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WO2024158039A1 - Sugar responsive gel - Google Patents

Sugar responsive gel Download PDF

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Publication number
WO2024158039A1
WO2024158039A1 PCT/JP2024/002308 JP2024002308W WO2024158039A1 WO 2024158039 A1 WO2024158039 A1 WO 2024158039A1 JP 2024002308 W JP2024002308 W JP 2024002308W WO 2024158039 A1 WO2024158039 A1 WO 2024158039A1
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Prior art keywords
gel
sugar
mol
formula
responsive gel
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PCT/JP2024/002308
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French (fr)
Japanese (ja)
Inventor
美智子 伊藤
裕子 松本
紗綾香 金井
亮 松元
Original Assignee
地方独立行政法人神奈川県立産業技術総合研究所
国立大学法人 東京医科歯科大学
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Publication of WO2024158039A1 publication Critical patent/WO2024158039A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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 sugar-responsive gel, a drug delivery device using said gel, and a method for producing said gel.
  • the glucose concentration in the blood (blood glucose level) is regulated within a certain range by the action of various hormones such as insulin, but if this regulatory function breaks down, the sugar content in the blood increases abnormally, resulting in diabetes.
  • Treatment of diabetes usually involves measuring blood glucose levels and injecting insulin. However, excessive insulin intake can cause brain damage. Therefore, in the treatment of diabetes, it is important to adjust the amount of insulin delivered according to blood glucose levels.
  • Phenylboronic acid which can reversibly bind to glucose, is extremely effective in detecting glucose and delivering insulin in a self-regulating manner, and the development of an insulin delivery device that utilizes the properties of phenylboronic acid is underway.
  • Patent Document 1 discloses a sugar-responsive gel and an insulin administration device that can release insulin from the gel body in response to an increase in glucose concentration under biological conditions of pKa 7.4 or less and a temperature of 35°C to 40°C, and can suppress the insulin released from the gel body when the glucose concentration decreases.
  • Patent Document 2 JP Patent Publication 2016-209372 A discloses an insulin delivery device that has a gel-filled section containing a copolymer gel composition containing a phenylboronic acid monomer as a monomer, an aqueous insulin solution-filled section surrounded by the gel-filled section, and a catheter or needle that contains the gel-filled section and has an opening for releasing insulin.
  • the gel-filled portion is inserted subcutaneously while being housed inside a catheter or needle.
  • the gel composition in the gel-filled portion binds with the glucose and expands, and insulin that has diffused into the gel-filled portion is released into the blood through the opening of the catheter or needle.
  • the gel composition contracts, suppressing the release of insulin. This makes it possible to deliver insulin according to the glucose concentration.
  • Patent Document 3 describes that a sugar-responsive gel obtained from a composition containing a phenylboronic acid monomer and a hydroxyl monomer represented by a specific formula exhibits excellent temperature resistance.
  • sugar-responsive gels are produced by thermal polymerization of monomers. Meanwhile, currently, in order to improve the mass production of sugar-responsive gels, production of gels by photopolymerization is being considered. In general, since the reaction mechanisms of thermal polymerization and photopolymerization are different, it is necessary to change the production conditions to apply photopolymerization, which is thought to affect the properties of the sugar-responsive gel. In addition, there has been a demand for the development of a sugar-responsive gel that responds more accurately to changes in sugar concentration, can sufficiently suppress leakage of drugs (e.g., insulin) when the sugar concentration is below a certain level (e.g., normal blood glucose level), and has high resistance to temperature changes. Therefore, one embodiment of the present invention aims to provide a sugar-responsive gel produced by photopolymerization, which responds accurately to changes in sugar concentration and has resistance to temperature changes, and a drug delivery device using the same.
  • drugs e.g., insulin
  • a gelling agent comprising at least one selected from the group consisting of N-isopropyl methacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm);
  • B a compound represented by the following general formula (1): [In the formula, R is H or CH3 , F is present independently, n is 1, 2, 3 or 4, and m is 0 or an integer of 1 or more.]
  • C a compound represented by the following general formula (2): [In the formula, R 1 is H or CH 3 , m is 0 or an integer of 1 or more, and R 2 is OH, a saturated or unsaturated C 1-6 alkyl group substituted with one or more hydroxyl groups, a saturated or unsaturated C 3-10 cycloalkyl group substituted with one or more hydroxyl groups, a C
  • a drug delivery device comprising the sugar-responsive gel described in any one of paragraphs 1 to 5 above.
  • a drug delivery device as described in paragraphs 6 or 7 above, which is a device for use in delivering insulin.
  • FIG. 1 is a side view of a microneedle according to one embodiment of the present invention.
  • FIG. 1 is a cross-sectional view of one form of microneedle having a reservoir.
  • FIG. 13 is a cross-sectional view of another form of microneedle having a reservoir.
  • FIG. 13 is a cross-sectional view of yet another form of microneedle having a reservoir.
  • FIG. 2 is a cross-sectional view of one form of a mold used to manufacture the microneedle shown in FIG.
  • FIG. 1 shows the results of Example 1.
  • FIG. 1 shows the results of Example 2.
  • 1 is a photograph of insulin-containing gel tablets 1 and 5 produced in Production Example 3.
  • 1 is a photograph of mice implanted with gel tablets in the glucose tolerance test of Example 3.
  • FIG. 1 shows the change in blood glucose level before and after embedding of a gel tablet in the glucose tolerance test of Example 3.
  • FIG. 1 shows changes in blood glucose levels in the glucose tolerance test of Example 3.
  • the sugar-responsive gel of this embodiment (also referred to as a "gel composition” or “gel”) utilizes a mechanism in which a phenylboronic acid monomer changes its structure depending on the glucose concentration, as described below.
  • Phenylboronic acid (PBA) dissociated in water reversibly binds to sugar molecules, maintaining the above-mentioned equilibrium state.
  • glucose concentration increases, glucose binds to the boronic acid and the gel expands in volume, but when the glucose concentration is low, the gel contracts.
  • this reaction occurs at the gel interface in contact with blood, and the gel contracts only at the interface, resulting in a dehydrated contraction layer that the inventors call the "skin layer.”
  • An insulin delivery device utilizes this property to control the release of insulin.
  • the sugar-responsive gel of this embodiment is (A) a gelling agent comprising at least one selected from the group consisting of N-isopropylmethacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm); (B) a compound represented by the following general formula (1): [In the formula, R is H or CH3 , F is present independently, n is 1, 2, 3 or 4, and m is 0 or an integer of 1 or more.] A phenylboronic acid monomer represented by the formula: (C) a compound represented by the following general formula (2): [In the formula, R 1 is H or CH 3 , m is 0 or an integer of 1 or more, and R 2 is OH, a saturated or unsaturated C 1-6 alkyl group substituted with one or more hydroxyl groups, a saturated or unsaturated C 3-10 cycloalkyl group substituted with one or
  • the sugar-responsive gel of this embodiment is a copolymer containing monomer units based on components (A) to (D).
  • monomer unit means a structural unit in a (co)polymer derived from a monomer, and the word “monomer” is sometimes used to mean “monomer unit”.
  • the present invention will be described in detail below.
  • the mixture used to prepare the sugar-responsive gel of this embodiment contains (A) a gelling agent (also referred to as "component (A)") containing at least one selected from the group consisting of N-isopropylmethacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm).
  • a gelling agent also referred to as "component (A)
  • the gelling agent forms the main chain of the sugar-responsive gel.
  • the gelling agent may be any biocompatible material that is biocompatible and capable of gelling, such as a biocompatible acrylamide compound (a compound having one acrylamide or methacrylamide group).
  • a biocompatible acrylamide compound a compound having one acrylamide or methacrylamide group.
  • the gelling agent preferably contains at least one compound selected from the group consisting of N-isopropylmethacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm), and may contain two or more types.
  • the gelling agent (component (A)) can be contained in a proportion of, for example, 50 mol% or more, 60 mol% or more, 70 mol% or more, or 80 mol% or more relative to the total of components (A) to (E).
  • the gelling agent can be contained in a proportion of, for example, 90 mol% or less, 80 mol% or less, 70 mol% or less, or 60 mol% or less relative to the total of components (A) to (E).
  • the concentration of the gelling agent relative to the total of components (A) to (E) is preferably 50 mol% or more, more preferably 60 mol% or more, even more preferably 65 mol% or more, and is preferably 90 mol% or less, more preferably 80 mol% or less.
  • the mixture used to prepare the sugar-responsive gel of this embodiment is (B) a compound represented by the following general formula (1): [In the formula, R is H or CH3 , F is present independently, n is 1, 2, 3 or 4, and m is 0 or an integer of 1 or more.] (“Component (B)”, also simply referred to as “phenylboronic acid monomer” or “phenylboronic acid”).
  • the above phenylboronic acid monomer has a fluorinated phenylboronic acid group in which the hydrogen on the phenyl ring is replaced with one to four fluorines, and has a structure in which the carbon of the amide group is bonded to the phenyl ring.
  • the phenylboronic acid monomer having the above structure has high hydrophilicity, and the pKa can be set to the biological level of 7.4 or less because the phenyl ring is fluorinated.
  • this phenylboronic acid monomer not only acquires sugar recognition ability in a biological environment, but also allows copolymerization with the gelling agent of component (A), the hydroxyl monomer of component (C), and the crosslinking agent of component (D) due to the unsaturated bond, and can become a gel that undergoes a phase change depending on the glucose concentration.
  • the introduction site of F and B(OH) 2 may be any of ortho, meta, and para.
  • a phenylboronic acid monomer in which m is 1 or more can have a lower pKa than a phenylboronic acid monomer in which m is 0.
  • m there is no particular upper limit to m, but it is, for example, 20 or less, preferably 10 or less, and more preferably 4 or less.
  • phenylboronic acid monomer is a phenylboronic acid monomer in which R is hydrogen, n is 1, and m is 2, which is 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA), which is a particularly preferred phenylboronic acid monomer.
  • the phenylboronic acid monomer may be a single compound or a combination of two or more compounds.
  • the phenylboronic acid monomer represented by general formula (1) (component (B)) can be contained in a ratio of, for example, 5 mol% or more, 10 mol% or more, or 15 mol% or more relative to the total of components (A) to (E). Furthermore, the phenylboronic acid monomer represented by general formula (1) can be contained in a ratio of, for example, 35 mol% or less, 30 mol% or less, 25 mol% or less, or 20 mol% or less relative to the total of components (A) to (E).
  • the concentration of the phenylboronic acid monomer relative to the total of components (A) to (E) is, for example, preferably 5 mol% or more, more preferably 10 mol% or more, and also preferably 30 mol% or less, more preferably 25 mol% or less.
  • the mixture used to prepare the sugar-responsive gel of this embodiment is a mixture represented by the following general formula (2):
  • R 1 is H or CH 3
  • m is 0 or an integer of 1 or more
  • R 2 is OH, a saturated or unsaturated C 1-6 alkyl group substituted with one or more hydroxyl groups, a saturated or unsaturated C 3-10 cycloalkyl group substituted with one or more hydroxyl groups, a C 3-12 heterocyclic group containing 1 to 4 heteroatoms selected from NH, O and S substituted with one or more hydroxyl groups, a C 6-12 aryl group substituted with one or more hydroxyl groups, a monosaccharide group, or a polysaccharide group.
  • the hydroxyl monomer (“component (C)", also simply referred to as "hydroxyl monomer”) is represented by the following formula:
  • the monomer of the above general formula (2) has a hydroxyl group in the molecule. Without being bound to a particular theory, it is believed that this hydroxyl group increases the hydrophilicity of the gel, offsetting the hydrophobicity of the boronic acid, and acts on the boronic acid in the gel to prevent excessive swelling of the gel.
  • m There is no particular upper limit for m, but it is, for example, 20 or less, preferably 10 or less, and more preferably 4 or less.
  • hydroxyl monomer is a monomer in which R 1 is hydrogen, m is 1, and R 2 is OH, which is N-(hydroxyethyl)acrylamide (NHEAAm), which is particularly preferred as a hydroxyl monomer.
  • NHEAAm N-(hydroxyethyl)acrylamide
  • R 2 may be, for example, a sugar derivative such as a catechol group or a glycolyl group.
  • the monosaccharide may be, for example, glucose.
  • the hydroxyl monomer may be a single compound or a combination of two or more compounds.
  • the hydroxyl monomer represented by general formula (2) (component (C)) can be contained in an amount, for example, of 8 mol% or more, 10 mol% or more, 12 mol% or more, 13 mol% or more, or 15 mol% or more relative to the total of components (A) to (E).
  • the concentration of the hydroxyl monomer represented by general formula (2) (component (C)) relative to the total of components (A) to (E) can be, for example, 21 mol% or less, 20 mol% or less, 18 mol% or less, 17 mol% or less, 16 mol% or less, 15 mol% or less, or 14 mol% or less.
  • the concentration range can be specified by any combination of the upper and lower limits above.
  • the preferred concentration range of component (C) relative to the total of components (A) to (E) is, for example, preferably 11 mol% or more, more preferably 12 mol% or more, even more preferably 13 mol% or more, and preferably 20 mol% or less, more preferably 18 mol% or less, even more preferably 16 mol% or less, and even more preferably 15 mol% or less.
  • the mixture used to prepare the sugar-responsive gel of this embodiment contains (D) a crosslinker (also referred to as "component (D)").
  • the crosslinker may be any substance that is biocompatible and capable of crosslinking monomers, and preferably includes a compound having at least two acrylamide or methacrylamide groups in the molecule.
  • Examples of the crosslinker include N,N'-methylenebisacrylamide (MBAAm), ethylene glycol dimethacrylate (EGDMA), and N,N'-methylenebismethacrylamide (MBMAAm).
  • the crosslinker may be a single compound or a combination of two or more compounds.
  • the crosslinking agent (component (D)) can be contained in an amount, for example, of 1 mol% or more, 1.5 mol% or more, 2 mol% or more, 2.3 mol% or more, or 2.5 mol% or more relative to the total of components (A) to (E). Also, component (D) can be contained in an amount, for example, of 5 mol% or less, 4.5 mol% or less, 4 mol% or less, 3.5 mol% or less, 3 mol% or less, or 2.5 mol% or less relative to the total of components (A) to (E).
  • the concentration range is a combination of the above upper and lower limits.
  • the mixture used to prepare the sugar-responsive gel of this embodiment contains (E) a photopolymerization initiator (also referred to as “component (E)").
  • the photopolymerization initiator generates radicals, acids, bases, etc. when irradiated with active light such as ultraviolet rays, and can be appropriately selected depending on the type of monomer, etc., and it is preferable to use a photoradical polymerization initiator.
  • the photo-radical polymerization initiator is preferably one that is sensitive to ultraviolet light with a wavelength shorter than 405 nm, and from the viewpoint of being able to fully utilize the energy emitted from the light source and having excellent productivity, it is preferable that the maximum absorption wavelength is 300 nm to 400 nm, and more preferably 300 nm to 380 nm.
  • the photo-radical polymerization initiator is not particularly limited, but examples include alkylphenone radical polymerization initiators, acylphosphine oxide radical polymerization initiators, and oxime ester radical polymerization initiators. These photo-polymerization initiators may be used alone or in combination of two or more types.
  • alkylphenone photopolymerization initiators examples include 2,2-dimethoxy-1,2-diphenylethan-1-one (IGM Resins, Omnirad 651), 1-hydroxy-cyclohexyl-phenyl-ketone (IGM Resins, Omnirad 184), 2-hydroxy-2-methyl-1-phenyl-propan-1-one (IGM Resins, Omnirad 1173), 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propan-1-one, 2-hydroxy-1- ⁇ 4-[4-(2-hydroxy-2- 2-methyl-1-(4-methylthiophenyl)-2-morpholinopropan-1-one (IGM Resins, Omnirad 907), 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-butanone-1, 2-(dimethylamino)-2-[(4-methylphenyl)methyl]-1-[4-(4-morpholinyl)phenyl]-1-butanone
  • acylphosphine oxide photopolymerization initiators include 2,4,6-trimethylbenzoyl-diphenyl-phosphine oxide (IGM Resins, Omnirad TPO H) and bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (IGM Resins, Omnirad 819).
  • oxime ester radical polymerization initiators examples include 1-[4-(phenylthio)phenyl]-1,2-octanedione-2-(O-benzoyloxime) (product name: OmniradOXE-01, manufactured by IGM Resins).
  • the content of the photopolymerization initiator (component (E)) is not particularly limited, but is, for example, preferably 1 mol% or more, more preferably 2 mol% or more, and also preferably 11 mol% or less, more preferably 5 mol% or less, based on the total of components (A) to (E).
  • the concentration of the photopolymerization initiator is, for example, preferably 1.3 (w/v)% or more, more preferably 1.6 (w/v)% or more, even more preferably 3.2 (w/v)% or more, and also preferably 15.0 (w/v)% or less, more preferably 10 (w/v)% or less, even more preferably 7 (w/v)% or less. If the content of the photopolymerization initiator is too low, polymerization may be insufficient. On the other hand, if the content of the photopolymerization initiator is too high, the gel may become non-uniform and brittle.
  • a preferred embodiment of the sugar-responsive gel is, for example, a polymer of a mixture of N-isopropylmethacrylamide (NIPMAAm) as a gelling agent (main chain), 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA) as a phenylboronic acid monomer, N-hydroxyethylacrylamide (HEAAm) as a hydroxyl monomer, N,N'-methylenebisacrylamide (MBAAm) as a crosslinking agent, and 2,2-dimethoxy-1,2-diphenylethan-1-one as a photopolymerization initiator, mixed in a predetermined molar ratio.
  • NIPMAAm N-isopropylmethacrylamide
  • AmECFPBA 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid
  • HEAAm N-hydroxyethylacrylamide
  • a more preferred embodiment of the sugar-responsive gel of this embodiment is, for example, a polymer of a mixture in which the molar ratio of (NIPMAAm/AmECFPBA/HEAAm/MBAAm/2,2-dimethoxy-1,2-diphenylethan-1-one) is adjusted to 65-70/10-15/10-15/1-5/1-5. As an example, it is preferable to adjust it to 68.66/12.11/13.46/2.8/2.94.
  • the inventors of the present invention have conducted detailed studies on the composition of the sugar-responsive gel produced by photopolymerization. As a result, they have found that by setting the molar ratio of (the sum of components (A) and (B)):component (C) within a predetermined range and setting the concentration of the crosslinking agent of component (D) within a predetermined range (i.e., setting the crosslinking density within a predetermined range), a gel can be obtained that is accurate in response to changes in sugar concentration even when there is a temperature change, and is excellent in suppressing drug release (leakage) when the sugar concentration is below the normal value.
  • the body temperature of mammals is kept almost constant, but for example, when starting treatment with a drug delivery device, the patient's body temperature may temporarily drop after anesthetizing the patient or immediately after the drug delivery device is attached to the patient's body.
  • the sugar-responsive gel of this embodiment is accurate in response to changes in sugar concentration and is excellent in suppressing drug release (leakage) when the sugar concentration is below the normal value.
  • the mixture for preparing the sugar-responsive gel of this embodiment has a molar ratio (the sum of the gelling agent (A) and the phenylboronic acid monomer (B)) of the hydroxyl monomer (C) (also referred to as the "molar ratio of (A+B):C”) of preferably 4.5:1 to 6.5:1, more preferably 4.8:1 to 6.3:1, even more preferably 5.0:1 to 6.3:1, and even more preferably 5.5:1 to 6.3:1. If the total amount of components (A) and (B) is too small compared to the amount of component (C), the drug may be released even when the glucose concentration is below the normal value, or the drug may not respond accurately to changes in the glucose concentration. If the total amount of components (A) and (B) is too large compared to the amount of component (C), the drug may not be released easily when the glucose concentration is high.
  • the ratio of the crosslinker of component (D) to the total of 100 mol% of components (A), (B), and (C) (also referred to as "crosslink density”) is preferably 1.5 mol% or more, more preferably 2.0 mol% or more, even more preferably 2.5 mol% or more, even more preferably 2.8 mol% or more, and is preferably 4 mol% or less, more preferably 3.5 mol% or less. If the crosslink density is too small, the gel may have poor moldability and strength, while if the crosslink density is too large, the amount of drug released may be insufficient. Furthermore, by keeping the crosslink density within the above range, the gel can respond more accurately to changes in sugar concentration.
  • the sugar-responsive gel may contain other components such as silk fibroin and polyglycerol, if necessary, or may form a complex with other components.
  • the total content of components (A) to (E) in the mixture used to prepare the sugar-responsive gel is preferably 90% by mass or more, more preferably 95% by mass or more, and may be 100% by mass, out of a total amount (100% by mass) of the mixture.
  • the gel can be prepared by mixing the above components (A) to (E) and copolymerizing the monomers by a photopolymerization reaction.
  • the order and means of mixing the components are not particularly limited.
  • the components are preferably mixed in a solvent. Any solvent that dissolves the monomers can be used as the solvent. Examples of such solvents include water, alcohol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), ionic liquids, and combinations of two or more of these.
  • aqueous methanol solution and 2-methoxyethanol can be preferably used as the solvent, and 2-methoxyethanol is particularly preferred.
  • the total monomer concentration of components (A), (B), (C), and (D) in the solution is preferably 1 to 10 M in the solution, and more preferably 3 to 8 M.
  • the unit “M” means "mol/L".
  • a mixing means for example, a known device such as an ultrasonic dispersion device can be used.
