JP6533189B2 - Method of manufacturing mold for pattern array sheet, and method of manufacturing microneedle array - Google Patents

Description

  The present invention relates to a method of manufacturing a pattern array sheet forming mold and a method of manufacturing a microneedle array.

  In recent years, a microneedle array (Micro-Needle Array) has been known as a novel dosage form that can be administered without pain pain and drugs such as insulin and vaccines (Vaccines) and hGH (human Growth Hormone) into the skin. ing. The self-dissolving microneedle array is an array of biodegradable microneedles (also referred to as microneedles or microneedles) containing drugs. By applying the microneedle array to the skin, each microneedle is pierced into the skin, the microneedles are absorbed in the skin, and the drug contained in each microneedle can be administered into the skin. The microneedle array is also called a percutaneous absorption sheet.

  The above-described microneedle array prepares a resin mold having a concave pattern which is a reverse shape of the shape of the microneedle array, for example, supplies a polymer solution which is a raw material of the microneedle array, and dries the polymer solution. The microneedle array is manufactured by curing, curing and peeling from the resin mold.

  The resin mold described above can be manufactured, for example, by manufacturing a mold having the same shape as the shape of the microneedle array and transferring the mold to a resin sheet.

  Patent Document 1 discloses that, in order to manufacture a mold, machining such as cutting of a substrate is performed.

International Publication No. 2008/013282

  When administering a drug into the skin using a microneedle array, the microneedle array is required to have controllability of the amount of the drug. Since the amount of drug in the microneedle array is affected by the shape (total volume) of the microneedles, it is necessary to form the microneedles with high accuracy. As described above, since the microneedle depends on the shape of the concave portion of the resin mold, and the concave portion of the resin mold depends on the shape of the mold, it is necessary to manufacture the mold with high accuracy.

  When manufacturing a type | mold by machining, such as cutting of patent document 1, there exists a concern that a type | mold can not be manufactured with sufficient precision from a viewpoint of precision, such as a grinding device, or abrasion of a blade.

  The present invention has been made in view of such circumstances, and it is an object of the present invention to provide a method of manufacturing a pattern array molding mold and a method of manufacturing a microneedle array capable of improving the controllability of the amount of medicine.

According to one aspect of the present invention, a method of manufacturing a pattern array sheet molding die is arranged in an array by machining a substrate, has a height of 100 μm to 1500 μm, and has a multistage shape. Forming a plurality of needle-like protrusions, measuring the volume of the needle-like protrusions by non-contact measurement, and adjusting the volume of the needle-like protrusions, based on the measurement results in the step of measuring And the step of

  Preferably, the step of adding comprises machining the needle projections.

  Preferably, the step of adding includes forming an inorganic film on the needle-like protrusions after machining the needle-like protrusions.

  Preferably, the thickness of the inorganic film at the bottom of the needle-like protrusion is larger than the thickness of the inorganic film at the tip of the needle-like protrusion.

  Preferably, the thickness of the inorganic film is 100 nm or more.

  Preferably, the additional processing step includes thinning the inorganic film after film formation.

  Preferably, adjusting the shape of the tip of the needle-like protrusion by thinning the inorganic film formed on the tip of the needle-like protrusion is included.

  Preferably, the step of forming a release film on the needle-like projections is included after the step of additional processing.

  Preferably, the release film is made of at least one of a fluorine-based material and a hydrocarbon-based material.

  Preferably, the thickness of the release film is 20 nm or more and 50 nm or less.

  According to another aspect of the present invention, a method of manufacturing a microneedle array includes the steps of: manufacturing a pattern array sheet using the pattern array sheet forming mold manufactured by the method of manufacturing a pattern array sheet forming mold described above; A process of producing a replica mold using a pattern array sheet, a process of producing a resin mold having a concave pattern using a replica mold, a process of supplying a polymer solution to a concave pattern of a resin mold, a polymer dissolution Drying the liquid to form a polymer sheet; and releasing the polymer sheet from the resin mold.

  According to the method of manufacturing a pattern array molding die of the present invention, controllability of the amount of medicine can be improved. According to the method of manufacturing the microneedle array, it is possible to improve the controllability of the amount of drug.

It is a flowchart of the manufacturing method of the type | mold for pattern array sheet formation. It is a figure which shows the process of forming a needle-like protrusion. It is a figure which shows the process of forming a needle-like protrusion. It is a figure which shows the process of forming a needle-like protrusion. It is sectional drawing of a needle-like protrusion. It is a perspective view of a mold for pattern array sheet formation. It is a perspective view of a mold for pattern array sheet formation. It is a schematic block diagram of a non-contact measuring instrument. It is a graph which makes a volume ratio to design value the vertical axis, and makes processing order of needlelike projections the horizontal axis. It is a graph which makes a volume ratio to a design value after additional processing a vertical axis, and makes a processing order of needlelike projections a horizontal axis. It is a graph which makes frequency a vertical axis | shaft and the volume of a needlelike protrusion a horizontal axis. It is a graph which makes a volume ratio to a design value before film formation and after film formation a vertical axis, and makes processing order of needlelike projections a horizontal axis. It is a side view which shows the state which formed the inorganic film into a film on needle-like protrusions. It is a graph which makes an integral volume ratio a vertical axis | shaft, and makes a horizontal axis the ratio of the height of the needlelike protrusion with respect to the total height of a needlelike protrusion. It is a graph which makes an integral volume ratio a vertical axis | shaft, and makes a horizontal axis the ratio of the height of the needlelike protrusion with respect to the total height of a needlelike protrusion. It is a flowchart of the manufacturing method of microneedle array. It is process drawing which shows the process of manufacturing a pattern array sheet. It is process drawing which shows the process of manufacturing a pattern array sheet. It is process drawing which shows the process of manufacturing a pattern array sheet. It is process drawing which shows the process of manufacturing an electroforming metal mold | die. It is process drawing which shows the process of manufacturing an electroforming metal mold | die. It is process drawing which shows the procedure of the manufacturing process of resin-made molds. It is process drawing which shows the procedure of the manufacturing process of resin-made molds. It is process drawing which shows the process of supplying a polymer solution. It is process drawing which shows the process of drying a polymer solution in order to set it as a polymer sheet. It is process drawing which shows the process of releasing a polymer sheet from resin-made molds. It is process drawing which shows the process of cutting a microneedle array.

