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WO2010110397A1 - Micro-aiguilles, et leur procédé de fabrication et leur moule - Google Patents

Micro-aiguilles, et leur procédé de fabrication et leur moule Download PDF

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Publication number
WO2010110397A1
WO2010110397A1 PCT/JP2010/055291 JP2010055291W WO2010110397A1 WO 2010110397 A1 WO2010110397 A1 WO 2010110397A1 JP 2010055291 W JP2010055291 W JP 2010055291W WO 2010110397 A1 WO2010110397 A1 WO 2010110397A1
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WO
WIPO (PCT)
Prior art keywords
mold
main surface
resin
shape
microneedle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2010/055291
Other languages
English (en)
Japanese (ja)
Inventor
豊 三原
英徳 吉村
文和 大平
辰憲 岡本
洋介 迫
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MedRx Co Ltd
Kagawa University NUC
Original Assignee
MedRx Co Ltd
Kagawa University NUC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MedRx Co Ltd, Kagawa University NUC filed Critical MedRx Co Ltd
Publication of WO2010110397A1 publication Critical patent/WO2010110397A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C45/00—Injection moulding, i.e. forcing the required volume of moulding material through a nozzle into a closed mould; Apparatus therefor
    • B29C45/17—Component parts, details or accessories; Auxiliary operations
    • B29C45/26—Moulds
    • B29C45/37—Mould cavity walls, i.e. the inner surface forming the mould cavity, e.g. linings
    • 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
    • A61M2037/0046—Solid 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
    • A61M2037/0053—Methods for producing microneedles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
    • B29L2031/00—Other particular articles
    • B29L2031/753—Medical equipment; Accessories therefor
    • B29L2031/7544—Injection needles, syringes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
    • B29L2031/00—Other particular articles
    • B29L2031/756—Microarticles, nanoarticles

Definitions

  • the present invention relates to a method for manufacturing a microneedle.
  • the present invention relates to a press manufacturing method for producing a large number of needle-like protrusions that are constructed of a biodegradable material and formed so as to protrude in an array (matrix) shape on the main surface of a substrate (or base).
  • the present invention relates to a manufacturing method for overcoming the distortion of needle-like protrusions peculiar to the pressing method, and to a mold used for the manufacturing method.
  • drugs that cannot be administered orally are administered by injection. Administration with a syringe causes severe skin damage and is painful.
  • transdermal administration such as a patch is simple, and further, it is possible to control the drug delivery for locally delivering the drug. In addition, side effects of the drug can be reduced or avoided.
  • a patch when used, it takes time to develop the drug effect, and the usable drugs can be used because the chemical properties are not suitable for transdermal absorption, and good results cannot be obtained. Drugs are greatly restricted.
  • iontophoresis requires the drug to be charged in an aqueous solution
  • sonophoresis and electroporation have limitations such as the molecular weight of the drug must be small.
  • a microneedle is a device in which a large number of minute needle-like protrusions are arranged in an array (matrix) on the main surface of a substrate.
  • the overall shape of the microneedle is completely different in size, but it is a form like a so-called sword mountain (a device for decorating cut flowers with a large number of needles provided on a plate).
  • the microneedle has a substrate and a large number of needle-like protrusions integrally provided on the main surface thereof.
  • the substrate of the microneedle is usually a flat plate having a thickness of about 0.3 mm to 5 mm or more.
  • the acicular protrusion has a large aspect ratio (ratio of protrusion length to diameter), and generally has a protrusion length from the main surface of the substrate of 200 ⁇ m to 1 mm and a diameter of about several tens of ⁇ m to 200 ⁇ m.
  • Microneedles are known to be used as devices for drug delivery and body fluid sampling.
  • the acicular process has a length enough to penetrate the upper stratum corneum of the skin but not reach the pain point. Therefore, the microneedle has an advantage that it is not necessary to feel pain associated with skin penetration during application. Since the diameter of the needle-like projection of the microneedle is as small as several tens of ⁇ m to 200 ⁇ m, damage to the skin is much smaller than when an injection needle or a microblade is applied.
  • microneedles using a resin such as polyamide or polyester have also been proposed (see Patent Document 3).
  • microneedles produced using polylactic acid resin or polyglycolic acid as polyester resin are biodegradable and are considered to be safer than metal or silicon microneedles.
  • the molding needle has a main surface for forming the substrate surface of the microneedle and a plurality of through holes 2 provided on the main surface. It becomes the structure which has.
  • the through hole 2 is a cavity for forming a needle-like protrusion.
  • the molding procedure is as follows. Is pressed against the resin to transfer the unevenness of the mold, and then the resin and the mold are cooled to room temperature to solidify the resin and release the product from the mold.
  • the present inventors have observed in detail the microneedles formed by the molding procedure as described above. As a result, the needle-like protrusions formed in the region near the end of the outer periphery of the main surface of the substrate of the microneedles. It was found that the root portion was deformed by the action of shear stress caused by cooling shrinkage of the resin. As a result, the needle-like protrusion is curved at the root.
  • an object of the present invention is to provide a method for producing a microneedle that is suitable for transdermal administration of a drug, is difficult to bend, and is difficult to bend, and a microneedle thereby.
  • the further objective of this invention is to provide the metal mold
  • PGA resin needs to be heated to a temperature higher than that of other materials at the time of molding, so that larger shrinkage occurs in the process of cooling to room temperature.
  • the thermal expansion coefficient of PGA resin is about 10 times higher, and the temperature difference of about 200 ° C. during the manufacturing process. In some cases, the volume shrinkage of the PGA resin reaches about 6-8%.
  • the substrate of the microneedle after cooling is contracted (in the lateral direction along the surface of the substrate).
  • Shrinkage reduces the distance between the central needle-like protrusion and the peripheral needle-like protrusion by about 30 to 40 ⁇ m.
