WO2010016218A1 - Microneedle and jig of the same - Google Patents
Microneedle and jig of the same Download PDFInfo
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- WO2010016218A1 WO2010016218A1 PCT/JP2009/003671 JP2009003671W WO2010016218A1 WO 2010016218 A1 WO2010016218 A1 WO 2010016218A1 JP 2009003671 W JP2009003671 W JP 2009003671W WO 2010016218 A1 WO2010016218 A1 WO 2010016218A1
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- microneedle
- shape
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- cross
- pga
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/003—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a lumen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0038—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a channel at the side surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Definitions
- the present invention relates to a sword mountain type microneedle made of a biodegradable resin.
- the present invention relates to a PGA microneedle having a groove that can easily hold a chemical solution and having a high material strength, and a jig used for the manufacture thereof.
- Patent Document 2 describes a method of manufacturing a microneedle by pulling up a droplet resin using an ultraviolet curable acrylate adhesive or an epoxy resin.
- Patent Document 2 describes a method of manufacturing a microneedle by pulling up a droplet resin using an ultraviolet curable acrylate adhesive or an epoxy resin.
- it is difficult to manufacture a large number of microneedle arrays (Kenyama-type microneedles) with a uniform standard for the height and width of microneedles. It was thought.
- Patent Document 3 describes that a glass rod is pressed against a pasty base and gradually separated to produce a needle-like or thread-like solid.
- a glass rod is pressed against a pasty base and gradually separated to produce a needle-like or thread-like solid.
- biomanufacturable resin microneedles which are considered to be highly versatile, have yet been reported on a practical production method that can be industrially mass-produced, and various methods are still being sought and studied. It is a situation.
- An object of the present invention is to provide a production method capable of industrially mass-producing microneedles of a biodegradable resin and a jig used therefor. More specifically, it is to provide a method for producing microneedles using PGA resin, which is a biodegradable resin having high material strength.
- the present inventors have intensively studied to achieve the above problems. That is, a method has been found so far in which a sword-shaped jig is brought into contact with a polylactic acid (PLA) sheet, the resin is heated and melted away, and a PLA microneedle is formed into a PLA sheet (PCT / JP2008). / 051317). As a result of further investigations, the present inventors manufactured PGA-made Kenyama microneedles with high reproducibility using polyglycolic acid (PGA), a biodegradable resin having higher material strength than PLA. I found out that I can do it.
- PGA polyglycolic acid
- microneedles having concave or groove-like depressions or hollow microneedles can be efficiently manufactured. I found. Such a microneedle having a recess or a hollow is useful for storing and holding a drug solution, and can greatly contribute to skin permeation of a medicinal component.
- the shape of the microneedle of the present invention has a shape in which the bottom portion is derived from the cross-section of the columnar protrusion of the jig due to the manufacturing method, and from a cylindrical shape to a conical shape as it goes to the tip.
- the length of the microneedle of the microneedle is also affected by the contact area of the jig (the contact area of the cross section of the columnar protrusion). For example, it has been found that when the contact area of the jig is large, the amount of PGA to be melted increases, and long microneedles are formed in proportion thereto.
- the interval (pitch) between the microneedles is too small, the microneedles are difficult to be separated and formed one by one, and therefore a certain interval or more is naturally required.
- the pitch is at least 300 ⁇ m or more and 2 mm or less.
- the inventors have found that a range of 500 ⁇ m to 1 mm is preferable, centering around 800 ⁇ m. Based on the above knowledge, it has been found that by selecting an appropriate jig, it is possible to easily produce many kinds of PGA microneedles having high strength and easy to puncture the skin, and the present invention has been completed.
- the gist of the present invention is as follows.
- a microneedle in which a plurality of PGA microneedles are arranged on a substrate made of polyglycolic acid (PGA) with a constant interval (pitch), The microneedles have a structure in which the cross-sectional shape decreases from the bottom to the top of the microneedles in contact with the substrate, and the reduction rate of the cross-sectional shape in the vicinity of the bottom is larger than that in the vicinity of the top.
- a microneedle having a structure having at least one of a continuous groove, a depression, and a continuous hollow portion in a direction toward the top.
- the height of the micro needle is 150 ⁇ m to 1 mm, The outer shape of the bottom of the microneedle is 100 to 450 ⁇ m; The microneedle according to [1] above, wherein the interval between the microneedles is 100 ⁇ m to 2 mm. [3] The microneedle according to the above [1] or [2], wherein the interval between the microneedles is 300 ⁇ m to 2 mm. [4] The microneedle according to any one of the above [1] to [3], wherein the interval between the microneedles is 500 ⁇ m to 1 mm.
- PGA polyglycolic acid
- the cross-sectional shape of the microneedle is a circle, a polygon, a cross, a square shape, a circle with a portion missing (C shape) or a polygon with a partial deletion at the bottom, and the tip In a circle,
- the microneedle according to any one of [4] to [6] above, wherein the polygon having a partial deletion is a U shape or a V shape.
- the microneedle described in [8] above, wherein the microneedle holding a groove-like recess is used as a shape of the microneedle between the tip and the bottom having a pointed cylindrical or conical shape. needle.
- a silicon or metal jig having a columnar protrusion having the following shape on a flat plate (1)
- the length of the columnar protrusion is 200 ⁇ m to 1 mm, (2)
- the interval between the columnar protrusions is 300 ⁇ m to 2 mm, (3)
- the number of columnar protrusions is plural, (4)
- the outer diameter of the cross-section of the columnar protrusion is 100 to 450 ⁇ m, (5)
- the cross-sectional shape of the columnar protrusion is a circle, a polygon, a cross, a square shape, a circle with a part missing (C shape) or a polygon with a partial deletion.
- a method for producing a microneedle made of PGA comprising the following steps (1) to (6).
- (1) Set the temperature of the jig above the temperature at which the PGA becomes viscoplastic.
- (2) The jig is brought into contact with the PGA plate, and the PGA at the contact portion is viscoplasticized.
- (3) The jig and the PGA plate are separated from each other by 0.2 to 2 mm at a speed of 2 to 6 mm / sec, and the viscoplasticized PGA is stretched into a thread shape.
- the sword mountain type microneedle made of PGA of the present invention is strong, and therefore, when puncturing the skin, it is hardly deformed and can be effectively inserted into the skin.
- PGA microneedles having various shapes can be easily manufactured by selecting a jig.
- a jig it is possible to produce a hollow microneedle or a microneedle having a recess or groove on the side surface, and a medicinal component can be carried in the hollow or recess.
- the medicinal component can be injected more effectively subcutaneously.
- Photograph of the microneedle of the present invention obtained using a square column jig Enlarged photo of microneedles obtained using a square column jig Dimensions of U-shaped and V-shaped jigs Photo of U-shaped jig (example) Photo of V-shaped jig Enlarged photo of microneedles made using a U-shaped jig Enlarged photo of microneedle made using V-shaped jig Enlarged photo of a cross-shaped (420 ⁇ 420 ⁇ m) jig and the microneedle produced Cross-section of a U-shaped columnar protrusion and enlarged photo of a microneedle made with a jig having the columnar protrusion Cross-section of a U-shaped columnar protrusion and enlarged photo of a microneedle made with a jig having the columnar protrusion Cross-section of a U-shaped columnar protrusion and enlarged photo of a microneedle made with
- the jig used for manufacturing the microneedle of the present invention is a silicon (Si) or metal jig manufactured by a semiconductor process or the like.
- a semiconductor process or the like used here a well-known fine fabrication process used in the production of microneedles can be used as appropriate. Examples thereof include lithography such as X-ray lithography and photolithography, and etching such as ion etching and plasma etching.
- ICP-RIE inductively coupled plasma reactive ion etching
- ICP-RIE inductively coupled plasma reactive ion etching
- a desired jig can be produced by cutting a silicon flat plate surface separately by semiconductor dicing. For example, by using a dicing machine (manufactured by DISCO Corporation) and cutting with a grindstone made of sintered diamond, a jig having square columnar protrusions having a desired pitch interval can be created.
- the PGA is softened and melted by bringing it into contact with the PGA sheet using the jig obtained above. Thereafter, the jig is pulled away, and the PGA attached to the jig is pulled out.
- the PGA extends in the form of a thread, the jig separating speed is reduced or stopped, and the extended thread-like PGA is cut by surface tension.
- polyglycolic acid (PGA) used in the present invention includes a repeating unit (OCH 2 CO) of 50% by mass or more, preferably 70% by mass or more, more preferably 90% by mass or more.
- OCH 2 CO repeating unit
- microneedles that are stronger in strength can be produced by using PGA.
- PGA polylactic acid
- FIG. 20 the microneedle photograph after puncture was broken or bent. The needle was not found, and the change was not seen as a whole.
- PLA polylactic acid
- FIG. 21 the microneedle of FIG. 21 bends as shown in FIG. 22 after the puncture of the rat skin, or the tip of the microneedle is crushed as shown in FIG. Many things were found.
- the PGA microneedles were found to be highly versatile with unexpectedly superior strength.
- the “microneedle” referred to in the present invention is a microneedle in which a plurality of PGA microneedles are arranged at a constant interval (pitch) on a polyglycolic acid (PGA) substrate.
- the microneedle has a structure in which the cross-sectional shape decreases from the bottom to the top (tip) of the microneedle in contact with the substrate, and the reduction rate of the cross-sectional shape in the vicinity of the bottom is larger than that in the vicinity of the top.
- a microneedle having a structure having at least one of a groove, a recess, and a continuous hollow portion extending from the bottom to the top.
- microneedle in which the height of the microneedle is 150 ⁇ m to 1 mm, the outer shape of the bottom of the microneedle is 100 to 450 ⁇ m, and the interval between the microneedles is 100 ⁇ m to 2 mm. More specifically, it refers to a sword-mount PGA substrate (plate) on which a plurality of microneedles as described below are installed.
- the height of the micro needle is 150 ⁇ m to 1 mm
- the maximum outer diameter of the bottom of the microneedle is 100 ⁇ m to 450 ⁇ m
- the tip of the microneedle has a sharp cylindrical shape (conical shape with a rounded tip), and the outer diameter is several to several tens of ⁇ m.
- the cross-sectional shape of the micro needle is a circle, a polygon, a cross, a polygon lacking one side, a circle lacking a part (C-shaped) at the bottom, and a circle at the tip.
- the number of microneedles can be selected as necessary, and is preferably 9 to 500, for example.
- the preferred sword mountain type microneedle has a fine needle density of 9 to 500 needles / cm 2 .
- the thickness is 200 ⁇ m or more. More preferably, the height of the microneedle is in the range of 300 to 500 ⁇ m.
- the size of the microneedles of the present invention (the portion where the microneedles are present) varies depending on the size and number of the microneedles, and preferred examples include those having a length and width in the range of 0.5 to 1.5 cm. Note that the number of microneedles and the size of the microneedles are determined in accordance with the number and size of the columnar protrusions of the jig (portions where the columnar protrusions are present). Therefore, the number of microneedles and the size of the microneedles (the portion where the microneedles are present) can be determined by appropriately selecting a jig as necessary.
- the microneedle of the present invention is attributed to the manufacturing method, and the bottom of the needle is determined by the width of the outer diameter of the columnar projection of the jig used, and the height of the needle is determined by the amount of viscoplasticized PGA. .
- the amount of PGA depends on the amount of PGA softened and melted based on the contact between the jig and the PGA, viscoplasticized, and pulled up to the jig.
- a 200 ⁇ m ⁇ 200 ⁇ m prism as a jig is used to contact the PGA plate, the PGA is viscoplasticized, and the jig is pulled away to form a pyramid-shaped microneedle (bottom of about 150 ⁇ m, height) as shown in FIGS. About 350 ⁇ m) can be produced.
- the amount of the above-mentioned viscoplastic PGA varies depending on the temperature of the jig, the temperature of the PGA plate, the cross-sectional area of the jig, the contact time of the jig, the insertion distance to the PGA plate, and the like. Therefore, these conditions can be appropriately selected according to the desired microneedle size.
- the contact time between the jig and the PGA plate is such that when a jig having a prismatic projection of 200 ⁇ m ⁇ 200 ⁇ m is used as the jig, the amount of PGA that melts is small if it is 1 second, and PGA melts if it exceeds 7 seconds. Too much. From around 10 seconds, PGA begins to burn. A range of 2-7 seconds seems to be appropriate, and around 5 seconds is considered suitable. If the insertion distance of the jig with respect to the PGA plate is large, the jig and the PGA come into contact with each other, and the softening and melting amount of the PGA increases, so that the size of the micro needle can be increased.
- the insertion distance is preferably in the range of 0.1 to 0.25 mm.
- the microneedle shown in FIGS. 1 and 2 is obtained with an insertion distance of 0.1 mm.
- the height of the microneedles is about 350 ⁇ m, and the outer diameter of the bottom of the microneedles is about 150 ⁇ m.
- the outer diameter of the bottom of the microneedle is substantially the same as or slightly smaller than the cross section of the columnar protrusion of the jig.
- the bottom of the microneedle is slightly pushed away by the contact of the jig, and then the viscoplasticized PGA is pulled out. As shown in FIG. 6, FIG. 8, or FIG. It is slightly depressed toward it.
- the microneedle stands up from the recess (concave portion). Therefore, since the bottom of the microneedle is pulled out by the jig, it has a shape substantially corresponding to the cross section of the jig.
- the outer diameter of the bottom of the micro needle is approximately the same as or slightly smaller than the cross section of the columnar protrusion of the jig.
- a jig with a prismatic protrusion of 0.2 mm side 0.2 mm ⁇ 0.2 mm, height 0.35 mm, pitch 0.8 mm
- the outer diameter was about 150 ⁇ m.
- the U-shaped jig (300 ⁇ m ⁇ 300 ⁇ m) shown in FIG. 4 the outer diameter of the bottom of the microneedle is about 300 ⁇ m as shown in the right figure of FIG. It was.
- the “tip portion of the microneedle” referred to in the present invention refers to a columnar (slightly conical) portion of the tip portion that is pulled out by a jig, extended into a thread shape, and cut.
- PGA is extended so that the outer diameter of the cylindrical portion is several to several tens of ⁇ m, and a microneedle is formed.
- “several to several tens of ⁇ m” represents a range of 2 to 3 ⁇ m or more and 20 to 30 ⁇ m or less.
- a more preferable outer diameter of the tip of the microneedle is 2 to 20 ⁇ m, and the range can be appropriately selected in consideration of the puncture property to the skin and the hardness of the material.
- the “microneedle cross section” referred to in the present invention refers to a cross section obtained by cutting a microneedle along a plane parallel to the PGA plate.
- the cross-section of the bottom of the microneedle shows almost the same shape as the cross-section of the jig, but as it goes to the top, as shown in FIGS. 6 to 12, the tip of the microneedle is stretched by the stretching and surface tension of the PGA.
- the outer shape is a pointed cylinder or cone. For this reason, the cross-section of the tip of the microneedle has a substantially circular shape.
- the reduction rate of the cross-sectional shape in the vicinity of the bottom (of the microneedle) is larger than that in the vicinity of the top (of the microneedle) means that the PGA having a viscous composition by the jig is pulled out from the substrate. Therefore, as shown in FIG. 6 and FIG. 8, the diameter of the microneedle is rapidly reduced in the vicinity of the bottom. The diameter of the microneedle is gradually reduced at the top (tip) of the microneedle.
- the “jig” referred to in the present invention refers to a silicon or metal jig used in the above-described microneedle production method. These jigs are manufactured using the above-mentioned general-purpose means used in semiconductor manufacturing processes and fine manufacturing processes. Examples of metals include titanium, palladium, nickel, and copper.
- the “columnar protrusion” as used in the present invention is a circular columnar shape having a circular, polygonal, cross-shaped, square-shaped, a partially circular shape (C-shaped), or a partial deletion. Is a protrusion.
- the polygon refers to a polygon such as a triangle, a quadrangle, and a pentagon.
- the polygon having a partial deletion is illustrated in, for example, a V shape, a U shape, or FIGS. Such a cross-sectional shape (having a deletion portion).
- the length of the columnar protrusion is in the range of 200 ⁇ m to 1 mm, and preferably 250 to 500 ⁇ m. More preferably, 300 to 400 ⁇ m can be mentioned.
- the “interval between columnar protrusions” referred to in the present invention refers to the distance between the centers of the columnar protrusions. When the interval between the columnar protrusions is narrow, the thread-like PGA formed on the adjacent columnar protrusions is joined to form a wide single thread.
- the interval between the columnar protrusions needs to be constant. For example, when the outer diameter of the columnar protrusion of the jig is 200 to 300 ⁇ m, as shown in FIG. 2 and FIG. 6, the range in which the PGA plate becomes viscoplastic extends to a range about 2 to 3 times that of the columnar protrusion. Yes.
- the interval (pitch) between the columnar protrusions is desirably about 1.5 times or more the longest outer diameter of the columnar protrusions. If the ranges of PGA to be viscoplasticized overlap, the lengths of the microneedles will be uneven. Accordingly, when the outer diameter of the cross-section of the columnar protrusions of the jig of the present invention is 200 to 450 ⁇ m as shown in FIGS. 6, 8, 10 or 11, the interval between the columnar protrusions is 300 ⁇ m to 1 mm. It may be in the range.
- the interval between the columnar protrusions is 300 to 600 ⁇ m.
- the jig size the portion where the columnar protrusions are present
- the number of columnar protrusions is related to each other. For example, when the number of columnar protrusions is 10 in length and width and the interval (pitch) is 800 ⁇ m, the size of the jig is 7.2 mm.
