JP2008006178A - Manufacturing method and device for microneedle sheet - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a manufacturing method for a microneedle sheet, which has a low cost and high yield rate. <P>SOLUTION: The manufacturing method for the microneedle sheet 16 having a microneedle array 17 on its surface includes the step of applying a solution in which a resin polymer is dissolved to a stamper 13 for molding the microneedle array 17, the step of bonding overlapped sheetlike base materials 15 to an outer surface of the resin polymer concretion 14 that is formed during a dehydration step of the applied solution, and the step of peeling the sheetlike base materials 15 to which the resin polymer concretion 14 is bonded away from the stamper 13. The microneedle sheet 16 is characterized by being composed of the resin polymer concretion 14. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method and an apparatus for producing a microneedle sheet, and in particular, a microneedle sheet capable of simply, safely and efficiently injecting a drug or the like in a skin surface layer or a skin stratum corneum. The present invention relates to a manufacturing method and a manufacturing apparatus.

  Conventionally, as a method for administering a drug or the like from the surface of a living body, that is, skin, mucous membrane, etc., most of the methods are mainly 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 and the like may be removed by sweating or contact with foreign matter, and it is 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 the penetration by diffusion of the medicine. It was difficult.

For this reason, the method of inject | pouring a chemical | medical agent by inserting the front-end | tip in skin using the functional micropile etc. which are described in patent documents 1 to 3 is indicated.
Special Table 2002-517300 JP 2003-238347 A JP 2006-51361 A

  However, in the invention disclosed in Patent Document 1, when the functional micropile is manufactured, the surface of the substrate made of Si, metal or the like is manufactured by direct etching, so that the productivity is low and the cost is high. There was a problem of becoming. In addition, in the inventions disclosed in Patent Documents 2 and 3, since a method for producing a functional micropile by injection molding of a resin material, in a functional micropile having a high aspect ratio structure, a mold is used. It is difficult to peel off from the substrate, defects are easily generated at the tip, it is very difficult to obtain a complete product, and the manufacturing yield is low.

  In addition, in the methods described in Patent Documents 2 and 3, it is necessary to heat at 100 [° C.] or more at the time of production, but depending on the chemical, there are chemicals that decompose at a temperature of 100 [° C.]. There is also a problem that it cannot be used for chemicals that are not heat resistant.

  The present invention has been made in view of the above circumstances, and provides a method and an apparatus for manufacturing a microneedle sheet having an array of microneedles at a low manufacturing cost and high yield without performing heating during manufacturing. It is intended.

  The invention according to claim 1 is a method of manufacturing a microneedle sheet having a microneedle array on a surface thereof, wherein the microneedle sheet applies a solution in which a resin polymer is dissolved in a stamper for forming the microneedle array. A step of superposing a sheet-like base material on the surface of the resin polymer coagulated body formed by drying the applied solution, and the resin adhering to the sheet-like base material A method for producing a microneedle sheet, characterized in that the resin polymer coagulated product is produced by a step of peeling a polymer coagulated product from the stamper.

  The invention described in claim 2 is the method of manufacturing a microneedle sheet according to claim 1, wherein the material constituting the stamper is a resin material.

  The invention described in claim 3 is a manufacturing method of a microneedle sheet having a microneedle array on a surface thereof, wherein the microneedle sheet is a master corresponding to a shape of the microneedle array on a Si substrate, a glass substrate or a metal substrate. Forming a stamper by pouring a resin material into the original plate and curing it, applying a solution in which a resin polymer is dissolved in the stamper, and drying the applied solution. And a step of laminating and adhering a sheet-like base material on the surface of the resin polymer solidified body, and a step of peeling the resin polymer solidified body adhered to the sheet-like base material from the stamper. A method for producing a microneedle sheet, characterized in that it is a resin polymer coagulated product.

  According to a fourth aspect of the present invention, the shape of the microneedles of the microneedle array is a pyramid having a side or a bottom having a diameter of 30 to 300 [μm] and a height of 50 to 1000 [μm]. Or it is a cone shape, The manufacturing method of the microneedle sheet | seat of Claim 1 to 3 characterized by the above-mentioned.

