CN116867537A - Method for manufacturing microneedle structure and microneedle structure - Google Patents
Method for manufacturing microneedle structure and microneedle structure Download PDFInfo
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- CN116867537A CN116867537A CN202280014739.0A CN202280014739A CN116867537A CN 116867537 A CN116867537 A CN 116867537A CN 202280014739 A CN202280014739 A CN 202280014739A CN 116867537 A CN116867537 A CN 116867537A
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- water
- needle
- base material
- microneedle structure
- portions
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
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- 229920001577 copolymer Polymers 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
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- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14503—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
- A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
- A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
-
- A—HUMAN NECESSITIES
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- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150969—Low-profile devices which resemble patches or plasters, e.g. also allowing collection of blood samples for testing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/151—Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/153—Devices specially adapted for taking samples of venous or arterial blood, e.g. with syringes
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- A—HUMAN NECESSITIES
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- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
- A61B5/685—Microneedles
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- A—HUMAN NECESSITIES
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- 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
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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
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- A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61M2207/00—Methods of manufacture, assembly or production
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medical Informatics (AREA)
- General Health & Medical Sciences (AREA)
- Pathology (AREA)
- Surgery (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Optics & Photonics (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Anesthesiology (AREA)
- Emergency Medicine (AREA)
- Media Introduction/Drainage Providing Device (AREA)
Abstract
The method for producing a microneedle structure 10 according to the present invention is a method for producing a microneedle structure 10 having needle-like portions 12 having hole portions 13 on one surface side of a base material 11 having liquid permeability in a thickness direction, the method comprising: a forming step of forming the protruding portion 5 using a composition 3 for forming a needle-like portion, the composition containing a first water-insoluble material and a first water-soluble material; a bonding step of bonding the composition 3 or the protrusion 5 formed in the forming step to the base material 11; and a removal step in which the protrusions 5 and the base material 11 are immersed in water, and the first water-soluble material is dissolved and removed, whereby the needle-like portions 12 and the hole portions 13 are formed from the protrusions 5. According to the method for manufacturing the microneedle structure, a microneedle structure having a base material and securing a flow path can be provided.
Description
Technical Field
The present invention relates to a method for producing a microneedle structure and a microneedle structure.
Background
In recent years, a solution has been proposed in which a drug is supplied into the body through a through hole formed in a microneedle, and a body fluid is collected from the body. For example, as a microneedle excellent in diffusibility of a substance for supplying a drug into a body, a microneedle is known which has a height of 20 μm or more and less than 500 μm, an aspect ratio (h/a) of a height h to a maximum length a of a base of 2 or more, and is composed of a mesoporous material (patent document 1). In order to more appropriately grasp the symptoms of a patient, etc., an analysis patch has been proposed in which a small burden is placed on the body, and a minute microneedle having a length of less than 1 mm is inserted into the skin of the patient to collect blood, and the blood is analyzed. As a low invasive test patch which allows a patient to easily and continuously monitor blood glucose, patent document 2 discloses a test patch in which a substrate is a base plate on which a microchannel is formed, and an adhesive material for forming needle-like portions is slowly discharged from a dispenser (dispenser) on the base plate to form a plurality of needle-like portions. In this test patch, a needle is inserted into a patient, blood is continuously collected from the needle by a capillary pump portion of a microchannel provided in a base plate by capillary action, and the collected blood is measured by a sensor provided in a reaction chamber provided in the base plate.
Prior art literature
Patent literature
Patent document 1: japanese patent laid-open No. 2014-094171
Patent document 2: WO 2019/1761126
Disclosure of Invention
Technical problem to be solved by the invention
The base plate used in the above-mentioned test patch requires a minute capillary pump portion, a minute micro flow path, and the like to be formed on the plate, but it is desired to manufacture the test patch and the microneedle structure ensuring the flow path more inexpensively and easily. In addition, even in the case of an inspection patch or the like manufactured by a simple method, it is necessary to form a needle-like portion in a desired shape and to secure a flow path.
The present invention has been made in view of the above-described circumstances, and an object of the present invention is to provide a microneedle structure capable of easily obtaining a microneedle structure that ensures a flow path, and a method for manufacturing the microneedle structure.
Technical means for solving the technical problems
In order to achieve the above object, in a first aspect, the present invention provides a method for producing a microneedle structure having needle-like portions having hole portions on one surface side of a base material having liquid permeability in a thickness direction, the method comprising: a forming step of forming a protrusion using a composition for forming a needle-like portion, the composition containing a first water-insoluble material and a first water-soluble material; a bonding step of bonding the composition or the protrusion formed in the forming step to the base material; and a removal step of immersing the protruding portion and the base material in water to dissolve and remove the first water-soluble material, thereby forming the needle-like portion and the hole portion from the protruding portion (invention 1).
In the invention (invention 1), the use of the substrate having liquid permeability in the thickness direction allows the flow path to be formed in the microneedle structure easily. In addition, after the base material is bonded to the protrusions formed in the composition or formation step, holes are formed in the protrusions in the removal step, so that the holes in the protrusions and the holes in the base material are easily connected, and a flow path is easily formed in the microneedle structure.
In the above invention (invention 1), it is preferable that: the base material having liquid permeability in the thickness direction is a porous base material, the bonding step is a step of bonding the protrusion formed in the forming step to a sheet containing a second water-soluble material and the porous base material, and the removing step is a step of dissolving and removing the first water-soluble material and the second water-soluble material (invention 2).
By incorporating the second water-soluble material into the porous base material, the base material can be prevented from absorbing the composition of the protrusions when the base material is bonded to the protrusions formed. As a result, since excessive voids are not formed in the protruding portions, i.e., the needle-like portions, particularly in the root portions, the needle-like portions can be prevented from collapsing, and needle-like portions having a shape suitable for adhesion to the base material serving as the flow path can be formed, and a microneedle structure having excellent adhesion between the needle-like portions and the base material can be produced.
In the above invention (invention 2), it is preferable that: the porous substrate is a fibrous substrate (invention 3).
In the above inventions (inventions 2 and 3), it is preferable that: the sheet comprises a second water insoluble material (invention 4).
In the above invention (invention 4), it is preferable that: the first water-insoluble material is the same as the second water-insoluble material (invention 5).
In the above inventions (inventions 2 to 5), it is preferable that: the sheet is a sheet obtained by impregnating the base material with a second water-soluble material (invention 6).
