WO2019088227A1 - 歯科用局所麻酔マイクロニードルアレイ - Google Patents

歯科用局所麻酔マイクロニードルアレイ Download PDF

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Publication number
WO2019088227A1
WO2019088227A1 PCT/JP2018/040719 JP2018040719W WO2019088227A1 WO 2019088227 A1 WO2019088227 A1 WO 2019088227A1 JP 2018040719 W JP2018040719 W JP 2018040719W WO 2019088227 A1 WO2019088227 A1 WO 2019088227A1
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WIPO (PCT)
Prior art keywords
microneedle array
microneedle
local anesthetic
anesthetic
dental
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Ceased
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PCT/JP2018/040719
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English (en)
French (fr)
Japanese (ja)
Inventor
英淑 権
文男 神山
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CosMED Pharmaceutical Co Ltd
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CosMED Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by CosMED Pharmaceutical Co Ltd filed Critical CosMED Pharmaceutical Co Ltd
Priority to KR1020197036710A priority Critical patent/KR102380428B1/ko
Priority to AU2018360546A priority patent/AU2018360546B2/en
Priority to US16/623,748 priority patent/US20200170940A1/en
Priority to CN202210877331.8A priority patent/CN115252593B/zh
Priority to CN201880040871.2A priority patent/CN110799238B/zh
Priority to CA3067660A priority patent/CA3067660C/en
Priority to EP18873082.4A priority patent/EP3705155A4/en
Publication of WO2019088227A1 publication Critical patent/WO2019088227A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C19/00—Dental auxiliary appliances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C19/00—Dental auxiliary appliances
    • A61C19/001—Holders for absorbent pads
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C19/00—Dental auxiliary appliances
    • A61C19/06—Implements for therapeutic treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C19/00—Dental auxiliary appliances
    • A61C19/06—Implements for therapeutic treatment
    • A61C19/063—Medicament applicators for teeth or gums, e.g. treatment with fluorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C19/00—Dental auxiliary appliances
    • A61C19/06—Implements for therapeutic treatment
    • A61C19/08—Implements for therapeutic treatment combined with anaesthetising implements
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • 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
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    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays or needleless injectors
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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    • 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
    • A61M19/00—Local anaesthesia; Hypothermia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles
    • A—HUMAN NECESSITIES
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    • 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
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    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061—Methods for using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0468—Liquids non-physiological
    • A61M2202/048—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0244—Micromachined materials, e.g. made from silicon wafers, microelectromechanical systems [MEMS] or comprising nanotechnology
    • A—HUMAN NECESSITIES
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    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0625—Mouth
    • A61M2210/0631—Gums

Definitions

  • the present invention relates to the technical field of microneedles applied to dental (oral) local anesthesia.
  • an anesthetic is applied to the oral (gum) mucosa, or an anesthetic is injected into the gum.
  • dental topical anesthetics There are many commercially available dental topical anesthetics. They are mainly topical anesthetic agent-containing solutions, gels, jellies and the like, and the solutions are applied to the oral cavity by dipping in cotton wool or the like. Gel and jelly are applied as they are to the oral cavity. In either case, the time to effect is long because absorption of the anesthetic from the mucous membrane is slow, and the time it takes to lie down for a long time for the patient to wait and variations in mucosal absorption often cause a loss of QOL. .
  • the microneedle preparation has high percutaneous absorbability, and development of cosmetics and medicines has been attempted.
  • the application site of the microneedle preparation is the skin epidermis, but, for example, a microneedle patch as a vaccination by transoral buccal administration is known (Patent Document 1).
  • the microneedle patch is designed to penetrate the outer layer of the inner buccal mucosa.
  • microneedles for the transfer of dental substances such as local anesthetics for dental use have been developed (Patent Documents 2 and 3).
  • Patent Document 2 includes a microneedle array and a hollow spherical container internally containing a dental local anesthetic, and the anesthetic is locally delivered through an opening penetrating the microneedle.
  • Patent Document 3 is a microneedle provided with a base portion that bends along the skin shape inside the oral cavity, a microneedle main body portion, and an active ingredient coating portion coated on the surface of the needle main body portion.