  • the temperature during mixing is not particularly limited, and may be, for example, room temperature (preferably 5 to 40° C., more preferably 10 to 35° C.).
  • a monomer solution is prepared by mixing components (A) to (D), and component (E) is added thereto immediately before the polymerization reaction to form a pregel solution.
  • two or more monomer solutions having different compositions are prepared, and the solutions are mixed to obtain a desired composition, to which component (E) is added.
  • the sugar-responsive gel of this embodiment is obtained by irradiating a pre-gel solution containing components (A) to (E) with light to polymerize the monomers.
  • the light to be irradiated include one or more types of light selected from the group consisting of visible light, ultraviolet light, infrared light, X-rays, ⁇ -rays, ⁇ -rays, and ⁇ -rays, and active electron beams.
  • ultraviolet light is preferred because it is easy to control the progress of the polymerization reaction and because it can be used with a photopolymerization device that is widely used.
  • Examples of light sources include low-pressure mercury lamps, medium-pressure mercury lamps, high-pressure mercury lamps, ultra-high-pressure mercury lamps, xenon lamps, halogen lamps, carbon arc lamps, tungsten lamps, gallium lamps, excimer lasers, LED light sources, chemical lamps, black light lamps, microwave-excited mercury lamps, and metal halide lamps.
  • the ultraviolet irradiation intensity is not particularly limited, but is preferably 10 to 3,000 mW/cm 2 , more preferably 10 to 1000 mW/cm 2 , and even more preferably 10 to 500 mW/cm 2 .
  • the ultraviolet irradiation intensity is preferably an intensity in a wavelength region effective for activating a photopolymerization initiator.
  • the light irradiation time is preferably 0.1 seconds to 10 minutes, more preferably 0.1 seconds to 5 minutes, and even more preferably 0.1 seconds to 3 minutes.
  • the integrated light amount is preferably 10 to 3,000 mJ/cm 2 , more preferably 50 to 2,000 mJ/cm 2 , and even more preferably 100 to 1,000 mJ/cm 2 .
  • Drug delivery devices One embodiment of the present invention relates to a drug delivery device (also referred to as a "drug delivery device” or simply “device”) comprising the sugar-responsive gel.
  • the drug delivery device is preferably used for delivering insulin.
  • the drug delivery device according to the present invention may take any form, such as a body-implantable type, a microneedle type, a tablet type, or the like.
  • body-implantable devices for example, JP 2016-209372 A and WO 2017/069282 can be referred to.
  • the drug delivery device may also be implanted in the body as a gel tablet (see the Examples described below).
  • the shape and size of the gel tablet are not particularly limited.
  • the gel may already contain a drug (e.g., insulin).
  • a drug e.g., insulin
  • the gel is immersed in an aqueous solution (e.g., phosphate buffer solution) containing a prescribed concentration of the drug, allowing the drug to diffuse into the gel.
  • the gel is then removed from the aqueous solution and immersed in, for example, hydrochloric acid for a prescribed period of time, forming a thin dehydrated contraction layer (called a skin layer) on the surface of the gel body, thereby encapsulating (loading) the drug and obtaining a gel that can be filled into the device.
  • the sugar-responsive gel of the drug delivery device already contains a drug (e.g., insulin).
  • a drug e.g., insulin
  • the gel can be immersed in an aqueous solution, such as a phosphate buffer solution, that contains a prescribed concentration of the drug, to allow the drug to diffuse into the gel.
  • the gel is then removed from the aqueous solution and immersed in, for example, hydrochloric acid for a prescribed period of time, forming a thin dehydration contraction layer (called a skin layer) on the surface of the gel body, thereby encapsulating (loading) the drug and obtaining a gel that can be filled into the device.
  • a phenylboronic acid monomer and a hydroxyl monomer are copolymerized with a gelling agent and a crosslinking agent to form the gel body.
  • Drugs such as insulin can be diffused into this gel, and the surface of the gel body can be surrounded by a dehydration shrinkage layer.
  • physiological conditions e.g., pKa 7.4 or less, temperature 35°C to 40°C
  • the gel expands and the dehydration shrinkage layer disappears, allowing the drug (e.g., insulin) in the gel to be released to the outside.
  • the sugar-responsive gel used in the present invention can autonomously release a drug (e.g., insulin) in response to the glucose concentration.
  • Drugs that can be delivered using the sugar-responsive gel of this embodiment include, but are not limited to, proteins, peptides, nucleic acids, other high molecular weight polymers, low molecular weight compounds, etc. Drugs may be therapeutic agents, preventive agents, vaccines, nutritional supplements, etc. A particularly preferred drug is insulin.
  • Various natural insulins or modified insulins are available commercially or by synthesis.
  • Humulin registered trademark
  • Humulin registered trademark
  • Humulin is a human (recombinant) insulin sold by Eli Lilly and Company.
  • Various insulin preparations, including fast-acting, intermediate-acting, and sustained-acting have been developed, and can be appropriately selected and used.
  • a microneedle 10 according to an embodiment of the present invention is shown, which has a base portion 100 and a plurality of needles 110 and is provided as a patch to be attached to the skin.
  • the base portion 100 is a sheet-like portion that supports the plurality of needles 110.
  • the plurality of needles 110 are supported by the base portion 100, and are configured as a needle array.
  • the needle 110 is a portion that is pierced into the skin when the microneedle 10 is used, and has a sharp tip.
  • the base portion 100 and the needle 110 may be made of different materials or may be made of the same material.
  • the base portion 100 and the needle 110 are made of the same material, they can be made at the same time.
  • At least the needle 110 has hydrophilicity, and before use of the microneedle 10, the drug is permeated into the needle 110, thereby carrying the drug therein.
  • the needle 110 has a high mechanical strength sufficient to puncture the skin before puncturing the skin, and has a property of absorbing water and releasing a drug immediately after puncturing the skin.
  • the microneedle is also referred to as a "drug delivery microneedle.”
  • the base portion 100 can be made of various materials as long as the materials have the necessary mechanical strength to allow the needles 110 to pierce the skin well against the elasticity of the skin when the needles 110 pierce the skin. Examples of such materials include polymer materials, ceramic materials having a porous structure, and metal materials.
  • the base portion 100 is preferably made of a material having biocompatibility. In one aspect, the base portion is preferably flexible enough to be deformed along the skin.
  • the base portion 100 can have a reservoir for the drug to be released from the needle 110.
  • the drug can be released over a long period of time (e.g., 7 days).
  • a microneedle capable of releasing a drug over a long period of time can be suitably used as an insulin delivery microneedle that administers insulin as a drug depending on the blood glucose concentration.
  • the reservoir can be constructed, for example, by forming the base part 100 into a concave (cup-shaped) shape with an open top.
  • the base part 100 can be formed from the same material as the needles 110, and the base part 100 itself, permeated with the drug, can serve as the reservoir.
  • the base part 100 and the multiple needles 110 can be formed simultaneously by integral molding.
  • the base part 100 is preferably constructed from a material that does not impede the continuity of drug flow from the needles 110 to the base part 100. The structure of a microneedle with a reservoir will be described in detail later.
  • the planar shape of the base portion 100 may be any shape, such as a circle, an ellipse, or a polygon, and may be, for example, a rectangle.
  • the length of the needle 110 is not limited as long as the needle 110 has a sufficient length to reach the stratum corneum when the needle 110 is punctured into the skin, and may be, for example, preferably 5 mm or less, more preferably 2 mm or less, and even more preferably 1 mm or less, and is preferably 100 ⁇ m or more, more preferably 500 ⁇ m or more, and even more preferably 1 mm or more in one embodiment.
  • the number and arrangement of the needles 110 may be arbitrary. For example, a plurality of needles 110 may be arranged in a matrix of M ⁇ N (M and N are integers of 1 to 30).
  • 10 ⁇ 12 needles 110 are arranged at a pitch of 500 ⁇ m in a rectangular area of 8 mm ⁇ 8 mm.
  • 11 ⁇ 11 needles 110 are arranged at a pitch of 1.2 mm in a circular area of 12 mm in diameter.
  • the shape of the needle 110 may be arbitrary as long as it has a tip that can puncture the skin, and may preferably be a pyramid shape.
  • the base portion 100 is formed in a concave (cup-like) shape, and the open upper surface of the base portion 100 is sealed with a sheet 102 to form a space, which constitutes the reservoir 101.
  • a water-resistant adhesive 103 can be used to adhere the sheet 102.
  • the sheet 102 There are no particular limitations on the sheet 102, but from the standpoint of water resistance and flexibility, for example, a silicone sheet with a thickness of 0.3 mm can be used.
  • the drug can be filled into the reservoir 101 through the sheet 102 by syringe injection.
  • the reservoir 101 is sealed by, for example, a silicone sheet 102 with adhesive 103, as in the embodiment shown in FIG. 2A.
  • the base portion 100 is formed with a step having a flange 100b on the open end side of the reservoir 101.
  • the sheet 102 also hangs down beyond the flange 100b toward the bottom surface 100a having the needle 110, covering the base portion 100 in the height direction of the base portion 100.
  • the adhesive 103 is applied around the entire circumference of the base portion 100, between the base portion 100 and the sheet 102, in the hanging portion of the sheet 102.
  • the sheet 102 can be adhered to the base portion 100 over a larger adhesion area, and the reservoir 101 can be sealed more effectively. As a result, leakage of the drug from between the base portion 100 and the sheet 102 can be effectively prevented. Moreover, the expansion of the area of the microneedle can be minimized.
  • the amount of protrusion A of the flange 100b can be, for example, 0.2 mm.
  • the thickness B of the flange 100b can be, for example, 0.1 mm, and the height C from the flange 100b to the bottom surface of the base portion 100 can be, for example, 0.2 mm.
  • the planar shape of the microneedle may be any shape, such as a rectangle or a circle.
  • the outer shape of the flange 100b and the shape of the bottom surface 100a of the base portion 100 on which the needle 110 is disposed may be the same or different. From the viewpoint of suppressing deformation during the manufacture of the microneedle, it is preferable that the outer shape of the flange 100b and the shape of the bottom surface 100a are both circular.
  • the adhesion area can be increased by increasing the amount of protrusion of the flange 100b and adhering the sheet 102 to the upper surface of the flange 100b via adhesive 103, as shown in Figure 2C.
  • the base part 100 and the needle 110 can be formed by using a micromolding technique using a mold. Since the needle 110 can be formed integrally with the base part 100, it is preferable to use a mold 200 having a cavity (recess) 201 formed in a shape of the needle and the base part combined as shown in FIG. 3.
  • a material for forming the mold 200 for example, a silicone material such as polydimethylsiloxane (PDMS) can be used.
  • the material for forming the mold 200 is preferably a material that can transmit light for photopolymerizing the monomer in the pre-gel solution.
  • the base part 100 and the needle 110 can be formed in one process.
  • a solution pre-gel solution in which the material constituting the needle 110 is dissolved in a solvent is poured into the part of the mold 200 corresponding to the needle 110, and the monomer is polymerized by light irradiation, and this is dried (the solvent is removed) to form the needle 110.
  • Pouring and drying of the solution can also be performed multiple times.
  • a solution in which the material constituting the base part 100 is dissolved in a solvent is poured into the mold 200 and dried. The obtained molded body is removed from the mold 200. In this way, the base part 100 and the needle 110 formed integrally can be obtained.
  • a solution (pre-gel solution) in which a monomer mixture containing the monomers constituting the needle 110 is dissolved in a solvent is poured (injected) into the cavity 201 corresponding to the needle 110 of the microneedle mold 200.
  • the amount of solution poured into the microneedle mold 200 is an amount that fills at least the cavity 201 corresponding to the needle 110 with the solution.
  • a sheet corresponding to the base part 100 is inserted into the microneedle mold 200 from above the poured solution.
  • An example of the sheet corresponding to the base part 100 is a PE (polyethylene) sheet, which may be a porous PE sheet.
  • the porous body is inserted into the microneedle mold 200 so that the liquid surface of the solution contacts the porous body in the portion where the solution and the PE sheet face each other.
  • a PE sheet having a gel layer of the same composition as the needle 110 may be prepared, and the PE sheet may be arranged so that the gel layer portion on the PE sheet contacts the solution in the portion corresponding to the needle 110.
  • the needle 110 has a very fine structure, it is important to fill the solution up to the tip of the needle 110 when forming the needle 110. Therefore, after filling the solution, centrifugation, vacuum treatment, or degassing treatment may be performed.
  • the sugar-responsive gel constituting the microneedle of this embodiment is formed by a photopolymerization reaction of components (A) to (E).
  • the solution (containing the monomer mixture) poured into the needle 110, or into the mold of the base part 100 and the needle 110, is degassed, and then the monomer mixture is polymerized by light irradiation.
  • the method of light irradiation is as described in the above method for preparing the gel.
  • the direction of light irradiation is not particularly limited, but it is preferable to irradiate from the tip of the needle, for example.
  • ⁇ Production Example 1 Preparation of pregel solution>
  • the materials (monomers) used in preparing the monomer solution are as follows: (Gelling agent (main chain)) NIPAAm: N-isopropylacrylamide (Phenylboronic acid) AmECFPBA: 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (Hydroxyl monomer) NHEAAm: N-hydroxyethylacrylamide (Crosslinking agent) MBAAm: N,N'-methylenebisacrylamide
  • the total concentration of monomers other than the crosslinker is 5M
  • the crosslink density is 3%, which is described as “5M3%", and the same applies to other compositions.
  • Crosslink density refers to the molar concentration of the crosslinker relative to the total amount of the gelling agent, phenylboronic acid, and hydroxyl monomer.
  • ⁇ Crosslink density 1%, 5M 1% monomer solution A1, 5M 1% monomer solution B1>
  • the above-mentioned monomer solution A and monomer solution B were mixed with a vortex mixer to obtain the mixing ratio (volume ratio) in Table 1 below.
  • 40 mg of a photopolymerization initiator (Irgacure 651 (Omnirad 651), manufactured by BASF Japan) was added to 1 mL of the mixed solution, and the solution was completely dissolved by ultrasonication for 10 minutes to produce pregel solutions 1 to 7.
  • the mixing ratio of monomer solution A to monomer solution B corresponds to the molar ratio of ⁇ (NIPAAm + AmECFPBA):NHEAAm ⁇ , that is, ⁇ (gelling agent + phenylboronic acid monomer):hydroxyl monomer ⁇ .
  • the concentration of the crosslinking agent (crosslinking density) represents the ratio (mol) of MBAAm to the total of AmECFPBA, NIPAAm, and NHEAAm in the mixed monomer solution.
  • ⁇ Production Example 2 Preparation of Microneedles> (Preparation of PE plate with gel layer)
  • the PE plates with a gel layer were prepared using each of the pre-gel solutions 1 to 7 listed in Table 1 above as the pre-gel solution.
  • pregel solution 1 125 ⁇ L of pregel solution 1 kept at 50 ° C. was placed in the cavity corresponding to the needle of the mold of the microneedle of silicone (made of polydimethylsiloxane (PDMS)) previously warmed to 50 ° C., and the operation of removing air bubbles by decompressing with a water flow pump was repeated twice.
  • the PE plate with the gel layer prepared above PE plate prepared using pregel solution 1) was gently inserted, and UV irradiation (wavelength 365 nm, 150 mW / cm 2 , irradiation time 1 minute) was performed from the needle tip side to polymerize the monomer and gel the pregel solution in the mold.
  • microneedle 1 After a few minutes of irradiation, when the mold cooled to about room temperature, the microneedle gel was gently removed from the mold and air-dried at room temperature overnight to obtain a molded body in which the PE plate and the needle were integrated.
  • pre-gel solutions 2 to 7 instead of pre-gel solution 1, microneedles 2 to 7, which are PE plate-attached microneedles, were prepared in a similar manner.
  • ⁇ Production Example 3 Preparation of gel tablets> 55 ⁇ l of each pregel solution (containing each monomer and photopolymerization initiator (Irgacure 651)) with the composition shown in Table 1 was placed in a cylindrical mold made of polypropylene (diameter 4 mm, height 3 mm). Then, UV irradiation (150 mW/cm 2 , irradiation time 1 minute) was performed to polymerize the monomer and gel the pregel solution in the mold. After a few minutes of irradiation, when the mold cooled to about room temperature, it was air-dried at room temperature overnight, and then the gel was gently removed from the mold to obtain a molded body.
  • UV irradiation 150 mW/cm 2 , irradiation time 1 minute
  • the gel was gently immersed in a sufficient amount of 100% methanol solution, and washing was repeated for two days until the washing solution reached pH 6.5 or higher, with the washing solution being replaced every half day. Finally, it was replaced with water overnight and then dried to obtain a gel tablet.
  • the gel tablets obtained using pregel solutions 1 to 7 (Table 1) are referred to as gel tablets 1 to 7, respectively.
  • Example 1 Relationship between crosslink density and insulin release amount
  • Gel tablet 7 crosslink density 1%
  • gel tablet 6 crosslink density 2%
  • gel tablet 3 crosslink density 5%
  • PBS glucose concentration: 0 g/L, 137 mM NaCl
  • PBS glucose concentration: 0 g/L, 137 mM NaCl
  • PBS glucose concentration: 0 g/L, 137 mM NaCl
  • each glucose concentration (0 g/L or 5 g/L (corresponding to high blood glucose level)
  • the collected samples were analyzed using an insulin ELISA kit to quantify the amount of insulin released from the gel tablets containing insulin. The results are shown in FIG. 4.
  • Example 2 Relationship between gel composition and crosslink density and insulin release amount Using the pre-gel solutions 1 to 6, gel tablets 1 to 6 containing insulin were prepared as in Production Example 3 above.
  • Each gel tablet containing insulin was transferred to PBS (glucose concentration: 0 g/L, 137 mM NaCl) and pre-cultured for 2 hours, then transferred to PBS with each glucose concentration (0 g/L, 1 g/L (corresponding to normal blood glucose level), 5 g/L (corresponding to hyperglycemia)) and cultured at 30°C for 30 minutes, 1 hour, and 2 hours, at which point PBS solution samples were taken. The collected samples were analyzed using an insulin ELISA kit to quantify the amount of insulin released from the gel tablet containing insulin.
  • each tablet was transferred to PBS with each glucose concentration (0 g/L, 1 g/L, 5 g/L) and cultured at 37°C for 30 minutes, 1 hour, and 2 hours, at which point PBS solution samples were taken and the amount of insulin released was quantified.
  • the results of using insulin-containing gel tablets 1 to 6 are shown in Figure 5.
  • the upper row of Figure 5 shows the results of culturing at 30°C, and the lower row shows the results of culturing at 37°C.
  • Example 3 Subcutaneous implantation experiment of gel tablets> To evaluate glucose-responsive insulin release in vivo, a glucose tolerance test (GTT) was performed on mice implanted with the gel tablets.
  • GTT glucose tolerance test
  • Gel tablets 1 and 5 were produced by the method of Production Example 3 using pregel solution 1 and pregel solution 5, respectively, and insulin was incorporated therein.
  • One gel tablet containing insulin was embedded subcutaneously in one wild-type (C57BL/6J, male) mouse that had been fasted overnight under anesthesia (see Figure 7).
  • glucose was administered intraperitoneally at 2 g/kg using a 20% glucose aqueous solution, and a glucose tolerance test was performed. Blood glucose levels were measured every 15 to 30 minutes using a blood glucose meter until 150 minutes after glucose administration. Blood was also collected at those times, plasma was collected, and plasma insulin concentrations were measured by ELISA.
  • Similar measurements were performed using gel tablet 5 produced using pregel solution 5 that did not contain insulin (empty gel). In the test using gel tablets containing insulin, the average value was calculated for four mice in each group, and in the test using control gel tablets, the average value was calculated for three mice.
  • Figure 8 shows the blood glucose levels of mice before and 3 hours after implanting gel tablets containing insulin (before glucose administration).
  • gel tablet 5 (5M 3% 6:1)
  • blood glucose levels did not change before and after the gel tablet was implanted, indicating that insulin was not released before glucose administration.
  • gel tablet 1 (5M 5% 3:1)
  • blood glucose levels dropped before glucose administration, indicating that insulin was released.
  • Figure 9 shows the change in blood glucose level in mice that underwent a glucose tolerance test.
  • the horizontal axis shows the time that has passed since glucose was administered, and the vertical axis shows the blood glucose level.
  • the control in Figure 9 is the result of using gel tablet 5 that does not contain insulin (empty gel).
  • Figure 10 shows the change in plasma insulin concentration in mice that underwent a glucose tolerance test.
  • the horizontal axis shows the time that has passed since glucose was administered, and the vertical axis shows the amount of plasma insulin.
  • mice using gel tablet 5 had blood glucose levels at the same level as the control before glucose administration (0 minutes) and no insulin was released, but after glucose administration, insulin was released and blood glucose levels returned to normal 90 minutes later.
  • gel tablet 1 5M 5% 3:1
  • insulin was already released before glucose administration, indicating that blood glucose levels were already low at this point.

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Abstract

Provided are: a sugar responsive gel that is produced by a photopolymerization reaction and that has an accurate response to a change in sugar concentration; and a drug delivery device using said sugar responsive gel. The present embodiment relates to a sugar responsive gel including a polymerization reaction product which is a mixture including (A) a prescribed gelling agent, (B) a phenylboronic acid-based monomer represented by a prescribed formula, (C) a hydroxyl-based monomer represented by a prescribed formula, (D) a crosslinking agent, and (E) a photopolymerization initiation agent, wherein: the molar ratio of (the total of component (A) and component (B))∶component (C) is within the range of 4.5∶1 to 6.5∶1; and the proportion of the crosslinking agent relative to the total of component (A), component (B), and component (C) is 1.5-4 mol%.