- the “number of columnar protrusions” in the present invention a necessary number is selected corresponding to the number of microneedles to be produced. Accordingly, the present invention is not particularly limited, and a plurality of them are sufficient. For example, it can be selected in the range of 9 to 500, for example, corresponding to the number of microneedles of the desired microneedle. According to the density of the sword mountain type microneedle, the same density of the columnar protrusions in the jig is selected. For example, in the present invention, since the outer diameter of the cross-section of the columnar protrusions is 100 to 450 ⁇ m, as described above, the interval (pitch) between the columnar protrusions is preferably 150 to 1 mm or more.
- the density of the columnar protrusions is preferably 9 to 500 / cm 2 .
- the “cross-sectional shape of the columnar protrusion” of the present invention is not particularly limited, and various shapes can be used as necessary. For example, a quadrangle, a U-shape, a cross shape, a circle, an e-shape, a circle with a portion missing (C-shape), a polygon with a partial deletion, or the like can be used.
- the size of the outer diameter of the cross-section of the columnar protrusion can be selected according to the size of the microneedle to be manufactured.
- a 200 ⁇ 200 ⁇ m square prism jig is used as shown in FIG. I found it good.
- a jig whose cross section of the columnar protrusion is a polygon with a partial deletion.
- the polygon having a partial deletion include those having a cross-section of a columnar protrusion having a U shape, a V shape, and a cross shape. As shown in FIG. 3, FIG. 4, and FIG. 9 to FIG.
- the U-shaped shape is 250 to 350 ⁇ m in the vertical and horizontal outer diameters, and the U-shaped wall thickness is 40 to 60 ⁇ m. Things can be used. Preferred ratios of the U-shaped vertical bars and horizontal bars include those in which the vertical bar is 1 and the horizontal bar is in the range of 1 to 1.5.
- the U-shape may be continuous, or one or more gaps may be opened. For example, a gap (interval) exists between two U-shaped horizontal bars and vertical bars as shown in FIGS. 15 to 16, or vertical bars as shown in FIGS. One may be present in the part.
- the cross-shaped shape for example, as shown in FIG.
- the vertical and horizontal outer diameters are 300 to 450 ⁇ m and the thickness of the cross is 40 to 60 ⁇ m.
- a cross formed by combining four rectangles with a gap at the center of the cross can also be used.
- the cross-section jig shown in FIG. 17 can be produced assuming that the cross-section of the columnar protrusion is a polygon having a partial deletion.
- a hollow microneedle can be formed.
- a jig having a non-uniform square cross section is used, for example, a cross section shown in FIG. 18, hollow microneedles are formed.
- a microneedle having two tips and concave portions on both sides is obtained. It will be.
- hollow microneedles, microneedles with recesses or grooves can be created by appropriately selecting the cross-section of the columnar protrusions of the jig according to the purpose.
- a drug can be efficiently carried by applying a medicinal component and a drug solution to the microneedle having such a microneedle.
- a known coating / immersion method can be used. As a result, a microneedle carrying a desired drug can be easily produced.
- Example 1 Manufacturing method of microneedle A silicon jig in which 10 square pillars each having a side of 0.2 mm ⁇ 0.2 mm and a height of 0.35 mm stand on a flat plate every 0.8 mm pitch ( 1 cm ⁇ 1 cm) was used. A PGA plate (radius 11 mm, thickness 1 mm) was attached to the horizontal surface of an autograph (manufactured by Shimadzu Corporation) with Capcom tape. The jig was placed on a hot plate at 250 ° C., the jig was brought into contact with the PGA plate, the PGA plate was pulled up, and microneedles were produced on the surface of the PGA plate. The obtained microneedle is shown in FIG. 1 and FIG.
- a PGA sword mountain type microneedle having 100 microneedles having a height of about 350 ⁇ m and a bottom having a quadrangular prism shape having a bottom portion of about 150 ⁇ m and a tip portion having a conical shape was obtained.
- the microneedle size (microneedle portion) was about 7.2 mm ⁇ 7.2 mm.
- Example 2 Manufacturing method of microneedles with U-shaped and V-shaped jigs
- the jig shown in FIGS. 4 and 5 having the cross-sectional shape of FIG. 3 was produced.
- the height of the columnar protrusions of the jig is about 350 ⁇ m.
- microneedles were produced using the same production apparatus and production conditions as in Example 1. The obtained microneedle is shown in the right view of FIG. 6 and FIG. From this result, when a U-shaped jig was used, a microneedle having a desired concave shape could be produced.
- Example 3 Kind of U-shaped jig and influence on needle shape Based on the result of Example 2 , the influence of the U-shaped jig on the shape of the formed micro needle was examined.
- jigs having cross-sectional figures shown in the left diagrams of FIGS. 9 to 11 were prepared. A microneedle was produced using the same apparatus and conditions as in Example 1. And the needle shape of the obtained microneedle was observed. The results are shown in the right diagrams of FIGS. When a jig having two U-shaped horizontal bars having an outer diameter of 350 ⁇ m, a vertical bar having an outer diameter of 250 ⁇ m, and a vertical bar having a thickness of 40 ⁇ m is used as a jig, the right diagram in FIG.
- the needle-shaped one obtained in Example 3 was a groove (concave portion) that further improved the ability to carry a chemical solution.
- Example 4 Production of jig (1) Production of square columnar jig by ICP-RIE method A 700 ⁇ m thick Si flat plate (4 ⁇ 4 inches) was coated with a photosensitive resist by spin coating. A drawing pattern of microneedles was drawn by UV exposure. Development was performed by a dipping method to transfer a microneedle pattern (200 ⁇ 200 ⁇ m square). By inductively coupled plasma reactive ion etching (ICP-RIE) method using CF 4 gas, 10 ⁇ 10 square pillars (columnar protrusion length is about 350 ⁇ m) (pitch interval between columnar protrusions is 800 ⁇ m). A Si flat plate was obtained.
- ICP-RIE inductively coupled plasma reactive ion etching
- the photosensitive resist remaining on the prisms was removed by the RIE method using O 2 gas.
- (2) Production of square columnar jig by high-precision dicing method A 700 ⁇ m thick Si flat plate (4 ⁇ 4 inches) is fixed, and a dicing saw (manufactured by DISCO) is used to grind and remove the portion between the columnar protrusions. A square columnar protrusion was cut out. A Si flat plate having 10 ⁇ 10 square columnar protrusions having a pitch interval of the columnar protrusions of about 720 ⁇ m and a length of the columnar protrusions of about 350 ⁇ m was obtained.
- V-shaped columnar protrusions (length: about 350 ⁇ m) are formed in the same manner as (1) above. A 3 ⁇ 3 Si flat plate was obtained. The obtained Si jig is shown in FIG.
- Example 5 Production of microneedle using cross-shaped jig Using the cross-shaped jig produced in Example 4 (4) and using the apparatus and production conditions of Example 1, production of microneedle It was investigated.
- the obtained microneedle is shown in the right figure of FIG.
- the bottom of the microneedle forms a cross shape derived from a jig.
- it converges and shows a shape close to a cone.
- the lifting speed of the jig is high, so that it is necessary to reduce the lifting speed of the jig in order to form the recess necessary for holding the medicine. I found out that
- the jig and manufacturing method of the present invention enable easy mass production of PGA microneedles with high material strength. Further, by devising the shape of the jig (cross-sectional shape of the columnar protrusion), for example, by using a U-shaped jig in addition to FIG. 1, the right diagram in FIG. 6 and the right diagrams in FIGS. As shown in the figure, it became possible to produce a microneedle as shown in the right figure of FIG. 6 and the groove shown in FIG.
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Abstract
Provided is a method for efficiently producing a microneedle which comprises PGA having a high material strength and is provided with a groove (depression) wherein a drug solution can be easily held. Also provided is a jig required for the method. A desired microneedle comprising PGA can be formed by bringing a PGA plate into contact with a jig, thus melting PGA at the contact site and then stretching the same. It is found out that the shape of the microneedle thus obtained is affected by the shape of the employed jig. For producing a microneedle provided with a groove (depression) wherein a drug solution can be easily held, it is particularly effective to use a U-shaped jig. Thus, it becomes possible to form a large number of microneedles while controlling the material strength and the needle shape.
Description
本発明は、生体内分解性樹脂で作製された剣山型マイクロニードルに関するものである。特に薬液を保持し易い溝を持ち、材質強度の高いPGA製のマイクロニードルと、その製造に使用する冶具に関するものである。
The present invention relates to a sword mountain type microneedle made of a biodegradable resin. In particular, the present invention relates to a PGA microneedle having a groove that can easily hold a chemical solution and having a high material strength, and a jig used for the manufacture thereof.
薬剤を経皮的に投与する方法として、各種の液剤・軟膏剤の塗布、貼付剤型の経皮投与製剤が開発されているが、上記角質層のバリヤー作用のため、あまり薬効成分の吸収が改善されていない状況にある。そこで、薬剤の皮膚透過性を上げるための方法の一つとして、特許文献1に示されるように、微小針を使用し、角質層を局所的に破壊して薬剤を真皮層に強制的に投与すると言うことが試みられてきた。
この目的で使用される微小針は、真皮層に微小針が到達すればよいことから、その針の長さは30μm以上であることが望ましく、その針を支持するために必要な基盤があればよいとされている。そして、この微小針は、神経の末端が存在する真皮層に到達しないので痛くない。それ故、小児などに恐怖感を与えることなく薬剤の投与ができると言う長所が存在する。 As a method for transdermal administration of drugs, various liquid and ointment coatings and patch-type transdermal administration formulations have been developed. However, due to the barrier action of the stratum corneum, absorption of medicinal ingredients is not so much. The situation is not improved. Therefore, as one of the methods for increasing the skin permeability of the drug, as shown inPatent Document 1, a microneedle is used, the stratum corneum is locally destroyed, and the drug is forcibly administered to the dermis layer. It has been attempted to say so.
Since the microneedle used for this purpose only needs to reach the dermis layer, the length of the needle is preferably 30 μm or more, and there is a base necessary to support the needle. It is said to be good. This microneedle does not hurt because it does not reach the dermis layer where the nerve ends are present. Therefore, there is an advantage that the drug can be administered without giving fear to children.
この目的で使用される微小針は、真皮層に微小針が到達すればよいことから、その針の長さは30μm以上であることが望ましく、その針を支持するために必要な基盤があればよいとされている。そして、この微小針は、神経の末端が存在する真皮層に到達しないので痛くない。それ故、小児などに恐怖感を与えることなく薬剤の投与ができると言う長所が存在する。 As a method for transdermal administration of drugs, various liquid and ointment coatings and patch-type transdermal administration formulations have been developed. However, due to the barrier action of the stratum corneum, absorption of medicinal ingredients is not so much. The situation is not improved. Therefore, as one of the methods for increasing the skin permeability of the drug, as shown in
Since the microneedle used for this purpose only needs to reach the dermis layer, the length of the needle is preferably 30 μm or more, and there is a base necessary to support the needle. It is said to be good. This microneedle does not hurt because it does not reach the dermis layer where the nerve ends are present. Therefore, there is an advantage that the drug can be administered without giving fear to children.
以上のことから、これまで微小針の製造方法に関して、色々な方法が開発され報告されてきた。例えば特許文献2では、紫外線硬化性アクリレート接着剤やエポキシ樹脂を使用して、液滴状樹脂を引上げて微小針を製作する方法が記載されている。
しかし、このような樹脂液滴由来の製造方法では、微小針の高さや幅等の規格が統一された形のマイクロニードル・アレイ(剣山型マイクロニードル)を大量に製造することは困難であると考えられていた。 In view of the above, various methods have been developed and reported for microneedle manufacturing methods. For example,Patent Document 2 describes a method of manufacturing a microneedle by pulling up a droplet resin using an ultraviolet curable acrylate adhesive or an epoxy resin.
However, with such a manufacturing method derived from resin droplets, it is difficult to manufacture a large number of microneedle arrays (Kenyama-type microneedles) with a uniform standard for the height and width of microneedles. It was thought.
しかし、このような樹脂液滴由来の製造方法では、微小針の高さや幅等の規格が統一された形のマイクロニードル・アレイ(剣山型マイクロニードル)を大量に製造することは困難であると考えられていた。 In view of the above, various methods have been developed and reported for microneedle manufacturing methods. For example,
However, with such a manufacturing method derived from resin droplets, it is difficult to manufacture a large number of microneedle arrays (Kenyama-type microneedles) with a uniform standard for the height and width of microneedles. It was thought.
また、特許文献3では、糊状基剤にガラス棒を押し当て徐々に引き離して針状または糸状の固形物を作製したと記載している。しかし、具体的にどのような物が作製されたのかについては、あまり明確な記載は見当たらない。
現在のところ、汎用性が高いと考えられる生体内分解性樹脂のマイクロニードルに関しては、工業的に量産可能な現実的製造方法は未だ報告されておらず、今なお種々の方法が模索、検討されている状況である。Patent Document 3 describes that a glass rod is pressed against a pasty base and gradually separated to produce a needle-like or thread-like solid. However, there is no clear description as to what was specifically produced.
At present, no biomanufacturable resin microneedles, which are considered to be highly versatile, have yet been reported on a practical production method that can be industrially mass-produced, and various methods are still being sought and studied. It is a situation.
現在のところ、汎用性が高いと考えられる生体内分解性樹脂のマイクロニードルに関しては、工業的に量産可能な現実的製造方法は未だ報告されておらず、今なお種々の方法が模索、検討されている状況である。
At present, no biomanufacturable resin microneedles, which are considered to be highly versatile, have yet been reported on a practical production method that can be industrially mass-produced, and various methods are still being sought and studied. It is a situation.
本発明の課題は、生体内分解性樹脂のマイクロニードルを工業的に量産できる製造方法と、それに用いる冶具を提供することを目的とする。更に詳しくは材質強度の高い生体内分解性樹脂である、PGA樹脂を用いるマイクロニードルの製造方法を提供することである。
An object of the present invention is to provide a production method capable of industrially mass-producing microneedles of a biodegradable resin and a jig used therefor. More specifically, it is to provide a method for producing microneedles using PGA resin, which is a biodegradable resin having high material strength.
本発明者らは、上記課題を達成すべく鋭意検討を行ってきた。即ち、ポリ乳酸(PLA)シートに剣山状の冶具を接触させ、樹脂を加熱溶解して引き離し、PLAシート状にPLA微小針を作製する方法をこれまでに見出している(これについてはPCT/JP2008/051317に記載)。本発明者らは、更に検討を進めた結果、PLAよりも材質強度が高い生体内分解性の樹脂であるポリグリコール酸(PGA)を使用して再現性よくPGA製の剣山型マイクロニードルを製造できることを見出した。更に、治具の形(柱状突起)を検討することにより、円錐状や角錐状のマイクロニードルだけでなく、凹部あるいは溝状の窪みを持ったマイクロニードルや中空状のマイクロニードルを効率よく製造できることを見出した。このような凹部や中空を持ったマイクロニードルは薬液を貯留、保持するために有用であり、薬効成分の皮膚透過に大きく寄与することができる。
The present inventors have intensively studied to achieve the above problems. That is, a method has been found so far in which a sword-shaped jig is brought into contact with a polylactic acid (PLA) sheet, the resin is heated and melted away, and a PLA microneedle is formed into a PLA sheet (PCT / JP2008). / 051317). As a result of further investigations, the present inventors manufactured PGA-made Kenyama microneedles with high reproducibility using polyglycolic acid (PGA), a biodegradable resin having higher material strength than PLA. I found out that I can do it. Furthermore, by examining the shape of the jig (columnar protrusions), not only conical or pyramidal microneedles, but also microneedles having concave or groove-like depressions or hollow microneedles can be efficiently manufactured. I found. Such a microneedle having a recess or a hollow is useful for storing and holding a drug solution, and can greatly contribute to skin permeation of a medicinal component.
本発明のマイクロニードルの形状は、その製造方法に起因して、底辺部分が治具の柱状突起の断面に由来する形状を持ち、先端部に行くに従って円柱形状から円錐形状を持つようになる。また、マイクロニードルの微小針の長さも、冶具の接触面積(柱状突起の断面の接触面積)に影響される。例えば冶具の接触面積が大きい場合、熔解されるPGAの量が多くなり、それに比例して長い微小針が形成されることを見出した。更にマイクロニードル同士の間隔(ピッチ)は、狭すぎれば、マイクロニードルが一本一本分離して形成されにくくなるため、自ずと一定以上の間隔が要求されることになる。本発明の製造方法においては、柱状突起の外径の大きさにもよるが、概ね柱状突起の外径の2倍前後の間隔が望ましく、そのピッチは少なくとも300μm以上であり、2mm以下である。特に800μm前後を中心として500μm~1mmの範囲が好適であることを見出した。
以上の知見により、治具を適宜選択することにより、強度が高く皮膚に穿刺し易い、PGA製のマイクロニードルを容易に多種類製造できることを見出し、本発明を完成することが出来た。 The shape of the microneedle of the present invention has a shape in which the bottom portion is derived from the cross-section of the columnar protrusion of the jig due to the manufacturing method, and from a cylindrical shape to a conical shape as it goes to the tip. The length of the microneedle of the microneedle is also affected by the contact area of the jig (the contact area of the cross section of the columnar protrusion). For example, it has been found that when the contact area of the jig is large, the amount of PGA to be melted increases, and long microneedles are formed in proportion thereto. Furthermore, if the interval (pitch) between the microneedles is too small, the microneedles are difficult to be separated and formed one by one, and therefore a certain interval or more is naturally required. In the production method of the present invention, although it depends on the size of the outer diameter of the columnar protrusions, an interval of about twice the outer diameter of the columnar protrusion is desirable, and the pitch is at least 300 μm or more and 2 mm or less. In particular, the inventors have found that a range of 500 μm to 1 mm is preferable, centering around 800 μm.
