WO2017090254A1 - マイクロニードル及びその製造方法 - Google Patents
マイクロニードル及びその製造方法 Download PDFInfo
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- WO2017090254A1 WO2017090254A1 PCT/JP2016/004967 JP2016004967W WO2017090254A1 WO 2017090254 A1 WO2017090254 A1 WO 2017090254A1 JP 2016004967 W JP2016004967 W JP 2016004967W WO 2017090254 A1 WO2017090254 A1 WO 2017090254A1
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- tip
- microneedle
- region
- cone
- drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- 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
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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
-
- 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
- B29C39/02—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles
- B29C39/021—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles by casting in several steps
-
- 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
- A61M2037/0023—Drug applicators using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- 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
- B29C39/02—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles
- B29C39/12—Making multilayered or multicoloured articles
- B29C39/123—Making multilayered articles
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
- B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
- B29K2105/0005—Condition, form or state of moulded material or of the material to be shaped containing compounding ingredients
- B29K2105/0035—Medical or pharmaceutical agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
- B29K2995/00—Properties of moulding materials, reinforcements, fillers, preformed parts or moulds
- B29K2995/0037—Other properties
- B29K2995/0059—Degradable
- B29K2995/006—Bio-degradable, e.g. bioabsorbable, bioresorbable or bioerodible
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
- B29L2031/00—Other particular articles
- B29L2031/753—Medical equipment; Accessories therefor
- B29L2031/7544—Injection needles, syringes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
- B29L2031/00—Other particular articles
- B29L2031/756—Microarticles, nanoarticles
Definitions
- the present invention relates to a microneedle having improved penetrability and improved shape retention (deformation preventing ability) for percutaneously reaching a predetermined drug in the dermis, and a method for producing the same.
- microneedles have been increasingly used in the fields related to medicine, beauty and health, and regenerative medicine. Specifically, by using a microneedle patch having a certain size on which a plurality of microneedles are installed, for example, the target drug, vaccine, etc. from the body surface such as human skin, mucous membrane, etc. Attempts have been made to administer it.
- Patent Document 1 As a method for producing such a microneedle, for example, a method (Patent Document 1) in which a needle-shaped material having a plurality of recesses is filled with a needle forming material using a squeegee, and then dried and cured (Patent Document 1), An ink jet method in which a droplet of a microneedle forming material is ejected by computer control using a jet part for an ink jet printer to a female type having a concave part, filled into the female type, and then dried and cured (Patent Document 2) and the like are known.
- Patent Document 2 An ink jet method in which a droplet of a microneedle forming material is ejected by computer control using a jet part for an ink jet printer to a female type having a concave part, filled into the female type, and then dried and cured
- the microneedle In human skin, since the elasticity and hardness of the skin differ depending on the site and age, the microneedle is often not penetrated well and can not be dispensed well in a predetermined place. Further, in the case of a microneedle with a low degree of penetration, it is necessary to increase the pressing strength of the applicator against the skin, which causes pain and fear to the patient. Therefore, proposals for improving the penetrability of the microneedle have been made so far.
- Patent Document 3 a method of reducing the curvature radius of the tip portion by contracting the surface by drying the microneedle to thereby reduce the curvature radius of the tip portion (Patent Document 3), and the first portion on the tip side having high hardness A microneedle (Patent Document 4) composed of a second part on the base side having low hardness has been proposed.
- JP 2012-200572 A JP2015-136422A JP 2008-142183 A Japanese Patent Laid-Open No. 2015-016160
- An object of the present invention is to solve the above-mentioned problems of the microneedles according to the conventional method, and to provide a microneedle having improved penetrability and shape retention (deformation preventing ability).
- the inventors of the present invention have intensively studied to solve the above problems, and are cone-shaped microneedles having a tip portion containing a drug and a biodegradable polymer and a base portion not containing the drug, the tip side being A microneedle is formed as a tip strengthening region, a base side adjacent to the tip strengthening region is formed as a non-strengthening region, and the hardness of the tip strengthening region is higher than the hardness of the non-strengthening region, The inventors have found that the penetrability and the shape retention are high, and have completed the present invention.
- the present invention is as follows.
- a cone-shaped microneedle having a distal end portion containing a drug and a biodegradable polymer and a base portion not containing the drug, The tip side is formed as a tip strengthening region, the base side adjacent to the tip strengthening region is formed as a non-strengthening region,
- the tip reinforcing region is a region where the tip side of the microneedle is covered with a coating material containing a curing agent.
- the tip reinforcing region is a region that occupies a length of 30 to 85% of the tip side of the perpendicular drawn from the tip of the cone to the base surface.
- the tip reinforcing region is a tip side region of the tip part which further contains a curing agent in addition to the drug and the biodegradable polymer.
- the tip reinforcing region is a tip side region of the tip part which further contains a curing agent in addition to the biodegradable polymer.
- the tip reinforcing region is a region occupying a length of 1 to 50% of the tip side of the perpendicular drawn from the tip of the cone to the basal plane needle.
- the above (2), (3) and (3), wherein the hardness of the coating portion is increased and the frictional resistance of the coating portion is reduced by 5% or more as compared to before coating with the coating material The microneedle according to any one of (7).
- the curing agent is selected from calcium chloride, sodium chloride, polysaccharides, dextran, hyaluronic acid, chondroitin sulfate, carboxy polymer, polyacrylic acid, polylactic acid, hydroxyapatite, polyethylene glycol, fluorine-based compound, and silicon-based compound.
- (11) The microneedle according to any one of (1) to (10) above, wherein the dryness of the tip reinforcing region is higher than that of other portions.
- microneedle according to any one of (1) to (15) above, wherein the non-strengthened region contains a hardness reducing agent.
- a microneedle patch comprising a plurality of microneedles according to any one of (1) to (16) above on a substrate.
- a cone-shaped microneedle having a tip portion and a base portion including the following steps (A) to (D), the tip reinforcing region having a tip side coated with a coating material containing a curing agent
- a method of manufacturing a microneedle comprising: (A) A step of filling a cone-forming original plate with a tip-forming material containing a drug and a biodegradable polymer, and drying the tip-forming material; (B) A step of filling the original plate with a base-forming material not containing a drug and overlaying the base on the tip to form a cone; (C) removing the dried cone from which the cone was dried from the original plate; (D) coating the tip of the dry cone with a coating material containing a curing agent to form a tip reinforcing region; (19) A tip-shaped microneedle comprising the following steps (A) to (D), having a tip portion and a base portion, further including a curing agent in addition to the biodegradable poly
- B A step of filling the original plate with a non-reinforced region forming material containing a drug and a biodegradable polymer, and forming a tip portion by overlaying the non-reinforced region on the tip reinforced region;
- C A step of filling the original plate with a base portion forming material not containing a drug and overlaying the base portion on the tip portion to form a cone;
- D removing the dried cone obtained by drying the cone from the original plate; (20)
- (E) A step of coating the dry cone with a coating material containing a curing agent; (21) The production method according to the above (19) or (20), wherein the non-reinforced region forming material contains a hardness reducing agent. (22) The production method according to any one of the above (18) to (21), further comprising the following step (X): (X) drying the tip of the microneedle and reducing the radius of curvature; (23) The production method according to any one of (18) to (22) above, further comprising the following step (Y): (Y) A step of extending the tip of the microneedle to reduce the radius of curvature;
- a microneedle having improved penetrability and shape retention and a microneedle patch comprising the microneedle, which can be inserted into the skin with a low pressing strength and can be administered with a drug.
- Drug administration with less burden on the patient is possible.
- the application of a microneedle patch without using a special applicator is possible, the application range of the microneedle patch can be expanded.