Description

糖応答性ゲルSugar-responsive gel
　本発明は、糖応答性ゲル、当該ゲルを用いた薬剤送達デバイス、および当該ゲルの製造方法に関する。 The present invention relates to a sugar-responsive gel, a drug delivery device using said gel, and a method for producing said gel.
　血中のグルコース濃度（血糖値）は、インスリンなど様々なホルモンの働きによって一定の範囲内に調整されているが、この調整機能が破綻すると、血液中の糖分が異常に増加し、糖尿病になる。糖尿病の治療では、通常、血中グルコース濃度の測定及びインスリンの注射が行われる。しかし、インスリンの過剰摂取は、脳の損傷を引き起こすことがある。したがって、糖尿病の治療においては、血中グルコース濃度に応じてインスリンの送達量を調整することが重要である。 The glucose concentration in the blood (blood glucose level) is regulated within a certain range by the action of various hormones such as insulin, but if this regulatory function breaks down, the sugar content in the blood increases abnormally, resulting in diabetes. Treatment of diabetes usually involves measuring blood glucose levels and injecting insulin. However, excessive insulin intake can cause brain damage. Therefore, in the treatment of diabetes, it is important to adjust the amount of insulin delivered according to blood glucose levels.
　ところで、グルコースと可逆的に結合することができるフェニルボロン酸（ＰＢＡ）は、グルコースの検知及び自己調節型のインスリン送達に極めて有効であり、このようなフェニルボロン酸の性質を利用したインスリン送達デバイスの開発が進められている。例えば、特許文献１には、ｐＫａ７．４以下、温度３５℃～４０℃の生体条件下で、グルコース濃度が高くなると、これに応じてゲル本体からインスリンを放出させることができるともに、グルコース濃度が低くなると、当該ゲル本体から放出されるインスリンを抑制できる糖応答性ゲル、及びインスリン投与デバイスが開示されている。また、特許文献２（特開２０１６－２０９３７２号公報）には、フェニルボロン酸系単量体を単量体として含む共重合体ゲル組成物が存在するゲル充填部と、ゲル充填部に囲まれたインスリン水溶液充填部と、ゲル充填部を収容する、インスリン放出用の開口部を有するカテーテル又は針と、を有するインスリン送達デバイスが開示されている。 Phenylboronic acid (PBA), which can reversibly bind to glucose, is extremely effective in detecting glucose and delivering insulin in a self-regulating manner, and the development of an insulin delivery device that utilizes the properties of phenylboronic acid is underway. For example, Patent Document 1 discloses a sugar-responsive gel and an insulin administration device that can release insulin from the gel body in response to an increase in glucose concentration under biological conditions of pKa 7.4 or less and a temperature of 35°C to 40°C, and can suppress the insulin released from the gel body when the glucose concentration decreases. Patent Document 2 (JP Patent Publication 2016-209372 A) discloses an insulin delivery device that has a gel-filled section containing a copolymer gel composition containing a phenylboronic acid monomer as a monomer, an aqueous insulin solution-filled section surrounded by the gel-filled section, and a catheter or needle that contains the gel-filled section and has an opening for releasing insulin.
　例えば、特許文献２に開示されたインスリン送達デバイスによれば、ゲル充填部はカテーテル又は針の内部に収容された状態で皮下に挿入される。この状態で血液中のグルコース濃度が高くなると、ゲル充填部のゲル組成物がグルコースと結合して膨張し、ゲル充填部に拡散しているインスリンが、カテーテル又は針の開口部を通じて血液中に放出される。グルコース濃度が低い場合はゲル組成物が収縮し、インスリンの放出が抑制される。これによって、グルコース濃度に応じたインスリンの送達が可能となる。 For example, according to the insulin delivery device disclosed in Patent Document 2, the gel-filled portion is inserted subcutaneously while being housed inside a catheter or needle. When the glucose concentration in the blood increases in this state, the gel composition in the gel-filled portion binds with the glucose and expands, and insulin that has diffused into the gel-filled portion is released into the blood through the opening of the catheter or needle. When the glucose concentration is low, the gel composition contracts, suppressing the release of insulin. This makes it possible to deliver insulin according to the glucose concentration.
　特許文献３には、フェニルボロン酸系単量体と所定の式で表されるヒドロキシル系単量体を含む組成物から得られる糖応答性ゲルが、優れた温度耐性を示すことが記載されている。 Patent Document 3 describes that a sugar-responsive gel obtained from a composition containing a phenylboronic acid monomer and a hydroxyl monomer represented by a specific formula exhibits excellent temperature resistance.
特開２０１５－１１０６２３号公報JP 2015-110623 A 特開２０１６－２０９３７２号公報JP 2016-209372 A ＷＯ２０１９／２３０９６１号WO2019/230961
　特許文献１～３では、糖応答性ゲルを、単量体を熱重合することにより作製している。一方、現在、糖応答性ゲルの量産性を向上させるため、光重合反応によりゲルを製造することが検討されている。一般的に、熱重合と光重合では反応機構が異なるために、光重合を適用するには製造条件を変更する必要があり、それにより糖応答性ゲルの特性にも影響を与えることが考えられる。また、糖濃度の変化に対する応答がより正確で、かつ、所定の糖濃度（例えば正常血糖値）以下のときの薬剤（例えばインスリン）のもれを十分に抑制でき、かつ、温度変化に対する耐性が高い糖応答性ゲルの開発が求められていた。そこで本願発明の一実施形態は、光重合反応により製造する糖応答性ゲルであって、糖濃度の変化に対する応答が正確で、かつ、温度変化に対する耐性を備えた糖応答性ゲル、およびこれを用いた薬剤送達デバイスを提供することを目的とする。 In Patent Documents 1 to 3, sugar-responsive gels are produced by thermal polymerization of monomers. Meanwhile, currently, in order to improve the mass production of sugar-responsive gels, production of gels by photopolymerization is being considered. In general, since the reaction mechanisms of thermal polymerization and photopolymerization are different, it is necessary to change the production conditions to apply photopolymerization, which is thought to affect the properties of the sugar-responsive gel. In addition, there has been a demand for the development of a sugar-responsive gel that responds more accurately to changes in sugar concentration, can sufficiently suppress leakage of drugs (e.g., insulin) when the sugar concentration is below a certain level (e.g., normal blood glucose level), and has high resistance to temperature changes. Therefore, one embodiment of the present invention aims to provide a sugar-responsive gel produced by photopolymerization, which responds accurately to changes in sugar concentration and has resistance to temperature changes, and a drug delivery device using the same.
　本実施形態の好ましい態様は下記のとおりである。 The preferred aspects of this embodiment are as follows:
　１．（Ａ）Ｎ－イソプロピルメタクリルアミド（ＮＩＰＭＡＡｍ）、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＡｍ）、Ｎ，Ｎ－ジメチルアクリルアミド（ＤＭＡＡｍ）、およびＮ，Ｎ－ジエチルアクリルアミド（ＤＥＡＡｍ）からなる群から選ばれる少なくとも一種を含むゲル化剤と；
　（Ｂ）下記一般式（１）：
Figure JPOXMLDOC01-appb-C000005
 ［式中、ＲはＨ又はＣＨ３であり、Ｆは独立に存在し、ｎが１、２、３又は４のいずれかであり、ｍは０又は１以上の整数である。］
で表されるフェニルボロン酸系単量体と；
　（Ｃ）下記一般式（２）：
Figure JPOXMLDOC01-appb-C000006
 ［式中、Ｒ１はＨ又はＣＨ３であり、ｍは０又は１以上の整数であり、Ｒ２はＯＨ、１以上の水酸基で置換された飽和若しくは不飽和のＣ１－６アルキル基、１以上の水酸基で置換された飽和若しくは不飽和のＣ３－１０シクロアルキル基、１以上の水酸基で置換されたＮＨ、Ｏ及びＳより選ばれる１～４個のヘテロ原子を含有するＣ３－１２複素環式基、１以上の水酸基で置換されたＣ６－１２アリール基、単糖基、又は多糖基である。］
で表されるヒドロキシル系単量体と；
（Ｄ）架橋剤と；
（Ｅ）光重合開始剤と；
を含む混合物の重合反応物を含み、
　（成分（Ａ）と成分（Ｂ）との合計）：成分（Ｃ）のモル比が、４．５：１～６．５：１の範囲内であり、かつ、
　成分（Ａ）、成分（Ｂ）、および成分（Ｃ）の合計に対し、（Ｄ）架橋剤の割合が１．５ｍｏｌ％以上４ｍｏｌ％以下である、糖応答性ゲル。 1. (A) a gelling agent comprising at least one selected from the group consisting of N-isopropyl methacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm);
(B) a compound represented by the following general formula (1):
Figure JPOXMLDOC01-appb-C000005
 [In the formula, R is H or CH3 , F is present independently, n is 1, 2, 3 or 4, and m is 0 or an integer of 1 or more.]
A phenylboronic acid monomer represented by the formula:
(C) a compound represented by the following general formula (2):
Figure JPOXMLDOC01-appb-C000006
 [In the formula, R 1 is H or CH 3 , m is 0 or an integer of 1 or more, and R 2 is OH, a saturated or unsaturated C 1-6 alkyl group substituted with one or more hydroxyl groups, a saturated or unsaturated C 3-10 cycloalkyl group substituted with one or more hydroxyl groups, a C 3-12 heterocyclic group containing 1 to 4 heteroatoms selected from NH, O and S substituted with one or more hydroxyl groups, a C 6-12 aryl group substituted with one or more hydroxyl groups, a monosaccharide group, or a polysaccharide group.]
and a hydroxyl monomer represented by the formula:
(D) a crosslinker;
(E) a photopolymerization initiator;
The polymerization reaction product of the mixture comprising:
The molar ratio of (the sum of components (A) and (B)):component (C) is within the range of 4.5:1 to 6.5:1, and
A sugar-responsive gel, in which the ratio of the crosslinker (D) is 1.5 mol % or more and 4 mol % or less with respect to the total of the components (A), (B), and (C).
　２．前記架橋剤が、Ｎ，Ｎ’－メチレンビスアクリルアミド（ＭＢＡＡｍ）を含む、上記項１に記載の糖応答性ゲル。 2. The sugar-responsive gel described in item 1 above, in which the crosslinking agent contains N,N'-methylenebisacrylamide (MBAAm).
　３．前記一般式（１）で表されるフェニルボロン酸系単量体が、４－（２－アクリルアミドエチルカルバモイル）－３－フルオロフェニルボロン酸（ＡｍＥＣＦＰＢＡ）を含む、上記項１または２に記載の糖応答性ゲル。 3. The sugar-responsive gel according to item 1 or 2 above, in which the phenylboronic acid monomer represented by the general formula (1) includes 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA).
　４．前記一般式（２）で表される単量体がＮ－ヒドロキシエチルアクリルアミド（ＮＨＥＡＡｍ）を含む、上記項１～３のいずれか一項に記載の糖応答性ゲル。 4. The sugar-responsive gel according to any one of items 1 to 3 above, wherein the monomer represented by the general formula (2) contains N-hydroxyethylacrylamide (NHEAAm).
　５．前記ゲル化剤が、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＡｍ）を含む、上記項１～４のいずれか一項に記載の糖応答性ゲル。 5. The sugar-responsive gel according to any one of items 1 to 4 above, wherein the gelling agent comprises N-isopropylacrylamide (NIPAAm).
　６．上記項１～５のいずれか一項に記載の糖応答性ゲルを含む、薬剤送達デバイス。 6. A drug delivery device comprising the sugar-responsive gel described in any one of paragraphs 1 to 5 above.
　７．体内埋込型、又はマイクロニードル型のデバイスである、上記項６記載の薬剤送達デバイス。 7. The drug delivery device described in paragraph 6 above, which is an implantable or microneedle type device.
　８．インスリンの送達に使用するためのデバイスである、上記項６または７に記載の薬剤送達デバイス。 8. A drug delivery device as described in paragraphs 6 or 7 above, which is a device for use in delivering insulin.
　９．（Ａ）Ｎ－イソプロピルメタクリルアミド（ＮＩＰＭＡＡｍ）、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＡｍ）、Ｎ，Ｎ－ジメチルアクリルアミド（ＤＭＡＡｍ）、およびＮ，Ｎ－ジエチルアクリルアミド（ＤＥＡＡｍ）からなる群から選ばれる少なくとも一種を含むゲル化剤と；
　（Ｂ）下記一般式（１）：
Figure JPOXMLDOC01-appb-C000007
 ［式中、ＲはＨ又はＣＨ３であり、Ｆは独立に存在し、ｎが１、２、３又は４のいずれかであり、ｍは０又は１以上の整数である。］
で表されるフェニルボロン酸系単量体と；
　（Ｃ）下記一般式（２）：
Figure JPOXMLDOC01-appb-C000008
 ［式中、Ｒ１はＨ又はＣＨ３であり、ｍは０又は１以上の整数であり、Ｒ２はＯＨ、１以上の水酸基で置換された飽和若しくは不飽和のＣ１－６アルキル基、１以上の水酸基で置換された飽和若しくは不飽和のＣ３－１０シクロアルキル基、１以上の水酸基で置換されたＮＨ、Ｏ及びＳより選ばれる１～４個のヘテロ原子を含有するＣ３－１２複素環式基、１以上の水酸基で置換されたＣ６－１２アリール基、単糖基、又は多糖基である。］
で表されるヒドロキシル系単量体と；
（Ｄ）架橋剤と；
（Ｅ）光重合開始剤と；
を含み、
　（成分（Ａ）と成分（Ｂ）との合計）：成分（Ｃ）のモル比が、４．５：１～６．５：１の範囲内であり、かつ、
　成分（Ａ）、成分（Ｂ）、および成分（Ｃ）の合計に対し、（Ｄ）架橋剤の割合が１．５ｍｏｌ％以上４ｍｏｌ％以下である混合物を調製する工程と、
　前記混合物に光を照射して重合反応させる工程と、
を含む、糖応答性ゲルの製造方法。 9. (A) a gelling agent comprising at least one selected from the group consisting of N-isopropyl methacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm);
(B) a compound represented by the following general formula (1):
Figure JPOXMLDOC01-appb-C000007
 [In the formula, R is H or CH3 , F is present independently, n is 1, 2, 3 or 4, and m is 0 or an integer of 1 or more.]
A phenylboronic acid monomer represented by the formula:
(C) a compound represented by the following general formula (2):
Figure JPOXMLDOC01-appb-C000008
 [In the formula, R 1 is H or CH 3 , m is 0 or an integer of 1 or more, and R 2 is OH, a saturated or unsaturated C 1-6 alkyl group substituted with one or more hydroxyl groups, a saturated or unsaturated C 3-10 cycloalkyl group substituted with one or more hydroxyl groups, a C 3-12 heterocyclic group containing 1 to 4 heteroatoms selected from NH, O and S substituted with one or more hydroxyl groups, a C 6-12 aryl group substituted with one or more hydroxyl groups, a monosaccharide group, or a polysaccharide group.]
and a hydroxyl monomer represented by the formula:
(D) a crosslinker;
(E) a photopolymerization initiator;
Including,
The molar ratio of (the sum of components (A) and (B)):component (C) is within the range of 4.5:1 to 6.5:1, and
A step of preparing a mixture in which the ratio of the crosslinking agent (D) is 1.5 mol % or more and 4 mol % or less with respect to the total of the components (A), (B), and (C);
a step of irradiating the mixture with light to cause a polymerization reaction;
The method for producing a sugar-responsive gel comprises:
　本実施形態によると、糖濃度の変化に対する応答性がより正確な糖応答性ゲルおよびこれを用いた薬剤送達デバイスを提供することができる。 According to this embodiment, it is possible to provide a sugar-responsive gel that is more responsive to changes in sugar concentration, and a drug delivery device using the same.
本発明の一実施形態によるマイクロニードルの側面図である。FIG. 1 is a side view of a microneedle according to one embodiment of the present invention. リザーバを有するマイクロニードルの一形態の断面図である。FIG. 1 is a cross-sectional view of one form of microneedle having a reservoir. リザーバを有するマイクロニードルの他の形態の断面図である。FIG. 13 is a cross-sectional view of another form of microneedle having a reservoir. リザーバを有するマイクロニードルのさらに他の形態の断面図である。FIG. 13 is a cross-sectional view of yet another form of microneedle having a reservoir. 図１に示すマイクロニードルの製造に用いられる型の一形態の断面図である。FIG. 2 is a cross-sectional view of one form of a mold used to manufacture the microneedle shown in FIG. 例１の結果を示す図である。FIG. 1 shows the results of Example 1. 例２の結果を示す図である。FIG. 1 shows the results of Example 2. 製造例３で製造したインスリンを内包するゲルタブレット１および５の写真である。1 is a photograph of insulin-containing gel tablets 1 and 5 produced in Production Example 3. 例３のグルコース負荷試験でゲルタブレットが埋め込まれたマウスの写真である。1 is a photograph of mice implanted with gel tablets in the glucose tolerance test of Example 3. 例３のグルコース負荷試験でゲルタブレットの埋め込み前後の血糖値の変化を示す図である。FIG. 1 shows the change in blood glucose level before and after embedding of a gel tablet in the glucose tolerance test of Example 3. 例３のグルコース負荷試験における血糖値の変化を示す図である。FIG. 1 shows changes in blood glucose levels in the glucose tolerance test of Example 3. 例３のグルコース負荷試験における血漿インスリン濃度の変化を示す図である。FIG. 1 shows the change in plasma insulin concentration in the glucose tolerance test of Example 3.
＜糖応答性ゲル＞
　本実施形態の糖応答性ゲル（「ゲル組成物」、「ゲル」とも記載）は、以下に記載するような、フェニルボロン酸系単量体がグルコース濃度に依存して構造を変化させるメカニズムを利用するものである。 <Sugar-responsive gel>
The sugar-responsive gel of this embodiment (also referred to as a "gel composition" or "gel") utilizes a mechanism in which a phenylboronic acid monomer changes its structure depending on the glucose concentration, as described below.
　水中で解離したフェニルボロン酸（ＰＢＡ）は糖分子と可逆的に結合し、上記の平衡状態を保っている。グルコース濃度が高くなると、ボロン酸にグルコースが結合してゲルの体積が膨張するが、グルコース濃度が低い場合には収縮する。薬剤送達用デバイスにゲルを充填した状態では、血液と接触したゲル界面でこの反応が生じ、界面でのみゲルが収縮して本発明者らが「スキン層」と呼ぶ脱水収縮層を生じる。本発明の一実施態様に係るインスリン送達デバイスはこの性質をインスリンの放出制御のために利用するものである。 Phenylboronic acid (PBA) dissociated in water reversibly binds to sugar molecules, maintaining the above-mentioned equilibrium state. When the glucose concentration increases, glucose binds to the boronic acid and the gel expands in volume, but when the glucose concentration is low, the gel contracts. When the gel is filled in a drug delivery device, this reaction occurs at the gel interface in contact with blood, and the gel contracts only at the interface, resulting in a dehydrated contraction layer that the inventors call the "skin layer." An insulin delivery device according to one embodiment of the present invention utilizes this property to control the release of insulin.
　本実施形態の糖応答性ゲルは、
　（Ａ）Ｎ－イソプロピルメタクリルアミド（ＮＩＰＭＡＡｍ）、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＡｍ）、Ｎ，Ｎ－ジメチルアクリルアミド（ＤＭＡＡｍ）、およびＮ，Ｎ－ジエチルアクリルアミド（ＤＥＡＡｍ）からなる群から選ばれる少なくとも一種を含むゲル化剤と；
　（Ｂ）下記一般式（１）：
Figure JPOXMLDOC01-appb-C000010
 ［式中、ＲはＨ又はＣＨ３であり、Ｆは独立に存在し、ｎが１、２、３又は４のいずれかであり、ｍは０又は１以上の整数である。］
で表されるフェニルボロン酸系単量体と；
　（Ｃ）下記一般式（２）：
Figure JPOXMLDOC01-appb-C000011
 ［式中、Ｒ１はＨ又はＣＨ３であり、ｍは０又は１以上の整数であり、Ｒ２はＯＨ、１以上の水酸基で置換された飽和若しくは不飽和のＣ１－６アルキル基、１以上の水酸基で置換された飽和若しくは不飽和のＣ３－１０シクロアルキル基、１以上の水酸基で置換されたＮＨ、Ｏ及びＳより選ばれる１～４個のヘテロ原子を含有するＣ３－１２複素環式基、１以上の水酸基で置換されたＣ６－１２アリール基、単糖基、又は多糖基である。］
で表されるヒドロキシル系単量体と；
　（Ｄ）架橋剤と；
　（Ｅ）光重合開始剤と；
を含む混合物の重合反応物を含み、
　（成分（Ａ）と成分（Ｂ）との合計）：成分（Ｃ）のモル比が、４．５：１～６．５：１の範囲内であり、かつ、
　成分（Ａ）、成分（Ｂ）、および成分（Ｃ）の合計に対し、架橋剤の割合が１．５ｍｏｌ％以上４ｍｏｌ％以下である。本実施形態の糖応答性ゲルは、成分（Ａ）～成分（Ｄ）に基づく単量体ユニットを含む共重合体である。なお、本明細書において「単量体ユニット」という用語は、単量体に由来する（共）重合体中の構造単位を意味し、「単量体」の文言を「単量体ユニット」の意味で使用することもある。以下、本発明を詳細に説明する。 The sugar-responsive gel of this embodiment is
(A) a gelling agent comprising at least one selected from the group consisting of N-isopropylmethacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm);
(B) a compound represented by the following general formula (1):
Figure JPOXMLDOC01-appb-C000010
 [In the formula, R is H or CH3 , F is present independently, n is 1, 2, 3 or 4, and m is 0 or an integer of 1 or more.]