Based on the above knowledge, it has been found that by selecting an appropriate jig, it is possible to easily produce many kinds of PGA microneedles having high strength and easy to puncture the skin, and the present invention has been completed.
以上の知見により、治具を適宜選択することにより、強度が高く皮膚に穿刺し易い、PGA製のマイクロニードルを容易に多種類製造できることを見出し、本発明を完成することが出来た。 The shape of the microneedle of the present invention has a shape in which the bottom portion is derived from the cross-section of the columnar protrusion of the jig due to the manufacturing method, and from a cylindrical shape to a conical shape as it goes to the tip. The length of the microneedle of the microneedle is also affected by the contact area of the jig (the contact area of the cross section of the columnar protrusion). For example, it has been found that when the contact area of the jig is large, the amount of PGA to be melted increases, and long microneedles are formed in proportion thereto. Furthermore, if the interval (pitch) between the microneedles is too small, the microneedles are difficult to be separated and formed one by one, and therefore a certain interval or more is naturally required. In the production method of the present invention, although it depends on the size of the outer diameter of the columnar protrusions, an interval of about twice the outer diameter of the columnar protrusion is desirable, and the pitch is at least 300 μm or more and 2 mm or less. In particular, the inventors have found that a range of 500 μm to 1 mm is preferable, centering around 800 μm.
Based on the above knowledge, it has been found that by selecting an appropriate jig, it is possible to easily produce many kinds of PGA microneedles having high strength and easy to puncture the skin, and the present invention has been completed.
本発明の要旨は以下の通りである。
[1]ポリグリコール酸(PGA)製の基板上に、複数のPGA製の微小針が一定の間隔(ピッチ)を持って配設されているマイクロニードルであって、
前記微小針は、前記基板に接する微小針の底部から頂部にかけて断面形状が小さくなる構造を有し、かつ前記底部近傍での断面形状の減少率が前記頂部近傍に比べて大きく、前記底部から前記頂部方向にかけて連続した溝、くぼみ及び連続した中空部の少なくとも1つを有する構造からなるマイクロニードル。
[2]前記微小針の高さが150μm~1mmであり、
前記微小針の前記底部の外形が100~450μmであり、
前記微小針の間隔が100μm~2mmである、上記[1]に記載のマイクロニードル。
[3]前記微小針の間隔が300μm~2mmである、上記[1]又は[2]に記載のマイクロニードル。
[4]前記微小針の間隔が500μm~1mmである、上記[1]~[3]のいずれかに記載のマイクロニードル。 The gist of the present invention is as follows.
[1] A microneedle in which a plurality of PGA microneedles are arranged on a substrate made of polyglycolic acid (PGA) with a constant interval (pitch),
The microneedles have a structure in which the cross-sectional shape decreases from the bottom to the top of the microneedles in contact with the substrate, and the reduction rate of the cross-sectional shape in the vicinity of the bottom is larger than that in the vicinity of the top. A microneedle having a structure having at least one of a continuous groove, a depression, and a continuous hollow portion in a direction toward the top.
[2] The height of the micro needle is 150 μm to 1 mm,
The outer shape of the bottom of the microneedle is 100 to 450 μm;
The microneedle according to [1] above, wherein the interval between the microneedles is 100 μm to 2 mm.
[3] The microneedle according to the above [1] or [2], wherein the interval between the microneedles is 300 μm to 2 mm.
[4] The microneedle according to any one of the above [1] to [3], wherein the interval between the microneedles is 500 μm to 1 mm.
[1]ポリグリコール酸(PGA)製の基板上に、複数のPGA製の微小針が一定の間隔(ピッチ)を持って配設されているマイクロニードルであって、
前記微小針は、前記基板に接する微小針の底部から頂部にかけて断面形状が小さくなる構造を有し、かつ前記底部近傍での断面形状の減少率が前記頂部近傍に比べて大きく、前記底部から前記頂部方向にかけて連続した溝、くぼみ及び連続した中空部の少なくとも1つを有する構造からなるマイクロニードル。
[2]前記微小針の高さが150μm~1mmであり、
前記微小針の前記底部の外形が100~450μmであり、
前記微小針の間隔が100μm~2mmである、上記[1]に記載のマイクロニードル。
[3]前記微小針の間隔が300μm~2mmである、上記[1]又は[2]に記載のマイクロニードル。
[4]前記微小針の間隔が500μm~1mmである、上記[1]~[3]のいずれかに記載のマイクロニードル。 The gist of the present invention is as follows.
[1] A microneedle in which a plurality of PGA microneedles are arranged on a substrate made of polyglycolic acid (PGA) with a constant interval (pitch),
The microneedles have a structure in which the cross-sectional shape decreases from the bottom to the top of the microneedles in contact with the substrate, and the reduction rate of the cross-sectional shape in the vicinity of the bottom is larger than that in the vicinity of the top. A microneedle having a structure having at least one of a continuous groove, a depression, and a continuous hollow portion in a direction toward the top.
[2] The height of the micro needle is 150 μm to 1 mm,
The outer shape of the bottom of the microneedle is 100 to 450 μm;
The microneedle according to [1] above, wherein the interval between the microneedles is 100 μm to 2 mm.
[3] The microneedle according to the above [1] or [2], wherein the interval between the microneedles is 300 μm to 2 mm.
[4] The microneedle according to any one of the above [1] to [3], wherein the interval between the microneedles is 500 μm to 1 mm.
[5]以下の形状を有するポリグリコール酸(PGA)製のマイクロニードル。
(1)微小針の本数が複数であり、
(2)微小針の高さが150μm~1mmであり、
(3)微小針の底部の外径が100~450μmであり、
(4)微小針の先端部が尖った円柱状又は円錐状となり、その外径が数μm~数十μmであり、
(5)微小針の断面の形状が底部では円形、多角形、十字型、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形であり、先端部では円形である、
[6]前記微小針の間隔(ピッチ)が300μm~2mmである、上記[5]記載のマイクロニードル。
[7]多角形が四角形である、上記[4]又は[5]に記載のマイクロニードル。
[8]部分的な欠失がある多角形が、コの字型、V字型である、上記[4]~[6]のいずれかに記載のマイクロニードル。
[9]尖った円柱状又は円錐状になった先端部と底部の間の微小針の形状として、溝状の凹部を保持する微小針であることを特徴とする、上記[8]記載のマイクロニードル。 [5] A microneedle made of polyglycolic acid (PGA) having the following shape.
(1) The number of microneedles is plural,
(2) The height of the micro needle is 150 μm to 1 mm,
(3) The outer diameter of the bottom of the microneedle is 100 to 450 μm,
(4) The tip of the microneedle has a pointed cylindrical or conical shape, and its outer diameter is several μm to several tens of μm.
(5) The cross-sectional shape of the microneedle is a circle, a polygon, a cross, a square shape, a circle with a portion missing (C shape) or a polygon with a partial deletion at the bottom, and the tip In a circle,
[6] The microneedle according to the above [5], wherein an interval (pitch) between the microneedles is 300 μm to 2 mm.
[7] The microneedle according to the above [4] or [5], wherein the polygon is a quadrangle.
[8] The microneedle according to any one of [4] to [6] above, wherein the polygon having a partial deletion is a U shape or a V shape.
[9] The microneedle described in [8] above, wherein the microneedle holding a groove-like recess is used as a shape of the microneedle between the tip and the bottom having a pointed cylindrical or conical shape. needle.
(1)微小針の本数が複数であり、
(2)微小針の高さが150μm~1mmであり、
(3)微小針の底部の外径が100~450μmであり、
(4)微小針の先端部が尖った円柱状又は円錐状となり、その外径が数μm~数十μmであり、
(5)微小針の断面の形状が底部では円形、多角形、十字型、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形であり、先端部では円形である、
[6]前記微小針の間隔(ピッチ)が300μm~2mmである、上記[5]記載のマイクロニードル。
[7]多角形が四角形である、上記[4]又は[5]に記載のマイクロニードル。
[8]部分的な欠失がある多角形が、コの字型、V字型である、上記[4]~[6]のいずれかに記載のマイクロニードル。
[9]尖った円柱状又は円錐状になった先端部と底部の間の微小針の形状として、溝状の凹部を保持する微小針であることを特徴とする、上記[8]記載のマイクロニードル。 [5] A microneedle made of polyglycolic acid (PGA) having the following shape.
(1) The number of microneedles is plural,
(2) The height of the micro needle is 150 μm to 1 mm,
(3) The outer diameter of the bottom of the microneedle is 100 to 450 μm,
(4) The tip of the microneedle has a pointed cylindrical or conical shape, and its outer diameter is several μm to several tens of μm.
(5) The cross-sectional shape of the microneedle is a circle, a polygon, a cross, a square shape, a circle with a portion missing (C shape) or a polygon with a partial deletion at the bottom, and the tip In a circle,
[6] The microneedle according to the above [5], wherein an interval (pitch) between the microneedles is 300 μm to 2 mm.
[7] The microneedle according to the above [4] or [5], wherein the polygon is a quadrangle.
[8] The microneedle according to any one of [4] to [6] above, wherein the polygon having a partial deletion is a U shape or a V shape.
[9] The microneedle described in [8] above, wherein the microneedle holding a groove-like recess is used as a shape of the microneedle between the tip and the bottom having a pointed cylindrical or conical shape. needle.
[10]平板上に以下の形状の柱状突起を有するシリコン製または金属製の冶具。
(1)柱状突起の長さが200μm~1mmであり、
(2)柱状突起の間隔が300μm~2mmであり、
(3)柱状突起の本数が複数であり、
(4)柱状突起の断面の外径が、100~450μmであり、
(5)柱状突起の断面形状が、円形、多角形、十字型、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形である、
[11]前記柱状突起の間隔が500μm~1mmである、上記[10]に記載のマイクロニードル。
[12]部分的な欠失がある多角形がコの字型、V字型である、上記[10]又は[11]に記載の冶具。
[13]コの字型の一部に欠失がある、上記[11]又は[12]に記載の冶具。
[14]コの字の2本の横棒と一本の縦棒の長さの比率として、縦棒を1として、横棒が1~1.5の範囲である、上記[12]又は[13]に記載の治具。
[15]コの字の2本の横棒の肉厚が40~80μmであり、縦棒の肉厚が20~50μmであることを特徴とする、上記[14]に記載の冶具。
[16]一つまたは複数の隙間が、コの字の2本の横棒と縦棒の間に存在する、あるいは縦棒の部分に一つ存在することを特徴とする、上記[15]に記載の冶具。
[17]柱状突起の断面形状が、十字型であることを特徴とする、上記[10]記載の冶具。
[18]十字の縦横の外径が400~450μmであり、肉厚が40~80μmであることを特徴とする、上記[17]記載の冶具。 [10] A silicon or metal jig having a columnar protrusion having the following shape on a flat plate.
(1) The length of the columnar protrusion is 200 μm to 1 mm,
(2) The interval between the columnar protrusions is 300 μm to 2 mm,
(3) The number of columnar protrusions is plural,
(4) The outer diameter of the cross-section of the columnar protrusion is 100 to 450 μm,
(5) The cross-sectional shape of the columnar protrusion is a circle, a polygon, a cross, a square shape, a circle with a part missing (C shape) or a polygon with a partial deletion.
[11] The microneedle according to [10] above, wherein the interval between the columnar protrusions is 500 μm to 1 mm.
[12] The jig according to [10] or [11] above, wherein the polygon having a partial deletion is a U shape or a V shape.
[13] The jig according to [11] or [12] above, wherein a part of the U-shape is deleted.
[14] The ratio of the length of two U-shaped horizontal bars to one vertical bar, where the vertical bar is 1, and the horizontal bar is in the range of 1 to 1.5 above [12] or [ 13].
[15] The jig according to [14] above, wherein the thickness of the two U-shaped horizontal bars is 40 to 80 μm and the thickness of the vertical bar is 20 to 50 μm.
[16] In the above [15], one or more gaps exist between two horizontal bars and vertical bars of a U-shape, or one exists in a vertical bar portion. The described jig.
[17] The jig according to [10] above, wherein the cross-sectional shape of the columnar protrusion is a cross shape.
[18] The jig according to [17] above, wherein the cross has a vertical and horizontal outer diameter of 400 to 450 μm and a wall thickness of 40 to 80 μm.
(1)柱状突起の長さが200μm~1mmであり、
(2)柱状突起の間隔が300μm~2mmであり、
(3)柱状突起の本数が複数であり、
(4)柱状突起の断面の外径が、100~450μmであり、
(5)柱状突起の断面形状が、円形、多角形、十字型、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形である、
[11]前記柱状突起の間隔が500μm~1mmである、上記[10]に記載のマイクロニードル。
[12]部分的な欠失がある多角形がコの字型、V字型である、上記[10]又は[11]に記載の冶具。
[13]コの字型の一部に欠失がある、上記[11]又は[12]に記載の冶具。
[14]コの字の2本の横棒と一本の縦棒の長さの比率として、縦棒を1として、横棒が1~1.5の範囲である、上記[12]又は[13]に記載の治具。
[15]コの字の2本の横棒の肉厚が40~80μmであり、縦棒の肉厚が20~50μmであることを特徴とする、上記[14]に記載の冶具。
[16]一つまたは複数の隙間が、コの字の2本の横棒と縦棒の間に存在する、あるいは縦棒の部分に一つ存在することを特徴とする、上記[15]に記載の冶具。
[17]柱状突起の断面形状が、十字型であることを特徴とする、上記[10]記載の冶具。
[18]十字の縦横の外径が400~450μmであり、肉厚が40~80μmであることを特徴とする、上記[17]記載の冶具。 [10] A silicon or metal jig having a columnar protrusion having the following shape on a flat plate.
(1) The length of the columnar protrusion is 200 μm to 1 mm,
(2) The interval between the columnar protrusions is 300 μm to 2 mm,
(3) The number of columnar protrusions is plural,
(4) The outer diameter of the cross-section of the columnar protrusion is 100 to 450 μm,
(5) The cross-sectional shape of the columnar protrusion is a circle, a polygon, a cross, a square shape, a circle with a part missing (C shape) or a polygon with a partial deletion.
[11] The microneedle according to [10] above, wherein the interval between the columnar protrusions is 500 μm to 1 mm.
[12] The jig according to [10] or [11] above, wherein the polygon having a partial deletion is a U shape or a V shape.
[13] The jig according to [11] or [12] above, wherein a part of the U-shape is deleted.
[14] The ratio of the length of two U-shaped horizontal bars to one vertical bar, where the vertical bar is 1, and the horizontal bar is in the range of 1 to 1.5 above [12] or [ 13].
[15] The jig according to [14] above, wherein the thickness of the two U-shaped horizontal bars is 40 to 80 μm and the thickness of the vertical bar is 20 to 50 μm.
[16] In the above [15], one or more gaps exist between two horizontal bars and vertical bars of a U-shape, or one exists in a vertical bar portion. The described jig.
[17] The jig according to [10] above, wherein the cross-sectional shape of the columnar protrusion is a cross shape.
[18] The jig according to [17] above, wherein the cross has a vertical and horizontal outer diameter of 400 to 450 μm and a wall thickness of 40 to 80 μm.
[19]以下の工程(1)~(6)を含むPGA製のマイクロニードルの製造方法。
(1)PGAの粘塑性状態になる温度以上に、冶具の温度を設定する、
(2)冶具をPGAプレートに接触させ、接触部位のPGAを粘塑性化する、
(3)冶具とPGAプレートを2~6mm/秒の速度で、0.2~2mm引き離し、粘塑性化したPGAを糸状に引き伸ばす、
(4)冶具とPGAプレートの引き離しを停止し、糸状のPGAを切断して、針状突起を形成させる、
[20]冶具の温度をPGAの融点付近に設定することを特徴とする、上記[19]記載の製造方法。
[21]冶具の温度を250℃付近(240~260℃)に設定することを特徴とする、上記[19]又は[20]に記載の製造方法。
[22]上記[10]の冶具を用いて製造することを特徴とする、上記[19]~[21]のいずれかに記載の製造方法。 [19] A method for producing a microneedle made of PGA, comprising the following steps (1) to (6).
(1) Set the temperature of the jig above the temperature at which the PGA becomes viscoplastic.
(2) The jig is brought into contact with the PGA plate, and the PGA at the contact portion is viscoplasticized.
(3) The jig and the PGA plate are separated from each other by 0.2 to 2 mm at a speed of 2 to 6 mm / sec, and the viscoplasticized PGA is stretched into a thread shape.
(4) Stop the separation of the jig and the PGA plate, cut the thread-like PGA, and form the needle-like protrusions;
[20] The method according to [19] above, wherein the temperature of the jig is set in the vicinity of the melting point of PGA.
[21] The method according to [19] or [20] above, wherein the temperature of the jig is set to around 250 ° C. (240 to 260 ° C.).
[22] The production method according to any one of [19] to [21], wherein the production is performed using the jig according to [10].