  • An object of the present invention is to provide a microneedle array which is easy to apply to the oral cavity and can exert an anesthetic effect according to the application site.
  • the rapid surface anesthesia can be performed to a depth of 1 to 2 mm of the skin before injection of an anesthetic, the patient's QOL can be significantly improved.
  • the present inventors have specified the shape and material of the microneedle array, thereby making the microneedle array suitable for dental local anesthesia. It came to invent.
  • the present invention is as follows.
  • An immediate-acting dental local anesthetic preparation which comprises a microneedle array containing a local anesthetic, and the needle portion dissolves in the mucous membrane by being attached to the oral mucosa or gum.
  • the water-soluble polymer is one or more selected from the group consisting of hyaluronic acid and derivatives thereof, collagen, proteoglycan, hydroxypropylcellulose, chondroitin sulfate, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol, and dextran
  • the dental local anesthetic preparation as described in, [3].
  • a microneedle array based on a water-soluble polymer and containing a local anesthetic wherein the height of the microneedle is 50 ⁇ m to 300 ⁇ m, and the tip of the microneedle is a circle having a diameter of 1 ⁇ m to 50 ⁇ m Or the microneedle array which is a plane which has the same area as it, and the thickness of the substrate of a microneedle array is 5 micrometers or more and 100 micrometers or less.
  • the water-soluble polymer is one or more selected from the group consisting of hyaluronic acid and derivatives thereof, collagen, proteoglycan, hydroxypropylcellulose, chondroitin sulfate, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol, and dextran , [11].
  • microneedle array according to any one of [11] to [13], wherein the local anesthetic is selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine and salts thereof.
  • the local anesthetic is a mixture of one or more selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine and salts thereof and ethyl aminobenzoate Microneedle array described in.
  • microneedle array according to any one of [11] to [16], wherein the concentration of the local anesthetic in the base is 1% by mass to 80% by mass.
  • concentration of the local anesthetic in the base is 1% by mass to 80% by mass.
  • a microneedle patch comprising the microneedle array according to any one of [11] to [18] and a support provided on the back of the microneedle array.
  • the microneedle patch according to [19], wherein the support has intraoral adhesiveness.
  • the microneedle patch according to [20], wherein the support is coated with an adhesive substance.
  • microneedle patch according to [20], wherein the support is water soluble.
  • the microneedle array of the present invention is easy to manufacture because the substrate and the microneedles are integrally formed on the basis of a water-soluble polymer, and the amount of the local anesthetic contained and the size of the microneedle array By adjusting the height, the anesthetic effect according to the purpose can be achieved in a short time. Since the microneedle array and microneedle patch of the present invention use a water-soluble polymer as a base, they easily adhere to the bending of the oral mucous membrane or gums in a high humidity environment, and for topical administration in the oral cavity Is suitable.
  • microneedle array and microneedle patch of the present invention can also be used as a dental local anesthetic preparation, and also as a pre-anesthetic for reducing pain at the administration site before administering a dental local anesthetic injection solution It is.
  • FIG. 1 is a schematic view of a microneedle patch of the present invention.
  • FIG. 1A uses the polyethylene adhesive film 1 as a support, the polyethylene adhesive film does not exist at the center of the back surface of the microneedle portion 3.
  • the sterile paper 4 is used as a support, and the sterile paper is not present on the back of the microneedle portion 5 to form the outer frame of the microneedle patch.
  • FIG. 2 is a schematic view of a microneedle patch with an ear for hand holding at a part of its end, with no support in the center of the back of the microneedle part 7.
  • the microneedle array of the present invention is suitable for local anesthesia, particularly for dental local anesthesia.
  • the microneedle array of the present invention comprises a substrate and a plurality of microneedles on the substrate, and is integrally formed of the same water-soluble polymer as a water-soluble polymer as a base.
  • the base of the microneedle array is a water soluble polymer.
  • the local anesthetic is contained not only in the microneedle portion but also in the substrate portion.
  • the microneedle portion can reach in the mucous membrane or in the gums, whereby the microneedle portion dissolves in the mucous membrane and the included local anesthesia Promote the delivery of the agent to the target site.