  Hereinafter, preferred embodiments of the present invention will be described with reference to the attached drawings. The invention is illustrated by the following preferred embodiments. Changes can be made in a number of ways without departing from the scope of the present invention, and other embodiments than the present embodiment can be used. Therefore, all the modifications within the scope of the present invention are included in the claims.

  Here, in the drawings, portions indicated by the same symbols are similar elements having similar functions. Further, in the present specification, when a numerical range is expressed using “to”, numerical values of upper limit and lower limit indicated by “to” are also included in the numerical range.

(Method of manufacturing mold for pattern array sheet)
A method of manufacturing a pattern array sheet forming mold will be described with reference to the drawings. FIG. 1 is a flowchart of a method of manufacturing a pattern array sheet forming mold. As shown in FIG. 1, the method of manufacturing a pattern array sheet molding die includes at least a needle-like projection forming step (step S1), a measuring step (step S2), and an additional processing step (step S3).

In the needle-like protrusion forming step (step S1), the substrate is machined to form a plurality of needle-like protrusions arranged in an array , having a height of 100 μm or more and 1500 μm or less, and having a multistage shape. Do. In the measurement step (step S2), the volume of the needle-like projections is measured by non-contact measurement. In the additional processing step (step S3), in order to adjust the volume of the needle projections, the needle projections are added based on the measurement result in the measuring step. Each step will be described below.

<Needle-like projection forming step (step S1)>
The needle-like protrusion forming step will be described based on FIG. 2 to FIG. 2 to 4 are views showing steps of forming needle projections.

  As shown in FIG. 2, a substrate 20 for preparing a pattern array sheet forming mold 10 (see FIG. 6) is prepared. As a material of the base material 20, a metal of iron, stainless alloy, aluminum alloy, Ni alloy (including plating) can be used.

  As shown in FIG. 3, by machining (cutting) the base material 20 using the first cutting blade 30, the first portion 12A constituting the needle-like projections 12 of the pattern array sheet forming mold 10 is a base material Formed in twenty. Various conditions (type of first cutting edge 30, cutting speed, etc.) for forming the first portion 12A are appropriately selected.

  Machining means the method of processing an object with tools, such as a cutting blade and a grindstone.

  As shown in FIG. 4, by cutting the base 20 using the second cutting blade 32, a second portion 12 </ b> B that constitutes the needle-like protrusion 12 is formed on the base 20. The second cutting edge 32 may be the same as or different from the first cutting edge 30. Various conditions (a type of the second cutting edge 32, a cutting speed, etc.) for forming the second portion 12B are appropriately selected. When forming the second portion 12B, the first surface 10A of the pattern array sheet forming mold 10 is formed. When the necessary number of needle projections 12 including the first portion 12A and the second portion 12B are produced on the base 20, the needle projection forming process is completed. Although machining using the first cutting edge 30 and the second cutting edge 32 is shown in the present embodiment, the present invention is not limited to this. For example, when only one of the first cutting edge 30 and the second cutting edge 32 is used, a third cutting edge (not shown) may be used.

  FIG. 5 is a cross-sectional view of the needle-like protrusion after the needle-like protrusion forming step.

  As shown in FIG. 5, the needle-like protrusions 12 have a pyramidal structure that tapers in a direction away from the first surface 10A. In the present embodiment, the needle-like protrusion 12 has the second portion 12B and the first portion 12A from the side of the first surface 10A, and the angle θ2 formed by the side surface of the second portion 12B and the first surface 10A The size of the angle θ1 between the side surface of the first portion 12A and the first surface 10A is different. Therefore, in the present embodiment, since there is one second portion 12B and one first portion 12A, it has a step having one step with two side faces having different angles formed with the first surface 10A. The multistage shape is a shape having at least one level difference. In addition, since the needle-like protrusion 12 is manufactured by cutting etc., the front-end | tip is curved surface shape. The tip diameter is preferably 50 μm or less, more preferably 30 μm or less.

  The height H1 of the needle-like protrusions 12 is preferably 100 μm or more and 1500 μm or less, and more preferably 500 μm or more and 1200 μm or less. The height H1 of the needle-like protrusion 12 is the distance from the first surface 10A to the tip of the needle-like protrusion 12. The ratio (H1-H2) / H2, which is the ratio of the height (H1-H2) of the first portion 12A to the height H2 of the second portion 12B, is in the range of 1 to 10, preferably 1 .5 or more and 8 or less.

  The distance L (pitch) of the needle-like projections 12 is preferably 300 μm to 2000 μm, more preferably 500 μm to 1500 μm, and still more preferably 700 μm to 1250 μm. By setting the distance L of the needle-like protrusions 12 to the above-mentioned range, machining such as cutting becomes easy. The distance L between the adjacent needle-like protrusions 12 is the distance to another needle-like protrusion 12 located closest to a certain needle-like protrusion 12, and as shown in FIG. 5, two needle-like protrusions 12. The distance between the tips of the

FIG. 6 is a perspective view of a pattern array sheet forming mold. As shown in FIG. 6, the pattern array sheet forming mold 10 has a substantially rectangular parallelepiped shape, and a plurality of needle-like protrusions 12 are arranged in an array on the first surface 10A. An array means an aligned state. The needle projections 12 may be aligned, and the number, arrangement, pitch and the like may be appropriately selected. The second surface 10B, which is a surface opposite to the first surface 10A composed of the first portion 12A and the second portion 12B, is a substantially flat surface.

  As described later, the pattern array sheet is formed from the pattern array sheet forming mold 10. An electroforming mold is produced from the pattern array sheet, and a resin mold having a concave pattern is produced from the electroforming mold. The microneedle array which is a molded article is manufactured from a resin mold. The needle-like projections 12 of the pattern array sheet forming mold 10 are replicated on the microneedle array. Therefore, it is important to control the shape of the needle-like projections 12.

  FIG. 7 has the shape of needle-like projections 12 different from the pattern array sheet forming mold 10 of FIG. The needle-like protrusion 12 of FIG. 7 is shaped to have a two-step difference including the first portion 12A, the second portion 12B, and the third portion 12C from the tip to the skirt. In FIG. 7, the first portion 12A has a conical shape, the second portion 12B has a cylindrical shape, and the third portion 12C has a frusto-conical shape. However, it is not limited to these shapes.

