WO2023286796A1 - Oral composition - Google Patents

Oral composition Download PDF

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Publication number
WO2023286796A1
WO2023286796A1 PCT/JP2022/027523 JP2022027523W WO2023286796A1 WO 2023286796 A1 WO2023286796 A1 WO 2023286796A1 JP 2022027523 W JP2022027523 W JP 2022027523W WO 2023286796 A1 WO2023286796 A1 WO 2023286796A1
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WIPO (PCT)
Prior art keywords
aluminum
composition
mass
intraoral
hypromellose
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PCT/JP2022/027523
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French (fr)
Japanese (ja)
Inventor
成彦 青野
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富士フイルム株式会社
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Priority to JP2023534829A priority Critical patent/JPWO2023286796A1/ja
Publication of WO2023286796A1 publication Critical patent/WO2023286796A1/en

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    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention relates to an intraoral composition.
  • cancer treatment affects the mucous membrane of the mouth, and stomatitis is likely to occur.
  • anticancer drug therapy when drugs that cause stomatitis are administered, and in radiation therapy for head and neck cancer (cancer that covers the head and neck), radiation is directed directly to the mucous membranes of the mouth. When it hits, mouth ulcers are inevitable. The pain of stomatitis is so strong that I cannot even take food by mouth.
  • Symptomatic treatment of stomatitis includes a patch directly applied to the affected area (e.g., Aphtaseal (registered trademark) 25 ⁇ g, manufactured by Taisho Pharmaceutical Co., Ltd.; active ingredient triamcinolone acetonide), an ointment applied to the affected area (e.g., dexartin oral ointment, Nippon Kayaku Co., Ltd.; active ingredient dexamethasone), and sprays to be sprayed onto the affected area (for example, Salcort (registered trademark) capsules 50 ⁇ g for external use, Teijin Pharma; active ingredient beclomethasone propionate).
  • Aphtaseal registered trademark 25 ⁇ g, manufactured by Taisho Pharmaceutical Co., Ltd.
  • active ingredient triamcinolone acetonide an ointment applied to the affected area
  • an ointment applied to the affected area e.g., dexartin oral ointment, Nippon Kayaku
  • the patch pasted on the affected area may come off, or the ointment or spray applied to the affected area may be lost, making it impossible to suppress the pain of stomatitis.
  • Patent Document 1 discloses an oral composition containing ethyl aminobenzoate, carboxyvinyl polymer, hypromellose, and hydroxypropyl cellulose and substantially free of water.
  • the wear resistance was not necessarily sufficient.
  • the gel formed using the intraoral composition is required to have abrasion resistance so that it can remain even when it comes into contact with the tongue or teeth during eating or the like.
  • the oral composition is required to be easily spreadable, that is, to have applicability.
  • an object of the present invention is to provide an intraoral composition that can form a gel with excellent abrasion resistance and that has excellent applicability.
  • the present inventor has completed the present invention as a result of diligent studies aimed at solving the above problems. That is, the inventors have found that the above problems can be solved by the following configuration.
  • the content of the specific polymer is 5 to 20% by mass with respect to the total mass of the oral composition,
  • the content of the hypromellose is 10 to 30% by mass with respect to the total mass of the oral composition
  • the intraoral composition wherein the total content of the specific polymer and the hypromellose is 25 to 40% by mass relative to the total mass of the intraoral composition.
  • the oral composition according to [3], wherein the aluminum compound is at least one selected from the group consisting of aluminum lactate, aluminum chloride, aluminum ammonium sulfate and aluminum potassium sulfate.
  • the intraoral composition according to [3] or [4], wherein the aluminum compound is aluminum lactate.
  • the content of the aluminum lactate is 0.5 to 4% by mass relative to the total mass of the intraoral composition.
  • an intraoral composition that can form a gel with excellent abrasion resistance and that has excellent applicability.
  • FIG. 2 is a front view of an aluminum head used for evaluation of wear resistance
  • FIG. 4 is a top view of an aluminum head used for evaluation of wear resistance
  • FIG. 4 is a side view of an aluminum head used for evaluation of wear resistance
  • the oral composition of the present invention comprises at least one specific polymer selected from the group consisting of carboxyvinyl polymer and polyacrylic acid, hypromellose, and an oily base material, and the content of the specific polymer is 5 to 20% by mass relative to the total mass of the intraoral composition, the content of hypromellose is 10 to 30% by mass relative to the total mass of the oral composition, and the total content of the specific polymer and hypromellose The amount is 25-40% by weight relative to the total weight of the oral composition.
  • the intraoral composition of the present invention gels by absorbing water, and can protect the affected area in the oral cavity from external stimuli.
  • the intraoral composition contains a specific polymer and hypromellose, and the content of the specific polymer, the content of hypromellose, and the total content of the specific polymer and hypromellose are each at least the lower limit of the above range, a gel formed It is considered to be excellent in wear resistance of
  • the content of the specific polymer, the content of hypromellose, and the total content of the specific polymer and hypromellose are below the upper limits of the above ranges, respectively, so that the viscosity of the oral composition does not become too high, and the applicability is improved. considered to be excellent.
  • the intraoral composition may further contain an aluminum compound in addition to the above components. Moreover, the intraoral composition may contain other additives as needed. Hereinafter, each component contained in the intraoral composition will be described in detail. In addition, hereinafter, when at least one of the coatability and the abrasion resistance of the formed gel is superior, it is also referred to as "the effect of the present invention is superior".
  • the oral composition of the present invention contains at least one specific polymer selected from the group consisting of carboxyvinyl polymer and polyacrylic acid.
  • a carboxy vinyl polymer is a water-soluble vinyl polymer having a carboxy group, and refers to a polymer having a crosslinked structure. Specifically, it is a polymer having a crosslinked structure with acrylic acid and/or methacrylic acid as a main chain.
  • the crosslinked structure includes, for example, a crosslinked structure formed by allyl sucrose, allyl ether of pentaerythritol, or the like.
  • Polyacrylic acid is a polymer synthesized using acrylic acid as a monomer, and refers to a polymer that does not have a crosslinked structure.
  • the viscosity of the specific polymer is not particularly limited, the viscosity in a 0.5% by mass aqueous solution of the specific polymer (25° C.) adjusted to pH 7.5 is preferably 20000 mPa s or less from the viewpoint that the effects of the present invention are more excellent. 2000 mPa ⁇ s to 20000 mPa ⁇ s is more preferable.
  • the above viscosity is a value obtained by measuring the above aqueous solution with a rheometer (MCR301, manufactured by Anton Paar) at a shear rate of 1 (s -1 ), a GAP of 0.05 mm, and a temperature of 25°C.
  • a commercially available product can be used as the specific polymer in the oral cavity composition of the present invention.
  • Specific examples of commercially available carboxyvinyl polymers include “Carbopol (registered trademark) 971", “Carbopol 974", “Carbopol 980", and “Carbopol 981” manufactured by Lubrizol Advanced Materials; “AQUPEC HV805", “AQUPEC HV-501E”, and “AQUPEC HV-505E” manufactured by Sumitomo Seika; , and "Hibisu Wako 105";”Junron (registered trademark) PW-120", “Junron PW-121", and “Junron PW-312S” manufactured by Toagosei Co., Ltd.; Trademark) K” and “Syntaren L”; “NTC-CARBOMER 380” and “NTC-CARBOMER 381” manufactured by Nikko Chemicals.
  • specific examples of commercial products of polyacrylic acid include “poly
  • One type of specific polymer may be used alone, or two or more types may be used in combination.
  • the content of the specific polymer in the oral cavity composition of the present invention is 5 to 20% by mass relative to the total mass of the oral cavity composition.
  • the content of the specific polymer is preferably 7.5 to 17.5% by mass, more than 10% by mass and 17.5% by mass or less, relative to the total mass of the oral cavity composition, from the viewpoint that the effects of the present invention are more excellent. is more preferred, and 12.5 to 15% by mass is even more preferred.
  • the total content is preferably within the above range.
  • Hypromellose The oral composition of the present invention contains hypromellose.
  • Hypromellose is also called hydroxypropylmethylcellulose.
  • Hypromellose is listed in the Pharmaceutical Excipients Dictionary 2021 and the Japanese Pharmacopoeia 18th Edition, and can be easily obtained.
  • Hypromellose is classified according to the degree of substitution of methoxy groups and hydroxypropoxy groups in the cellulose backbone, and the classification is called degree of substitution type. Substitution types include 1828, 2208, 2906 and 2910, and hypromellose may be used singly or in combination of two or more.
  • substitution degree types 2208, 2906 and 2910 are preferably used, and substitution degree type 2208 is more preferably used alone.
  • the weight average molecular weight of hypromellose is preferably 80,000 to 1,200,000, more preferably 150,000 to 800,000.
  • the weight average molecular weight of hypromellose can be measured using gel permeation chromatography (GPC: Gel Permeation Chromatography).
  • GPC Gel Permeation Chromatography
  • the GPC measurement conditions for measuring the weight average molecular weight of hypromellose are described below. GPC measurement conditions/column: Shodex DS-4 ⁇ Eluent: 0.1 mol/L NaNO3 ⁇ Flow rate: 1.0 mL/min ⁇ Injection volume: 200 ⁇ L ⁇ Detection: RI (Refractive Index)
  • the content of hypromellose in the intraoral composition of the present invention is 10 to 30% by mass relative to the total mass of the intraoral composition. From the viewpoint that the effect of the present invention is more excellent, the content of hypromellose is preferably more than 10% by mass and 25% by mass or less, more preferably 15 to 25% by mass, based on the total mass of the oral cavity composition. % by mass is more preferred.
  • the total content of the specific polymer and hypromellose is 25-40% by mass relative to the total mass of the intraoral composition. From the viewpoint that the effect of the present invention is more excellent, the total content is preferably more than 25% by mass and 37.5% by mass or less, more preferably 27.5 to 35% by mass, based on the total mass of the oral composition. , 27.5 to 32.5 mass % is more preferable.
  • a commercial product can be used as hypromellose in the oral cavity composition of the present invention.
  • Commercial products of hypromellose include the "METOLOSE (registered trademark)” series and “METOLOSE (registered trademark) SR” series manufactured by Shin-Etsu Chemical Co., Ltd.
  • the oral composition of the present invention contains an oil base.
  • An oily base means a component that is immiscible with water.
  • Examples of the oily base include raw materials used for ordinary oily ointments.
  • Oil bases include, for example, hydrocarbons (preferably gelatinized hydrocarbons), waxes, vegetable oils, animal oils, neutral lipids, synthetic oils, sterol derivatives, monoalcohol carboxylic acid esters, oxyacid esters, Examples include polyhydric alcohol fatty acid esters, silicones, higher alcohols, higher fatty acids, and fluorine oils.
  • the viscosity of the oil base is not particularly limited, but is preferably 100 to 1,000,000 mPa ⁇ s, more preferably 1,000 to 100,000 mPa ⁇ s.
  • Viscosity is measured at a temperature of 25° C. and a shear rate of 1 (s ⁇ 1 ) using a viscoelasticity measuring device (manufactured by Anton Paar, MCR302).
  • the oil base may be used alone or in combination of two or more.
  • hydrocarbons preferably gelling hydrocarbons
  • liquid paraffin is preferred.
  • gelling hydrocarbon those conforming to the standards for pharmaceutical excipients "gelating hydrocarbon” can be used, and more specifically, gelling hydrocarbon obtained by gelling liquid paraffin with polyethylene is preferably used. can.