A phenylboronic acid monomer represented by the formula:
(C) a compound represented by the following general formula (2):
Figure JPOXMLDOC01-appb-C000011
 [In the formula, R 1 is H or CH 3 , m is 0 or an integer of 1 or more, and R 2 is OH, a saturated or unsaturated C 1-6 alkyl group substituted with one or more hydroxyl groups, a saturated or unsaturated C 3-10 cycloalkyl group substituted with one or more hydroxyl groups, a C 3-12 heterocyclic group containing 1 to 4 heteroatoms selected from NH, O and S substituted with one or more hydroxyl groups, a C 6-12 aryl group substituted with one or more hydroxyl groups, a monosaccharide group, or a polysaccharide group.]
and a hydroxyl monomer represented by the formula:
(D) a crosslinker;
(E) a photopolymerization initiator;
The polymerization reaction product of the mixture comprising:
The molar ratio of (the sum of components (A) and (B)):component (C) is within the range of 4.5:1 to 6.5:1, and
The ratio of the crosslinker to the total of components (A), (B), and (C) is 1.5 mol % or more and 4 mol % or less. The sugar-responsive gel of this embodiment is a copolymer containing monomer units based on components (A) to (D). In this specification, the term "monomer unit" means a structural unit in a (co)polymer derived from a monomer, and the word "monomer" is sometimes used to mean "monomer unit". The present invention will be described in detail below.
＜（Ａ）ゲル化剤＞
　本実施形態の糖応答性ゲルの調製に使用する混合物は、（Ａ）Ｎ－イソプロピルメタクリルアミド（ＮＩＰＭＡＡｍ）、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＡｍ）、Ｎ，Ｎ－ジメチルアクリルアミド（ＤＭＡＡｍ）、およびＮ，Ｎ－ジエチルアクリルアミド（ＤＥＡＡｍ）からなる群から選ばれる少なくとも一種を含むゲル化剤（「成分（Ａ）」とも記載）を含む。ゲル化剤は、糖応答性ゲルの主鎖を形成する。 <(A) Gelling Agent>
The mixture used to prepare the sugar-responsive gel of this embodiment contains (A) a gelling agent (also referred to as "component (A)") containing at least one selected from the group consisting of N-isopropylmethacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm). The gelling agent forms the main chain of the sugar-responsive gel.
　ゲル化剤としては、生体適合性を有し、かつゲル化し得る生体適合性材料であればよく、例えば生体適合性のあるアクリルアミド系化合物（アクリルアミド基またはメタクリルアミド基を１個有する化合物）が挙げられる。ゲル化剤としては、Ｎ－イソプロピルメタクリルアミド（ＮＩＰＭＡＡｍ）、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＡｍ）、Ｎ，Ｎ－ジメチルアクリルアミド（ＤＭＡＡｍ）、およびＮ，Ｎ－ジエチルアクリルアミド（ＤＥＡＡｍ）からなる群から選ばれる少なくとも一種の化合物を含むのが好ましく、二種以上を含んでもよい。 The gelling agent may be any biocompatible material that is biocompatible and capable of gelling, such as a biocompatible acrylamide compound (a compound having one acrylamide or methacrylamide group). The gelling agent preferably contains at least one compound selected from the group consisting of N-isopropylmethacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm), and may contain two or more types.
　ゲル化剤（成分（Ａ））は、成分（Ａ）～成分（Ｅ）の合計に対して、例えば、５０ｍｏｌ％以上、６０ｍｏｌ％以上、７０ｍｏｌ％以上、又は８０ｍｏｌ％以上の割合で含まれることができる。また、ゲル化剤は、成分（Ａ）～成分（Ｅ）の合計に対して、例えば、９０ｍｏｌ％以下、８０ｍｏｌ％以下、７０ｍｏｌ％以下、６０ｍｏｌ％以下の割合で含まれることができる。一実施形態において、成分（Ａ）～成分（Ｅ）の合計に対するゲル化剤の濃度は、好ましくは５０ｍｏｌ％以上、より好ましくは６０ｍｏｌ％以上、さらに好ましくは６５ｍｏｌ％以上であり、また、好ましくは９０ｍｏｌ％以下、より好ましくは８０ｍｏｌ％以下である。 The gelling agent (component (A)) can be contained in a proportion of, for example, 50 mol% or more, 60 mol% or more, 70 mol% or more, or 80 mol% or more relative to the total of components (A) to (E). The gelling agent can be contained in a proportion of, for example, 90 mol% or less, 80 mol% or less, 70 mol% or less, or 60 mol% or less relative to the total of components (A) to (E). In one embodiment, the concentration of the gelling agent relative to the total of components (A) to (E) is preferably 50 mol% or more, more preferably 60 mol% or more, even more preferably 65 mol% or more, and is preferably 90 mol% or less, more preferably 80 mol% or less.
＜（Ｂ）フェニルボロン酸系単量体＞
　本実施形態の糖応答性ゲルの調製に使用する混合物は、（Ｂ）下記一般式（１）：
Figure JPOXMLDOC01-appb-C000012
 ［式中、ＲはＨ又はＣＨ３であり、Ｆは独立に存在し、ｎが１、２、３又は４のいずれかであり、ｍは０又は１以上の整数である。］
で表されるフェニルボロン酸系単量体（「成分（Ｂ）」、単に「フェニルボロン酸系単量体」、「フェニルボロン酸」とも記載）を含む。 <(B) Phenylboronic Acid Monomer>
The mixture used to prepare the sugar-responsive gel of this embodiment is (B) a compound represented by the following general formula (1):
Figure JPOXMLDOC01-appb-C000012
 [In the formula, R is H or CH3 , F is present independently, n is 1, 2, 3 or 4, and m is 0 or an integer of 1 or more.]
("Component (B)", also simply referred to as "phenylboronic acid monomer" or "phenylboronic acid").
　上記のフェニルボロン酸系単量体は、フェニル環上の水素が、１～４個のフッ素で置換されたフッ素化フェニルボロン酸基を有し、当該フェニル環にアミド基の炭素が結合した構造を有する。上記構造を有するフェニルボロン酸系単量体は、高い親水性を有しており、またフェニル環がフッ素化されていることにより、ｐＫａを生体レベルの７．４以下に設定し得る。さらに、このフェニルボロン酸系単量体は、生体環境下での糖認識能を獲得するのみならず、不飽和結合により成分（Ａ）のゲル化剤、成分（Ｃ）のヒドロキシル系単量体、および成分（Ｄ）の架橋剤との共重合が可能となり、グルコース濃度に依存して相変化を生じるゲルとなり得る。 The above phenylboronic acid monomer has a fluorinated phenylboronic acid group in which the hydrogen on the phenyl ring is replaced with one to four fluorines, and has a structure in which the carbon of the amide group is bonded to the phenyl ring. The phenylboronic acid monomer having the above structure has high hydrophilicity, and the pKa can be set to the biological level of 7.4 or less because the phenyl ring is fluorinated. Furthermore, this phenylboronic acid monomer not only acquires sugar recognition ability in a biological environment, but also allows copolymerization with the gelling agent of component (A), the hydroxyl monomer of component (C), and the crosslinking agent of component (D) due to the unsaturated bond, and can become a gel that undergoes a phase change depending on the glucose concentration.
　フェニルボロン酸系単量体において、フェニル環上の１つの水素がフッ素で置換されている場合、Ｆ及びＢ（ＯＨ）２の導入箇所は、オルト、メタ、パラのいずれであってもよい。 In the phenylboronic acid monomer, when one hydrogen atom on the phenyl ring is replaced by fluorine, the introduction site of F and B(OH) 2 may be any of ortho, meta, and para.
　一般に、ｍを１以上としたときのフェニルボロン酸系単量体は、ｍを０としたときのフェニルボロン酸系単量体に比べて、ｐＫａを低くすることができる。ｍの上限は特に限定されないが、例えば２０以下、好ましくは１０以下、さらに好ましくは４以下である。 In general, a phenylboronic acid monomer in which m is 1 or more can have a lower pKa than a phenylboronic acid monomer in which m is 0. There is no particular upper limit to m, but it is, for example, 20 or less, preferably 10 or less, and more preferably 4 or less.
　上記のフェニルボロン酸系単量体の一例としては、Ｒが水素であり、ｎが１、ｍが２であるフェニルボロン酸系単量体があり、これはフェニルボロン酸系単量体として特に好ましい４－（２－アクリルアミドエチルカルバモイル）－３－フルオロフェニルボロン酸（4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid、ＡｍＥＣＦＰＢＡ）である。フェニルボロン酸系単量体は、一種の化合物であってもよいし、二種以上の化合物の組み合わせであってもよい。 One example of the above phenylboronic acid monomer is a phenylboronic acid monomer in which R is hydrogen, n is 1, and m is 2, which is 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA), which is a particularly preferred phenylboronic acid monomer. The phenylboronic acid monomer may be a single compound or a combination of two or more compounds.
　一般式（１）で表されるフェニルボロン酸系単量体（成分（Ｂ））は、成分（Ａ）～成分（Ｅ）の合計に対して、例えば、５ｍｏｌ％以上、１０ｍｏｌ％以上、１５ｍｏｌ％以上の割合で含まれることができる。また、成分（Ａ）～成分（Ｅ）の合計に対して、一般式（１）で表されるフェニルボロン酸系単量体は、例えば、３５ｍｏｌ％以下、３０ｍｏｌ％以下、２５ｍｏｌ％以下、又は２０ｍｏｌ％以下の割合で含まれることができる。一実施形態において、成分（Ａ）～成分（Ｅ）の合計に対するフェニルボロン酸系単量体の濃度は、例えば、好ましくは５ｍｏｌ％以上、より好ましくは１０ｍｏｌ％以上であり、また、好ましくは３０ｍｏｌ％以下、より好ましくは２５ｍｏｌ％以下である。 The phenylboronic acid monomer represented by general formula (1) (component (B)) can be contained in a ratio of, for example, 5 mol% or more, 10 mol% or more, or 15 mol% or more relative to the total of components (A) to (E). Furthermore, the phenylboronic acid monomer represented by general formula (1) can be contained in a ratio of, for example, 35 mol% or less, 30 mol% or less, 25 mol% or less, or 20 mol% or less relative to the total of components (A) to (E). In one embodiment, the concentration of the phenylboronic acid monomer relative to the total of components (A) to (E) is, for example, preferably 5 mol% or more, more preferably 10 mol% or more, and also preferably 30 mol% or less, more preferably 25 mol% or less.
＜（Ｃ）ヒドロキシル系単量体＞
　本実施形態の糖応答性ゲルの調製に使用する混合物は、（Ｃ）下記一般式（２）： <(C) Hydroxyl-Based Monomer>
The mixture used to prepare the sugar-responsive gel of this embodiment is a mixture represented by the following general formula (2):
Figure JPOXMLDOC01-appb-C000013
 ［式中、Ｒ１はＨ又はＣＨ３であり、ｍは０又は１以上の整数であり、Ｒ２はＯＨ、１以上の水酸基で置換された飽和若しくは不飽和のＣ１－６アルキル基、１以上の水酸基で置換された飽和若しくは不飽和のＣ３－１０シクロアルキル基、１以上の水酸基で置換されたＮＨ、Ｏ及びＳより選ばれる１～４個のヘテロ原子を含有するＣ３－１２複素環式基、１以上の水酸基で置換されたＣ６－１２アリール基、単糖基、又は多糖基である。］
で表されるヒドロキシル系単量体（「成分（Ｃ）」、単に「ヒドロキシル系単量体」とも記載）を含む。ヒドロキシル系単量体を用いることにより、温度変化に対する耐性が高く、特に低温において薬剤を多量に放出してしまうのを抑制できるゲルを形成できる。
Figure JPOXMLDOC01-appb-C000013
 [In the formula, R 1 is H or CH 3 , m is 0 or an integer of 1 or more, and R 2 is OH, a saturated or unsaturated C 1-6 alkyl group substituted with one or more hydroxyl groups, a saturated or unsaturated C 3-10 cycloalkyl group substituted with one or more hydroxyl groups, a C 3-12 heterocyclic group containing 1 to 4 heteroatoms selected from NH, O and S substituted with one or more hydroxyl groups, a C 6-12 aryl group substituted with one or more hydroxyl groups, a monosaccharide group, or a polysaccharide group.]
The hydroxyl monomer ("component (C)", also simply referred to as "hydroxyl monomer") is represented by the following formula: By using the hydroxyl monomer, it is possible to form a gel that has high resistance to temperature changes and can suppress the release of a large amount of a drug, particularly at low temperatures.
　上記一般式（２）の単量体は、分子内に水酸基を有している。特定の理論に拘束するものではないが、この水酸基は、ゲルの親水性を高めて、ボロン酸による疎水性を相殺するとともに、ゲル中のボロン酸に作用して、ゲルの過度な膨潤を防ぐ効果を有すると考えられる。ｍの上限は特に限定されないが、例えば２０以下、好ましくは１０以下、さらに好ましくは４以下である。 The monomer of the above general formula (2) has a hydroxyl group in the molecule. Without being bound to a particular theory, it is believed that this hydroxyl group increases the hydrophilicity of the gel, offsetting the hydrophobicity of the boronic acid, and acts on the boronic acid in the gel to prevent excessive swelling of the gel. There is no particular upper limit for m, but it is, for example, 20 or less, preferably 10 or less, and more preferably 4 or less.
　上記のヒドロキシル系単量体の一例としては、Ｒ１が水素であり、ｍが１であり、Ｒ２がＯＨである単量体が挙げられ、これはヒドロキシル系単量体として特に好ましいＮ－ヒドロキシエチルアクリルアミド（N-(Hydroxyethyl)acrylamide、ＮＨＥＡＡｍ）である。特に、側鎖をメチルの代わりにエチルとすることで、側鎖の回転自由度を高め、分子間（ボロン酸側鎖との）架橋反応の効率を格段に向上させる効果がある。そのため、ＮＨＥＡＡｍとすることにより、グルコース濃度に依存して相変化を生じる最適なゲルとなり得る。なお、他のヒドロキシル系単量体の例においては、Ｒ２は例えば、カテコール基あるいはグリコリル基等の糖誘導体であってもよい。単糖は例えばグルコースでありうる。ヒドロキシル系単量体は、一種の化合物であってもよいし、二種以上の化合物の組み合わせであってもよい。 An example of the above hydroxyl monomer is a monomer in which R 1 is hydrogen, m is 1, and R 2 is OH, which is N-(hydroxyethyl)acrylamide (NHEAAm), which is particularly preferred as a hydroxyl monomer. In particular, by using ethyl instead of methyl as the side chain, the rotational freedom of the side chain is increased, and the efficiency of the intermolecular crosslinking reaction (with the boronic acid side chain) is significantly improved. Therefore, by using NHEAAm, an optimal gel that undergoes a phase change depending on the glucose concentration can be obtained. In addition, in other examples of hydroxyl monomers, R 2 may be, for example, a sugar derivative such as a catechol group or a glycolyl group. The monosaccharide may be, for example, glucose. The hydroxyl monomer may be a single compound or a combination of two or more compounds.
　一般式（２）で表されるヒドロキシル系単量体（成分（Ｃ））は、成分（Ａ）～成分（Ｅ）の合計に対して、例えば、８ｍｏｌ％以上、１０ｍｏｌ％以上、１２ｍｏｌ％以上、１３ｍｏｌ％以上、１５ｍｏｌ％以上の割合で含まれることができる。また、成分（Ａ）～成分（Ｅ）の合計に対する一般式（２）で表されるヒドロキシル系単量体（成分（Ｃ））の濃度は、例えば、２１ｍｏｌ％以下、２０ｍｏｌ％以下、１８ｍｏｌ％以下、１７ｍｏｌ％以下、１６ｍｏｌ％以下、１５ｍｏｌ％以下、１４ｍｏｌ％以下の割合で含まれることができる。濃度範囲は、上記の上限と下限の任意の組み合わせにより特定されうる。成分（Ａ）～成分（Ｅ）の合計に対する成分（Ｃ）の好ましい濃度範囲としては、例えば、好ましくは１１ｍｏｌ％以上、より好ましくは１２ｍｏｌ％以上、さらに好ましくは１３ｍｏｌ％以上であり、また、好ましくは２０ｍｏｌ％以下、より好ましくは１８ｍｏｌ％以下、さらに好ましくは１６ｍｏｌ％以下、よりさらに好ましくは１５ｍｏｌ％以下である。 The hydroxyl monomer represented by general formula (2) (component (C)) can be contained in an amount, for example, of 8 mol% or more, 10 mol% or more, 12 mol% or more, 13 mol% or more, or 15 mol% or more relative to the total of components (A) to (E). The concentration of the hydroxyl monomer represented by general formula (2) (component (C)) relative to the total of components (A) to (E) can be, for example, 21 mol% or less, 20 mol% or less, 18 mol% or less, 17 mol% or less, 16 mol% or less, 15 mol% or less, or 14 mol% or less. The concentration range can be specified by any combination of the upper and lower limits above. The preferred concentration range of component (C) relative to the total of components (A) to (E) is, for example, preferably 11 mol% or more, more preferably 12 mol% or more, even more preferably 13 mol% or more, and preferably 20 mol% or less, more preferably 18 mol% or less, even more preferably 16 mol% or less, and even more preferably 15 mol% or less.
＜（Ｄ）架橋剤＞
　本実施形態の糖応答性ゲルの調製に使用する混合物は、（Ｄ）架橋剤（「成分（Ｄ）」とも記載）を含む。架橋剤としては、生体適合性を有し、モノマーを架橋できる物質であればよく、好ましくは分子内にアクリルアミド基またはメタクリルアミド基を少なくとも２つ有する化合物が挙げられる。架橋剤としては、例えばＮ，Ｎ’－メチレンビスアクリルアミド（ＭＢＡＡｍ）、エチレングリコールジメタクリレート（ＥＧＤＭＡ）、Ｎ，Ｎ’－メチレンビスメタクリルアミド（ＭＢＭＡＡｍ）等が挙げられる。架橋剤は、一種の化合物であってもよいし、二種以上の化合物の組み合わせであってもよい。 <(D) Crosslinking Agent>
The mixture used to prepare the sugar-responsive gel of this embodiment contains (D) a crosslinker (also referred to as "component (D)"). The crosslinker may be any substance that is biocompatible and capable of crosslinking monomers, and preferably includes a compound having at least two acrylamide or methacrylamide groups in the molecule. Examples of the crosslinker include N,N'-methylenebisacrylamide (MBAAm), ethylene glycol dimethacrylate (EGDMA), and N,N'-methylenebismethacrylamide (MBMAAm). The crosslinker may be a single compound or a combination of two or more compounds.
　架橋剤（成分（Ｄ））は、成分（Ａ）～成分（Ｅ）の合計に対して、例えば、１ｍｏｌ％以上、１．５ｍｏｌ％以上、２ｍｏｌ％以上、２．３ｍｏｌ％以上、２．５ｍｏｌ％以上の割合で含まれることができる。また、成分（Ｄ）は、成分（Ａ）～成分（Ｅ）の合計に対して、５ｍｏｌ％以下、４．５ｍｏｌ％以下、４ｍｏｌ％以下、３．５ｍｏｌ％以下、３ｍｏｌ％以下、２．５ｍｏｌ％以下の割合で含まれることができる。濃度範囲は、上記の上限と下限が組み合わされる。 The crosslinking agent (component (D)) can be contained in an amount, for example, of 1 mol% or more, 1.5 mol% or more, 2 mol% or more, 2.3 mol% or more, or 2.5 mol% or more relative to the total of components (A) to (E). Also, component (D) can be contained in an amount, for example, of 5 mol% or less, 4.5 mol% or less, 4 mol% or less, 3.5 mol% or less, 3 mol% or less, or 2.5 mol% or less relative to the total of components (A) to (E). The concentration range is a combination of the above upper and lower limits.
＜（Ｅ）光重合開始剤＞
　本実施形態の糖応答性ゲルの調製に使用する混合物は、（Ｅ）光重合開始剤（「成分（Ｅ）とも記載）を含む。光重合開始剤は、紫外線等の活性光線の照射により、ラジカル、酸、塩基等を発生するものであり、モノマーの種類等に応じて適宜選択でき、光ラジカル重合開始剤を用いることが好ましい。 <(E) Photopolymerization initiator>
The mixture used to prepare the sugar-responsive gel of this embodiment contains (E) a photopolymerization initiator (also referred to as "component (E)"). The photopolymerization initiator generates radicals, acids, bases, etc. when irradiated with active light such as ultraviolet rays, and can be appropriately selected depending on the type of monomer, etc., and it is preferable to use a photoradical polymerization initiator.