(1)PGAの粘塑性状態になる温度以上に、冶具の温度を設定する、
(2)冶具をPGAプレートに接触させ、接触部位のPGAを粘塑性化する、
(3)冶具とPGAプレートを2~6mm/秒の速度で、0.2~2mm引き離し、粘塑性化したPGAを糸状に引き伸ばす、
(4)冶具とPGAプレートの引き離しを停止し、糸状のPGAを切断して、針状突起を形成させる、
[20]冶具の温度をPGAの融点付近に設定することを特徴とする、上記[19]記載の製造方法。
[21]冶具の温度を250℃付近(240~260℃)に設定することを特徴とする、上記[19]又は[20]に記載の製造方法。
[22]上記[10]の冶具を用いて製造することを特徴とする、上記[19]~[21]のいずれかに記載の製造方法。 [19] A method for producing a microneedle made of PGA, comprising the following steps (1) to (6).
(1) Set the temperature of the jig above the temperature at which the PGA becomes viscoplastic.
(2) The jig is brought into contact with the PGA plate, and the PGA at the contact portion is viscoplasticized.
(3) The jig and the PGA plate are separated from each other by 0.2 to 2 mm at a speed of 2 to 6 mm / sec, and the viscoplasticized PGA is stretched into a thread shape.
(4) Stop the separation of the jig and the PGA plate, cut the thread-like PGA, and form the needle-like protrusions;
[20] The method according to [19] above, wherein the temperature of the jig is set in the vicinity of the melting point of PGA.
[21] The method according to [19] or [20] above, wherein the temperature of the jig is set to around 250 ° C. (240 to 260 ° C.).
[22] The production method according to any one of [19] to [21], wherein the production is performed using the jig according to [10].
本発明のPGA製の剣山型マイクロニードルは強度が強靭であるため、皮膚を穿刺する場合において、変形することが少なく、効果的に皮膚に挿入することができる。しかも、治具を選択することにより、容易に多種類の形状を持ったPGA製マイクロニードルを製造することができる。特に治具を選択することにより、中空のマイクロニードルあるいは側面に凹部あるいは溝を持ったマイクロニードルを作製することが可能であり、その中空部や凹部等に薬効成分を担持させることができる。このようなPGA製マイクロニードルを使用することにより、より効果的に薬効成分を皮下に注入することが可能になった。
The sword mountain type microneedle made of PGA of the present invention is strong, and therefore, when puncturing the skin, it is hardly deformed and can be effectively inserted into the skin. In addition, PGA microneedles having various shapes can be easily manufactured by selecting a jig. In particular, by selecting a jig, it is possible to produce a hollow microneedle or a microneedle having a recess or groove on the side surface, and a medicinal component can be carried in the hollow or recess. By using such a PGA microneedle, the medicinal component can be injected more effectively subcutaneously.
本発明のマイクロニードルの製造に使用される冶具は、半導体プロセス等にて作製されるシリコン(Si)製あるいは金属製の治具である。ここで使用される半導体プロセス等としては、微小針の作製で使用される公知の微細製作プロセスを適宜使用することができる。例えばX線リソグラフィー、フォトリソグラフィー等のリソグラフィー、例えばイオンエッチング、プラズマエッチィング等のエッチングを挙げることができる。好ましくは、イオンで深くエッチングできる誘導結合型プラズマ反応型イオンエッチィング(Inductively Coupled Plasma Reactive Ion Etching:ICP-RIEと略称する)を挙げることができる。これらの技術は一般的な成書に記載されており、例えば、谷口淳著、「はじめてのナノプリント技術」(工業調査会、2005年)、M.エルベンスポーク著、「シリコンマイクロ加工の基礎」(シュプリンガー・フェアラーク東京、2001年)、Jaeger,Introduction to Microelectronic Fabrication(Addison-Wesley Publishing Co.,Reading MA 1988)、Runyan,ら、Semiconductor Integrated Circuit Processing Technology(Addison-Wesley Publishing Co.,Reading MA 1990)、Proceedings of the IEEE Micro Electro Mechanical Systems Conference 1987-1998、Rai-Choudhury編、Handbook of Microlithography,Micromachining & Microfabrication(SSPIE Optical Engineering Press,Bellingham,WA 1997)を挙げることができる。
更に、別途、半導体ダイシング加工により、シリコン製平板表面をカッティングすることにより、所望の冶具を作成することが出来る。例えば、ダイシング装置(デイスコ社製)を用いて焼結ダイヤ製砥石による切削により、所望のピッチ間隔を持った四角柱状突起を持った冶具を作成することが出来る。 The jig used for manufacturing the microneedle of the present invention is a silicon (Si) or metal jig manufactured by a semiconductor process or the like. As the semiconductor process or the like used here, a well-known fine fabrication process used in the production of microneedles can be used as appropriate. Examples thereof include lithography such as X-ray lithography and photolithography, and etching such as ion etching and plasma etching. Preferably, inductively coupled plasma reactive ion etching (abbreviated as ICP-RIE) that can be deeply etched with ions can be used. These techniques are described in general books, for example, by Taniguchi Satoshi, “First Nanoprint Technology” (Industry Research Committee, 2005), M.M. Elben Spoke, "Silicon Microfabrication Fundamentals" (Springer Fairlark Tokyo, 2001), Jaeger, Induction to Microelectronic Fabrication (Addison-Wesley Public Publishing Co., Reading MA 1988), Reading MA 1988. Technology (Addison-Wesley Publishing Co., Reading MA 1990), Processeds of the IEEE Micro Electro Mechanical Systems Conference 1987-1998, Rai-Chur. Ed., Handbook of Microlithography, Micromachining & Microfabrication (SSPIE Optical Engineering Press, Bellingham, WA 1997).
Furthermore, a desired jig can be produced by cutting a silicon flat plate surface separately by semiconductor dicing. For example, by using a dicing machine (manufactured by DISCO Corporation) and cutting with a grindstone made of sintered diamond, a jig having square columnar protrusions having a desired pitch interval can be created.
更に、別途、半導体ダイシング加工により、シリコン製平板表面をカッティングすることにより、所望の冶具を作成することが出来る。例えば、ダイシング装置(デイスコ社製)を用いて焼結ダイヤ製砥石による切削により、所望のピッチ間隔を持った四角柱状突起を持った冶具を作成することが出来る。 The jig used for manufacturing the microneedle of the present invention is a silicon (Si) or metal jig manufactured by a semiconductor process or the like. As the semiconductor process or the like used here, a well-known fine fabrication process used in the production of microneedles can be used as appropriate. Examples thereof include lithography such as X-ray lithography and photolithography, and etching such as ion etching and plasma etching. Preferably, inductively coupled plasma reactive ion etching (abbreviated as ICP-RIE) that can be deeply etched with ions can be used. These techniques are described in general books, for example, by Taniguchi Satoshi, “First Nanoprint Technology” (Industry Research Committee, 2005), M.M. Elben Spoke, "Silicon Microfabrication Fundamentals" (Springer Fairlark Tokyo, 2001), Jaeger, Induction to Microelectronic Fabrication (Addison-Wesley Public Publishing Co., Reading MA 1988), Reading MA 1988. Technology (Addison-Wesley Publishing Co., Reading MA 1990), Processeds of the IEEE Micro Electro Mechanical Systems Conference 1987-1998, Rai-Chur. Ed., Handbook of Microlithography, Micromachining & Microfabrication (SSPIE Optical Engineering Press, Bellingham, WA 1997).
Furthermore, a desired jig can be produced by cutting a silicon flat plate surface separately by semiconductor dicing. For example, by using a dicing machine (manufactured by DISCO Corporation) and cutting with a grindstone made of sintered diamond, a jig having square columnar protrusions having a desired pitch interval can be created.
本発明のマイクロニードルの作製方法として、ます上記で得られた冶具を用いて、PGAシートに接触させPGAを軟化熔融させる。その後、冶具を引き離し、冶具に付着したPGAを引き出す操作を行なう。PGAが糸状に伸展した時点で冶具引き離し速度を低下または停止し、伸展した糸状のPGAを表面張力により切断する。これにより、微小針の長さが揃ったマイクロニードルを作製することができる(これらはPCT/JP2008/051317に記載している。)。
本発明で言う「ポリグリコール酸(PGA)」とは、繰り返し単位(OCH2CO)を50質量%以上含む、好ましくは70質量%以上含む、より好ましくは90質量%以上含む、重量平均分子量が2万から100万の、好ましくは5万から80万の、より好ましくは7万から50万の、融点がある場合はそれが180℃から230℃の、好ましくは200℃から230℃の、より好ましくは210~230℃の、270℃での溶融粘度1Pa・sから10000Pa・sの、より好ましくは10Pa・sから5000Pa・sの、ガラス転移点が約40℃の物性を持つ樹脂である。
これまでよく使用されてきたポリ乳酸(PLA)と比較して、本発明ではPGAを使用することにより、強度的にもより強靭なマイクロニードルを作製できる。例えば、本発明の図1又は図2のマイクロニードルを用いて、ラット皮膚の穿刺実験を行ったが、図20に示されるように、穿刺後のマイクロニードルの写真には折れたり曲がったりした微小針は見当たらず、全体としてあまり変化が見られなかった。一方、PLAを使用した場合には、図21のマイクロニードルがラット皮膚への穿刺後には、図22のように曲がったり、図23のように微小針の針先が押し潰されてしまったりするようなことが多く見出された。以上のように、PGA製のマイクロニードルは、予想外に優れた強度を持った汎用性の高いものであることが分かった。 As a method for producing the microneedle of the present invention, the PGA is softened and melted by bringing it into contact with the PGA sheet using the jig obtained above. Thereafter, the jig is pulled away, and the PGA attached to the jig is pulled out. When the PGA extends in the form of a thread, the jig separating speed is reduced or stopped, and the extended thread-like PGA is cut by surface tension. Thereby, microneedles having the same length of microneedles can be produced (these are described in PCT / JP2008 / 051317).
The term “polyglycolic acid (PGA)” used in the present invention includes a repeating unit (OCH 2 CO) of 50% by mass or more, preferably 70% by mass or more, more preferably 90% by mass or more. 20,000 to 1,000,000, preferably 50,000 to 800,000, more preferably 70,000 to 500,000, if there is a melting point it is 180 ° C to 230 ° C, preferably 200 ° C to 230 ° C, more A resin having a physical property of 210 to 230 ° C., a melt viscosity at 270 ° C. of 1 Pa · s to 10,000 Pa · s, more preferably 10 Pa · s to 5000 Pa · s, and a glass transition point of about 40 ° C.
Compared with polylactic acid (PLA), which has been frequently used so far, in the present invention, microneedles that are stronger in strength can be produced by using PGA. For example, a rat skin puncture experiment was performed using the microneedle of FIG. 1 or FIG. 2 of the present invention. As shown in FIG. 20, the microneedle photograph after puncture was broken or bent. The needle was not found, and the change was not seen as a whole. On the other hand, when PLA is used, the microneedle of FIG. 21 bends as shown in FIG. 22 after the puncture of the rat skin, or the tip of the microneedle is crushed as shown in FIG. Many things were found. As described above, the PGA microneedles were found to be highly versatile with unexpectedly superior strength.
本発明で言う「ポリグリコール酸(PGA)」とは、繰り返し単位(OCH2CO)を50質量%以上含む、好ましくは70質量%以上含む、より好ましくは90質量%以上含む、重量平均分子量が2万から100万の、好ましくは5万から80万の、より好ましくは7万から50万の、融点がある場合はそれが180℃から230℃の、好ましくは200℃から230℃の、より好ましくは210~230℃の、270℃での溶融粘度1Pa・sから10000Pa・sの、より好ましくは10Pa・sから5000Pa・sの、ガラス転移点が約40℃の物性を持つ樹脂である。
これまでよく使用されてきたポリ乳酸(PLA)と比較して、本発明ではPGAを使用することにより、強度的にもより強靭なマイクロニードルを作製できる。例えば、本発明の図1又は図2のマイクロニードルを用いて、ラット皮膚の穿刺実験を行ったが、図20に示されるように、穿刺後のマイクロニードルの写真には折れたり曲がったりした微小針は見当たらず、全体としてあまり変化が見られなかった。一方、PLAを使用した場合には、図21のマイクロニードルがラット皮膚への穿刺後には、図22のように曲がったり、図23のように微小針の針先が押し潰されてしまったりするようなことが多く見出された。以上のように、PGA製のマイクロニードルは、予想外に優れた強度を持った汎用性の高いものであることが分かった。 As a method for producing the microneedle of the present invention, the PGA is softened and melted by bringing it into contact with the PGA sheet using the jig obtained above. Thereafter, the jig is pulled away, and the PGA attached to the jig is pulled out. When the PGA extends in the form of a thread, the jig separating speed is reduced or stopped, and the extended thread-like PGA is cut by surface tension. Thereby, microneedles having the same length of microneedles can be produced (these are described in PCT / JP2008 / 051317).
The term “polyglycolic acid (PGA)” used in the present invention includes a repeating unit (OCH 2 CO) of 50% by mass or more, preferably 70% by mass or more, more preferably 90% by mass or more. 20,000 to 1,000,000, preferably 50,000 to 800,000, more preferably 70,000 to 500,000, if there is a melting point it is 180 ° C to 230 ° C, preferably 200 ° C to 230 ° C, more A resin having a physical property of 210 to 230 ° C., a melt viscosity at 270 ° C. of 1 Pa · s to 10,000 Pa · s, more preferably 10 Pa · s to 5000 Pa · s, and a glass transition point of about 40 ° C.
Compared with polylactic acid (PLA), which has been frequently used so far, in the present invention, microneedles that are stronger in strength can be produced by using PGA. For example, a rat skin puncture experiment was performed using the microneedle of FIG. 1 or FIG. 2 of the present invention. As shown in FIG. 20, the microneedle photograph after puncture was broken or bent. The needle was not found, and the change was not seen as a whole. On the other hand, when PLA is used, the microneedle of FIG. 21 bends as shown in FIG. 22 after the puncture of the rat skin, or the tip of the microneedle is crushed as shown in FIG. Many things were found. As described above, the PGA microneedles were found to be highly versatile with unexpectedly superior strength.
本発明で言う「マイクロニードル」とは、ポリグリコール酸(PGA)製の基板上に、複数のPGA製の微小針が一定の間隔(ピッチ)を持って配設されているマイクロニードルであって、前記微小針は、前記基板に接する微小針の底部から頂部(先端部)にかけて断面形状が小さくなる構造を有し、かつ前記底部近傍での断面形状の減少率が前記頂部近傍に比べて大きく、前記底部から前記頂部方向にかけて連続した溝、くぼみ及び連続した中空部の少なくとも1つを有する構造からなるマイクロニードルのことを言う。例えば、前記微小針の高さが150μm~1mmであり、前記微小針の前記底部の外形が100~450μmであり、前記微小針の間隔が100μm~2mmであるようなマイクロニードルのことを言う。より具体的には、次のような微小針が複数設置されている剣山状のPGA製の基板(プレート)のことを言う。
a)微小針の高さが150μm~1mmであり、
b)微小針の底部の外径の最大径が100μm~450μmであり、
c)微小針の先端部(針先サイズ)が尖った円柱状(先端が丸みを帯びた円錐状)となり、その外径が数~数十μmであり、
d)微小針の断面の形状が底部では円形、多角形、十字形、一辺を欠く多角形、一部を欠く円形(C字型)であり、先端部では円形である。
なお、微小針の本数としては必要に応じて選択することができ、例えば9~500本であることが望ましい。好ましい剣山状のプレートとしては、一定の間隔で微小針が縦3列~30列、横3列~30列で並んでいることが望ましい。従って、好ましい剣山型マイクロニードルの微小針密度は、9~500本/cm2である。
また、微小針の高さが低い場合には、薬液を塗布し難いので、200μm以上であることが望ましい。より好ましくは微小針の高さが300~500μmの範囲であることが挙げられる。 The “microneedle” referred to in the present invention is a microneedle in which a plurality of PGA microneedles are arranged at a constant interval (pitch) on a polyglycolic acid (PGA) substrate. The microneedle has a structure in which the cross-sectional shape decreases from the bottom to the top (tip) of the microneedle in contact with the substrate, and the reduction rate of the cross-sectional shape in the vicinity of the bottom is larger than that in the vicinity of the top. And a microneedle having a structure having at least one of a groove, a recess, and a continuous hollow portion extending from the bottom to the top. For example, it refers to a microneedle in which the height of the microneedle is 150 μm to 1 mm, the outer shape of the bottom of the microneedle is 100 to 450 μm, and the interval between the microneedles is 100 μm to 2 mm. More specifically, it refers to a sword-mount PGA substrate (plate) on which a plurality of microneedles as described below are installed.
a) The height of the micro needle is 150 μm to 1 mm,
b) The maximum outer diameter of the bottom of the microneedle is 100 μm to 450 μm,
c) The tip of the microneedle (needle tip size) has a sharp cylindrical shape (conical shape with a rounded tip), and the outer diameter is several to several tens of μm.
d) The cross-sectional shape of the micro needle is a circle, a polygon, a cross, a polygon lacking one side, a circle lacking a part (C-shaped) at the bottom, and a circle at the tip.
The number of microneedles can be selected as necessary, and is preferably 9 to 500, for example. As a preferred sword mountain-like plate, it is desirable that microneedles are arranged in a vertical row of 3 to 30 rows and in a horizontal row of 3 to 30 at regular intervals. Therefore, the preferred sword mountain type microneedle has a fine needle density of 9 to 500 needles / cm 2 .
