WO2010137319A1 - Procédé de production de micro-aiguilles de type trou d'épingle, et micro-aiguille - Google Patents

Procédé de production de micro-aiguilles de type trou d'épingle, et micro-aiguille Download PDF

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Publication number
WO2010137319A1
WO2010137319A1 PCT/JP2010/003544 JP2010003544W WO2010137319A1 WO 2010137319 A1 WO2010137319 A1 WO 2010137319A1 JP 2010003544 W JP2010003544 W JP 2010003544W WO 2010137319 A1 WO2010137319 A1 WO 2010137319A1
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Prior art keywords
resin
microneedle
substrate
shape
molten resin
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PCT/JP2010/003544
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English (en)
Japanese (ja)
Inventor
三原豊
大平文和
吉村英徳
大須賀健士
Original Assignee
株式会社メドレックス
国立大学法人 香川大学
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Publication of WO2010137319A1 publication Critical patent/WO2010137319A1/fr

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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
    • B29C67/00—Shaping techniques not covered by groups B29C39/00 - B29C65/00, B29C70/00 or B29C73/00
    • 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
    • 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
    • B29C55/00—Shaping by stretching, e.g. drawing through a die; Apparatus therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C1/00—Manufacture or treatment of devices or systems in or on a substrate
    • B81C1/00015—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems
    • B81C1/00023—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems without movable or flexible elements
    • B81C1/00111—Tips, pillars, i.e. raised structures
    • 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
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2067/00—Use of polyesters or derivatives thereof, as moulding material
    • B29K2067/04—Polyesters derived from hydroxycarboxylic acids
    • B29K2067/043—PGA, i.e. polyglycolic acid or polyglycolide
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2067/00—Use of polyesters or derivatives thereof, as moulding material
    • B29K2067/04—Polyesters derived from hydroxycarboxylic acids
    • B29K2067/046—PLA, i.e. polylactic acid or polylactide
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2995/00—Properties of moulding materials, reinforcements, fillers, preformed parts or moulds
    • B29K2995/0037—Other properties
    • B29K2995/0059—Degradable
    • B29K2995/006—Bio-degradable, e.g. bioabsorbable, bioresorbable or bioerodible
    • 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
    • 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
    • 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
    • B29L2031/759—Needles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81B—MICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
    • B81B2201/00—Specific applications of microelectromechanical systems
    • B81B2201/05—Microfluidics
    • B81B2201/055—Microneedles

Definitions

  • the present invention is a method of manufacturing a microneedle using a dispenser and fine multiple nozzles.
  • the present invention relates to a method for manufacturing resin microneedles and resin microneedles.
  • transdermal drug delivery is an important route for drug activity
  • human skin is composed of a stratum corneum approximately 20-80 ⁇ m thick, an epidermis approximately 300-400 ⁇ m, and a dermis approximately 500 ⁇ m from the surface.
  • stratum corneum is an effective barrier against many chemical substances, and therefore the number of pharmaceutically active substances that can penetrate the skin through the skin is very limited.
  • the ease of penetration of the stratum corneum is believed to depend on factors such as the polarity of the compound, log P, and molecular size.
  • many drugs have been synthesized, but many are not suitable for oral administration (for example, due to instability in the liver metabolism of the gastrointestinal tract or the first route). Therefore, the transdermal route of administration is still uncertain but remains an attractive route for drug administration.
  • Patent Document 1 discloses the production of microneedles using a UV curable acrylate adhesive as a new attempt.
  • a solution is attached to the head of a pin, and UV irradiation is performed by bringing the solution into contact with a flat plate.
  • the solution starts to solidify, the flat plate is pulled away to form a sharp needle-like structure. It is.
  • An object of the present invention is to provide a production method capable of industrially mass-producing resin microneedles and a strong microneedle obtained by the method. More specifically, the present invention provides a method for producing microneedles using a biodegradable material as a resin.
  • the present inventors have intensively studied to achieve the above-mentioned problems, and as shown in FIGS. 1 to 3, have found a new method for producing microneedles using a dispenser and fine multiple nozzles. It was.
