WO2015129807A1 - Microneedle - Google Patents

Microneedle Download PDF

Info

Publication number
WO2015129807A1
WO2015129807A1 PCT/JP2015/055614 JP2015055614W WO2015129807A1 WO 2015129807 A1 WO2015129807 A1 WO 2015129807A1 JP 2015055614 W JP2015055614 W JP 2015055614W WO 2015129807 A1 WO2015129807 A1 WO 2015129807A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
microneedle
arginine
microneedles
physiologically active
Prior art date
Application number
PCT/JP2015/055614
Other languages
French (fr)
Japanese (ja)
Inventor
卓哉 菅原
真平 西村
誠治 徳本
Original Assignee
久光製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 久光製薬株式会社 filed Critical 久光製薬株式会社
Priority to JP2016505294A priority Critical patent/JP6211169B2/en
Publication of WO2015129807A1 publication Critical patent/WO2015129807A1/en

Links

Images

Classifications

    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta
    • 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
    • A61K38/23—Calcitonins
    • 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
    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • 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
    • A61K38/26—Glucagons
    • 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
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • 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
    • 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
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles

Definitions

  • the present invention relates to a microneedle.
  • transdermal administration of physiologically active substances can be administered even when the user has difficulty swallowing, and is a versatile administration because it does not require water.
  • the method of transdermal administration of a physiologically active substance is an administration method that is easy for a user to handle because it can be easily administered even in situations where a medical worker is not in the vicinity, compared to an injection. is there.
  • Examples of such a preparation for transdermal administration include a patch and a microneedle device.
  • a conventional microneedle device is manufactured by coating a microprotrusion with a coating solution containing a physiologically active substance in a microneedle device having microprotrusions (Patent Document 1).
  • self-dissolving microneedles include microneedles using a mixture of maltose and dextran as a main component material, and microneedles made of a water-soluble polymer such as sodium carboxymethylcellulose (Patent Documents 2 and 3).
  • an object of the present invention is to provide a self-dissolving microneedle excellent in moldability and strength.
  • microneedle containing a physiologically active substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40 ° C. or higher is moldable. And it discovered that it was excellent in intensity
  • the acid is preferably one or more acids selected from the group consisting of citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid and aspartic acid, and one selected from the group consisting of citric acid, tartaric acid and aspartic acid. More preferred are the acids mentioned above.
  • the amino acid is preferably arginine.
  • the present invention also provides a method for producing the microneedle.
  • the present invention also provides a microneedle comprising, on a substrate, a microneedle containing a physiologically active substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40 ° C. or higher.
  • a microneedle comprising, on a substrate, a microneedle containing a physiologically active substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40 ° C. or higher.
  • the present invention also provides a method for using the microneedle device, including the step of applying the microneedle device to the skin of a subject requiring administration of a physiologically active substance contained in the microneedle.
  • the microneedle of the present invention is excellent in moldability and strength, has not only self-solubility, but also excellent storage stability of physiologically active substances.
  • the microneedle of the present invention is a self-dissolving microneedle, a bioactive substance can be contained inside the microneedle, and the skin permeability of the bioactive substance is higher than that of a conventional microneedle. Even in the case where the microneedle is broken and remains on the skin at the time of use, it is highly reliable in terms of point, and the physical burden on the user can be reduced because it dissolves gradually.
  • the microneedle of the present invention since it rapidly dissolves after puncturing the skin, the application time can be shortened compared with the conventional microneedle.
  • the microneedle according to one embodiment of the present invention contains a physiologically active substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40 ° C. or higher.
  • microneedle material among the components constituting the microneedle, components other than the physiologically active substance may be collectively referred to as “microneedle material”.
  • Physiologically active substances that can be used in the present embodiment include not only low molecular compounds but also high molecular compounds such as peptides, proteins, DNA, RNA, and vaccines.
  • the physiologically active substance include naltrexone, cetrorelix acetate, tartilelin, nafarelin acetate, prostaglandin A1, alprostadil, ⁇ -interferon, zolmitriptan, ⁇ -interferon, erythropoietin, follitropin ⁇ , follitropin Tropine ⁇ , G-CSF, GM-CSF, human chorionic gonadotropin, luteinizing hormone, salmon calcitonin, glucagon, GNRH antagonist, insulin, human growth hormone, filgrastin, heparin, low molecular weight heparin, somatropin, Examples include incretin and GLP-1 derivatives.
  • the physiologically active substance may be
  • the content of the physiologically active substance may be 0.1% by mass or more, 1% by mass or more, or 10% by mass or more based on the total mass of the microneedles. Further, the content of the physiologically active substance may be 90% by mass or less, 75% by mass or less, or 50% by mass or less based on the total mass of the microneedles.
  • amino acids selected from the group consisting of arginine and histidine examples include L-arginine, D-arginine, L-histidine, and D-histidine.
  • a preferred amino acid is L-arginine or L-histidine.
  • the above amino acids may be used alone or in combination of two or more.
  • amino acid may be used in a free form, a known acid addition salt may be used, or the salt may be used after desalting by a method well known to those skilled in the art. Good.
  • amino acid a commercially available product may be used, or one synthesized by a chemical method may be used.
  • the content of one or more amino acids selected from the group consisting of arginine and histidine can be 1 to 99% by mass based on the total mass of the microneedle, and is 5 to 95% by mass. It is preferably 10 to 90% by mass.
  • the said content is corresponded to the total amount of the amino acid used for the microneedle.
  • Examples of the acid having a melting point of 40 ° C. or higher that can be used in this embodiment include one or more acids selected from the group consisting of citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid, and aspartic acid. Specific examples of these acids are citric acid, L-lactic acid, D-lactic acid, L-tartaric acid, D-tartaric acid, succinic acid, phosphoric acid, L-aspartic acid and D-aspartic acid. In the microneedle according to the present embodiment, the acid may be used alone, or two or more kinds may be mixed and used. The acid having a melting point of 40 ° C.
  • the or higher that can be used in the present embodiment may be an acid having a melting point of 50 ° C. or higher, or an acid having a melting point of 150 ° C. or higher.
  • the melting point can be measured, for example, according to the description of the melting point measurement method of the 15th revised Japanese pharmacopoeia general test method.
  • the content of the acid having a melting point of 40 ° C. or higher in the present embodiment can be 1 to 99% by mass, preferably 5 to 95% by mass, based on the total mass of the microneedles. More preferably, it is 90 mass%. In addition, when using 2 or more types of acids mixed, the said content is corresponded to the total amount of the acid used for the microneedle.
  • the preferred molar ratio of acid to arginine varies depending on the type of acid.
  • arginine it is preferable to use lactic acid, tartaric acid, citric acid, succinic acid, phosphoric acid or aspartic acid as the acid having a melting point of 40 ° C. or higher. In the case of such a combination, a microneedle having better moldability can be obtained.
  • the acid is lactic acid
  • the number of moles of arginine with respect to the number of moles of acid is preferably 0.5 to 4, and more preferably 0.5 to 3.
  • the number of moles of arginine with respect to the number of moles of acid is preferably 0.5 to 6, and more preferably 0.5 to 5.
  • the number of moles of arginine with respect to the number of moles of acid is preferably 0.5 to 9, and more preferably 0.5 to 8.
  • the acid is succinic acid
  • the number of moles of arginine with respect to the number of moles of acid is preferably 0.5 to 6, and more preferably 1 to 5.
  • the acid is phosphoric acid, it is preferably from 0.5 to 9, more preferably from 2 to 5.
  • the number of moles of arginine relative to the number of moles of acid is preferably 1 to 4.
  • the number of moles of arginine relative to the number of moles of acid is within the above range, the moldability and strength of the microneedle are more excellent.
  • the excellent moldability of the microneedle means that when the appearance of the molded microneedle is observed with a microscope, it maintains a uniform needle shape and a transparent amorphous microneedle. Means.
  • the preferred molar ratio of acid to histidine varies depending on the type of acid.
  • histidine is used as the amino acid
  • tartaric acid, citric acid or aspartic acid is preferably used as the acid having a melting point of 40 ° C. or higher.
  • the acid is tartaric acid
  • the number of moles of histidine relative to the number of moles of acid is preferably 0.5 to 3, and more preferably 0.5 to 2.
  • the acid is citric acid
  • the number of moles of histidine relative to the number of moles of acid is preferably 0.5 to 4, and more preferably 0.5 to 2.
  • the number of moles of histidine relative to the number of moles of acid is preferably 0.5 to 1.
  • the number of moles of histidine relative to the number of moles of acid is within the above range, the moldability and strength of the microneedle are more excellent.
  • the shape of the microneedle according to the present embodiment may be, for example, a polygonal pyramid shape such as a triangular pyramid or a quadrangular pyramid; a polygonal pyramid shape such as a triangular pyramid or a quadrangular pyramid; a conical shape; A conical shape is preferable because it is easy to puncture and can reduce pain during application.
  • the microneedle according to the present embodiment is preferably amorphous. If the microneedles are amorphous, the strength tends to be excellent, and the solubility tends to increase.
  • the length in the puncturing direction is preferably 10 ⁇ m to 2 mm, and more preferably 50 ⁇ m to 1 mm.
  • the area of the surface in contact with the substrate is preferably preferably from 100 ⁇ 10000 2, a 200 ⁇ 5000 ⁇ m 2. Pain can be further reduced when the area of the surface in contact with the substrate is 10000 ⁇ m 2 or less.
  • the microneedle of the present embodiment can be manufactured, for example, according to the following method.
  • a microneedle mold is manufactured by a method well known to those skilled in the art.
  • One or more amino acids selected from the group consisting of a physiologically active substance, arginine and histidine, and an acid having a melting point of 40 ° C. or higher are dissolved in an arbitrary amount of water and dropped into the template.
  • the microneedles of this embodiment are produced by drying overnight at ° C.
  • it is preferable to remove bubbles from the mold by using the mold after immersing it in water, degassing it under reduced pressure, and then taking it out.
  • the template can be produced by a method well known to those skilled in the art.
  • the material of the mold may be a metal or a nonmetal, for example.
  • Examples of the non-metallic mold include silicone rubber.
  • the microneedle of this embodiment is a mixture of a physiologically active substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40 ° C. or higher, and is heated to an appropriate temperature. It may be produced by pouring a liquid material ensuring fluidity into the mold or by casting and gradually cooling.
  • the microneedle device 1 has a plurality of microneedles 3 arranged on a substrate 2 as shown in FIG.
  • the number of the microneedles 3 can be arbitrarily set by those skilled in the art.
  • the substrate 2 may be manufactured integrally with the microneedle 3, and in this case, the substrate 2 and the microneedle 3 are made of the same material.
  • the microneedle device according to the present embodiment may further include an applicator.
  • an applicator those well known to those skilled in the art can be used.
  • microneedles of Examples, Comparative Examples, and Reference Examples were manufactured according to the following method.
  • citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid, hydrochloric acid, glacial acetic acid, and aspartic acid are respectively anhydrous citric acid, L-lactic acid, L-tartaric acid, and succinic acid.
  • Phosphoric anhydride, concentrated hydrochloric acid (37% by mass aqueous hydrogen chloride solution), glacial acetic acid and L-aspartic acid were used.
  • L-arginine and L-histidine were used as arginine and histidine, respectively.
  • a silicone rubber mold was immersed in water, degassed under reduced pressure, and taken out of the water. Next, an aqueous solution of an amino acid and an acid (additive concentration: 15 w / v%) was dropped onto the mold and dried at 37 ° C. overnight to obtain a microneedle. The obtained microneedle was evaluated by the following test.
  • Microneedles were prepared from a combination of arginine and citric acid, a combination of arginine and hydrochloric acid, arginine alone or citric acid alone, and the appearances of the obtained microneedles were compared.
  • FIG. 1 (a) A photograph of a microneedle prepared from a combination of arginine and citric acid, a combination of arginine and hydrochloric acid, arginine alone or citric acid alone is shown in FIG.
  • the microneedle produced from the combination of arginine and citric acid (FIG. 1 (a)) was in a transparent amorphous state, had good moldability, and maintained a conical shape.
  • the microneedles prepared from the combination of arginine and hydrochloric acid FIG. 1 (b)
  • arginine alone FIG. 1 (c)
  • citric acid alone FIG. 1 (d)
  • Formability test (2) Using one or more amino acids selected from the group consisting of arginine and histidine and one or more acids selected from the group consisting of citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid, hydrochloric acid, glacial acetic acid and aspartic acid
  • one or more amino acids selected from the group consisting of arginine and histidine and one or more acids selected from the group consisting of citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid, hydrochloric acid, glacial acetic acid and aspartic acid Thus, microneedles were manufactured by the above manufacturing method. Next, the state of the obtained microneedle was observed using a microscope, and it was evaluated whether or not salt crystals were precipitated and whether or not the microneedle could be molded.
  • the skin permeability test was performed according to the following method.
  • a microneedle device (Reference Example 1) was applied to human isolated skin using an applicator. Subsequently, the skin to which the microneedle device was applied was fixed to a Franz-type cell, the receptor liquid 24 hours later was collected, and the permeation amount was measured by measuring the concentration of edible red No. 40 by HPLC. Note that phosphate buffered saline (PBS) was used as the receptor solution in this test.
  • PBS phosphate buffered saline
  • the cumulative permeation amount of the physiologically active substance after 24 hours from the application was about 5 ⁇ g. It was confirmed that the individual microneedles rapidly dissolved, and the physiologically active substance (food red No. 40) contained in the microneedles was released, indicating sufficient skin permeability. On the other hand, when the microneedle is simply brought into contact with the skin without using the applicator (“no pressing” in FIG. 3), the microneedle does not penetrate the epidermis, and after 24 hours from the application, The accumulated permeation amount of the physiologically active substance was 0 ⁇ g.
  • Shape stability test Observation of changes in shape when a 15% aqueous solution of a mixture of arginine and citric acid, maltose, polyvinylpyrrolidone (PVP-K12), polyvinylpyrrolidone (PVP-K90), pullulan or gelatin is dried at 40 ° C. did.
  • PVP-K90 polyvinylpyrrolidone
  • pullulan or gelatin were dried overnight at 40 ° C.
  • a mixture of arginine and citric acid, maltose or polyvinylpyrrolidone In the microneedle prepared from PVP-K12), the shape of the microneedle did not change.
  • a microneedle was manufactured by mixing an amino acid and an acid at the ratio shown in Table 2.
  • a urethane sheet (trade name: Hypergel sheet hardness 50, Shore C hardness: 50) manufactured by Exeal Corporation is coated with an aluminum foil and applied using an applicator equipped with the obtained microneedle. Was evaluated whether it penetrates aluminum foil.
  • microneedles prepared from a combination of arginine and citric acid is equivalent to microneedles prepared from polyvinylpyrrolidone (PVP-K12), although it is inferior to microneedles prepared from maltose. It was shown to have
  • the mass of the physiologically active substance contained in the microneedle was calculated in the same manner. A value obtained by dividing the mass of the obtained physiologically active substance by the mass of the physiologically active substance used in the production was recorded as “content of physiologically active substance (%) (50 ° C., 1 week)”.
  • the results are shown in Table 6 and FIG.
  • the microneedle of Example 1 had a high initial insulin content, and the insulin content value did not decrease even after storage for 1 week at 50 ° C.
  • the microneedle of Comparative Example 1 had a high initial insulin content, the insulin content after storage for 1 week at 50 ° C. decreased to 65%.
  • the microneedle of Comparative Example 2 had an initial insulin content of 50%, and the insulin content after storage for 1 week at 50 ° C. was 17%.
  • the microneedle of Example 1 showed a high insulin content even after being stored at 50 ° C. for 1 week, which revealed that the bioactive substance has high stability.
  • microneedles of Examples 1 to 6 had the necessary strength at the time of puncturing and could maintain the stability of the physiologically active substance high.
  • the microneedles of Comparative Examples 3 and 4 were excellent in the stability of the physiologically active substance in the storage period of 50 ° C. and 1 week, but the content of the physiologically active substance was significantly reduced during the production of the microneedle.
  • the results are shown in FIG.
  • the microneedles of Reference Examples 15 and 16 reached a steady state when 3 minutes passed after immersion, and the value was about 17 ⁇ g / mL.
  • the microneedle of Reference Example 17 reached a steady state when 7 minutes passed after immersion, and the value was about 15 ⁇ g / mL.
  • the concentration is 17 ⁇ g / mL.
  • the microneedles of Reference Examples 15 and 16 were able to elute the physiologically active substance more rapidly.
  • Formability test (3) Naltrexone, arginine, histidine and citric acid were mixed at a mass ratio shown in Table 8 to prepare microneedles of Examples 7 and 8. The appearances of the microneedles of Examples 1 to 4 and 7 to 8 were compared.
  • microneedles of Examples 1 to 4 and 7 to 8 were in a transparent amorphous state, had good moldability, and maintained a conical shape as in FIG. 1 (a).
  • Strength test (3) A urethane sheet (trade name: Hypergel sheet hardness 50, Shore C hardness: 50, manufactured by Exeal Corporation) coated with an aluminum foil having a thickness of 12 ⁇ m and having a thickness of 0.5 mm was prepared.
  • the microneedle device having 100 microneedles of Examples 1 to 8 is applied to the aluminum foil surface using an applicator (impact speed: 7 m / sec), the microneedle penetrates the aluminum foil. Was evaluated. Of the 100 microneedles, the number of penetrating aluminum foils was counted.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

　Provided is a microneedle containing a bioactive substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40ºC or higher.

