not stably formed because the volume of the polymer layer forming solution 24 is further contracted by the polymer layer forming solution drying step after the polymer layer forming solution supplying step. Will occur.
  • the same material as that of the mold described above can be used.
  • the better the wettability with the polymer layer forming liquid the more uniform and gentle the liquid level during drying, and the local change in the liquid surface shape of the polymer layer forming liquid can be prevented.
  • the polymer layer forming liquid is repelled by the mold 14 and contracted to be fixed at the stepped portion. Therefore, the material forming the mold must have water repellency with respect to the polymer layer forming liquid. is there.
  • the material for forming the mold is preferably a material having controlled water repellency and wettability with respect to the polymer layer forming liquid, and the contact angle of the mold with respect to the polymer layer forming liquid is more than 90 °. It is preferably close to °.
  • the liquid surface of the coating liquid becomes a liquid surface with a high curvature, and even a slight unevenness in shape causes a large difference in surface tension. It is not preferable because it will be broken and repelled from the formwork.
  • it is also an effective means to make the material of the mold form hydrophilic, or to add a material having surface activity such as protein to the polymer layer forming solution.
  • the installation of the mold 14 may be performed from the medicine filling step, or may be performed before the polymer layer forming liquid supply step.
  • the height of the mold 14 is preferably 10 ⁇ m or more and 5000 ⁇ m or less. In order to fix the polymer layer forming liquid 24 at the stepped portion, it is necessary to apply the polymer layer forming liquid 24 at a height higher than the mold 14 and in a range higher than the mold 14. By setting the height within this range, the amount of the polymer layer forming liquid to be used can be suppressed. Therefore, the drying time can be shortened. If the height of the mold 14 is lower than 10 ⁇ m, the polymer layer forming liquid 24 is not fixed by the mold 14, the mold 13 repels the polymer layer forming liquid, and the sheet portion 116 is not formed. An absorbent sheet may not be manufactured.
  • the thickness of the polymer layer forming solution at the time of application is not less than the height of the mold 14 and not more than 5000 ⁇ m from the region 16 where the needle-like recess 15 of the mold 13 is formed. It is preferable. In order to fix the polymer layer forming liquid at the position of the mold 14, it is necessary to make the height higher than that of the mold 14. If the coating thickness of the polymer layer forming liquid after coating exceeds 5000 ⁇ m, it takes time to dry. This is because of this.
  • the film thickness near the mold is increased and the film near the center is increased. It is good also as a film thickness distribution which made the film thickness thin.
  • the polymer layer forming liquid 24 may be applied to each of the needle-like recesses 15 surrounded by the mold 14. As shown in FIG. 24C, the entire surface of the mold 13 may be coated so as to cover the mold 14. As shown in FIG. 23A, when the polymer layer forming liquid 24 is applied to each mold 14, the polymer layer forming liquid can be fixed with the mold 14 as shown in FIG. 23B after the application. As a method of applying for each mold 14, it can be performed by methods such as intermittent stripe coating using a slit coater, dispenser, ink jet, letterpress printing, planographic printing, screen printing and the like.
  • the polymer layer forming liquid 24 when the entire surface of the mold 13 is applied, if the amount of the polymer layer forming liquid is large, the polymer layer forming liquid 24 is uniformly applied as shown in FIG. 24B. A layer formation liquid drying process is performed. Even in this case, the polymer layer 122 can be stably formed in the subsequent polymer layer forming liquid drying step.
  • the amount of the polymer layer forming liquid 24 is small, as shown in FIG. 24C, the polymer layer forming liquid 24 contracts toward the inside of the mold 14 (the area where the needle-like recess 15 is formed), and the mold 14 By fixing with, the transdermal absorption sheet can be manufactured in a stable shape.
  • general coating methods such as slit coating, slide coating, blade coating, bar coating, roll coating, gravure coating, dip coating, and spray coating can be used.
  • FIG. 25A to FIG. 27C are diagrams for explaining the contraction of the polymer layer forming liquid due to the shape of the mold.
  • FIG. 25A is a diagram in the case where the polymer layer forming liquid 24 is applied in a circular shape and the polymer layer forming liquid 24 is applied using the circular mold 14. Since the polymer layer forming liquid 24 isotropically contracts as shown in FIG. 25B, the polymer layer forming liquid 24 applied wider than the mold 14 is formed by a step formed by the mold 14 as shown in FIG. 25C. It can be fixed at the position of the part.
  • FIG. 26A is a diagram in which a polymer layer forming liquid 24 is applied in a square shape using a circular mold 14. Even when the polymer layer forming liquid 24 is applied in a square shape, the polymer layer forming liquid 24 isotropically contracts toward the step portion of the circular mold 14 as shown in FIG. 26B. As shown in FIG. 26C, the polymer layer forming liquid 24 can be fixed at the position of the step portion formed by the mold 14, although there is a residue on the mold 14.
  • FIG. 27A is a diagram in which a polymer layer forming liquid 24 is applied in a circular shape using a square mold 14.
  • the shape of the mold 14 is quadrangular, when the polymer layer forming liquid 24 isotropically contracts, the polymer layer forming liquid 24 is fixed at the square corners of the mold 14 as shown in FIG. 27B. In some cases, the polymer layer forming liquid 24 may get wet from the mold 14.
  • FIG. 27C the polymer layer forming liquid 24 that has been wetted from the mold 14 is further contracted on the mold, and the polymer layer is not formed in the portion where the needle-like recess 15 is formed.
  • the absorbent sheet may not be formed stably.
  • the polymer layer forming liquid in the case where the polymer layer forming liquid is uniformly applied onto the mold, the polymer layer forming liquid remains in the mold even if the shape of the mold 14 is square.
  • the polymer layer forming liquid supply step can be performed without getting wet.
  • the shape around the area where the needle-like concave portion formed by providing the mold is formed is viewed from the top. It is preferable that the polygon is a hexagon or more polygon formed with an angle of 120 ° or more, and more preferably a regular hexagon or more polygon or a circle.
  • each side which comprises a polygon is equal with a "regular polygon", it can change in the range which has the effect of this invention.
  • FIG. 28A and FIG. 28B are views for explaining a polymer layer forming liquid supply step using a mold 17 that is tapered in a direction that widens upward from the region side where the needle-like concave portion of the mold 13 is formed.
  • the polymer layer forming liquid 24 is applied in a range equal to or larger than the region on the upper side of the mold 17 (FIG. 28A), and then contracted by surface tension, thereby forming the mold.
  • the polymer layer forming liquid 24 can be fixed by the step portion formed by 17 (FIG. 28B).
  • the taper angle ⁇ of the mold 17 is preferably 45 ° or more and 75 ° or less with respect to the mold 13.
  • FIG. 29A and FIG. 29B are diagrams showing a modification of the first embodiment.
  • the mold 73 shown in FIGS. 29A and 29B is different from the above embodiment in that the stepped portion 74 is formed in the mold 73 itself. Even in the case where the mold 73 has the stepped portion 74, the polymer layer forming liquid 24 can be fixed by the stepped portion 74 as described above, and the transdermal absorption sheet can be manufactured stably. .
  • FIG. 30A and FIG. 30B are views for explaining a polymer layer forming liquid supply step of the second embodiment of the present invention.
  • the stepped portion 84 of the mold 83 having the needle-like recess 15 is lower than the region 16 in which the needle-like recess 15 is formed.
  • This embodiment is different from the first embodiment in that a step portion is provided in the first embodiment.
  • the stepped portion 84 is made lower than the region 16 of the mold 83 where the acicular recess 15 is formed, and the polymer layer forming liquid 24 is formed of the acicular recess 15.
  • the coating is applied up to a wide area, that is, the stepped portion 84 beyond the region 16.
  • the polymer layer forming liquid 24 starts to contract due to surface tension, and the polymer layer forming liquid 24 is fixed at the boundary between the region 16 and the stepped portion 84 as shown in FIG. 30B. Since the contraction does not proceed any further, the transdermal absorption sheet can be formed stably.
  • the thickness from the region where the needle-like recess 15 is formed when the polymer layer forming liquid is applied is preferably 5000 ⁇ m or less.
  • FIG. 31A is a view in which the entire surface of the mold 83 having the stepped portion 84 lower than the region 16 where the needle-like recess 15 is formed is uniformly applied around the needle-like recess 15.
  • the polymer layer forming liquid contracts toward the stepped portion 84 that is a concave portion of the mold 83. Therefore, when uniformly applied to the entire surface of the mold 83, as shown in FIG. 31B, the polymer layer forming liquid 24 is repelled from the region 16 where the needle-like recesses 15 are formed, and the percutaneous absorption sheet has a stable shape. May not be formed.
  • the shape formed by the stepped portion around the region where the needle-like recess is formed can be the same shape as the first embodiment.
  • Polymer layer forming liquid drying process 20A to 20D, after the polymer layer forming liquid supply step, as shown in FIG. 20D, the polymer layer forming liquid 24 is dried and solidified to form the polymer layer 122 on the drug layer 120.
  • the polymer sheet 1 having the drug layer 120 and the polymer layer 122 is manufactured.
  • the volume of the polymer layer formation liquid 24 is reduced by drying. If the polymer layer forming liquid 24 is in close contact with the mold 13 during drying, the volume reduction occurs in the film thickness direction of the sheet, and the film thickness decreases.
  • the polymer sheet 1 may contract in the surface direction and may be distorted or curled. If the polymer sheet 1 is peeled off from the mold 13 in a state where the polymer layer forming liquid 24 in the needle-like concave portion 15 is not sufficiently dried, the shape of the needle-like convex portion of the polymer sheet 1 is broken or bent. Defects are likely to occur. For this reason, it is preferable that the polymer sheet 1 does not peel from the mold 13 during drying.
  • a layer that contracts to the same extent as the surface having the needle-like convex portions may be formed on the back surface of the polymer sheet 1 (the surface opposite to the surface on which the needle-like convex portions are formed).
  • the same polymer solution as that on the front surface side is applied to the back surface side, and the layer is formed so as to have a film thickness in which the effect of curling suppression is confirmed in advance.
  • the method for peeling the polymer sheet 1 from the mold 13 is not limited. It is desired that the needle-like convex portion does not bend or break during peeling. Specifically, after attaching a sheet-like base material on which an adhesive pressure-sensitive adhesive layer is formed on the polymer sheet 1, peeling can be performed so as to turn the base material from the end. Further, a method of installing a suction cup on the back surface of the polymer sheet 1 and pulling it up vertically while sucking with air can be applied. By peeling the polymer sheet 1 from the mold 13, the transdermal absorption sheet 100 is manufactured.
  • Deaeration process It is preferable to deaerate the chemical liquid 22 and / or the polymer layer forming liquid 24 before the chemical liquid filling process and / or before the polymer layer forming liquid supply process.
  • the bubbles contained in the chemical liquid 22 and the polymer layer forming liquid 24 can be removed before filling the needle-like recess 15 of the mold 13. For example, in the deaeration process, bubbles having a diameter of 100 ⁇ m to several mm are removed.
  • a degassing method for example, (1) a method of exposing the chemical liquid 22 to a reduced pressure environment for 1 to 15 minutes, (2) a method of ultrasonically vibrating a container storing the chemical liquid 22 for 5 to 10 minutes, and (3) a chemical liquid 22 Examples include a method of applying ultrasonic waves while being exposed to a reduced pressure environment, and (4) a method of replacing dissolved gas with helium by sending helium gas into the chemical liquid 22.
  • the degassing methods (1) to (4) can also be applied to the polymer layer forming liquid 24.
  • the film was heat-cured in a state where the tip of the cone 11 of the original plate 11 protruded from the film surface, and then the cured film was peeled off.
  • This silicone rubber reversal product in which needle-like concave portions arranged two-dimensionally in 10 columns ⁇ 10 rows in the center portion, was cut off from a flat portion of 30 mm on a side, was used as a mold. The wider one of the needle-like recesses was the mold surface, and the surface having a 30 ⁇ m diameter through hole (air vent hole) was the mold back surface.
  • the polymer layer forming liquid drying step from the chemical solution filling step was performed in an environment of a temperature of 5 ° C. and a relative humidity of 35% RH.
  • the chemical filling device has a drive unit that controls the relative position coordinates of the mold and nozzle consisting of the X and Z axes, a liquid supply device that can be attached to the nozzle (ultra-trace quantity dispenser SMP-III manufactured by Musashi Engineering Co., Ltd.), and a fixed mold.
  • Suction table, laser displacement meter for measuring mold surface shape (HL-C201A, manufactured by Panasonic), load cell for measuring nozzle indentation pressure (LCX-A-500N, manufactured by Kyowa Denki Co., Ltd.), surface shape and measured pressure values A control system for controlling the Z-axis based on the data.
  • a gas permeable film with a side of 15 mm (PORFLON (registered trademark) FP-010, manufactured by Sumitomo Electric Industries, Ltd.) was placed on a horizontal suction table, and a mold was placed on the surface so that the surface was on top.
  • the gas permeable film and the mold were fixed to a suction table by reducing the pressure from the back side of the mold with a gauge pressure of ⁇ 90 kPa.
  • a SUS (stainless steel) nozzle having a shape as shown in FIG. 14 was prepared, and a slit-like opening having a length of 12 mm and a width of 0.2 mm was formed in the center of a lip portion having a length of 20 mm and a width of 2 mm. .
  • This nozzle was connected to a chemical tank. 3 mL of chemical solution was loaded into the chemical solution tank and the nozzle. The nozzles were adjusted so that the openings were parallel to the first row composed of a plurality of needle-like recesses formed on the surface of the mold.
  • the nozzle was pressed against the mold with a pressure (pressing force) of 0.14 kgf / cm 2 (1.4 N / cm 2 ) at a position 2 mm away from the first row in the direction opposite to the second row. While controlling the Z axis so that the fluctuation of the pressing force is within ⁇ 0.05 kgf / cm 2 (0.49 N / cm 2 ) with the nozzle pressed, the direction perpendicular to the length direction of the opening is 1 mm / sec.
  • the chemical solution was discharged from the opening at 0.31 ⁇ L / sec for 10 seconds with the liquid supply device.
  • the movement of the nozzle was stopped at a position spaced by 2 mm in the opposite direction to the ninth row with respect to the tenth row of the plurality of needle-shaped concave portions arranged two-dimensionally, and the nozzle was separated from the mold.
  • the mold filled with the chemical solution was placed in a windshield (25 cm 3 ) having an opening with a diameter of 5 mm and dried.
  • the windshield here has a structure in which a gas permeable film (PORFLON (registered trademark) FP-010 manufactured by Sumitomo Electric Industries, Ltd.) is attached to the opening, and is not directly exposed to wind.
  • PORFLON registered trademark
  • FP-010 manufactured by Sumitomo Electric Industries, Ltd.
  • Example 1 By the above-described method, coating was performed using a circular mold made of SUS at the time of supplying the polymer layer forming liquid.
  • the polymer layer forming solution was applied to the mold in a range larger by 1 mm as the radius than the mold.
  • the mold diameter is the diameter of the mold
  • the liquid level is the coating thickness of the polymer layer forming liquid
  • Experiments were conducted using molds with diameters of 10, 20, and 30 mm, with the same number of needle-shaped recesses and the same position. Therefore, the distance from the needle-like recess to the mold can be changed by changing the mold diameter.
  • the polymer layer to be formed was evaluated by changing the height of the mold from 10 to 10000 ⁇ m and changing the liquid surface height after application of the polymer layer forming solution with respect to the height of the mold. The results are shown in Table 1.
  • the liquid level could be fixed at the step.
  • the liquid level was 10,000 ⁇ m
  • the liquid level of the polymer layer forming liquid was fixed at the step portion, but it took time to dry and was not dried even after 12 hours.
  • the mold diameters were 10 mm, 20 mm, and 30 mm, they are collectively shown.
  • Example 2 The polymer layer forming liquid was applied to Experimental Example 1 using a mold having a stepped portion in which a needle-like concave portion was formed in a convex shape and the periphery was a concave shape. The results are shown in Table 2.
  • the polymer layer could be fixed at the step by setting the liquid level height to be equal to or greater than the thickness of the mold. Further, when the liquid level was 10000 ⁇ m, the polymer layer was fixed at the stepped portion as in Experimental Example 1, but could not be dried in 12 hours.
  • the mold was shaped like a square to a regular dodecagon (distance from the center to each apex was 10 mm), a circle with a diameter of 20 mm, and the liquid level was 100 ⁇ m. Further, the mold is formed with a step portion so that the region where the needle-like recess is formed becomes a convex portion. 10 mm) and a mold having a circular shape with a diameter of 20 mm was used for the experiment. The polymer layer forming liquid was applied to these molds, and the immobilization of the polymer layer at the stepped portion was confirmed. The results are shown in Table 3.
  • the angle is relatively small, such as when the shape of the stepped portion is a square or a regular pentagon.
  • the polymer layer forming liquid was repelled from the apex portion of the shape of the step portion, and the polymer layer could not be fixed at the step portion.
  • Example 4 Using the circular SUS mold having a diameter of 20 mm and a thickness of 100 ⁇ m used in Example 1, the step portion was formed so that the region having the needle-like recess was concave. Liquid level of the polymer layer by changing the liquid level height to 200 ⁇ m and changing the amount of protrusion to the stepped part (with the stepped part as the reference, the stepped part side is the outside and the needle-shaped recessed part is the inside) confirmed. The results are shown in Table 4.
  • Test No. When 81 to 85 polymer layer forming liquids were applied at the same position as the stepped portion or wider than the stepped portion, the polymer layer could be fixed at the stepped portion. Test No. in which the polymer layer forming solution was applied to the inside of the mold. Regarding 86 to 88, the polymer layer could not be fixed at the stepped portion, and it was bounced in the region where the needle-like concave portion of the mold was formed, and a percutaneous absorption sheet having a good shape could not be formed.

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Abstract

Provided is a process for producing, with a simple device configuration, a sheet for percutaneous absorption which has a stable shape. The process for producing a sheet for percutaneous absorption comprises: a drug-solution filling step in which a drug solution 22 that is a polymer solution containing a drug is filled into the acicular recesses 15 of a mold 13; a drug-solution drying step in which the drug solution 22 filled into the acicular recesses 15 is dried to form a drug layer 120 containing the drug; a polymer-layer-forming-liquid supply step in which the mold 13 is provided with a dam part that surrounds the region 16 where the acicular recesses 15 have been formed and that extends above the region 16 where the acicular recesses 15 have been formed, and a polymer-layer-forming liquid 120 is supplied to the mold 13 so that the liquid 24 fills a space which extends to at least the height of the dam part and which, when viewed from above, at least reaches the dam part; and a polymer-layer-forming-liquid drying step in which the polymer-layer-forming liquid 24 supplied to the mold 13 is dried to form a polymer layer 122.

Description

経皮吸収シートの製造方法Method for producing transdermal absorption sheet
　本発明は、経皮吸収シートの製造方法に係り、特に、薬剤を含む針状凸部がシート部上に配列された経皮吸収シートの製造方法に関する。 The present invention relates to a method for producing a transdermal absorption sheet, and more particularly to a method for producing a transdermal absorption sheet in which needle-like convex portions containing a drug are arranged on a sheet portion.
　生体表面、即ち皮膚や粘膜などより、薬品などを投与する方法として、薬剤を含有する高アスペクト比の針状凸部（微小針、又は、マイクロニードルともいう）が形成された経皮吸収シートを用い、微小針を皮膚内に挿入することにより、薬品を注入する方法が行われている。経皮吸収シートとして使用するためには、薬剤を混入させる必要があるが、薬剤は高価なものが多いことから、微小針に集中させて薬剤を含有させることが必要になる。 As a method for administering a medicine from the surface of a living body, that is, skin or mucous membrane, a percutaneous absorption sheet formed with a high aspect ratio needle-like convex part (also referred to as a microneedle or microneedle) containing a drug is used. A method of injecting a medicine by inserting a microneedle into the skin is used. In order to use as a transdermal absorption sheet, it is necessary to mix a medicine, but since many medicines are expensive, it is necessary to concentrate the medicine on a microneedle and to contain the medicine.
　経皮吸収シートを製造する方法として、針状凸部の反転形状である針状凹部が形成されたモールドにポリマー溶解液などを流し込み、形状転写する方法が知られている。例えば、凹部の底に母材を貫通する貫通孔を穿設したマイクロニードルシートのモールドを使用し、このモールドの上に最初に薬物を希釈した溶液を塗布し、その後、スキージなどで余分な溶液を掻き取り、薬液を乾燥した後、次にニードル原料を塗布する方法がある。 As a method for producing a percutaneous absorption sheet, there is known a method of transferring a shape by pouring a polymer solution or the like into a mold in which a needle-like concave portion which is an inverted shape of the needle-like convex portion is formed. For example, using a microneedle sheet mold with a through-hole penetrating the base material at the bottom of the recess, first apply the drug-diluted solution on the mold, and then use the squeegee to remove the excess solution There is a method in which the needle raw material is applied after scraping off and drying the chemical solution.
　また、柔軟性基板に目的物質、及び基剤の混和物から成る濃厚な液体を、遠心力を利用して充填しながら乾燥して硬化させることにより高精度で１ステップの工程で製造する微小針状突起物製剤を集積させたシートの製造方法がある。 Microneedles that are manufactured in a one-step process with high accuracy by filling a flexible substrate with a concentrated liquid consisting of an admixture of a target substance and a base using a centrifugal force while drying and curing. There is a method for producing a sheet in which a ridge-shaped projection preparation is accumulated.
　針状凹版による形状転写を用いたマイクロニードル形成においては、薬液を含むか含まないかに関わらず、ポリマー溶解液を何らかの方法で、針状凹版上に塗布することが必要である。例えば、下記の特許文献１には、凹部アレイが形成された型に、ポリマー樹脂の溶解液を塗布し、加圧流体で加圧することにより、ポリマー樹脂の溶解液を凹部アレイに充填する機能性膜の製造方法が記載されている。特許文献２についても、ポリマー溶液を針状凹部に充填するため、加圧充填装置を用いることが記載されている。また、特許文献３には、凹版を傾斜した状態で針状体形成液を供給し、針状体形成液を上方から下方に移動することで、凹部に針状体形成液を充填させることが記載されている。 In microneedle formation using shape transfer by needle-shaped intaglio, it is necessary to apply a polymer solution on the needle-shaped intaglio by some method regardless of whether or not it contains a chemical solution. For example, in Patent Document 1 below, the functionality of filling a concave array with a polymer resin solution by applying a polymer resin solution to a mold having a concave array and pressurizing with a pressurized fluid. A method for manufacturing the membrane is described. Patent Document 2 also describes the use of a pressure filling device to fill the needle-shaped recess with the polymer solution. Further, in Patent Document 3, the needle-shaped body forming liquid is supplied in a state where the intaglio is inclined, and the needle-shaped body forming liquid is moved downward from above to fill the concave portion with the needle-shaped body forming liquid. Are listed.