- FIG. 1 It is a schematic diagram of a type I microneedle. It is a schematic diagram of a type II microneedle. It is the figure which illustrated the cross section of the microneedle front-end
- FIG. It is a figure which shows the change of the front-end
- FIG. It is a figure which shows the change of the full length of the microneedle immediately after manufacture of Example 2, and after 3 months frozen storage.
- the curvature radius of the tip is 20 ⁇ m or more. It is a figure which shows the state of the front-end
- FIG. It is an enlarged photograph of the tip reinforcement type microneedle of Example 6. On the left is the appearance of the tip-enhanced microneedle. On the right is the appearance of the tip-enhanced microneedle in which a blue pigment is added in place of the drug in the non-reinforced region.
- FIG. It is a figure which shows the damage state of the microneedle after driving the tip reinforcement
- FIG. It is an enlarged photograph which shows the state of the skin after treating the human thigh of Example 6 with the tip reinforcement
- the microneedle of the present invention is a cone-shaped microneedle having a tip portion containing a drug and a biodegradable polymer and a base portion not containing the drug, the tip side is formed as a tip strengthening region, The base side adjacent to the tip reinforced region is formed as a non-reinforced region, and is not particularly limited as long as the hardness of the tip reinforced region is higher than the hardness of the non-reinforced region.
- the hardness of the non-strengthened region is 1.1 times or more, more preferably 1.3 times or more, and still more preferably 1.5 times or more.
- the hardness is a hardness value measured by the Rockwell method or the Brinell hardness test method.
- the hardness of the base portion is preferably equal to or lower than the hardness of the tip reinforced region and / or higher than the hardness of the non-reinforced region.
- the microneedle of the present invention includes a mode (type I) in which the tip side is coated with a coating material containing a curing agent to form a tip strengthening region, and the tip side region of the tip further includes a curing agent.
- the mode (type II) in which the tip reinforcing region is formed.
- the drug contained in the tip of the microneedle of the present invention is not particularly limited.
- a drug that requires subcutaneous injection can be preferably exemplified.
- the content of the drug can be appropriately determined according to the type and form.
- the biodegradable polymer used for forming the tip of the microneedle is not particularly limited as long as it is capable of being decomposed in the body after being injected into the skin and releasing the drug.
- proteins such as gluten and gelatin And polysaccharides such as hyaluronic acid, chondroitin sulfate, alginic acid, starch, dextran, polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, polycaprolactone, polyhydroxybutyrate, polyethylene glycol, polypropylene glycol, etc. It is possible to control the solubility of the biodegradable polymer by polymerizing with the drug so that the drug can be released slowly.
- Microneedle base materials include gluten, gelatin and other proteins, hyaluronic acid, chondroitin sulfate, alginic acid, starch, dextran and other polysaccharides, polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, polycaprolactone Biodegradable polymers selected from polyhydroxybutyrate, polyethylene glycol, polypropylene glycol, etc., biodegradable polymers selected from polyolefins such as polyethylene and polypropylene, polystyrene, polyester, polyurethane, polyamide, fluorine resins, etc. There may be mentioned polymers.
- the base forming material may be the same as the non-reinforced region forming material excluding the drug. At this time, the hardness of the base not including the drug is higher than that of the non-reinforced region including the drug. Become.
- the microneedle of the present invention may be manufactured using any known method. For example, an original plate having a plurality of concave portions having the shape of a microneedle is prepared, and a dispenser, an inkjet device, a squeegee, etc. are used for the original plate. And a method of filling the microneedle forming material.
- the microneedle 10 has a tip 2 including a tip 1, a base 4 including a base 3, a tip reinforcing region 6 covered with a coating layer 5, and a non-reinforced region 7 not covered with the coating layer 5. is doing.
- the distal end reinforcing region 6 extends over the entire distal end portion 2 and a part on the distal end side of the base portion 4.
- the tip 2 contains a drug, but the base 4 does not contain a drug.
- the coating layer 5 containing a curing agent may or may not contain a drug, but preferably contains it.
- the length of the tip reinforcing region in this type I is 30 to 85% of the total length, more preferably 40 to 40% of the total length from the tip of the cone forming the microneedle to the basal plane.
- a preferred example is 75%, more preferably 50 to 65%.
- the tip part and the base part are It is possible to surely break near the boundary of the part, and it is possible to release the entire amount of the drug contained at a desired site.
- the coating material examples include proteins such as gluten and gelatin, polysaccharides such as chondroitin sulfate, alginic acid, starch and dextran, polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, polycaprolactone, polyhydroxybutyrate, polyethylene Biodegradable polymers selected from glycols, polypropylene glycols, silicon compounds, etc., surfactants selected from amphoteric, anionic, cationic and nonionic surfactants, ethyl alcohol, physiological saline, Water etc. can be illustrated.
- the coating material may contain a target drug.
- Coating with a coating material can be performed using any known technique, and examples thereof include a dip coating method, an ink jet method, a spray coating method, and a vapor deposition method.
- the thickness of the coating include 10 ⁇ m or less, preferably 5 ⁇ m or less, and more preferably 3 ⁇ m or less.
- the coating with the coating material smoothens the surface of the tip of the microneedle and reduces the frictional resistance when inserted into the skin, thereby improving the penetration of the microneedle.
- the frictional resistance is preferably reduced by 5% or more, more preferably reduced by 10% or more, and particularly preferably reduced by 20% or more compared to before the coating with the coating material.
- the microneedle 20 is formed of a tip portion 2 including a tip 1 and a base portion 4 including a base 3, and the tip portion 2 includes a curing agent and a biodegradable polymer but does not include a drug. It consists of a tip strengthening region 8 and a non-strengthening region 9 containing a drug and optionally a hardness reducing agent.
- the length of the tip reinforcing region is 1 to 50% of the total length, more preferably 3 to 5% from the tip side of the perpendicular line extending from the tip of the cone forming the microneedle to the basal plane.
- a preferred example is 40%, more preferably 5 to 30%.
- the tip reinforcing region may be formed by dropping the tip reinforcing region forming material of the minimum possible dripping amount by the ink jet apparatus onto the original plate.
- the tip reinforcing region forming material may or may not contain a drug, but from the viewpoint of increasing the hardness, it is preferable that the material does not contain a drug.
- the microneedle produced in this embodiment may be coated with the above-mentioned coating, and the length of the coating portion is preferably 30 to 85%, more preferably 40 to 75%, and still more preferably the total length of the microneedle. It accounts for 50-65%.
- the curing agent in the present invention means a material capable of making the hardness of the tip reinforced region higher than the hardness of the non-reinforced region, for example, polysaccharides such as calcium chloride, sodium chloride, dextran, hyaluronic acid, chondroitin sulfate, Examples thereof include a carboxy polymer, polyacrylic acid, polylactic acid, hydroxyapatite, polyethylene glycol, a fluorine compound, and a silicon compound.
- These curing agents may be added to the coating material or the tip reinforcing region forming material, and the amount of the curing agent can be appropriately set according to the type and purpose of the curing agent.
- the curing agent is a solid material
- the curing agent is a material that can improve the shape retention of the microneedles and can maintain the sharpness during the storage period from manufacture to use.
- the hardness reducing agent in the present invention means a material that can make the hardness of the non-reinforced region lower than the hardness of the tip-reinforced region, for example, monosaccharides such as sucrose and glucose, disaccharides and oligosaccharides, poly Examples include lactic acid and lactic acid.
- the dryness of only the tip reinforcing region may be increased.
- the hardness can be increased and the radius of curvature of the tip can be reduced.
- the tip may be pulled and stretched to reduce the radius of curvature.
- the radius of curvature of the tip of the microneedle of the present invention is preferably 10 ⁇ m or less, more preferably 7 ⁇ m or less, further preferably 5 ⁇ m or less, and particularly preferably 3 ⁇ m or less.