  The invention according to claim 5 is the method for producing a microneedle sheet according to claims 1 to 4, wherein the material constituting the stamper is plastic.

  The invention according to claim 6 is the method for producing a microneedle sheet according to claim 5, wherein the material constituting the stamper is any one of a thermoplastic material, a silicone resin, and a fluorine resin. is there.

  The invention according to claim 7 is the method for producing a microneedle sheet according to claims 1 to 6, wherein the resin polymer is water-soluble.

  The invention according to claim 8 is characterized in that the resin polymer is a material made of any material of gelatin, agarose, pectin, duran gum, carrageenan, xanthan gum, alginic acid, starch, or a combination of these materials. The method for producing a microneedle sheet according to claim 7.

  The invention according to claim 9 is the microneedle sheet according to claim 7 or 8, wherein the resin polymer is a material whose volume is reduced by drying the solution to become the resin solidified body. It is a manufacturing method.

  The invention according to claim 10 is characterized in that after the solution in which the resin polymer is dissolved is applied, the solution is gelled, and then the water in the solution is evaporated. It is a manufacturing method.

  The invention according to claim 11 is the method for producing a microneedle sheet according to claim 1, wherein when the solution in which the resin polymer is dissolved is applied to the stamper, the solution is performed under reduced pressure. .

  The invention according to claim 12 is characterized in that a pressure-sensitive adhesive layer is formed on the adhesive surface of the sheet-like base material with the resin polymer coagulum. It is a manufacturing method.

  According to a thirteenth aspect of the present invention, when the resin polymer solidified body adhered to the sheet-like base material is peeled off, the resin polymer solidified body is peeled off from one end thereof. It is a manufacturing method of the microneedle sheet | seat as described in above.

  The invention according to claim 14 is an apparatus for manufacturing a microneedle sheet having a microneedle array on a surface thereof, a solution application unit for applying a solution in which a resin polymer is dissolved in a stamper for forming the microneedle array; An adhesive part that overlaps and adheres a sheet-like base material to the surface of the resin polymer solidified body formed by drying the applied solution, and the resin polymer solidified body adhered to the sheet-like base material The microneedle sheet manufacturing apparatus is characterized in that a microneedle sheet made of the resin polymer solidified body is manufactured.

  As described above, according to the manufacturing method and the manufacturing apparatus of the microneedle array of the present invention, the shape of the formed microneedles is not impaired, and heating is not performed at the time of manufacturing, with low manufacturing cost and high yield. There is an effect that a microneedle sheet having an array of microneedles can be manufactured.

  The microneedle sheet manufacturing method and manufacturing apparatus in the embodiment of the present invention will be described below. FIG. 1 is a flowchart of the present embodiment, and FIG. 2 is an example of an apparatus used for manufacturing.

  First, an original plate production process in step 102 (S102) shown in FIG. 1 is performed. 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 portions 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 quadrangular 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 bite.

  Next, a stamper manufacturing process in step 104 (S104) shown in FIG. 1 is performed. 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. In this embodiment, there are three 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 (polymethyl methacrylate) dissolved in an organic solvent is poured into the original plate 11 coated with a release agent and dried to evaporate the organic solvent and cure. This is a method of peeling from the original plate 11 after being made.

  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.

  Next, the polymer solution coating process of step 106 (S106) shown in FIG. 1 is performed. Specifically, a solution in which a resin polymer is dissolved is applied to the surface of the stamper 13 manufactured in the above-described stamper manufacturing process on which the concave and convex pattern corresponding to the micro needles is formed. An appropriate amount of medicine to be administered can be mixed in this.

  The resin polymer used for coating is prepared, for example, by dissolving powders such as gelatin, agarose, pectin, duran gum, carrageenan, xanthan gum, alginic acid, and starch with hot water. The concentration varies depending on the material, but is preferably 10 to 20%. Note that the solvent used for dissolution may be volatile even if it is other than warm water, and for example, alcohol or the like can also be used.

