US20180140815A1 - Microneedle patch, method for manufacturing same, and apparatus for manufacturing microneedle array - Google Patents
Microneedle patch, method for manufacturing same, and apparatus for manufacturing microneedle array Download PDFInfo
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- US20180140815A1 US20180140815A1 US15/535,111 US201515535111A US2018140815A1 US 20180140815 A1 US20180140815 A1 US 20180140815A1 US 201515535111 A US201515535111 A US 201515535111A US 2018140815 A1 US2018140815 A1 US 2018140815A1
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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
- B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
- B29C39/22—Component parts, details or accessories; Auxiliary operations
- B29C39/24—Feeding the material into the mould
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B12/00—Arrangements for controlling delivery; Arrangements for controlling the spray area
- B05B12/08—Arrangements for controlling delivery; Arrangements for controlling the spray area responsive to condition of liquid or other fluent material to be discharged, of ambient medium or of target ; responsive to condition of spray devices or of supply means, e.g. pipes, pumps or their drive means
- B05B12/12—Arrangements for controlling delivery; Arrangements for controlling the spray area responsive to condition of liquid or other fluent material to be discharged, of ambient medium or of target ; responsive to condition of spray devices or of supply means, e.g. pipes, pumps or their drive means responsive to conditions of ambient medium or target, e.g. humidity, temperature position or movement of the target relative to the spray apparatus
- B05B12/122—Arrangements for controlling delivery; Arrangements for controlling the spray area responsive to condition of liquid or other fluent material to be discharged, of ambient medium or of target ; responsive to condition of spray devices or of supply means, e.g. pipes, pumps or their drive means responsive to conditions of ambient medium or target, e.g. humidity, temperature position or movement of the target relative to the spray apparatus responsive to presence or shape of target
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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
- B29C65/00—Joining or sealing of preformed parts, e.g. welding of plastics materials; Apparatus therefor
- B29C65/002—Joining methods not otherwise provided for
- B29C65/004—Cold joining
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B81—MICROSTRUCTURAL TECHNOLOGY
- B81B—MICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
- B81B1/00—Devices without movable or flexible elements, e.g. microcapillary devices
-
- 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
Definitions
- the present invention relates to a microneedle patch capable of achieving fast and reliable drug administration by improving performance of a microneedle array for causing predetermined drug to intradermally reach into dermis and improving a breaking property of the drug at administration, and a method for manufacturing the same.
- microneedles have been increasingly used in, for example, fields related to the medical field and beauty, cosmetic and health care.
- drug is administered through the body surface of a human body, such as skin and mucous membrane, by using a microneedle array consisting of a plurality of microneedles.
- methods for manufacturing such a microneedle array include a known method of filling, with needle raw material, a plurality of recesses included in a mold by using a squeegee, and solidifying the needle raw material by drying, as disclosed in patent document 1 (Japanese unexamined Patent Application Publication No. 2012-200572).
- Patent Document 1 Japanese unexamined Patent Application Publication No. 2012-200572
- the present invention provides a technology of fine and mass manufacturing of a microneedle array having highly accurate appearance and accuracy by an inkjet method, and details of an excellent mass production technology of controlling the internal structure of a microneedle so that, when administered to skin or mucous membrane, the microneedle breaks at an end of a drug containing part, which is closer to a bottom-section layer, immediately after inserted into skin, and leaves a top section as the drug containing part in target epidermis or dermis to reliably achieve an initial purpose so that a treatment is reliably completed in a short time.
- a microneedle capable of administering contained drug to a target site appropriately by controlling the shape of a boundary of a bottom-section layer and manufacturing an intermediate layer having strength clearly different from those of other sites and locally having a high breaking property.
- the intermediate layer includes two layers, a first intermediate layer is formed of a raw material having a high hardness and a low absorbability, and a second intermediate layer is formed of a raw material having relatively low hardness and high absorbability, which intends to cause a top-section layer containing released drug to be reliably left inside dermis.
- a microneedle array manufacturing apparatus including a plurality of the droplet discharging apparatuses each capable of discharging a raw material obtained by changing, as appropriate, a mixture ratio and concentration of a bioabsorbable formulation that forms a microneedle to achieve the present invention was developed, and an apparatus exploiting a high technology and combined with a control device configured to control the operation state thereof was achieved.
- the raw material for the intermediate part may or may not include drug.
- a microneedle array manufacturing apparatus includes a plurality of the droplet discharging apparatuses capable of discharging raw material obtained by changing, as appropriate, a mixture ratio and concentration of a bioabsorbable formulation that forms a microneedle.
- a microneedle patch according to an aspect of the present invention is a microneedle patch produced by a droplet discharging apparatus capable of separately discharging, as raw material liquid, for example, first liquid, second liquid, third liquid, and fourth liquid containing components different from each other, wherein an intermediate layer having a breaking property higher than a breaking property of a top-section layer comprising a biologically active material, having a function to prevent backflow of, through a penetrating hole, drug released in dermis, and having a thickness of 5 ⁇ m to 100 ⁇ m is formed after discharge, drying, and hardening of the top-section layer, and the intermediate layer is configured to break in the dermis in 5 seconds to 20 seconds approximately.
- a microneedle patch according to another aspect of the present invention is a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein the strength of a microneedle is highest in a bottom-section layer, followed in order by a top section comprising drug, and an intermediate layer set as a layer having a lowest strength.
- a microneedle patch according to yet another aspect of the present invention is a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein a weight-average molecular weight of a microneedle is largest in a top section comprising drug, followed in order by a bottom-section layer, and an intermediate layer set as a layer having a lowest weight-average molecular weight.
- the microneedle patch may be a microneedle patch produced by discharging different kinds of raw material liquid from a droplet discharging apparatus, wherein the intermediate layer includes one or more layers.
- a microneedle patch according to yet another aspect of the present invention is a microneedle patch produced by discharging different kinds of raw material liquid from a droplet discharging apparatus and including two or more intermediate layers, wherein a first intermediate layer is formed of a polymer material having a high hardness and a low absorbability and selected as a raw material selected to have high concentration, a dissolution time of the first intermediate layer is controlled to be 10 minutes to 24 hours, and drug contained in a top section and released in dermis is prevented from flowing back in a direction toward epidermis through a penetrating hole.
- the microneedle patch produced by discharging different kinds of raw material liquid from a droplet discharging apparatus may include two or more intermediate layers, wherein a second intermediate layer is formed of a polymer material having a low hardness and a high absorbability and selected as a raw material selected to have low concentration, and a function to easily break and separate a top section from a bottom-section layer and reliably leave the top section in dermis in a short time is provided.
- a microneedle patch according to yet another aspect of the present invention is a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein the microneedle patch is produced integrally with a bonding surface and a flat surface adhering to a substrate when part or all of a bottom-section layer is produced, collapse of microneedles due to piercing is prevented, a top section containing drug easily and reliably breaks from the bottom-section layer, and a plurality of intermediate layers each having a function to prevent backflow of the drug from inside of dermis are provided.
- a microneedle patch according to yet another aspect of the present invention is a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein an intermediate layer is provided between a top section and a bottom-section layer, and the intermediate layer is configured to break in dermis in 5 seconds to 20 seconds approximately to leave the top section in the dermis.
- the microneedle patch may be a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein an intermediate layer is inside a bottom-section layer.
- a microneedle array manufacturing apparatus is a microneedle array manufacturing apparatus for shaping a microneedle array consisting of a plurality of microneedles by filling a plurality of recesses formed in a mold with raw material liquid for forming the microneedles, the apparatus comprising: at least one droplet discharging apparatus capable of discharging, to each recess, a droplet of the raw material liquid in a predetermined amount equal to or smaller than the volume of the recess; and a positioning apparatus capable of adjusting relative positions of the droplet discharging apparatus and the mold so as to land the droplet into the recess from the droplet discharging apparatus, wherein the at least one droplet discharging apparatus are a plurality of droplet discharging apparatuses each capable of discharging raw material obtained by changing, as appropriate, a mixture ratio and concentration of a bioabsorbable formulation that forms a microneedle.
- a microneedle array manufacturing method is a microneedle patch manufacturing method comprising the processes of: forming a top-section layer in a recess of a mold; discharging, onto the top-section layer in the recess, a plurality of droplets of first intermediate-layer raw material liquid from a droplet discharging apparatus; hardening the second intermediate-layer raw material liquid to form an intermediate layer having a breaking strength weaker than a breaking strength of the top-section layer; discharging, onto the intermediate layer in the recess, a plurality of droplets of bottom-section-layer raw material liquid from the droplet discharging apparatus; and hardening the bottom-section-layer raw material liquid to form a bottom-section layer having a breaking strength stronger than the breaking strength of the intermediate layer.
- a microneedle patch according to the present invention can achieve fine and mass manufacturing of a microneedle array having highly accurate appearance and accuracy by an inkjet method, can reliably achieve an initial purpose so that a treatment is reliably completed in a short time when microneedles are administered to skin or mucous membrane, because each microneedle breaks at a stump of a top section as a drug containing part, which is closer to a bottom-section layer, immediately after insertion into the skin to leave the top section as a drug containing part in target epidermis or dermis, and can achieve excellent mass productivity.
- FIG. 1 Schematic perspective view illustrating the outline of an apparatus for manufacturing a microneedle array according to a first embodiment.
- FIG. 2 Block diagram for description of a control system of the apparatus for manufacturing a microneedle array in FIG. 1 .
- FIG. 3 Perspective view illustrating an exemplary product including a microneedle array according to the first embodiment.
- FIG. 4 Partially enlarged perspective view of part of FIG. 3 .
- FIG. 5 Perspective view illustrating an exemplary mold according to the first embodiment.
- FIG. 6 Flowchart of an exemplary method for manufacturing the microneedle array according to the first embodiment.
- FIG. 7 Schematic cross-sectional view for description of discharge of a droplet toward recesses.
- FIG. 8 Schematic enlarged cross-sectional view for description of landing of droplets on a recess.
- FIG. 10 Schematic cross-sectional view for description of discharge of droplets toward recesses in a second embodiment.
- FIG. 11 Perspective view illustrating an exemplary product including a microneedle array according to the second embodiment.
- FIG. 12 Partially enlarged perspective view of part of FIG. 11 .
- FIG. 13 Perspective view illustrating another exemplary product including the microneedle array according to the second embodiment.
- FIG. 14 Partially enlarged perspective view of part of FIG. 13 .
- FIG. 15 ( a ) Schematic cross-sectional view for description of a microneedle array according to a modification 2 C, ( b ) Conceptual diagram for description of an exemplary product including the microneedle array according to the modification 2 C, and ( c ) Conceptual diagram for description of another exemplary product including the microneedle array according to the modification 2 C.
- FIG. 16 Conceptual diagram for description of an apparatus for manufacturing a microneedle array according to a third embodiment.
- FIG. 17 ( a ) Schematic cross-sectional view for description of a method for manufacturing a microneedle array according to a modification 1 C, and ( b ) Conceptual diagram for description of an exemplary product including the microneedle array according to the modification 1 C.
- FIG. 18 ( a ) Schematic cross-sectional view for description of a method for manufacturing a conventional microneedle array, ( b ) Schematic cross-sectional view illustrating a process of manufacturing the conventional microneedle array, ( c ) Schematic cross-sectional view of a mold in which a conventional top-section layer is formed, ( d ) Schematic cross-sectional view for description of a process of filling the conventional microneedle array, and ( e ) Schematic cross-sectional view illustrating a process of fixing the conventional microneedle array.
- FIG. 19 Schematic cross-sectional view illustrating a process of forming a top-section layer of a microneedle patch.
- FIG. 20 Schematic cross-sectional view illustrating a process of forming an intermediate layer of the microneedle patch.
- FIG. 21 Schematic cross-sectional view illustrating a process of forming the intermediate layer of the microneedle patch and a state after the formation.
- FIG. 22 Schematic cross-sectional view illustrating a process of forming a bottom-section layer of the microneedle patch.
- FIG. 23 Schematic cross-sectional view illustrating a state in which the microneedle patch is inserted.
- FIG. 24 Schematic cross-sectional view illustrating a state when the microneedle patch is removed.
- FIG. 25 Schematic cross-sectional view for description of dissolution of a microneedle.
- FIG. 26 Schematic cross-sectional view for description of dissolution of the intermediate layer of the microneedle.
- FIG. 27 Schematic cross-sectional view illustrating a process of forming a top-section layer of a microneedle patch.
- FIG. 28 Schematic cross-sectional view illustrating a process forming a first intermediate layer of the microneedle patch.
- FIG. 29 Schematic cross-sectional view illustrating a process of forming a second intermediate layer of the microneedle patch.
- FIG. 30 Schematic cross-sectional view illustrating a process of forming a bottom-section layer of the microneedle patch.
- FIG. 31 Schematic cross-sectional view illustrating a state in which the microneedle patch is inserted.
- FIG. 32 Schematic cross-sectional view illustrating a state when the microneedle patch is removed.
- FIG. 33 Schematic cross-sectional view for description of dissolution of a microneedle.
- FIG. 34 Schematic cross-sectional view for description of dissolution of the intermediate layer of the microneedle.
- the present invention is related to an apparatus for manufacturing a microneedle array, a method for manufacturing a microneedle array having an optimized breaking property to allow fast drug administration, and a product including the microneedle array.
- FIG. 1 is a schematic perspective view illustrating the outline of the apparatus for manufacturing a microneedle array.
- the microneedle array manufacturing apparatus 1 includes a droplet discharging apparatus 10 and a positioning apparatus 20 .
- the positioning apparatus 20 includes an XYZ stage 21 , a CCD camera 22 , and an alignment monitor 23 .
- the droplet discharging apparatus 10 is provided with a nozzle 11 a for discharging droplets, and a cartridge 13 a containing raw material liquid supplied to the nozzle 11 a .
- the droplet discharging apparatus 10 also includes another nozzle 11 b and another cartridge 13 b illustrated in FIG. 10 .
- the microneedle array manufacturing apparatus 1 includes a control device 30 configured to control the droplet discharging apparatus 10 and the positioning apparatus 20 .
- the control device 30 controls a first discharge head actuator 12 a and a second discharge head actuator 12 b .
- the control device 30 controls the first discharge head actuator 12 a and the second discharge head actuator 12 b to finely adjust the number of droplets discharged from the nozzles 11 a and 11 b .
- the control device 30 controls an X-axis stepping motor 21 a , a Y-axis stepping motor 21 b , a Z-axis stepping motor 21 c , and a ⁇ -axis stepping motor 21 d of the XYZ stage 21 , the CCD camera 22 , and the alignment monitor 23 .
- a mold 80 placed on the XYZ stage 21 is moved in an X-axis direction by the X-axis stepping motor 21 a , in a Y-axis direction by the Y-axis stepping motor 21 b , and in a Z-axis direction by the Z-axis stepping motor 21 c , and rotated about a central axis extending in the vertical direction (Z-axis direction) at the center of the XYZ stage 21 by the ⁇ -axis stepping motor 21 d.
- the following describes a product including a microneedle array manufactured by using the microneedle array manufacturing apparatus 1 .
- the microneedle array manufacturing apparatus 1 forms a microneedle array 110 consisting of a plurality of microneedles 103 illustrated in FIG. 3 .
- Each microneedle 103 is set to have, for example, a height of 10 ⁇ m to 1 mm, a maximum bottom-surface width of 10 ⁇ m to 1 mm, and an aspect ratio of 0.5 to 4.
- An interval dl between the microneedles 103 adjacent to each other is set to be, for example, 10 ⁇ m to 2 mm.
- the microneedles 103 included in the microneedle array 110 are set to have a density of, for example, several microneedles to 10 5 microneedles for one square centimeter approximately.
- the microneedle array manufacturing apparatus 1 is capable of repeating across a travel distance equal to or smaller than the interval dl of the microneedles 103 . Error in the travel distance of the microneedle array manufacturing apparatus 1 is set to be smaller than the maximum bottom-surface width of each microneedle 103 .
- the microneedle array 110 is fixed to the surface 102 of a plate base member 101 .
- the base member 101 has an outer dimension of, for example, 2 mm ⁇ 17 mm ⁇ 17 mm approximately.
- a lamination film 109 having a composition same as that of a bottom-section layer 105 is formed on the surface 102 of the base member 101 .
- a product 100 including the microneedle array 110 fixed to the base member 101 is formed.
- each microneedle 103 has a spired leading end part, a section of the leading end part taken along the vertical direction is angled at, for example, 30°.
- a recess 81 (refer to FIG. 8 ) on which droplets land has a tilted wall, which facilitates formation of the recess 81 having a shape suitable to be filled with droplets.
- the landing of a droplet on the recess 81 means hitting and adhesion of the droplet to the surface of the wall of the recess 81 .
- the plate base member 101 allows ventilation and is, for example, a porous base member.
- porous base members include a porous base member mainly made of cellulose acetate, a porous ceramic base member, a porous metal base member, a pulp molded product obtained by forming pulp in a plate shape, and a porous resin base member.
- FIG. 4 illustrates a partial region EA 1 of FIG. 3 in an enlarged manner.
- Each microneedle 103 has a two-layer structure consisting of a top-section layer 104 at a leading end and the bottom-section layer 105 therebelow.
- the top-section layer 104 and the bottom-section layer 105 have compositions different from each other.
- the component does not necessarily need to be dissolved in the raw material liquid.
- the suspended liquid may have a component of, for example, microcapsules or liposomes.
- the mold 80 illustrated in FIG. 5 only needs to be formed of a material hygienic against the raw material liquid, but preferably has high gas permeability.
- the mold 80 may be formed of plastic, elastomer, ceramic, or metal.
- the mold 80 is preferably formed of silicone rubber.
- the plastic of which the mold 80 is formed is preferably, for example, polymethylpentene (TPX (registered trademark)) or polytetrafluoroethylene.
- the metal of which the mold 80 is formed is preferably, for example, stainless steel, which does not transmit gas but is unlikely to rust.
- a horizontal section of the recess 81 of the mold 80 along a surface 82 of the mold 80 has, for example, a circular shape, a polygonal shape, or an elliptical shape.
- the recess 81 includes an internal space having, for example, a circular cone shape, a pyramid shape, a cylindrical shape, or a rectangular column shape.
- Alignment marks 83 are formed on the surface 82 of the mold 80 .
- the alignment marks 83 are read by the CCD camera 22 of the microneedle array manufacturing apparatus 1 .
- the alignment marks 83 are used as references to control landing of a droplet discharged from the droplet discharging apparatus 10 in the recess 81 , and thus the position of each recess 81 is determined with reference to the alignment marks 83 .
- the alignment marks 83 are hygienic and formed as, for example, bumps on the surface 82 .
- the mold 80 when formed of silicone rubber has an outer dimension of, for example, 6 mm ⁇ 20 mm ⁇ 20 mm, and the recesses 81 are formed in a region having a size of, for example, 15 mm ⁇ 15 mm.
- Top-section-layer raw material liquid 91 (refer to FIG. 7 ) for forming the top-section layer 104 of each microneedle 103 is, for example, solution of a solid raw material in water, a mixed solvent of water and alcohol, or another solvent, or suspension liquid of a solid raw material in water, a mixed solvent of water and alcohol, or another solvent, or a mixture of the solution and the suspension liquid.
- the solid raw material is a polymer substance harmless to a human body and is, for example, a resin harmless to a human body, a polysaccharide harmless to a human body, a protein harmless to a human body, or a compound thereof harmless to a human body.
- Examples of compounds to be introduced into a human body include a biologically active substance used for treatment, diagnosis, and prevention of injuries and diseases.
- the top-section-layer raw material liquid is, for example, a solvent of aqueous polysaccharide (comprising derivatives and salts thereof) containing a biologically active substance administered for diagnosis, treatment, and prevention of diseases.
- a solvent of the top-section-layer raw material liquid is evaporated to form, in a substrate of polysaccharide, the top-section layer 104 comprising the biologically active substance.
- the aqueous polysaccharide include sodium chondroitin sulfate, hyaluronic acid, dextran, and carboxymethyl cellulose.
- the biologically active substance include insulin and growth hormone.
- Bottom-section-layer raw material liquid for forming the bottom-section layer 105 of the microneedle 103 is different from the top-section-layer raw material liquid in a composition of at least one of solid raw material and solvent.
- the top-section layer 104 and the bottom-section layer 105 of the microneedle 103 have different compositions.
- the present embodiment describes exemplary medical usage of the microneedle 103 in which the top-section layer 104 comprises a biologically active medicinal substance and the bottom-section layer 105 comprises no biologically active substance.
- the top-section layer 104 and the bottom-section layer 105 may both comprise biologically active medicinal substances. Differences can be obtained between a medical effect provided by the top-section layer 104 and the duration thereof and a medical effect provided by the bottom-section layer and the duration thereof, by providing differences between the kind and amount of the biologically active substance comprised in the top-section layer 104 and the kind and amount of the biologically active substance comprised in the bottom-section layer 105 .