In the above inventions (inventions 2 to 6), it is preferable that: the substrate made of the fibrous material is a nonwoven fabric, woven fabric, knitted fabric or paper (invention 7).
In the above invention (invention 1), it is preferable that: the base material is a base material made of a material having liquid impermeability, and has a through hole formed in the thickness direction (invention 8).
Since the liquid absorption of the base material can be suppressed by making the base material liquid impermeable, the liquid can pass through only the inside of the through-holes formed in the thickness direction in the base material. Therefore, the body fluid obtained from the needle portion or the chemical liquid supplied to the needle portion does not penetrate into the base material, and can flow through all the through holes. In addition, after the base material is bonded to the protrusions formed in the composition or formation step, holes are formed in the protrusions in the removal step, so that the holes of the protrusions are easily connected to the through holes in the base material, and a flow path is easily formed in the microneedle structure.
In the above inventions (inventions 1 to 8), it is preferable that: the method comprises a filling step in which the composition for forming needle-shaped portions is filled into a mold having recessed portions (invention 9).
In the above invention (invention 9), it is preferable that: in the filling step, the composition for forming needle-like portions contains a solvent, and in the forming step, the solvent is evaporated (invention 10).
In the above inventions (inventions 1 to 10), it is preferable that: the method comprises a setting step of setting an analysis means of body fluid and/or a storage means of physiologically active substance on the surface of the base material opposite to the surface on which the needle-like portion is provided (invention 11).
In a second aspect, the present invention provides a microneedle structure comprising a porous substrate and needle-like portions having holes on one surface side of the porous substrate, wherein the needle-like portions are made of a first water-insoluble material and are directly provided on the porous substrate, and the porous substrate contains a second water-insoluble material (invention 12).
Effects of the invention
According to the method for producing a microneedle structure of the present invention, a microneedle structure can be provided in which needle-like portions that ensure a flow path can be easily obtained, the needle-like portions can be formed in a desired shape, and the needle-like portions and the flow path can be well bonded.
Drawings
Fig. 1 is a schematic partial cross-sectional view of a microneedle structure of the present invention.
Fig. 2 is a cross-sectional view of an inspection patch using the microneedle structure of the present invention.
Fig. 3 is an explanatory diagram showing steps of a method for manufacturing a microneedle structure.
Detailed Description
Hereinafter, embodiments of the present invention will be described.
[ microneedle Structure ]
A microneedle structure 10 according to one embodiment of the present invention is shown in fig. 1. The microneedle structure 10 includes a plurality of needle-like portions 12 separated from each other at predetermined intervals on one surface side of a base material 11. The microneedle structure 10 may be used as: an inspection patch for absorbing interstitial fluid from the skin via the needle-like portion 12 and performing an inspection using the obtained interstitial fluid; and a drug administration patch for administering a drug from the skin into the body from the base 11 via the needle 12.
(1) Needle-like part
The shape, size, formation interval, formation number of the needle-like portions 12 can be appropriately selected according to the purpose, that is, the purpose of the microneedle, and the like. Examples of the shape of the needle-like portion 12 include a cylindrical shape, a prismatic shape, a conical shape, and a pyramidal shape in the present embodiment. The maximum diameter or the maximum dimension of the cross section of the needle-like portion 12 may be, for example, 25 to 1000 μm, the diameter or the cross section of the tip may be, for example, 1 to 100 μm, and the height of the needle-like portion 12 may be, for example, 50 to 2000 μm. The needle-like portions 12 are arranged in a plurality of rows in one direction of the base material 11, and are arranged in a matrix by forming a plurality of rows.
The needle-shaped portion 12 is made of a first water-insoluble material that is insoluble in water contained in a cleaning liquid used in a removing step described later. The first water-insoluble material is preferably a water-insoluble resin in view of ease of handling in the manufacturing process. The water-insoluble resin is preferably a water-insoluble resin having a melting point higher than normal temperature and 250 ℃ or lower, more preferably a water-insoluble resin having a melting point higher than 40 ℃ and 200 ℃ or lower, particularly preferably a water-insoluble resin having a melting point higher than 45 ℃ and 150 ℃ or lower, and particularly preferably a water-insoluble resin having a melting point higher than 45 ℃ and 80 ℃ or lower. Since the melting point is higher than normal temperature, the water-insoluble resin is solid at normal temperature, and needle-like portions 12 can be formed, and if the melting point is lower than 150 ℃, the degree of freedom in selecting materials usable as a base material increases, and workability increases.
The water-insoluble resin is preferably a water-insoluble biodegradable resin which is not easily affected by the human body. The biodegradable resin is preferably an aliphatic polyester or a derivative thereof, and further, at least 1 selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, and a copolymer obtained by copolymerizing monomers constituting the same. In addition, biodegradable resins such as polybutylene succinate, aliphatic aromatic copolyesters, and polyhydroxybutyrate may be used. In addition, a mixture of two or more of these biodegradable resins may also be used. Most preferably: the first water-insoluble material is polycaprolactone or a copolymer of caprolactone as a biodegradable resin having a melting point of 60 ℃ with a monomer constituting the other biodegradable resin. The molecular weight of the water insoluble resin is generally 5,000 ～ 300,000, preferably 7,000 ～ 200,000, more preferably 8,000 ～ 150,000.
Each needle portion 12 has a hole 13 formed in the surface and the inside thereof. The hole 13 is formed by removing the first water-soluble material in a removing step described later, and body fluid and chemical liquid pass through the hole 13. The hole portion 13 is formed in the needle portion 12 in a porous structure. If the needle-like portion 12 is formed in a porous structure, a flow path through which the body fluid or the chemical solution passes as the hole portion 13 is formed relatively inside the needle-like portion, and thus, a nano-sized flow path is not required to be mechanically formed, which is preferable. In addition, since the body fluid or the chemical liquid can pass through the entire portion of the needle-like body where the porous structure is formed, the flow rate can be increased as compared with a simple communication hole. Further, when the needle-shaped portion 12 is formed so as to have a porous structure as described above, the hole portion 13 opens to the side surface of the needle-shaped portion 12 if the porous structure is uncovered at part or all of the side surfaces of the needle-shaped portion. In this case, the flow rate of the liquid can be increased as compared with the case where the needle 12 is opened only at the tip end portion. The hole 13 is provided to extend toward the base material 11 in accordance with the formed hole 13, as shown in the cross section. The opening size of the hole 13 is determined according to the application of the test patch or the like using the microneedle structure 10, but the opening size is preferably 0.1 to 50.0 μm, more preferably 0.5 to 25.0 μm, and even more preferably 1.0 to 10.0 μm, from the viewpoint of easy liquid permeation or the like. In addition, in the present invention, body fluid includes blood, lymph fluid, interstitial fluid and the like.