  • needle-like protrusions having curved roots are formed in the peripheral portion of the main surface of the substrate.
  • the present inventors have found that if the ridge line-shaped protrusion is formed on the first main surface of the mold corresponding to the main surface of the microneedle substrate, the resin is solidified (crystallized) by cooling. )
  • the present invention has been completed by finding that the ridge-like projections can block the stress generated when shrinking.
  • the ridge line-like protrusion will be referred to as a shielding plate and the present invention will be described.
  • the gist of the present invention is as follows. (1) A method of manufacturing a microneedle having a structure in which needle-like protrusions are integrally formed on a main surface of a resin substrate, Heating the mold and crimping the resin, Cooling the resin and releasing the molded resin,
  • the mold has a main surface for forming a main surface of a substrate of a microneedle to be manufactured, and the main surface of the mold has a through hole for forming a needle-like protrusion, and the mold And a shielding plate protruding in a ridge shape from the main surface of
  • the shielding plate is provided at a position capable of suppressing lateral shrinkage that occurs in the microneedle substrate when the resin is cooled, and the height of the projection of the shielding plate is the height of the microneedle substrate to be manufactured.
  • the shape of the shielding plate on the main surface of the mold is a shape that divides the central region of the main surface of the mold, a shape that surrounds the central region of the main surface of the mold, and the outer periphery of the main surface of the mold.
  • the shape of the shielding plate on the main surface of the mold is a cross shape that divides the central region of the main surface of the mold, the circle that surrounds the central region of the main surface of the mold, the shape of the main surface of the mold It is a circular shape that surrounds the outer periphery, or a shape that overlaps these shapes,
  • the cross-sectional shape of the shielding plate is a wedge, square, rectangle, or trapezoid,
  • the through hole is a cylindrical or conical hole,
  • the opening of the through hole in the main surface of the mold is provided with a tapered chamfer,
  • the distance between the central axes of each through hole is 0.4 mm to 1 mm,
  • the number of through holes is 50 to 500;
  • the shielding plate has a shape that divides a region having a through hole into two or more.
  • the resin is a biodegradable resin.
  • the biodegradable resin is a resin mainly composed of polyglycolic acid.
  • the heating temperature of the mold is a temperature within a range of ⁇ 10 degrees to +30 degrees centering on a temperature of a melting point of the resin.
  • the mold has an upper mold and a lower mold opposite to the upper mold, and resin is molded into microneedles between these molds, and the upper mold is the main surface of the microneedle substrate.
  • the lower die forms the back surface of the microneedle substrate, has the main surface for holding the substrate in the upper die crimping process or mold releasing process,
  • the lower mold is provided with a recess that can be engaged with the upper mold, Placing the biodegradable resin in the recess of the lower mold, Heating the upper mold to the melting point of the resin and crimping the resin to the resin; Cooling the resin and releasing the molded resin.
  • the mold has an upper mold and a lower mold opposite to the upper mold, and the resin is molded into microneedles between these molds, and the upper mold is the main surface of the microneedle substrate.
  • the lower mold has a main surface for forming the back surface of the microneedle substrate, (1)
  • a pressing member made of an elastic material is disposed on the back surface of the upper mold so as to close the opening of the through hole, and the leakage of the resin material to the back surface of the upper mold is suppressed by the pressing member.
  • the production method according to any of (8) to (8).
  • the shielding plate is provided at a position capable of suppressing lateral shrinkage that occurs in the microneedle substrate when the resin is cooled, and the height of the projection of the shielding plate is the height of the microneedle substrate to be manufactured. Less than the thickness, The mold.
  • the shape of the shielding plate on the main surface of the mold is a shape that divides the central region of the main surface of the mold, a shape that surrounds the central region of the main surface of the mold, and the outer periphery of the main surface of the mold.
  • the mold according to (11) above which has a shape that surrounds or a combination of two or more of the shapes.
  • (13) The mold according to (11) or (12), wherein the shielding plate has a shape that divides a region having a through hole into two or more.
  • the shape of the shielding plate on the main surface of the mold is a cross shape that divides the central region of the main surface of the mold, the circle that surrounds the central region of the main surface of the mold, the shape of the main surface of the mold It is a circular shape that surrounds the outer periphery, or a shape that overlaps these shapes,
  • the cross-sectional shape of the shielding plate is a wedge, square, rectangle, or trapezoid,
  • the through hole is a cylindrical or conical hole,
  • the opening of the through hole in the main surface of the mold is provided with a tapered chamfer,
  • the distance between the central axes of each through hole is 0.4 mm to 1 mm,
  • the number of through holes is 50 to 500;
  • the mold according to any one of (11) to (13) above.
  • the mold according to any one of (11) to (14) above, wherein the region in which the through hole is formed is a flat plate having a thickness of 0.3 mm to 1 mm.
  • the shielding plate is provided so as to include a shape surrounding the outer periphery of the main surface of the mold, The mold according to any one of (11) to (15) above, wherein the shielding plate has a width of 0.5 mm.
  • a streak-like protrusion is provided in the through-hole from the end of the hole on the main surface side to the tip of the hole, and the cross-sectional shape of the streaky protrusion is wedge-shaped.
  • the mold according to any one of the above (11) to (16) which has a quadrangular shape.
  • the structure of a mold for forming a microneedle is important.
  • the shape of the main surface of the substrate 4 of the microneedle 10 to be manufactured (the surface on which the needle-like protrusions 12 are present) is formed.
  • the mold 3 is called an upper mold.
  • this upper mold structure is important.
  • the mold (upper mold) 3 has a main surface 3 ⁇ / b> A for forming the main surface 4 ⁇ / b> A of the substrate 4 of the microneedle 10.
  • the upper mold main surface 3A is referred to as an “upper mold main surface”.
