WO2016195119A1 - Micro-aiguille, microréseau, et procédés pour leur fabrication - Google Patents

Micro-aiguille, microréseau, et procédés pour leur fabrication Download PDF

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Publication number
WO2016195119A1
WO2016195119A1 PCT/JP2016/067464 JP2016067464W WO2016195119A1 WO 2016195119 A1 WO2016195119 A1 WO 2016195119A1 JP 2016067464 W JP2016067464 W JP 2016067464W WO 2016195119 A1 WO2016195119 A1 WO 2016195119A1
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Prior art keywords
microneedle
hydrogel
microarray
manufacturing
fiber
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PCT/JP2016/067464
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English (en)
Japanese (ja)
Inventor
松彦 西澤
洋行 甲斐
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国立大学法人東北大学
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Priority claimed from JP2016055428A external-priority patent/JP2017000724A/ja
Application filed by 国立大学法人東北大学 filed Critical 国立大学法人東北大学
Publication of WO2016195119A1 publication Critical patent/WO2016195119A1/fr

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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

Definitions

  • the present invention relates to a microneedle having a continuous porous structure (microchannel structure), a microarray, and a manufacturing method thereof.
  • Minimally invasive microneedles and microarrays that do not give pain to the subject during insertion are useful for sampling body fluids such as subcutaneous tissue fluid, sensing biological information by measuring the concentration of components in body fluids, and transdermally administering drugs. It is useful and already in practical use in the field of medication.
  • microneedles are solid bodies made of resin, and are sometimes used as a microarray by arranging microneedles.
  • the solid microneedle can be used for subcutaneous administration of a drug, for example, by applying a drug on the surface and inserting the needle into the skin.
  • liquid injection may be required for the microneedle in order to perform injection of a drug solution and sampling and measurement of tissue fluid with the microneedle.
  • a technique for producing a microneedle having a hollow structure composed of linear voids provided in an injection needle using fine processing of metal or oxide see Patent Document 1
  • NaHCO 3 which is a foaming agent 3 has been developed to prepare a microneedle having a hollow structure composed of a number of spherical voids
  • Patent Document 1 there is a problem that a hollow structure that becomes a flow path is clogged at the time of insertion.
  • a microneedle having a conventional hollow structure does not have a sufficient water absorption rate, and body fluid collection or biological information In the field of sensing, there is a risk that the application range will be narrowed.
  • an object of the present invention is to provide a microneedle excellent in water absorption speed, a microarray including the microneedle, and a method for producing the same.
  • the gist of the present invention is as follows.
  • the microneedle of the present invention is characterized by having a flow path extending in a mesh shape inside.
  • the diameter R of the channel is preferably more than 50 nm and not more than 30 ⁇ m.
  • the ratio (L / R) of the extension length L of the flow path to the diameter R of the flow path is preferably 2 or more.
  • the porosity of the hydrogel is preferably 5 to 50%.
  • the microneedle of the present invention may include at least one selected from the group consisting of a hydrogel material, a xerogel, and a hydrogel.
  • the microneedle of the present invention may particularly contain a hydrogel.
  • the tensile fracture stress of the hydrogel is preferably 10 kPa to 50 MPa.
  • the water content of the hydrogel is preferably 30 to 99.9% by mass.
  • the hydrogel preferably contains a cross-linked product of poly (methyl vinyl ether-alt-maleic anhydride) and polyethylene glycol, and the poly (methyl vinyl ether-alt-maleic anhydride) and the polyethylene glycol Is preferably 100: 1 to 1: 100.
  • the microarray of the present invention is characterized in that any one of the above microneedles is erected on a base material.
  • the intermediate layer of the three-phase solution including an aqueous phase, an oil phase, and an intermediate phase in which the aqueous phase and the oil phase form both continuous phases A gel microneedle material and / or the microarray material is prepared.
  • the three-phase solution is a solution containing water, butanol, and toluene, and the hydrogel material is polyacrylamide.
  • the manufacturing method of the microneedle and the microarray of the present invention includes a mixture preparation step for preparing a mixture containing a solid substance and a hydrogel material, and a solid substance removal step for removing the solid substance from the mixture.
  • the solid body may be a fiber.
  • a fiber-containing hydrogel is prepared by adding an aqueous solution of a hydrogel material to a fiber made of a water-insoluble resin.