  • the gelling hydrocarbon is preferably a gelling hydrocarbon (manufactured by Contract Pharmaceuticals Limited Canada), Plastibase (registered trademark) (manufactured by Taisho Pharmaceutical Co., Ltd.), or Hicol Gel (registered trademark) (manufactured by Kaneda Corporation). .
  • hydrocarbons examples include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, ⁇ -olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, vaseline, and solid paraffin.
  • the petrolatum is preferably selected from those conforming to the Japanese Pharmacopoeia or equivalent standards of “petroleum jelly”, “white petrolatum”, or “yellow petrolatum”.
  • Waxes include, for example, candelilla wax, carnauba wax, rice wax, Japan wax, beeswax, montan wax, ozokerite, ceresin, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax, and ethylene/propylene copolymers. mentioned.
  • Vegetable oils include, for example, soybean oil, sesame oil, olive oil, coconut oil, palm oil, rice bran oil, cottonseed oil, sunflower oil, rice bran oil, cocoa butter, corn oil, safflower oil, and rapeseed oil.
  • Animal oils include, for example, mink oil, turtle oil, fish oil, beef oil, horse oil, pork oil, and shark squalane.
  • Neutral lipids include, for example, triolein, trilinolein, trimyristin, tristearin, and triarachidonine.
  • Synthetic fats and oils include, for example, phospholipids and azone.
  • Sterol derivatives include, for example, dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterols, cholic acid, and cholesteryl linolate.
  • Monoalcohol carboxylic acid esters include, for example, octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, and cetyl palmitate.
  • oxyacid esters include cetyl lactate, diisostearyl malate, and hydrogenated castor oil monoisostearate.
  • Polyhydric alcohol fatty acid esters include, for example, glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, and tri(caprylic/capric)glyceryl.
  • silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), and phenyltrimethicone.
  • higher alcohols include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, and stearyl alcohol.
  • higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, and palmitoleic acid.
  • Fluorinated oils include, for example, perfluorodecane, perfluorooctane, and perfluoropolyether.
  • the oil base may be used alone or in combination of two or more.
  • the content of the oil-based base is preferably 40-75% by mass, more preferably 60-75% by mass, and even more preferably 65-70% by mass, relative to the total mass of the oral cavity composition.
  • the oral cavity composition of the present invention preferably contains an aluminum compound from the viewpoint that the effects of the present invention are more excellent.
  • the inclusion of an aluminum compound in the oral composition further improves the abrasion resistance of the formed gel.
  • the aluminum compound is not particularly limited as long as it contains aluminum, but is preferably a water-soluble aluminum compound, more preferably an aluminum carboxylate, more preferably an aluminum hydroxycarboxylate, and particularly preferably aluminum lactate. When the aluminum compound is aluminum lactate, the gel formed has better abrasion resistance.
  • water-soluble aluminum compound examples include, but are not limited to, aluminum chloride (AlCl 3 ), aluminum sulfate (Al 2 (SO 4 ) 3 ), aluminum nitrate (Al(NO 3 ) 3 ), aluminum ammonium sulfate (AlNH 4 ( SO4 ) 2.12H2O ), potassium aluminum sulfate ( AlK ( SO4 ) 2.12H2O ), aluminum acetate, aluminum propionate, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate , aluminum tartrate, aluminum citrate, and aluminum isocitrate.
  • the water-soluble aluminum compound is preferably at least one selected from the group consisting of aluminum chloride, aluminum ammonium sulfate, potassium aluminum sulfate, and aluminum lactate, more preferably aluminum lactate.
  • Aluminum acetate, aluminum propionate, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartrate, aluminum citrate, and aluminum isocitrate correspond to the carboxylates of aluminum.
  • aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartrate, aluminum citrate, and aluminum isocitrate correspond to the hydroxycarboxylates of aluminum.
  • the content of the aluminum compound is preferably 0.1 to 10% by mass, more preferably 0.4 to 4% by mass, based on the total mass of the oral cavity composition. 0.5 to 4 mass % is more preferred. Further, from the point of view that the effect of the present invention is more excellent, the content of aluminum lactate is preferably 0.1 to 10% by mass, more preferably 0.4 to 4% by mass, relative to the total mass of the oral composition. , 0.5 to 4 mass % is more preferred.
  • the intraoral composition of the present invention may contain additives other than those mentioned above.
  • Other additives include, but are not limited to, drugs, wetting agents, excipients, emulsifiers, thickeners, preservatives, coloring agents, stabilizers, cooling agents, flavoring agents, perfumes, and the like. be done.
  • the oral compositions of the present invention are substantially free of water.
  • the term “substantially free of water” means that a small amount of water that does not affect the effects of the present invention (for example, a trace amount of water contained in the ingredients of the oral composition of the present invention) is not included. It means that it is within acceptable limits.
  • “substantially free of water” means that the content of water in the oral composition is 3% by mass or less with respect to the total mass of the oral composition. . Especially, it is preferable that it is 1 mass % or less.
  • the lower limit is not particularly limited, it may be 0% by mass or more based on the total mass of the intraoral composition.
  • the adhesion of the gel formed when the intraoral composition is applied to the living body is further improved, and the protective performance is also improved.
  • the storage stability of the intraoral composition is further improved.
  • Methods for measuring the water content in the oral composition of the present invention include, for example, the water content measurement method (Karl Fischer method) described in the Japanese Pharmacopoeia. Among others, it is preferable to add a step of dispersing the sample in methanol for moisture measurement and extracting the moisture, and subjecting the extracted liquid to a coulometric titration test.
  • the oral composition of the present invention can form a gel by contacting the oral composition with water. By forming a gel, for example, the affected area can be protected from external stimuli.
  • Forms of the intraoral composition of the present invention include, for example, ointments, creams, and semi-solids.
  • the viscosity of the intraoral composition of the present invention is preferably less than 1300000 mPa ⁇ s, more preferably less than 750000 mPa ⁇ s, from the viewpoint of applicability.
  • the lower limit is not particularly limited, it may be 10000 mPa ⁇ s or more.
  • the viscosity is measured at a temperature of 25° C. and a shear rate of 1 s ⁇ 1 using a viscoelasticity measuring device (manufactured by Anton Paar, MCR302).
  • the intraoral composition of the present invention can be produced by mixing a specific polymer, hypromellose, and an oily base material. If necessary, each material and/or oral composition may be subjected to degassing treatment or dehydration treatment.
  • the mixing method is not particularly limited, and conventionally known methods used when mixing powder components can be used.
  • a stepwise mixing method may be implemented in which some of the components constituting the oral composition are mixed in advance and then mixed with the rest of the components.
  • the mixing method and order of the aluminum compound are not particularly limited, but after obtaining a mixture by mixing a specific polymer, an oily base material and an aluminum compound, the resulting mixture and hypromellose It is preferable to mix with.
  • oral composition of the present invention includes, for example, oral protection. Specifically, it can be used as an oral mucosa protective agent.
  • the oral cavity composition of the present invention can also be used as a wound dressing, a drug sustained release base material, an oral moistening agent, a hemostatic agent, and the like.
  • the intraoral composition of the present invention is used as a sustained-release drug carrier, the type of drug to be sustained-released is not particularly limited, and known drugs can be used.
  • the oral composition of the present invention When the oral composition of the present invention is applied to the oral mucosa, the oral composition is placed on the oral mucosa, and when water or a solution containing water is added, the resulting gel forms a gel. adheres more firmly. That is, as a method for using the oral composition of the present invention (or a method for producing a gel), the oral composition is placed on the oral mucosa, and the oral composition and water are placed on the oral mucosa. Examples include a method of forming a gel on the oral mucosa by contact. In addition, since the intraoral composition is gelled by water in saliva in the oral cavity, it is easy to handle. In addition, if the amount of saliva is small, water may be supplied by, for example, spraying water or artificial saliva after applying the oral composition to the oral mucosa.
  • the oral composition of the present invention When the oral composition of the present invention is adhered to the oral mucosa, gelation is initiated by the moisture in saliva, and at the same time, attractive force due to hydrogen bonding acts between mucin and hypromellose on the surface of the oral mucosa, and the oral mucosa and the intraoral composition adhere to each other. It is believed that the gel formed by the intraoral composition exhibits excellent wear resistance due to such a mechanism, but is not necessarily limited to such a mechanism.
  • Example 1 150 g of gelatinized hydrocarbon (manufactured by Contract Pharmaceuticals Limited Canada) and 30 g of carboxyvinyl polymer (manufactured by Lubrizol, "Carbopol 971P NF") were mixed with a kneader (manufactured by Primix, "HP-2P-03"). Mixed at 50 rpm for 1 minute.
  • Examples 2 to 20 In the same procedure as in Example 1, each component was mixed so that the contents shown in Tables 1 and 2 below were obtained to obtain intraoral compositions used in Examples 2 to 18. Further, in the same procedure as in Example 1, each component was mixed so that the content shown in Table 3 below was obtained, and oral compositions used in Examples 19 and 20 were obtained.
  • Examples 21 to 26 139.4 g of the gelled hydrocarbon, 27.2 g of the carboxyvinyl polymer, and 0.6 g of aluminum lactate (manufactured by Musashino Chemical Laboratory) were mixed with a kneader ("HP-2P-03" manufactured by Primix). , for 2 minutes at 50 rpm. After mixing, 32.8 g of the above hypromellose was added and mixed for 10 minutes at 50 rpm to obtain an intraoral composition used in Example 21. In the same procedure as in Example 21, each component was mixed so that the content shown in Table 3 below was obtained, and oral compositions used in Examples 21 to 26 were obtained.
  • Examples 27-29 136 g of the gelled hydrocarbon, 27.2 g of the carboxyvinyl polymer, and 4 g of aluminum chloride hexahydrate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., special grade reagent) are mixed with a kneader (manufactured by Primix, "HP-2P-03 ”) for 2 minutes at 50 rpm. After mixing, 32.8 g of the above hypromellose was added and mixed for 10 minutes at 50 rpm to obtain an intraoral composition used in Example 27.
  • TDAB tetradodecylammonium bromide, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; 50 mg
  • polyvinyl chloride manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; 800 mg
  • DOPP di-n-octylphosphonate, Fujifilm Wako Pure Chemical Industries, Ltd.
  • THF tetrahydrofuran, Fujifilm Wako Pure Chemical Industries, Ltd.; 10 mL
  • a hydrogel consisting of agar (Calcorican (registered trademark), manufactured by Ina Food Industry; 0.5 g), gellan gum (Kelcogel (registered trademark), manufactured by CP Kelco; 0.1 g) and distilled water (49.4 g)
  • the prepared lipid membrane was attached to the gel.
  • the lipid membrane surface was coated with MPC (2-methacryloyloxyethylphosphorylcholine) polymer (LIPIDURE®-CM5206, manufactured by NOF CORPORATION) to obtain a simulated biomembrane.
  • MPC 2-methacryloyloxyethylphosphorylcholine
  • the intraoral composition was gelled by hand for 1 minute to prepare a sample for evaluation. .
  • the prepared evaluation sample was repeatedly worn with the abrasion tester, and the number of reciprocations until the evaluation sample peeled off or dissolved from the simulated biological membrane was measured, and the abrasion resistance was evaluated according to the following criteria.
  • the aluminum head 10 manufactured by Watanabe Seisakusho
  • FIGS. 1 to 3 was used as the head of the abrasion tester, and the test was conducted under the conditions of a load of 30 g, an amplitude of 30 mm, and a speed of 6000 mm/min.
  • FIG. 1 is a front view of the aluminum head 10
  • FIG. 2 is a top view of the aluminum head 10
  • FIG. 3 is a side view of the aluminum head 10.