- the cross section of the tip is not limited to a circle, and may be processed into an ellipse, triangle, quadrangle, + shape, * shape, or the shape illustrated in FIG. 3, and the tip is cut obliquely.
- the sharpness may be increased.
- by continuously forming a spiral groove on the outside of the tip of the microneedle so that the microneedle rotates by driving the microneedle can be driven easily, and the microneedle can be broken and removed from the substrate. Liberation can be promoted.
- the total length of the microneedle of the present invention is preferably 100 to 1000 ⁇ m, more preferably 250 to 750 ⁇ m, and further preferably 400 to 600 ⁇ m. Further, the diameter of the base portion is preferably 30 to 1000 ⁇ m, more preferably 150 to 500 ⁇ m, and further preferably 200 to 350 ⁇ m.
- the microneedle patch means a patch having a plurality of microneedles on a substrate.
- proteins such as gluten and gelatin, polysaccharides such as chondroitin sulfate, alginic acid, starch and dextran, polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, polycaprolactone, polyhydroxybutyrate, polyethylene Biodegradable polymers selected from glycol, polypropylene glycol, etc., polyolefins such as polyethylene and polypropylene, biodegradable polymers selected from polystyrene, polyester, polyurethane, polyamide, fluororesin, paper, non-woven fabric, A sheet made of cloth can be exemplified.
- the microneedle patch of the present invention may have an adhesive surface, or may be a structure in which the substrate and the base portion are integrated. By setting it as such a structure, the chemical
- the microneedle of the present invention has improved penetrability as compared with the conventional microneedle, even when the microneedle is arranged at a high density in the microneedle patch, the resistance at the time of insertion is small, and the substrate It can be arranged at a density of, for example, 30 to 300 lines / cm 2 , preferably 60 to 200 lines / cm 2 , more preferably 80 to 140 lines / cm 2 . As a result, the amount of medicine loaded per unit area can be increased as compared with the conventional microneedle patch.
- the microneedle patch of the present invention can set the pressure applied to the skin by the applicator to be lower than that of a conventional microneedle patch, and can reduce pain and fear when applied to the skin.
- the pressure strength to the skin is preferably 11N or less, more preferably 9N or less, further preferably 7N or less, and particularly preferably 5N or less.
- the microneedle patch of the present invention may be applied using a simple driving device without using a special applicator.
- the microneedle patch of the present invention is preferably stored with the tip of the microneedle facing downward because the deformation at the time of storage increases due to the influence of gravity if the tip of the microneedle is stored upward or sideways. Therefore, the package for storing the microneedle patch is preferably one in which the tip of the microneedle is maintained downward, and examples thereof include a package to which a gyro function, weight, and magnetic force are applied. Such a package may be integrated with the refrigerator.
- the package is not limited to a box shape, and the bottom surface may be a curved surface or a spherical surface so that the downward direction is maintained by a gyro function, a weight, a magnetic force, or the like.
- the storage period is preferably 6 months or longer in the refrigerator, more preferably 1 year or longer, more preferably 2 years or longer, which is the normal shelf life of pharmaceutical products, or preferably 2 years or longer in the freezer, more preferably 5 years.
- the storage period is preferably 6 months or longer in the refrigerator, more preferably 1 year or longer, more preferably 2 years or longer, which is the normal shelf life of pharmaceutical products, or preferably 2 years or longer in the freezer, more preferably 5 years.
- the microneedle of the present invention can be manufactured by a manufacturing method including the following steps (A) to (D).
- D coating the tip of the dry cone with a coating material containing a curing agent to form a tip reinforcing region;
- the coating material containing the curing agent may be a substance having high hardness and / or improving smoothness, such as proteins such as gluten and gelatin, chondroitin sulfate, alginic acid, starch, dextran, and the like.
- Biodegradable polymers selected from polysaccharides, polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, polycaprolactone, polyhydroxybutyrate, polyethylene glycol, polypropylene glycol, silicon compounds, etc., amphoteric, anionic Coating materials selected from surfactants, ethyl alcohol, physiological saline, water, etc.
- a fluorine-based compound selected from surfactants, cationic and nonionic surfactants, calcium chloride, sodium chloride, polysaccharides, hyaluronic acid, chondroitin Sulfuric acid, carboxy polymer, Riakuriru acid, polylactic acid, hydroxyapatite, polyethylene glycol, a fluorine-based compound include those obtained by adding a curing agent selected from the silicon compound or the like.
- the coating by the step (D) is applied to the tip reinforcing region, for example, 30 to 85%, preferably 40 to 75%, more preferably 50 to 65% of the total length of the microneedle.
- mode the coating
- the microneedle of the present invention can be manufactured by a manufacturing method including the following steps (A) to (D).
- C A step of filling the original plate with a base portion forming material not containing a drug and overlaying the base portion on the tip portion to form a cone;
- D removing the dried cone obtained by drying the cone from the original plate;
- the step (X) of drying the tip reinforcing region of the microneedle and reducing the curvature radius may be included after the step (A) and / or (D).
- the microneedle of the present invention can be manufactured by a manufacturing method including the following steps (A) to (E).
- the step (X) of drying the tip reinforcing region of the microneedle and reducing the curvature radius may be included after the steps (A), (D) and / or (E).
- microneedle patch Using a forming material consisting of chondroitin sulfate and dextran, a portion of about 570 ⁇ m in length and 255 ⁇ m from the tip by inkjet method A microneedle patch containing fibroblast growth factor (bFGF) was prepared.
- a forming material consisting of chondroitin sulfate and dextran
- microneedle patch prepared in 1-1-1 was stored in a refrigerator at 4 ° C. for 6 months with the tip part facing up or down. After storage, the total length and curvature of the tip of the microneedle were compared with those of the microneedle patch immediately after production.
- microneedle patch 2-1-1 Preparation of microneedle patch Using a forming material consisting of chondroitin sulfate and dextran, a portion of about 548 ⁇ m in length and 255 ⁇ m from the tip by inkjet method A microneedle patch containing fibroblast growth factor (bFGF) was prepared.
- a forming material consisting of chondroitin sulfate and dextran
- FIGS. 7 to 9 Results The results are shown in FIGS. 7 to 9. As shown in FIG. 7, the total length was 548.0 ⁇ m immediately after the production, but there was no difference from 548.0 ⁇ m even after freezing. Moreover, as shown in the enlarged photograph of FIG. 8, the big change in the shape of the microneedle was not able to be confirmed before and after freezing preservation. Further, as shown in FIG. 9, when the driving pressure was changed to 7N, 9N, 11N, and 14N into the human thigh skin, there was no great difference in all driving pressures. In the microneedles, the remaining distance from the base portion was 293.0 ⁇ m, whereas after freezing storage, no difference was observed with 291 ⁇ m. From this point of view, it was found that there was no change in shape and performance in frozen storage. In addition, as shown in FIG. 10, no difference was observed in the degree of appearance of erythema at the implantation site after treatment before and after freezing.
- a solution was prepared by adding 1.2 ⁇ g of fibroblast growth factor (bFGF) to 0.1 ml of a mixture of polyethylene glycol 6000 and ethyl alcohol 1: 1.
- the prepared solution is poured into a vat to a depth of 0.3 mm, prepared by the method of 3-1-1, immersed so that only the tip of the dried microneedle patch is in contact, and 5 seconds later
- a microneedle patch in which 300 ⁇ m from the tip was coated with a polyethylene glycol ethyl alcohol solution was produced.
- FIGS. 11 and 14 results The microneedle with the coating before storage is shown in FIGS. 11 and 14 for 2 months at room temperature and the uncoated microneedle is shown in FIGS. 12 and 15 with room temperature for 2 months at room temperature.