Description

マイクロニードルMicro needle
　本発明は、マイクロニードルに関する。 The present invention relates to a microneedle.
　生理活性物質の経皮投与製剤は、経口投与製剤と比較して、使用者が嚥下困難な場合であっても投与することができ、かつ、水を必要としない点で、汎用性のある投与方法である。また、生理活性物質を経皮投与する方法は、注射剤と比較しても、医療従事者が周囲にいない状況でも簡便に投与することができる点で、使用者にとって取り扱いの容易な投与方法である。このような経皮投与製剤には、例えば、貼付剤やマイクロニードルデバイスが挙げられる。 Compared to oral dosage forms, transdermal administration of physiologically active substances can be administered even when the user has difficulty swallowing, and is a versatile administration because it does not require water. Is the method. In addition, the method of transdermal administration of a physiologically active substance is an administration method that is easy for a user to handle because it can be easily administered even in situations where a medical worker is not in the vicinity, compared to an injection. is there. Examples of such a preparation for transdermal administration include a patch and a microneedle device.
　従来のマイクロニードルデバイスは、微小突起を備えるマイクロニードルデバイスにおいて、該微小突起を、生理活性物質を含むコーティング溶液でコーティングすることによって製造している（特許文献１）。 A conventional microneedle device is manufactured by coating a microprotrusion with a coating solution containing a physiologically active substance in a microneedle device having microprotrusions (Patent Document 1).
　近年、微小突起を自己溶解型の材質とすることで、皮膚刺激及び廃棄物を低減させる方法が開発されている。自己溶解型のマイクロニードルとしては、マルトースとデキストランの混合物を主成分材質として使用したマイクロニードルや、カルボキシメチルセルロースナトリウムなどの水溶性高分子からなるマイクロニードルが挙げられる（特許文献２、３）。 Recently, a method for reducing skin irritation and waste by using a self-dissolving material as a microprojection has been developed. Examples of self-dissolving microneedles include microneedles using a mixture of maltose and dextran as a main component material, and microneedles made of a water-soluble polymer such as sodium carboxymethylcellulose (Patent Documents 2 and 3).
特表２００８－５２８５０９号公報Special table 2008-528509 gazette 特開２００５－１５２１８０号公報JP 2005-152180 A 特許４８２９４９７号公報Japanese Patent No. 4829497
　しかしながら、特許文献２に記載のマイクロニードルでは、マルトースと生理活性物質とを混合した後に、マルトースの融点以上に加熱してニードルの形状に成型する必要があり、熱安定性に劣る生理活性物質を使用することは困難である。さらに、生理活性物質がタンパク質である場合には、生理活性物質とマルトースとによりメイラード反応が進行し、生理活性物質の保存安定性が低下する。 However, in the microneedle described in Patent Document 2, after mixing maltose and a physiologically active substance, it is necessary to heat the maltose to a melting point or higher to mold it into a needle shape. It is difficult to use. Further, when the physiologically active substance is a protein, the Maillard reaction proceeds by the physiologically active substance and maltose, and the storage stability of the physiologically active substance is lowered.
　一方、特許文献３に記載のマイクロニードルでは、マイクロニードルの材質である水溶性高分子（カルボキシメチルセルロースナトリウム）が、乾燥工程中に変形し、マイクロニードルを安定的に製造することが困難な場合がある。 On the other hand, in the microneedle described in Patent Document 3, the water-soluble polymer (sodium carboxymethylcellulose) that is the material of the microneedle is deformed during the drying process, and it may be difficult to stably manufacture the microneedle. is there.
　本発明は、上記事情に鑑み、成型性及び強度に優れる自己溶解型のマイクロニードルを提供することを目的とする。 In view of the above circumstances, an object of the present invention is to provide a self-dissolving microneedle excellent in moldability and strength.
　本発明者らは、鋭意検討した結果、生理活性物質、アルギニン及びヒスチジンからなる群から選択される一以上のアミノ酸、並びに、融点が４０℃以上である酸、を含有するマイクロニードルが、成型性及び強度に優れ、自己溶解性を有することを見出し、本発明を完成させた。 As a result of intensive studies, the present inventors have found that a microneedle containing a physiologically active substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40 ° C. or higher is moldable. And it discovered that it was excellent in intensity | strength and had self-solubility, and completed this invention.
　上記酸はクエン酸、乳酸、酒石酸、コハク酸、リン酸及びアスパラギン酸からなる群から選択される一以上の酸であることが好ましく、クエン酸、酒石酸及びアスパラギン酸からなる群から選択される一以上の酸であることがより好ましい。上記アミノ酸はアルギニンであることが好ましい。
　本発明は、上記マイクロニードルの製造方法も提供する。 The acid is preferably one or more acids selected from the group consisting of citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid and aspartic acid, and one selected from the group consisting of citric acid, tartaric acid and aspartic acid. More preferred are the acids mentioned above. The amino acid is preferably arginine.
The present invention also provides a method for producing the microneedle.
　また、本発明は、基板上に、生理活性物質、アルギニン及びヒスチジンからなる群から選択される一以上のアミノ酸、並びに、融点が４０℃以上である酸、を含有するマイクロニードルを備える、マイクロニードルデバイスを提供する。 The present invention also provides a microneedle comprising, on a substrate, a microneedle containing a physiologically active substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40 ° C. or higher. Provide a device.
　さらに、本発明は、上記マイクロニードルデバイスを、当該マイクロニードルに含まれる生理活性物質の投与を必要とする対象の皮膚に適用するステップを含む、マイクロニードルデバイスの使用方法も提供する。 Furthermore, the present invention also provides a method for using the microneedle device, including the step of applying the microneedle device to the skin of a subject requiring administration of a physiologically active substance contained in the microneedle.
　本発明のマイクロニードルによれば、成型性及び強度に優れ、自己溶解性を有するだけでなく、生理活性物質の保存安定性にも優れる。また、本発明のマイクロニードルは、自己溶解型のマイクロニードルであるため、マイクロニードル内部に生理活性物質を含有させることができ、従来のマイクロニードルと比較して、生理活性物質の皮膚透過性の点で信頼性が高く、かつ、使用時にマイクロニードルが折れて皮膚に残るような場合であっても、徐々に溶解するため使用者への身体的負担を低減することができる。さらに、本発明のマイクロニードルによれば、皮膚に穿刺後、迅速に溶解することから、従来のマイクロニードルと比較して適用時間を短縮することができる。 The microneedle of the present invention is excellent in moldability and strength, has not only self-solubility, but also excellent storage stability of physiologically active substances. In addition, since the microneedle of the present invention is a self-dissolving microneedle, a bioactive substance can be contained inside the microneedle, and the skin permeability of the bioactive substance is higher than that of a conventional microneedle. Even in the case where the microneedle is broken and remains on the skin at the time of use, it is highly reliable in terms of point, and the physical burden on the user can be reduced because it dissolves gradually. Furthermore, according to the microneedle of the present invention, since it rapidly dissolves after puncturing the skin, the application time can be shortened compared with the conventional microneedle.
本発明の一実施形態に係るマイクロニードルの成型性を示す写真である。It is a photograph which shows the moldability of the microneedle which concerns on one Embodiment of this invention. 本発明の一実施形態に係るマイクロニードルデバイスを示す模式図である。It is a mimetic diagram showing a microneedle device concerning one embodiment of the present invention. 皮膚透過性試験の結果を示すグラフである。It is a graph which shows the result of a skin permeability test. 強度試験（２）の結果を示すグラフである。It is a graph which shows the result of an intensity test (2). 生理活性物質の安定性試験の結果を示すグラフである。It is a graph which shows the result of the stability test of a bioactive substance. 溶出性試験の結果を示すグラフである。It is a graph which shows the result of a dissolution test.
　本発明の一実施形態に係るマイクロニードルは、生理活性物質、アルギニン及びヒスチジンからなる群から選択される一以上のアミノ酸、並びに、融点が４０℃以上である酸、を含有する。 The microneedle according to one embodiment of the present invention contains a physiologically active substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40 ° C. or higher.
　本明細書中、マイクロニードルを構成する成分のうち、生理活性物質以外の成分をまとめて、「マイクロニードルの材質」という場合がある。 In the present specification, among the components constituting the microneedle, components other than the physiologically active substance may be collectively referred to as “microneedle material”.