  • the substrate of the microneedle array also adheres following the bending of the oral mucosa or gums in a high humidity environment in the oral cavity, and the water-soluble polymer of the substrate dissolves, and the local anesthetic present there is also the target site Delivered to
  • water-soluble polymers examples include hyaluronic acid and derivatives thereof (eg sodium salt, polyethylene oxide graft hyaluronic acid), collagen, proteoglycan, hydroxypropyl cellulose, chondroitin sulfate, carboxymethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol or dextran, etc. And one or more selected from these may be mixed and used.
  • hyaluronic acid or a derivative thereof is preferred.
  • Hyaluronic acid is a type of glycosaminoglycan (mucopolysaccharide), and has a structure in which disaccharide units of N-acetylglucosamine and glucuronic acid are linked.
  • examples of hyaluronic acid include hyaluronic acid derived from organisms isolated from chicken crown, umbilical cord and the like, and hyaluronic acid derived from culture mass-produced by lactic acid bacteria, streptococcus and the like. Since hyaluronic acid of biological origin can not completely remove the collagen possessed by the organism from which it is derived, it may have a negative effect on the remaining collagen, and therefore, hyaluronic acid derived from a culture not containing collagen is preferred. Therefore, the hyaluronic acid preferably contains 50% by mass or more of hyaluronic acid derived from culture.
  • the microneedle array molded from these polymer substances becomes harder as the weight average molecular weight decreases
  • the weight average molecular weight is preferably 5,000 to 2,000,000.
  • the microneedle array When applying the microneedle array to the oral cavity, it is hard to break with an appropriate hardness, and a high molecular weight polymer substance with a weight average molecular weight of 100,000 or more and a weight average molecular weight to facilitate penetration of the local anesthetic
  • the microneedle array may be formed from a mixture of low molecular weight polymer substances having a molecular weight of 50,000 or less.
  • the weight average molecular weight of the high molecular weight polymer substance may be 50,000 or more, 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 1,000 or more.
  • the weight average molecular weight is a value measured by gel permeation chromatography (GPC).
  • the ratio in mixing the high molecular weight polymer substance and the low molecular weight polymer substance varies depending on the type and weight average molecular weight of each polymer substance, and accordingly, it may be appropriately determined so as to obtain preferable mechanical strength and hardness. In general, it is preferable that the content is 1% by mass or more of the high molecular weight polymer substance and 99% by mass or less of the low molecular weight polymer substance.
  • a soluble agent may be added to the above-mentioned polymer substance in order to rapidly exert an anesthetic effect.
  • the dissolvable agent include trehalose, monosaccharides such as glucose, disaccharides, polyhydric alcohols such as glycerin, propylene glycol (PG), butylene glycol (BG) and polyethylene glycol (PEG).
  • the addition amount of the soluble agent is preferably 1% by mass or more and 50% by mass or less as the concentration in the base.
  • polyvinyl pyrrolidone (PVP) and dextran may be added.
  • the base of the microneedle array can contain a water soluble low molecular weight compound in addition to the water soluble polymer.
  • the water-soluble low molecular weight compound is a monosaccharide, disaccharide or polyhydric alcohol used as the above-mentioned soluble agent, and is a compound having a molecular weight of 500 or less.
  • monosaccharides include glucose and fructose
  • disaccharides include sucrose, lactose, trehalose and maltose.
  • polyhydric alcohols glycerin, propylene glycol (PG), butylene glycol (BG), polyethylene glycol (PEG) 200, PEG 400 and the like can be mentioned.
  • the addition amount of the water-soluble low molecular weight compound is 2% by mass or more and 50% by mass or less as a concentration in the base, preferably 2% by mass or more and 35% by mass or less, more preferably 2% by mass or more and 30% by mass It is below.
  • the height of the microneedles is preferably 50 ⁇ m or more and 300 ⁇ m or less, and more preferably 100 ⁇ m or more and 250 ⁇ m or less. Below 50 ⁇ m, it is disadvantageous for the delivery of local anesthetics. If it exceeds 300 ⁇ m, it may be accompanied by pain or bleeding when applied.