In addition, when the height of the microneedles is low, it is difficult to apply the chemical solution, and thus it is desirable that the thickness is 200 μm or more. More preferably, the height of the microneedle is in the range of 300 to 500 μm.
a)微小針の高さが150μm~1mmであり、
b)微小針の底部の外径の最大径が100μm~450μmであり、
c)微小針の先端部(針先サイズ)が尖った円柱状(先端が丸みを帯びた円錐状)となり、その外径が数~数十μmであり、
d)微小針の断面の形状が底部では円形、多角形、十字形、一辺を欠く多角形、一部を欠く円形(C字型)であり、先端部では円形である。
なお、微小針の本数としては必要に応じて選択することができ、例えば9~500本であることが望ましい。好ましい剣山状のプレートとしては、一定の間隔で微小針が縦3列~30列、横3列~30列で並んでいることが望ましい。従って、好ましい剣山型マイクロニードルの微小針密度は、9~500本/cm2である。
また、微小針の高さが低い場合には、薬液を塗布し難いので、200μm以上であることが望ましい。より好ましくは微小針の高さが300~500μmの範囲であることが挙げられる。 The “microneedle” referred to in the present invention is a microneedle in which a plurality of PGA microneedles are arranged at a constant interval (pitch) on a polyglycolic acid (PGA) substrate. The microneedle has a structure in which the cross-sectional shape decreases from the bottom to the top (tip) of the microneedle in contact with the substrate, and the reduction rate of the cross-sectional shape in the vicinity of the bottom is larger than that in the vicinity of the top. And a microneedle having a structure having at least one of a groove, a recess, and a continuous hollow portion extending from the bottom to the top. For example, it refers to a microneedle in which the height of the microneedle is 150 μm to 1 mm, the outer shape of the bottom of the microneedle is 100 to 450 μm, and the interval between the microneedles is 100 μm to 2 mm. More specifically, it refers to a sword-mount PGA substrate (plate) on which a plurality of microneedles as described below are installed.
a) The height of the micro needle is 150 μm to 1 mm,
b) The maximum outer diameter of the bottom of the microneedle is 100 μm to 450 μm,
c) The tip of the microneedle (needle tip size) has a sharp cylindrical shape (conical shape with a rounded tip), and the outer diameter is several to several tens of μm.
d) The cross-sectional shape of the micro needle is a circle, a polygon, a cross, a polygon lacking one side, a circle lacking a part (C-shaped) at the bottom, and a circle at the tip.
The number of microneedles can be selected as necessary, and is preferably 9 to 500, for example. As a preferred sword mountain-like plate, it is desirable that microneedles are arranged in a vertical row of 3 to 30 rows and in a horizontal row of 3 to 30 at regular intervals. Therefore, the preferred sword mountain type microneedle has a fine needle density of 9 to 500 needles / cm 2 .
In addition, when the height of the microneedles is low, it is difficult to apply the chemical solution, and thus it is desirable that the thickness is 200 μm or more. More preferably, the height of the microneedle is in the range of 300 to 500 μm.
本発明のマイクロニードルのサイズ(微小針が存在する部分)は微小針の大きさや本数によって異なるが、好ましいものとして縦横が0.5~1.5cmの範囲のものを挙げることが出来る。なお、微小針の本数やマイクロニードルのサイズは、治具の柱状突起の本数とサイズ(柱状突起が存在する部分)に対応して決まるものである。それ故、必要に応じて治具を適宜選択することにより、微小針の本数とマイクロニードルのサイズ(微小針が存在する部分)を決定することが出来る。
本発明の微小針は、製造方法に起因し、針の底部は使用する冶具の柱状突起の外径の幅で決まり、針の高さは、おおむね粘塑性化されたPGA量で決まると考えられる。このPGA量は、冶具とPGAの接触に基づいてPGAが軟化・熔解し、粘塑性化して冶具に引き上げられる量に依存する。従って、例えば冶具として200μm×200μmの角柱を用いてPGAプレートに接触させ、PGAを粘塑性化して冶具を引き離し、図1~図2に示すような角錐形の微小針(底部約150μm、高さ約350μm)を作製することができる。
冶具の温度やPGAプレートの温度、あるいは冶具の断面積、冶具の接触時間、PGAプレートへの嵌入距離等により、上記の粘塑性化されたPGAの量は異なってくる。従って、所望の微小針のサイズに合わせて、適宜、これらの条件を選択することが出来る。例えば、冶具とPGAプレートとの接触時間としては、冶具として200μm×200μmの角柱状突起を持つものを使用する場合、1秒であればPGAの溶ける量が少なく、7秒を超えるとPGAが溶けすぎる。10秒を過ぎた辺りから、PGAが焦げ付き始める。2~7秒の範囲が適切なようであり、5秒付近が好適と考えられる。
PGAプレートに対する冶具の嵌入距離が大きければ、冶具とPGAが接触し、PGAの軟化融解量が大きくなるので、微小針のサイズが大きくできる。即ち、微小針の高さや太さを大きくすることができる。嵌入距離は0.1~0.25mmの範囲が好適であり、例えば0.1mmの挿入距離で、図1と図2に示されるマイクロニードルが得られている。該微小針の高さは約350μmであり、微小針の底部の外径は約150μmと好適なものが得られている。 The size of the microneedles of the present invention (the portion where the microneedles are present) varies depending on the size and number of the microneedles, and preferred examples include those having a length and width in the range of 0.5 to 1.5 cm. Note that the number of microneedles and the size of the microneedles are determined in accordance with the number and size of the columnar protrusions of the jig (portions where the columnar protrusions are present). Therefore, the number of microneedles and the size of the microneedles (the portion where the microneedles are present) can be determined by appropriately selecting a jig as necessary.
The microneedle of the present invention is attributed to the manufacturing method, and the bottom of the needle is determined by the width of the outer diameter of the columnar projection of the jig used, and the height of the needle is determined by the amount of viscoplasticized PGA. . The amount of PGA depends on the amount of PGA softened and melted based on the contact between the jig and the PGA, viscoplasticized, and pulled up to the jig. Accordingly, for example, a 200 μm × 200 μm prism as a jig is used to contact the PGA plate, the PGA is viscoplasticized, and the jig is pulled away to form a pyramid-shaped microneedle (bottom of about 150 μm, height) as shown in FIGS. About 350 μm) can be produced.
The amount of the above-mentioned viscoplastic PGA varies depending on the temperature of the jig, the temperature of the PGA plate, the cross-sectional area of the jig, the contact time of the jig, the insertion distance to the PGA plate, and the like. Therefore, these conditions can be appropriately selected according to the desired microneedle size. For example, the contact time between the jig and the PGA plate is such that when a jig having a prismatic projection of 200 μm × 200 μm is used as the jig, the amount of PGA that melts is small if it is 1 second, and PGA melts if it exceeds 7 seconds. Too much. From around 10 seconds, PGA begins to burn. A range of 2-7 seconds seems to be appropriate, and around 5 seconds is considered suitable.
If the insertion distance of the jig with respect to the PGA plate is large, the jig and the PGA come into contact with each other, and the softening and melting amount of the PGA increases, so that the size of the micro needle can be increased. That is, the height and thickness of the micro needle can be increased. The insertion distance is preferably in the range of 0.1 to 0.25 mm. For example, the microneedle shown in FIGS. 1 and 2 is obtained with an insertion distance of 0.1 mm. The height of the microneedles is about 350 μm, and the outer diameter of the bottom of the microneedles is about 150 μm.
本発明の微小針は、製造方法に起因し、針の底部は使用する冶具の柱状突起の外径の幅で決まり、針の高さは、おおむね粘塑性化されたPGA量で決まると考えられる。このPGA量は、冶具とPGAの接触に基づいてPGAが軟化・熔解し、粘塑性化して冶具に引き上げられる量に依存する。従って、例えば冶具として200μm×200μmの角柱を用いてPGAプレートに接触させ、PGAを粘塑性化して冶具を引き離し、図1~図2に示すような角錐形の微小針(底部約150μm、高さ約350μm)を作製することができる。
冶具の温度やPGAプレートの温度、あるいは冶具の断面積、冶具の接触時間、PGAプレートへの嵌入距離等により、上記の粘塑性化されたPGAの量は異なってくる。従って、所望の微小針のサイズに合わせて、適宜、これらの条件を選択することが出来る。例えば、冶具とPGAプレートとの接触時間としては、冶具として200μm×200μmの角柱状突起を持つものを使用する場合、1秒であればPGAの溶ける量が少なく、7秒を超えるとPGAが溶けすぎる。10秒を過ぎた辺りから、PGAが焦げ付き始める。2~7秒の範囲が適切なようであり、5秒付近が好適と考えられる。
PGAプレートに対する冶具の嵌入距離が大きければ、冶具とPGAが接触し、PGAの軟化融解量が大きくなるので、微小針のサイズが大きくできる。即ち、微小針の高さや太さを大きくすることができる。嵌入距離は0.1~0.25mmの範囲が好適であり、例えば0.1mmの挿入距離で、図1と図2に示されるマイクロニードルが得られている。該微小針の高さは約350μmであり、微小針の底部の外径は約150μmと好適なものが得られている。 The size of the microneedles of the present invention (the portion where the microneedles are present) varies depending on the size and number of the microneedles, and preferred examples include those having a length and width in the range of 0.5 to 1.5 cm. Note that the number of microneedles and the size of the microneedles are determined in accordance with the number and size of the columnar protrusions of the jig (portions where the columnar protrusions are present). Therefore, the number of microneedles and the size of the microneedles (the portion where the microneedles are present) can be determined by appropriately selecting a jig as necessary.
The microneedle of the present invention is attributed to the manufacturing method, and the bottom of the needle is determined by the width of the outer diameter of the columnar projection of the jig used, and the height of the needle is determined by the amount of viscoplasticized PGA. . The amount of PGA depends on the amount of PGA softened and melted based on the contact between the jig and the PGA, viscoplasticized, and pulled up to the jig. Accordingly, for example, a 200 μm × 200 μm prism as a jig is used to contact the PGA plate, the PGA is viscoplasticized, and the jig is pulled away to form a pyramid-shaped microneedle (bottom of about 150 μm, height) as shown in FIGS. About 350 μm) can be produced.
The amount of the above-mentioned viscoplastic PGA varies depending on the temperature of the jig, the temperature of the PGA plate, the cross-sectional area of the jig, the contact time of the jig, the insertion distance to the PGA plate, and the like. Therefore, these conditions can be appropriately selected according to the desired microneedle size. For example, the contact time between the jig and the PGA plate is such that when a jig having a prismatic projection of 200 μm × 200 μm is used as the jig, the amount of PGA that melts is small if it is 1 second, and PGA melts if it exceeds 7 seconds. Too much. From around 10 seconds, PGA begins to burn. A range of 2-7 seconds seems to be appropriate, and around 5 seconds is considered suitable.
If the insertion distance of the jig with respect to the PGA plate is large, the jig and the PGA come into contact with each other, and the softening and melting amount of the PGA increases, so that the size of the micro needle can be increased. That is, the height and thickness of the micro needle can be increased. The insertion distance is preferably in the range of 0.1 to 0.25 mm. For example, the microneedle shown in FIGS. 1 and 2 is obtained with an insertion distance of 0.1 mm. The height of the microneedles is about 350 μm, and the outer diameter of the bottom of the microneedles is about 150 μm.
本発明で言う「微小針の底部の外径」とは、概ね冶具の柱状突起の断面とほぼ同じか少し小さいものである。微小針の底部は、PGAが冶具の接触で少し押し退けられ、その後粘塑性化されたPGAが引き出されるため、図6、図8または図12に示されるように、周辺が少し盛り上がり、中心部に向けて少し窪んでいる。微小針は、その窪み(凹部)の中から立ち上がっている。従って、微小針の底部は、冶具によって引き出されることから、ほぼ冶具の断面に対応する形状になっている。そこで、微小針の底部の外径は、概ね冶具の柱状突起の断面とほぼ同じか少し小さいものとなっている。例えば、0.2mmの角柱状突起(一辺0.2mm×0.2mm、高さ0.35mm、ピッチ0.8mm)の冶具を用いた場合、図2に示されるように、微小針の底部の外径は約150μmになっていた。
更に例えば、図4に示されるコの字型の冶具(300μm×300μm)を用いた場合には、図6の右図に示されるように、微小針の底部の外径は約300μmになっていた。 In the present invention, “the outer diameter of the bottom of the microneedle” is substantially the same as or slightly smaller than the cross section of the columnar protrusion of the jig. The bottom of the microneedle is slightly pushed away by the contact of the jig, and then the viscoplasticized PGA is pulled out. As shown in FIG. 6, FIG. 8, or FIG. It is slightly depressed toward it. The microneedle stands up from the recess (concave portion). Therefore, since the bottom of the microneedle is pulled out by the jig, it has a shape substantially corresponding to the cross section of the jig. Therefore, the outer diameter of the bottom of the micro needle is approximately the same as or slightly smaller than the cross section of the columnar protrusion of the jig. For example, when a jig with a prismatic protrusion of 0.2 mm (side 0.2 mm × 0.2 mm, height 0.35 mm, pitch 0.8 mm) is used, as shown in FIG. The outer diameter was about 150 μm.
Further, for example, when the U-shaped jig (300 μm × 300 μm) shown in FIG. 4 is used, the outer diameter of the bottom of the microneedle is about 300 μm as shown in the right figure of FIG. It was.
更に例えば、図4に示されるコの字型の冶具(300μm×300μm)を用いた場合には、図6の右図に示されるように、微小針の底部の外径は約300μmになっていた。 In the present invention, “the outer diameter of the bottom of the microneedle” is substantially the same as or slightly smaller than the cross section of the columnar protrusion of the jig. The bottom of the microneedle is slightly pushed away by the contact of the jig, and then the viscoplasticized PGA is pulled out. As shown in FIG. 6, FIG. 8, or FIG. It is slightly depressed toward it. The microneedle stands up from the recess (concave portion). Therefore, since the bottom of the microneedle is pulled out by the jig, it has a shape substantially corresponding to the cross section of the jig. Therefore, the outer diameter of the bottom of the micro needle is approximately the same as or slightly smaller than the cross section of the columnar protrusion of the jig. For example, when a jig with a prismatic protrusion of 0.2 mm (side 0.2 mm × 0.2 mm, height 0.35 mm, pitch 0.8 mm) is used, as shown in FIG. The outer diameter was about 150 μm.
Further, for example, when the U-shaped jig (300 μm × 300 μm) shown in FIG. 4 is used, the outer diameter of the bottom of the microneedle is about 300 μm as shown in the right figure of FIG. It was.
本発明で言う「微小針の先端部」とは、冶具によって引き出されて糸状に伸展され、切断される先端部の円柱状(やや円錐状)の部分のことを言う。この円柱部の外径が数~数十μmになるようにPGAが伸展され、微小針が形成される。
本発明で言う「数~数十μm」とは、2~3μm以上で、20~30μm以下の範囲を表わす。微小針の先端部のより好ましい外径としては2~20μmであり、皮膚への穿刺性と材質の硬度を考慮し、その範囲を適宜選択することができる。
本発明で言う「微小針の断面」とは、微小針をPGAプレートと平行な面で切断した断面のことを言う。微小針の底部の断面は、治具の断面とほぼ同様の形状を示すが、上部に行くに従って、図6~12に示されるように、PGAの引き伸ばしと表面張力により、微小針の先端部の外形は尖った円柱状あるいは円錐状になる。そのため、微小針の先端部の断面は、ほぼ円形の形状を呈することになる。
本発明で言う「(微小針の)底部近傍での断面形状の減少率が(微小針の)前記頂部近傍に比べて大き(い)」とは、冶具により粘組成化したPGAが基板より引き出されるため、図6や図8に見られるように、底部の近傍では、微小針の径が急速に細くなっていることを表わす。そして、微小針の頂部(先端部)では、微小針の径はゆっくりと細くなっていることを表わすものである。 The “tip portion of the microneedle” referred to in the present invention refers to a columnar (slightly conical) portion of the tip portion that is pulled out by a jig, extended into a thread shape, and cut. PGA is extended so that the outer diameter of the cylindrical portion is several to several tens of μm, and a microneedle is formed.
In the present invention, “several to several tens of μm” represents a range of 2 to 3 μm or more and 20 to 30 μm or less. A more preferable outer diameter of the tip of the microneedle is 2 to 20 μm, and the range can be appropriately selected in consideration of the puncture property to the skin and the hardness of the material.
The “microneedle cross section” referred to in the present invention refers to a cross section obtained by cutting a microneedle along a plane parallel to the PGA plate. The cross-section of the bottom of the microneedle shows almost the same shape as the cross-section of the jig, but as it goes to the top, as shown in FIGS. 6 to 12, the tip of the microneedle is stretched by the stretching and surface tension of the PGA. The outer shape is a pointed cylinder or cone. For this reason, the cross-section of the tip of the microneedle has a substantially circular shape.
In the present invention, “the reduction rate of the cross-sectional shape in the vicinity of the bottom (of the microneedle) is larger than that in the vicinity of the top (of the microneedle)” means that the PGA having a viscous composition by the jig is pulled out from the substrate. Therefore, as shown in FIG. 6 and FIG. 8, the diameter of the microneedle is rapidly reduced in the vicinity of the bottom. The diameter of the microneedle is gradually reduced at the top (tip) of the microneedle.