  • the head 10 made of aluminum is composed of a substrate 12 and a contact portion 14 arranged on the substrate 12 .
  • the contact portion 14 is a portion that contacts the evaluation sample and extends along the longitudinal direction of the substrate 12 .
  • the width W1 of the substrate 12 was 26 mm
  • the length L of the substrate 12 was 36 mm
  • the thickness T of the substrate 12 was 2 mm.
  • the width W2 of the contact portion 14 was 8 mm
  • the height H of the contact portion 14 was approximately 8 mm.
  • the tip of the contact portion 14 was polished to form a smooth curved surface.
  • the aluminum head 10 When installing the aluminum head 10 in the abrasion tester, the aluminum head 10 is rubbed so that the longitudinal direction of the contact portion 12 of the aluminum head 10 and the reciprocating direction of the abrasion tester are perpendicular to each other. installed in the test machine.
  • the intraoral composition when applied with a finger, it can be easily applied when the viscosity is less than 7.5 ⁇ 10 5 mPa s, and when it is 7.5 ⁇ 10 5 mPa s or more and less than 13 ⁇ 10 5 mPa s While coating was possible, coating was difficult at 13 ⁇ 10 5 mPa ⁇ s or more.
  • Tables 1 to 4 show the content of each component in the oral cavity composition of each example and each comparative example and the evaluation results.
  • the comprehensive evaluation column is based on the following criteria.
  • AA Evaluation of abrasion resistance is AA, and evaluation of applicability is A
  • A Wear resistance evaluation is A
  • applicability evaluation is A
  • B At least one of wear resistance and applicability evaluation is B
  • the other evaluation is other than C
  • At least one of wear resistance and applicability evaluation is C
  • the notation " ⁇ 13" in the viscosity column indicates that the viscosity was 1300000 mPa ⁇ s or more and could not be measured.

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Abstract

The present invention addresses the problem of providing an oral composition which can form a gel having excellent wear resistance and has excellent applicability. This oral composition comprises at least one specific polymer selected from the group consisting of carboxyvinyl polymers and poly(acrylic acid), hypromellose, and an oily base, wherein the content of the specific polymer is 5-20 mass% with respect to the whole mass of the oral composition, the content of the hypromellose is 10-30 mass% with respect to the whole mass of the oral composition, and the total content of the specific polymer and the hypromellose is 25-40 mass% with respect to the whole mass of the oral composition.

Description

口腔内組成物oral composition
　本発明は、口腔内組成物に関する。 The present invention relates to an intraoral composition.
　がん患者においては、がん治療が口の粘膜に影響して口内炎が起こりやすい。例えば、抗がん剤治療では、口内炎を起こしやすい薬剤の投与を受けたときに、また、頭頸部がん（頭から首の範囲のがん）の放射線治療では、口の粘膜に放射線が直接当たったときに、口内炎が必発である。口内炎の痛みは強く、食事を口からとることもできないほどである。 In cancer patients, cancer treatment affects the mucous membrane of the mouth, and stomatitis is likely to occur. For example, in anticancer drug therapy, when drugs that cause stomatitis are administered, and in radiation therapy for head and neck cancer (cancer that covers the head and neck), radiation is directed directly to the mucous membranes of the mouth. When it hits, mouth ulcers are inevitable. The pain of stomatitis is so strong that I cannot even take food by mouth.
　口内炎の対症療法としては、患部に直接貼り付ける貼付剤（例えば、アフタシール（登録商標）２５μｇ、大正製薬社製；有効成分　トリアムシノロンアセトニド）、患部に塗り付ける軟膏剤（例えば、デキサルチン口腔用軟膏、日本化薬社製；有効成分　デキサメタゾン）、および患部に吹き付ける噴霧剤（例えば、サルコート（登録商標）カプセル外用５０μｇ、帝人ファーマ社製；有効成分　ベクロメタゾンプロピオン酸エステル）などがある。 Symptomatic treatment of stomatitis includes a patch directly applied to the affected area (e.g., Aphtaseal (registered trademark) 25 μg, manufactured by Taisho Pharmaceutical Co., Ltd.; active ingredient triamcinolone acetonide), an ointment applied to the affected area (e.g., dexartin oral ointment, Nippon Kayaku Co., Ltd.; active ingredient dexamethasone), and sprays to be sprayed onto the affected area (for example, Salcort (registered trademark) capsules 50 μg for external use, Teijin Pharma; active ingredient beclomethasone propionate).
　しかし、これらの治療剤は免疫抑制剤であるステロイドを有効成分とするため、がん患者にとって望ましいものとはいえない。 However, since these therapeutic agents contain steroids, which are immunosuppressants, as active ingredients, they are not desirable for cancer patients.
　また、食事を口から摂る際に、患部に貼り付けた貼付剤が剥がれたり、患部に塗布した軟膏剤または噴霧剤が失われたりして、口内炎の痛みを抑制することができない。 In addition, when eating orally, the patch pasted on the affected area may come off, or the ointment or spray applied to the affected area may be lost, making it impossible to suppress the pain of stomatitis.
　このような口内炎の痛みを抑制できる口腔内組成物が望まれている。 There is a demand for an oral composition that can suppress the pain of such stomatitis.
　例えば、特許文献１には、アミノ安息香酸エチル、カルボキシビニルポリマー、ヒプロメロース、および、ヒドロキシプロピルセルロースを含み、実質的に水を含有しない口腔用組成物が開示されている。 For example, Patent Document 1 discloses an oral composition containing ethyl aminobenzoate, carboxyvinyl polymer, hypromellose, and hydroxypropyl cellulose and substantially free of water.
特開２０１９－１６３２３８号公報JP 2019-163238 A
　一方で、特許文献１に記載された組成物を用いて形成されたゲルの特性を評価したところ、耐摩耗性が必ずしも十分でなかった。口腔内組成物を用いて形成されるゲルに関しては、食事等の際に舌もしくは歯または食品等が接触した際にも残存できるように、耐摩耗性が求められる。
　また、口腔内組成物においては、口腔内組成物を患部に塗布する際、容易に塗り広げることができること、すなわち塗布性が求められる。 On the other hand, when the properties of the gel formed using the composition described in Patent Document 1 were evaluated, the wear resistance was not necessarily sufficient. The gel formed using the intraoral composition is required to have abrasion resistance so that it can remain even when it comes into contact with the tongue or teeth during eating or the like.
In addition, when the oral composition is applied to the affected area, the oral composition is required to be easily spreadable, that is, to have applicability.
　そこで本発明は、耐摩耗性に優れるゲルを形成でき、かつ、塗布性に優れる口腔内組成物の提供を課題とする。 Therefore, an object of the present invention is to provide an intraoral composition that can form a gel with excellent abrasion resistance and that has excellent applicability.
　本発明者は、上記課題を解決すべく鋭意検討した結果、本発明を完成させるに至った。すなわち、以下の構成により上記課題が解決されることを見出した。 The present inventor has completed the present invention as a result of diligent studies aimed at solving the above problems. That is, the inventors have found that the above problems can be solved by the following configuration.
　〔１〕　カルボキシビニルポリマーおよびポリアクリル酸からなる群より選択される少なくとも１種の特定ポリマーと、
　ヒプロメロースと、
　油性基材と、を含む口腔内組成物であって、
　上記特定ポリマーの含有量が、上記口腔内組成物の全質量に対して、５～２０質量％であり、
　上記ヒプロメロースの含有量が、上記口腔内組成物の全質量に対して、１０～３０質量％であり、
　上記特定ポリマーおよび上記ヒプロメロースの合計含有量が、上記口腔内組成物の全質量に対して、２５～４０質量％である、口腔内組成物。
　〔２〕　上記油性基材が、ゲル化炭化水素を含む、〔１〕に記載の口腔内組成物。
　〔３〕　さらにアルミニウム化合物を含む、〔１〕または〔２〕に記載の口腔内組成物。
　〔４〕　上記アルミニウム化合物が、乳酸アルミニウム、塩化アルミニウム、硫酸アンモニウムアルミニウムおよび硫酸カリウムアルミニウムからなる群より選択される少なくとも１種である、〔３〕に記載の口腔内組成物。
　〔５〕　上記アルミニウム化合物が、乳酸アルミニウムである、〔３〕または〔４〕に記載の口腔内組成物。
　〔６〕　上記乳酸アルミニウムの含有量が、上記口腔内組成物の全質量に対して、０．５～４質量％である、〔５〕に記載の口腔内組成物。 [1] at least one specific polymer selected from the group consisting of carboxyvinyl polymer and polyacrylic acid;
hypromellose and
An oral composition comprising an oily base,
The content of the specific polymer is 5 to 20% by mass with respect to the total mass of the oral composition,
The content of the hypromellose is 10 to 30% by mass with respect to the total mass of the oral composition,
The intraoral composition, wherein the total content of the specific polymer and the hypromellose is 25 to 40% by mass relative to the total mass of the intraoral composition.
[2] The intraoral composition according to [1], wherein the oily base material contains a gelling hydrocarbon.
[3] The intraoral composition of [1] or [2], further comprising an aluminum compound.
[4] The oral composition according to [3], wherein the aluminum compound is at least one selected from the group consisting of aluminum lactate, aluminum chloride, aluminum ammonium sulfate and aluminum potassium sulfate.
[5] The intraoral composition according to [3] or [4], wherein the aluminum compound is aluminum lactate.
[6] The intraoral composition according to [5], wherein the content of the aluminum lactate is 0.5 to 4% by mass relative to the total mass of the intraoral composition.
　本発明によれば、耐摩耗性に優れるゲルを形成でき、かつ、塗布性に優れる口腔内組成物を提供できる。 According to the present invention, it is possible to provide an intraoral composition that can form a gel with excellent abrasion resistance and that has excellent applicability.
耐摩耗性の評価に用いたアルミニウム製ヘッドの正面図である。FIG. 2 is a front view of an aluminum head used for evaluation of wear resistance; 耐摩耗性の評価に用いたアルミニウム製ヘッドの上面図である。FIG. 4 is a top view of an aluminum head used for evaluation of wear resistance; 耐摩耗性の評価に用いたアルミニウム製ヘッドの側面図である。FIG. 4 is a side view of an aluminum head used for evaluation of wear resistance;
　以下、本発明について詳細に説明する。
　以下に記載する構成要件の説明は、本発明の代表的な実施態様に基づいてなされる場合があるが、本発明はそのような実施態様に制限されない。 The present invention will be described in detail below.
The description of the constituent elements described below may be made based on representative embodiments of the present invention, but the present invention is not limited to such embodiments.
　以下、本明細書における各記載の意味を表す。
　本明細書において、「～」を用いて表される数値範囲は、「～」の前後に記載される数値を下限値および上限値として含む範囲を意味する。 Hereinafter, the meaning of each description in this specification is expressed.
In the present specification, a numerical range represented by "to" means a range including the numerical values before and after "to" as lower and upper limits.