<Measurement Process (Step S2)>
In the measurement step, the pattern array sheet forming mold 10 in which a plurality of needle-like protrusions 12 are formed in an array is measured by non-contact measurement, and the volume of the needle-like protrusions 12 is measured. Non-contact measurement can be realized by using a laser microscope or a white light interferometer. Non-contact measurement is a method of measuring without directly contacting the object to be measured, and can be, for example, a method of measuring using light.

  As the laser microscope, for example, VK-X260 manufactured by Keyence Corporation, OLS 4100 manufactured by Olympus Corporation, or the like can be used. As a white light interferometer, for example, a white light interferometer made by Zygo, Wyko made by Bruker, etc. can be used.

  FIG. 8 is a schematic block diagram of a noncontact measuring machine. As shown in FIG. 8, the non-contact measurement system 40 includes, for example, a non-contact measurement system 42 and a control device 60. The noncontact measuring device 42 and the control device 60 are electrically connected. The controller 60 controls the overall operation of the noncontact measuring system 40.

  The non-contact measuring device 42 includes an imaging device 44, a measuring device main body 46, a light source 48, and a table 50 on which the pattern array sheet forming mold 10 which is a measurement object is placed. As the noncontact measuring device 42, the above-mentioned laser microscope, a white light interferometer or the like is used.

  The control device 60 includes a keyboard 62 which is an operation input unit, a display 64 which is a display unit, and a control unit 66. The control unit 66 includes an operation unit that performs various processes, a storage unit in which various programs, data, and the like are stored.

  A pattern array sheet forming mold 10 having a plurality of needle projections 12 is placed on a table 50. The non-contact measuring device 42 measures the shape of the needle-like protrusion 12. The result measured by the noncontact measuring device 42 is input to the control device 60. The result input to the control device 60 is processed by the calculation unit of the control unit 66, and the volume of the needle-like protrusion 12 is measured.

  There are several methods for determining the volume of needle projections 12. In one method, the center of gravity of the bottom of the needle-like protrusion 12 is calculated for one needle-like protrusion 12 measured, and the diameter is calculated from the cross section at the height of the position of the center of gravity. The volume can be determined by integrating in the height direction based on the calculated diameter.

  As another method, the diameter is calculated by 3D fitting based on the position information of the ideal shape and the measured needle-like protrusion 12, and the volume is integrated by integrating in the height direction based on the calculated diameter. It can be asked.

  The volume determined by the above method is the total volume of the plurality of needle projections 12 of one pattern array sheet molding die 10.

  In the present embodiment, the case of measuring all needle projections 12 has been described. However, when the number of needle-like projections 12 to be measured is large, an evaluation number capable of grasping the tendency of increase or decrease of the total volume to the design value of needle-like projections 12 is statistically determined and all needle-like projections 12 are calculated. The measurement may not be performed.

  An example of the result of measuring the pattern array sheet forming mold 10 having a plurality of needle-like protrusions 12 will be described. A pattern array sheet forming mold 10 having 100 needle projections 12 is prepared. The needle-like projections 12 of the pattern array sheet forming mold 10 are measured by the non-contact measuring system 40. FIG. 9 is a graph in which the volume ratio to the design value is the vertical axis, and the processing order of the needle-like projections is the horizontal axis. The volume ratio can be determined by the equation of measured value / design value.

  As shown in FIG. 9, in this example, it can be read that as the processing order is later, the volume ratio is larger. It is considered that the cutting blade for forming the needle-like protrusions 12 wears as the processing progresses, and as a result, the shape of the needle-like protrusions 12 deviates from the design value.

  If the volumes of the needle-like protrusions 12 are not equal, the shape of the microneedle array manufactured from the pattern array sheet forming mold 10 is not equal, and there is a concern that the controllability of the amount of medicine will be a problem.

<Additional work process (step S3)>
In the present embodiment, in the additional processing step, in order to adjust the volume of each needle-like protrusion 12, the needle-like protrusion 12 is added based on the measurement result in the measurement step.

  As a process of additional processing, based on the measurement result of the volume of each needle-like protrusion 12, cutting etc. can be carried out so that the volume of each needle-like protrusion 12 may be adjusted by machining. When the needle projections 12 are machined with the same cutting blade, for example, the processing order can be reversed, and machining can be performed in the order from the needle projections 12 with the slow processing order to the needle projections 12 with the earliest processing order. Even when the cutting blade wears, highly accurate additional machining can be realized.

  FIG. 10 is a graph in which the volume ratio to the design value after the additional processing is the vertical axis, and the processing order of the needle-like projections is the horizontal axis. Each needle-like protrusion 12 after additional processing is measured, and the measurement result is plotted on the graph of FIG. As shown in FIG. 10, the volume of each needle-like protrusion 12 can be adjusted to be substantially equal by performing additional machining by the needle-like protrusion 12. The fact that the volumes are substantially equal means that the volumes are the same or that the variation of the volumes is included in a certain range. The fixed range is determined from the precision required of the microneedle array to be manufactured.

  Next, six pattern array sheet forming molds 10 having 100 needle projections 12 are prepared, and additional machining is performed on the six pattern array sheet forming molds 10. FIG. 11 is a graph in which frequency is taken along the vertical axis and volume of needle projections is taken along the horizontal axis. Graphs A, B, C, D, E, and F are graphs in which volumes and frequencies of the respective needle-like protrusions 12 of the six pattern array sheet forming molds 10 are plotted.

  As shown in FIG. 11, according to the graphs A, B, C, D, E and F, the volumes of the needle-like projections 12 of each pattern array sheet forming mold 10 are adjusted to be approximately equal. There is. According to the graphs A, B, C, D, E and F, the volume of the needle-like projections 12 of each pattern array sheet forming mold 10 is included within ± 3% of the design value. If the volume of the needle-like projections 12 of the pattern array sheet forming mold 10 is within the above range, the controllability of the amount of medicine of the microneedle array can be improved.