  • an organic solvent is added to the fiber-containing hydrogel. It is preferable to elute the fiber by adding
  • the water-insoluble resin is polystyrene
  • the hydrogel material is a crosslinked product of poly (methyl vinyl ether-alt-maleic anhydride) and polyethylene glycol
  • the organic solvent is toluene.
  • the solid body may be a porous body.
  • the porous body is preferably a freeze-dried product of chitosan.
  • the present invention it is possible to provide a microneedle excellent in water absorption speed, a microarray including the microneedle, and a manufacturing method thereof.
  • the microneedle and microarray of 1st embodiment of this invention are shown.
  • (A) shows a cross-sectional view of the microneedle, and (b) shows a cross-sectional view of the microarray.
  • the microneedle and microarray of 2nd embodiment of this invention are shown.
  • (A) shows a cross-sectional view of the microneedle, and (b) shows a cross-sectional view of the microarray.
  • Explanatory drawing which shows the dimension of the microneedle and microarray of embodiment of this invention is shown.
  • (A) shows an explanatory view showing the dimensions of the microneedle, and (b) shows an explanatory view showing the dimensions of the microarray.
  • Explanatory drawing which shows the outline of the manufacturing method of the microneedle and microarray of 1st embodiment of this invention is shown.
  • Explanatory drawing which shows the outline of the manufacturing method of the microneedle and microarray of 2nd embodiment of this invention is shown.
  • the explanatory view showing the outline of the manufacturing method of the microneedle and microarray of the suitable example of the second embodiment of the present invention is shown.
  • the explanatory view showing the outline of the manufacturing method of the microneedle and microarray of the further suitable example of the second embodiment of the present invention is shown.
  • the graph showing the result of the water absorption rate evaluation of the hydrogel sheet which has a microchannel structure is shown.
  • the horizontal axis represents time (minutes), and the vertical axis represents swelling ratio (% by weight).
  • template used for the manufacturing method of the microneedle and microarray of the Example of this invention is shown.
  • the microneedle and microarray of Example 1 of this invention are shown.
  • (A) shows a photograph when the microneedle is observed using an electron microscope, and
  • the outline of the manufacturing method of the microneedle of Example 2 of this invention and a microarray is shown.
  • (A) shows a photograph when the polystyrene fiber is observed using an electron microscope
  • (b) shows a photograph when the state when the polystyrene fiber is deposited in the mold is observed using an electron microscope. Show.
  • the microneedle and microarray of Example 2 of this invention are shown.
  • (A) shows a photograph when the microneedle is observed using an electron microscope (an external view is shown on the left and an enlarged view is shown on the right), and (b) is a view when the microarray is observed using an electron microscope.
  • a photograph is shown (a top view is shown throughout, and a side view is shown in the lower right).
  • FIG. 1 shows the outline of the evaluation method of the water absorption speed
  • (A) shows the state of disassembly and assembly of the kit for evaluating the water absorption rate
  • photographing the state of the sweating checker in 0 minute after insertion and 10 minutes after insertion when the microneedle of Example 1 of this invention was inserted in the agarose gel is shown.
  • Example 2 of the present invention When the microneedle of Example 2 of the present invention is inserted into an agarose gel, photographs are taken of the state of the sweat checker at 0 hours, 1.5 hours, 3 hours, and 12 hours after insertion (left In the case of control, the case of Example 2 is shown on the right).
  • a microneedle 1 (hereinafter, also referred to as “microneedle 1”) according to an embodiment of the present invention includes a flow path 2 extending in a mesh shape inside.
  • FIG. 1 shows a microneedle and a microarray according to the first embodiment of the present invention.
  • (A) shows a cross-sectional view of the microneedle, and
  • (b) shows a cross-sectional view of the microarray.
  • FIG. 2nd embodiment of this invention are shown.
  • (A) shows a cross-sectional view of the microneedle, and (b) shows a cross-sectional view of the microarray.
  • the cross-sectional shape of the flow path 2 varies depending on the position in the extending direction of the flow path 2, and the cross-sectional area of the flow path 2 is the extension of the flow path 2. More specifically, it is indefinite in the present direction, and more specifically, the cross-sectional area of the flow path 2 repeatedly increases and decreases irregularly.
  • the cross-sectional shape of the flow channel 2 is the same over the extending direction of the flow channel 2, and the cross-sectional area of the flow channel 2 is the same. It is constant over the extending direction of the path 2.
  • each microneedle 1 includes a flow path 2 extending in a mesh shape inside.