＜口腔内組成物＞
　本発明の口腔内組成物は、カルボキシビニルポリマーおよびポリアクリル酸からなる群より選択される少なくとも１種の特定ポリマーと、ヒプロメロースと、油性基材と、を含み、特定ポリマーの含有量が、口腔内組成物の全質量に対して、５～２０質量％であり、ヒプロメロースの含有量が、口腔内組成物の全質量に対して、１０～３０質量％であり、特定ポリマーおよびヒプロメロースの合計含有量が、口腔内組成物の全質量に対して、２５～４０質量％である。
　後述するように、本発明の口腔内組成物は、水を吸収することによりゲル化し、口腔内の患部を外部刺激から保護できる。
　本発明の口腔内組成物が、塗布性に優れ、かつ、形成されるゲルの耐摩耗性に優れる機序は必ずしも明らかではないが、本発明者は以下のように推測している。
　口腔内組成物が特定ポリマーとヒプロメロースとを含み、特定ポリマーの含有量、ヒプロメロースの含有量、および、特定ポリマーおよびヒプロメロースの合計含有量がそれぞれ上記範囲の下限以上であることで、形成されるゲルの耐摩耗性に優れると考えられる。また、特定ポリマーの含有量、ヒプロメロースの含有量、および、特定ポリマーおよびヒプロメロースの合計含有量がそれぞれ上記範囲の上限以下であることで、口腔内組成物の粘度が高くなりすぎず、塗布性に優れると考えられる。 <Oral composition>
The oral composition of the present invention comprises at least one specific polymer selected from the group consisting of carboxyvinyl polymer and polyacrylic acid, hypromellose, and an oily base material, and the content of the specific polymer is 5 to 20% by mass relative to the total mass of the intraoral composition, the content of hypromellose is 10 to 30% by mass relative to the total mass of the oral composition, and the total content of the specific polymer and hypromellose The amount is 25-40% by weight relative to the total weight of the oral composition.
As will be described later, the intraoral composition of the present invention gels by absorbing water, and can protect the affected area in the oral cavity from external stimuli.
Although the mechanism by which the intraoral composition of the present invention has excellent applicability and excellent abrasion resistance of the formed gel is not necessarily clear, the present inventors presume as follows.
The intraoral composition contains a specific polymer and hypromellose, and the content of the specific polymer, the content of hypromellose, and the total content of the specific polymer and hypromellose are each at least the lower limit of the above range, a gel formed It is considered to be excellent in wear resistance of In addition, the content of the specific polymer, the content of hypromellose, and the total content of the specific polymer and hypromellose are below the upper limits of the above ranges, respectively, so that the viscosity of the oral composition does not become too high, and the applicability is improved. considered to be excellent.
　なお、口腔内組成物は、上記成分に加えて、さらにアルミニウム化合物を含んでいてもよい。また、口腔内組成物は必要に応じて他の添加剤を含んでいてもよい。
　以下、口腔内組成物が含む各成分について詳述する。
　なお、以下、塗布性および形成されるゲルの耐摩耗性の少なくとも一方がより優れる場合、「本発明の効果がより優れる」ともいう。 The intraoral composition may further contain an aluminum compound in addition to the above components. Moreover, the intraoral composition may contain other additives as needed.
Hereinafter, each component contained in the intraoral composition will be described in detail.
In addition, hereinafter, when at least one of the coatability and the abrasion resistance of the formed gel is superior, it is also referred to as "the effect of the present invention is superior".
［特定ポリマー］
　本発明の口腔内組成物は、カルボキシビニルポリマーおよびポリアクリル酸からなる群より選択される少なくとも１種の特定ポリマーを含む。
　カルボキシビニルポリマーとは、カルボキシ基を有する水溶性のビニルポリマーであり、架橋構造を有するポリマーをいう。具体的には、アクリル酸および／またはメタクリル酸を主鎖として、架橋構造を有するポリマーである。架橋構造としては、例えば、アリルショ糖、または、ペンタエリスリトールのアリルエーテル等による架橋構造が挙げられる。
　ポリアクリル酸とは、アクリル酸をモノマーとして合成されるポリマーであり、架橋構造を有さないポリマーをいう。 [Specific polymer]
The oral composition of the present invention contains at least one specific polymer selected from the group consisting of carboxyvinyl polymer and polyacrylic acid.
A carboxy vinyl polymer is a water-soluble vinyl polymer having a carboxy group, and refers to a polymer having a crosslinked structure. Specifically, it is a polymer having a crosslinked structure with acrylic acid and/or methacrylic acid as a main chain. The crosslinked structure includes, for example, a crosslinked structure formed by allyl sucrose, allyl ether of pentaerythritol, or the like.
Polyacrylic acid is a polymer synthesized using acrylic acid as a monomer, and refers to a polymer that does not have a crosslinked structure.
　特定ポリマーの粘度は特に制限されないが、本発明の効果がより優れる点で、ｐＨ７．５に調整した０．５質量％の特定ポリマー水溶液（２５℃）における粘度が、２００００ｍＰａ・ｓ以下が好ましく、２０００ｍＰａ・ｓ～２００００ｍＰａ・ｓがより好ましい。
　上記粘度は、上記水溶液を、レオメータ（ＭＣＲ３０１、アントンパール社製）において、ｓｈｅｒｅ　ｒａｔｅ　１（ｓ－１）、ＧＡＰ　０．０５ｍｍ、温度２５℃で測定した値である。 Although the viscosity of the specific polymer is not particularly limited, the viscosity in a 0.5% by mass aqueous solution of the specific polymer (25° C.) adjusted to pH 7.5 is preferably 20000 mPa s or less from the viewpoint that the effects of the present invention are more excellent. 2000 mPa·s to 20000 mPa·s is more preferable.
The above viscosity is a value obtained by measuring the above aqueous solution with a rheometer (MCR301, manufactured by Anton Paar) at a shear rate of 1 (s -1 ), a GAP of 0.05 mm, and a temperature of 25°C.
　本発明の口腔内組成物において、特定ポリマーは、市販品を使用することができる。カルボキシビニルポリマーの市販品としては、具体的には、Ｌｕｂｒｉｚｏｌ　Ａｄｖａｎｃｅｄ　Ｍａｔｅｒｉａｌｓ社製の「カーボポール（登録商標）９７１」、「カーボポール９７４」、「カーボポール９８０」、および、「カーボポール９８１」；住友精化社製の「ＡＱＵＰＥＣ　ＨＶ８０５」、「ＡＱＵＰＥＣ　ＨＶ－５０１Ｅ」、および、「ＡＱＵＰＥＣ　ＨＶ－５０５Ｅ」；富士フイルム和光純薬社製の「ハイビスワコー（登録商標）１０３」、「ハイビスワコー１０４」、および、「ハイビスワコー１０５」；東亞合成社製の「ジュンロン（登録商標）ＰＷ－１２０」、「ジュンロンＰＷ－１２１」、および、「ジュンロンＰＷ－３１２Ｓ」；３Ｖシグマ社製の「シンタレン（登録商標）Ｋ」、および、「シンタレンＬ」；日光ケミカルズ社製の「ＮＴＣ－ＣＡＲＢＯＭＥＲ　３８０」、および、「ＮＴＣ－ＣＡＲＢＯＭＥＲ　３８１」が挙げられる。
　また、ポリアクリル酸の市販品としては、具体的には、富士フイルム和光純薬社製の「ポリアクリル酸２５０，０００」、および、「ポリアクリル酸１，０００，０００」が挙げられる。 A commercially available product can be used as the specific polymer in the oral cavity composition of the present invention. Specific examples of commercially available carboxyvinyl polymers include "Carbopol (registered trademark) 971", "Carbopol 974", "Carbopol 980", and "Carbopol 981" manufactured by Lubrizol Advanced Materials; "AQUPEC HV805", "AQUPEC HV-501E", and "AQUPEC HV-505E" manufactured by Sumitomo Seika; , and "Hibisu Wako 105";"Junron (registered trademark) PW-120", "Junron PW-121", and "Junron PW-312S" manufactured by Toagosei Co., Ltd.; Trademark) K” and “Syntaren L”; “NTC-CARBOMER 380” and “NTC-CARBOMER 381” manufactured by Nikko Chemicals.
In addition, specific examples of commercial products of polyacrylic acid include “polyacrylic acid 250,000” and “polyacrylic acid 1,000,000” manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.
　特定ポリマーは、１種を単独で用いてもよく、２種類以上を組み合わせて用いてもよい。 One type of specific polymer may be used alone, or two or more types may be used in combination.
　本発明の口腔内組成物における特定ポリマーの含有量は、口腔内組成物の全質量に対して、５～２０質量％である。本発明の効果がより優れる点で、特定ポリマーの含有量は、口腔内組成物の全質量に対して、７．５～１７．５質量％が好ましく、１０質量％超１７．５質量％以下がより好ましく、１２．５～１５質量％がさらに好ましい。
　特定ポリマーを２種類以上用いる場合、その合計含有量が上記範囲内であることが好ましい。 The content of the specific polymer in the oral cavity composition of the present invention is 5 to 20% by mass relative to the total mass of the oral cavity composition. The content of the specific polymer is preferably 7.5 to 17.5% by mass, more than 10% by mass and 17.5% by mass or less, relative to the total mass of the oral cavity composition, from the viewpoint that the effects of the present invention are more excellent. is more preferred, and 12.5 to 15% by mass is even more preferred.
When two or more types of specific polymers are used, the total content is preferably within the above range.
［ヒプロメロース］
　本発明の口腔内組成物は、ヒプロメロースを含む。
　ヒプロメロースは、ヒドロキシプロピルメチルセルロースとも呼ばれる。
　ヒプロメロースは、医薬品添加物事典２０２１や第１８改正日本薬局方に収載されており、容易に入手することができる。ヒプロメロースは、セルロース骨格が有するメトキシ基およびヒドロキシプロポキシ基の置換度によって分類され、その分類は、置換度タイプと呼ばれる。置換度タイプとしては、１８２８、２２０８、２９０６および２９１０があるが、ヒプロメロースは、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
　ヒプロメロースは、置換度タイプ２２０８、２９０６および２９１０からなる群より選択される１種以上を用いることが好ましく、置換度タイプ２２０８を単独で使用することがより好ましい。 [Hypromellose]
The oral composition of the present invention contains hypromellose.
Hypromellose is also called hydroxypropylmethylcellulose.
Hypromellose is listed in the Pharmaceutical Excipients Dictionary 2021 and the Japanese Pharmacopoeia 18th Edition, and can be easily obtained. Hypromellose is classified according to the degree of substitution of methoxy groups and hydroxypropoxy groups in the cellulose backbone, and the classification is called degree of substitution type. Substitution types include 1828, 2208, 2906 and 2910, and hypromellose may be used singly or in combination of two or more.
For hypromellose, one or more selected from the group consisting of substitution degree types 2208, 2906 and 2910 are preferably used, and substitution degree type 2208 is more preferably used alone.
　ヒプロメロースの重量平均分子量は、８００００～１２０００００が好ましく、１５００００～８０００００がより好ましい。
　ヒプロメロースの重量平均分子量は、ゲル浸透クロマトグラフィー（ＧＰＣ：Ｇｅｌ　Ｐｅｒｍｅａｔｉｏｎ　Ｃｈｒｏｍａｔｏｇｒａｐｈｙ）を用いて測定できる。
　以下に、ヒプロメロースの重量平均分子量を測定する際のＧＰＣ測定条件を記載する。
　ＧＰＣ測定条件
・カラム：　Ｓｈｏｄｅｘ　ＤＳ－４
・溶離液：　０．１ｍｏｌ／Ｌ　ＮａＮＯ３
・流速：　１．０ｍＬ／ｍｉｎ
・注入量：２００μＬ
・検出：　ＲＩ（Ｒｅｆｒａｃｔｉｖｅ　Ｉｎｄｅｘ：示差屈折） The weight average molecular weight of hypromellose is preferably 80,000 to 1,200,000, more preferably 150,000 to 800,000.
The weight average molecular weight of hypromellose can be measured using gel permeation chromatography (GPC: Gel Permeation Chromatography).
The GPC measurement conditions for measuring the weight average molecular weight of hypromellose are described below.