  A specific method for applying a solution in which such a resin polymer is dissolved includes an application method using a spin coater. In order to form the microneedles formed on the stamper 13, there may be a case where the solution in which the resin polymer is dissolved does not enter the recess due to the presence of air, and this step is preferably performed in a reduced pressure state. The polymer solution coating process in step 106 is performed in the solution coating unit 32 of the microneedle sheet manufacturing apparatus 30 shown in FIG.

  Next, the polymer solution drying process of step 108 (S108) shown in FIG. 1 is performed. Specifically, it is dried by blowing warm air on a solution in which the applied resin polymer is dissolved.

  In one method, cold air of 10 to 15 [° C.] is first 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.], relative humidity of 15 [%] or less, more preferably 10 [%] or less.

  In addition, in the case of reducing the shape and improving the peelability from the stamper 13 by gelling the solution in which the applied resin polymer is dissolved, the solution in which the resin polymer is dissolved is gelled by flowing low-humidity cold air. It can be made. In this case, 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. Also, in this case, when flowing hot air for subsequent drying, if the temperature of the hot air is too high, gelation in the solution in which the resin polymer is dissolved may return, or depending on the chemical. Careful attention must be paid to the temperature of the hot air to be blown, because the efficacy changes due to decomposition or the like due to heating. In this way, the solution in which the applied resin polymer is dissolved is dried, or the polymer solution is gelled and then dried to solidify into the resin polymer 14 as shown in FIG. When the resin polymer 14 is solidified, the resin polymer 14 is reduced more than the state when the solution in which the resin polymer is dissolved is applied, and particularly when gelation is performed, the resin polymer 14 is significantly reduced. Thereby, peeling of the resin polymer 14 from the stamper 13 described later becomes easy. Further, in this drying step, if the water content of the resin polymer 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 resin polymer, when the moisture content becomes 10 to 20%, the drying is stopped or 25 [° C.] and the relative humidity is 40 [%]. A degree of wind is blown.

  Next, the peeling process of step 110 (S110) shown in FIG. 1 is performed. Specifically, as shown in FIG. 4B, a sheet-like adhesive layer having an adhesive layer formed on the resin polymer 14 dried and solidified on the stamper 13 in the previous polymer solution drying step. After a PET (polyethylene terephthalate) sheet 15 as a base material is attached, peeling is performed so as to turn the PET sheet 15 from the end. In this way, the microneedle sheet 16 is completed as shown in FIG. The adhesion of the PET sheet 15 in the separation process of Step 110 is performed in the adhesion part 34 in the microneedle sheet manufacturing apparatus 30 shown in FIG. 2, and the separation of the resin polymer 14 solidified together with the adhered PET sheet 15 is illustrated in FIG. 2 is performed in the peeling unit 36 in the microneedle sheet manufacturing apparatus 30 shown in FIG.

  The drying process in step 110 is the most important process in the present embodiment. Normally, when a fine needle structure having a high aspect ratio is peeled from the stamper 13 as in the present embodiment, the contact area is large, so that a strong stress is applied and the fine needle is broken and peeled off from the stamper 13. The microneedle sheet 16 which remains in the stamper 13 without being produced has a fatal defect. In view of this point, in the present embodiment, the material constituting the stamper 13 is preferably composed 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. Further, in the peeling step, the stress can be further relaxed by using a roller 18 from the end as shown in FIG. From the above viewpoint, in the present embodiment, the material constituting the stamper 13 is preferably a material that is easily elastically deformed, such as a silicone resin.

  In addition, in order to evaporate the water | moisture content which remain | survives on the microneedle 17 on the surface of the resin polymer 14, a dry wind may be sprayed again after peeling. Specifically, it is preferable to pack the resin polymer after the moisture content in the resin polymer is set to 10% or less, preferably 5% or less, immediately before packing.

