WO2020256130A1 - Composition for disinfecting teeth - Google Patents

Composition for disinfecting teeth Download PDF

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Publication number
WO2020256130A1
WO2020256130A1 PCT/JP2020/024201 JP2020024201W WO2020256130A1 WO 2020256130 A1 WO2020256130 A1 WO 2020256130A1 JP 2020024201 W JP2020024201 W JP 2020024201W WO 2020256130 A1 WO2020256130 A1 WO 2020256130A1
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Prior art keywords
pharmaceutical composition
nanofibers
acid
composition according
methacrylate
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PCT/JP2020/024201
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French (fr)
Japanese (ja)
Inventor
拓也 栗山
実久 栗山
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Ｃｅｌｕｍｉｘ株式会社
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Publication of WO2020256130A1 publication Critical patent/WO2020256130A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/327—Peroxy compounds, e.g. hydroperoxides, peroxides, peroxyacids
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics

Definitions

  • the present invention relates to a slurry-like pharmaceutical composition for sterilizing and disinfecting teeth.
  • Various disinfectants such as hypochlorous acid are used to treat or prevent dental caries and periodontal disease represented by oral infections (Patent Document 1), but their effects alone are weak and intermittent. Is the target.
  • the dentin is composed of enamel rods and ivory tubules, and in infectious diseases, bacteria (biofilm) often erode into the tubules.
  • existing treatments using disinfectants make it difficult to deliver the active ingredient into the enamel rods and dentinal tubules of the dentin and maintain it on the site of application of the dental treatment (eg, the surface of the tooth). Is.
  • Infectious diseases can also be treated by removing bacterial products using a laser (for example, application of erbinium laser) and sterilization with ozone gas, but the conventional treatment method also has a problem of pulp harmfulness. ..
  • the present invention has been made in view of the above circumstances, and can be delivered to a target site (for example, in an ivory canaliculus) where disinfection has been insufficient in the past, and a site to which the composition is applied (for example, in the dentinal canaliculus)
  • a target site for example, in an ivory canaliculus
  • a site to which the composition is applied for example, in the dentinal canaliculus
  • the present inventor has found that by applying an antibacterial substance and nanofibers to teeth, especially tooth root canals, it is possible to maintain the disinfectant for a long time after delivering it to the application site.
  • the invention has been completed.
  • a slurry-like pharmaceutical composition for disinfecting teeth which comprises nanofibers and an antibacterial substance.
  • the antibacterial substance is one or more selected from the group consisting of peracetic acid, acetic acid, octanoic acid and 1-hydroxyethidronic acid-1,1-diphosphonic acid (HEDP), [1] or [2].
  • the pharmaceutical composition according to. [4] The pharmaceutical composition according to [3], wherein the antibacterial substance is peracetic acid.
  • the pharmaceutical composition according to [7], wherein the viscosity at 20 ° C. to 37 ° C. is in the range of 5000 to 130000 mPa ⁇ s in order to disinfect caries.
  • nanofiber refers to a fibrous substance having an average outer diameter in the range of 1 nm to 100 nm and having a length of 100 times or more the average outer diameter.
  • nanofibers include nanotubes having a hollow structure, nanorods having no hollow structure, and nanowires having conductive or semi-conductive properties.
  • tooth refers to an organ for mastication in the oral cavity and refers to a general tooth, but in some cases, it also means a root canal (tooth root canal).
  • biocompatibility exceeds at least the desired intended effect with respect to the interaction between the pharmaceutical composition and the organism, as well as the local and systemic reactions of tissues adjacent to the pharmaceutical composition. It means that it does no harm.
  • Nanofibers Since nanofibers are biocompatible and renewable natural resources, they are preferably used from the viewpoint of environmental protection and resource recycling in addition to the viewpoint of obtaining the required properties as a pharmaceutical composition. it can.
  • Examples of nanofibers include cellulose nanofibers.
  • the cellulose nanofibers are not particularly limited, and commercially available products or those produced by a known production method may be used.
  • the raw materials used for producing cellulose nanofibers include plant-derived fibers contained in wood, bamboo, hemp, jute, kenaf, cotton, beet and the like.
  • Preferred raw materials include wood, and examples thereof include pine, sugi, cypress, eucalyptus, acacia and the like.
  • paper obtained from these woods as a raw material, used paper, or the like can also be used.
  • the plant-derived fiber one type may be used alone, or two or more types may be used in combination.
  • cellulose nanofibers examples include pulps obtained from the material containing the plant-derived fibers, mercerized cellulose nanofibers, and regenerated cellulose nanofibers such as rayon, cellophane, and lyocell. From the viewpoint of resource recycling, it is preferable to use cellulose nanofibers obtained from waste materials and agricultural waste.
  • the cellulose nanofibers are used as a composite (referred to as "cellulose nanofiber composite" in the present specification) complexed with other substances according to the type and use of the composition, required properties and the like. May be done.
  • examples of other substances complexed with cellulose nanofibers include calcium carbonate, tricalcium phosphate, calcium sulfate and the like. Of these, it is preferable to use a composite of cellulose nanofibers and calcium carbonate, or a composite of cellulose nanofibers and tricalcium phosphate.
  • the cellulose nanofibers one type may be used alone, or two or more types may be used in combination.
  • one type of nanofiber may be used alone, or two or more types may be used in combination.
  • the nanofibers preferably further contain one or more of chitosan nanofibers and chitin nanofibers in addition to the cellulose nanofibers.
  • the antibacterial property of the pharmaceutical composition can be further improved.
  • the type of nanofibers and the combination of a plurality of types of nanofibers can be appropriately selected according to the type and use of the pharmaceutical composition, the required properties, and the like.
  • the size of the nanofibers in the pharmaceutical composition allows the antibacterial substance to be delivered within the target site (eg, dentinal tubule inner diameter of about 0.1-4 ⁇ m) and is maintained at the application site (eg, tooth surface). There is no particular limitation as long as it exhibits the characteristic of being used.