GPC measurement conditions/column: Shodex DS-4
・ Eluent: 0.1 mol/L NaNO3
・Flow rate: 1.0 mL/min
・Injection volume: 200 μL
・Detection: RI (Refractive Index)
　本発明の口腔内組成物において、ヒプロメロースの含有量は、口腔内組成物の全質量に対して、１０～３０質量％である。本発明の効果がより優れる点で、ヒプロメロースの含有量は、口腔内組成物の全質量に対して、１０質量％超２５質量％以下が好ましく、１５～２５質量％がより好ましく、１５～２０質量％がさらに好ましい。 The content of hypromellose in the intraoral composition of the present invention is 10 to 30% by mass relative to the total mass of the intraoral composition. From the viewpoint that the effect of the present invention is more excellent, the content of hypromellose is preferably more than 10% by mass and 25% by mass or less, more preferably 15 to 25% by mass, based on the total mass of the oral cavity composition. % by mass is more preferred.
　また、本発明の口腔内組成物において、特定ポリマーおよびヒプロメロースの合計含有量は、口腔内組成物の全質量に対して、２５～４０質量％である。本発明の効果がより優れる点で、上記合計含有量は、口腔内組成物の全質量に対して、２５質量％超３７．５質量％以下が好ましく、２７．５～３５質量％がより好ましく、２７．５～３２．５質量％がさらに好ましい。 In addition, in the intraoral composition of the present invention, the total content of the specific polymer and hypromellose is 25-40% by mass relative to the total mass of the intraoral composition. From the viewpoint that the effect of the present invention is more excellent, the total content is preferably more than 25% by mass and 37.5% by mass or less, more preferably 27.5 to 35% by mass, based on the total mass of the oral composition. , 27.5 to 32.5 mass % is more preferable.
　本発明の口腔内組成物において、ヒプロメロースは、市販品を使用することができる。ヒプロメロースの市販品としては、信越化学工業社製の「ＭＥＴＯＬＯＳＥ（登録商標）」シリーズ、および、「ＭＥＴＯＬＯＳＥ（登録商標）　ＳＲ」シリーズが挙げられる。 A commercial product can be used as hypromellose in the oral cavity composition of the present invention. Commercial products of hypromellose include the "METOLOSE (registered trademark)" series and "METOLOSE (registered trademark) SR" series manufactured by Shin-Etsu Chemical Co., Ltd.
［油性基材］
　本発明の口腔内組成物は、油性基材を含む。
　油性基材とは、水とは交じり合わない成分を意味する。
　油性基材としては、通常の油性軟膏に用いる原料が挙げられる。油性基材としては、例えば、炭化水素類（好ましくは、ゲル化炭化水素）、ワックス類、植物油、動物油、中性脂質、合成油脂、ステロール誘導体、モノアルコールカルボン酸エステル類、オキシ酸エステル類、多価アルコール脂肪酸エステル類、シリコーン類、高級アルコール類、高級脂肪酸類、および、フッ素系油剤類が挙げられる。
　油性基材の粘度は特に制限されないが、１００～１００００００ｍＰａ・ｓが好ましく、１０００～１０００００ｍＰａ・ｓがより好ましい。粘度の測定は、粘弾性測定装置（アントンパール社製、ＭＣＲ３０２）を使用して、温度２５℃にて、せん断速度１（ｓ－１）で測定する。
　油性基材は１種を単独で使用してもよいし、２種以上を組み合わせて使用してもよい。
　２種以上の油性基材を用いる場合、炭化水素類（好ましくは、ゲル化炭化水素）と流動パラフィンとの組み合わせが好ましい。
　なお、ゲル化炭化水素としては、医薬品添加物規格の「ゲル化炭化水素」に適合するものを使用でき、より具体的には、流動パラフィンをポリエチレンでゲル化したゲル化炭化水素を好適に使用できる。
　なお、ゲル化炭化水素としては、ゲル化炭化水素（Ｃｏｎｔｒａｃｔ　Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ　Ｌｉｍｉｔｅｄ　Ｃａｎａｄａ社製）、プラスチベース（登録商標）（大正製薬社製）、または、ハイコールジェル（登録商標）（カネダ社製）が好ましい。 [Oil base]
The oral composition of the present invention contains an oil base.
An oily base means a component that is immiscible with water.
Examples of the oily base include raw materials used for ordinary oily ointments. Oil bases include, for example, hydrocarbons (preferably gelatinized hydrocarbons), waxes, vegetable oils, animal oils, neutral lipids, synthetic oils, sterol derivatives, monoalcohol carboxylic acid esters, oxyacid esters, Examples include polyhydric alcohol fatty acid esters, silicones, higher alcohols, higher fatty acids, and fluorine oils.
The viscosity of the oil base is not particularly limited, but is preferably 100 to 1,000,000 mPa·s, more preferably 1,000 to 100,000 mPa·s. Viscosity is measured at a temperature of 25° C. and a shear rate of 1 (s −1 ) using a viscoelasticity measuring device (manufactured by Anton Paar, MCR302).
The oil base may be used alone or in combination of two or more.
When two or more types of oily base materials are used, a combination of hydrocarbons (preferably gelling hydrocarbons) and liquid paraffin is preferred.
As the gelling hydrocarbon, those conforming to the standards for pharmaceutical excipients "gelating hydrocarbon" can be used, and more specifically, gelling hydrocarbon obtained by gelling liquid paraffin with polyethylene is preferably used. can.
The gelling hydrocarbon is preferably a gelling hydrocarbon (manufactured by Contract Pharmaceuticals Limited Canada), Plastibase (registered trademark) (manufactured by Taisho Pharmaceutical Co., Ltd.), or Hicol Gel (registered trademark) (manufactured by Kaneda Corporation). .
　炭化水素類としては、例えば、流動パラフィン（ミネラルオイル）、重質流動イソパラフィン、軽質流動イソパラフィン、α－オレフィンオリゴマー、ポリイソブテン、水添ポリイソブテン、ポリブテン、スクワラン、オリーブ由来スクワラン、スクワレン、ワセリン、および、固形パラフィンが挙げられる。
　なお、ワセリンとしては、日本薬局方もしくはそれに準ずる規格の「ワセリン」、「白色ワセリン」、または、「黄色ワセリン」に適合するものから選択するのが好ましい。 Examples of hydrocarbons include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, vaseline, and solid paraffin.
The petrolatum is preferably selected from those conforming to the Japanese Pharmacopoeia or equivalent standards of “petroleum jelly”, “white petrolatum”, or “yellow petrolatum”.
　ワックス類としては、例えば、キャンデリラワックス、カルナウバワックス、ライスワックス、木ろう、みつろう、モンタンワックス、オゾケライト、セレシン、マイクロクリスタリンワックス、ペトロラタム、フィッシャートロプシュワックス、ポリエチレンワックス、および、エチレン／プロピレンコポリマーが挙げられる。 Waxes include, for example, candelilla wax, carnauba wax, rice wax, Japan wax, beeswax, montan wax, ozokerite, ceresin, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax, and ethylene/propylene copolymers. mentioned.
　植物油としては、例えば、大豆油、ゴマ油、オリーブ油、やし油、パーム油、こめ油、綿実油、ひまわり油、コメヌカ油、カカオ脂、コーン油、べに花油、および、なたね油が挙げられる。
　動物油としては、例えば、ミンク油、タートル油、魚油、牛油、馬油、豚油、および、鮫スクワランが挙げられる。
　中性脂質としては、例えば、トリオレイン、トリリノレイン、トリミリスチン、トリステアリン、および、トリアラキドニンが挙げられる。
　合成油脂としては、例えば、リン脂質、および、アゾンが挙げられる。
　ステロール誘導体としては、例えば、ジヒドロコレステロール、ラノステロール、ジヒドロラノステロール、フィトステロール、コール酸、および、コレステリルリノレートが挙げられる。
　モノアルコールカルボン酸エステル類としては、例えば、ミリスチン酸オクチルドデシル、ミリスチン酸ヘキシルデシル、イソステアリン酸オクチルドデシル、および、パルミチン酸セチルが挙げられる。
　オキシ酸エステル類としては、例えば、乳酸セチル、リンゴ酸ジイソステアリル、および、モノイソステアリン酸水添ヒマシ油が挙げられる。
　多価アルコール脂肪酸エステル類としては、例えば、トリオクタン酸グリセリル、トリオレイン酸グリセリル、トリイソステアリン酸グリセリル、ジイソステアリン酸グリセリル、および、トリ（カプリル酸／カプリン酸）グリセリルが挙げられる。
　シリコーン類としては、例えば、ジメチコン（ジメチルポリシロキサン）、高重合ジメチコン（高重合ジメチルポリシロキサン）、シクロメチコン（環状ジメチルシロキサン、デカメチルシクロペンタシロキサン）、および、フェニルトリメチコンが挙げられる。
　高級アルコール類としては、例えば、セタノール、ミリスチルアルコール、オレイルアルコール、ラウリルアルコール、セトステアリルアルコール、および、ステアリルアルコールが挙げられる。
　高級脂肪酸類としては、例えば、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、イソステアリン酸、ベヘン酸、ウンデシレン酸、１２－ヒドロキシステアリン酸、および、パルミトレイン酸が挙げられる。
　フッ素系油剤類としては、例えば、パーフルオロデカン、パーフルオロオクタン、および、パーフルオロポリエーテルが挙げられる。 Vegetable oils include, for example, soybean oil, sesame oil, olive oil, coconut oil, palm oil, rice bran oil, cottonseed oil, sunflower oil, rice bran oil, cocoa butter, corn oil, safflower oil, and rapeseed oil.
Animal oils include, for example, mink oil, turtle oil, fish oil, beef oil, horse oil, pork oil, and shark squalane.
Neutral lipids include, for example, triolein, trilinolein, trimyristin, tristearin, and triarachidonine.
Synthetic fats and oils include, for example, phospholipids and azone.
Sterol derivatives include, for example, dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterols, cholic acid, and cholesteryl linolate.
Monoalcohol carboxylic acid esters include, for example, octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, and cetyl palmitate.
Examples of oxyacid esters include cetyl lactate, diisostearyl malate, and hydrogenated castor oil monoisostearate.
Polyhydric alcohol fatty acid esters include, for example, glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, and tri(caprylic/capric)glyceryl.
Examples of silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), and phenyltrimethicone.
Examples of higher alcohols include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, and stearyl alcohol.
Examples of higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, and palmitoleic acid.
Fluorinated oils include, for example, perfluorodecane, perfluorooctane, and perfluoropolyether.
　油性基材は、１種を単独で使用してもよいし、２種以上を組み合わせて使用してもよい。 The oil base may be used alone or in combination of two or more.
　油性基材の含有量は、口腔内組成物の全質量に対して、４０～７５質量％が好ましく、６０～７５質量％がより好ましく、６５～７０質量％がさらに好ましい。 The content of the oil-based base is preferably 40-75% by mass, more preferably 60-75% by mass, and even more preferably 65-70% by mass, relative to the total mass of the oral cavity composition.
［アルミニウム化合物］
　本発明の口腔内組成物は、本発明の効果がより優れる点で、アルミニウム化合物を含むことが好ましい。口腔内組成物がアルミニウム化合物を含むことで、形成されるゲルの耐摩耗性がさらに向上する。
　アルミニウム化合物は、アルミニウムを含む化合物であれば特に限定されないが、水溶性のアルミニウム化合物が好ましく、アルミニウムのカルボン酸塩がより好ましく、アルミニウムのヒドロキシカルボン酸塩がさらに好ましく、乳酸アルミニウムが特に好ましい。アルミニウム化合物が乳酸アルミニウムである場合、形成されるゲルの耐摩耗性がより優れる。 [Aluminum compound]
The oral cavity composition of the present invention preferably contains an aluminum compound from the viewpoint that the effects of the present invention are more excellent. The inclusion of an aluminum compound in the oral composition further improves the abrasion resistance of the formed gel.