  Further, since the stamper 13 can be used a plurality of times, using the stamper 13 after the peeling process of Step 110, the polymer solution coating process of Step 106, the polymer solution drying process of Step 108, and the peeling of Step 110 are performed. By repeating the process, a plurality of microneedle sheets 16 can be produced at a low cost in a short time. Since the stamper 13 cannot be used permanently, if it can no longer be used, it can be manufactured by performing the stamper manufacturing process in step 104.

  In actual manufacturing of the microneedle sheet 16, a plurality of stampers 13 are prepared and manufactured simultaneously, whereby manufacturing can be performed with high productivity.

  Examples of the present embodiment are shown below.

[Example 1]
In Example 1, a metal plate made of Ni was cut with a diamond bite, and the quadrangular pyramid shape portion 12 in FIG. 5A has a bottom surface of 100 μm, a height of 300 μm, and a pitch of 200 μm. The original plate 11 on which the quadrangular pyramid array was formed was prepared.

  Silicone resin (PDMS) is poured into the original plate 11 and cured to produce a stamper 13 having a shape reverse to that of the original plate 11 shown in FIG.

  Gelatin is dissolved in water, stirred and swollen, and then heated and dissolved at 40 [° C.] to prepare a solution in which a resin polymer having a gelatin concentration of 20% is dissolved. This solution is applied to the surface of the stamper 13 where the irregularities are formed by a spin coater. This solution contains an appropriate amount of drug to be administered. At this time, the pressure reduction is performed in a vacuum chamber or the like.

  After applying a solution in which a resin polymer in which gelatin is dissolved in water is applied, a cold air of 15 [° C.] is applied for 20 [seconds] to completely gelate, then 40 [° C.] and a relative humidity of 15 [%]. For 30 minutes to dry and solidify.

  Thereafter, as shown in FIG. 4B, a 160 [μm] thick PET sheet on which an adhesive layer is formed is adhered to and adhered to the solidified resin polymer 14 on the stamper 13, and then shown in FIG. In this way, the solidified resin polymer 14 is peeled off from the end by the roller 18. Thereby, the highly accurate microneedle sheet | seat 16 as shown in FIG.5 (b) can be produced efficiently. The height of the microneedles 17 of the produced microneedle sheet 16 was 180 [μm].

[Example 2]
In the first embodiment, a metal plate made of Ni is cut with a diamond cutting tool, and a quadrangular pyramid array having a quadrangular pyramid shape portion 12 having a bottom surface of 50 [μm], a height of 150 [μm] and a pitch of 200 [μm]. An original plate 11 having a formed thereon was prepared.

  Silicone resin (PDMS) is poured into the original plate 11 and cured to produce a stamper 13 having a shape reversed to that of the original plate 11.

  Gelatin is dissolved in water, stirred and swollen, and then heated and dissolved at 40 [° C.] to prepare a solution in which a resin polymer having a gelatin concentration of 16% is dissolved. This solution contains an appropriate amount of drug to be administered. Moreover, you may mix the peeling material containing a fluorine in this solution for a peelable improvement. This solution is applied to the surface of the stamper 13 where the irregularities are formed by a spin coater. At this time, the pressure reduction is performed in a vacuum chamber or the like.

  Apply a solution of gelatin-dissolved resin polymer in water and apply 15 [° C] cold air for 5 seconds, then give 40 [° C] hot air for 30 minutes Dry and solidify.

  Thereafter, after a PET sheet having a thickness of 160 [μm] on which the adhesive layer is formed is adhered and adhered to the solidified resin polymer 14 on the stamper 13, as shown in FIG. It peels so that the solidified resin polymer 14 may be turned. Thereby, the highly accurate microneedle sheet | seat 16 was able to be produced efficiently. The microneedle sheet thus produced has microneedles close to the shape of the produced original plate 11.

  As mentioned above, although the manufacturing method and manufacturing apparatus of the microneedle sheet | seat which concern on this invention were demonstrated in detail, this invention is not limited to the above example, In the range which does not deviate from the summary of this invention, various improvement and deformation | transformation are carried out. Can be done.

