JP2009082206A - Method of manufacturing functional film - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a manufacturing method of a functional film having a high aspect ratio structure having the uniform and fine tip, and having the high aspect ratio structure formed in an array shape of reducing a defect. <P>SOLUTION: This functional film manufacturing method comprises an applying process of applying a dissolving liquid 16 of a polymer resin to a stamper 13 forming a fine recessed part array, an adhering process of superposably adhering a base material 20 to a surface of the dissolving liquid 16 of the polymer resin, a drying process of drying the dissolving liquid 16 of the polymer resin, and a separation process of separating the resin polymer dried and solidified by the drying process from the stamper 13 together with the base material 20. The functional film manufacturing method is characterized in that the adhering process forms a mixing layer 24 of the dissolving liquid 16 of the polymer resin and a gelling material 23 by applying the gelling material 23 to the adhesive surface side with the dissolving liquid 16 of the polymer resin of the base material 20. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing a functional film having a high aspect ratio structure, and in particular, a functional film referred to as a microneedle sheet for injecting a drug or the like simply and efficiently in the skin surface layer or the skin stratum corneum. It relates to the manufacturing method.

  Conventionally, most of the methods for administering a drug or the like from the surface of a living body, that is, skin or mucous membrane, are mainly methods of attaching a liquid substance or a powdery substance. However, since the adhesion area of these substances was limited to the surface of the skin, the adhering chemicals may be removed by sweating or contact with foreign matter, and it was difficult to administer an appropriate amount. It was. In addition, in order to penetrate the drug deep into the skin, it is difficult to reliably control the penetration depth by such a method using penetration by diffusion of the drug, so that sufficient medicinal effect can be obtained. It was difficult.

Therefore, a method of injecting a medicine by using a functional film having a high aspect ratio structure and inserting its tip into the skin has been performed. As a method for forming such a functional film having a high aspect ratio structure, for example, in Patent Documents 1 and 2, a mold is prepared, a material is injected therein, and a needle structure is formed by injection molding. How to do is described. Patent Document 3 describes a method of forming a needle structure by attaching and extending the tip of a needle-like material to a fluid material on a substrate.
JP 2003-238347 A JP 2006-05361 A JP 2006-345993 A

  However, the method described in Patent Document 1 or 2 has a problem in that it is difficult to inject a material to the tip of a concave portion in a fine shape with respect to the arrayed concave mold, resulting in a defect defect. For example, air has accumulated at the end of the concave metal, and injection defects have occurred due to air bubbles accumulated during the material injection. In addition, there is a problem that the tip end portion which is a fine shape is not uniformly hollow, it is difficult to fill the solution, and productivity is inferior. Thereby, there exists a problem that the convex part front-end | tip of the formed convex part array is not formed sharply. Furthermore, since the material described in Patent Document 3 is stretched by tension, it has been difficult to form a needle shape such as the tip shape and height with high accuracy. In particular, since the tip portion is fine, deformation is likely to occur, and there is a problem that molding is difficult unless the material is cured immediately after stretching. In addition, the stretching method is not a method suitable for mass production, and there is a problem that the productivity is low and the cost is high.

  In addition, hard (high Young's modulus) materials such as maltose are fragile (easy to break when stress is concentrated on a part). There is also a problem that it is difficult to stably mass-produce functional films having an aspect ratio structure.

  The present invention has been made in view of such circumstances, and has a high aspect ratio structure with a uniform and sharp tip using a melted and dissolved polymer material, and is formed in an array with few defects. Another object of the present invention is to provide a method for producing a functional film having a high aspect ratio structure.

  According to a first aspect of the present invention, in order to achieve the above object, a polymer resin coating step of coating a polymer resin solution for forming a functional film on a stamper on which a fine concave array is formed, and a sheet A gelling material application step of applying a gelling material having adhesiveness to the substrate on the surface of the substrate, and the surface of the solution and the surface of the gelling material are aligned with each other. An adhesion step of forming an adhesive layer for adhering the solution and the base material by placing the base material on the surface and mixing the gelled material with a surface layer portion of the solution; and A drying step of forming a solidified polymer resin obtained by drying and solidifying the formed solution, and a peeling step of peeling the solidified product together with the base material from the stamper. A method for producing a functional film is provided.

  In the conventional peeling process, when the solidified product that has been dried and solidified is peeled from the stamper, it is necessary to peel it by applying stress upward. At that time, the substrate is peeled off by adhering the base material to the solidified material, but even if a normal medical adhesive such as acrylic, rubber or silicone is used, the interface cannot be bonded sufficiently, resulting in poor adhesion. End up.

  According to the first aspect, the adhesive layer is formed by applying the gelling material to the adhesive surface of the base material with the polymer resin solution and mixing the polymer resin solution and the gel material. Then, a solid adhesive layer can be formed by cooling and solidifying by a drying step, and defective adhesion can be reduced.