- the microneedle with the coating after storage is shown in FIGS.
- the coated microneedle had no change in tip even after being stored at room temperature for 2 months, but the tip of the uncoated microneedle was dissolved by storage.
- Fibroblast growth factor (bFGF) is added to 0.1 ml of a mixture of polyethylene glycol 6000 and ethyl alcohol 1: 1. A solution with 1.2 ⁇ g added was prepared. The prepared solution is poured into a vat to a depth of 0.3 mm, prepared by the method of 3-1-1, immersed so that only the tip of the dried microneedle patch is in contact, and 15 seconds later Raised slowly. With the tip of the microneedle facing downward (in the direction of gravity), the microneedle was left in a refrigerator at 4 ° C., dried for 24 hours, returned to room temperature, and the change in tip shape was observed.
- bFGF Fibroblast growth factor
- FIG. 17 shows a microneedle that has not been coated before drying
- FIG. 18 shows a microneedle that has been coated after drying.
- the radius of curvature of the tip of the microneedle before drying was 20 ⁇ m or more, whereas the radius of curvature after drying was improved to 3 ⁇ m, indicating that the radius of curvature of the tip is reduced by drying after coating. It was.
- a solution in which 2.4 ⁇ g of fibroblast growth factor (bFGF) was added to 0.2 ml of a mixture of polyethylene glycol 6000 and ethyl alcohol in a ratio of 1: 1 was prepared.
- the prepared solution is applied to a sterilized flat plate so as to have a thickness of 0.6 mm, prepared by the method 1-1-1, and immersed so that the whole dried microneedle is in contact, and slowly after 15 seconds. Raised. Then, it dried in a 4 degreeC refrigerator for 24 hours, and produced the microneedle which coated the full length.
- Fig. 19 shows the state after driving the uncoated microneedle
- Fig. 20 shows the state after driving the microneedle coated 60% from the tip.
- Table 1 shows the damage distance from the tip of the microneedle and the damage rate.
- the microneedle patch coated up to 60% from the tip was inserted deeper than the uncoated microneedle patch (see Table 1), and it was confirmed that the microneedle itself was also damaged at the base. .
- the breakability of the microneedle coated with the entire length was extremely reduced.
- FIG. 21 shows the skin condition after driving the microneedle.
- the microneedle with no coating on the left in FIG. 21 bleeding at the treatment site was hardly seen and the erythema caused by the drug was weak, but with the microneedle with the coating on the right in FIG. In many cases, the desired result was obtained that the erythema caused by the drug was also strong.
- Test 5′-1 Method with Microneedle with Large Tip Radius of Curvature 5′-1 Method A microneedle patch with a tip radius of curvature of 15 ⁇ m was prepared by the method 3-1-1. The prepared microneedle patch was driven into a human skin using an applicator with a driving pressure of 14 N, and the state of the microneedle was observed.
- FIGS. FIG. 22 shows that the tip portion is depressed and deformed toward the drug-containing portion because the tip portion is driven at a high driving speed even though the sharpness of the tip portion is low, and the drug administration has failed. . Further, in FIG. 23, although the sharpness of the tip portion was low, the microneedle was peeled off at the base portion and collapsed because it was driven at a high driving speed.
- 6-1-2 Human skin driving test Two types of tip-enhanced microneedle patches prepared by the method of 6-1-1 and conventional microneedle patches prepared by the method of 3-1-1 An applicator was used to drive the human thigh skin with a pressure of 7N, 9N, 11N, and 14N. The state of the skin after implantation and the state of the microneedle after implantation were observed.
- Table 2 and FIG. 27 show the measurement results of the remaining distance from the base portion after implanting the tip-enhanced microneedle and the conventional microneedle into the skin. Indicates.
- the remaining distance from the base after treatment is clearly shortened compared to the conventional microneedle, and the conventional microneedle has a minimum of 11 N in order to completely drive the drug-containing portion.
- the drug-containing portion can be completely driven with a low driving pressure of 7N or 9N with the tip-enhanced microneedles.
- 25 and 26 show a broken state of the microneedles after the tip-enhanced microneedles are driven with 9N or 11N, respectively. It was found that the drug-containing part was reliably driven even when it was driven into the human thigh.
- FIG. 28 shows the progress of the skin after the tip-reinforced microneedle is driven.
- erythema caused by the drug was observed immediately after the driving (left side in FIG. 28).
- medical agent was seen not only 11N but 9N also in the treatment site
- a solution was prepared by adding 1.2 ⁇ g of fibroblast growth factor (bFGF) to 0.1 ml of a mixture of polyethylene glycol 6000 and ethyl alcohol 1: 1.
- the prepared solution is applied to a sterilized flat plate so as to have a thickness of 0.3 mm, prepared by the above method, and immersed so that only the tip of the dried tip-reinforced microneedle is in contact, and slowly after 15 seconds. Raised. Then, it was dried in a refrigerator at 4 ° C. for 24 hours to produce a tip-enhanced microneedle coated with 60% of the total length.
- bFGF fibroblast growth factor
- FIGS. 29 and 30 show the broken state of the coated microneedle after driving the coated tip-enhanced microneedle with 9N or 11N, respectively.
- the microneedles of FIGS. 29 and 30 are both broken at the tip, and it can be seen that the drug-containing portion is reliably driven even when driven into the human thigh. Table 3 and FIG.
- FIG. 32 shows the condition of the human thigh skin after driving of the coated tip-enhanced microneedle.
- the tip-enhanced microneedle with a coating obtained a desirable result that there was much bleeding at the treatment site immediately after treatment with 7N and erythema caused by the drug was sufficiently strong.
- strong erythema was formed in the result of 7N, and it was confirmed that the tip-enhanced microneedle with a coating has a therapeutic effect even at a very low driving pressure of 7N. It was.
- microneedle of the present invention Since the microneedle of the present invention has higher penetrability and shape retention than conventional microneedles and can be driven into a patient with a low pressing strength, treatment with less burden on the patient compared to conventional microneedles can be achieved. In addition to being able to be stored for a long time, it is highly industrially useful in the medical field.