- the product 100 including the microneedle array the product 100 is applicable to various kinds of drug administration when each microneedle 103 has a two-layer structure in this manner.
- the top-section-layer raw material liquid is discharged as a droplet from, for example, the droplet discharging apparatus 10 , and the amount of the droplet is set to be, for example, 0.1 nanoliter/droplet to 1 microliter/droplet.
- the amount of the droplet is set to be, for example, 0.1 nanoliter/droplet to 1 microliter/droplet.
- each recess 81 for forming one microneedle 103 has a capacity of 20 nanoliters
- one droplet has 1 nanoliter to fill the recess 81 with 20 droplets.
- Filling with such a minute droplet preferably requires a low viscosity such as, 0.1 mPa ⁇ sec to 100 mPa ⁇ sec, preferably 1 mPa ⁇ sec to 10 mPa ⁇ sec.
- FIG. 6 is a flowchart for description of a process of manufacturing the product 100 including the above-described microneedle array by using the microneedle array manufacturing apparatus 1 .
- an operation from step S 1 to step S 5 and an operation from step S 11 to step S 15 in FIG. 6 can be performed in parallel independently from each other. However, the two operations may share any operation if possible.
- operation of the microneedle array manufacturing apparatus 1 at each step is controlled by the control device 30
- the following description omits part of description of control of each component of the microneedle array manufacturing apparatus 1 by the control device 30 .
- the first discharge head actuator 12 a is used to discharge droplets from the nozzle 11 a , whereas a manufacturing method using the second discharge head actuator 12 b will be described in a second embodiment.
- the ⁇ -axis stepping motor 21 d is not used, whereas a manufacturing method using the ⁇ -axis stepping motor 21 d will be described in a third embodiment.
- step S 1 An operation using the mold 80 is performed at steps S 1 to S 5 in FIG. 6 .
- the mold 80 illustrated in FIG. 5 is prepared (step S 1 ).
- a predetermined number of molds 80 are washed by water and arranged at a predetermined place.
- the prepared molds 80 are all sterilized through, for example, an autoclave (not illustrated) (step S 2 ).
- the sterilized molds 80 are placed on the XYZ stage 21 of the microneedle array manufacturing apparatus 1 in a clean environment, and subjected to positioning (step S 3 ).
- each sterilized mold 80 is performed after the mold 80 is placed on the XYZ stage 21 by, for example, a sterilized robotic arm.
- the CCD camera 22 captures an image of the alignment marks 83 of the mold 80 on the XYZ stage 21 , and the control device 30 recognizes the alignment marks 83 as references, thereby performing the positioning.
- the control device 30 specifies the position of each recess 81 with reference to the alignment marks 83 of the mold 80 , which allows the XYZ stage 21 to move the mold 80 relative to the nozzle 11 a of the droplet discharging apparatus 10 so that the nozzle 11 a of the droplet discharging apparatus 10 unicursally and sequentially follows the adjacent recesses 81 .
- step S 4 as illustrated in FIGS. 7 and 8 , the mold 80 is moved relative to the nozzle 11 a so that a droplet discharged from the nozzle 11 a directly lands in each recess 81 of the mold 80 to fill the recess 81 with the top-section-layer raw material liquid 91 .
- a droplet discharged from the nozzle 11 a directly lands in each recess 81 of the mold 80 to fill the recess 81 with the top-section-layer raw material liquid 91 .
- the top-section-layer raw material liquid 91 can be dried in a shorter time.
- FIG. 8 illustrates five droplets 91 a , 91 b , 91 c , 91 d , and 91 e of the top-section-layer raw material liquid 91 discharged from the nozzle 11 a for each recess 81 , and landing points Lp 1 , Lp 2 , Lp 3 , Lp 4 , and Lp 5 of the respective droplets 91 a , 91 b , 91 c , 91 d , and 91 e .
- the landing points Lp 1 , Lp 2 , Lp 3 , Lp 4 , and Lp 5 are at positions different from each other in the recess 81 .
- the landing points Lp 1 , Lp 2 , Lp 3 , Lp 4 , and Lp 5 are different from each other.
- each mold 80 can be filled in a shorter time, and accordingly, a product including the microneedle array can be manufactured in a short time.
- the speed of the nozzle 11 a relative to the mold 80 may be set to change between start and completion of the landing on each recess 81 .
- the number of droplets of the discharged top-section-layer raw material liquid 91 is not limited to five but may be set as appropriate.
- the number of droplets for each recess 81 is set to be, for example, one to several tens.
- the amount of droplets of the discharged top-section-layer raw material liquid 91 may be set as appropriate.
- the amounts of the droplets 91 a , 91 b , 91 c , 91 d , and 91 e may be identical to each other or different from each other.
- the amount of droplets may be reduced at a position closer to the edge of the recess 81 and increased at a position closer to the center of the recess 81 , or the amount of droplets may be increased at a position closer to the edge of the recess 81 and reduced at a position closer to the center of the recess 81 , the amount of droplets may be reduced toward the end of discharging at the recess 81 , or the amount of droplets may be increased toward the end of discharging at the recess 81 .
- the total volume of the five droplets of the top-section-layer raw material liquid 91 discharged into each recess 81 is set to be equal to the volume of the internal space of the recess 81 (volume of the recess 81 ).
- the filling amount of the top-section-layer raw material liquid 91 may set to differ in accordance with the position of each recess 81 within the mold 80 .
- the filling amount of the top-section-layer raw material liquid 91 is set to be larger for the recess 81 closer to the center of the mold 80 and be smaller for the recess 81 closer to an end part of the mold 80 , or the filling amount of the top-section-layer raw material liquid 91 is set to be larger for the recess 81 closer to the center of the mold 80 and be smaller for the recess 81 closer to an end part of the mold 80 .
- the filling amount may be changed by changing, for example, the amount of one droplet, the number of droplets for each recess 81 , or both the amount and number of droplets.
- the relative movement of the nozzle 11 a to each recess 81 is mainly performed on the XY coordinate of the XYZ stage 21 , that is, in the in-plane direction of the surface 82 of the mold 80 , but may involve movement in the Z-axis direction.
- the nozzle 11 a may be moved toward or away from the mold 80 to change the accuracy of landing.
- the mold 80 is moved from the XYZ stage 21 to a wind dry unit (not illustrated) by, for example, a sterilized robotic arm.
- a wind dry unit for example, the filled mold 80 is sequentially placed on a belt conveyer (not illustrated) and moved through clean dry air.
- the mold 80 with the dried and solidified top-section-layer raw material liquid 91 is sequentially taken out and subjected to the following combination process.
- the operation at steps S 11 to S 15 which is performed in parallel with the operation at steps S 1 to S 5 described above, is performed by using a porous base member 85 (see FIG. 9( a ) ).
- a porous base member 85 First, in a process of preparing the porous base member 85 , surfaces of a predetermined number of the porous base members 85 are cleaned by, for example, air and then the porous base members 85 are arranged at a predetermined place.
- the prepared porous base members 85 are all sterilized through, for example, an autoclave (not illustrated) (step S 12 ). Each sterilized porous base member 85 is sequentially subjected to positioning with respect to a dispenser (not illustrated) in a dispense unit by a feeder device (not illustrated) (step S 13 ).
- bottom-section-layer raw material liquid 92 is distributed by the dispenser to the porous base members 85 and placed on the porous base member 85 in contact with the porous base member 85 as illustrated in FIG. 9( a ) .
- the bottom-section-layer raw material liquid 92 is set to have, for example, a viscosity larger than 1 Pa ⁇ sec and smaller than 1000 Pa ⁇ sec, and the amount of the bottom-section-layer raw material liquid 92 is set to several tens mg for the mold 80 having a size of 20 mm ⁇ 20 mm.
- the bottom-section-layer raw material liquid 92 is a material that forms the lamination film 109 by a method to be described later, and thus preferably has a relatively high viscosity as described above.
- the manufacturing method does not transition to a drying and bonding process (step S 20 ) soon after the bottom-section-layer raw material liquid 92 is filled.
- the method includes a curing process (step S 15 ) for allocating a time in which the bottom-section-layer raw material liquid 92 penetrates into the porous base member 85 by, for example, capillary action.
- the curing process only waits for an appropriate time of, for example, several seconds to several tens seconds.
- the curing process may involve, for example, a penetration promoting means that applies vibration or high pressure while the bottom-section-layer raw material liquid 92 is in contact with the porous base member 85 .
- step S 20 the mold 80 is fixed on a suction stage 41 by suction as illustrated in FIG. 9( a ) .
- the porous base member 85 is placed on a placement stage 42 .
- step S 5 the mold 80 subjected to the drying process (step S 5 ) is placed on the suction stage 41 by, for example, a sterilized robotic arm, and the porous base member 85 subjected to the curing process (step S 15 ) is placed on the placement stage 42 by, for example, a sterilized robotic arm.
- the suction stage 41 is moved up and inverted so that the mold 80 fixed to the suction stage 41 is placed over the porous base member 85 placed on the placement stage 42 . While the mold 80 is placed over on the porous base member 85 as illustrated in FIG. 9( b ) , the suction stage 41 is pressed toward the placement stage 42 to receive application of predetermined pressure. This predetermined pressure spreads the bottom-section-layer raw material liquid 92 sandwiched between the porous base member 85 and the mold 80 . However, applied pressure is adjusted to the predetermined pressure to prevent the bottom-section-layer raw material liquid 92 from spreading out of the porous base member 85 .
- a preliminary experiment is performed to find an appropriate value of the predetermined pressure.
- the fixation of the mold 80 to the suction stage 41 may be maintained or canceled when the suction stage 41 applies pressure to the mold 80 .
- the suction stage 41 is removed from the mold 80 while the fixation of the suction stage 41 to the mold 80 is canceled.
- the volume of the top-section-layer raw material liquid 91 decreases through drying, which leaves a step between the surface 82 of the mold 80 and the surface of a substance produced through solidification of the top-section-layer raw material liquid 91 .
- the bottom-section-layer raw material liquid 92 enters into a space created inside each recess 81 due to this step, thereby forming the bottom-section layer 105 of the microneedles 103 .
- the mold 80 and the porous base member 85 in the state illustrated in FIG. 9( c ) is moved from the placement stage 42 to a stock unit (not illustrated).
- the bottom-section-layer raw material liquid 92 between the mold 80 and the porous base member 85 is dried while a load is applied on the mold 80 from above.
- the load is applied on the mold 80 from above by, for example, a method of placing a weight on the mold 80 or a method of setting an assembly of the mold 80 and the porous base member 85 to a load stock dedicated machine configured to apply a load by air pressure or pressure through a spring.
- the first embodiment describes the microneedles 103 having a two-layer structure in which the bottom-section layer 105 comprises no biologically active substance and provides no medical effect and the top-section layer 104 comprises a biologically active substance and provides a medical effect.
- the amount of raw material liquid filling each recess needs to be extremely accurately controlled.
- the amount of the raw material liquid can be accurately controlled by the microneedle array manufacturing apparatus 1 and the microneedle array manufacturing method according to the first embodiment described above, in which the recess is filled with the raw material liquid in a predetermined number of droplets each having an adjusted fluid amount, and thus the amount of drug can be extremely accurately adjusted.
- a microneedle array manufactured by the microneedle array manufacturing apparatus 1 and the microneedle array manufacturing method described in the first embodiment is not limited to the microneedle array 110 consisting of the microneedles 103 each having a two-layer structure described above.
- the microneedle array manufacturing apparatus 1 and the microneedle array manufacturing method can manufacture a microneedle array consisting of microneedles each having a two-layer structure in which the top-section layer 104 comprises no biologically active substance and provides no medical effect and the bottom-section layer 105 comprises a biologically active substance and provides a medical effect.
- the top-section layer and the bottom-section layer of each microneedle may both comprise biologically active medicinal substances.
- the microneedle array manufacturing apparatus 1 and the microneedle array manufacturing method can manufacture a microneedle array consisting of microneedles each having a multi-layer structure consisting of three or more layers. In this manner, the microneedle array manufacturing apparatus 1 and the microneedle array manufacturing method described in the first embodiment are suitable for manufacturing of a product including a microneedle array consisting of a plurality of microneedles each comprising a plurality of layers having compositions different from each other.
- the microneedles 103 may each have a two-layer structure in which the top-section layer 104 and the bottom-section layer 105 both comprise no biologically active substance and provide no medical effect.
- At least one of the top-section layer 104 and the bottom-section layer 105 may be formed of biologically active substances without using polysaccharide exemplarily described in the first embodiment.
- the top-section-layer raw material liquid described above may be, for example, solution of at least one or combination of aqueous polysaccharide, aqueous protein, polyvinyl alcohol, carboxy vinyl polymer, sodium polyacrylate described above.
- aqueous protein include serum albumin.
- the top-section-layer raw material liquid may comprise another substance such as monosaccharide or oligosaccharide. Examples of monosaccharide include glucose, and examples of oligosaccharide include disaccharide such as sucrose.
- positioning is performed by capturing images of the alignment marks 83 through the CCD camera 22 and moving the XYZ stage 21 with reference to the alignment marks 83 , but is not limited to such a method.
- the positioning may be performed by pressing a side surface of the mold 80 to a jig to set a reference position.
- the base member 101 has a flat plate shape, but may have a thin sheet shape or a three-dimensional shape with a curved surface.
- a surface 82 A of a mold 80 A may have a curved shape like a concave mirror, and the nozzle 11 a may be moved along this curved surface of the surface 82 to fill each recess 81 with the top-section-layer raw material liquid 91 .
- a plurality of microneedles 103 f can be constantly formed in parallel to each other irrespective of a curved shape of a surface 102 f of a fixing part 109 f as illustrated in FIG. 17( b ) .
- This configuration facilitates insertion of the microneedles 103 f at any places of a microneedle array 110 E.
- microneedles are substantially vertical to a curved surface, but not in parallel to each other. This configuration makes difficult insertion of some of the microneedles and makes the microneedles prone to damage.
- the fixing part 109 f can be formed by a method same as that of the first embodiment by using the bottom-section-layer raw material liquid 92 .
- the amount of composition comprised in each microneedle 103 f can be accurately adjusted to an amount set in advance depending on the number of droplets of the top-section-layer raw material liquid 91 .
- the fixing part 109 f may have any other three-dimensional shape.
- the above-described effect can be obtained when the microneedles 103 f are three-dimensionally disposed on the surface 102 f of the fixing part 109 f and formed in parallel to each other.
- the droplet discharging apparatus 10 uses the single nozzle 11 a , but in the second embodiment, as illustrated in FIG. 10 , the two nozzles 11 a and 11 b are used.
- the two cartridges 13 a and 13 b illustrated in FIG. 10 contain top-section-layer raw material liquid 91 and 93 having different compositions.
- the droplet discharging apparatus 10 illustrated in FIG. 10 discharges, to the recesses 81 adjacent to each other, droplets of the top-section-layer raw material liquid 91 and droplets of the top-section-layer raw material liquid 93 alternately with the nozzle 11 a and the nozzle 11 b .
- the total amount of droplets discharged by the nozzles 11 a and 11 b differs between the recesses 81 .
- FIG. 11 illustrates a product 100 A including a microneedle array 110 A formed by the above-described manufacturing method.
- FIG. 12 illustrates a partial region EA 2 of FIG. 11 in an enlarged manner.
- a first microneedle 103 a and a second microneedle 103 b according to the second embodiment have two-layer structures consisting of top-section layers 104 a and 104 b at leading ends and bottom-section layers 105 a and 105 b next to the top-section layers 104 a and 104 b , respectively.
- the bottom-section layers 105 a and 105 b are second layers next to the top-section layers 104 a and 104 b .
- the top-section layer 104 a and the bottom-section layer 105 a of the first microneedle 103 a are different from each other, and the top-section layer 104 b and the bottom-section layer 105 b of the second microneedle 103 b are different from each other.
- the bottom-section layers 105 a and 105 b are formed of identical components by a method same as the first embodiment, but the top-section layers 104 a and 104 b have thickness different from each other, and thus the bottom-section layers 105 a and 105 b have thickness different from each other.
- the kind of the composition (first composition) of the top-section layer 104 a of the first microneedle 103 a is different from the kind of the composition (third composition) of the bottom-section layer 105 a of the first microneedle 103 a
- the kind of the composition (second composition) of the top-section layer 104 b of the second microneedle 103 b is different from the kind of the composition (fourth composition) of the bottom-section layer 105 b of the second microneedle 103 b .
- the kind and amount of the composition (first composition) of the top-section layer 104 a of the first microneedle 103 a are different from the kind and amount of the composition (second composition) of the top-section layer 104 b of the second microneedle 103 b .
- the amount of the composition (third composition) of the bottom-section layer 105 a of the first microneedle 103 a is different from the amount of the composition (fourth composition) of the bottom-section layer 105 b of the second microneedle 103 b.
- a first area Ar 1 is a line in which the first microneedle 103 a is formed
- a second area Ar 2 is a line in which the second microneedle 103 b is formed.
- the first area Ar 1 is sandwiched by the second areas Ar 2 on both sides.
- each second area Ar 2 is sandwiched by the first areas Ar 1 on both sides.
- a plurality of the first areas Ar 1 and a plurality of the second areas Ar 2 are alternately arranged.
- microneedle array manufacturing method using a squeegee it is difficult to have microneedles in different structures alternately in lines adjacent to each other and accurately adjust the thicknesses of each layer in each microneedle, which can be, however, achieved by a method for manufacturing the microneedle array 110 A according to the second embodiment.
- step S 4 the top-section-layer raw material liquid filling process illustrated in FIG. 6 is changed as described above, whereas the other processes are performed in a manner same as that of the first embodiment.
- the kind of the first composition is different from the kind of the third composition
- the kind of the second compositions different from the kind of the fourth composition.
- the kind and amount of the first composition are different from the kind and amount of the second composition.
- the amount of the third composition is different from the amount of the fourth composition.
- the kind of the first composition is different from the kind of the third composition
- the kind of the second composition is different from the kind of the fourth composition
- the kind or amount of the first composition is different from the kind or amount of the second composition
- the kinds and amounts of the third composition and the fourth composition are different from each other.
- the first composition is different from the kind of the third composition
- the second composition is different from the kind of the fourth composition
- only the amounts of the first composition and the second composition are different from each other
- only the amounts of the third composition and the fourth composition are different from each other.
- the second embodiment describes lines of the first microneedles 103 a arranged straight and the second microneedles 103 b arranged straight as illustrated in FIGS. 11 and 12 .
- the arrangement of microneedles in different structures is not limited to the arrangement illustrated in FIGS. 11 and 12 .
- m 1 lines (m 1 is a natural number) of the first microneedles 103 a are arranged
- n 1 lines (n 1 is a natural number) of the second microneedles 103 b are arranged next
- m 2 lines (m 2 is a natural number) of the first microneedles 103 a are arranged next
- n 2 lines (n 2 is a natural number) of the second microneedles 103 b are arranged next.
- first microneedles 103 a and the second microneedles 103 b may be arranged alternately in an optional number of lines.
- a ratio of the total volume of the top-section layers 104 a of the first microneedles 103 a and the total volume of the top-section layer 104 b of the second microneedle 103 b comprised in one microneedle array is adjusted by adjusting each number of lines, thereby adjusting, for example, the administration amounts of two kinds of drugs.
- lines of the first microneedles 103 a may be arranged in a first area Ar 3 having a circular shape and a first area Ar 5 having a ring shape, and a second area Ar 4 in which lines of the second microneedles 103 b are arranged may be disposed surrounding the lines of the first microneedles 103 a in the first area Ar 3 .
- the first area Ar 5 is disposed surrounding the second area Ar 4 .
- the microneedles 103 a are same in the two first areas Ar 3 and Ar 5 , but the kind (the kind and amount of a contained composition) of microneedles may be different between the two first areas Ar 3 and Ar 5 , and the region denoted by Ar 5 may be a third area.
- drug ⁇ of 20 wt % may be administered through microneedles in the first area Ar 3
- drug ⁇ of 35 wt % may be administered through microneedles in the second area Ar 4
- drug ⁇ of 45 wt % may be administered through microneedles in the third area.
- the microneedles 103 , 103 a , and 103 b have the two-layer structures in which the bottom-section layers 105 , 105 a , and 105 b are formed next to the top-section layers 104 , 104 a , and 104 b , respectively.
- each microneedle may have a structure of three layers or more.
- intermediate layers 106 c , 106 d , and 106 e may be formed between top-section layers 104 c , 104 d , and 104 e and bottom-section layers 105 c , 105 d , and 105 e , respectively.
- the intermediate layers 106 c , 106 d , and 106 e are provided, but any number of a plurality of intermediate layers may be provided.