Flowchart of manufacturing method of microneedle sheet according to the present invention Configuration diagram of a microneedle sheet manufacturing apparatus according to the present invention Process drawing (1) of the manufacturing method of the microneedle sheet | seat which concerns on this invention Process drawing (2) of the manufacturing method of the microneedle sheet | seat which concerns on this invention Sectional drawing of the microneedle sheet manufactured by Example 1 Explanatory drawing of the peeling process in this invention

Explanation of symbols

  DESCRIPTION OF SYMBOLS 11 ... Original plate, 12 ... Shape part of cone or pyramid, 13 ... Stamper, 14 ... Resin polymer, 15 ... PET sheet, 16 ... Microneedle sheet, 17 ... Microneedle

Claims (14)

In the method for producing a microneedle sheet having a microneedle array on the surface,
The microneedle sheet is
Applying a solution in which a resin polymer is dissolved in a stamper for forming the microneedle array;
A step of overlaying and adhering a sheet-like base material on the surface of the resin polymer coagulated body formed by drying the applied solution;
Peeling the resin polymer solidified body adhered to the sheet-like base material from the stamper;
A method for producing a microneedle sheet, wherein the resin polymer coagulated body is produced by the method described above.   2. The method of manufacturing a microneedle sheet according to claim 1, wherein the material constituting the stamper is a resin material. In the method for producing a microneedle sheet having a microneedle array on the surface,
The microneedle sheet is
Producing an original plate corresponding to the shape of the microneedle array on a Si substrate, a glass substrate or a metal substrate;
Pouring a resin material into the master and curing it to produce a stamper;
Applying a solution in which a resin polymer is dissolved in the stamper;
A step of overlaying and adhering a sheet-like base material on the surface of the resin polymer coagulated body formed by drying the applied solution;
Peeling the resin polymer solidified body adhered to the sheet-like base material from the stamper;
A method for producing a microneedle sheet, characterized in that the resin polymer coagulated body is produced by the method described above.   The shape of the microneedles of the microneedle array is a pyramid having a side or diameter of 30 to 300 [μm] and a height of 50 to 1000 [μm], or a conical shape. The method for producing a microneedle sheet according to claim 1.   The method for producing a microneedle sheet according to claim 1, wherein the material constituting the stamper is plastic.   6. The method of manufacturing a microneedle sheet according to claim 5, wherein the material constituting the stamper is any one of a thermoplastic material, a silicone resin, and a fluorine resin.   The method for producing a microneedle sheet according to claim 1, wherein the resin polymer is water-soluble.   The microneedle according to claim 7, wherein the resin polymer is a material made of any one of gelatin, agarose, pectin, duran gum, carrageenan, xanthan gum, alginic acid, starch, or a combination of these materials. Sheet manufacturing method.   The method for producing a microneedle sheet according to claim 7 or 8, wherein the resin polymer is a material whose volume is reduced by drying the solution to form the resin solidified body.   10. The method for producing a microneedle sheet according to claim 7, wherein after the solution in which the resin polymer is dissolved is applied, the solution is gelled and then the water in the solution is evaporated.   11. The method of manufacturing a microneedle sheet according to claim 1, wherein when the solution in which the resin polymer is dissolved is applied to the stamper, it is performed in a reduced pressure state.   The method for producing a microneedle sheet according to claim 1, wherein an adhesive layer is formed on an adhesive surface of the sheet-like substrate with the resin polymer coagulated body.   The method for producing a microneedle sheet according to claim 12, wherein when the resin polymer coagulated body adhered to the sheet-like substrate is peeled, the resin polymer coagulated body is peeled off from one end of the resin polymer coagulated body. . In a microneedle sheet manufacturing apparatus having a microneedle array on the surface,
A solution application part for applying a solution in which a resin polymer is dissolved in a stamper for forming the microneedle array;
An adhesive part that overlaps and adheres a sheet-like base material to the surface of the resin polymer coagulated body formed by drying the applied solution;
A peeling portion that peels off the resin polymer solidified body adhered to the sheet-like base material from the stamper;
A microneedle sheet manufacturing apparatus for manufacturing a microneedle sheet made of the resin polymer coagulated body.

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