　本実施形態に使用可能な生理活性物質としては、例えば、低分子化合物だけでなく、ペプチド、タンパク質、ＤＮＡ、ＲＮＡ等の高分子化合物、ワクチンなどであってもよい。上記生理活性物質としては、例えば、ナルトレキソン、酢酸セトロレリクス、タルチレリン、ナファレリン酢酸塩、プロスタグランジンＡ１、アルプロスタジル、α－インターフェロン、ゾルミトリプタン、β－インターフェロン、エリスロポイエチン、フォリトロピンβ、フォリトロピンα、Ｇ－ＣＳＦ、ＧＭ－ＣＳＦ、ヒト絨毛性腺刺激ホルモン、黄体形成（ｌｅｕｔｉｎｉｚｉｎｇ）ホルモン、サケカルシトニン、グルカゴン、ＧＮＲＨアンタゴニスト、インスリン、ヒト成長ホルモン、フィルグラスチン、ヘパリン、低分子ヘパリン、ソマトロピン、インクレチン、ＧＬＰ－１誘導体等が挙げられる。本実施形態に係るマイクロニードルにおいて、上記生理活性物質を単独で使用してもよく、２種以上を混合して使用してもよい。 Physiologically active substances that can be used in the present embodiment include not only low molecular compounds but also high molecular compounds such as peptides, proteins, DNA, RNA, and vaccines. Examples of the physiologically active substance include naltrexone, cetrorelix acetate, tartilelin, nafarelin acetate, prostaglandin A1, alprostadil, α-interferon, zolmitriptan, β-interferon, erythropoietin, follitropin β, follitropin Tropine α, G-CSF, GM-CSF, human chorionic gonadotropin, luteinizing hormone, salmon calcitonin, glucagon, GNRH antagonist, insulin, human growth hormone, filgrastin, heparin, low molecular weight heparin, somatropin, Examples include incretin and GLP-1 derivatives. In the microneedle according to the present embodiment, the physiologically active substance may be used alone, or two or more kinds may be mixed and used.
　生理活性物質の含有量は、マイクロニードルの全質量を基準として、０．１質量％以上であってもよく、１質量％以上であってもよく、１０質量％以上であってもよい。また、生理活性物質の含有量は、マイクロニードルの全質量を基準として、９０質量％以下であってもよく、７５質量％以下であってもよく、５０質量％以下であってもよい。 The content of the physiologically active substance may be 0.1% by mass or more, 1% by mass or more, or 10% by mass or more based on the total mass of the microneedles. Further, the content of the physiologically active substance may be 90% by mass or less, 75% by mass or less, or 50% by mass or less based on the total mass of the microneedles.
　本実施形態に使用可能なアルギニン及びヒスチジンからなる群から選択される一以上のアミノ酸としては、例えば、Ｌ－アルギニン、Ｄ－アルギニン、Ｌ－ヒスチジン及びＤ－ヒスチジンが挙げられる。好ましいアミノ酸は、Ｌ－アルギニン又はＬ－ヒスチジンである。本実施形態に係るマイクロニードルにおいて、上記アミノ酸を単独で使用してもよく、２種以上を混合して使用してもよい。 Examples of one or more amino acids selected from the group consisting of arginine and histidine that can be used in this embodiment include L-arginine, D-arginine, L-histidine, and D-histidine. A preferred amino acid is L-arginine or L-histidine. In the microneedle according to the present embodiment, the above amino acids may be used alone or in combination of two or more.
　また、上記アミノ酸は、フリー体のものを使用してもよく、周知の酸付加塩を使用してもよく、塩の状態のものを当業者に周知の方法により脱塩した後に使用してもよい。上記アミノ酸は、市販品を使用してもよく、化学的手法により合成したものを用いてもよい。 In addition, the amino acid may be used in a free form, a known acid addition salt may be used, or the salt may be used after desalting by a method well known to those skilled in the art. Good. As the amino acid, a commercially available product may be used, or one synthesized by a chemical method may be used.
　本実施形態におけるアルギニン及びヒスチジンからなる群から選択される一以上のアミノ酸の含有量は、マイクロニードルの全質量を基準として、１～９９質量％とすることができ、５～９５質量％であることが好ましく、１０～９０質量％であることがより好ましい。なお、２種以上のアミノ酸を混合して使用した場合、上記含有量は、マイクロニードルに使用したアミノ酸の合計量に相当する。 In the present embodiment, the content of one or more amino acids selected from the group consisting of arginine and histidine can be 1 to 99% by mass based on the total mass of the microneedle, and is 5 to 95% by mass. It is preferably 10 to 90% by mass. In addition, when using 2 or more types of amino acids in mixture, the said content is corresponded to the total amount of the amino acid used for the microneedle.
　本実施形態に使用可能な融点が４０℃以上である酸としては、例えば、クエン酸、乳酸、酒石酸、コハク酸、リン酸及びアスパラギン酸からなる群から選択される一以上の酸が挙げられる。これら酸の具体例としては、クエン酸、Ｌ－乳酸、Ｄ－乳酸、Ｌ－酒石酸、Ｄ－酒石酸、コハク酸、リン酸、Ｌ－アスパラギン酸及びＤ－アスパラギン酸である。本実施形態に係るマイクロニードルにおいて、上記酸を単独で使用してもよく、２種以上を混合して使用してもよい。本実施形態に使用可能な融点が４０℃以上である酸は、融点が５０℃以上である酸であってもよく、融点が１５０℃以上である酸であってもよい。なお、融点の測定は、例えば、第十五改正日本薬局方　一般試験法の融点測定法の記載に準じて行うことができる。融点が４０℃以上である酸を含有することにより、アルギニン又はヒスチジンと混合してマイクロニードルを調製した場合に、マイクロニードルの成型性が優れたものになる。 Examples of the acid having a melting point of 40 ° C. or higher that can be used in this embodiment include one or more acids selected from the group consisting of citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid, and aspartic acid. Specific examples of these acids are citric acid, L-lactic acid, D-lactic acid, L-tartaric acid, D-tartaric acid, succinic acid, phosphoric acid, L-aspartic acid and D-aspartic acid. In the microneedle according to the present embodiment, the acid may be used alone, or two or more kinds may be mixed and used. The acid having a melting point of 40 ° C. or higher that can be used in the present embodiment may be an acid having a melting point of 50 ° C. or higher, or an acid having a melting point of 150 ° C. or higher. The melting point can be measured, for example, according to the description of the melting point measurement method of the 15th revised Japanese pharmacopoeia general test method. By containing an acid having a melting point of 40 ° C. or higher, when the microneedle is prepared by mixing with arginine or histidine, the moldability of the microneedle becomes excellent.
　本実施形態における融点が４０℃以上である酸の含有量は、マイクロニードルの全質量を基準として、１～９９質量％とすることができ、５～９５質量％であることが好ましく、１０～９０質量％であることがより好ましい。なお、２種以上の酸を混合して使用した場合、上記含有量は、マイクロニードルに使用した酸の合計量に相当する。 The content of the acid having a melting point of 40 ° C. or higher in the present embodiment can be 1 to 99% by mass, preferably 5 to 95% by mass, based on the total mass of the microneedles. More preferably, it is 90 mass%. In addition, when using 2 or more types of acids mixed, the said content is corresponded to the total amount of the acid used for the microneedle.
　アミノ酸としてアルギニンを用いたマイクロニードルにおいて、酸の種類により、酸とアルギニンの好ましいモル比は異なる。アミノ酸としてアルギニンを用いる場合には、融点が４０℃以上である酸として、乳酸、酒石酸、クエン酸、コハク酸、リン酸又はアスパラギン酸を用いることが好ましい。このような組み合わせの場合に、成型性がより優れたマイクロニードルを得ることができる。酸が乳酸である場合、酸のモル数に対するアルギニンのモル数が０．５～４であることが好ましく、０．５～３であることがより好ましい。酸が酒石酸である場合、酸のモル数に対するアルギニンのモル数が０．５～６であることが好ましく、０．５～５であることがより好ましい。酸がクエン酸である場合、酸のモル数に対するアルギニンのモル数が０．５～９であることが好ましく、０．５～８であることがより好ましい。酸がコハク酸である場合、酸のモル数に対するアルギニンのモル数が０．５～６であることが好ましく、１～５であることがより好ましい。酸がリン酸である場合、０．５～９であることが好ましく、２～５であることがより好ましい。酸がアスパラギン酸である場合、酸のモル数に対するアルギニンのモル数が１～４であることが好ましい。酸のモル数に対するアルギニンのモル数が上記範囲内であると、マイクロニードルの成型性及び強度がより優れる。 In a microneedle using arginine as an amino acid, the preferred molar ratio of acid to arginine varies depending on the type of acid. When arginine is used as the amino acid, it is preferable to use lactic acid, tartaric acid, citric acid, succinic acid, phosphoric acid or aspartic acid as the acid having a melting point of 40 ° C. or higher. In the case of such a combination, a microneedle having better moldability can be obtained. When the acid is lactic acid, the number of moles of arginine with respect to the number of moles of acid is preferably 0.5 to 4, and more preferably 0.5 to 3. When the acid is tartaric acid, the number of moles of arginine with respect to the number of moles of acid is preferably 0.5 to 6, and more preferably 0.5 to 5. When the acid is citric acid, the number of moles of arginine with respect to the number of moles of acid is preferably 0.5 to 9, and more preferably 0.5 to 8. When the acid is succinic acid, the number of moles of arginine with respect to the number of moles of acid is preferably 0.5 to 6, and more preferably 1 to 5. When the acid is phosphoric acid, it is preferably from 0.5 to 9, more preferably from 2 to 5. When the acid is aspartic acid, the number of moles of arginine relative to the number of moles of acid is preferably 1 to 4. When the number of moles of arginine relative to the number of moles of acid is within the above range, the moldability and strength of the microneedle are more excellent.