  • the length of the nanofibers is 0.01 ⁇ m to 500 ⁇ m, preferably 0.5 ⁇ m to 400 ⁇ m, more preferably 0.5 ⁇ m to 300 ⁇ m, even more preferably 0.5 ⁇ m to 200 ⁇ m, most preferably 0. It is, but is not limited to, 5 ⁇ m to 100 ⁇ m.
  • the outer diameter of the nanofiber is about 1 nm to 100 nm, preferably 3 nm to 50 nm, and more preferably about 3 nm to 30 nm, but is not limited thereto.
  • the size of nanofibers can be measured by observation with an electron microscope.
  • the pharmaceutical composition contains, for example, about 0.1% by mass to 50% by mass, preferably 5% or more and 50% or less, and more preferably 10% or more and 50% or less of nanofibers.
  • Nanofibers are added to the pharmaceutical composition alone or in a slurry with a biocompatible material.
  • Biocompatible materials are not limited as long as they are biocompatible, and examples thereof include biocompatible resins.
  • monomers, oligomers and polymers such as acrylic acid, acrylic acid ester, methacrylic acid, methacrylic acid ester, carbonate, propylene, styrene, amide, imide, glycolic acid, lactic acid, maltose and dextrin can be mentioned as biocompatible materials.
  • biocompatible materials include, for example, methyl methacrylate (MMA), polymethyl methacrylate (PMMA); ethyl methacrylate (EMA), n-butyl methacrylate, tri-n-butyl boron partial oxide, isobutyl.
  • Alkyl esters of methacrylates such as methacrylate, tert-butyl methacrylate, 2-ethylhexyl methacrylate, n-lauryl methacrylate, alkyl (C12-13) methacrylate, n-stearyl methacrylate, tridecyl methacrylate; dimethylaminoethyl methacrylate, dimethylaminoethyl methacrylate Dialkylaminoethyl ester of methacrylic acid such as methyl chloride salt, benzyl chloride salt of dimethylaminoethyl methacrylate, diethylaminoethyl methacrylate; methacryl such as metharoxyethyl phthalate, 2-methacryloyloxyethyl phthalate, 2-methacryloyloxyethyl hexahydrophthalate.
  • the pharmaceutical composition according to the present embodiment contains an antibacterial substance. This allows disinfection of teeth, especially tooth root canals, and thus treatment or prevention of caries or infected root canals.
  • the antibacterial substance is not particularly limited as long as it is a substance having antibacterial activity and does not adversely affect the human body, and can be appropriately selected depending on the type and use of the composition, required properties, and the like.
  • Examples of the antibacterial substance include peracetic acid preparations, that is, preparations containing peracetic acid, acetic acid, hydrogen peroxide solution, octanoic acid, peroctanoic acid, 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP), and sahoride ( Registered trademark), Calisolve (registered trademark), sodium hypochlorite, amino acid preparation, dog vest cement, copper ion cement, combination of hydrogen peroxide and hypochlorous water, formalin guayacol (FG) and formalin cresol (FC)
  • peracetic acid preparations that is, preparations containing peracetic acid, acetic acid, hydrogen peroxide solution, octanoic acid, peroctanoic acid, 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP), and sahoride ( Registered trademark), Calisolve (registered trademark), sodium hypochlorite, amino acid preparation, dog vest cement,
  • the antibacterial substance is preferably a peracetic acid preparation.
  • the target bacteria of the antibacterial substance are not particularly limited as long as they require disinfection in the teeth, and examples thereof include the caries-related bacteria Streptococcus mutans and Streptococcus sobrinus (Streptococcus mutans). Streptococcus sobrinus), Porphyromonas gingivalis, which is a periodontal disease bacterium, and the like.
  • the content of the antibacterial substance in the composition is, for example, 0.1 to 31% by mass, preferably 0.3 to 10% by mass.
  • the content of antibacterial substance can be adjusted as appropriate according to the application.
  • the content of peracetic acid in the preparation containing only nanofibers and peracetic acid is preferably about 0.3 to 15% by mass, more preferably about 10% by mass, and finally.
  • the content of peracetic acid in a typical pharmaceutical composition is preferably 0.3 to 12% by mass, more preferably about 6% by mass.
  • the content of peracetic acid in the preparation containing only nanofibers and peracetic acid is preferably about 4-16% by weight, more preferably about 8% by weight, in the final pharmaceutical composition.
  • the content of peracetic acid is preferably about 3 to 12% by mass, more preferably about 6% by mass.
  • lubricants if necessary, lubricants, waxes, colorants, stabilizers, fillers, water, buffer salts, etc. are added to the pharmaceutical composition as long as the effects of the present invention are not impaired.
  • Metal ion sealants and surfactants and various other additives may be included.
  • a compatibilizer may be added to the pharmaceutical composition to facilitate mixing of the nanofibers with the biocompatible resin.
  • the pharmaceutical composition according to this embodiment can be typically used as a dental infection therapeutic agent and / or a dental preventive agent, and can deliver an antibacterial substance to a target site (for example, in an dentinal canaliculus). It exhibits the property of being able to be formed and maintained at the application site (for example, the surface of the tooth).
  • the pharmaceutical composition according to the present embodiment exerts a remarkably improved bactericidal effect, it is possible to reduce the amount of dentin removed.
  • the pharmaceutical composition according to the present embodiment is applied by spreading the composition over the affected area, for example, teeth.
  • the pharmaceutical composition may be applied using, for example, a brush with a fine hair bundle.
  • the composition of the present invention can be injected into the root canal. A thick needle and a syringe can be used for injection. After applying the composition to the affected area, if necessary, leave it for about 10 minutes and wash it with water.
  • the pharmaceutical composition is preferably retained in the affected area for a certain period or longer, and the period is not limited, but is, for example, 2 minutes or longer, preferably 4 minutes or longer, and more preferably 6 minutes or longer.