  • the tip of the microneedle is desirably a circle having a diameter of 1 ⁇ m or more or a flat surface having the same area.
  • the tip of the microneedle is preferably a circle having a diameter of 50 ⁇ m or less or a flat surface having the same area. Being within this range is advantageous for the delivery of local anesthetics.
  • the needle shape may, for example, be a rod shape, a truncated cone shape or a conedite shape, preferably a truncated cone shape or a conede shape.
  • the microneedle array comprises a flexible substrate.
  • the thickness of the substrate of the microneedle array is desirably 5 ⁇ m or more and 100 ⁇ m or less, and more preferably 10 ⁇ m or more and 50 ⁇ m or less.
  • the shape of the substrate of the microneedle array can be appropriately set according to the application site, and examples thereof include a circle, an ellipse, a triangle, a square, and a polygon.
  • the size of the shape is usually 2 mm or more and 100 mm or less, preferably 5 mm or more and 50 mm or less, as represented by the diameter (long diameter) or the length of one side (long side). Also, when expressed by area the size of the microneedle array is usually 5 mm 2 or more 1000 mm 2 or less, preferably 10 mm 2 or more 500 mm 2 or less.
  • the active ingredient contained in the microneedle array of the present invention is a local anesthetic.
  • Local anesthetics include procaine, tetracaine, lidocaine, dibucaine, bupivacaine or their salts.
  • the local anesthetic may be ethyl aminobenzoate (benzocaine).
  • two or more of these local anesthetics can be mixed and 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 with ethyl aminobenzoate.
  • lidocaine or a salt thereof is preferred, and as a salt of lidocaine, lidocaine hydrochloride is preferred.
  • additives which are usually contained as a pharmaceutical may be contained.
  • concentration of the additive contained in the microneedle array of the present invention can be set in an appropriate range according to the type of additive and the purpose of addition.
  • the concentration of the local anesthetic in the base is 1% by mass to 80% by mass, and more preferably 10% by mass to 70% by mass.
  • 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 a suitable solvent such as water, and the content of the local anesthetic is quantitatively analyzed, the microneedles Drug content in the solid mass of the array).
  • the method for producing the microneedle array of the present invention is not particularly limited, and may be produced by any conventionally known method, for example, the above water-soluble polymer and the topical agent in a mold in which the shape of the microneedle is drilled. There is a method of casting an aqueous solution containing an anesthetic and, if necessary, other components, drying and peeling. The peeled microneedle array sheet is used by cutting in accordance with the shape of the application site in the oral cavity.
  • microneedle array of the present invention can be used alone as a dental topical anesthetic preparation.
  • the following microneedle patch may be used for the convenience of intraoral application.
  • the microneedle patch of the present invention comprises the microneedle array and a support provided on the back of the microneedle array.
  • the back surface of the microneedle array is a substrate portion on the side opposite to the surface on which the microneedles protrude.
  • the support is not essential, but the presence of the support is easy to handle and can prevent the application site from slipping or moving inside the lip.
  • a microneedle patch lined with a hydrophobic or non-dissolving film as a support on the back of the microneedle array is one embodiment of a dental topical anesthetic formulation. This dental local anesthetic preparation is a rapid acting dental local anesthetic preparation having immediate effects.
  • the dosage form of the present invention can be in various forms. These will be described one by one.
  • a microneedle patch in which a polymer film is backed as a support on the back of the dried microneedle array manufactured by the method for manufacturing a microneedle array as described above.
  • the microneedle array is dried, and a polymer dissolved in water or a low boiling point organic solvent is applied to the back surface of the microneedle array by a method such as spraying, and then dried.
  • the polymer is a water-soluble polymer such as polyvinyl alcohol, high molecular weight polyvinyl pyrrolidone, hydroxypropyl cellulose, or polyacrylic acid, and is a polymer that does not dissolve instantaneously in the oral cavity. More specifically, since the polymer film is backed as a support, it is necessary that the microneedle substrate does not dissolve and its shape does not collapse at least within 30 minutes after the application.