　本明細書において、優れたマイクロニードルの成型性とは、成型されたマイクロニードルの外観を顕微鏡で観察した場合に、均質な針形状であり、かつ透明な非晶質のマイクロニードルを維持することを意味する。 In the present specification, the excellent moldability of the microneedle means that when the appearance of the molded microneedle is observed with a microscope, it maintains a uniform needle shape and a transparent amorphous microneedle. Means.
　アミノ酸としてヒスチジンを用いたマイクロニードルにおいて、酸の種類により、酸とヒスチジンの好ましいモル比は異なる。アミノ酸としてヒスチジンを用いる場合には、融点が４０℃以上である酸として、酒石酸、クエン酸又はアスパラギン酸を用いることが好ましい。このような組み合わせの場合に、成型性がより優れたマイクロニードルを得ることができる。酸が酒石酸である場合、酸のモル数に対するヒスチジンのモル数が０．５～３であることが好ましく、０．５～２であることがより好ましい。酸がクエン酸である場合、酸のモル数に対するヒスチジンのモル数が０．５～４であることが好ましく、０．５～２であることがより好ましい。酸がアスパラギン酸である場合、酸のモル数に対するヒスチジンのモル数が０．５～１であることが好ましい。酸のモル数に対するヒスチジンのモル数が上記範囲内であると、マイクロニードルの成型性及び強度がより優れる。 In a microneedle using histidine as an amino acid, the preferred molar ratio of acid to histidine varies depending on the type of acid. When histidine is used as the amino acid, tartaric acid, citric acid or aspartic acid is preferably used as the acid having a melting point of 40 ° C. or higher. In the case of such a combination, a microneedle having better moldability can be obtained. When the acid is tartaric acid, the number of moles of histidine relative to the number of moles of acid is preferably 0.5 to 3, and more preferably 0.5 to 2. When the acid is citric acid, the number of moles of histidine relative to the number of moles of acid is preferably 0.5 to 4, and more preferably 0.5 to 2. When the acid is aspartic acid, the number of moles of histidine relative to the number of moles of acid is preferably 0.5 to 1. When the number of moles of histidine relative to the number of moles of acid is within the above range, the moldability and strength of the microneedle are more excellent.
　本実施形態に係るマイクロニードルの形状としては、例えば、三角錐、四角錐等の多角錐状；三角錐、四角錐等の多角錐台状；円錐状；円錐台状であってもよい。穿刺しやすい点及び適用時の痛みを低減できる点から、円錐状であることが好ましい。また、本実施形態に係るマイクロニードルは、非晶質であることが好ましい。マイクロニードルが非晶質であると、強度が優れる傾向があり、さらに溶解性も高くなる傾向がある。 The shape of the microneedle according to the present embodiment may be, for example, a polygonal pyramid shape such as a triangular pyramid or a quadrangular pyramid; a polygonal pyramid shape such as a triangular pyramid or a quadrangular pyramid; a conical shape; A conical shape is preferable because it is easy to puncture and can reduce pain during application. In addition, the microneedle according to the present embodiment is preferably amorphous. If the microneedles are amorphous, the strength tends to be excellent, and the solubility tends to increase.
　本実施形態に係るマイクロニードルにおいて、穿刺する方向の長さは１０μｍ～２ｍｍであることが好ましく、５０μｍ～１ｍｍであることが好ましい。穿刺する方向の長さが１０μｍ以上であると、穿刺における信頼性がより向上する。また、本実施形態に係るマイクロニードルにおいて、基板と接する面の面積は、１００～１００００μｍ２であることが好ましく、２００～５０００μｍ２であることが好ましい。基板と接する面の面積が１００００μｍ２以下であると、痛みをより低減することができる。 In the microneedle according to this embodiment, the length in the puncturing direction is preferably 10 μm to 2 mm, and more preferably 50 μm to 1 mm. When the length in the puncturing direction is 10 μm or more, the reliability in puncturing is further improved. Further, in the micro-needle according to the present embodiment, the area of the surface in contact with the substrate is preferably preferably from 100 ~ 10000 2, a 200 ~ 5000μm 2. Pain can be further reduced when the area of the surface in contact with the substrate is 10000 μm 2 or less.
＜本実施形態に係るマイクロニードルの製造方法＞
　本実施形態のマイクロニードルは、例えば、以下の方法にしたがい、製造することができる。
（１）当業者に周知な方法でマイクロニードルの鋳型を製造する。
（２）生理活性物質、アルギニン及びヒスチジンからなる群から選択される一以上のアミノ酸、並びに、融点が４０℃以上である酸を任意の量の水に溶解させ、上記鋳型に滴下した後、３７℃で終夜乾燥させ、本実施形態のマイクロニードルを作製する。また、上記鋳型は、水に浸漬させ、減圧下脱気した後、取り出した後に使用することにより、鋳型の気泡を除くことが好ましい。 <The manufacturing method of the microneedle which concerns on this embodiment>
The microneedle of the present embodiment can be manufactured, for example, according to the following method.
(1) A microneedle mold is manufactured by a method well known to those skilled in the art.
(2) One or more amino acids selected from the group consisting of a physiologically active substance, arginine and histidine, and an acid having a melting point of 40 ° C. or higher are dissolved in an arbitrary amount of water and dropped into the template. The microneedles of this embodiment are produced by drying overnight at ° C. Moreover, it is preferable to remove bubbles from the mold by using the mold after immersing it in water, degassing it under reduced pressure, and then taking it out.
　本実施形態のマイクロニードルを作製するにあたり、鋳型は当業者に周知の方法で作製することができる。また、上記鋳型の材質は、例えば、金属であってもよく、非金属であってもよい。非金属の鋳型としては、例えば、シリコーンゴムが挙げられる。 In producing the microneedle of the present embodiment, the template can be produced by a method well known to those skilled in the art. The material of the mold may be a metal or a nonmetal, for example. Examples of the non-metallic mold include silicone rubber.
　また、本実施形態のマイクロニードルは、生理活性物質、アルギニン及びヒスチジンからなる群から選択される一以上のアミノ酸、並びに、融点が４０℃以上である酸を混合し、適当な温度に加熱し、流動性を確保した液状物を上記鋳型に流し込み、又は、キャスティング成型を行い、徐々に冷却して製造してもよい。 Further, the microneedle of this embodiment is a mixture of a physiologically active substance, one or more amino acids selected from the group consisting of arginine and histidine, and an acid having a melting point of 40 ° C. or higher, and is heated to an appropriate temperature. It may be produced by pouring a liquid material ensuring fluidity into the mold or by casting and gradually cooling.
　本発明の一実施形態であるマイクロニードルデバイス１は、図２に示すように、複数の上記マイクロニードル３が基板２上に配置されている。マイクロニードル３の本数は、当業者が任意に設定することができる。 The microneedle device 1 according to an embodiment of the present invention has a plurality of microneedles 3 arranged on a substrate 2 as shown in FIG. The number of the microneedles 3 can be arbitrarily set by those skilled in the art.
　本実施形態に係る基板２としては、当業者に周知な材料を使用することができる。上記基板２をマイクロニードル３と一体的に製造してもよく、その場合、上記基板２と上記マイクロニードル３は同一の素材である。 As the substrate 2 according to the present embodiment, materials well known to those skilled in the art can be used. The substrate 2 may be manufactured integrally with the microneedle 3, and in this case, the substrate 2 and the microneedle 3 are made of the same material.
　また、本実施形態に係るマイクロニードルデバイスは、さらにアプリケータを備えていてもよい。アプリケータとしては、当業者に周知なものを使用することができる。 Moreover, the microneedle device according to the present embodiment may further include an applicator. As the applicator, those well known to those skilled in the art can be used.
　実施例、比較例及び参考例のマイクロニードルは、以下の方法にしたがい、製造した。なお、本実施例においては、特記しない限り、クエン酸、乳酸、酒石酸、コハク酸、リン酸、塩酸、氷酢酸及びアスパラギン酸として、それぞれ、無水クエン酸、Ｌ－乳酸、Ｌ－酒石酸、コハク酸、無水リン酸、濃塩酸（３７質量％塩化水素水溶液）、氷酢酸及びＬ－アスパラギン酸を使用した。また、アルギニン及びヒスチジンとして、それぞれ、Ｌ－アルギニン及びＬ－ヒスチジンを使用した。
　シリコーンゴム製の鋳型を水に浸漬させ、減圧下脱気を行い、水から取り出した。次に、アミノ酸及び酸の水溶液（添加剤濃度：１５ｗ／ｖ％）を、上記鋳型に滴下し、３７℃で終夜乾燥させることによって、マイクロニードルを得た。得られたマイクロニードルを、以下の試験にて評価した。 The microneedles of Examples, Comparative Examples, and Reference Examples were manufactured according to the following method. In this example, unless otherwise specified, citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid, hydrochloric acid, glacial acetic acid, and aspartic acid are respectively anhydrous citric acid, L-lactic acid, L-tartaric acid, and succinic acid. , Phosphoric anhydride, concentrated hydrochloric acid (37% by mass aqueous hydrogen chloride solution), glacial acetic acid and L-aspartic acid were used. Further, L-arginine and L-histidine were used as arginine and histidine, respectively.