特開２００９－０８２２０７号公報JP 2009-082207 A 特開２０１１－２２４３３２号公報JP 2011-224332 A 特開２０１４－０２３６９８号公報JP 2014-023698 A
　針状凹版は、形成された針状凸部の離形性を向上させるため、表面張力の低い素材を用いたり、表面処理が施されている場合がある。そのため、直接ポリマー溶液を塗布しようとすると、固体と液体の表面張力差、および、ぬれ性（wettability）の悪さによって液が収縮し、液を弾いてしまい、膜を形成できないという課題があった。 The needle-shaped intaglio may be made of a material having a low surface tension or may be surface-treated in order to improve the releasability of the formed needle-shaped convex portion. Therefore, when the polymer solution is directly applied, there is a problem that the liquid contracts due to the difference in surface tension between the solid and the liquid and the poor wettability, repels the liquid and cannot form a film.
　液を弾かせないためには、針状凹版部分の表面張力を上げて、ポリマー溶解液の表面張力を下げることが考えられるが、針状凹版部分は前述の離形性の点から表面張力を上げることは難しい。また、ポリマー溶解液についても界面活性剤を添加することは性能上望ましくない場合がある。また、別の観点として、ポリマー溶解液の塗工膜厚を厚くすることも考えられるが、乾燥工程に負荷をかけることや、性能上不要な量のシート形成をすることは生産コスト上好ましくない。 In order to prevent the liquid from repelling, it is conceivable to increase the surface tension of the needle-shaped intaglio part and decrease the surface tension of the polymer solution. It is difficult to raise. In addition, it may be undesirable in terms of performance to add a surfactant to the polymer solution. As another viewpoint, it may be possible to increase the coating film thickness of the polymer solution, but it is not preferable in terms of production cost to place a burden on the drying process or to form an unnecessary amount of sheet in terms of performance. .
　特許文献１～３に記載の方法では、表面張力を抑制し、型枠で形状を維持することができるが、装置全体を包含するような大掛かりな装置が必要となり、設備コストも大きくなる。また、静的な状態で、より精密に塗布乾燥させることはできていなかった。 In the methods described in Patent Documents 1 to 3, the surface tension can be suppressed and the shape can be maintained by the formwork, but a large-scale device including the entire device is required, and the equipment cost is increased. In addition, it could not be applied and dried more precisely in a static state.
　本発明は、このような事情に鑑みてなされたものであり、ポリマー溶解液を区画させる型枠へのポリマー溶解液の投入方法を制御することにより、設備コストを抑えながら安定してポリマー溶解液を各固体形状に維持したまま乾燥させることができる経皮吸収シートの製造方法を提供することを目的とする。 The present invention has been made in view of such circumstances, and by controlling the method of introducing the polymer solution into the mold for partitioning the polymer solution, the polymer solution can be stably suppressed while reducing the equipment cost. An object of the present invention is to provide a method for producing a percutaneous absorption sheet that can be dried while being maintained in a solid form.
　本発明は、上記目的を達成するために、針状凹部を有するモールドの針状凹部に薬剤を含むポリマー溶解液である薬液を充填する薬液充填工程と、針状凹部に充填された薬液を乾燥させて、薬剤を含む薬剤層を形成する薬液乾燥工程と、モールドは、針状凹部が形成された領域の周囲に針状凹部が形成された領域より高い段差部を備え、モールドに対し、段差部以上の高さであり、かつ、上面から見て段差部以上の範囲に、ポリマー層形成液を供給するポリマー層形成液供給工程と、モールドに供給されたポリマー層形成液を乾燥させて、ポリマー層を形成するポリマー層形成液乾燥工程と、を有する経皮吸収シートの製造方法を提供する。 In order to achieve the above object, the present invention provides a chemical solution filling step of filling a needle solution in a mold having a needle recess with a chemical solution that is a polymer solution containing a drug, and drying the drug solution filled in the needle recess. And a chemical solution drying step for forming a drug layer containing a drug, and the mold includes a step portion higher than the region in which the needle-like recess is formed around the region in which the needle-like recess is formed. The polymer layer forming liquid supplying step for supplying the polymer layer forming liquid to the range of the stepped part or more when viewed from the top, and the polymer layer forming liquid supplied to the mold, There is provided a method for producing a transdermal absorption sheet having a polymer layer forming liquid drying step for forming a polymer layer.
　本発明によれば、針状凹部が形成されたモールドの針状凹部が形成された領域の周囲に、針状凹部が形成された領域より高い段差部を備え、ポリマー層を形成するポリマー層形成液を、この段差部以上の高さであり、かつ、段差部以上の広さで供給することで、針状凹部が形成された領域内で、ポリマー層形成液がモールドにはじかれることを防止することができる。したがって、経皮吸収シートの形状を維持した状態で、安定して経皮吸収シートを製造することができる。なお、「段差部以上の高さにポリマー層形成液を供給する」とは、針状凹部が形成された領域の周囲の段差部をすりきった面以上の高さにポリマー層形成液を供給することをいう。 According to the present invention, the polymer layer is formed so as to have a step portion higher than the region where the needle-like recess is formed around the region where the needle-like recess is formed in the mold where the needle-like recess is formed, By supplying the liquid at a height higher than this step and wider than the step, the polymer layer forming liquid is prevented from being repelled by the mold in the area where the needle-shaped recess is formed. can do. Therefore, the transdermal absorption sheet can be stably produced while maintaining the shape of the transdermal absorption sheet. “Supply the polymer layer forming liquid to a height higher than the stepped portion” means to supply the polymer layer forming liquid to a height higher than the surface where the stepped portion around the region where the needle-like concave portion is formed is cut. To do.
　本発明の別の態様においては、ポリマー層形成液供給工程は、ポリマー層形成液を、段差部より高く、かつ、上面から見て段差部より広い範囲に供給した後、ポリマー層形成液を収縮させながら、ポリマー層形成液とモールドとの接触位置を段差部に固定することが好ましい。 In another aspect of the present invention, the polymer layer forming liquid supply step supplies the polymer layer forming liquid to a range higher than the stepped portion and wider than the stepped portion as viewed from above, and then shrinks the polymer layer forming liquid. It is preferable to fix the contact position between the polymer layer forming liquid and the mold to the stepped portion.
　この態様によれば、ポリマー層形成液をモールドの段差部より高く、かつ、段差部より広い範囲で供給した後、供給されたポリマー層形成液を、収縮させながら段差部で固定することで、針状凹部が形成された領域内で、ポリマー層形成液がモールドにはじかれることを防止することができる。したがって、経皮吸収シートの形状を維持した状態で、安定して経皮吸収シートを製造することができる。なお、「ポリマー層形成液とモールドとの接触位置」とは、ポリマー層形成液が、針状凹部が形成されている領域側に収縮した時のポリマー層形成液の液滴の周囲であり、「接触位置を段差部に固定する」とは、ポリマー層形成液の液滴の周囲が、段差部の上側で固定することをいう。また、ポリマー層形成液の収縮は、表面張力を利用して行われることが好ましい。 According to this aspect, after the polymer layer forming liquid is supplied in a range higher than the stepped portion of the mold and wider than the stepped portion, the supplied polymer layer forming liquid is fixed at the stepped portion while being contracted, It is possible to prevent the polymer layer forming liquid from being repelled by the mold in the region where the needle-like recess is formed. Therefore, the transdermal absorption sheet can be stably produced while maintaining the shape of the transdermal absorption sheet. In addition, the “contact position between the polymer layer forming liquid and the mold” is the periphery of the droplet of the polymer layer forming liquid when the polymer layer forming liquid contracts to the region side where the needle-like recess is formed, “Fixing the contact position to the stepped portion” means that the periphery of the polymer layer forming liquid droplet is fixed above the stepped portion. Moreover, it is preferable that shrinkage | contraction of a polymer layer forming liquid is performed using surface tension.
　本発明の別の態様においては、モールドの段差部の高さが１０μｍ以上５０００μｍ以下であることが好ましい。 In another aspect of the present invention, the height of the step portion of the mold is preferably 10 μm or more and 5000 μm or less.
　この態様は、モールドの段差部の高さを規定したものであり、段差部の高さを上記範囲とすることで、供給するポリマー層形成液の量を少なくすることができるので、ポリマー層形成液乾燥工程を短縮することができ、生産コストを下げることができる。 In this aspect, the height of the step portion of the mold is defined, and the amount of the polymer layer forming liquid to be supplied can be reduced by setting the height of the step portion in the above range. The liquid drying process can be shortened and the production cost can be reduced.
　本発明の別の態様においては、ポリマー層形成液供給工程において、ポリマー層形成液の厚みが５０００μｍ以下であることが好ましい。 In another aspect of the present invention, in the polymer layer forming solution supply step, the thickness of the polymer layer forming solution is preferably 5000 μm or less.
　この態様は、ポリマー層形成液供給工程におけるポリマー層形成液の厚みを規定したものである。ポリマー層形成液の厚みを上記範囲とすることで、供給するポリマー層形成液の量を少なくすることができるので、ポリマー層形成液乾燥工程を短縮することができ、生産コストを下げることができる。なお、「ポリマー層形成液の厚み」とは、ポリマー層形成液供給工程後の、針状凹部が形成された領域からの厚みであり、ポリマー層形成液の最も厚い部分の厚みである。 This aspect defines the thickness of the polymer layer forming liquid in the polymer layer forming liquid supplying step. By setting the thickness of the polymer layer forming liquid in the above range, the amount of the polymer layer forming liquid to be supplied can be reduced, so that the polymer layer forming liquid drying step can be shortened and the production cost can be reduced. . The “thickness of the polymer layer forming liquid” is the thickness from the region where the needle-like recess is formed after the polymer layer forming liquid supplying step, and is the thickness of the thickest part of the polymer layer forming liquid.
　本発明の別の態様においては、段差部は、モールドとは分離可能に設けられた型枠であることが好ましい。 In another aspect of the present invention, the stepped portion is preferably a mold provided so as to be separable from the mold.
　この態様によれば、段差部を型枠により形成することで、薬液充填工程、薬液乾燥工程を平坦なモールドで行うことができ、各工程を効率良く行うことができる。また、製造する経皮吸収シートに合わせて型枠を設置することができる。 According to this aspect, by forming the step portion with the mold, the chemical solution filling step and the chemical solution drying step can be performed with a flat mold, and each step can be performed efficiently. Moreover, a formwork can be installed according to the transdermal absorption sheet to manufacture.
　本発明の別の態様においては、段差部は、モールド自身に段差を有することが好ましい。 In another aspect of the present invention, the stepped portion preferably has a step in the mold itself.
　この態様によれば、モールド自身に段差を設け、段差部を形成することで、安定してポリマー層形成液の供給を行うことができる。 According to this aspect, by providing a step in the mold itself and forming the step portion, the polymer layer forming liquid can be stably supplied.
　本発明の別の態様においては、段差部は、針状凹部が形成された領域側から鉛直方向上側に向かって広がる方向にテーパ形状であることが好ましい。 In another aspect of the present invention, the stepped portion is preferably tapered in a direction extending from the region side where the needle-like concave portion is formed toward the upper side in the vertical direction.
　この態様によれば、段差部が上側に向かってテーパ形状とすることで、ポリマー層形成液中に混入した泡の泡抜き（defoam）の効果がある。ポリマー層形成液中に混入した泡の泡抜きを行うことで、剥離工程における針状凸部の欠損、穿刺時における針状凸部の破損を防止することができる。 According to this aspect, since the stepped portion is tapered upward, there is an effect of defoaming bubbles mixed in the polymer layer forming liquid. By defoaming the bubbles mixed in the polymer layer forming liquid, it is possible to prevent the needle-like projections from being lost in the peeling step and the needle-like projections from being damaged during puncturing.
　本発明は上記目的を達成するために、針状凹部を有するモールドの針状凹部に薬剤を含むポリマー溶解液である薬液を充填する薬液充填工程と、針状凹部に充填された薬液を乾燥させて、薬剤を含む薬剤層を形成する薬液乾燥工程と、モールドは、針状凹部が形成された領域の周囲に針状凹部が形成された領域より低い段差部を備え、モールドに対し、上面から見て段差部以上の範囲に、ポリマー層形成液を供給した後、ポリマー層形成液を収縮させながら、ポリマー層形成液とモールドの接触位置を段差部に固定するポリマー層形成液供給工程と、モールドに供給されたポリマー層形成液を乾燥させて、ポリマー層を形成するポリマー層形成液乾燥工程と、を有する経皮吸収シートの製造方法を提供する。 In order to achieve the above object, the present invention provides a chemical solution filling step of filling a chemical solution, which is a polymer solution containing a drug, into a needle-shaped recess of a mold having a needle-shaped recess, and drying the chemical solution filled in the needle-shaped recess. The chemical solution drying step for forming the drug layer containing the drug, and the mold includes a step portion lower than the area where the needle-shaped recess is formed around the area where the needle-shaped recess is formed. A polymer layer forming liquid supply step for fixing the contact position of the polymer layer forming liquid and the mold to the stepped part while shrinking the polymer layer forming liquid after supplying the polymer layer forming liquid to the range of the stepped part or more as seen. There is provided a method for producing a percutaneous absorption sheet, comprising: drying a polymer layer forming solution supplied to a mold to form a polymer layer.
　本発明によれば、針状凹部が形成されたモールドの針状凹部が形成された領域の周囲に、針状凹部が形成された領域より低い段差部を備え、ポリマー層を形成するポリマー層形成液を、この段差部以上の広さで供給し、収縮により段差部で固定することで、針状凹部が形成された領域内で、ポリマー層形成液がモールドにはじかれることを防止することができる。したがって、経皮吸収シートの形状を維持した状態で、安定して経皮吸収シートを製造することができる。ポリマー層形成液の収縮は、表面張力を利用して行われることが好ましい。 According to the present invention, the polymer layer is formed so as to have a step portion lower than the region where the needle-like recess is formed around the region where the needle-like recess is formed in the mold where the needle-like recess is formed. By supplying the liquid in a width larger than the stepped portion and fixing the stepped portion by contraction, it is possible to prevent the polymer layer forming liquid from being repelled by the mold in the region where the needle-like concave portion is formed. it can. Therefore, the transdermal absorption sheet can be stably produced while maintaining the shape of the transdermal absorption sheet. The shrinkage of the polymer layer forming liquid is preferably performed using surface tension.
　本発明の別の態様においては、ポリマー層形成液供給工程は、ポリマー層形成液の供給を、段差部が設けられた針状凹部ごとに行うことが好ましい。 In another aspect of the present invention, it is preferable that the polymer layer forming liquid supply step supplies the polymer layer forming liquid for each needle-like concave portion provided with a stepped portion.
　この態様によれば、ポリマー層形成液の供給を、段差部ごとに行うことで、供給されたポリマー層形成液をそれぞれの段差部で固定することができる。 According to this aspect, by supplying the polymer layer forming liquid for each stepped portion, the supplied polymer layer forming liquid can be fixed at each stepped portion.
　本発明の別の態様においては、ポリマー層形成液供給工程において、ポリマー層形成液の厚みが５０００μｍ以下であることが好ましい。 In another aspect of the present invention, in the polymer layer forming solution supply step, the thickness of the polymer layer forming solution is preferably 5000 μm or less.
　この態様は、ポリマー層形成液供給工程におけるポリマー層形成液の厚みを規定したものであり、ポリマー層形成液の厚みを上記範囲とすることで、供給するポリマー層形成液の量を少なくすることができるので、ポリマー層形成液乾燥工程を短縮することができ、生産コストを下げることができる。 In this embodiment, the thickness of the polymer layer forming liquid in the polymer layer forming liquid supplying step is defined. By setting the thickness of the polymer layer forming liquid within the above range, the amount of the polymer layer forming liquid to be supplied is reduced. Therefore, the polymer layer forming liquid drying step can be shortened, and the production cost can be reduced.
　本発明の別の態様においては、段差部は、モールド自身に段差を有することが好ましい。 In another aspect of the present invention, the stepped portion preferably has a step in the mold itself.
　この態様によれば、モールド自身に段差を設け、段差部を形成することで、安定してポリマー層形成液の供給を行うことができる。 According to this aspect, by providing a step in the mold itself and forming the step portion, the polymer layer forming liquid can be stably supplied.
　本発明の別の態様においては、ポリマー層形成液を供給した際、モールドに設置した段差部分に働くポリマー層形成液の収縮力を均一にするため、針状凹部が形成された領域の周囲の段差部により形成される形状が、段差を上面から見てすべての角が１２０°以上の角度で形成される六角形以上の多角形であることが好ましく、正六角形以上の正多角形、または、円形であることがさらに好ましい。 In another aspect of the present invention, when the polymer layer forming liquid is supplied, in order to make the shrinkage force of the polymer layer forming liquid acting on the stepped portion installed in the mold uniform, Preferably, the shape formed by the stepped portion is a hexagonal or more polygon formed at all angles of 120 ° or more when the step is viewed from the top, a regular hexagon or more regular polygon, or More preferably, it is circular.
　ポリマー層形成液は、等方的に収縮するため、段差部により形成される形状を、すべての角が１２０°以上の角度で形成される六角形以上の多角形、好ましくは、正六角形以上の正多角形、または、円形とすることで、多角形の角部でポリマー層形成液の収縮が進む。これにより、段差部でポリマー層形成液が固定されず、針状凹部が形成される領域にポリマー層形成液の液滴が落ちることを防止することができる。針状凹部が形成される領域にポリマー層形成領域の液滴が落ちると、ポリマー層形成液がはじかれ、経皮吸収シートの形状が安定しないため好ましくない。 Since the polymer layer forming liquid contracts isotropically, the shape formed by the stepped portion is a hexagon or more polygon, preferably a regular hexagon or more, with all angles formed at an angle of 120 ° or more. By making it a regular polygon or a circle, the shrinkage of the polymer layer forming liquid proceeds at the corners of the polygon. Thereby, the polymer layer forming liquid is not fixed at the stepped portion, and it is possible to prevent the liquid droplets of the polymer layer forming liquid from dropping into the region where the needle-like recess is formed. If a droplet in the polymer layer forming region falls in the region where the needle-like recess is formed, the polymer layer forming liquid is repelled, and the shape of the transdermal absorption sheet is not stable, which is not preferable.
　本発明の経皮吸収シートの製造方法によれば、簡単な装置構成で、薄い膜においても液面を安定して維持することができる。また、簡単な構成とすることで、コストダウンを図ることができる。 According to the method for producing a percutaneous absorption sheet of the present invention, the liquid level can be stably maintained even with a thin film with a simple apparatus configuration. In addition, the cost can be reduced with a simple configuration.