  • the method shown in FIG. 2 was found as a method for producing a microneedle having a particularly high microneedle height. That is, molten resin (for example, biodegradable material such as polyglycolic acid resin or polylactic acid resin) is discharged from a fine multiple nozzle using a dispenser, and at the same time, the multiple nozzle is brought close to the resinous substrate. Then, the molten resin is firmly fixed to the resin substrate. Next, the nozzle is separated from the substrate, and the molten resin is discharged.
  • molten resin for example, biodegradable material such as polyglycolic acid resin or polylactic acid resin
  • the nozzle and the substrate are further separated to produce a microneedle integrated with resin.
  • the molten resin and the resin substrate are integrated, and a microneedle having a large needle height and high strength can be obtained.
  • the needle height and thickness can be changed by appropriately selecting the conditions such as the temperature of the multiple nozzles, the temperature of the resin substrate, and the separation speed and distance between the nozzle and the resin substrate. It was found that the desired resin microneedles can be easily produced, and the present invention has been completed.
  • the present invention has been completed by further research based on the above findings, and the gist thereof is as follows.
  • a method of manufacturing a resin microneedle using a liquid discharge device and a multiple nozzle having a fine inner diameter Melting the resin, discharging it from the multiple nozzles using a liquid discharge device, and bonding the molten resin to the substrate, Stretch the bonded molten resin to form microneedles, A method for producing a resin-made microneedle.
  • a method of manufacturing a resin microneedle using a liquid discharge device and a multiple nozzle having a fine inner diameter Melting the resin, discharging it from the multiple nozzles using a liquid discharge device, and bonding the molten resin to the substrate, While separating the multiple nozzle and the substrate, the molten resin is discharged from the multiple nozzle one or more times. Filling between the multiple nozzles and the substrate with multiple times of discharged molten resin, Separate the multiple nozzles from the substrate and extend the molten resin to form microneedles.
  • a manufacturing method comprising: a) After the fine needles are formed and the molten resin is cured, the molten resin is again discharged from the multiple nozzles. Separate the multiple nozzles from the substrate and extend the discharged molten resin to form microneedles, or b) A microneedle is formed, and after curing of the molten resin, a multiple nozzle heated to a high temperature is brought into contact with the microneedle. Melt the tip of the microneedle, Separate the multiple nozzles and the substrate, and re-melt the melted resin to form microneedles.
  • a method for producing a microneedle which is characterized in that
  • a resin microneedle, Resin microneedles have a single-stage or multi-stage resin shape, On the substrate, the microneedle is installed in close contact, The resin shape as a whole is a microneedle formed by being stretched, A microneedle made of resin.
  • a resin microneedle, A resin microneedle has a two-stage resin shape, The resin shape of the bottom of the microneedle is a truncated cone, The resin shape at the top of the microneedle is an arc conical shape with a steep side surface.
  • a microneedle made of resin A resin microneedle has a three-stage resin shape, The resin shape of the bottom of the microneedle is a truncated cone, The resin shape at the center of the microneedle is an arc conical shape with a steep side surface. The resin shape of the tip portion of the microneedle is a sharp needle shape, The resin-made microneedle according to (9) above, wherein (12) The resin-made microneedle according to any one of (9) to (11) above, wherein the resin is any one of PLA, PGA, and PLGA.
  • a resin microneedle, A resin microneedle has a two-stage resin shape, The resin shape of the bottom of the microneedle is a truncated cone, The resin shape at the top of the microneedle is an arc conical shape with a steep side surface.
  • a resin microneedle, A resin microneedle has a three-stage resin shape, The resin shape of the bottom of the microneedle is a truncated cone, The resin shape at the center of the microneedle is an arc conical shape with a steep side surface.
  • the resin shape of the tip portion of the microneedle is a sharp needle shape, A resin-made microneedle characterized by the above.
  • microneedles having a length exceeding 500 ⁇ m which has been considered difficult to manufacture, can be manufactured with high standard quality, and the length and thickness of the microneedles are controlled as necessary. I was able to do it.
  • a biodegradable resin for example, PGA resin
  • PGA resin was used as the resin, and as shown in FIG. 5 and FIG. 9, a strong and sharp microneedle could be produced.
  • This PGA microneedle is a good quality microneedle that is easy to puncture the skin and does not cause breakage of the needle tip of the microneedle.