　光ラジカル重合開始剤としては、波長４０５ｎｍよりも短波長の紫外線に対して感度を有するものが好ましく、光源から発せられるエネルギーを十分に活用でき、生産性に優れる観点から、極大吸収波長が３００ｎｍ～４００ｎｍであると好ましく、３００ｎｍ～３８０ｎｍであるとより好ましい。光ラジカル重合開始剤としては、特に限定はされないが、例えば、アルキルフェノン系ラジカル重合開始剤、アシルフォスフィンオキサイド系ラジカル重合開始剤、オキシムエステル系ラジカル重合開始剤等が挙げられる。これら光重合開始剤は、単独で用いてもよく、２種以上を組み合わせて用いてもよい。 The photo-radical polymerization initiator is preferably one that is sensitive to ultraviolet light with a wavelength shorter than 405 nm, and from the viewpoint of being able to fully utilize the energy emitted from the light source and having excellent productivity, it is preferable that the maximum absorption wavelength is 300 nm to 400 nm, and more preferably 300 nm to 380 nm. The photo-radical polymerization initiator is not particularly limited, but examples include alkylphenone radical polymerization initiators, acylphosphine oxide radical polymerization initiators, and oxime ester radical polymerization initiators. These photo-polymerization initiators may be used alone or in combination of two or more types.
　アルキルフェノン系光重合開始剤としては、例えば、２，２－ジメトキシ－１，２－ジフェニルエタン－１－オン（ＩＧＭ　Ｒｅｓｉｎｓ社、Ｏｍｎｉｒａｄ　６５１）、１－ヒドロキシ－シクロヘキシル－フェニル－ケトン（ＩＧＭ　Ｒｅｓｉｎｓ社、Ｏｍｎｉｒａｄ　１８４）、２－ヒドロキシ－２－メチル－１－フェニル－プロパン－１－オン（ＩＧＭ　Ｒｅｓｉｎｓ社、Ｏｍｎｉｒａｄ　１１７３）、１－［４－（２－ヒドロキシエトキシ）－フェニル］－２－ヒドロキシ－２－メチル－１－プロパン－１－オン、２－ヒロドキシ－１－｛４－［４－（２－ヒドロキシ－２－メチル－プロピオニル）－ベンジル］フェニル｝－２－メチル－プロパン－１－オン（ＩＧＭ　Ｒｅｓｉｎｓ社、Ｏｍｎｉｒａｄ　１２７）、２－メチル－１－（４－メチルチオフェニル）－２－モルフォリノプロパン－１－オン（ＩＧＭ　Ｒｅｓｉｎｓ社、Ｏｍｎｉｒａｄ　９０７）、２－ベンジル－２－ジメチルアミノ－１－（４－モルフォリノフェニル）－ブタノン－１、２－（ジメチルアミノ）－２－［（４－メチルフェニル）メチル］－１－［４－（４－モルホリニル）フェニル］－１－ブタノン（ＩＧＭ　Ｒｅｓｉｎｓ社、Ｏｍｎｉｒａｄ　３７９ＥＧ）などが挙げられる。 Examples of alkylphenone photopolymerization initiators include 2,2-dimethoxy-1,2-diphenylethan-1-one (IGM Resins, Omnirad 651), 1-hydroxy-cyclohexyl-phenyl-ketone (IGM Resins, Omnirad 184), 2-hydroxy-2-methyl-1-phenyl-propan-1-one (IGM Resins, Omnirad 1173), 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propan-1-one, 2-hydroxy-1-{4-[4-(2-hydroxy-2- 2-methyl-1-(4-methylthiophenyl)-2-morpholinopropan-1-one (IGM Resins, Omnirad 907), 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-butanone-1, 2-(dimethylamino)-2-[(4-methylphenyl)methyl]-1-[4-(4-morpholinyl)phenyl]-1-butanone (IGM Resins, Omnirad 379EG), etc.
　アシルフォスフィンオキサイド系光重合開始剤としては、例えば、２，４，６－トリメチルベンゾイル－ジフェニル－フォスフィンオキサイド（ＩＧＭ　Ｒｅｓｉｎｓ社、Ｏｍｎｉｒａｄ　ＴＰＯ　Ｈ）、ビス（２，４，６－トリメチルベンゾイル）－フェニルフォスフィンオキサイド（ＩＧＭ　Ｒｅｓｉｎｓ社、Ｏｍｎｉｒａｄ　８１９）が挙げられる。 Examples of acylphosphine oxide photopolymerization initiators include 2,4,6-trimethylbenzoyl-diphenyl-phosphine oxide (IGM Resins, Omnirad TPO H) and bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (IGM Resins, Omnirad 819).
　オキシムエステル系ラジカル重合開始剤としては、１－［４－（フェニルチオ）フェニル］－１，２－オクタンジオン－２－（Ｏ－ベンゾイルオキシム）（商品名：ＯｍｎｉｒａｄＯＸＥ－０１、ＩＧＭ　Ｒｅｓｉｎｓ社製）等が挙げられる。 Examples of oxime ester radical polymerization initiators include 1-[4-(phenylthio)phenyl]-1,2-octanedione-2-(O-benzoyloxime) (product name: OmniradOXE-01, manufactured by IGM Resins).
　光重合開始剤（成分（Ｅ））の含有量は、特に限定はされないが、成分（Ａ）～成分（Ｅ）の合計に対して、例えば、好ましくは１ｍｏｌ％以上、より好ましくは２ｍｏｌ％以上であり、また、好ましくは１１ｍｏｌ％以下、より好ましくは５ｍｏｌ％以下である。また、重合反応を溶媒中で行う場合は、光重合開始剤の濃度は、例えば、好ましくは１．３（ｗ／ｖ）％以上、より好ましくは１．６（ｗ／ｖ）％以上、さらに好ましくは３．２（ｗ／ｖ）％以上であり、また、好ましくは１５．０（ｗ／ｖ）％以下、より好ましくは１０（ｗ／ｖ）％以下、さらに好ましくは７（ｗ／ｖ）％以下である。光重合開始剤の含有量が少なすぎると重合が不十分になってしまう場合がある。一方、光重合開始剤の含有量が多すぎるとゲルが不均一化し脆くなってしまう場合がある。 The content of the photopolymerization initiator (component (E)) is not particularly limited, but is, for example, preferably 1 mol% or more, more preferably 2 mol% or more, and also preferably 11 mol% or less, more preferably 5 mol% or less, based on the total of components (A) to (E). When the polymerization reaction is carried out in a solvent, the concentration of the photopolymerization initiator is, for example, preferably 1.3 (w/v)% or more, more preferably 1.6 (w/v)% or more, even more preferably 3.2 (w/v)% or more, and also preferably 15.0 (w/v)% or less, more preferably 10 (w/v)% or less, even more preferably 7 (w/v)% or less. If the content of the photopolymerization initiator is too low, polymerization may be insufficient. On the other hand, if the content of the photopolymerization initiator is too high, the gel may become non-uniform and brittle.
　糖応答性ゲルの好ましい一実施形態として、例えば、ゲル化剤（主鎖）としてＮ－イソプロピルメタクリルアミド（ＮＩＰＭＡＡｍ）、フェニルボロン酸系単量体として４－（２－アクリルアミドエチルカルバモイル）－３－フルオロフェニルボロン酸（ＡｍＥＣＦＰＢＡ）、ヒドロキシル系単量体としてＮ－ヒドロキシエチルアクリルアミド（ＨＥＡＡｍ）、架橋剤としてＮ，Ｎ’－メチレンビスアクリルアミド（ＭＢＡＡｍ）、光重合開始剤として２，２－ジメトキシ－１，２－ジフェニルエタン－１－オンを、所定の仕込みモル比で混合した混合物の重合物が挙げられる。本実施形態の糖応答性ゲルのより好ましい態様として、例えば、（ＮＩＰＭＡＡｍ／ＡｍＥＣＦＰＢＡ／ＨＥＡＡｍ／ＭＢＡＡｍ／２，２－ジメトキシ－１，２－ジフェニルエタン－１－オン）の仕込みモル比を６５～７０／１０～１５／１０～１５／１～５／１～５に調整した混合物の重合物が挙げられる。一例として６８．６６／１２．１１／１３．４６／２．８／２．９４に調整するのが好ましい。 A preferred embodiment of the sugar-responsive gel is, for example, a polymer of a mixture of N-isopropylmethacrylamide (NIPMAAm) as a gelling agent (main chain), 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA) as a phenylboronic acid monomer, N-hydroxyethylacrylamide (HEAAm) as a hydroxyl monomer, N,N'-methylenebisacrylamide (MBAAm) as a crosslinking agent, and 2,2-dimethoxy-1,2-diphenylethan-1-one as a photopolymerization initiator, mixed in a predetermined molar ratio. A more preferred embodiment of the sugar-responsive gel of this embodiment is, for example, a polymer of a mixture in which the molar ratio of (NIPMAAm/AmECFPBA/HEAAm/MBAAm/2,2-dimethoxy-1,2-diphenylethan-1-one) is adjusted to 65-70/10-15/10-15/1-5/1-5. As an example, it is preferable to adjust it to 68.66/12.11/13.46/2.8/2.94.
　本発明の発明者らは、光重合反応により作製する糖応答性ゲルの組成について詳細に検討した。その結果、（成分（Ａ）と成分（Ｂ）の合計）：成分（Ｃ）のモル比を所定の範囲内にし、かつ、成分（Ｄ）の架橋剤の濃度を所定の範囲内にする（すなわち架橋密度を所定の範囲内にする）ことにより、温度変化がある場合でも、糖濃度の変化に対する応答性が正確で、かつ、糖濃度が正常値以下のときは薬剤の放出（もれ）の抑制に優れるゲルが得られることを見出した。通常、ヒトを含む哺乳動物の体温はほぼ一定に保たれているが、例えば、薬剤送達デバイスによる治療を開始するにあたって、患者に麻酔を行った後や、体内に薬剤送達デバイスを装着した直後などに、患者の体温が一時的に低下する場合がある。このような場合でも本実施形態の糖応答性ゲルは、糖濃度の変化に対する応答性が正確で、かつ、糖濃度が正常値以下のときは薬剤の放出（もれ）の抑制に優れるものである。 The inventors of the present invention have conducted detailed studies on the composition of the sugar-responsive gel produced by photopolymerization. As a result, they have found that by setting the molar ratio of (the sum of components (A) and (B)):component (C) within a predetermined range and setting the concentration of the crosslinking agent of component (D) within a predetermined range (i.e., setting the crosslinking density within a predetermined range), a gel can be obtained that is accurate in response to changes in sugar concentration even when there is a temperature change, and is excellent in suppressing drug release (leakage) when the sugar concentration is below the normal value. Normally, the body temperature of mammals, including humans, is kept almost constant, but for example, when starting treatment with a drug delivery device, the patient's body temperature may temporarily drop after anesthetizing the patient or immediately after the drug delivery device is attached to the patient's body. Even in such cases, the sugar-responsive gel of this embodiment is accurate in response to changes in sugar concentration and is excellent in suppressing drug release (leakage) when the sugar concentration is below the normal value.
　本実施形態の糖応答性ゲルを調製するための混合物は、（成分（Ａ）のゲル化剤と成分（Ｂ）のフェニルボロン酸系単量体との合計）：成分（Ｃ）のヒドロキシル系単量体のモル比（「（Ａ＋Ｂ）：Ｃのモル比」とも記載）が、４．５：１～６．５：１であるのが好ましく、４．８：１～６．３：１であるのがより好ましく、５．０：１～６．３：１であるのがさらに好ましく、５．５：１～６．３：１であるのがよりさらに好ましい。成分（Ａ）と成分（Ｂ）との合計量が成分（Ｃ）の量に対して小さすぎると、糖濃度が正常値以下のときにも薬剤が放出されてしまったり、糖濃度の変化に正確に応答できなかったりする場合がある。成分（Ａ）と成分（Ｂ）との合計量が成分（Ｃ）の量に対して大きすぎると、グルコース濃度が高いときに薬剤を放出しにくくなってしまう場合がある。 The mixture for preparing the sugar-responsive gel of this embodiment has a molar ratio (the sum of the gelling agent (A) and the phenylboronic acid monomer (B)) of the hydroxyl monomer (C) (also referred to as the "molar ratio of (A+B):C") of preferably 4.5:1 to 6.5:1, more preferably 4.8:1 to 6.3:1, even more preferably 5.0:1 to 6.3:1, and even more preferably 5.5:1 to 6.3:1. If the total amount of components (A) and (B) is too small compared to the amount of component (C), the drug may be released even when the glucose concentration is below the normal value, or the drug may not respond accurately to changes in the glucose concentration. If the total amount of components (A) and (B) is too large compared to the amount of component (C), the drug may not be released easily when the glucose concentration is high.
　本実施形態の糖応答性ゲルを調製するための混合物において、成分（Ａ）、成分（Ｂ）、および成分（Ｃ）の合計１００ｍｏｌ％に対する成分（Ｄ）の架橋剤の割合（「架橋密度」とも記載）が、好ましくは１．５ｍｏｌ％以上、より好ましくは２．０ｍｏｌ％以上、さらに好ましくは２．５ｍｏｌ％以上、よりさらに好ましくは２．８ｍｏｌ％以上であり、また、好ましくは４ｍｏｌ％以下、より好ましくは３．５ｍｏｌ％以下である。架橋密度が小さすぎると成形性および強度に劣るゲルとなってしまう場合があり、一方、架橋密度が大きすぎると、薬剤の放出量が十分でなくなってしまう場合がある。また、架橋密度を上記範囲内にすることにより、糖濃度の変化に対してゲルがより正確に応答できる。 In the mixture for preparing the sugar-responsive gel of this embodiment, the ratio of the crosslinker of component (D) to the total of 100 mol% of components (A), (B), and (C) (also referred to as "crosslink density") is preferably 1.5 mol% or more, more preferably 2.0 mol% or more, even more preferably 2.5 mol% or more, even more preferably 2.8 mol% or more, and is preferably 4 mol% or less, more preferably 3.5 mol% or less. If the crosslink density is too small, the gel may have poor moldability and strength, while if the crosslink density is too large, the amount of drug released may be insufficient. Furthermore, by keeping the crosslink density within the above range, the gel can respond more accurately to changes in sugar concentration.
　糖応答性ゲルは、必要に応じて、シルクフィブロイン、ポリグリセロール等の他の成分を含んでもよく、他の成分と複合体を形成していてもよい。 The sugar-responsive gel may contain other components such as silk fibroin and polyglycerol, if necessary, or may form a complex with other components.
　一実施態様において、糖応答性ゲルの調製に使用する混合物の全量１００質量％中、成分（Ａ）～成分（Ｅ）の合計含有量が、９０質量％以上が好ましく、９５質量％以上がより好ましく、１００質量％であってもよい。 In one embodiment, the total content of components (A) to (E) in the mixture used to prepare the sugar-responsive gel is preferably 90% by mass or more, more preferably 95% by mass or more, and may be 100% by mass, out of a total amount (100% by mass) of the mixture.
＜糖応答性ゲルの調製方法＞
　ゲルは、上記成分（Ａ）～（Ｅ）を混合し、光重合反応によりモノマーを共重合させて調製することができる。各成分を混合する順序および手段は特に制限されない。成分の混合は溶媒中で行うのが好ましい。溶媒としては、単量体を可溶な任意の溶媒を用いることができる。そのような溶媒として、例えば、水、アルコール、ジメチルスルホキシド（ＤＭＳＯ）、ジメチルホルムアミド（ＤＭＦ）、テトラヒドロフラン（ＴＨＦ）、イオン液体およびそれらの２種以上の組み合わせが挙げられる。これらの中でも例えば、メタノール水溶液、２－メトキシエタノールを溶媒として好ましく用いることができ、特に２－メトキシエタノールが好ましい。溶媒を用いてゲルを調製する場合、特に限定はされないが、溶液中の成分（Ａ）、（Ｂ）、（Ｃ）および（Ｄ）の合計のモノマー濃度が溶液中１～１０Ｍであるのが好ましく、３～８Ｍであるのがより好ましい。なお、本明細書において、単位「Ｍ」は、「ｍｏｌ／Ｌ」を意味する。混合手段としては、例えば超音波分散装置等の公知の装置を用いることができる。混合時の温度は特に限定されず、たとえば室温（好ましくは５～４０℃、より好ましくは１０～３５℃）であってよい。一態様において、成分（Ａ）～成分（Ｄ）を混合して得られたモノマー溶液を調製し、重合反応の直前に成分（Ｅ）をこれに添加してプレゲル溶液としてもよい。別の一態様においては、組成の異なる２つ以上のモノマー溶液を調製し、所望の組成になるように混合して得られた混合物に、成分（Ｅ）を添加してもよい。 <Method for preparing sugar-responsive gel>
The gel can be prepared by mixing the above components (A) to (E) and copolymerizing the monomers by a photopolymerization reaction. The order and means of mixing the components are not particularly limited. The components are preferably mixed in a solvent. Any solvent that dissolves the monomers can be used as the solvent. Examples of such solvents include water, alcohol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), ionic liquids, and combinations of two or more of these. Among these, for example, aqueous methanol solution and 2-methoxyethanol can be preferably used as the solvent, and 2-methoxyethanol is particularly preferred. When preparing the gel using a solvent, although there is no particular limitation, the total monomer concentration of components (A), (B), (C), and (D) in the solution is preferably 1 to 10 M in the solution, and more preferably 3 to 8 M. In this specification, the unit "M" means "mol/L". As a mixing means, for example, a known device such as an ultrasonic dispersion device can be used. The temperature during mixing is not particularly limited, and may be, for example, room temperature (preferably 5 to 40° C., more preferably 10 to 35° C.). In one embodiment, a monomer solution is prepared by mixing components (A) to (D), and component (E) is added thereto immediately before the polymerization reaction to form a pregel solution. In another embodiment, two or more monomer solutions having different compositions are prepared, and the solutions are mixed to obtain a desired composition, to which component (E) is added.
　本実施形態の糖応答性ゲルは、成分（Ａ）～（Ｅ）を含むプレゲル溶液に光照射をすることによりモノマーが重合反応することにより得られる。照射する光の具体例としては、可視光、紫外光、赤外光、Ｘ線、α線、β線およびγ線からなる群より選択される１種以上の光や活性電子線が挙げられる。中でも、重合反応の進行を制御し易い点や、光重合装置として広範に用いられているものが使用できるという点で、紫外光が好ましい。光源としては、例えば、低圧水銀ランプ、中圧水銀ランプ、高圧水銀ランプ、超高圧水銀ランプ、キセノンランプ、ハロゲンランプ、カーボンアーク灯、タングステンランプ、ガリウムランプ、エキシマレーザー、ＬＥＤ光源、ケミカルランプ、ブラックライトランプ、マイクロウェーブ励起水銀灯、メタルハライドランプ等が挙げられる。 The sugar-responsive gel of this embodiment is obtained by irradiating a pre-gel solution containing components (A) to (E) with light to polymerize the monomers. Specific examples of the light to be irradiated include one or more types of light selected from the group consisting of visible light, ultraviolet light, infrared light, X-rays, α-rays, β-rays, and γ-rays, and active electron beams. Among these, ultraviolet light is preferred because it is easy to control the progress of the polymerization reaction and because it can be used with a photopolymerization device that is widely used. Examples of light sources include low-pressure mercury lamps, medium-pressure mercury lamps, high-pressure mercury lamps, ultra-high-pressure mercury lamps, xenon lamps, halogen lamps, carbon arc lamps, tungsten lamps, gallium lamps, excimer lasers, LED light sources, chemical lamps, black light lamps, microwave-excited mercury lamps, and metal halide lamps.
　紫外光で光重合反応を行う場合、紫外線照射強度は、特に限定はされないが、好ましくは１０～３，０００ｍＷ／ｃｍ２、より好ましくは１０～１０００ｍＷ／ｃｍ２、さらに好ましくは１０～５００ｍＷ／ｃｍ２である。紫外線照射強度は、好ましくは光重合開始剤の活性化に有効な波長領域における強度である。光を照射する時間は、好ましくは０．１秒～１０分であり、より好ましくは０．１秒～５分、さらに好ましくは０．１秒～３分である。このような紫外線照射強度で１回または複数回照射すると、その積算光量は、好ましくは１０～３，０００ｍＪ／ｃｍ２、より好ましくは５０～２，０００ｍＪ／ｃｍ２、さらに好ましくは１００～１，０００ｍＪ／ｃｍ２である。 When photopolymerization reaction is carried out with ultraviolet light, the ultraviolet irradiation intensity is not particularly limited, but is preferably 10 to 3,000 mW/cm 2 , more preferably 10 to 1000 mW/cm 2 , and even more preferably 10 to 500 mW/cm 2 . The ultraviolet irradiation intensity is preferably an intensity in a wavelength region effective for activating a photopolymerization initiator. The light irradiation time is preferably 0.1 seconds to 10 minutes, more preferably 0.1 seconds to 5 minutes, and even more preferably 0.1 seconds to 3 minutes. When irradiating once or multiple times with such ultraviolet irradiation intensity, the integrated light amount is preferably 10 to 3,000 mJ/cm 2 , more preferably 50 to 2,000 mJ/cm 2 , and even more preferably 100 to 1,000 mJ/cm 2 .