  On the other hand, with respect to the shape of the microneedle array which is a molded article, it may be required that the tolerance to the design value is smaller, that is, the variation is smaller. For example, it is necessary to bring the volumes of the needle-like projections 12 of the pattern array sheet forming mold 10 shown by the graphs A, B, C, D, E and F close to the design value.

  Needle-like projections by performing additional machining by additional machining on a pattern array sheet forming mold 10 having a volume of needle-like projections 12 larger than a design value, represented by graphs D, E, and F. The 12 volumes can be brought close to the design value.

  With respect to the pattern array sheet forming mold 10 having a volume of needle projections 12 smaller than the design value represented by graphs A, B, and C, depending on the additional machining by additional machining, The volume can not be close to the design value.

  In the present embodiment, after adjusting the volume of the needle projections 12 by machining, an inorganic film is formed on the needle projections 12 smaller than the design value to make the volume of the needle projections 12 approach the design value. be able to. FIG. 12 is a graph in which the volume ratio to the design value before film formation and after film formation is on the vertical axis, and the processing order of needle projections is on the horizontal axis. As shown in FIG. 12, by forming the inorganic film on each needle-like protrusion 12, the volume of each needle-like protrusion 12 can be made larger than that in the state before film deposition.

Examples of the material of the inorganic film include DLC (Diamond-like Carbon), TaC (Tetrahedral amorphous Carbon), sputtered carbon and the like in the case of carbon. In addition, as the material of the inorganic film, CrN, TiN, PtFe, Ni-W, TiO ₂ , SiO _{2 and the} like can be included as the alloy film. As a material of the inorganic film, Au, Pt, Cu, Ni, Cr and the like can be mentioned as the metal film. As a method of forming an inorganic film on the needle-like protrusions 12, a known vacuum film forming method can be used.

  The thickness of the inorganic film to be formed is preferably 100 nm or more. By setting the thickness of the inorganic film to 100 nm or more, the volume of the needle-like protrusions 12 can be effectively increased. The larger the thickness of the inorganic film, the more effectively the volume of the needle-like projections 12 can be increased. The thickness of the inorganic film is appropriately determined based on the size of the volume to be increased, the height of the formed needle-like projections 12, the distance between the adjacent needle-like projections 12, and the like.

  FIG. 13 is a side view showing a state in which an inorganic film is formed on needle-like protrusions. As shown in FIG. 13, the inorganic film 34 is formed on the plurality of needle-like protrusions 12 of the pattern array sheet forming mold 10. In the case of forming an inorganic film, it is preferable to deposit the inorganic material from a direction (90 °) perpendicular to the first surface 10A of the pattern array sheet forming mold 10. By depositing the inorganic substance in the vertical direction, the thickness of the inorganic film 34 at the bottom of the needle-like protrusion 12 can be made larger than the thickness of the inorganic film 34 at the tip of the needle-like protrusion 12.

  The thickness of the inorganic film 34 can be made thinner at the tip of the needle-like protrusion 12 than at the bottom of the needle-like protrusion 12, and blunting of the tip of the needle-like protrusion 12 can be suppressed. Since the tip of the needle-like protrusion 12 is replicated on the tip of the microneedle array, it is preferable that the tip of the needle-like protrusion 12 does not become blunt in order to ensure the puncturing property of the microneedle array.

  The needle-like protrusions 12 can be efficiently increased by forming the inorganic film 34 at the bottom of the needle-like protrusions 12 thicker than the thickness of the inorganic film 34 at the tip of the needle-like protrusions 12. .

  Further, by rotating the pattern array sheet forming mold 10, the inorganic film 34 can be formed over the entire surface of the needle-like protrusions 12.

  Although the case where the inorganic material is deposited from the direction perpendicular to the first surface 10A has been described in the present embodiment, the present invention is not limited to this aspect. Therefore, the inorganic film may be formed in a state in which the direction in which the inorganic material for the pattern array sheet forming die 10 is deposited is inclined from 90 ° with respect to the first surface 10A. It is preferable that the thickness of the inorganic film 34 at the tip of the needle-like protrusion 12 be such that the film thickness can be larger than the thickness of the inorganic film 34 at the bottom of the needle-like protrusion 12.

  FIG. 14 shows the integrated volume ratio on the vertical axis, and the ratio of the height of the needle projections to the total height of the needle projections (height of the needle projections / total height of the needle projections: hereinafter also referred to as height ratio) on the horizontal axis. Is a graph. In the horizontal axis, the height of the needle-like protrusion is the distance from the tip of the needle-like protrusion to the position where the needle-like protrusion is located, with the tip of the needle-like protrusion as the starting point (0). Further, the total height of the needle projections is the distance from the tip of the needle projections to the first surface.

  In FIG. 14, as the numerical value of the horizontal axis increases, the cross-sectional area at the position of the needle-like protrusion corresponding to the numerical value increases. From this, it can be read that the volume increase rate on the foot side of the needle-like protrusion is larger than the volume increase rate on the foot side of the needle-like protrusion. Therefore, it can be understood that it is preferable to deposit the inorganic film on the foot side of the needle-like projections rather than forming the inorganic film on the tip side of the needle-like projections when increasing the volume of the needle-like projections. .

  FIG. 15 is a graph in which the integrated volume ratio is on the vertical axis, and the ratio of the height of the needle projections to the total height of the needle projections is on the horizontal axis. The abscissa represents the height ratio in the range of 0.8 to 1.0. The vertical axis shows the increase rate of the volume when forming the inorganic film of uniform thickness with respect to the reference value of the needle-like projections.

  Graph A shows the reference value, Graph B shows the case where an inorganic film with a thickness of 1 μm is formed on the needle-like projections of the reference value in the height ratio range of 0.8 to 1.0, Graph C shows When an inorganic film with a thickness of 2 μm is formed on a needle-like protrusion of a reference value in a height ratio range of 0.8 to 1.0, graph D is 3 μm on the needle-like protrusion of the reference value. In the case of forming an inorganic film having a thickness of 1 in a range of height ratio of 0.8 to 1.0 is shown.

  According to the graph of FIG. 15, when an inorganic film with a thickness of 3 μm is formed on a needle-like protrusion of a reference value in a height ratio range of 0.8 to 1.0, the volume of the needle-like protrusion is It can be understood that it can be increased by about 4%. If the volume of the needle projections can be increased by about 4%, the volume of the needle projections can be brought close to the design value.