- a process of filling intermediate-layer raw material liquid and another drying process for drying the intermediate layer are added between the drying process (step S 5 ) and the combination process (step S 20 ) illustrated in FIG. 6 .
- filling of the intermediate-layer raw material liquid can be achieved by using the droplet discharging apparatus 10 in a manner similar to the top-section-layer raw material liquid filling process. As illustrated in FIG.
- the cartridge 13 a or the cartridge 13 b may be replaced after filling for the microneedles 103 c and 103 d of two kinds is finished by using the droplet discharging apparatus 10 , and then filling for the microneedles 103 e of another kind may be performed.
- another droplet discharging apparatus (not illustrated) further including a third nozzle other than the nozzles 11 a and 11 b and a third cartridge other than the cartridges 13 a and 13 b is used, the replacement of a cartridge is not needed, thereby reducing a manufacturing time.
- the intermediate-layer raw material liquid is, for example, solution of a solid raw material in water, a mixed solvent of water and alcohol, or another solvent, or suspension liquid of a solid raw material in water, a mixed solvent of water and alcohol, or another solvent, or a mixture of the solution and the suspension liquid.
- a microneedle array 110 C may be provided that has a structure in which the microneedles 103 c described above are arranged in a first area Ar 6 , the microneedles 103 d are arranged in a second area Ar 7 , and the microneedles 103 e are arranged in a third area Ar 8 as illustrated in FIG. 15( b ) .
- a microneedle array 110 D may be provided that has a structure in which the microneedles 103 c are arranged in a first area Arg, the microneedles 103 d are arranged in a second area Ar 10 , and the microneedles 103 e are arranged in a third area Ar 11 , as illustrated in FIG. 15( c ) .
- the kind of the composition (first composition) of a top-section layer 104 c of each first microneedle 103 c may be different from the kind of the composition (third composition) of the intermediate layer 106 c of the first microneedle 103 c
- the kind of the composition (second composition) of the top-section layer 104 d of each second microneedle 103 d may be different from the kind of the composition (fourth composition) of the intermediate layer 106 d of the second microneedle 103 d .
- At least one of the kind and amount of the composition (first composition) of the top-section layer 104 c of the first microneedle 103 c may be different from the corresponding one of the kind and amount of the composition (second composition) of the top-section layer 104 d of the second microneedle 103 d .
- at least one of the kind and amount of the composition (third composition) of the intermediate layer 106 c of the first microneedle 103 c may be different from the corresponding one of the kind and amount of the composition (fourth composition) of the intermediate layer 106 d of the second microneedle 103 d .
- the intermediate layers 106 c and 106 d correspond to second layers.
- a medicine in usage in the medical field, consists of a first drug ⁇ 1 including a first component P 1 in the top-section layer 104 c and a second component P 2 in the intermediate layer 106 c in each first microneedle 103 c , a second drug ⁇ 1 including a third component Q 1 in the top-section layer 104 d and a fourth component Q 2 in the intermediate layer 106 d in each second microneedle 103 d , and a third drug ⁇ 1 including a fifth component R 1 in the top-section layer 104 e and a sixth component R 2 in the intermediate layer 106 e in each third microneedle 103 e .
- a drug administration amount can be adjusted by adjusting a ratio among the area of the first areas Ar 6 and Ar 9 , the area of the second areas Ar 7 and Ar 10 , and the area of the third areas Ar 8 and Ar 11 while the first microneedle 103 c , the second microneedle 103 d , and the third microneedle 103 e are set to have identical weights and identical densities in the corresponding regions.
- a medicine comprising the drug ⁇ 1 of 20 wt %, the drug ⁇ 1 of 35 wt %, and the drug ⁇ 1 of 45 wt % can be prepared.
- FIG. 13 illustrates the case in which the first area Ar 3 is concentrically comprised in the second area Ar 4
- the first area Ar 3 may be comprised in the second area Ar 4 in any other configuration.
- a microneedle array may have a sea-island structure in which a plurality of first regions are scattered as islands in the sea of a second region.
- the single nozzles 11 a and 11 b are used to filling for one microneedle.
- nozzles may be arrayed to perform the filling for one microneedle on a plurality of recesses 81 all at once.
- a droplet discharging apparatus 10 A according to the third embodiment illustrated in FIG. 16 includes arrayed nozzles 11 c and 11 d .
- the thirteen first discharge head actuators 12 a are attached to the thirteen nozzles 11 c
- the thirteen second discharge head actuators 12 b are attached to the thirteen nozzles 11 d.
- Molds 80 A, 80 B, and 80 C which are continuously moved in the X-axis direction while being placed on the one XYZ stage 21 , each include a matrix of the ten recesses 81 in the X-axis direction and the ten recesses 81 in the Y-axis direction.
- each line of a plurality of the recesses 81 arranged parallel to the X axis droplets can be discharged into the recesses 81 in single lines through a nozzle 11 ca and a nozzle 11 da illustrated in FIG. 16 .
- This configuration of each single line is same as that of the droplet discharging apparatus 10 according to the second embodiment described with reference to FIG. 10 .
- the top-section-layer raw material liquid filling process (step S 4 ) illustrated in FIG. 6 can be performed on the recesses 81 in each line by the filling method in the second embodiment.
- nozzles having no corresponding recesses 81 in the mold 80 are controlled not to discharge droplets by stopping operation of the corresponding first discharge head actuators 12 a and stopping operation of the corresponding second discharge head actuators 12 b.
- the nozzle 11 ca of one nozzle array discharges droplets to the mold 80 A, while another nozzle 11 cc discharges droplets to the next mold 80 B.
- a time taken for filling by the droplet discharging apparatus 10 A can be shortened.
- the ⁇ -axis stepping motor 21 d illustrated in FIG. 2 adjusts an angle ⁇ between a direction Dr 2 in which the nozzles 11 c and 11 d of the droplet discharging apparatus 10 A are arranged and a relative moving direction Dr 1 of the nozzles 11 c and 11 d . Accordingly, the Y coordinates of the plurality of nozzles 11 c and 11 d can be matched with the Y coordinates of the recesses 81 .
- An unillustrated configuration of a microneedle array manufacturing apparatus 1 A in FIG. 16 may be same as that of the microneedle array manufacturing apparatus 1 according to the first embodiment.
- the nozzles 11 c and 11 d are arranged in two lines, but the droplet discharging apparatus 10 A may include nozzles in three lines or more. Alternatively, the droplet discharging apparatus 10 A may only include the nozzles 11 c arranged in one line.
- the recesses 81 are arranged in a square shape. However, when the recesses 81 are arranged in a circular shape, droplets may be discharged while a mold is rotated in the direction of ⁇ .
- the microneedle array manufacturing apparatuses 1 and 1 A are configured to shape the microneedle arrays 110 and 110 A to 110 E consisting of the microneedles 103 and 103 a to 103 f by filling the recesses 81 formed in the molds 80 , 80 A, 80 B, and 80 C with raw material liquid for shaping the microneedles 103 and 103 a to 103 f , and include the droplet discharging apparatuses 10 and 10 A and the positioning apparatus 20 . As illustrated in, for example, FIG.
- the positioning apparatus 20 adjusts, through the XYZ stage 21 of the positioning apparatus 20 , the relative positions of the nozzles 11 a , 11 b , 11 c , and 11 d of the droplet discharging apparatuses 10 and 10 A and the mold 80 so that droplets land into each recess 81 from the droplet discharging apparatuses 10 and 10 A. Then, as illustrated in, for example, FIG.
- the droplet discharging apparatuses 10 and 10 A fill each recess 81 by discharging, to the recess 81 , droplets 91 a to 91 e of the top-section-layer raw material liquid 91 , each having a predetermined amount equal to or smaller than the volume of the recess 81 .
- the top-section-layer raw material liquid filling process (step S 4 ) illustrated in FIG. 6 is a first filling process of filling the recesses 81 with the top-section-layer raw material liquid 91 by landing, into the recesses 81 (exemplary first recesses) of the molds 80 and 80 A to 80 C, the droplets 91 a to 91 e of the top-section-layer raw material liquid 91 (exemplary first raw material liquid) in amounts equal to or smaller than the volumes of the recesses 81 .
- FIG. 6 is a drying process of drying the top-section-layer raw material liquid 91 in the recesses 81 to form the microneedle arrays 110 and 110 A to 110 E each consisting of the microneedles 103 and 103 a to 103 f.
- the amount of the top-section-layer raw material liquid 91 for each recess 81 is accurately adjusted by adjusting the total amount of the droplets 91 a to 91 e discharged to each recess 81 . Since the concentration of any composition in the top-section-layer raw material liquid 91 is substantially uniform, the amount of any composition comprised in the top-section layers 104 and 104 a to 104 e formed by solidifying the top-section-layer raw material liquid 91 is accurately adjusted. As a result, the distribution of any composition of the microneedle arrays 110 and 110 A to 110 E is accurately adjusted.
- the droplet discharging apparatuses 10 and 10 A are configured to discharge the droplets 91 a to 91 e as illustrated in FIG. 8 in a total amount equal to or smaller than the volume of each recess 81 .
- the recess 81 having a circular cone shape as illustrated in FIG. 8 is filled with one droplet of the top-section-layer raw material liquid 91 , air bubbles are more likely to be included at a bottom part of the recess 81 , and the top-section-layer raw material liquid 91 is more likely to spill out of the recess 81 due to bounce at landing.
- the filling is performed with a plurality of droplets, less air bubbles are likely to be included at the bottom part, and the top-section-layer raw material liquid 91 is less likely to spill out of the recess 81 , which facilitates accurate adjustment of the filling amount.
- each single recess 81 is filled with the five droplets 91 a to 91 e in the above-described case illustrated in FIG. 8
- the droplet discharging apparatuses 10 and 10 A are configured to achieve such adjustment that the amount of one droplet at each discharge is equal to or smaller than one third of the volume of the recess 81 .
- the droplet discharging apparatuses 10 and 10 A and the positioning apparatus 20 are configured to achieve such positioning that three or more droplets land on different positions inside the recess 81 .
- the landing positions are landing points Lp 1 to Lp 5 different from each other.
- the droplet discharging apparatuses 10 and 10 A can separately discharge, as raw material liquid, the top-section-layer raw material liquid 91 and 93 having components different from each other by using the nozzle 11 a and the nozzle 11 b , or the nozzle 11 c and the nozzle 11 d .
- the various microneedles 103 and 103 a to 103 f can be combined to easily form the microneedle arrays 110 and 110 A to 110 E in various forms as illustrated in FIG. 4 , FIGS. 11 to 15 , and FIG. 17 for example.
- the droplet discharging apparatuses 10 and 10 A and the positioning apparatus 20 are configured to fill the recesses 81 in the first areas Ar 1 , AR 3 , Ar 5 , Ar 6 , and Ar 9 of the mold 80 with a first amount of raw material liquid, and fill the recesses 81 in the second area Ar 2 , AR 4 , Ar 7 , Ar 6 , and Ar 10 of the mold 80 with a second amount of raw material liquid.
- the amount of composition in the first areas Ar 1 , AR 3 , Ar 5 , Ar 6 , and Ar 9 and the amount of composition in the second area Ar 2 , AR 4 , Ar 7 , Ar 6 , and Ar 10 can be accurately adjusted.
- each recess 81 in which the top-section-layer raw material liquid 93 lands described with reference to FIG. 10 can be regarded as a second recess.
- the top-section-layer raw material liquid filling process (step S 4 ) in FIG. 6 for filling the top-section-layer raw material liquid 93 is a second filling process of filling the recess 81 with the top-section-layer raw material liquid 93 by landing, in the recess 81 of the mold 80 , droplets of the top-section-layer raw material liquid 93 (exemplary second raw material liquid) in an amount equal to or smaller than the volume of the recess 81 .
- the drying process (step S 5 ) in FIG. 6 can be regarded as a drying process of drying the top-section-layer raw material liquid 93 in the recesses 81 to form the microneedle arrays 110 A to 110 E consisting of the microneedles 103 a to 103 f.
- various kinds of microneedle arrays can be manufactured through various combinations of a region in which microneedles manufactured of the top-section-layer raw material liquid 91 (exemplary first raw material liquid) are arranged and a region in which microneedles manufactured of the top-section-layer raw material liquid 93 (exemplary second raw material liquid) are arranged.
- any recess 81 partially filled with the dried and solidified top-section-layer raw material liquid 91 and 93 (exemplary first raw material liquid) can be regarded as a second recess.
- the intermediate-layer raw material liquid filling process according to the modification 2 C is a second filling process of filling the recess 81 with the intermediate-layer raw material liquid by landing, in a recess (exemplary second recess) of the mold 80 , in which the top-section-layer raw material liquid 91 and 93 is dried, droplets of the intermediate-layer raw material liquid in an amount equal to or smaller than the volume of the recess 81 (in this case, a volume except for the volume of the dried and solidified top-section-layer raw material liquid 91 and 93 ).
- the intermediate-layer raw material liquid drying process can be regarded as a drying process of drying the intermediate-layer raw material liquid in the recesses 81 to form the microneedle arrays 110 A to 110 E consisting of the microneedles 103 a to 103 f.
- various kinds of the microneedle arrays 110 C and 110 D can be manufactured through various combinations of the top-section layers 104 c , 104 d , and 104 e manufactured of the top-section-layer raw material liquid 91 and 93 (exemplary first raw material liquid) and the intermediate layers 106 c , 106 d , and 106 e manufactured of the intermediate-layer raw material liquid (exemplary second raw material liquid).
- the combination process (step S 20 ) and the drying and bonding process (step S 21 ) in FIG. 6 are a fixation process of fixing the microneedles 103 a to 103 f comprising parts shaped with the dried top-section-layer raw material liquid 91 and 93 onto the porous base member 85 by placing the porous base member 85 , at least part of a surface of which is covered by the bottom-section-layer raw material liquid 92 (exemplary third raw material liquid), over a surface of the mold 80 , on which the recesses 81 are formed, and drying the bottom-section-layer raw material liquid 92 .
- the bottom-section-layer raw material liquid 92 Since at least part of the surface of the porous base member 85 is covered by the bottom-section-layer raw material liquid 92 , the bottom-section-layer raw material liquid 92 is more likely to penetrate into pores of the porous base member 85 , which facilitates formation of the products 100 and 100 A having microneedles firmly fixed to the porous base member 85 . This effect improves when the curing process (step S 15 ) is provided before the fixation process.
- the first microneedles 103 a and 103 c are formed in at least one of the first areas Ar 1 , Ar 3 , Ar 5 , Ar 6 , and Ar 9 , and comprise the first composition in the top-section layers 104 a and 104 c at the leading ends thereof, and the third composition in the bottom-section layer 105 a (exemplary second layer of the first microneedle) or the intermediate layer 106 c (exemplary second layer of the first microneedle) provided next.
- the second microneedles 103 b and 103 d are formed in at least one of the second areas Ar 2 , Ar 4 , Ar 7 , and Ar 10 adjacent to the first areas Ar 1 , Ar 3 , Ar 5 , Ar 6 , and Ar 9 , and comprise the second composition in the top-section layers 104 b and 104 d at the leading ends thereof and the fourth composition in the bottom-section layer 105 b (exemplary second layer of the second microneedle) or the intermediate layer 106 d (exemplary second layer of the second microneedle) provided next.
- the kind of the first composition is different from the kind of the third composition
- the kind of the second composition is different from the kind of the fourth composition
- at least one of the kind and amount of the first composition is different from the corresponding one of the kind and amount of the second composition
- at least one of the kind and amount of the third composition is different from the corresponding one of the kind and amount of the fourth composition.
- products 100 , 100 A, 100 C, and 100 D including microneedle arrays are used in, for example, the medical field, various drugs can be prepared and the products can be used in various situations of drug administration.
- At least one of the second areas Ar 2 , AR 4 , and Ar 7 can be disposed surrounding at least one of the first areas Ar 1 , AR 3 , and Ar 6 .
- the products 100 , 100 A, and 100 C including microneedle arrays can prevent failure of usage of only microneedles in one of the areas when not all microneedles contact skin, for example.
- a product 100 E including a microneedle array includes the fixing part 109 f and the microneedles 103 f .
- the surface 102 f of the fixing part 109 f has a three-dimensional shape curved like a concave mirror.
- the microneedles 103 f are three-dimensionally arranged on the surface 102 f of the fixing part 109 f along the three-dimensional shape curved like a concave mirror.
- the microneedles 103 f are formed in parallel to each other, all microneedles 103 f extend in a pressing direction, which facilitates insertion. This configuration also facilitates attachment to a relatively small place such as an ear having a complicated three-dimensional shape.
- a microneedle is largely divided into a top section comprising drug and a bottom-section layer comprising no drug.
- the present invention provides a microneedle producing method in which, in production of the microneedle, the top section is first produced and then a thin layer (intermediate layer) is produced by using raw material that has a strength clearly different from that of raw material for producing the other two layers and has a high breaking property, instead of spraying the raw material for producing the bottom-section layer immediately after the drying process is completed, thereby enabling restriction of a damaged part of the microneedle to this fragile boundary.
- the intermediate layer is produced at an end of a top section as a drug containing part, which is closer to the bottom-section layer, the top section containing drug breaks at a basis-side stump and is left in a target dermis, thereby achieving administration of the entire amount of this drug.
- the strength of raw material for producing this intermediate part, after drying, is set to be clearly different from those of the other two parts (the top section and the bottom-section layer).
- this intermediate part is set between a part that breaks and is left in skin epidermis and dermis and a bottom-section layer.
- an intermediate part is formed between a part that breaks and is left in skin and a bottom-section layer.
- the position of this intermediate layer is not limited to the position described in the previous section because of the characteristic of drug contained in the microneedle and an administration purpose.
- the intermediate layer produced in the previous section has a single-layer structure and a strength clearly different from those of other sites, and is specialized to provoke reliable breaking. Instead, an intermediate layer (first intermediate layer) produced after a top section containing drug is manufactured and hardened by drying is manufactured and hardened by drying, and then the same operation is repeated to separately form, manufacture, and hardened by drying an intermediate layer (second intermediate layer).
- the ratio of the thicknesses of the intermediate layers may be 1:1 but may be optionally set as long as the thicknesses satisfy thicknesses to be described later.
- an intermediate layer of a microneedle in the previous section may have a thickness of 5 ⁇ m to 50 ⁇ m, preferably a thickness of 10 ⁇ m to 30 ⁇ m, more preferably a thickness of 15 ⁇ m to 20 ⁇ m.
- the second intermediate layer thicknesses substantially twice as large as the thicknesses listed above are applicable.
- the intermediate layers may have an entire thickness of 10 ⁇ m to 100 ⁇ m, preferably an entire thickness of 20 ⁇ m to 60 ⁇ m, more preferably an entire thickness of 30 ⁇ m to 40 ⁇ m.
- a microneedle acquires capability of reliably breaking at a specified position to be reliably left in a short time and can be formed to have a function to prevent backflow of, through a penetrating hole, drug released from the top section into dermis, when a raw material having a dissolution speed slower than that of a top section is selected as a raw material for producing the first intermediate layer.
- the following describes the strength of each component of a microneedle according to the present invention in an example with a microneedle containing one kind of drug and including a bottom-section layer comprising no drug, and describes setting of the strength of each layer.
- the strength of a microneedle produced in the present invention is highest in the bottom-section layer, followed in order by a top section comprising the drug, and an intermediate layer.
- the top section as a drug containing part includes two or more layers
- an intermediate part is set between a part that breaks and is left in skin and the bottom-section layer, the strength is also highest in the bottom-section layer, followed in order by the top section comprising the drug, and the intermediate layer.
- the weight-average molecular weight of a polymer compound included in each layer is highest in the top section, followed by the bottom-section layer, and can be set further lower in the intermediate part.
- the weight-average molecular weight for each layer may be the same or in the inverse order when a strength condition is satisfied.
- the hardness and weight-average molecular weight of the intermediate layer may be highest.
- the first intermediate layer is formed of a polymer material having a high hardness and a low absorbability and selected as a raw material set to have high concentration
- the second intermediate layer has a strength clearly weaker than those of the first intermediate layer and the bottom-section layer, has a high absorbability, and is formed of a polymer material selected as a raw material set to low concentration.
- setting of the strengths of the intermediate layers or the like is not limited to the above-described relation because of, for example, difference in used drug, and only one of the intermediate layers may be formed. To further efficiently achieve this process, a larger number of intermediate layers may be formed, and drug may or may not be contained in any of the intermediate layers.
- the intermediate layers may be produced after part of the bottom-section-layer raw material is discharged and hardened, and then the rest of the bottom-section layer raw material may be discharged to complete formation of the entire bottom-section layer.
- Each intermediate layer of a microneedle produced in this manner is formed not at a joint surface of the top section and lower-layer sections but in the bottom-section layer. Any kind of drug may be added.
