JP2011245055A - Method for manufacturing needle sheet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To mass-produce needle sheets having constriction parts at needle-shaped projection parts easily and highly precisely.SOLUTION: A method for manufacturing a needle sheet includes: a solution preparation step for preparing a polymer solution 32 obtained by dissolving or dispersing at least a polymer material into a solvent; a solution adding step for adding the polymer solution 32 to a mold 28 having a needle-shaped recessed part 30 to be the inverted shape of a needle-shaped metal 10 where the constriction part 12 is formed to fill the inside the needle-shaped recessed part 30 with it; a drying and shrinking step for forming a polymer molding 36 obtained by drying and solidifying the polymer solution 32 into a scaled-down shape of the needle-shaped recessed part; and a peeling step for peeling the molded polymer molding 36 from the mold 28. When the maximum diameter of the mold 28 is defined as Mmax, the minimum diameter is defined as Mmin, and a solid content volume concentration of the polymer solution 32 is defined as D, the shape of the needle-shaped recessed part 30 of the mold 28 and the solid content volume concentration D of the polymer solution 32 are adjusted so that an expression D≤(Mmin/Mmax)is satisfied.

Description

  The present invention relates to a method for manufacturing a needle sheet, and more particularly to a method for manufacturing a needle sheet in which a needle-like convex portion is formed on the surface of a sheet portion and a constricted portion is formed on the needle-like convex portion.

  In recent years, a needle sheet in which needle-like convex portions having a high aspect ratio structure are formed on the surface of a sheet portion has been applied in various fields as a functional film. For example, in the medical technology field, a percutaneous absorption sheet that efficiently administers a drug to a patient through the patient's skin surface or skin stratum corneum by using a needle sheet having a high aspect ratio structure has attracted attention. Yes.

  As the outer diameter of the needle-like convex portion of the needle seat, various outer shapes such as a needle shape, a tip knife shape, and a twist shape have been proposed. The needle sheet has needle-shaped convex portions having a diameter of 50 to 200 μm and a height of 100 to 2000 μm arranged in an array on the surface of the sheet portion, and is thin and has an aspect ratio to puncture the skin without pain. It is preferable that the tip is a needle-like convex portion that is high and has a sharp tip as much as possible.

  Moreover, the transdermal absorption sheet which is one aspect using a needle sheet as a functional membrane uses a biocompatible and biodegradable polymer material as a material, and a drug is added in advance to the polymer material. Thereby, a chemical | medical agent can be discharge | released in skin by sticking a percutaneous absorption sheet on skin in the state which made the needle-shaped convex part puncture in skin. As such a percutaneous absorption sheet, there exist patent documents 1, 2, 3, etc., for example.

  However, the conventional transdermal absorption sheet has the following drawbacks.

  (1) It is necessary to keep the sheet portion stuck to the skin until the needle-like convex portion punctured in the body (in the skin) is dissolved, which is troublesome for the recipient.

  (2) When the sheet part is peeled off from the skin, the needle-like convex part inserted in the skin comes off.

  (3) It cannot be visually determined whether or not the needle-like convex portion has dissolved in the skin, that is, whether or not the drug has been released.

  As a method for solving these problems, for example, Patent Documents 4, 5, and 6 disclose that the needle-like convex portion is pierced into the skin and then the needle-like convex portion is broken and remains in the skin. A structure that makes the base part easy to break has been proposed. In Patent Document 4, a constricted portion is provided in the intermediate portion of the needle so as to be easily broken. In patent document 5, it is made easy to break by forming in the level | step difference structure from which a diameter differs in the intermediate part of a needle | hook. Patent Document 6 proposes forming a constricted portion by pressing and grinding a wire having a diameter of 20 μm near the boundary between the sheet portion and the needle portion.

  In this way, by allowing only the needle-like convex portions to remain in the skin, the dose (dose) of the drug can be made constant.

JP 2007-37885 A JP 2007-87992 A JP 2008-228958 A JP 2003-238347 A JP 2005-154321 A JP 2009-138010 A

  However, Patent Documents 4 and 5 describe that a constriction is formed at the central portion of the needle-like convex portion, but does not describe how to actually manufacture a needle having the constricted portion.

  In addition, the method of forming the constricted portion by grinding each needle-like convex portion with a wire as in Patent Document 6 is not suitable for mass production and the productivity is deteriorated.

  The present invention has been made in view of such circumstances, and an object of the present invention is to provide a method for manufacturing a needle sheet that can easily and accurately mass-produce a needle sheet having a constricted portion on a needle-like convex portion. And

In order to achieve the above object, the needle sheet manufacturing method according to claim 1 has a needle-like convex portion formed on the surface of the sheet portion and a constricted portion formed on the needle-like convex portion. In the production method of the above, a solution preparation step of preparing a polymer solution in which at least a polymer material is dissolved or dispersed in a solvent, and a mold having a needle-like concave portion that is an inverted shape of the needle-like convex portion on which the constricted portion is formed A solution application step of applying the prepared polymer solution to fill the needle-like recesses, and drying and shrinking the applied polymer solution in a gelled state, thereby reducing the scale of the needle-like recesses. A drying shrinkage step for forming a polymer molded body dried and solidified into a shape, and a peeling step for peeling the molded polymer molded body from the mold. The diameter and Mmax, the minimum diameter with a Mmin, the solid volume concentration of the polymer solution is D, the following formula D ≦ (Mmin / Mmax) ³ the mold of needle-like recess shaped so as to satisfy And the solid content volume concentration D of the polymer solution is adjusted.