本発明で言う「数~数十μm」とは、2~3μm以上で、20~30μm以下の範囲を表わす。微小針の先端部のより好ましい外径としては2~20μmであり、皮膚への穿刺性と材質の硬度を考慮し、その範囲を適宜選択することができる。
本発明で言う「微小針の断面」とは、微小針をPGAプレートと平行な面で切断した断面のことを言う。微小針の底部の断面は、治具の断面とほぼ同様の形状を示すが、上部に行くに従って、図6~12に示されるように、PGAの引き伸ばしと表面張力により、微小針の先端部の外形は尖った円柱状あるいは円錐状になる。そのため、微小針の先端部の断面は、ほぼ円形の形状を呈することになる。
本発明で言う「(微小針の)底部近傍での断面形状の減少率が(微小針の)前記頂部近傍に比べて大き(い)」とは、冶具により粘組成化したPGAが基板より引き出されるため、図6や図8に見られるように、底部の近傍では、微小針の径が急速に細くなっていることを表わす。そして、微小針の頂部(先端部)では、微小針の径はゆっくりと細くなっていることを表わすものである。 The “tip portion of the microneedle” referred to in the present invention refers to a columnar (slightly conical) portion of the tip portion that is pulled out by a jig, extended into a thread shape, and cut. PGA is extended so that the outer diameter of the cylindrical portion is several to several tens of μm, and a microneedle is formed.
In the present invention, “several to several tens of μm” represents a range of 2 to 3 μm or more and 20 to 30 μm or less. A more preferable outer diameter of the tip of the microneedle is 2 to 20 μm, and the range can be appropriately selected in consideration of the puncture property to the skin and the hardness of the material.
The “microneedle cross section” referred to in the present invention refers to a cross section obtained by cutting a microneedle along a plane parallel to the PGA plate. The cross-section of the bottom of the microneedle shows almost the same shape as the cross-section of the jig, but as it goes to the top, as shown in FIGS. 6 to 12, the tip of the microneedle is stretched by the stretching and surface tension of the PGA. The outer shape is a pointed cylinder or cone. For this reason, the cross-section of the tip of the microneedle has a substantially circular shape.
In the present invention, “the reduction rate of the cross-sectional shape in the vicinity of the bottom (of the microneedle) is larger than that in the vicinity of the top (of the microneedle)” means that the PGA having a viscous composition by the jig is pulled out from the substrate. Therefore, as shown in FIG. 6 and FIG. 8, the diameter of the microneedle is rapidly reduced in the vicinity of the bottom. The diameter of the microneedle is gradually reduced at the top (tip) of the microneedle.
本発明で言う「冶具」とは、上記マイクロニードルの製造方法に使用されるシリコン製または金属製の冶具を言う。これらの冶具は、半導体の製造プロセスや微細作製プロセスにおいて使用されている上述の汎用手段を用いて作製されるものであり、金属としては例えばチタン、パラジウム、ニッケル、銅を挙げることができる。
本発明で言う「柱状突起」とは、断面の形状が円形、多角形、十字型、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形の柱状の突起である。ここで多角形とは、例えば三角形、四角形、五角形等の多角形を言い、部分的な欠失がある多角形とは、例えばV字型、コの字型、あるいは図13~17に示されるような断面形状のもの(欠失部分を持つもの)を言う。
柱状突起の長さは、200μm~1mmの範囲のものであり、好ましくは250~500μmを挙げることができる。より好ましくは、300~400μmを挙げることができる。
本発明で言う「柱状突起の間隔」とは、柱状突起の中心間の距離のことを言う。柱状突起の間隔が狭い場合には、隣り合う柱状突起に形成される糸状のPGAが接合して幅広い一本の糸になってしまう。また、柱状突起の断面が大きく、多量のPGAを引上げ(あるいは引き下げ)て、糸状PGAを形成させる場合には、粘塑性化したPGAが重なり合うと、どちらか一方の柱状突起の方により多くの粘塑性化PGAが付着する事態が起こり、作製される微小針が不揃いになる。以上のことから、柱状突起の間隔は一定の間隔が必要になる。例えば、冶具の柱状突起の外径が200~300μmである場合、図2や図6に示されるように、PGAプレートが粘塑性化する範囲は柱状突起の約2~3倍の範囲に広がっている。従って、粘塑性化するPGAの範囲が重ならないようにするためには、柱状突起の間隔(ピッチ)は、柱状突起の最長外径の約1.5倍以上あることが望ましい。粘塑性化するPGAの範囲が重なれば、微小針の長さに不均一が生じることになる。
従って、図6、図8、図10あるいは図11に示されるように本発明の治具の柱状突起の断面の外径が、200~450μmである場合には、柱状突起の間隔は300μm~1mmの範囲であればよい。例えば、柱状突起が200μm×200μmの四角柱状である場合には、柱状突起の間隔は300~600μmであれば充分である。より好ましい間隔としては、約800μmの前後を挙げることができる。
以上のように、治具のサイズ(柱状突起が存在する部分)と柱状突起の本数と柱状突起の間隔は相互に関連することになる。例えば、柱状突起の本数が縦横10本であり、間隔(ピッチ)が800μmの場合、治具のサイズは7.2mmとなる。 The “jig” referred to in the present invention refers to a silicon or metal jig used in the above-described microneedle production method. These jigs are manufactured using the above-mentioned general-purpose means used in semiconductor manufacturing processes and fine manufacturing processes. Examples of metals include titanium, palladium, nickel, and copper.
The “columnar protrusion” as used in the present invention is a circular columnar shape having a circular, polygonal, cross-shaped, square-shaped, a partially circular shape (C-shaped), or a partial deletion. Is a protrusion. Here, the polygon refers to a polygon such as a triangle, a quadrangle, and a pentagon. For example, the polygon having a partial deletion is illustrated in, for example, a V shape, a U shape, or FIGS. Such a cross-sectional shape (having a deletion portion).
The length of the columnar protrusion is in the range of 200 μm to 1 mm, and preferably 250 to 500 μm. More preferably, 300 to 400 μm can be mentioned.
The “interval between columnar protrusions” referred to in the present invention refers to the distance between the centers of the columnar protrusions. When the interval between the columnar protrusions is narrow, the thread-like PGA formed on the adjacent columnar protrusions is joined to form a wide single thread. In addition, when the cross-section of the columnar protrusion is large and a large amount of PGA is pulled up (or pulled down) to form a thread-like PGA, if the viscoplasticized PGA overlaps, one of the columnar protrusions has a larger viscosity. A situation occurs in which the plasticized PGA adheres, and the produced microneedles become uneven. From the above, the interval between the columnar protrusions needs to be constant. For example, when the outer diameter of the columnar protrusion of the jig is 200 to 300 μm, as shown in FIG. 2 and FIG. 6, the range in which the PGA plate becomes viscoplastic extends to a range about 2 to 3 times that of the columnar protrusion. Yes. Therefore, in order to prevent the ranges of PGA to be viscoplasticized from overlapping, the interval (pitch) between the columnar protrusions is desirably about 1.5 times or more the longest outer diameter of the columnar protrusions. If the ranges of PGA to be viscoplasticized overlap, the lengths of the microneedles will be uneven.
Accordingly, when the outer diameter of the cross-section of the columnar protrusions of the jig of the present invention is 200 to 450 μm as shown in FIGS. 6, 8, 10 or 11, the interval between the columnar protrusions is 300 μm to 1 mm. It may be in the range. For example, in the case where the columnar protrusions have a square columnar shape of 200 μm × 200 μm, it is sufficient that the interval between the columnar protrusions is 300 to 600 μm. As a more preferable interval, about 800 μm can be mentioned.
As described above, the jig size (the portion where the columnar protrusions are present), the number of columnar protrusions, and the interval between the columnar protrusions are related to each other. For example, when the number of columnar protrusions is 10 in length and width and the interval (pitch) is 800 μm, the size of the jig is 7.2 mm.
本発明で言う「柱状突起」とは、断面の形状が円形、多角形、十字型、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形の柱状の突起である。ここで多角形とは、例えば三角形、四角形、五角形等の多角形を言い、部分的な欠失がある多角形とは、例えばV字型、コの字型、あるいは図13~17に示されるような断面形状のもの(欠失部分を持つもの)を言う。
柱状突起の長さは、200μm~1mmの範囲のものであり、好ましくは250~500μmを挙げることができる。より好ましくは、300~400μmを挙げることができる。
本発明で言う「柱状突起の間隔」とは、柱状突起の中心間の距離のことを言う。柱状突起の間隔が狭い場合には、隣り合う柱状突起に形成される糸状のPGAが接合して幅広い一本の糸になってしまう。また、柱状突起の断面が大きく、多量のPGAを引上げ(あるいは引き下げ)て、糸状PGAを形成させる場合には、粘塑性化したPGAが重なり合うと、どちらか一方の柱状突起の方により多くの粘塑性化PGAが付着する事態が起こり、作製される微小針が不揃いになる。以上のことから、柱状突起の間隔は一定の間隔が必要になる。例えば、冶具の柱状突起の外径が200~300μmである場合、図2や図6に示されるように、PGAプレートが粘塑性化する範囲は柱状突起の約2~3倍の範囲に広がっている。従って、粘塑性化するPGAの範囲が重ならないようにするためには、柱状突起の間隔(ピッチ)は、柱状突起の最長外径の約1.5倍以上あることが望ましい。粘塑性化するPGAの範囲が重なれば、微小針の長さに不均一が生じることになる。
従って、図6、図8、図10あるいは図11に示されるように本発明の治具の柱状突起の断面の外径が、200~450μmである場合には、柱状突起の間隔は300μm~1mmの範囲であればよい。例えば、柱状突起が200μm×200μmの四角柱状である場合には、柱状突起の間隔は300~600μmであれば充分である。より好ましい間隔としては、約800μmの前後を挙げることができる。
以上のように、治具のサイズ(柱状突起が存在する部分)と柱状突起の本数と柱状突起の間隔は相互に関連することになる。例えば、柱状突起の本数が縦横10本であり、間隔(ピッチ)が800μmの場合、治具のサイズは7.2mmとなる。 The “jig” referred to in the present invention refers to a silicon or metal jig used in the above-described microneedle production method. These jigs are manufactured using the above-mentioned general-purpose means used in semiconductor manufacturing processes and fine manufacturing processes. Examples of metals include titanium, palladium, nickel, and copper.
The “columnar protrusion” as used in the present invention is a circular columnar shape having a circular, polygonal, cross-shaped, square-shaped, a partially circular shape (C-shaped), or a partial deletion. Is a protrusion. Here, the polygon refers to a polygon such as a triangle, a quadrangle, and a pentagon. For example, the polygon having a partial deletion is illustrated in, for example, a V shape, a U shape, or FIGS. Such a cross-sectional shape (having a deletion portion).
The length of the columnar protrusion is in the range of 200 μm to 1 mm, and preferably 250 to 500 μm. More preferably, 300 to 400 μm can be mentioned.
The “interval between columnar protrusions” referred to in the present invention refers to the distance between the centers of the columnar protrusions. When the interval between the columnar protrusions is narrow, the thread-like PGA formed on the adjacent columnar protrusions is joined to form a wide single thread. In addition, when the cross-section of the columnar protrusion is large and a large amount of PGA is pulled up (or pulled down) to form a thread-like PGA, if the viscoplasticized PGA overlaps, one of the columnar protrusions has a larger viscosity. A situation occurs in which the plasticized PGA adheres, and the produced microneedles become uneven. From the above, the interval between the columnar protrusions needs to be constant. For example, when the outer diameter of the columnar protrusion of the jig is 200 to 300 μm, as shown in FIG. 2 and FIG. 6, the range in which the PGA plate becomes viscoplastic extends to a range about 2 to 3 times that of the columnar protrusion. Yes. Therefore, in order to prevent the ranges of PGA to be viscoplasticized from overlapping, the interval (pitch) between the columnar protrusions is desirably about 1.5 times or more the longest outer diameter of the columnar protrusions. If the ranges of PGA to be viscoplasticized overlap, the lengths of the microneedles will be uneven.
Accordingly, when the outer diameter of the cross-section of the columnar protrusions of the jig of the present invention is 200 to 450 μm as shown in FIGS. 6, 8, 10 or 11, the interval between the columnar protrusions is 300 μm to 1 mm. It may be in the range. For example, in the case where the columnar protrusions have a square columnar shape of 200 μm × 200 μm, it is sufficient that the interval between the columnar protrusions is 300 to 600 μm. As a more preferable interval, about 800 μm can be mentioned.
As described above, the jig size (the portion where the columnar protrusions are present), the number of columnar protrusions, and the interval between the columnar protrusions are related to each other. For example, when the number of columnar protrusions is 10 in length and width and the interval (pitch) is 800 μm, the size of the jig is 7.2 mm.
本発明の「柱状突起の本数」としては、作製される微小針の本数に対応して必要な本数を選択する。従って、本発明では特に限定されることはなく、複数本あれば充分である。例えば、所望のマイクロニードルの微小針の本数に対応して、例えば9~500本の範囲で選択することができる。剣山型マイクロニードルの密度に合わせて、冶具における柱状突起の密度も同じものを選択することになる。例えば、本発明の場合、柱状突起の断面の外径が100~450μmであるので、上述のように、柱状突起の間隔(ピッチ)は150~1mm以上であることが好ましい。しかし、必要に応じて柱状突起の本数を選択できるため、柱状突起の密度としては、9~500本/cm2であることが望ましい。
本発明の「柱状突起の断面形状」としては、特に限定されることではなく、必要に応じて色々な形状のものを使用することができる。例えば、四角形、コの字型、十字型、円形、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形等が使用可能である。また、柱状突起の断面の外径の大きさは作製するマイクロニードルのサイズに合わせて選択することができる。例えばシャープな針(針の底部が150~200μmで、針の高さが300~400μmのもの)を作製するためには、図1に示されるように200×200μmの四角柱の冶具を用いればよいことが分かった。また、薬剤を担持するための凹部または溝を持った針を形成するためには、柱状突起の断面が部分的な欠失がある多角形である冶具を使用することが望ましい。部分的な欠失がある多角形として、例えば柱状突起の断面がコの字型、V字型等のもの、更には十字型のものを挙げることができる。
コの字型の形状としては、図3、図4、図9~図11に示されるように外径の縦と横が250~350μmであり、コの字の肉厚が40~60μmであるものを使用することができる。コの字の縦棒と横棒の比率として、好ましいものとしては、縦棒を1として横棒が1~1.5の範囲にあるものを挙げることができる。なお、コの字は連続していてもよく、一つまたは複数の隙間が開いていてもよい。例えば、図15~図16に示されるように隙間(間隔)がコの字の2本の横棒と縦棒の間に存在するか、あるいは図13~図14に示されるように縦棒の部分に一つ存在してもよい。
十字型の形状としては、例えば図8に示されるように、外径の縦と横が300~450μmであり、十字の肉厚が40~60μmであるものを使用することができる。更には、十字の中心に間隙があり、4本の長方形が組み合わさった形で形成される十字であっても使用することができる。
また、同様に柱状突起の断面が部分的な欠失がある多角形であるものとして、図17で示される断面の治具を作製することができ、例えば図17の断面の冶具を用いた場合には中空の微小針が形成できる。同様に四角形の断面が不均一なものである冶具として、例えば図18の断面のものを用いた場合にも、中空の微小針が成型される。 As the “number of columnar protrusions” in the present invention, a necessary number is selected corresponding to the number of microneedles to be produced. Accordingly, the present invention is not particularly limited, and a plurality of them are sufficient. For example, it can be selected in the range of 9 to 500, for example, corresponding to the number of microneedles of the desired microneedle. According to the density of the sword mountain type microneedle, the same density of the columnar protrusions in the jig is selected. For example, in the present invention, since the outer diameter of the cross-section of the columnar protrusions is 100 to 450 μm, as described above, the interval (pitch) between the columnar protrusions is preferably 150 to 1 mm or more. However, since the number of columnar protrusions can be selected as necessary, the density of the columnar protrusions is preferably 9 to 500 / cm 2 .
The “cross-sectional shape of the columnar protrusion” of the present invention is not particularly limited, and various shapes can be used as necessary. For example, a quadrangle, a U-shape, a cross shape, a circle, an e-shape, a circle with a portion missing (C-shape), a polygon with a partial deletion, or the like can be used. The size of the outer diameter of the cross-section of the columnar protrusion can be selected according to the size of the microneedle to be manufactured. For example, in order to produce a sharp needle (with a needle bottom of 150 to 200 μm and a needle height of 300 to 400 μm), a 200 × 200 μm square prism jig is used as shown in FIG. I found it good. Further, in order to form a needle having a recess or groove for carrying a drug, it is desirable to use a jig whose cross section of the columnar protrusion is a polygon with a partial deletion. Examples of the polygon having a partial deletion include those having a cross-section of a columnar protrusion having a U shape, a V shape, and a cross shape.
As shown in FIG. 3, FIG. 4, and FIG. 9 to FIG. 11, the U-shaped shape is 250 to 350 μm in the vertical and horizontal outer diameters, and the U-shaped wall thickness is 40 to 60 μm. Things can be used. Preferred ratios of the U-shaped vertical bars and horizontal bars include those in which the vertical bar is 1 and the horizontal bar is in the range of 1 to 1.5. The U-shape may be continuous, or one or more gaps may be opened. For example, a gap (interval) exists between two U-shaped horizontal bars and vertical bars as shown in FIGS. 15 to 16, or vertical bars as shown in FIGS. One may be present in the part.
As the cross-shaped shape, for example, as shown in FIG. 8, it is possible to use a shape in which the vertical and horizontal outer diameters are 300 to 450 μm and the thickness of the cross is 40 to 60 μm. Furthermore, a cross formed by combining four rectangles with a gap at the center of the cross can also be used.
Similarly, the cross-section jig shown in FIG. 17 can be produced assuming that the cross-section of the columnar protrusion is a polygon having a partial deletion. For example, when a jig having a cross-section shown in FIG. 17 is used. A hollow microneedle can be formed. Similarly, when a jig having a non-uniform square cross section is used, for example, a cross section shown in FIG. 18, hollow microneedles are formed.