  • the pharmaceutical composition according to this embodiment is in the form of a slurry by containing nanofibers.
  • the viscosity is appropriately adjusted with pure water or physiological saline according to the object of disinfection and the application.
  • the viscosity of the composition at 20 ° C. to 37 ° C. is preferably in the range of 0.5 to 10000 mPa ⁇ s, more preferably 1 to 5000 mPa ⁇ s.
  • the viscosity of the composition at 20 ° C. to 37 ° C. is preferably in the range of 2500 to 130000 mPa ⁇ s, more preferably 5000 to 6000 mPa ⁇ s.
  • Nanofibers having an outer diameter of 10 to 20 nm and a length of several ⁇ m containing cellulose, chitin, and chitosan (BINFI-s manufactured by Sugino Machine Limited: product name BM-a10010; nanofibers having a long fiber length It contains 10% by mass and has a maximum viscosity at 25 ° C. of about 130000 mPa ⁇ s), and a methacrylate monomer and polymethacrylate were prepared as biocompatible resins. They were dispersed in water so that the mass ratio of the cellulose nanofibers and the biocompatible resin was 85:15, stirred well, and then put into a kneader.
  • a slurry-like composition was prepared by melting and kneading at a predetermined temperature for an appropriate time (Example 1).
  • a 6% aceside disinfectant manufactured by Saraya Co., Ltd.
  • the viscosity of the slurry-like composition was about 5000 to 6000 mPa ⁇ s.
  • Example 1 Measurement of the number of caries-related bacteria Using the composition of Example 1, Streptococcus mutans, Streptococcus sobrinus, and Streptococcus sobrinus, which are typical caries-related bacteria in the oral cavity of a subject, The number was measured. Saline was used for control.
  • composition and control were applied to the different teeth of the subjects for several minutes, and then stained plaque was collected from each application site. DNA was extracted from the collected plaque and subjected to PCR measurement. As a result, it became clear that caries-related bacteria, especially Streptococcus mutans, tended to decrease.
  • Sterilization performance experiment In order to examine the effect of the composition for disinfecting teeth, a columnar silica monolith with a length of 5 mm and a diameter of 5 mm is regarded as artificial dentin, and streptococcus mutans, which is a caries bacterium, and periodontal disease. A sterilization performance experiment was conducted on the pathogen Porphyromonas gingivalis.
  • cellulose nanofiber (CNF) outer diameter: 3 to 5 nm; length: 0.5 to 1.2 ⁇ m
  • a slurry was prepared by mixing 1 g of dry powder of CNF with 10 ml (10 g) of 6% peracetic acid added.
  • each bacterium was inoculated on the upper part of multiple monoliths with a cotton swab.
  • the bacteria on the monolith were anaerobically cultured for 3 days in a culture incubator set at 100% humidity and 37 ° C.
  • the surface of the monolith was irradiated with an external laser (DIAGNOdent manufactured by Cabo), and the fluorescence emission of porphyrin as a metabolite of the above bacteria was confirmed.
  • a monolith with a high porphyrin reaction kept horizontal is grasped with mosquito forceps, and a liquid 6% peracetic acid or a prepared slurry is placed on the monolith for a predetermined time (2 minutes, 4 minutes, 6 minutes, 8 minutes, or 10 minutes). ) It was allowed to act. After washing with pure water, the cells were further cultured in an incubator for 3 days, and the results obtained as + for those showing a porphyrin reaction,-for those showing no porphyrin reaction, and ⁇ for those showing a partial porphyrin reaction. It is shown below.
  • the upper surface of the monolith was allowed to act for 2 minutes, 4 minutes, 6 minutes, 8 minutes, and 10 minutes using peracetic acid mixed with the slurry, washed with pure water, and then cultured for 3 days.
  • the porphyrin reaction was confirmed, the disinfectant effect was high when the peracetic acid remained on the upper part of the monolith due to surface tension. Therefore, it can be said that the slurry-like peracetic acid has a good yield and a high disinfecting effect. Those that used 5 of each and stayed on the surface for a long time due to surface tension had high disinfection performance.
  • the disinfectant composition agent stays on the surface of the monolith for a certain period of time or longer to show the disinfecting effect, and tilt the monolith to about 50 degrees so that it is not affected by surface tension. Repeated. The results are shown below.
  • a silicon tube having an inner diameter of 5 mm was cut to a length of 1.5 cm and then attached to a monolith, and an experiment was conducted in which this was regarded as a tooth root trunk.
  • the action time was 2 minutes, 4 minutes, 6 minutes, 8 minutes, and 10 minutes as in the above experiment.

Abstract

The present invention provides a slurry-like pharmaceutical composition which is for sterilizing and disinfecting teeth, and comprises nanofibers and an antibacterial substance.

Description

歯牙消毒用組成物Tooth disinfectant composition
　本発明は、歯牙を滅菌、消毒するためのスラリー状の医薬組成物に関する。 The present invention relates to a slurry-like pharmaceutical composition for sterilizing and disinfecting teeth.
　口腔感染症に代表される齲蝕や歯周病を治療又は予防するために、次亜塩素酸などの各種の消毒剤が使われているが（特許文献１）、その単独での効果は弱く断続的である。歯質はエナメル柱および象牙細管などで構成されており、感染症においては細管の内部まで細菌（バイオフィルム）が浸食している場合が多い。しかしながら、消毒剤を用いる既存の治療法では、歯質のエナメル柱および象牙細管の内部にまで有効成分を送達し、歯科治療剤の適用部位（例えば、歯の表面）上で維持することが困難である。 Various disinfectants such as hypochlorous acid are used to treat or prevent dental caries and periodontal disease represented by oral infections (Patent Document 1), but their effects alone are weak and intermittent. Is the target. The dentin is composed of enamel rods and ivory tubules, and in infectious diseases, bacteria (biofilm) often erode into the tubules. However, existing treatments using disinfectants make it difficult to deliver the active ingredient into the enamel rods and dentinal tubules of the dentin and maintain it on the site of application of the dental treatment (eg, the surface of the tooth). Is.