(2) Substrate material
The base material 11 is not particularly limited as long as it has liquid permeability in the thickness direction. The base material 11 is preferably a porous material in which minute base material pores penetrating from one surface to the other surface are formed. As the porous substrate 11, a known substrate may be used, and examples thereof include a substrate made of a foaming material such as a foaming urethane resin, a porous material such as a porous ceramic, or a fibrous material. The porous substrate 11 is generally insoluble in water or is formed of a material that is poorly soluble in water. Preferably a substrate composed of an easily handled fibrous substance. The fibrous material in the present invention means fibers such as natural fibers and chemical fibers. Examples of the base material made of a fibrous material include nonwoven fabric, woven fabric, knitted fabric, paper, and the like made of the above fibers.
The pores of the porous substrate 11 communicate with the pores 13 of the needle-like portions 12 to form communication holes. The shape of the substrate hole depends on the material of the substrate. The porosity of the porous substrate 11 due to the substrate pores is preferably 1 to 70%, more preferably 5 to 50%, and particularly preferably 10 to 30%. By setting the porosity within this range, the body fluid absorbed by the needle 12 can be sufficiently absorbed. As described below, the porous base material 11 preferably contains a second water-insoluble material, and the base material 11 containing the second water-insoluble material also maintains the base material pores. The needle-like portions 12 are directly bonded to the base material 11. For example, when the base material 11 and the needle-shaped portions 12 are bonded by an adhesive layer or the like, a gap may be generated between the base material 11 and the needle-shaped portions 12, which may cause leakage of the liquid, or the passage of the liquid between the base material 11 and the needle-shaped portions 12 may be hindered by the adhesive layer, but the flow paths of the base material 11 and the needle-shaped portions 12 are easily connected by directly bonding the two.
As the base material having liquid permeability in the thickness direction, a base material that is made of a material having liquid impermeability and is configured so that liquid can pass through the through holes formed in the base material 11 in the thickness direction of the base material 11 may be used, instead of the base material 11 itself being made of a material having liquid permeability. By making the base material 11 liquid impermeable, the absorption of the liquid by the base material 11 can be suppressed, and therefore, the liquid can pass through only the inside of the through holes in the base material 11. Therefore, the body fluid obtained from the needle-shaped portion 12 or the chemical liquid supplied to the needle-shaped portion 12 does not penetrate into the base material 11, and can flow through all the through holes. Thus, when the microneedle structure 10 is used as an inspection patch, since body fluid can pass through the base material 11 quickly, analysis can be performed quickly, and when the microneedle structure 10 is used as a drug administration patch, the drug solution does not leak out, and the drug solution can be supplied to the skin entirely quickly.
Examples of the material having liquid impermeability include a resin film, a metal foil, and a glass film, and a resin film is preferably used. The shape of the through-holes is not particularly limited, but from the viewpoint of generating capillary phenomenon and securing sufficient flow rate, a structure in which a plurality of through-holes having a small diameter are provided is preferable. The diameter of the through hole is, for example, 2mm or less, preferably 0.05 to 1mm, and more preferably 0.1 to 0.8mm. The through hole may be provided by punching, laser perforation, or the like. Examples of the resin used for the resin film include polybutylene terephthalate, polyethylene, polypropylene, an ethylene-vinyl acetate copolymer, vinyl chloride, an acrylic resin, polyurethane, and polylactic acid. The substrate 11 may be a laminate substrate in which a resin film having through holes and a porous substrate are laminated.
When the pressure-sensitive adhesive layer is provided on the surface of the substrate 11 on which the needle-like portions 12 are formed, a bonding step described later can be performed at normal temperature, and the adhesion between the substrate 11 and the needle-like portions 12 can be improved. At this time, a gap may be generated between the base material 11 and the needle-shaped portion 12 due to the presence of the adhesive layer, so that the liquid may leak out, or the passage of the liquid between the base material 11 and the needle-shaped portion 12 may be hindered by the adhesive layer. Therefore, it is preferable that: in the base material 11, an adhesive layer is provided so as to surround a region through which a liquid should pass, and a region in which the adhesive layer is not formed is provided in the central portion.
As described above, the microneedle structure 10 of the present embodiment forms the needle-like portions 12 in a desired shape, and the needle-like portions 12 are well bonded to the base material 11, so that the liquid permeability of the flow path formed by the hole portions 13 of the needle-like portions 12 and the base material hole portions of the base material 11 is good.
[ inspection Patch ]
The microneedle structure 10 is preferably used for an inspection patch 20 that absorbs body fluid from the inside of the skin via the needle 12 and performs inspection using the obtained body fluid. As shown in fig. 2, the test patch 20 has a microneedle structure 10, and includes an analysis sheet 21 and an adhesive tape 22 on the surface (hereinafter, sometimes referred to as "back surface") of the substrate 11 opposite to the surface on which the needle-like portion 12 is provided. The microneedle structure 10 can also be used as a drug administration patch for administering a drug from the skin into the body through the needle-like portion 12 from the base material 11. At this time, a tablet containing a physiologically active substance is provided on the back surface side of the base material 11 of the microneedle structure 10, and a drug administration patch is configured so that a physiologically active substance from the tablet containing a physiologically active substance can be administered into the skin via the base material 11 and the needle-like portion 12.
The analysis sheet 21 is provided on the back surface side of the substrate 11 for analyzing and examining body fluids such as blood and interstitial fluid obtained subcutaneously. When the needle-shaped portion 12 is pierced into the skin of the subject, the body fluid flows in from the hole portion 13 of the needle-shaped portion 12, is absorbed by the base material 11, passes through the base material hole portion, and reaches the analysis chip 21. The analysis chip 21 may be appropriately selected according to the required inspection content, and an analysis chip formed by including a component as an analysis means in a base material such as paper may be used. Examples of the analytical sheet 21 include a glucose test paper which changes color according to the concentration of glucose in a body fluid. When glucose test paper is used as the analytical sheet 21, the analytical sheet 21 is used as an inspection patch 20 for detecting a blood glucose level, and the blood glucose level is detected with time by the degree of discoloration of the interstitial fluid collected by the microneedle structure 10 by the analytical sheet 21.