  The tip of the needle-like protrusion is in the range of height ratio of 0 or more and 0.2 or less, and the bottom of the needle-like protrusion is in the range of height ratio of 0.8 or more and 1.0 or less. The difference in the thickness of the inorganic film between the tip of the needle-like protrusion and the foot of the needle-like protrusion is obtained by comparing the average film thickness at the tip of the needle-like protrusion with the average film thickness at the foot of the needle-like protrusion It can be asked.

  The case where an inorganic film is formed on the needle-like protrusions after machining is described as a process of additional processing for the needle-like protrusions. It is preferable that the process of the additional processing further includes thinning of the formed inorganic film. Thinning the inorganic film means reducing the thickness of the inorganic film.

  When an inorganic film is formed on the needle-like protrusions after machining the needle-like protrusions to adjust the volume of the needle-like protrusions, the inorganic film is formed thicker than the thickness previously obtained from the measurement result. There is a thing. When a thick inorganic film is formed, there is a concern that the volume of the needle-like projections may deviate from the design value.

  Therefore, in the present embodiment, it is preferable to thin the thick inorganic film. By thinning the inorganic film, the volume of the needle-like projections can be brought close to the design value.

  A dry etching process can be mentioned as a method of thinning the inorganic film. The dry etching process includes a physical etching method in which ions etc. collide with the object without using a liquid, a chemical etching method in which a chemical reaction is caused by a reactive gas, or an etching method in which both are combined. be able to. It is not limited to the dry etching process as long as the inorganic film can be thinned.

  In the case of thinning the inorganic film, it is preferable to reduce the thickness of the inorganic film formed at the tip of the needle-like protrusion. When the inorganic film at the tip of the needle-like protrusion is formed, there is a concern that the shape of the tip may become dull. Therefore, it is preferable to reduce the thickness of the inorganic film formed at the tip of the needle-like protrusion. Therefore, the shape of the tip can be made close to the design value.

  It is preferable to appropriately change the method of thinning the inorganic film depending on the type of the inorganic film. In addition, it is preferable to thin the inorganic film from an angle perpendicular to the angle of the tip of the needle-like protrusion, that is, perpendicular to the first surface. By thinning the inorganic film in the vertical direction, it is possible to adjust the shape of the tip of the needle-like protrusion.

<Removal film formation process)>
After the step of additional processing, the step of forming a release film on the needle-like projections may be included. By forming the mold release film on the needle-like projections, it becomes possible to easily release the pattern array sheet from the pattern array sheet molding die.

  The release film is preferably made of at least one of a fluorine-based material and a hydrocarbon-based material. As a fluorine-based material, PTFE (polytetrafluoroethylene: polytetrafluoroethylene), PFA (tetrafluoroethylene-perfluorovinylether copolymer: Tetrafluoroethylene-PerfluoroalkylvinyletherCopolymer) and the like can be mentioned. As the fluorine-based material, for example, OPTOOL (registered trademark) HD 2100 manufactured by Daikin Industries, Ltd. can be used.

  The release film formed on the needle-like projections preferably has a thickness of 20 nm or more and 50 nm or less. By setting the release film in the range of 20 nm or more and 50 nm or less, it is possible to prevent the volume of the needle-like projections from being significantly changed. It is preferable to prevent the size of the volume-adjusted needle projections from deviating from the design value. The release film can be applied to the needle-like projections by spraying or the like. However, the method for forming the release film is not particularly limited.

(Method of manufacturing microneedle array)
The method of manufacturing the microneedle array will be described with reference to the drawings. FIG. 16 is a flow chart of a method of manufacturing a microneedle array. As shown in FIG. 16, in the method of manufacturing a microneedle array, a pattern array sheet manufacturing process (step S21), a replication mold manufacturing process (step S22), a resin mold manufacturing process (step S23), a polymer solution supply process. (Step S24), a drying process (step S25), and a mold release process (step S26) are provided at least.

<Pattern array sheet manufacturing process (step S21)>
In the pattern array sheet manufacturing process, the pattern array sheet is manufactured using the pattern array sheet molding die manufactured by the method of manufacturing the pattern array sheet molding die. FIG. 17 to FIG. 19 are process drawings showing the procedure of the manufacturing process of the pattern array sheet.

  As shown in FIG. 17, a pattern array sheet molding die 10 and a thermoplastic resin sheet 80 which is a material of the pattern array sheet are prepared.

  It does not specifically limit as a thermoplastic resin which comprises the thermoplastic resin sheet 80. As shown in FIG. For example, polyethylene terephthalate, polycarbonate, polymethyl methacrylate, polystyrene, polyethylene, liquid crystal polymer, polylactic acid and the like can be suitably used. The thermoplastic resin sheet 80 means a thermoplastic resin having a thin film thickness and having a self-supporting property at normal temperature. "Self-supporting" refers to being able to maintain its form alone without support from other members.

  The pattern array sheet forming mold 10 and the thermoplastic resin sheet 80 are relatively moved to determine the position (for example, the area A1) at which the pattern array sheet forming mold 10 is pressed against the thermoplastic resin sheet 80. Positioning is performed, for example, by providing a table (not shown) supporting the thermoplastic resin sheet 80 with an X-axis drive mechanism and a Y-axis drive mechanism which move in a direction perpendicular to each other in a horizontal plane.

  The heated pattern array sheet forming mold 10 is pressed to the surface 80 A side of the thermoplastic resin sheet 80. The plurality of needle-like projections 12 of the pattern array sheet forming mold 10 are pressed against the thermoplastic resin sheet 80.

  The pattern array sheet molding die 10 is heated to a temperature equal to or higher than the Vicat temperature of the thermoplastic resin material constituting the thermoplastic resin sheet 80. Heating is performed by a heater (not shown). Depending on the type of thermoplastic resin constituting the thermoplastic resin sheet 80, the pattern array sheet molding die 10 is heated to an appropriate temperature.

  In order to press the pattern array sheet forming mold 10 toward the surface 80A of the thermoplastic resin sheet 80, for example, a Z-axis drive mechanism which moves vertically to a table (not shown) supporting the thermoplastic resin sheet 80. Is implemented by providing When the Z-axis drive mechanism is provided on the table, the thermoplastic resin sheet 80 is moved to the pattern array sheet forming mold 10. The pattern array sheet forming mold 10 can also be attached by a Z-axis drive mechanism that moves in the vertical direction. In this case, the pattern array sheet molding die 10 is moved to the thermoplastic resin sheet 80.