図１は、針状凸部を有する経皮吸収シートの斜視図である。FIG. 1 is a perspective view of a transdermal absorption sheet having needle-like convex portions. 図２は、別の形状の針状凸部を有する経皮吸収シートの斜視図である。FIG. 2 is a perspective view of a transdermal absorption sheet having a needle-like convex portion having another shape. 図３は、図１及び図２に示す経皮吸収シートの針状凸部の断面図である。FIG. 3 is a cross-sectional view of the needle-like convex portion of the transdermal absorption sheet shown in FIGS. 1 and 2. 図４は、別の形状の針状凸部を有する経皮吸収シートの斜視図である。FIG. 4 is a perspective view of a transdermal absorption sheet having a needle-like convex portion having another shape. 図５は、別の形状の針状凸部を有する経皮吸収シートの斜視図である。FIG. 5 is a perspective view of a transdermal absorption sheet having a needle-like convex portion having another shape. 図６は、図４及び図５に示す経皮吸収シートの針状凸部の断面図である。FIG. 6 is a cross-sectional view of the needle-like convex portion of the transdermal absorption sheet shown in FIGS. 4 and 5. 図７Ａは、モールドの製造方法の工程図である。FIG. 7A is a process diagram of a mold manufacturing method. 図７Ｂは、モールドの製造方法の工程図である。FIG. 7B is a process diagram of a mold manufacturing method. 図７Ｃは、モールドの製造方法の工程図である。FIG. 7C is a process diagram of a mold manufacturing method. 図８Ａは、別微形状のモールドの製造方法の工程図である。FIG. 8A is a process diagram of a method for producing another finely shaped mold. 図８Ｂは、別微形状のモールドの製造方法の工程図である。FIG. 8B is a process diagram of a method for manufacturing another finely shaped mold. 図８Ｃは、別微形状のモールドの製造方法の工程図である。FIG. 8C is a process diagram of a method for manufacturing another finely shaped mold. 図９Ａは、別の形状のモールドの製造方法の工程図である。FIG. 9A is a process diagram of a method for manufacturing a mold having another shape. 図９Ｂは、別の形状のモールドの製造方法の工程図である。FIG. 9B is a process diagram of a method for manufacturing a mold having another shape. 図９Ｃは、別の形状のモールドの製造方法の工程図である。FIG. 9C is a process diagram of a method for manufacturing a mold having another shape. 図１０は、モールドの部分拡大図である。FIG. 10 is a partially enlarged view of the mold. 図１１は、モールドの部分拡大図である。FIG. 11 is a partially enlarged view of the mold. 図１２は、経皮吸収シートの製造方法のフロー図である。FIG. 12 is a flowchart of a method for producing a transdermal absorption sheet. 図１３Ａは、薬液をモールドの針状凹部に充填する工程を示す概略図である。FIG. 13A is a schematic diagram showing a process of filling a liquid medicine into a needle-like recess of a mold. 図１３Ｂは、薬液をモールドの針状凹部に充填する工程を示す概略図である。FIG. 13B is a schematic view showing a step of filling the needle-shaped concave portion of the mold with the chemical solution. 図１３Ｃは、薬液をモールドの針状凹部に充填する工程を示す概略図である。FIG. 13C is a schematic view showing a step of filling the needle-shaped concave portion of the mold with the chemical solution. 図１４は、ノズルの先端を示す斜視図である。FIG. 14 is a perspective view showing the tip of the nozzle. 図１５は、別のノズルの先端を示す斜視図である。FIG. 15 is a perspective view showing the tip of another nozzle. 図１６は、充填中のノズルの先端とモールドとの部分拡大図である。FIG. 16 is a partially enlarged view of the tip of the nozzle during filling and the mold. 図１７は、走査中のノズルの先端とモールドとの部分拡大図である。FIG. 17 is a partially enlarged view of the nozzle tip and the mold during scanning. 図１８は、薬液充填装置の概略構成図である。FIG. 18 is a schematic configuration diagram of a chemical liquid filling apparatus. 図１９は、ノズル内の液圧と薬剤を含む溶解液の供給との関係を示す説明図である。FIG. 19 is an explanatory diagram showing the relationship between the fluid pressure in the nozzle and the supply of a solution containing a drug. 図２０Ａは、経皮吸収シートの製造工程の一部を示す概略図である。FIG. 20A is a schematic view showing a part of the production process of a transdermal absorption sheet. 図２０Ｂは、経皮吸収シートの製造工程の一部を示す概略図である。FIG. 20B is a schematic diagram illustrating a part of the manufacturing process of the transdermal absorption sheet. 図２０Ｃは、経皮吸収シートの製造工程の一部を示す概略図である。FIG. 20C is a schematic diagram illustrating a part of the manufacturing process of the transdermal absorption sheet. 図２０Ｄは、経皮吸収シートの製造工程の一部を示す概略図である。FIG. 20D is a schematic diagram illustrating a part of the manufacturing process of the transdermal absorption sheet. 図２１Ａは、第１実施形態のポリマー層形成液供給工程を説明する図である。FIG. 21A is a diagram illustrating a polymer layer forming liquid supply step of the first embodiment. 図２１Ｂは、第１実施形態のポリマー層形成液供給工程を説明する図である。FIG. 21B is a diagram illustrating a polymer layer forming liquid supply step of the first embodiment. 図２２Ａは、ポリマー層形成液供給工程の好ましくない例を説明する図である。FIG. 22A is a diagram for explaining an unfavorable example of the polymer layer forming liquid supply step. 図２２Ｂは、ポリマー層形成液供給工程の好ましくない例を説明する図である。FIG. 22B is a diagram for explaining an undesirable example of the polymer layer forming liquid supply step. 図２３Ａは、モールドへのポリマー層形成液の塗布方法を説明する図である。FIG. 23A is a diagram illustrating a method for applying a polymer layer forming liquid onto a mold. 図２３Ｂは、モールドへのポリマー層形成液の塗布方法を説明する図である。FIG. 23B is a diagram illustrating a method for applying a polymer layer forming liquid onto a mold. 図２４Ａは、モールドへのポリマー側形成液の別の塗布方法を説明する図である。FIG. 24A is a diagram illustrating another application method of the polymer side forming liquid to the mold. 図２４Ｂは、モールドへのポリマー側形成液の別の塗布方法を説明する図である。FIG. 24B is a diagram illustrating another application method of the polymer side forming liquid to the mold. 図２４Ｃは、モールドへのポリマー側形成液の別の塗布方法を説明する図である。FIG. 24C is a diagram illustrating another method of applying the polymer side forming liquid to the mold. 図２５Ａは、型枠の形状によるポリマー層形成液の収縮を説明する図である。FIG. 25A is a diagram for explaining the contraction of the polymer layer forming liquid due to the shape of the mold. 図２５Ｂは、型枠の形状によるポリマー層形成液の収縮を説明する図である。FIG. 25B is a diagram for explaining the contraction of the polymer layer forming liquid due to the shape of the mold. 図２５Ｃは、型枠の形状によるポリマー層形成液の収縮を説明する図である。FIG. 25C is a diagram for explaining the contraction of the polymer layer forming liquid due to the shape of the mold. 図２６Ａは、ポリマー層形成液の塗布形状による収縮を説明する図である。FIG. 26A is a diagram illustrating shrinkage due to the coating shape of the polymer layer forming liquid. 図２６Ｂは、ポリマー層形成液の塗布形状による収縮を説明する図である。FIG. 26B is a diagram illustrating shrinkage due to the application shape of the polymer layer forming liquid. 図２６Ｃは、ポリマー層形成液の塗布形状による収縮を説明する図である。FIG. 26C is a diagram illustrating shrinkage due to the application shape of the polymer layer forming liquid. 図２７Ａは、型枠の他の形状によるポリマー層形成液の収縮を説明する図である。FIG. 27A is a diagram for explaining the contraction of the polymer layer forming liquid due to another shape of the mold. 図２７Ｂは、型枠の他の形状によるポリマー層形成液の収縮を説明する図である。FIG. 27B is a diagram for explaining the contraction of the polymer layer forming liquid due to another shape of the mold. 図２７Ｃは、型枠の他の形状によるポリマー層形成液の収縮を説明する図である。FIG. 27C is a diagram for explaining the contraction of the polymer layer forming liquid due to another shape of the mold. 図２８Ａは、別の形状の型枠によるポリマー層形成液供給工程を説明する図である。FIG. 28A is a diagram for explaining a polymer layer forming liquid supply step using a mold having another shape. 図２８Ｂは、別の形状の型枠によるポリマー層形成液供給工程を説明する図である。FIG. 28B is a diagram illustrating a polymer layer forming liquid supply step using a mold having another shape. 図２９Ａは、第１実施形態の変形例のポリマー層形成液供給工程を説明する図である。FIG. 29A is a diagram illustrating a polymer layer forming liquid supply step according to a modification of the first embodiment. 図２９Ｂは、第１実施形態の変形例のポリマー層形成液供給工程を説明する図である。FIG. 29B is a diagram illustrating a polymer layer forming liquid supply step according to a modification of the first embodiment. 図３０Ａは、第２実施形態のポリマー層形成液供給工程を説明する図である。FIG. 30A is a diagram illustrating a polymer layer forming liquid supply step of the second embodiment. 図３０Ｂは、第２実施形態のポリマー層形成液供給工程を説明する図である。FIG. 30B is a diagram illustrating a polymer layer forming liquid supply step of the second embodiment. 図３１Ａは、ポリマー層形成液供給工程の好ましくない例を説明する図である。FIG. 31A is a diagram illustrating an undesirable example of the polymer layer forming liquid supply step. 図３１Ｂは、ポリマー層形成液供給工程の好ましくない例を説明する図である。FIG. 31B is a diagram for explaining an undesirable example of the polymer layer forming liquid supply step. 図３２Ａは、実施例で用いた原版の平面図である。FIG. 32A is a plan view of the original plate used in the examples. 図３２Ｂは、実施例で用いた原版の断面図である。FIG. 32B is a cross-sectional view of the original plate used in the examples.
　以下、添付図面に従って、本発明に係る経皮吸収シートの製造方法について説明する。なお、本明細書において、「～」とは、その前後に記載される数値を下限値および上限値として含む意味で使用される。 Hereinafter, a method for producing a transdermal absorption sheet according to the present invention will be described with reference to the accompanying drawings. In the present specification, “˜” is used to mean that the numerical values described before and after it are included as a lower limit value and an upper limit value.
　（経皮吸収シート）
　本実施の形態で製造される経皮吸収シートについて説明する。図１及び図２は、経皮吸収シート１００の一部拡大図である針状凸部１１０（微小針、マイクロニードルとも称する）を示している。 (Transdermal absorption sheet)
The percutaneous absorption sheet manufactured by this Embodiment is demonstrated. 1 and 2 show a needle-like convex portion 110 (also referred to as a microneedle or a microneedle), which is a partially enlarged view of the transdermal absorption sheet 100.
　経皮吸収シート１００は、皮膚に貼付することにより、皮膚内に薬剤を供給する。図１に示すように、経皮吸収シート１００は、先細り形状のニードル部１１２と、ニードル部１１２と接続された錐台部１１４と、錐台部１１４と接続された平板形状のシート部１１６とを有している。先細り形状のニードル部１１２と錐台部１１４とにより針状凸部１１０が構成される。 The transdermal absorption sheet 100 supplies the drug into the skin by being affixed to the skin. As shown in FIG. 1, a transdermal absorption sheet 100 includes a tapered needle portion 112, a frustum portion 114 connected to the needle portion 112, and a flat sheet portion 116 connected to the frustum portion 114. have. The tapered needle part 112 and the frustum part 114 constitute the needle-like convex part 110.
　シート部１１６の表面には複数個の錐台部１１４が形成される（図１においては一つの錐台部１１４のみ表示）。錐台部１１４の２つの端面のうち面積の広い端面（下底）がシート部１１６と接続される。錐台部１１４の２つの端面のうち面積の狭い端面（上底）がニードル部１１２と接続される。つまり、錐台部１１４の２つの端面のうち、シート部１１６と離れる方向にある端面の面積が小さくなっている。ニードル部１１２の面積の広い面が、錐台部１１４の面積の狭い端面と接続されているので、ニードル部１１２は錐台部１１４と離れる方向に漸次先細り形状となっている。 A plurality of frustum portions 114 are formed on the surface of the sheet portion 116 (only one frustum portion 114 is shown in FIG. 1). Of the two end faces of the frustum part 114, an end face (lower base) having a large area is connected to the sheet part 116. Of the two end faces of the frustum part 114, the end face (upper bottom) having a small area is connected to the needle part 112. That is, the area of the end surface in the direction away from the sheet portion 116 of the two end surfaces of the frustum portion 114 is small. Since the surface of the needle portion 112 having a large area is connected to the end surface of the frustum portion 114 having a small area, the needle portion 112 is gradually tapered away from the frustum portion 114.
　図１において、錐台部１１４は円錐台の形状を有し、ニードル部１１２は円錐の形状を有している。ニードル部１１２の皮膚への挿入の程度に応じて、ニードル部１１２の先端の形状を、０．０１μｍ以上５０μｍ以下の曲率半径の曲面や、平坦面等に適宜変更することができる。 1, the frustum portion 114 has a truncated cone shape, and the needle portion 112 has a cone shape. Depending on the degree of insertion of the needle portion 112 into the skin, the shape of the tip of the needle portion 112 can be appropriately changed to a curved surface with a radius of curvature of 0.01 μm or more and 50 μm or less, a flat surface, or the like.
　図２は、別の形状を有する針状凸部１１０を示している。図２においては、錐台部１１４は四角錐台の形状を有し、ニードル部１１２は四角錐の形状を有している。 FIG. 2 shows a needle-like convex part 110 having another shape. In FIG. 2, the frustum portion 114 has a quadrangular frustum shape, and the needle portion 112 has a quadrangular pyramid shape.
　図３は、図１及び図２に示される経皮吸収シート１００の断面図である。図３に示されるように、経皮吸収シート１００は所定量の薬剤を含む薬剤層１２０と、ポリマー層１２２とにより構成されている。ここで、所定量の薬剤を含むとは、体表に穿刺した際に薬効を発揮する量の薬剤を含むことを意味する。薬剤を含む薬剤層１２０は針状凸部１１０の先端（ニードル部１１２の先端）に形成されている。薬剤層１２０を針状凸部１１０の先端に形成することにより、皮膚内に効率よく薬剤を送達することができる。以下、「所定量の薬剤を含む」を「薬剤を含む」と必要に応じて称する。 FIG. 3 is a cross-sectional view of the transdermal absorption sheet 100 shown in FIGS. 1 and 2. As shown in FIG. 3, the transdermal absorption sheet 100 includes a drug layer 120 containing a predetermined amount of drug and a polymer layer 122. Here, the phrase “containing a predetermined amount of drug” means including an amount of drug that exhibits a medicinal effect when puncturing the body surface. The drug layer 120 containing a drug is formed at the tip of the needle-like convex part 110 (tip of the needle part 112). By forming the drug layer 120 at the tip of the needle-like convex part 110, the drug can be efficiently delivered into the skin. Hereinafter, “containing a predetermined amount of drug” is referred to as “containing a drug” as necessary.
　ニードル部１１２の薬剤層１２０を除く部分には、ポリマー層１２２が形成されている。錐台部１１４はポリマー層１２２により構成されている。シート部１１６はポリマー層１２２により構成されている。ニードル部１１２、錐台部１１４、およびシート部１１６を構成する薬剤層１２０およびポリマー層１２２の配分は、適宜設定することができる。 A polymer layer 122 is formed on a portion of the needle portion 112 excluding the drug layer 120. The frustum 114 is composed of a polymer layer 122. The sheet part 116 is constituted by a polymer layer 122. The distribution of the drug layer 120 and the polymer layer 122 constituting the needle part 112, the frustum part 114, and the sheet part 116 can be set as appropriate.
　シート部１１６の厚さＴは、１０μｍ以上２０００μｍ以下の範囲であり、好ましくは１０μｍ以上１０００μｍ以下の範囲である。錐台部１１４とシート部１１６との接する部分（下底）の幅Ｗ１は、１００μｍ以上１５００μｍ以下の範囲であり、好ましくは１００μｍ以上１０００μｍ以下の範囲である。錐台部１１４とニードル部１１２との接する部分（上底）の幅Ｗ２は、１００μｍ以上１５００μｍ以下の範囲であり、好ましくは１００μｍ以上１０００μｍ以下の範囲である。幅Ｗ１と幅Ｗ２は、上記の数値範囲内で、Ｗ１＞Ｗ２を満たすものとする。 The thickness T of the sheet part 116 is in the range of 10 μm to 2000 μm, and preferably in the range of 10 μm to 1000 μm. The width (W1) of the part (lower base) in contact with the frustum part 114 and the sheet part 116 is in the range of 100 μm to 1500 μm, preferably in the range of 100 μm to 1000 μm. The width (W2) of the portion (upper base) where the frustum portion 114 and the needle portion 112 are in contact is in the range of 100 μm to 1500 μm, and preferably in the range of 100 μm to 1000 μm. The width W1 and the width W2 satisfy W1> W2 within the above numerical range.
　針状凸部１１０の高さＨは、１００μｍ以上２０００μｍ以下の範囲であり、好ましくは２００μｍ以上１５００μｍ以下の範囲である。また、ニードル部１１２の高さＨ１と錐台部１１４の高さＨ２との比であるＨ１／Ｈ２について、Ｈ１／Ｈ２は１以上１０以下の範囲であり、好ましくは１．５以上８以下の範囲である。また、錐台部１１４の高さＨ２は１０μｍ以上１０００μｍ以下の範囲であることが好ましい。 The height H of the needle-like convex part 110 is in the range of 100 μm to 2000 μm, and preferably in the range of 200 μm to 1500 μm. Further, regarding H1 / H2, which is the ratio of the height H1 of the needle portion 112 and the height H2 of the frustum portion 114, H1 / H2 is in the range of 1 to 10, preferably 1.5 to 8. It is a range. Further, the height H2 of the frustum portion 114 is preferably in the range of 10 μm or more and 1000 μm or less.
　錐台部１１４の側面とシート部１１６の表面に平行な面とのなす角度αは、１０°以上６０°以下の範囲であり、好ましくは２０°以上５０°以下の範囲である。また、ニードル部１１２の側面と錐台部１１４の上底に平行な面とのなす角度βは、４５°以上８５°以下の範囲であり、好ましくは６０°以上８０°以下の範囲である。 The angle α formed between the side surface of the frustum portion 114 and the plane parallel to the surface of the sheet portion 116 is in the range of 10 ° to 60 °, and preferably in the range of 20 ° to 50 °. The angle β formed between the side surface of the needle portion 112 and the surface parallel to the upper base of the frustum portion 114 is in the range of 45 ° to 85 °, and preferably in the range of 60 ° to 80 °.
　角度βは角度α以上であることが好ましい。皮膚に対して針状凸部１１０を挿入しやすくなるからである。 The angle β is preferably not less than the angle α. This is because it becomes easier to insert the needle-like convex portion 110 into the skin.
　図４及び図５は別の形状を有する針状凸部１１０を示している。図１と図４とに示される経皮吸収シート１００と、図２と図５とに示される経皮吸収シート１００は、錐台部１１４の形状が同一で、ニードル部１１２の形状がそれぞれ異なっている。図４と図５に示されるニードル部１１２は、先細り形状の針状部１１２Ａと筒状の胴体部１１２Ｂとを有している。針状部１１２Ａの底面と胴体部１１２Ｂの端面とが接続されている。胴体部１１２Ｂの端面のうち針状部１１２Ａと接続されていない端面と錐台部１１４の上底とが接続される。 4 and 5 show a needle-like convex portion 110 having another shape. The percutaneous absorption sheet 100 shown in FIGS. 1 and 4 and the percutaneous absorption sheet 100 shown in FIGS. 2 and 5 have the same shape of the frustum portion 114 and different shapes of the needle portions 112. ing. The needle part 112 shown in FIGS. 4 and 5 has a tapered needle-like part 112A and a cylindrical body part 112B. The bottom surface of the needle-like part 112A and the end face of the body part 112B are connected. Of the end surface of the body portion 112B, the end surface not connected to the needle-like portion 112A and the upper base of the frustum portion 114 are connected.
　図４に示される針状部１１２Ａは円錐の形状を有し、胴体部１１２Ｂは円柱の形状を有している。図５に示される針状部１１２Ａは四角錐の形状を有し、胴体部１１２Ｂは四角柱の形状を有している。 The needle-like portion 112A shown in FIG. 4 has a conical shape, and the body portion 112B has a cylindrical shape. The needle-like portion 112A shown in FIG. 5 has a quadrangular pyramid shape, and the body portion 112B has a quadrangular prism shape.
　ニードル部１１２は胴体部１１２Ｂを有しているので、ニードル部１１２は錐台部１１４と離れる方向に一定の幅を有する形状となる。ニードル部１１２の先細り針状部１１２Ａは、胴体部１１２Ｂから離れる方向に漸次先細りの形状を有している。筒状の胴体部１１２Ｂは、対向する２つの端面の面積がほぼ同一である。ニードル部１１２は全体として先細りの形状を有している。ニードル部１１２の皮膚への挿入の程度に応じて、ニードル部１１２の先端の形状を０．０１μｍ以上５０μｍ以下の曲率半径の曲面や、平坦面等に適宜変更することができる。 Since the needle portion 112 has the body portion 112B, the needle portion 112 has a shape having a certain width in a direction away from the frustum portion 114. The tapered needle part 112A of the needle part 112 has a gradually tapered shape in a direction away from the body part 112B. The cylindrical body portion 112B has substantially the same area of two opposing end faces. The needle part 112 has a tapered shape as a whole. Depending on the degree of insertion of the needle portion 112 into the skin, the shape of the tip of the needle portion 112 can be appropriately changed to a curved surface with a radius of curvature of 0.01 μm or more and 50 μm or less, a flat surface, or the like.
　図６は、図４及び図５に示される経皮吸収シート１００の断面図である。図６に示されるように、経皮吸収シート１００は薬剤を含む薬剤層１２０と、ポリマー層１２２とにより構成されている。薬剤を含む薬剤層１２０は針状凸部１１０の先端（ニードル部１１２の先端）に形成されている。薬剤層１２０を針状凸部１１０の先端に形成することにより、皮膚内に効率よく薬剤を供給することができる。 FIG. 6 is a cross-sectional view of the transdermal absorption sheet 100 shown in FIGS. As shown in FIG. 6, the transdermal absorption sheet 100 includes a drug layer 120 containing a drug and a polymer layer 122. The drug layer 120 containing a drug is formed at the tip of the needle-like convex part 110 (tip of the needle part 112). By forming the drug layer 120 at the tip of the needle-like convex part 110, the drug can be efficiently supplied into the skin.
　ニードル部１１２の薬剤層１２０を除く部分には、ポリマー層１２２が形成されている。錐台部１１４はポリマー層１２２により構成されている。シート部１１６はポリマー層１２２により構成されている。ニードル部１１２、錐台部１１４、およびシート部１１６を構成する薬剤層１２０およびポリマー層１２２の配分は、適宜設定することができる。 A polymer layer 122 is formed on a portion of the needle portion 112 excluding the drug layer 120. The frustum 114 is composed of a polymer layer 122. The sheet part 116 is constituted by a polymer layer 122. The distribution of the drug layer 120 and the polymer layer 122 constituting the needle part 112, the frustum part 114, and the sheet part 116 can be set as appropriate.
　シート部１１６の厚さＴ、錐台部１１４の下底の幅Ｗ１、錐台部１１４の上底の幅Ｗ２、針状凸部１１０の高さＨ、および錐台部１１４の高さＨ２を、図３に示す経皮吸収シート１００と同様の長さにすることができる。ニードル部１１２の高さＨ１と錐台部１１４の高さＨ２との比であるＨ１／Ｈ２について、図３に示す経皮吸収シート１００と同様の比にすることができる。 The thickness T of the sheet part 116, the width W1 of the lower base of the frustum part 114, the width W2 of the upper base of the frustum part 114, the height H of the needle-like convex part 110, and the height H2 of the frustum part 114 The length can be the same as that of the transdermal absorption sheet 100 shown in FIG. The ratio H1 / H2, which is the ratio of the height H1 of the needle portion 112 and the height H2 of the frustum portion 114, can be set to the same ratio as that of the transdermal absorption sheet 100 shown in FIG.
　針状部１１２Ａの高さＨ１Ａと胴体部１１２Ｂの高さＨ１Ｂの比であるＨ１Ｂ／Ｈ１Ａについて、Ｈ１Ｂ／Ｈ１Ａは０．１以上４以下の範囲であり、好ましくは０．３以上２以下の範囲である。 Regarding H1B / H1A, which is the ratio of the height H1A of the needle-like portion 112A and the height H1B of the body portion 112B, H1B / H1A is in the range of 0.1 to 4, preferably 0.3 to 2. It is.
　錐台部１１４の側面とシート部１１６の表面に平行な面とのなす角度αは、１０°以上６０°以下の範囲であり、好ましくは２０°以上５０°以下の範囲である。また、針状部１１２Ａの側面と胴体部１１２Ｂの端面に平行な面とのなす角度βは、４５°以上８５°以下の範囲であり、好ましくは６０°以上８０°以下の範囲である。 The angle α formed between the side surface of the frustum portion 114 and the plane parallel to the surface of the sheet portion 116 is in the range of 10 ° to 60 °, and preferably in the range of 20 ° to 50 °. Further, the angle β formed between the side surface of the needle-like portion 112A and the surface parallel to the end face of the body portion 112B is in the range of 45 ° to 85 °, and preferably in the range of 60 ° to 80 °.
　角度βは角度α以上であることが好ましい。皮膚に対して針状凸部１１０を挿入しやすくなるからである。 The angle β is preferably not less than the angle α. This is because it becomes easier to insert the needle-like convex portion 110 into the skin.
　本実施の形態では、図１、２、４及び５に示すニードル部１１２を有する経皮吸収シート１００を示したが、経皮吸収シート１００はこれらの形状に限定されない。 In the present embodiment, the percutaneous absorption sheet 100 having the needle portion 112 shown in FIGS. 1, 2, 4 and 5 is shown, but the percutaneous absorption sheet 100 is not limited to these shapes.
　（モールド）
　図７Ａから図７Ｃは、モールド（型）の作製の工程図である。 (mold)
FIG. 7A to FIG. 7C are process diagrams for producing a mold.
　図７Ａに示すように、経皮吸収シートを製造するためのモールドを作製するための原版を先ず作製する。 As shown in FIG. 7A, an original plate for producing a mold for producing a transdermal absorption sheet is first produced.
　この原版１１の作製方法は２種類あり、１番目の方法は、Ｓｉ基板上にフォトレジストを塗布した後、露光及び現像を行う。そして、ＲＩＥ（リアクティブイオンエッチング：Reactive Ion Etching）等によるエッチングを行うことにより、原版１１の表面に、経皮吸収シートの針状凸部と同形状である複数の凸部１２をアレイ状に作製する。尚、原版１１の表面に凸部１２を形成するためにＲＩＥ等のエッチングを行う際には、Ｓｉ基板を回転させながら斜め方向からのエッチングを行うことにより、凸部１２を形成することが可能である。 There are two kinds of methods for producing the original plate 11, and the first method is to apply a photoresist on a Si substrate, and then perform exposure and development. Then, by performing etching by RIE (Reactive Ion Etching) or the like, a plurality of convex portions 12 having the same shape as the needle-like convex portions of the percutaneous absorption sheet are formed in an array on the surface of the original plate 11. Make it. When etching such as RIE is performed to form the convex portion 12 on the surface of the original plate 11, the convex portion 12 can be formed by performing etching from an oblique direction while rotating the Si substrate. It is.