The tape 22 is made of a material having biosafety, and is preferably made of a material having flexibility, stretchability, and even contractibility, in view of following the skin to which it is attached, but is not limited to these materials. Preferable materials for the tape 22 include stretchable woven fabrics, and conventionally known materials can be used.
[ method for producing microneedle Structure ]
(filling Process)
Fig. 3 shows a method of manufacturing the microneedle structure 10 according to an embodiment of the present invention. In the present embodiment, as shown in fig. 3 (a), a liquid composition 3 is filled into a mold (mold) 2 in which a plurality of recesses 1 are formed (filling step). The recess 1 is filled with the filled liquid composition 3.
The material of the mold 2 is not particularly limited, but is preferably formed of, for example, a silicone compound or the like that facilitates the production of a correct mold and the cured liquid composition 3 is easily peeled off, and in the present embodiment, is formed of polydimethylsiloxane. The concave portion 1 is configured to form a needle portion 12 shown in fig. 1, and is configured to be able to form a needle portion 12 having a desired shape. In the mold 2, a plurality of rows of the concave portions 1 are provided at predetermined positions with a spacing therebetween.
The liquid composition 3 contains the first water-insoluble material (schematically shown as a light gray circle in fig. 3 (a)), the water-soluble first water-soluble material (schematically shown as a dark gray circle in fig. 3 (a)), and a solvent. In the drawings, for the sake of explanation, each material is schematically drawn in a granular form, and a state in which it is dispersed and exists in a solvent is shown. The liquid composition 3 may be one in which at least one of the first water-insoluble material and the first water-soluble material (composition for forming needle-like portions) is dissolved in a solvent, and it is preferable that at least the first water-insoluble material is dissolved in view of ease of forming a porous structure in the needle-like portions 12. The viscosity of the liquid composition 3 is preferably 0.1 to 1000 mPas, more preferably 0.5 to 100 mPas, and particularly preferably 1.0 to 10 mPas. In this range, the liquid composition 3 can be injected into the mold 2 with good workability, and the composition in the filling step can be filled into the concave portion 1 with good filling properties, so that the desired needle-like portion 12 can be formed.
As the first water-soluble material, a water-soluble material having a melting point higher than normal temperature is preferable. The water-soluble material may be organic or inorganic, and examples thereof include sodium chloride, potassium chloride, mirabilite, sodium carbonate, potassium nitrate, alum, granulated sugar, and water-soluble resins. The water-soluble resin is preferably a water-soluble thermoplastic resin, and preferably a water-soluble resin having a melting point higher than normal temperature. Examples of the water-soluble thermoplastic resin include hydroxypropyl cellulose, polyvinylpyrrolidone, and the like, in addition to the biodegradable resin described later. The water-soluble thermoplastic resin is more preferably a biodegradable resin in view of further influence on the human body. The biodegradable resin may be at least 1 selected from the group consisting of polyolefin glycol such as polyethylene glycol and polypropylene glycol, polyvinyl alcohol, collagen, and a mixture thereof, and polyethylene glycol is particularly preferred. The molecular weight of polyethylene glycol is, for example, preferably 200 ～ 4,000,000, more preferably 600 to 500,000, particularly preferably 1,000 ～ 100,000.
The first water-insoluble material and the first water-soluble material are preferably mixed in a mass ratio of 9:1 to 1:9, more preferably 8:2 to 2:8, and particularly preferably 7:3 to 3:7. By constituting the liquid composition 3 in this ratio, the needle-like portions 12 having a desired porosity are formed, and the liquid permeability and strength of the needle-like portions 12 can be easily achieved.
In the present embodiment, the liquid composition 3 contains a solvent in order to contain each material and be in a liquid state. The solvent may be water or an organic solvent, but in the case of dissolving the first water-insoluble material, the liquid composition 3 preferably contains an organic solvent. The organic solvent may be an organic solvent that can dissolve or disperse the first water-insoluble material and the first water-soluble material, and for example, aliphatic hydrocarbons such as hexane, heptane, and cyclohexane, aromatic hydrocarbons such as toluene, and xylene, halogenated hydrocarbons such as methylene chloride and dichloroethane, alcohols such as methanol, ethanol, propanol, butanol, and 1-methoxy-2-propanol, acetone, methyl ethyl ketone, 2-pentanone, ketones such as isophorone and cyclohexanone, esters such as ethyl acetate and butyl acetate, cellosolve (cellosolve) solvents such as ethyl cellosolve, and the like can be used.
The total content of the first water-insoluble material and the second water-insoluble material in all the components of the liquid composition 3 is preferably 40% or less, more preferably 35% or less, and particularly preferably 30% or less, on a mass basis. By including the composition in this range relative to the total amount of the liquid composition 3, the liquid composition 3 can be formed with a desired viscosity for easily producing the needle-like portions 12 of the microneedle structure 10, and as a result, the needle-like portions 12 can be formed with a desired shape.
The liquid composition 3 may further contain, as a nonvolatile solid component, not only the resin and the first water-soluble material as the first water-insoluble material, but also other materials.
In the present embodiment, although the liquid composition 3 in which each material is dissolved or dispersed in a solvent is used, the liquid composition 3 may be composed of only a composition containing no solvent, and the liquid composition 3 may further include a dispersant. For example, in order to further improve the strength of the needle-like portion, a water-insoluble material other than the resin, such as a silica filler, may be contained. In the case of filling the mold with the composition containing no solvent, the composition is preferably heated and flowed.
(vibration step)
Next, as the vibration step, preferable is: the mold 2 is placed in an ultrasonic cleaning device, and the mold 2 is subjected to ultrasonic vibration. The means for applying vibration is not limited to the ultrasonic cleaning device as long as fine vibration can be applied to the die 2. By performing this vibration step, as shown in fig. 3 (b), the filling of the liquid composition 3 into the recess 1 can be promoted, and the first water-insoluble material and the first water-soluble material in the recess 1 can be further filled into the corners in the recess 1. By this filling, the needle-like portion 12 having high transferability corresponding to the shape of the concave portion 1 can be formed without defects due to air bubbles, and the strength of the needle-like portion 12 can be increased.