  • microneedles having uniform standards and easy to puncture can be supplied at an industrial level.
  • FIG. 4 is a perspective view (photograph) of a PGA microneedle obtained in Example 3.
  • FIG. It is the microneedle part enlarged photograph (left figure) of the microneedle of FIG. 5, and the schematic diagram (right figure) of a microneedle.
  • It is a perspective view (photograph) of the microneedle made from PGA with a candle-shaped microneedle. It is the figure (photograph which showed the mode of the skin surface) showing the puncture result to the skin of the hairless rat using the microneedle made from PGA.
  • a 1st aspect of this invention is related with the manufacturing method of a microneedle.
  • the outline is shown in FIG. 1 and FIG. 1 and 2 typically illustrate one nozzle (1) of the multiple nozzles.
  • a resin for example, a biodegradable resin such as PGA
  • the molten resin is discharged from the nozzle (1).
  • a substrate (2) of a resin for example, a biodegradable resin such as PGA
  • a minute distance moving device such as a Z lift stage
  • the molten resin is brought into intimate contact with the substrate by the nozzle (1) and the substrate, and the molten resin discharged in a small amount is intimately fixed to the substrate (2).
  • the distance between the tip of the nozzle (1) and the substrate (2) is related to the discharge amount of the molten resin, and thus greatly affects the formation of microneedles (needle height and root diameter). Accordingly, it has been found that this interval is preferably 50 ⁇ m or more, and more preferably, a high needle having a microneedle height of about 500 ⁇ m or more can be obtained if the distance is about 200 ⁇ m or more.
  • the diameter of the root of the microneedle is about 200 ⁇ m wide, and it was found that a thin microneedle can be obtained.
  • the substrate (2) is lowered, and the molten resin between the nozzles (1) is extended and cooled.
  • the lowering speed of the substrate is slow (for example, 100 ⁇ m / sec)
  • the height of the formed microneedle is low and tends to form a thick needle
  • the lowering speed of the substrate is high (for example, 500 ⁇ m / sec)
  • the height of the microneedles was high and there was a tendency to make fine needles.
  • the molten resin is stretched into a thread shape, and the resin formed into a thread shape is cut and solidified by the surface tension of the resin to form microneedles.
  • the moving distance to which the substrate is separated is small (for example, 600 ⁇ m)
  • the height of the micro needle is low (about 350 ⁇ m), and a thick needle tends to be easily formed.
  • the moving distance is large (for example, 1000 ⁇ m)
  • the height of the micro needle is high (about 500 ⁇ m), and a thin needle tends to be easily formed.
  • the substrate (2) or the nozzle (1) may move.
  • the relative distance may be changed as described above.
  • a long microneedle (about 500 ⁇ m) can be obtained.
  • the substrate (2) is lowered as in the case of FIG. 1, and the molten resin between the nozzles (1) is extended and cooled.
  • the molten resin discharged in a small amount in the second stage and adhered to the substrate and the molten resin discharged thereon in the third stage are extended together.
  • the molten resin discharged first becomes a substantially frustoconical base, and the molten resin discharged for the second time is extended into a thread shape, and the thinned portion is the surface tension of the molten resin.
  • the microneedle as shown in FIG. 5 can be produced by separating the nozzle (1) and the resin substrate (2) by about 200 ⁇ m and adjusting the discharge amount of the molten resin, the moving speed of the resin substrate, and the like.
  • An enlarged photograph of the state of the microneedles is the left view of FIG. 6, and a right side view of FIG. 6 shows it as a side view.
  • the “liquid ejecting apparatus (dispenser)” of the present invention is a precision liquid ejecting apparatus that ejects a small amount of fluid, and is an apparatus that is generally used for dot printers such as printing.
  • the dispenser device is not particularly limited as long as it is a high temperature specification dispenser device. For example, it is possible to use a dispenser device manufactured by Musashi Engineering.
  • the “multiple nozzle” of the present invention is one in which minute nozzles are arranged in an array at intervals of about 300 ⁇ m to 1 mm corresponding to the positions of the microneedles of the microneedles to be produced.