Abstract
Description
(1)薬剤及び生体分解性高分子を含む先端部と、薬剤を含まない基底部とを有する錐体形状のマイクロニードルであって、
先端側が先端強化領域として形成され、該先端強化領域に隣接する基底側が非強化領域として形成されており、
前記先端強化領域の硬度が、前記非強化領域の硬度より高いことを特徴とする前記マイクロニードル。
(2)先端強化領域が、硬化剤を含むコーティング材料でマイクロニードルの先端側を被覆した領域であることを特徴とする上記(1)記載のマイクロニードル。
(3)先端強化領域が、錐体の先端から基底面に下ろした垂線の先端側30~85%の長さを占める領域であることを特徴とする上記(2)記載のマイクロニードル。
(4)先端強化領域が、薬剤及び生体分解性高分子に加えてさらに硬化剤を含む、先端部の先端側領域であることを特徴とする上記(1)記載のマイクロニードル。
(5)先端強化領域が、生体分解性高分子に加えてさらに硬化剤を含む、先端部の先端側領域であることを特徴とする上記(1)記載のマイクロニードル。
(6)先端強化領域が、錐体の先端から基底面に下ろした垂線の先端側1~50%の長さを占める領域であることを特徴とする上記(4)又は(5)記載のマイクロニードル。
(7)硬化剤を含むコーティング材料によって、少なくとも先端強化領域が被覆されたことを特徴とする上記(4)~(6)のいずれか記載のマイクロニードル。
(8)コーティング材料によって被覆される前と比較して、コーティング部の硬度が上昇し、コーティング部の摩擦抵抗が5%以上低下していることを特徴とする上記(2)、(3)及び(7)のいずれか記載のマイクロニードル。
(9)コーティング材料が、薬剤をさらに含むことを特徴とする上記(2)、(3)、(7)及び(8)のいずれか記載のマイクロニードル。
(10)硬化剤が、塩化カルシウム、塩化ナトリウム、多糖類、デキストラン、ヒアルロン酸、コンドロイチン硫酸、カルボキシポリマー、ポリアクリル酸、ポリ乳酸、ハイドロキシアパタイト、ポリエチレングリコール、フッ素系化合物及びシリコン系化合物から選択される1又は2以上であることを特徴とする上記(2)~(9)のいずれか記載のマイクロニードル。
(11)先端強化領域の乾燥度が他の部分より高いことを特徴とする上記(1)~(10)のいずれか記載のマイクロニードル。
(12)先端の曲率半径が5μm以下であることを特徴とする上記(1)~(11)のいずれか記載のマイクロニードル。
(13)先端強化領域の硬度が、非強化領域の硬度の1.1倍以上、1.3倍以上又は1.5倍以上であることを特徴とする上記(1)~(12)のいずれか記載のマイクロニードル。
(14)基底部の硬度が、非強化領域の硬度より高いことを特徴とする上記(4)~(13)のいずれか記載のマイクロニードル。
(15)基底部の硬度が、先端強化領域の硬度と同等か、より低いことを特徴とする、上記(4)~(14)のいずれか記載のマイクロニードル。
(16)非強化領域が、硬度低下剤を含むことを特徴とする上記(1)~(15)のいずれか記載のマイクロニードル。
(17)上記(1)~(16)のいずれか記載のマイクロニードルが基板上に複数備えられたことを特徴とするマイクロニードルパッチ。
(18)以下の工程(A)~(D)を含み、先端部と基底部とを有する錐体形状のマイクロニードルであって、硬化剤を含むコーティング材料で先端側を被覆した先端強化領域を備えたことを特徴とするマイクロニードルの製造方法。
(A)錐体形成用原版に、薬剤及び生体分解性高分子を含む先端部形成材料を充填し、乾燥させて先端部を形成する工程;
(B)前記原版に、薬剤を含まない基底部形成材料を充填し、前記先端部に基底部を重層して錐体を形成する工程;
(C)前記錐体を乾燥させた乾燥錐体を原版から取り外す工程;
(D)前記乾燥錐体の先端側に、硬化剤を含むコーティング材料で被覆を施し、先端強化領域を形成する工程;
(19)以下の工程(A)~(D)を含み、先端部と基底部とを有する錐体形状のマイクロニードルであって、生体分解性高分子に加えてさらに硬化剤を含む、先端部の先端側領域を備えたことを特徴とするマイクロニードルの製造方法。
(A)錐体形成用原版に、生体分解性高分子及び硬化剤を含む先端強化領域形成材料を充填し、乾燥させて先端強化領域を形成する工程;
(B)前記原版に、薬剤及び生体分解性高分子を含む非強化領域形成材料を充填し、前記先端強化領域に非強化領域を重層して先端部を形成する工程;
(C)前記原版に、薬剤を含まない基底部形成材料を充填し、前記先端部に基底部を重層して錐体を形成する工程;
(D)前記錐体を乾燥させた乾燥錐体を原版から取り外す工程;
(20)以下の工程(E)をさらに含む、上記(19)記載の製造方法。
(E)乾燥錐体の先端側に、硬化剤を含むコーティング材料で被覆を施す工程;
(21)非強化領域形成材料が硬度低下剤を含むことを特徴とする上記(19)又は(20)記載の製造方法。
(22)以下の工程(X)をさらに含むことを特徴とする上記(18)~(21)のいずれか記載の製造方法。
(X)マイクロニードルの先端部を乾燥し、曲率半径を小さくする工程;
(23)以下の工程(Y)をさらに含むことを特徴とする上記(18)~(22)のいずれか記載の製造方法。
(Y)マイクロニードルの先端部を延伸し、曲率半径を小さくする工程;
また、本発明のマイクロニードルとしては、その先端側に硬化剤を含むコーティング材料で被覆を施し、先端強化領域とした態様(タイプI)と、先端部の先端側領域に、さらに硬化剤を含ませることで先端強化領域とした態様(タイプII)とを好適に例示することができる。
マイクロニードルの全長にコーティングを行うと強度は上昇するが、体内で破断しなくなり、体内への留置が達成されないため、薬剤の投与が困難となる。また、あらかじめ薬剤を含有させた先端部と薬剤を含有していない基底部との境界でマイクロニードルを破損させたいときは、その境界部位付近までの長さにコーティングを行うと、先端部と基底部の境界付近で確実に破損させることができ、所望の部位での含有させた全量の薬剤の放出が可能となる。
(A)錐体形成用原版に、薬剤及び生体分解性高分子を含む先端部形成材料を充填し、乾燥させて先端部を形成する工程;
(B)前記原版に、薬剤を含まない基底部形成材料を充填し、前記先端部に基底部を重層して錐体を形成する工程;
(C)前記錐体を乾燥させた乾燥錐体を原版から取り外す工程;
(D)前記乾燥錐体の先端側に、硬化剤を含むコーティング材料で被覆を施し、先端強化領域を形成する工程;
(A)錐体形成用原版に、生体分解性高分子及び硬化剤を含む先端強化領域形成材料を充填し、乾燥させて先端強化領域を形成する工程;
(B)前記原版に、薬剤及び生体分解性高分子を含む非強化領域形成材料を充填し、前記先端強化領域に非強化領域を重層して先端部を形成する工程;
(C)前記原版に、薬剤を含まない基底部形成材料を充填し、前記先端部に基底部を重層して錐体を形成する工程;
(D)前記錐体を乾燥させた乾燥錐体を原版から取り外す工程;
(A)錐体形成用原版に、生体分解性高分子及び硬化剤を含む先端強化領域形成材料を充填し、乾燥させて先端強化領域を形成する工程;
(B)前記原版に、薬剤及び生体分解性高分子を含む非強化領域形成材料を充填し、前記先端強化領域に非強化領域を重層して先端部を形成する工程;
(C)前記原版に、薬剤を含まない基底部形成材料を充填し、前記先端部に基底部を重層して錐体を形成する工程;
(D)前記錐体を乾燥させた乾燥錐体を原版から取り外す工程;
(E)前記マイクロニードルの先端側に硬化剤を含むコーティング材料で被覆を施す工程;
1-1 方法
1-1-1 マイクロニードルパッチの作製
コンドロイチン硫酸及びデキストランからなる形成材料を用いて、インクジェット法により、長さ約570μmで、先端から255μmの部分まで線維芽細胞増殖因子(bFGF)を含むマイクロニードルパッチを作製した。
1-1-1で作製したマイクロニードルパッチを、先端部を上向き又は下向きにして4℃の冷蔵庫で6ヶ月間保存した。保存後に、マイクロニードルの全長及び先端部曲率を、製造直後のマイクロニードルパッチと比較検討した。