In the ultrasonic treatment as the vibration step, the heating may be performed simultaneously, and in this case, the heating is preferably performed at a temperature equal to or higher than a temperature at which evaporation/drying can be promoted (for example, 45 ℃ or higher), and particularly preferably at a temperature equal to or higher than the melting point (for example, 60 ℃ or higher) of at least one of the first water-insoluble material and the first water-soluble material. By heating at this temperature, the surface solidification of the liquid composition 3 can be suppressed, and the evaporation and drying of the organic solvent can be promoted, thereby promoting the filling of the recess 1 with the first water-insoluble material and the first water-soluble material in the liquid composition 3. In particular, by heating at a temperature of 60 ℃ or higher, evaporation/drying of the organic solvent can be further promoted, thereby further promoting filling of the recess 1 with the first water-insoluble material and the first water-soluble material.
The frequency in the vibration step is preferably selected in a low frequency range having a high filling promoting effect, preferably from 10 to 200kHz, more preferably from 20 to 150kHz, and particularly preferably from 30 to 80kHz. In the vibration step, the time for performing ultrasonic treatment is preferably 0.5 to 10 minutes, more preferably 2 to 7 minutes. By vibrating the mold 2 in this range, the filling of the recess 1 with the first water-insoluble material and the first water-soluble material in the liquid composition 3 can be further promoted.
(degassing step)
The degassing step is preferably performed after the vibrating step. This allows the air contained in the recess 1 to be deaerated, and further facilitates the filling of the recess 1 with the first water-insoluble material and the first water-soluble material, and at the same time, the evaporation/drying of the organic solvent. The degassing step is preferably performed at 0.01 to 0.05MPa and 20 to 25℃when ethyl acetate is used as a solvent, as described in examples below. By degassing in this pressure range, solidification of the liquid composition 3 on the surface can be suppressed, and the organic solvent can be easily evaporated and dried, thereby further promoting filling of the recess 1 with the first water-insoluble material and the first water-soluble material.
(heating step)
After that, a heating step of heating at 80 to 120℃is preferably performed. As a result, as shown in fig. 3 (c), when the solvent is heated to a temperature equal to or higher than the melting point of any one of the first water-insoluble material and the first water-soluble material, the material is in a molten state, and the filling of the recess 1 with the first water-insoluble material and the first water-soluble material can be promoted. In the present embodiment, the heating step is performed after the degassing step, but the heating step may be performed first.
Thereafter, the solvent is evaporated and dried, and the first water-insoluble material and the first water-soluble material contained in the liquid composition 3 are sufficiently filled in the concave portion 1, and the sheet 4 is placed on the mold 2 in a state where the protruding portion 5 is formed in the concave portion 1, as shown in fig. 3 (d). As described above, since the filling of the recess 1 with the first water-insoluble material and the first water-soluble material is sufficiently performed, the needle-like portions 12 can be provided in a desired shape in the present embodiment, and the adhesion between the needle-like portions 12 and the base material 11 is also good. As described above, in the present embodiment, the step of forming the protrusion 5 is performed by the filling step, the vibration step, the degassing step, and the heating step. In addition, the vibration step and/or the degassing step may be omitted. Alternatively, the protrusion 5 may be formed by drying the solvent at room temperature without performing the heating step.
(sheet)
The sheet 4 is a sheet containing a water-soluble second water-soluble material and a water-insoluble second water-insoluble material in the porous base material 11. Since the mold 2 is heated in the previous step, the first water-insoluble material and the first water-soluble material in the concave portion 1 are in a molten state, and the protrusion 5 made of the molten first water-insoluble material and the first water-soluble material in the concave portion 1 is directly bonded to the sheet 4 when the sheet 4 is placed. At this time, since the sheet 4 contains the second water-insoluble material and the second water-soluble material, the substrate 11 can be restrained from absorbing the melted composition in the concave portion 1. As a result, even if the microneedle structure 10 is formed using a liquid material while having the porous base material 11, the needle-like portions 12 are prevented from collapsing because excessive voids are not formed in the root portions of the protruding portions 5, in particular. Therefore, the needle-shaped portion 12 having a shape suitable for bonding with the substrate 11 can be formed, and the microneedle structure 10 having good bonding between the needle-shaped portion 12 and the substrate 11 can be manufactured. Further, since the sheet 4 contains not only the second water-soluble material but also the second water-insoluble material, the adhesiveness between the sheet 4 and the protrusions 5 is further improved by welding the melted first water-insoluble material in the concave portion 1 to the second water-insoluble material contained in the sheet 4.
As the second water-soluble material, a water-soluble material exemplified for the first water-soluble material may be used, but as described below, a water-soluble resin is preferable, a water-soluble thermoplastic resin is preferable, and a water-soluble biodegradable resin is further preferable in order to facilitate impregnation of the second water-soluble material into the porous base material 11. Preferably the second water-soluble material is the same as the first water-soluble material. By making the second water-soluble material the same as the first water-soluble material, the second water-soluble material and the first water-soluble material can be easily removed in a subsequent removal step, and thus the desired hole portion 13 of the needle portion 12 can be formed.
As the second water-insoluble material, the water-insoluble materials listed for the first water-insoluble material can be used, but it is preferable that the second water-insoluble material is the same as the first water-insoluble material. By making the second water-insoluble material the same as the first water-insoluble material, the second water-insoluble material and the first water-insoluble material are more easily welded, and the adhesiveness of the protrusions 5 to the sheet 4 is increased.
As the second water-insoluble material, a water-insoluble resin is preferable in order to facilitate impregnation of the porous base material 11 with the second water-soluble material, as described below. The water-insoluble resin is preferably a water-insoluble resin having a melting point higher than normal temperature and 250 ℃ or lower, more preferably a water-insoluble resin having a melting point higher than 40 ℃ and 200 ℃ or lower, and particularly preferably a water-insoluble resin having a melting point higher than 45 ℃ and 150 ℃ or lower. The resin used as the second water-insoluble material is also preferably biodegradable.