  • minute nozzles are arranged in an array at intervals of about 300 ⁇ m to 1 mm corresponding to the positions of the microneedles of the microneedles to be produced.
  • needles having an outer diameter of 350 to 830 ⁇ m and an inner diameter of about 150 to 390 ⁇ m can be used, and the number of needles can be set to 50 to 500 as necessary.
  • the “resin” in the present invention means a general-purpose petrochemical resin or biodegradable resin.
  • petrochemical resins include synthetic resins such as polyethylene resins, polypropylene resins, polystyrene resins, polymethacrylic acid resins, polyacrylic acid resins, and polyvinyl chloride resins.
  • the biodegradable resin is a resinous polymer compound that is degradable in vivo.
  • polylactic acid (PLA), polyglycolic acid (PGA), lactic acid / glycolic acid copolymer (PLGA) And the like, and polysaccharides such as maltose, lactose, sucrose, mannitol and sorbitol.
  • polyglycolic acid polylactic acid, and lactic acid / glycolic acid copolymer are preferable, and polylactic acid and polyglycolic acid are particularly preferable.
  • maltose is suitable as the polysaccharide.
  • polylactic acid (PLA) is a polymer containing L-lactic acid and / or D-lactic acid as a main monomer component.
  • Polylactic acid has desired physical properties, for example, by mixing with lactic acid esters such as methyl lactate, butyl lactate, and hexadecyl lactate, or by mixing with additives such as plasticizers and antioxidants that can be used as transdermal preparations. You can get things.
  • the “polyglycolic acid (PGA)” of the present invention is a polymer having glycolic acid as a main monomer component.
  • the polymer contains 70% by mass or more, more preferably 90% by mass or more of repeating units (OCH 2 CO), and has a weight average molecular weight of 20,000 to 1,000,000.
  • Preferred molecular weights are 50,000 to 800,000, more preferably 70,000 to 500,000.
  • PGA has a melting point in the range of 180 ° C. to 230 ° C., preferably a polymer in the range of 200 ° C. to 230 ° C., more preferably a polymer having a melting point of 210 to 230 ° C. .
  • the temperature of the molten resin discharged from the liquid discharge device is set to a temperature that is 10 to 20 ° C. higher than the melting point of the resin to be used.
  • a temperature 10 to 20 ° C. higher than the melting point of the resin to be used.
  • the discharge amount of the molten resin discharged from the liquid discharge device is set by the discharge pressure (MPa) and discharge time (sec) to the molten resin. Therefore, when the discharge pressure is constant, the discharge amount of the molten resin can be adjusted with the length of the discharge time.
  • the “substrate” in the present invention refers to a flat plate having a horizontal uniform plane made of metal, Si, glass or resin.
  • the metal substrate include a flat plate made of stainless steel, copper, nickel, or brass.
  • the Si substrate include a flat plate such as a silicon wafer.
  • a general-purpose glass flat plate can be used, and examples thereof include a glass flat plate such as a micro cover glass.
  • the resin substrate refers to the above-described synthetic resin or biodegradable resin flat plate.
  • the temperature of the substrate is appropriately selected to be heated or cooled so that when the molten resin is in close contact and the substrate is separated, the molten resin is stretched and cooled to form appropriate microneedles. Is done.
  • the temperature difference from the substrate is large, so the molten resin quickly cools and solidifies and does not adhere to the substrate. Therefore, the temperature of the substrate must be high to some extent. Further, when the temperature of the substrate is too high, the molten resin is not cooled and solidified, and the microneedles cannot be shaped.
  • These temperature ranges can be appropriately selected depending on the type of the molten resin and the type of the substrate.
  • the temperature of the substrate is 160 ° C. or higher, the temperature of the discharged molten resin does not fall down and cannot be formed into a needle shape. . If the temperature of the substrate was lowered, the resin hardened to the tip of the microneedle that was gradually formed, and the needle became easier to form. However, when the temperature of the substrate is lower than about 95 ° C., the adhesion between the molten resin and the substrate tends to deteriorate.
  • a preferable temperature range may be about 95 to 150, and a more preferable temperature range is considered to be a range of about 95 to 120.
  • the range of 120 to 150 ° C. is preferable, and the range of 130 to 140 ° C. is more preferable.