  In addition, the scale shape said here does not mean a perfect scale shape, and the polymer molded object formed by drying shrinkage should just be substantially the same as the scale shape of a needle-shaped recessed part shape. Moreover, at least the polymer material is contained in the solid content of the solid content volume concentration of the polymer solution.

  According to the present invention, by using a mold having a needle-like concave portion that is an inverted shape of the needle-like convex portion formed with the constricted portion, the polymer solution is applied to the mold and solidified by drying, whereby the needle-like concave portion of the mold is obtained. A polymer molded body having a transferred shape was obtained. As described above, since the needle sheet in which the constricted portion is formed on the needle-like convex portion is manufactured by the transfer method using the mold, mass production can be achieved.

  However, in the case of this transfer method, it is important to dry and solidify the polymer solution so as to be substantially the same as the scale shape of the needle-like recess. For this purpose, the polymer solution filled in the needle-like recess is gelled. It is necessary to dry shrink in the state.

  Furthermore, the polymer molded body obtained by drying shrinkage must be peeled off from the needle-shaped recess so as not to be caught by the constricted portion of the mold.

Therefore, in the present invention, in the drying shrinkage process, when the maximum diameter of the mold is Mmax, the minimum diameter is Mmin, and the solid content volume concentration of the polymer solution is D, the following formula D ≦ (Mmin / Mmax ) Since the shape of the mold and the solid content volume concentration D of the polymer solution are adjusted so as to satisfy ³ , the polymer molded body can be easily and accurately peeled when peeling from the mold.

  Thereby, the needle seat which has a constriction in a needle-like convex part can be mass-produced easily and with high precision. In addition, although the position of the constriction part formed in a needle-like convex part can also be formed in the intermediate part of a needle-like convex part, it is more preferable that it is a root part vicinity.

  In the present invention, in the drying shrinkage step, the polymer solution is cooled to a gelation temperature at which the polymer solution gels to stop the fluidity of the polymer solution, and then dried with low-temperature drying air that does not restore the fluidity. It is preferable to solidify.

  In order for the polymer molded body formed by drying shrinkage in the drying shrinkage step to have a shrink shape with a needle-like recess shape, it is necessary to dry the polymer solution in a gelled state, that is, in a state where the flow of the polymer solution is stopped. is there.

  From this point of view, in the present invention, the polymer solution is cooled to a gelation temperature at which the polymer solution is gelled to stop the fluidity of the polymer solution, and then dried and solidified with low-temperature drying air that does not restore the fluidity. Therefore, the polymer molded body can be formed in a contracted shape having a needle-like concave shape. Here, it is preferable that the low-temperature drying air has a gelation temperature of + 20 ° C. or lower.

  Whether or not the fluidity of the polymer solution is stopped may be determined so long as the polymer solution in the needle-like recess does not move by tilting the mold. In this case, it is preferable to use dehumidified low-humidity drying air with a humidity of 20% or less so that drying is not slow because it is a low-temperature drying air.

  In the present invention, it is preferable to use a mold made of an elastic material having gas permeability, for example, a silicone resin, as the mold. This is because when the volume of the polymer solution is dried and shrunk in the drying shrinkage process, the air outside the mold passes through the mold so that the solid content in the polymer solution does not adhere to the wall of the mold-like recess. It is because it is necessary to invade. As the volume of the polymer solution is dried and contracted, air enters the needle-like recesses, so that an air layer is formed between the polymer solution and the needle-like recess walls. Shrinks without sticking to. Thereby, the polymer molding which satisfies d> = D in a drying shrinkage process can be fabricated.

  Moreover, although the acicular convex part of a polymer molded object shrinks and it is easy to come out from an acicular concave part, the sheet | seat part is closely_contact | adhered to the mold surface and is hard to peel off. Therefore, by forming the mold from an elastic material, if the mold is peeled while being elastically deformed in the peeling step, the sheet portion of the polymer molded body can be easily peeled from the mold surface. If the sheet portion is peeled off, the needle-like convex portion reduced by drying shrinkage can be easily extracted from the needle-like concave portion of the mold.

  In the present invention, the mold is formed by grinding a wire-like metal to form a needle-like convex shape having the constricted portion, and fixing the formed plurality of wire-like metals to a pedestal to produce an original plate. Produced by an original plate production step, an inversion type production step of producing an inversion type of the original plate using an elastic material having gas permeability, and a peeling step of separating the inversion type from the original plate to form a mold. It is preferable. This specifically shows a method for producing a mold having a constricted portion in a needle-like concave portion.

  In the present invention, the mold is preferably produced by drilling a needle-like concave portion having a constricted portion by grinding using a drill in an elastic material having gas permeability. This specifically shows still another aspect of a mold manufacturing method having a constricted portion in a needle-like concave portion.