The second water-soluble material and the second water-insoluble material may be contained in any form in the sheet 4, and at least the second water-soluble material may be contained so that the sheet 4 does not absorb the first water-insoluble material and the first water-soluble material from the recess 1 from the surface side of the substrate 11 to which the protrusion 5 (needle-like portion 12) is bonded. That is, the sheet 4 may be configured to contain at least the second water-soluble material and to be capable of blocking at least a part of the pores of the porous base material 11 by the second water-soluble material, thereby suppressing the absorption of the first water-insoluble material and the first water-soluble material. For example, a layer including the second water-soluble material and the second water-insoluble material may be laminated on the surface of the porous substrate 11 on the side of the adhesive protrusion 5. The porous base material 11 is preferably impregnated with the second water-soluble material and the second water-insoluble material. As a method of impregnating the porous base material 11 with the second water-soluble material and the second water-insoluble material, for example, the porous base material 11 may be immersed in a solution containing the second water-soluble material and the second water-insoluble material. The solution containing the second water-soluble material and the second insoluble material may be applied to the porous base material 11 by an inkjet method or the like. The solution having the second water-soluble material and the second water-insoluble material impregnated into the porous base material 11 is preferably dried, because the second water-soluble material and the second water-insoluble material remain in the base material pores of the base material 11 as a simple impregnation means. The solution may further have a solvent in addition to the second water-soluble material and the second water-insoluble material. The total content concentration of the second water-soluble material and the second water-insoluble material in all the components of the solution is preferably 1 to 35%, more preferably 3 to 30%, particularly preferably 5 to 25% by mass. The solution preferably contains the second water-soluble material and the second water-insoluble material in a mass ratio of 9:1 to 1:9. Within this range, in the removal step described later, the effect of recovering the substrate hole portion of the substrate 11 is easily obtained, and the adhesion between the substrate 11 and the needle portion 12 is easily improved.
When the porous base material 11 is immersed in a solution containing the second water-soluble material and the second water-insoluble material, for example, the base material 11 is immersed in the solution at 10 to 60 ℃ for 1 to 60 minutes, and then the solvent is evaporated and dried, whereby the second water-soluble material and the second water-insoluble material can be impregnated into the base material 11. In particular, when the base material 11 is made of a fibrous material, the second water-soluble material and the second water-insoluble material can be easily and sufficiently absorbed by immersing in the solution, thereby impregnating the base material 11 with the solution.
In the present embodiment, the sheet 4 is configured to contain the second water-insoluble material, but is not limited thereto. Even if the sheet 4 does not contain the second water-insoluble material, the first water-insoluble material and the first water-soluble material in the concave portion 1 are melted by the heating of the mold 2, and when the sheet 4 is placed, the protrusion 5 made of the melted first water-insoluble material and the first water-soluble material in the concave portion 1 adheres to the surface of the placed sheet 4. When the sheet 4 does not contain the second water-insoluble material, for example, the adhesion between the sheet 4 and the protrusion 5 can be improved by providing a certain adhesion means, for example, an adhesion part using a known adhesive, on the surface of the sheet 4 on the side placed on the mold 2.
(pressurizing step)
Next, as shown in fig. 3 (e), a pressurizing step of applying pressure to the sheet 4 is performed. The pressurizing method is not particularly limited, and a known method can be used. In the pressurizing step, the heating step of heating at 60 to 120 ℃ may be performed simultaneously. By simultaneously performing the heating steps, the adhesion can be further improved. Then, by maintaining the state at a low temperature of-10 to 3 ℃, the protrusion 5 in the recess 1 is cured, and the adhesion of the protrusion 5 to the sheet 4 is completed at the same time. As described above, in the present embodiment, the bonding step of bonding the protruding portion 5 to the sheet 4 is performed by the heating step, the pressurizing step subsequent thereto, and the curing of the protruding portion 5. In addition, the protrusion 5 and the sheet 4 may be bonded by a heating step alone without performing the pressurizing step. Alternatively, the protrusion 5 and the sheet 4 may be bonded by the above bonding means without the heating step or the pressurizing step. In the case where the liquid composition 3 contains a solvent as in the present embodiment, the shape of the composition for forming needle-like portions is first fixed by evaporating the solvent after the filling step (forming step). Therefore, the bonding step of the composition for forming needle-like portions and the base material 11 cannot be performed before the forming step, and the bonding step must be performed after the forming step, but in the present invention, since the sheet 4 contains the water-soluble material, absorption of the composition for forming needle-like portions by the base material 11 is suppressed, and needle-like portions can be obtained in a desired shape.
(removal step)
After the bonding step is completed, as shown in fig. 3 (f), a removal step is performed in which the substance obtained by bonding the cured protrusion 5 and the sheet 4 is separated from the mold 2, and the water-soluble materials of the protrusion 5 and the sheet 4 are removed.
The cleaning liquid in the removal step includes water, and the removal step is performed, for example, by leaving a substance formed by bonding the protruding portion 5 and the sheet 4 in the cleaning liquid. The portions of the first water-soluble material and the second water-soluble material contained in the protruding portions 5 and the sheet 4, which communicate with the outside, are dissolved by being left standing in the washing liquid containing water, and flow into the water, and are removed. The cleaning liquid may be a mixed solvent of water and alcohol. By this removal, as shown in fig. 3 (g), the hole portion 13 is formed in the protruding portion 5, and the needle portion 12 is formed. Thereby, the microneedle structure 10 is obtained. In the removing step, the second water-soluble material is removed, and the substrate hole portions of the substrate 11 once clogged with the second water-soluble material are at least partially restored, so that the sheet 4 exhibits good liquid permeability. In addition, in the case where the sheet 4 contains the second water-soluble material and the second water-insoluble material, the base material 11 contains the second water-insoluble material and the base material hole portion has been restored. At this time, the second water-insoluble material remains in the base material 11 by dissolving the portion of the first water-soluble material in contact with the second water-soluble material, and the hole portion 13 of the needle-shaped portion 12 extending to the side of the base material 11 is further connected to the base material hole portion of the base material 11. The hole 13 connected to the hole of the base material constitutes a flow path for the liquid. Thus, in the microneedle structure 10, the liquid easily passes through the interface between the needle-like portion 12 and the base material 11.
(modification of the means for forming the protrusion)
In the present embodiment, the needle-like portion 12 is formed by filling the liquid composition 3 into the recess 1, but the present invention is not limited thereto. For example, the forming step may be based on the following method: the needle-shaped portion 12 is formed by preparing the liquid composition 3 with a high viscosity and dropping the high viscosity liquid composition 3 onto the porous substrate 11 by a dispenser or the like. Even in this case, by including at least the first water-soluble material in the base material 11, the liquid composition 3 can be suppressed from being absorbed by the base material 11, so that the needle-like portions 12 cannot obtain a desired shape.