　そのため、細管の内部まで細菌が侵食した場合には、感染歯質を全て取り除き、歯質を大幅に削合することが必要となり、その結果、歯質の多くが失われる、という問題がある。 Therefore, when bacteria invade the inside of the capillary tube, it is necessary to remove all the infected tooth substance and sharply grind the tooth substance, and as a result, there is a problem that most of the tooth substance is lost.
　感染症はレーザーを用いる菌の産生物の除去（例えば、エルビニュームレーザーの応用）、および、オゾンガスによる殺菌等によっても治療可能であるが、従来の治療方法には歯髄為害性という問題もあった。 Infectious diseases can also be treated by removing bacterial products using a laser (for example, application of erbinium laser) and sterilization with ozone gas, but the conventional treatment method also has a problem of pulp harmfulness. ..
　また、齲蝕の治療には感染歯質を除去したあとに、コンポジットレジン、グラスアイオノマーセメント、金銀パラジウム合金等を患部に充てんする方法が用いられているが、これらに消毒、滅菌レベルの抗菌性はなく、歯牙削合が不十分であれば材料表面及び内面には歯と同様に細菌が付着し増殖してしまう。 In addition, for the treatment of dental caries, a method of filling the affected area with composite resin, glass ionomer cement, gold-silver-palladium alloy, etc. after removing the infected tooth substance is used, but these have antibacterial properties at the disinfection and sterilization level. If the tooth grinding is insufficient, bacteria will adhere to and proliferate on the surface and inner surface of the material in the same manner as teeth.
国際公開第２００９／０９８８７０号公報International Publication No. 2009/098870
　本発明は、以上のとおりの事情に鑑みてなされたものであり、従来消毒が不十分であった目的部位（例えば、象牙細管内）に送達することができ、かつ、組成物の適用部位（例えば、歯の表面）に維持されるという特性を発揮する組成物を提供することを目的とする。 The present invention has been made in view of the above circumstances, and can be delivered to a target site (for example, in an ivory canaliculus) where disinfection has been insufficient in the past, and a site to which the composition is applied (for example, in the dentinal canaliculus) For example, it is an object of the present invention to provide a composition exhibiting a property of being maintained on the surface of a tooth.
　本発明者は、抗菌物質とナノファイバーとを組み合わせて歯牙、特に歯牙根管に適用することで、適用部位に送達した上で消毒剤を長時間維持することが可能であることを見出し、本発明を完成させるに至った。 The present inventor has found that by applying an antibacterial substance and nanofibers to teeth, especially tooth root canals, it is possible to maintain the disinfectant for a long time after delivering it to the application site. The invention has been completed.
　すなわち、本発明は以下の発明を包含する。
［１］ナノファイバーと抗菌物質とを含む、歯牙を消毒するためのスラリー状の医薬組成物。
［２］ナノファイバーがセルロースナノファイバーである、［１］に記載の医薬組成物。
［３］抗菌物質が過酢酸、酢酸、オクタン酸及び１－ヒドロキシエチリデン－１，１－ジホスホン酸（ＨＥＤＰ）からなる群より選択される１種又は複数種である、［１］又は［２］に記載の医薬組成物。
［４］抗菌物質が過酢酸である、［３］に記載の医薬組成物。
［５］歯牙が歯牙根管である、［１］～［４］のいずれかに記載の医薬組成物。
［６］２０℃～３７℃での粘度が、１～６０００ｍＰａ・ｓの範囲である、［５］に記載の記載の組成物。
［７］歯牙の消毒が齲蝕又は感染根管の治療又は予防のためである［１］～［６］のいずれかに記載の医薬組成物。
［８］齲蝕を消毒するために、２０℃～３７℃での粘度が、５０００～１３００００ｍＰａ・ｓの範囲である、［７］に記載の医薬組成物。
［９］ナノファイバーの外径が１ｎｍ～１００ｎｍの範囲であり、長さが０．０１μｍ～５００μｍの範囲である、［１］～［８］のいずれかに記載の医薬組成物。 That is, the present invention includes the following inventions.
[1] A slurry-like pharmaceutical composition for disinfecting teeth, which comprises nanofibers and an antibacterial substance.
[2] The pharmaceutical composition according to [1], wherein the nanofibers are cellulose nanofibers.
[3] The antibacterial substance is one or more selected from the group consisting of peracetic acid, acetic acid, octanoic acid and 1-hydroxyethidronic acid-1,1-diphosphonic acid (HEDP), [1] or [2]. The pharmaceutical composition according to.
[4] The pharmaceutical composition according to [3], wherein the antibacterial substance is peracetic acid.
[5] The pharmaceutical composition according to any one of [1] to [4], wherein the tooth is a root canal.
[6] The composition according to [5], wherein the viscosity at 20 ° C. to 37 ° C. is in the range of 1 to 6000 mPa · s.
[7] The pharmaceutical composition according to any one of [1] to [6], wherein the disinfection of teeth is for the treatment or prevention of dental caries or infected root canals.
[8] The pharmaceutical composition according to [7], wherein the viscosity at 20 ° C. to 37 ° C. is in the range of 5000 to 130000 mPa · s in order to disinfect caries.
[9] The pharmaceutical composition according to any one of [1] to [8], wherein the outer diameter of the nanofiber is in the range of 1 nm to 100 nm and the length is in the range of 0.01 μm to 500 μm.