  • the upper mold main surface 3A is provided with a through hole 2 for forming needle-like protrusions and a shielding plate 1 protruding in a ridge shape from the upper mold main surface 3A.
  • the shielding plate 1 is projected on the upper mold main surface 3 in a ridgeline shape, thereby suppressing the shrinkage of the material resin, and the internal stress resulting from the shrinkage is divided. The deformation is suppressed.
  • a groove 11 corresponding to the shielding plate 1 is formed on the main surface 4A of the substrate 4 of the microneedle 10 obtained by projecting the shielding plate 1 on the upper mold main surface 3, and the groove 11 corresponding to the shielding plate 1 is divided or Resin shrinkage occurs for each enclosed block. As shown in FIGS.
  • the mold of the present invention has a lower mold 5 facing the upper mold, and a resin is molded into microneedles between these molds.
  • the lower mold is a mold for forming the back surface (usually a flat surface) of the substrate 4 of the microneedle 10.
  • the upper surface 5B of the lower mold is referred to as a “lower mold main surface”.
  • the lower mold 5 may be a part of a mold for resin molding paired with the upper mold 3 or a base of a press apparatus (stage receiving pressure) for applying a compressive force during molding. May be. When the lower mold is the base of the press apparatus, the mold according to the present invention can be interpreted as only the upper mold.
  • FIG. 3 is a schematic view showing an arrangement pattern of the shielding plate and the through holes when the upper mold main surface is viewed.
  • the shielding plate protrudes in a ridge shape so as to draw a cross on the upper mold main surface.
  • the substrate of the microneedle is divided into four blocks by the shielding plate, so that the surface of each block as shown in FIG. It is sufficient to consider the contraction at Therefore, it is considered that the lateral deviation occurring at the base of the needle-like projections in each divided block is 1 ⁇ 4.
  • the needle-like projection is a columnar shape having a diameter of about 100 ⁇ m
  • the lateral displacement due to the contraction on the surface of the microneedle substrate is about 10 ⁇ m or less, the needle-like projection is not greatly affected.
  • a microneedle mold having the shielding plate exemplified in FIGS. 5, 6, and 7A was prepared.
  • the shielding plate protrudes so as to draw a circle in an intermediate region between the center of the upper die main surface and the outer peripheral edge, and the inside of the shielding plate that draws this circle.
  • through holes for acicular protrusions are arranged in the outer region.
  • the shielding plate has a shape in which the cross in FIG. 3 is superimposed on the circle in FIG. Further, in the mold mode illustrated in FIG. 7A, the shielding plate protrudes in a circular shape on the outer peripheral edge side so as to surround all the through holes provided in the upper mold main surface.
  • these molds are pressure-bonded to PGA resin softened by heating to produce microneedles, compared to the microneedles of FIG. 2 obtained without a shielding plate, for example, in the photograph of FIG. As shown, almost no curvature is seen in the needle-like protrusions of the fabricated microneedles.
  • a mold having a conical through hole as shown in FIG. 9 is used to improve the releasability after pressing the mold against the resin material and improve the puncture ability to the skin.
  • a conical tapered surface acts as a draft and is a preferred embodiment.
  • the shrinkage during cooling of the resin material used, particularly the biodegradable resin was alleviated, and the needle-like protrusions around the microneedles were not bent or broken as shown in FIG.
  • high-quality PGA resin microneedles can be produced as shown in FIGS.
  • FIG. 1 is a cross-sectional view schematically showing a state in a molding die in a conventional microneedle manufacturing method.
  • a mold without a shielding plate when pressed as a material, when the PGA resin is cooled and solidified, the resin shrinks toward the center along the substrate.
  • a thick arrow drawn inside the PGA resin plate indicates the direction of contraction.
  • FIG. 2 is an enlarged photograph showing the root portion of the needle-like protrusion of the microneedle obtained using a mold without a shielding plate. It is shown that the needle-like projections located on the outer peripheral portion of the main surface are curved by undergoing shear deformation at the base thereof.
  • FIG. 1 is a cross-sectional view schematically showing a state in a molding die in a conventional microneedle manufacturing method.
  • FIG. 2 is an enlarged photograph showing the root portion of the needle-like protrusion of the microneedle obtained using a mold without a shielding plate. It is shown that the needle-like projections
  • FIG. 3 is a front view illustrating an embodiment of the mold (upper mold) of the present invention (a view showing the upper mold main surface of the mold).
  • a cross-shaped shielding plate is arranged at the center of the upper mold main surface.
  • FIG. 4 is a schematic view (cross-sectional view) showing that when a shielding plate is placed on a mold for forming microneedles, resin shrinkage during cooling and solidification is divided.
  • a thick arrow drawn inside the PGA resin plate (substrate made of PGA resin) indicates the direction of contraction.
  • FIG. 5 is a front view illustrating another aspect of the mold of the present invention. In the embodiment shown in the figure, a circular shielding plate is disposed in the central region of the upper mold main surface.
  • FIG. 6 is a front view illustrating another aspect of the mold of the present invention.
  • a shielding plate having a combination of a cross shape and a circular shape is disposed in the central region of the upper mold main surface.
  • FIG. 7A is a front view illustrating another embodiment of the mold of the present invention.
  • a circular shielding plate is disposed in the outer peripheral region of the upper mold main surface so as to surround all the through holes.
  • the through holes are cylindrical and are arranged in an 8 ⁇ 8 matrix.
  • FIG. 7B is a cross-sectional view taken along the line XX of FIG. 7A and shows only a cut surface.
  • FIG. 9 is a partially enlarged view of the cross section of the mold of the present invention, and is a view cut along a plane including the central axis of the through hole.
  • the through hole has a conical shape.
  • the space in the through hole is hatched.