  • the size of the microneedle to be manufactured can be selected as appropriate.
  • the distance between the nozzle (1) and the substrate (2) is about 200 to 500 ⁇ m.
  • the distance between the nozzle (1) and the substrate (2) is about 200 to 300 ⁇ m.
  • the distance between the nozzle (1) and the substrate (2) when discharging the first and second molten resins is the same as described above.
  • the distance between the nozzle (1) and the substrate (2) during the first and second molten resin discharges can be appropriately selected.
  • the distance between the nozzle (1) and the substrate (2) when the molten resin is discharged for the first time is about 50 to 300 ⁇ m.
  • about 50 to 250 ⁇ m can be mentioned.
  • the distance between the nozzle (1) and the substrate (2) is further separated by about 200 to 500 ⁇ m.
  • a preferable separation distance can be about 200 to 300 ⁇ m.
  • the nozzle (1) and the substrate (2) are pulled apart, and the second molten resin is discharged to fill the space between the nozzle (1) and the substrate (2) with resin.
  • the substrate is lowered.
  • the distance to be lowered is about 400 to 1000 ⁇ m.
  • about 600 to 700 ⁇ m can be mentioned.
  • the lowering speed of the substrate is preferably about 200 to 400 ⁇ m / sec.
  • the sharpness of the tip portion of the microneedle can be increased by performing the following operation. That is, when the nozzle (1) and the substrate (2) are separated from each other by 400 to 600 ⁇ m, the molten resin is extended and cooled, and when the resin is extended in the form of a thread, a smaller amount of the molten resin is discharged (0.2 MPa, 0.01 ⁇ 1.0 sec). Then, the nozzle (1) and the substrate (2) are further separated by 50 to 300 ⁇ m.
  • the same result is obtained by melting the tip of the microneedle 10 to 200 ⁇ m by bringing a multiple nozzle heated to high temperature into contact with the tip of the microneedle and separating at a speed of 400 to 700 ⁇ m / sec. can get.
  • the tip portion of the microneedle became sharp as shown in FIG.
  • the second aspect of the present invention relates to a microneedle in which a resinous microneedle is closely fixed to a resin substrate.
  • the microneedle of the present invention is obtained by one or more discharge methods of molten resin, and the formed microneedle has the following characteristics corresponding to the number of discharge times of the molten resin. . That is, when the number of times of ejection is one (one-stage ejection method), as shown in the final stage diagram of FIG. 1, arc-shaped conical microneedles with a steep side surface are placed on the substrate. When the number of times of ejection is 2 (two-stage ejection method), it has the shape of a side view as shown in the right figure of FIG. 6 and is shown in the left figure of FIG.
  • microneedles The shape of the microneedles is affected by the distance between the multiple nozzle (1) and the substrate (2), the discharge amount of the molten resin, the moving speed of the substrate, the external temperature, and the like.
  • the same biodegradable resin microneedles On the biodegradable resin substrate, the same biodegradable resin microneedles have a two-tiered shape.
  • the shape of the bottom of the two-tiered superposition of the microneedles is a truncated cone, and the shape of the upper part of the microneedles placed thereon is a conical shape with an arcuate side.
  • micro needles that are almost integrated are formed by an extension method.
  • the discharge method When the discharge method is three times (three-step discharge method), it is the same as the two-step discharge method. Similarly, the distance between the multiple nozzle (1) and the substrate (2), the discharge amount of the molten resin, the moving speed of the substrate, It is affected by external temperature.
  • a microneedle composed of three parts can be manufactured. That is, the bottom portion that is in close contact with the substrate has a truncated cone shape, and the central portion has a cylindrical shape from a gentle cone shape.
  • the upper tip has a sharp conical shape, and the tip has a sharp diameter of about 10 ⁇ m. Therefore, in order to improve the puncture property of the microneedle into the skin, it is possible to sharpen the tip of the microneedle by using this method.
  • the length of the microneedle is about 100 ⁇ m to 1 mm, and preferably the length of the needle is about 200 to 600 ⁇ m.
  • the length of the microneedle may be in a range that does not reach this point because nerves that cause pain exist in the dermis. Therefore, a length of about 500 ⁇ m is considered preferable.
