WO2022215693A1 - Microneedle array for local anesthesia for dental use - Google Patents

Microneedle array for local anesthesia for dental use Download PDF

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Publication number
WO2022215693A1
WO2022215693A1 PCT/JP2022/017101 JP2022017101W WO2022215693A1 WO 2022215693 A1 WO2022215693 A1 WO 2022215693A1 JP 2022017101 W JP2022017101 W JP 2022017101W WO 2022215693 A1 WO2022215693 A1 WO 2022215693A1
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Prior art keywords
microneedle array
microneedle
water
local anesthetic
mass
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PCT/JP2022/017101
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French (fr)
Japanese (ja)
Inventor
英淑 権
美生 斎藤
裕史 山下
文男 神山
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コスメディ製薬株式会社
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Publication of WO2022215693A1 publication Critical patent/WO2022215693A1/en

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics

Definitions

  • the present invention relates to the technical field of microneedles applied to dental (oral) local anesthesia.
  • an anesthetic is applied to the mucous membrane of the oral cavity (gums) or injected into the gums.
  • an anesthetic is applied to the mucous membrane of the oral cavity (gums) or injected into the gums.
  • local anesthetics for dentistry. They are mainly local anesthetic-containing liquid agents, gel agents, jelly agents, etc., and the liquid agents are soaked in absorbent cotton or the like and applied to the oral cavity. Gels and jellies are applied to the oral cavity as they are. In both cases, the absorption of the anesthetic from the mucous membrane is slow, so it takes a long time for the effect to occur, and the long waiting time for the patient to lie down and the variability in mucosal absorption often impairs QOL. .
  • Microneedle formulations have high percutaneous absorbability, and attempts are being made to develop cosmetics and pharmaceuticals.
  • the application site of a microneedle preparation is the skin epidermis, and for example, a microneedle patch is known for vaccination by intrabuccal administration (Patent Document 1).
  • the present microneedle patch is designed to penetrate the outer layer of the inner buccal mucosa.
  • microneedles for delivery of dental substances such as dental local anesthetics have been developed (Patent Documents 2, 3, 4).
  • Patent Document 2 includes a microneedle array and a hollow spherical container containing a dental local anesthetic inside, and the anesthetic is locally delivered through an opening passing through the microneedles.
  • Patent Document 3 is a microneedle that includes a base that bends along the shape of the skin inside the oral cavity, a microneedle body, and an active ingredient coating that coats the surface of the needle body.
  • Patent Document 4 is composed of a substrate integrally formed from the same water-soluble polymer and water-soluble low-molecular compound using a water-soluble polymer and a water-soluble low-molecular compound as a base, and a plurality of microneedles on the substrate. be.
  • An object of the present invention is to provide a microneedle array that can be easily applied to the oral cavity, exhibits an anesthetic effect suitable for the application site, and has excellent stability.
  • the patient's QOL can be significantly improved if rapid topical anesthesia can be applied to a depth of 1-2 mm in the skin before the injection of the anesthetic.
  • the present inventors have made intensive studies in view of the particularities of oral tissues and the field of dentistry. I came up with the invention (Japanese Patent Application Laid-Open No. 2019-084352). Furthermore, in order to increase the stability of the drug, ethyl aminobenzoate, as a result of intensive studies, it was found that the intended purpose can be achieved by incorporating the drug in a specific ratio in a microneedle array manufactured using a specific base. and completed the present invention.
  • a rapid-acting dental local anesthetic preparation comprising a microneedle array containing ethyl aminobenzoate, wherein the content of ethyl aminobenzoate in the microneedle array is 5 to 30% by mass, and A dental local anesthetic preparation in which ethyl aminobenzoate and polyvinylpyrrolidone coexist in the microneedle array, and the ethyl aminobenzoate is dissolved or uniformly dispersed in the microneedle array.
  • a rapid-acting dental local anesthetic preparation comprising a microneedle array containing ethyl aminobenzoate,
  • the microneedle array consists of a substrate and a plurality of microneedles on the substrate, is integrally formed from the same water-soluble polymer with a water-soluble polymer as a base, and has a flexible substrate,
  • the water-soluble polymer is one or two selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone, hyaluronic acid and its derivatives, hydroxypropylcellulose, collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran.
  • the dental local anesthetic preparation according to any one of [5] to [10], wherein the concentration of ethyl aminobenzoate in the base is 5% by mass or more and 30% by mass or less.
  • the height of the microneedle is 50 ⁇ m or more and 500 ⁇ m or less
  • the tip of the microneedle is a circle having a diameter of 1 ⁇ m or more and 50 ⁇ m or less or a flat surface having the same area
  • the thickness of the substrate of the microneedle array is 5 ⁇ m or more and 100 ⁇ m.
  • the water-soluble polymer is one or two selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone, hyaluronic acid and its derivatives, hydroxypropylcellulose, collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran.
  • a microneedle array is a mixture of A microneedle array, wherein the polyvinylpyrrolidone accounts for 50 to 100% by mass of the water-soluble polymer.
  • a microneedle patch comprising the microneedle array according to any one of [12] to [14] and a support provided on the back surface of the microneedle array.
  • microneedle patch of [15], wherein the support has intraoral adhesiveness.
  • the microneedle patch of [16], wherein the support is coated with an adhesive substance.
  • the microneedle patch of [16], wherein the support is water-soluble.
  • the microneedle patch according to any one of [15] to [18], wherein the support is in the form of a film and partially has a defective portion that does not contain a film.
  • the microneedle patch of any one of [15] to [18], wherein the support is sterile paper and forms an outer frame enclosing the microneedle array.
  • the microneedle array of the present invention uses a water-soluble polymer containing polyvinylpyrrolidone as a main component as a base, the active ingredient, ethyl aminobenzoate, is excellent in stability.
  • the substrate and the microneedles are integrally formed using a water-soluble polymer as a base, so that it is easy to manufacture, and the content of the local anesthetic and the microneedle array By adjusting the size, the desired anesthetic effect can be achieved in a short period of time.
  • microneedle array and microneedle patch of the present invention use a water-soluble polymer as a base, they can easily adhere to the bending of the oral mucosa or gums in a high-humidity environment, and are suitable for topical administration in the oral cavity. Are suitable.
  • the microneedle array and microneedle patch of the present invention can be used as a dental local anesthetic formulation, and also as a pre-anesthetic to reduce pain at the administration site before administering a dental local anesthetic injection. is.
  • FIG. 1 is a schematic diagram of the microneedle patch of the present invention.
  • the polyethylene adhesive film 1 is used as the support, but the polyethylene adhesive film does not exist in the center of the back surface of the microneedle part 3 .
  • sterile paper 4 is used as a support, and sterile paper is not present on the back surface of microneedle part 5, forming the outer frame of the microneedle patch.
  • FIG. 2 is a schematic diagram of a microneedle patch with no support in the center of the back surface of the microneedle part 7 and a part of the end with ears for holding by hand.
  • 3 is a micrograph of the microneedle patch used in Examples 7 and 8.
  • FIG. The microneedle height is 350 ⁇ m
  • the needle density is 1070/cm 2
  • the patch size is 1 cm in diameter.
  • the microneedle array of the present invention is suitable for local anesthesia, especially dental local anesthesia.
  • the microneedle array of the present invention comprises a substrate and a plurality of microneedles on the substrate, is integrally formed from the same water-soluble polymer with a water-soluble polymer as a base, and has a flexible substrate portion It has
  • the base of the microneedle array is a water-soluble polymer containing polyvinylpyrrolidone as a main component.
  • a microneedle array uniformly containing a local anesthetic is produced using such a material by a conventional method, the local anesthetic is contained not only in the microneedle portion but also in the substrate portion.
  • this microneedle array is applied to the oral cavity (oral mucosa, gums, etc.), the microneedle part can reach the mucosa or gums, thereby promoting the delivery of the contained local anesthetic to the target site. do.
  • the substrate of the microneedle array also follows the bending of the oral mucosa or gums in the high humidity environment of the oral cavity and adheres closely, the water-soluble polymer of the substrate dissolves, and the local anesthetic present there also reaches the target site. delivered to
  • the water-soluble polymer may be polyvinylpyrrolidone alone, or from the group consisting of polyvinylpyrrolidone, hyaluronic acid and its derivatives, hydroxypropylcellulose, collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran. It may be a mixture of selected one or two or more.
  • the proportion of polyvinylpyrrolidone in the water-soluble polymer is 50 to 100% by mass, preferably 70 to 100% by mass. When the water-soluble polymer is a mixture of polyvinylpyrrolidone and the above specific component, the proportion of polyvinylpyrrolidone in the water-soluble polymer is less than 100% by mass.
  • Water-soluble macromolecules include water-soluble and ethanol-soluble macromolecules (polymers).
  • Water-soluble and ethanol-soluble polymers include polyvinylpyrrolidone, hydroxypropylcellulose, and the like.
  • the microneedle array preferably contains a water-soluble and ethanol-soluble polymer as a base.
  • polyvinylpyrrolidone alone or a mixture of polyvinylpyrrolidone and hydroxypropylcellulose.
  • Polyvinylpyrrolidone having various weight-average molecular weights can be used, but a weight-average molecular weight of 200,000 or more is preferable, and about 360,000 is particularly preferable.
  • polyvinylpyrrolidone K90 manufactured by Tokyo Chemical Industry Co., Ltd., weight average molecular weight: 360,000 is desirable.
  • hyaluronic acid and its derivatives eg, sodium salt, polyethylene oxide-grafted hyaluronic acid
  • hyaluronic acid and its derivatives preferably have a weight average molecular weight of 5,000 to 2,000,000.
  • Hydroxypropyl cellulose with various weight average molecular weights can be used, but a weight average molecular weight of 100,000 or more is preferable, and about 140,000 is particularly preferable.
  • Commercial products include HPC-SSL (weight average molecular weight 40,000), HPC-SL (weight average molecular weight 100,000), HPC-L (weight average molecular weight 140,000), HPC-M (weight average molecular weight 700,000), HPC -H (weight average molecular weight: 1,000,000); all manufactured by Nippon Soda Co., Ltd., but HPC-L is preferred.
  • Collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran can also be used as commercially available products with a weight average molecular weight of 5,000 to 2,000,000.
  • a microneedle array may be formed from a mixture of low-molecular-weight high-molecular-weight substances having a value of 50,000 or less.
  • the weight-average molecular weight of the high-molecular weight polymeric substance may be 50,000 or more, preferably more than 50,000, preferably 100,000 or more, and preferably 2,000,000 or less.
  • the weight average molecular weight of the low-molecular-weight polymer substance may be 50,000 or less, preferably less than 50,000, and preferably 1,000 or more.
  • the weight average molecular weight is a value measured by gel permeation chromatography (GPC).
  • the mixing ratio of the high-molecular-weight high-molecular substance and the low-molecular-weight high-molecular-weight substance varies depending on the type and weight-average molecular weight of each high-molecular-weight substance. However, in general, it is preferable that the content of the high-molecular-weight polymer is 1% by mass or more and the low-molecular-weight polymer is 99% by mass or less.
  • a solubilizing agent may be added to the above polymer substance in order to quickly exert the anesthetic effect.
  • Solubilizers include monosaccharides such as glucose; disaccharides such as trehalose; and polyhydric alcohols such as glycerin, propylene glycol (PG), butylene glycol (BG) and polyethylene glycol (PEG).
  • the amount of the solubilizing agent to be added is desirably 1% by mass or more and 50% by mass or less as a concentration in the base.
  • the base of the microneedle array can contain a water-soluble low-molecular-weight compound in addition to the water-soluble polymer.
  • Water-soluble low-molecular-weight compounds include monosaccharides, disaccharides, and polyhydric alcohols used as the above-described solubilizers, and have a molecular weight of 500 or less.
  • Monosaccharides include glucose, fructose and the like, and disaccharides include sucrose, lactose, trehalose, maltose and the like.
  • Polyhydric alcohols include glycerin, propylene glycol (PG), butylene glycol (BG), polyethylene glycol (PEG) 200, PEG400 and the like.
  • the amount of the water-soluble low-molecular weight compound added is 2% by mass or more and 50% by mass or less, preferably 2% by mass or more and 35% by mass or less, more preferably 2% by mass or more and 30% by mass or less, as a concentration in the base. It is below.
  • the height of the microneedles is desirably 50 ⁇ m or more and 500 ⁇ m or less, more preferably 100 ⁇ m or more and 350 ⁇ m or less, still more preferably 300 ⁇ m or less, and particularly preferably 250 ⁇ m or less. Below 50 ⁇ m, it is unfavorable for delivery of local anesthetics. If the thickness exceeds 500 ⁇ m, pain and bleeding may occur during application.
  • the needle density of the microneedles is desirably 20/cm 2 or more and 2000/cm 2 or less, more preferably 100/cm 2 or more and 1500/cm 2 or less. Below 20 lines/cm 2 , there is a disadvantage in the amount of local anesthetic delivered. If it exceeds 2000 needles/cm 2 , the needle density is too high and the needles remain on the mucous membrane surface during application, making it difficult to exhibit the characteristics of microneedles.