  While pressing the heated pattern array sheet forming mold 10, the surface 80A side of the thermoplastic resin sheet 80 is heated for a certain time. Next, in a state where the pattern array sheet forming mold 10 is pressed against the thermoplastic resin sheet 80, the pattern array sheet forming mold 10 is cooled so that the thermoplastic resin sheet 80 is cooled to the softening temperature or lower.

  As shown in FIG. 18, the pattern array sheet molding die 10 and the thermoplastic resin sheet 80 are pulled apart, and a plurality of inverted shapes of the plurality of needle-like projections 12 are formed on the surface 80A side of the thermoplastic resin sheet 80. The recess 82 is formed. The separation between the pattern array sheet forming mold 10 and the thermoplastic resin sheet 80 can be performed by the above-described Z-axis drive mechanism. Since the plurality of recesses 82 have the inverted shape of the plurality of needle projections 12, the plurality of recesses 82 are arranged in an array. The size, number and arrangement of the recesses of the plurality of recesses 82 will be essentially the same of the plurality of needle-like protrusions 12. The recessed portion 82 has a shape in which the tip is tapered from the surface 80A of the thermoplastic resin sheet 80 to the other surface.

  Next, as shown in FIG. 18, when the formation of the recess 82 is finished in the area A1, positioning of the pattern array sheet forming mold 10 and the thermoplastic resin sheet 80 (here, the area A2) is performed. In the region A2, the heated pattern array sheet molding die 10 is pressed to the surface 80A side of the thermoplastic resin sheet 80. The needle-like projections 12 of the pattern array sheet molding die 10 are pressed to the surface 80 A side of the thermoplastic resin sheet 80.

  In the region A2, while pressing the heated pattern array sheet forming mold 10, the surface 80A side of the thermoplastic resin sheet 80 is heated for a predetermined time. With the pattern array sheet forming mold 10 pressed against the thermoplastic resin sheet 80, the pattern array sheet forming mold 10 is cooled so that the thermoplastic resin sheet 80 is cooled to the softening temperature or lower. The pattern array sheet molding die 10 and the thermoplastic resin sheet 80 are pulled apart to form recessed portions 82 of inverted shapes of the plurality of needle-like protrusions 12 on the surface 80A of the thermoplastic resin sheet 80.

  Further, the pattern array sheet forming mold 10 and the thermoplastic resin sheet 80 are positioned (here, the region A3), and the heated pattern array sheet forming mold 10 is pressed against the surface 80A of the thermoplastic resin sheet 80.

  The positioning of the pattern array sheet forming mold 10 and the thermoplastic resin sheet 80 described with reference to FIGS. 17 and 18 and the concave portion 82 of the inverted shape of the needle-like protrusion 12 of the pattern array sheet forming mold 10 Repeat to form.

  As shown in FIG. 19, when a plurality of recesses 82 are formed in a predetermined area on the side of surface 80 A of thermoplastic resin sheet 80, pattern array sheet 84 is manufactured from thermoplastic resin sheet 80. .

<Replication Type Manufacturing Process (Step S22)>
In the replication mold manufacturing process, a pattern array sheet is used to manufacture a replication mold which is a replication of a mold for molding a pattern array sheet. An electroforming process will be described as an example of manufacturing a replica mold. FIG. 20 and FIG. 21 are process drawings showing the procedure of the manufacturing process of the electroforming mold.

  As shown in FIG. 20, a pattern array sheet 84 in which a plurality of recesses 82 are arranged in an array is prepared in a plurality of regions of the surface 80A, and the pattern array sheet 84 is electroformed. In the electroforming process, first, the pattern array sheet 84 is subjected to a conductive process. A metal (for example, nickel) is sputtered onto the pattern array sheet 84, and the metal is attached to the surface 80A of the pattern array sheet 84 and the plurality of recesses 82. The pattern array sheet 84 subjected to the conductive processing is held on the cathode. The metal pellet is held in a metal case and used as an anode. The cathode holding the pattern array sheet 84 and the anode holding the metal pellet are immersed in the electroforming liquid and energized. By the electroforming process, the metal is embedded in the plurality of concave portions 82 of the pattern array sheet 84, and the metal body 90 is formed. The electroforming process refers to a method of depositing metal on the surface of the mold (pattern array sheet 84) by electroplating.

  As shown in FIG. 21, the metal body 90 is released from the pattern array sheet 84 to produce an electroformed mold 92 having a plurality of needle-like protrusions 94. The plurality of needle projections 94 have an inverted shape of the plurality of recesses 82. The plurality of needle projections 94 are arranged in a pattern. The needle-like projections 94 of the electroforming mold 92 have substantially the same shape as the needle-like projections 12 of the pattern array sheet forming mold 10. In the present embodiment, the electroforming mold 92 is a replica mold.

  In this embodiment, the pattern array sheet 84 is manufactured using the pattern array sheet forming mold 10, and the electroformed mold 92 is manufactured from the pattern array sheet 84. Therefore, the needle projections 12 of the pattern array sheet molding die 10 and the needle projections 94 of the electroforming die 92 have substantially the same shape, and the electroforming die 92 is compared with the pattern array sheet molding die 10. Have a large area. That is, since the large-sized electroformed mold 92 which is a duplicate of the small pattern array sheet forming mold 10 can be obtained, the cost associated with the machining can be reduced.

  The replication type is not limited to the electroforming process, and a resin replication type can also be manufactured using the pattern array sheet 84.

<Resin mold manufacturing process (step S23)>
In the resin mold manufacturing process, a resin mold having a plurality of recesses is manufactured using a replication mold. 22 and 23 are process diagrams showing the procedure of the process of manufacturing a resin mold. In addition, the example using the electroforming metal mold | die 92 as a duplication type | mold is demonstrated. The replication type is not limited to the electroforming mold 92.