　従来、抗菌物質単独又はそれらの組み合わせで歯牙を消毒しても殺菌、消毒は不十分であった。本発明によれば、抗菌物質にスラリー状のナノファイバーを組み合わせることで、歯牙や、歯牙根管のような従来抗菌物質が留まることが不可能であった部位にも抗菌物質が長時間留まることができ、殺菌効果も顕著に向上する。 Conventionally, sterilization and disinfection were insufficient even if teeth were disinfected with antibacterial substances alone or in combination thereof. According to the present invention, by combining an antibacterial substance with slurry-like nanofibers, the antibacterial substance stays for a long time even in a part such as a tooth or a tooth root canal where the antibacterial substance could not stay in the past. And the bactericidal effect is significantly improved.
　以下、本発明の実施形態について、より詳細に説明する。ただし、本発明はこれらの実施形態に限定されるものではない。本発明は、その要旨を逸脱しない範囲で様々な変形が可能である。 Hereinafter, embodiments of the present invention will be described in more detail. However, the present invention is not limited to these embodiments. The present invention can be modified in various ways without departing from the gist thereof.
　＜定義＞
　本明細書において、「ナノファイバー」とは、外径の平均値が１ｎｍ～１００ｎｍの範囲内のナノスケールであり、長さが外径の平均値の１００倍以上である繊維状物質を指すものとする。ナノファイバーとしては、中空構造を有するナノチューブ、中空構造を有しないナノロッド、導電性もしくは半導電性の性質を有するナノワイヤーが挙げられる。 <Definition>
As used herein, the term "nanofiber" refers to a fibrous substance having an average outer diameter in the range of 1 nm to 100 nm and having a length of 100 times or more the average outer diameter. And. Examples of nanofibers include nanotubes having a hollow structure, nanorods having no hollow structure, and nanowires having conductive or semi-conductive properties.
　本明細書において、「歯牙」とは、口腔内で咀嚼するための器官であって一般的な歯を指すが、場合によってはその根管（歯牙根管）をも意味する。 In the present specification, "tooth" refers to an organ for mastication in the oral cavity and refers to a general tooth, but in some cases, it also means a root canal (tooth root canal).
　本明細書において、「生体適合性」とは、医薬組成物と生体間の相互作用、ならびに、医薬組成物に隣接する組織の局所的反応および全身的反応に関し、少なくとも所望の意図した効果を超える害を与えないことを意味する。 As used herein, "biocompatibility" exceeds at least the desired intended effect with respect to the interaction between the pharmaceutical composition and the organism, as well as the local and systemic reactions of tissues adjacent to the pharmaceutical composition. It means that it does no harm.
ナノファイバー
　ナノファイバーは、生体適合性を有し、再生可能な天然資源であるため、医薬組成物としての所要の特性を得る観点に加えて、環境保護や資源リサイクルの観点からも好ましく用いることができる。ナノファイバーとしては、例えばセルロースナノファイバーが挙げられる。 Nanofibers Since nanofibers are biocompatible and renewable natural resources, they are preferably used from the viewpoint of environmental protection and resource recycling in addition to the viewpoint of obtaining the required properties as a pharmaceutical composition. it can. Examples of nanofibers include cellulose nanofibers.
　セルロースナノファイバーとしては、特に限定されず、市販品を用いても、公知の製造方法により製造したものを用いてもよい。セルロースナノファイバーを製造するのに使用する原料としては、例えば、木材、竹、麻、ジュート、ケナフ、綿、ビート等に含まれる植物由来の繊維が挙げられる。好ましい原料としては木材が挙げられ、例えば、マツ、スギ、ヒノキ、ユーカリ、アカシア等が挙げられる。また、これらの木材を原料として得られる紙、あるいは古紙等を用いることもできる。なお、植物由来の繊維は、一種を単独で用いてもよく、二種以上を併用してもよい。 The cellulose nanofibers are not particularly limited, and commercially available products or those produced by a known production method may be used. Examples of the raw materials used for producing cellulose nanofibers include plant-derived fibers contained in wood, bamboo, hemp, jute, kenaf, cotton, beet and the like. Preferred raw materials include wood, and examples thereof include pine, sugi, cypress, eucalyptus, acacia and the like. Further, paper obtained from these woods as a raw material, used paper, or the like can also be used. As the plant-derived fiber, one type may be used alone, or two or more types may be used in combination.
　また、セルロースナノファイバーとしては、前記植物由来の繊維を含有する材料から得られるパルプ、マーセル化を施したセルロースナノファイバー、レーヨンやセロファン、リヨセル等の再生セルロースナノファイバー等を含むものも挙げられる。また、資源リサイクルの観点から、廃材や農業廃棄物から得られるセルロースナノファイバーを用いることが好ましい。 Examples of the cellulose nanofibers include pulps obtained from the material containing the plant-derived fibers, mercerized cellulose nanofibers, and regenerated cellulose nanofibers such as rayon, cellophane, and lyocell. From the viewpoint of resource recycling, it is preferable to use cellulose nanofibers obtained from waste materials and agricultural waste.
　また、セルロースナノファイバーは、組成物の種類や用途、所要の特性等に応じて、他の物質と複合化した複合体（本明細書では、「セルロースナノファイバー複合体」と称する。）として用いられてもよい。セルロースナノファイバーと複合化される他の物質としては、例えば、炭酸カルシウム、リン酸三カルシウム、硫酸カルシウム等が挙げられる。これらのうち、セルロースナノファイバーと炭酸カルシウムとの複合体、セルロースナノファイバーとリン酸三カルシウムとの複合体を用いることが好ましい。なお、セルロースナノファイバーは、一種を単独で用いてもよく、二種以上を併用してもよい。 Further, the cellulose nanofibers are used as a composite (referred to as "cellulose nanofiber composite" in the present specification) complexed with other substances according to the type and use of the composition, required properties and the like. May be done. Examples of other substances complexed with cellulose nanofibers include calcium carbonate, tricalcium phosphate, calcium sulfate and the like. Of these, it is preferable to use a composite of cellulose nanofibers and calcium carbonate, or a composite of cellulose nanofibers and tricalcium phosphate. As the cellulose nanofibers, one type may be used alone, or two or more types may be used in combination.