  • the tip of the microneedle is desirably circular with a diameter of 1 ⁇ m or more or flat with the same area.
  • the tip of the microneedle is desirably circular with a diameter of 1 ⁇ m or more, or flat with the same area as a circle with a diameter of 1 ⁇ m or more.
  • the tip of the microneedle is desirably circular with a diameter of 50 ⁇ m or more, or flat with the same area as a circle with a diameter of 50 ⁇ m or more.
  • the needle shape includes a rod shape, a truncated cone shape, or a cornide shape, preferably a truncated cone shape or a cornide shape.
  • the substrate of the microneedle array preferably has a flexible substrate portion.
  • the substrate of the microneedle array is preferably a flexible substrate.
  • the thickness of the substrate of the microneedle array is desirably 5 ⁇ m or more and 100 ⁇ m or less, more preferably 10 ⁇ m or more and 50 ⁇ m or less, so as to provide a flexible substrate portion.
  • the shape of the substrate of the microneedle array can be appropriately set according to the application site, and examples thereof include circular, elliptical, triangular, quadrangular, polygonal and the like.
  • the size of the shape is typically 2 mm or more and 100 mm or less, preferably 5 mm or more and 50 mm or less, when represented by the diameter (major diameter) or the length of one side (long side).
  • the size of the microneedle array is expressed in terms of area, it is usually 5 mm 2 or more and 1000 mm 2 or less, preferably 10 mm 2 or more and 500 mm 2 or less.
  • the active ingredient contained in the microneedle array of the present invention is a local anesthetic.
  • the local anesthetic in the present invention is ethyl aminobenzoate (benzocaine).
  • a mixture of two or more local anesthetics can be used.
  • a preferred combination is a combination (mixture) of one or more selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine and salts thereof, and ethyl aminobenzoate.
  • additives that are usually included as pharmaceuticals may be included.
  • concentration of the additive contained in the microneedle array of the present invention can be set within an appropriate range depending on the type of additive, purpose of addition, and the like.
  • the concentration of the local anesthetic in the base is 1% by mass or more and 50% by mass or less, preferably 5% by mass or more and 30% by mass or less.
  • the concentration of ethyl aminobenzoate in the base is 1% by mass or more and 50% by mass or less, preferably 5% by mass or more and 30% by mass or less.
  • the concentration of the local anesthetic in the base means the mass in the total weight of the microneedle array (the microneedle array is dissolved in an appropriate solvent such as water and the content of the local anesthetic is quantitatively analyzed, and the microneedle drug content in the solid mass of the array).
  • the concentration of the local anesthetic in the microneedle array the above concentration is applied as long as the dental local anesthetic preparation of the present invention consists of the microneedle array.
  • the method for producing the microneedle array of the present invention is not particularly limited, and it may be produced by any conventionally known method.
  • a method of casting a solution in which an anesthetic and, if necessary, other components are dissolved in a solvent is cast, dried, and then peeled off.
  • the solvent include polar solvents such as water, ethanol, isopropyl alcohol, dimethylsulfoxide and dimethylformamide, and mixed solvents thereof. , or a mixed solvent of water and ethanol is preferred.
  • the above production method comprises the steps of preparing a solution containing ethanol in which ethyl aminobenzoate and polyvinylpyrrolidone are allowed to coexist, and casting the above solution onto a mold for molding a microneedle array, drying and then peeling off the mold. is preferred.
  • the peeled microneedle array sheet is cut according to the shape of the application site in the oral cavity.
  • the microneedle array of the present invention can be used alone as a dental local anesthetic preparation.
  • the content of ethyl aminobenzoate in the microneedle array is 5 to 30% by mass, ethyl aminobenzoate and polyvinylpyrrolidone coexist in the microneedle array, Ethyl aminobenzoate is dissolved or uniformly dispersed in the microneedle array.
  • the content ratio of polyvinylpyrrolidone and ethyl aminobenzoate is 1:1 (parts by mass) or more, preferably 2:1 (parts by mass) to 10:1 (parts by mass).
  • the dental local anesthetic preparation of the present invention can contain ethyl aminobenzoate, which is poorly soluble in water, at a high concentration. and excellent stability.
  • the microneedle array of the present invention can be made into the following microneedle patch for convenience of intraoral application.
  • the microneedle patch of the present invention comprises the microneedle array and a support provided on the back surface of the microneedle array.
  • the back surface of the microneedle array is the surface of the substrate opposite to the surface from which the microneedles protrude.
  • a support is not essential, but if there is a support, it is easy to handle and can prevent slippage from the application site or movement to the inside of the lips.
  • a microneedle patch backed with a hydrophobic or non-dissolving film as a backing behind a microneedle array is one embodiment of a dental topical anesthetic formulation.
  • a microneedle patch in which a polymer film is lined as a support on the back surface of the dried microneedle array produced by the above microneedle array production method There are various production methods. For example, the microneedle array is dried, and a polymer dissolved in water or a low-boiling-point organic solvent is coated, sprayed, or the like on the back surface of the microneedle array before it is separated from the mold, and then dried.
  • the polymer is a water-soluble polymer such as polyvinyl alcohol, high-molecular-weight polyvinylpyrrolidone, high-molecular-weight hydroxypropylcellulose, or polyacrylic acid, which does not dissolve instantaneously in the oral cavity. More specifically, it is necessary that the microneedle substrate does not dissolve or lose its shape within at least 30 minutes after attachment due to the polymer film being lined as the support.
  • the support may be organic solvent-soluble polymers such as polyvinyl acetate, polyvinyl chloride, nylon, or the like, or those made flexible by a plasticizer. These are suitable examples of hydrophobic or non-dissolving films. 2.
  • the formulation is integrated with the polymer film and the back surface of the microneedle array with an adhesive or pressure-sensitive adhesive.
  • the size of the microneedle array and the polymer film may be the same, or the polymer film may be larger and the film surface may be treated to have intraoral adhesiveness.
  • the polymeric film may be porous or water permeable, such as a woven fabric.
  • plastic sheets or films such as polyethylene, polypropylene, polyethylene terephthalate, ethylene vinyl acetate copolymer (EVA); paper sheets such as sterilized paper, cellophane, non-woven fabrics, woven fabrics; Fluorine oil thin film by coating, and the like.
  • the size of the support may be the same shape and size as the microneedle array, but is preferably larger than the microneedle array in order to reinforce the adhesion force of the microneedle array in the oral cavity from the back.
  • the support can be set to a size and shape that are easy to handle depending on the application site.
  • the thickness of the support may be the same as the thickness of the microneedle array substrate, or may be thicker or thinner than it, and is a thickness that can support a flexible and thin microneedle array and is easy to handle. can be set as appropriate. It may be shaped like an ear for holding the end of the microneedle array by hand (FIG. 2, polyethylene adhesive film 6). A part or the entire surface of the support may be colored. After the end of anesthesia, the doctor can easily remove the colored eyes without forgetting.
  • the support preferably has intraoral adhesiveness in order to reinforce the adhesion of the microneedle array in the oral cavity from the back.
  • the backing is coated with an adhesive substance, that is, a backing coated with an adhesive.
  • the adhesive substance includes adhesives that are commonly used in patch preparations, and for example, acrylic, silicone, and rubber adhesives with wet surface adhesiveness are preferred.
  • the support is water-soluble.
  • Low-molecular-weight water-soluble films such as polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), and polyvinyl alcohol (PVA), which are self-adhesive with intraoral moisture, are also preferred.
  • PVP polyvinylpyrrolidone
  • CMC carboxymethylcellulose
  • PVA polyvinyl alcohol
  • a film that laminates to the back is effective because without it the back of the microneedle array tends to adhere to the oral mucosa opposite the patch mucosa.
  • an essential requirement of the present invention is drug delivery to deep mucosal membranes by microneedles. If the microneedle base is water-soluble but has a slow water dissolution rate, the dissolution of the drug in the microneedle portion is much faster than that in the back surface, so the purpose is served without the backing agent. That is, the microneedle array of the present invention itself is provided as a dental local anesthetic preparation.
  • the missing part can be provided in the central part of the film-like support. have parts that are not covered).
  • the defective part is not limited to the central part, and a part that does not contain the film to the extent that it does not hinder the penetration of the needle when the injection needle is inserted into the site to which the microneedle patch of the present invention is applied may be secured.
  • the support when the support is sterile paper, the support may form an outer frame that encloses the microneedle array.
  • the support may form an outer frame that encloses the microneedle array.
  • FIG. 1B a hole is provided in the center of the sterilized paper, the back surface of the microneedle portion is not covered with the sterilized paper, and the sterilized paper forms the outer frame of the microneedle array (microneedle array).
  • the back of the needle array has a portion not covered with sterile paper).
  • the outer frame may be provided to such an extent that when the site to which the microneedle patch of the present invention is applied is pierced with an injection needle, the sterilized paper covers the entire back surface of the substrate of the microneedle array and does not interfere with the penetration of the needle.
  • the microneedle patch of the present invention can be produced by covering the back surface of the microneedle array with a support.
  • the back surface of the microneedle portion is pressed to administer the local anesthetic. Since the microneedle array and microneedle patch of the present invention use a water-soluble polymer as a base, they dissolve rapidly in a high-humidity environment and can efficiently deliver an anesthetic into the oral mucosa or gums. , the effect of local anesthesia can be exerted in a short time (within 1 to 10 minutes).
  • the preparation can be evaluated by applying it to the gums of volunteers, peeling it off after 5 to 10 minutes, and then sticking a toothpick or an injection needle into the application site to see if pain is felt or not.
  • Example 1-4 Comparative Example 1-3
  • Manufacture of ethyl aminobenzoate-containing microneedle patch 1 g of ethyl aminobenzoate (purchased from Wakoyaku Co., Ltd.) and 4 g of polyvinylpyrrolidone (PVP K90) are dissolved in ethanol, filled into a mold and dried to obtain a diameter of 1 cm. of microneedle arrays were manufactured (Example 1).
  • the height of the microneedles in this microarray was 300 ⁇ m, and the needle density was 260/cm 2 .
  • the content of ethyl aminobenzoate in the microneedle array was 20% by mass.
  • microneedle arrays of Examples 2-4 and Comparative Examples 1-3 were produced in the same manner as in Example 1 with the compositions shown in Table 1, and were made into microneedle patches in the same manner as in Example 1. Crystal precipitation of ethyl aminobenzoate was not observed in the microneedle array immediately after production in Examples 1-4.
  • Example 1-4 and Comparative Example 1-3 were subjected to a heat cycle test (a test in which a low-temperature and high-temperature environment of 10 ° C. to 50 ° C. was repeated every 3 days). , with respect to decrease in drug content and crystal precipitation after 3 months. Table 1 shows the results. In the formulations of Examples in which PVP was 50% by mass or more of the base, the stability of the drug was generally good. Also, after 3 months, no crystal precipitation was observed for all formulations tested. Crystal precipitation was observed in the comparative formulation after the heat cycle test.
  • microneedle patches of Examples 1, 2, 3, and 4 were lined with a support made of a polyethylene film coated with an acrylic pressure-sensitive adhesive and having a diameter of 2 cm. peeled off. No pain was felt even when the application site was stimulated with a needle. A surface anesthesia effect was confirmed.
  • Microneedle formulations containing the base and anesthetic shown in Table 3 were produced according to the method described in Example 1.
  • the microneedles had a height of 350 ⁇ m and a needle density of 1070/cm 2 , and were molded into a patch with a diameter of 1 cm. A photomicrograph of this patch is shown in FIG.
  • the resulting microneedle preparation was strongly pressed against the exfoliated rat skin with a fingertip for 10 seconds, and then left for 5 minutes to allow the drug to permeate the skin. After leaving for 5 minutes, the formulation was removed and the skin surface was wiped off.
  • the part to which the formulation was applied was cut off and homogenized, and the drug was extracted with ethanol.
  • the amount of drug in the extract was quantified by HPLC, and the amount of drug permeation into the skin was quantified.
  • a commercially available ethyl aminobenzoate-containing gel (Hurricane Gel) was applied to the skin in an amount that would give the same amount of drug to the same area (1 cm 2 ) as the application of the microneedle formulation. After 5 minutes, the skin surface was wiped off, the area to which the formulation was applied was cut off and homogenized, and the drug was extracted with ethanol. The drug in the extract was quantified by HPLC to quantify the amount of drug permeated through the skin.
  • HPLC condition equipment Hitachi L-7000 series HPLC Column: 5 ⁇ m ODS packed column 4.6 ⁇ x250mm Column temperature: 40°C Mobile phase: acetonitrile: 0.2% acetic acid acid water (28:72) Flow rate: 0.8ml/min Detection wavelength: 310 nm
  • microneedle patch 12 microneedle patch 13 microneedle patch

Abstract

The present invention provides a microneedle preparation which can be applied to an oral cavity easily, exerts an anesthetic effect suitable for a site of application, and has excellent stability.　Provided is a quick-acting local anesthetic preparation for dental use, which comprises a microneedle array containing ethyl aminobenzoate, in which the content of ethyl aminobenzoate in the microneedle array is 5 to 30% by mass, ethyl aminobenzoate and polyvinylpyrrolidone coexist in the microneedle array, and ethyl aminobenzoate is dissolved or is uniformly dispersed in the microneedle array.