The aluminum compound is not particularly limited as long as it contains aluminum, but is preferably a water-soluble aluminum compound, more preferably an aluminum carboxylate, more preferably an aluminum hydroxycarboxylate, and particularly preferably aluminum lactate. When the aluminum compound is aluminum lactate, the gel formed has better abrasion resistance.
　上記水溶性のアルミニウム化合物としては、特に限定されないが、例えば、塩化アルミニウム（ＡｌＣｌ３）、硫酸アルミニウム（Ａｌ２（ＳＯ４）３）、硝酸アルミニウム（Ａｌ（ＮＯ３）３）、硫酸アンモニウムアルミニウム（ＡｌＮＨ４（ＳＯ４）２・１２Ｈ２Ｏ）、硫酸カリウムアルミニウム（ＡｌＫ（ＳＯ４）２・１２Ｈ２Ｏ）、酢酸アルミニウム、プロピオン酸アルミニウム、グリコール酸アルミニウム（ヒドロキシ酢酸アルミニウム）、乳酸アルミニウム、リンゴ酸アルミニウム、酒石酸アルミニウム、クエン酸アルミニウム、および、イソクエン酸アルミニウムが挙げられる。
　上記水溶性のアルミニウム化合物は、塩化アルミニウム、硫酸アンモニウムアルミニウム、硫酸カリウムアルミニウム、および、乳酸アルミニウムからなる群より選択される少なくとも１種が好ましく、乳酸アルミニウムがより好ましい。 Examples of the water-soluble aluminum compound include, but are not limited to, aluminum chloride (AlCl 3 ), aluminum sulfate (Al 2 (SO 4 ) 3 ), aluminum nitrate (Al(NO 3 ) 3 ), aluminum ammonium sulfate (AlNH 4 ( SO4 ) 2.12H2O ), potassium aluminum sulfate ( AlK ( SO4 ) 2.12H2O ), aluminum acetate, aluminum propionate, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate , aluminum tartrate, aluminum citrate, and aluminum isocitrate.
The water-soluble aluminum compound is preferably at least one selected from the group consisting of aluminum chloride, aluminum ammonium sulfate, potassium aluminum sulfate, and aluminum lactate, more preferably aluminum lactate.
　なお、酢酸アルミニウム、プロピオン酸アルミニウム、グリコール酸アルミニウム（ヒドロキシ酢酸アルミニウム）、乳酸アルミニウム、リンゴ酸アルミニウム、酒石酸アルミニウム、クエン酸アルミニウム、および、イソクエン酸アルミニウムは、上記アルミニウムのカルボン酸塩に該当する。
　また、グリコール酸アルミニウム（ヒドロキシ酢酸アルミニウム）、乳酸アルミニウム、リンゴ酸アルミニウム、酒石酸アルミニウム、クエン酸アルミニウム、および、イソクエン酸アルミニウムは、上記アルミニウムのヒドロキシカルボン酸塩に該当する。 Aluminum acetate, aluminum propionate, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartrate, aluminum citrate, and aluminum isocitrate correspond to the carboxylates of aluminum.
In addition, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartrate, aluminum citrate, and aluminum isocitrate correspond to the hydroxycarboxylates of aluminum.
　本発明の効果がより優れる点で、アルミニウム化合物の含有量は、口腔内組成物の全質量に対して、０．１～１０質量％が好ましく、０．４～４質量％がより好ましく、０．５～４質量％がさらに好ましい。
　また、本発明の効果がより優れる点で、乳酸アルミニウムの含有量は、口腔内組成物の全質量に対して、０．１～１０質量％が好ましく、０．４～４質量％がより好ましく、０．５～４質量％がさらに好ましい。 From the viewpoint that the effect of the present invention is more excellent, the content of the aluminum compound is preferably 0.1 to 10% by mass, more preferably 0.4 to 4% by mass, based on the total mass of the oral cavity composition. 0.5 to 4 mass % is more preferred.
Further, from the point of view that the effect of the present invention is more excellent, the content of aluminum lactate is preferably 0.1 to 10% by mass, more preferably 0.4 to 4% by mass, relative to the total mass of the oral composition. , 0.5 to 4 mass % is more preferred.
［他の添加剤］
　本発明の口腔内組成物は、上記以外の他の添加剤を含んでいてもよい。
　他の添加剤としては、特に制限されないが、薬剤、湿潤剤、賦形剤、乳化剤、増粘剤、保存剤、着色剤、安定化剤、清涼化剤、矯味剤、および、香料等が挙げられる。 [Other additives]
The intraoral composition of the present invention may contain additives other than those mentioned above.
Other additives include, but are not limited to, drugs, wetting agents, excipients, emulsifiers, thickeners, preservatives, coloring agents, stabilizers, cooling agents, flavoring agents, perfumes, and the like. be done.
　本発明の口腔内組成物は、実質的に水を含まないことが好ましい。
　「実質的に水を含まない」とは、本発明の効果に影響を及ぼさない程度の少量の水（例えば、本発明の口腔内組成物の原料中に含まれる微量の水分）を含むことは許容範囲にあるということを意味する。具体的には、「実質的に水を含まない」とは、口腔内組成物中の水の含有量が、口腔内組成物の全質量に対して、３質量％以下であることを意味する。なかでも、１質量％以下であることが好ましい。下限は特に限定されないが、口腔内組成物の全質量に対して、０質量％以上が挙げられる。
　口腔内組成物が水を実質的に含まない場合、口腔内組成物を生体に適用した際に、形成されるゲルの付着性がより向上し、保護性能も向上する。また、口腔内組成物の保存安定性もより向上する。
　本発明の口腔内組成物中における水の含有量の測定方法としては、例えば、日本薬局方記載の水分測定法(カールフィッシャー法)が挙げられる。なかでも、水分測定用メタノールに試料を分散させ水分を抽出する工程を追加し、抽出した液に対して電量滴定法による試験を行うことが好ましい。 Preferably, the oral compositions of the present invention are substantially free of water.
The term "substantially free of water" means that a small amount of water that does not affect the effects of the present invention (for example, a trace amount of water contained in the ingredients of the oral composition of the present invention) is not included. It means that it is within acceptable limits. Specifically, "substantially free of water" means that the content of water in the oral composition is 3% by mass or less with respect to the total mass of the oral composition. . Especially, it is preferable that it is 1 mass % or less. Although the lower limit is not particularly limited, it may be 0% by mass or more based on the total mass of the intraoral composition.
When the intraoral composition does not substantially contain water, the adhesion of the gel formed when the intraoral composition is applied to the living body is further improved, and the protective performance is also improved. In addition, the storage stability of the intraoral composition is further improved.
Methods for measuring the water content in the oral composition of the present invention include, for example, the water content measurement method (Karl Fischer method) described in the Japanese Pharmacopoeia. Among others, it is preferable to add a step of dispersing the sample in methanol for moisture measurement and extracting the moisture, and subjecting the extracted liquid to a coulometric titration test.
＜口腔内組成物の性状＞
　本発明の口腔内組成物は、口腔内組成物と水とを接触させることにより、ゲルを形成し得る。ゲルが形成されることにより、例えば患部等を外部刺激から保護できる。
　本発明の口腔内組成物の形態は、例えば、軟膏状、クリーム状、および、半固体状が挙げられる。 <Properties of intraoral composition>
The oral composition of the present invention can form a gel by contacting the oral composition with water. By forming a gel, for example, the affected area can be protected from external stimuli.
Forms of the intraoral composition of the present invention include, for example, ointments, creams, and semi-solids.
　また、本発明の口腔内組成物の粘度は、塗布性の点で、１３０００００ｍＰａ・ｓ未満が好ましく、７５００００ｍＰａ・ｓ未満がより好ましい。下限は特に制限されないが、１００００ｍＰａ・ｓ以上が挙げられる。
　なお、上記粘度は、粘弾性測定装置（アントンパール社製、ＭＣＲ３０２）を使用して、温度２５℃にて、せん断速度１ｓ－１で測定する。 Moreover, the viscosity of the intraoral composition of the present invention is preferably less than 1300000 mPa·s, more preferably less than 750000 mPa·s, from the viewpoint of applicability. Although the lower limit is not particularly limited, it may be 10000 mPa·s or more.
The viscosity is measured at a temperature of 25° C. and a shear rate of 1 s −1 using a viscoelasticity measuring device (manufactured by Anton Paar, MCR302).
＜口腔内組成物の製造方法＞
　本発明の口腔内組成物は、特定ポリマーと、ヒプロメロースと、油性基材とを混合することにより製造できる。必要に応じて、各材料、および／または、口腔内組成物に対して脱気処理または脱水処理を実施してもよい。 <Method for producing intraoral composition>
The intraoral composition of the present invention can be produced by mixing a specific polymer, hypromellose, and an oily base material. If necessary, each material and/or oral composition may be subjected to degassing treatment or dehydration treatment.
　混合の方法は特に限定されず、粉末成分を混合する際に用いられる、従来公知の方法を用いることができる。
　例えば、口腔内組成物を構成する成分のうち、一部の成分を事前に混合して、その後、残りの成分と混合するような、段階的な混合方法を実施してもよい。なかでも、特定ポリマーと油性基材とを混合して混合物を得た後、得られた混合物とヒプロメロースとを混合することが好ましい。上記手順によれば、成分がより均一に分散された口腔内組成物を得ることができる。
　口腔内組成物がアルミニウム化合物を含む場合、アルミニウム化合物の混合方法および順序は特に制限されないが、特定ポリマーと油性基材とアルミニウム化合物とを混合して混合物を得た後、得られた混合物とヒプロメロースとを混合することが好ましい。 The mixing method is not particularly limited, and conventionally known methods used when mixing powder components can be used.
For example, a stepwise mixing method may be implemented in which some of the components constituting the oral composition are mixed in advance and then mixed with the rest of the components. Among them, it is preferable to mix the specific polymer and the oily base material to obtain a mixture, and then mix the obtained mixture with hypromellose. According to the above procedure, it is possible to obtain an oral composition in which the components are more uniformly dispersed.
When the oral composition contains an aluminum compound, the mixing method and order of the aluminum compound are not particularly limited, but after obtaining a mixture by mixing a specific polymer, an oily base material and an aluminum compound, the resulting mixture and hypromellose It is preferable to mix with.
＜口腔内組成物の用途および使用方法＞
　本発明の口腔内組成物の用途としては、例えば、口腔内保護が挙げられる。具体的には、口腔粘膜保護剤として利用され得る。
　また、本発明の口腔内組成物は、創傷被覆材、薬剤徐放基材、口腔内湿潤材、および、止血材等としても使用できる。
　本発明の口腔内組成物が薬剤徐放基材として用いられる場合、徐放される薬剤の種類は特に制限されず、公知の薬剤が挙げられる。 <Application and method of use of intraoral composition>
Applications of the oral composition of the present invention include, for example, oral protection. Specifically, it can be used as an oral mucosa protective agent.
The oral cavity composition of the present invention can also be used as a wound dressing, a drug sustained release base material, an oral moistening agent, a hemostatic agent, and the like.
When the intraoral composition of the present invention is used as a sustained-release drug carrier, the type of drug to be sustained-released is not particularly limited, and known drugs can be used.