結果を図4及び5に示す。全長は、製造直後は566.9μmであったのに対し、下向き保存では567.0μmと大差なかったが、上向き保存では564.9μmと若干短縮した。一方、先端部の曲率は製造直後は5.8μmであったのに対し、下向き保存では5.3μmと若干縮小し、上向き保存では6.8μmと拡大した。この結果から、冷蔵保存では下向きに保存する方が形状変化が少ないことが判明した。また、図6に示した拡大写真からも、製造直後と下向き保存では先端部の形状に差がなかったのに対して、上向き保存では先端部の形状が鈍化しているのが確認できた。
2-1 方法
2-1-1 マイクロニードルパッチの作製
コンドロイチン硫酸及びデキストランからなる形成材料を用いて、インクジェット法により、長さ約548μmで、先端から255μmの部分まで線維芽細胞増殖因子(bFGF)を含むマイクロニードルパッチを作製した。
2-1-1で作製したマイクロニードルを、-80℃の冷凍庫で3ヶ月間保存した後、製造直後のマイクロニードルと、形状及び打ち込み後の破損状態の観点から比較検討した。なお、上記1-2の冷蔵保存の結果を踏まえ、本実施例ではマイクロニードルの先端を下向きにして冷凍保存した。打ち込み後の破損状態の検討は、製造直後と冷凍保存後のマイクロニードルを、ヒト大腿部皮膚に7N、9N、11N、14Nと打ち込み圧を変更して打ち込んでその使用後の状態を観察することで行った。
結果を図7~9に示す、図7に示した様に、全長は製造直後は548.0μmであったのに対し、冷凍保存後でも548.0μmと全く差がなかった。また、図8の拡大写真に示した様に、冷凍保存前後でマイクロニードルの形状に大きな変化は確認できなかった。また、図9に示した様に、ヒト大腿部皮膚に7N、9N、11N、14Nと打ち込み圧を変更して打ち込んだところ、全ての打ち込み圧で大差なく、特に常用する11Nでは、製造直後のマイクロニードルにおいて基底部からの残存距離が293.0μmであったのに対して、冷凍保存後は291μmと、差が認められなかった。この観点から冷凍保存では形状ならびに性能に変化が無いことが判明した。また、図10に示した様に、治療後の打ち込み部の紅斑の出現程度も冷凍保存前後で全く差が認められなかった。
3-1 方法
3-1-1 マイクロニードルパッチの作製
コンドロイチン硫酸及びデキストランからなる形成材料を用いて、インクジェット法により、長さ570μmで、先端から255μmの部分まで線維芽細胞増殖因子(bFGF)を含むマイクロニードルパッチを作製した。
ポリエチレングリコール6000、エチルアルコールを1:1で混合した溶液0.1mlに、線維芽細胞増殖因子(bFGF)を1.2μg加えた溶液を作製した。作製した溶液を、0.3mmの深さになるようにバットに注ぎ、3-1-1の方法で作製し、乾燥したマイクロニードルパッチの先端部のみを接するように浸した後、5秒後にゆっくり引き上げ、乾燥させることで、先端から300μmをポリエチレングリコールエチルアルコール溶液でコーティングしたマイクロニードルパッチを作製した。
コーティングを施されたマイクロニードル及びコーティングを施していないマイクロニードルを、室温で2ヶ月間保存して、先端形状の経時的変化を観察した。
保存前のコーティングが施されたマイクロニードルを図11及び14に、2ヶ月間室温で保存した後のコーティングが施されていないマイクロニードルを図12及び15に、2ヶ月間室温で保存した後のコーティングが施されたマイクロニードルを図13及び16に示す。コーティングが施されたマイクロニードルは、室温で2ヶ月間保存した後も先端に変化がなかったが、コーティングが施されていないマイクロニードルは、保存により先端が溶解した。
4-1 方法
ポリエチレングリコール6000、エチルアルコールを1:1で混合した溶液0.1mlに、線維芽細胞増殖因子(bFGF)を1.2μg加えた溶液を作製した。作製した溶液を、0.3mmの深さになるようにバットに注ぎ、3-1-1の方法で作製し、乾燥したマイクロニードルパッチの先端部のみを接するように浸した後、15秒後にゆっくり引き上げた。マイクロニードル先端を下方(重力方向)に向けた状態で4℃の冷蔵庫内に静置し、24時間乾燥させた上で室温に戻し、先端形状の変化を観察した。
乾燥前のコーティングが施されていないマイクロニードルを図17に、乾燥後のコーティングが施されたマイクロニードルを図18に示す。乾燥前のマイクロニードルの先端の曲率半径は20μm以上であったのに対し、乾燥後の曲率半径は3μmに改善しており、コーティング後の乾燥により、先端の曲率半径が小さくなることが示された。
5-1 方法
5-1-1 コーティングが施されたマイクロニードルの作製
ポリエチレングリコール6000、エチルアルコールを1:1で混合した溶液0.1mlに、線維芽細胞増殖因子(bFGF)を1.2μg加えた溶液を作製した。作製した溶液を、0.3mmの厚さになるように滅菌平板に塗布し、3-1-1の方法で作製し、乾燥したマイクロニードルの先端部のみを接するように浸した後、15秒後にゆっくり引き上げた。その後、4℃の冷蔵庫内で24時間乾燥させ、全長の60%をコーティングしたマイクロニードルを作製した。また、ポリエチレングリコール6000、エチルアルコールを1:1で混合した溶液0.2mlに、線維芽細胞増殖因子(bFGF)を2.4μg加えた溶液を作製した。作製した溶液を、0.6mmの厚さになるように滅菌平板に塗布し、1-1-1の方法で作製し、乾燥したマイクロニードルの全体を接するように浸した後、15秒後にゆっくり引き上げた。その後、4℃の冷蔵庫内で24時間乾燥させて、全長をコーティングしたマイクロニードルを作製した。
3-1-1の方法で作成したコーティングを施していない長さ560μmのマイクロニードルパッチと、5-1-1の方法で作製したコーティングを施したマイクロニードルパッチを、ヒトの皮膚に対してアプリケーターを用いて打ち込み圧7Nで打ち込んだ。打ち込み後の皮膚の状態と、打ち込み後のマイクロニードルの状態を観察した。
5-2-1 マイクロニードルの状態
コーティングを施していないマイクロニードルの打ち込み後の状態を図19に、先端から60%までコーティングを施したマイクロニードルの打ち込み後の状態を図20に示す。また、マイクロニードルの先端からの破損距離及び破損率を表1にまとめた。先端から60%までコーティングしたマイクロニードルパッチの方が、コーティングを施していないマイクロニードルパッチより深部へ挿入されるとともに(表1参照)、マイクロニードル自体も基部で破損されていることが確認された。一方で、全長をコーティングしたマイクロニードルは、破断性が極端に低下していた。
マイクロニードルの打ち込み後の皮膚の状態を、図21に示す。図21左のコーティングを施していないマイクロニードルでは、治療部位の出血がほとんど見られず、薬剤に起因する紅斑も弱かったが、図21右のコーティングを施したマイクロニードルでは、治療部位の出血も多く、薬剤に起因する紅斑も強いという望ましい結果が得られた。
5’-1 方法
3-1-1の方法により、先端の曲率半径が15μmのマイクロニードルパッチを作製した。作製したマイクロニードルパッチを、ヒトの皮膚に対してアプリケーターを用いて打ち込み圧14Nで打ち込んだ後、マイクロニードルの状態を観察した。
結果を図22及び23に示す。図22は、先端部の尖鋭度が低いのにも関わらず高い打ち込みスピードで打ち込んだために、先端部分が薬剤含有部に向かって陥没して変形し、薬剤投与に失敗していることがわかる。また、図23において、先端部の尖鋭度が低いのにも関わらず高い打ち込みスピードで打ち込んだために、マイクロニードルが基底部で剥離して倒壊した。
6-1 方法
6-1-1 先端強化型マイクロニードルパッチの作製
スキージ法を用いて、全長540.0μmで、先端から70μmがデキストランとコンドロイチン硫酸からなる形成材料、先端から70μmから255μmまでがデキストランとコンドロイチン硫酸に加え、線維芽細胞増殖因子(bFGF)とショ糖を添加した形成材料、先端部から255μmから基底部までがデキストランとコンドロイチン硫酸からなる形成材料からなり、薬剤を含まない先端部が、引き続く薬剤含有層よりも1.5倍硬度が高いマイクロニードルを作製した。また、同様の方法で、線維芽細胞増殖因子(bFGF)に代えて青色色素(インジゴカルミン)を添加したマイクロニードルを作製した。
6-1-1の方法で作成した先端強化型マイクロニードルパッチと、3-1-1の方法で作製した従来型マイクロニードルパッチの2種類を、アプリケーターを用いてヒト大腿部皮膚に打ち込み圧7N、9N、11N、14Nで打ち込んだ。打ち込み後の皮膚の状態と、打ち込み後のマイクロニードルの状態を観察した。