  • the support may be a polymer soluble in an organic solvent such as polyvinyl acetate, polyvinyl chloride, nylon or the like, or a polymer obtained by softening them with a plasticizer. These are preferred embodiments of hydrophobic or non-dissolving films. 2.
  • the formulation is integrated with the polymer film and the back of the microneedle array with an adhesive or adhesive.
  • the size of the microneedle array and the polymer film may be equal, and the polymer film may be treated to have larger intraoral adhesion on the film surface.
  • the polymeric film may be porous or water permeable, such as woven.
  • plastic sheets or films such as polyethylene, polypropylene, polyethylene terephthalate, ethylene vinyl acetate copolymer (EVA); sterile paper, cellophane, nonwovens, paper sheets such as woven fabrics, silicone resin thin film by spray or application, spray or A fluorine oil thin film by coating, etc. may be mentioned.
  • the size of the support may be the same size as that of the microneedle array, but is preferably larger than the microneedle array in order to reinforce the adhesion in the oral cavity of the microneedle array from the back.
  • the support can be set to a size and a shape that can be easily handled according to the application site, and for example, it is appropriate to make it about 3 to 20 mm larger from the outer edge of the microneedle array.
  • the thickness of the support may be equal to, greater than or less than the thickness of the microneedle array substrate, 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 hand holding at the end of the microneedle array (FIG. 2, polyethylene adhesive film 6). A part or the whole surface of the support may be colored, and it is easy for the doctor to forget to remove it after anesthesia, if there is a colored mark.
  • the support is desirably intraoral adhesive in order to reinforce the intraoral adhesion of the microneedle array from the back.
  • One embodiment for securing the intraoral adhesiveness of the support includes a support coated with an adhesive substance, that is, a support coated with an adhesive.
  • an adhesive substance an adhesive generally used in patch preparations can be mentioned, and for example, a grade having an adhesive property of an acrylic, silicone, rubber adhesive having a wet surface is preferable.
  • the support is water soluble. It is also preferable to use a low molecular weight water-soluble film such as polyvinyl pyrrolidone (PVP), carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA) and the like and water self-adhesive in the oral cavity.
  • PVP polyvinyl pyrrolidone
  • CMC carboxymethyl cellulose
  • PVA polyvinyl alcohol
  • a film laminated to the back is effective because otherwise the back of the microneedle array tends to adhere to the oral mucosa opposite the patch mucosa.
  • microneedle array of the present invention itself is provided as a dental local anesthetic preparation.
  • part of the film-like support may have a defect not containing a film.
  • the defect can be provided at the center of the film-like support, in which case the back of the microneedle is not covered by the film.
  • the defective portion is not limited to the central portion, and when the injection needle is pierced at the site to which the microneedle patch of the present invention is applied, a portion not containing the film may be secured to the extent that the penetration of the needle is not prevented.
  • the support may form an outer frame that encloses the microneedle array.
  • the support may form an outer frame that encloses the microneedle array.
  • a hole is provided in the center of the sterile paper, the back of the microneedle portion is not covered with the sterile paper, and the sterile paper forms the outer frame of the microneedle array.
  • the outer frame may be provided to the extent that the sterile paper covers the entire back surface of the substrate of the microneedle array and does not prevent the penetration of the needle when the injection needle is pierced at the site to which the microneedle patch of the present invention is applied.
  • the microneedle patch of the present invention can be manufactured by covering the back of the microneedle array with a support.
  • the microneedle array and microneedle patch of the present invention are applied to the oral mucous membrane or gum, and then a local anesthetic is administered by pressing the back of the microneedle portion.
  • the microneedle array and microneedle patch of the present invention use a water-soluble polymer as a base, so that they can be dissolved rapidly in a high humidity environment and can efficiently deliver an anesthetic agent in the oral mucosa or gum.
  • the effect of local anesthesia can be exhibited in a short time (within 1 to 10 minutes).
  • the preparation is applied to the gum of a volunteer and peeled off after 5 to 10 minutes, and then it can be confirmed by a test of whether or not it feels pain by sticking a toothpick or an injection needle to the application site.