Description

歯科用局所麻酔マイクロニードルアレイdental local anesthesia microneedle array
　本発明は、歯科（口腔内）局所麻酔に適用するマイクロニードルの技術分野に関する。 The present invention relates to the technical field of microneedles applied to dental (oral) local anesthesia.
　歯科治療においては、痛みの軽減のため口腔内に局所麻酔が施され、口腔（歯茎）粘膜に麻酔薬を塗布したり、歯茎内に麻酔薬を注射する。
　歯科用市販局所麻酔剤は数多く使用されている。それらは局所麻酔剤含有液剤、ゲル剤、ゼリー剤、などが主であり、液剤は脱脂綿などに浸して口腔内に適用する。ゲル剤、ゼリー剤はそのまま口腔内に適用する。いずれも、粘膜からの麻酔薬の吸収が遅いため効果が発生するまでの時間が長く、患者が横になって待つ時間が長いことや粘膜吸収のばらつきが生じることにより、QOLを損なうことが多い。また、麻酔薬が適用局所から流れて口腔内の広い部分が麻酔されることも、これらの局所表面麻酔剤の欠点である。麻酔薬の注射は、麻酔薬を注射される時点で痛みを感じて治療前に恐怖心が高まり、このことが歯科治療を敬遠する原因のひとつとなっている。 In dental treatment, local anesthesia is applied to the oral cavity to reduce pain, and an anesthetic is applied to the mucous membrane of the oral cavity (gums) or injected into the gums.
There are many commercially available local anesthetics for dentistry. They are mainly local anesthetic-containing liquid agents, gel agents, jelly agents, etc., and the liquid agents are soaked in absorbent cotton or the like and applied to the oral cavity. Gels and jellies are applied to the oral cavity as they are. In both cases, the absorption of the anesthetic from the mucous membrane is slow, so it takes a long time for the effect to occur, and the long waiting time for the patient to lie down and the variability in mucosal absorption often impairs QOL. . It is also a drawback of these topical topical anesthetics that the anesthetic flows away from the application site and anesthetizes a large area of the oral cavity. Injection of an anesthetic is one of the reasons why patients avoid dental treatment because they feel pain when the anesthetic is injected and fear increases before treatment.
　マイクロニードル製剤は、経皮吸収性が高く、化粧品及び医薬品等の開発が試みられている。一般に、マイクロニードル製剤の適用部位は皮膚表皮であるが、例えば、経内頬投与によるワクチン接種としての微小針パッチが知られている（特許文献１）。本微小針パッチは、内頬粘膜の外側層を貫通するように設計されている。また、歯科用局所麻酔薬等の歯科用物質伝達のためのマイクロニードルが開発されている（特許文献２、３、４）。特許文献２は、マイクロニードルアレイと、歯科用局所麻酔薬を内部に含む中空型球状容器とを備え、マイクロニードルを貫通する開口部を通じて麻酔薬が局所に送達される。特許文献３は、口腔内部の皮膚形状に沿って曲がるベース部とマイクロニードル本体部と該ニードル本体部の表面にコーティングされた有効成分コーティング部とを備えたマイクロニードルである。特許文献４は、水溶性高分子及び水溶性低分子化合物を基剤として同一の水溶性高分子及び水溶性低分子化合物から一体的に形成された基板と基板上の複数のマイクロニードルから構成される。 Microneedle formulations have high percutaneous absorbability, and attempts are being made to develop cosmetics and pharmaceuticals. In general, the application site of a microneedle preparation is the skin epidermis, and for example, a microneedle patch is known for vaccination by intrabuccal administration (Patent Document 1). The present microneedle patch is designed to penetrate the outer layer of the inner buccal mucosa. Also, microneedles for delivery of dental substances such as dental local anesthetics have been developed ( Patent Documents 2, 3, 4). Patent document 2 includes a microneedle array and a hollow spherical container containing a dental local anesthetic inside, and the anesthetic is locally delivered through an opening passing through the microneedles. Patent Document 3 is a microneedle that includes a base that bends along the shape of the skin inside the oral cavity, a microneedle body, and an active ingredient coating that coats the surface of the needle body. Patent Document 4 is composed of a substrate integrally formed from the same water-soluble polymer and water-soluble low-molecular compound using a water-soluble polymer and a water-soluble low-molecular compound as a base, and a plurality of microneedles on the substrate. be.
特表２０１５－５１５４７４号公報Japanese Patent Publication No. 2015-515474 特表２０１７－５０７７３４号公報Japanese Patent Publication No. 2017-507734 特開２０１７－０６１４４７号公報JP 2017-061447 A 特開２０１９－０８４３５２号公報（特許第６６７１６１６号公報）Japanese Patent Application Laid-Open No. 2019-084352 (Patent No. 6671616)
　マイクロニードル技術は歯科用局所麻酔への適用が試みられているが、マイクロニードルデバイスとしての装置が複雑であり、より簡便で麻酔効果が得られるマイクロニードル製剤が求められている。また、歯科用局所麻酔に汎用されるアミノ安息香酸エチルは、製剤化工程及び保存工程で、結晶が析出する問題点が生じた。本発明の目的は、口腔内への適用が容易であり、適用部位に則した麻酔効果を発揮でき、安定性に優れたマイクロニードルアレイを提供することにある。 Attempts have been made to apply microneedle technology to dental local anesthesia, but the device as a microneedle device is complicated, and there is a demand for a microneedle formulation that is simpler and provides an anesthetic effect. In addition, ethyl aminobenzoate, which is widely used for dental local anesthesia, has a problem of precipitation of crystals during formulation and storage steps. An object of the present invention is to provide a microneedle array that can be easily applied to the oral cavity, exhibits an anesthetic effect suitable for the application site, and has excellent stability.
　麻酔薬の注射の前に、まず皮膚の１～２ｍｍの深部まで迅速表面麻酔ができれば、患者のQOLは著しく改善ができる。本発明者らは、口腔内組織及び歯科分野の特殊性に鑑みて鋭意検討した結果、マイクロニードルアレイの形状及び材質を特定のものとすることで、歯科用局所麻酔に適したマイクロニードルアレイを発明するに至った（特開２０１９－０８４３５２号公報）。さらに、薬物のアミノ安息香酸エチルの安定性を高めるため、鋭意検討した結果、特定の基剤を用いて製造したマイクロニードルアレイに特定の割合で薬物を含有させることにより所期の目的を達成できることを見出し、本発明を完成させるに至った。 The patient's QOL can be significantly improved if rapid topical anesthesia can be applied to a depth of 1-2 mm in the skin before the injection of the anesthetic. The present inventors have made intensive studies in view of the particularities of oral tissues and the field of dentistry. I came up with the invention (Japanese Patent Application Laid-Open No. 2019-084352). Furthermore, in order to increase the stability of the drug, ethyl aminobenzoate, as a result of intensive studies, it was found that the intended purpose can be achieved by incorporating the drug in a specific ratio in a microneedle array manufactured using a specific base. and completed the present invention.
　本発明は、以下に示す通りである。
〔１〕　アミノ安息香酸エチルを含有するマイクロニードルアレイからなる即効性歯科局所麻酔製剤であって、マイクロニードルアレイ中のアミノ安息香酸エチルの含有量は５～３０質量％であり、マイクロニードルアレイ中にアミノ安息香酸エチルとポリビニルピロリドンとが共存し、アミノ安息香酸エチルはマイクロニードルアレイ中に溶解又は均一分散している、歯科局所麻酔製剤。
〔２〕　ポリビニルピロリドンの含有量がアミノ安息香酸エチル１００質量部に対し１００質量部以上である、〔１〕に記載の歯科局所麻酔製剤。
〔３〕　アミノ安息香酸エチルとポリビニルピロリドンとを共存させたエタノールを含む溶液を用いて鋳型充填法により製造される、〔１〕又は〔２〕に記載の歯科局所麻酔製剤。
〔４〕　前記マイクロニードルアレイが水溶性かつエタノール溶解性のポリマーを基剤として含有する、〔１〕～〔３〕のいずれかに記載の歯科局所麻酔製剤。
〔５〕　アミノ安息香酸エチルを含有するマイクロニードルアレイからなる即効性歯科局所麻酔製剤であって、
該マイクロニードルアレイは基板と基板上の複数のマイクロニードルとからなり、水溶性高分子を基剤として同一の水溶性高分子から一体的に形成され、かつ、柔軟な基板部を有し、
該水溶性高分子はポリビニルピロリドン、又はポリビニルピロリドンと、ヒアルロン酸及びその誘導体、ヒドロキシプロピルセルロース、コラーゲン、プロテオグリカン、コンドロイチン硫酸、カルボキシメチルセルロース、ポリエチレングリコール、並びにデキストランからなる群より選ばれる１種又は２種以上との混合物であり、
該ポリビニルピロリドンの該水溶性高分子に占める割合は５０～１００質量％であり、
口腔粘膜又は歯茎に貼付することによりニードル部が粘膜内溶解する即効性歯科局所麻酔製剤。
〔６〕　前記マイクロニードルアレイの背面に疎水性または非溶解フィルムを裏打ちしている、〔１〕～〔５〕のいずれかに記載の歯科局所麻酔製剤。
〔７〕　前記マイクロニードルアレイの基板の厚さが５μｍ以上１００μｍ以下である、〔５〕又は〔６〕に記載の歯科局所麻酔製剤。
〔８〕　マイクロニードルの高さが５０μｍ以上５００μｍ以下である、〔５〕～〔７〕のいずれかに記載の歯科局所麻酔製剤。
〔９〕　マイクロニードルの針密度が２０本／ｃｍ２以上２０００本／ｃｍ２以下である、〔５〕～〔８〕のいずれかに記載の歯科局所麻酔製剤。
〔１０〕　前記マイクロニードルアレイの基剤が水溶性高分子以外に水溶性低分子化合物を２質量％以上含有する、〔５〕～〔９〕のいずれかに記載の歯科局所麻酔製剤。
〔１１〕　アミノ安息香酸エチルの基剤中の濃度が５質量％以上３０質量％以下である、〔５〕～〔１０〕のいずれかに記載の歯科局所麻酔製剤。
〔１２〕　水溶性高分子を基剤とし、基板と基板上の複数のマイクロニードルとが同一の水溶性高分子から一体的に形成されている、アミノ安息香酸エチルを含有するマイクロニードルアレイであって、
該マイクロニードルの高さは５０μｍ以上５００μｍ以下であり、該マイクロニードルの先端は直径１μｍ以上５０μｍ以下の円形又はそれと同面積を有する平面であり、該マイクロニードルアレイの基板の厚さは５μｍ以上１００μｍ以下であり、かつ、前記基板が柔軟な基板であり、
該水溶性高分子はポリビニルピロリドン、又はポリビニルピロリドンと、ヒアルロン酸及びその誘導体、ヒドロキシプロピルセルロース、コラーゲン、プロテオグリカン、コンドロイチン硫酸、カルボキシメチルセルロース、ポリエチレングリコール、並びにデキストランからなる群より選ばれる１種又は２種以上との混合物であり、
該ポリビニルピロリドンの該水溶性高分子に占める割合は５０～１００質量％である、マイクロニードルアレイ。
〔１３〕　基剤が水溶性高分子以外に水溶性低分子化合物を２質量％以上含有する、〔１２〕に記載のマイクロニードルアレイ。
〔１４〕　アミノ安息香酸エチルの基剤中の濃度が５質量％以上３０質量％以下である、〔１２〕又は〔１３〕に記載のマイクロニードルアレイ。
〔１５〕　〔１２〕～〔１４〕のいずれかに記載のマイクロニードルアレイと、該マイクロニードルアレイの背面に備えられた支持体とからなるマイクロニードルパッチ。
〔１６〕　支持体が口腔内粘着性を有する、〔１５〕に記載のマイクロニードルパッチ。
〔１７〕　支持体に粘着性物質がコーティングされている、〔１６〕に記載のマイクロニードルパッチ。
〔１８〕　支持体が水溶性である、〔１６〕に記載のマイクロニードルパッチ。
〔１９〕　支持体がフィルム状であり、一部にフィルムを含まない欠損部分を有する、〔１５〕～〔１８〕のいずれかに記載のマイクロニードルパッチ。
〔２０〕　支持体が滅菌紙であり、マイクロニードルアレイを内包する外枠を形成している、〔１５〕～〔１８〕のいずれか１項に記載のマイクロニードルパッチ。
〔２１〕　アミノ安息香酸エチルとポリビニルピロリドンとを共存させたエタノールを含む溶液を調製する工程、及び
前記溶液をマイクロニードルアレイ成型用鋳型に流延し、乾燥した後剥離する工程を含む、
アミノ安息香酸エチルがマイクロニードルアレイ中に溶解又は均一分散している即効性歯科局所麻酔製剤の製造方法。 The present invention is as described below.