＜薬剤送達用デバイス＞
　本発明の一実施形態は、上記糖応答性ゲルを含む薬剤送達用デバイス（「薬剤送達デバイス」、または、単に「デバイス」とも記載）に関する。薬剤送達用デバイスは、好ましくはインスリンの送達に使用されるものである。本発明に係る薬剤送達デバイスは、体内埋込型、マイクロニードル型、タブレット型等、任意の形態をとりうる。体内埋込型のデバイスについては、例えば、特開２０１６－２０９３７２号公報及び国際公開パンフレットＷＯ２０１７／０６９２８２号を参照することができる。また、薬剤送達用デバイスは、ゲルタブレットとして体内に埋め込まれてもよい（後述の実施例参照）。ゲルタブレットの形状、大きさは特に限定されない。 Drug delivery devices
One embodiment of the present invention relates to a drug delivery device (also referred to as a "drug delivery device" or simply "device") comprising the sugar-responsive gel. The drug delivery device is preferably used for delivering insulin. The drug delivery device according to the present invention may take any form, such as a body-implantable type, a microneedle type, a tablet type, or the like. For body-implantable devices, for example, JP 2016-209372 A and WO 2017/069282 can be referred to. The drug delivery device may also be implanted in the body as a gel tablet (see the Examples described below). The shape and size of the gel tablet are not particularly limited.
　薬剤送達用デバイスでは、ゲル中に予め薬剤（例えばインスリン）が含まれていてもよい。そのためには、所定濃度の薬剤が含まれた水溶液（例えばリン酸緩衝水溶液）中にゲルを浸すことにより、ゲル内に薬剤を拡散させることができる。次いで、水溶液中から取り出したゲルを、例えば塩酸中に所定時間浸すことで、ゲル本体の表面に薄い脱水収縮層（スキン層と呼ぶ）を形成することにより、薬剤を内包（ローディング）させ、デバイスに充填可能なゲルを得ることができる。 In drug delivery devices, the gel may already contain a drug (e.g., insulin). To achieve this, the gel is immersed in an aqueous solution (e.g., phosphate buffer solution) containing a prescribed concentration of the drug, allowing the drug to diffuse into the gel. The gel is then removed from the aqueous solution and immersed in, for example, hydrochloric acid for a prescribed period of time, forming a thin dehydrated contraction layer (called a skin layer) on the surface of the gel body, thereby encapsulating (loading) the drug and obtaining a gel that can be filled into the device.
　本実施形態において、薬剤送達用デバイスの糖応答性ゲル中には、予め薬剤（例えばインスリン）が含まれていることが好ましい。そのためには、薬剤が所定濃度で含まれたリン酸緩衝水溶液等の水溶液中にゲルを浸すことにより、ゲル内に薬剤を拡散させることができる。次いで、水溶液中から取り出したゲルを、例えば塩酸中に所定時間浸すことで、ゲル本体の表面に薄い脱水収縮層（スキン層と呼ぶ）を形成することにより、薬剤を内包（ローディング）し、デバイスに充填可能なゲルを得ることができる。 In this embodiment, it is preferable that the sugar-responsive gel of the drug delivery device already contains a drug (e.g., insulin). To achieve this, the gel can be immersed in an aqueous solution, such as a phosphate buffer solution, that contains a prescribed concentration of the drug, to allow the drug to diffuse into the gel. The gel is then removed from the aqueous solution and immersed in, for example, hydrochloric acid for a prescribed period of time, forming a thin dehydration contraction layer (called a skin layer) on the surface of the gel body, thereby encapsulating (loading) the drug and obtaining a gel that can be filled into the device.
　本実施形態の糖応答性ゲルでは、フェニルボロン酸系単量体及びヒドロキシル系単量体がゲル化剤及び架橋剤と共重合してゲル本体を形成している。このゲルにインスリンなどの薬剤を拡散させるとともに、ゲル本体の表面を脱水収縮層で取り囲む構成とすることができる。これにより、生理的条件下（例えば、ｐＫａ７．４以下、温度３５℃～４０℃）において、グルコース濃度が高くなると膨張して脱水収縮層が消失し、ゲル内の薬剤（例えばインスリン）を外部へ放出させることができる。一方、グルコース濃度が再び低くなると、膨張していたゲルが収縮して表面全体に再び脱水収縮層（スキン層）が形成され、ゲル内の薬剤（例えばインスリン）が外部へ放出されることを抑制できる。従って、本発明で使用する糖応答性ゲルは、グルコース濃度に応答して薬剤（例えばインスリン）を自律的に放出させることができる。 In the sugar-responsive gel of this embodiment, a phenylboronic acid monomer and a hydroxyl monomer are copolymerized with a gelling agent and a crosslinking agent to form the gel body. Drugs such as insulin can be diffused into this gel, and the surface of the gel body can be surrounded by a dehydration shrinkage layer. As a result, under physiological conditions (e.g., pKa 7.4 or less, temperature 35°C to 40°C), when the glucose concentration increases, the gel expands and the dehydration shrinkage layer disappears, allowing the drug (e.g., insulin) in the gel to be released to the outside. On the other hand, when the glucose concentration decreases again, the expanded gel contracts and a dehydration shrinkage layer (skin layer) is formed again over the entire surface, preventing the drug (e.g., insulin) in the gel from being released to the outside. Therefore, the sugar-responsive gel used in the present invention can autonomously release a drug (e.g., insulin) in response to the glucose concentration.
＜薬剤＞
　本実施形態の糖応答性ゲルを用いて送達されうる薬剤としては、タンパク質、ペプチド、核酸、他の高分子ポリマー、低分子化合物などが挙げられるが、これらに限定はされない。薬剤は、疾患の治療剤、予防薬、ワクチン、栄養サプリメントなどであってもよい。特に好ましい薬剤は、インスリンである。様々な天然型インスリンあるいは改変インスリンが市販品の購入あるいは合成により利用可能となっている。インスリンとしては、例えば、ヒューマリン（登録商標）を使用してもよい。ヒューマリン（登録商標）は、イーライリリー社が販売しているヒト（遺伝子組換え）インスリンである。インスリン製剤には、速効型、中間型、持効型を含む各種製剤が開発されており、適宜選択して使用することができる。 <Drugs>
Drugs that can be delivered using the sugar-responsive gel of this embodiment include, but are not limited to, proteins, peptides, nucleic acids, other high molecular weight polymers, low molecular weight compounds, etc. Drugs may be therapeutic agents, preventive agents, vaccines, nutritional supplements, etc. A particularly preferred drug is insulin. Various natural insulins or modified insulins are available commercially or by synthesis. For example, Humulin (registered trademark) may be used as insulin. Humulin (registered trademark) is a human (recombinant) insulin sold by Eli Lilly and Company. Various insulin preparations, including fast-acting, intermediate-acting, and sustained-acting, have been developed, and can be appropriately selected and used.
＜マイクロニードル＞
　薬剤送達用デバイスの一例として、マイクロニードルについて説明する。図１を参照すると、ベース部１００と、複数のニードル１１０とを有し、皮膚に貼付するパッチとして提供される、本発明の一実施形態によるマイクロニードル１０が示されている。ベース部１００は、複数のニードル１１０を支持するシート状の部分である。複数のニードル１１０がベース部１００に支持されることで、複数のニードル１１０は、ニードルアレイとして構成される。ニードル１１０は、マイクロニードル１０の使用時に皮膚に穿刺される部分であり、鋭利な先端を有する。ベース部１００とニードル１１０とは、別々の材料で作られていてもよいし、同じ材料で作られてもよい。ベース部１００とニードル１１０とが同じ材料で作られている場合、これらは同時に作製することができる。少なくともニードル１１０は、親水性を有しており、マイクロニードル１０の使用前は、薬剤が浸透することによって内部に薬剤を担持している。ニードル１１０は、皮膚に穿刺される前は皮膚に穿刺されるのに十分な高い力学的強度を有し、かつ、皮膚に穿刺されると直ちに吸水して薬剤を放出する性質を有する。本明細書においては、マイクロニードルのことを「薬剤送達マイクロニードル」とも記載する。 <Microneedle>
A microneedle will be described as an example of a drug delivery device. Referring to FIG. 1, a microneedle 10 according to an embodiment of the present invention is shown, which has a base portion 100 and a plurality of needles 110 and is provided as a patch to be attached to the skin. The base portion 100 is a sheet-like portion that supports the plurality of needles 110. The plurality of needles 110 are supported by the base portion 100, and are configured as a needle array. The needle 110 is a portion that is pierced into the skin when the microneedle 10 is used, and has a sharp tip. The base portion 100 and the needle 110 may be made of different materials or may be made of the same material. When the base portion 100 and the needle 110 are made of the same material, they can be made at the same time. At least the needle 110 has hydrophilicity, and before use of the microneedle 10, the drug is permeated into the needle 110, thereby carrying the drug therein. The needle 110 has a high mechanical strength sufficient to puncture the skin before puncturing the skin, and has a property of absorbing water and releasing a drug immediately after puncturing the skin. In this specification, the microneedle is also referred to as a "drug delivery microneedle."
　［ベース部］
　ベース部１００は、複数のニードル１１０を皮膚に穿刺する際に皮膚の弾性力に抗してニードル１１０が良好に皮膚に穿刺されるように必要な機械的強度を有して構成されていれば、様々な材料で構成することができる。そのような材料としては、ポリマー材料、多孔質構造を有するセラミックス材料および金属材料などが挙げられる。また、ベース部１００は、生体適合性を有する材料で構成されることが好ましい。また、一態様において、ベース部は、皮膚に沿って変形できる程度の可撓性を有しているのが好ましい。 [Base section]
The base portion 100 can be made of various materials as long as the materials have the necessary mechanical strength to allow the needles 110 to pierce the skin well against the elasticity of the skin when the needles 110 pierce the skin. Examples of such materials include polymer materials, ceramic materials having a porous structure, and metal materials. The base portion 100 is preferably made of a material having biocompatibility. In one aspect, the base portion is preferably flexible enough to be deformed along the skin.
　ベース部１００は、ニードル１１０から放出される薬剤のリザーバを有することができる。リザーバを有することにより、薬剤を長期間（例えば７日間）にわたって放出することができるようになる。長期間にわたる薬剤の放出が可能なマイクロニードルは、血中グルコース濃度に応じて薬剤としてインスリンを投与するインスリン送達マイクロニードルとして好適に用いることができる。 The base portion 100 can have a reservoir for the drug to be released from the needle 110. By having a reservoir, the drug can be released over a long period of time (e.g., 7 days). A microneedle capable of releasing a drug over a long period of time can be suitably used as an insulin delivery microneedle that administers insulin as a drug depending on the blood glucose concentration.
　リザーバは、例えば、ベース部１００を上面が開口した凹状（カップ状）に形成することによって構成することができる。あるいは、ニードル１１０と同じ材料でベース部１００を形成し、薬剤を浸透させたベース部１００そのものをリザーバとすることもできる。この場合、ベース部１００および複数のニードル１１０を一体成形により同時に形成することができる。また、いずれの場合でも、ベース部１００は、ニードル１１０からベース部１００への薬剤の流通の連続性が阻害されない材料で構成されることが好ましい。リザーバを有するマイクロニードルの構造について詳しくは後述する。 The reservoir can be constructed, for example, by forming the base part 100 into a concave (cup-shaped) shape with an open top. Alternatively, the base part 100 can be formed from the same material as the needles 110, and the base part 100 itself, permeated with the drug, can serve as the reservoir. In this case, the base part 100 and the multiple needles 110 can be formed simultaneously by integral molding. In either case, the base part 100 is preferably constructed from a material that does not impede the continuity of drug flow from the needles 110 to the base part 100. The structure of a microneedle with a reservoir will be described in detail later.
　ベース部１００の平面形状は、円形、楕円形および多角形など任意の形状であってよく、例えば矩形状とすることができる。 The planar shape of the base portion 100 may be any shape, such as a circle, an ellipse, or a polygon, and may be, for example, a rectangle.
　［ニードル］
　（配置および形状）
　ニードル１１０の長さは、ニードル１１０を皮膚に穿刺したときにニードル１１０が角質層に達する十分な長さを有していればよく、限定はされないが、例えば、好ましくは５ｍｍ以下、より好ましくは２ｍｍ以下、さらに好ましくは１ｍｍ以下であってよく、また、好ましくは１００μｍ以上、より好ましくは５００μｍ以上、一態様においてさらに好ましくは１ｍｍ以上である。ニードル１１０の数および配置は任意であってよい。例えば、複数のニードル１１０を、Ｍ×Ｎ（Ｍ、Ｎはそれぞれ１～３０の整数）のマトリックス状に配列することができる。具体的な配置の一例としては、８ｍｍ×８ｍｍの矩形領域中に、１０×１２本のニードル１１０が５００μｍピッチで配置される。別の配置の一例としては、直径１２ｍｍの円形領域中に、１１×１１本のニードル１１０が１．２ｍｍピッチで配置される。ニードル１１０の形状は、皮膚に穿刺できる先端を有していれば任意であってよく、好ましくはピラミッド形状とすることができる。 [needle]
(Layout and Shape)
The length of the needle 110 is not limited as long as the needle 110 has a sufficient length to reach the stratum corneum when the needle 110 is punctured into the skin, and may be, for example, preferably 5 mm or less, more preferably 2 mm or less, and even more preferably 1 mm or less, and is preferably 100 μm or more, more preferably 500 μm or more, and even more preferably 1 mm or more in one embodiment. The number and arrangement of the needles 110 may be arbitrary. For example, a plurality of needles 110 may be arranged in a matrix of M×N (M and N are integers of 1 to 30). As an example of a specific arrangement, 10×12 needles 110 are arranged at a pitch of 500 μm in a rectangular area of 8 mm×8 mm. As another example of an arrangement, 11×11 needles 110 are arranged at a pitch of 1.2 mm in a circular area of 12 mm in diameter. The shape of the needle 110 may be arbitrary as long as it has a tip that can puncture the skin, and may preferably be a pyramid shape.
　［リザーバを有するマイクロニードルの構造］
　本実施形態の一態様として、リザーバを有するマイクロニードルの構造の幾つかの形態について、図２Ａ～図２Ｃを参照して説明する。 [Structure of microneedle having reservoir]
As one aspect of this embodiment, several configurations of microneedle structures having reservoirs are described with reference to Figures 2A to 2C.
　図２Ａに示す形態では、ベース部１００を凹状（カップ状）に形成し、ベース部１００の開放した上面をシート１０２で密閉することによって形成された空間でリザーバ１０１が構成される。シート１０２の接着には、例えば耐水性の接着剤１０３を用いることができる。シート１０２としては特に制限されないが、耐水性および柔軟性の観点から、例えば厚さが０．３ｍｍのシリコーンシートを用いることができる。薬剤は、シリンジ注射によってシート１０２を介してリザーバ１０１に充填することができる。 In the embodiment shown in FIG. 2A, the base portion 100 is formed in a concave (cup-like) shape, and the open upper surface of the base portion 100 is sealed with a sheet 102 to form a space, which constitutes the reservoir 101. For example, a water-resistant adhesive 103 can be used to adhere the sheet 102. There are no particular limitations on the sheet 102, but from the standpoint of water resistance and flexibility, for example, a silicone sheet with a thickness of 0.3 mm can be used. The drug can be filled into the reservoir 101 through the sheet 102 by syringe injection.
　図２Ｂに示す形態では、図２Ａに示したものと同様、リザーバ１０１が、接着剤１０３によって、例えばシリコーン製のシート１０２で密閉されている。ただし、ベース部１００は、リザーバ１０１の開放端側にフランジ１００ｂを有する段付きに形成されている。また、シート１０２は、フランジ１００ｂを越えて、ニードル１１０を有する底面１００ａに向かって垂れ下がり、ベース部１００の高さ方向でもベース部１００を覆っている。接着剤１０３は、シート１０２の垂れ下がった部分において、ベース部１００とシート１０２との間に、ベース部１００の全周にわたって塗布される。 In the embodiment shown in FIG. 2B, the reservoir 101 is sealed by, for example, a silicone sheet 102 with adhesive 103, as in the embodiment shown in FIG. 2A. However, the base portion 100 is formed with a step having a flange 100b on the open end side of the reservoir 101. The sheet 102 also hangs down beyond the flange 100b toward the bottom surface 100a having the needle 110, covering the base portion 100 in the height direction of the base portion 100. The adhesive 103 is applied around the entire circumference of the base portion 100, between the base portion 100 and the sheet 102, in the hanging portion of the sheet 102.
　このような構造によれば、図２Ａに示した構造と比較して、より大きな接着面積でシート１０２をベース部１００に接着し、より効果的にリザーバ１０１を密閉することができる。結果的に、ベース部１００とシート１０２との間からの薬剤の漏出を効果的に防止することができる。しかも、マイクロニードルの面積の拡大を最小限に抑えることができる。 With this structure, compared to the structure shown in FIG. 2A, the sheet 102 can be adhered to the base portion 100 over a larger adhesion area, and the reservoir 101 can be sealed more effectively. As a result, leakage of the drug from between the base portion 100 and the sheet 102 can be effectively prevented. Moreover, the expansion of the area of the microneedle can be minimized.
　フランジ１００ｂの張り出し量Ａは、例えば、０．２ｍｍとすることができる。また、フランジ１００ｂの厚さＢは、例えば０．１ｍｍとすることができ、フランジ１００ｂからベース部１００の底面までの高さＣは、例えば０．２ｍｍとすることができる。 The amount of protrusion A of the flange 100b can be, for example, 0.2 mm. The thickness B of the flange 100b can be, for example, 0.1 mm, and the height C from the flange 100b to the bottom surface of the base portion 100 can be, for example, 0.2 mm.
　本形態においても、マイクロニードルの平面形状は、四角形や円形など任意の形状であってよい。また、フランジ１００ｂの外形状と、ニードル１１０が配置されるベース部１００の底面１００ａの形状とは、同じであってもよいし異なっていてもよい。マイクロニードルの製造時の変形を抑制する観点からは、フランジ１００ｂの外形状および底面１００ａの形状は、ともに円形であることが好ましい。 In this embodiment, the planar shape of the microneedle may be any shape, such as a rectangle or a circle. Furthermore, the outer shape of the flange 100b and the shape of the bottom surface 100a of the base portion 100 on which the needle 110 is disposed may be the same or different. From the viewpoint of suppressing deformation during the manufacture of the microneedle, it is preferable that the outer shape of the flange 100b and the shape of the bottom surface 100a are both circular.
　また、マイクロニードルの面積が拡大することが許容される場合は、図２Ｃに示すように、フランジ１００ｂの張り出し量を大きくし、フランジ１００ｂの上面において接着剤１０３を介してシート１０２を接着することによって接着面積を大きくすることもできる。 Also, if it is acceptable for the area of the microneedle to be enlarged, the adhesion area can be increased by increasing the amount of protrusion of the flange 100b and adhering the sheet 102 to the upper surface of the flange 100b via adhesive 103, as shown in Figure 2C.
　［ベース部およびニードルの形成］
　ベース部１００およびニードル１１０は、型を用いたマイクロモールディング技術を用いて形成することができる。ニードル１１０はベース部１００と一体的に形成することができるので、図３に示すような、ニードルおよびベース部を合わせた形状で形成されたキャビティ（凹部）２０１を有する型２００とすることが好ましい。型２００を構成する材料としては、例えばポリジメチルシロキサン（ＰＤＭＳ）等のシリコーン材料を用いることができる。本実施形態において、型２００を構成する材料は、プレゲル溶液中のモノマーを光重合するための光が透過できる材料であるのが好ましい。 [Formation of base and needle]
The base part 100 and the needle 110 can be formed by using a micromolding technique using a mold. Since the needle 110 can be formed integrally with the base part 100, it is preferable to use a mold 200 having a cavity (recess) 201 formed in a shape of the needle and the base part combined as shown in FIG. 3. As a material for forming the mold 200, for example, a silicone material such as polydimethylsiloxane (PDMS) can be used. In this embodiment, the material for forming the mold 200 is preferably a material that can transmit light for photopolymerizing the monomer in the pre-gel solution.
　このような型２００を用いることにより、ベース部１００およびニードル１１０を１つの工程で形成することができる。ただし、ベース部１００を構成する材料とニードル１１０を構成する材料が異なる場合は、まず、ニードル１１０を構成する材料を溶媒に溶解させた溶液（プレゲル溶液）を、型２００のニードル１１０に相当する部分に流し込み、光照射により単量体を重合させ、これを乾燥させて（溶媒を除去して）ニードル１１０を形成する。溶液の流し込みおよび乾燥は、複数回に分けて行うこともできる。次いで、ベース部１００を構成する材料を溶媒に溶解させた溶液を型２００に流し込み、これを乾燥させる。得られた成型体を型２００から取り出す。これによって、一体に形成されたベース部１００およびニードル１１０を得ることができる。 By using such a mold 200, the base part 100 and the needle 110 can be formed in one process. However, if the material constituting the base part 100 and the material constituting the needle 110 are different, first, a solution (pre-gel solution) in which the material constituting the needle 110 is dissolved in a solvent is poured into the part of the mold 200 corresponding to the needle 110, and the monomer is polymerized by light irradiation, and this is dried (the solvent is removed) to form the needle 110. Pouring and drying of the solution can also be performed multiple times. Next, a solution in which the material constituting the base part 100 is dissolved in a solvent is poured into the mold 200 and dried. The obtained molded body is removed from the mold 200. In this way, the base part 100 and the needle 110 formed integrally can be obtained.