  • FIG. 10 is an enlarged photograph showing the root portion of the needle-like protrusion of the microneedle obtained using the mold shown in FIG.
  • FIG. 11 is a perspective view illustrating a mold of the present invention and a microneedle manufactured thereby.
  • FIG. 12 is a perspective view illustrating a mold of the present invention and a microneedle manufactured thereby.
  • FIG. 13 is a photograph showing a pressing member for solving the problem of resin leaking to the back surface of the upper mold and its action.
  • FIG. 14 is a diagram illustrating another embodiment of the mold of the present invention.
  • FIG. 14A is a YY cross-sectional view of FIG. 14B, and shows only the cut surface and the shielding plate.
  • FIG. 15 is a photograph showing a puncture confirmation experiment.
  • FIG. 11 and FIG. 12 are perspective views showing an example of a mold of the present invention and a microneedle manufactured by the mold.
  • the mold is opened up and down, and a product of the microneedle is placed between them.
  • It is the figure which arranged and showed like an exploded assembly drawing.
  • the mold shown in the figure shows only main parts for easy understanding.
  • the actual mold is additionally provided with a portion for attaching to the press device or performing alignment.
  • the outer diameter of the microneedle is drawn in a disk shape similar to the upper mold, but the outer shape is arbitrary.
  • the number of needle-like projections of the microneedle is reduced.
  • the method for producing the microneedle according to the present invention include a general forging method in resin molding (a method in which the unevenness of the mold is pressed against the resin and transferred in a reverse manner), an injection molding method, or the like.
  • the main steps in the case of molding a microneedle by compressing a resin material using the mold illustrated in FIG. 11 are, for example, as described in (i) to (iv) below.
  • a plate-like material resin for example, biodegradable resin, particularly PGA
  • the upper die 3 is attached to the upper movable part (so-called ram) of the press device, and the upper die is heated to near the melting point of the resin.
  • the movable part of the pressing device is lowered, and the upper die 3 is pressure-bonded to the resin, and the resin is caused to flow, so that the resin is spread between the upper die main surface and the through hole.
  • the heating temperature of the upper mold is preferably near the melting point of the resin to be used, and a temperature of ⁇ 10 ° C. to + 30 ° C. of the melting temperature can be used. More preferably, the melting point temperature can be ⁇ 5 to +20 degrees.
  • the upper mold is cooled to near room temperature (glass transition point to room temperature).
  • the upper mold 3 is raised, the molded resin is removed, and the resinous microneedle 10 is obtained.
  • the microneedle obtained by the manufacturing method of the present invention has a groove 11 formed by transferring the upper shielding plate 1 to the main surface 4A of the substrate 4 as shown in FIGS.
  • the shielding plate 1 is provided on the outer periphery of the upper mold main surface, an annular groove corresponding to the outer surface of the main surface 4A of the microneedle substrate 4 is also formed. That part may be cut off in a later step so that it is not included in the process.
  • a lower mold 5 having a recess 5B is used, and the upper mold is recessed.
  • the inside of the mold can be hermetically sealed and molded.
  • a strip-shaped resin material unrolled from a long shape or a roll is transported and inserted into a press machine, and an upper die heated near the melting point is crimped on one side surface in the same manner as described above.
  • the manufacturing method may be such that, after cooling, the mold is removed after cooling, and then cut into a predetermined drug device size.
  • the material of the upper mold and the lower mold is not particularly limited as long as it is a metal suitable for the purpose, but preferable examples include steel, copper, brass, and the like. Can be mentioned. More preferably, a steel material such as stainless steel (especially 18% Cr, 8% Ni, high S-added austenitic stainless steel) is used in consideration of the durability of the mold, the ability to cut fine holes, and the safety to the living body. Can be mentioned.
  • the biodegradable resin for example, a polyester resin such as PLA or PGA, a polyamide resin, or a mixture or copolymer thereof can be used.
  • a resin mainly composed of PGA can be mentioned in terms of the strength of the acicular protrusion.
  • the resin mainly composed of PGA is a resin composed only of PGA or a resin to which an additive necessary for PGA is further added.
  • the temperature of the lower mold and the initial temperature of the material resin placed on the lower mold may be room temperature.
  • the temperature of the upper die attached to the upper press device needs to be set to be equal to or higher than the glass transition temperature of the resin used (PLA, PGA, etc.).
  • the temperature is set near the melting point.
  • PGA it can be 240 to 250 ° C.
  • the mold of the present invention has at least an upper mold 3 as illustrated in FIGS. 3 to 7, 11, and 12, and the upper mold is deformed by being pressed against a material resin. Thus, a substrate surface having needle-like protrusions is formed.
  • the upper mold 3 has an upper mold main surface 3A for forming a substrate surface 4A of the microneedle 10, and the upper mold main surface 3A has a shielding plate 1 having the following shape. It protrudes and a through hole 2 is provided.
  • the shielding plate 1 is a ridge-like protrusion that extends continuously on the upper mold main surface 3A. The shielding plate is formed so as to avoid the positions of the through holes, that is, to pass between the through holes.
  • a shielding plate may be formed first, and the position of the through hole may be determined so as to avoid the shielding plate.
  • the cross-sectional shape when the shielding plate 1 is cut perpendicularly to the longitudinal direction thereof (hereinafter simply referred to as “the cross-sectional shape of the shielding plate”) is obtained when the resin molded into microneedles is cooled.
  • Any needle member 4 may be used as long as it serves to prevent and prevent the needle substrate 4 from contracting in the lateral direction.
  • a preferable cross-sectional shape is a wedge shape (for example, about 1 to 10 degrees). And a square, a rectangle, or a trapezoid. In FIG. 7, a rectangular cross-sectional shape is shown.