  In this invention, it is preferable to peel in the said peeling process, elastically deforming the said mold. As described above, the sheet portion of the polymer molded body is in close contact with the mold surface and is not easily peeled off. Therefore, the sheet portion can be easily peeled by peeling while elastically deforming the mold. Accordingly, the polymer molded body and the mold are not forcibly separated from each other, so that the needle-like convex portion is not damaged in the separation step.

  In the present invention, the polymer material is preferably a material that easily shrinks upon drying, such as gelatin. Thereby, since the density | concentration of a polymer solution can be raised, it becomes easy to ensure intensity | strength required for the acicular convex part of a needle seat.

  In the present invention, the needle sheet is preferably a transdermal absorption sheet in which a drug and a pigment are contained in a polymer material.

  The needle sheet can be used as various functional membranes, but the present invention is particularly effective when the needle sheet is used as a transdermal absorption sheet.

  ADVANTAGE OF THE INVENTION According to this invention, the needle seat which has a constriction part in a needle-like convex part can be mass-produced easily and with high precision.

Explanatory drawing explaining the production process of a mold in one Embodiment of the manufacturing method of the needle seat of this invention. Explanatory drawing explaining the formation process of a needle seat in one Embodiment of the manufacturing method of the needle seat of this invention. Configuration diagram showing an example of a pressure filling device Explanatory drawing explaining the difference between the case where the polymer solution is gelated and dried and solidified, and the case where the polymer solution is dried and solidified without gelation Explanatory drawing for the needle-like convex part of the polymer molding to come out without being caught by the constricted part of the needle-like concave part in the mold Explanatory drawing explaining the cross-sectional shape of the mold Explanatory drawing explaining the one aspect | mode of the needle seat manufactured by this invention

  Hereinafter, preferred embodiments of a method for producing a needle seat according to the present invention will be described with reference to the accompanying drawings.

  FIGS. 1A to 1C are diagrams showing a process for producing an original plate and forming an inverted mold from the original plate in the needle sheet manufacturing method. Moreover, (A)-(D) of FIG. 2 is a figure explaining the process until it manufactures a needle sheet using the mold produced in FIG.

[Mold making process]
As a mold manufacturing method in the embodiment of the present invention, (a) a method of drilling a needle-like concave portion having a constricted portion by grinding using a drill in an elastic material having gas permeability, or (b) grinding There is a method in which an original plate is prepared, and the original plate is molded with a gas-permeable elastic material to prepare an inverted mold. A method for manufacturing a mold by the method (b) will be described below.

  As shown in FIG. 1A, the wire-like metal 10 is ground to form a desired needle-like convex shape having a constricted portion 12. For example, the tip portion 14 having a diameter of 100 μm is ground into a conical shape having a radius of curvature of 5 μm from the tip of the wire-like metal 10 having a diameter of 150 μm, and the diameter is set to 100 μm at a position 500 μm from the tip of the wire-like metal 10. The constricted portion 12 is formed by grinding. The lower side of the constricted portion 12 of the wire-like metal 10 is referred to as a base end portion 16.

  The length and thickness of the wire-like metal 10, the shape of the tip end portion 14 of the wire-like metal 10, and the position and amount of the constricted portion 12 are the needle-like convexity of the needle sheet 40 (see FIG. 4) as the final product. It may be adjusted appropriately according to the part 34. A plurality of, for example, 100 wire-like metals 10 thus ground are prepared (only five are shown in FIG. 1A).

  Next, as shown in FIG. 1 (B), a hole 20 is formed in the center of a smooth rectangular metal plate 18, and the base end 16 of the wire-like metal 10 ground is inserted into the hole 20. Stick. The wire-like metal 10 is inserted so that the constricted portion 12 of the wire-like metal 10 is exposed from the surface of the metal plate 18. For example, a length of about 600 μm is projected from the surface of the metal plate 18 from the tip of the wire-like metal 10. The metal plate 18 is preferably a copper plate having a relatively small hardness so that the holes 20 can be easily formed.

  A plurality of holes 20 are formed in a grid pattern at equal pitch intervals in the vertical direction and the horizontal direction, using one ground metal wire 10 arranged at the center of the metal plate 18 as a reference for alignment. The wire-like metal 10 that has been ground is inserted into the hole 20 and disposed. The number of the wire-like metals 10 to be arranged is preferably about 100 in total, 10 in the vertical direction and 10 in the horizontal direction. Thereby, the original 22 is produced.

  Next, as shown in FIG. 1C, a rectangular mold 24 is provided around the original plate 22, and a resin material 26 that has gas permeability and is easily elastically deformed is poured into the mold 24. Next, after solidifying the resin material 26 and transferring the shape of the wire-like metal 10, the mold 24 is removed. Then, the solidified resin material 26 is peeled from the original plate 22. Even if the wire-like metal 10 has the constricted portion 12 when it is peeled off, it can be peeled off from the original plate 22 by elastically deforming the resin material 26.

  The resin material 26 may be any resin as long as it has gas permeability and is easily elastically deformed. For example, a silicone resin can be suitably used.