　別の実施態様として、ニードル１１０を構成する単量体を含む単量体混合物を溶媒に溶解させた溶液（プレゲル溶液）を、マイクロニードル型２００のニードル１１０に相当するキャビティ２０１の部分に流し込む（注入する）。マイクロニードル型２００に流し込む溶液の量は、少なくともニードル１１０に相当するキャビティ２０１の部分が溶液で充填される量である。次いで、ベース部１００に相当するシートを、流し込んだ溶液の上からマイクロニードル型２００内に挿入する。ベース部１００に相当するシートとしては例えば、ＰＥ（ポリエチレン）シートが挙げられ、多孔質ＰＥシートであってもよい。溶液とＰＥシートとが対向する部分において溶液の液面が多孔質体と接するように多孔質体をマイクロニードル型２００に挿入する。あるいは、ニードル１１０と同じ組成のゲル層を有するＰＥシートを用意し、ＰＥシート上のゲル層部分とニードル１１０に相当する部分の溶液とが接するようにＰＥシートを配置してもよい。 In another embodiment, a solution (pre-gel solution) in which a monomer mixture containing the monomers constituting the needle 110 is dissolved in a solvent is poured (injected) into the cavity 201 corresponding to the needle 110 of the microneedle mold 200. The amount of solution poured into the microneedle mold 200 is an amount that fills at least the cavity 201 corresponding to the needle 110 with the solution. Next, a sheet corresponding to the base part 100 is inserted into the microneedle mold 200 from above the poured solution. An example of the sheet corresponding to the base part 100 is a PE (polyethylene) sheet, which may be a porous PE sheet. The porous body is inserted into the microneedle mold 200 so that the liquid surface of the solution contacts the porous body in the portion where the solution and the PE sheet face each other. Alternatively, a PE sheet having a gel layer of the same composition as the needle 110 may be prepared, and the PE sheet may be arranged so that the gel layer portion on the PE sheet contacts the solution in the portion corresponding to the needle 110.
　ニードル１１０は非常に微細な構造を有するので、ニードル１１０の形成に際しては、ニードル１１０の先端部分まで溶液を充填することが重要である。そのため、溶液の充填後に、遠心処理、真空処理、または脱気処理を行ってもよい。 Because the needle 110 has a very fine structure, it is important to fill the solution up to the tip of the needle 110 when forming the needle 110. Therefore, after filling the solution, centrifugation, vacuum treatment, or degassing treatment may be performed.
　上述のとおり、本実施形態のマイクロニードルを構成する糖応答性ゲルは、成分（Ａ）～（Ｅ）の光重合反応により形成される。一実施形態において、ニードル１１０、または、ベース部１００およびニードル１１０の型に流し込んだ溶液（モノマー混合物を含む）を脱気した後、光照射によりモノマー混合物を重合反応させる。光照射の方法は、上記ゲルの調製方法で記載したとおりである。光を照射する方向は特に限定はされないが、例えば、ニードルの先端方向から照射するのが好ましい。 As described above, the sugar-responsive gel constituting the microneedle of this embodiment is formed by a photopolymerization reaction of components (A) to (E). In one embodiment, the solution (containing the monomer mixture) poured into the needle 110, or into the mold of the base part 100 and the needle 110, is degassed, and then the monomer mixture is polymerized by light irradiation. The method of light irradiation is as described in the above method for preparing the gel. The direction of light irradiation is not particularly limited, but it is preferable to irradiate from the tip of the needle, for example.
　本発明を以下の実施例によって具体的に説明するが、本発明はこれらの実施例によって限定されるものではない。 The present invention will be specifically described with reference to the following examples, but the present invention is not limited to these examples.
＜製造例１：プレゲル溶液の調製＞
　モノマー溶液の調製に用いた材料（モノマー）は下記のとおりである。
　（ゲル化剤（主鎖））ＮＩＰＡＡｍ：Ｎ－イソプロピルアクリルアミド
　（フェニルボロン酸）ＡｍＥＣＦＰＢＡ：４－（２－アクリルアミドエチルカルバモイル）－３－フルオロフェニルボロン酸
　（ヒドロキシル系単量体）ＮＨＥＡＡｍ：Ｎ－ヒドロキシエチルアクリルアミド
　（架橋剤）ＭＢＡＡｍ：Ｎ，Ｎ’－メチレンビスアクリルアミド <Production Example 1: Preparation of pregel solution>
The materials (monomers) used in preparing the monomer solution are as follows:
(Gelling agent (main chain)) NIPAAm: N-isopropylacrylamide (Phenylboronic acid) AmECFPBA: 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (Hydroxyl monomer) NHEAAm: N-hydroxyethylacrylamide (Crosslinking agent) MBAAm: N,N'-methylenebisacrylamide
　本実施例においては、架橋剤以外のモノマー（ゲル化剤とフェニルボロン酸とヒドロキシル系単量体）の合計濃度が５Ｍであり、かつ、架橋密度３％であることを「５Ｍ３％」と記載し、他の組成についても同様に記載する。「架橋密度」は、ゲル化剤とフェニルボロン酸とヒドロキシル系単量体との総量に対する架橋剤のモル濃度を表す。 In this example, the total concentration of monomers other than the crosslinker (gelling agent, phenylboronic acid, and hydroxyl monomer) is 5M, and the crosslink density is 3%, which is described as "5M3%", and the same applies to other compositions. "Crosslink density" refers to the molar concentration of the crosslinker relative to the total amount of the gelling agent, phenylboronic acid, and hydroxyl monomer.
＜モノマー溶液の調製＞
　５Ｍ３％のゲルを製造するためのモノマー溶液として、５Ｍ３％モノマー溶液Ａ３（「モノマー溶液Ａ３」とも記載）および５Ｍ３％モノマー溶液Ｂ３（「モノマー溶液Ｂ３」とも記載）を調製した。下記の濃度となるように、試薬（モノマー）を、それぞれ溶媒としての２－メトキシエタノールに加えて室温で５分超音波照射することにより溶解させ、モノマー溶液Ａ３およびモノマー溶液Ｂ３を調製した。得られたモノマー溶液Ａ３とＢ３は、冷蔵保存した。 <Preparation of Monomer Solution>
As monomer solutions for producing a 5M 3% gel, 5M 3% monomer solution A3 (also referred to as "monomer solution A3") and 5M 3% monomer solution B3 (also referred to as "monomer solution B3") were prepared. The reagents (monomers) were added to 2-methoxyethanol as a solvent and dissolved by ultrasonic irradiation at room temperature for 5 minutes so as to have the following concentrations, to prepare monomer solutions A3 and B3. The resulting monomer solutions A3 and B3 were stored in a refrigerator.
＜架橋密度：３％、５Ｍ３％モノマー溶液Ａ３＞
・（架橋剤）ＭＢＡＡｍ：５Ｍ×０．０３×１５４．１７＝２３．１２ｍｇ／ｍＬ
・（ゲル化剤）ＮＩＰＡＡｍ：５Ｍ×０．８５×１１３．１６＝４８０．９３ｍｇ／ｍＬ
・（フェニルボロン酸系単量体）ＡｍＥＣＦＰＢＡ：５Ｍ×０．１５×２８０＝２１０ｍｇ／ｍＬ <Crosslink density: 3%, 5M3% monomer solution A3>
(Crosslinking agent) MBAAm: 5M x 0.03 x 154.17 = 23.12 mg/mL
(Gelling agent) NIPAAm: 5M x 0.85 x 113.16 = 480.93 mg/mL
(Phenylboronic acid monomer) AmECFPBA: 5M x 0.15 x 280 = 210 mg/mL
＜架橋密度：３％、５Ｍ３％モノマー溶液Ｂ３＞
・（架橋剤）ＭＢＡＡｍ：５Ｍ×０．０３×１５４．１７＝２３．１２ｍｇ／ｍＬ
・（ヒドロキシル系単量体）ＮＨＥＡＡｍ：５Ｍ×１１５．１３＝５７５．６５ｍｇ／ｍＬ <Crosslink density: 3%, 5M3% monomer solution B3>
(Crosslinking agent) MBAAm: 5M x 0.03 x 154.17 = 23.12 mg/mL
(Hydroxyl monomer) NHEAAm: 5M x 115.13 = 575.65 mg/mL
＜架橋密度：５％、５Ｍ５％モノマー溶液Ａ５、５Ｍ５％モノマー溶液Ｂ５＞
　ＭＢＡＡｍの量を、５Ｍ×０．０５×１５４．１７＝３８．５４ｍｇ／ｍＬとした以外は、溶液Ａ３およびＢ３それぞれと同様にして、モノマー溶液Ａ５およびモノマー溶液Ｂ５を作製した。 <Crosslink density: 5%, 5M5% monomer solution A5, 5M5% monomer solution B5>
Monomer solutions A5 and B5 were prepared in the same manner as solutions A3 and B3, respectively, except that the amount of MBAAm was 5M×0.05×154.17=38.54 mg/mL.
＜架橋密度：２％、５Ｍ２％モノマー溶液Ａ２、５Ｍ２％モノマー溶液Ｂ２＞
　ＭＢＡＡｍの量を、５Ｍ×０．０２×１５４．１７＝１５．４２ｍｇ／ｍＬとした以外は、モノマー溶液Ａ３およびＢ３とそれぞれ同様にして、モノマー溶液Ａ２およびモノマー溶液Ｂ２を作製した。 <Crosslink density: 2%, 5M2% monomer solution A2, 5M2% monomer solution B2>
Monomer solutions A2 and B2 were prepared in the same manner as monomer solutions A3 and B3, respectively, except that the amount of MBAAm was 5M×0.02×154.17=15.42 mg/mL.
＜架橋密度：１％、５Ｍ１％モノマー溶液Ａ１、５Ｍ１％モノマー溶液Ｂ１＞
　ＭＢＡＡｍの量を、５Ｍ×０．０１×１５４．１７＝７．７１ｍｇ／ｍＬとした以外は、モノマー溶液Ａ３およびＢ３とそれぞれ同様にして、モノマー溶液Ａ１およびプレゲル溶液Ｂ１を作製した。 <Crosslink density: 1%, 5M 1% monomer solution A1, 5M 1% monomer solution B1>
Monomer solution A1 and pre-gel solution B1 were prepared in the same manner as monomer solutions A3 and B3, respectively, except that the amount of MBAAm was 5M×0.01×154.17=7.71 mg/mL.
　マイクロニードルまたはゲルタブレット作製時に、上記モノマー溶液Ａとモノマー溶液Ｂを下記表１の混合比（容積比）となるようにそれぞれボルテックスで混合し、これら混合溶液１ｍＬに対し、４０ｍｇの光重合開始剤（イルガキュア６５１（Ｏｍｎｉｒａｄ　６５１）、ＢＡＳＦジャパン社製）を加え、超音波１０分で完全に溶解させてプレゲル溶液１～７を製造した。モノマー溶液Ａとモノマー溶液Ｂとの混合比は、｛（ＮＩＰＡＡｍ＋ＡｍＥＣＦＰＢＡ）：ＮＨＥＡＡｍ｝、すなわち｛（ゲル化剤＋フェニルボロン酸系単量体）：ヒドロキシル系単量体｝のモル比に該当する。また、架橋剤の濃度（架橋密度）は、混合したモノマー溶液中のＡｍＥＣＦＰＢＡ、ＮＩＰＡＡｍおよびＮＨＥＡＡｍの合計に対するＭＢＡＡｍの割合（モル）を表す。 When preparing the microneedles or gel tablets, the above-mentioned monomer solution A and monomer solution B were mixed with a vortex mixer to obtain the mixing ratio (volume ratio) in Table 1 below. 40 mg of a photopolymerization initiator (Irgacure 651 (Omnirad 651), manufactured by BASF Japan) was added to 1 mL of the mixed solution, and the solution was completely dissolved by ultrasonication for 10 minutes to produce pregel solutions 1 to 7. The mixing ratio of monomer solution A to monomer solution B corresponds to the molar ratio of {(NIPAAm + AmECFPBA):NHEAAm}, that is, {(gelling agent + phenylboronic acid monomer):hydroxyl monomer}. The concentration of the crosslinking agent (crosslinking density) represents the ratio (mol) of MBAAm to the total of AmECFPBA, NIPAAm, and NHEAAm in the mixed monomer solution.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
＜製造例２：マイクロニードルの作製＞
（ゲル層付ＰＥ板の作製）
　深さ０．５ｍｍ、底面が直径Φ＝１１ｍｍの円形で、上面が開口した凹状のモールドに注入した１６５μＬのプレゲル溶液の上に、厚み２ｍｍ、Φ＝１１ｍｍのＰＥ（ポリエチレン）板を静かに置き、ただちにＵＶ照射（波長３６５ｎｍ、１５０ｍＷ／ｃｍ２で３０秒）を行った後、一晩風乾して、ゲル層付ＰＥ板を作製した。プレゲル溶液として、上記表１に記載のプレゲル溶液１～７のそれぞれを用いてゲル層付ＰＥ板を作製した。 <Production Example 2: Preparation of Microneedles>
(Preparation of PE plate with gel layer)
A PE (polyethylene) plate with a thickness of 2 mm and a diameter of 11 mm was gently placed on 165 μL of pre-gel solution poured into a concave mold with a depth of 0.5 mm, a bottom surface having a diameter of Φ = 11 mm, and an open top surface, and the plate was immediately irradiated with UV light (wavelength 365 nm, 150 mW/ cm2 for 30 seconds) and then air-dried overnight to prepare a PE plate with a gel layer. The PE plates with a gel layer were prepared using each of the pre-gel solutions 1 to 7 listed in Table 1 above as the pre-gel solution.
（マイクロニードルの作製）
　あらかじめ５０℃に温めておいたシリコーン（ポリジメチルシロキサン（ＰＤＭＳ）製）のマイクロニードルのモールドのニードルに対応するキャビティの部分に５０℃に保温したプレゲル溶液１を１２５μＬ入れ、水流ポンプにより減圧して気泡を取り除く操作を２回繰り返した。続いて、上記で作製したゲル層つきＰＥ板（プレゲル溶液１を用いて作製したＰＥ板）を静かに挿入し、針先端部側からＵＶ照射（波長３６５ｎｍ、１５０ｍＷ／ｃｍ２、照射時間１分）を行い、モノマーを重合させて、型内のプレゲル溶液をゲル化した。照射数分後、モールドが室温程度に冷めたところでモールドから静かにマイクロニードルゲルを外し、室温で１晩風乾し、ＰＥ板とニードルが一体化した成形体を得た。充分量の６０％メタノール溶液（水／メタノール＝４／６（体積比））および純水で洗浄し、室温で１晩乾燥させることで、ＰＥ板付マイクロニードル（マイクロニードル１）を得た。
　プレゲル溶液１に代えて、プレゲル溶液２～７それぞれを用いて、同様の方法により、ＰＥ板付マイクロニードルであるマイクロニードル２～７を作製した。 (Preparation of microneedles)
125 μL of pregel solution 1 kept at 50 ° C. was placed in the cavity corresponding to the needle of the mold of the microneedle of silicone (made of polydimethylsiloxane (PDMS)) previously warmed to 50 ° C., and the operation of removing air bubbles by decompressing with a water flow pump was repeated twice. Next, the PE plate with the gel layer prepared above (PE plate prepared using pregel solution 1) was gently inserted, and UV irradiation (wavelength 365 nm, 150 mW / cm 2 , irradiation time 1 minute) was performed from the needle tip side to polymerize the monomer and gel the pregel solution in the mold. After a few minutes of irradiation, when the mold cooled to about room temperature, the microneedle gel was gently removed from the mold and air-dried at room temperature overnight to obtain a molded body in which the PE plate and the needle were integrated. The microneedle with the PE plate (microneedle 1) was obtained by washing with a sufficient amount of 60% methanol solution (water / methanol = 4 / 6 (volume ratio)) and pure water, and drying at room temperature overnight.
Using pre-gel solutions 2 to 7 instead of pre-gel solution 1, microneedles 2 to 7, which are PE plate-attached microneedles, were prepared in a similar manner.
＜製造例３：ゲルタブレットの作製＞
　ポリプロピレン製の円柱形状（直径４ｍｍ、高さ３ｍｍ）のモールドに、表１の組成の各プレゲル溶液（各単量体と光重合開始剤（イルガキュア６５１）を含む）５５μｌを入れた。続いて、ＵＶ照射（１５０ｍＷ／ｃｍ２、照射時間１分）を行い、モノマーを重合させて、型内のプレゲル溶液をゲル化した。照射数分後、モールドが室温程度に冷めたところで、室温で１晩風乾し、その後モールドから静かにゲルを外して成形体を得た。充分量の１００％メタノール溶液中に静かにゲルを浸し、半日毎に洗浄液交換を行いながら洗浄液がｐＨ６．５以上になるまで２日間洗浄を繰り返した。最後に水で１晩置換した後乾燥させてゲルタブレットを得た。プレゲル溶液１～７（表１）を用いて得られたゲルタブレットを、それぞれ、ゲルタブレット１～７と記載する。 <Production Example 3: Preparation of gel tablets>
55 μl of each pregel solution (containing each monomer and photopolymerization initiator (Irgacure 651)) with the composition shown in Table 1 was placed in a cylindrical mold made of polypropylene (diameter 4 mm, height 3 mm). Then, UV irradiation (150 mW/cm 2 , irradiation time 1 minute) was performed to polymerize the monomer and gel the pregel solution in the mold. After a few minutes of irradiation, when the mold cooled to about room temperature, it was air-dried at room temperature overnight, and then the gel was gently removed from the mold to obtain a molded body. The gel was gently immersed in a sufficient amount of 100% methanol solution, and washing was repeated for two days until the washing solution reached pH 6.5 or higher, with the washing solution being replaced every half day. Finally, it was replaced with water overnight and then dried to obtain a gel tablet. The gel tablets obtained using pregel solutions 1 to 7 (Table 1) are referred to as gel tablets 1 to 7, respectively.
（インスリンを内包するゲルタブレットの作製）
　上記で作製した乾燥した各ゲルタブレットを、インスリンを３．６ｍｇ／ｍＬの濃度で含むｐＨ７．４のリン酸緩衝生理食塩水（ＰＢＳ，１３７ｍＭ　ＮａＣｌ）中に入れて、４℃で一晩浸漬し、ゲル中にインスリンを拡散させた。次いで、ゲルタブレットを、３７℃に保温した０．１Ｍ　ＨＣｌに移し、ゲル本体の表面に薄い脱水収縮層（スキン層）を形成させて、インスリンを内包（ローディング）するゲルタブレットを得た。ゲルタブレット１と５の写真を図６に示す。ゲルタブレット５の方が表面のスキン層がよりシャープに形成された。 (Preparation of gel tablets containing insulin)
Each of the dried gel tablets prepared above was placed in phosphate buffered saline (PBS, 137 mM NaCl) at pH 7.4 containing insulin at a concentration of 3.6 mg/mL and soaked overnight at 4°C to diffuse insulin into the gel. Next, the gel tablet was transferred to 0.1 M HCl kept at 37°C to form a thin dehydration contraction layer (skin layer) on the surface of the gel body, thereby obtaining gel tablets containing insulin (loading). Photographs of gel tablets 1 and 5 are shown in Figure 6. The skin layer on the surface of gel tablet 5 was formed more sharply.
＜例１：架橋密度とインスリン放出量との関係＞
　上記製造例３で製造したインスリンを内包する、ゲルタブレット７（架橋密度１％）、ゲルタブレット６（架橋密度２％）、およびゲルタブレット３（架橋密度５％）を、それぞれ、ＰＢＳ（グルコース濃度：０ｇ／Ｌ、１３７ｍＭ　ＮａＣｌ）に移して２時間前培養した後、各グルコース濃度（０ｇ／Ｌまたは５ｇ／Ｌ（高血糖値に相当））のＰＢＳに移し、３０℃で１時間、２時間、および４時間培養した時点でＰＢＳ溶液のサンプルを採取した。採取したサンプルについて、インスリンＥＬＩＳＡキットを用いて分析し、インスリンを内包するゲルタブレットからのインスリンの放出量を定量した。結果を図４に示す。 Example 1: Relationship between crosslink density and insulin release amount
Gel tablet 7 (crosslink density 1%), gel tablet 6 (crosslink density 2%), and gel tablet 3 (crosslink density 5%) containing insulin produced in Production Example 3 were transferred to PBS (glucose concentration: 0 g/L, 137 mM NaCl) and pre-cultured for 2 hours, then transferred to PBS with each glucose concentration (0 g/L or 5 g/L (corresponding to high blood glucose level)) and cultured at 30° C. for 1 hour, 2 hours, and 4 hours, at which point samples of the PBS solution were taken. The collected samples were analyzed using an insulin ELISA kit to quantify the amount of insulin released from the gel tablets containing insulin. The results are shown in FIG. 4.
　図４に示すように、架橋密度（架橋剤の濃度）が低いほど、インスリンの放出量が大きいことがわかった。 As shown in Figure 4, the lower the cross-linking density (concentration of the cross-linking agent), the greater the amount of insulin released.
＜例２：ゲル組成および架橋密度と、インスリン放出量との関係＞
　プレゲル溶液１～６を用いて上記製造例３のようにインスリンを内包するゲルタブレット１～６を作製した。 Example 2: Relationship between gel composition and crosslink density and insulin release amount
Using the pre-gel solutions 1 to 6, gel tablets 1 to 6 containing insulin were prepared as in Production Example 3 above.