  • the shape of the shielding plate 1 on the upper mold main surface (that is, the pattern drawn by the ridge line of the shielding plate on the upper mold main surface) is obtained by dividing the main surface 4A of the substrate 4 of the microneedle 10 in the lateral direction ( Any shape that can disperse the shrinkage of the resin in the direction along the upper mold main surface is acceptable. Although it is considered that the maximum shrinkage and dispersion effect can be obtained by placing a shielding plate around each through-hole (corresponding to the needle-like protrusion), the specifications of the microneedle are taken into consideration from the viewpoint of the difficulty in machining the mold and the cost. What is necessary is just to arrange
  • a shield plate having a cross shape, a circular shape, or a shape obtained by superimposing them may be installed at the center of the microneedle substrate.
  • the width of the shielding plate 1 that is, the maximum dimension in the direction along the upper mold main surface in the sectional shape of the shielding plate
  • the height of the protrusion can be appropriately changed according to the purpose.
  • the width is preferably equal to or less than the distance between adjacent through holes, particularly in a range that does not affect the through holes. What is necessary is just to determine the minimum of the width
  • a cylindrical or conical through hole may be installed avoiding the shielding plate.
  • a shielding plate is further installed on the outer periphery of the mold main surface (position corresponding to the outer periphery of the microneedle substrate) so as to surround the entire needle-like protrusion. May be.
  • the height of the protrusion from the upper mold main surface is important for the shielding plate.
  • the height of the projection of the shielding plate is deeper than the portion where a resin material such as PGA melts in contact with the upper mold during molding.
  • the depth at which the resin material melts can be determined by, for example, observing a cross section after processing and changing the state of the resin material.
  • the depth of the melted portion of the resin material varies depending on the conditions and the shape of the product. For example, in the case of PGA, the depth of about 0.05 mm to 0.1 mm from the surface of the microneedle substrate is melted. Examples are listed.
  • the height of the projection of the shielding plate is preferably in the range of 0.3 mm to 0.4 mm or more.
  • the upper limit of the height of the projection of the shielding plate may be determined so that the microneedle is not divided into a plurality of pieces, and it is preferable to appropriately determine a value smaller than the thickness of the substrate throughout.
  • the projection of the shielding plate may locally have a portion penetrating the microneedle substrate.
  • the substrate of the microneedle is usually a flat plate having a thickness of about 0.5 mm to 5 mm.
  • the upper limit of the height of the projection of the shielding plate is not particularly limited, but may be about 0.3 mm to 1 mm.
  • the width of the shielding plate and the height of the protrusion need not be constant throughout.
  • the circular shielding plate on the outer periphery is higher and wider than the central cross shielding plate.
  • the overall shape of the through hole is not limited, a cylindrical shape, a conical shape, and a truncated cone shape are preferable shapes. Further, as in the cross-sectional shape of the through-hole appearing in FIG. 7B or the cross-sectional shape of the through-hole in FIG. An inclination (tapered chamfer) is provided at an angle and a depth, and a cylindrical through hole or a conical through hole is formed at the tip.
  • the formed needle-like protrusions have a shape in which cylindrical needle-like protrusions are stacked on a truncated cone as shown in FIG. 8 (a shape in which the base of the cylinder is widened), or a shape shown in FIG.
  • the shape of the conical needle-like protrusions is stacked on the truncated cone (the shape of the base of the cone is wider than the upper part), and the needle-like protrusions may break due to buckling or the like when puncturing the skin. It is hard to occur.
  • the tip diameter of the needle-like protrusion is important, and as the tip diameter becomes smaller, the surface of the skin can be penetrated with a smaller force.
  • the entire needle-like projection is made thin, the strength is reduced, and the needle-like projection may be damaged because it cannot withstand the force applied during puncture. Therefore, a conical needle-like projection having a thickened vicinity near the base of the needle-like projection, having sufficient strength, becoming thinner toward the tip, and having a sharp tip is a preferred embodiment.
  • the inner shape of the upper through hole may be conical.
  • the internal shape of the through hole conical By making the internal shape of the through hole conical, it can be expected that the resistance to punching at the time of mold release is reduced and the loss of needle-like protrusions is reduced.
  • a processing method for making the inner shape of the upper mold through hole conical for example, metal is deposited by plating (such as hard chrome plating) so that the inside of the hole is conical with respect to the cylindrical through hole. And a method of forming a conical through hole by machining.
  • the distance between the through holes (that is, the distance between the central axes of the adjacent through holes) is preferably 400 ⁇ m to 1 mm in consideration of puncture properties with respect to the skin. If it is 400 micrometers or less, the resistance with respect to the needle
  • the number of through holes can be appropriately selected according to the purpose. For example, 50 to 500 can be mentioned.
  • the diameter of the through-hole especially the diameter of the thickest part, varies depending on the shape of the necessary needle-like protrusions in consideration of puncture properties, but the diameter of the opening of the through-hole in the upper mold main surface of the mold is In addition, a range of about 200 ⁇ m to 500 ⁇ m including the diameter of the countersinks is preferable. More preferably, the range is about 200 to 350 ⁇ m.
  • a streak-like protruding portion may be provided in the cylindrical or conical through-hole from the mold surface to the tip portion.
  • the cross-sectional shape of the streak-like protrusion (the shape of the cross section when the protrusion is cut perpendicular to the longitudinal direction) is preferably a wedge shape or a quadrangle.
  • the pressure-bonding of the mold to the resin refers to pressing the upper mold main surface against the resin so that the resin fills the through-holes, depending on the softened state of the resin.
  • the PGA sheet is softened at the temperature of the mold (upper mold), and the mold is pressure-bonded to the material resin within a pressure range of 2 to 5 kg / cm 2 .
  • the pressure bonding may be performed under normal pressure (atmospheric pressure), but if the pressure bonding is performed under reduced pressure, the filling of the resin into the through hole can be accelerated.