  • the thickness of the microneedles varies depending on the required amount of the drug to be injected by punching the skin and the degree of skin damage, but it is preferable that the diameter width is small in order to reduce the skin damage as much as possible.
  • the diameter of the tip of the microneedle is about 30 to 200 ⁇ m, preferably 100 ⁇ m or less.
  • the viscoelasticity of the resin used the discharge amount of the resin, the number of discharges and the separation speed, the distance between the nozzle and the substrate, the substrate temperature, the environmental temperature of the apparatus, etc.
  • the height of the microneedle of the microneedle can be increased or decreased as necessary, and the tip diameter of the microneedle can be changed.
  • the produced microneedles can be cooled and given an impact or the like, whereby the microneedles can be easily peeled off from the substrate. Thereby, only a microneedle can be acquired.
  • the manufacturing process of the present invention comprises the following processes. First, the multiple nozzles (1) (10 ⁇ 10) made of stainless steel are vertically installed with an interval of about 300 ⁇ m with respect to the micro cover glass substrate (2). In addition, a 135 ° C. hot plate was placed on the horizontal surface of the Z lifting stage (ALV-600-H1M manufactured by Chuo Seiki), and a micro cover glass substrate (2) was placed on the hot plate. Next, while discharging the melted PGA from the nozzle (1) using a dispenser, the glass substrate (2) is raised to approach the multiple nozzles (1), and the distance between the substrate (2) and the nozzle (1) is 200 ⁇ m.
  • the settings were as follows. Thereafter, the substrate (2) was lowered (moving speed: 500 ⁇ m / sec or less, moving distance: 700 ⁇ m or more), the molten PGA was cooled, and microneedles were formed while stretching. The obtained microneedle is shown in FIG. From this result, it was found that when a microneedle is formed, the distance between the nozzle and the substrate and the moving distance when separating are greatly affected. It was also found that the moving speed affects the microneedle taper. The moving distance greatly affects the height of the micro needle.
  • the distance is 50 ⁇ m or less, the molten resin is spread on the substrate, so that the diameter of the base of the microneedle is as wide as about 300 to 400 ⁇ m. Moreover, it is as low as about 350 ⁇ m.
  • the distance is around 200 ⁇ m, the molten resin is bonded to the substrate without being spread, so the base diameter of the microneedle is as thin as about 200 ⁇ m, and the height of the microneedle is about 500 ⁇ m or more. Sharp micro-needles can be made.
  • Example 2 Manufacture of PGA microneedles by a one-step discharge method of molten resin
  • the temperature of the nozzle (1) for discharging the molten PGA was 250 ° C.
  • the discharge amount discharge pressure was 0.2 MPa, discharge time was 4 sec
  • the temperature of the PGA substrate (2) was gradually lowered from 150 ° C., and the temperature range of the PGA substrate where the material was hardened to the tip of the fine needle and the shape of the needle could be shaped was measured.
  • the molten PGA after discharge gradually became solidified. It has been found that when the substrate temperature is 95 ° C. or lower, the adhesion of the molten PGA also deteriorates. As a result, it was found that when the temperature of the PGA substrate was set to around 95 ° C., the molten PGA was in close contact with the PGA substrate, and fine needles having a good shape were obtained. Further, it is understood that when the molten PGA is ejected from the nozzle (1) and the molten PGA is brought into close contact with the nozzle (1) and the PGA substrate (2), the generated microneedles strongly adhere to the substrate (2). It was.
  • Example 3 Manufacture of microneedles by a two-stage discharge method of molten resin
  • PGA is discharged from the stainless steel multiple nozzles (1), and at the same time, the multiple nozzles are bonded to the PGA substrate (2).
  • the dissolved PGA is brought into close contact with the PGA substrate.
  • the nozzle and the substrate are separated by about 200 ⁇ m, and the molten PGA is discharged. Thereafter, the microneedle shown in FIGS.
  • the microneedle of the microneedle had a height of about 500 ⁇ m, the thickness of the tip of the microneedle was about 100 ⁇ m or less, and the thickness of the root of the microneedle was about 150 ⁇ m.
  • the same operation was repeated to produce PGA microneedles, but stable microneedles could be produced.
  • the variation in the height of the microneedle was also within 20%.