  • the microneedle 1 When the microneedle 1 according to the embodiment of the present invention is inserted into the skin (not shown), a capillary phenomenon occurs between the subcutaneous tissue fluid and the mesh-like flow path 2 provided in the microneedle 1. Subcutaneous tissue fluid can be sucked up at high speed through the flow path 2 of the microneedle 1. Therefore, the microneedle 1 has an excellent water absorption speed. Due to this effect, for example, the collection of body fluids such as subcutaneous tissue fluid (sampling) and the sensing of biological information by measuring the concentration of components in the body fluid are efficient at high speed (for example, about 10 minutes or less, which is practically preferable). Can be performed automatically.
  • the drug solution can be rapidly administered subcutaneously through the channel 2 of the microneedle 1.
  • the diameter R of the flow path 2 is preferably 30 ⁇ m or less from the viewpoint of sufficiently obtaining the effect of the capillary phenomenon described above. More preferably, it is 10 ⁇ m or less, particularly preferably 5 ⁇ m or less, preferably more than 50 nm, more preferably 100 nm or more, more preferably 500 nm or more, particularly Preferably it is 1 ⁇ m or more.
  • the diameter R of the flow path 2 is an average value of diameters when the diameter (maximum diameter) is measured over the extension length of all the flow paths 2 provided inside the microneedle 1. Point to.
  • the extension length L of the flow path 2 may be 10 to 1000 ⁇ m, and is preferably 100 to 1000 ⁇ m from the viewpoint of sufficiently obtaining the effect of the capillary phenomenon described above, and further manufactured. From the viewpoint of simplicity, it is more preferably 100 to 300 ⁇ m.
  • the extension length L of the channel 2 refers to the average value of the extension lengths when the extension lengths of all the channels 2 provided inside the microneedle 1 are measured.
  • the ratio (L / R) of the extension length L of the flow path 2 to the diameter R of the flow path 2 is such that the flow path 2 is provided more continuously inside the microneedle 1, From the viewpoint of further increasing the water absorption speed of the needle 1, it is preferably 2 or more, more preferably 10 or more, particularly preferably 100 or more, and most preferably 1000 or more.
  • the microneedle 1 includes at least one flow path 2 that penetrates the microneedle 1.
  • the pressure in the channel 2 is increased and the introduction of the subcutaneous tissue fluid into the channel 2 is delayed, whereas in the penetrating channel 2, the subcutaneous tissue fluid is flowed by capillary action.
  • the increase in pressure in the flow path 2 is suppressed, and the introduction of subcutaneous tissue fluid into the flow path 2 is accelerated.
  • the porosity of the microneedle 1 is preferably 5 to 50%, more preferably 10 to 30%, from the viewpoint of obtaining sufficient mechanical strength while further increasing the water absorption rate.
  • FIG. 3 is an explanatory diagram showing dimensions of the microneedles and the microarray according to the embodiment of the present invention.
  • A shows an explanatory view showing the dimensions of the microneedle
  • b shows an explanatory view showing the dimensions of the microarray.
  • the diameter Rb of the bottom circle in the frustoconical shape of the microneedle 1 may be 20 to 500 ⁇ m. From the viewpoint of ease of production, ease of insertion into the skin, and mechanical strength, 100 to 400 ⁇ m. For example, it may be 300 ⁇ m.
  • the diameter Rt of the circle on the top surface may be 1 to 50 ⁇ m, and is preferably 5 to 20 ⁇ m, for example, 10 ⁇ m from the viewpoint of ease of production and ease of insertion into the skin. .
  • the height H may be 20 to 1000 ⁇ m, and is preferably 30 to 600 ⁇ m from the viewpoint of securing a sufficient contact area with the epidermis after penetrating the stratum corneum and preventing invasion to the dermis, for example, 600 ⁇ m It may be.
  • the three-dimensional shape of the microneedle of the present invention is not limited to the truncated cone shape, and may be other shapes such as a truncated cone shape, a quadrangular pyramid shape, and a truncated pyramid shape as long as it can be inserted into the skin. It is good also as a shape.
  • the material of the microneedle 1 according to the embodiment of the present invention is not particularly limited, and examples thereof include a hydrogel material, a resin, an oxide, and a metal.
  • the hydrogel material refers to a material that forms a hydrogel by being dispersed in water (dispersion medium).