  FIG. 22 shows a process of manufacturing the resin mold 100 using the electroforming mold 92, and FIG. 23 shows a process of releasing the resin mold 100 from the electroforming mold 92. As shown in FIG. A resin mold 100 having a plurality of recesses 102 arranged in an array can be manufactured by the following first to third methods.

  First, the first method will be described. A UV curable resin is prepared which cures upon irradiation with UV light. The plurality of needle-like projections 94 of the electroforming die 92 are pressed against the ultraviolet curing resin. While the electroforming die 92 is pressed against the ultraviolet curing resin, the ultraviolet curing resin is irradiated with ultraviolet rays to cure the ultraviolet curing resin. The cured UV curable resin is released from the electroforming die 92. It is possible to manufacture a resin mold 100 having a plurality of recesses 102 which is the inverted shape of the plurality of needle-like protrusions 94 of the electroforming die 92.

  The second method will be described. A thermoplastic resin sheet to be a material of the resin mold 100 is prepared. An electroformed mold 92 having a plurality of needle projections 94 is heated. The heated electroforming molds 92 are pressed against the surface of the thermoplastic resin sheet. Since the surface of the thermoplastic resin is softened, the inverted shapes of the plurality of needle-like protrusions 94 are transferred to the thermoplastic resin sheet.

  While the electroforming die 92 is pressed against the thermoplastic resin sheet, the thermoplastic resin sheet and the electroforming die 92 are cooled. By cooling the electroforming mold 92, the thermoplastic resin sheet is cured. Thereafter, the thermoplastic resin sheet is released from the electroforming die 92. It is possible to manufacture a resin mold 100 having a plurality of recesses 102 which is the inverted shape of the plurality of needle-like protrusions 94 of the electroforming die 92.

  Next, the third method will be described. A silicone resin is prepared by adding a curing agent to PDMS (polydimethyl siloxane: polydimethylsiloxane, for example, Silgard 184 manufactured by Dow Corning). The plurality of needle projections 94 of the electroforming die 92 are pressed against the silicone resin. While the electroforming die 92 is pressed against the silicone resin, the silicone resin is heat treated at 100 ° C. to be cured. The cured silicone resin is released from the electroforming die 92. It is possible to manufacture a resin mold 100 having a plurality of recesses 102 which is the inverted shape of the plurality of needle-like protrusions 94 of the electroforming die 92.

  Since the plurality of recesses 102 have the inverted shape of the plurality of needle projections 94, the size of each recess of the plurality of recesses 102 is substantially the same as the size of the plurality of needle projections 94. However, the method for manufacturing the resin mold 100 and the first to third methods are not limited.

<Polymer Solution Supply Step (Step S24)>
In the polymer solution supplying step, as shown in FIG. 24, the polymer solution 112 is supplied to the plurality of recesses 102 of the resin mold 100.

  As a material of the polymer solution 112 forming the microneedle array 110 (see FIG. 26), a water-soluble material is preferably used. As a resin polymer material of the polymer solution 112 used for manufacturing the microneedle array 110, it is preferable to use a biocompatible resin. As such a resin, saccharides such as glucose, maltose, pullulan, sodium chondroitin sulfate, sodium hyaluronate, hydroxyethyl starch, proteins such as gelatin, biodegradable polymers such as polylactic acid, lactic acid / glycolic acid copolymer It is preferred to use. Among these, gelatin-based materials have adhesiveness with many substrates, and have strong gel strength as a material to be gelled, so that they can be in close contact with the substrates. When releasing the microneedle array 110 from the resin mold 100, since the microneedle array 110 can be released using a base material (not shown), it can be suitably used. Although the concentration varies depending on the material, it is preferable to set a concentration of 10 to 50% by mass of the resin polymer in the drug-free polymer solution 112. The solvent used for the polymer solution 112 may be any solvent other than warm water as long as it has volatility, and an alcohol such as ethanol can be used. Then, in the polymer solution 112, it is possible to dissolve together a drug for supply into the body depending on the use. The polymer concentration of the polymer solution 112 containing a drug (the concentration of the polymer excluding the drug when the drug itself is a polymer) is preferably 0 to 30% by mass.

  As a method of preparing the polymer solution 112, in the case of using a water-soluble polymer (such as gelatin), a water-soluble powder may be dissolved in water and a drug may be added after dissolution, or a liquid in which the drug is dissolved The powder of the water-soluble polymer may be added to the When it is difficult to dissolve in water, it may be dissolved by heating. Although the temperature can be appropriately selected depending on the type of the polymer material, it is preferable to heat at a temperature of about 20 to 40 ° C., if necessary. The viscosity of the polymer solution 112 is preferably 200 mPa · s or less, and more preferably 50 mPa · s or less in the case of a drug-containing solution. In the case of a solution containing no drug, the viscosity is preferably 2000 mPa · s or less, more preferably 500 mPa · s or less. By appropriately adjusting the viscosity of the polymer solution 112, the polymer solution 112 can be easily injected into the recess 102 of the resin mold 100. For example, the viscosity of the polymer solution 112 can be measured with a capillary viscometer, a falling ball viscometer, a rotary viscometer, or a vibrating viscometer.

  The drug to be contained in the polymer solution 112 is not limited as long as it has a function as a drug. In particular, it is preferable to select from peptides, proteins, nucleic acids, polysaccharides, vaccines, pharmaceutical compounds belonging to water-soluble low molecular weight compounds, or cosmetic ingredients.

  Examples of the method for injecting the polymer solution 112 into the resin mold 100 include application using a nozzle, a spin coater, a squeegee, and the like.

  The through hole may or may not be formed at the tip of the recess 102 of the resin mold 100. When the through hole is formed, the air in the recess 102 can be released from the through hole. Therefore, the polymer solution 112 can be easily introduced into the recess 102 of the resin mold 100. Moreover, it is preferable to carry out this process under reduced pressure.

<Drying Step (Step S25)>
In the drying step, as shown in FIG. 25, the polymer solution 112 is dried to form a polymer sheet 114. For example, the polymer solution 112 supplied to the resin mold 100 can be dried by blowing air. The polymer sheet 114 means a state after the polymer solution 112 is subjected to a desired drying process. The water content and the like of the polymer sheet 114 are appropriately set. In addition, since it will become difficult to mold-release when the water content of a polymer becomes low too much by drying, it is preferable to leave the water content of the state which has maintained elasticity.