　２番目の方法は、Ｎｉ等の金属基板に、ダイヤモンドバイト等の切削工具を用いた加工により、原版１１の表面に複数の凸部１２をアレイ状に作製する方法がある。 The second method is a method in which a plurality of convex portions 12 are formed in an array on the surface of the original 11 by processing a metal substrate such as Ni using a cutting tool such as a diamond bite.
　次に、図７Ｂに示すように、原版１１を利用してモールド１３を作製する。通常のモールド１３の作製には、Ｎｉ電鋳などによる方法が用いられる。原版１１は、先端が鋭角な円錐形又は角錐形（例えば四角錐）の形状の凸部１２を有しているため、モールド１３に原版１１の形状が正確に転写され、モールド１３を原版１１から剥離することができる。しかもモールド１３を安価に製造することが可能な４つの方法が考えられる。 Next, as shown in FIG. 7B, a mold 13 is produced using the original 11. For producing the normal mold 13, a method using Ni electroforming or the like is used. Since the original plate 11 has a convex portion 12 having a conical shape or a pyramid shape (for example, a quadrangular pyramid) with a sharp tip, the shape of the original plate 11 is accurately transferred to the mold 13, and the mold 13 is transferred from the original plate 11. Can be peeled off. Moreover, four methods that can manufacture the mold 13 at low cost are conceivable.
　１番目の方法は、原版１１にＰＤＭＳ（ポリジメチルシロキサン：polydimethylsiloxane、例えば、ダウ・コーニング社製シルガード（登録商標）１８４）に硬化剤を添加したシリコーン樹脂を流し込み、１００℃で加熱処理し硬化した後に、原版１１からモールド１３を剥離する方法である。２番目の方法は、紫外線を照射することにより硬化するＵＶ硬化樹脂を原版１１に流し込み、窒素雰囲気中で紫外線を照射した後に、原版１１からモールド１３を剥離する方法である。３番目の方法は、ポリスチレンやＰＭＭＡ（ポリメチルメタクリレート：polymethyl methacrylate）等のプラスチック樹脂を有機溶剤に溶解させたものを剥離剤の塗布された原版１１に流し込み、乾燥させることにより有機溶剤を揮発させて硬化させた後に、原版１１からモールド１３を剥離する方法である。４番目の方法は、Ｎｉ電鋳により反転品を作成する方法である。 The first method is to pour PDMS (polydimethylsiloxane, for example, Sylgard (registered trademark) 184 manufactured by Dow Corning) into the original plate 11 and heat cure at 100 ° C. to cure. This is a method of peeling the mold 13 from the original plate 11 later. The second method is a method in which a UV curable resin that is cured by irradiating ultraviolet rays is poured into the original 11, and after irradiating ultraviolet rays in a nitrogen atmosphere, the mold 13 is peeled off from the original 11. In the third method, a plastic resin such as polystyrene or PMMA (polymethyl methacrylate) dissolved in an organic solvent is poured into the original plate 11 coated with a release agent, and dried to volatilize the organic solvent. In this method, the mold 13 is peeled from the original plate 11 after being cured. The fourth method is a method of creating a reverse product by Ni electroforming.
　これにより、原版１１の凸部１２の反転形状である針状凹部１５を２次元で配列したモールド１３が作製される。このようにして作製されたモールド１３を図７Ｃに示す。尚、上記４つのいずれの方法においてもモールド１３は、何度でも容易に作製することが可能である。 Thereby, the mold 13 is produced in which the needle-like concave portions 15 which are the inverted shapes of the convex portions 12 of the original 11 are two-dimensionally arranged. The mold 13 produced in this way is shown in FIG. 7C. In any of the above four methods, the mold 13 can be easily manufactured any number of times.
　モールド自身に段差部を有する場合は、原版に段差部を設けることで、その反転形状であるモールドを作製することができる。図８Ａから図８Ｃは、針状凹部１５が形成された領域の周囲に、針状凹部１５が形成された領域より高い段差部７４を有するモールド７３の作製の工程図である。 When the mold itself has a stepped portion, a mold having the inverted shape can be produced by providing the original plate with a stepped portion. 8A to 8C are process diagrams for producing a mold 73 having a stepped portion 74 higher than the region where the needle-like recess 15 is formed around the region where the needle-like recess 15 is formed.
　段差部を有さないモールドを形成する場合と同様に、図８Ａに示すように、段差部７４を有するモールド７３を作製するための原版７１を作製する。原版７１は、凸部１２が形成された領域よりも低い段差部７５が形成されている。原版の作製は、図７Ａと同様の方法により行うことができる。 As in the case of forming a mold having no stepped portion, as shown in FIG. 8A, an original plate 71 for producing a mold 73 having a stepped portion 74 is produced. The original plate 71 has a stepped portion 75 that is lower than the region where the convex portion 12 is formed. The original plate can be produced by the same method as in FIG. 7A.
　次に、図８Ｂに示すように、原版７１を利用してモールド７３を作製する。モールド１３の作製も図７Ｂと同様の方法により行うことができる。これにより、図８Ｃに示すように、原版７１の凸部１２および段差部７５の反転形状である、針状凹部１５を２次元で配列し、その周囲に段差部７４を有するモールド７３が作製される。 Next, as shown in FIG. 8B, a mold 73 is produced using the original plate 71. The mold 13 can also be produced by the same method as in FIG. 7B. As a result, as shown in FIG. 8C, a mold 73 is produced in which the needle-like concave portions 15, which are the inverted shapes of the convex portions 12 and the step portions 75 of the original plate 71, are arranged two-dimensionally and have step portions 74 around the needle-like concave portions 15. The
　また、図９Ａから図９Ｃは、針状凹部１５が形成された領域の周囲に、針状凹部１５が形成された領域より低い段差部８４を有するモールド８３の作製の工程図である。 9A to 9C are process diagrams for producing a mold 83 having a stepped portion 84 lower than the region where the needle-like recess 15 is formed around the region where the needle-like recess 15 is formed.
　図７Ａ及び図８Ａと同様に、図９Ａに示すように、段差部８４を有するモールド８３を作製するための原版８１を作製する。原版８１は、凸部１２が形成された領域よりも高い段差部８５が形成されている。 As in FIGS. 7A and 8A, as shown in FIG. 9A, an original plate 81 for producing a mold 83 having a stepped portion 84 is produced. The original plate 81 has a stepped portion 85 higher than the region where the convex portion 12 is formed.
　次に図９Ｂに示すように、原版８１を利用してモールド８３を作製する。これにより、図９Ｃに示すように、原版８１の凸部１２および段差部８５の反転形状である、針状凹部１５を２次元で配列し、その周囲に段差部８５を有するモールド８３が作製される。なお、原版の作製方法、モールドの作製方法は、図７Ａ、図７Ｂ、図８Ａ及び図８Ｂと同様の方法により行うことができる。 Next, as shown in FIG. 9B, a mold 83 is manufactured using the original plate 81. As a result, as shown in FIG. 9C, a mold 83 is produced in which the needle-like concave portions 15, which are the inverted shapes of the convex portions 12 and the step portions 85 of the original plate 81, are arranged two-dimensionally and have the step portions 85 around the two. The Note that the method for producing the original plate and the method for producing the mold can be performed in the same manner as in FIGS. 7A, 7B, 8A, and 8B.
　図１０は、モールド１３の針状凹部１５の部分拡大図である。なお、モールド７３及び８３の針状凹部１５も同様の構成である。針状凹部１５は、モールド１３の表面から深さ方向に狭くなるテーパ状の入口部１５Ａと、深さ方向に先細りの先端凹部１５Ｂとを備えている。入口部１５Ａのテーパの角度α１は、経皮吸収シートの錐台部の側面とシート部とで構成される角度αと基本的に一致する。また、先端凹部１５Ｂのテーパの角度β１は、ニードル部の側面と錐台部の上底とで構成される角度βと基本的に一致する。 FIG. 10 is a partial enlarged view of the needle-like recess 15 of the mold 13. The needle-like recesses 15 of the molds 73 and 83 have the same configuration. The needle-like recess 15 includes a tapered inlet portion 15A that narrows in the depth direction from the surface of the mold 13 and a tip recess 15B that tapers in the depth direction. The taper angle α1 of the inlet portion 15A basically matches the angle α formed by the side surface of the frustum portion of the percutaneous absorption sheet and the sheet portion. The taper angle β1 of the tip recess 15B basically matches the angle β formed by the side surface of the needle portion and the upper base of the frustum portion.
　図１１は、経皮吸収シートの製造方法を行う上で、より好ましいモールド複合体１８の態様を示したものである。図１１に示すように、モールド複合体１８は、針状凹部１５の先端に貫通孔１５Ｃが形成されたモールド１３と、モールド１３の貫通孔１５Ｃの側に貼り合わされ、気体は透過するが液体は透過しない材料で形成された気体透過シート１９と、で構成される。貫通孔１５Ｃにより、針状凹部１５の先端は気体透過シート１９を介して大気と連通する。針状凹部１５の先端とは、モールド１３の深さ方向に先細りになっている側を意味し、薬液、ポリマー層形成液が充填される側と反対側を意味する。 FIG. 11 shows a more preferable embodiment of the mold composite 18 in carrying out the method for producing a transdermal absorption sheet. As shown in FIG. 11, the mold composite 18 is bonded to the mold 13 having a through-hole 15C formed at the tip of the needle-like recess 15 and the through-hole 15C side of the mold 13 so that the gas can permeate but the liquid is And a gas permeable sheet 19 formed of a non-permeable material. Through the through hole 15 </ b> C, the tip of the needle-like recess 15 communicates with the atmosphere via the gas permeable sheet 19. The tip of the needle-like recess 15 means the side tapered in the depth direction of the mold 13 and means the side opposite to the side filled with the chemical solution and the polymer layer forming solution.
　このようなモールド複合体１８を使用することで、針状凹部１５に充填される経皮吸収材料溶液は透過せず、針状凹部１５に存在する空気のみを針状凹部１５から貫通孔１５Ｃを介して抜くことができる。針状凹部１５の形状を経皮吸収材料に転写する際の転写性が良くなり、よりシャープな針状凸部を形成することができる。 By using such a mold composite 18, the percutaneous absorption material solution filled in the needle-like recess 15 does not permeate, and only the air present in the needle-like recess 15 passes from the needle-like recess 15 to the through hole 15C. Can be pulled out. Transferability when transferring the shape of the needle-like concave portion 15 to the transdermal absorption material is improved, and a sharper needle-like convex portion can be formed.
　貫通孔１５Ｃの径Ｄ（直径）としては、１～５０μｍの範囲が好ましい。この範囲とすることで、空気の抜けが容易となり、また、経皮吸収シートの針状凸部の先端部をシャープな形状とすることができる。気体は透過するが液体は透過しない材料で形成された気体透過シート１９としては、例えばポアフロン（商標、住友電気工業株式会社）を好適に使用できる。 The diameter D (diameter) of the through hole 15C is preferably in the range of 1 to 50 μm. By setting it within this range, air can be easily removed, and the tip of the needle-like convex portion of the transdermal absorption sheet can be made sharp. As the gas permeable sheet 19 formed of a material that allows gas to permeate but not liquid, for example, Poeflon (trademark, Sumitomo Electric Industries, Ltd.) can be suitably used.
　モールド１３に用いる材料としては、樹脂系の素材、金属製の素材を用いることができる。中でも樹脂系の素材であることが好ましく、気体透過性の高い素材であることが更に好ましい。気体透過性の代表である酸素透過性は、１×１０－１２（ｍＬ／ｓ・ｍ・Ｐａ）より大きいことが好ましく、１×１０－１０（ｍＬ／ｓ・ｍ・Ｐａ）より大きいことがさらに好ましい。気体透過性を上記範囲とすることにより、モールド１３の針状凹部１５に存在する空気をモールド１３側から追い出すことができる。欠陥の少ない経皮吸収シートを製造することができる。このような材料として、樹脂系の素材としては、シリコーン樹脂、エポキシ樹脂、ＰＥＴ（ポリエチレンテレフタレート：polyethylene terephthalate）、ＰＭＭＡ（ポリメチルメタクリレート：polymethyl methacrylate）ＰＳ（ポリスチレン：polystyrene）、ＰＥ（ポリエチレン：polyethylene）、ＰＯＭ（ポリアセタール：polyacetal、ポリオキシメチレン：polyoxymethylene）、ＰＴＦＥ（ポリテトラフルオロエチレン：polytetrafluoroethylene）、ＵＶ（ultraviolet）硬化樹脂、フェノール樹脂、ウレタン樹脂などの一般的なエンジニアリングプラスチックを用いることができる。また、金属製の素材としては、Ｎｉ、Ｃｕ、Ｃｒ、Ｍｏ、Ｗ、Ｉｒ、Ｔｒ、Ｆｅ、Ｃｏ、ＭｇＯ、Ｔｉ、Ｚｒ、Ｈｆ、Ｖ、Ｎｂ、Ｔａ、α－酸化アルミニウム，ステンレスおよびその合金を挙げることができる。また、後述するように、モールド１３は、ポリマー層形成液供給工程において、段差部でポリマー層形成液を固定する必要があるため、撥水性とぬれ性を制御した材料を用いることが好ましい。例えば、モールドとポリマー層形成液との接触角が９０°を超え９０°に近いことが好ましい。 As a material used for the mold 13, a resin material or a metal material can be used. Among these, a resin-based material is preferable, and a material having high gas permeability is more preferable. The oxygen permeability, which is representative of gas permeability, is preferably greater than 1 × 10 −12 (mL / s · m · Pa), and preferably greater than 1 × 10 −10 (mL / s · m · Pa). Further preferred. By setting the gas permeability to the above range, air existing in the needle-like recess 15 of the mold 13 can be driven out from the mold 13 side. A transdermal absorption sheet with few defects can be produced. Examples of such materials include silicone resins, epoxy resins, PET (polyethylene terephthalate), PMMA (polymethyl methacrylate) PS (polystyrene: polystyrene), PE (polyethylene: polyethylene). Common engineering plastics such as POM (polyacetal: polyoxymethylene), PTFE (polytetrafluoroethylene), UV (ultraviolet) curable resin, phenol resin, and urethane resin can be used. In addition, the metal materials include Ni, Cu, Cr, Mo, W, Ir, Tr, Fe, Co, MgO, Ti, Zr, Hf, V, Nb, Ta, α-aluminum oxide, stainless steel and alloys thereof. Can be mentioned. Further, as will be described later, since the mold 13 needs to fix the polymer layer forming liquid at the step portion in the polymer layer forming liquid supply step, it is preferable to use a material whose water repellency and wettability are controlled. For example, the contact angle between the mold and the polymer layer forming liquid is preferably more than 90 ° and close to 90 °.
　（ポリマー溶解液）
　本実施形態に使用されるポリマー樹脂の溶解液であるポリマー溶解液について説明する。 (Polymer solution)
A polymer solution that is a polymer resin solution used in the present embodiment will be described.
　本実施の形態では所定量の薬剤を含有するポリマー溶解液を、薬剤を含むポリマー溶解液又は薬剤を含む溶解液と必要に応じて称している。また、所定量の薬剤を含むポリマー溶解液を薬液と称している。所定量の薬剤を含むか否かは、体表に穿刺した際に薬効を発揮できるか否かで判断される。したがって、所定量の薬剤を含むとは、体表に穿刺した際に薬効を発揮する量の薬剤を含むことを意味する。 In this embodiment, a polymer solution containing a predetermined amount of drug is referred to as a polymer solution containing a drug or a solution containing a drug as necessary. A polymer solution containing a predetermined amount of drug is called a drug solution. Whether or not a predetermined amount of drug is contained is determined by whether or not the drug effect can be exhibited when the body surface is punctured. Therefore, the phrase “containing a predetermined amount of drug” means including an amount of drug that exhibits a medicinal effect when puncturing the body surface.
　ポリマー溶解液に用いられる樹脂ポリマーの素材としては、生体適合性のある樹脂を用いることが好ましい。このような樹脂としては、グルコース、マルトース、プルラン、コンドロイチン硫酸、ヒアルロン酸ナトリウム、ヒドロキシエチルデンプンなどの糖類、ゼラチンなどのタンパク質、ポリ乳酸、乳酸・グリコール酸共重合体などの生分解性ポリマーを使用することが好ましい。これらの中でもゼラチン系の素材は多くの基材と密着性をもち、ゲル化する材料としても強固なゲル強度を持つため、後述する剥離工程において、基材と密着させることができ、モールドから基材を用いてポリマーシートを剥離することができるので、好適に利用することができる。濃度は材料によっても異なるが、ポリマー層１２２を形成するポリマー溶解液中に樹脂ポリマーが１０～５０質量％含まれる濃度とすることが好ましい。また、溶解に用いる溶媒は、温水以外であっても揮発性を有するものであればよく、メチルエチルケトン（ＭＥＫ：methyl ethyl ketone）、アルコールなどを用いることができる。そして、ポリマー樹脂の溶解液中には、用途に応じて体内に供給するための薬剤を共に溶解させることが可能である。薬剤層１２０を形成する薬剤を含むポリマー溶解液のポリマー濃度（薬剤自体がポリマーである場合は薬剤を除いたポリマーの濃度）としては、０～３０質量％含まれることが好ましい。 As the material of the resin polymer used for the polymer solution, it is preferable to use a biocompatible resin. Such resins include glucose, maltose, pullulan, chondroitin sulfate, sodium hyaluronate, hydroxyethyl starch and other sugars, gelatin and other proteins, polylactic acid, and lactic acid / glycolic acid copolymers. It is preferable to do. Among these materials, gelatin-based materials have adhesive properties with many substrates, and have strong gel strength as a material to be gelled. Since a polymer sheet can be peeled off using a material, it can be suitably used. The concentration varies depending on the material, but it is preferable that the concentration is such that 10 to 50 mass% of the resin polymer is contained in the polymer solution forming the polymer layer 122. In addition, the solvent used for dissolution may be volatile even if it is other than warm water, and methyl ethyl ketone (MEK), alcohol, or the like can be used. And in the solution of polymer resin, it is possible to dissolve together the medicine for supplying into the body according to the use. The polymer concentration of the polymer solution containing the drug that forms the drug layer 120 (concentration of the polymer excluding the drug when the drug itself is a polymer) is preferably 0 to 30% by mass.
　ポリマー溶解液の調製方法としては、水溶性の高分子（ゼラチンなど）を用いる場合は、水溶性粉体を水に溶解し、溶解後に薬剤を添加してもよいし、薬剤が溶解した液体に水溶性高分子の粉体を入れて溶かしても良い。ポリマー樹脂が水に溶解しにくい場合、加温して溶解してもよい。温度は高分子材料の種類により、適宜選択可能であるが、約６０℃以下の温度で加温することが好ましい。ポリマー樹脂の溶解液の粘度は、薬剤層１２０を形成する薬剤を含む溶解液では１００Ｐａ・ｓ以下であることが好ましく、より好ましくは１０Ｐａ・ｓ以下とすることが好ましい。ポリマー層１２２を形成する溶解液では２０００Ｐａ・ｓ以下であることが好ましく、より好ましくは１０００Ｐａ・ｓ以下とすることが好ましい。ポリマー樹脂の溶解液の粘度を適切に調整することにより、モールドの針状凹部に容易に溶解液を注入することが容易となる。例えば、ポリマー樹脂の溶解液の粘度は、細管式粘度計、落球式粘度計、回転式粘度計または振動式粘度計で測定することができる。 As a method for preparing a polymer solution, when a water-soluble polymer (such as gelatin) is used, a water-soluble powder may be dissolved in water, and a drug may be added after the dissolution. A water-soluble polymer powder may be added and dissolved. If the polymer resin is difficult to dissolve in water, it may be dissolved by heating. The temperature can be appropriately selected depending on the type of the polymer material, but it is preferable to heat at a temperature of about 60 ° C. or lower. The viscosity of the polymer resin solution is preferably 100 Pa · s or less, and more preferably 10 Pa · s or less, in the solution containing the drug forming the drug layer 120. In the solution for forming the polymer layer 122, the pressure is preferably 2000 Pa · s or less, and more preferably 1000 Pa · s or less. By appropriately adjusting the viscosity of the polymer resin solution, it becomes easy to inject the solution into the needle-shaped recess of the mold. For example, the viscosity of the polymer resin solution can be measured with a capillary tube viscometer, falling ball viscometer, rotary viscometer or vibration viscometer.
　（薬剤）
　ポリマー溶解液に含有させる薬剤は、薬剤としての機能を有するものであれば限定されない。特に、ペプチド、タンパク質、核酸、多糖類、ワクチン、水溶性低分子化合物に属する医薬化合物、又は化粧品成分から選択することが好ましい。 (Drug)
The drug contained in the polymer solution is not limited as long as it has a function as a drug. In particular, it is preferable to select from peptides, proteins, nucleic acids, polysaccharides, vaccines, pharmaceutical compounds belonging to water-soluble low molecular weight compounds, or cosmetic ingredients.
　（経皮吸収シートの製造方法）
　本実施の形態の経皮吸収シートの製造方法は、図１２に示すように、薬液充填工程と、薬液乾燥工程と、ポリマー層形成液供給工程と、ポリマー層形成液乾燥工程と、剥離工程との少なくとも５つの工程をこの順で備えている。 (Method for producing transdermal absorption sheet)
As shown in FIG. 12, the method for producing a transdermal absorption sheet of the present embodiment includes a chemical solution filling step, a chemical solution drying step, a polymer layer forming solution supplying step, a polymer layer forming solution drying step, and a peeling step. These steps are provided in this order.
　（薬液充填工程）
　モールド１３を用いた経皮吸収シートの製造方法について説明する。図１３Ａに示すように、２次元配列された針状凹部１５を有するモールド１３が、基台２０の上に配置される。モールド１３には、５×５の２次元配列された、２組の複数の針状凹部１５が形成されている。所定量の薬剤を含むポリマー溶解液である薬液２２を収容する送液タンク３０と、送液タンク３０に接続される配管３２と、配管３２の先端に接続されたノズル３４と、を有する液供給装置３６が準備される。薬液２２はノズル３４の先端から吐出される。 (Chemical solution filling process)
A method for producing a transdermal absorption sheet using the mold 13 will be described. As shown in FIG. 13A, a mold 13 having needle-like recesses 15 arranged two-dimensionally is disposed on a base 20. The mold 13 is formed with two sets of a plurality of needle-like recesses 15 that are two-dimensionally arranged in a 5 × 5 manner. A liquid supply having a liquid feed tank 30 that stores a chemical liquid 22 that is a polymer solution containing a predetermined amount of drug, a pipe 32 connected to the liquid feed tank 30, and a nozzle 34 connected to the tip of the pipe 32. A device 36 is prepared. The chemical liquid 22 is discharged from the tip of the nozzle 34.