[1] A rapid-acting dental local anesthetic preparation comprising a microneedle array containing ethyl aminobenzoate, wherein the content of ethyl aminobenzoate in the microneedle array is 5 to 30% by mass, and A dental local anesthetic preparation in which ethyl aminobenzoate and polyvinylpyrrolidone coexist in the microneedle array, and the ethyl aminobenzoate is dissolved or uniformly dispersed in the microneedle array.
[2] The dental local anesthetic preparation according to [1], wherein the content of polyvinylpyrrolidone is 100 parts by mass or more per 100 parts by mass of ethyl aminobenzoate.
[3] The dental local anesthetic preparation according to [1] or [2], which is produced by a mold filling method using a solution containing ethanol in which ethyl aminobenzoate and polyvinylpyrrolidone are allowed to coexist.
[4] The dental local anesthetic preparation according to any one of [1] to [3], wherein the microneedle array contains a water-soluble and ethanol-soluble polymer as a base.
[5] A rapid-acting dental local anesthetic preparation comprising a microneedle array containing ethyl aminobenzoate,
The microneedle array consists of a substrate and a plurality of microneedles on the substrate, is integrally formed from the same water-soluble polymer with a water-soluble polymer as a base, and has a flexible substrate,
The water-soluble polymer is one or two selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone, hyaluronic acid and its derivatives, hydroxypropylcellulose, collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran. is a mixture of
The proportion of the polyvinylpyrrolidone in the water-soluble polymer is 50 to 100% by mass,
A rapid-acting dental local anesthetic preparation that dissolves in the mucous membrane of the needle when applied to the oral mucosa or gums.
[6] The dental local anesthetic preparation according to any one of [1] to [5], wherein the back surface of the microneedle array is lined with a hydrophobic or non-dissolving film.
[7] The dental local anesthetic preparation of [5] or [6], wherein the microneedle array substrate has a thickness of 5 μm or more and 100 μm or less.
[8] The dental local anesthetic preparation according to any one of [5] to [7], wherein the microneedles have a height of 50 μm or more and 500 μm or less.
[9] The dental local anesthetic preparation according to any one of [5] to [8], wherein the density of microneedles is 20/cm 2 or more and 2000/cm 2 or less.
[10] The dental local anesthetic preparation according to any one of [5] to [9], wherein the base of the microneedle array contains 2% by mass or more of a water-soluble low-molecular-weight compound in addition to the water-soluble polymer.
[11] The dental local anesthetic preparation according to any one of [5] to [10], wherein the concentration of ethyl aminobenzoate in the base is 5% by mass or more and 30% by mass or less.
[12] A microneedle array containing ethyl aminobenzoate, wherein a water-soluble polymer is used as a base, and a substrate and a plurality of microneedles on the substrate are integrally formed from the same water-soluble polymer. hand,
The height of the microneedle is 50 μm or more and 500 μm or less, the tip of the microneedle is a circle having a diameter of 1 μm or more and 50 μm or less or a flat surface having the same area, and the thickness of the substrate of the microneedle array is 5 μm or more and 100 μm. and wherein the substrate is a flexible substrate,
The water-soluble polymer is one or two selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone, hyaluronic acid and its derivatives, hydroxypropylcellulose, collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran. is a mixture of
A microneedle array, wherein the polyvinylpyrrolidone accounts for 50 to 100% by mass of the water-soluble polymer.
[13] The microneedle array of [12], wherein the base contains 2% by mass or more of a water-soluble low-molecular-weight compound in addition to the water-soluble polymer.
[14] The microneedle array of [12] or [13], wherein the concentration of ethyl aminobenzoate in the base is 5% by mass or more and 30% by mass or less.
[15] A microneedle patch comprising the microneedle array according to any one of [12] to [14] and a support provided on the back surface of the microneedle array.
[16] The microneedle patch of [15], wherein the support has intraoral adhesiveness.
[17] The microneedle patch of [16], wherein the support is coated with an adhesive substance.
[18] The microneedle patch of [16], wherein the support is water-soluble.
[19] The microneedle patch according to any one of [15] to [18], wherein the support is in the form of a film and partially has a defective portion that does not contain a film.
[20] The microneedle patch of any one of [15] to [18], wherein the support is sterile paper and forms an outer frame enclosing the microneedle array.
[21] preparing a solution containing ethanol in which ethyl aminobenzoate and polyvinylpyrrolidone coexist;
A method for producing a rapid-acting dental local anesthetic preparation in which ethyl aminobenzoate is dissolved or uniformly dispersed in a microneedle array.
　本発明のマイクロニードルアレイは、基剤としてポリビニルピロリドンを主成分とする水溶性高分子を使用しているので、有効成分であるアミノ安息香酸エチルの安定性に優れている。
　本発明のマイクロニードルアレイは、水溶性高分子を基剤として基板とマイクロニードルとが一体的に形成されているので、製造が容易であり、また、局所麻酔剤の含有量及びマイクロニードルアレイの大きさを調整することにより、目的に応じた麻酔効果を短時間で達成することができる。
　本発明のマイクロニードルアレイ及びマイクロニードルパッチは、水溶性高分子を基剤として用いているので、高湿度環境下で口腔粘膜又は歯茎の屈曲に追随して密着し易く、口腔内の局所投与に適している。
　本発明のマイクロニードルアレイ及びマイクロニードルパッチは、歯科用局所麻酔製剤として、さらには、歯科用局所麻酔注射液を投与する前に、投与部位の痛みを軽減するためのプレ麻酔薬としても使用可能である。 Since the microneedle array of the present invention uses a water-soluble polymer containing polyvinylpyrrolidone as a main component as a base, the active ingredient, ethyl aminobenzoate, is excellent in stability.
In the microneedle array of the present invention, the substrate and the microneedles are integrally formed using a water-soluble polymer as a base, so that it is easy to manufacture, and the content of the local anesthetic and the microneedle array By adjusting the size, the desired anesthetic effect can be achieved in a short period of time.
Since the microneedle array and microneedle patch of the present invention use a water-soluble polymer as a base, they can easily adhere to the bending of the oral mucosa or gums in a high-humidity environment, and are suitable for topical administration in the oral cavity. Are suitable.
The microneedle array and microneedle patch of the present invention can be used as a dental local anesthetic formulation, and also as a pre-anesthetic to reduce pain at the administration site before administering a dental local anesthetic injection. is.
図１は、本発明のマイクロニードルパッチの模式図である。図１Ａはポリエチレン粘着フィルム１を支持体としているが、マイクロニードル部３の背面の中央にはポリエチレン粘着フィルムが存在しない。図１Ｂは滅菌紙４を支持体とし、マイクロニードル部５の背面には滅菌紙が存在せず、マイクロニードルパッチの外枠を形成している。FIG. 1 is a schematic diagram of the microneedle patch of the present invention. In FIG. 1A, the polyethylene adhesive film 1 is used as the support, but the polyethylene adhesive film does not exist in the center of the back surface of the microneedle part 3 . In FIG. 1B, sterile paper 4 is used as a support, and sterile paper is not present on the back surface of microneedle part 5, forming the outer frame of the microneedle patch. 図２は、マイクロニードル部７の背面の中央には支持体が存在しない、端の一部に手で持つための耳が付いているマイクロニードルパッチの模式図である。FIG. 2 is a schematic diagram of a microneedle patch with no support in the center of the back surface of the microneedle part 7 and a part of the end with ears for holding by hand. 図３は、実施例７，８において使用したマイクロニードルパッチの顕微鏡写真である。マイクロニードルの高さは３５０μｍ、針密度は１０７０本／ｃｍ２であり、パッチの大きさは直径１ｃｍである。3 is a micrograph of the microneedle patch used in Examples 7 and 8. FIG. The microneedle height is 350 μm, the needle density is 1070/cm 2 , and the patch size is 1 cm in diameter.
　本発明のマイクロニードルアレイは、局所麻酔、特に歯科用局所麻酔に適するものである。本発明のマイクロニードルアレイは、基板と基板上の複数のマイクロニードルとからなり、水溶性高分子を基剤として同一の水溶性高分子から一体的に形成されており、かつ、柔軟な基板部を有するものである。 The microneedle array of the present invention is suitable for local anesthesia, especially dental local anesthesia. The microneedle array of the present invention comprises a substrate and a plurality of microneedles on the substrate, is integrally formed from the same water-soluble polymer with a water-soluble polymer as a base, and has a flexible substrate portion It has
マイクロニードルアレイの基剤
　マイクロニードルアレイの基剤は、ポリビニルピロリドンを主成分とする水溶性高分子である。このような素材を用い均一に局所麻酔剤を含有するマイクロニードルアレイを常法により作製すると、局所麻酔剤はマイクロニードル部のみならず基板部にも含まれることとなる。このマイクロニードルアレイを口腔内（口腔粘膜又は歯茎等）に適用すると、マイクロニードル部は粘膜内又は歯茎内に到達することができ、それにより、含まれる局所麻酔剤の目的部位への送達を促進する。マイクロニードルアレイの基板も、口腔内の高湿度環境下で口腔粘膜又は歯茎の屈曲に追随して密着し、基板の水溶性高分子が溶解し、そこに存在する局所麻酔剤もまた、目的部位へ送達される。 Base of Microneedle Array The base of the microneedle array is a water-soluble polymer containing polyvinylpyrrolidone as a main component. When a microneedle array uniformly containing a local anesthetic is produced using such a material by a conventional method, the local anesthetic is contained not only in the microneedle portion but also in the substrate portion. When this microneedle array is applied to the oral cavity (oral mucosa, gums, etc.), the microneedle part can reach the mucosa or gums, thereby promoting the delivery of the contained local anesthetic to the target site. do. The substrate of the microneedle array also follows the bending of the oral mucosa or gums in the high humidity environment of the oral cavity and adheres closely, the water-soluble polymer of the substrate dissolves, and the local anesthetic present there also reaches the target site. delivered to
　水溶性高分子としては、ポリビニルピロリドン単独であってもよく、又はポリビニルピロリドンと、ヒアルロン酸及びその誘導体、ヒドロキシプロピルセルロース、コラーゲン、プロテオグリカン、コンドロイチン硫酸、カルボキシメチルセルロース、ポリエチレングリコール、並びにデキストランからなる群より選ばれる１種又は２種以上との混合物であってもよい。ポリビニルピロリドンの水溶性高分子に占める割合は５０～１００質量％であり、７０～１００質量％が好ましい。なお、水溶性高分子が、ポリビニルピロリドンと上記の特定の成分との混合物である場合に、ポリビニルピロリドンの水溶性高分子に占める割合は１００質量％未満である。
　水溶性高分子は、水溶性かつエタノール溶解性の高分子（ポリマー）を含む。水溶性かつエタノール溶解性の高分子としては、ポリビニルピロリドン、ヒドロキシプロピルセルロース、等が挙げられる。本発明においては、水溶性かつエタノール溶解性の高分子を用いることも望ましい。言い換えると、マイクロニードルアレイが水溶性かつエタノール溶解性のポリマーを基剤として含有することが好ましい。具体的には、ポリビニルピロリドン単独、又はポリビニルピロリドンとヒドロキシプロピルセルロースとの混合物を用いることが望ましい。 The water-soluble polymer may be polyvinylpyrrolidone alone, or from the group consisting of polyvinylpyrrolidone, hyaluronic acid and its derivatives, hydroxypropylcellulose, collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran. It may be a mixture of selected one or two or more. The proportion of polyvinylpyrrolidone in the water-soluble polymer is 50 to 100% by mass, preferably 70 to 100% by mass. When the water-soluble polymer is a mixture of polyvinylpyrrolidone and the above specific component, the proportion of polyvinylpyrrolidone in the water-soluble polymer is less than 100% by mass.
Water-soluble macromolecules include water-soluble and ethanol-soluble macromolecules (polymers). Water-soluble and ethanol-soluble polymers include polyvinylpyrrolidone, hydroxypropylcellulose, and the like. In the present invention, it is also desirable to use a water-soluble and ethanol-soluble polymer. In other words, the microneedle array preferably contains a water-soluble and ethanol-soluble polymer as a base. Specifically, it is desirable to use polyvinylpyrrolidone alone or a mixture of polyvinylpyrrolidone and hydroxypropylcellulose.
　ポリビニルピロリドンは、種々の重量平均分子量のものを使用することができるが、重量平均分子量２０万以上が好ましく、特に３６万程度が好ましい。市販品としては、ポリビニルピロリドンＫ９０（東京化成工業株式会社製、重量平均分子量３６万）が望ましい。 Polyvinylpyrrolidone having various weight-average molecular weights can be used, but a weight-average molecular weight of 200,000 or more is preferable, and about 360,000 is particularly preferable. As a commercially available product, polyvinylpyrrolidone K90 (manufactured by Tokyo Chemical Industry Co., Ltd., weight average molecular weight: 360,000) is desirable.
　ヒアルロン酸及びその誘導体（例、ナトリウム塩、ポリエチレンオキサイドグラフトヒアルロン酸）は、本発明の目的においては、重量平均分子量５千～２００万が好ましい。 For the purposes of the present invention, hyaluronic acid and its derivatives (eg, sodium salt, polyethylene oxide-grafted hyaluronic acid) preferably have a weight average molecular weight of 5,000 to 2,000,000.