  • it can be performed under a negative pressure in the vicinity of 10 Pa. Thereby, it can avoid that a bubble and a void
  • the surface of the mold may be coated with a coating for facilitating release of the resin, such as metal plating or Teflon coating.
  • the metal plating may be a general one applied to the inner surface of the resin mold, and examples thereof include hard chrome plating.
  • To release the resin from the mold means to separate the molded product of the microneedle from the mold.
  • the resin temperature at the time of mold release it is desirable to separate the resin needle-like protrusions at a temperature in the vicinity of the transition point that exceeds the transition point. In order to prevent deformation, it is desirable to be below the transition point.
  • the resin may leak from the tip of the through-hole to the back side of the upper mold and solidify. It is preferable to cleanly remove the resin portion that has leaked and solidified so as not to affect the mold release. Also, leakage can be suppressed by reducing the through hole outlet on the opposite side of the crimping surface.
  • FIG. 13A is a photograph showing the resin leaking out to the back surface of the upper mold. According to the study by the present inventors, when the product is released without removing the resin material that has been leaked and solidified (so-called molding burr), there is a problem that the tip portion or the whole of the needle-like protrusion is lost. all right.
  • a pressing member made of an elastic material in particular, a resin material as shown in FIG. 13B is arranged between the back surface of the upper mold and the upper movable part of the pressing device. Then, it is proposed to block the opening of the through hole and suppress the leakage of the resin material.
  • the arrangement of the pressing member as described above does not completely seal the opening at the upper end of the through hole, but properly closes it as if a relief valve was attached, and loses the function of the through hole. In addition, leakage of a large amount of resin is suppressed, and the needle-like protrusions can be smoothly removed from the through holes.
  • the region where the pressing member is to be arranged is relatively recessed, and the pressing member is disposed inside the depression. It is preferable that the pressing force from the ram of the pressing device does not act only on the pressing member.
  • the material of the pressing member is not particularly limited, but (i) is a material that does not melt even when heated during molding, and (ii) is a material with good releasability because the lower surface of the pressing member is in contact with the molding resin. (Iii) It is preferable that the elastic material has such a degree that a minute gap that allows only air in the hole to escape when pressure is applied from the inside of the through hole during molding. Examples of such a material include a fluororesin (in particular, polytetrafluoroethylene marketed as Teflon (registered trademark)). Moreover, the composite member which arrange
  • FIG. 13D is a photographic diagram showing the appearance of the upper mold back surface when a pressing member made of fluororesin is disposed on the back surface of the upper mold and pressure molding is performed. Compared with the state of FIG. 13A in which molding was performed without installing anything on the back side of the upper mold, in FIG.
  • the preferable aspect of the manufacturing method of this invention is as follows.
  • a method for producing a biodegradable resin microneedle Using a metal mold having a shielding plate having the following characteristics (a) to (c) and the following through holes (d) to (g): Heating the mold and pressing the resin to form a microneedle; After molding, cooling the resin and releasing the molded microneedles,
  • the shape of the shielding plate when viewed from the upper mold main surface is a cross shape, a circular shape, or a shape obtained by superimposing these, and is installed at a position corresponding to the central portion of the microneedle substrate. ing.
  • the shielding board may be installed in the position corresponding to the outer peripheral part of the board
  • a cylindrical or conical through hole is provided to avoid the shielding plate.
  • the opening portion of the through hole in the upper mold main surface is inclined (tapered chamfer), and as a result, the needle-like protrusions formed are cylindrical or conical needles on the truncated cone. It becomes the shape where the protrusions are stacked.
  • the interval between the through holes is 400 ⁇ m to 1 mm.
  • the number of through holes is 50 to 500.
  • a method for producing a microneedle comprising the following steps, Storing the biodegradable resin in the recess of the metal base (lower mold); Using a metal mold (upper mold) having the shielding plate having the characteristics (a) to (c) and the through holes (d) to (g) and engaging with the recesses, Heating the mold to the melting point of the resin, pressing the resin to form a microneedle, Cooling the resin and releasing the molded and solidified resin, A method for producing a microneedle, comprising:
  • die of this invention for manufacturing a microneedle is as follows.
  • a microneedle was manufactured using a hermetic press method.
  • the hermetic press method is a method in which a concave part is provided in the lower mold to surround the periphery so that the material resin does not escape from the periphery of the mold and is pressed while the material resin is confined between the upper mold and the lower mold. is there.
  • the inside and outside of the mold communicate with each other through the upper mold through hole.
  • a flat plate mold having a thickness of 1 mm was used as the upper mold, and cylindrical through holes having a diameter of about 100 ⁇ m were formed on the upper mold main surface so as to be arranged in a matrix of 8 rows and 8 columns. The distance between the central axes between the through holes was about 800 ⁇ m in both length and width.
  • This metal mold is not provided with a shielding plate.
  • the lower mold is a metal flat plate having a recess into which the upper mold can be fitted, and the lower mold is disposed on the base of the press apparatus. The temperature of the lower mold was set to room temperature (26 ° C.).
  • a PGA plate having a thickness of 1.5 mm was used and placed in the recess of the lower mold.
  • the upper mold was attached to a ram, which is the upper movable part of the press device, and the temperature of the upper mold was set to about 245 ° C.
  • the ram of the press device was lowered, and the upper mold main surface was pressure-bonded to the PGA plate. Pressurization was performed until the height of the upper mold main surface was further lowered by about 0.3 mm from the original upper surface height of the PGA plate at a pressure drop rate of 50 ⁇ m / s.
  • the PGA microneedle was released from the upper mold.
  • the obtained microneedles were almost uniform in the diameter and height of the needle-like protrusions, but as shown in FIG. 2, the needle-like protrusions formed in the end region of the outer peripheral portion were near the root. It was bent.