　図１４はノズルの先端部の概略斜視図を示している。図１４に示すように、ノズル３４は、先端側に平坦面であるリップ部３４Ａと、スリット形状の開口部３４Ｂと、リップ部３４Ａに沿って開口部３４Ｂから離れる方向に広がる２つの傾斜面３４Ｃと、を備えている。スリット形状の開口部３４Ｂにより、例えば、１列を構成する複数の針状凹部１５に同時に、薬液２２を充填することが可能となる。開口部３４Ｂの大きさ（長さと幅）は、一度に充填すべき針状凹部１５の数に応じて適宜選択される。  FIG. 14 shows a schematic perspective view of the tip of the nozzle. As shown in FIG. 14, the nozzle 34 has a lip portion 34A that is a flat surface on the tip side, a slit-shaped opening portion 34B, and two inclined surfaces 34C that extend in a direction away from the opening portion 34B along the lip portion 34A. And. With the slit-shaped opening 34B, for example, the plurality of needle-like recesses 15 constituting one row can be filled simultaneously with the chemical solution 22. The size (length and width) of the opening 34B is appropriately selected according to the number of needle-like recesses 15 to be filled at a time.
　開口部３４Ｂの長さを長くすることで、より多くの針状凹部１５に一度に薬液２２を充填することができる。これにより生産性を向上させることが可能となる。 By increasing the length of the opening 34B, more needle-like recesses 15 can be filled with the chemical solution 22 at a time. This makes it possible to improve productivity.
　図１５は別のノズルの先端部の概略斜視図を示している。図１５に示すように、ノズル３４は、先端側に平坦面であるリップ部３４Ａと、２つのスリット形状の開口部３４Ｂと、リップ部３４Ａに沿って開口部３４Ｂから離れる方向に広がる２つの傾斜面３４Ｃと、を備えている。２つの開口部３４Ｂにより、例えば、２列を構成する複数の針状凹部１５に同時に、薬剤を含む薬液２２を充填することが可能となる。 FIG. 15 shows a schematic perspective view of the tip of another nozzle. As shown in FIG. 15, the nozzle 34 has a lip portion 34A that is a flat surface on the tip side, two slit-shaped openings 34B, and two slopes that extend along the lip portion 34A away from the openings 34B. 34C. With the two openings 34B, for example, the plurality of needle-like recesses 15 constituting two rows can be simultaneously filled with the drug solution 22 containing the drug.
　ノズル３４に用いる材料としては、弾性のある素材、金属製の素材を用いることができる。例えば、テフロン（登録商標）、ステンレス鋼（ＳＵＳ）、チタン等が挙げられる。 As the material used for the nozzle 34, an elastic material or a metal material can be used. Examples thereof include Teflon (registered trademark), stainless steel (SUS), and titanium.
　図１３Ｂを参照して充填工程を説明する。図１３Ｂに示すように、ノズル３４の開口部３４Ｂが針状凹部１５の上に位置調整される。薬液２２を吐出するノズル３４がモールド１３に押し付けられ、ノズル３４のリップ部３４Ａとモールド１３の表面とは接触している。液供給装置３６から薬液２２がモールド１３に供給され、ノズル３４の開口部３４Ｂから薬液２２が針状凹部１５に充填される。本実施形態では、１列を構成する複数の針状凹部１５に薬液２２が同時に充填される。ただし、これに限定されず、薬液２２を針状凹部１５に一つずつ充填することができる。また、図１５に示すノズル３４を使用することで、複数列を構成する複数の針状凹部１５に対し、複数列毎に薬液２２を同時に充填することもできる。 The filling process will be described with reference to FIG. 13B. As shown in FIG. 13B, the position of the opening 34 </ b> B of the nozzle 34 is adjusted on the needle-like recess 15. A nozzle 34 for discharging the chemical liquid 22 is pressed against the mold 13, and the lip portion 34 </ b> A of the nozzle 34 and the surface of the mold 13 are in contact with each other. The chemical liquid 22 is supplied from the liquid supply device 36 to the mold 13, and the chemical liquid 22 is filled into the needle-shaped recess 15 from the opening 34 </ b> B of the nozzle 34. In the present embodiment, a plurality of needle-like recesses 15 constituting one row are filled with the chemical liquid 22 at the same time. However, it is not limited to this, The chemical | medical solution 22 can be filled into the needle-shaped recessed part 15 one by one. Moreover, the chemical | medical solution 22 can also be simultaneously filled for every several row | line | column with respect to the some acicular recessed part 15 which comprises a plurality of rows by using the nozzle 34 shown in FIG.
　モールド１３が気体透過性を有する素材で構成される場合、モールド１３の裏面から吸引することで薬液２２を吸引でき、針状凹部１５内への薬液２２の充填を促進させることができる。 When the mold 13 is made of a material having gas permeability, the chemical liquid 22 can be sucked by sucking from the back surface of the mold 13 and the filling of the chemical liquid 22 into the needle-shaped recess 15 can be promoted.
　図１３Ｂに示す充填工程に次いで、図１３Ｃに示すように、ノズル３４のリップ部３４Ａとモールド１３の表面とを接触させながら、開口部３４Ｂの長さ方向に対して垂直方向に液供給装置３６を相対的に走査させている。ノズル３４をモールド１３の上を走査させ、薬液２２が充填されていない針状凹部１５にノズル３４を移動させる。ノズル３４の開口部３４Ｂが針状凹部１５の上に位置調整される。本実施の形態では、ノズル３４を走査させる例で説明したが、モールド１３を走査させてもよい。 Following the filling step shown in FIG. 13B, as shown in FIG. 13C, the liquid supply device 36 is perpendicular to the length direction of the opening 34 </ b> B while contacting the lip 34 </ b> A of the nozzle 34 and the surface of the mold 13. Are relatively scanned. The nozzle 34 is scanned over the mold 13, and the nozzle 34 is moved to the needle-like recess 15 that is not filled with the chemical liquid 22. The position of the opening 34 </ b> B of the nozzle 34 is adjusted on the needle-like recess 15. In the present embodiment, the example in which the nozzle 34 is scanned has been described, but the mold 13 may be scanned.
　ノズル３４のリップ部３４Ａとモールド１３の表面とを接触させながらノズル３４をモールド１３の上を走査させているので、ノズル３４がモールド１３の針状凹部１５以外の表面に残る薬液２２を掻き取ることができる。薬剤を含む薬液２２をモールド１３の針状凹部１５以外に残らないようにすることができる。また、本実施の形態では、ノズル３４の傾斜面３４Ｃは、矢印で示す走査方向に対して直交する位置となるよう配置されている。したがって、ノズル３４はモールド１３の上をスムーズに走査させることができる。 Since the nozzle 34 is scanned over the mold 13 while the lip portion 34A of the nozzle 34 and the surface of the mold 13 are in contact with each other, the nozzle 34 scrapes off the chemical liquid 22 remaining on the surface other than the needle-like recess 15 of the mold 13. be able to. It is possible to prevent the chemical solution 22 containing the drug from remaining other than the needle-like recess 15 of the mold 13. In the present embodiment, the inclined surface 34 </ b> C of the nozzle 34 is disposed so as to be orthogonal to the scanning direction indicated by the arrow. Therefore, the nozzle 34 can smoothly scan the mold 13.
　モールド１３へのダメージを減らし、モールド１３の圧縮による変形をできるだけ抑制するため、走査される際のノズル３４のモールド１３への押し付け程度を、制御することが好ましい。例えば、ノズル３４のモールド１３への押し付け力や、ノズル３４のモールド１３への押し込み距離を制御することが好ましい。また、薬液２２がモールド１３の針状凹部１５以外に残らないようにするため、モールド１３もしくはノズル３４の少なくとも一方がフレキシブルな弾性変形する素材であることが望ましい。 In order to reduce damage to the mold 13 and suppress deformation due to compression of the mold 13 as much as possible, it is preferable to control the degree of pressing of the nozzle 34 to the mold 13 during scanning. For example, it is preferable to control the pressing force of the nozzle 34 to the mold 13 and the pressing distance of the nozzle 34 to the mold 13. Further, in order to prevent the chemical liquid 22 from remaining other than the needle-like recess 15 of the mold 13, it is desirable that at least one of the mold 13 or the nozzle 34 is a flexible elastically deformable material.
　図１３Ｂに示す充填工程と、図１３Ｃに示す走査工程とを繰り返すことで、５×５の２次元配列された針状凹部１５に薬液２２が充填される。５×５の２次元配列された針状凹部１５に薬液２２が充填されると、隣接する５×５の２次元配列された針状凹部１５に液供給装置３６を移動し、図１３Ｂに示す充填工程と、図１３Ｃに示す走査工程とを繰り返す。隣接する５×５の２次元配列された針状凹部１５にも薬液２２が充填される。 By repeating the filling step shown in FIG. 13B and the scanning step shown in FIG. 13C, the medicinal solution 22 is filled into the 5 × 5 two-dimensionally arranged needle-like recesses 15. When the medical solution 22 is filled in the 5 × 5 two-dimensionally arranged needle-like recesses 15, the liquid supply device 36 is moved to the adjacent 5 × 5 two-dimensionally arranged needle-like recesses 15, as shown in FIG. 13B. The filling process and the scanning process shown in FIG. 13C are repeated. Adjacent 5 × 5 two-dimensionally arranged needle-like recesses 15 are also filled with the chemical solution 22.
　上述の充填工程と走査工程について、（１）ノズル３４を走査させながら薬液２２を針状凹部１５に充填する態様でもよいし、（２）ノズル３４の走査中に針状凹部１５の上でノズル３４を一旦静止して薬液２２を充填し、充填後にノズル３４を再度走査させる態様でもよい。充填工程中及び走査工程中に、ノズル３４のリップ部３４Ａがモールド１３の表面に押し付けられている。液供給装置３６から吐出される薬液２２の量は、充填されるモールド１３の複数の針状凹部１５の総体積と等しい量とすることが好ましい。薬液２２をモールド１３の針状凹部１５以外の表面に残らないようにし、薬剤の無駄を低減することができる。 With respect to the above-described filling step and scanning step, (1) the liquid medicine 22 may be filled into the needle-like recess 15 while scanning the nozzle 34, or (2) the nozzle on the needle-like recess 15 during the scanning of the nozzle 34. Alternatively, the liquid 34 may be temporarily stopped, the chemical liquid 22 is filled, and the nozzle 34 is scanned again after filling. The lip portion 34 </ b> A of the nozzle 34 is pressed against the surface of the mold 13 during the filling process and the scanning process. The amount of the chemical liquid 22 discharged from the liquid supply device 36 is preferably equal to the total volume of the plurality of needle-like recesses 15 of the mold 13 to be filled. It is possible to prevent the chemical liquid 22 from remaining on the surface of the mold 13 other than the needle-like concave portion 15 and reduce the waste of the chemical.
　図１６は、薬液２２を針状凹部１５に充填中におけるノズル３４の先端とモールド１３との部分拡大図である。図１６に示すように、ノズル３４内に加圧力Ｐ１を加えることで、針状凹部１５内へ薬液２２を充填することを促進することができる。さらに、針状凹部１５内へ薬液２２を充填する際、ノズル３４をモールド１３の表面に接触させる押し付け力Ｐ２を、ノズル３４内の加圧力Ｐ１以上とすることが好ましい。押し付け力Ｐ２≧加圧力Ｐ１とすることにより、薬液２２が針状凹部１５からモールド１３の表面に漏れ出すことを抑制することができる。 FIG. 16 is a partially enlarged view of the tip of the nozzle 34 and the mold 13 during filling of the chemical liquid 22 into the needle-like recess 15. As shown in FIG. 16, by applying the pressurizing force P <b> 1 in the nozzle 34, it is possible to facilitate filling the medicinal liquid 22 into the needle-like recess 15. Furthermore, when the chemical liquid 22 is filled into the needle-shaped recess 15, it is preferable that the pressing force P <b> 2 for bringing the nozzle 34 into contact with the surface of the mold 13 is equal to or greater than the pressure P <b> 1 in the nozzle 34. By setting the pressing force P2 ≧ the applied pressure P1, it is possible to suppress the chemical liquid 22 from leaking from the needle-like recess 15 to the surface of the mold 13.
　図１７は、ノズル３４の移動中における、ノズル３４の先端とモールド１３との部分拡大図である。ノズル３４をモールド１３に対して相対的に走査する際、ノズル３４をモールド１３の表面に接触させる押し付け力Ｐ３を、充填中のノズル３４をモールド１３の表面に接触させる押し付け力Ｐ２より小さくすることが好ましい。モールド１３へのダメージを減らし、モールド１３の圧縮による変形を抑制するためである。 FIG. 17 is a partial enlarged view of the tip of the nozzle 34 and the mold 13 during the movement of the nozzle 34. When scanning the nozzle 34 relative to the mold 13, the pressing force P <b> 3 for bringing the nozzle 34 into contact with the surface of the mold 13 is made smaller than the pressing force P <b> 2 for bringing the nozzle 34 being filled into contact with the surface of the mold 13. Is preferred. This is for reducing damage to the mold 13 and suppressing deformation due to compression of the mold 13.
　ノズル３４のリップ部３４Ａはモールド１３の表面に対して平行であることが好ましい。ノズル３４の取り付け部に関節駆動機構を設けることにより、ノズル３４の姿勢を制御してもよい。 The lip portion 34A of the nozzle 34 is preferably parallel to the surface of the mold 13. The posture of the nozzle 34 may be controlled by providing a joint drive mechanism at the attachment portion of the nozzle 34.
　モールド１３の表面形状に合わせてＺ軸方向にノズル３４を駆動して、ノズル３４のモールド１３への押し付け力及び／又は押し込み距離を制御することが好ましい。図１８は、押し付け力及び／又は押し込み距離を制御することができる薬液充填装置４８の概略構成図である。薬液充填装置４８は、薬液を貯留する送液タンク３０と送液タンク３０に取り付けられたノズル３４とを有する液供給装置３６と、送液タンク３０とノズル３４とをＺ軸方向に駆動するＺ軸駆動部５０と、モールド１３を載置するための吸引台５２と、吸引台５２をＸ軸方向に駆動するＸ軸駆動部５４と、上記装置を支持する架台５６と、制御システム５８と、を有している。 It is preferable to control the pressing force and / or pressing distance of the nozzle 34 against the mold 13 by driving the nozzle 34 in the Z-axis direction according to the surface shape of the mold 13. FIG. 18 is a schematic configuration diagram of a chemical liquid filling device 48 that can control the pressing force and / or the pressing distance. The chemical solution filling device 48 includes a liquid supply device 36 having a liquid supply tank 30 for storing a chemical solution and a nozzle 34 attached to the liquid supply tank 30, and a Z for driving the liquid supply tank 30 and the nozzle 34 in the Z-axis direction. An axis driving unit 50, a suction table 52 for placing the mold 13, an X-axis driving unit 54 for driving the suction table 52 in the X-axis direction, a gantry 56 for supporting the device, a control system 58, have.
　押し付け力を一定に制御する場合について説明する。所望の押し付け力となるＺ座標までＺ軸駆動部５０によりノズル３４をモールド１３に近づける。モールド１３に接触したノズル３４をＸ軸駆動部５４を用いて走査させながら、押し付け力が一定となるようにＺ軸座標を制御しつつ薬液２２を吐出する。接触圧力測定の方式は特に限定はしないが、例えば、各種ロードセルを、例えば吸引台５２の下に、又は吸引台５２に代えて用いることができる。ロードセルとは厚み方向に圧縮する力を測定できる測定器具を意味する。押し付け力は、モールド１３に対して１～１０００ｋＰａの範囲内の任意の圧力で一定に制御可能であることが好ましい。 The case where the pressing force is controlled to be constant will be described. The nozzle 34 is brought close to the mold 13 by the Z-axis drive unit 50 up to the Z coordinate that provides a desired pressing force. While the nozzle 34 in contact with the mold 13 is scanned using the X-axis drive unit 54, the chemical solution 22 is discharged while controlling the Z-axis coordinates so that the pressing force is constant. The method for measuring the contact pressure is not particularly limited. For example, various load cells can be used, for example, under the suction table 52 or in place of the suction table 52. The load cell means a measuring instrument capable of measuring a force compressing in the thickness direction. The pressing force is preferably controllable to an arbitrary pressure within a range of 1 to 1000 kPa with respect to the mold 13.
　押し込み距離を一定に制御する場合について説明する。ノズル３４を接触する前に、モールド１３の表面形状をあらかじめ測定する。モールド１３に接触したノズル３４をＸ軸駆動部５４を用いて走査させながら、制御システム５８はモールド１３の表面形状に対して所望の押し込み距離になるようにＺ軸座標をオフセットさせた値をＺ軸駆動部５０にフィードバックする。フィードバックと並行して薬液２２は吐出される。 The case where the pushing distance is controlled to be constant will be described. Before contacting the nozzle 34, the surface shape of the mold 13 is measured in advance. While scanning the nozzle 34 in contact with the mold 13 using the X-axis drive unit 54, the control system 58 sets a value obtained by offsetting the Z-axis coordinate so as to obtain a desired pushing distance with respect to the surface shape of the mold 13. Feedback is made to the shaft drive unit 50. In parallel with the feedback, the chemical liquid 22 is discharged.
　形状測定の方式は特に限定はしないが、例えば、非接触式のレーザー変位計６０などの光学測定機器、接触式の触針式段差計など、を用いることができる。さらに、ノズル３４のスリット方向の姿勢をモールド１３の表面形状に合わせて制御してもよい。押し込み距離は、モールド１３の厚みに対して１～１５％の範囲で制御されることが好ましい。モールド１３の形状に合わせてノズル３４とモールド１３と距離を、Ｚ軸駆動部５０によりＺ軸方向に制御しながら動作することで、圧縮変形率が均一化され、充填量精度を向上できる。 The method of shape measurement is not particularly limited, and for example, an optical measuring instrument such as a non-contact type laser displacement meter 60, a contact type stylus type step gauge, or the like can be used. Further, the posture of the nozzle 34 in the slit direction may be controlled in accordance with the surface shape of the mold 13. The indentation distance is preferably controlled in the range of 1 to 15% with respect to the thickness of the mold 13. By operating while controlling the distance between the nozzle 34 and the mold 13 in the Z-axis direction by the Z-axis drive unit 50 in accordance with the shape of the mold 13, the compression deformation rate can be made uniform and the filling amount accuracy can be improved.
　押し付け力および押し込み距離の制御に関して、押し込み距離が小さい場合は押し付け力を制御することが好ましく、押し込み距離が大きい場合は、押し込み距離を直接制御することが好ましい。 Regarding the control of the pressing force and the pressing distance, it is preferable to control the pressing force when the pressing distance is small, and it is preferable to directly control the pressing distance when the pressing distance is large.
　図１９は、ノズル内の液圧と薬剤を含む溶解液の供給との関係を示す説明図である。図１９に示すように薬液２２の供給は、ノズル３４が針状凹部１５の上に位置する前から開始される。薬液２２を針状凹部１５に確実に充填するためである。５×５で構成される複数の針状凹部１５への充填が完了するまで、薬液２２はモールド１３に連続して供給される。ノズル３４が５列目の針状凹部１５の上に位置する前に薬液２２をモールド１３に供給することを停止する。薬液２２が針状凹部１５からあふれ出ることを防止できる。ノズル３４内の液圧に関して、薬液２２の供給が開始されると、ノズル３４が針状凹部１５に位置しない領域では高くなる。一方、ノズル３４が針状凹部１５の上に位置すると、薬液２２が針状凹部１５に充填され、ノズル３４内の液圧が低くなる。このような液圧の変動が繰り返される。 FIG. 19 is an explanatory diagram showing the relationship between the fluid pressure in the nozzle and the supply of the solution containing the drug. As shown in FIG. 19, the supply of the chemical liquid 22 is started before the nozzle 34 is positioned on the needle-like recess 15. This is because the medical solution 22 is surely filled into the needle-like recess 15. The chemical liquid 22 is continuously supplied to the mold 13 until the filling of the plurality of needle-like concave portions 15 configured by 5 × 5 is completed. The supply of the chemical liquid 22 to the mold 13 is stopped before the nozzles 34 are positioned on the needle-like recesses 15 in the fifth row. The chemical liquid 22 can be prevented from overflowing from the needle-like recess 15. Regarding the liquid pressure in the nozzle 34, when the supply of the chemical liquid 22 is started, it becomes higher in a region where the nozzle 34 is not located in the needle-like recess 15. On the other hand, when the nozzle 34 is positioned on the needle-like recess 15, the chemical liquid 22 is filled in the needle-like recess 15, and the hydraulic pressure in the nozzle 34 is lowered. Such fluid pressure fluctuations are repeated.
　５×５で構成される複数の針状凹部１５への充填が完了すると、ノズル３４は、隣接する５×５で構成される複数の針状凹部１５へ移動される。液供給に関して、隣接する５×５で構成される複数の針状凹部１５へ移動する際、薬液２２の供給を停止することが好ましい。５列目の針状凹部１５から次の１列目の針状凹部１５までは距離がある。その間をノズル３４が走査される間、薬液２２を供給し続けると、ノズル３４内の液圧が高くなりすぎる場合がある。その結果、ノズル３４から薬液２２がモールド１３の針状凹部１５以外に流れ出る場合があり、これを抑制するため薬液２２の供給を停止することが好ましい。 When the filling of the plurality of needle-shaped recesses 15 configured by 5 × 5 is completed, the nozzle 34 is moved to the plurality of needle-shaped recesses 15 configured by adjacent 5 × 5. Regarding the liquid supply, it is preferable to stop the supply of the chemical liquid 22 when moving to the plurality of adjacent needle-like recesses 15 constituted by 5 × 5. There is a distance from the needle-like recess 15 in the fifth row to the needle-like recess 15 in the next first row. If the chemical liquid 22 is continuously supplied while the nozzle 34 is scanned in the meantime, the liquid pressure in the nozzle 34 may become too high. As a result, the chemical liquid 22 may flow from the nozzle 34 to other than the needle-like recess 15 of the mold 13, and it is preferable to stop the supply of the chemical liquid 22 in order to suppress this.
　薬液２２の充填を行う際には、ノズル３４の先端をクリーニングしてから使用することが好ましい。充填前にノズル３４のリップ部３４Ａの表面に付着物があると、薬液２２の充填量の精度が低下してしまうためである。クリーニングは、不織布によるワイプが一般的である。ワイプの際に、不織布を水や溶剤などで浸潤させると効果的にクリーニングできる。 When the chemical liquid 22 is filled, it is preferable to use after cleaning the tip of the nozzle 34. This is because if there is a deposit on the surface of the lip portion 34A of the nozzle 34 before filling, the accuracy of the filling amount of the chemical liquid 22 is lowered. For cleaning, a wipe with a nonwoven fabric is generally used. When wiping, the nonwoven fabric can be effectively cleaned by infiltrating it with water or a solvent.