　本発明の口腔内組成物を口腔粘膜に対して使用する場合、口腔内組成物を口腔粘膜上に配置し、水または水を含む溶液を添加すれば、ゲル化して、形成されるゲルが粘膜により強固に付着する。つまり、本発明の口腔内組成物の使用方法（または、ゲルの製造方法）として、口腔内組成物を口腔粘膜上に配置して、口腔粘膜上に配置された口腔内組成物と水とを接触させることにより、口腔粘膜上にゲルを形成する方法が挙げられる。なお、口腔内の唾液中の水分によって口腔内組成物がゲル化するため、取扱いが簡便である。また、仮に、唾液量が少ない場合には、口腔内組成物を口腔粘膜に付着させた後、水、または、人工唾液をスプレーする等して、水分を供給すればよい。 When the oral composition of the present invention is applied to the oral mucosa, the oral composition is placed on the oral mucosa, and when water or a solution containing water is added, the resulting gel forms a gel. adheres more firmly. That is, as a method for using the oral composition of the present invention (or a method for producing a gel), the oral composition is placed on the oral mucosa, and the oral composition and water are placed on the oral mucosa. Examples include a method of forming a gel on the oral mucosa by contact. In addition, since the intraoral composition is gelled by water in saliva in the oral cavity, it is easy to handle. In addition, if the amount of saliva is small, water may be supplied by, for example, spraying water or artificial saliva after applying the oral composition to the oral mucosa.
　本発明の口腔内組成物を口腔粘膜に付着させると、唾液中の水分によりゲル化が開始すると同時に、口腔粘膜表面のムチンとヒプロメロースとの間に、水素結合による引力が作用し、口腔内粘膜と口腔内組成物とが接着すると考えられる。このような機序により、口腔内組成物により形成されるゲルは、優れた耐摩耗性を発揮するものと考えられるが、このような機序に必ずしも限定されるわけではない。 When the oral composition of the present invention is adhered to the oral mucosa, gelation is initiated by the moisture in saliva, and at the same time, attractive force due to hydrogen bonding acts between mucin and hypromellose on the surface of the oral mucosa, and the oral mucosa and the intraoral composition adhere to each other. It is believed that the gel formed by the intraoral composition exhibits excellent wear resistance due to such a mechanism, but is not necessarily limited to such a mechanism.
　以下に実施例に基づいて本発明をさらに詳細に説明する。
　以下の実施例に示す材料、使用量、割合、処理内容、および、処理手順等は、本発明の趣旨を逸脱しない限り適宜変更できる。したがって、本発明の範囲は以下に示す実施例により限定的に解釈されるべきではない。 The present invention will be described in further detail based on examples below.
The materials, amounts used, proportions, processing details, processing procedures, etc. shown in the following examples can be changed as appropriate without departing from the gist of the present invention. Therefore, the scope of the present invention should not be construed as limited by the examples shown below.
＜口腔内組成物の調製＞
　以下、口腔内組成物の調製手順について説明する。
［実施例１］
　ゲル化炭化水素（Ｃｏｎｔｒａｃｔ　Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ　Ｌｉｍｉｔｅｄ　Ｃａｎａｄａ社製）１５０ｇ、および、カルボキシビニルポリマー（Ｌｕｂｒｉｚｏｌ社製、「Ｃａｒｂｏｐｏｌ　９７１Ｐ　ＮＦ」）３０ｇを混練機（Ｐｒｉｍｉｘ社製、「ＨＰ－２Ｐ－０３」）で、２分間、５０ｒｐｍの条件で混合した。
　混合後、得られた混合物にヒプロメロース（信越化学工業社、「ＭＥＴＯＲＯＳＥ（登録商標）　ＳＲ　９０ＳＨ－１０００００ＳＲ」）２０ｇを加え、１０分間、５０ｒｐｍの条件で混合し、実施例１に用いた口腔内組成物を得た。 <Preparation of intraoral composition>
The procedure for preparing the intraoral composition will be described below.
[Example 1]
150 g of gelatinized hydrocarbon (manufactured by Contract Pharmaceuticals Limited Canada) and 30 g of carboxyvinyl polymer (manufactured by Lubrizol, "Carbopol 971P NF") were mixed with a kneader (manufactured by Primix, "HP-2P-03"). Mixed at 50 rpm for 1 minute.
After mixing, 20 g of hypromellose (Shin-Etsu Chemical Co., Ltd., "METOROSE (registered trademark) SR 90SH-100000SR") was added to the resulting mixture, mixed for 10 minutes at 50 rpm, and the oral composition used in Example 1. got stuff
［実施例２～２０］
　実施例１と同様の手順で、後段の表１および２に示す含有量となるように各成分を混合して、実施例２～１８に用いた口腔内組成物を得た。また、実施例１と同様の手順で、後段の表３に示す含有量となるように各成分を混合して、実施例１９および２０に用いた口腔内組成物を得た。 [Examples 2 to 20]
In the same procedure as in Example 1, each component was mixed so that the contents shown in Tables 1 and 2 below were obtained to obtain intraoral compositions used in Examples 2 to 18. Further, in the same procedure as in Example 1, each component was mixed so that the content shown in Table 3 below was obtained, and oral compositions used in Examples 19 and 20 were obtained.
［実施例２１～２６］
　上記ゲル化炭化水素１３９．４ｇ、上記カルボキシビニルポリマー２７．２ｇ、および、乳酸アルミニウム（株式会社武蔵野化学研究所製）０．６ｇを混練機（Ｐｒｉｍｉｘ社製、「ＨＰ－２Ｐ－０３」）で、２分間、５０ｒｐｍの条件で混合した。
　混合後、上記ヒプロメロース３２．８ｇを加え、１０分間、５０ｒｐｍの条件で混合し、実施例２１に用いた口腔内組成物を得た。
　実施例２１と同様の手順で、後段の表３に示す含有量となるように各成分を混合して、実施例２１～２６に用いた口腔内組成物を得た。 [Examples 21 to 26]
139.4 g of the gelled hydrocarbon, 27.2 g of the carboxyvinyl polymer, and 0.6 g of aluminum lactate (manufactured by Musashino Chemical Laboratory) were mixed with a kneader ("HP-2P-03" manufactured by Primix). , for 2 minutes at 50 rpm.
After mixing, 32.8 g of the above hypromellose was added and mixed for 10 minutes at 50 rpm to obtain an intraoral composition used in Example 21.
In the same procedure as in Example 21, each component was mixed so that the content shown in Table 3 below was obtained, and oral compositions used in Examples 21 to 26 were obtained.
［比較例１～７］
　実施例１と同様の手順で、後段の表４に示す含有量となるように各成分を混合して、比較例１～６に用いた口腔内組成物を得た。また、実施例１と同様の手順で、カルボキシビニルポリマーに代えて、ポリアクリル酸ナトリウム（和光純薬工業社製、重合度３００００～４００００）を用い、表４に示す含有量となるように各成分を混合して、比較例７に用いた口腔内組成物を得た。 [Comparative Examples 1 to 7]
In the same procedure as in Example 1, each component was mixed so that the content shown in Table 4 below was obtained, and oral compositions used in Comparative Examples 1 to 6 were obtained. Further, in the same procedure as in Example 1, instead of the carboxyvinyl polymer, sodium polyacrylate (manufactured by Wako Pure Chemical Industries, Ltd., polymerization degree 30000 to 40000) was used, and the content shown in Table 4 was adjusted. The components were mixed to obtain an oral composition used in Comparative Example 7.
［実施例２７～２９］
　上記ゲル化炭化水素１３６ｇ、上記カルボキシビニルポリマー２７．２ｇ、および、塩化アルミニウム六水和物（富士フイルム和光純薬社製、特級試薬）４ｇを混練機（Ｐｒｉｍｉｘ社製、「ＨＰ－２Ｐ－０３」）で、２分間、５０ｒｐｍの条件で混合した。
　混合後、上記ヒプロメロース３２．８ｇを加え、１０分間、５０ｒｐｍの条件で混合し、実施例２７に用いた口腔内組成物を得た。
　また、塩化アルミニウム六水和物の代わりに、硫酸アンモニウムアルミニウム十二水和物（富士フイルム和光純薬社製、特級試薬）、または、硫酸カリウムアルミニウム十二水和物（富士フイルム和光純薬社製、一級試薬）を用いた以外は、実施例２７と同様の手順で、後段の表５に示す含有量となるように各成分を混合して、実施例２８および２９に用いた口腔内組成物を得た。 [Examples 27-29]
136 g of the gelled hydrocarbon, 27.2 g of the carboxyvinyl polymer, and 4 g of aluminum chloride hexahydrate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., special grade reagent) are mixed with a kneader (manufactured by Primix, "HP-2P-03 ”) for 2 minutes at 50 rpm.
After mixing, 32.8 g of the above hypromellose was added and mixed for 10 minutes at 50 rpm to obtain an intraoral composition used in Example 27.
Also, instead of aluminum chloride hexahydrate, ammonium aluminum sulfate dodecahydrate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., special grade reagent) or potassium aluminum sulfate dodecahydrate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) , First grade reagent), in the same procedure as in Example 27, by mixing each component so that the content shown in Table 5 below was used, and the oral composition used in Examples 28 and 29 got
＜評価＞
［耐摩耗性評価］
（疑似生体膜の作製）
　ＴＤＡＢ（テトラドデシルアンモニウムブロミド、富士フイルム和光純薬株式会社製；５０ｍｇ）、ポリ塩化ビニル（富士フイルム和光純薬株式会社製；８００ｍｇ）、およびＤＯＰＰ（ジ－ｎ－オクチルホスホナート、富士フイルム和光純薬株式会社製；０．６ｍＬ）をＴＨＦ（テトラヒドロフラン、富士フイルム和光純薬株式会社製；１０ｍＬ）に溶解したものをシャーレで室温乾燥し、脂質膜（約２００μｍ厚）を得た。
　次に、寒天（カリコリカン（登録商標）、伊那食品工業社製；０．５ｇ）、ジェランガム（ケルコゲル（登録商標）、ＣＰケルコ社製；０．１ｇ）および蒸留水（４９．４ｇ）からなるハイドロゲルに、作製した脂質膜を貼り合わせた。
　続いて、脂質膜表面をＭＰＣ（２－メタクリロイルオキシエチルホスホリルコリン）ポリマー（ＬＩＰＩＤＵＲＥ（登録商標）－ＣＭ５２０６、日油社製）でコートして、疑似生体膜を得た。 <Evaluation>
[Abrasion resistance evaluation]
(Preparation of pseudo-biological membrane)
TDAB (tetradodecylammonium bromide, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; 50 mg), polyvinyl chloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; 800 mg), and DOPP (di-n-octylphosphonate, Fujifilm Wako Pure Chemical Industries, Ltd.) Yaku Co., Ltd.; 0.6 mL) dissolved in THF (tetrahydrofuran, Fujifilm Wako Pure Chemical Industries, Ltd.; 10 mL) was dried in a petri dish at room temperature to obtain a lipid film (about 200 μm thick).
Next, a hydrogel consisting of agar (Calcorican (registered trademark), manufactured by Ina Food Industry; 0.5 g), gellan gum (Kelcogel (registered trademark), manufactured by CP Kelco; 0.1 g) and distilled water (49.4 g) The prepared lipid membrane was attached to the gel.
Subsequently, the lipid membrane surface was coated with MPC (2-methacryloyloxyethylphosphorylcholine) polymer (LIPIDURE®-CM5206, manufactured by NOF CORPORATION) to obtain a simulated biomembrane.