  The polymer sheet 114 is formed with needle-like protrusions 116 which will be described later, which are inverted shapes of the plurality of recesses 102.

<Release Process (Step S26)>
In the release step, as shown in FIG. 26, the polymer sheet 114 is released from the resin mold 100, and the microneedle array 110 is manufactured. The microneedle array 110 is formed with a plurality of needle-like protrusions 116 which are the inverted shape of the recess 102 of the resin mold 100.

  For example, a sheet-like substrate (not shown) on which an adhesive layer is formed is attached to the surface of the polymer sheet 114 on the opposite side of the resin mold 100, and the polymer sheet 114 is resin by pulling up the substrate. The mold can be released from the mold 100. The polymer sheet 114 can be released from the resin mold 100 by grasping the both ends of the polymer sheet 114 and gradually pulling up the both ends.

<Cutting process>
In the cutting step, the manufactured microneedle array 110 is cut into individual microneedle arrays 110A, 110B, 110C, 110D. The microneedle array 110 released from the resin mold 100 is set in a cutting device (not shown), and the position to cut the microneedle array 110 is determined. Basically, the cutting position is determined for each of the areas 116A, 116B, 116C, and 116D having an assembly of a plurality of needle-like projections 116 arranged in an array. As shown in FIG. 27, the microneedle array 110 is cut to produce a plurality of individual microneedle arrays 110A, 110B, 110C, 110D.

  In the present embodiment, the case where the polymer sheet 114 is formed by filling the polymer solution 112 in the concave portion 102 of the resin mold 100 and drying is described, but the present invention is not limited thereto.

  For example, the polymer solution 112 containing a drug is filled in the plurality of recesses 102 of the resin mold 100 and dried, and then the drug solution 112 is filled in the plurality of recesses 102 of the resin mold 100. By drying, a two-layered polymer sheet 114 (microneedle array 110) can be manufactured.

  The plurality of needle-like projections 116 (areas 116A, 116B, 116C, 116D) of the microneedle array 110 to be manufactured mean the shape of the needle-like projections 116 tapered toward the tip end, and the pyramidal shape and multistage Including the pyramidal shape of The multistage pyramidal shape means a pyramidal shape having side surfaces with different angles from the bottom to the tip.

  The height of the needle-like projections 116 is preferably 100 μm or more and 1500 μm or less, and is 500 μm or more and 1000 μm or less.

  The plurality of needle-like projections 116 of the microneedle array 110 to be manufactured is a duplicate of the pattern array sheet forming mold 10. By making the shape and arrangement of the needle-like protrusions 12 of the pattern array sheet forming mold 10 into a desired shape, it is possible to make the needle-like protrusions 116 of the manufactured microneedle array 110 into a desired shape. In particular, in the present embodiment, since the shape of the needle-like projections of the pattern array sheet forming mold is adjusted, the shapes of the needle-like projections 116 are almost equalized, which makes it possible to improve the control of the amount of medicine.

10 Pattern Array Sheet Forming Mold 10A First Surface 10B Second Surface 12 Needle-like Protrusions 12A First Part 12B Second Part 12C Third Part 20 Base Material 30 First Cutting Edge 32 Second Cutting Edge 34 Inorganic Film 40 Non-Contact Measurement Machine system 42 Non-contact measurement machine 44 Image pickup device 46 Measurement machine main body 48 Light source 50 Table 60 Control device 62 Keyboard 64 Display 66 Control part 80 Thermoplastic resin sheet 80A Surface 82 Recess 84 Pattern array sheet 90 Metal body 92 Electroforming mold 94 needle Protrusion 100 resin mold 102 recess 110, 110A, 110B, 110C, 110D microneedle array 112 polymer solution 114 polymer sheet 116 needle-like protrusion 116A, 116B, 116C, 116D area A1, A2, A3 area L interval S1, S2 , S3, S21, S2 2, S23, S24, S25, S26 Step θ1, θ2 Angle

Claims (11)

Forming a plurality of needle-like projections arranged in an array , having a height of 100 μm to 1500 μm, and having a multistage shape by machining the base material;
Measuring the volume of the needle-like projections by non-contact measurement;
And adjusting the volume of the needle-like protrusion based on the measurement result in the measuring step.
A method of manufacturing a mold for forming a pattern array sheet, comprising:   The method of manufacturing a pattern array sheet molding die according to claim 1, wherein the step of additionally processing includes machining the needle-like projections.   The method for manufacturing a pattern array sheet molding die according to claim 2, wherein the step of additionally processing includes forming an inorganic film on the needle-like protrusions after machining the needle-like protrusions.   The method for manufacturing a pattern array sheet molding die according to claim 3, wherein a thickness of the inorganic film at the bottom of the needle-like protrusion is thicker than a thickness of the inorganic film at the tip of the needle-like protrusion.   The method for manufacturing a pattern array sheet molding die according to claim 3 or 4, wherein the thickness of the inorganic film is 100 nm or more.   The method for manufacturing a pattern array sheet molding die according to any one of claims 3 to 5, wherein the step of performing the additional processing includes thinning the inorganic film after film formation.   7. The mold for forming a pattern array sheet according to claim 6, wherein the shape of the tip of the needle-like protrusion is adjusted by thinning the inorganic film formed on the tip of the needle-like protrusion. Method.   The method for manufacturing a pattern array sheet molding die according to any one of claims 1 to 7, further comprising the step of forming a release film on the needle-like projections after the step of performing additional processing.   The method for manufacturing a pattern array sheet molding die according to claim 8, wherein the release film is made of at least one of a fluorine-based material and a hydrocarbon-based material.   The method for manufacturing a pattern array sheet molding die according to claim 8 or 9, wherein a thickness of the release film is 20 nm or more and 50 nm or less. A process of manufacturing a pattern array sheet using the pattern array sheet molding die manufactured by the method of manufacturing a pattern array sheet molding die according to any one of claims 1 to 10;
Manufacturing a replica mold using the pattern array sheet;
Producing a resin mold having a concave pattern using the replica mold;
Supplying a polymer solution to the concave pattern of the resin mold;
Drying the polymer solution to form a polymer sheet;
Releasing the polymer sheet from the resin mold;
A method of manufacturing a microneedle array comprising:

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