本発明の「柱状突起の断面形状」としては、特に限定されることではなく、必要に応じて色々な形状のものを使用することができる。例えば、四角形、コの字型、十字型、円形、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形等が使用可能である。また、柱状突起の断面の外径の大きさは作製するマイクロニードルのサイズに合わせて選択することができる。例えばシャープな針(針の底部が150~200μmで、針の高さが300~400μmのもの)を作製するためには、図1に示されるように200×200μmの四角柱の冶具を用いればよいことが分かった。また、薬剤を担持するための凹部または溝を持った針を形成するためには、柱状突起の断面が部分的な欠失がある多角形である冶具を使用することが望ましい。部分的な欠失がある多角形として、例えば柱状突起の断面がコの字型、V字型等のもの、更には十字型のものを挙げることができる。
コの字型の形状としては、図3、図4、図9~図11に示されるように外径の縦と横が250~350μmであり、コの字の肉厚が40~60μmであるものを使用することができる。コの字の縦棒と横棒の比率として、好ましいものとしては、縦棒を1として横棒が1~1.5の範囲にあるものを挙げることができる。なお、コの字は連続していてもよく、一つまたは複数の隙間が開いていてもよい。例えば、図15~図16に示されるように隙間(間隔)がコの字の2本の横棒と縦棒の間に存在するか、あるいは図13~図14に示されるように縦棒の部分に一つ存在してもよい。
十字型の形状としては、例えば図8に示されるように、外径の縦と横が300~450μmであり、十字の肉厚が40~60μmであるものを使用することができる。更には、十字の中心に間隙があり、4本の長方形が組み合わさった形で形成される十字であっても使用することができる。
また、同様に柱状突起の断面が部分的な欠失がある多角形であるものとして、図17で示される断面の治具を作製することができ、例えば図17の断面の冶具を用いた場合には中空の微小針が形成できる。同様に四角形の断面が不均一なものである冶具として、例えば図18の断面のものを用いた場合にも、中空の微小針が成型される。 As the “number of columnar protrusions” in the present invention, a necessary number is selected corresponding to the number of microneedles to be produced. Accordingly, the present invention is not particularly limited, and a plurality of them are sufficient. For example, it can be selected in the range of 9 to 500, for example, corresponding to the number of microneedles of the desired microneedle. According to the density of the sword mountain type microneedle, the same density of the columnar protrusions in the jig is selected. For example, in the present invention, since the outer diameter of the cross-section of the columnar protrusions is 100 to 450 μm, as described above, the interval (pitch) between the columnar protrusions is preferably 150 to 1 mm or more. However, since the number of columnar protrusions can be selected as necessary, the density of the columnar protrusions is preferably 9 to 500 / cm 2 .
The “cross-sectional shape of the columnar protrusion” of the present invention is not particularly limited, and various shapes can be used as necessary. For example, a quadrangle, a U-shape, a cross shape, a circle, an e-shape, a circle with a portion missing (C-shape), a polygon with a partial deletion, or the like can be used. The size of the outer diameter of the cross-section of the columnar protrusion can be selected according to the size of the microneedle to be manufactured. For example, in order to produce a sharp needle (with a needle bottom of 150 to 200 μm and a needle height of 300 to 400 μm), a 200 × 200 μm square prism jig is used as shown in FIG. I found it good. Further, in order to form a needle having a recess or groove for carrying a drug, it is desirable to use a jig whose cross section of the columnar protrusion is a polygon with a partial deletion. Examples of the polygon having a partial deletion include those having a cross-section of a columnar protrusion having a U shape, a V shape, and a cross shape.
As shown in FIG. 3, FIG. 4, and FIG. 9 to FIG. 11, the U-shaped shape is 250 to 350 μm in the vertical and horizontal outer diameters, and the U-shaped wall thickness is 40 to 60 μm. Things can be used. Preferred ratios of the U-shaped vertical bars and horizontal bars include those in which the vertical bar is 1 and the horizontal bar is in the range of 1 to 1.5. The U-shape may be continuous, or one or more gaps may be opened. For example, a gap (interval) exists between two U-shaped horizontal bars and vertical bars as shown in FIGS. 15 to 16, or vertical bars as shown in FIGS. One may be present in the part.
As the cross-shaped shape, for example, as shown in FIG. 8, it is possible to use a shape in which the vertical and horizontal outer diameters are 300 to 450 μm and the thickness of the cross is 40 to 60 μm. Furthermore, a cross formed by combining four rectangles with a gap at the center of the cross can also be used.
Similarly, the cross-section jig shown in FIG. 17 can be produced assuming that the cross-section of the columnar protrusion is a polygon having a partial deletion. For example, when a jig having a cross-section shown in FIG. 17 is used. A hollow microneedle can be formed. Similarly, when a jig having a non-uniform square cross section is used, for example, a cross section shown in FIG. 18, hollow microneedles are formed.
コの字型が二つ組み合わさった、図19で示されるエの字型の断面の柱状突起の冶具を用いた場合には、2つの先端を持ち両面に凹部を持った微小針が得られることになる。
以上のように、冶具の柱状突起の断面を目的に応じて適宜選択することにより、中空のある微小針、凹部または溝のある微小針を作成することができる。このような微小針を持つマイクロニードルに薬効成分、薬液を塗布して、効率的に薬剤を担持させることができる。薬剤を担持させる方法としては、公知の塗布・浸漬方法を用いることが出来る。その結果、容易に所望の薬剤が担持されたマイクロニードルを容易に作成することができる。 In the case of using a jig with a columnar projection having a U-shaped cross section as shown in FIG. 19 in which two U-shapes are combined, a microneedle having two tips and concave portions on both sides is obtained. It will be.
As described above, hollow microneedles, microneedles with recesses or grooves can be created by appropriately selecting the cross-section of the columnar protrusions of the jig according to the purpose. A drug can be efficiently carried by applying a medicinal component and a drug solution to the microneedle having such a microneedle. As a method for supporting the drug, a known coating / immersion method can be used. As a result, a microneedle carrying a desired drug can be easily produced.
以上のように、冶具の柱状突起の断面を目的に応じて適宜選択することにより、中空のある微小針、凹部または溝のある微小針を作成することができる。このような微小針を持つマイクロニードルに薬効成分、薬液を塗布して、効率的に薬剤を担持させることができる。薬剤を担持させる方法としては、公知の塗布・浸漬方法を用いることが出来る。その結果、容易に所望の薬剤が担持されたマイクロニードルを容易に作成することができる。 In the case of using a jig with a columnar projection having a U-shaped cross section as shown in FIG. 19 in which two U-shapes are combined, a microneedle having two tips and concave portions on both sides is obtained. It will be.
As described above, hollow microneedles, microneedles with recesses or grooves can be created by appropriately selecting the cross-section of the columnar protrusions of the jig according to the purpose. A drug can be efficiently carried by applying a medicinal component and a drug solution to the microneedle having such a microneedle. As a method for supporting the drug, a known coating / immersion method can be used. As a result, a microneedle carrying a desired drug can be easily produced.
以下に本発明について実施例により具体的に説明する。但し、本発明は以下の実施例になんら限定されるものではない。
Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to the following examples.
(実施例1)マイクロニードルの製造法
平板上に、一辺が0.2mm×0.2mmで高さが0.35mmの四角柱がピッチ0.8mm毎に10本立っている、シリコン製冶具(1cm×1cm)を使用した。オートグラフ(島津製作所製)の水平表面にカプコンテープでPGAプレート(半径11mm、厚さ1mm)を貼付した。上記冶具を250℃のホットプレートに設置し、PGAプレートに冶具を接触させ、該PGAプレートを引上げて、PGAプレート表面にマイクロニードルを作製した。
得られたマイクロニードルを図1と図2に示す。底部が約150μmの四角柱推状であり、先端部が円錐状である高さが約350μmの微小針が100本のPGA製の剣山型マイクロニードルが得られた。マイクロニードルのサイズ(微小針の部分)は約7.2mm×7.2mmであった。 (Example 1) Manufacturing method of microneedle A silicon jig in which 10 square pillars each having a side of 0.2 mm × 0.2 mm and a height of 0.35 mm stand on a flat plate every 0.8 mm pitch ( 1 cm × 1 cm) was used. A PGA plate (radius 11 mm,thickness 1 mm) was attached to the horizontal surface of an autograph (manufactured by Shimadzu Corporation) with Capcom tape. The jig was placed on a hot plate at 250 ° C., the jig was brought into contact with the PGA plate, the PGA plate was pulled up, and microneedles were produced on the surface of the PGA plate.
The obtained microneedle is shown in FIG. 1 and FIG. A PGA sword mountain type microneedle having 100 microneedles having a height of about 350 μm and a bottom having a quadrangular prism shape having a bottom portion of about 150 μm and a tip portion having a conical shape was obtained. The microneedle size (microneedle portion) was about 7.2 mm × 7.2 mm.
平板上に、一辺が0.2mm×0.2mmで高さが0.35mmの四角柱がピッチ0.8mm毎に10本立っている、シリコン製冶具(1cm×1cm)を使用した。オートグラフ(島津製作所製)の水平表面にカプコンテープでPGAプレート(半径11mm、厚さ1mm)を貼付した。上記冶具を250℃のホットプレートに設置し、PGAプレートに冶具を接触させ、該PGAプレートを引上げて、PGAプレート表面にマイクロニードルを作製した。
得られたマイクロニードルを図1と図2に示す。底部が約150μmの四角柱推状であり、先端部が円錐状である高さが約350μmの微小針が100本のPGA製の剣山型マイクロニードルが得られた。マイクロニードルのサイズ(微小針の部分)は約7.2mm×7.2mmであった。 (Example 1) Manufacturing method of microneedle A silicon jig in which 10 square pillars each having a side of 0.2 mm × 0.2 mm and a height of 0.35 mm stand on a flat plate every 0.8 mm pitch ( 1 cm × 1 cm) was used. A PGA plate (radius 11 mm,
The obtained microneedle is shown in FIG. 1 and FIG. A PGA sword mountain type microneedle having 100 microneedles having a height of about 350 μm and a bottom having a quadrangular prism shape having a bottom portion of about 150 μm and a tip portion having a conical shape was obtained. The microneedle size (microneedle portion) was about 7.2 mm × 7.2 mm.
(実施例2)コの字型およびV字型冶具によるマイクロニードルの製造法
薬液の担持性を向上させるため、溝を持った針形状が作製できるかを検討した。そのため、図3の断面形状を持つ、図4、図5に示される冶具を作製した。冶具の柱状突起の高さは約350μmである。この冶具を使用し、実施例1と同じ作製装置、作製条件を用いて、マイクロニードルの作製を行なった。得られたマイクロニードルを図6の右図と図7に示す。
この結果から、コの字型の冶具を使用した場合には、所望の凹部を持った形状の微小針が作製できたが、V字型の冶具を使用した場合には、PGAプレートに対する接触面積が少ないので、軟化・熔解して表面張力によって引き上げられるPGA量に限界があり、図7に示されるように微小針の高さがあまり高くなかった。
また、コの字型の冶具の場合、6パターンの冶具の中では、縦横300μm、肉厚が60μmのコの字型冶具を用いた場合に、図6の右図に示されるように、好適な高さと凹部を持つ微小針(針に高さ約440μm、底辺の幅約300μm)が得られることが分かった。 (Example 2) Manufacturing method of microneedles with U-shaped and V-shaped jigs In order to improve the carrying ability of chemicals, it was examined whether a needle shape with a groove could be produced. Therefore, the jig shown in FIGS. 4 and 5 having the cross-sectional shape of FIG. 3 was produced. The height of the columnar protrusions of the jig is about 350 μm. Using this jig, microneedles were produced using the same production apparatus and production conditions as in Example 1. The obtained microneedle is shown in the right view of FIG. 6 and FIG.
From this result, when a U-shaped jig was used, a microneedle having a desired concave shape could be produced. However, when a V-shaped jig was used, the contact area with the PGA plate Therefore, there is a limit to the amount of PGA that can be softened, melted, and pulled up by surface tension, and the height of the microneedles was not so high as shown in FIG.
In addition, in the case of a U-shaped jig, among the six patterns of jigs, when a U-shaped jig having a vertical and horizontal length of 300 μm and a wall thickness of 60 μm is used, as shown in the right diagram of FIG. It was found that a microneedle having a high height and a recess (the height of the needle is about 440 μm and the width of the base is about 300 μm) can be obtained.
薬液の担持性を向上させるため、溝を持った針形状が作製できるかを検討した。そのため、図3の断面形状を持つ、図4、図5に示される冶具を作製した。冶具の柱状突起の高さは約350μmである。この冶具を使用し、実施例1と同じ作製装置、作製条件を用いて、マイクロニードルの作製を行なった。得られたマイクロニードルを図6の右図と図7に示す。
この結果から、コの字型の冶具を使用した場合には、所望の凹部を持った形状の微小針が作製できたが、V字型の冶具を使用した場合には、PGAプレートに対する接触面積が少ないので、軟化・熔解して表面張力によって引き上げられるPGA量に限界があり、図7に示されるように微小針の高さがあまり高くなかった。
また、コの字型の冶具の場合、6パターンの冶具の中では、縦横300μm、肉厚が60μmのコの字型冶具を用いた場合に、図6の右図に示されるように、好適な高さと凹部を持つ微小針(針に高さ約440μm、底辺の幅約300μm)が得られることが分かった。 (Example 2) Manufacturing method of microneedles with U-shaped and V-shaped jigs In order to improve the carrying ability of chemicals, it was examined whether a needle shape with a groove could be produced. Therefore, the jig shown in FIGS. 4 and 5 having the cross-sectional shape of FIG. 3 was produced. The height of the columnar protrusions of the jig is about 350 μm. Using this jig, microneedles were produced using the same production apparatus and production conditions as in Example 1. The obtained microneedle is shown in the right view of FIG. 6 and FIG.
From this result, when a U-shaped jig was used, a microneedle having a desired concave shape could be produced. However, when a V-shaped jig was used, the contact area with the PGA plate Therefore, there is a limit to the amount of PGA that can be softened, melted, and pulled up by surface tension, and the height of the microneedles was not so high as shown in FIG.
In addition, in the case of a U-shaped jig, among the six patterns of jigs, when a U-shaped jig having a vertical and horizontal length of 300 μm and a wall thickness of 60 μm is used, as shown in the right diagram of FIG. It was found that a microneedle having a high height and a recess (the height of the needle is about 440 μm and the width of the base is about 300 μm) can be obtained.
(実施例3)コの字型冶具の種類と針形状への影響
実施例2の結果に基づき、形成される微小針の形状に関するコの字型の冶具の影響を検討した。まず、図9~11の各左図に示される断面図形の冶具を作成した。実施例1と同様の装置、条件でマイクロニードルの作製を行った。そして、得られたマイクロニードルの針形状を観察した。その結果を、図9~11の各右図に示す。
冶具として、コの字の2本の横棒の外径が350μmで、縦棒の外径が250μmで、縦棒の肉厚が40μmのものを使用した場合、図11の右図、図12で示されるような、良好な溝(凹部)を持つマイクロニードルが製造できた。実施例2で得られた針形状のものと対比し、実施例3で得られた針形状のものは、薬液の担持性がより向上する溝(凹部)になっていた。 (Example 3) Kind of U-shaped jig and influence on needle shape Based on the result of Example 2 , the influence of the U-shaped jig on the shape of the formed micro needle was examined. First, jigs having cross-sectional figures shown in the left diagrams of FIGS. 9 to 11 were prepared. A microneedle was produced using the same apparatus and conditions as in Example 1. And the needle shape of the obtained microneedle was observed. The results are shown in the right diagrams of FIGS.
When a jig having two U-shaped horizontal bars having an outer diameter of 350 μm, a vertical bar having an outer diameter of 250 μm, and a vertical bar having a thickness of 40 μm is used as a jig, the right diagram in FIG. A microneedle having a good groove (concave portion) as shown in FIG. In contrast to the needle-shaped one obtained in Example 2, the needle-shaped one obtained in Example 3 was a groove (concave portion) that further improved the ability to carry a chemical solution.
実施例2の結果に基づき、形成される微小針の形状に関するコの字型の冶具の影響を検討した。まず、図9~11の各左図に示される断面図形の冶具を作成した。実施例1と同様の装置、条件でマイクロニードルの作製を行った。そして、得られたマイクロニードルの針形状を観察した。その結果を、図9~11の各右図に示す。
冶具として、コの字の2本の横棒の外径が350μmで、縦棒の外径が250μmで、縦棒の肉厚が40μmのものを使用した場合、図11の右図、図12で示されるような、良好な溝(凹部)を持つマイクロニードルが製造できた。実施例2で得られた針形状のものと対比し、実施例3で得られた針形状のものは、薬液の担持性がより向上する溝(凹部)になっていた。 (Example 3) Kind of U-shaped jig and influence on needle shape Based on the result of Example 2 , the influence of the U-shaped jig on the shape of the formed micro needle was examined. First, jigs having cross-sectional figures shown in the left diagrams of FIGS. 9 to 11 were prepared. A microneedle was produced using the same apparatus and conditions as in Example 1. And the needle shape of the obtained microneedle was observed. The results are shown in the right diagrams of FIGS.
When a jig having two U-shaped horizontal bars having an outer diameter of 350 μm, a vertical bar having an outer diameter of 250 μm, and a vertical bar having a thickness of 40 μm is used as a jig, the right diagram in FIG. A microneedle having a good groove (concave portion) as shown in FIG. In contrast to the needle-shaped one obtained in Example 2, the needle-shaped one obtained in Example 3 was a groove (concave portion) that further improved the ability to carry a chemical solution.