  Also, in the peeling process, if the adhesion of the polymer resin to the stamper is high, there is a risk that stress will concentrate on some parts (such as the base material and fine convex parts) and the fine convex parts will break. There is. According to claim 1, since the base material and the polymer resin can be firmly bonded, it is possible to uniformly apply stress to the convex portion, and to prevent a peeling failure even with a material weak in stress concentration. it can. As a result, a functional film having a high aspect ratio structure having a convex array to which the concave array of the stamper is transferred can be manufactured.

  In the present invention, the concave array means a state in which a plurality of concave portions are arranged vertically and horizontally, and the convex array means a state in which a plurality of convex portions are arranged vertically and horizontally.

  A second aspect of the present invention is the method according to the first aspect, wherein the bonding step pressurizes the base material toward the stamper.

  According to the second aspect, in the bonding step, a stronger adhesive layer can be formed with a stronger polymer resin and a gelling material by pressing the substrate toward the stamper side.

  A third aspect of the present invention is the method according to the first or second aspect, wherein the fine convex array formed on the functional film has a bottom surface with a side or diameter of 0.1 to 1000 μm and a height of 0.3 to It is a 3000 μm pyramid type or conical type, and has a curvature radius R at the tip of 300 μm or less.

  The third aspect defines a preferable size of the convex array formed on the functional film. According to the production method of the present invention, since the adhesion between the base material and the polymer resin can be improved, it is possible to uniformly apply stress to the polymer resin. Therefore, since it is possible to prevent a peeling failure even with respect to a functional film having a sharp tip of the convex portion, it is particularly effective for a functional film having a fine concave array such as the above size. Can be manufactured.

  A fourth aspect of the present invention is characterized in that in any one of the first to third aspects, the polymer resin is a saccharide.

  According to the fourth aspect, by using saccharides as the polymer resin, it is possible to enhance the adhesion between the base material and the polymer resin, and therefore it is possible to apply stress uniformly to the functional film. Therefore, good peelability can be obtained, and the functional film having a fine concave array can be manufactured particularly effectively.

  A fifth aspect of the present invention according to any one of the second to fourth aspects is characterized in that, in the bonding step, the adhesive layer is formed by pressurization, and at the same time, the dissolving solution is injected to the tips of the concave portions of the concave portion array.

  According to the fifth aspect, the polymer resin solution applied to the stamper is pressurized to the stamper side, thereby forming the adhesive layer and simultaneously injecting the polymer resin solution to the tip of the recess of the stamper. Further, by applying pressure, the air present in the recesses can be expelled, and a functional film with less contamination such as bubbles can be manufactured. Furthermore, even when the stamper and the polymer resin are in close contact with each other, the base material and the polymer resin are firmly adhered to each other at the time of peeling, so that a uniform stress can be applied to the polymer resin. A functional membrane can be manufactured.

  A sixth aspect of the present invention is characterized in that in any one of the second to fifth aspects, the pressurizing time for pressurizing the solution is 10 seconds or more.

  According to the sixth aspect, since the pressurization is performed for 10 seconds or more and the solution is injected into the recess of the stamper, the air present in the stamper recess can be expelled. Therefore, since the solution can be easily injected into the stamper recess, a functional film with less air can be formed.

  A seventh aspect of the present invention is characterized in that, in any one of the second to sixth aspects, a pressure applied to the solution is in a range of 0.05 to 30 MPa.

  According to claim 7, by making the applied pressure in the range of 0.05 to 30 MPa, it is possible to improve the adhesion between the base material and the polymer resin, and efficiently expel the air present in the stamper recess. it can.

  An eighth aspect of the present invention is characterized in that in any one of the first to seventh aspects, the temperature of the melting station in the bonding step is 20 ° C. or higher and 100 ° C. or lower.

  According to the eighth aspect, by setting the temperature of the solution in the bonding step within the above range, the fluidity of the polymer resin solution can be maintained and the gelling material can be gelled. The adhesion between the material and the polymer resin can be improved.

A ninth aspect according to any one of the first to eighth aspects is characterized in that the amount of the gelling material is 0.01 g / cm ² or more and 1 g / cm ² or less per unit area of the base material.

  According to the ninth aspect, the adhesiveness between the polymer resin and the base material can be improved by setting the amount of the gelling material in the above range. A functional film having a high aspect ratio structure with a simple tip and an array shape with few defects can be manufactured.

  A tenth aspect of the present invention is characterized in that in any one of the first to ninth aspects, the gelling material is selected from proteins and saccharides.

  According to the tenth aspect, a gelling material selected from proteins and saccharides is used. Proteins and saccharides can be suitably used as gelling materials because they have adhesiveness to many substrates and have strong gel strength as materials for sol-gelling.