A silicone rubber mold was immersed in water, degassed under reduced pressure, and taken out of the water. Next, an aqueous solution of an amino acid and an acid (additive concentration: 15 w / v%) was dropped onto the mold and dried at 37 ° C. overnight to obtain a microneedle. The obtained microneedle was evaluated by the following test.
１．成型性試験（１）
　アルギニンとクエン酸の組み合わせ、アルギニンと塩酸の組み合わせ、アルギニンのみ又はクエン酸のみから、マイクロニードルを調製し、得られたマイクロニードルの外観を比較した。 1. Formability test (1)
Microneedles were prepared from a combination of arginine and citric acid, a combination of arginine and hydrochloric acid, arginine alone or citric acid alone, and the appearances of the obtained microneedles were compared.
　アルギニンとクエン酸の組み合わせ、アルギニンと塩酸の組み合わせ、アルギニンのみ又はクエン酸のみから調製されたマイクロニードルの写真を、図１に示した。アルギニンとクエン酸の組み合わせ（図１（ａ））から作製したマイクロニードルは、透明な非晶質様状態になり、成型性が良好であり、円錐形の形状を維持した。一方、アルギニンと塩酸の組み合わせ（図１（ｂ））、アルギニン単独（図１（ｃ））、クエン酸単独（図１（ｄ））から作製したマイクロニードルは、いずれも乾燥後に結晶の析出が確認され、成型性が不良であり、円錐形の形状を維持することができなかった。 A photograph of a microneedle prepared from a combination of arginine and citric acid, a combination of arginine and hydrochloric acid, arginine alone or citric acid alone is shown in FIG. The microneedle produced from the combination of arginine and citric acid (FIG. 1 (a)) was in a transparent amorphous state, had good moldability, and maintained a conical shape. On the other hand, the microneedles prepared from the combination of arginine and hydrochloric acid (FIG. 1 (b)), arginine alone (FIG. 1 (c)), and citric acid alone (FIG. 1 (d)) all had crystals precipitated after drying. It was confirmed that the moldability was poor and the conical shape could not be maintained.
２．成型性試験（２）
　アルギニン及びヒスチジンからなる群から選択される一以上のアミノ酸と、クエン酸、乳酸、酒石酸、コハク酸、リン酸、塩酸、氷酢酸及びアスパラギン酸からなる群から選択される一以上の酸とを用いて上記製造方法により、マイクロニードルを製造した。次に、顕微鏡を用いて、得られたマイクロニードルの状態を観察し、塩の結晶が析出するか否か、マイクロニードルを成型できるか否かについて評価した。 2. Formability test (2)
Using one or more amino acids selected from the group consisting of arginine and histidine and one or more acids selected from the group consisting of citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid, hydrochloric acid, glacial acetic acid and aspartic acid Thus, microneedles were manufactured by the above manufacturing method. Next, the state of the obtained microneedle was observed using a microscope, and it was evaluated whether or not salt crystals were precipitated and whether or not the microneedle could be molded.
　アルギニンと、乳酸、酒石酸、クエン酸、コハク酸、リン酸又はアスパラギン酸とを使用した場合に、透明な非晶質のマイクロニードルを製造することができたのに対し、アルギニンと、塩酸又は氷酢酸とを使用した場合には、マイクロニードルが得られなかった。また、ヒスチジンと、酒石酸、クエン酸又はアスパラギン酸とを使用した場合に、透明な非晶質のマイクロニードルを製造することができたのに対し、ヒスチジンと、塩酸又は氷酢酸とを使用した場合には、マイクロニードルが得られなかった。 When arginine and lactic acid, tartaric acid, citric acid, succinic acid, phosphoric acid or aspartic acid were used, transparent amorphous microneedles could be produced, whereas arginine and hydrochloric acid or ice When acetic acid was used, microneedles were not obtained. In addition, when histidine and tartaric acid, citric acid or aspartic acid were used, transparent amorphous microneedles could be produced, whereas histidine and hydrochloric acid or glacial acetic acid were used. No microneedle was obtained.
３．皮膚透過性試験
　本試験では、表１に示す割合で食用赤色４０号（Ｒ４０又はＡｌｌｕｒａ　Ｒｅｄ　ＡＣともいう）、アルギニン及びクエン酸を混合して調製された１００本のマイクロニードルを備えたマイクロニードルデバイス（参考例１）を使用した。なお、表１の数値は、使用した各成分の質量比を表す。また、食用赤色４０号は、生理活性物質の代わりとして使用した。
Figure JPOXMLDOC01-appb-T000001
 3. Skin Permeability Test In this test, a microneedle device comprising 100 microneedles prepared by mixing edible red No. 40 (also referred to as R40 or Allura Red AC), arginine and citric acid in the proportions shown in Table 1. (Reference Example 1) was used. In addition, the numerical value of Table 1 represents the mass ratio of each component used. Edible red No. 40 was used as a substitute for the physiologically active substance.
Figure JPOXMLDOC01-appb-T000001
　皮膚透過性試験は、以下の方法にしたがい、行った。
　マイクロニードルデバイス（参考例１）を、ヒト摘出皮膚にアプリケータを用いて適用した。続いて、マイクロニードルデバイスを適用した皮膚を、フランツ型セルに固定し、２４時間後のレセプター液を回収し、ＨＰＬＣにて食用赤色４０号の濃度を測定することによって透過量を測定した。なお、本試験のレセプター液にはリン酸緩衝生理食塩水（ＰＢＳ）を使用した。 The skin permeability test was performed according to the following method.
A microneedle device (Reference Example 1) was applied to human isolated skin using an applicator. Subsequently, the skin to which the microneedle device was applied was fixed to a Franz-type cell, the receptor liquid 24 hours later was collected, and the permeation amount was measured by measuring the concentration of edible red No. 40 by HPLC. Note that phosphate buffered saline (PBS) was used as the receptor solution in this test.
　アプリケータを使用して、マイクロニードルを皮膚に適用した場合（図３中、「アプリケータ適用」）、適用から２４時間経過後の生理活性物質の累積透過量は約５μｇであった。個々のマイクロニードルが迅速に溶解し、マイクロニードル中に含有される生理活性物質（食用赤色４０号）が放出され、十分な皮膚透過性を示すことが確認された。一方、アプリケータを使用せずに、マイクロニードルを皮膚に単に接触させただけの場合（図３中、「押し付け無し」）では、マイクロニードルが表皮を貫通せず、適用から２４時間経過後の生理活性物質の累積透過量は０μｇであった。 When the microneedle was applied to the skin using the applicator (“applicator application” in FIG. 3), the cumulative permeation amount of the physiologically active substance after 24 hours from the application was about 5 μg. It was confirmed that the individual microneedles rapidly dissolved, and the physiologically active substance (food red No. 40) contained in the microneedles was released, indicating sufficient skin permeability. On the other hand, when the microneedle is simply brought into contact with the skin without using the applicator (“no pressing” in FIG. 3), the microneedle does not penetrate the epidermis, and after 24 hours from the application, The accumulated permeation amount of the physiologically active substance was 0 μg.
４．形状安定性試験
　アルギニンとクエン酸の混合物、マルトース、ポリビニルピロリドン（ＰＶＰ－Ｋ１２）、ポリビニルピロリドン（ＰＶＰ－Ｋ９０）、プルラン又はゼラチンの１５％水溶液を、４０℃で乾燥した際の形状の変化を観察した。 4). Shape stability test Observation of changes in shape when a 15% aqueous solution of a mixture of arginine and citric acid, maltose, polyvinylpyrrolidone (PVP-K12), polyvinylpyrrolidone (PVP-K90), pullulan or gelatin is dried at 40 ° C. did.
　ポリビニルピロリドン（ＰＶＰ－Ｋ９０）、プルラン又はゼラチンから調製したマイクロニードルでは、４０℃において終夜乾燥させた場合、マイクロニードルの形状が変化したのに対し、アルギニンとクエン酸の混合物、マルトース又はポリビニルピロリドン（ＰＶＰ－Ｋ１２）から調製したマイクロニードルでは、マイクロニードルの形状は変化しなかった。 When microneedles prepared from polyvinylpyrrolidone (PVP-K90), pullulan or gelatin were dried overnight at 40 ° C., the shape of the microneedles changed, whereas a mixture of arginine and citric acid, maltose or polyvinylpyrrolidone ( In the microneedle prepared from PVP-K12), the shape of the microneedle did not change.
５．強度試験（１）
　表２に記載の比率で、アミノ酸と酸を混合し、マイクロニードルを製造した。ウレタンシート（（株）エクシールコーポレーション製、商品名：ハイパーゲルシート硬度５０、ショアＣ硬度：５０）をアルミ箔で被覆し、得られたマイクロニードルを備えたアプリケータを使用して適用し、マイクロニードルがアルミ箔を貫通するかを評価した。 5. Strength test (1)
A microneedle was manufactured by mixing an amino acid and an acid at the ratio shown in Table 2. A urethane sheet (trade name: Hypergel sheet hardness 50, Shore C hardness: 50) manufactured by Exeal Corporation is coated with an aluminum foil and applied using an applicator equipped with the obtained microneedle. Was evaluated whether it penetrates aluminum foil.
　結果を表２に示した。参考例２～１１のマイクロニードルは、全てアルミ箔を貫通する強度を有していた。
Figure JPOXMLDOC01-appb-T000002
 The results are shown in Table 2. The microneedles of Reference Examples 2 to 11 all had the strength to penetrate the aluminum foil.
Figure JPOXMLDOC01-appb-T000002
６．強度試験（２）
　表３に記載にしたがい、参考例１２～１４のマイクロニードルを製造し、テクスチャーアナライザー（ＴＡ．ＸＴ　ｐｌｕｓ　ｔｅｘｔｕｒｅ　ａｎａｌｙｚｅｒ、Ｓｔａｂｌｅ　Ｍｉｃｒｏ　Ｓｙｓｔｅｍｓ社製）を用いて、得られたマイクロニードルが破断した時の最大応力を測定した。 6). Strength test (2)