　薬液２２の充填後、ノズル３４をモールド１３から離す際に、モールド１３の表面に薬液２２が残留する可能性がある。針状凹部１５への充填が完了後、ノズル３４の開口部３４Ｂから薬液２２を吸引するサックバック制御を行うことで、吐出余剰分の薬液２２を吸い上げ、モールド１３の表面への液残りを低減することもできる。 When the nozzle 34 is separated from the mold 13 after the chemical liquid 22 is filled, the chemical liquid 22 may remain on the surface of the mold 13. After the filling into the needle-shaped recess 15 is completed, the sucking back control for sucking the chemical liquid 22 from the opening 34B of the nozzle 34 is performed, so that the excessive liquid chemical 22 is sucked up and the liquid remaining on the surface of the mold 13 is reduced. You can also
　薬液充填工程について、図１１に示すモールド複合体１８を利用し、貫通孔１５Ｃ側から吸引して、薬液２２を針状凹部１５内に充填させることができる。 In the chemical solution filling step, the chemical solution 22 can be filled into the needle-shaped recess 15 by using the mold complex 18 shown in FIG.
　薬液２２の針状凹部１５への充填が完了すると、薬液乾燥工程、ポリマー層形成液供給工程、ポリマー層形成液乾燥工程、剥離工程へと進む。 When the filling of the chemical liquid 22 into the needle-like recess 15 is completed, the process proceeds to the chemical liquid drying process, the polymer layer forming liquid supply process, the polymer layer forming liquid drying process, and the peeling process.
　図２０Ａに示すように、薬液充填工程にてモールド１３の針状凹部１５に薬液２２をノズル３４から充填する。薬液充填工程は上述した方法で実施される。 As shown in FIG. 20A, the chemical liquid 22 is filled into the needle-like concave portion 15 of the mold 13 from the nozzle 34 in the chemical liquid filling step. The chemical solution filling step is performed by the method described above.
　（薬液乾燥工程）
　図２０Ｂに示すように、薬液乾燥工程では、薬液２２を乾燥させ、固化させることで、薬剤を含む第１層１２０を針状凹部１５内に形成する。 (Chemical solution drying process)
As shown in FIG. 20B, in the chemical solution drying step, the chemical solution 22 is dried and solidified to form the first layer 120 containing the drug in the needle-like recess 15.
　薬液乾燥工程は、モールド１３の針状凹部１５に充填された薬液２２を乾燥し、針状凹部１５の先端に局在させる工程である。薬液乾燥工程は、温度１℃以上１０℃以下の環境下で行うことが好ましい。この範囲で行うことで、気泡欠陥発生を低減することができる。また、薬液乾燥工程の温湿度条件を制御して乾燥速度を最適化することにより、針状凹部１５のモールド１３の壁面に薬液２２が固着することを低減することができ、乾燥により薬液２２が針状凹部１５の先端に集まりながら乾燥が進む。 The chemical solution drying step is a step of drying the chemical solution 22 filled in the needle-like recess 15 of the mold 13 and localizing it at the tip of the needle-like recess 15. It is preferable to perform a chemical | medical solution drying process in the environment of the temperature of 1 degreeC or more and 10 degrees C or less. By performing in this range, bubble defect generation can be reduced. In addition, by controlling the temperature and humidity conditions in the chemical solution drying process and optimizing the drying speed, the chemical solution 22 can be prevented from sticking to the wall surface of the mold 13 of the needle-like recess 15, and the chemical solution 22 can be reduced by drying. Drying proceeds while gathering at the tip of the needle-like recess 15.
　薬液乾燥工程のおける薬液２２の乾燥は無風状態で行うことが好ましい。不均一な風が薬液２２に直接当たると乾燥ムラが生じる。強く風が当たる部分は乾燥速度が上昇し、モールド１３の壁面への薬液２２の固着が発生し、針状凹部１５の先端に薬液２２が局在化することを妨げる可能性があるからである。 It is preferable to dry the chemical liquid 22 in the chemical liquid drying process in a windless state. If the non-uniform wind directly hits the chemical liquid 22, uneven drying occurs. This is because the portion where the wind strongly hits increases the drying speed, and the chemical liquid 22 is fixed to the wall surface of the mold 13, which may prevent the chemical liquid 22 from being localized at the tip of the needle-like recess 15. .
　無風状態での乾燥実現するため、例えば、風防を設置することが好ましい。風防は、モールド１３に直接風が当たらないように設置される。風防として、蓋、庇、衝立、囲いなどの物理的障害物を設置する方法が簡便であるので好ましい。また、風防を設置する際は、モールド１３の設置空間が密閉状態にならないように通気口等を確保することが好ましい。密閉状態にしてしまうと密閉空間の水蒸気が飽和し、薬液２２の乾燥が進行しなくなる可能性がある。通気口は蒸気の出入りができれば好ましく、風防内の気流を安定化するには水蒸気透過性のフィルムなどで通気口を覆うことが更に好ましい。なお、乾燥時間は、針状凹部１５の形状、針状凹部１５の配置や数、薬剤の種類、薬液２２の充填量や濃度、などを考慮して適宜調整される。 In order to achieve drying in a windless state, for example, it is preferable to install a windshield. The windshield is installed so that the wind does not directly hit the mold 13. As a windshield, a method of installing a physical obstacle such as a lid, a fence, a screen, or an enclosure is preferable because it is simple. Moreover, when installing a windshield, it is preferable to secure a vent etc. so that the installation space of the mold 13 may not be sealed. If it is in a sealed state, the water vapor in the sealed space is saturated and there is a possibility that the drying of the chemical liquid 22 will not proceed. The vent is preferable if the vapor can enter and exit, and in order to stabilize the airflow in the windshield, it is more preferable to cover the vent with a water vapor permeable film or the like. The drying time is appropriately adjusted in consideration of the shape of the needle-like recess 15, the arrangement and number of the needle-like recess 15, the type of medicine, the filling amount and concentration of the drug solution 22, and the like.
　無風状態とは、風が全くない状態に加えて、風速が０．５ｍ／ｓ以下である場合をいう。この範囲であれば、乾燥ムラがほとんど生じないからである。 “No wind” refers to a case where the wind speed is 0.5 m / s or less in addition to a state where there is no wind. This is because within this range, drying unevenness hardly occurs.
　薬液乾燥工程では、薬液２２を乾燥させることにより固化し、薬液２２を充填した際の状態よりも縮小させている。これにより、剥離工程において、モールド１３の針状凹部１５から薬剤層１２０を容易に剥離することが可能となる。 In the chemical solution drying step, the chemical solution 22 is solidified by drying, and is smaller than the state when the chemical solution 22 is filled. Thereby, in the peeling step, the drug layer 120 can be easily peeled from the needle-like recess 15 of the mold 13.
　（ポリマー層形成液供給工程）
　次に、図２０Ｃに示すように、所定量の薬剤を含む薬剤層１２０の上にポリマー層１２２を形成するポリマー溶解液であるポリマー層形成液２４を供給し、ポリマー層形成液２４を針状凹部１５に充填する。ポリマー層形成液の供給は、ディスペンサーによる塗布、バー塗布やスピン塗布、スプレーなどによる塗布などを適用することができるがこれに限定されない。以下、ポリマー層形成液２４を塗布によりモールド１３に供給する態様で説明する。薬剤を含む薬剤層１２０は乾燥により固化されているので、薬剤層１２０に含まれる薬剤がポリマー層形成液２４に拡散することを抑制できる。 (Polymer layer forming liquid supply process)
Next, as shown in FIG. 20C, a polymer layer forming solution 24, which is a polymer solution for forming the polymer layer 122, is supplied onto the drug layer 120 containing a predetermined amount of drug, and the polymer layer forming solution 24 is needle-shaped. The recess 15 is filled. The supply of the polymer layer forming liquid can be applied by a dispenser, bar coating, spin coating, spraying, or the like, but is not limited thereto. Hereinafter, a mode in which the polymer layer forming liquid 24 is supplied to the mold 13 by coating will be described. Since the drug layer 120 containing the drug is solidified by drying, the drug contained in the drug layer 120 can be prevented from diffusing into the polymer layer forming liquid 24.
　＜第１実施形態＞
　図２１Ａ及び図２１Ｂは、ポリマー層形成液供給工程を説明する図である。第１実施形態のポリマー層形成液供給工程は、針状凹部１５が形成された領域１６の周囲に型枠１４を設置し、針状凹部１５が形成された領域１６より高い段差部を有するモールド１３に、ポリマー層形成液２４を塗布する。型枠１４は、モールド１３と分離可能に設置することができる。 <First Embodiment>
21A and 21B are diagrams for explaining the polymer layer forming liquid supply step. In the polymer layer forming liquid supply step of the first embodiment, the mold 14 is installed around the region 16 where the needle-like recess 15 is formed, and the mold has a step portion higher than the region 16 where the needle-like recess 15 is formed. 13 is coated with a polymer layer forming liquid 24. The mold 14 can be installed so as to be separable from the mold 13.
　ポリマー層形成液供給工程は、図２１Ａに示すように、針状凹部１５の周囲に設置された型枠１４により形成された段差部以上の高さであり、かつ、上面から見て段差部以上の範囲に、ポリマー層形成液２４を、塗布手段９２により塗布する。ポリマー層形成液を型枠１４以上の高さに塗布するとは、ポリマー層形成液２４と型枠１４とが接している部分のポリマー層形成液２４の高さが、型枠１４以上の高さになるようにすることである。製造された経皮吸収シートを剥離し易くするため、型枠１４はポリマー層形成液を弾き易くする材質で形成されており、ポリマー層形成液２４の塗布後、ポリマー層形成液２４は型枠１４により弾かれ、表面張力により収縮する。収縮したポリマー層形成液２４は、図２１Ｂに示すように、モールド１３との接触位置が型枠１４の段差部で固定される。型枠１４で固定された状態で、ポリマー層形成液を乾燥することにより、経皮吸収シートのポリマー層１２２の形状（シート部１１６の形状）を安定して形成することができる。 As shown in FIG. 21A, the polymer layer forming liquid supply step has a height higher than the stepped portion formed by the mold 14 installed around the needle-like recess 15 and is higher than the stepped portion when viewed from above. In this range, the polymer layer forming liquid 24 is applied by the applying means 92. The application of the polymer layer forming liquid to a height higher than the mold 14 means that the height of the polymer layer forming liquid 24 at the portion where the polymer layer forming liquid 24 and the mold 14 are in contact is higher than the mold 14. Is to be. In order to make it easy to peel the manufactured percutaneous absorption sheet, the mold 14 is formed of a material that makes it easy to play the polymer layer forming liquid. After the polymer layer forming liquid 24 is applied, the polymer layer forming liquid 24 is 14 and is shrunk by surface tension. As shown in FIG. 21B, the contracted polymer layer forming liquid 24 is fixed at the stepped portion of the mold 14 at the contact position with the mold 13. The shape of the polymer layer 122 of the percutaneous absorption sheet (the shape of the sheet portion 116) can be stably formed by drying the polymer layer forming liquid in a state of being fixed by the mold 14.
　図２２Ａ及び２２Ｂは、ポリマー層形成液供給工程の好ましくない例を説明する図である。図２２Ａに示すように、ポリマー層形成液２４を型枠１４内であり、型枠１４より低い高さで塗布する。塗布後、図２２Ｂに示すように、ポリマー層形成液２４は、表面張力により針状凹部１５が形成された領域１６で収縮する。図２２Ｂは、ポリマー層形成液供給工程後であり、ポリマー層形成液乾燥工程により、さらにポリマー層形成液２４の体積が収縮するため、経皮吸収シートのシート部１１６が安定して形成されない部分が生じてしまう。 22A and 22B are diagrams for explaining an unfavorable example of the polymer layer forming liquid supply step. As shown in FIG. 22A, the polymer layer forming liquid 24 is applied in the mold 14 at a height lower than that of the mold 14. After the application, as shown in FIG. 22B, the polymer layer forming liquid 24 contracts in the region 16 where the needle-like recess 15 is formed due to the surface tension. FIG. 22B shows a portion where the sheet portion 116 of the percutaneous absorption sheet is not stably formed because the volume of the polymer layer forming solution 24 is further contracted by the polymer layer forming solution drying step after the polymer layer forming solution supplying step. Will occur.
　モールド１３に設けられる型枠１４の材質としては、上述したモールドの材質と同様のものを用いることができる。また、ポリマー層形成液とのぬれ性が良いほど、乾燥時の液面が均一で緩やかな局面とすることができ、ポリマー層形成液の液面形状の局所的な変化を防止することができる。本発明においては、ポリマー層形成液が型枠１４に弾かれ、収縮することで、段差部で固定されるため、型枠を形成する材質はポリマー層形成液に対して撥水性を有する必要がある。したがって、型枠を形成する材質は、ポリマー層形成液に対し、撥水性とぬれ性を制御した材料であることが好ましく、型枠のポリマー層形成液に対する接触角が、９０°を超え、９０°に近いことが好ましい。型枠の材質として、ポリマー層形成液とのぬれ性の良い材料を用いることにより、ポリマー層形成液の塗布直後の形状を安定させることができ、泡の巻き込みを防止することができる。また、乾燥時の風や温度ムラなどの外乱に強く安定的な液面を固定することができる。一方、型枠を形成する材質とポリマー層形成液とのぬれ性が悪いと、塗布液の液面が曲率の高い液面となり、わずかな形状ムラでも大きな表面張力差が生じ、塗布液の形がくずれ、型枠からはじかれてしまうため好ましくない。ぬれ性を向上させるためには、型枠の素材を親水性にすることや、ポリマー層形成液にタンパク質などの界面活性能を有する素材を添加することも有効な手段である。また、型枠１４の設置は、薬剤充填工程から設置してもよく、ポリマー層形成液供給工程の前に設置してもよい。 As the material of the mold 14 provided in the mold 13, the same material as that of the mold described above can be used. In addition, the better the wettability with the polymer layer forming liquid, the more uniform and gentle the liquid level during drying, and the local change in the liquid surface shape of the polymer layer forming liquid can be prevented. . In the present invention, the polymer layer forming liquid is repelled by the mold 14 and contracted to be fixed at the stepped portion. Therefore, the material forming the mold must have water repellency with respect to the polymer layer forming liquid. is there. Therefore, the material for forming the mold is preferably a material having controlled water repellency and wettability with respect to the polymer layer forming liquid, and the contact angle of the mold with respect to the polymer layer forming liquid is more than 90 °. It is preferably close to °. By using a material having good wettability with the polymer layer forming liquid as the material of the mold, the shape immediately after application of the polymer layer forming liquid can be stabilized, and foam entrainment can be prevented. Further, it is possible to fix a stable liquid surface that is resistant to disturbances such as wind and temperature unevenness during drying. On the other hand, if the wettability between the material forming the mold and the polymer layer forming liquid is poor, the liquid surface of the coating liquid becomes a liquid surface with a high curvature, and even a slight unevenness in shape causes a large difference in surface tension. It is not preferable because it will be broken and repelled from the formwork. In order to improve the wettability, it is also an effective means to make the material of the mold form hydrophilic, or to add a material having surface activity such as protein to the polymer layer forming solution. Moreover, the installation of the mold 14 may be performed from the medicine filling step, or may be performed before the polymer layer forming liquid supply step.
　型枠１４の高さは、１０μｍ以上５０００μｍ以下であることが好ましい。ポリマー層形成液２４を段差部で固定するためには、型枠１４以上の高さで、かつ、型枠１４以上の範囲でポリマー層形成液２４を塗布する必要があるため、型枠１４の高さをこの範囲とすることで、使用するポリマー層形成液の量を抑えることができる。したがって、乾燥時間を短縮することができる。また、型枠１４の高さが１０μｍより低いと、ポリマー層形成液２４が型枠１４で固定されず、モールド１３がポリマー層形成液を弾いてしまい、シート部１１６が形成されないなど、経皮吸収シートが製造できない場合がある。 The height of the mold 14 is preferably 10 μm or more and 5000 μm or less. In order to fix the polymer layer forming liquid 24 at the stepped portion, it is necessary to apply the polymer layer forming liquid 24 at a height higher than the mold 14 and in a range higher than the mold 14. By setting the height within this range, the amount of the polymer layer forming liquid to be used can be suppressed. Therefore, the drying time can be shortened. If the height of the mold 14 is lower than 10 μm, the polymer layer forming liquid 24 is not fixed by the mold 14, the mold 13 repels the polymer layer forming liquid, and the sheet portion 116 is not formed. An absorbent sheet may not be manufactured.
　ポリマー層形成液供給工程における、塗布時のポリマー層形成解液の厚みはモールド１３の針状凹部１５が形成された領域１６から、型枠１４の高さ以上であり、且つ、５０００μｍ以下とすることが好ましい。型枠１４の位置でポリマー層形成液を固定するためには、型枠１４の高さ以上とする必要があり、塗布後のポリマー層形成液の塗布厚みが５０００μｍを超えると、乾燥に時間がかかるからである。また、乾燥負荷の低減、製造コストを下げるため、全体に液面を薄くしながら、ポリマー層を型枠に安定して固定するためには、型枠付近の膜厚を厚くし、中央付近の膜厚を薄くした膜厚分布としてもよい。 In the polymer layer forming solution supply step, the thickness of the polymer layer forming solution at the time of application is not less than the height of the mold 14 and not more than 5000 μm from the region 16 where the needle-like recess 15 of the mold 13 is formed. It is preferable. In order to fix the polymer layer forming liquid at the position of the mold 14, it is necessary to make the height higher than that of the mold 14. If the coating thickness of the polymer layer forming liquid after coating exceeds 5000 μm, it takes time to dry. This is because of this. In addition, in order to reduce the drying load and reduce the manufacturing cost, in order to stably fix the polymer layer to the mold while thinning the liquid surface as a whole, the film thickness near the mold is increased and the film near the center is increased. It is good also as a film thickness distribution which made the film thickness thin.
　ポリマー層形成液２４を、モールド１３に塗布する方法としては、図２３Ａ及び図２３Ｂに示すように、型枠１４で周囲を囲まれた針状凹部１５ごとに塗布してもよく、図２４Ａから図２４Ｃに示すように、型枠１４を覆ってモールド１３全面に塗布を行ってもよい。図２３Ａに示すように、ポリマー層形成液２４を型枠１４ごとに塗布した場合、塗布後、図２３Ｂに示すように、型枠１４でポリマー層形成液を固定することができる。型枠１４ごとに塗布する方法としては、スリットコーターを使った間歇ストライプ塗布、ディスペンサー、インクジェット、凸版印刷、平版印刷、スクリーン印刷などの方式により行うことができる。 As a method of applying the polymer layer forming liquid 24 to the mold 13, as shown in FIGS. 23A and 23B, the polymer layer forming liquid 24 may be applied to each of the needle-like recesses 15 surrounded by the mold 14. As shown in FIG. 24C, the entire surface of the mold 13 may be coated so as to cover the mold 14. As shown in FIG. 23A, when the polymer layer forming liquid 24 is applied to each mold 14, the polymer layer forming liquid can be fixed with the mold 14 as shown in FIG. 23B after the application. As a method of applying for each mold 14, it can be performed by methods such as intermittent stripe coating using a slit coater, dispenser, ink jet, letterpress printing, planographic printing, screen printing and the like.
　また、図２４Ａに示すように、モールド１３全面に塗布を行った場合、ポリマー層形成液の量が多いと、図２４Ｂに示すように、ポリマー層形成液２４が均一に塗布されたまま、ポリマー層形成液乾燥工程が行われる。この場合においても、次のポリマー層形成液乾燥工程において、ポリマー層１２２を安定して形成することができる。ポリマー層形成液２４の量が少ない場合は、図２４Ｃに示すように、型枠１４の内側（針状凹部１５が形成された領域）に向かってポリマー層形成液２４が収縮し、型枠１４で固定されることで、安定した形状で経皮吸収シートの製造を行うことができる。均一に塗布する方法としては、スリットコート、スライドコート、ブレードコート、バーコート、ロールコート、グラビアコート、ディップコート、スプレーコートなど、一般的な塗工方法を用いることができる。 As shown in FIG. 24A, when the entire surface of the mold 13 is applied, if the amount of the polymer layer forming liquid is large, the polymer layer forming liquid 24 is uniformly applied as shown in FIG. 24B. A layer formation liquid drying process is performed. Even in this case, the polymer layer 122 can be stably formed in the subsequent polymer layer forming liquid drying step. When the amount of the polymer layer forming liquid 24 is small, as shown in FIG. 24C, the polymer layer forming liquid 24 contracts toward the inside of the mold 14 (the area where the needle-like recess 15 is formed), and the mold 14 By fixing with, the transdermal absorption sheet can be manufactured in a stable shape. As a method of uniformly applying, general coating methods such as slit coating, slide coating, blade coating, bar coating, roll coating, gravure coating, dip coating, and spray coating can be used.
　図２５Ａから図２７Ｃは、型枠の形状によるポリマー層形成液の収縮を説明する図である。図２５Ａは、ポリマー層形成液２４を円形状に塗布し、円形の型枠１４を用いてポリマー層形成液２４を塗布した場合の図である。ポリマー層形成液２４は、図２５Ｂに示すように等方的に収縮するため、図２５Ｃに示すように、型枠１４より広く塗布したポリマー層形成液２４は、型枠１４により形成された段差部の位置で固定することができる。 FIG. 25A to FIG. 27C are diagrams for explaining the contraction of the polymer layer forming liquid due to the shape of the mold. FIG. 25A is a diagram in the case where the polymer layer forming liquid 24 is applied in a circular shape and the polymer layer forming liquid 24 is applied using the circular mold 14. Since the polymer layer forming liquid 24 isotropically contracts as shown in FIG. 25B, the polymer layer forming liquid 24 applied wider than the mold 14 is formed by a step formed by the mold 14 as shown in FIG. 25C. It can be fixed at the position of the part.
　図２６Ａは、円形の型枠１４を用いて、ポリマー層形成液２４を四角形状に塗布した図である。ポリマー層形成液２４を四角形状に塗布した場合においても、図２６Ｂに示すようにポリマー層形成液２４は円形の型枠１４の段差部に向かって、等方的に収縮する。図２６Ｃに示すように、型枠１４上にはじき残しはあるものの、型枠１４により形成された段差部の位置で、ポリマー層形成液２４を固定することができる。 FIG. 26A is a diagram in which a polymer layer forming liquid 24 is applied in a square shape using a circular mold 14. Even when the polymer layer forming liquid 24 is applied in a square shape, the polymer layer forming liquid 24 isotropically contracts toward the step portion of the circular mold 14 as shown in FIG. 26B. As shown in FIG. 26C, the polymer layer forming liquid 24 can be fixed at the position of the step portion formed by the mold 14, although there is a residue on the mold 14.