  • examples of the hydrogel material include agar, gelatin, agarose, xanthan gum, gellan gum, sclerotia gum, arabiya gum, tragacanth gum, karaya gum, cellulose gum, tamarind gum, guar gum, locust bean gum, glucomannan, chitosan, carrageenan, quince seed, galactan, Mannan, starch, dextrin, curdlan, casein, pectin, collagen, fibrin, peptide, chondroitin sulfate such as sodium chondroitin sulfate, hyaluronic acid salts such as hyaluronic acid (mucopolysaccharide) and sodium hyaluronate, alginic acid, sodium alginate, And natural polymers such as alginates such as calcium alginate and derivatives thereof
  • hydrogel collagen, glucomannan; carboxymethylcellulose, sodium carboxymethylcellulose; polyacrylic acid, sodium polyacrylate; interpenetrating network hydrogel and A semi-interpenetrating network hydrogel is preferred, and from the viewpoint of obtaining excellent mechanical strength and excellent biocompatibility, a crosslinked product of poly (methyl vinyl ether-alt-maleic anhydride) and polyethylene glycol is preferred. From the viewpoint of ensuring the electrical neutrality of the hydrogel, crosslinked polyethylene glycol is preferred.
  • the mass ratio of poly (methyl vinyl ether-alt-maleic anhydride) to polyethylene glycol is 100: 1 to 1. : 100, preferably 10: 1 to 1:10, more preferably 3: 2 to 4: 3, from the viewpoint of increasing the ease of penetration of the microneedle 1 into the skin. Particularly preferred.
  • Examples of the resin include polycarbonate, acrylonitrile-butadiene-styrene (ABS) resin, phenol resin, acrylic resin, and methacrylic resin.
  • Examples of the oxide include inorganic oxides and derivatives thereof. Examples of the inorganic oxide include silicon oxide, tin oxide, zirconia, titanium oxide, niobium oxide, tantalum oxide, aluminum oxide, tungsten oxide, and hafnium oxide. And zinc oxide. Examples of the metal include nickel, iron, and alloys thereof.
  • the material of the microneedle 1 is a hydrogel material from the viewpoint of further increasing the water absorption rate by imparting liquid permeability to the microneedle 1 itself while increasing the water absorption rate by the flow path 2 extending in a mesh shape. It is preferable.
  • the microneedle 1 of the embodiment of the present invention preferably contains a hydrogel material, and may be made of a hydrogel material.
  • the hydrogel material can be made into a hydrogel by absorbing bodily fluids such as subcutaneous tissue fluid when the needle is inserted into the skin.
  • the microneedle 1 preferably includes a hydrogel material, water, and a hydrogel containing a drug or the like depending on the purpose, and preferably includes a xerogel obtained by drying the hydrogel. In the xerogel, the ratio of the mass of water to the mass of the xerogel may be 0 to 5% by mass.
  • microneedle 1 is good also as what consists of said hydrogel and / or xerogel.
  • water used for hydrogel ultrapure water etc. are mentioned, for example.
  • the drug include insulin, DNA, vaccine, and the like.
  • insulin is preferably used by subcutaneous injection and has a small molecular weight.
  • the microneedle 1 shown in FIGS. 1 and 2 is made of a hydrogel containing a hydrogel material and water.
  • the elastic modulus of the hydrogel material or xerogel is preferably 0.1 kPa to 100 MPa, and more preferably 100 kPa to 50 MPa.
  • the “elastic modulus” can be measured by subjecting a bulk test piece to a tensile test. Examples of the measuring apparatus include a tensile tester 5960 series manufactured by Instron.
  • the water content of the hydrogel is 30 to 99.9% by mass from the viewpoint of increasing the amount of the drug contained in the hydrogel when the microneedle 1 is used for subcutaneous administration (or transdermal administration) of the drug. It is preferably 30 to 80% by mass, more preferably 50 to 80% by mass, for example 70% by mass.
  • the “moisture content” refers to the ratio (mass%) of the mass of water to the mass of the hydrogel.
  • the bending rupture stress of the hydrogel is preferably 10 kPa to 50 MPa, more preferably 100 kPa to 30 MPa, and more preferably 300 kPa to 20 MPa from the viewpoint of sufficiently obtaining the mechanical strength of the microneedle 1. Even more preferably, it is particularly preferably 1 MPa to 20 MPa, and most preferably 2 MPa to 5 MPa.