　ヒドロキシプロピルセルロースは、種々の重量平均分子量のものを使用することができるが、重量平均分子量１０万以上が好ましく、特に１４万程度が好ましい。市販品としては、ＨＰＣ－ＳＳＬ（重量平均分子量４万）、ＨＰＣ-ＳＬ（重量平均分子量１０万）、ＨＰＣ-Ｌ（重量平均分子量１４万）、ＨＰＣ-Ｍ（重量平均分子量７０万）、ＨＰＣ-Ｈ（重量平均分子量１００万）；すべて日本曹達株式会社製、が挙げられるが、ＨＰＣ-Ｌが望ましい。 Hydroxypropyl cellulose with various weight average molecular weights can be used, but a weight average molecular weight of 100,000 or more is preferable, and about 140,000 is particularly preferable. Commercial products include HPC-SSL (weight average molecular weight 40,000), HPC-SL (weight average molecular weight 100,000), HPC-L (weight average molecular weight 140,000), HPC-M (weight average molecular weight 700,000), HPC -H (weight average molecular weight: 1,000,000); all manufactured by Nippon Soda Co., Ltd., but HPC-L is preferred.
　コラーゲン、プロテオグリカン、コンドロイチン硫酸、カルボキシメチルセルロース、ポリエチレングリコール、及びデキストランも、重量平均分子量が５千～２００万の市販品を使用することができる。 Collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran can also be used as commercially available products with a weight average molecular weight of 5,000 to 2,000,000.
　マイクロニードルアレイを口腔内に適用する際には、適度な硬度で折れにくく、且つ、局所麻酔薬を浸透しやすくするために、重量平均分子量が５万以上の高分子量高分子物質と重量平均分子量が５万以下の低分子量高分子物質の混合物からマイクロニードルアレイを形成してもよい。上記高分子量高分子物質の重量平均分子量は５万以上であればよく、５万を超えることが好ましく、１０万以上が好ましく、２００万以下が好ましい。また、低分子量高分子物質の重量平均分子量は５万以下であればよく、５万未満が好ましく、１０００以上が好ましい。尚、本発明において、重量平均分子量はゲルパーミエーションクロマトグラフィー（ＧＰＣ）によって測定された値である。 When applying the microneedle array to the oral cavity, it is necessary to have a high molecular weight substance with a weight average molecular weight of 50,000 or more and a weight average molecular weight in order to prevent it from breaking due to moderate hardness and to facilitate the penetration of the local anesthetic. A microneedle array may be formed from a mixture of low-molecular-weight high-molecular-weight substances having a value of 50,000 or less. The weight-average molecular weight of the high-molecular weight polymeric substance may be 50,000 or more, preferably more than 50,000, preferably 100,000 or more, and preferably 2,000,000 or less. Moreover, the weight average molecular weight of the low-molecular-weight polymer substance may be 50,000 or less, preferably less than 50,000, and preferably 1,000 or more. Incidentally, in the present invention, the weight average molecular weight is a value measured by gel permeation chromatography (GPC).
　高分子量高分子物質と低分子量高分子物質を混合する際の比率は、各高分子物質の種類及び重量平均分子量によっても異なるので、好ましい機械的強度及び硬さになるように適宜決定されればよいが、一般に、高分子量高分子物質1質量％以上、低分子量高分子物質９９質量％以下であることが好ましい。 The mixing ratio of the high-molecular-weight high-molecular substance and the low-molecular-weight high-molecular-weight substance varies depending on the type and weight-average molecular weight of each high-molecular-weight substance. However, in general, it is preferable that the content of the high-molecular-weight polymer is 1% by mass or more and the low-molecular-weight polymer is 99% by mass or less.
　麻酔効果を速発揮するために、上記高分子物質に可溶解剤を添加してもよい。可溶解剤としては、グルコースなどの単糖；トレハロースなどの二糖類；グリセリン、プロピレングリコール（PG）、ブチレングリコール（BG）及びポリエチレングリコール（PEG）などの多価アルコールなどが挙げられる。可溶解剤の添加量は、基剤中の濃度として１質量％以上５０質量％以下が望ましい。 A solubilizing agent may be added to the above polymer substance in order to quickly exert the anesthetic effect. Solubilizers include monosaccharides such as glucose; disaccharides such as trehalose; and polyhydric alcohols such as glycerin, propylene glycol (PG), butylene glycol (BG) and polyethylene glycol (PEG). The amount of the solubilizing agent to be added is desirably 1% by mass or more and 50% by mass or less as a concentration in the base.
　マイクロニードルアレイの基剤は、水溶性高分子以外に水溶性低分子化合物を含有することができる。水溶性低分子化合物としては、上記した可溶解剤として使用される単糖、二糖類、多価アルコールであって、分子量が500以下の化合物である。単糖としては、グルコース、フルクトース等が挙げられ、二糖類としては、シュクロース、ラクトース、トレハロース、マルトース等が挙げられる。多価アルコールとしては、グリセリン、プロピレングリコール（PG）、ブチレングリコール（BG）、ポリエチレングリコール（PEG）200、PEG400等が挙げられる。
　水溶性低分子化合物の添加量は、基剤中の濃度として２質量％以上５０質量％以下であり、好ましくは２質量％以上３５質量％以下であり、より好ましくは２質量％以上３０質量％以下である。 The base of the microneedle array can contain a water-soluble low-molecular-weight compound in addition to the water-soluble polymer. Water-soluble low-molecular-weight compounds include monosaccharides, disaccharides, and polyhydric alcohols used as the above-described solubilizers, and have a molecular weight of 500 or less. Monosaccharides include glucose, fructose and the like, and disaccharides include sucrose, lactose, trehalose, maltose and the like. Polyhydric alcohols include glycerin, propylene glycol (PG), butylene glycol (BG), polyethylene glycol (PEG) 200, PEG400 and the like.
The amount of the water-soluble low-molecular weight compound added is 2% by mass or more and 50% by mass or less, preferably 2% by mass or more and 35% by mass or less, more preferably 2% by mass or more and 30% by mass or less, as a concentration in the base. It is below.
マイクロニードルアレイの形状
　マイクロニードルの高さは、５０μｍ以上５００μｍ以下であることが望ましく、１００μｍ以上３５０μｍ以下がより好ましく、更に好ましくは３００μｍ以下、特に好ましくは２５０μｍ以下である。５０μｍ未満では、局所麻酔剤の送達に不利である。５００μｍを超えると、適用時に痛みや出血を伴うことがある。
　マイクロニードルの針密度は２０本／ｃｍ２以上２０００本／ｃｍ２以下であることが望ましく、１００本／ｃｍ２以上１５００本／ｃｍ２以下がより好ましい。２０本／ｃｍ２未満では、局所麻酔剤の送達量において不利である。２０００本／ｃｍ２を超えると、針密度が高すぎて適用時に針が粘膜表面に留まりマイクロニードルとしての特徴を発揮しがたい。 Shape of Microneedle Array The height of the microneedles is desirably 50 μm or more and 500 μm or less, more preferably 100 μm or more and 350 μm or less, still more preferably 300 μm or less, and particularly preferably 250 μm or less. Below 50 μm, it is unfavorable for delivery of local anesthetics. If the thickness exceeds 500 μm, pain and bleeding may occur during application.
The needle density of the microneedles is desirably 20/cm 2 or more and 2000/cm 2 or less, more preferably 100/cm 2 or more and 1500/cm 2 or less. Below 20 lines/cm 2 , there is a disadvantage in the amount of local anesthetic delivered. If it exceeds 2000 needles/cm 2 , the needle density is too high and the needles remain on the mucous membrane surface during application, making it difficult to exhibit the characteristics of microneedles.
　マイクロニードルの先端は、直径１μｍ以上の円形又はそれと同面積を有する平面であることが望ましい。言い換えると、マイクロニードルの先端は、直径１μｍ以上の円形であるか、又は、直径１μｍ以上の円と同面積を有する平面であることが望ましい。また、マイクロニードル先端部は、直径５０μｍ以下の円形又はそれと同面積を有する平面であることが望ましい。言い換えると、マイクロニードルの先端は、直径５０μｍ以上の円形であるか、又は、直径５０μｍ以上の円と同面積を有する平面であることが望ましい。この範囲内であると、局所麻酔薬の送達に有利である。針形状は、棒状、円錐台形状又はコニーデが挙げられ、円錐台又はコニーデ形状が望ましい。 The tip of the microneedle is desirably circular with a diameter of 1 μm or more or flat with the same area. In other words, the tip of the microneedle is desirably circular with a diameter of 1 μm or more, or flat with the same area as a circle with a diameter of 1 μm or more. Moreover, it is desirable that the tip of the microneedle be circular with a diameter of 50 μm or less or a flat surface having the same area. In other words, the tip of the microneedle is desirably circular with a diameter of 50 μm or more, or flat with the same area as a circle with a diameter of 50 μm or more. Within this range is advantageous for delivery of local anesthetics. The needle shape includes a rod shape, a truncated cone shape, or a cornide shape, preferably a truncated cone shape or a cornide shape.
　マイクロニードルアレイの基板は、柔軟な基板部を有することが好ましい。マイクロニードルアレイの基板は、柔軟な基板であることが好ましい。マイクロニードルアレイの基板の厚さは、柔軟な基板部となるように、５μｍ以上１００μｍ以下であることが望ましく、１０μｍ以上５０μｍ以下がより好ましい。 The substrate of the microneedle array preferably has a flexible substrate portion. The substrate of the microneedle array is preferably a flexible substrate. The thickness of the substrate of the microneedle array is desirably 5 μm or more and 100 μm or less, more preferably 10 μm or more and 50 μm or less, so as to provide a flexible substrate portion.
　マイクロニードルアレイの基板の形状は、適用部位に応じて適宜設定することができ、円形、楕円形、三角形、四角形、多角形等が挙げられる。形状の大きさは、直径（長径）又は一辺（長辺）の長さで代表して表すと、通常２ｍｍ以上１００ｍｍ以下であり、５ｍｍ以上５０ｍｍ以下が好ましい。また、マイクロニードルアレイの大きさを面積で表すと、通常５ｍｍ２以上１０００ｍｍ２以下であり、１０ｍｍ２以上５００ｍｍ２以下が好ましい。 The shape of the substrate of the microneedle array can be appropriately set according to the application site, and examples thereof include circular, elliptical, triangular, quadrangular, polygonal and the like. The size of the shape is typically 2 mm or more and 100 mm or less, preferably 5 mm or more and 50 mm or less, when represented by the diameter (major diameter) or the length of one side (long side). In addition, when the size of the microneedle array is expressed in terms of area, it is usually 5 mm 2 or more and 1000 mm 2 or less, preferably 10 mm 2 or more and 500 mm 2 or less.
局所麻酔剤
　本発明のマイクロニードルアレイに含まれる有効成分は、局所麻酔剤である。本発明における局所麻酔剤は、アミノ安息香酸エチル（ベンゾカイン）である。
　本発明においては、局所麻酔剤を２種以上混合して使用することができる。好ましい組み合わせとしては、プロカイン、テトラカイン、リドカイン、ジブカイン、ブピバカイン及びそれらの塩からなる群より選ばれる１又は複数とアミノ安息香酸エチルとの組み合わせ（混合物）である。 Local Anesthetic The active ingredient contained in the microneedle array of the present invention is a local anesthetic. The local anesthetic in the present invention is ethyl aminobenzoate (benzocaine).
In the present invention, a mixture of two or more local anesthetics can be used. A preferred combination is a combination (mixture) of one or more selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine and salts thereof, and ethyl aminobenzoate.
　上記局所麻酔剤の外に、医薬品として通常含まれる添加剤を含んでいてもよい。本発明のマイクロニードルアレイに含まれる添加剤の濃度は、添加剤の種類及び添加目的等に応じて、適切な範囲に設定することができる。 In addition to the above local anesthetics, additives that are usually included as pharmaceuticals may be included. The concentration of the additive contained in the microneedle array of the present invention can be set within an appropriate range depending on the type of additive, purpose of addition, and the like.
　局所麻酔剤の基剤中の濃度は、１質量％以上５０質量％以下であり、５質量％以上３０質量％以下が好ましい。アミノ安息香酸エチルの基剤中の濃度は、１質量％以上５０質量％以下であり、５質量％以上３０質量％以下が好ましい。上記範囲内であれば、麻酔の効果が発揮され、結晶析出の蓋然性は低い。ここで、局所麻酔剤の基剤中の濃度とは、マイクロニードルアレイの総重量中の質量（水など適当な溶媒でマイクロニードルアレイを溶解し局所麻酔剤の含有量を定量分析し、マイクロニードルアレイの固形質量中の薬物含有量）である。
　局所麻酔剤のマイクロニードルアレイ中の濃度は、本発明の歯科局所麻酔製剤がマイクロニードルアレイからなるものである限り、上記濃度が適用される。 The concentration of the local anesthetic in the base is 1% by mass or more and 50% by mass or less, preferably 5% by mass or more and 30% by mass or less. The concentration of ethyl aminobenzoate in the base is 1% by mass or more and 50% by mass or less, preferably 5% by mass or more and 30% by mass or less. Within the above range, the effect of anesthesia is exhibited, and the probability of crystal precipitation is low. Here, the concentration of the local anesthetic in the base means the mass in the total weight of the microneedle array (the microneedle array is dissolved in an appropriate solvent such as water and the content of the local anesthetic is quantitatively analyzed, and the microneedle drug content in the solid mass of the array).
