WO2022215693A1 - Réseau de micro-aiguilles pour anesthésie locale à usage dentaire - Google Patents

Réseau de micro-aiguilles pour anesthésie locale à usage dentaire 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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English (en)
Japanese (ja)
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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/fr

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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

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Abstract

La présente invention concerne une préparation pour micro-aiguilles qui peut être appliquée facilement à une cavité buccale, qui exerce un effet anesthésique approprié pour un site d'application, et qui présente une excellente stabilité.　L'invention concerne une préparation anesthésique locale à action rapide à usage dentaire, qui comprend un réseau de micro-aiguilles contenant de l'aminobenzoate d'éthyle, dans laquelle la teneur en aminobenzoate d'éthyle dans le réseau de micro-aiguilles est compris entre 5 et 30 % en masse, l'aminobenzoate d'éthyle et la polyvinylpyrrolidone coexistent dans le réseau de micro-aiguilles, et l'aminobenzoate d'éthyle est dissous ou est uniformément dispersé dans le réseau de micro-aiguilles.
PCT/JP2022/017101 2021-04-05 2022-04-05 Réseau de micro-aiguilles pour anesthésie locale à usage dentaire WO2022215693A1 (fr)

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JP2019084352A (ja) * 2017-11-02 2019-06-06 コスメディ製薬株式会社 歯科用局所麻酔マイクロニードルアレイ

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JP2019084352A (ja) * 2017-11-02 2019-06-06 コスメディ製薬株式会社 歯科用局所麻酔マイクロニードルアレイ

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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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