  • the toothpick or injection needle it is possible to prevent the toothpick or injection needle from getting deeper than 1 mm in the gum even if it is strongly pushed by putting a rubber ring as a stopper at a position of 1 mm from the tip of the toothpick or injection needle.
  • the amount of the 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 for reducing pain at the administration site prior to administration of a dental local anesthetic injection solution.
  • the microneedle array and the microneedle patch of the present invention are applied to the oral mucosa or gums, it is possible to continuously apply a dental local anesthetic injection to the application site.
  • Example 1 Manufacture of microneedle patch containing local anesthetic 50 parts by mass of lidocaine hydrochloride (purchased from Wiken Pharmaceutical Co., Ltd.) and 50 parts by mass of sodium hyaluronate (FCH-SU, Kikkoman) were weighed, and water was added to prepare a solution having a solid content of 10% by mass. The aqueous solution was poured into a mold having a needle length of 200 ⁇ m, dried at room temperature for 24 hours, and demolded to produce a microneedle array. A perforated polyethylene (PE) adhesive film was then adhered to the back of the array.
  • PE polyethylene
  • the preparation was applied to the gums of five volunteers and peeled off after 5 minutes, and a toothpick was pierced at the application site to test whether pain was felt or not. All were able to confirm the anesthetic effect without feeling pain.
  • Benzocaine ethyl aminobenzoate
  • the microneedle arrays molded in Examples 4 to 9 were subjected to a compression test using a small desktop tester EZ Test EZSX (manufactured by Shimadzu Corporation) to measure the mechanical strength of the needle.
  • the microneedle array was formed into a diameter of 1 cm, fixed between two stainless steel plates, and compressed at a speed of 1 mm / min to obtain a stress / strain curve. From the stress-strain curves, elastic coefficients were obtained and compared as evaluation criteria for mechanical strength of the needle.
  • the elastic modulus was calculated from a linear gradient at a strain of 0.1 to 0.2 mm, which is an initial steady state in a stress-strain curve consisting of stress on the vertical axis and strain on the horizontal axis. The results are shown in Table 1.
  • microneedle preparations of Examples 4 to 9 were all able to exert an anesthetic effect on all volunteers within 10 minutes.
  • the sheet preparation and the gel ointment were difficult to exert an anesthetic effect within 10 minutes.
  • microneedle patch 12 microneedle patch 13 microneedle patch

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KR1020197036710A KR102380428B1 (ko) 2017-11-02 2018-11-01 치과용 국소 마취 마이크로니들 어레이
AU2018360546A AU2018360546B2 (en) 2017-11-02 2018-11-01 Dental local anesthetic microneedle array
US16/623,748 US20200170940A1 (en) 2017-11-02 2018-11-01 Dental local anesthetic microneedle array
CN202210877331.8A CN115252593B (zh) 2017-11-02 2018-11-01 齿科用局部麻醉微针阵列
CN201880040871.2A CN110799238B (zh) 2017-11-02 2018-11-01 齿科用局部麻醉微针阵列
CA3067660A CA3067660C (en) 2017-11-02 2018-11-01 Dental local anesthetic microneedle array
EP18873082.4A EP3705155A4 (en) 2017-11-02 2018-11-01 LOCAL DENTAL ANESTHESIA MICRO-NEEDLE NETWORK

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JP2024039002A (ja) 2022-09-08 2024-03-21 コスメディ製薬株式会社 局所適用システム
KR102853223B1 (ko) 2023-01-30 2025-08-29 선문대학교 산학협력단 치과 치료를 위한 국소 마취용 마이크로 니들 패치
KR20240150287A (ko) * 2023-04-07 2024-10-15 연세대학교 산학협력단 점막 면역을 위한 설하 용해성 마이크로니들 어레이 및 이의 제조방법
KR102853390B1 (ko) * 2023-04-12 2025-09-01 연세대학교 산학협력단 마이크로니들 패키지 및 이를 구비하는 마이크로니들 어플리케이터
KR102853389B1 (ko) * 2023-04-12 2025-09-01 연세대학교 산학협력단 마이크로니들 어플리케이터
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