In the present embodiment, the needle-like portion 12 is formed by filling the liquid composition 3 containing the first water-insoluble material, the water-soluble first water-soluble material, and the solvent into the recess 1, but the protrusion 5 may be formed by filling the composition containing the first water-insoluble material and the water-soluble first water-soluble material, and containing no solvent into the recess 1 while melting. Specifically, the composition is first molded into an appropriate shape (for example, a disk shape) to prepare a solid composition. Then, an adhesive layer is provided on the sheet 4 in advance, and the adhesive layer of the sheet 4 is bonded to one surface of the solid composition. Thus, a bonding step of bonding the composition before the needle-like portions 12 are formed to the substrate 11 is performed at normal temperature. Then, the surface of the solid composition with the base material opposite to the surface to which the base material is attached is made to face the concave portion 1, the solid composition is melted by heating and filled into the concave portion 1, and then the protrusion portion 5 is formed by cooling. In the microneedle structure 10, if the needle-like portions 12 have a porous structure, the adhesion area of the needle-like portions 12 to the substrate 11 becomes small, which is disadvantageous in terms of adhesion between the two, but the adhesion between the needle-like portions 12 and the substrate 11 can be improved by heating in the forming step in a state where the substrate 11 and the solid composition are adhered in the above-described manner.
[ method for producing inspection Patch ]
The analysis sheet 21 is disposed at a predetermined position on the back surface side of the substrate 11 of the obtained microneedle structure 10 (a mounting step), and the adhesive tape 22 is laminated so as to cover the analysis sheet 21, whereby an inspection patch can be manufactured. The lamination method may be a conventionally known method, and for example, an adhesive tape 22 in which an adhesive layer such as a rubber-based adhesive, an acrylic-based adhesive, or a silicone-based adhesive, which is generally used, is formed on a tape base material is laminated after the analysis sheet 21 is placed on the back surface side of the base material 11, so that an inspection patch can be manufactured. The drug administration patch can also be manufactured by the same method.
Modification of microneedle structure and method for producing the same
In the embodiment of the microneedle structure and the method for producing the same, although the plurality of needle-like portions 12 are directly provided on the base material 11, the needle-like portions 12 may have a base portion which is a base of each needle-like portion 12 and which has a hole portion similarly to each needle-like portion 12, and each needle-like portion 12 may be provided on the base material 11 through the base portion. In this case, if the base portion is made of the same material as that described for the needle portion 12 or is formed by the same process, good adhesion between the needle portion 12 and the base material 11 can be obtained by the base portion. In the filling step, in order to form the base portion, the mold 2 may be filled with the liquid composition 3 in excess of the volume corresponding to the recess 1, and the liquid composition may be overflowed from the recess 1. At this time, the base can be formed by providing a liquid storage portion by providing a wall portion or the like on the surface of the mold 2 where the recess 1 is formed, and accumulating the liquid composition overflowing from the recess 1 in the liquid storage portion.
In the present embodiment, the sheet 4 is used in which the porous base material 11 contains the water-soluble second water-soluble material and the water-insoluble second water-insoluble material, but instead, a resin film having through holes may be bonded to the protrusions 5. At this time, in the removal step, the hole portion 13 of the needle portion 12 extending to the substrate 11 side is further connected to the through hole of the substrate 11 by dissolving the first water-soluble material. The hole 13 connected to the through hole constitutes a flow path for the liquid. In this way, in the microneedle structure 10, the liquid easily passes through the through-holes of the base material 11 from the needle-like portions 12, and reaches the surface of the base material 11 opposite to the surface on which the needle-like portions 12 are provided.
Examples
Hereinafter, the present invention will be described in more detail with reference to examples.
A liquid composition having a solid content of 20% was prepared by blending 100 parts by weight of polyethylene glycol (molecular weight 4000, melting point 40 ℃ C.), 100 parts by weight of polycaprolactone (molecular weight 10,000, melting point 60 ℃ C.) as the first water-insoluble material, and 800 parts by weight of ethyl acetate as a solvent (organic solvent).
0.7ml of the liquid composition was poured into a mold having a recess of the following shape and made of polydimethylsiloxane. The area of the mold filled with the liquid composition had a square shape with four sides of 15mm, and a liquid storage portion was provided above the recess forming surface. The liquid composition is filled above the recess forming surface, and the needle-shaped portion is provided with a base portion.
Concave shape: quadrangular pyramid shape with square cross section
Length of one side of the largest section of the recess: 500 μm
Height of recess: 900 μm
Interval of recesses: 1000 μm
Number of recesses: the columns are 13, and the total of 13 columns is 169
Configuration of the recess: square lattice shape
Next, the mold was placed in an ultrasonic cleaning apparatus (manufactured by ultrasonic cleaner AU-10C/Aiwa Medical Industry co., ltd.) and subjected to ultrasonic treatment at a temperature of 23 ℃ for 1 minute.
Next, as a deaeration step, vacuum drying was performed at a temperature of 23℃under a reduced pressure of 0.05MPa for 30 minutes. Then, the mixture was heated at 110℃for 30 minutes in an environment without humidity adjustment.
On the other hand, 100 parts by weight of polyethylene glycol (same as the first water-soluble material) as the second water-soluble material, 100 parts by weight of polycaprolactone (same as the first water-insoluble material) as the second water-insoluble material, 1800 parts by weight of ethyl acetate as the solvent (organic solvent) were blended to prepare a solution having a solid content concentration of 10%. Further, a filter paper (manufactured by WHATMAN FILTER PAPER GRADE/GE Healthcare Life Siences corporation) as a porous base material was immersed in the above solution, and then taken out, and dried at 23 ℃ for 60 minutes, thereby producing a sheet.
The pressing step is performed by placing the sheet on the exposed surface of the base provided above the protrusion formed in the recess in the heated mold, and placing a weight (500 g) on the placed sheet. Then, after holding at a low temperature of 3 ℃ for 10 minutes, the material obtained by bonding the protrusion, the base and the sheet was peeled off from the mold, immersed in purified water at 23 ℃ for 24 hours, and dissolved and removed the first water-soluble material and the second water-soluble material in the protrusion, the base and the sheet.
Then, the first water-soluble material and the second water-soluble material were dissolved and removed, and the material obtained by bonding the projections, the base and the sheet was left standing at 23 ℃ under a relative humidity of 50% for 24 hours, and the water was evaporated and dried to produce a microneedle structure.
As a comparative example, a microneedle structure was produced in the same manner as in example, except that the step of immersing the porous substrate in the solution was not performed.