- a microneedle array forming method in which, when produced by an inkjet method, a microneedle array is formed integrally with a bonding surface and a flat surface adhering to a substrate when part or all of the bottom-section layer is produced, whereby collapse of microneedles due to piercing is prevented and a top section containing drug easily and reliably breaks from the bottom-section layer.
- the bonding surface of the bottom-section layer with the top section may be flat, but does not necessarily limited thereto.
- the intermediate layer may have a two-layer structure or a multi-layer structure as described in the previous section.
- a microneedle patch In treatment with a microneedle patch produced by a conventional method and thus including no intermediate layer, in order to reliably perform drug administration, a microneedle patch needs to be fixed to an administration site for 10 minutes to 30 minutes at minimum to one hour to two hours at maximum in accordance with a dissolution time of the raw material of the top section as a drug containing part, until the drug containing part dissolves and drug administration is completed.
- the top section containing drug is instantaneously separated at the intermediate part in dermis substantially simultaneously with insertion and left in the dermis, and thus the bottom-section layer can be removed right after the top section is separated irrespective of the dissolution time of a polymer raw material of the top section as a drug containing part. Accordingly, the series of the drug administration of the microneedle patch is completed within 5 seconds to 20 seconds approximately.
- a formed polymer compound spontaneously dissolves to release the contained drug in the dermis.
- an intermediate layer having a weak strength and a high absorbability is provided at a basis side of the top section containing the drug, backflow through the penetrating hole is prevented to certain extent.
- the first intermediate layer in the previous section is produced in addition, the first intermediate layer is formed of a polymer material having a high hardness and a low absorbability and selected as the raw material set to have high concentration, and thus provides an effect of preventing the backflow by completely closing the penetrating hole for a certain duration after the polymer compound forming the top section is dissolved to release the drug.
- This complete closure duration may be freely set to a desired duration by controlling a dissolution property of the polymer material used in the formation.
- the dissolution time of this layer is 10 minutes to 24 hours, preferably 15 minutes to 6 hours, more preferably 30 minutes to 3 hours.
- the present invention is not limited to these time durations but may be any duration as long as the entire amount of the drug contained in the top section and administered is reliably dissolved and released at the target site inside the dermis.
- FIG. 19 illustrates a state in which droplets 91 a and 91 b for filling with the top-section-layer raw material liquid 91 (first raw material liquid) comprising drug are discharged into a top-section layer formation site 86 of each recess 81 of the mold 80 by using the microneedle array manufacturing apparatuses 1 and 1 B described above.
- the top-section layer formation site 86 from a central part CP to a height illustrated with a dashed line in FIG. 19 is filled with the top-section-layer raw material liquid 91 (first raw material liquid)
- the top-section-layer raw material liquid 91 (first raw material liquid) is hardened by drying.
- the hardening by drying means solidification.
- FIG. 20 illustrates a state in which droplets 94 a and 94 b for filling with the intermediate-layer raw material liquid 94 (second raw material liquid) are discharged onto the hardened top-section layer 104 by using the above-described microneedle array manufacturing apparatuses 1 and 1 B.
- FIG. 21 illustrates a state in which the intermediate-layer raw material liquid 94 (second raw material liquid) is hardened by drying to form the intermediate layer 106 on the top-section layer 104 in contact.
- the intermediate-layer raw material liquid 94 (second raw material liquid) is dried for a slightly longer time.
- FIG. 22 illustrates a state in which the bottom-section layer 105 is formed on the intermediate layer 106 , while being in contact with the intermediate layer 106 .
- the bottom-section layer 105 is formed through filling with the bottom-section-layer raw material liquid 92 (third raw material liquid) by using the microneedle array manufacturing apparatuses 1 and 1 B.
- An upper surface of the bottom-section layer 105 which is opposite the intermediate layer 106 , is a bonding surface AF onto which a support member 120 illustrated in FIG. 23 is to be bonded.
- the following describes, with reference to FIGS. 23 to 26 , a method of using the above-described microneedle patch having a plurality of microneedles each including the top-section layer 104 , the intermediate layer 106 , and the bottom-section layer 105 .
- FIG. 23 illustrates a microneedle 103 g inserted into a dermis 310 through an epidermis 300 .
- the microneedle 103 g includes the top-section layer 104 , the intermediate layer 106 , and the bottom-section layer 105 described above with reference to FIGS. 19 to 22 .
- a microneedle patch 100 F having a plurality of the microneedles 103 g and the support member 120 is a product including a microneedle array.
- arrow K 1 indicates a direction in which the microneedle 103 g is inserted.
- Arrow K 2 indicates a place where the microneedle 103 g breaks.
- FIG. 24 illustrates a state in which the intermediate layer 106 of the microneedle 103 g inserted into the dermis 310 is broken.
- arrow K 3 indicates a direction in which the microneedle patch 100 F is removed from skin.
- the intermediate layer 106 having a weakest breaking strength in the microneedle 103 g breaks, and the top-section layer 104 is left in the dermis 310 .
- FIG. 25 illustrates dissolution of the top-section layer 104 as a drug containing part containing drug and release of the drug.
- an extremely small insertion hole 320 is formed on the epidermis 300 as illustrated in FIG. 25 .
- arrow K 4 represents release of the drug contained in the top-section layer 104 .
- FIG. 26 illustrates a state in which the intermediate layer 106 dissolves following the top-section layer 104 .
- arrow K 5 represents dissolution of the intermediate layer 106 .
- a range enclosed by a dashed line represents a range in which the dissolved top-section layer 104 diffuses.
- FIG. 27 illustrates a state in which droplets 91 a and 91 b for filling with the top-section-layer raw material liquid 91 (first raw material liquid) comprising drug are discharged at the top-section layer formation site 86 of each recess 81 of the mold 80 by using the above-described microneedle array manufacturing apparatuses 1 and 1 B.
- the top-section layer formation site 86 from the central part CP to a height illustrated with a dashed line in FIG. 27 is filled with the top-section-layer raw material liquid 91 (first raw material liquid), the top-section-layer raw material liquid 91 (first raw material liquid) is hardened by drying.
- FIG. 28 illustrates a state in which droplets 94 c and 94 d for filling with first intermediate-layer raw material liquid 941 (second raw material liquid) are discharged onto the hardened top-section layer 104 , by using the above-described microneedle array manufacturing apparatuses 1 and 1 B.
- FIG. 29 illustrates a state in which the first intermediate-layer raw material liquid 941 (second raw material liquid) is hardened by drying to form the first intermediate layer 1061 on the top-section layer 104 in contact.
- FIG. 29 illustrates a state in which droplets 94 e and 94 f for filling with second intermediate-layer raw material liquid 942 are discharged onto the first intermediate layer 1061 by using the above-described microneedle array manufacturing apparatuses 1 and 1 B.
- the second intermediate-layer raw material liquid 942 (third raw material liquid) is dried for a slightly longer time.
- FIG. 30 illustrates a state in which the bottom-section layer 105 is formed on the second intermediate layer 1062 while being in contact with the second intermediate layer 1062 .
- the bottom-section layer 105 is formed through filling with the bottom-section-layer raw material liquid 92 (fourth raw material liquid) by using the microneedle array manufacturing apparatuses 1 and 1 B.
- An upper surface of the bottom-section layer 105 which is opposite the second intermediate layer 1062 , is a bonding surface AF to which the support member 120 illustrated in FIG. 31 is to be bonded.
- the following describes, with reference to FIGS. 31 to 34 , a method of using the above-described microneedle patch having a plurality of microneedles each including the top-section layer 104 , the first intermediate layer 1061 , the second intermediate layer 1062 , and the bottom-section layer 105 .
- FIG. 31 illustrates a microneedle 103 h inserted into dermis 310 through epidermis 300 .
- the microneedle 103 h includes the top-section layer 104 , the first intermediate layer 1061 , the second intermediate layer 1062 , and the bottom-section layer 105 described above with reference to FIGS. 27 to 30 .
- a microneedle patch 100 G having a plurality of the microneedles 103 h and the support member 120 is a product including a microneedle array.
- arrow K 1 indicates a direction in which the microneedle 103 h is inserted.
- Arrow K 2 indicates a place at which the microneedle 103 h breaks.
- FIG. 32 illustrates a state in which the second intermediate layer 1062 of the microneedle 103 h inserted into the dermis 310 is broken.
- arrow K 3 indicates a direction in which the microneedle patch 100 G is removed from skin.
- the second intermediate layer 1062 having a weakest breaking strength in the microneedle 103 h breaks, and the top-section layer 104 is left in the dermis 310 .
- FIG. 33 illustrates dissolution of the top-section layer 104 as a drug containing part containing drug and release of the drug.
- an extremely small insertion hole 320 is formed in the epidermis 300 as illustrated in FIG. 33 .
- arrow K 4 represents release of the drug contained in the top-section layer 104 .
- FIG. 34 illustrates a state in which the intermediate layer 106 dissolves following the top-section layer 104 .
- arrow K 5 represents dissolution of the first intermediate layer 1061 .
- a range enclosed by a dashed line represents a range in which the dissolved top-section layer 104 diffuses.
- This prior art relates to a microneedle array manufacturing apparatus and a microneedle array manufacturing method for manufacturing a microneedle array consisting of a plurality of microneedles, and a product including the microneedle array.
- difference is generated between the thicknesses Lh 1 , Lh 2 , Lh 3 , and Lh 4 of upper layers 231 , 232 , 233 , and 234 of microneedles 221 , 222 , 223 , and 224 .
- the difference in these layer thicknesses degrades the accuracy of composition distribution, and accordingly, the amount of drug differs between the four microneedles 221 , 222 , 223 , and 224 , or large error occurs in the amount of drug as a whole.
- production of a thin uniform plane layer such as an intermediate layer according to the present invention can be optimally performed by the microneedle array manufacturing apparatuses 1 and 1 A described above, and a highly useful product can be provided by the microneedle manufacturing apparatus according to the present invention.
- the prior art is intended to provide a microneedle array manufacturing apparatus and a microneedle array manufacturing method capable of accurately adjusting composition distribution of a microneedle array and provide a product including the microneedle array having accurately adjusted composition distribution.
- a microneedle patch includes a base member and a plurality of microneedles supported by the base member.
- Each microneedle includes a top-section layer comprising a biologically active substance to be pierced into dermis, and an intermediate layer provided between the top-section layer and the base member, including composition having breaking strength weaker than breaking strength of composition of the top-section layer, and having a thickness of 5 ⁇ m to 100 ⁇ m inclusive.
- a microneedle patch according to a second aspect is the microneedle patch according to the first aspect in which the intermediate layer has a thickness of 10 ⁇ m to 30 ⁇ m inclusive.
- a microneedle patch according to a third aspect is the microneedle patch according to the second aspect in which the intermediate layer has a thickness of 15 ⁇ m to 20 ⁇ m inclusive.
- a microneedle patch according to a fourth aspect is the microneedle patch according to any one of the first to third aspects in which the intermediate layer is made of a material that dissolves in dermis following the top-section layer.
- a microneedle patch according to a fifth aspect is the microneedle patch according to any one of the first to fourth aspects in which the intermediate layer is adjusted to break in dermis in 20 seconds or less.
- a microneedle patch according to a sixth aspect is the microneedle patch according to the fifth aspect in which the intermediate layer is adjusted to break in dermis in 5 seconds or less.
- a microneedle patch according to a seventh aspect is the microneedle patch according to any one of the first to sixth aspects further including a bottom-section layer joining the intermediate layer and the base member, in which the intermediate layer has breaking strength weaker than breaking strength of the top-section layer, and the top-section layer has breaking strength weaker than breaking strength of the bottom-section layer.
- a microneedle patch according to an eighth aspect is the microneedle patch according to any one of the first to sixth aspects further including a bottom-section layer joining the intermediate layer and the base member, in which the intermediate layer has a weight-average molecular weight lighter than the weight-average molecular weight of the bottom-section layer, and the bottom-section layer has a weight-average molecular weight lighter than the weight-average molecular weight of the top-section layer.
- a microneedle patch according to a ninth aspect is the microneedle patch according to any one of the first to eighth aspects in which the intermediate layer comprises a first intermediate layer made of, as a primary material, a polymer material having a water absorbability lower than the water absorbability of the top-section layer and is adjusted to dissolve in dermis following the top-section layer.
- the primary material is a material of a content percentage exceeding 50%.
- a microneedle patch according to a tenth aspect is the microneedle patch according to the ninth aspect in which the intermediate layer comprises a second intermediate layer made of, as a primary material, a polymer material having a water absorbability higher than the water absorbability of the top-section layer and is adjusted to dissolve in dermis preceding the top-section layer.
- the primary material is a material of a content percentage exceeding 50%.
- a microneedle patch includes a base member and a plurality of microneedles supported by the base member.
- Each microneedle includes a top-section layer comprising a biologically active substance to be pierced into dermis, and an intermediate layer provided between the top-section layer and the base member.
- the intermediate layer is made of, as a primary material, a polymer material having a water absorbability higher than the water absorbability of the top-section layer, and is adjusted to break in dermis in 20 seconds or less.
- a microneedle patch according to a twelfth aspect is the microneedle patch according to any one of the first to eleventh aspects in which the biologically active substance is drug.
- a microneedle patch according to a thirteenth aspect is the microneedle patch according to any one of the first to twelfth aspects further including a bottom-section layer joining the intermediate layer and the base member, in which the intermediate layer is inside the bottom-section layer.
- a microneedle patch according to a fourteenth aspect is the microneedle patch according to any one of the first to thirteenth aspects further including a bottom-section layer joining the intermediate layer and the base member, in which the bottom-section layer has a thickness larger than the thickness of epidermis, and the intermediate layer reaches at the dermis when a surface of the base member contacts the epidermis.
- the biologically active substance when the microneedles are administered to skin or mucous membrane, the biologically active substance can be reliably left in the mucous membrane, epidermis, or dermis in a short time. As a result, when the microneedles are administered to skin or mucous membrane, a treatment is reliably completed in a short time.
- a microneedle array manufacturing apparatus provides a technology of fine and mass manufacturing of a microneedle array having highly accurate appearance and accuracy by an inkjet method, provides details of an extremely realistic, reproductive, excellent mass production technology providing a new technology that could not achieve by a conventional method of a technology of controlling the breaking property and internal structure of the microneedle, and relates to development of an apparatus configured to manufacture a microneedle having an excellent breaking property at administration to achieve a desired purpose, thereby allowing fast treatment using a microneedle patch, and having a function to prevent backflow of, through a penetrating hole, drug administered in dermis, thereby providing high industrial applicability in the medical field.
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Abstract
Description
- The present invention relates to a microneedle patch capable of achieving fast and reliable drug administration by improving performance of a microneedle array for causing predetermined drug to intradermally reach into dermis and improving a breaking property of the drug at administration, and a method for manufacturing the same.
- Recently, microneedles have been increasingly used in, for example, fields related to the medical field and beauty, cosmetic and health care. For example, drug is administered through the body surface of a human body, such as skin and mucous membrane, by using a microneedle array consisting of a plurality of microneedles. Examples of methods for manufacturing such a microneedle array include a known method of filling, with needle raw material, a plurality of recesses included in a mold by using a squeegee, and solidifying the needle raw material by drying, as disclosed in patent document 1 (Japanese unexamined Patent Application Publication No. 2012-200572).
- [Patent Document 1] Japanese unexamined Patent Application Publication No. 2012-200572
- The present invention provides a technology of fine and mass manufacturing of a microneedle array having highly accurate appearance and accuracy by an inkjet method, and details of an excellent mass production technology of controlling the internal structure of a microneedle so that, when administered to skin or mucous membrane, the microneedle breaks at an end of a drug containing part, which is closer to a bottom-section layer, immediately after inserted into skin, and leaves a top section as the drug containing part in target epidermis or dermis to reliably achieve an initial purpose so that a treatment is reliably completed in a short time.
- The present investors have intensively studied to solve the problem and have produced a microneedle capable of administering contained drug to a target site appropriately by controlling the shape of a boundary of a bottom-section layer and manufacturing an intermediate layer having strength clearly different from those of other sites and locally having a high breaking property. When the intermediate layer includes two layers, a first intermediate layer is formed of a raw material having a high hardness and a low absorbability, and a second intermediate layer is formed of a raw material having relatively low hardness and high absorbability, which intends to cause a top-section layer containing released drug to be reliably left inside dermis. A microneedle array manufacturing apparatus including a plurality of the droplet discharging apparatuses each capable of discharging a raw material obtained by changing, as appropriate, a mixture ratio and concentration of a bioabsorbable formulation that forms a microneedle to achieve the present invention was developed, and an apparatus exploiting a high technology and combined with a control device configured to control the operation state thereof was achieved. In this case, the raw material for the intermediate part may or may not include drug.
- The following describes a plurality of embodiments as means for solving the above-described problems. These embodiments may be optionally combined as necessary.
- To achieve the present invention, a microneedle array manufacturing apparatus according to an aspect of the present invention includes a plurality of the droplet discharging apparatuses capable of discharging raw material obtained by changing, as appropriate, a mixture ratio and concentration of a bioabsorbable formulation that forms a microneedle.
- A microneedle patch according to an aspect of the present invention is a microneedle patch produced by a droplet discharging apparatus capable of separately discharging, as raw material liquid, for example, first liquid, second liquid, third liquid, and fourth liquid containing components different from each other, wherein an intermediate layer having a breaking property higher than a breaking property of a top-section layer comprising a biologically active material, having a function to prevent backflow of, through a penetrating hole, drug released in dermis, and having a thickness of 5 μm to 100 μm is formed after discharge, drying, and hardening of the top-section layer, and the intermediate layer is configured to break in the dermis in 5 seconds to 20 seconds approximately.
- A microneedle patch according to another aspect of the present invention is a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein the strength of a microneedle is highest in a bottom-section layer, followed in order by a top section comprising drug, and an intermediate layer set as a layer having a lowest strength.
- A microneedle patch according to yet another aspect of the present invention is a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein a weight-average molecular weight of a microneedle is largest in a top section comprising drug, followed in order by a bottom-section layer, and an intermediate layer set as a layer having a lowest weight-average molecular weight.
- The microneedle patch may be a microneedle patch produced by discharging different kinds of raw material liquid from a droplet discharging apparatus, wherein the intermediate layer includes one or more layers.
- A microneedle patch according to yet another aspect of the present invention is a microneedle patch produced by discharging different kinds of raw material liquid from a droplet discharging apparatus and including two or more intermediate layers, wherein a first intermediate layer is formed of a polymer material having a high hardness and a low absorbability and selected as a raw material selected to have high concentration, a dissolution time of the first intermediate layer is controlled to be 10 minutes to 24 hours, and drug contained in a top section and released in dermis is prevented from flowing back in a direction toward epidermis through a penetrating hole.
- The microneedle patch produced by discharging different kinds of raw material liquid from a droplet discharging apparatus may include two or more intermediate layers, wherein a second intermediate layer is formed of a polymer material having a low hardness and a high absorbability and selected as a raw material selected to have low concentration, and a function to easily break and separate a top section from a bottom-section layer and reliably leave the top section in dermis in a short time is provided.
- A microneedle patch according to yet another aspect of the present invention is a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein the microneedle patch is produced integrally with a bonding surface and a flat surface adhering to a substrate when part or all of a bottom-section layer is produced, collapse of microneedles due to piercing is prevented, a top section containing drug easily and reliably breaks from the bottom-section layer, and a plurality of intermediate layers each having a function to prevent backflow of the drug from inside of dermis are provided.
- A microneedle patch according to yet another aspect of the present invention is a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein an intermediate layer is provided between a top section and a bottom-section layer, and the intermediate layer is configured to break in dermis in 5 seconds to 20 seconds approximately to leave the top section in the dermis.
- The microneedle patch may be a microneedle patch produced by discharging raw material liquid from a droplet discharging apparatus, wherein an intermediate layer is inside a bottom-section layer.
- A microneedle array manufacturing apparatus according to an aspect of the present invention is a microneedle array manufacturing apparatus for shaping a microneedle array consisting of a plurality of microneedles by filling a plurality of recesses formed in a mold with raw material liquid for forming the microneedles, the apparatus comprising: at least one droplet discharging apparatus capable of discharging, to each recess, a droplet of the raw material liquid in a predetermined amount equal to or smaller than the volume of the recess; and a positioning apparatus capable of adjusting relative positions of the droplet discharging apparatus and the mold so as to land the droplet into the recess from the droplet discharging apparatus, wherein the at least one droplet discharging apparatus are a plurality of droplet discharging apparatuses each capable of discharging raw material obtained by changing, as appropriate, a mixture ratio and concentration of a bioabsorbable formulation that forms a microneedle.