According to the description in Table 3, the microneedles of Reference Examples 12 to 14 were produced, and the obtained microneedles were ruptured using a texture analyzer (TA.XT plus texture analyzer, manufactured by Stable Micro Systems). Stress was measured.
　結果を表３及び図４に示した。アルギニンとクエン酸の組み合わせから調製されたマイクロニードルの強度は、マルトースから調製されたマイクロニードルに劣るものの、ポリビニルピロリドン（ＰＶＰ－Ｋ１２）から調製されたマイクロニードルと同等であり、穿刺に必要な強度を有していることが示された。
Figure JPOXMLDOC01-appb-T000003
 The results are shown in Table 3 and FIG. The strength of microneedles prepared from a combination of arginine and citric acid is equivalent to microneedles prepared from polyvinylpyrrolidone (PVP-K12), although it is inferior to microneedles prepared from maltose. It was shown to have
Figure JPOXMLDOC01-appb-T000003
７．生理活性物質の安定性試験
　表４及び表５の記載にしたがい、実施例１～６及び比較例１～６のマイクロニードルを製造した。なお、表４及び表５中に記載の数値は、質量部を意味する。製造直後のマイクロニードルに含有される生理活性物質の質量は、生理活性物質がインスリン又はヒト成長ホルモンである場合には、全自動エンザイムイムノアッセイ装置（ＡＩＡ－３６０、東ソー株式会社製）を使用し、生理活性物質がリキシセナチドである場合には、ＨＰＬＣを使用して算出した。得られた生理活性物質の質量を、製造時に使用した生理活性物質の質量で除した値を、「初期生理活性物質の含有量（％）」として記録した。次に、得られたマイクロニードルを５０℃で、１週間保存した後に、マイクロニードルに含有される生理活性物質の質量を同様にして算出した。得られた生理活性物質の質量を、製造時に使用した生理活性物質の質量で除した値を、「生理活性物質の含有量（％）（５０℃、１週間）」として記録した。
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
 7). Stability test of physiologically active substances According to the descriptions in Tables 4 and 5, microneedles of Examples 1 to 6 and Comparative Examples 1 to 6 were produced. In addition, the numerical value as described in Table 4 and Table 5 means a mass part. The mass of the physiologically active substance contained in the microneedle immediately after production is determined using a fully automatic enzyme immunoassay device (AIA-360, manufactured by Tosoh Corporation) when the physiologically active substance is insulin or human growth hormone. When the physiologically active substance was lixisenatide, it was calculated using HPLC. A value obtained by dividing the mass of the obtained physiologically active substance by the mass of the physiologically active substance used at the time of production was recorded as “content of initial physiologically active substance (%)”. Next, after the obtained microneedle was stored at 50 ° C. for one week, the mass of the physiologically active substance contained in the microneedle was calculated in the same manner. A value obtained by dividing the mass of the obtained physiologically active substance by the mass of the physiologically active substance used in the production was recorded as “content of physiologically active substance (%) (50 ° C., 1 week)”.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
　結果を表６及び図５に示した。実施例１のマイクロニードルは、初期インスリン含有量が高く、５０℃で１週間保存した後であってもインスリン含有量の値は低下しなかった。これに対し、比較例１のマイクロニードルは、初期インスリン含有量は高いものの、５０℃で１週間保存後のインスリン含有量は６５％に低下した。また、比較例２のマイクロニードルは、初期インスリン含有量が５０％であり、５０℃で１週間保存後のインスリン含有量は１７％であった。実施例１のマイクロニードルは、５０℃で１週間保存した後であっても、高いインスリン含有量を示したことから、生理活性物質の安定性が高いことが明らかとなった。一方、実施例１～６のマイクロニードルは、穿刺時に必要な強度を有し、かつ生理活性物質の安定性を高く維持できた。比較例３及び４のマイクロニードルは、５０℃、１週間の保存期間において、生理活性物質の安定性が優れていたが、マイクロニードルの製造時に生理活性物質の含有量が顕著に低下した。
Figure JPOXMLDOC01-appb-T000006
 The results are shown in Table 6 and FIG. The microneedle of Example 1 had a high initial insulin content, and the insulin content value did not decrease even after storage for 1 week at 50 ° C. In contrast, although the microneedle of Comparative Example 1 had a high initial insulin content, the insulin content after storage for 1 week at 50 ° C. decreased to 65%. In addition, the microneedle of Comparative Example 2 had an initial insulin content of 50%, and the insulin content after storage for 1 week at 50 ° C. was 17%. The microneedle of Example 1 showed a high insulin content even after being stored at 50 ° C. for 1 week, which revealed that the bioactive substance has high stability. On the other hand, the microneedles of Examples 1 to 6 had the necessary strength at the time of puncturing and could maintain the stability of the physiologically active substance high. The microneedles of Comparative Examples 3 and 4 were excellent in the stability of the physiologically active substance in the storage period of 50 ° C. and 1 week, but the content of the physiologically active substance was significantly reduced during the production of the microneedle.
Figure JPOXMLDOC01-appb-T000006
８．溶出性試験
　表７の記載にしたがい、食用赤色４０号（Ｒ４０）の濃度が１質量％、かつマイクロニードルの材質に相当する成分が１５％となる水溶液を調製し、参考例１５～１７のマイクロニードルを製造した。なお、Ｒ４０は、生理活性物質の代わりとして使用した。得られたマイクロニードルを、以下の方法にしたがい、ＰＢＳ中に浸漬させて、一定時間経過後におけるＲ４０の累積溶出量を測定した。
Figure JPOXMLDOC01-appb-T000007
 8). Elution test According to the description in Table 7, an aqueous solution in which the concentration of edible red No. 40 (R40) was 1% by mass and the component corresponding to the material of the microneedle was 15% was prepared. A needle was manufactured. R40 was used as a substitute for a physiologically active substance. The obtained microneedle was immersed in PBS according to the following method, and the accumulated amount of R40 eluted after a lapse of a certain time was measured.
Figure JPOXMLDOC01-appb-T000007
　結果を図６に示した。参考例１５及び１６のマイクロニードルは、浸漬後３分経過した時点で、定常状態に達し、その値は約１７μｇ／ｍＬであった。一方、参考例１７のマイクロニードルは、浸漬後７分経過した時点で、定常状態に達し、その値は約１５μｇ／ｍＬであった。なお、マイクロニードルから全てのＲ４０が溶出すると、その濃度は１７μｇ／ｍＬとなる。参考例１５及び１６のマイクロニードルは、より迅速に生理活性物質を溶出することができた。 The results are shown in FIG. The microneedles of Reference Examples 15 and 16 reached a steady state when 3 minutes passed after immersion, and the value was about 17 μg / mL. On the other hand, the microneedle of Reference Example 17 reached a steady state when 7 minutes passed after immersion, and the value was about 15 μg / mL. When all R40 is eluted from the microneedle, the concentration is 17 μg / mL. The microneedles of Reference Examples 15 and 16 were able to elute the physiologically active substance more rapidly.
９．成型性試験（３）
　表８に記載の質量比で、ナルトレキソン、アルギニン、ヒスチジン及びクエン酸を混合し、実施例７及び８のマイクロニードルを調製した。実施例１～４及び７～８のマイクロニードルの外観を比較した。
Figure JPOXMLDOC01-appb-T000008
 9. Formability test (3)
Naltrexone, arginine, histidine and citric acid were mixed at a mass ratio shown in Table 8 to prepare microneedles of Examples 7 and 8. The appearances of the microneedles of Examples 1 to 4 and 7 to 8 were compared.
Figure JPOXMLDOC01-appb-T000008
　実施例１～４及び７～８のマイクロニードルは、図１（ａ）と同様に、透明な非晶質様状態になり、成型性が良好であり、円錐形の形状を維持した。 The microneedles of Examples 1 to 4 and 7 to 8 were in a transparent amorphous state, had good moldability, and maintained a conical shape as in FIG. 1 (a).
１０．強度試験（３）
　厚みが１２μｍであるアルミ箔で被覆された、厚みが０．５ｍｍであるウレタンシート（（株）エクシールコーポレーション製、商品名：ハイパーゲルシート硬度５０、ショアＣ硬度：５０）を用意した。実施例１～８のマイクロニードル１００本を備えたマイクロニードルデバイスを、アプリケータ（衝突速度７ｍ／秒）を使用して、上記アルミ箔表面に適用した場合に、マイクロニードルがアルミ箔を貫通するかを評価した。１００本のマイクロニードルのうち、アルミ箔を貫通した本数を計数した。 10. Strength test (3)
A urethane sheet (trade name: Hypergel sheet hardness 50, Shore C hardness: 50, manufactured by Exeal Corporation) coated with an aluminum foil having a thickness of 12 μm and having a thickness of 0.5 mm was prepared. When the microneedle device having 100 microneedles of Examples 1 to 8 is applied to the aluminum foil surface using an applicator (impact speed: 7 m / sec), the microneedle penetrates the aluminum foil. Was evaluated. Of the 100 microneedles, the number of penetrating aluminum foils was counted.
　実施例１～４及び７～８のマイクロニードルを用いた場合、全てのマイクロニードルがアルミ箔を貫通する強度を示した。 When using the microneedles of Examples 1 to 4 and 7 to 8, all the microneedles showed strength to penetrate the aluminum foil.
１…マイクロニードルデバイス、２…基板、３…マイクロニードル。 DESCRIPTION OF SYMBOLS 1 ... Microneedle device, 2 ... Substrate, 3 ... Microneedle.