　図２７Ａは、四角形状の型枠１４を用いて、ポリマー層形成液２４を円形状に塗布した図である。型枠１４の形状が四角形状の場合、ポリマー層形成液２４が等方的に収縮する際に、図２７Ｂに示すように、型枠１４の四角形状の角部でポリマー層形成液２４を固定することができず、型枠１４からポリマー層形成液２４がぬれ落ちてしまう場合がある。図２７Ｃに示すように、型枠１４からぬれ落ちたポリマー層形成液２４は、モールド上で、さらに収縮が進行し、針状凹部１５が形成された部分にポリマー層が形成されず、経皮吸収シートが安定して形成されない場合がある。 FIG. 27A is a diagram in which a polymer layer forming liquid 24 is applied in a circular shape using a square mold 14. When the shape of the mold 14 is quadrangular, when the polymer layer forming liquid 24 isotropically contracts, the polymer layer forming liquid 24 is fixed at the square corners of the mold 14 as shown in FIG. 27B. In some cases, the polymer layer forming liquid 24 may get wet from the mold 14. As shown in FIG. 27C, the polymer layer forming liquid 24 that has been wetted from the mold 14 is further contracted on the mold, and the polymer layer is not formed in the portion where the needle-like recess 15 is formed. The absorbent sheet may not be formed stably.
　図２４Ａから図２４Ｃで示すように、モールド上にポリマー層形成液を均一に塗布するような場合であれば、型枠１４の形状が四角形状であっても、ポリマー層形成液が型枠内にぬれ落ちることなく、ポリマー層形成液供給工程を行うことができる。型枠により形成された段差部で、ポリマー層形成液を固定するためには、型枠を設けることで形成される針状凹部が形成された領域の周囲の形状を、上面から見てすべての角が１２０°以上の角度で形成される六角形以上の多角形とすることが好ましく、さらに好ましくは、正六角形以上の多角形、または、円形とすることが好ましい。型枠の段差部の形状を上記の形状とすることで、ポリマー層形成液を塗布した際、モールドに設置した段差部分に働くポリマー層形成液の表面張力による収縮力を均一にすることができる。なお、「正多角形」とは、多角形を構成する各辺が等しいことが好ましいが、本発明の効果を有する範囲で変更が可能である。 As shown in FIGS. 24A to 24C, in the case where the polymer layer forming liquid is uniformly applied onto the mold, the polymer layer forming liquid remains in the mold even if the shape of the mold 14 is square. The polymer layer forming liquid supply step can be performed without getting wet. In order to fix the polymer layer forming liquid at the step portion formed by the mold, the shape around the area where the needle-like concave portion formed by providing the mold is formed is viewed from the top. It is preferable that the polygon is a hexagon or more polygon formed with an angle of 120 ° or more, and more preferably a regular hexagon or more polygon or a circle. By making the shape of the step portion of the mold form the above shape, the shrinkage force due to the surface tension of the polymer layer forming liquid acting on the step portion installed in the mold can be made uniform when the polymer layer forming liquid is applied. . In addition, although it is preferable that each side which comprises a polygon is equal with a "regular polygon", it can change in the range which has the effect of this invention.
　図２８Ａ及び図２８Ｂは、モールド１３の針状凹部が形成された領域側から上側に向かって広がる方向にテーパ形状とした型枠１７を用いたポリマー層形成液供給工程を説明する図である。テーパ形状を有する型枠１７の場合においても、型枠１７の上部側の領域以上の範囲で、ポリマー層形成液２４を塗布し（図２８Ａ）、その後、表面張力により収縮させることで、型枠１７により形成された段差部でポリマー層形成液２４を固定することができる（図２８Ｂ）。 FIG. 28A and FIG. 28B are views for explaining a polymer layer forming liquid supply step using a mold 17 that is tapered in a direction that widens upward from the region side where the needle-like concave portion of the mold 13 is formed. Even in the case of the mold 17 having a tapered shape, the polymer layer forming liquid 24 is applied in a range equal to or larger than the region on the upper side of the mold 17 (FIG. 28A), and then contracted by surface tension, thereby forming the mold. The polymer layer forming liquid 24 can be fixed by the step portion formed by 17 (FIG. 28B).
　また、型枠１４を、鉛直方向上側に広がる方向にテーパ形状とすることで、ポリマー層形成液２４中に混入した泡の泡抜き（defoam）の効果がある。ポリマー層形成液２４中に混入した泡の泡抜きを行うことで、剥離工程における針状凸部の欠損、穿刺時における針状凸部の破損を防止することができる。 Further, by forming the mold 14 in a taper shape extending in the vertical direction upward, there is an effect of defoaming bubbles mixed in the polymer layer forming liquid 24. By defoaming the bubbles mixed in the polymer layer forming liquid 24, it is possible to prevent the needle-like protrusions from being lost in the peeling step and the needle-like protrusions from being damaged during puncturing.
　型枠１７のテーパの角度θとしては、モールド１３とのなす角度を、４５°以上７５°以下とすることが好ましい。 The taper angle θ of the mold 17 is preferably 45 ° or more and 75 ° or less with respect to the mold 13.
　（変形例）
　図２９Ａ及び図２９Ｂは、第１実施形態の変形例を示す図である。図２９Ａ及び図２９Ｂに示すモールド７３は、段差部７４がモールド７３自身に形成されている点が、上記の実施形態と異なっている。モールド７３に段差部７４を有している場合においても、上記と同様に、段差部７４でポリマー層形成液２４を固定することができ、安定して経皮吸収シートの製造を行うことができる。段差部７４の針状凹部１５が形成された領域１６からの高さ、ポリマー層形成液２４の塗布厚み、段差部により形成される上面からみた針状凹部が形成された領域の周囲の形状などについても、上記の実施形態と同様に行うことができる。 (Modification)
FIG. 29A and FIG. 29B are diagrams showing a modification of the first embodiment. The mold 73 shown in FIGS. 29A and 29B is different from the above embodiment in that the stepped portion 74 is formed in the mold 73 itself. Even in the case where the mold 73 has the stepped portion 74, the polymer layer forming liquid 24 can be fixed by the stepped portion 74 as described above, and the transdermal absorption sheet can be manufactured stably. . The height of the stepped portion 74 from the region 16 where the needle-like concave portion 15 is formed, the coating thickness of the polymer layer forming liquid 24, the shape of the periphery of the region where the needle-like concave portion is formed as viewed from the upper surface formed by the stepped portion, etc. This can be performed in the same manner as in the above embodiment.
　＜第２実施形態＞
　図３０Ａ及び図３０Ｂは、本発明の第２実施形態のポリマー層形成液供給工程を説明する図である。第２実施形態のポリマー層形成液供給工程は、針状凹部１５を有するモールド８３の段差部８４が、針状凹部１５が形成された領域１６よりも低くなるように、針状凹部１５の周囲に段差部を備える点が第１実施形態と異なっている。 Second Embodiment
FIG. 30A and FIG. 30B are views for explaining a polymer layer forming liquid supply step of the second embodiment of the present invention. In the polymer layer forming liquid supply process of the second embodiment, the stepped portion 84 of the mold 83 having the needle-like recess 15 is lower than the region 16 in which the needle-like recess 15 is formed. This embodiment is different from the first embodiment in that a step portion is provided in the first embodiment.
　第２実施形態においては、図３０Ａに示すように、段差部８４をモールド８３の針状凹部１５が形成されている領域１６よりも低くし、ポリマー層形成液２４を針状凹部１５が形成されている領域１６以上に広い範囲、すなわち、段差部８４まで塗布する。ポリマー層形成液２４を塗布した後、表面張力によりポリマー層形成液２４の収縮が開始し、図３０Ｂに示すように、領域１６と段差部８４との境界で、ポリマー層形成液２４が固定され、それ以上収縮が進まないため、経皮吸収シートを安定して形成することができる。 In the second embodiment, as shown in FIG. 30A, the stepped portion 84 is made lower than the region 16 of the mold 83 where the acicular recess 15 is formed, and the polymer layer forming liquid 24 is formed of the acicular recess 15. The coating is applied up to a wide area, that is, the stepped portion 84 beyond the region 16. After application of the polymer layer forming liquid 24, the polymer layer forming liquid 24 starts to contract due to surface tension, and the polymer layer forming liquid 24 is fixed at the boundary between the region 16 and the stepped portion 84 as shown in FIG. 30B. Since the contraction does not proceed any further, the transdermal absorption sheet can be formed stably.
　ポリマー層形成液の塗布時の針状凹部１５が形成された領域からの厚みは、５０００μｍ以下とすることが好ましい。ポリマー溶解液の塗布厚みを５０００μｍ以下とすることで、次のポリマー層形成液乾燥工程の乾燥速度を向上させることができる。 The thickness from the region where the needle-like recess 15 is formed when the polymer layer forming liquid is applied is preferably 5000 μm or less. By setting the coating thickness of the polymer solution to 5000 μm or less, it is possible to improve the drying speed in the subsequent polymer layer forming solution drying step.
　また、第２実施形態においては、ポリマー層形成液２４の塗布は、段差部８４で囲まれた針状凹部１５の領域ごとに行うことが好ましい。図３１Ａは、針状凹部１５の周囲に、針状凹部１５が形成された領域１６より低い段差部８４を有するモールド８３全面に均一塗布した図である。第２実施形態において、モールド８３全面に均一塗布した場合、ポリマー層形成液は、モールド８３の凹部である段差部８４に向かって収縮が起こる。したがって、モールド８３全面に均一に塗布した場合は、図３１Ｂに示すように、針状凹部１５が形成された領域１６からポリマー層形成液２４が弾かれてしまい、安定した形状で経皮吸収シートが形成されない場合がある。 Further, in the second embodiment, it is preferable to apply the polymer layer forming liquid 24 for each region of the needle-like recess 15 surrounded by the stepped portion 84. FIG. 31A is a view in which the entire surface of the mold 83 having the stepped portion 84 lower than the region 16 where the needle-like recess 15 is formed is uniformly applied around the needle-like recess 15. In the second embodiment, when uniformly applied to the entire surface of the mold 83, the polymer layer forming liquid contracts toward the stepped portion 84 that is a concave portion of the mold 83. Therefore, when uniformly applied to the entire surface of the mold 83, as shown in FIG. 31B, the polymer layer forming liquid 24 is repelled from the region 16 where the needle-like recesses 15 are formed, and the percutaneous absorption sheet has a stable shape. May not be formed.
　第２実施形態においても、針状凹部が形成された領域の周囲の段差部により形成される形状は、第１実施形態と同様の形状とすることができる。 Also in the second embodiment, the shape formed by the stepped portion around the region where the needle-like recess is formed can be the same shape as the first embodiment.
　（ポリマー層形成液乾燥工程）
　図２０Ａから図２０Ｄに戻って、ポリマー層形成液供給工程後、図２０Ｄに示すように、ポリマー層形成液２４を乾燥固化させることで、ポリマー層１２２を、薬剤層１２０の上に形成する。薬剤層１２０とポリマー層１２２とを有するポリマーシート１が製造される。 (Polymer layer forming liquid drying process)
20A to 20D, after the polymer layer forming liquid supply step, as shown in FIG. 20D, the polymer layer forming liquid 24 is dried and solidified to form the polymer layer 122 on the drug layer 120. The polymer sheet 1 having the drug layer 120 and the polymer layer 122 is manufactured.
　ポリマー層を型枠に安定的に固定するためには、段差部のポリマー層形成液を速く乾燥することが有効である。モールドに対し、垂直な乾燥風で、風速を上げ、高温で低湿度の乾燥風を用いて、段差部を乾燥固化させることが好ましい。 In order to stably fix the polymer layer to the mold, it is effective to quickly dry the polymer layer forming liquid in the stepped portion. It is preferable to dry and solidify the stepped portion with a drying air perpendicular to the mold by increasing the air speed and using a high-temperature, low-humidity drying air.
　ポリマー層形成乾燥工程では、ポリマー層形成液２４が乾燥により体積が縮小する。ポリマー層形成液２４が乾燥中にモールド１３に密着していれば体積の縮小はシートの膜厚方向に起こり、膜厚が薄くなる。 In the polymer layer formation drying step, the volume of the polymer layer formation liquid 24 is reduced by drying. If the polymer layer forming liquid 24 is in close contact with the mold 13 during drying, the volume reduction occurs in the film thickness direction of the sheet, and the film thickness decreases.
　乾燥中にポリマー層形成液２４がモールド１３から剥離してしまうと、ポリマーシート１が面方向にも収縮するため歪んでしまったり、カールしたりする場合がある。針状凹部１５内のポリマー層形成液２４が十分に乾燥していない状態でポリマーシート１がモールド１３から剥離してしまうと、ポリマーシート１の針状凸部の形状が折れたり、曲がったりする不良が発生しやすい。このため、乾燥中にポリマーシート１がモールド１３から剥離しないことが好ましい。また、カールを抑制するためにポリマーシート１の裏面（針状凸部の形成される面と反対の面）に針状凸部のある表面と同程度に収縮する層を形成してもよい。例えば、裏面側にも表面側と同じポリマー溶解液を塗布し、カール抑制の効果を予め確認した膜厚となるように層形成する。 If the polymer layer forming liquid 24 is peeled off from the mold 13 during drying, the polymer sheet 1 may contract in the surface direction and may be distorted or curled. If the polymer sheet 1 is peeled off from the mold 13 in a state where the polymer layer forming liquid 24 in the needle-like concave portion 15 is not sufficiently dried, the shape of the needle-like convex portion of the polymer sheet 1 is broken or bent. Defects are likely to occur. For this reason, it is preferable that the polymer sheet 1 does not peel from the mold 13 during drying. In order to suppress curling, a layer that contracts to the same extent as the surface having the needle-like convex portions may be formed on the back surface of the polymer sheet 1 (the surface opposite to the surface on which the needle-like convex portions are formed). For example, the same polymer solution as that on the front surface side is applied to the back surface side, and the layer is formed so as to have a film thickness in which the effect of curling suppression is confirmed in advance.
　（剥離工程）
　ポリマーシート１をモールド１３から剥離する方法は限定されるものではない。剥離の際に針状凸部が曲がったり折れたりしないことが望まれる。具体的には、ポリマーシート１の上に、粘着性の粘着層が形成されているシート状の基材を付着させた後、端部から基材をめくるように剥離を行うことができる。また、ポリマーシート１の裏面に吸盤を設置し、エアーで吸引しながら垂直に引き上げる方法を適用することができる。ポリマーシート１をモールド１３から剥離することにより、経皮吸収シート１００を製造する。 (Peeling process)
The method for peeling the polymer sheet 1 from the mold 13 is not limited. It is desired that the needle-like convex portion does not bend or break during peeling. Specifically, after attaching a sheet-like base material on which an adhesive pressure-sensitive adhesive layer is formed on the polymer sheet 1, peeling can be performed so as to turn the base material from the end. Further, a method of installing a suction cup on the back surface of the polymer sheet 1 and pulling it up vertically while sucking with air can be applied. By peeling the polymer sheet 1 from the mold 13, the transdermal absorption sheet 100 is manufactured.
　（脱気工程）
　薬液充填工程の前、及び／又はポリマー層形成液供給工程の前に、薬液２２及び／又はポリマー層形成液２４を脱気することが好ましい。脱気することにより、モールド１３の針状凹部１５に充填する前に、薬液２２およびポリマー層形成液２４に含まれる気泡を除去することができる。例えば、脱気工程では１００μｍ～数ｍｍの直径の気泡が除去される。 (Deaeration process)
It is preferable to deaerate the chemical liquid 22 and / or the polymer layer forming liquid 24 before the chemical liquid filling process and / or before the polymer layer forming liquid supply process. By deaeration, the bubbles contained in the chemical liquid 22 and the polymer layer forming liquid 24 can be removed before filling the needle-like recess 15 of the mold 13. For example, in the deaeration process, bubbles having a diameter of 100 μm to several mm are removed.
　脱気方法として、例えば、（１）薬液２２を１～１５分間減圧環境下に晒す方法、（２）薬液２２を貯留する容器を５～１０分間超音波振動させる方法、（３）薬液２２を減圧環境下に晒しながら超音波を印加する方法、（４）薬液２２の中にヘリウムガスを送り込むことで溶存気体をヘリウムに置換する方法、等が挙げられる。ポリマー層形成液２４についても（１）～（４）の脱気方法を適用することができる。 As a degassing method, for example, (1) a method of exposing the chemical liquid 22 to a reduced pressure environment for 1 to 15 minutes, (2) a method of ultrasonically vibrating a container storing the chemical liquid 22 for 5 to 10 minutes, and (3) a chemical liquid 22 Examples include a method of applying ultrasonic waves while being exposed to a reduced pressure environment, and (4) a method of replacing dissolved gas with helium by sending helium gas into the chemical liquid 22. The degassing methods (1) to (4) can also be applied to the polymer layer forming liquid 24.
　以下に、本発明の実施例を挙げて本発明をさらに具体的に説明する。なお、以下の実施例に示される材料、使用量、割合、処理内容、処理手順等は、本発明の趣旨を逸脱しない限り適宜変更することができる。したがって、本発明の範囲は以下に示す具体例により限定的に解釈されるべきものではない。 Hereinafter, the present invention will be described in more detail with reference to examples of the present invention. In addition, the material, usage-amount, ratio, processing content, processing procedure, etc. which are shown in the following Examples can be changed suitably unless it deviates from the meaning of this invention. Therefore, the scope of the present invention should not be construed as being limited by the specific examples shown below.
　（モールドの作製）
　一辺４０ｍｍの平滑なＮｉ板の表面に、図３２Ａ及び３２Ｂに示すような、底面が５００μｍの直径Ｄ１で、且つ１５０μｍの高さＨ１の円錐台１２Ｂ上に、３００μｍの直径Ｄ２で、且つ５００μｍの高さＨ２の円錐１２Ａが形成された針状構造の凸部１２を、１０００μｍのピッチＬにて１０列×１０行の２次元配列に研削加工することで、原版１１を作製した。この原版１１の上に、シリコーンゴム（ダウ・コーニング社製ＳＩＬＡＳＴＩＣ（登録商標）－ＭＤＸ４－４２１０）を材料として、０．６ｍｍの厚みで膜を形成した。膜面から原版１１の円錐先端部５０μｍを突出させた状態で熱硬化させ、その後、硬化した膜を剥離した。これにより、約３０μｍの直径の貫通孔を有するシリコーンゴムの反転品を作製した。このシリコーンゴム反転品の、中央部に１０列×１０行の２次元配列された針状凹部が形成された、一辺３０ｍｍの平面部外を切り落としたものをモールドとして用いた。針状凹部の開口部が広い方をモールドの表面とし、３０μｍの直径の貫通孔（空気抜き孔）を有する面をモールドの裏面とした。 (Mold production)
As shown in FIGS. 32A and 32B, on the surface of a smooth Ni plate having a side of 40 mm, on the truncated cone 12B having a bottom surface of 500 μm and a height H1 of 150 μm, a diameter D2 of 300 μm and 500 μm. The original plate 11 was produced by grinding the convex portion 12 having a needle-like structure on which the cone 12A having a height H2 was formed into a two-dimensional array of 10 columns × 10 rows at a pitch L of 1000 μm. A film having a thickness of 0.6 mm was formed on the original plate 11 using silicone rubber (SILASTIC (registered trademark) -MDX4-4210 manufactured by Dow Corning) as a material. The film was heat-cured in a state where the tip of the cone 11 of the original plate 11 protruded from the film surface, and then the cured film was peeled off. This produced a reversal product of silicone rubber having a through-hole with a diameter of about 30 μm. This silicone rubber reversal product, in which needle-like concave portions arranged two-dimensionally in 10 columns × 10 rows in the center portion, was cut off from a flat portion of 30 mm on a side, was used as a mold. The wider one of the needle-like recesses was the mold surface, and the surface having a 30 μm diameter through hole (air vent hole) was the mold back surface.
　（薬剤を含むポリマー溶解液（薬液）の調製）
　ヒドロキシエチルスターチ（Ｆｒｅｓｅｎｉｕｓ　Ｋａｂｉ社製）を水で溶解し、８％の水溶液に調液したものに、薬剤としてヒト血清アルブミン（和光純薬製）を２質量％添加し、薬液とした。調液後、３ｋＰａの減圧環境下に４分間晒し、十分な脱気を行った。 (Preparation of polymer solution (drug) containing drug)
Hydroxyethyl starch (manufactured by Fresenius Kabi) was dissolved in water and prepared into an 8% aqueous solution, and 2% by mass of human serum albumin (manufactured by Wako Pure Chemical Industries) was added as a drug to prepare a drug solution. After the preparation, it was exposed to a reduced pressure environment of 3 kPa for 4 minutes to perform sufficient deaeration.
　（ポリマー溶解液（ポリマー層形成液）の調製）
　コンドロイチン硫酸（マルハニチロ食品社製）を水で溶解し、４０％の水溶液に調液したものを、ポリマー層形成液とした。調液後、３ｋＰａの減圧環境下に４分間晒し、十分な脱気を行った。 (Preparation of polymer solution (polymer layer forming solution))
Chondroitin sulfate (manufactured by Maruha Nichiro Foods Co., Ltd.) was dissolved in water and prepared into a 40% aqueous solution as a polymer layer forming solution. After the preparation, it was exposed to a reduced pressure environment of 3 kPa for 4 minutes to perform sufficient deaeration.
　以下、薬液充填工程からポリマー層形成液乾燥工程を温度５℃、相対湿度３５％ＲＨの環境下で実施した。 Hereinafter, the polymer layer forming liquid drying step from the chemical solution filling step was performed in an environment of a temperature of 5 ° C. and a relative humidity of 35% RH.
　（薬液充填工程、薬液乾燥工程）
　薬液充填装置は、Ｘ軸、Ｚ軸からなるモールドとノズルの相対位置座標を制御する駆動部、ノズルを取り付け可能な液供給装置（武蔵エンジニアリング社製超微量定量ディスペンサーＳＭＰ－ＩＩＩ）、モールドを固定する吸引台、モールド表面形状を測定するレーザー変位計（パナソニック社製ＨＬ－Ｃ２０１Ａ）、ノズル押し込み圧力を測定するロードセル（共和電業製ＬＣＸ－Ａ－５００Ｎ）、表面形状及び押し付け圧力の測定値のデータを基にＺ軸を制御する制御システム、を備える。 (Chemical solution filling process, chemical solution drying process)
The chemical filling device has a drive unit that controls the relative position coordinates of the mold and nozzle consisting of the X and Z axes, a liquid supply device that can be attached to the nozzle (ultra-trace quantity dispenser SMP-III manufactured by Musashi Engineering Co., Ltd.), and a fixed mold. Suction table, laser displacement meter for measuring mold surface shape (HL-C201A, manufactured by Panasonic), load cell for measuring nozzle indentation pressure (LCX-A-500N, manufactured by Kyowa Denki Co., Ltd.), surface shape and measured pressure values A control system for controlling the Z-axis based on the data.
　水平な吸引台上に一辺１５ｍｍの気体透過性フィルム（住友電工社製ポアフロン（登録商標）ＦＰ－０１０）を置き、その上に表面が上になるようにモールドを設置した。モールド裏面方向からゲージ圧－９０ｋＰａの吸引圧で減圧して、気体透過性フィルムとモールドを吸引台に固定した。 A gas permeable film with a side of 15 mm (PORFLON (registered trademark) FP-010, manufactured by Sumitomo Electric Industries, Ltd.) was placed on a horizontal suction table, and a mold was placed on the surface so that the surface was on top. The gas permeable film and the mold were fixed to a suction table by reducing the pressure from the back side of the mold with a gauge pressure of −90 kPa.