6-2-1 先端強化型マイクロニードルの外観の評価
先端強化型マイクロニードルの拡大写真を図24(左:薬剤含有、右:青色色素含有)に示す。治療前の先端強化型マイクロニードルは、図24左に示す拡大した外観からは従来型のマイクロニードルと差は認められなかった。また、図24右に示す青色色素を含有する先端強化型マイクロニードルでは、先端から、透明な先端強化部に引き続いて青色の薬剤含有部が形成され、さらに透明な基底部が作成されていることが明らかであった。この透明な先端強化領域の長さを実測した結果、74.3μmであった。
表2及び図27に、先端強化型マイクロニードル及び従来型のマイクロニードルの、皮膚への打ち込み後の基底部からの残存距離の測定結果を示す。先端強化型マイクロニードルでは、治療した後の基底部からの残存距離は従来型マイクロニードルと比較して明らかに短縮しており、従来型マイクロニードルでは薬剤含有部を完全に打ち込むために最低でも11Nの打ち込み圧が必要であったのに対し、先端強化型マイクロニードルでは7Nや9Nという低い打ち込み圧で薬剤含有部を完全に打ち込むことが可能となることが判明した。図25及び26に、先端強化型マイクロニードルをそれぞれ9N又は11Nで打ち込んだ後のマイクロニードルの破損状態を示す。ヒトの大腿部への打ち込みでも薬剤含有部が確実に打ち込まれていることがわかった。
先端強化型マイクロニードルの打ち込み後の皮膚の経過を図28に示す。ヒトの大腿部に先端強化型マイクロニードルを打ち込んだ皮膚は、打ち込み直後に薬剤に起因する紅斑が認められた(図28左)。また、治療後2日後の治療部位においても、薬剤に起因する紅斑が、11Nのみならず9Nでも強く見られるという望ましい結果が得られた(図28右)。
7-1 方法
7-1-1 コーティング処理先端強化型マイクロニードルパッチの作製
スキージ法を用いて、先端から70μmがデキストランとコンドロイチン硫酸からなる形成材料、先端から70μmから255μmまでがデキストランとコンドロイチン硫酸に加え、線維芽細胞増殖因子(bFGF)とショ糖を添加した形成材料、先端部から255μmから基底部までがデキストランとコンドロイチン硫酸からなる形成材料からなり、薬剤を含まない先端部が、引き続く薬剤含有層よりも2倍硬度が高いマイクロニードルを作製した。コーティング材料として、ポリエチレングリコール6000、エチルアルコールを1:1で混合した溶液0.1mlに、線維芽細胞増殖因子(bFGF)を1.2μg加えた溶液を作製した。作製した溶液を、0.3mmの厚さになるように滅菌平板に塗布し、上記方法で作成し、乾燥した先端強化型マイクロニードルの先端部のみを接するように浸した後、15秒後にゆっくり引き上げた。その後、4℃の冷蔵庫内で24時間乾燥させ、全長の60%をコーティングした先端強化型マイクロニードルを作製した。
上記で作製したコーティング無しの先端強化型マイクロニードルとコーティング有りの先端強化型マイクロニードルの2種類を、ヒト大腿部皮膚に7N、9N、11N、14Nと打ち込み圧を変更して打ち込んだ。打ち込み後の皮膚の状態と、打ち込み後のマイクロニードルの状態を観察した。
7-2-1 マイクロニードルの打ち込み後の状態
治療前のコーティング無しの先端強化型マイクロニードル(図24)とコーティング有りの先端強化型マイクロニードルの外観に差は認められなかった。図29及び30に、コーティング有りの先端強化型マイクロニードルをそれぞれ9N又は11Nで打ち込んだ後のコーティグ有のマイクロニードルの破損状態を示す。図29及び30のマイクロニードルは、いずれも先端部が破損しており、ヒトの大腿部への打ち込みでも薬剤含有部が確実に打ち込まれていることがわかる。表3及び図31に、コーティング無しの先端強化型マイクロニードルとコーティング有りの先端強化型マイクロニードルの、皮膚への打ち込み後の基底部からの残存距離の測定結果を示した。表3及び図31に示すように、コーティング有りの先端強化型マイクロニードルでは治療した後の基底部からの残存距離はコーティング無しの先端強化型マイクロニードルに比較して明らかに短縮しており、従来型マイクロニードルでは薬剤含有部を完全に打ち込むのに最低でも11Nの打ち込み圧が必要であったのに加え、コーティング無しの先端強化型マイクロニードルでも最低でも9N必要であったが、コーティング有りの先端強化型マイクロニードルでは7Nという極めて低い打ち込み圧でも薬剤含有部の完全な打ち込みが可能となることが判明した。
コーティング有りの先端強化型マイクロニードルの、打ち込み後のヒトの大腿部皮膚の状態を図32に示す。図32左に示すように、コーティング有りの先端強化型マイクロニードルでは、7Nでの治療直後においても治療部位の出血が多く、薬剤に起因する紅斑も十分に強いという望ましい結果が得られた。また、図32右に示す治療後2日目でも、7Nの結果において強い紅斑を形成しており、コーティング有りの先端強化型マイクロニードルでは7Nという極めて低い打ち込み圧でも治療効果があることが確認された。
2 先端部
3 基底
4 基底部
5 コーティング層
6、8 先端強化領域
7、9 非強化領域
10 マイクロニードル(タイプI)
20 マイクロニードル(タイプII)
Claims (23)
- 薬剤及び生体分解性高分子を含む先端部と、薬剤を含まない基底部とを有する錐体形状のマイクロニードルであって、
先端側が先端強化領域として形成され、該先端強化領域に隣接する基底側が非強化領域として形成されており、
前記先端強化領域の硬度が、前記非強化領域の硬度より高いことを特徴とする前記マイクロニードル。 - 先端強化領域が、硬化剤を含むコーティング材料でマイクロニードルの先端側を被覆した領域であることを特徴とする請求項1記載のマイクロニードル。
- 先端強化領域が、錐体の先端から基底面に下ろした垂線の先端側30~85%の長さを占める領域であることを特徴とする請求項2記載のマイクロニードル。
- 先端強化領域が、薬剤及び生体分解性高分子に加えてさらに硬化剤を含む、先端部の先端側領域であることを特徴とする請求項1記載のマイクロニードル。
- 先端強化領域が、生体分解性高分子に加えてさらに硬化剤を含む、先端部の先端側領域であることを特徴とする請求項1記載のマイクロニードル。
- 先端強化領域が、錐体の先端から基底面に下ろした垂線の先端側1~50%の長さを占める領域であることを特徴とする請求項4又は5記載のマイクロニードル。
- 硬化剤を含むコーティング材料によって、少なくとも先端強化領域が被覆されたことを特徴とする請求項4~6のいずれか記載のマイクロニードル。
- コーティング材料によって被覆される前と比較して、コーティング部の硬度が上昇し、コーティング部の摩擦抵抗が5%以上低下していることを特徴とする請求項2、3及び7のいずれか記載のマイクロニードル。
- コーティング材料が、薬剤をさらに含むことを特徴とする請求項2、3、7及び8のいずれか記載のマイクロニードル。
- 硬化剤が、塩化カルシウム、塩化ナトリウム、多糖類、デキストラン、ヒアルロン酸、コンドロイチン硫酸、カルボキシポリマー、ポリアクリル酸、ポリ乳酸、ハイドロキシアパタイト、ポリエチレングリコール、フッ素系化合物及びシリコン系化合物から選択される1又は2以上であることを特徴とする請求項2~9のいずれか記載のマイクロニードル。
- 先端強化領域の乾燥度が他の部分より高いことを特徴とする請求項1~10のいずれか記載のマイクロニードル。
- 先端の曲率半径が5μm以下であることを特徴とする請求項1~11のいずれか記載のマイクロニードル。
- 先端強化領域の硬度が、非強化領域の硬度の1.1倍以上、1.3倍以上又は1.5倍以上であることを特徴とする請求項1~12のいずれか記載のマイクロニードル。
- 基底部の硬度が、非強化領域の硬度より高いことを特徴とする請求項4~13のいずれか記載のマイクロニードル。
- 基底部の硬度が、先端強化領域の硬度と同等か、より低いことを特徴とする、請求項4~14のいずれか記載のマイクロニードル。
- 非強化領域が、硬度低下剤を含むことを特徴とする請求項1~15のいずれか記載のマイクロニードル。
- 請求項1~16のいずれか記載のマイクロニードルが基板上に複数備えられたことを特徴とするマイクロニードルパッチ。
- 以下の工程(A)~(D)を含み、先端部と基底部とを有する錐体形状のマイクロニードルであって、硬化剤を含むコーティング材料で先端側を被覆した先端強化領域を備えたことを特徴とするマイクロニードルの製造方法。