　本実施形態に係る医薬組成物において、ナノファイバーは、一種を単独で用いてもよく、二種以上を併用してもよい。一実施形態において、ナノファイバーは、セルロースナノファイバーに加え、キトサンナノファイバーおよびキチンナノファイバーのうちの一種以上をさらに含むことが好ましい。これにより、医薬組成物の抗菌性をより向上させることができる。このように、医薬組成物の種類や用途、所要の特性等に応じて、ナノファイバーの種類や複数種のナノファイバーの組み合わせを適宜選択することができる。 In the pharmaceutical composition according to the present embodiment, one type of nanofiber may be used alone, or two or more types may be used in combination. In one embodiment, the nanofibers preferably further contain one or more of chitosan nanofibers and chitin nanofibers in addition to the cellulose nanofibers. Thereby, the antibacterial property of the pharmaceutical composition can be further improved. As described above, the type of nanofibers and the combination of a plurality of types of nanofibers can be appropriately selected according to the type and use of the pharmaceutical composition, the required properties, and the like.
　医薬組成物中のナノファイバーのサイズは、抗菌物質を目的部位（例えば、象牙細管内径０．１～４μｍ程度）内に送達することができ、かつ、適用部位（例えば、歯の表面）に維持されるという特性を発揮する限り、特に限定されることはない。代表的には、ナノファイバーの長さは、０．０１μｍ～５００μｍ、好ましくは０．５μｍ～４００μｍ、より好ましくは０．５μｍ～３００μｍ、さらにより好ましくは０．５μｍ～２００μｍ、最も好ましくは０．５μｍ～１００μｍであるが、これらに限定されない。代表的には、ナノファイバーの外径は、１ｎｍ～１００ｎｍ、好ましくは３ｎｍ～５０ｎｍ、より好ましくは３ｎｍ～３０ｎｍ程度であるが、これらに限定されない。ナノファイバーのサイズは、電子顕微鏡による観察により測定することができる。 The size of the nanofibers in the pharmaceutical composition allows the antibacterial substance to be delivered within the target site (eg, dentinal tubule inner diameter of about 0.1-4 μm) and is maintained at the application site (eg, tooth surface). There is no particular limitation as long as it exhibits the characteristic of being used. Typically, the length of the nanofibers is 0.01 μm to 500 μm, preferably 0.5 μm to 400 μm, more preferably 0.5 μm to 300 μm, even more preferably 0.5 μm to 200 μm, most preferably 0. It is, but is not limited to, 5 μm to 100 μm. Typically, the outer diameter of the nanofiber is about 1 nm to 100 nm, preferably 3 nm to 50 nm, and more preferably about 3 nm to 30 nm, but is not limited thereto. The size of nanofibers can be measured by observation with an electron microscope.
　医薬組成物は、例えば、０．１質量％～５０質量％程度、好ましくは５％以上５０％以下、より好ましくは１０％以上５０％以下のナノファイバーを含む。 The pharmaceutical composition contains, for example, about 0.1% by mass to 50% by mass, preferably 5% or more and 50% or less, and more preferably 10% or more and 50% or less of nanofibers.
　ナノファイバーは、単独で、又は生体適合性材料とともにスラリー状にした上で医薬組成物に配合される。 Nanofibers are added to the pharmaceutical composition alone or in a slurry with a biocompatible material.
生体適合性材料
　生体適合性材料は、生体適合性がある限り限定されず、その例として生体適合性樹脂などがある。例えば、アクリル酸、アクリル酸エステル、メタクリル酸、メタクリル酸エステル、カーボネート、プロピレン、スチレン、アミド、イミド、グリコール酸、乳酸、マルトース、デキストリン等のモノマー、オリゴマーおよびポリマーが生体適合性材料として挙げられるが、これらに限定されない。より具体的には、生体適合性材料としては、例えば、メチルメタクリレート（ＭＭＡ）、ポリメチルメタクリレート（ＰＭＭＡ）；エチルメタクリレート（ＥＭＡ）、ｎ－ブチルメタクリレート、トリ-ｎ-ブチルホウ素部分酸化物、イソブチルメタクリレート、ｔｅｒｔ－ブチルメタクリレート、２－エチルヘキシルメタクリレート、ｎ－ラウリルメタクリレート、アルキル（Ｃ１２～１３）メタクリレート、ｎ－ステアリルメタクリレート、トリデシルメタクリレート等のメタクリル酸のアルキルエステル；ジメチルアミノエチルメタクリレート、ジメチルアミノエチルメタクリレートのメチルクロライド塩、ジメチルアミノエチルメタクリレートのベンジルクロライド塩、ジエチルアミノエチルメタクリレート等のメタクリル酸のジアルキルアミノエチルエステル；メタクリロキシエチルフタレート、２－メタクリロイルオキシエチルフタレート、２－メタクリロイルオキシエチルヘキサヒドロフタレート等のメタクリル酸のカルボン酸含有エステル；２，２，２－トリフルオロエチルメタクリレート等のメタクリル酸のフルオロアルキルエステル；シクロヘキシルメタクリレート、フェニルメタクリレート、ベンジルメタクリレート、イソボルニルメタクリレート、グリシジルメタクリレート、テトラヒドロフルフリルメタクリレート、アリルメタクリレート、２－ヒドロキシエチルメタクリレート（ＨＥＭＡ）、２－ヒドロキシプロピルメタクリレート、２－メトキシエチルメタクリレート、２－エトキシエチルメタクリレート、ヒドロキシナフトキシプロピルメタクリレート（ＨＮＰＭ）、エチレングリコールジメタクリレート（ＥＤＭＡ）、トリエチレングリコールジメタクリレート（ＴｒｉＥＤＭＡ）、１，３－ブタンジオールジメタクリレート（１，３－ＢｕＤＭＡ）、１，３－ブチレングリコールジメタクリレート、１，６－ヘキサンジオールジメタクリレート、ポリプロピレングリコールメタクリレート、トリメチロールプロパントリメタクリレート、２，２－ビス［４－（２－ヒドロキシ－３－メタクリロキシプロポキシ）フェニル］プロパン（Ｂｉｓ－ＧＭＡ）、２，２－ビス（４－メタクリロキシフェニル）プロパン（ＢＰＤＭＡ）、２，２－ビス（４－メタクリロキシエトキシフェニル）プロパン（Ｂｉｓ－ＭＥＰＰ）、ジ（メタクリロキシエチル）トリメチルヘキサメチレンジウレタン（ＵＤＭＡ）、トリ－ｎ－ブチルボラン（ＴＢＢ）、メタクリロキシエチルフェニルホスフェート（Ｐｈｅｎｙｌ－Ｐ）、４－メタクリロキシエチルトリメリテートアンハイドライド（４－ＭＥＴＡ）、４－メタクリロキシエチルトリメリット酸（４－ＭＥＴ）、１１－メタクリロキシ－１，１－ウンデカジカルボン酸（ＭＡＣ－１０）、１０－メタクリロキシデカメチレンリン酸（ＭＤＰ）、４－アクリロキシエチルトリメリット酸（４－ＡＥＴ）等が挙げられるが、これらに限定されない。これらのうち、ＭＭＡ、ＰＭＭＡ、ＨＥＭＡ、ＴＢＢ、４－ＭＥＴＡを用いることが好ましい。なお、生体適合性材料は、一種を単独でも用いてもよく、二種以上を併用してもよい。 Biocompatible materials Biocompatible materials are not limited as long as they are biocompatible, and examples thereof include biocompatible resins. For example, monomers, oligomers and polymers such as acrylic acid, acrylic acid ester, methacrylic acid, methacrylic acid ester, carbonate, propylene, styrene, amide, imide, glycolic acid, lactic acid, maltose and dextrin can be mentioned as biocompatible materials. , Not limited to these. More specifically, biocompatible materials include, for example, methyl methacrylate (MMA), polymethyl methacrylate (PMMA); ethyl methacrylate (EMA), n-butyl methacrylate, tri-n-butyl boron partial oxide, isobutyl. Alkyl esters of methacrylates such as methacrylate, tert-butyl methacrylate, 2-ethylhexyl methacrylate, n-lauryl methacrylate, alkyl (C12-13) methacrylate, n-stearyl methacrylate, tridecyl methacrylate; dimethylaminoethyl methacrylate, dimethylaminoethyl methacrylate Dialkylaminoethyl ester of methacrylic acid such as methyl chloride salt, benzyl chloride salt of dimethylaminoethyl methacrylate, diethylaminoethyl methacrylate; methacryl such as metharoxyethyl phthalate, 2-methacryloyloxyethyl phthalate, 2-methacryloyloxyethyl hexahydrophthalate. Carboxy acid-containing ester of acid; Fluoroalkyl ester of methacrylic acid such as 2,2,2-trifluoroethyl methacrylate; cyclohexyl methacrylate, phenyl methacrylate, benzyl methacrylate, isobornyl methacrylate, glycidyl methacrylate, tetrahydrofurfuryl methacrylate, allyl methacrylate , 2-Hydroxyethyl methacrylate (HEMA), 2-Hydroxypropyl methacrylate, 2-methoxyethyl methacrylate, 2-ethoxyethyl methacrylate, hydroxynaphthoxypropyl methacrylate (HNPM), ethylene glycol dimethacrylate (EDMA), triethylene glycol dimethacrylate (TriEDM), 1,3-butanediol dimethacrylate (1,3-BuDMA), 1,3-butylene glycol dimethacrylate, 1,6-hexanediol dimethacrylate, polypropylene glycol methacrylate, trimethylpropantrimethacrylate, 2, 2-Bis [4- (2-Hydroxy-3-methacryloxypropoxy) phenyl] propane (Bis-GMA), 2,2-bis (4-methacryloxyphenyl) propane (BPDMA), 2,2-bis (4) -Methyloxyethoxyphenyl) Propane (Bis-MEPP), Di (Methyloxyethyl) Trimethylhexamethylenediurethane ( UDMA), tri-n-butylborane (TBB), methacryloxyethylphenyl phosphate (Phenyl-P), 4-methacryloxyethyl trimellitate anhydride (4-META), 4-methacryloxyethyl trimellitic acid (4-META) MET), 11-methacryloxy-1,1-undecadicarboxylic acid (MAC-10), 10-methacryloxydecamethylene phosphate (MDP), 4-acryloxyethyltrimellitic acid (4-AET) and the like. However, it is not limited to these. Of these, MMA, PMMA, HEMA, TBB, and 4-META are preferably used. As the biocompatible material, one type may be used alone, or two or more types may be used in combination.