Claims (5)

  1. 　生理活性物質、
    　アルギニン及びヒスチジンからなる群から選択される一以上のアミノ酸、並びに、
    　融点が４０℃以上である酸、
    を含有するマイクロニードル。     Physiologically active substances,
    One or more amino acids selected from the group consisting of arginine and histidine, and
    An acid having a melting point of 40 ° C. or higher,
    Containing microneedles.
  2. 　前記酸がクエン酸、乳酸、酒石酸、コハク酸、リン酸及びアスパラギン酸からなる群から選択される一以上の酸である、請求項１に記載のマイクロニードル。 The microneedle according to claim 1, wherein the acid is one or more acids selected from the group consisting of citric acid, lactic acid, tartaric acid, succinic acid, phosphoric acid and aspartic acid.
  3. 　前記アミノ酸がアルギニンである、請求項１又は２に記載のマイクロニードル。 The microneedle according to claim 1 or 2, wherein the amino acid is arginine.
  4. 　前記酸がクエン酸、酒石酸及びアスパラギン酸からなる群から選択される一以上の酸である、請求項１～３のいずれか一項に記載のマイクロニードル。 The microneedle according to any one of claims 1 to 3, wherein the acid is one or more acids selected from the group consisting of citric acid, tartaric acid and aspartic acid.
  5. 　基板上に、請求項１～４のいずれか一項に記載のマイクロニードルを備える、マイクロニードルデバイス。 A microneedle device comprising the microneedle according to any one of claims 1 to 4 on a substrate.
PCT/JP2015/055614 2014-02-27 2015-02-26 Microneedle WO2015129807A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2016505294A JP6211169B2 (en) 2014-02-27 2015-02-26 Micro needle