- A microneedle array manufacturing method according to an aspect of the present invention is a microneedle patch manufacturing method comprising the processes of: forming a top-section layer in a recess of a mold; discharging, onto the top-section layer in the recess, a plurality of droplets of first intermediate-layer raw material liquid from a droplet discharging apparatus; hardening the second intermediate-layer raw material liquid to form an intermediate layer having a breaking strength weaker than a breaking strength of the top-section layer; discharging, onto the intermediate layer in the recess, a plurality of droplets of bottom-section-layer raw material liquid from the droplet discharging apparatus; and hardening the bottom-section-layer raw material liquid to form a bottom-section layer having a breaking strength stronger than the breaking strength of the intermediate layer.
- A microneedle patch according to the present invention can achieve fine and mass manufacturing of a microneedle array having highly accurate appearance and accuracy by an inkjet method, can reliably achieve an initial purpose so that a treatment is reliably completed in a short time when microneedles are administered to skin or mucous membrane, because each microneedle breaks at a stump of a top section as a drug containing part, which is closer to a bottom-section layer, immediately after insertion into the skin to leave the top section as a drug containing part in target epidermis or dermis, and can achieve excellent mass productivity.
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FIG. 1 Schematic perspective view illustrating the outline of an apparatus for manufacturing a microneedle array according to a first embodiment. -
FIG. 2 Block diagram for description of a control system of the apparatus for manufacturing a microneedle array inFIG. 1 . -
FIG. 3 Perspective view illustrating an exemplary product including a microneedle array according to the first embodiment. -
FIG. 4 Partially enlarged perspective view of part ofFIG. 3 . -
FIG. 5 Perspective view illustrating an exemplary mold according to the first embodiment. -
FIG. 6 Flowchart of an exemplary method for manufacturing the microneedle array according to the first embodiment. -
FIG. 7 Schematic cross-sectional view for description of discharge of a droplet toward recesses. -
FIG. 8 Schematic enlarged cross-sectional view for description of landing of droplets on a recess. -
FIG. 9 (a) Schematic cross-sectional view illustrating a state before assembly through an assembly process, (b) Schematic cross-sectional view illustrating a state during the assembly through the assembly process, and (c) Schematic cross-sectional view illustrating a state after completion of the assembly through the assembly process. -
FIG. 10 Schematic cross-sectional view for description of discharge of droplets toward recesses in a second embodiment. -
FIG. 11 Perspective view illustrating an exemplary product including a microneedle array according to the second embodiment. -
FIG. 12 Partially enlarged perspective view of part ofFIG. 11 . -
FIG. 13 Perspective view illustrating another exemplary product including the microneedle array according to the second embodiment. -
FIG. 14 Partially enlarged perspective view of part ofFIG. 13 . -
FIG. 15 (a) Schematic cross-sectional view for description of a microneedle array according to a modification 2C, (b) Conceptual diagram for description of an exemplary product including the microneedle array according to the modification 2C, and (c) Conceptual diagram for description of another exemplary product including the microneedle array according to the modification 2C. -
FIG. 16 Conceptual diagram for description of an apparatus for manufacturing a microneedle array according to a third embodiment. -
FIG. 17 (a) Schematic cross-sectional view for description of a method for manufacturing a microneedle array according to a modification 1C, and (b) Conceptual diagram for description of an exemplary product including the microneedle array according to the modification 1C. -
FIG. 18 (a) Schematic cross-sectional view for description of a method for manufacturing a conventional microneedle array, (b) Schematic cross-sectional view illustrating a process of manufacturing the conventional microneedle array, (c) Schematic cross-sectional view of a mold in which a conventional top-section layer is formed, (d) Schematic cross-sectional view for description of a process of filling the conventional microneedle array, and (e) Schematic cross-sectional view illustrating a process of fixing the conventional microneedle array. -
FIG. 19 Schematic cross-sectional view illustrating a process of forming a top-section layer of a microneedle patch. -
FIG. 20 Schematic cross-sectional view illustrating a process of forming an intermediate layer of the microneedle patch. -
FIG. 21 Schematic cross-sectional view illustrating a process of forming the intermediate layer of the microneedle patch and a state after the formation. -
FIG. 22 Schematic cross-sectional view illustrating a process of forming a bottom-section layer of the microneedle patch. -
FIG. 23 Schematic cross-sectional view illustrating a state in which the microneedle patch is inserted. -
FIG. 24 Schematic cross-sectional view illustrating a state when the microneedle patch is removed. -
FIG. 25 Schematic cross-sectional view for description of dissolution of a microneedle. -
FIG. 26 Schematic cross-sectional view for description of dissolution of the intermediate layer of the microneedle. -
FIG. 27 Schematic cross-sectional view illustrating a process of forming a top-section layer of a microneedle patch. -
FIG. 28 Schematic cross-sectional view illustrating a process forming a first intermediate layer of the microneedle patch. -
FIG. 29 Schematic cross-sectional view illustrating a process of forming a second intermediate layer of the microneedle patch. -
FIG. 30 Schematic cross-sectional view illustrating a process of forming a bottom-section layer of the microneedle patch. -
FIG. 31 Schematic cross-sectional view illustrating a state in which the microneedle patch is inserted. -
FIG. 32 Schematic cross-sectional view illustrating a state when the microneedle patch is removed. -
FIG. 33 Schematic cross-sectional view for description of dissolution of a microneedle. -
FIG. 34 Schematic cross-sectional view for description of dissolution of the intermediate layer of the microneedle. - The present invention is related to an apparatus for manufacturing a microneedle array, a method for manufacturing a microneedle array having an optimized breaking property to allow fast drug administration, and a product including the microneedle array.
- The following describes an apparatus for manufacturing a microneedle array, a method for manufacturing the microneedle array, and a product including the manufactured microneedle array according to a first embodiment of the present invention with reference to the accompanying drawings.
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FIG. 1 is a schematic perspective view illustrating the outline of the apparatus for manufacturing a microneedle array. As illustrated inFIG. 1 , the microneedlearray manufacturing apparatus 1 includes adroplet discharging apparatus 10 and apositioning apparatus 20. Thepositioning apparatus 20 includes anXYZ stage 21, aCCD camera 22, and analignment monitor 23. As illustrated inFIG. 1 , thedroplet discharging apparatus 10 is provided with anozzle 11 a for discharging droplets, and acartridge 13 a containing raw material liquid supplied to thenozzle 11 a. Although not illustrated inFIG. 1 , thedroplet discharging apparatus 10 also includes anothernozzle 11 b and anothercartridge 13 b illustrated inFIG. 10 . - In a control system of the microneedle
array manufacturing apparatus 1, as illustrated inFIG. 2 , the microneedlearray manufacturing apparatus 1 includes acontrol device 30 configured to control thedroplet discharging apparatus 10 and thepositioning apparatus 20. In thedroplet discharging apparatus 10, thecontrol device 30 controls a first discharge head actuator 12 a and a seconddischarge head actuator 12 b. In the microneedlearray manufacturing apparatus 1, thecontrol device 30 controls the first discharge head actuator 12 a and the seconddischarge head actuator 12 b to finely adjust the number of droplets discharged from thenozzles positioning apparatus 20, thecontrol device 30 controls anX-axis stepping motor 21 a, a Y-axis stepping motor 21 b, a Z-axis stepping motor 21 c, and a θ-axis stepping motor 21 d of theXYZ stage 21, theCCD camera 22, and thealignment monitor 23. Amold 80 placed on theXYZ stage 21 is moved in an X-axis direction by theX-axis stepping motor 21 a, in a Y-axis direction by the Y-axis stepping motor 21 b, and in a Z-axis direction by the Z-axis stepping motor 21 c, and rotated about a central axis extending in the vertical direction (Z-axis direction) at the center of theXYZ stage 21 by the θ-axis stepping motor 21 d. - The following describes a product including a microneedle array manufactured by using the microneedle
array manufacturing apparatus 1. The microneedlearray manufacturing apparatus 1 forms amicroneedle array 110 consisting of a plurality ofmicroneedles 103 illustrated inFIG. 3 . - Each
microneedle 103 is set to have, for example, a height of 10 μm to 1 mm, a maximum bottom-surface width of 10 μm to 1 mm, and an aspect ratio of 0.5 to 4. - An interval dl between the
microneedles 103 adjacent to each other (distance between nearest places on a surface 102) is set to be, for example, 10 μm to 2 mm. Themicroneedles 103 included in themicroneedle array 110 are set to have a density of, for example, several microneedles to 105 microneedles for one square centimeter approximately. To manufacture such amicroneedle array 110, the microneedlearray manufacturing apparatus 1 is capable of repeating across a travel distance equal to or smaller than the interval dl of themicroneedles 103. Error in the travel distance of the microneedlearray manufacturing apparatus 1 is set to be smaller than the maximum bottom-surface width of each microneedle 103. - The
microneedle array 110 is fixed to thesurface 102 of aplate base member 101. Thebase member 101 has an outer dimension of, for example, 2 mm×17 mm×17 mm approximately. To achieve the fixation of themicroneedle array 110 to thesurface 102, alamination film 109 having a composition same as that of a bottom-section layer 105 is formed on thesurface 102 of thebase member 101. In this manner, aproduct 100 including themicroneedle array 110 fixed to thebase member 101 is formed. When each microneedle 103 has a spired leading end part, a section of the leading end part taken along the vertical direction is angled at, for example, 30°. In this manner, when themicroneedle 103 has the spired leading end part, a recess 81 (refer toFIG. 8 ) on which droplets land has a tilted wall, which facilitates formation of therecess 81 having a shape suitable to be filled with droplets. The landing of a droplet on therecess 81 means hitting and adhesion of the droplet to the surface of the wall of therecess 81. - The
plate base member 101 allows ventilation and is, for example, a porous base member. Examples of porous base members include a porous base member mainly made of cellulose acetate, a porous ceramic base member, a porous metal base member, a pulp molded product obtained by forming pulp in a plate shape, and a porous resin base member. -
FIG. 4 illustrates a partial region EA1 ofFIG. 3 in an enlarged manner. Eachmicroneedle 103 has a two-layer structure consisting of a top-section layer 104 at a leading end and the bottom-section layer 105 therebelow. The top-section layer 104 and the bottom-section layer 105 have compositions different from each other. - In the following description of a component of raw material liquid, the component does not necessarily need to be dissolved in the raw material liquid. For example, when the raw material liquid is suspended liquid, the suspended liquid may have a component of, for example, microcapsules or liposomes.
- The
mold 80 illustrated inFIG. 5 only needs to be formed of a material hygienic against the raw material liquid, but preferably has high gas permeability. For example, themold 80 may be formed of plastic, elastomer, ceramic, or metal. Themold 80 is preferably formed of silicone rubber. The plastic of which themold 80 is formed is preferably, for example, polymethylpentene (TPX (registered trademark)) or polytetrafluoroethylene. The metal of which themold 80 is formed is preferably, for example, stainless steel, which does not transmit gas but is unlikely to rust. A horizontal section of therecess 81 of themold 80 along asurface 82 of themold 80 has, for example, a circular shape, a polygonal shape, or an elliptical shape. Therecess 81 includes an internal space having, for example, a circular cone shape, a pyramid shape, a cylindrical shape, or a rectangular column shape. - Alignment marks 83 are formed on the
surface 82 of themold 80. The alignment marks 83 are read by theCCD camera 22 of the microneedlearray manufacturing apparatus 1. The alignment marks 83 are used as references to control landing of a droplet discharged from thedroplet discharging apparatus 10 in therecess 81, and thus the position of eachrecess 81 is determined with reference to the alignment marks 83. The alignment marks 83 are hygienic and formed as, for example, bumps on thesurface 82. - The
mold 80 when formed of silicone rubber has an outer dimension of, for example, 6 mm×20 mm×20 mm, and therecesses 81 are formed in a region having a size of, for example, 15 mm×15 mm. - Top-section-layer raw material liquid 91 (refer to
FIG. 7 ) for forming the top-section layer 104 of each microneedle 103 is, for example, solution of a solid raw material in water, a mixed solvent of water and alcohol, or another solvent, or suspension liquid of a solid raw material in water, a mixed solvent of water and alcohol, or another solvent, or a mixture of the solution and the suspension liquid. The solid raw material is a polymer substance harmless to a human body and is, for example, a resin harmless to a human body, a polysaccharide harmless to a human body, a protein harmless to a human body, or a compound thereof harmless to a human body. Examples of compounds to be introduced into a human body include a biologically active substance used for treatment, diagnosis, and prevention of injuries and diseases. - The top-section-layer raw material liquid is, for example, a solvent of aqueous polysaccharide (comprising derivatives and salts thereof) containing a biologically active substance administered for diagnosis, treatment, and prevention of diseases. Such a solvent of the top-section-layer raw material liquid is evaporated to form, in a substrate of polysaccharide, the top-
section layer 104 comprising the biologically active substance. Examples of the aqueous polysaccharide (comprising derivatives and salts thereof) include sodium chondroitin sulfate, hyaluronic acid, dextran, and carboxymethyl cellulose. Examples of the biologically active substance include insulin and growth hormone. - Bottom-section-layer raw material liquid for forming the bottom-
section layer 105 of themicroneedle 103 is different from the top-section-layer raw material liquid in a composition of at least one of solid raw material and solvent. When the top-section-layer raw material liquid and the bottom-section-layer raw material liquid have different compositions in this manner, the top-section layer 104 and the bottom-section layer 105 of themicroneedle 103 have different compositions. The present embodiment describes exemplary medical usage of themicroneedle 103 in which the top-section layer 104 comprises a biologically active medicinal substance and the bottom-section layer 105 comprises no biologically active substance. However, for example, in medical usage of themicroneedle 103, the top-section layer 104 and the bottom-section layer 105 may both comprise biologically active medicinal substances. Differences can be obtained between a medical effect provided by the top-section layer 104 and the duration thereof and a medical effect provided by the bottom-section layer and the duration thereof, by providing differences between the kind and amount of the biologically active substance comprised in the top-section layer 104 and the kind and amount of the biologically active substance comprised in the bottom-section layer 105. In medical usage of theproduct 100 including the microneedle array, theproduct 100 is applicable to various kinds of drug administration when each microneedle 103 has a two-layer structure in this manner. - The top-section-layer raw material liquid is discharged as a droplet from, for example, the
droplet discharging apparatus 10, and the amount of the droplet is set to be, for example, 0.1 nanoliter/droplet to 1 microliter/droplet. For example, when eachrecess 81 for forming onemicroneedle 103 has a capacity of 20 nanoliters, one droplet has 1 nanoliter to fill therecess 81 with 20 droplets. Filling with such a minute droplet preferably requires a low viscosity such as, 0.1 mPa·sec to 100 mPa·sec, preferably 1 mPa·sec to 10 mPa·sec. -
FIG. 6 is a flowchart for description of a process of manufacturing theproduct 100 including the above-described microneedle array by using the microneedlearray manufacturing apparatus 1. In the process of manufacturing theproduct 100 including the microneedle array, an operation from step S1 to step S5 and an operation from step S11 to step S15 inFIG. 6 can be performed in parallel independently from each other. However, the two operations may share any operation if possible. Although operation of the microneedlearray manufacturing apparatus 1 at each step is controlled by thecontrol device 30, the following description omits part of description of control of each component of the microneedlearray manufacturing apparatus 1 by thecontrol device 30. In the first embodiment, only the first discharge head actuator 12 a is used to discharge droplets from thenozzle 11 a, whereas a manufacturing method using the seconddischarge head actuator 12 b will be described in a second embodiment. In the first embodiment, the θ-axis stepping motor 21 d is not used, whereas a manufacturing method using the θ-axis stepping motor 21 d will be described in a third embodiment. - An operation using the
mold 80 is performed at steps S1 to S5 inFIG. 6 . First, themold 80 illustrated inFIG. 5 is prepared (step S1). In the process of preparing themold 80 at step S1, for example, a predetermined number ofmolds 80 are washed by water and arranged at a predetermined place. Theprepared molds 80 are all sterilized through, for example, an autoclave (not illustrated) (step S2). The sterilizedmolds 80 are placed on theXYZ stage 21 of the microneedlearray manufacturing apparatus 1 in a clean environment, and subjected to positioning (step S3). - The positioning of each sterilized
mold 80 is performed after themold 80 is placed on theXYZ stage 21 by, for example, a sterilized robotic arm. TheCCD camera 22 captures an image of the alignment marks 83 of themold 80 on theXYZ stage 21, and thecontrol device 30 recognizes the alignment marks 83 as references, thereby performing the positioning. Thecontrol device 30 specifies the position of eachrecess 81 with reference to the alignment marks 83 of themold 80, which allows theXYZ stage 21 to move themold 80 relative to thenozzle 11 a of thedroplet discharging apparatus 10 so that thenozzle 11 a of thedroplet discharging apparatus 10 unicursally and sequentially follows the adjacent recesses 81. - At step S4, as illustrated in
FIGS. 7 and 8 , themold 80 is moved relative to thenozzle 11 a so that a droplet discharged from thenozzle 11 a directly lands in eachrecess 81 of themold 80 to fill therecess 81 with the top-section-layerraw material liquid 91. As illustrated inFIG. 8 , when small droplets land in therecess 81, a larger part of the droplets contacts air, and as a result, the top-section-layerraw material liquid 91 can be dried in a shorter time. Thedroplet discharging apparatus 10 and theXYZ stage 21 are controlled to operate in synchronization so that the top-section-layerraw material liquid 91 discharged from thenozzle 11 a does not land on thesurface 82 of themold 80.FIG. 8 illustrates fivedroplets raw material liquid 91 discharged from thenozzle 11 a for eachrecess 81, and landing points Lp1, Lp2, Lp3, Lp4, and Lp5 of therespective droplets recess 81. For example, when the droplets are sequentially discharged while thenozzle 11 a is moved relative to themold 80 at a constant speed, the landing points Lp1, Lp2, Lp3, Lp4, and Lp5 are different from each other. When the discharging is repeated to cause droplets to land on different positions while thenozzle 11 a is moved in this manner, eachmold 80 can be filled in a shorter time, and accordingly, a product including the microneedle array can be manufactured in a short time. The speed of thenozzle 11 a relative to themold 80 may be set to change between start and completion of the landing on eachrecess 81. - The number of droplets of the discharged top-section-layer
raw material liquid 91 is not limited to five but may be set as appropriate. The number of droplets for eachrecess 81 is set to be, for example, one to several tens. The amount of droplets of the discharged top-section-layerraw material liquid 91 may be set as appropriate. For example, the amounts of thedroplets recess 81 and increased at a position closer to the center of therecess 81, or the amount of droplets may be increased at a position closer to the edge of therecess 81 and reduced at a position closer to the center of therecess 81, the amount of droplets may be reduced toward the end of discharging at therecess 81, or the amount of droplets may be increased toward the end of discharging at therecess 81. - In this example, the total volume of the five droplets of the top-section-layer
raw material liquid 91 discharged into eachrecess 81 is set to be equal to the volume of the internal space of the recess 81 (volume of the recess 81). Thus, when the top-section-layer raw material liquid filling process at step S4 is completed, all recesses 81 are fully filled with the top-section-layerraw material liquid 91. However, the filling amount of the top-section-layerraw material liquid 91 may set to differ in accordance with the position of eachrecess 81 within themold 80. For example, the filling amount of the top-section-layerraw material liquid 91 is set to be larger for therecess 81 closer to the center of themold 80 and be smaller for therecess 81 closer to an end part of themold 80, or the filling amount of the top-section-layerraw material liquid 91 is set to be larger for therecess 81 closer to the center of themold 80 and be smaller for therecess 81 closer to an end part of themold 80. The filling amount may be changed by changing, for example, the amount of one droplet, the number of droplets for eachrecess 81, or both the amount and number of droplets. - The relative movement of the
nozzle 11 a to eachrecess 81 is mainly performed on the XY coordinate of theXYZ stage 21, that is, in the in-plane direction of thesurface 82 of themold 80, but may involve movement in the Z-axis direction. For example, when therecesses 81 of themold 80 have different sizes at different places, thenozzle 11 a may be moved toward or away from themold 80 to change the accuracy of landing. - When the top-section-layer raw material liquid filling process (step S4) is completed, the
mold 80 is moved from theXYZ stage 21 to a wind dry unit (not illustrated) by, for example, a sterilized robotic arm. At the wind dry unit, for example, the filledmold 80 is sequentially placed on a belt conveyer (not illustrated) and moved through clean dry air. Then, at the end point of the belt conveyer, themold 80 with the dried and solidified top-section-layerraw material liquid 91 is sequentially taken out and subjected to the following combination process. - The operation at steps S11 to S15, which is performed in parallel with the operation at steps S1 to S5 described above, is performed by using a porous base member 85 (see
FIG. 9(a) ). First, in a process of preparing theporous base member 85, surfaces of a predetermined number of theporous base members 85 are cleaned by, for example, air and then theporous base members 85 are arranged at a predetermined place. The preparedporous base members 85 are all sterilized through, for example, an autoclave (not illustrated) (step S12). Each sterilizedporous base member 85 is sequentially subjected to positioning with respect to a dispenser (not illustrated) in a dispense unit by a feeder device (not illustrated) (step S13). - At step S14, bottom-section-layer
raw material liquid 92 is distributed by the dispenser to theporous base members 85 and placed on theporous base member 85 in contact with theporous base member 85 as illustrated inFIG. 9(a) . The bottom-section-layerraw material liquid 92 is set to have, for example, a viscosity larger than 1 Pa·sec and smaller than 1000 Pa·sec, and the amount of the bottom-section-layerraw material liquid 92 is set to several tens mg for themold 80 having a size of 20 mm×20 mm. The bottom-section-layerraw material liquid 92 is a material that forms thelamination film 109 by a method to be described later, and thus preferably has a relatively high viscosity as described above. To settle the bottom-section-layerraw material liquid 92 having such a relatively high viscosity on theporous base member 85, the manufacturing method does not transition to a drying and bonding process (step S20) soon after the bottom-section-layerraw material liquid 92 is filled. The method includes a curing process (step S15) for allocating a time in which the bottom-section-layerraw material liquid 92 penetrates into theporous base member 85 by, for example, capillary action. The curing process only waits for an appropriate time of, for example, several seconds to several tens seconds. The curing process may involve, for example, a penetration promoting means that applies vibration or high pressure while the bottom-section-layerraw material liquid 92 is in contact with theporous base member 85. - In the subsequent combination process (step S20), the
mold 80 is fixed on asuction stage 41 by suction as illustrated inFIG. 9(a) . Theporous base member 85 is placed on aplacement stage 42. To perform step S20, themold 80 subjected to the drying process (step S5) is placed on thesuction stage 41 by, for example, a sterilized robotic arm, and theporous base member 85 subjected to the curing process (step S15) is placed on theplacement stage 42 by, for example, a sterilized robotic arm. - Subsequently, as illustrated in