  An eleventh aspect is characterized in that in any one of the first to tenth aspects, a mixed layer in which the solidified polymer resin and the gelled material are mixed is provided between the solidified polymer resin and the gelled material. And

  According to the eleventh aspect, since there is a mixed layer in which the solidified polymer resin and the gelled material are mixed between the solidified polymer resin and the gelled material after the drying step, Since the solidified product can be uniformly and firmly adhered to the entire solidified product, defective peeling can be prevented.

A twelfth aspect of the present invention is characterized in that, in any one of the first to eleventh aspects, the material of the stamper is made of a material having a gas permeability greater than 1 × 10 ⁻¹² (mL / (s · m · Pa)). And

According to the twelfth aspect, since the gas permeability of the stamper is greater than 1 × 10 ⁻¹² (mL / (s · m · Pa)), the gas easily passes and exists in the stamper recess. Can be expelled from the stamper side. Accordingly, since the solution can be easily injected into the stamper recess, a functional film with less air mixing can be manufactured.

  According to the present invention, it is possible to manufacture a functional film having a high aspect ratio structure having a high aspect ratio structure with a uniform and sharp tip and formed in an array with few defects. In particular, when peeling, it is possible to improve the adhesion between the base material and the polymer resin, it is possible to apply a uniform stress to the base material, and a method for producing a functional film with good peelability between the polymer resin and the stamper Can be provided.

  Hereinafter, a method for producing a microneedle sheet will be described as an example of a functional film having a high aspect ratio structure in an embodiment of the present invention. In addition, although described about a microneedle sheet | seat below, this invention is applicable also to the functional film | membrane which has a high aspect ratio structure other than a microneedle sheet | seat.

  FIG. 1 shows a pyramidal perspective view (a) and a sectional view (b) of a microneedle sheet manufactured by the manufacturing method and manufacturing apparatus of the present invention.

  The shape of the microneedles (fine projections) 22 formed on the microneedle sheet sheet is as follows. (1) The tip is sufficiently sharp and the skin is pierced to the skin surface at a depth of several hundred μm. It is also necessary that the diameter of the needle that enters is sufficiently thin (the aspect ratio of length / diameter is high), and (2) that it has sufficient strength (the needle does not bend).

  Therefore, in order to satisfy the requirement of (1), a thin and sharp shape is necessary, but this is contrary to (2). If it is too thin, it will bend at the tip and root, and if it is too thick, it will not stab. Therefore, as shown in FIG. 1A, it is preferable that the ridge line 22A of the microneedle 22 has a curved shape inside the microneedle. By adopting such a shape, the tip can be made sufficiently sharp, while it can be made difficult to break by widening the root. Moreover, it is preferable that the ridge lines 22A and 22A of the pyramid-shaped microneedle protrude beyond the pyramid surface 22C between the ridge lines.

  The shape of the microneedles 22 is preferably such that one side X of the bottom surface is in the range of 0.1 to 1000 μm and the height is in the range of 0.3 to 3000 μm. More preferably, the side X is in the range of 50 μm to 300 μm, and the height is 10 μm to 400 μm.

  The maximum bending depth Z of the ridge line 22A is preferably 0.04 × L or more and 0.2 × L or less, where L is the length of the line segment connecting the start point and the end point of the ridge line. Moreover, it is preferable that the curvature radius R of the microneedle tip 22B which shows the sharpness of a microneedle is 200 micrometers or less, More preferably, it is 10 micrometers or less.

  Although FIG. 1 shows the quadrangular pyramid-shaped microneedles 22, it is preferable that the cone-shaped and other pyramid-shaped microneedles shown in FIG. 2 have the same size. In the case of a conical shape, the diameter X of the bottom surface is preferably in the range of 0.1 μm to 1000 μm, more preferably in the range of 50 μm to 300 μm. Further, the maximum curvature depth Z ′ of the conical surface is 0.04 × L ′ or more and 0.2 × L ′ or less, where L ′ is the length of the segment connecting the start point and the end point of the generatrix surface. It is preferable that

  As described above, the microneedle array is a micro convex array, and in order to easily pierce the skin surface, the tip of the convex portion 22 is sufficiently sharpened, and the curvature radius R of the tip of the convex portion 22 is set to 10 μm or less. preferable. In order to form the convex portion 22 having a tip having a radius of curvature R of 10 μm or less, a polymer resin solution is injected precisely to the tip of the concave portion of the concave array that is the inverted type of the convex array formed on the stamper. Whether it can be done is an important point. Moreover, since the curvature radius R of a convex part is small and the front-end | tip is sharp, when peeling, stress concentrates on one part and a convex part may fracture | rupture. Therefore, it is an important point whether the peeling defect at the time of peeling a polymer resin can be reduced.