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2014-036626 2014-02-27
JP2014036626 2014-02-27

Publications (1)

Publication Number Publication Date
WO2015129807A1 true WO2015129807A1 (en) 2015-09-03

Family

ID=54009121

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2015/055614 WO2015129807A1 (en) 2014-02-27 2015-02-26 Microneedle

Country Status (3)

Country Link
JP (1) JP6211169B2 (en)
TW (1) TW201620508A (en)
WO (1) WO2015129807A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017179615A1 (en) * 2016-04-15 2017-10-19 富士フイルム株式会社 Microneedle array and method for fabricating microneedle array
WO2018224559A1 (en) * 2017-06-07 2018-12-13 Lts Lohmann Therapie-Systeme Ag Microneedle system for applying glucagon-like peptide analogues
WO2020250210A1 (en) * 2019-06-10 2020-12-17 University College Cork - National University Of Ireland, Cork Microneedles, and methods for the manufacture thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3416618A1 (en) 2016-02-19 2018-12-26 ZP Opco, Inc. Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines
US11660264B2 (en) 2017-08-23 2023-05-30 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches
US11660265B2 (en) 2018-06-28 2023-05-30 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013082427A1 (en) * 2011-11-30 2013-06-06 3M Innovative Properties Company Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
WO2014126105A1 (en) * 2013-02-13 2014-08-21 久光製薬株式会社 Microneedle coating composition and microneedle device
WO2014126104A1 (en) * 2013-02-13 2014-08-21 久光製薬株式会社 Microneedle-coating composition and microneedle device

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013082427A1 (en) * 2011-11-30 2013-06-06 3M Innovative Properties Company Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
WO2014126105A1 (en) * 2013-02-13 2014-08-21 久光製薬株式会社 Microneedle coating composition and microneedle device
WO2014126104A1 (en) * 2013-02-13 2014-08-21 久光製薬株式会社 Microneedle-coating composition and microneedle device

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017179615A1 (en) * 2016-04-15 2017-10-19 富士フイルム株式会社 Microneedle array and method for fabricating microneedle array
WO2018224559A1 (en) * 2017-06-07 2018-12-13 Lts Lohmann Therapie-Systeme Ag Microneedle system for applying glucagon-like peptide analogues
CN110769812A (en) * 2017-06-07 2020-02-07 Lts勒曼治疗系统股份公司 Microneedle system for administering glucagon-like peptide analogs
JP2020522354A (en) * 2017-06-07 2020-07-30 エルテーエス ローマン テラピー−ジステーメ アーゲー Microneedle system for applying glucagon-like peptide analogs
WO2020250210A1 (en) * 2019-06-10 2020-12-17 University College Cork - National University Of Ireland, Cork Microneedles, and methods for the manufacture thereof

Also Published As

Publication number Publication date
JP6211169B2 (en) 2017-10-11
JPWO2015129807A1 (en) 2017-03-30
TW201620508A (en) 2016-06-16

Similar Documents

Publication Publication Date Title
JP6211169B2 (en) Micro needle
JP6894455B2 (en) Microarrays, usage and manufacturing methods for delivery of therapeutic agents
KR101728194B1 (en) Micro-needle device and preparation method
TWI625128B (en) Microneedle coating composition and microneedle device
US20200237654A1 (en) Microstructure array, methods of making, and methods of use
TW200528154A (en) Composition and apparatus for transdermal delivery
JP5695731B2 (en) Bioactive nonaqueous composition for microneedle device and bioactive nonaqueous composition attached on microneedle
JP2016512754A5 (en)
WO2013057819A1 (en) Microneedle deposition technique
JP2021072884A (en) Microneedle array coated with drug composition
US9173924B2 (en) Stable glucagon peptide formulations
TW201832758A (en) Method for producing microneedle device
JP5688752B2 (en) Transdermal absorption preparation and method for producing the same
EP2957298B1 (en) Microneedle coating composition and microneedle device
US20180153798A1 (en) Stable Glucagon Peptide Formulations
JP2024500424A (en) Insoluble transdermal microneedle patch and its preparation method and application
JP2019508175A5 (en)
JP2022106846A (en) Microneedle device and method for manufacturing the same
JP7008684B2 (en) Microneedle device
JP6621754B2 (en) Microneedle device containing recombinant follicle stimulating hormone
JP6081215B2 (en) Coating and microneedle devices
TWI631965B (en) Microneedle device and its manufacturing method
Dillon et al. Development of Novel Transdermal Drug Delivery Technologies for Therapeutic Peptides

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15756103

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2016505294

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15756103

Country of ref document: EP

Kind code of ref document: A1