　インスリンを内包する各ゲルタブレットを、ＰＢＳ（グルコース濃度：０ｇ／Ｌ、１３７ｍＭ　ＮａＣｌ）に移して２時間前培養した後、各グルコース濃度（０ｇ／Ｌ，１ｇ／Ｌ（正常血糖値に相当），５ｇ／Ｌ（高血糖値に相当））のＰＢＳに移し、３０℃で３０分、１時間、および２時間培養した時点でＰＢＳ溶液のサンプルを採取した。採取したサンプルについて、インスリンＥＬＩＳＡキットを用いて分析し、インスリンを内包するゲルタブレットからのインスリンの放出量を定量した。同様に前培養後に各グルコース濃度（０ｇ／Ｌ，１ｇ／Ｌ，５ｇ／Ｌ）のＰＢＳに移し、３７℃で３０分、１時間、および２時間の時点でＰＢＳ溶液のサンプルを採取してインスリンの放出量を定量した。インスリンを内包するゲルタブレット１～６を用いた結果を図５に示す。図５の上段は３０℃、下段は３７℃で培養した結果を示す。 Each gel tablet containing insulin was transferred to PBS (glucose concentration: 0 g/L, 137 mM NaCl) and pre-cultured for 2 hours, then transferred to PBS with each glucose concentration (0 g/L, 1 g/L (corresponding to normal blood glucose level), 5 g/L (corresponding to hyperglycemia)) and cultured at 30°C for 30 minutes, 1 hour, and 2 hours, at which point PBS solution samples were taken. The collected samples were analyzed using an insulin ELISA kit to quantify the amount of insulin released from the gel tablet containing insulin. Similarly, after pre-culture, each tablet was transferred to PBS with each glucose concentration (0 g/L, 1 g/L, 5 g/L) and cultured at 37°C for 30 minutes, 1 hour, and 2 hours, at which point PBS solution samples were taken and the amount of insulin released was quantified. The results of using insulin-containing gel tablets 1 to 6 are shown in Figure 5. The upper row of Figure 5 shows the results of culturing at 30°C, and the lower row shows the results of culturing at 37°C.
　ゲルタブレット４、５および６において、グルコース濃度が５ｇ／Ｌ（高血糖）のときにインスリンが大きく放出された。特にゲルタブレット５を用いた場合は、グルコース濃度が０ｇ／Ｌ、１ｇ／Ｌ（正常血糖）のときはインスリンの漏れが少なく放出が十分に抑制され、グルコース濃度が５ｇ／Ｌ（高血糖）のときはインスリンが大きく放出され、糖濃度に対する応答性が正確であることが示された。一方、ゲルタブレット１～３を用いた場合は、架橋密度が５％と高いにも関わらず正常血糖で３０分後にはインスリンの漏れが観察されたのに加え、高血糖におけるインスリンの放出量はゲルタブレット４～６に比べて小さい傾向にあった。 In gel tablets 4, 5 and 6, insulin was released in large amounts when the glucose concentration was 5 g/L (hyperglycemia). In particular, when gel tablet 5 was used, there was little insulin leakage and release was sufficiently suppressed when the glucose concentration was 0 g/L and 1 g/L (normal blood sugar), and insulin was released in large amounts when the glucose concentration was 5 g/L (hyperglycemia), demonstrating accurate responsiveness to sugar concentration. On the other hand, when gel tablets 1 to 3 were used, insulin leakage was observed after 30 minutes in normal blood sugar, despite the high crosslink density of 5%, and the amount of insulin released in hyperglycemia tended to be smaller than that of gel tablets 4 to 6.
＜例３：ゲルタブレットの皮下埋め込み実験＞
　生体内でのグルコース応答性インスリン放出を評価するため、ゲルタブレットを埋め込んだマウスに対してグルコース負荷試験（ＧＴＴ）を行った。 <Example 3: Subcutaneous implantation experiment of gel tablets>
To evaluate glucose-responsive insulin release in vivo, a glucose tolerance test (GTT) was performed on mice implanted with the gel tablets.
　プレゲル溶液１およびプレゲル溶液５をそれぞれ用いて、製造例３の方法によりゲルタブレット１および５を製造し、インスリンを包含させた。インスリンを包含したゲルタブレット１または５を、麻酔下に一晩絶食した野生型（Ｃ５７ＢＬ／６Ｊ、雄）マウス１匹の皮下にゲルタブレットを１つ埋め込んだ（図７参照）。３時間後に２０％グルコース水溶液を用いて、２ｇ／ｋｇとなるようにグルコースを腹腔内に投与し、グルコース負荷試験を行った。グルコースを投与してから１５０分後まで、１５分～３０分おきに血糖測定器により血糖値の測定を行った。さらに、その時点で採血も行い、血漿を収集し、ＥＬＩＳＡにより血漿インスリン濃度を測定した。また、コントロールとして、プレゲル溶液５を用いて製造したゲルタブレット５でインスリンを包含していないもの（空ゲル）を用いて同様の測定を行った。インスリンを含むゲルタブレットを用いた試験では各群４匹のマウスについての平均値を算出し、コントロールのゲルタブレットを用いた試験では３匹のマウスについての平均値を算出した。 Gel tablets 1 and 5 were produced by the method of Production Example 3 using pregel solution 1 and pregel solution 5, respectively, and insulin was incorporated therein. One gel tablet containing insulin was embedded subcutaneously in one wild-type (C57BL/6J, male) mouse that had been fasted overnight under anesthesia (see Figure 7). Three hours later, glucose was administered intraperitoneally at 2 g/kg using a 20% glucose aqueous solution, and a glucose tolerance test was performed. Blood glucose levels were measured every 15 to 30 minutes using a blood glucose meter until 150 minutes after glucose administration. Blood was also collected at those times, plasma was collected, and plasma insulin concentrations were measured by ELISA. As a control, similar measurements were performed using gel tablet 5 produced using pregel solution 5 that did not contain insulin (empty gel). In the test using gel tablets containing insulin, the average value was calculated for four mice in each group, and in the test using control gel tablets, the average value was calculated for three mice.
　図８に、マウスにインスリンを含むゲルタブレットを埋め込む前と埋め込んで３時間後（グルコース投与前）のマウスの血糖値を示す。ゲルタブレット５（５Ｍ３％　６：１）では、ゲルタブレットの埋め込み前後で血糖値は変化せず、グルコース投与前にインスリンの放出がなかったことが示された。一方、ゲルタブレット１（５Ｍ５％　３：１）を用いたマウスでは、グルコース投与前に血糖値が下がってしまい、インスリンの放出があったことが示された。 Figure 8 shows the blood glucose levels of mice before and 3 hours after implanting gel tablets containing insulin (before glucose administration). In the case of gel tablet 5 (5M 3% 6:1), blood glucose levels did not change before and after the gel tablet was implanted, indicating that insulin was not released before glucose administration. On the other hand, in mice that had received gel tablet 1 (5M 5% 3:1), blood glucose levels dropped before glucose administration, indicating that insulin was released.
　図９にグルコース負荷試験を行ったマウスの血糖値の変化を示す。横軸はグルコースを投与してからの経過時間、縦軸は血糖値を示す。図９のコントロールは、ゲルタブレット５でインスリンを包含していないもの（空ゲル）を用いた結果である。また、図１０は、グルコース負荷試験を行ったマウスの血漿インスリン濃度の変化を示す。横軸はグルコースを投与してからの経過時間、縦軸は血漿インスリン量を表す。 Figure 9 shows the change in blood glucose level in mice that underwent a glucose tolerance test. The horizontal axis shows the time that has passed since glucose was administered, and the vertical axis shows the blood glucose level. The control in Figure 9 is the result of using gel tablet 5 that does not contain insulin (empty gel). Figure 10 shows the change in plasma insulin concentration in mice that underwent a glucose tolerance test. The horizontal axis shows the time that has passed since glucose was administered, and the vertical axis shows the amount of plasma insulin.
　図９および図１０に示したように、ゲルタブレット５（５Ｍ３％　６：１）を用いたマウスは、グルコース投与前（０分）にコントロールと同レベルの血糖値であってインスリンの放出がなく、グルコース投与後にはインスリンが放出され、９０分後には元の血糖値に戻った。一方、ゲルタブレット１（５Ｍ５％　３：１）を用いたマウスでは、グルコース投与前の時点で既にインスリンが放出されてしまい、この時点で血糖値が低くなってしまっていることが示された。 As shown in Figures 9 and 10, mice using gel tablet 5 (5M 3% 6:1) had blood glucose levels at the same level as the control before glucose administration (0 minutes) and no insulin was released, but after glucose administration, insulin was released and blood glucose levels returned to normal 90 minutes later. On the other hand, in mice using gel tablet 1 (5M 5% 3:1), insulin was already released before glucose administration, indicating that blood glucose levels were already low at this point.
　本明細書には、本発明の好ましい実施態様を示してあるが、そのような実施態様が単に例示の目的で提供されていることは、当業者には明らかであり、当業者であれば、本発明から逸脱することなく、様々な変形、変更、置換を加えることが可能であろう。本明細書に記載されている発明の様々な代替的実施形態が、本発明を実施する際に使用されうることが理解されるべきである。また、本明細書中において参照している特許及び特許出願書類を含む、全ての刊行物に記載の内容は、その引用によって、本明細書中に明記された内容と同様に取り込まれていると解釈すべきである。 Although preferred embodiments of the present invention are shown herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only, and that various modifications, changes, and substitutions may be made by those skilled in the art without departing from the invention. It should be understood that various alternative embodiments of the invention described herein may be used in practicing the invention. In addition, the contents of all publications, including patents and patent applications, referenced in this specification should be construed as being incorporated by reference as if set forth herein.
　この出願は、２０２３年１月２６日に出願された日本出願特願２０２３－０１０５３３を基礎とする優先権を主張し、その開示の全てをここに取り込む。 This application claims priority based on Japanese Patent Application No. 2023-010533, filed on January 26, 2023, the entire disclosure of which is incorporated herein by reference.
　１０　　マイクロニードル
　１００　　ベース部
　１０１　　リザーバ
　１０２　　シート
　１０３　　接着剤
　１１０　　ニードル
　２００　　型
　２０１　　キャビティ REFERENCE SIGNS LIST 10 Microneedle 100 Base portion 101 Reservoir 102 Sheet 103 Adhesive 110 Needle 200 Mold 201 Cavity

Claims (9)

  1. 　（Ａ）Ｎ－イソプロピルメタクリルアミド（ＮＩＰＭＡＡｍ）、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＡｍ）、Ｎ，Ｎ－ジメチルアクリルアミド（ＤＭＡＡｍ）、およびＮ，Ｎ－ジエチルアクリルアミド（ＤＥＡＡｍ）からなる群から選ばれる少なくとも一種を含むゲル化剤と；
    　（Ｂ）下記一般式（１）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、ＲはＨ又はＣＨ３であり、Ｆは独立に存在し、ｎが１、２、３又は４のいずれかであり、ｍは０又は１以上の整数である。］
    で表されるフェニルボロン酸系単量体と；
    　（Ｃ）下記一般式（２）：
    Figure JPOXMLDOC01-appb-C000002
     ［式中、Ｒ１はＨ又はＣＨ３であり、ｍは０又は１以上の整数であり、Ｒ２はＯＨ、１以上の水酸基で置換された飽和若しくは不飽和のＣ１－６アルキル基、１以上の水酸基で置換された飽和若しくは不飽和のＣ３－１０シクロアルキル基、１以上の水酸基で置換されたＮＨ、Ｏ及びＳより選ばれる１～４個のヘテロ原子を含有するＣ３－１２複素環式基、１以上の水酸基で置換されたＣ６－１２アリール基、単糖基、又は多糖基である。］
    で表されるヒドロキシル系単量体と；
    （Ｄ）架橋剤と；
    （Ｅ）光重合開始剤と；
    を含む混合物の重合反応物を含み、
    　（成分（Ａ）と成分（Ｂ）との合計）：成分（Ｃ）のモル比が、４．５：１～６．５：１の範囲内であり、かつ、
    　成分（Ａ）、成分（Ｂ）、および成分（Ｃ）の合計に対し、（Ｄ）架橋剤の割合が１．５ｍｏｌ％以上４ｍｏｌ％以下である、糖応答性ゲル。     (A) a gelling agent comprising at least one selected from the group consisting of N-isopropylmethacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm);
    (B) a compound represented by the following general formula (1):
    Figure JPOXMLDOC01-appb-C000001
     [In the formula, R is H or CH3 , F is present independently, n is 1, 2, 3 or 4, and m is 0 or an integer of 1 or more.]
    A phenylboronic acid monomer represented by the formula:
    (C) a compound represented by the following general formula (2):
    Figure JPOXMLDOC01-appb-C000002
     [In the formula, R 1 is H or CH 3 , m is 0 or an integer of 1 or more, and R 2 is OH, a saturated or unsaturated C 1-6 alkyl group substituted with one or more hydroxyl groups, a saturated or unsaturated C 3-10 cycloalkyl group substituted with one or more hydroxyl groups, a C 3-12 heterocyclic group containing 1 to 4 heteroatoms selected from NH, O and S substituted with one or more hydroxyl groups, a C 6-12 aryl group substituted with one or more hydroxyl groups, a monosaccharide group, or a polysaccharide group.]
    and a hydroxyl monomer represented by the formula:
    (D) a crosslinker;
    (E) a photopolymerization initiator;
    The polymerization reaction product of the mixture comprising:
    The molar ratio of (the sum of components (A) and (B)):component (C) is within the range of 4.5:1 to 6.5:1, and
    A sugar-responsive gel, in which the ratio of the crosslinker (D) is 1.5 mol % or more and 4 mol % or less with respect to the total of the components (A), (B), and (C).
  2. 　前記架橋剤が、Ｎ，Ｎ’－メチレンビスアクリルアミド（ＭＢＡＡｍ）を含む、請求項１に記載の糖応答性ゲル。 The sugar-responsive gel of claim 1, wherein the crosslinking agent comprises N,N'-methylenebisacrylamide (MBAAm).
  3. 　前記一般式（１）で表されるフェニルボロン酸系単量体が、４－（２－アクリルアミドエチルカルバモイル）－３－フルオロフェニルボロン酸（ＡｍＥＣＦＰＢＡ）を含む、請求項１または２に記載の糖応答性ゲル。 The sugar-responsive gel according to claim 1 or 2, wherein the phenylboronic acid monomer represented by the general formula (1) includes 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA).
  4. 　前記一般式（２）で表される単量体がＮ－ヒドロキシエチルアクリルアミド（ＮＨＥＡＡｍ）を含む、請求項１又は２に記載の糖応答性ゲル。 The sugar-responsive gel according to claim 1 or 2, wherein the monomer represented by the general formula (2) contains N-hydroxyethylacrylamide (NHEAAm).
  5. 　前記ゲル化剤が、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＡｍ）を含む、請求項１または２に記載の糖応答性ゲル。 The sugar-responsive gel according to claim 1 or 2, wherein the gelling agent comprises N-isopropylacrylamide (NIPAAm).
  6. 　請求項１または２に記載の糖応答性ゲルを含む、薬剤送達デバイス。 A drug delivery device comprising the sugar-responsive gel according to claim 1 or 2.
  7. 　体内埋込型、又はマイクロニードル型のデバイスである、請求項６記載の薬剤送達デバイス。 The drug delivery device of claim 6, which is an implantable or microneedle type device.
  8. 　インスリンの送達に使用するためのデバイスである、請求項６に記載の薬剤送達デバイス。 The drug delivery device of claim 6, which is a device for use in delivering insulin.
  9. 　（Ａ）Ｎ－イソプロピルメタクリルアミド（ＮＩＰＭＡＡｍ）、Ｎ－イソプロピルアクリルアミド（ＮＩＰＡＡｍ）、Ｎ，Ｎ－ジメチルアクリルアミド（ＤＭＡＡｍ）、およびＮ，Ｎ－ジエチルアクリルアミド（ＤＥＡＡｍ）からなる群から選ばれる少なくとも一種を含むゲル化剤と；
    　（Ｂ）下記一般式（１）：
    Figure JPOXMLDOC01-appb-C000003
     ［式中、ＲはＨ又はＣＨ３であり、Ｆは独立に存在し、ｎが１、２、３又は４のいずれかであり、ｍは０又は１以上の整数である。］
    で表されるフェニルボロン酸系単量体と；
    　（Ｃ）下記一般式（２）：
    Figure JPOXMLDOC01-appb-C000004
     ［式中、Ｒ１はＨ又はＣＨ３であり、ｍは０又は１以上の整数であり、Ｒ２はＯＨ、１以上の水酸基で置換された飽和若しくは不飽和のＣ１－６アルキル基、１以上の水酸基で置換された飽和若しくは不飽和のＣ３－１０シクロアルキル基、１以上の水酸基で置換されたＮＨ、Ｏ及びＳより選ばれる１～４個のヘテロ原子を含有するＣ３－１２複素環式基、１以上の水酸基で置換されたＣ６－１２アリール基、単糖基、又は多糖基である。］
    で表されるヒドロキシル系単量体と；
    （Ｄ）架橋剤と；
    （Ｅ）光重合開始剤と；
    を含み、
    　（成分（Ａ）と成分（Ｂ）との合計）：成分（Ｃ）のモル比が、４．５：１～６．５：１の範囲内であり、かつ、
    　成分（Ａ）、成分（Ｂ）、および成分（Ｃ）の合計に対し、（Ｄ）架橋剤の割合が１．５ｍｏｌ％以上４ｍｏｌ％以下である混合物を調製する工程と、
    　前記混合物に光を照射して重合反応させる工程と、
    を含む、糖応答性ゲルの製造方法。     (A) a gelling agent comprising at least one selected from the group consisting of N-isopropylmethacrylamide (NIPMAAm), N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), and N,N-diethylacrylamide (DEAAm);
    (B) a compound represented by the following general formula (1):
    Figure JPOXMLDOC01-appb-C000003
     [In the formula, R is H or CH3 , F is present independently, n is 1, 2, 3 or 4, and m is 0 or an integer of 1 or more.]
    A phenylboronic acid monomer represented by the formula:
    (C) a compound represented by the following general formula (2):
    Figure JPOXMLDOC01-appb-C000004
     [In the formula, R 1 is H or CH 3 , m is 0 or an integer of 1 or more, and R 2 is OH, a saturated or unsaturated C 1-6 alkyl group substituted with one or more hydroxyl groups, a saturated or unsaturated C 3-10 cycloalkyl group substituted with one or more hydroxyl groups, a C 3-12 heterocyclic group containing 1 to 4 heteroatoms selected from NH, O and S substituted with one or more hydroxyl groups, a C 6-12 aryl group substituted with one or more hydroxyl groups, a monosaccharide group, or a polysaccharide group.]
    and a hydroxyl monomer represented by the formula:
    (D) a crosslinker;
    (E) a photopolymerization initiator;
    Including,
    The molar ratio of (the sum of components (A) and (B)):component (C) is within the range of 4.5:1 to 6.5:1, and
    A step of preparing a mixture in which the ratio of the crosslinking agent (D) is 1.5 mol % or more and 4 mol % or less with respect to the total of the components (A), (B), and (C);
    a step of irradiating the mixture with light to cause a polymerization reaction;
    The method for producing a sugar-responsive gel comprises:
PCT/JP2024/002308 2023-01-26 2024-01-25 Sugar responsive gel WO2024158039A1 (en)

Applications Claiming Priority (2)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015110623A (en) * 2010-05-26 2015-06-18 国立研究開発法人物質・材料研究機構 Sugar responsive gel and medicine administering device
JP2015537078A (en) * 2012-11-06 2015-12-24 サントル、ナショナール、ド、ラ、ルシェルシュ、シアンティフィク、（セーエヌエルエス） Glucose-responsive hydrogel comprising PBA grafted hyaluronic acid (HA)
JP2016209372A (en) * 2015-05-11 2016-12-15 国立大学法人 東京医科歯科大学 Insulin delivery device
CN109675185A (en) * 2019-01-02 2019-04-26 浙江大学 Quick microneedle patch of a kind of phenyl boric acid water-setting matrix sugar and preparation method thereof
WO2019230961A1 (en) * 2018-06-01 2019-12-05 国立大学法人名古屋大学 Temperature-resistant sugar-responsive gel

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015110623A (en) * 2010-05-26 2015-06-18 国立研究開発法人物質・材料研究機構 Sugar responsive gel and medicine administering device
JP2015537078A (en) * 2012-11-06 2015-12-24 サントル、ナショナール、ド、ラ、ルシェルシュ、シアンティフィク、（セーエヌエルエス） Glucose-responsive hydrogel comprising PBA grafted hyaluronic acid (HA)
JP2016209372A (en) * 2015-05-11 2016-12-15 国立大学法人 東京医科歯科大学 Insulin delivery device
WO2019230961A1 (en) * 2018-06-01 2019-12-05 国立大学法人名古屋大学 Temperature-resistant sugar-responsive gel
CN109675185A (en) * 2019-01-02 2019-04-26 浙江大学 Quick microneedle patch of a kind of phenyl boric acid water-setting matrix sugar and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MATSUMOTO AKIRA, MIYAHARA YUJI: "Current Development Status and Perspective of Self-Regulated Insulin Delivery Systems: A Review", IEEJ TRANSACTIONS ON SENSORS AND MICROMACHINES, vol. 132, no. 12, 1 January 2012 (2012-01-01), pages 455 - 458, XP093195113, DOI: 10.1541/ieejsms.132.455 *

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