  • the “tensile breaking stress” can be measured by measuring the stress at which the hydrogel breaks by a tensile load using a load cell. Examples of the measuring apparatus include a tensile tester 5960 series manufactured by Instron.
  • the pH of the hydrogel is preferably 5 to 9, more preferably 7 to 8, from the viewpoint of suppressing the occurrence of inflammation in the skin due to contact between the skin and the microneedles 1, for example, 7. It may be 4.
  • microarray 11 of the embodiment of the present invention (hereinafter also referred to as “microarray 11”) is characterized in that the microneedle 1 of the embodiment of the present invention is erected on a base material 12.
  • FIG. 1B shows a cross-sectional view of the microarray of the first embodiment of the present invention
  • FIG. 2B shows a cross-sectional view of the microarray of the second embodiment of the present invention.
  • the microneedles 1 of the embodiment of the present invention having a truncated cone shape are square.
  • the standing manner of the microneedles 1 in the microarray 11 is not particularly limited and can be appropriately determined according to the application site and the purpose of use.
  • the microneedles 1 may be erected uniformly or non-uniformly on the base material.
  • a plurality of microneedles 1 are arranged in a predetermined direction.
  • a plurality (11 in FIG. 3B) are provided upright in a direction orthogonal to the direction.
  • FIG. 3B is an explanatory diagram showing dimensions of the microarray according to the embodiment of the present invention.
  • the number of microneedles 1 is not particularly limited, and can be appropriately determined according to the application site and the purpose of use.
  • the distance d between the adjacent microneedles 1 (the shortest distance between the bottom surfaces of the microneedles 1) is not particularly limited, but may be 10 to 500 ⁇ m, and the amount per unit area of the needles to be inserted into the skin is sufficient. From the viewpoint of facilitating the insertion of the needle into the skin by sufficient force applied to each needle at the time of insertion, the thickness is preferably 20 to 300 ⁇ m, for example, 50 ⁇ m.
  • the material of the base material 12 of the microarray 11 is not particularly limited, but the base material 12 preferably contains hydrogel, and may be made of hydrogel.
  • the material of the substrate 12 may be the same as the material of the microneedle 1.
  • microneedle 1 and the base material 12 are integrated, and it is preferable that the channel 2 communicates with the microneedle 1 and the base material 12 from the viewpoint of enhancing the effect of the present invention.
  • the method for producing the microneedles and microarray of the embodiment of the present invention is not particularly limited, but the microneedle and microarray production methods of the following first and second embodiments of the present invention are preferably used. .
  • the microneedle and microarray manufacturing method includes a three-phase system including an aqueous phase 51, an oil phase 52, and an intermediate phase 53 in which the aqueous phase 51 and the oil phase 52 form both continuous phases.
  • a microneedle material and / or a microarray material 54 is prepared in the intermediate layer 53 of the solution 55.
  • an O / W phase state and a W are obtained by using a surfactant and / or a co-surfactant having an appropriate HLB value. It is known that it is a phase state positioned in the middle of the / O phase and can form a state in which both the water phase and the oil phase are not closed (both continuous phase states) (for example, Kawano et al. . “Construction of Continuous Porous Organogels, Hydrogels, and Biotinous Organo / Hydro Hybrid Gels from Microtinous Micros. 2010):? 473 79.doi:. 10.1021 / ma901624p reference).
  • FIG. 4 is an explanatory diagram showing an outline of a method for manufacturing a microneedle and a microarray as an example of the first embodiment of the present invention.
  • the manufacturing method 50 of the microneedle 1 and the microarray 11 of the first embodiment of the present invention (hereinafter also referred to as “the manufacturing method 50 of the first embodiment”) includes an aqueous phase 51, an oil phase 52, and an aqueous phase 51.
  • the hydrogel 54 is prepared in the intermediate layer 53 of the three-phase solution 55 including the intermediate phase 53 in which the oil phase 52 forms both continuous phases.
  • Such a hydrogel 54 is characterized by having a co-continuous structure.
  • a continuous oil in the intermediate layer 53 is prepared while preparing a hydrogel 54 having a network structure by polymerizing monomers in the continuous aqueous phase 51 of the intermediate layer 53.
  • a portion occupied by the phase 52 is formed as a flow path 2 extending in a mesh shape inside the hydrogel 54.
  • Examples of the oil component constituting the oil phase 52 include toluene, hexane, benzene, mineral oil, and the like, and in particular, the viewpoint of the domain size of the two continuous phases formed, and the ease of removal after gelation. From the viewpoint, toluene is preferable.