As for the concentration of the local anesthetic in the microneedle array, the above concentration is applied as long as the dental local anesthetic preparation of the present invention consists of the microneedle array.
　本発明のマイクロニードルアレイの製造方法は、特に限定されず、従来公知の任意の方法で製造されればよく、例えば、マイクロニードルの形状が穿設された型に、上記水溶性高分子及び局所麻酔剤、必要に応じてその他の成分を溶媒に溶解した溶解液を流延し、乾燥した後剥離する方法が挙げられる。ここで、溶媒としては、水、エタノール、イソプロピルアルコール、ジメチルスルホキシド、ジメチルホルムアミド等の極性溶媒、及びこれらの混合溶媒等が挙げられるが、基剤とアミノ安息香酸エチルの溶解性の観点から、エタノール、又は水とエタノールの混合溶媒が好ましい。上記製造方法では、アミノ安息香酸エチルとポリビニルピロリドンとを共存させたエタノールを含む溶液を用いて鋳型充填法により製造されることが好ましい。上記製造方法は、アミノ安息香酸エチルとポリビニルピロリドンとを共存させたエタノールを含む溶液を調製する工程、及び上記溶液をマイクロニードルアレイ成型用鋳型に流延し、乾燥した後剥離する工程を含むことが好ましい。
　剥離したマイクロニードルアレイシートは、口腔内の適用部位の形状に則して裁断して用いる。 The method for producing the microneedle array of the present invention is not particularly limited, and it may be produced by any conventionally known method. A method of casting a solution in which an anesthetic and, if necessary, other components are dissolved in a solvent is cast, dried, and then peeled off. Examples of the solvent include polar solvents such as water, ethanol, isopropyl alcohol, dimethylsulfoxide and dimethylformamide, and mixed solvents thereof. , or a mixed solvent of water and ethanol is preferred. In the above production method, it is preferable to produce by a mold filling method using a solution containing ethanol in which ethyl aminobenzoate and polyvinylpyrrolidone are allowed to coexist. The above production method comprises the steps of preparing a solution containing ethanol in which ethyl aminobenzoate and polyvinylpyrrolidone are allowed to coexist, and casting the above solution onto a mold for molding a microneedle array, drying and then peeling off the mold. is preferred.
The peeled microneedle array sheet is cut according to the shape of the application site in the oral cavity.
　本発明のマイクロニードルアレイは、単独で歯科用局所麻酔製剤として使用することができる。１つの実施態様において、歯科局所麻酔製剤は、マイクロニードルアレイ中のアミノ安息香酸エチルの含有量は５～３０質量％であり、マイクロニードルアレイ中にアミノ安息香酸エチルとポリビニルピロリドンとが共存し、アミノ安息香酸エチルはマイクロニードルアレイ中に溶解又は均一分散している。
　ポリビニルピロリドンとアミノ安息香酸エチルの含有量の比は１：１（質量部）以上であり、好ましくは２：１（質量部）～１０：１（質量部）である。このように、本発明の歯科用局所麻酔製剤は、水に難溶性のアミノ安息香酸エチルを高濃度で含むことができるが、ポリビニルピロリドンが共存するために溶解又は均一分散した状態を長期間維持し、安定性に優れる。
　あるいは、本発明のマイクロニードルアレイは、口腔内適用の便宜に供するために、下記マイクロニードルパッチとすることもできる。 The microneedle array of the present invention can be used alone as a dental local anesthetic preparation. In one embodiment, in the dental local anesthetic preparation, the content of ethyl aminobenzoate in the microneedle array is 5 to 30% by mass, ethyl aminobenzoate and polyvinylpyrrolidone coexist in the microneedle array, Ethyl aminobenzoate is dissolved or uniformly dispersed in the microneedle array.
The content ratio of polyvinylpyrrolidone and ethyl aminobenzoate is 1:1 (parts by mass) or more, preferably 2:1 (parts by mass) to 10:1 (parts by mass). As described above, the dental local anesthetic preparation of the present invention can contain ethyl aminobenzoate, which is poorly soluble in water, at a high concentration. and excellent stability.
Alternatively, the microneedle array of the present invention can be made into the following microneedle patch for convenience of intraoral application.
マイクロニードルパッチ
　本発明のマイクロニードルパッチは、前記マイクロニードルアレイと、該マイクロニードルアレイの背面に備えられた支持体とからなる。ここで、マイクロニードルアレイの背面とは、マイクロニードルが突出している面とは反対側の基板の表面である。支持体は必須ではないが、支持体があれば扱いやすく、貼付部位から滑る又は***の内側に移ることを防止することができる。マイクロニードルアレイの背面に疎水性または非溶解フィルムを支持体として裏打ちしたマイクロニードルパッチは、歯科局所麻酔製剤の一実施形態である。 Microneedle Patch The microneedle patch of the present invention comprises the microneedle array and a support provided on the back surface of the microneedle array. Here, the back surface of the microneedle array is the surface of the substrate opposite to the surface from which the microneedles protrude. A support is not essential, but if there is a support, it is easy to handle and can prevent slippage from the application site or movement to the inside of the lips. A microneedle patch backed with a hydrophobic or non-dissolving film as a backing behind a microneedle array is one embodiment of a dental topical anesthetic formulation.
　本発明における製剤剤形は様々な様態が可能である。それらを順次説明する。
１．上記マイクロニードルアレイの製造方法によって製造された乾燥したマイクロニードルアレイの背面に、支持体として高分子フィルムが裏打ちされたマイクロニードルパッチ。その製法は種々ある。例えば、マイクロニードルアレイを乾燥させ、型から剥離する前にその背面に水もしくは低沸点有機溶媒に溶解させた高分子を塗布、スプレー等により積層し、乾燥させる。ここで高分子とは、ポリビニルアルコール、高分子量のポリビニルピロリドン、高分子量のヒドロキシプロピルセルロース、ポリアクリル酸、のような水溶性高分子であって、口腔内で瞬時に溶解しない高分子である。より具体的には、支持体として高分子フィルムが裏打ちされていることによって、少なくとも貼付後３０分以内、マイクロニードル基板が溶解しない、形状が崩れないことが必要である。支持体としては、ポリ酢酸ビニル、ポリ塩化ビニル、ナイロン、等の有機溶媒可溶な高分子あるいはそれらを可塑剤により柔軟にしたものであっても良い。これらは、疎水性または非溶解フィルムの好適な具体例である。
２．上記マイクロニードルアレイの製造方法によって製造された乾燥したマイクロニードルアレイの背面に、高分子フィルムが支持体として裏打ちされたマイクロニードルパッチ。本製剤は、高分子フィルムとマイクロニードルアレイの背面に接着剤もしくは粘着剤により一体化されている。マイクロニードルアレイと高分子フィルムとのサイズは同等でもよく、また高分子フィルムがより大きくフィルム面に口腔内接着性を有するような処理をしてもよい。高分子フィルムは多孔性あるいは織り布、のような水透過性であっても良い。典型的には、ポリエチレン、ポリプロピレン、ポリエチレンテレフタレート、エチレン酢酸ビニルコポリマー（ＥＶＡ）等のプラスチックシート又はフィルム；滅菌紙、セロハン、不織布、織布等の紙シート、スプレーまたは塗布によるシリコン樹脂薄膜、スプレーまたは塗布によるフッ素オイル薄膜、等が挙げられる。 Various modes are possible for the dosage forms of the present invention. They are explained one by one.
1. A microneedle patch in which a polymer film is lined as a support on the back surface of the dried microneedle array produced by the above microneedle array production method. There are various production methods. For example, the microneedle array is dried, and a polymer dissolved in water or a low-boiling-point organic solvent is coated, sprayed, or the like on the back surface of the microneedle array before it is separated from the mold, and then dried. Here, the polymer is a water-soluble polymer such as polyvinyl alcohol, high-molecular-weight polyvinylpyrrolidone, high-molecular-weight hydroxypropylcellulose, or polyacrylic acid, which does not dissolve instantaneously in the oral cavity. More specifically, it is necessary that the microneedle substrate does not dissolve or lose its shape within at least 30 minutes after attachment due to the polymer film being lined as the support. The support may be organic solvent-soluble polymers such as polyvinyl acetate, polyvinyl chloride, nylon, or the like, or those made flexible by a plasticizer. These are suitable examples of hydrophobic or non-dissolving films.
2. A microneedle patch in which a polymer film is lined as a support on the back surface of the dried microneedle array produced by the above microneedle array production method. The formulation is integrated with the polymer film and the back surface of the microneedle array with an adhesive or pressure-sensitive adhesive. The size of the microneedle array and the polymer film may be the same, or the polymer film may be larger and the film surface may be treated to have intraoral adhesiveness. The polymeric film may be porous or water permeable, such as a woven fabric. Typically, plastic sheets or films such as polyethylene, polypropylene, polyethylene terephthalate, ethylene vinyl acetate copolymer (EVA); paper sheets such as sterilized paper, cellophane, non-woven fabrics, woven fabrics; Fluorine oil thin film by coating, and the like.
　支持体の大きさは、マイクロニードルアレイと同型同大であってもよいが、マイクロニードルアレイの口腔内での密着力を背面から補強するため、マイクロニードルアレイより大きいことが好ましい。支持体は、適用部位に応じて、取り扱い易い大きさと形状に設定することができ、例えば、マイクロニードルアレイの外縁から３～２０ｍｍ程度大きくすることが適当である。支持体の厚さは、マイクロニードルアレイ基板の厚さと同等であっても、それよりも厚くても薄くてもよく、柔軟で薄いマイクロニードルアレイを支持することができ、かつ、取り扱い易い厚さに適宜設定することができる。マイクロニードルアレイの端に手で持つための耳のような形状でもよい（図２、ポリエチレン粘着フィルム６）。支持体の一部または全面を着色してもよい、医師が麻酔終了後、着色の目付きがあれば忘れず剥がすことが容易である。 The size of the support may be the same shape and size as the microneedle array, but is preferably larger than the microneedle array in order to reinforce the adhesion force of the microneedle array in the oral cavity from the back. The support can be set to a size and shape that are easy to handle depending on the application site. The thickness of the support may be the same as the thickness of the microneedle array substrate, or may be thicker or thinner than it, and is a thickness that can support a flexible and thin microneedle array and is easy to handle. can be set as appropriate. It may be shaped like an ear for holding the end of the microneedle array by hand (FIG. 2, polyethylene adhesive film 6). A part or the entire surface of the support may be colored. After the end of anesthesia, the doctor can easily remove the colored eyes without forgetting.
　支持体は、マイクロニードルアレイの口腔内での密着力を背面から補強するために、口腔内粘着性を有することが望ましい。 The support preferably has intraoral adhesiveness in order to reinforce the adhesion of the microneedle array in the oral cavity from the back.
　支持体の口腔内粘着性を確保するための１つの態様として、支持体に粘着性物質がコーティングされている態様、すなわち、粘着剤を塗布した支持体が挙げられる。ここで、粘着性物質としては、パッチ製剤に通常使用される粘着剤が挙げられ、例えば、アクリル系、シリコン系、ゴム系粘着剤の湿潤面接着性があるグレードが好ましい。 One aspect for ensuring the intraoral adhesiveness of the backing is an aspect in which the backing is coated with an adhesive substance, that is, a backing coated with an adhesive. Here, the adhesive substance includes adhesives that are commonly used in patch preparations, and for example, acrylic, silicone, and rubber adhesives with wet surface adhesiveness are preferred.
　支持体の口腔内粘着性を確保するための別の態様として、支持体が水溶性であることが挙げられる。ポリビニルピロリドン（ＰＶＰ）、カルボキシメチルセルロース（ＣＭＣ）、ポリビニルアルコール（ＰＶＡ）などの低分子量水溶性フィルムを用い、口腔内の水分で自粘着性があるものも好ましい。この場合は、適用する口腔面の反対側口腔面へ接着しないように、水溶性支持体の反対側口腔面に対峙する面は非水溶性高分子フィルムをさらに積層することが望ましい。
　背面に積層するフィルムは、それがないとマイクロニードルアレイの背面が貼付部粘膜の反対側の口腔粘膜に付着しがちであるが故に有効ではある。しかしながら、それは本発明の必須要件ではなく、本発明の必須要件はマイクロニードルによる粘膜深部への薬物送達である。マイクロニードル基剤が水溶性であるがその水溶解速度が遅い場合、マイクロニードル部での薬物溶解が遙かに背面に比べて早いので、裏打ち剤がなくても目的にはかなう。すなわち、本発明のマイクロニードルアレイそのものが歯科局所麻酔製剤として提供される。 Another aspect for ensuring the intraoral adhesiveness of the support is that the support is water-soluble. Low-molecular-weight water-soluble films such as polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), and polyvinyl alcohol (PVA), which are self-adhesive with intraoral moisture, are also preferred. In this case, it is desirable to further laminate a water-insoluble polymer film on the surface of the water-soluble support that faces the oral cavity surface opposite to the oral cavity surface to which it is applied so as not to adhere to the oral cavity surface.