  • Example 1 Manufacture of microneedles using an upper mold provided with a cylindrical through hole and a shielding plate
  • PGA microneedles were manufactured by the hermetic press method under the same conditions as in Reference Example 1 above, and the bending of the needle root portion was suppressed. Checked whether it is valid.
  • the upper die is a flat plate die having a thickness of 1 mm, as in Reference Example 1, and columnar through holes having a diameter of about 100 ⁇ m are arranged in a matrix of 8 rows and 8 columns on the main surface of the upper die. Formed as follows. The distance between the central axes between the through holes was about 800 ⁇ m in both length and width.
  • the height of the projection of the shielding plate was set to 0.4 mm so that the shielding plate could be sufficiently deeper than the depth at which the resin material (PGA) melts.
  • the upper mold has a circular ridge line projection as a shielding plate on the outer periphery of the upper mold main surface so as to surround all the through holes with a single circle for the purpose of suppressing shrinkage during cooling of the PGA.
  • the lower mold, the resin material, and the molding conditions are the same as in Reference Example 1.
  • the produced microneedle had almost no curvature at the base of the needle-like protrusion at the outer peripheral end. From the above points, it was found that by providing a shielding plate so as to surround the outer periphery, it is possible to block the stress generated when the resin material is contracted, and it is effective in suppressing the bending of the needle-like protrusion.
  • Example 2 Manufacture of microneedles using an upper die provided with a conical through hole and a shielding plate
  • a PGA microneedle is manufactured by a hermetic press method under the same conditions as in Example 1 except that an upper die having a conical through hole is used. did.
  • the thickness of the upper mold and the arrangement of the through holes are the same as in Example 1.
  • a dish-shaped spot facing was applied to the opening to widen the conical base further thickly.
  • the produced microneedle did not have the base of the needle-like protrusion at the outer peripheral end curved, and the tip of the needle-like protrusion was sharp.
  • Example 3 In this embodiment, as shown in FIG. 14B, a circular shielding plate 1a surrounding all the through holes is provided on the outer peripheral portion of the upper mold main surface 3A, and a cross-shaped shielding plate 1b is provided in the center. It was. Further, the arrangement of the through holes in the upper mold main surface was concentric. The tip diameter of the needle-like protrusion was about 0.03 mm, and the needle height was about 0.6 mm. Under the same molding conditions as in Example 1, PGA microneedles were produced by a hermetic press method. The produced microneedle was found to have a more suppressed bending of the needle-like projections and the needle-like projections having a substantially uniform shape as compared with those obtained in Example 1. . Further, since the needle-like projections were not bent at the central portion of the main surface of the manufactured microneedle, it was found that the influence on the needle-like projections at the central portion by the shielding plate was small.
  • Example 4 In this example, a microneedle was produced under the same conditions as in Example 1 above using an upper mold provided with a cross-shaped shielding plate shown in FIG. 3 and a conical through hole shown in FIG. The puncture property and strength of the conical needle-like projection were confirmed.
  • a skin model that approximates the surface characteristics of the human forearm skin to confirm the puncture properties and strength of the needle-like projections (the resistance is almost the same as the load-stroke relationship when the human forearm is pushed with a round bar. Model) was constructed, and a puncture confirmation experiment was conducted.
  • the procedure of the puncture confirmation experiment is as follows. As shown in FIG. 15A, the microneedle used in the experiment has a cross-shaped groove formed on the main surface at the center due to the cross-shaped shielding plate. None of the needle-like protrusions before puncturing was deformed by molding. First, the microneedle is attached to the tip of a rheometer (SHIMADZU EZTest) that can be controlled to move up and down. Then, the microneedle is pressed against the skin model until the tip of the needle-like protrusion is further lowered by 12 mm from the height at which the tip of the needle-like protrusion contacts the skin model.
  • SHIMADZU EZTest SHIMADZU EZTest
  • the microneedle is removed from the skin model, and a chemical capable of being dyed only at the portion where the needle-like protrusion is stuck is applied to the skin model and dyed for about 1 minute. If it is difficult to determine whether or not the needle-like protrusions have been punctured, it is difficult to do just by staining after puncturing.
  • the needle may be confirmed. When the surface of the skin model after the puncture experiment was confirmed, it was confirmed that about 80% of the needle-like projections of the microneedle were punctured. Further, when the needle-like projections of the microneedle after the puncture experiment were confirmed, it was found that all the needle-like projections remained without bending at the roots, although there were needle-like projections with only the tip bent. . As a result, it was confirmed that the microneedle obtained by the present invention has a needle-like projection having sufficient puncture properties with respect to the skin and no problem in strength.
  • the needle root is formed at the needle-like protrusion at the end of the outer peripheral portion of the microneedle. It became possible to manufacture high-quality microneedles in which no curvature was observed at the part. This makes it possible to use PGA resin which has excellent puncture ability to the skin as a microneedle, but has high thermal expansibility, and the needle-like projections in the peripheral portion are easy to bend at the root. It became possible to provide made microneedles.
  • PGA resin which has excellent puncture ability to the skin as a microneedle, but has high thermal expansibility, and the needle-like projections in the peripheral portion are easy to bend at the root.
  • This application is based on Japanese Patent Application No. 2009-073664 filed in Japan, the contents of which are incorporated in full herein.