  Thereby, the mold 28 shown in FIG. 2A can be manufactured. The mold 28 is gas permeable and easily elastically deformed, and is formed with a plurality of needle-like recesses 30 to which the distal end portion 14, the proximal end portion 16 and the constricted portion 12 formed on the wire-like metal 10 are transferred. ing. The diameter of the constricted portion 28A of the mold 28 is dmm.

  The mold 28 produced by the above-described method may be used alone, or a plurality of molds 28 may be used side by side.

[Needle sheet forming process]
Next, a forming process for forming the needle sheet 40 will be described.

  First, as shown in FIG. 2A, the mold 28 produced as described above is prepared.

  On the other hand, a polymer solution 32 in which a polymer material is dissolved or dispersed in a solvent is prepared (solution preparation step).

  The polymer solution 32 is a solution in which at least a polymer material is dissolved or dispersed in a solvent such as water, alcohol, or methyl ethyl ketone (MEK). In addition to the polymer material and the solvent, the polymer solution may contain various additives depending on the purpose of use of the needle sheet 40. For example, when manufacturing the transdermal absorption sheet which is one aspect | mode of the needle sheet 40 (refer FIG. 7), a chemical | medical agent and a pigment | dye can be contained in a polymer solution. If the dye is added, when only the needle-like convex part of the percutaneous absorption sheet is left in the skin, the solubility of the needle-like convex part 34 (see FIG. 7) in the body can be determined based on the disappearance of the dye. .

  The polymer material of the polymer solution 32 is preferably a material that easily undergoes drying shrinkage in a drying process described later.

  Moreover, it is preferable that it is a polymer material (biodegradable material) which is easily decomposed | disassembled in_vivo | within_body, and a polymer material (biocompatible material) which has biocompatibility.

  Examples of polymer materials having these properties include saccharides such as glucose, maltose, and pullulan, and biodegradable polymers such as gelatin, polylactic acid, and lactic acid / glycolic acid copolymers.

  Among them, gelatin is a material that has a large drying shrinkage and can be cast at a low temperature. Therefore, when a drug is added to a polymer solution, the volume shrinkage ratio increases during the drying process of molding the polymer molded body. At the same time, it is preferable in that the thermal deterioration of the drug can be prevented.

  The viscosity of the polymer solution 32 is preferably 5 Pa · s or less in consideration of the fact that the polymer solution 32 is easily filled into the needle-shaped recess 30 of the mold 28 in the solution application step described later. More preferably, it is as follows.

  Next, as shown in FIG. 2 (B), the prepared polymer solution 32 is applied to the surface 28B of the mold 28 and filled into the needle-shaped recess 30 (solution application step). The needle-like recess 30 of the mold 28 is a recessed area compared to the surface 28B of the mold 28, and is defined by the recess wall surface 30A.

  Examples of a method for applying the polymer solution 32 to the mold 28 include methods such as bar coating, spin coating, spray coating, and dropping using a dispenser. Especially, since the aspect which dripped the polymer solution 32 using a dispenser can control a dripping amount with high precision irrespective of the viscosity of the polymer solution 32, it is preferable.

  Further, it is difficult to quickly fill the needle-like recesses 30 only by applying the polymer solution 32 to the surface 28 </ b> B of the mold 28. Therefore, as a method for accelerating the filling of the polymer solution 32 into the needle-shaped concave portion 30, a method in which the polymer solution 32 is pressurized after being applied to the mold surface 28B, or a method in which the polymer solution 32 is applied to the mold 28 under reduced pressure. The method of returning to atmospheric pressure after doing is mentioned.

  FIG. 3 is an example of a pressure filling device 50 that performs the pressure method. The pressure filling device 50 includes a pressure vessel 52 having an inlet 58 and a discharge port 60, a pedestal 54 provided inside the pressure vessel 52, and a compressor 56 that sends pressurized fluid to the pressure vessel 52. By operating the pressure filling device 50 according to the following procedure, the polymer solution 32 applied to the mold surface 28B can be filled into the needle-like recess 30. In a state where the mold 28 to which the polymer solution 32 is applied is placed on the pedestal 54, the pressurized fluid is sent into the pressure resistant container 52 through the inlet 58 by the compressor 56. As the pressurized fluid, gas or liquid can be used. Examples of the gas that can be used as the pressurized fluid include air. From the viewpoint of preventing dissolution of the pressurized fluid in the polymer solution 32, it is preferable to select a gas having a low dissolution rate in the polymer solution 32. . From the viewpoint of preventing an increase in viscosity due to volatilization of the polymer solution 32, a liquid of the same type as the solvent of the polymer solution 32 is previously stored in the pressure resistant container 52, and the pressure resistant container 52 is saturated with the vapor of the liquid. It is preferable to do. By operating the pressure filling device 50 according to the above procedure, the polymer solution 32 is quickly filled into the needle-like recess 30.