The root of the needle-like portion of the microneedle structure obtained in examples and comparative examples was peeled off from the substrate with forceps, and the interior of the needle-like portion was observed with an optical microscope (magnification: 50 times and 100 times). In the case of the microneedle structure of the example, the resin was filled in the root portion of the needle-like portion almost without any gap, but in the microneedle structure of the comparative example, there were gaps, holes, and the like, and the filling was insufficient.
Next, in examples and comparative examples, the projections were formed by cooling the composition, and after peeling from the mold and before immersing in purified water, the projections were observed by an optical microscope (magnification: 50 times and 100 times), and the number of needle-like portions remained on the substrate was counted. The ratio of the number of residues to the total number of needle-like portions in design was calculated as the transfer rate. In the microneedle structures obtained in examples, the transfer ratio was 50% or more, and the transferability was good, whereas in the microneedle structures obtained in comparative examples, the transfer ratio was less than 50%, and the transferability was low.
Industrial applicability
The microneedle structure of the present invention can be used as an inspection patch by disposing an analysis sheet on the back side and stacking the analysis sheet with an adhesive tape, for example.
Description of the reference numerals
1: a concave portion; 2: a mold; 3: a liquid composition; 4: a sheet; 5: a protruding portion; 10: a microneedle structure; 11: a substrate; 12: a needle-like portion; 13: a hole portion; 20: checking the patch; 21: an analytical chip; 22: and (3) adhesive tape.
Claims (12)
1. A method for producing a microneedle structure comprising needle-like portions having hole portions on one surface side of a base material having liquid permeability in a thickness direction, the method comprising:
A forming step of forming a protrusion using a composition for forming a needle-like portion, the composition containing a first water-insoluble material and a first water-soluble material;
a bonding step of bonding the composition or the protrusion formed in the forming step to the base material; and
and a removal step of immersing the protruding portion and the base material in water to dissolve and remove the first water-soluble material, thereby forming the needle-like portion and the hole portion from the protruding portion.
2. The method of manufacturing a microneedle structure according to claim 1, wherein the substrate having liquid permeability in the thickness direction is a porous substrate,
the bonding step is a step of bonding the protrusion formed in the forming step to a sheet comprising a second water-soluble material and the porous base material,
the removing step is a step of dissolving and removing the first water-soluble material and the second water-soluble material.
3. The method of manufacturing a microneedle structure according to claim 2, wherein the porous base material is a base material made of a fibrous material.
4. A method of manufacturing a microneedle structure according to claim 2 or 3, wherein the sheet comprises a second water insoluble material.
5. The method of manufacturing a microneedle structure according to claim 4, wherein the first water-insoluble material is the same as the second water-insoluble material.
6. The method of manufacturing a microneedle structure according to any one of claims 2 to 5, wherein the sheet is a sheet obtained by impregnating the base material with a second water-soluble material.
7. The method of producing a microneedle structure according to any one of claims 2 to 6, wherein the base material made of a fibrous material is a nonwoven fabric, a woven fabric, a knitted fabric, or paper.
8. The method of manufacturing a microneedle structure according to claim 1, wherein the base material is a base material made of a material having liquid impermeability, and has a through hole formed in a thickness direction.
9. The method of manufacturing a microneedle structure according to any one of claims 1 to 8, wherein the forming step includes: and a filling step in which the composition for forming needle-shaped portions is filled into a mold having a concave portion.
10. The method of manufacturing a microneedle structure according to claim 9, wherein in the filling step, the composition for forming needle-like portions contains a solvent, and in the forming step, the solvent is evaporated.
11. The method for producing a microneedle structure according to any one of claims 1 to 10, comprising: and a setting step of setting an analysis means for body fluid and/or a storage means for physiologically active substance on a surface of the base material opposite to the surface on which the needle-like portion is provided.
12. A microneedle structure comprising a porous substrate and needle-like portions having holes on one surface side of the porous substrate, characterized in that,
the needle-like portion is made of a first water-insoluble material and is provided directly on the porous base material,
the porous substrate contains a second water insoluble material.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2021-062451 | 2021-03-31 | ||
| JP2021062451 | 2021-03-31 | ||
| PCT/JP2022/016675 WO2022211058A1 (en) | 2021-03-31 | 2022-03-31 | Microneedle structure produciton method and microneedle structure |
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| Publication Number | Publication Date |
|---|---|
| CN116867537A true CN116867537A (en) | 2023-10-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202280014739.0A Pending CN116867537A (en) | 2021-03-31 | 2022-03-31 | Method for manufacturing microneedle structure and microneedle structure |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPWO2022211058A1 (en) |
| KR (1) | KR20230163360A (en) |
| CN (1) | CN116867537A (en) |
| TW (1) | TW202304546A (en) |
| WO (1) | WO2022211058A1 (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8101114B2 (en) * | 2006-05-01 | 2012-01-24 | Georgia Tech Research Corporation | Particle based molding |
| JP2014094171A (en) | 2012-11-09 | 2014-05-22 | Canon Inc | Microneedle and microneedle array |
| JP2017000724A (en) * | 2015-06-05 | 2017-01-05 | 国立大学法人東北大学 | Micro needle and micro array and method for producing the same |
| KR101621945B1 (en) * | 2015-07-02 | 2016-05-17 | 주식회사 엘지생활건강 | Nano-porous microneedle having two layers and its manufacturing method |
| JP7229483B2 (en) * | 2017-08-30 | 2023-02-28 | 国立大学法人東北大学 | Skin patch devices and kits comprising skin patch devices for the detection, diagnosis or treatment of skin diseases or conditions. |
| CN111836582A (en) * | 2018-03-16 | 2020-10-27 | 国立大学法人东京大学 | Detection chip and detection device |
-
2022
- 2022-03-31 TW TW111112637A patent/TW202304546A/en unknown
- 2022-03-31 JP JP2023511729A patent/JPWO2022211058A1/ja active Pending
- 2022-03-31 WO PCT/JP2022/016675 patent/WO2022211058A1/en active Application Filing
- 2022-03-31 KR KR1020237026976A patent/KR20230163360A/en unknown
- 2022-03-31 CN CN202280014739.0A patent/CN116867537A/en active Pending
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| JPWO2022211058A1 (en) | 2022-10-06 |
| WO2022211058A1 (en) | 2022-10-06 |
| KR20230163360A (en) | 2023-11-30 |
| TW202304546A (en) | 2023-02-01 |
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