  Next, the manufacturing method of a microneedle sheet | seat is demonstrated. FIG. 3 is a process diagram of a stamper manufacturing method, FIG. 4 is a process diagram of a polymer resin coating process, FIG. 5 is a process diagram of an adhesion process and an adhesion process, and FIG. 6 is a process diagram of a peeling process.

  First, make the original plate. Specifically, as shown in FIG. 3A, an original plate for producing a stamper for producing a microneedle sheet is produced.

  There are two methods for producing the original plate 11. The first method is to apply a photoresist on a Si substrate, and then perform exposure and development, and then perform etching by RIE (reactive ion etching) or the like. An array of conical shaped parts (convex parts) 12 is produced on the surface of 11. When performing etching such as RIE, it is possible to form a cone shape by performing etching from an oblique direction while rotating the Si substrate.

  The second method is a method of forming an array of shape portions 12 such as square pyramids on the surface of the original plate 11 by processing a metal substrate such as Ni using a cutting tool such as a diamond tool.

  Next, a stamper is manufactured. Specifically, as shown in FIG. 3B, the stamper 13 is produced from the original plate 11. A method using Ni electroforming or the like is used to manufacture a normal stamper 13. However, since the original plate 11 has a conical or pyramidal shape with a sharp tip, the shape is accurately transferred to the stamper 13. 4 methods that can be manufactured at low cost so that they can be peeled off.

  In the first method, a silicone resin with a curing agent added to PDMS (polydimethylsiloxane, for example, Sylgard 184 manufactured by Dow Corning) is poured into the original 11, and after heat treatment at 100 ° C. and cured, the original 11 is peeled off. It is a method to do. The second method is a method in which a UV curable resin that is cured by irradiating ultraviolet rays is poured into the original plate 11 and irradiated from the original plate 11 after being irradiated with ultraviolet rays in a nitrogen atmosphere. In the third method, a plastic resin such as polystyrene or PMMA (polymethylmethacrylate) dissolved in an organic solvent is poured into the original plate 11 coated with a release agent, and dried to evaporate and cure the organic solvent. And then peeling from the original plate 11. The fourth method is a method of creating a reverse product by Ni electroforming.

  The stamper 13 produced in this way is shown in FIG. In any of the above three methods, the stamper 13 can be easily manufactured any number of times.

As a material used for the stamper, an elastic material or a metal material can be used, but an elastic material is preferable, and a resin having high gas permeability is more preferable. The gas permeability is preferably greater than 1 × 10 ⁻¹² (mL / s · m · Pa), and more preferably 1 × 10 ⁻¹⁰ (mL / s · m · Pa). By setting the gas permeability to the above range, the air present in the recess of the stamper 13 can be expelled from the stamper side, and a microarray needle with few defects can be manufactured. As such a material, specifically, a silicone resin (eg, Sylgard 184, 1310ST), a UV curable resin, or a plastic resin (eg, polystyrene, PMMA (polymethyl methacrylate)) is melted or dissolved in a solvent. And so on. Among these, a silicone rubber-based material can be suitably used because it is durable for transfer by repeated pressurization and has good releasability from the material. Moreover, as a metal material, Ni, Cu, Cr, Mo, W, Ir, Tr, Fe, Co, MgO, Ti, Zr, Hf, V, Nb, Ta, α-aluminum oxide, zirconium oxide, stainless steel (Stubbax material) and its alloys can be mentioned.

  Next, a polymer resin coating step of applying a polymer resin solution (hereinafter also referred to as “polymer solution”) to the stamper will be described. FIG. 4 is a process diagram showing a polymer resin coating process.

  Specifically, in the polymer resin application step, as shown in FIG. 4B, a polymer solution 16 in which a polymer resin is dissolved is applied to the surface of the produced stamper 13 on which the uneven pattern corresponding to the microneedles is formed. Apply. An appropriate amount of medicine to be administered can be mixed in this.

  It is preferable to use a biocompatible resin as the material of the polymer resin used in the polymer solution. Examples of such resins include gelatin, agarose, pectin, gellan gum, carrageenan, xanthan gum, alginic acid, starch, cellulose, triacetylcellulose, pullulan, polylactic acid, dextrin, and other materials that dissolve in warm water, or And a resin that melts by heating, such as maltose. Among these, maltose, starch, cellulose, triacetyl cellulose, pullulan, and dextrin which are sugars can be preferably used. Furthermore, maltose can enhance the adhesion between the base material and the polymer resin, and can be used for functional films. Since it can apply stress uniformly, it can be suitably used. The concentration varies depending on the material, but is preferably 10 to 30%. The solvent used for dissolution is not limited to hot water as long as it has volatility, and for example, alcohol can be used.