FIG. 9(b) , thesuction stage 41 is moved up and inverted so that themold 80 fixed to thesuction stage 41 is placed over theporous base member 85 placed on theplacement stage 42. While themold 80 is placed over on theporous base member 85 as illustrated inFIG. 9(b) , thesuction stage 41 is pressed toward theplacement stage 42 to receive application of predetermined pressure. This predetermined pressure spreads the bottom-section-layerraw material liquid 92 sandwiched between theporous base member 85 and themold 80. However, applied pressure is adjusted to the predetermined pressure to prevent the bottom-section-layerraw material liquid 92 from spreading out of theporous base member 85. To obtain such a result, for example, a preliminary experiment is performed to find an appropriate value of the predetermined pressure. The fixation of themold 80 to thesuction stage 41 may be maintained or canceled when thesuction stage 41 applies pressure to themold 80. Subsequently, as illustrated inFIG. 9(c) , thesuction stage 41 is removed from themold 80 while the fixation of thesuction stage 41 to themold 80 is canceled. The volume of the top-section-layerraw material liquid 91 decreases through drying, which leaves a step between thesurface 82 of themold 80 and the surface of a substance produced through solidification of the top-section-layerraw material liquid 91. The bottom-section-layerraw material liquid 92 enters into a space created inside eachrecess 81 due to this step, thereby forming the bottom-section layer 105 of themicroneedles 103. - The
mold 80 and theporous base member 85 in the state illustrated inFIG. 9(c) is moved from theplacement stage 42 to a stock unit (not illustrated). At the stock unit, the bottom-section-layerraw material liquid 92 between themold 80 and theporous base member 85 is dried while a load is applied on themold 80 from above. The load is applied on themold 80 from above by, for example, a method of placing a weight on themold 80 or a method of setting an assembly of themold 80 and theporous base member 85 to a load stock dedicated machine configured to apply a load by air pressure or pressure through a spring. - The first embodiment describes the
microneedles 103 having a two-layer structure in which the bottom-section layer 105 comprises no biologically active substance and provides no medical effect and the top-section layer 104 comprises a biologically active substance and provides a medical effect. For example, to extremely reduce a manufacturing error in the amount of drug comprised in the top-section layer 104, the amount of raw material liquid filling each recess needs to be extremely accurately controlled. In such a case, as compared to a conventional case in which the recess is filled with the raw material liquid by using a squeegee, the amount of the raw material liquid can be accurately controlled by the microneedlearray manufacturing apparatus 1 and the microneedle array manufacturing method according to the first embodiment described above, in which the recess is filled with the raw material liquid in a predetermined number of droplets each having an adjusted fluid amount, and thus the amount of drug can be extremely accurately adjusted. - However, a microneedle array manufactured by the microneedle
array manufacturing apparatus 1 and the microneedle array manufacturing method described in the first embodiment is not limited to themicroneedle array 110 consisting of themicroneedles 103 each having a two-layer structure described above. For example, the microneedlearray manufacturing apparatus 1 and the microneedle array manufacturing method can manufacture a microneedle array consisting of microneedles each having a two-layer structure in which the top-section layer 104 comprises no biologically active substance and provides no medical effect and the bottom-section layer 105 comprises a biologically active substance and provides a medical effect. Alternatively, as in the above description of (4) Raw material liquid, the top-section layer and the bottom-section layer of each microneedle may both comprise biologically active medicinal substances. In addition, the microneedlearray manufacturing apparatus 1 and the microneedle array manufacturing method can manufacture a microneedle array consisting of microneedles each having a multi-layer structure consisting of three or more layers. In this manner, the microneedlearray manufacturing apparatus 1 and the microneedle array manufacturing method described in the first embodiment are suitable for manufacturing of a product including a microneedle array consisting of a plurality of microneedles each comprising a plurality of layers having compositions different from each other. - When a microneedle array is used in a field other than the medical field, for example, in fields related to beauty care and healthcare, the
microneedles 103 may each have a two-layer structure in which the top-section layer 104 and the bottom-section layer 105 both comprise no biologically active substance and provide no medical effect. - At least one of the top-
section layer 104 and the bottom-section layer 105 may be formed of biologically active substances without using polysaccharide exemplarily described in the first embodiment. - The top-section-layer raw material liquid described above may be, for example, solution of at least one or combination of aqueous polysaccharide, aqueous protein, polyvinyl alcohol, carboxy vinyl polymer, sodium polyacrylate described above. Examples of aqueous protein include serum albumin. The top-section-layer raw material liquid may comprise another substance such as monosaccharide or oligosaccharide. Examples of monosaccharide include glucose, and examples of oligosaccharide include disaccharide such as sucrose.
- In the above-described first embodiment, positioning is performed by capturing images of the alignment marks 83 through the
CCD camera 22 and moving theXYZ stage 21 with reference to the alignment marks 83, but is not limited to such a method. For example, the positioning may be performed by pressing a side surface of themold 80 to a jig to set a reference position. - In the above-described first embodiment, the
base member 101 has a flat plate shape, but may have a thin sheet shape or a three-dimensional shape with a curved surface. As illustrated inFIG. 17(a) , a surface 82A of amold 80A may have a curved shape like a concave mirror, and thenozzle 11 a may be moved along this curved surface of thesurface 82 to fill eachrecess 81 with the top-section-layerraw material liquid 91. Accordingly, a plurality ofmicroneedles 103 f can be constantly formed in parallel to each other irrespective of a curved shape of asurface 102 f of a fixingpart 109 f as illustrated inFIG. 17(b) . This configuration facilitates insertion of themicroneedles 103 f at any places of amicroneedle array 110E. For example, when a microneedle array is formed on a sheet and the sheet is three-dimensionally deformed, microneedles are substantially vertical to a curved surface, but not in parallel to each other. This configuration makes difficult insertion of some of the microneedles and makes the microneedles prone to damage. - The fixing
part 109 f can be formed by a method same as that of the first embodiment by using the bottom-section-layerraw material liquid 92. The amount of composition comprised in each microneedle 103 f can be accurately adjusted to an amount set in advance depending on the number of droplets of the top-section-layerraw material liquid 91. - The fixing
part 109 f may have any other three-dimensional shape. The above-described effect can be obtained when themicroneedles 103 f are three-dimensionally disposed on thesurface 102 f of the fixingpart 109 f and formed in parallel to each other. - In the above-described first embodiment, the
droplet discharging apparatus 10 uses thesingle nozzle 11 a, but in the second embodiment, as illustrated inFIG. 10 , the twonozzles cartridges FIG. 10 contain top-section-layerraw material liquid - The
droplet discharging apparatus 10 illustrated inFIG. 10 discharges, to therecesses 81 adjacent to each other, droplets of the top-section-layerraw material liquid 91 and droplets of the top-section-layerraw material liquid 93 alternately with thenozzle 11 a and thenozzle 11 b. The total amount of droplets discharged by thenozzles recesses 81. -
FIG. 11 illustrates aproduct 100A including amicroneedle array 110A formed by the above-described manufacturing method.FIG. 12 illustrates a partial region EA2 ofFIG. 11 in an enlarged manner. Similarly to themicroneedles 103 according to the first embodiment, afirst microneedle 103 a and asecond microneedle 103 b according to the second embodiment have two-layer structures consisting of top-section layers section layers section layers section layers section layers section layer 104 a and the bottom-section layer 105 a of thefirst microneedle 103 a are different from each other, and the top-section layer 104 b and the bottom-section layer 105 b of thesecond microneedle 103 b are different from each other. The bottom-section layers section layers section layers - In this example, the kind of the composition (first composition) of the top-
section layer 104 a of thefirst microneedle 103 a is different from the kind of the composition (third composition) of the bottom-section layer 105 a of thefirst microneedle 103 a, and the kind of the composition (second composition) of the top-section layer 104 b of thesecond microneedle 103 b is different from the kind of the composition (fourth composition) of the bottom-section layer 105 b of thesecond microneedle 103 b. The kind and amount of the composition (first composition) of the top-section layer 104 a of thefirst microneedle 103 a are different from the kind and amount of the composition (second composition) of the top-section layer 104 b of thesecond microneedle 103 b. In addition, the amount of the composition (third composition) of the bottom-section layer 105 a of thefirst microneedle 103 a is different from the amount of the composition (fourth composition) of the bottom-section layer 105 b of thesecond microneedle 103 b. - In
FIGS. 11 and 12 , a first area Ar1 is a line in which thefirst microneedle 103 a is formed, and a second area Ar2 is a line in which thesecond microneedle 103 b is formed. The first area Ar1 is sandwiched by the second areas Ar2 on both sides. Simultaneously, each second area Ar2 is sandwiched by the first areas Ar1 on both sides. In other words, a plurality of the first areas Ar1 and a plurality of the second areas Ar2 are alternately arranged. - With a conventional microneedle array manufacturing method using a squeegee, it is difficult to have microneedles in different structures alternately in lines adjacent to each other and accurately adjust the thicknesses of each layer in each microneedle, which can be, however, achieved by a method for manufacturing the
microneedle array 110A according to the second embodiment. - As described above, in the method for manufacturing the
microneedle array 110A according to the second embodiment, only the top-section-layer raw material liquid filling process (step S4) illustrated inFIG. 6 is changed as described above, whereas the other processes are performed in a manner same as that of the first embodiment. - In the above-described second embodiment, the kind of the first composition is different from the kind of the third composition, and the kind of the second compositions different from the kind of the fourth composition. The kind and amount of the first composition are different from the kind and amount of the second composition. In addition, in the second embodiment, the amount of the third composition is different from the amount of the fourth composition. However, other combinations are possible as described below.
- Specifically, the kind of the first composition is different from the kind of the third composition, the kind of the second composition is different from the kind of the fourth composition, the kind or amount of the first composition is different from the kind or amount of the second composition, and the kinds and amounts of the third composition and the fourth composition are different from each other.
- For example, when the
cartridge 13 a and thecartridge 13 b contain the top-section-layerraw material liquid 91 having the same composition, the first composition is different from the kind of the third composition, the second composition is different from the kind of the fourth composition, only the amounts of the first composition and the second composition are different from each other, and only the amounts of the third composition and the fourth composition are different from each other. - The second embodiment describes lines of the
first microneedles 103 a arranged straight and thesecond microneedles 103 b arranged straight as illustrated inFIGS. 11 and 12 . However, the arrangement of microneedles in different structures is not limited to the arrangement illustrated inFIGS. 11 and 12 . For example, m1 lines (m1 is a natural number) of thefirst microneedles 103 a are arranged, n1 lines (n1 is a natural number) of thesecond microneedles 103 b are arranged next, m2 lines (m2 is a natural number) of thefirst microneedles 103 a are arranged next, and n2 lines (n2 is a natural number) of thesecond microneedles 103 b are arranged next. In other words, thefirst microneedles 103 a and thesecond microneedles 103 b may be arranged alternately in an optional number of lines. A ratio of the total volume of the top-section layers 104 a of thefirst microneedles 103 a and the total volume of the top-section layer 104 b of thesecond microneedle 103 b comprised in one microneedle array is adjusted by adjusting each number of lines, thereby adjusting, for example, the administration amounts of two kinds of drugs. - For example, as illustrated in
FIGS. 13 and 14 , lines of thefirst microneedles 103 a may be arranged in a first area Ar3 having a circular shape and a first area Ar5 having a ring shape, and a second area Ar4 in which lines of thesecond microneedles 103 b are arranged may be disposed surrounding the lines of thefirst microneedles 103 a in the first area Ar3. In such a case, the first area Ar5 is disposed surrounding the second area Ar4. In this manner, when amicroneedle array 110B is arranged in a circle and themicroneedles - In this example, the
microneedles 103 a are same in the two first areas Ar3 and Ar5, but the kind (the kind and amount of a contained composition) of microneedles may be different between the two first areas Ar3 and Ar5, and the region denoted by Ar5 may be a third area. For example, in usage in the medical field, drug α of 20 wt % may be administered through microneedles in the first area Ar3, drug β of 35 wt % may be administered through microneedles in the second area Ar4, and drug γ of 45 wt % may be administered through microneedles in the third area. - In the above-described first and second embodiments, the
microneedles microneedles FIG. 15(a) ,intermediate layers section layers section layers intermediate layers - When such three-layer structures of the
microneedles FIG. 6 . In the intermediate-layer raw material liquid filling process, filling of the intermediate-layer raw material liquid can be achieved by using thedroplet discharging apparatus 10 in a manner similar to the top-section-layer raw material liquid filling process. As illustrated inFIG. 15(a) , in manufacturing of a microneedle array having themicroneedles cartridge 13 a or thecartridge 13 b may be replaced after filling for themicroneedles droplet discharging apparatus 10, and then filling for themicroneedles 103 e of another kind may be performed. However, when another droplet discharging apparatus (not illustrated) further including a third nozzle other than thenozzles cartridges - Similarly to the top-section-layer raw material liquid, the intermediate-layer raw material liquid is, for example, solution of a solid raw material in water, a mixed solvent of water and alcohol, or another solvent, or suspension liquid of a solid raw material in water, a mixed solvent of water and alcohol, or another solvent, or a mixture of the solution and the suspension liquid.
- A microneedle array 110C may be provided that has a structure in which the
microneedles 103 c described above are arranged in a first area Ar6, themicroneedles 103 d are arranged in a second area Ar7, and themicroneedles 103 e are arranged in a third area Ar8 as illustrated inFIG. 15(b) . Alternatively, amicroneedle array 110D may be provided that has a structure in which themicroneedles 103 c are arranged in a first area Arg, themicroneedles 103 d are arranged in a second area Ar10, and themicroneedles 103 e are arranged in a third area Ar11, as illustrated inFIG. 15(c) . - In such a case, as for
first microneedles 103 c arranged in the first areas Ar6 and Arg andsecond microneedles 103 d arranged in the second areas Ar7 and Ar10, the kind of the composition (first composition) of a top-section layer 104 c of eachfirst microneedle 103 c may be different from the kind of the composition (third composition) of theintermediate layer 106 c of thefirst microneedle 103 c, and the kind of the composition (second composition) of the top-section layer 104 d of eachsecond microneedle 103 d may be different from the kind of the composition (fourth composition) of theintermediate layer 106 d of thesecond microneedle 103 d. At least one of the kind and amount of the composition (first composition) of the top-section layer 104 c of thefirst microneedle 103 c may be different from the corresponding one of the kind and amount of the composition (second composition) of the top-section layer 104 d of thesecond microneedle 103 d. In addition, at least one of the kind and amount of the composition (third composition) of theintermediate layer 106 c of thefirst microneedle 103 c may be different from the corresponding one of the kind and amount of the composition (fourth composition) of theintermediate layer 106 d of thesecond microneedle 103 d. In this example, theintermediate layers - Then, in usage in the medical field, a medicine can be produced that consists of a first drug α1 including a first component P1 in the top-
section layer 104 c and a second component P2 in theintermediate layer 106 c in eachfirst microneedle 103 c, a second drug β1 including a third component Q1 in the top-section layer 104 d and a fourth component Q2 in theintermediate layer 106 d in eachsecond microneedle 103 d, and athird drug γ 1 including a fifth component R1 in the top-section layer 104 e and a sixth component R2 in theintermediate layer 106 e in eachthird microneedle 103 e. In this medicine, for example, a drug administration amount can be adjusted by adjusting a ratio among the area of the first areas Ar6 and Ar9, the area of the second areas Ar7 and Ar10, and the area of the third areas Ar8 and Ar11 while thefirst microneedle 103 c, thesecond microneedle 103 d, and thethird microneedle 103 e are set to have identical weights and identical densities in the corresponding regions. For example, when the ratio among the area of the first areas Ar6 and Ar9, the area of the second areas Ar7 and Ar10, and the area of the third areas Ar8 and Ar11 is set to 4:7:9, a medicine comprising the drug α1 of 20 wt %, the drug β1 of 35 wt %, and thedrug γ 1 of 45 wt % can be prepared. - Although
FIG. 13 illustrates the case in which the first area Ar3 is concentrically comprised in the second area Ar4, the first area Ar3 may be comprised in the second area Ar4 in any other configuration. For example, a microneedle array may have a sea-island structure in which a plurality of first regions are scattered as islands in the sea of a second region. - In the above-described first and second embodiments, the
single nozzles recesses 81 all at once. - A
droplet discharging apparatus 10A according to the third embodiment illustrated inFIG. 16 includes arrayednozzles discharge head actuators 12 a are attached to the thirteennozzles 11 c, and the thirteen seconddischarge head actuators 12 b are attached to the thirteennozzles 11 d. -
Molds XYZ stage 21, each include a matrix of the tenrecesses 81 in the X-axis direction and the tenrecesses 81 in the Y-axis direction. - As for each line of a plurality of the
recesses 81 arranged parallel to the X axis, for example, droplets can be discharged into therecesses 81 in single lines through anozzle 11 ca and anozzle 11 da illustrated inFIG. 16 . This configuration of each single line is same as that of thedroplet discharging apparatus 10 according to the second embodiment described with reference toFIG. 10 . Thus, the top-section-layer raw material liquid filling process (step S4) illustrated inFIG. 6 can be performed on therecesses 81 in each line by the filling method in the second embodiment. - In this case, nozzles having no corresponding
recesses 81 in themold 80, for example,nozzles 11 cb and 11 db, are controlled not to discharge droplets by stopping operation of the corresponding firstdischarge head actuators 12 a and stopping operation of the corresponding seconddischarge head actuators 12 b. - Since the
molds nozzle 11 ca of one nozzle array discharges droplets to themold 80A, while anothernozzle 11 cc discharges droplets to thenext mold 80B. In this manner, when thedroplet discharging apparatus 10A discharges droplets simultaneously to the plurality ofsequential molds droplet discharging apparatus 10A can be shortened. - In manufacturing of another lot, when droplets are discharged to molds between which the arrangement interval of the
recesses 81 are different, the θ-axis stepping motor 21 d illustrated inFIG. 2 adjusts an angle θ between a direction Dr2 in which thenozzles droplet discharging apparatus 10A are arranged and a relative moving direction Dr1 of thenozzles nozzles recesses 81. - An unillustrated configuration of a microneedle array manufacturing apparatus 1A in
FIG. 16 may be same as that of the microneedlearray manufacturing apparatus 1 according to the first embodiment. - In the above-described third embodiment, the
nozzles droplet discharging apparatus 10A may include nozzles in three lines or more. Alternatively, thedroplet discharging apparatus 10A may only include thenozzles 11 c arranged in one line. - In the above-described third embodiment, the
recesses 81 are arranged in a square shape. However, when therecesses 81 are arranged in a circular shape, droplets may be discharged while a mold is rotated in the direction of θ. - (11-1)
- As described above, the microneedle
array manufacturing apparatuses 1 and 1A are configured to shape themicroneedle arrays microneedles recesses 81 formed in themolds microneedles droplet discharging apparatuses positioning apparatus 20. As illustrated in, for example,FIG. 8 , thepositioning apparatus 20 adjusts, through theXYZ stage 21 of thepositioning apparatus 20, the relative positions of thenozzles droplet discharging apparatuses mold 80 so that droplets land into eachrecess 81 from thedroplet discharging apparatuses FIG. 8 , thedroplet discharging apparatuses recess 81 by discharging, to therecess 81,droplets 91 a to 91 e of the top-section-layerraw material liquid 91, each having a predetermined amount equal to or smaller than the volume of therecess 81. - In the microneedle array manufacturing method, the top-section-layer raw material liquid filling process (step S4) illustrated in
FIG. 6 is a first filling process of filling therecesses 81 with the top-section-layerraw material liquid 91 by landing, into the recesses 81 (exemplary first recesses) of themolds droplets 91 a to 91 e of the top-section-layer raw material liquid 91 (exemplary first raw material liquid) in amounts equal to or smaller than the volumes of therecesses 81. The drying process (step S5) illustrated inFIG. 6 is a drying process of drying the top-section-layerraw material liquid 91 in therecesses 81 to form themicroneedle arrays microneedles - In this manner, the amount of the top-section-layer
raw material liquid 91 for eachrecess 81 is accurately adjusted by adjusting the total amount of thedroplets 91 a to 91 e discharged to eachrecess 81. Since the concentration of any composition in the top-section-layerraw material liquid 91 is substantially uniform, the amount of any composition comprised in the top-section layers raw material liquid 91 is accurately adjusted. As a result, the distribution of any composition of themicroneedle arrays - (11-2)
- As described above, the
droplet discharging apparatuses droplets 91 a to 91 e as illustrated inFIG. 8 in a total amount equal to or smaller than the volume of eachrecess 81. When therecess 81 having a circular cone shape as illustrated inFIG. 8 is filled with one droplet of the top-section-layerraw material liquid 91, air bubbles are more likely to be included at a bottom part of therecess 81, and the top-section-layerraw material liquid 91 is more likely to spill out of therecess 81 due to bounce at landing. However, when the filling is performed with a plurality of droplets, less air bubbles are likely to be included at the bottom part, and the top-section-layerraw material liquid 91 is less likely to spill out of therecess 81, which facilitates accurate adjustment of the filling amount. - (11-3)
- Although each
single recess 81 is filled with the fivedroplets 91 a to 91 e in the above-described case illustrated inFIG. 8 , thedroplet discharging apparatuses recess 81. Thedroplet discharging apparatuses positioning apparatus 20 are configured to achieve such positioning that three or more droplets land on different positions inside therecess 81. For example, in the case illustrated inFIG. 8 , the landing positions are landing points Lp1 to Lp5 different from each other. In this manner, when thedroplets 91 a to 91 e land at different positions, air bubbles included in therecess 81 can be reduced and external spill of the top-section-layerraw material liquid 91 can be prevented for the top-section-layerraw material liquid 91 having a high viscosity. - (11-4)
- As described in the above-described second and third embodiments, when the
cartridges droplet discharging apparatuses raw material liquid nozzle 11 a and thenozzle 11 b, or thenozzle 11 c and thenozzle 11 d. As a result, thevarious microneedles microneedle arrays FIG. 4 ,FIGS. 11 to 15 , andFIG. 17 for example. - (11-5)
- As described with reference to
FIGS. 10 to 14 , thedroplet discharging apparatuses positioning apparatus 20 are configured to fill therecesses 81 in the first areas Ar1, AR3, Ar5, Ar6, and Ar9 of themold 80 with a first amount of raw material liquid, and fill therecesses 81 in the second area Ar2, AR4, Ar7, Ar6, and Ar10 of themold 80 with a second amount of raw material liquid. As a result, the amount of composition in the first areas Ar1, AR3, Ar5, Ar6, and Ar9 and the amount of composition in the second area Ar2, AR4, Ar7, Ar6, and Ar10 can be accurately adjusted. - (11-6)
- Each
recess 81 in which the top-section-layerraw material liquid 93 lands described with reference toFIG. 10 can be regarded as a second recess. In this case, the top-section-layer raw material liquid filling process (step S4) inFIG. 6 for filling the top-section-layerraw material liquid 93 is a second filling process of filling therecess 81 with the top-section-layerraw material liquid 93 by landing, in therecess 81 of themold 80, droplets of the top-section-layer raw material liquid 93 (exemplary second raw material liquid) in an amount equal to or smaller than the volume of therecess 81. The drying process (step S5) inFIG. 6 can be regarded as a drying process of drying the top-section-layerraw material liquid 93 in therecesses 81 to form themicroneedle arrays 110A to 110E consisting of themicroneedles 103 a to 103 f. - In this case, various kinds of microneedle arrays can be manufactured through various combinations of a region in which microneedles manufactured of the top-section-layer raw material liquid 91 (exemplary first raw material liquid) are arranged and a region in which microneedles manufactured of the top-section-layer raw material liquid 93 (exemplary second raw material liquid) are arranged.