  • Examples of the surfactant and co-surfactant include sodium dodecyl sulfate, 2-butanol, hexaethylene glycol monohexadecyl ether and the like, and in particular, the viewpoint of the domain size of both continuous phases to be formed, and gelation From the viewpoint of ease of subsequent removal, sodium dodecyl sulfate and 2-butanol are preferred.
  • hydrogel material 54m examples include materials constituting the microneedles 1 and the microarray 11 as described above, and a polymer constituting the hydrogel 54 is preferable.
  • a combination of toluene as an oil component, sodium dodecyl sulfate and 2-butanol as a surfactant and a cosurfactant, and polyacrylamide as a hydrogel material 54m is particularly preferable.
  • the hydrogel material 54m is dissolved in the aqueous phase 51, and then, as shown in FIG. 4, the intermediate layer 53 of the three-phase solution 55 is placed in the female mold 100 (described later). Hydrogel 54 may be prepared thereafter. At this time, in order to adjust the overall shape of the microneedle 1, it is preferable to sufficiently deaerate the oil component, water, hydrogel material and the like constituting the oil phase 52 under reduced pressure before use.
  • the manufacturing method 60 of the microneedles 1 and the microarray 11 of the second embodiment of the present invention (hereinafter also referred to as “the manufacturing method 60 of the second embodiment”) is a mixture 63 containing a solid body 61 and a hydrogel material 62. And a solid substance removing step of removing the solid substance 61 from the mixture 63.
  • a feature is that the trace 61 h of the removed solid body 61 becomes the flow path 2 in the microneedle 1 and the microarray 11.
  • the hydrogel material is a polymer
  • the polymer may be polymerized in advance or polymerized in the mixture preparation process.
  • the solid body 61 in the manufacturing method 60 of the second embodiment a porous body (represented by 61f in FIG. 6 described later), a lyophilized product of chitosan, etc. (represented by 61p in FIG. 7 described later). ) And the like.
  • the solid body 61 is a fiber 61f.
  • FIG. 6 is an explanatory view showing an outline of a preferred example of a method for manufacturing microneedles and a microarray as a preferred example of the second embodiment of the present invention.
  • the mixture 63 is added by adding the aqueous solution of the hydrogel material 62m to the fiber 61f which consists of water-insoluble resin.
  • the fiber-containing hydrogel 63f is prepared, and the organic solvent 64 is added to the fiber-containing hydrogel 63f to elute the fiber 61f in the solid removal step (fiber removal step) (see FIG. 5).
  • a fiber 63 as a mixture 63 is added.
  • a containing hydrogel 63 is prepared.
  • the temperature of the aqueous solution of the hydrogel material 62m when it is added to the female mold 100 may be a temperature at which the aqueous solution is not in a gel state but in a solution state.
  • the fiber 61 f can be easily fixed to the portion corresponding to the microneedle 1 of the female mold 100. As a result, it is possible to provide a sufficient flow path 2 in the microneedle 1 and improve the quality of the microneedle 1 and the microarray 11.
  • Examples of the hydrogel material 62m include the hydrogel materials constituting the microneedles 1 and the microarray 11 as described above, and polymers are preferable.
  • Examples of the fiber 61f include polystyrene, cellulose, maltose, and the like, and polystyrene and cellulose are preferable from the viewpoint of stability in the manufacturing process of the fiber 61f and easy removal of the solid body.
  • the diameter of the fiber 61f may be the same as the diameter R of the channel 2 described above, preferably 30 ⁇ m or less, more preferably 10 ⁇ m or less, and particularly preferably 5 ⁇ m or less.
  • the length of the fiber 61f may be the same as the extension length L of the flow path 2 described above, may be 10 to 1000 ⁇ m, preferably 100 to 1000 ⁇ m, and more preferably 100 to 300 ⁇ m. .
  • the organic solvent 64 is added to the fiber-containing hydrogel 63f prepared in the female mold 100 in the mixture preparation step, and the fiber 61f made of a water-insoluble resin is eluted. And the organic solvent 64 solution of the fiber 61f is taken out.
  • the organic solvent 64 in order to efficiently elute the fiber 61f deep in the hydrogel, it is preferable to add the organic solvent 64 under heating or ultrasonic irradiation conditions.
  • organic solvent 64 examples include toluene, benzene, chloroform, and the like, and tetrahydrofuran is also preferable from the viewpoint of ease of solvent removal.