  • Embodiment 4 Sharpening of the tip of a microneedle of a microneedle (two-stage discharge method)
  • multiple nozzles (1) and a PGA substrate (2) are formed by a two-stage discharge method of PGA.
  • the melted PGA filled in between is pulled apart and stretched into a thread shape, the melted PGA is further discharged in an amount of 0.2 MPa and 0.1 sec. Thereafter, the substrate is further separated at about 100 ⁇ m and a moving speed of 500 ⁇ m / sec.
  • the tip of the microneedle is melted by bringing a multiple nozzle heated to a high temperature into contact with the microneedle and separated at a speed of 500 ⁇ m / sec.
  • microneedles with sharp microneedles could be manufactured.
  • the microneedle shown in FIG. 9 was obtained.
  • the shape of the obtained microneedle is composed of three parts depending on the number of times the molten resin is discharged.
  • the frustoconical portion constituting the lower part of the microneedle has a root diameter of about 200 ⁇ m and an upper diameter of about 150 ⁇ m.
  • the central part has a gentle conical shape with a diameter of about 70 to 80 ⁇ m.
  • the upper tip has a sharp conical shape, and the tip has a diameter of about 10 ⁇ m.
  • the height of the entire microneedle was also about 800 ⁇ m.
  • Example 5 PGA microneedles having microneedles of various shapes
  • Example 3 shows a shape reflecting the manufacturing method (two-stage discharge process of molten PGA).
  • the base portion of the microneedle has a shape (conical frustum shape slightly deformed) indicating that when the multiple nozzles are brought close to the PGA substrate, the melted PGA is sandwiched and overflows a little.
  • thin, elongated conical microneedles formed by the second discharge of molten PGA and the PGA stretching process are formed.
  • the shape of the truncated cone had an average ( ⁇ 30 ⁇ m), the lower part being about 400 ⁇ m and the upper part being about 300 ⁇ m. Further, the thin and elongated conical microneedle formed thereon has a lower portion of about 200 to 250 ⁇ m, and is thinning rapidly. The width of the microneedle is about 100 ⁇ m at a position 1/3 of the length of the cone from the bottom. The tip of the microneedle was about 50 to 90 ⁇ m.
  • the candle-shaped microneedles shown in FIG. 7 could be manufactured by increasing the discharge amount of molten PGA and slowing the separation speed between the multiple nozzles and the glass substrate in accordance with Example 1.
  • PGA microneedle puncture evaluation test PGA microneedle devices and PLA microneedles were produced in the same manner as in Example 3, and the puncture properties of these microneedles were evaluated. Using hairless rats, each microneedle was placed on the skin of a hairless rat, and each microneedle was pressed against the skin with a finger. Then, after removing each microneedle, the applicable part was dye
  • FIG. 8 shows the results of skin puncture using PGA microneedles.
  • the punctured portions corresponding to the microneedles appear as regular blue spots. Moreover, the change of the micro needle made from PGA before and after use was checked, but there was no place where the micro needle was broken. Thus, it was shown that the microneedles produced by the method of the present invention (dispenser method) are sufficiently practical. Moreover, the same evaluation test was performed on the microneedle made of PLA. As a result, it was found that PGA is sufficiently stronger than PLA.
  • the production method of the present invention makes it possible to easily mass-produce microneedles made of biodegradable resins (PGA, PLA).
  • the microneedles of the manufactured microneedles have the same needle length in terms of quality, and there are no microneedles that break. Accordingly, it has become possible to supply microneedles that are industrially manufacturable and strong.

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Abstract

La présente invention se rapporte à un procédé de production d'une micro-aiguille composée d'une résine. L'invention se rapporte à un procédé de production d'une aiguille minuscule ayant une taille souhaitée dans lequel, grâce à un dispositif de rejet de liquide et à de multiples buses ayant un diamètre intérieur minuscule, une résine fondue est rejetée sur une plaque de base une ou plusieurs fois, et la résine fondue attachée est étirée pour former une aiguille minuscule. L'aiguille minuscule obtenue d'une micro-aiguille comporte une ou plusieurs couches de résine, et la totalité des couches sont intégrées pour former une aiguille minuscule de type extension. L'invention se rapporte également à un procédé de production d'une micro-aiguille caractérisé en ce qu'une résine fondue est rejetée une ou plusieurs fois sur une plaque de base, et la résine fondue attachée est étirée pour former une aiguille minuscule, ainsi qu'à une micro-aiguille ayant une aiguille minuscule caractéristique obtenue par ce procédé de production.