(実施例4)冶具の作製
(1)ICP-RIE法による四角柱状治具の作製
感光性レジストをスピンコート法により、厚さ700μmのSi平板(4×4インチ)を被膜した。微小針の描画パターンをUV露光で描画した。デッピング法により現像し、微小針のパターン(200×200μmの四角形)を転写した。CF4ガスを用いた、誘導結合型プラズマ反応性イオンエッチィング(ICP-RIE)方法により、四角柱(柱状突起の長さ約350μm)を10×10個(柱状突起のピッチ間隔は800μm)を有するSi平板を得た。角柱上に残存する感光性レジストをO2ガスを用いたRIE方法により除去した。
(2)高精度ダイシング法による四角柱状治具の作製
厚さ700μmのSi平板(4×4インチ)を固定し、ダイシングソー(デイスコ社製)を用いて柱状突起間の部分を研削除去し、四角柱状の柱状突起を切り出した。柱状突起のピッチ間隔が約720μmであり、柱状突起の長さが約350μmである、10×10個の四角柱状突起を持つSi平板を得た。 (Example 4) Production of jig (1) Production of square columnar jig by ICP-RIE method A 700 μm thick Si flat plate (4 × 4 inches) was coated with a photosensitive resist by spin coating. A drawing pattern of microneedles was drawn by UV exposure. Development was performed by a dipping method to transfer a microneedle pattern (200 × 200 μm square). By inductively coupled plasma reactive ion etching (ICP-RIE) method using CF 4 gas, 10 × 10 square pillars (columnar protrusion length is about 350 μm) (pitch interval between columnar protrusions is 800 μm). A Si flat plate was obtained. The photosensitive resist remaining on the prisms was removed by the RIE method using O 2 gas.
(2) Production of square columnar jig by high-precision dicing method A 700 μm thick Si flat plate (4 × 4 inches) is fixed, and a dicing saw (manufactured by DISCO) is used to grind and remove the portion between the columnar protrusions. A square columnar protrusion was cut out. A Si flat plate having 10 × 10 square columnar protrusions having a pitch interval of the columnar protrusions of about 720 μm and a length of the columnar protrusions of about 350 μm was obtained.
(1)ICP-RIE法による四角柱状治具の作製
感光性レジストをスピンコート法により、厚さ700μmのSi平板(4×4インチ)を被膜した。微小針の描画パターンをUV露光で描画した。デッピング法により現像し、微小針のパターン(200×200μmの四角形)を転写した。CF4ガスを用いた、誘導結合型プラズマ反応性イオンエッチィング(ICP-RIE)方法により、四角柱(柱状突起の長さ約350μm)を10×10個(柱状突起のピッチ間隔は800μm)を有するSi平板を得た。角柱上に残存する感光性レジストをO2ガスを用いたRIE方法により除去した。
(2)高精度ダイシング法による四角柱状治具の作製
厚さ700μmのSi平板(4×4インチ)を固定し、ダイシングソー(デイスコ社製)を用いて柱状突起間の部分を研削除去し、四角柱状の柱状突起を切り出した。柱状突起のピッチ間隔が約720μmであり、柱状突起の長さが約350μmである、10×10個の四角柱状突起を持つSi平板を得た。 (Example 4) Production of jig (1) Production of square columnar jig by ICP-RIE method A 700 μm thick Si flat plate (4 × 4 inches) was coated with a photosensitive resist by spin coating. A drawing pattern of microneedles was drawn by UV exposure. Development was performed by a dipping method to transfer a microneedle pattern (200 × 200 μm square). By inductively coupled plasma reactive ion etching (ICP-RIE) method using CF 4 gas, 10 × 10 square pillars (columnar protrusion length is about 350 μm) (pitch interval between columnar protrusions is 800 μm). A Si flat plate was obtained. The photosensitive resist remaining on the prisms was removed by the RIE method using O 2 gas.
(2) Production of square columnar jig by high-precision dicing method A 700 μm thick Si flat plate (4 × 4 inches) is fixed, and a dicing saw (manufactured by DISCO) is used to grind and remove the portion between the columnar protrusions. A square columnar protrusion was cut out. A Si flat plate having 10 × 10 square columnar protrusions having a pitch interval of the columnar protrusions of about 720 μm and a length of the columnar protrusions of about 350 μm was obtained.
(3)コの字型治具の作製
図3の上図に示されるコの字型の微小針描画パターンを用いて、上記(1)と同様にして、コの字型の柱状突起(長さ約350μm)を3×3個有するSi平板を得た。得られたSi製冶具を図4に示す。
同様に、図9~11の各左図を用いて、これに対応するSi製冶具を作製することができる。 (3) Fabrication of a U-shaped jig A U-shaped columnar protrusion (long) using the U-shaped microneedle drawing pattern shown in the upper diagram of FIG. 3 in the same manner as (1) above. A Si flat plate having 3 × 3 (about 350 μm) was obtained. The obtained Si jig is shown in FIG.
Similarly, a Si jig corresponding to this can be manufactured using the left diagrams of FIGS.
図3の上図に示されるコの字型の微小針描画パターンを用いて、上記(1)と同様にして、コの字型の柱状突起(長さ約350μm)を3×3個有するSi平板を得た。得られたSi製冶具を図4に示す。
同様に、図9~11の各左図を用いて、これに対応するSi製冶具を作製することができる。 (3) Fabrication of a U-shaped jig A U-shaped columnar protrusion (long) using the U-shaped microneedle drawing pattern shown in the upper diagram of FIG. 3 in the same manner as (1) above. A Si flat plate having 3 × 3 (about 350 μm) was obtained. The obtained Si jig is shown in FIG.
Similarly, a Si jig corresponding to this can be manufactured using the left diagrams of FIGS.
(4)欠失のあるコの字型治具の作製
図14の左図と図16図の左図に示される欠失のあるコの字型の微小針描画パターンを用いて、上記(1)と同様にして、コの字型の柱状突起(長さ約350μm)を3×3個有するSi平板を得た。得られたSi製冶具を図13と図15に示す。 (4) Preparation of U-shaped jig with deletion Using the U-shaped microneedle drawing pattern with deletion shown in the left figure of FIG. 14 and the left figure of FIG. ) To obtain a Si flat plate having 3 × 3 U-shaped columnar protrusions (length: about 350 μm). The obtained Si jig is shown in FIGS.
図14の左図と図16図の左図に示される欠失のあるコの字型の微小針描画パターンを用いて、上記(1)と同様にして、コの字型の柱状突起(長さ約350μm)を3×3個有するSi平板を得た。得られたSi製冶具を図13と図15に示す。 (4) Preparation of U-shaped jig with deletion Using the U-shaped microneedle drawing pattern with deletion shown in the left figure of FIG. 14 and the left figure of FIG. ) To obtain a Si flat plate having 3 × 3 U-shaped columnar protrusions (length: about 350 μm). The obtained Si jig is shown in FIGS.
(5)V字型冶具の作製
図3の下図に示されるV字型の微小針描画パターンを用いて、上記(1)と同様にして、V字型の柱状突起(長さ約350μm)を3×3個有するSi平板を得た。得られたSi製冶具を図5に示す。 (5) Fabrication of V-shaped jig Using the V-shaped microneedle drawing pattern shown in the lower part of FIG. 3, V-shaped columnar protrusions (length: about 350 μm) are formed in the same manner as (1) above. A 3 × 3 Si flat plate was obtained. The obtained Si jig is shown in FIG.
図3の下図に示されるV字型の微小針描画パターンを用いて、上記(1)と同様にして、V字型の柱状突起(長さ約350μm)を3×3個有するSi平板を得た。得られたSi製冶具を図5に示す。 (5) Fabrication of V-shaped jig Using the V-shaped microneedle drawing pattern shown in the lower part of FIG. 3, V-shaped columnar protrusions (length: about 350 μm) are formed in the same manner as (1) above. A 3 × 3 Si flat plate was obtained. The obtained Si jig is shown in FIG.
(4)十字型冶具の作製
図8の左図に示されるV字型の微小針描画パターンを用いて、上記(1)と同様にして、十字型の柱状突起(長さ約350μm)を3×3個有するSi平板を得た。 (4) Fabrication of cross-shaped jig Using the V-shaped microneedle drawing pattern shown in the left diagram of FIG. 8, the cross-shaped columnar projection (length: about 350 μm) is formed in the same manner as (1) above. × 3 Si flat plates were obtained.
図8の左図に示されるV字型の微小針描画パターンを用いて、上記(1)と同様にして、十字型の柱状突起(長さ約350μm)を3×3個有するSi平板を得た。 (4) Fabrication of cross-shaped jig Using the V-shaped microneedle drawing pattern shown in the left diagram of FIG. 8, the cross-shaped columnar projection (length: about 350 μm) is formed in the same manner as (1) above. × 3 Si flat plates were obtained.
(実施例5)十字型冶具を用いたマイクロニードルの作製
実施例4(4)で作製された十字型治具を使用し、実施例1の装置と製造条件を使用して、マイクロニードルの作製を検討した。得られたマイクロニードルを図8の右図に示す。
得られた微小針の外観は、微小針の底部が治具由来の十字型を形成している。しかし、約100μm程度のところで、収斂して円錐状に近い形状を示している。
以上のように、実施例1と同様の製造条件では、冶具の引上げ速度等が速いと考えられることから、薬剤保持用に必要な凹部を形成させるためには、冶具の引上げ速度を低下させる必要があることが分かった。 (Example 5) Production of microneedle using cross-shaped jig Using the cross-shaped jig produced in Example 4 (4) and using the apparatus and production conditions of Example 1, production of microneedle It was investigated. The obtained microneedle is shown in the right figure of FIG.
As for the appearance of the obtained microneedle, the bottom of the microneedle forms a cross shape derived from a jig. However, at about 100 μm, it converges and shows a shape close to a cone.
As described above, under the same manufacturing conditions as in Example 1, it is considered that the lifting speed of the jig is high, so that it is necessary to reduce the lifting speed of the jig in order to form the recess necessary for holding the medicine. I found out that
実施例4(4)で作製された十字型治具を使用し、実施例1の装置と製造条件を使用して、マイクロニードルの作製を検討した。得られたマイクロニードルを図8の右図に示す。
得られた微小針の外観は、微小針の底部が治具由来の十字型を形成している。しかし、約100μm程度のところで、収斂して円錐状に近い形状を示している。
以上のように、実施例1と同様の製造条件では、冶具の引上げ速度等が速いと考えられることから、薬剤保持用に必要な凹部を形成させるためには、冶具の引上げ速度を低下させる必要があることが分かった。 (Example 5) Production of microneedle using cross-shaped jig Using the cross-shaped jig produced in Example 4 (4) and using the apparatus and production conditions of Example 1, production of microneedle It was investigated. The obtained microneedle is shown in the right figure of FIG.
As for the appearance of the obtained microneedle, the bottom of the microneedle forms a cross shape derived from a jig. However, at about 100 μm, it converges and shows a shape close to a cone.
As described above, under the same manufacturing conditions as in Example 1, it is considered that the lifting speed of the jig is high, so that it is necessary to reduce the lifting speed of the jig in order to form the recess necessary for holding the medicine. I found out that
(実施例6)分割型四角形の治具の作製
図17に示される柱状突起の断面の微小針描画パターンを用いて、上記(1)と同様にして、欠失のある四角形の柱状突起(長さ約350μm)を3×3個有するSi平板を得ることが出来る。 (Embodiment 6) Production of split quadrangular jig Using the microneedle drawing pattern of the cross-section of the columnar protrusion shown in FIG. 17, in the same manner as in the above (1), a rectangular columnar protrusion with a deletion (long Si plate having 3 × 3 (about 350 μm) can be obtained.
図17に示される柱状突起の断面の微小針描画パターンを用いて、上記(1)と同様にして、欠失のある四角形の柱状突起(長さ約350μm)を3×3個有するSi平板を得ることが出来る。 (Embodiment 6) Production of split quadrangular jig Using the microneedle drawing pattern of the cross-section of the columnar protrusion shown in FIG. 17, in the same manner as in the above (1), a rectangular columnar protrusion with a deletion (long Si plate having 3 × 3 (about 350 μm) can be obtained.
本発明の冶具と製造方法により、材質強度の高いPGA製のマイクロニードルを容易に大量製造することが出来るようになった。また、冶具の形状(柱状突起の断面形状)を工夫することによって、例えば図1以外にも、コの字型の冶具を使用することにより、図6の右図、図9~11の各右図に示されるような、薬液の担持性が向上した溝(凹部)を持つ図6の右図や図12のようなマイクロニードルを作製できることが可能になった。
The jig and manufacturing method of the present invention enable easy mass production of PGA microneedles with high material strength. Further, by devising the shape of the jig (cross-sectional shape of the columnar protrusion), for example, by using a U-shaped jig in addition to FIG. 1, the right diagram in FIG. 6 and the right diagrams in FIGS. As shown in the figure, it became possible to produce a microneedle as shown in the right figure of FIG. 6 and the groove shown in FIG.
Claims (11)
- 以下の形状を有するポリグリコール酸(PGA)製のマイクロニードル。
(1)微小針の本数が複数であり、
(2)微小針の高さが150μm~1mmであり、
(3)微小針の底部の外径が100~450μmであり、
(4)微小針の先端部が尖った円柱状又は円錐状となり、その外径が数μm~数十μmであり、
(5)微小針の断面の形状が底部では円形、多角形、十字型、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形であり、先端部では円形である、 A microneedle made of polyglycolic acid (PGA) having the following shape.
(1) The number of microneedles is plural,
(2) The height of the micro needle is 150 μm to 1 mm,
(3) The outer diameter of the bottom of the microneedle is 100 to 450 μm,
(4) The tip of the microneedle has a pointed cylindrical or conical shape, and its outer diameter is several μm to several tens of μm.
(5) The cross-sectional shape of the microneedle is a circle, a polygon, a cross, a square shape, a circle with a portion missing (C shape) or a polygon with a partial deletion at the bottom, and the tip In a circle, - 多角形が四角形である、請求項1記載のマイクロニードル。 The microneedle according to claim 1, wherein the polygon is a quadrangle.
- 部分的な欠失がある多角形が、コの字型、V字型である、請求項1記載のマイクロニードル。 The microneedle according to claim 1, wherein the polygon having a partial deletion is a U shape or a V shape.
- 尖った円柱状又は円錐状になった先端部と底部の間の微小針の形状として、溝状の凹部を保持する微小針であることを特徴とする、請求項3記載のマイクロニードル。 4. The microneedle according to claim 3, wherein the microneedle is a microneedle that holds a groove-like recess as a shape of a microneedle between a tip portion and a bottom portion having a sharp cylindrical shape or a conical shape.
- 平板上に以下の形状の柱状突起を有するシリコン製または金属製の冶具。
(1)柱状突起の長さが200μm~1mmであり、
(2)柱状突起の間隔が400μm~2mmであり、
(3)柱状突起の本数が複数であり、
(4)柱状突起の断面の外径が、100~450μmであり、
(5)柱状突起の断面形状が、円形、多角形、十字型、エの字型、一部を欠く円形(C字型)または部分的な欠失がある多角形である、 A jig made of silicon or metal having a columnar protrusion having the following shape on a flat plate.
(1) The length of the columnar protrusion is 200 μm to 1 mm,
(2) The interval between the columnar protrusions is 400 μm to 2 mm,
(3) The number of columnar protrusions is plural,
(4) The outer diameter of the cross-section of the columnar protrusion is 100 to 450 μm,
(5) The cross-sectional shape of the columnar protrusion is a circle, a polygon, a cross, a square shape, a circle with a part missing (C shape) or a polygon with a partial deletion. - 部分的な欠失がある多角形がコの字型、V字型である、請求項5記載の冶具。 The jig according to claim 5, wherein the polygon having a partial deletion is a U-shape or a V-shape.
- コの字型の一部に欠失がある、請求項6に記載の冶具。 The jig according to claim 6, wherein there is a deletion in a part of the U-shape.
- コの字の2本の横棒と一本の縦棒の長さの比率として、縦棒を1として、横棒が1~1.5の範囲である、請求項6又は7に記載の治具。 The treatment according to claim 6 or 7, wherein the ratio of the length of the two U-shaped horizontal bars and the length of one vertical bar is 1 and the horizontal bar is in the range of 1 to 1.5. Ingredients.
- コの字の2本の横棒の肉厚が40~80μmであり、縦棒の肉厚が20~50μmであることを特徴とする、請求項8に記載の冶具。 The jig according to claim 8, wherein the thickness of the two U-shaped horizontal bars is 40 to 80 µm, and the thickness of the vertical bar is 20 to 50 µm.
- 一つまたは複数の隙間が、コの字の2本の横棒と縦棒の間に存在する、あるいは縦棒の部分に一つ存在することを特徴とする、請求項9に記載の冶具。 10. The jig according to claim 9, wherein one or a plurality of gaps are present between two U-shaped horizontal bars and vertical bars, or one vertical bar part.
- 前記柱状突起の断面形状が十字型の場合、前記十字型の縦横の外径が400~450μmであり、肉厚が40~80μmであることを特徴とする、請求項11記載の冶具。 12. The jig according to claim 11, wherein when the cross-sectional shape of the columnar protrusion is a cross shape, the cross shape has a vertical and horizontal outer diameter of 400 to 450 μm and a wall thickness of 40 to 80 μm.
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