- As in the modification 2C described with reference to
FIG. 15 , anyrecess 81 partially filled with the dried and solidified top-section-layerraw material liquid 91 and 93 (exemplary first raw material liquid) can be regarded as a second recess. Thus, the intermediate-layer raw material liquid filling process according to the modification 2C is a second filling process of filling therecess 81 with the intermediate-layer raw material liquid by landing, in a recess (exemplary second recess) of themold 80, in which the top-section-layerraw material liquid raw material liquid 91 and 93). The intermediate-layer raw material liquid drying process can be regarded as a drying process of drying the intermediate-layer raw material liquid in therecesses 81 to form themicroneedle arrays 110A to 110E consisting of themicroneedles 103 a to 103 f. - In this case, various kinds of the
microneedle arrays 110C and 110D can be manufactured through various combinations of the top-section layers raw material liquid 91 and 93 (exemplary first raw material liquid) and theintermediate layers - (11-7)
- The combination process (step S20) and the drying and bonding process (step S21) in
FIG. 6 are a fixation process of fixing themicroneedles 103 a to 103 f comprising parts shaped with the dried top-section-layerraw material liquid porous base member 85 by placing theporous base member 85, at least part of a surface of which is covered by the bottom-section-layer raw material liquid 92 (exemplary third raw material liquid), over a surface of themold 80, on which therecesses 81 are formed, and drying the bottom-section-layerraw material liquid 92. - Since at least part of the surface of the
porous base member 85 is covered by the bottom-section-layerraw material liquid 92, the bottom-section-layerraw material liquid 92 is more likely to penetrate into pores of theporous base member 85, which facilitates formation of theproducts porous base member 85. This effect improves when the curing process (step S15) is provided before the fixation process. - (11-8)
- For example, as described with reference to
FIGS. 11 to 15 , thefirst microneedles section layers section layer 105 a (exemplary second layer of the first microneedle) or theintermediate layer 106 c (exemplary second layer of the first microneedle) provided next. Thesecond microneedles section layers section layer 105 b (exemplary second layer of the second microneedle) or theintermediate layer 106 d (exemplary second layer of the second microneedle) provided next. When the above-described microneedle array manufacturing apparatus or microneedle array manufacturing method is used, the kind of the first composition is different from the kind of the third composition, the kind of the second composition is different from the kind of the fourth composition, at least one of the kind and amount of the first composition is different from the corresponding one of the kind and amount of the second composition, and at least one of the kind and amount of the third composition is different from the corresponding one of the kind and amount of the fourth composition. - As a result, when
products - (11-9)
- When the above-described microneedle array manufacturing apparatus or microneedle array manufacturing method is used, at least one of the second areas Ar2, AR4, and Ar7 can be disposed surrounding at least one of the first areas Ar1, AR3, and Ar6. As a result, the
products - (11-10)
- As described above in the modification 1C with reference to
FIGS. 17(a) and 17(b) , aproduct 100E including a microneedle array includes the fixingpart 109 f and themicroneedles 103 f. Thesurface 102 f of the fixingpart 109 f has a three-dimensional shape curved like a concave mirror. Thus, themicroneedles 103 f are three-dimensionally arranged on thesurface 102 f of the fixingpart 109 f along the three-dimensional shape curved like a concave mirror. Moreover, since themicroneedles 103 f are formed in parallel to each other, allmicroneedles 103 f extend in a pressing direction, which facilitates insertion. This configuration also facilitates attachment to a relatively small place such as an ear having a complicated three-dimensional shape. - A microneedle is largely divided into a top section comprising drug and a bottom-section layer comprising no drug. The present invention provides a microneedle producing method in which, in production of the microneedle, the top section is first produced and then a thin layer (intermediate layer) is produced by using raw material that has a strength clearly different from that of raw material for producing the other two layers and has a high breaking property, instead of spraying the raw material for producing the bottom-section layer immediately after the drying process is completed, thereby enabling restriction of a damaged part of the microneedle to this fragile boundary. Thus, when the intermediate layer is produced at an end of a top section as a drug containing part, which is closer to the bottom-section layer, the top section containing drug breaks at a basis-side stump and is left in a target dermis, thereby achieving administration of the entire amount of this drug. The strength of raw material for producing this intermediate part, after drying, is set to be clearly different from those of the other two parts (the top section and the bottom-section layer). However, when two or more top-section layers comprise drug, this intermediate part is set between a part that breaks and is left in skin epidermis and dermis and a bottom-section layer. Similarly, in a microneedle including a larger number of top-section layers containing drug, an intermediate part is formed between a part that breaks and is left in skin and a bottom-section layer. However, the position of this intermediate layer is not limited to the position described in the previous section because of the characteristic of drug contained in the microneedle and an administration purpose.
- The intermediate layer produced in the previous section has a single-layer structure and a strength clearly different from those of other sites, and is specialized to provoke reliable breaking. Instead, an intermediate layer (first intermediate layer) produced after a top section containing drug is manufactured and hardened by drying is manufactured and hardened by drying, and then the same operation is repeated to separately form, manufacture, and hardened by drying an intermediate layer (second intermediate layer). The ratio of the thicknesses of the intermediate layers may be 1:1 but may be optionally set as long as the thicknesses satisfy thicknesses to be described later.
- When having a single-layer structure, an intermediate layer of a microneedle in the previous section may have a thickness of 5 μm to 50 μm, preferably a thickness of 10 μm to 30 μm, more preferably a thickness of 15 μm to 20 μm. When the second intermediate layer is included, thicknesses substantially twice as large as the thicknesses listed above are applicable. Specifically, when two intermediate layers of a microneedle are included, the intermediate layers may have an entire thickness of 10 μm to 100 μm, preferably an entire thickness of 20 μm to 60 μm, more preferably an entire thickness of 30 μm to 40 μm. After a layer comprising a biologically active material (drug) is produced and dried, this intermediate layer is formed by adjusting the raw material to have a plane surface and dried, and then a basis layer is produced. Through the present process, a microneedle acquires capability of reliably breaking at a specified position to be reliably left in a short time and can be formed to have a function to prevent backflow of, through a penetrating hole, drug released from the top section into dermis, when a raw material having a dissolution speed slower than that of a top section is selected as a raw material for producing the first intermediate layer.
- The following describes the strength of each component of a microneedle according to the present invention in an example with a microneedle containing one kind of drug and including a bottom-section layer comprising no drug, and describes setting of the strength of each layer. The strength of a microneedle produced in the present invention is highest in the bottom-section layer, followed in order by a top section comprising the drug, and an intermediate layer. However, when the top section as a drug containing part includes two or more layers, an intermediate part is set between a part that breaks and is left in skin and the bottom-section layer, the strength is also highest in the bottom-section layer, followed in order by the top section comprising the drug, and the intermediate layer. To achieve this purpose, the weight-average molecular weight of a polymer compound included in each layer is highest in the top section, followed by the bottom-section layer, and can be set further lower in the intermediate part. However, the weight-average molecular weight for each layer may be the same or in the inverse order when a strength condition is satisfied. Alternatively, the hardness and weight-average molecular weight of the intermediate layer may be highest. When an intermediate layer including two layers is produced, the first intermediate layer is formed of a polymer material having a high hardness and a low absorbability and selected as a raw material set to have high concentration, and the second intermediate layer has a strength clearly weaker than those of the first intermediate layer and the bottom-section layer, has a high absorbability, and is formed of a polymer material selected as a raw material set to low concentration. However, setting of the strengths of the intermediate layers or the like is not limited to the above-described relation because of, for example, difference in used drug, and only one of the intermediate layers may be formed. To further efficiently achieve this process, a larger number of intermediate layers may be formed, and drug may or may not be contained in any of the intermediate layers. Instead of producing the intermediate layers right after the top section as a drug containing part is produced, the intermediate layers may be produced after part of the bottom-section-layer raw material is discharged and hardened, and then the rest of the bottom-section layer raw material may be discharged to complete formation of the entire bottom-section layer. Each intermediate layer of a microneedle produced in this manner is formed not at a joint surface of the top section and lower-layer sections but in the bottom-section layer. Any kind of drug may be added. In this case, it is essential to include a plurality of droplet discharging apparatuses each capable of discharging raw material obtained by changing, as appropriate, the mixture ratio and concentration of a bioabsorbable formulation optimized for forming a microneedle produced by the microneedle array manufacturing apparatus according to the present invention.
- (16) Production of Basis Layer Integrated with Substrate Including Contact Surface
- A microneedle array forming method in which, when produced by an inkjet method, a microneedle array is formed integrally with a bonding surface and a flat surface adhering to a substrate when part or all of the bottom-section layer is produced, whereby collapse of microneedles due to piercing is prevented and a top section containing drug easily and reliably breaks from the bottom-section layer. In this case, the bonding surface of the bottom-section layer with the top section may be flat, but does not necessarily limited thereto. In such a case, when the bottom-section layer is formed after an intermediate layer in the previous section is formed by spraying the raw material, a microneedle can be formed to be capable of more reliably breaking at the intermediate layer to leave the top section. In this method, too, the intermediate layer may have a two-layer structure or a multi-layer structure as described in the previous section.
- In treatment with a microneedle patch produced by a conventional method and thus including no intermediate layer, in order to reliably perform drug administration, a microneedle patch needs to be fixed to an administration site for 10 minutes to 30 minutes at minimum to one hour to two hours at maximum in accordance with a dissolution time of the raw material of the top section as a drug containing part, until the drug containing part dissolves and drug administration is completed. However, with a microneedle patch including an intermediate layer having an excellent breaking property, the top section containing drug is instantaneously separated at the intermediate part in dermis substantially simultaneously with insertion and left in the dermis, and thus the bottom-section layer can be removed right after the top section is separated irrespective of the dissolution time of a polymer raw material of the top section as a drug containing part. Accordingly, the series of the drug administration of the microneedle patch is completed within 5 seconds to 20 seconds approximately.
- (18) Prevention of Backflow of Drug Dissolved and Released in Dermis Through Penetrating Hole Through which Microneedle is Inserted
- When a microneedle produced in the previous section invention is inserted into skin to allow the top section containing drug to reach at a target site inside the dermis, a formed polymer compound spontaneously dissolves to release the contained drug in the dermis. In this case, since an intermediate layer having a weak strength and a high absorbability is provided at a basis side of the top section containing the drug, backflow through the penetrating hole is prevented to certain extent. In such a case, when the first intermediate layer in the previous section is produced in addition, the first intermediate layer is formed of a polymer material having a high hardness and a low absorbability and selected as the raw material set to have high concentration, and thus provides an effect of preventing the backflow by completely closing the penetrating hole for a certain duration after the polymer compound forming the top section is dissolved to release the drug. This complete closure duration may be freely set to a desired duration by controlling a dissolution property of the polymer material used in the formation. The dissolution time of this layer is 10 minutes to 24 hours, preferably 15 minutes to 6 hours, more preferably 30 minutes to 3 hours. The present invention is not limited to these time durations but may be any duration as long as the entire amount of the drug contained in the top section and administered is reliably dissolved and released at the target site inside the dermis.
- (19) Description of the Invention with Reference to Drawings
- The following describes, with reference to
FIGS. 19 to 22 , a method for manufacturing a microneedle patch having a plurality of microneedles each including the top-section layer 104 (corresponding to the top section as a drug containing part described above) to be described later, an intermediate layer 106 (corresponding to a thin layer having a high breaking property described above), and the bottom-section layer 105 (corresponding to the bottom-section layer described above). -
FIG. 19 illustrates a state in whichdroplets layer formation site 86 of eachrecess 81 of themold 80 by using the microneedlearray manufacturing apparatuses 1 and 1B described above. - After the top-section
layer formation site 86 from a central part CP to a height illustrated with a dashed line inFIG. 19 is filled with the top-section-layer raw material liquid 91 (first raw material liquid), the top-section-layer raw material liquid 91 (first raw material liquid) is hardened by drying. The hardening by drying means solidification. -
FIG. 20 illustrates a state in whichdroplets section layer 104 by using the above-described microneedlearray manufacturing apparatuses 1 and 1B. -
FIG. 21 illustrates a state in which the intermediate-layer raw material liquid 94 (second raw material liquid) is hardened by drying to form theintermediate layer 106 on the top-section layer 104 in contact. When theintermediate layer 106 is formed, the intermediate-layer raw material liquid 94 (second raw material liquid) is dried for a slightly longer time. -
FIG. 22 illustrates a state in which the bottom-section layer 105 is formed on theintermediate layer 106, while being in contact with theintermediate layer 106. The bottom-section layer 105 is formed through filling with the bottom-section-layer raw material liquid 92 (third raw material liquid) by using the microneedlearray manufacturing apparatuses 1 and 1B. An upper surface of the bottom-section layer 105, which is opposite theintermediate layer 106, is a bonding surface AF onto which asupport member 120 illustrated inFIG. 23 is to be bonded. - The following describes, with reference to
FIGS. 23 to 26 , a method of using the above-described microneedle patch having a plurality of microneedles each including the top-section layer 104, theintermediate layer 106, and the bottom-section layer 105. -
FIG. 23 illustrates a microneedle 103 g inserted into adermis 310 through anepidermis 300. Themicroneedle 103 g includes the top-section layer 104, theintermediate layer 106, and the bottom-section layer 105 described above with reference toFIGS. 19 to 22 . Amicroneedle patch 100F having a plurality of themicroneedles 103 g and thesupport member 120 is a product including a microneedle array. - As illustrated in
FIG. 23 , when thesurface 102 of thebase member 101 contacts theepidermis 300, the bottom-section layer 105 penetrates through theepidermis 300, and theintermediate layer 106 and the top-section layer 104 reach at thedermis 310. InFIG. 23 , arrow K1 indicates a direction in which themicroneedle 103 g is inserted. Arrow K2 indicates a place where themicroneedle 103 g breaks. -
FIG. 24 illustrates a state in which theintermediate layer 106 of themicroneedle 103 g inserted into thedermis 310 is broken. InFIG. 24 , arrow K3 indicates a direction in which themicroneedle patch 100F is removed from skin. When themicroneedle patch 100F is removed, theintermediate layer 106 having a weakest breaking strength in themicroneedle 103 g breaks, and the top-section layer 104 is left in thedermis 310. -
FIG. 25 illustrates dissolution of the top-section layer 104 as a drug containing part containing drug and release of the drug. After themicroneedle patch 100F is removed from the skin, an extremelysmall insertion hole 320 is formed on theepidermis 300 as illustrated inFIG. 25 . InFIG. 25 , arrow K4 represents release of the drug contained in the top-section layer 104. -
FIG. 26 illustrates a state in which theintermediate layer 106 dissolves following the top-section layer 104. InFIG. 26 , arrow K5 represents dissolution of theintermediate layer 106. InFIG. 26 , a range enclosed by a dashed line represents a range in which the dissolved top-section layer 104 diffuses. - The following describes, with reference to
FIGS. 27 to 30 , a method for manufacturing a microneedle patch having a plurality of microneedles each including the top-section layer 104 (corresponding to a top section as a drug containing part described above) to be described later, a firstintermediate layer 1061, a secondintermediate layer 1062, and the bottom-section layer 105 (corresponding to a bottom-section layer described above). -
FIG. 27 illustrates a state in whichdroplets layer formation site 86 of eachrecess 81 of themold 80 by using the above-described microneedlearray manufacturing apparatuses 1 and 1B. - After the top-section
layer formation site 86 from the central part CP to a height illustrated with a dashed line inFIG. 27 is filled with the top-section-layer raw material liquid 91 (first raw material liquid), the top-section-layer raw material liquid 91 (first raw material liquid) is hardened by drying. -
FIG. 28 illustrates a state in whichdroplets section layer 104, by using the above-described microneedlearray manufacturing apparatuses 1 and 1B. -
FIG. 29 illustrates a state in which the first intermediate-layer raw material liquid 941 (second raw material liquid) is hardened by drying to form the firstintermediate layer 1061 on the top-section layer 104 in contact.FIG. 29 illustrates a state in whichdroplets raw material liquid 942 are discharged onto the firstintermediate layer 1061 by using the above-described microneedlearray manufacturing apparatuses 1 and 1B. When the secondintermediate layer 1062 is formed, the second intermediate-layer raw material liquid 942 (third raw material liquid) is dried for a slightly longer time. -
FIG. 30 illustrates a state in which the bottom-section layer 105 is formed on the secondintermediate layer 1062 while being in contact with the secondintermediate layer 1062. The bottom-section layer 105 is formed through filling with the bottom-section-layer raw material liquid 92 (fourth raw material liquid) by using the microneedlearray manufacturing apparatuses 1 and 1B. An upper surface of the bottom-section layer 105, which is opposite the secondintermediate layer 1062, is a bonding surface AF to which thesupport member 120 illustrated inFIG. 31 is to be bonded. - The following describes, with reference to
FIGS. 31 to 34 , a method of using the above-described microneedle patch having a plurality of microneedles each including the top-section layer 104, the firstintermediate layer 1061, the secondintermediate layer 1062, and the bottom-section layer 105. -
FIG. 31 illustrates a microneedle 103 h inserted intodermis 310 throughepidermis 300. Themicroneedle 103 h includes the top-section layer 104, the firstintermediate layer 1061, the secondintermediate layer 1062, and the bottom-section layer 105 described above with reference toFIGS. 27 to 30 . Amicroneedle patch 100G having a plurality of themicroneedles 103 h and thesupport member 120 is a product including a microneedle array. - As illustrated in
FIG. 31 , when thesurface 102 of thebase member 101 contacts theepidermis 300, the bottom-section layer 105 penetrates through theepidermis 300, and the firstintermediate layer 1061, the secondintermediate layer 1062, and the top-section layer 104 reach at thedermis 310. InFIG. 31 , arrow K1 indicates a direction in which themicroneedle 103 h is inserted. Arrow K2 indicates a place at which themicroneedle 103 h breaks. -
FIG. 32 illustrates a state in which the secondintermediate layer 1062 of themicroneedle 103 h inserted into thedermis 310 is broken. InFIG. 32 , arrow K3 indicates a direction in which themicroneedle patch 100G is removed from skin. When themicroneedle patch 100G is removed, the secondintermediate layer 1062 having a weakest breaking strength in themicroneedle 103 h breaks, and the top-section layer 104 is left in thedermis 310. -
FIG. 33 illustrates dissolution of the top-section layer 104 as a drug containing part containing drug and release of the drug. After themicroneedle patch 100G is removed from the skin, an extremelysmall insertion hole 320 is formed in theepidermis 300 as illustrated inFIG. 33 . InFIG. 33 , arrow K4 represents release of the drug contained in the top-section layer 104. -
FIG. 34 illustrates a state in which theintermediate layer 106 dissolves following the top-section layer 104. InFIG. 34 , arrow K5 represents dissolution of the firstintermediate layer 1061. InFIG. 34 , a range enclosed by a dashed line represents a range in which the dissolved top-section layer 104 diffuses. - MICRONEEDLE ARRAY MANUFACTURING APPARATUS, MICRONEEDLE ARRAY MANUFACTURING METHOD, AND PRODUCT INCLUDING MICRONEEDLE ARRAY
- This prior art relates to a microneedle array manufacturing apparatus and a microneedle array manufacturing method for manufacturing a microneedle array consisting of a plurality of microneedles, and a product including the microneedle array.