  As a method for preparing a polymer solution, when a water-soluble polymer (such as gelatin) is used, it can be produced by dissolving a water-soluble powder in water and adding a chemical after dissolution. If it 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. Moreover, when using the polymer (maltose etc.) fuse | melted with a heat | fever, it can manufacture by heating and melting a raw material and a chemical | medical agent. The heating temperature is preferably a temperature at which the raw material melts, and is specifically about 150 ° C. In addition, a polymer used for medical purposes, for example, an acrylic or polystyrene polymer can be dissolved in a solvent and used. As the solvent, solvents such as methyl ethyl ketone (MEK), isopropyl alcohol (IPA), ethanol, acetone, and trichloroethylene can be used.

  A specific method for applying such a polymer resin solution on the stamper 13 includes application using a spin coater. In the case of a stamper with a large area, it is conceivable that the solution is injected by dropping a solution only in the concave portion with a dispenser in order to form micro needles of the stamper.

  Next, the gelling material application process will be described. The gelling material application step is a step of applying a gelling material having adhesiveness to the base material to the surface of the base material. In the present invention, the gelling material refers to a substance having an action of solidifying (gelling) a liquid in a natural polymer.

  Examples of the base material 20 include, but are not limited to, polyvinyl chloride, polycarbonate, polymethyl methacrylate (PMMA), polystyrene, polyethylene, non-woven fabric, quartz, Si, and the like.

The gelling material is preferably a biocompatible material, and examples thereof include gelatin, agarose, pectin, gellan gum, carrageenan, xanthan gum, glucomannan, and alginic acid. Among these, protein gelatin, sugars agarose, pectin, gellan gum, and carrageenan can be preferably used. Especially, gelatin-based materials have adhesiveness to many substrates, and are sol-gel changing materials. Since it has a strong gel strength, it can be suitably used. The concentration of the gelling material varies depending on the material, but is preferably 10 to 30%. As a solvent used for dissolution, for example, water, ethanol or the like can be used. The coating amount is the amount of the gelling material, and is preferably 0.01 g / cm ² or more and 1 g / cm ² or less, more preferably 0.01 g / cm ² or more and 0.0. 1 g / cm ² or less. By setting the gelling material in the above range, an adhesive layer having sufficient strength can be formed with the base material and the polymer solution in the next bonding step.

  The method for applying the gelling material to the substrate can be performed without any particular limitation, and examples thereof include application using a spin coater.

  Next, the base material bonding step will be described. FIG. 5 is a process diagram for explaining the injection of the polymer solution and the bonding process of the base material. First, as shown in FIG. 5A, the base material 20 on which the gelling material 23 is applied on the side of the adhesive surface with the polymer solution 16 is placed on and attached to the polymer solution 16.

  Next, as shown in FIG.5 (b), the polymer solution 16 is pressurized using the press plate 17 of a press. Thereby, as shown in FIG. 5C, the polymer solution 16 applied to the stamper 13 is pressurized to the stamper side and injected to the tip of the recess 15 of the stamper 13. Moreover, since the internal bubbles in the concave portion 15 can be driven out by pressurizing and injecting, the convex portion array which is the inverted type of the concave portion array formed in the stamper 13 can be transferred to the polymer solution with high accuracy. it can. Thereby, a microarray needle sheet free from bubbles and the like can be manufactured.

  The pressure applied by the press plate 17 of the press machine during pressurization is preferably 0.05 to 30 MPa, more preferably 0.1 to 10 MPa, and still more preferably 0.5 to 1.5 MPa. By setting it as the said range, the bubble at the front-end | tip of the recessed part 15 is expelled, and the microneedle sheet | seat with a sharp tip and exact | precise can be formed. When the applied pressure is less than 0.1 MPa, the pressure is small, so that the bubbles are not sufficiently expelled. Moreover, even if it presses with the applied pressure over 30 Mpa, an effect does not change.

  Moreover, it is preferable that the time which pressurizes the polymer solution 16 with a press is 10 second or more. More preferably, it is 30 seconds or more, More preferably, it is 2 minutes or more. By setting the change time of the pressure state in the above range, bubbles at the tip of the recess 15 of the stamper 13 can be driven out.

  In the bonding step, the temperature of the stamper is preferably heated to a temperature of the glass transition point (Tg) of the polymer resin + 20 ° C. By performing at the above temperature, the injection can be performed while maintaining the fluidity of the polymer resin solution, so that it can be easily injected into the recess 15 of the stamper 13.

  Next, as shown in FIG. 5 (d), the polymer solution 16 and the gelling material 23 are mixed between the base material 20 and the polymer solution 16, whereby an adhesive layer 24 is formed and the polymer solution is dissolved. The liquid 16 and the substrate 20 are bonded. A solid mixed layer 25 can be formed by cooling and solidifying the adhesive layer 24 in a drying step described later.