  • Shielding plate 2 Through hole provided in main surface of mold (upper mold) 3: Mold (upper mold) 4: PGA resin plate (microneedle substrate)

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Abstract

L'invention porte sur un procédé de fabrication bien connue de micro-aiguilles par ramollissement ou fusion par chauffage d'une résine biodégradable, et pression de ladite résine avec un moule (matrice). Avec ce procédé, une rupture de la protubérance en forme d'aiguille est fréquente, le rendement pour un produit de qualité est faible et on observe une tendance à la courbure au niveau des bases d'aiguille autour de la périphérie et de régions d'extrémité. On observe une tendance à la courbure en ce qui concerne l'acide polyglycolique, qui a une vitesse de contraction particulièrement élevée. Ainsi, l'invention porte sur un procédé de fabrication de micro-aiguilles surmontant les inconvénients mentionnés ci-dessus. Afin de bloquer la génération d'une contrainte lors de la contraction par refroidissement d'une résine, on installe une gaine pour la contrainte mentionnée ci-dessus dans un moule métallique (matrice), et on fabrique des micro-aiguilles par un procédé de pression. Il en résulte que la courbure de protubérance en forme d'aiguille autour de la périphérie du réseau d'aiguilles est supprimée, et en particulier, même lorsqu'on utilise une résine d'acide polyglycolique avec une contraction par chaleur importante, on peut fabriquer des micro-aiguilles avec une excellente qualité telles que celles représentées sur la figure 8.
PCT/JP2010/055291 2009-03-25 2010-03-25 Micro-aiguilles, et leur procédé de fabrication et leur moule Ceased WO2010110397A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020250210A1 (fr) 2019-06-10 2020-12-17 University College Cork - National University Of Ireland, Cork Microaiguilles et leurs procédés de fabrication
CN112370649A (zh) * 2020-11-06 2021-02-19 华东师范大学 一种个性化定制的微针美容面罩及制备方法
CN113171551A (zh) * 2015-03-23 2021-07-27 考司美德制药株式会社 一种微针及其制造方法
CN114228054A (zh) * 2021-12-14 2022-03-25 优微（珠海）生物科技有限公司 一种微针模具及微针贴的制备方法

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013001114A (ja) * 2011-06-21 2013-01-07 Toyomasa Shinohara 部分ポッティングの製造法
JP2013028150A (ja) * 2011-06-22 2013-02-07 Teijin Chem Ltd 成形品の成形方法
JP5781035B2 (ja) * 2012-08-10 2015-09-16 株式会社東海理化電機製作所 ウェビング巻取装置
JP6232978B2 (ja) * 2013-11-29 2017-11-22 凸版印刷株式会社 針状体の製造方法及び製造装置
JP5931130B2 (ja) * 2014-06-20 2016-06-08 三島光産株式会社 マイクロニードルアレイの製造方法及びこれに用いる射出成形用金型
JP6476799B2 (ja) * 2014-12-02 2019-03-06 凸版印刷株式会社 針状体の製造方法
DE102020104306A1 (de) * 2020-02-19 2021-08-19 Lts Lohmann Therapie-Systeme Ag Formelement zur Herstellung von Mikrostrukturen

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003093521A (ja) * 2001-09-26 2003-04-02 Terumo Corp 薬剤投与具及び薬剤投与装置
JP2005501615A (ja) * 2001-09-05 2005-01-20 スリーエム イノベイティブ プロパティズ カンパニー マイクロニードルアレイおよびその製造方法
WO2005075016A1 (fr) * 2004-02-03 2005-08-18 Hisamitsu Pharmaceutical Co., Inc. Interface pour applicateur medical transdermique
JP2009045128A (ja) * 2007-08-15 2009-03-05 Toppan Printing Co Ltd 針状体、針状体の製造方法、針状体製造装置
JP2009509692A (ja) * 2005-09-30 2009-03-12 Ｔｔｉ・エルビュー株式会社 オピオイドアゴニスト及び／又はオピオイドアンタゴニストを用いる経皮薬剤送達システム、装置及び方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3814591B2 (ja) * 2002-07-29 2006-08-30 キヤノン株式会社 光学素子及び光学素子成形品およびその成形用金型及び射出成形方法
JP2009220350A (ja) * 2008-03-14 2009-10-01 Toppan Printing Co Ltd 針状体金型
JP2010030201A (ja) * 2008-07-30 2010-02-12 Toppan Printing Co Ltd 針状体製造方法、針状体および針状体複製版
EP2314436B1 (fr) * 2008-08-20 2015-04-01 Konica Minolta Opto, Inc. Procédé de fabrication d'une puce à micro-canal, matrice pour mouler une puce à micro-canal et puce à micro-canal
JP5183375B2 (ja) * 2008-09-04 2013-04-17 凸版印刷株式会社 針状体製造方法、針状体製造装置および針状体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005501615A (ja) * 2001-09-05 2005-01-20 スリーエム イノベイティブ プロパティズ カンパニー マイクロニードルアレイおよびその製造方法
JP2003093521A (ja) * 2001-09-26 2003-04-02 Terumo Corp 薬剤投与具及び薬剤投与装置
WO2005075016A1 (fr) * 2004-02-03 2005-08-18 Hisamitsu Pharmaceutical Co., Inc. Interface pour applicateur medical transdermique
JP2009509692A (ja) * 2005-09-30 2009-03-12 Ｔｔｉ・エルビュー株式会社 オピオイドアゴニスト及び／又はオピオイドアンタゴニストを用いる経皮薬剤送達システム、装置及び方法
JP2009045128A (ja) * 2007-08-15 2009-03-05 Toppan Printing Co Ltd 針状体、針状体の製造方法、針状体製造装置

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113171551A (zh) * 2015-03-23 2021-07-27 考司美德制药株式会社 一种微针及其制造方法
WO2020250210A1 (fr) 2019-06-10 2020-12-17 University College Cork - National University Of Ireland, Cork Microaiguilles et leurs procédés de fabrication
CN112370649A (zh) * 2020-11-06 2021-02-19 华东师范大学 一种个性化定制的微针美容面罩及制备方法
CN114228054A (zh) * 2021-12-14 2022-03-25 优微（珠海）生物科技有限公司 一种微针模具及微针贴的制备方法

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