  Next, as shown in FIG. 2C, a polymer molded body 36 obtained by drying and shrinking the applied polymer solution 32 to be solidified into the shape of the needle sheet 40 is formed (dry shrinkage step). Examples of the method for drying and shrinking the polymer solution 32 include a method for volatilizing the solvent of the polymer solution 32 by heating, blowing, or reducing pressure. In the process of drying shrinkage of the polymer solution 32, the polymer solution 32 shrinks at a constant volume shrinkage rate corresponding to the solid content volume concentration in the polymer solution. Accordingly, a polymer molded body 36 having a needle-like convex portion 34 in which the shape of the needle-like concave portion 30 is reduced is formed in the mold 28. The polymer molded body 36 and the needle sheet 40 are substantially the same, but the one before peeling from the mold 28 is referred to as the polymer molded body 36, and the one after peeling is referred to as the needle sheet 40. To.

  An important point in this drying shrinkage process is that the polymer solution 32 applied to the mold 28 and filled in the needle-shaped recess 30 is dried and shrunk in a gelled state. By drying and shrinking in such a gelled state, as shown in FIG. 4A, a polymer molded body 36 having needle-like convex portions 34 that are substantially the same as the scale shape of the needle-like concave portions 30 can be obtained. it can. Examples of a method for gelling the polymer solution 32 include a method for cooling the polymer solution 32 to a gelling temperature, a method using a gelling agent, and the like.

  Incidentally, FIG. 4B shows a case where the polymer solution 32 is dried and solidified without gelation, and the needle-like convex portion 34 is not dried and solidified so as to have a reduced-scale shape of the needle-like concave portion 30.

  Further, the more important point in the drying shrinkage step is that the needle-like convex portion 34 of the polymer molded body 36 can be pulled out without being caught by the constricted portion 28A of the needle-like concave portion 30 of the mold 28 in the next peeling step. .

  For this purpose, when the maximum diameter of the mold is Mmax, the minimum diameter is Mmin, and the solid content volume concentration of the polymer solution 32 is D, the mold 28 satisfies the following expression (1). It is important to adjust the shape of the needle-shaped recess 30 and the solid content volume concentration D of the polymer solution 32.

D ≦ (Mmin / Mmax) ³ (1)
The procedure for deriving this formula (1) will be described in detail. As shown in FIG. 5, the maximum diameter portion of the needle-like convex portion 34 of the polymer molded body 36 is Pmax, and the minimum diameter portion (constricted portion) is Pmin. When the maximum diameter portion of the mold 28 is Mmax and the minimum diameter portion (the portion corresponding to the constricted portion) is Mmin, the needle-like convex portion 34 is required to come out without being caught by the constricted portion 28A of the needle-like concave portion 30. A necessary condition is to satisfy the following expression (2).

Mmin ≧ Pmax (2)
FIG. 6 is a top view of the needle-like recess 30 of the mold 28. When the polymer solution 32 filled in the needle-like recess 30 is dried and shrunk in a gelled state, it shrinks from a solid line state to a dotted line state. To do. Therefore, if the radial cross section of the needle-like recess 30 is circular, Mmin ≧ Pmax can be applied as it is, but if it is square, it is necessary to satisfy Mmin ≧ Pmax in the diagonal direction.

  Here, in the drying shrinkage step, the polymer solution 32 filled in the needle-like concave portion 30 is dry-shrinked to the needle-like convex portion 34 of the polymer molded body 36 by drying and shrinking in a state where the polymer solution 32 is gelled. Assuming that the volumetric shrinkage is S, it can be expressed by the following equation (3).

S = (Pmax / Mmax) ³ (3)
Here, when the volume shrinkage rate S is expressed by the volume of the polymer solution 32 and the volume of the polymer molded body 36, the volume when the polymer solution 32 filled in the needle-like recess 30 gels and stops flowing is denoted by V1. The volume shrinkage ratio S can be defined as V2 / V1, where V2 is the volume of the polymer molded body 36 obtained by drying shrinkage.

  Furthermore, when the solid content volume concentration of the polymer solution 32 filled in the needle-shaped recess 30 of the mold 28 is D (%), the polymer solution 32 filled in the needle-shaped recess 30 is immediately polymerized. It gels without evaporation of the solvent in 32, and in this state, it is dried and shrunk to the reduced-scale shape of the needle-like recess 30, and all the solvent is removed and solidified by drying. The volume of the needle-like convex portion 34 of the polymer molded body 36 formed by drying and solidification corresponds to the solid content volume of the polymer solution 32 filled in the needle-like concave portion 30 of the mold 28. Therefore, assuming that the drying shrinkage has progressed in an ideal state, it can be considered that the volume shrinkage ratio S = the solid content volume concentration D of the polymer solution 32.

Thus, S = (Pmax / Mmax) ³ in the above equation (3) can be rewritten by the following equation (4).

D = (Pmax / Mmax) ³ (4)
Therefore, the equation (4) is substituted into the above equation (2), and the equation is arranged so that the solid content volume concentration D of the polymer solution 32 is on the left side, the maximum diameter of the mold is Mmax, and the minimum diameter is Mmin on the right side. Then, D ≦ (Mmin / Mmax) ³ in the formula (1) can be obtained. That is, the condition for the needle-like convex portion 34 of the polymer molded body 36 to come out without being caught by the constricted portion 28A of the mold 28 is expressed by the shape of the needle-like concave portion 30 of the mold 28 and the solid content volume concentration D of the polymer solution 32. Can do.