  In the bonding step, the temperature of the polymer solution 16 is preferably 20 ° C. or higher and 100 ° C. or lower, more preferably 30 ° C. or higher and 80 ° C. or lower, and further preferably 40 ° C. or higher and 60 ° C. or lower. . By maintaining the above range, since the gelled material is solated by heat, water as a solvent can be mixed with the polymer solution and mixed at the interface with the polymer solution to form the adhesive layer 24. . When the temperature is not more than the above range, the polymer solution is gelled and loses fluidity, so that it is difficult to form the bonding layer 24. Further, the gelled material is difficult to be sol and water is not generated, and it is difficult to form the adhesive layer 24. Moreover, since it decomposes | disassembles by heating depending on a chemical | drug | medicine, the effect of a chemical | medical agent changes that temperature is more than the said range, and is not preferable. The temperature can be adjusted by the heating means 18 provided at the lower part of the stamper 13.

  Moreover, it is preferable that the bonding step and the step of injecting the solution to the tip of the recess of the recess array are performed simultaneously. By performing the process while applying pressure, the polymer solution 16 and the gelling material 23 can be sufficiently mixed, and a strong adhesive layer 24 can be formed.

  Subsequently, a drying step of the polymer solution 16 is performed. Specifically, drying is performed by blowing warm air on the applied polymer solution.

  As a drying method, first, cold air of 10 to 15 ° C. is blown to gel the surface, and then hot air of 10 to 20 m / s is blown. The hot air is preferably dehumidified hot air, for example, 40 ° C. and a relative humidity of 15% or less, more preferably 10% or less.

  Further, by gelling the applied polymer solution 16, the shape can be reduced and the peelability from the stamper 13 can be improved. In this case, the polymer solution can be gelled by flowing cold air at a low temperature. At this time, in order to make it completely gelatinize, cool air of 10 to 15 ° C. is blown for a longer time than the above case, and then hot air is blown in the same manner as described above. Next, when hot hot air is passed to dry, if the temperature of the hot air is too high, gelation of the solution in which the polymer resin is dissolved may return, or some chemicals may be decomposed by heating. Because the efficacy changes, it is necessary to pay attention to the temperature of the hot air blown. The polymer solution applied in this manner is dried, or the polymer solution is gelled and then dried to solidify as shown in FIG. 6A to obtain a polymer resin solidified product 19. When the polymer resin becomes the solidified product 19, the polymer resin is reduced more than the state when the polymer solution 16 is applied, and particularly when gelation is performed, the polymer resin is significantly reduced. Thereby, the solidified material 19 can be easily peeled from the stamper 13. Further, in this drying step, if the water content of the solidified product 19 becomes too low, it becomes difficult to peel off. Therefore, it is preferable to leave the water content in a state of maintaining elasticity. Specifically, although depending on the material constituting the solidified product 19, when the moisture content becomes 10 to 20%, the drying is stopped or a wind of 25 ° C. and a relative humidity of about 40% is blown. It is preferable to attach.

  Next, a peeling process is performed. Specifically, as shown in FIG. 6A, in the drying step, the substrate 20 having the mixed layer 25 formed by drying and solidifying is peeled off by turning from the end. The mixed layer 25 is formed by drying and solidifying the adhesive layer 24. In this manner, as shown in FIG. 6B, a microneedle sheet (polymer resin solidified product 19) can be manufactured.

  The peeling process of peeling the solidified material 19 from the stamper 13 is an important process. Normally, when a fine needle structure having a high aspect ratio is peeled off from the stamper 13, the contact area is large, so that a strong stress is applied, the fine needle is broken, and the stamper 13 does not peel off from the stamper 13. The microneedle sheet produced by remaining in the recess 15 has a fatal defect. Considering this point, in the present invention, the solidified product 19 and the base material 20 form an adhesive layer 24 with good adhesion. Therefore, since stress can be applied uniformly to the needle portion, even if the material is weak against stress concentration, peeling failure can be prevented.

  Furthermore, it is preferable that the material constituting the stamper 13 is made of a material that is very easy to peel off. Further, by making the material constituting the stamper 13 a soft material having high elasticity, it is possible to relieve the stress applied to the microneedles during peeling.

  In addition, in order to evaporate the moisture remaining on the microneedles on the surface of the polymer resin, a dry wind may be blown again after peeling. Specifically, it is desirable to pack after the moisture content in the solidified product 19 is 10% or less, preferably 5% or less, just before packing.

  In addition, since the stamper can be used a plurality of times, a plurality of microneedle sheets are produced in a short time by repeating the polymer solution coating process and the polymer solution drying process using the stamper after the peeling process. be able to. In addition, since the stamper cannot be used permanently, when it cannot be used, it can be manufactured by performing a stamper manufacturing process.

  In actual manufacture of the microneedle sheet, a plurality of stampers are prepared and manufactured at the same time, whereby the manufacture can be performed with high productivity.