  • FIG. 7 is an explanatory diagram showing an outline of a preferred example of a method for manufacturing a microneedle and a microarray as a further preferred example of the second embodiment of the present invention.
  • the hydrogel material 62m is applied to the water-soluble porous body 61p such as a freeze-dried product of chitosan, By adding in the absence of water, a porous material-containing hydrogel 63p as a mixture 63 is prepared.
  • the porous material-containing hydrogel 63p is prepared. Water 65 is added to elute the porous body 61p.
  • the template used in the manufacturing method of the microneedle 1 and the microarray 11 of the embodiment of the present invention can be appropriately prepared by a conventional method.
  • the mold can be obtained by engraving a resin plate using a cutting machine or a drill. Further, another mold obtained using such a mold may also be used in the manufacturing method of the embodiment of the present invention.
  • microneedles and microarrays that do not give pain to the subject during insertion are useful for sampling body fluids such as subcutaneous tissue fluid, sensing biological information by measuring the concentration of components in body fluids, and transdermally administering drugs.
  • body fluids such as subcutaneous tissue fluid
  • the microneedles and microarrays of the embodiments of the present invention are particularly useful for the above-mentioned applications because they have excellent water absorption speed by providing a flow path extending in a mesh shape inside.
  • the microneedles and microarray of the preferred embodiment of the present invention can further increase the water absorption rate by including a hydrogel having a liquid permeability, thereby accelerating the practical use of the microneedles and microarrays. There is expected.
  • A-2 Preparation of polystyrene fiber (for Example 2) Using a nanofiber spinning device (NANON-03, MECC) under the conditions of voltage: 30 kV, flow rate: 0.1 mL / hour, capillary size: 0.92 mm ID, 1.28 mm OD), time: 40 minutes, A polystyrene fiber (PS fiber) having a diameter of 1 ⁇ m and a length of 100 to 300 ⁇ m was prepared by electrospinning (see FIG. 11A).
  • PS fiber polystyrene fiber having a diameter of 1 ⁇ m and a length of 100 to 300 ⁇ m was prepared by electrospinning (see FIG. 11A).
  • mold A mold made of PDMS (not shown) having a size of 1 cm in length, 1 cm in width, and 1 cm in height was prepared by a conventional method.
  • the mold was placed in an oven set at 85 ° C., and PMVE-PEG was heated for 24 hours to crosslink them.
  • the PMVE-PEG aqueous solution was solidified in a gel form to prepare a hydrogel (sheet form) composed of a crosslinked product of PMVE and PEG.
  • FIG. 9 shows an outline of the production method of the mold used in the production method of the microneedle and the microarray of the embodiment of the present invention.
  • the acrylic plate was engraved with a shape to be a micro-needle and microarray female mold using a cutting machine (PRODIA-M45, Modia Systems) and a needle-type drill.
  • the dimensions of the mold were as follows.
  • the PDMS and the female mold were taken out of the container, the female mold was removed, and the shape of the PDMS was adjusted to obtain a male mold made of PDMS. And the male mold
  • the surface of the obtained male mold was subjected to fluorination treatment using trichloro (1H, 1H, 2H, 2H-perfluorooctyl) silane (see FIG. 9D).
  • the PDMS prepolymer was poured again into the container to cure the PDMS (see FIG. 9E).
  • the male mold subjected to PDMS and fluorination treatment was taken out of the container, the male mold subjected to fluorination treatment was removed, and a female mold composed of PDMS was obtained (see FIG. 9F).
  • aqueous solution of PMVE-PEG was poured into the obtained female mold, and PMVE-PEG was heated for 24 hours to crosslink them (see FIG. 9 (g)).
  • Example 1 Production of Microneedle and Hydroarray Containing Hydrogel
  • Example 2 Production of Microneedle and Microarray Containing Hydrogel
  • FIG. 10 shows a microneedle and a microarray of Example 1 of the present invention.
  • A shows a photograph when the microneedle is observed using an electron microscope
  • (b) shows a photograph when the microarray is observed using an electron microscope.
  • FIG. 11 shows an outline of a method for producing the microneedle and microarray of Example 2 of the present invention.
  • (A) shows a photograph when the polystyrene fiber is observed using an electron microscope
  • (b) shows a photograph when the state when the polystyrene fiber is deposited in the mold is observed using an electron microscope.