（試験体の作製）
　作製した擬似生体膜上に極薄樹脂ワッシャ（ミスミ、ＳＷＳＰＳ２５－１２－０．５、外径２５ｍｍ、内径１２ｍｍ、厚さ０．５ｍｍ）を乗せ、ワッシャの内径部に口腔内組成物を詰めた。摩耗試験機（ＴＲＩＢＯＧＥＡＲ　ＴＹＰＥ－４０、新東科学社製）を用いて、３００ｍｍ／ｍｉｎの速度でワッシャ上の余分な口腔内組成物を取り去り、ワッシャを外すことで、試料を疑似生体膜上に塗布した。
　塗布した口腔内組成物に、人工唾液（サリベート（登録商標）、帝人ファーマ社製）を適量噴霧した後、１分間手で馴染ませて口腔内組成物をゲル化させ、評価用サンプルを作製した。
　作製した評価用サンプルを、上記摩耗試験機で繰り返し摩耗し、評価用サンプルが擬似生体膜から剥離または溶解するまでの往復回数を計測し、以下の基準により耐摩耗性を評価した。
　なお、摩耗試験機のヘッドには図１～３に示すアルミニウム製のヘッド１０（渡辺製作所製）を用い、荷重３０ｇ、振幅３０ｍｍ、速度６０００ｍｍ／ｍｉｎの条件で試験を行った。図１はアルミニウム製のヘッド１０の正面図、図２はアルミニウム製のヘッド１０の上面図、図３はアルミニウム製のヘッド１０の側面図である。アルミニウム製のヘッド１０は、基板１２と、基板１２上に配置された接触部１４とから構成される。接触部１４は、評価用サンプルと接触する部分であり、基板１２の長手方向に沿って延在している。基板１２の幅Ｗ１は２６ｍｍ、基板１２の長さＬは３６ｍｍ、基板１２の厚みＴは２ｍｍであった。また、接触部１４の幅Ｗ２は８ｍｍ、接触部１４の高さＨは約８ｍｍであった。接触部１４の先端部は研磨され、滑らかな曲面を形成していた。アルミニウム製のヘッド１０を摩耗試験機に設置する際には、アルミニウム製のヘッド１０の接触部１２の長手方向と摩耗試験機の往復運動方向とが直交するように、アルミニウム製のヘッド１０を摩擦試験機に設置した。 (Preparation of test body)
An ultra-thin resin washer (Misumi, SWSPS25-12-0.5, outer diameter 25 mm, inner diameter 12 mm, thickness 0.5 mm) was placed on the simulated biological membrane, and the inner diameter of the washer was filled with an oral composition. . Using an abrasion tester (TRIBOGEAR TYPE-40, manufactured by Shinto Kagaku Co., Ltd.), remove the excess oral composition on the washer at a speed of 300 mm / min, remove the washer, and place the sample on the pseudo biological membrane. applied.
After spraying an appropriate amount of artificial saliva (Sarivate (registered trademark), manufactured by Teijin Pharma) to the applied intraoral composition, the intraoral composition was gelled by hand for 1 minute to prepare a sample for evaluation. .
The prepared evaluation sample was repeatedly worn with the abrasion tester, and the number of reciprocations until the evaluation sample peeled off or dissolved from the simulated biological membrane was measured, and the abrasion resistance was evaluated according to the following criteria.
The aluminum head 10 (manufactured by Watanabe Seisakusho) shown in FIGS. 1 to 3 was used as the head of the abrasion tester, and the test was conducted under the conditions of a load of 30 g, an amplitude of 30 mm, and a speed of 6000 mm/min. 1 is a front view of the aluminum head 10, FIG. 2 is a top view of the aluminum head 10, and FIG. 3 is a side view of the aluminum head 10. FIG. The head 10 made of aluminum is composed of a substrate 12 and a contact portion 14 arranged on the substrate 12 . The contact portion 14 is a portion that contacts the evaluation sample and extends along the longitudinal direction of the substrate 12 . The width W1 of the substrate 12 was 26 mm, the length L of the substrate 12 was 36 mm, and the thickness T of the substrate 12 was 2 mm. The width W2 of the contact portion 14 was 8 mm, and the height H of the contact portion 14 was approximately 8 mm. The tip of the contact portion 14 was polished to form a smooth curved surface. When installing the aluminum head 10 in the abrasion tester, the aluminum head 10 is rubbed so that the longitudinal direction of the contact portion 12 of the aluminum head 10 and the reciprocating direction of the abrasion tester are perpendicular to each other. installed in the test machine.
（耐摩耗性試験の評価基準）
　ＡＡ：６００回以上で剥離または溶解した
　Ａ：５００回以上６００回未満で剥離または溶解した
　Ｂ：３００回以上５００回未満で剥離または溶解した
　Ｃ：３００回未満で剥離または溶解した
［塗布性評価］
　口腔内組成物の塗布性は、粘度に基づいて以下の評価基準で評価した。
　粘度は、室温条件にて保管した各実施例および各比較例に用いた口腔内組成物をサンプルとし、粘弾性測定装置（アントンパール社製、ＭＣＲ３０２）を使用して、温度２５℃にて、せん断速度１ｓ－１で測定した。
　なお、口腔内組成物を指で塗布した際、粘度が７．５×１０５ｍＰａ・ｓ未満では容易に塗布でき、７．５×１０５ｍＰａ・ｓ以上１３×１０５ｍＰａ・ｓ未満では塗布ができた一方、１３×１０５ｍＰａ・ｓ以上では塗布が困難であった。 (Evaluation criteria for wear resistance test)
AA: Peeled or dissolved at 600 times or more A: Peeled or dissolved at 500 times or more and less than 600 times B: Peeled or dissolved at 300 times or more and less than 500 times C: Peeled or dissolved at less than 300 times [Applicability evaluation ]
The applicability of the intraoral composition was evaluated according to the following evaluation criteria based on the viscosity.
The viscosity was measured at a temperature of 25°C using a viscoelasticity measuring device (manufactured by Anton Paar, MCR302) using the intraoral compositions of Examples and Comparative Examples stored at room temperature as samples. Measured at a shear rate of 1 s −1 .
In addition, when the intraoral composition is applied with a finger, it can be easily applied when the viscosity is less than 7.5 × 10 5 mPa s, and when it is 7.5 × 10 5 mPa s or more and less than 13 × 10 5 mPa s While coating was possible, coating was difficult at 13×10 5 mPa·s or more.
（塗布性の評価基準）
　Ａ：７．５×１０５ｍＰａ・ｓ未満（塗布が容易）
　Ｂ：７．５×１０５ｍＰａ・ｓ以上１３×１０５ｍＰａ・ｓ未満（塗布が可能）
　Ｃ：１３×１０５ｍＰａ・ｓ以上（塗布が困難） (Applicability evaluation criteria)
A: less than 7.5×10 5 mPa·s (easy to apply)
B: 7.5×10 5 mPa·s or more and less than 13×10 5 mPa·s (applicable)
C: 13×10 5 mPa·s or more (difficult to apply)
＜結果＞
　各実施例および各比較例の口腔内組成物における各成分の含有量および評価結果について、表１～４に示す。 <Results>
Tables 1 to 4 show the content of each component in the oral cavity composition of each example and each comparative example and the evaluation results.
　各表中、総合評価欄は、以下の基準による。
　ＡＡ：耐摩耗性の評価がＡＡ、かつ、塗布性の評価がＡ
　Ａ：耐摩耗性の評価がＡ、かつ、塗布性の評価がＡ
　Ｂ：耐摩耗性および塗布性の評価の少なくとも一方がＢ、かつ、もう一方の評価がＣ以外
　Ｃ：耐摩耗性および塗布性の評価の少なくとも一方がＣ In each table, the comprehensive evaluation column is based on the following criteria.
AA: Evaluation of abrasion resistance is AA, and evaluation of applicability is A
A: Wear resistance evaluation is A, and applicability evaluation is A
B: At least one of wear resistance and applicability evaluation is B, and the other evaluation is other than C C: At least one of wear resistance and applicability evaluation is C
　各表中、粘度の欄の「≧１３」の表記は、粘度が１３０００００ｍＰａ・ｓ以上であり、測定ができなかったことを示す。 In each table, the notation "≧13" in the viscosity column indicates that the viscosity was 1300000 mPa·s or more and could not be measured.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　実施例と比較例の対比から、本発明の口腔内組成物は所望の効果を奏することが確認された。
　表３の結果から、口腔内組成物がアルミニウム化合物（好ましくは乳酸アルミニウム）を含み、含有量が口腔内組成物全質量に対して、０．４～４質量％である場合、口腔内組成物によって形成されるゲルの耐摩耗性がより優れることが確認された。 Comparison between Examples and Comparative Examples confirmed that the oral cavity composition of the present invention exhibited the desired effects.
From the results of Table 3, when the oral composition contains an aluminum compound (preferably aluminum lactate) and the content is 0.4 to 4% by mass relative to the total mass of the oral composition, the oral composition It was confirmed that the abrasion resistance of the gel formed by
　１０　アルミニウム製ヘッド
　１２　基板
　１４　接触部 10 aluminum head 12 substrate 14 contact part

Claims (6)

  1. 　カルボキシビニルポリマーおよびポリアクリル酸からなる群より選択される少なくとも１種の特定ポリマーと、
    　ヒプロメロースと、
    　油性基材と、を含む口腔内組成物であって、
    　前記特定ポリマーの含有量が、前記口腔内組成物の全質量に対して、５～２０質量％であり、
    　前記ヒプロメロースの含有量が、前記口腔内組成物の全質量に対して、１０～３０質量％であり、
    　前記特定ポリマーおよび前記ヒプロメロースの合計含有量が、前記口腔内組成物の全質量に対して、２５～４０質量％である、口腔内組成物。     at least one specific polymer selected from the group consisting of carboxyvinyl polymer and polyacrylic acid;
    hypromellose and
    An oral composition comprising an oily base,
    The content of the specific polymer is 5 to 20% by mass with respect to the total mass of the oral composition,
    The content of the hypromellose is 10 to 30% by mass with respect to the total mass of the oral composition,
    The intraoral composition, wherein the total content of the specific polymer and the hypromellose is 25 to 40% by mass relative to the total mass of the intraoral composition.
  2. 　前記油性基材が、ゲル化炭化水素を含む、請求項１に記載の口腔内組成物。 The intraoral composition according to claim 1, wherein the oily base material contains a gelling hydrocarbon.
  3. 　さらにアルミニウム化合物を含む、請求項１または２に記載の口腔内組成物。 The intraoral composition according to claim 1 or 2, further comprising an aluminum compound.
  4. 　前記アルミニウム化合物が、乳酸アルミニウム、塩化アルミニウム、硫酸アンモニウムアルミニウムおよび硫酸カリウムアルミニウムからなる群より選択される少なくとも１種である、請求項３に記載の口腔内組成物。 The oral cavity composition according to claim 3, wherein the aluminum compound is at least one selected from the group consisting of aluminum lactate, aluminum chloride, aluminum ammonium sulfate and aluminum potassium sulfate.
  5. 　前記アルミニウム化合物が、乳酸アルミニウムである、請求項３に記載の口腔内組成物。 The intraoral composition according to claim 3, wherein the aluminum compound is aluminum lactate.
  6. 　前記乳酸アルミニウムの含有量が、前記口腔内組成物の全質量に対して、０．５～４質量％である、請求項５に記載の口腔内組成物。 The intraoral composition according to claim 5, wherein the content of said aluminum lactate is 0.5 to 4% by mass relative to the total mass of said intraoral composition.
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