  FIG. 7 shows another embodiment of the bonding process. In the present embodiment, the stamper frame 14 is provided around the side surface of the stamper 13 so as to be higher than the thickness of the stamper 13. Note that the stamper 13 and the stamper frame 14 can be integrally formed. The material of the stamper frame 14 can be the same material as the material of the stamper 13, but the stamper frame 14 is pressed to bring the pressure in the stamper frame 14 into a pressurized state. 14 is preferably an elastic body.

  Then, as shown in FIG. 7A, a polymer solution 16 is applied onto the stamper 13 provided with the stamper frame 14, and then the base material 20 to which the gelling material 23 is applied is applied to the polymer solution. 16 is attached and attached.

  Next, as shown in FIG. 7B, by pressing the stamper frame 14 with a press plate 17 of a press machine, the pressure in the stamper frame 14 can be brought into a pressurized state. It is injected into the recess 15 formed in the stamper 15 and the internal bubbles in the recess 15 can be driven out. Thereby, the convex part array which is the reverse type of the concave part array formed in the stamper 13 is transferred to the polymer solution with high accuracy, and a microneedle sheet with less mixing of bubbles and the like can be manufactured. Moreover, the adhesive layer 24 can be formed by mixing the polymer solution 16 and the gelling material 23.

  In the present embodiment, by pressing the stamper frame 14 with the press plate 17, even when the polymer solution 16 is indirectly pressurized, the same effect as when the polymer solution 16 is directly pressurized is obtained. be able to.

  In addition, about conditions, such as a pressurization force and a pressurization time, it can carry out on the same conditions.

  Hereinafter, practical effects of the present invention will be described by way of examples.

«Test Example 1: Effect of peeling due to adhesive layer»
[Example 1]
A master plate on which a square pyramid array is formed by cutting a metal plate made of Ni with a diamond bite and forming a quadrangular pyramid shape portion 12 in FIG. 3A having a bottom surface of 400 μm, a height of 1200 μm, a pitch of 1000 μm, and a tip R of 10 μm. 11 was created. A stamper 13 having a shape opposite to that of the original plate 11 shown in FIG. 3C was formed by pouring and curing a silicone resin on the original plate 11.

Next, maltose and chemicals were heated to 150 ° C. and dissolved to prepare a solution in which the polymer resin was dissolved. This solution was applied to the surface of the stamper 13 where the irregularities were formed by a spin coater. A base material (PET) coated with 0.1 g / cm ^{2 of a} gelling material (gelatin 20% solution) is placed thereon, and the silicone rubber stamper 13 and the press plate 17 of the press machine are 1 MPa, 120 ° C., 5 min. The polymer solution 16 was pressurized under the conditions.

  Then, 5 ° C. cold air was supplied for 10 minutes to cure the polymer solution. Finally, the solidified material 19 was peeled vertically so as not to apply force to the tip of the microneedles 22 to produce a microneedle sheet, and the peeled state at this time was confirmed. The peeling temperature at this time was 10 ° C.

[Comparative Example 1]
It was manufactured by the same method as in Example 1 except that the gelling material was an acrylic resin.

[Comparative Example 2]
It was produced by the same method as in Example 1 except that the gelling material was a rubber resin.

  The results are shown in Table 1.

  In Example 1 in which gelatin was used as the gelling material, the base material and the solidified product were sufficiently adhered, and the solidified product could be peeled well from the stamper. Moreover, about the comparative example 1 using an acrylic resin, and the comparative example 2 using a rubber-type resin, a base material and the solidified material did not adhere | attach and the mixed layer was not formed.

«Test Example 2: Polymer resin injection conditions and molding results»
[Example 2-8, Comparative Example 3]
A microneedle sheet was produced in the same manner as in Example 1. The injection conditions of the polymer solution into the stamper (pressing force, pressing temperature) and the amount of gelatin applied to the substrate (per 0.1 cm ² ) were performed under the conditions shown in Table 2. The pressing time was 5 minutes. Thereafter, in the same manner as in Example 1, a cold air was supplied to solidify the polymer solution, and the microneedle sheet was manufactured by peeling from the stamper, and this special molding result was confirmed. The results are shown in Table 2. The molding results were evaluated according to the following criteria.
A Sharp convex shape is molded to the tip, which is very good.
○: Transfer defects occur in some areas, but this is an acceptable range for the product.
X: Transfer defect has occurred and is unacceptable as a product.

  From Table 2, in Example 2, the fine shape was formed satisfactorily. In Examples 3 and 4 where the pressing force was low and Example 7 where the pressing temperature was low, the polymer solution was not partially injected into the recesses of the stamper, but this was in an acceptable range for the product. In Example 5 where the applied pressure was high, the stamper was broken, but the product itself could be produced without any problem. In Comparative Example 3 in which the amount of gelatin was not applied, an adhesive layer was not formed and transfer failure occurred. In Example 6 with a large coating amount, breakage was observed due to the influence of the adhesive layer, but it could be produced in a range acceptable as a product. From the above, it was confirmed that it is preferable to inject the polymer solution into the stamper under predetermined conditions.

≪Test Example 3: Stamper shape and molding result≫
[Examples 9-14]
The stamper was molded by the same method as in Example 1 except that the shape shown in Table 3 was used. The results are shown in Table 3. In addition, about the evaluation of the molding result, the evaluation was performed according to the same criteria as in Test Example 2.

  As shown in Table 3, with respect to the shapes of the stampers shown in Examples 9 to 14, good molding could be performed in any shape.

«Test Example 4: Effect of combination of polymer resin and gelling material»
[Examples 15-18, Comparative Examples 9-12]
A polymer resin and a gelling material were produced in the same manner as in Example 1 except that the materials shown in Table 4 were used. The results are shown in Table 4. In addition, about the evaluation of the molding result, the evaluation was performed according to the same criteria as in Test Example 2.

  As shown in Table 4, in Examples 15 to 18 in which 20% gelatin solution and 30% gelatin solution were used as the gelling material, good molding could be performed. However, in Comparative Examples 9 to 12 using an acrylic adhesive or a rubber adhesive as the gelling material, transfer defects occurred.

It is the perspective view (a) and sectional drawing (b) of the pyramidal microneedle of a microneedle sheet | seat. It is the perspective view (a) and sectional drawing (b) of the conical microneedle of a microneedle sheet | seat. It is process drawing of the manufacturing method of a stamper. It is process drawing of a polymer solution application | coating process. It is process drawing of a base-material adhesion | attachment process. It is process drawing of the peeling process of a microneedle sheet. It is process drawing of another embodiment of an injection | pouring process and an adhesion process.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 11 ... Original plate, 12 ... Shape part of cone or pyramid, 13 ... Stamper, 14 ... Stamper frame, 15 ... Recessed part, 16 ... Polymer solution, 17 ... Press plate, 18 ... Heating means, 19 ... Solidified product of polymer resin, DESCRIPTION OF SYMBOLS 20 ... Base material, 22 ... Convex part (microneedle), 23 ... Gelling material, 24 ... Adhesive layer, 25 ... Mixed layer

Claims (12)

A polymer resin coating step of applying a polymer resin solution for forming a functional film on a stamper having a fine concave array;
A gelling material application step of applying a gelling material having adhesiveness to the substrate to the surface of the sheet-like substrate;
The base material is placed on the stamper so that the surface of the dissolving liquid and the surface of the gelling material are combined, and the gelling material is mixed with the surface layer portion of the dissolving liquid to thereby dissolve the dissolution material. An adhesion step of forming an adhesive layer for adhering the liquid and the substrate;
A drying step of forming a solidified polymer resin obtained by drying and solidifying the solution in which the adhesive layer is formed;
And a peeling step of peeling the solidified material from the stamper together with the base material.   The method for producing a functional film according to claim 1, wherein the bonding step pressurizes the base material toward the stamper.   The shape of the fine convex array formed on the functional film is a pyramid or conical shape with a side or diameter of 0.1 to 1000 μm and a height of 0.3 to 3000 μm. The method of manufacturing a functional film according to claim 1, wherein the curvature radius R of the film is 300 μm or less.   The method for producing a functional film according to claim 1, wherein the polymer resin is a saccharide.   5. The method for producing a functional film according to claim 2, wherein, in the bonding step, the adhesive layer is formed by pressurization, and at the same time, the dissolving liquid is injected to a concave end of the concave array. .   6. The method for producing a functional film according to claim 2, wherein the pressurizing time for pressurizing the solution is 10 seconds or more.   The method for producing a functional film according to any one of claims 2 to 6, wherein the pressure for pressurizing the solution is in a range of 0.05 to 30 MPa.   The method for producing a functional film according to any one of claims 1 to 7, wherein the temperature of the solution in the bonding step is 20 ° C or higher and 100 ° C or lower. The method for producing a functional film according to claim 1, wherein the amount of the gelling material is 0.01 g / cm ² or more and 1 g / cm ² or less per unit area of the base material. .   The method for producing a functional film according to any one of claims 1 to 9, wherein the gelling material is selected from proteins and saccharides.   The function according to any one of claims 1 to 10, further comprising a mixed layer in which the solidified product of the polymer resin and the gelled material are mixed between the solidified product of the polymer resin and the gelled material. For producing a conductive film. 12. The function according to claim 1, wherein the material of the stamper is made of a material having a gas permeability greater than 1 × 10 ⁻¹² (mL / (s · m · Pa)). For producing a conductive film.

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