A film that laminates to the back is effective because without it the back of the microneedle array tends to adhere to the oral mucosa opposite the patch mucosa. However, it is not an essential requirement of the present invention, but an essential requirement of the present invention is drug delivery to deep mucosal membranes by microneedles. If the microneedle base is water-soluble but has a slow water dissolution rate, the dissolution of the drug in the microneedle portion is much faster than that in the back surface, so the purpose is served without the backing agent. That is, the microneedle array of the present invention itself is provided as a dental local anesthetic preparation.
　フィルム状支持体の場合、一部にフィルムを含まない欠損部分を有していてもよい。例えば、図１Ａに示すように、欠損部分はフィルム状支持体の中央部に設けることができ、この場合、マイクロニードル部の背面はフィルムで覆われていない（マイクロニードルアレイの背面はフィルムで覆われていない部分を有する）。欠損部分は中央部に限定されるものではなく、本発明のマイクロニードルパッチを適用した部位に注射針を刺す場合に、針の侵入を妨げない程度にフィルムを含まない部分を確保すればよい。マイクロニードルアレイの中央部に支持体を設けないことにより、プレ麻酔の場合マイクロニードルパッチを剥がさずそのまま背面から注射することができる。また、麻酔効果が十分であるかどうか、背面から試すことができる。 In the case of a film-like support, it may partially have a defective portion that does not contain the film. For example, as shown in FIG. 1A, the missing part can be provided in the central part of the film-like support. have parts that are not covered). The defective part is not limited to the central part, and a part that does not contain the film to the extent that it does not hinder the penetration of the needle when the injection needle is inserted into the site to which the microneedle patch of the present invention is applied may be secured. By not providing a support in the central part of the microneedle array, in the case of pre-anesthesia, the microneedle patch can be directly injected from the back without being peeled off. It can also be tested from the back to see if the anesthetic effect is sufficient.
　同様に、支持体が滅菌紙の場合、支持体がマイクロニードルアレイを内包する外枠を形成していてもよい。例えば、図１Ｂに示すように、滅菌紙の中央部に穴を設け、マイクロニードル部の背面が滅菌紙で覆われておらず、滅菌紙がマイクロニードルアレイの外枠を形成している（マイクロニードルアレイの背面は滅菌紙で覆われていない部分を有する）。外枠は、本発明のマイクロニードルパッチを適用した部位に注射針を刺す場合に、滅菌紙がマイクロニードルアレイの基板の背面全面を覆って針の侵入を妨げない程度に設ければよい。 Similarly, when the support is sterile paper, the support may form an outer frame that encloses the microneedle array. For example, as shown in FIG. 1B, a hole is provided in the center of the sterilized paper, the back surface of the microneedle portion is not covered with the sterilized paper, and the sterilized paper forms the outer frame of the microneedle array (microneedle array). The back of the needle array has a portion not covered with sterile paper). The outer frame may be provided to such an extent that when the site to which the microneedle patch of the present invention is applied is pierced with an injection needle, the sterilized paper covers the entire back surface of the substrate of the microneedle array and does not interfere with the penetration of the needle.
　本発明のマイクロニードルパッチは、前記マイクロニードルアレイの背面を支持体で覆うことにより、製造することができる。 The microneedle patch of the present invention can be produced by covering the back surface of the microneedle array with a support.
　本発明のマイクロニードルアレイ及びマイクロニードルパッチは、口腔粘膜又は歯茎に貼付後、マイクロニードル部の背面を押圧することで、局所麻酔剤が投与される。本発明のマイクロニードルアレイ及びマイクロニードルパッチは、水溶性高分子を基剤として用いているので高湿度環境下で迅速に溶解し、口腔粘膜内又は歯茎内に麻酔剤を効率的に送達できるため、短時間（１～１０分以内）に局所麻酔の効果を発揮することができる。製剤の評価はボランティアの歯茎に貼付し、５～１０分後に剥離した後、爪楊枝あるいは注射針を貼付部位に刺して痛みを感じるか否かの試験により確認できる。その際、爪楊枝あるいは注射針の先端部から１ｍｍの位置にストッパーとしてゴムリングをかぶせることによって強く推しても爪楊枝あるいは注射針が歯茎内１ｍｍより深部に入り込まないようにすることもできる。
　単位面積当たりのマイクロニードルアレイに含まれる局所麻酔剤の量及びマイクロニードルアレイの大きさを適宜設定することで、歯科用局所麻酔製剤として使用することができる。また、歯科用局所麻酔注射液を投与する前に、投与部位の痛みを軽減するためのプレ麻酔薬としても使用可能である。この場合、本発明のマイクロニードルアレイ及びマイクロニードルパッチを口腔粘膜又は歯茎に貼付した後、続けて、貼付部位に歯科用局所麻酔注射を施すことができる。 After the microneedle array and microneedle patch of the present invention are attached to the oral mucosa or gums, the back surface of the microneedle portion is pressed to administer the local anesthetic. Since the microneedle array and microneedle patch of the present invention use a water-soluble polymer as a base, they dissolve rapidly in a high-humidity environment and can efficiently deliver an anesthetic into the oral mucosa or gums. , the effect of local anesthesia can be exerted in a short time (within 1 to 10 minutes). The preparation can be evaluated by applying it to the gums of volunteers, peeling it off after 5 to 10 minutes, and then sticking a toothpick or an injection needle into the application site to see if pain is felt or not. At this time, it is possible to prevent the toothpick or injection needle from entering deeper than 1 mm into the gums even if the toothpick or injection needle is pushed strongly by covering a rubber ring as a stopper at a position 1 mm from the tip of the toothpick or injection needle.
By appropriately setting the amount of local anesthetic contained in the microneedle array per unit area and the size of the microneedle array, it can be used as a dental local anesthetic preparation. It can also be used as a pre-anesthetic to reduce pain at the injection site before administering a local anesthetic injection for dental use. In this case, after the microneedle array and microneedle patch of the present invention are applied to the oral mucosa or gums, injection of local anesthesia for dentistry can be subsequently applied to the application site.
　以下に実施例を例示して本発明を説明するが、本発明は実施例に限定されるものではない。 The present invention will be described below with reference to examples, but the present invention is not limited to the examples.
実施例１－４、比較例１－３
アミノ安息香酸エチル含有マイクロニードルパッチの製造
　アミノ安息香酸エチル（和研薬（株）より購入）１ｇ、及びポリビニルピロリドン（ＰＶＰ　Ｋ９０）４ｇをエタノールにて溶解し、鋳型に充填後乾燥させ、直径１ｃｍのマイクロニードルアレイを製造した（実施例１）。本マイクロアレイにおけるマイクロニードルの高さは３００μｍであり、針密度は２６０本／ｃｍ２であった。マイクロニードルアレイ中のアミノ安息香酸エチルの含量は、２０質量％であった。次に、マイクロニードルアレイの背面に穴あきポリエチレン粘着フィルムを接着させてマイクロニードルパッチとした。
　実施例２－４及び比較例１－３のマイクロニードルアレイは、表１に示す組成にて、実施例１と同様に製造し、実施例１と同様にマイクロニードルパッチとした。実施例１－４の製造直後のマイクロニードルアレイにおいて、アミノ安息香酸エチルの結晶析出は観察されなかった。 Example 1-4, Comparative Example 1-3
Manufacture of ethyl aminobenzoate-containing microneedle patch 1 g of ethyl aminobenzoate (purchased from Wakoyaku Co., Ltd.) and 4 g of polyvinylpyrrolidone (PVP K90) are dissolved in ethanol, filled into a mold and dried to obtain a diameter of 1 cm. of microneedle arrays were manufactured (Example 1). The height of the microneedles in this microarray was 300 μm, and the needle density was 260/cm 2 . The content of ethyl aminobenzoate in the microneedle array was 20% by mass. Next, a perforated polyethylene adhesive film was adhered to the back surface of the microneedle array to form a microneedle patch.
The microneedle arrays of Examples 2-4 and Comparative Examples 1-3 were produced in the same manner as in Example 1 with the compositions shown in Table 1, and were made into microneedle patches in the same manner as in Example 1. Crystal precipitation of ethyl aminobenzoate was not observed in the microneedle array immediately after production in Examples 1-4.
安定性試験
　実施例１－４及び比較例１－３で製造したマイクロニードルパッチに対して、ヒートサイクル試験（１０℃～５０℃の低温・高温環境下を３日ごとに繰り返す試験）を実施し、３か月後の薬物含量の減少及び結晶析出に関して評価した。結果を表１に示す。
　ＰＶＰが基剤の５０質量％以上である実施例製剤においては、薬物の安定性はほぼ良好であった。また、３か月後、試験したすべての製剤に結晶析出は観察されなかった。
　比較例製剤は、ヒートサイクル試験後に結晶析出が観察された。 Stability Test The microneedle patches produced in Example 1-4 and Comparative Example 1-3 were subjected to a heat cycle test (a test in which a low-temperature and high-temperature environment of 10 ° C. to 50 ° C. was repeated every 3 days). , with respect to decrease in drug content and crystal precipitation after 3 months. Table 1 shows the results.
In the formulations of Examples in which PVP was 50% by mass or more of the base, the stability of the drug was generally good. Also, after 3 months, no crystal precipitation was observed for all formulations tested.
Crystal precipitation was observed in the comparative formulation after the heat cycle test.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
効能試験
　実施例１、２、３、４のマイクロニードルパッチを直径２ｃｍのアクリル粘着剤塗布ポリエチレンフィルムからなる支持体で裏打ちし、ボランティア２名の歯茎に密着させて貼付し、２分後にパッチを剥離した。貼付部を針で刺激しても痛みを感じなかった。表面麻酔効果が確認できた。 Efficacy Test The microneedle patches of Examples 1, 2, 3, and 4 were lined with a support made of a polyethylene film coated with an acrylic pressure-sensitive adhesive and having a diameter of 2 cm. peeled off. No pain was felt even when the application site was stimulated with a needle. A surface anesthesia effect was confirmed.
実施例５、６
マイクロニードルの機械的強度と基剤の平均分子量との関係
　表２に記載の基剤及び麻酔剤を含むマイクロニードル製剤を、実施例１に記載の方法に準じて製造した（実施例５，６）。得られたマイクロニードルアレイを顕微鏡観察して比較した。結果を表２に示す。 Examples 5 and 6
Relationship between the mechanical strength of microneedles and the average molecular weight of the base Microneedle formulations containing the base and anesthetic shown in Table 2 were produced according to the method described in Example 1 (Examples 5 and 6 ). The obtained microneedle arrays were observed under a microscope and compared. Table 2 shows the results.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表２より、基剤のポリビニルピロリドンの重量平均分子量が低くなるとマイクロニードルアレイの機械的強度が低下することがわかった。 From Table 2, it was found that the mechanical strength of the microneedle array decreased as the weight average molecular weight of the base polyvinylpyrrolidone decreased.
実施例７，８比較例４
角質除去ラット皮膚を口腔内粘膜のモデルとして用いる薬物皮膚浸透量の評価
　表３に記載の基剤及び麻酔剤を含むマイクロニードル製剤を、実施例１に記載の方法に準じて製造した。マイクロニードルの高さは３５０μｍ、針密度は１０７０本／ｃｍ２であり、直径１ｃｍの大きさのパッチに成型した。本パッチの顕微鏡写真を図３に示す。得られたマイクロニードル製剤を角質除去ラット皮膚に指先で１０秒強く押しつけた後、５分間放置し薬物を皮膚浸透させた。５分間の放置後、製剤を取り除き、皮膚表面をふき取った。次いで、製剤適用部を切り取ってホモジナイズし、薬物をエタノール抽出した。ＨＰＬＣで抽出液中の薬物を定量し、薬物の皮膚浸透量を定量した。比較例４として市販のアミノ安息香酸エチル含有ゲル（ハリケインゲル）を用いてマイクロニードル製剤適用と同面積（１ｃｍ２）に薬物量が同量になるゲル量を皮膚適用した。５分後、皮膚表面をふき取り、製剤適用部を切り取ってホモジナイズし、薬物をエタノール抽出した。ＨＰＬＣで抽出液中の薬物を定量し薬物の皮膚浸透量を定量した。 Examples 7 and 8 Comparative example 4
Evaluation of drug skin permeation amount using exfoliated rat skin as a model of oral mucosa Microneedle formulations containing the base and anesthetic shown in Table 3 were produced according to the method described in Example 1. The microneedles had a height of 350 μm and a needle density of 1070/cm 2 , and were molded into a patch with a diameter of 1 cm. A photomicrograph of this patch is shown in FIG. The resulting microneedle preparation was strongly pressed against the exfoliated rat skin with a fingertip for 10 seconds, and then left for 5 minutes to allow the drug to permeate the skin. After leaving for 5 minutes, the formulation was removed and the skin surface was wiped off. Then, the part to which the formulation was applied was cut off and homogenized, and the drug was extracted with ethanol. The amount of drug in the extract was quantified by HPLC, and the amount of drug permeation into the skin was quantified. As Comparative Example 4, a commercially available ethyl aminobenzoate-containing gel (Hurricane Gel) was applied to the skin in an amount that would give the same amount of drug to the same area (1 cm 2 ) as the application of the microneedle formulation. After 5 minutes, the skin surface was wiped off, the area to which the formulation was applied was cut off and homogenized, and the drug was extracted with ethanol. The drug in the extract was quantified by HPLC to quantify the amount of drug permeated through the skin.