PCT/JP2010/003544 2009-05-27 2010-05-26 Procédé de production de micro-aiguilles de type trou d'épingle, et micro-aiguille WO2010137319A1 (fr)

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US20180056053A1 (en) * 2016-08-26 2018-03-01 Juvic Inc. Protruding microstructure for transdermal delivery
CN108939282A (zh) * 2018-07-10 2018-12-07 优微（珠海）生物科技有限公司 一种高强度可溶性微针
US10632653B2 (en) 2014-10-17 2020-04-28 Kao Corporation Fine hollow protrusion manufacturing method
WO2021113545A1 (fr) * 2019-12-03 2021-06-10 Transderm, Inc. Fabrication de microstructures
CN113766943A (zh) * 2019-04-25 2021-12-07 考司美德制药株式会社 水溶性片状制剂的敷料器2
CN115139514A (zh) * 2022-07-04 2022-10-04 湖南大学 一种3d打印可降解的易分离微针阵列的制备方法

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JP2013216044A (ja) * 2012-04-11 2013-10-24 Teijin Ltd 積層成形品の成形方法
KR101676861B1 (ko) 2015-04-10 2016-11-17 씨앤텍 주식회사 마이크로 니들 패치 제조장치와 방법, 및 이에 의해 제조되는 마이크로 니들 패치
KR101722923B1 (ko) * 2015-08-27 2017-04-04 주식회사 엔이케이 경피 전달 마이크로 니들 제조시스템
CN105903121A (zh) * 2016-06-22 2016-08-31 成都市亿泰科技有限公司 一种基于负光刻胶的高密度空心微针阵列及其制造工艺
EP3606309B1 (fr) 2017-03-30 2023-09-06 FUJIFILM Corporation Absorbeur d'ondes électromagnétiques et procédé de fabrication d'absorbeur d'ondes électromagnétiques
KR102237173B1 (ko) * 2019-01-21 2021-04-07 주식회사 페로카 3층 이상 구조의 마이크로 니들
WO2022005177A1 (fr) * 2020-06-29 2022-01-06 주식회사 페로카 Appareil et procédé de fabrication d'un timbre à micro-aiguilles en faisant intervenir l'impression électrohydrodynamique
KR20230094237A (ko) * 2021-12-20 2023-06-28 주식회사 페로카 마이크로니들 제조 장치 및 마이크로니들 제조 방법

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EP2653186A2 (fr) * 2010-12-17 2013-10-23 Nurim Wellness Co. Ltd. Procédé de fabrication d'un corps à microstructure
CN103501852A (zh) * 2010-12-17 2014-01-08 株式会社乐派司 微结构体的制造方法
EP2653186A4 (fr) * 2010-12-17 2014-08-13 Raphas Co Ltd Procédé de fabrication d'un corps à microstructure
CN105854172A (zh) * 2010-12-17 2016-08-17 株式会社乐派司 微结构体的制造方法
US10632653B2 (en) 2014-10-17 2020-04-28 Kao Corporation Fine hollow protrusion manufacturing method
US20180056053A1 (en) * 2016-08-26 2018-03-01 Juvic Inc. Protruding microstructure for transdermal delivery
CN108939282A (zh) * 2018-07-10 2018-12-07 优微（珠海）生物科技有限公司 一种高强度可溶性微针
CN113766943A (zh) * 2019-04-25 2021-12-07 考司美德制药株式会社 水溶性片状制剂的敷料器2
WO2021113545A1 (fr) * 2019-12-03 2021-06-10 Transderm, Inc. Fabrication de microstructures
CN115139514A (zh) * 2022-07-04 2022-10-04 湖南大学 一种3d打印可降解的易分离微针阵列的制备方法
CN115139514B (zh) * 2022-07-04 2023-04-07 湖南大学 一种3d打印可降解的易分离微针阵列的制备方法

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