　図１４に示すような形状のＳＵＳ製（ステンレス鋼）のノズルを準備し、長さ２０ｍｍ、幅２ｍｍのリップ部の中央に、長さ１２ｍｍ、幅０．２ｍｍのスリット状の開口部を形成した。このノズルを薬液タンクに接続した。３ｍＬの薬液を薬液タンクとノズル内部に装填した。開口部を、モールドの表面に形成された複数の針状凹部で構成される１列目と平行となるようにノズルを調整した。１列目に対して２列目と反対方向に２ｍｍの間隔をおいた位置で、ノズルを０．１４ｋｇｆ／ｃｍ２（１．４Ｎ／ｃｍ２）の圧力（押し付け力）でモールドに押し付けた。ノズルを押し付けたまま、押し付け力の変動が±０．０５ｋｇｆ／ｃｍ２（０．４９Ｎ／ｃｍ２）に収まるようにＺ軸を制御しつつ、１ｍｍ／ｓｅｃで開口部の長さ方向と垂直方向に移動させながら、液供給装置にて、薬液を、０．３１μＬ／ｓｅｃで１０秒間、開口部から放出した。２次元配列された複数の針状凹部の１０列目に対して９列目と反対方向に２ｍｍ間隔を置いた位置でノズルの移動を停止し、ノズルをモールドから離した。薬液を充填したモールドを、直径５ｍｍ開口部を持った風防（２５ｃｍ３）内に収め、乾燥した。ここでいう風防は、開口部に気体透過性フィルム（住友電工社製ポアフロン（登録商標）ＦＰ－０１０）が装着されており、直接風が当たらないような構造となっている。 A SUS (stainless steel) nozzle having a shape as shown in FIG. 14 was prepared, and a slit-like opening having a length of 12 mm and a width of 0.2 mm was formed in the center of a lip portion having a length of 20 mm and a width of 2 mm. . This nozzle was connected to a chemical tank. 3 mL of chemical solution was loaded into the chemical solution tank and the nozzle. The nozzles were adjusted so that the openings were parallel to the first row composed of a plurality of needle-like recesses formed on the surface of the mold. The nozzle was pressed against the mold with a pressure (pressing force) of 0.14 kgf / cm 2 (1.4 N / cm 2 ) at a position 2 mm away from the first row in the direction opposite to the second row. While controlling the Z axis so that the fluctuation of the pressing force is within ± 0.05 kgf / cm 2 (0.49 N / cm 2 ) with the nozzle pressed, the direction perpendicular to the length direction of the opening is 1 mm / sec. The chemical solution was discharged from the opening at 0.31 μL / sec for 10 seconds with the liquid supply device. The movement of the nozzle was stopped at a position spaced by 2 mm in the opposite direction to the ninth row with respect to the tenth row of the plurality of needle-shaped concave portions arranged two-dimensionally, and the nozzle was separated from the mold. The mold filled with the chemical solution was placed in a windshield (25 cm 3 ) having an opening with a diameter of 5 mm and dried. The windshield here has a structure in which a gas permeable film (PORFLON (registered trademark) FP-010 manufactured by Sumitomo Electric Industries, Ltd.) is attached to the opening, and is not directly exposed to wind.
　（ポリマー層形成液供給工程、ポリマー層形成液乾燥工程）
　薬液を充填したモールド上に、ステンレス製（ＳＵＳ３０４）の型枠を置いた。ここに、吐出量と、型枠とノズルのクリアランスと、を調整しながら、ポリマー層形成液を直接塗布した。その後、１２時間経過後の経皮吸収シートについて形状が維持されているかどうか確認した。評価は以下の基準で行った。 (Polymer layer forming liquid supply process, polymer layer forming liquid drying process)
A mold made of stainless steel (SUS304) was placed on a mold filled with a chemical solution. Here, the polymer layer forming liquid was directly applied while adjusting the discharge amount and the clearance between the mold and the nozzle. Thereafter, it was confirmed whether or not the shape of the transdermal absorption sheet after 12 hours was maintained. Evaluation was performed according to the following criteria.
　≪液面固定≫
Ａ・・・段差部でポリマー層が固定されている。
Ｂ・・・複数回行うと段差部でポリマー層が固定されていないものもあるが、問題ないレベルである。
Ｃ・・・段差部でポリマー層が固定されておらず、モールドでポリマー層形成液が弾かれ、経皮球種シートの形状が安定していない。 ≪Fixed liquid level≫
A: The polymer layer is fixed at the step portion.
B: Although there are some cases where the polymer layer is not fixed at the stepped portion when it is performed a plurality of times, it is at a satisfactory level.
C: The polymer layer is not fixed at the step portion, the polymer layer forming liquid is repelled by the mold, and the shape of the percutaneous spherical seed sheet is not stable.
　また、液面固定の評価が「Ａ」のサンプルについて、シートの剥離を確認した。 In addition, it was confirmed that the sheet was peeled from the sample having the liquid level evaluation of “A”.
　≪剥離≫
Ａ・・・問題なく剥離できる。
Ｂ・・・乾燥開始１２時間後では、乾燥しておらず剥離できないが、乾燥を進め、乾燥終了後は剥離が可能である。
Ｃ・・・剥離できない。 ≪Peeling≫
A ... It can peel without a problem.
B: After 12 hours from the start of drying, it is not dry and cannot be peeled off, but can be peeled off after completion of drying and drying.
C: Cannot be peeled off.
　（実験例１）
　上記の方法にて、ポリマー層形成液供給工程時にＳＵＳ製で円形の型枠を用いて、塗布を行った。ポリマー層形成液の塗布は、型枠に対して、型枠よりも半径として１ｍｍ大きい範囲で塗布を行った。型枠径は、型枠の直径であり、液面高さは、ポリマー層形成液の塗布厚みであり、型枠を設置することにより形成される段差部におけるモールド表面から液面までの高さを示す。型枠径は、１０、２０、３０ｍｍのものを用い、針状凹部の数、および、位置は同じにして実験を行った。したがって、型枠径を変更することで、針状凹部から型枠までの距離を変更することができる。また、型枠の高さを１０～１００００μｍで変化させ、型枠の高さに対するポリマー層形成液塗布後の液面高さを変更することで、形成されるポリマー層の評価を行った。結果を表１に示す。 (Experimental example 1)
By the above-described method, coating was performed using a circular mold made of SUS at the time of supplying the polymer layer forming liquid. The polymer layer forming solution was applied to the mold in a range larger by 1 mm as the radius than the mold. The mold diameter is the diameter of the mold, the liquid level is the coating thickness of the polymer layer forming liquid, and the height from the mold surface to the liquid level at the stepped portion formed by installing the mold. Indicates. Experiments were conducted using molds with diameters of 10, 20, and 30 mm, with the same number of needle-shaped recesses and the same position. Therefore, the distance from the needle-like recess to the mold can be changed by changing the mold diameter. Further, the polymer layer to be formed was evaluated by changing the height of the mold from 10 to 10000 μm and changing the liquid surface height after application of the polymer layer forming solution with respect to the height of the mold. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　モールドから液面までの高さが型枠以上となる場合は、段差部で液面を固定することができた。また、液面高さが１００００μｍの実験例においては、ポリマー層形成液の液面は段差部で固定されるが、乾燥に時間がかかり、１２時間経過後においても乾燥されなかった。なお、上記の表において、型枠径が１０ｍｍ、２０ｍｍ及び３０ｍｍでは同じ結果であったため、まとめて記載した。 ¡When the height from the mold to the liquid level was higher than the formwork, the liquid level could be fixed at the step. In the experimental example where the liquid level was 10,000 μm, the liquid level of the polymer layer forming liquid was fixed at the step portion, but it took time to dry and was not dried even after 12 hours. In the above table, since the same results were obtained when the mold diameters were 10 mm, 20 mm, and 30 mm, they are collectively shown.
　（実験例２）
　実験例１に対し、針状凹部が形成された領域を凸型とし、周囲を凹型とした段差部有するモールドを用いて、ポリマー層形成液の塗布を行った。結果を表２に示す。 (Experimental example 2)
The polymer layer forming liquid was applied to Experimental Example 1 using a mold having a stepped portion in which a needle-like concave portion was formed in a convex shape and the periphery was a concave shape. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表２に示すように、液面高さを型枠の厚さ以上とすることで、段差部でポリマー層を固定することができた。また、液面高さが１００００μｍの場合は、実験例１と同様に、段差部でポリマー層は固定されるが、１２時間では乾燥できなかった。 As shown in Table 2, the polymer layer could be fixed at the step by setting the liquid level height to be equal to or greater than the thickness of the mold. Further, when the liquid level was 10000 μm, the polymer layer was fixed at the stepped portion as in Experimental Example 1, but could not be dried in 12 hours.
　（実験例３）
　型枠を正方形から正１２角形の形状（中心から各頂点までの距離が１０ｍｍ）、直径２０ｍｍの円形状とし、液面高さを１００μｍとした。また、モールドを、針状凹部が形成されている領域が凸部となるように段差部を形成し、この段差部の形状が、正方形から正１２角形の形状（中心から各頂点までの距離が１０ｍｍ）、直径２０ｍｍの円形状であるモールドを用いて実験を行った。これらのモールドに対して、ポリマー層形成液の塗布を行い、段差部でのポリマー層の固定化について確認した。結果を表３に示す。 (Experimental example 3)
The mold was shaped like a square to a regular dodecagon (distance from the center to each apex was 10 mm), a circle with a diameter of 20 mm, and the liquid level was 100 μm. Further, the mold is formed with a step portion so that the region where the needle-like recess is formed becomes a convex portion. 10 mm) and a mold having a circular shape with a diameter of 20 mm was used for the experiment. The polymer layer forming liquid was applied to these molds, and the immobilization of the polymer layer at the stepped portion was confirmed. The results are shown in Table 3.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　型枠を用いた場合、針状凹部の領域が凸部となるように段差部を有するモールドを用いた場合においても、段差部の形状が、正方形及び正５角形の場合など、角度が比較的小さい場合は、段差部の形状の頂点部分からポリマー層形成液をはじいてしまい、ポリマー層を段差部で固定することができていないサンプルがあった。 When a mold is used, even when a mold having a stepped portion is used so that the needle-like recessed region becomes a convex portion, the angle is relatively small, such as when the shape of the stepped portion is a square or a regular pentagon. When it was small, there was a sample in which the polymer layer forming liquid was repelled from the apex portion of the shape of the step portion, and the polymer layer could not be fixed at the step portion.
　（実験例４）
　実施例１で用いた直径２０ｍｍ、厚み１００μｍの円形のＳＵＳ製の型枠を用いて、針状凹部を有する領域が凹型になるように段差部を形成した。液面高さを２００μｍとし、段差部へのはみ出し量（段差部の位置を基準とし、段差部側を外側、針状凹部側を内側とする）を変更して、ポリマー層の液面化について確認した。結果を表４に示す。 (Experimental example 4)
Using the circular SUS mold having a diameter of 20 mm and a thickness of 100 μm used in Example 1, the step portion was formed so that the region having the needle-like recess was concave. Liquid level of the polymer layer by changing the liquid level height to 200μm and changing the amount of protrusion to the stepped part (with the stepped part as the reference, the stepped part side is the outside and the needle-shaped recessed part is the inside) confirmed. The results are shown in Table 4.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　試験Ｎｏ．８１～８５のポリマー層形成液を段差部と同じ、または、段差部より広い位置に塗布した場合は、段差部でポリマー層を固定することができた。ポリマー層形成液の塗布を、型枠より内側とした試験Ｎｏ．８６～８８については、ポリマー層を段差部で固定することができず、モールドの針状凹部が形成された領域で弾いてしまい、良好な形状の経皮吸収シートは形成できなかった。 Test No. When 81 to 85 polymer layer forming liquids were applied at the same position as the stepped portion or wider than the stepped portion, the polymer layer could be fixed at the stepped portion. Test No. in which the polymer layer forming solution was applied to the inside of the mold. Regarding 86 to 88, the polymer layer could not be fixed at the stepped portion, and it was bounced in the region where the needle-like concave portion of the mold was formed, and a percutaneous absorption sheet having a good shape could not be formed.
１　ポリマーシート
１１、７１、８１　原版
１２　凸部
１３、７３、８３　モールド
１４、１７　型枠
１５　針状凹部
１５Ａ　入口部
１５Ｂ　先端凹部
１５Ｃ　貫通孔
１６　領域
１８　モールド複合体
１９　気体透過シート
２０　基台
２２　薬液
２４　ポリマー層形成液
３０　送液タンク
３２　配管
３４　ノズル
３４Ａ　リップ部
３４Ｂ　開口部
３４Ｃ　傾斜面
３６　液供給装置
４８　薬液充填装置
５０、５４　軸駆動部
５２　吸引台
５６　架台
５８　制御システム
６０　変位計
７４、７５、８４、８５　段差部
９２　塗布手段
１００　経皮吸収シート
１１０　針状凸部
１１２　ニードル部
１１２Ａ　針状部
１１２Ｂ　胴体部
１１４　錐台部
１１６　シート部
１２０　薬剤層
１２２　ポリマー層 DESCRIPTION OF SYMBOLS 1 Polymer sheet 11, 71, 81 Master 12 Protrusion part 13, 73, 83 Mold 14, 17 Mold 15 Needle-shaped recessed part 15A Entrance part 15B Tip recessed part 15C Through-hole 16 Area | region 18 Mold composite 19 Gas-permeable sheet 20 Base 22 Chemical liquid 24 Polymer layer forming liquid 30 Liquid feed tank 32 Pipe 34 Nozzle 34A Lip part 34B Opening 34C Inclined surface 36 Liquid supply device 48 Chemical liquid filling device 50, 54 Axis drive unit 52 Suction table 56 Base 58 Control system 60 Displacement meter 74 75, 84, 85 Step part 92 Application means 100 Transdermal absorption sheet 110 Needle-like convex part 112 Needle part 112A Needle part 112B Body part 114 Frustum part 116 Sheet part 120 Drug layer 122 Polymer layer

Claims (12)

  1. 　針状凹部を有するモールドの前記針状凹部に薬剤を含むポリマー溶解液である薬液を充填する薬液充填工程と、
    　前記針状凹部に充填された前記薬液を乾燥させて、前記薬剤を含む薬剤層を形成する薬液乾燥工程と、
    　前記モールドは、前記針状凹部が形成された領域の周囲に前記針状凹部が形成された領域より高い段差部を備え、前記モールドに対し、前記段差部以上の高さであり、かつ、上面から見て前記段差部以上の範囲に、ポリマー層形成液を供給するポリマー層形成液供給工程と、
    　前記モールドに供給されたポリマー層形成液を乾燥させて、ポリマー層を形成するポリマー層形成液乾燥工程と、を有する経皮吸収シートの製造方法。     A chemical solution filling step of filling the needle-shaped concave portion of the mold having the needle-shaped concave portion with a chemical solution that is a polymer solution containing a drug;
    A chemical solution drying step of drying the chemical solution filled in the needle-shaped recess to form a drug layer containing the drug;
    The mold includes a step portion higher than a region where the needle-like recess is formed around a region where the needle-like recess is formed, and is higher than the step portion with respect to the mold, and an upper surface A polymer layer forming liquid supply step for supplying the polymer layer forming liquid to the range of the stepped portion or more as viewed from
    A method for producing a percutaneous absorption sheet, comprising: drying a polymer layer forming liquid supplied to the mold to form a polymer layer.
  2. 　前記ポリマー層形成液供給工程は、前記ポリマー層形成液を、前記段差部より高く、かつ、上面から見て前記段差部より広い範囲に供給した後、前記ポリマー層形成液を収縮させながら、前記ポリマー層形成液と前記モールドとの接触位置を前記段差部に固定する請求項１に記載の経皮吸収シートの製造方法。 In the polymer layer forming liquid supply step, after supplying the polymer layer forming liquid to a range higher than the stepped portion and wider than the stepped portion as viewed from above, the polymer layer forming liquid is contracted while the polymer layer forming liquid is contracted. The manufacturing method of the transdermal absorption sheet of Claim 1 which fixes the contact position of a polymer layer forming liquid and the said mold to the said level | step difference part.
  3. 　前記モールドの段差部の高さが１０μｍ以上５０００μｍ以下である請求項１または２に記載の経皮吸収シートの製造方法。 The method for producing a transdermal absorption sheet according to claim 1 or 2, wherein the height of the step portion of the mold is 10 µm or more and 5000 µm or less.
  4. 　前記ポリマー層形成液供給工程において、前記ポリマー層形成液の厚みが５０００μｍ以下である請求項１から３のいずれか１項に記載の経皮吸収シートの製造方法。 The method for producing a transdermal absorption sheet according to any one of claims 1 to 3, wherein, in the polymer layer forming liquid supply step, the thickness of the polymer layer forming liquid is 5000 µm or less.
  5. 　前記段差部は、前記モールドとは分離可能に設けられた型枠である請求項１から４のいずれか１項に記載の経皮吸収シートの製造方法。 The method for producing a transdermal absorption sheet according to any one of claims 1 to 4, wherein the stepped portion is a mold provided so as to be separable from the mold.
  6. 　前記段差部は、前記モールド自身に段差を有する請求項１から４のいずれか１項に記載の経皮吸収シートの製造方法。 The method for producing a transdermal absorption sheet according to any one of claims 1 to 4, wherein the step portion has a step in the mold itself.
  7. 　前記段差部は、前記針状凹部が形成された領域側から鉛直方向上側に向かって広がる方向にテーパ形状である請求項１から６のいずれか１項に記載の経皮吸収シートの製造方法。 The method for producing a percutaneous absorption sheet according to any one of claims 1 to 6, wherein the stepped portion has a tapered shape in a direction extending from the region side where the needle-like concave portion is formed toward the upper side in the vertical direction.
  8. 　針状凹部を有するモールドの前記針状凹部に薬剤を含むポリマー溶解液である薬液を充填する薬液充填工程と、
    　前記針状凹部に充填された前記薬液を乾燥させて、前記薬剤を含む薬剤層を形成する薬液乾燥工程と、
    　前記モールドは、前記針状凹部が形成された領域の周囲に前記針状凹部が形成された領域より低い段差部を備え、前記モールドに対し、上面から見て前記段差部以上の範囲に、ポリマー層形成液を供給した後、前記ポリマー層形成液を収縮させながら、前記ポリマー層形成液と前記モールドの接触位置を前記段差部に固定するポリマー層形成液供給工程と、
    　前記モールドに供給されたポリマー層形成液を乾燥させて、ポリマー層を形成するポリマー層形成液乾燥工程と、を有する経皮吸収シートの製造方法。     A chemical solution filling step of filling the needle-shaped concave portion of the mold having the needle-shaped concave portion with a chemical solution that is a polymer solution containing a drug;
    A chemical solution drying step of drying the chemical solution filled in the needle-shaped recess to form a drug layer containing the drug;
    The mold includes a step portion lower than the region where the needle-like recess is formed around the region where the needle-like recess is formed, and the polymer is in a range of the step portion or more with respect to the mold as viewed from above. After supplying the layer forming liquid, the polymer layer forming liquid supplying step of fixing the contact position of the polymer layer forming liquid and the mold to the stepped portion while contracting the polymer layer forming liquid;
    A method for producing a percutaneous absorption sheet, comprising: drying a polymer layer forming liquid supplied to the mold to form a polymer layer.
  9. 　前記ポリマー層形成液供給工程は、前記ポリマー層形成液の供給を、前記段差部が設けられた前記針状凹部ごとに行う請求項８に記載の経皮吸収シートの製造方法。 The method for producing a percutaneous absorption sheet according to claim 8, wherein the polymer layer forming liquid supply step supplies the polymer layer forming liquid for each of the needle-like recesses provided with the stepped portions.
  10. 　前記ポリマー層形成液供給工程において、前記ポリマー層形成液の厚みが５０００μｍ以下である請求項８または９に記載の経皮吸収シートの製造方法。 The method for producing a percutaneous absorption sheet according to claim 8 or 9, wherein, in the polymer layer forming solution supplying step, the thickness of the polymer layer forming solution is 5000 µm or less.
  11. 　前記段差部は、前記モールド自身に段差を有する請求項８から１０のいずれか１項に記載の経皮吸収シートの製造方法。 The method for producing a transdermal absorption sheet according to any one of claims 8 to 10, wherein the step portion has a step in the mold itself.
  12. 　前記針状凹部が形成された領域の周囲の前記段差部により形成される形状が、正六角形以上の正多角形、または、円形である請求項１から１１のいずれか１項に記載の経皮吸収シートの製造方法。 The percutaneous body according to any one of claims 1 to 11, wherein a shape formed by the stepped portion around the region where the needle-like recess is formed is a regular polygon of a regular hexagon or more, or a circle. Production method of absorbent sheet.
PCT/JP2016/057197 2015-03-10 2016-03-08 Process for producing sheet for percutaneous absorption WO2016143792A1 (en)

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EP3278834A1 (en) * 2016-07-27 2018-02-07 Fujifilm Corporation Method of producing transdermal absorption sheet
CN108498936A (en) * 2017-02-28 2018-09-07 富士胶片株式会社 The manufacturing method of sheet material with needle-shaped protrusion
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EP3278834A1 (en) * 2016-07-27 2018-02-07 Fujifilm Corporation Method of producing transdermal absorption sheet
US10639822B2 (en) 2016-07-27 2020-05-05 Fujifilm Corporation Method of producing transdermal absorption sheet
CN108498936A (en) * 2017-02-28 2018-09-07 富士胶片株式会社 The manufacturing method of sheet material with needle-shaped protrusion
WO2019163805A1 (en) * 2018-02-20 2019-08-29 富士フイルム株式会社 Manufacturing method for microneedle array
JPWO2019163805A1 (en) * 2018-02-20 2021-02-25 富士フイルム株式会社 Manufacturing method of microneedle array
CN111801134A (en) * 2018-03-30 2020-10-20 富士胶片株式会社 Mold for producing transdermal absorption sheet, and apparatus and method for producing transdermal absorption sheet having needle-like projections
US20210001102A1 (en) * 2018-03-30 2021-01-07 Fujifilm Corporation Mold for manufacturing percutaneous absorption sheet, and apparatus and method for manufacturing percutaneous absorption sheet having needle-like protrusion
CN111801134B (en) * 2018-03-30 2022-06-14 富士胶片株式会社 Mold for producing transdermal absorption sheet, and apparatus and method for producing transdermal absorption sheet having needle-like projections
GB2607115A (en) * 2021-06-25 2022-11-30 Cipherx Tech Ltd Method of producing a microneedle array
WO2022269295A1 (en) * 2021-06-25 2022-12-29 Cipherx Technologies Ltd Method of producing a microneedle array, microneedle array and use thereof
GB2607115B (en) * 2021-06-25 2023-10-04 Cipherx Tech Ltd Method of producing a microneedle array

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