- In a method of alternately repeating filling with a needle raw material and drying thereof in the order of
FIG. 18(a) ,FIG. 18(b) ,FIG. 18(c) ,FIG. 18(d) , andFIG. 18(e) by using astamper 200 as a kind of mold disclosed inpatent document 1 and asqueegee 210, the filling amounts of microneedleraw materials recesses upper layers microneedles microneedles array manufacturing apparatuses 1 and 1A described above, and a highly useful product can be provided by the microneedle manufacturing apparatus according to the present invention. - The prior art is intended to provide a microneedle array manufacturing apparatus and a microneedle array manufacturing method capable of accurately adjusting composition distribution of a microneedle array and provide a product including the microneedle array having accurately adjusted composition distribution.
- A microneedle patch according to a first aspect includes a base member and a plurality of microneedles supported by the base member. Each microneedle includes a top-section layer comprising a biologically active substance to be pierced into dermis, and an intermediate layer provided between the top-section layer and the base member, including composition having breaking strength weaker than breaking strength of composition of the top-section layer, and having a thickness of 5 μm to 100 μm inclusive.
- A microneedle patch according to a second aspect is the microneedle patch according to the first aspect in which the intermediate layer has a thickness of 10 μm to 30 μm inclusive.
- A microneedle patch according to a third aspect is the microneedle patch according to the second aspect in which the intermediate layer has a thickness of 15 μm to 20 μm inclusive.
- A microneedle patch according to a fourth aspect is the microneedle patch according to any one of the first to third aspects in which the intermediate layer is made of a material that dissolves in dermis following the top-section layer.
- A microneedle patch according to a fifth aspect is the microneedle patch according to any one of the first to fourth aspects in which the intermediate layer is adjusted to break in dermis in 20 seconds or less.
- A microneedle patch according to a sixth aspect is the microneedle patch according to the fifth aspect in which the intermediate layer is adjusted to break in dermis in 5 seconds or less.
- A microneedle patch according to a seventh aspect is the microneedle patch according to any one of the first to sixth aspects further including a bottom-section layer joining the intermediate layer and the base member, in which the intermediate layer has breaking strength weaker than breaking strength of the top-section layer, and the top-section layer has breaking strength weaker than breaking strength of the bottom-section layer.
- A microneedle patch according to an eighth aspect is the microneedle patch according to any one of the first to sixth aspects further including a bottom-section layer joining the intermediate layer and the base member, in which the intermediate layer has a weight-average molecular weight lighter than the weight-average molecular weight of the bottom-section layer, and the bottom-section layer has a weight-average molecular weight lighter than the weight-average molecular weight of the top-section layer.
- A microneedle patch according to a ninth aspect is the microneedle patch according to any one of the first to eighth aspects in which the intermediate layer comprises a first intermediate layer made of, as a primary material, a polymer material having a water absorbability lower than the water absorbability of the top-section layer and is adjusted to dissolve in dermis following the top-section layer. The primary material is a material of a content percentage exceeding 50%.
- A microneedle patch according to a tenth aspect is the microneedle patch according to the ninth aspect in which the intermediate layer comprises a second intermediate layer made of, as a primary material, a polymer material having a water absorbability higher than the water absorbability of the top-section layer and is adjusted to dissolve in dermis preceding the top-section layer. The primary material is a material of a content percentage exceeding 50%.
- A microneedle patch according to an eleventh aspect includes a base member and a plurality of microneedles supported by the base member. Each microneedle includes a top-section layer comprising a biologically active substance to be pierced into dermis, and an intermediate layer provided between the top-section layer and the base member. The intermediate layer is made of, as a primary material, a polymer material having a water absorbability higher than the water absorbability of the top-section layer, and is adjusted to break in dermis in 20 seconds or less.
- A microneedle patch according to a twelfth aspect is the microneedle patch according to any one of the first to eleventh aspects in which the biologically active substance is drug.
- A microneedle patch according to a thirteenth aspect is the microneedle patch according to any one of the first to twelfth aspects further including a bottom-section layer joining the intermediate layer and the base member, in which the intermediate layer is inside the bottom-section layer.
- A microneedle patch according to a fourteenth aspect is the microneedle patch according to any one of the first to thirteenth aspects further including a bottom-section layer joining the intermediate layer and the base member, in which the bottom-section layer has a thickness larger than the thickness of epidermis, and the intermediate layer reaches at the dermis when a surface of the base member contacts the epidermis.
- With the microneedle patch according to the first to fourteenth aspects, when the microneedles are administered to skin or mucous membrane, the biologically active substance can be reliably left in the mucous membrane, epidermis, or dermis in a short time. As a result, when the microneedles are administered to skin or mucous membrane, a treatment is reliably completed in a short time.
- A microneedle array manufacturing apparatus according to the present invention provides a technology of fine and mass manufacturing of a microneedle array having highly accurate appearance and accuracy by an inkjet method, provides details of an extremely realistic, reproductive, excellent mass production technology providing a new technology that could not achieve by a conventional method of a technology of controlling the breaking property and internal structure of the microneedle, and relates to development of an apparatus configured to manufacture a microneedle having an excellent breaking property at administration to achieve a desired purpose, thereby allowing fast treatment using a microneedle patch, and having a function to prevent backflow of, through a penetrating hole, drug administered in dermis, thereby providing high industrial applicability in the medical field.
-
- 1, 1A apparatus for manufacturing a microneedle array
- 10, 10A droplet discharging apparatus
- 11 a, 11 b, 11 c, 11 d nozzle
- 12 a first discharge head actuator
- 12 b second discharge head actuator
- 13 a, 13 b cartridge
- 20 positioning apparatus
- 21 XYZ stage
- 22 CCD camera
- 23 alignment monitor
- 80, 80A, 80B, 80C mold
- 81 recess
- 83 alignment mark
- 85 porous base member
- 91, 93 top-section-layer raw material liquid
- 92 bottom-section-layer raw material liquid
- 100, 100A, 100C, 100D, 100E product including microneedle array
- 100F, 100G microneedle patch
- 101 base member
- 102 surface
- 103, 103 a to 103 h microneedle
- 104, 104 a to 104 e top-section layer
- 105, 105 a to 105 c, 105 e bottom-section layer
- 106, 106 c to 106 e intermediate layer
- 1061 first intermediate layer
- 1062 second intermediate layer
- 110, 110A to 110E microneedle array
Claims (11)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2014252907A JP6001043B2 (en) | 2014-12-15 | 2014-12-15 | Microneedle array manufacturing apparatus, microneedle array manufacturing method, and product having microneedle array |
JP2014-252907 | 2014-12-15 | ||
PCT/JP2015/085107 WO2016098780A1 (en) | 2014-12-15 | 2015-12-15 | Microneedle patch, method for manufacturing same, and apparatus for manufacturing microneedle array |
Publications (1)
Publication Number | Publication Date |
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US20180140815A1 true US20180140815A1 (en) | 2018-05-24 |
Family
ID=56126619
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US15/535,663 Active US10639823B2 (en) | 2014-12-15 | 2015-12-14 | Microneedle-array manufacturing apparatus, microneedle-array manufacturing method, and product having the microneedle array |
US15/535,111 Abandoned US20180140815A1 (en) | 2014-12-15 | 2015-12-15 | Microneedle patch, method for manufacturing same, and apparatus for manufacturing microneedle array |
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US15/535,663 Active US10639823B2 (en) | 2014-12-15 | 2015-12-14 | Microneedle-array manufacturing apparatus, microneedle-array manufacturing method, and product having the microneedle array |
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US (2) | US10639823B2 (en) |
EP (2) | EP3235537B1 (en) |
JP (1) | JP6001043B2 (en) |
KR (1) | KR20170122716A (en) |
CA (1) | CA2975067A1 (en) |
TW (2) | TW201628585A (en) |
WO (2) | WO2016098730A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020257548A1 (en) | 2019-06-21 | 2020-12-24 | Microneedles Inc | Microneedle patch and fabrication device for production of multilayered microneedles |
CN112839699A (en) * | 2018-10-08 | 2021-05-25 | 延世大学校产学协力团 | Microstructure body |
US11440264B2 (en) * | 2019-10-21 | 2022-09-13 | Seiko Epson Corporation | Three-dimensional shaped article manufacturing method and data processing device |
US11452854B2 (en) | 2018-05-16 | 2022-09-27 | Fujifilm Corporation | Method of manufacturing microneedle array |
US20220388211A1 (en) * | 2021-06-01 | 2022-12-08 | Xtpl S.A. | Method of filling a microcavity with a polymer material, a filler in a microcavity, and an apparatus for filling a microcavity on or in a substrate with a polymer material |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017175650A1 (en) * | 2016-04-07 | 2017-10-12 | 日本写真印刷株式会社 | Microneedle sheet |
JPWO2017213169A1 (en) * | 2016-06-07 | 2019-03-22 | 富士フイルム株式会社 | Micro needle array |
JP2018015322A (en) * | 2016-07-28 | 2018-02-01 | 富士フイルム株式会社 | Method of producing transdermal absorption sheet |
JP6691025B2 (en) * | 2016-09-06 | 2020-04-28 | 富士フイルム株式会社 | Method for manufacturing needle-shaped array sheet |
JP7152787B2 (en) | 2017-03-31 | 2022-10-13 | ヴァクザス ピーティーワイ リミテッド | Apparatus and method for coating surfaces |
US20200179895A1 (en) * | 2017-07-18 | 2020-06-11 | University Of Maryland, College Park | Multilayer Structures with Distinct Layers and Methods of Forming Same |
KR102145659B1 (en) * | 2018-01-09 | 2020-08-19 | 주식회사 페로카 | Method for manufacturing micro-needle using additive manufacturing and system therefor |
KR102094744B1 (en) * | 2018-01-26 | 2020-03-30 | 가천대학교 산학협력단 | Micro-needle and method of mamufacture |
WO2019188935A1 (en) | 2018-03-30 | 2019-10-03 | 富士フイルム株式会社 | Microneedle array manufacturing method |
CN111801134B (en) * | 2018-03-30 | 2022-06-14 | 富士胶片株式会社 | Mold for producing transdermal absorption sheet, and apparatus and method for producing transdermal absorption sheet having needle-like projections |
KR102237173B1 (en) * | 2019-01-21 | 2021-04-07 | 주식회사 페로카 | Micro-needle of three or more layers structure |
JP6956680B2 (en) * | 2018-05-16 | 2021-11-02 | 富士フイルム株式会社 | Manufacturing method of mold case and microneedle array |
KR102227989B1 (en) | 2018-09-18 | 2021-03-15 | 한국기계연구원 | Microstructure-based drug injection device and manufacturing method thereof |
JP2020137853A (en) | 2019-02-28 | 2020-09-03 | 富士フイルム株式会社 | Manufacturing method for microneedle arrays |
JP6850457B2 (en) * | 2019-03-12 | 2021-03-31 | シンクランド株式会社 | How to collect the stratum corneum |
US20220000711A1 (en) * | 2020-07-06 | 2022-01-06 | Roman BURKO | Acupressure medallion, method and device for its manufacture and method of reduction of pain from acupressure reflexotherapy |
KR102249513B1 (en) * | 2020-09-25 | 2021-05-06 | 연세대학교 산학협력단 | A candle-typed microstructure for transdermal delivery and a method for manufacturing the same |
KR102645357B1 (en) * | 2023-07-19 | 2024-03-11 | 주식회사 대웅테라퓨틱스 | Method for manufacturing microparticle and microparticle manufactured by the same method |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6395326B1 (en) * | 2000-05-31 | 2002-05-28 | Advanced Cardiovascular Systems, Inc. | Apparatus and method for depositing a coating onto a surface of a prosthesis |
WO2002064193A2 (en) * | 2000-12-14 | 2002-08-22 | Georgia Tech Research Corporation | Microneedle devices and production thereof |
US7342670B2 (en) * | 2005-10-19 | 2008-03-11 | Labcoat, Ltd. | In-flight drop location verification system |
CA2686093C (en) | 2007-04-16 | 2018-05-08 | Corium International, Inc. | Solvent-cast microneedle arrays containing active |
US7648220B2 (en) | 2007-04-23 | 2010-01-19 | Hewlett-Packard Development Company, L.P. | Sensing of fluid ejected by drop-on-demand nozzles |
JP5693228B2 (en) * | 2007-11-14 | 2015-04-01 | バイオセンサーズ インターナショナル グループ、リミテッド | Automatic coating apparatus and method |
EP2100850A1 (en) * | 2008-03-11 | 2009-09-16 | Stichting Voor De Technische Wetenschappen | Microneedle array and a method for manufacturing microneedles |
WO2009130926A1 (en) * | 2008-04-22 | 2009-10-29 | 南部化成株式会社 | Endermic method, needle organizer and endermic injector device |
JP2010131123A (en) | 2008-12-03 | 2010-06-17 | Medorekkusu:Kk | Method of carrying medicament to microneedle array |
AU2009329806A1 (en) * | 2008-12-22 | 2010-07-01 | The University Of Queensland | Patch production |
JP2010233674A (en) * | 2009-03-30 | 2010-10-21 | Fujifilm Corp | Microneedle sheet, its use method and method for producing the same |
EP2457592B1 (en) * | 2009-07-23 | 2020-09-16 | Hisamitsu Pharmaceutical Co., Inc. | Microneedle array |
JP2011224332A (en) * | 2010-03-29 | 2011-11-10 | Fujifilm Corp | Skin absorption sheet and method for manufacturing the same |
US10744759B2 (en) | 2010-06-29 | 2020-08-18 | CARDINAL HEALTH SWITZERLAND 515 GmbH | First drop dissimilarity in drop-on-demand inkjet devices and methods for its correction |
JP5770055B2 (en) | 2010-09-29 | 2015-08-26 | 富士フイルム株式会社 | Method for manufacturing needle-like array transdermal absorption sheet |
US20140052067A1 (en) | 2011-03-18 | 2014-02-20 | Universite Libre De Bruxelles | Devices for puncturing for a human or animal body's membrane |
JP5886535B2 (en) * | 2011-03-28 | 2016-03-16 | 東レエンジニアリング株式会社 | Manufacturing method of microneedle sheet |
JP2014082975A (en) * | 2012-10-23 | 2014-05-12 | Kri Inc | Droplet discharge apparatus for microorganism separation and/or arrangement |
US8851616B2 (en) * | 2012-12-19 | 2014-10-07 | Vistaprint Schweiz Gmbh | Print head pre-alignment systems and methods |
JP5954239B2 (en) * | 2013-03-29 | 2016-07-20 | 東京エレクトロン株式会社 | Liquid processing method |
CA3163792A1 (en) * | 2014-04-24 | 2015-10-29 | Georgia Tech Research Corporation | Microneedles and methods of manufacture thereof |
JP6207459B2 (en) * | 2014-05-15 | 2017-10-04 | 富士フイルム株式会社 | Method for producing transdermal absorption sheet |
-
2014
- 2014-12-15 JP JP2014252907A patent/JP6001043B2/en active Active
-
2015
- 2015-12-14 WO PCT/JP2015/084943 patent/WO2016098730A1/en active Application Filing
- 2015-12-14 EP EP15869935.5A patent/EP3235537B1/en active Active
- 2015-12-14 TW TW104141911A patent/TW201628585A/en unknown
- 2015-12-14 US US15/535,663 patent/US10639823B2/en active Active
- 2015-12-15 TW TW104142051A patent/TW201628586A/en unknown
- 2015-12-15 KR KR1020177019357A patent/KR20170122716A/en not_active Application Discontinuation
- 2015-12-15 EP EP15869985.0A patent/EP3235538A4/en not_active Withdrawn
- 2015-12-15 CA CA2975067A patent/CA2975067A1/en not_active Abandoned
- 2015-12-15 WO PCT/JP2015/085107 patent/WO2016098780A1/en active Application Filing
- 2015-12-15 US US15/535,111 patent/US20180140815A1/en not_active Abandoned
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3986526A4 (en) * | 2019-06-21 | 2023-11-29 | Microneedles Inc. | Microneedle patch and fabrication device for production of multilayered microneedles |
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US20220388211A1 (en) * | 2021-06-01 | 2022-12-08 | Xtpl S.A. | Method of filling a microcavity with a polymer material, a filler in a microcavity, and an apparatus for filling a microcavity on or in a substrate with a polymer material |
US11931935B2 (en) * | 2021-06-01 | 2024-03-19 | Xtpl S.A. | Method of filling a microcavity with layers of polymeric material |
Also Published As
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WO2016098730A1 (en) | 2016-06-23 |
CA2975067A1 (en) | 2016-06-23 |
TW201628585A (en) | 2016-08-16 |
EP3235537B1 (en) | 2019-08-07 |
KR20170122716A (en) | 2017-11-06 |
JP6001043B2 (en) | 2016-10-05 |
US10639823B2 (en) | 2020-05-05 |
WO2016098780A1 (en) | 2016-06-23 |
EP3235537A1 (en) | 2017-10-25 |
TW201628586A (en) | 2016-08-16 |
JP2016112169A (en) | 2016-06-23 |
EP3235537A4 (en) | 2018-04-18 |
EP3235538A1 (en) | 2017-10-25 |
US20170348880A1 (en) | 2017-12-07 |
EP3235538A4 (en) | 2019-04-03 |
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