In order to satisfy D ≦ (Mmin / Mmax) ³ in the drying shrinkage process, the following three factors are important. That is,
(A) As the polymer material of the polymer solution 32, a material that easily shrinks during drying, such as gelatin, is selected.
(B) The solid content volume concentration D of the polymer solution 32 is adjusted appropriately. For example, the solid content volume concentration D is preferably about 10 to 40% by mass. Therefore, since it is necessary to adjust the solid content volume concentration D of the polymer solution 32 widely, it is preferable that the polymer material has a high solubility in the solvent, and gelatin can be suitably used in the above-described polymer material. Further, if the solid content volume concentration D of the polymer solution 32 is reduced, the volume shrinkage S when the solid content in the polymer solution 32 is solidified in the drying shrinkage step is increased and satisfies Mmin ≧ Pmax. The needle-like convex portion 34 of the polymer molded body 36 becomes too thin, and the necessary strength for the needle-like convex portion 34 of the needle sheet 40 cannot be ensured. On the other hand, if the solid content volume concentration D of the polymer solution 32 is increased, the volume shrinkage rate S is reduced, and it is difficult to satisfy Mmin ≧ Pmax. Therefore, it is preferable to grasp the relationship between the strength of the needle-like convex portion 34 of the needle seat 40 and the volume shrinkage rate S in advance by a preliminary test or the like.
(C) The mold 28 has gas permeability.

  Here, the gas permeability of the mold 28 will be described.

  When the polymer solution 32 is dried and shrunk and solidified into the shape of the needle sheet 40 to form the polymer molded body 36, the solid content of the polymer solution 32 does not adhere to the wall surface 30 </ b> A of the needle-like recess 30, and the polymer solution 32. And an air layer is formed between the wall surface 30A. For this purpose, it is important for the mold 28 to have gas permeability, and as a result, the air passes through the needle-shaped recess 30 to the extent that the volume of the polymer solution 32 is reduced by drying and shrinking to form an air layer. To do. As a result, the solid needle-like convex portion 34 is formed, so that the needle-like convex portion 34 can be made smaller than the shape of the needle-like concave portion of the mold 28. As a result, a polymer molded body 36 that satisfies Mmin ≧ Pmax in the drying shrinkage step can be obtained.

  Incidentally, if the mold 28 is not gas permeable, the polymer in which the solid content in the polymer solution adheres to the concave wall surface 30A of the mold 28 when the volume of the polymer solution 32 shrinks in the drying shrinkage process, and follows the shape of the needle-shaped concave portion. Since the molded body is molded, a hollow polymer molded body is formed. As a result, the polymer molded body 36 that satisfies Mmin ≧ Pmax cannot be formed in the drying shrinkage step.

  Next, as shown in FIG. 2D, the molded polymer molded body 36 is peeled from the mold 28 (peeling step). As a peeling method of the polymer molded body 36, for example, a peeling sheet (not shown) having an adhesive layer on one side is attached to the sheet portion back surface 35 </ b> A of the polymer molded body 36 and peeled together with the peeling sheet, or polymer molding. Examples include a method of adsorbing a suction cup (not shown) to the sheet portion rear surface 35A of the body 36 and peeling it.

As described above, in drying shrinkage step, by adjusting the solid volume concentration D shape and the polymer solution 32 in the needle recess 30 so as to satisfy Mmin ≧ Mmax × ³ √D, satisfying Mmin ≧ Pmax Therefore, the polymer molded body 36 can be accurately peeled from the mold 28 without being caught by the constricted portion 28A of the mold 28 in the peeling step.

  In addition, the needle-like convex portion 34 of the polymer molded body 36 is reduced and is easily removed from the needle-like concave portion 30 of the mold 28, but the sheet portion 35 is in close contact with the mold surface 28B and is not easily peeled off. Therefore, if the mold 28 is formed of an elastic material such as silicone resin and is peeled while elastically deforming the mold 28 in the peeling step, the sheet portion 35 of the polymer molded body 36 is easily peeled off from the mold surface 28B. . If the sheet portion 35 is peeled off, the needle-like convex portion 34 reduced by drying shrinkage can be easily extracted from the needle-like concave portion 30 of the mold 28.

  In the elastic deformation of the mold 28, the mold 28 may be peeled off while being elastically deformed so that the opening (corresponding to the constricted portion 28A) of the needle-like recess 30 is expanded. As a result, the constricted portion 28 </ b> A expands, so that the needle-like convex portion 34 can be more easily extracted from the needle-like concave portion 30 of the mold 28. Thereby, the polymer molded body 36 can be peeled off from the mold 28 without damaging the needle-like convex portions 34 of the polymer molded body 36.

  As described above, according to the method for manufacturing a needle sheet in the embodiment of the present invention, a mold 28 having a needle-like recess 30 that is a reverse shape of the wire-like metal 10 on which the constricted portion 12 is formed is used. Since the needle sheet 40 in which the constricted portion 44 is formed on the needle-like convex portion 34 is manufactured by a transfer method in which the polymer solution 32 is applied and dried to transfer the shape of the needle-like concave portion of the mold 28. Can be achieved.