  • A-2 Add the PS fiber (see Fig. 11 (a)) prepared in step 1 to a 1: 4 (volume ratio) mixed solution of ethanol and water so that the fiber is 3.8 wt%, and stir at 600 rpm for 24 hours. To disperse the PS fiber in the solution.
  • PS fiber dispersion was dropped into a female mold made of PDMS (see FIG. 9 (f)), and PS fibers were deposited in the mold by vacuum degassing for 2 hours (see FIG. 11 (b)). ).
  • B-2 The prepared PMVE-PEG (4: 3 (mass ratio)) aqueous solution was poured by the same method as in the above, and the PMVE-PEG was crosslinked and solidified by heating to form a hydrogel composed of PMVE-PEG containing PS fibers.
  • the obtained fiber-containing hydrogel was immersed in toluene for 24 hours to elute PS fibers.
  • microneedles and microarrays composed of a crosslinked product of PMVE and PEG were produced.
  • FIG. 12 shows a microneedle and a microarray of Example 2 of the present invention.
  • A shows a photograph when the microneedle is observed using an electron microscope (an external view is shown on the left and an enlarged view is shown on the right), and
  • B is a view when the microarray is observed using an electron microscope.
  • a photograph is shown (a top view is shown throughout, and a side view is shown in the lower right).
  • (A) shows the state of disassembly and assembly of the kit for evaluating the water absorption rate
  • (b) shows the state when the kit shown in (a) is applied to an agarose gel. It is shown in a cross-sectional view by a surface corresponding to a surface along -A.
  • a 1% (w / v) agarose gel was prepared from agarose-I and 50 mM PBS (pH 7.0) and used in place of living skin in this experimental system.
  • the produced kit was applied to an agarose gel as shown in FIG. 12 (b), and microneedles were inserted into the agarose gel. And the state of the sweating checker was visually observed immediately after insertion and after a predetermined time had elapsed after insertion, and the water absorption rate of the microneedle was evaluated.
  • FIG. 14 shows a photograph of the sweating checker taken at 0 minutes and 10 minutes after insertion when the microneedle of Example 1 of the present invention was inserted into an agarose gel. From the results shown in FIG. 14, in the case of Example 1, water absorption of the microneedles was observed after 10 minutes. From this, it was shown that the water absorption speed of the microneedle containing hydrogel is improved by the presence of the microchannel structure.
  • FIG. 15 is a photograph of the sweating checker taken at 0 hours, 1.5 hours, 3 hours, and 12 hours after insertion when the microneedle of Example 2 of the present invention is inserted into an agarose gel. (In the case of a control on the left, the case of Example 1 is shown on the right). From the results shown in FIG.
  • the microneedle excellent in the water absorption speed, the microarray containing the same, and those manufacturing methods can be provided. Since the microneedles and microarray of the present invention have an excellent water absorption speed by providing a flow path extending in a mesh shape inside, sampling of body fluid such as subcutaneous tissue fluid (sampling), measurement of the concentration of components in the body fluid It is particularly useful for applications such as sensing biological information and transdermal administration of drugs. Furthermore, the preferred microneedles and microarrays of the present invention are expected to accelerate the practical application of microneedles and microarrays by including a hydrogel having liquid permeability per se to further increase the water absorption rate.

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Abstract

L'invention porte sur des micro-aiguilles caractérisées en ce qu'elles comportent des canaux internes s'étendant de façon réticulaire, sur un microréseau caractérisé en ce qu'il a une base sur laquelle les micro-aiguilles sont érigées, et sur des procédés de fabrication des micro-aiguilles et du microréseau.
PCT/JP2016/067464 2015-06-05 2016-06-06 Micro-aiguille, microréseau, et procédés pour leur fabrication WO2016195119A1 (fr)

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JPWO2020179850A1 (fr) * 2019-03-04 2020-09-10
CN111836582A (zh) * 2018-03-16 2020-10-27 国立大学法人东京大学 检测芯片以及检测装置
CN113699697A (zh) * 2021-10-11 2021-11-26 南京大学 一种无感式多功能电纺微金字塔阵列膜及其制备方法
CN113926072A (zh) * 2021-10-10 2022-01-14 北京化工大学 一种多流道微针电穿孔的复合经皮给药装置

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CN113699697B (zh) * 2021-10-11 2022-07-29 南京大学 一种无感式多功能电纺微金字塔阵列膜及其制备方法

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