(A)錐体形成用原版に、薬剤及び生体分解性高分子を含む先端部形成材料を充填し、乾燥させて先端部を形成する工程;
(B)前記原版に、薬剤を含まない基底部形成材料を充填し、前記先端部に基底部を重層して錐体を形成する工程;
(C)前記錐体を乾燥させた乾燥錐体を原版から取り外す工程;
(D)前記乾燥錐体の先端側に、硬化剤を含むコーティング材料で被覆を施し、先端強化領域を形成する工程; - 以下の工程(A)~(D)を含み、先端部と基底部とを有する錐体形状のマイクロニードルであって、生体分解性高分子に加えてさらに硬化剤を含む、先端部の先端側領域を備えたことを特徴とするマイクロニードルの製造方法。
(A)錐体形成用原版に、生体分解性高分子及び硬化剤を含む先端強化領域形成材料を充填し、乾燥させて先端強化領域を形成する工程;
(B)前記原版に、薬剤及び生体分解性高分子を含む非強化領域形成材料を充填し、前記先端強化領域に非強化領域を重層して先端部を形成する工程;
(C)前記原版に、薬剤を含まない基底部形成材料を充填し、前記先端部に基底部を重層して錐体を形成する工程;
(D)前記錐体を乾燥させた乾燥錐体を原版から取り外す工程; - 以下の工程(E)をさらに含む、請求項19記載の製造方法。
(E)乾燥錐体の先端側に、硬化剤を含むコーティング材料で被覆を施す工程; - 非強化領域形成材料が硬度低下剤を含むことを特徴とする請求項19又は20記載の製造方法。
- 以下の工程(X)をさらに含むことを特徴とする請求項18~21のいずれか記載の製造方法。
(X)マイクロニードルの先端部を乾燥し、曲率半径を小さくする工程; - 以下の工程(Y)をさらに含むことを特徴とする請求項18~22のいずれか記載の製造方法。
(Y)マイクロニードルの先端部を延伸し、曲率半径を小さくする工程;
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US (1) | US20180344998A1 (ja) |
EP (1) | EP3381498A4 (ja) |
JP (1) | JP6681626B2 (ja) |
KR (1) | KR20180087252A (ja) |
HK (1) | HK1254944A1 (ja) |
WO (1) | WO2017090254A1 (ja) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109876197A (zh) * | 2019-04-09 | 2019-06-14 | 珠海天威飞马打印耗材有限公司 | 一种3d打印皮肤及其制备方法 |
JP2021511124A (ja) * | 2018-01-18 | 2021-05-06 | シンビア カンパニー リミテッド | 植込み型マイクロニードルおよびその製造方法 |
JP2021535928A (ja) * | 2018-08-31 | 2021-12-23 | 中科微針(北京)科技有限公司 | 植込み型徐放微細針パッチ及びその調製方法 |
US11439323B2 (en) * | 2018-04-28 | 2022-09-13 | Beijing Boe Technology Development Co., Ltd. | Smart patch and method for fabricating the same |
CN109876197B (zh) * | 2019-04-09 | 2024-05-10 | 珠海天威增材有限公司 | 一种3d打印皮肤及其制备方法 |
Families Citing this family (3)
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CA3078251A1 (en) * | 2017-10-16 | 2019-10-24 | Trustees Of Tufts College | System and method for making microneedles |
WO2020200407A1 (en) * | 2019-03-29 | 2020-10-08 | L'oreal | Frozen micro-implants and method of making same |
KR102372290B1 (ko) * | 2020-02-11 | 2022-03-10 | 주식회사 일론 | 수용성 물질을 포함하는 화장용 마이크로니들 |
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2016
- 2016-11-25 US US15/779,605 patent/US20180344998A1/en not_active Abandoned
- 2016-11-25 KR KR1020187014194A patent/KR20180087252A/ko unknown
- 2016-11-25 JP JP2017552277A patent/JP6681626B2/ja active Active
- 2016-11-25 WO PCT/JP2016/004967 patent/WO2017090254A1/ja active Application Filing
- 2016-11-25 EP EP16868205.2A patent/EP3381498A4/en not_active Withdrawn
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2018
- 2018-11-02 HK HK18114047.4A patent/HK1254944A1/zh unknown
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JP2021511124A (ja) * | 2018-01-18 | 2021-05-06 | シンビア カンパニー リミテッド | 植込み型マイクロニードルおよびその製造方法 |
JP7055954B2 (ja) | 2018-01-18 | 2022-04-19 | シンビア カンパニー リミテッド | 植込み型マイクロニードルおよびその製造方法 |
US11938308B2 (en) | 2018-01-18 | 2024-03-26 | Snvia Co., Ltd. | Implantable microneedle and manufacturing method therefor |
US11439323B2 (en) * | 2018-04-28 | 2022-09-13 | Beijing Boe Technology Development Co., Ltd. | Smart patch and method for fabricating the same |
JP2021535928A (ja) * | 2018-08-31 | 2021-12-23 | 中科微針(北京)科技有限公司 | 植込み型徐放微細針パッチ及びその調製方法 |
JP7109675B2 (ja) | 2018-08-31 | 2022-07-29 | 中科微針(北京)科技有限公司 | 植込み型徐放微細針パッチ及びその調製方法 |
CN109876197A (zh) * | 2019-04-09 | 2019-06-14 | 珠海天威飞马打印耗材有限公司 | 一种3d打印皮肤及其制备方法 |
CN109876197B (zh) * | 2019-04-09 | 2024-05-10 | 珠海天威增材有限公司 | 一种3d打印皮肤及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
JP6681626B2 (ja) | 2020-04-15 |
JPWO2017090254A1 (ja) | 2018-07-12 |
US20180344998A1 (en) | 2018-12-06 |
EP3381498A1 (en) | 2018-10-03 |
KR20180087252A (ko) | 2018-08-01 |
HK1254944A1 (zh) | 2019-08-02 |
EP3381498A4 (en) | 2019-07-17 |
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