  As shown in FIG. 7, the needle-like convex portion 34 of the needle sheet 40 has a high aspect ratio in which the maximum diameter portion D of the needle-like convex portion 34 is in the range of 50 to 200 μm and the height H is in the range of 100 to 2000 μm. It is preferable that Here, the height H of the needle-like convex portion 34 means the length of protrusion from the surface of the sheet portion 35, and the aspect ratio of the needle-like convex portion 34 is the height H of the needle-like convex portion 34. And the maximum diameter portion D is defined by A = H / D, and is preferably 1 or more. Specifically, the ratio between the maximum diameter portion D and the height H is preferably in the range of 1: 2 to 1:10.

  In addition, the length H1 of the tip portion 42 (conical portion) of the needle-like convex portion 34 is also one of the important factors that determine the needle strength of the needle-like convex portion 34, and the needle-like concave portion 30 of the mold 28 has a length H1. It can be adjusted by appropriately changing the shape.

  When the needle sheet 40 is used as a transdermal absorption sheet that is one embodiment of the functional membrane, first, the manufactured percutaneous absorption sheet is placed on the skin, and the needle-like convex portions 34 are formed from the surface side of the sheet portion 35. By pressing, the needle-like convex part 34 containing the medicine is punctured into the skin. Next, while the sheet portion 35 of the percutaneous absorption sheet is lightly held from above, the sheet portion 35 is laterally displaced by about 1 cm, and then the sheet portion 35 is peeled off from the skin. Thereby, since the needle-like convex part 34 is easily broken at the constricted part 44, only the needle-like convex part 34 can be left in the skin.

  As described above, an example of the present invention has been described in detail. However, the present invention is not limited to this example, and various improvements and modifications may be made without departing from the scope of the present invention.

[Example]
An example in which a percutaneous absorption sheet is actually manufactured by the needle sheet manufacturing method described in the embodiment of the present invention will be described below.

<Mold production>
First, using a wire-like metal 10 having a diameter of 150 μm, the tip portion 14 having a diameter of 100 μm from the tip was ground into a conical shape having a radius of curvature of 5 μm. Further, the constricted portion 12 was formed by thinning a 500 μm portion from the tip of the wire-like metal 10 to 100 μm by grinding. 100 wire-like metals 10 ground in this way were produced.

  And after making the hole 20 in the center part of the smooth rectangular copper plate 18 of 40 mm x 40 mm, the front-end | tip end of the wire-like metal 10 protruded 600 micrometers from the surface (hole entrance) of the copper plate 18, and pitch 1mm 10 × 10 pieces were fixed in three dimensions. Thereby, an original plate 22 was produced. Then, by using this original plate 22, a mold 28 which is an inverted type inverted by silicone rubber (RTV rubber for Shin-Etsu silicone mold) was produced. The mold 28 has a rectangular shape with a length and width of 45 mm and a thickness of 5 mm, and 10 × 10 needle-like recesses 30 are arranged vertically and horizontally at a pitch of 1 mm on the mold surface 28B. At this time, since the material of the mold 28 is silicone rubber and is an elastic body, even if the constricted portion 12 is present on the wire-like metal 10 of the original plate 22, the mold 28 is deformed and peeled, whereby the needle-like shape of the mold 28 is obtained. It was possible to cleanly peel from the wire-like metal 10 without damaging the recess 30.

<Process for preparing polymer solution>
Fish gelatin was dissolved in water to form a 20% by mass aqueous solution, and this aqueous solution was stirred at 40 ° C. and then kept at the same temperature. And 1 mass% of ascorbic acid was added to this aqueous solution as a chemical | medical agent, and 0.01 mass% of indocyanine green which is a pigment | dye was added. Thereby, a polymer solution 32 was prepared.

<Solution application process>
1.5 mL of the polymer solution 32 was dropped on the silicone rubber mold 28 and processed by the pressure filling device 50. That is, the mold 28 provided with the polymer solution 32 was placed in a pressure resistant container 52 whose interior was heated to 40 ° C. by a jacket. Then, the pressure in the pressure vessel 52 was held at 0.5 MPa for 3 minutes by compressed air from the compressor 56, and the polymer solution 32 was filled in the needle-shaped recess 30 of the mold 28.

<Drying shrinkage process>
In the pressure vessel 52, hot air of 50 ° C. (relative humidity 40%) was applied to the mold 28 to perform a drying shrinkage treatment for 4 hours. As a result of the drying shrinkage treatment, the polymer solution 32 in the needle-shaped recess 30 was dried and shrunk to solidify, and a polymer molded body 36 was formed.

<Peeling process>
An adhesive tape was applied to the surface of the sheet portion 35 of the polymer molded body 36, and the polymer molded body 36 was peeled from the mold 28 together with the adhesive tape. Thus, a transdermal absorption sheet containing a drug and a pigment was produced. In this peeling step, the needle-like convex portion 34 of the molded polymer molded body 36 is dried and contracted, so that the maximum diameter portion of the needle-like convex portion 34 is not caught by the constricted portion 28A of the mold 28, and the mold 28 Could be easily peeled off.