　結果を表３に示す。なお表３中、％は質量％を表す。 The results are shown in Table 3. In Table 3, % represents % by mass.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　ＨＰＬＣ条件
装置：日立Ｌ－７０００シリーズ　ＨＰＬＣ
カラム：５μｍＯＤＳ充填カラム　４．６Φｘ２５０ｍｍ
カラム温度：４０℃
移動相：アセトニトリル：０．２％酢酸酸性水（２８：７２）
流速：０．８ｍｌ／ｍｉｎ
検出波長：３１０ｎｍ HPLC condition equipment: Hitachi L-7000 series HPLC
Column: 5 μm ODS packed column 4.6Φx250mm
Column temperature: 40°C
Mobile phase: acetonitrile: 0.2% acetic acid acid water (28:72)
Flow rate: 0.8ml/min
Detection wavelength: 310 nm
１　　ポリエチレン粘着フィルム
２　　粘着無しのポリエチレンフィルム
３　　マイクロニードル部
４　　滅菌紙
５　　マイクロニードル部
６　　ポリエチレン粘着フィルム
７　　マイクロニードル部
１１　マイクロニードルパッチ
１２　マイクロニードルパッチ
１３　マイクロニードルパッチ
  1 polyethylene adhesive film 2 polyethylene film without adhesive 3 microneedle part 4 sterile paper 5 microneedle part 6 polyethylene adhesive film 7 microneedle part 11 microneedle patch 12 microneedle patch 13 microneedle patch

Claims (21)

  1. 　アミノ安息香酸エチルを含有するマイクロニードルアレイからなる即効性歯科局所麻酔製剤であって、
    　マイクロニードルアレイ中のアミノ安息香酸エチルの含有量は５～３０質量％であり、
    　マイクロニードルアレイ中にアミノ安息香酸エチルとポリビニルピロリドンとが共存し、アミノ安息香酸エチルはマイクロニードルアレイ中に溶解又は均一分散している、歯科局所麻酔製剤。     A rapid-acting dental local anesthetic formulation comprising a microneedle array containing ethyl aminobenzoate,
    The content of ethyl aminobenzoate in the microneedle array is 5 to 30% by mass,
    A dental local anesthetic preparation, wherein ethyl aminobenzoate and polyvinylpyrrolidone coexist in a microneedle array, and the ethyl aminobenzoate is dissolved or uniformly dispersed in the microneedle array.
  2. 　ポリビニルピロリドンの含有量がアミノ安息香酸エチル１００質量部に対し１００質量部以上である、請求項１に記載の歯科局所麻酔製剤。 The dental local anesthetic preparation according to claim 1, wherein the content of polyvinylpyrrolidone is 100 parts by mass or more per 100 parts by mass of ethyl aminobenzoate.
  3. 　アミノ安息香酸エチルとポリビニルピロリドンとを共存させたエタノールを含む溶液を用いて鋳型充填法により製造される、請求項１又は２に記載の歯科局所麻酔製剤。 The dental local anesthetic preparation according to claim 1 or 2, which is produced by a mold filling method using a solution containing ethanol in which ethyl aminobenzoate and polyvinylpyrrolidone are allowed to coexist.
  4. 　前記マイクロニードルアレイが水溶性かつエタノール溶解性のポリマーを基剤として含有する、請求項１～３のいずれか１項に記載の歯科局所麻酔製剤。 The dental local anesthetic preparation according to any one of claims 1 to 3, wherein the microneedle array contains a water-soluble and ethanol-soluble polymer as a base.
  5. 　アミノ安息香酸エチルを含有するマイクロニードルアレイからなる即効性歯科局所麻酔製剤であって、
    　該マイクロニードルアレイは基板と基板上の複数のマイクロニードルとからなり、水溶性高分子を基剤として同一の水溶性高分子から一体的に形成され、かつ、柔軟な基板部を有し、
    　該水溶性高分子はポリビニルピロリドン、又はポリビニルピロリドンと、ヒアルロン酸及びその誘導体、ヒドロキシプロピルセルロース、コラーゲン、プロテオグリカン、コンドロイチン硫酸、カルボキシメチルセルロース、ポリエチレングリコール、並びにデキストランからなる群より選ばれる１種又は２種以上との混合物であり、
    　該ポリビニルピロリドンの該水溶性高分子に占める割合は５０～１００質量％であり、
    　口腔粘膜又は歯茎に貼付することによりニードル部が粘膜内溶解する、即効性歯科局所麻酔製剤。     A rapid-acting dental local anesthetic formulation comprising a microneedle array containing ethyl aminobenzoate,
    The microneedle array consists of a substrate and a plurality of microneedles on the substrate, is integrally formed from the same water-soluble polymer with a water-soluble polymer as a base, and has a flexible substrate,
    The water-soluble polymer is one or two selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone, hyaluronic acid and its derivatives, hydroxypropylcellulose, collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran. is a mixture of
    The proportion of the polyvinylpyrrolidone in the water-soluble polymer is 50 to 100% by mass,
    A rapid-acting dental local anesthetic preparation that dissolves in the mucous membrane of the needle when applied to the oral mucosa or gums.
  6. 　前記マイクロニードルアレイの背面に疎水性または非溶解フィルムを裏打ちしている、請求項１～５のいずれか１項に記載の歯科局所麻酔製剤。 The dental local anesthetic preparation according to any one of claims 1 to 5, wherein the back surface of the microneedle array is lined with a hydrophobic or non-dissolving film.
  7. 　前記マイクロニードルアレイの基板の厚さが５μｍ以上１００μｍ以下である、請求項５又は６に記載の歯科局所麻酔製剤。 The dental local anesthetic preparation according to claim 5 or 6, wherein the microneedle array substrate has a thickness of 5 µm or more and 100 µm or less.
  8. 　マイクロニードルの高さが５０μｍ以上５００μｍ以下である、請求項５～７のいずれか１項に記載の歯科局所麻酔製剤。 The dental local anesthetic preparation according to any one of claims 5 to 7, wherein the height of the microneedles is 50 µm or more and 500 µm or less.
  9. 　マイクロニードルの針密度が２０本／ｃｍ２以上２０００本／ｃｍ２以下である、請求項５～８のいずれか１項に記載の歯科局所麻酔製剤。 The dental local anesthetic preparation according to any one of claims 5 to 8, wherein the microneedles have a needle density of 20/cm 2 or more and 2000/cm 2 or less.
  10. 　前記マイクロニードルアレイの基剤が水溶性高分子以外に水溶性低分子化合物を２質量％以上含有する、請求項５～９のいずれか１項に記載の歯科局所麻酔製剤。 The dental local anesthetic preparation according to any one of claims 5 to 9, wherein the base of the microneedle array contains 2% by mass or more of a water-soluble low-molecular-weight compound in addition to a water-soluble polymer.
  11. 　アミノ安息香酸エチルの基剤中の濃度が５質量％以上３０質量％以下である、請求項５～１０のいずれか１項に記載の歯科局所麻酔製剤。 The dental local anesthetic preparation according to any one of claims 5 to 10, wherein the concentration of ethyl aminobenzoate in the base is 5% by mass or more and 30% by mass or less.
  12. 　水溶性高分子を基剤とし、基板と基板上の複数のマイクロニードルとが同一の水溶性高分子から一体的に形成されている、アミノ安息香酸エチルを含有するマイクロニードルアレイであって、
    　該マイクロニードルの高さは５０μｍ以上５００μｍ以下であり、該マイクロニードルの先端は直径１μｍ以上５０μｍ以下の円形又はそれと同面積を有する平面であり、該マイクロニードルアレイの基板の厚さは５μｍ以上１００μｍ以下であり、かつ、前記基板が柔軟な基板であり、
    　該水溶性高分子はポリビニルピロリドン、又はポリビニルピロリドンと、ヒアルロン酸及びその誘導体、ヒドロキシプロピルセルロース、コラーゲン、プロテオグリカン、コンドロイチン硫酸、カルボキシメチルセルロース、ポリエチレングリコール、並びにデキストランからなる群より選ばれる１種又は２種以上との混合物であり、
    　該ポリビニルピロリドンの該水溶性高分子に占める割合は５０～１００質量％である、マイクロニードルアレイ。     A microneedle array containing ethyl aminobenzoate, wherein a water-soluble polymer is used as a base, and a substrate and a plurality of microneedles on the substrate are integrally formed from the same water-soluble polymer,
    The height of the microneedle is 50 μm or more and 500 μm or less, the tip of the microneedle is a circle having a diameter of 1 μm or more and 50 μm or less or a flat surface having the same area, and the thickness of the substrate of the microneedle array is 5 μm or more and 100 μm. and wherein the substrate is a flexible substrate,
    The water-soluble polymer is one or two selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone, hyaluronic acid and its derivatives, hydroxypropylcellulose, collagen, proteoglycan, chondroitin sulfate, carboxymethylcellulose, polyethylene glycol, and dextran. is a mixture of
    A microneedle array, wherein the polyvinylpyrrolidone accounts for 50 to 100% by mass of the water-soluble polymer.
  13. 　基剤が水溶性高分子以外に水溶性低分子化合物を２質量％以上含有する、請求項１２に記載のマイクロニードルアレイ。 The microneedle array according to claim 12, wherein the base contains 2% by mass or more of a water-soluble low-molecular-weight compound in addition to the water-soluble polymer.
  14. 　アミノ安息香酸エチルの基剤中の濃度が５質量％以上３０質量％以下である、請求項１２に記載のマイクロニードルアレイ。 The microneedle array according to claim 12, wherein the concentration of ethyl aminobenzoate in the base is 5% by mass or more and 30% by mass or less.
  15. 　請求項１２～１４のいずれか１項に記載のマイクロニードルアレイと、該マイクロニードルアレイの背面に備えられた支持体とからなるマイクロニードルパッチ。 A microneedle patch comprising the microneedle array according to any one of claims 12 to 14 and a support provided on the back surface of the microneedle array.
  16. 　支持体が口腔内粘着性を有する、請求項１５に記載のマイクロニードルパッチ。 The microneedle patch according to claim 15, wherein the support has intraoral adhesiveness.
  17. 　支持体に粘着性物質がコーティングされている、請求項１６に記載のマイクロニードルパッチ。 The microneedle patch according to claim 16, wherein the support is coated with an adhesive substance.
  18. 　支持体が水溶性である、請求項１６に記載のマイクロニードルパッチ。 The microneedle patch according to claim 16, wherein the support is water-soluble.
  19. 　支持体がフィルム状であり、一部にフィルムを含まない欠損部分を有する、請求項１５～１８のいずれか１項に記載のマイクロニードルパッチ。 The microneedle patch according to any one of claims 15 to 18, wherein the support is in the form of a film and partially has a defective portion that does not contain a film.
  20. 　支持体が滅菌紙であり、マイクロニードルアレイを内包する外枠を形成している、請求項１５～１８のいずれか１項に記載のマイクロニードルパッチ。 The microneedle patch according to any one of claims 15 to 18, wherein the support is sterile paper and forms an outer frame enclosing the microneedle array.
  21. 　アミノ安息香酸エチルとポリビニルピロリドンとを共存させたエタノールを含む溶液を調製する工程、及び
    　前記溶液をマイクロニードルアレイ成型用鋳型に流延し、乾燥した後剥離する工程を含む、
    アミノ安息香酸エチルがマイクロニードルアレイ中に溶解又は均一分散している即効性歯科局所麻酔製剤の製造方法。     A step of preparing a solution containing ethanol in which ethyl aminobenzoate and polyvinylpyrrolidone coexist, and a step of casting the solution on a microneedle array molding mold, drying and then peeling off,
    A method for producing a rapid-acting dental local anesthetic preparation in which ethyl aminobenzoate is dissolved or uniformly dispersed in a microneedle array.
PCT/JP2022/017101 2021-04-05 2022-04-05 Microneedle array for local anesthesia for dental use WO2022215693A1 (en)

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Title
MA X, TAW J, CHIANG C-M: "Control of drug crystallization in transdermal matrix system", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 142, no. 01, 27 September 1996 (1996-09-27), NL , pages 115 - 119, XP008000957, ISSN: 0378-5173, DOI: 10.1016/0378-5173(96)04647-9 *

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