  As a result of measuring the maximum diameter portion (Pmax) in the needle-like convex portion 34 of the peeled polymer molded body 36, it was 100 μm. That is, when the maximum diameter portion of the needle-shaped convex portion 34 of the molded polymer molded body 36 is Pmax and the minimum diameter portion of the mold portion corresponding to the constricted portion 44 of the needle-shaped convex portion 34 is Mmin, drying shrinkage In the process, drying shrinkage could be performed so as to satisfy Mmin ≧ Pmax. Thus, a transdermal absorption sheet was produced.

<Use test of transdermal absorption sheet>
First, the manufactured percutaneous absorption sheet was placed on the skin and the needle-like convex portion 34 was pressed from the surface side of the sheet portion 35 to puncture the needle-like convex portion 34 into the skin. Next, while the sheet portion 35 of the transdermal absorption sheet was lightly held from above, the sheet portion 35 was laterally displaced by about 1 cm, and then the sheet portion 35 was peeled off from the skin. As a result, the needle-like convex portion 34 was bent at the position of the constricted portion 44, and only the needle-like convex portion could be left in the skin.

  DESCRIPTION OF SYMBOLS 10 ... Wire-like metal, 12 ... Constricted part, 14 ... The tip part of the needle-like convex part in wire-like metal, 16 ... Base end part of the needle-like convex part in wire-like metal, 18 ... Metal plate (copper plate), 20 ... Hole: 22 ... Original plate, 24 ... Formwork, 26 ... Resin material, 28 ... Mold, 28A ... Constricted part of mold, 28B ... Mold surface, 30 ... Needle-shaped recess, 32 ... Polymer solution, 34 ... Needle of polymer molding , Convex portion, 35 ... sheet portion of polymer molded body, 36 ... polymer molded body, 40 ... needle sheet, 42 ... tip portion of needle-like convex portion in polymer molded body, 44 ... constriction of needle-like convex portion in polymer molded body 50, pressure filling device, 52 ... pressure vessel, 54 ... pedestal, 56 ... compressor, 58 ... inlet, 60 ... outlet

Claims (11)

In the needle seat manufacturing method in which a needle-like convex portion is formed on the surface of the sheet portion and a constricted portion is formed on the needle-like convex portion,
A solution preparation step of preparing a polymer solution in which at least a polymer material is dissolved or dispersed in a solvent;
A solution application step of applying the prepared polymer solution to a mold having a needle-like concave portion that is an inverted shape of the needle-like convex portion in which the constricted portion is formed, and filling the needle-shaped concave portion into the mold,
A drying shrinkage step of forming a polymer molded body obtained by drying and solidifying the polymer solution into a reduced-scale shape of the needle-like recesses by drying and shrinking in the gelled state of the applied polymer solution;
A peeling step of peeling the molded polymer molded body from the mold, and
When the maximum diameter of the mold is Mmax, the minimum diameter is Mmin, and the solid content volume concentration of the polymer solution is D,
D ≦ (Mmin / Mmax) ³
The needle sheet manufacturing method is characterized by adjusting the shape of the needle-like concave portion of the mold and the solid content volume concentration D of the polymer solution so as to satisfy the above.   In the drying shrinkage step, the polymer solution is cooled to a gelation temperature at which the polymer solution gels to stop the fluidity of the polymer solution, and then dried and solidified with low-temperature drying air that does not restore the fluidity. The method for producing a needle sheet according to claim 1.   The method for producing a needle sheet according to claim 2, wherein the low-temperature drying air has a gelation temperature of + 20 ° C or lower.   The needle sheet manufacturing method according to any one of claims 1 to 3, wherein a mold made of an elastic material having gas permeability is used as the mold.   The needle mold manufacturing method according to any one of claims 1 to 4, wherein the mold is formed of a silicone resin. The mold is
Forming a needle-like convex shape having the constricted portion by grinding a wire-like metal, and fixing a plurality of the formed wire-like metals to a pedestal to prepare a master, and
A reversal type production step of producing a reversal type of the original plate using an elastic material having gas permeability;
The needle sheet manufacturing method according to any one of claims 1 to 5, wherein the needle sheet is manufactured by a peeling step in which the reverse mold is peeled from the original plate to form a mold. The mold is
The needle seat according to any one of claims 1 to 5, wherein the needle sheet is produced by drilling a needle-like concave portion having a constricted portion by a grinding process using a drill in an elastic material having gas permeability. Method.   In the said peeling process, it peels, elastically deforming the said mold, The manufacturing method of the needle sheet of any one of Claims 4-7 characterized by the above-mentioned.   The method for manufacturing a needle sheet according to any one of claims 1 to 8, wherein the polymer material is a material that is easily contracted by drying.   The method for manufacturing a needle sheet according to any one of claims 1 to 9, wherein the polymer material contains gelatin.   The method for producing a needle sheet according to any one of claims 1 to 10, wherein the needle sheet is a percutaneous absorption sheet in which a drug and a pigment are contained in a polymer material.

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