抗菌物質
　また、本実施形態に係る医薬組成物は、抗菌物質を含む。これにより、歯牙、特に歯牙根管の消毒、ひいては齲蝕又は感染根管の治療又は予防が可能になる。抗菌物質としては、抗菌活性を有する物質であって人体に悪影響を与えない限りにおいて特に限定されず、組成物の種類や用途、所要の特性等に応じて適宜選択することができる。抗菌物質としては、例えば、過酢酸製剤、すなわち、過酢酸、酢酸、過酸化水素水、オクタン酸、過オクタン酸、１－ヒドロキシエチリデン－１，１－ジホスホン酸（ＨＥＤＰ）を含む製剤、サホライド（登録商標）、カリソルブ（登録商標）、次亜塩素酸ナトリウム、アミノ酸製剤、ドッグベストセメント、銅イオンセメント、過酸化水素と次亜塩素水の組み合わせ、ホルマリングアヤコール（ＦＧ）及びフォルマリンクレゾール（ＦＣ）などが挙げられるが、これらに限定されない。いずれも市販されており、過酢酸を含む消毒剤としては、アセサイド（サラヤ株式会社製）、ダイヤパワー（三菱ガス化学社製）などがある。 Antibacterial substance The pharmaceutical composition according to the present embodiment contains an antibacterial substance. This allows disinfection of teeth, especially tooth root canals, and thus treatment or prevention of caries or infected root canals. The antibacterial substance is not particularly limited as long as it is a substance having antibacterial activity and does not adversely affect the human body, and can be appropriately selected depending on the type and use of the composition, required properties, and the like. Examples of the antibacterial substance include peracetic acid preparations, that is, preparations containing peracetic acid, acetic acid, hydrogen peroxide solution, octanoic acid, peroctanoic acid, 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP), and sahoride ( Registered trademark), Calisolve (registered trademark), sodium hypochlorite, amino acid preparation, dog vest cement, copper ion cement, combination of hydrogen peroxide and hypochlorous water, formalin guayacol (FG) and formalin cresol (FC) However, it is not limited to these. Both are commercially available, and examples of disinfectants containing peracetic acid include Aceside (manufactured by Saraya Co., Ltd.) and Diapower (manufactured by Mitsubishi Gas Chemical Company).
　抗菌物質は、過酢酸製剤であることが好ましい。 The antibacterial substance is preferably a peracetic acid preparation.
　抗菌物質が対象とする菌は歯牙において消毒が必要とされるものであれば特に限定されないが、その例として、例えば、齲蝕関連細菌であるストレプトコッカス・ミュータンス（Streptococcus mutans）、ストレプトコックス・ソブリヌス（Streptococcus sobrinus）、歯周病菌であるポルフィロモナス・ジンジバリス（Porphyromonas gingivalis）等が挙げられる。 The target bacteria of the antibacterial substance are not particularly limited as long as they require disinfection in the teeth, and examples thereof include the caries-related bacteria Streptococcus mutans and Streptococcus sobrinus (Streptococcus mutans). Streptococcus sobrinus), Porphyromonas gingivalis, which is a periodontal disease bacterium, and the like.
　組成物における抗菌物質の含有量は、例えば、０．１～３１質量％、好ましくは０．３～１０質量％である。 The content of the antibacterial substance in the composition is, for example, 0.1 to 31% by mass, preferably 0.3 to 10% by mass.
　抗菌物質の含有量は用途に応じて適宜調節され得る。例えば、齲蝕部分の消毒を行う場合、ナノファイバーと過酢酸のみを含む調製物における過酢酸の含有量は、好ましくは約０．３～１５質量％、より好ましくは約１０質量％であり、最終的な医薬組成物における過酢酸の含有量は、好ましくは０．３～１２質量％、より好ましくは約６質量％である。 The content of antibacterial substance can be adjusted as appropriate according to the application. For example, when disinfecting the carious portion, the content of peracetic acid in the preparation containing only nanofibers and peracetic acid is preferably about 0.3 to 15% by mass, more preferably about 10% by mass, and finally. The content of peracetic acid in a typical pharmaceutical composition is preferably 0.3 to 12% by mass, more preferably about 6% by mass.
　根管消毒の場合、ナノファイバーと過酢酸のみを含む調製物における過酢酸の含有量は、好ましくは約４～１６質量％、より好ましくは約８質量％であり、最終的な医薬組成物における過酢酸の含有量は好ましくは約３～１２質量％、より好ましくは約６質量％である。 In the case of root canal disinfection, the content of peracetic acid in the preparation containing only nanofibers and peracetic acid is preferably about 4-16% by weight, more preferably about 8% by weight, in the final pharmaceutical composition. The content of peracetic acid is preferably about 3 to 12% by mass, more preferably about 6% by mass.
その他の添加剤
　本実施形態においては、必要に応じて、本発明の効果を阻害しない範囲において、医薬組成物に滑材、ワックス類、着色剤、安定化剤、フィラー、水、緩衝用塩、金属イオン封鎖材、および、界面活性剤、その他の各種の添加剤を含めてもよい。例えば、ナノファイバーと生体適合性樹脂との混合を容易にするために、医薬組成物に相溶化剤を添加してもよい。 Other Additives In the present embodiment, if necessary, lubricants, waxes, colorants, stabilizers, fillers, water, buffer salts, etc. are added to the pharmaceutical composition as long as the effects of the present invention are not impaired. Metal ion sealants and surfactants and various other additives may be included. For example, a compatibilizer may be added to the pharmaceutical composition to facilitate mixing of the nanofibers with the biocompatible resin.
用途
　本実施形態に係る医薬組成物は、代表的には、歯科感染治療剤および／または歯科用予防剤として利用可能であり、抗菌物質を目的部位（例えば、象牙細管内）に送達することができ、かつ、適用部位（例えば、歯の表面）に維持されるという特性を発揮する。 Uses The pharmaceutical composition according to this embodiment can be typically used as a dental infection therapeutic agent and / or a dental preventive agent, and can deliver an antibacterial substance to a target site (for example, in an dentinal canaliculus). It exhibits the property of being able to be formed and maintained at the application site (for example, the surface of the tooth).
　本実施形態に係る医薬組成物は顕著に向上した殺菌効果を奏するため、歯質の削除量を軽減することもできる。 Since the pharmaceutical composition according to the present embodiment exerts a remarkably improved bactericidal effect, it is possible to reduce the amount of dentin removed.
　本実施形態に係る医薬組成物は、その組成物を患部、例えば歯牙などに行き渡らせることで適用される。歯牙表面のう蝕の場合、組成物の粘度を高くして患部に塗布するのが好ましい。また、その際、例えば、細い毛束のブラシなどを用いて、医薬組成物を適用してもよい。あるいは、本発明の組成物を歯根管に注入することもできる。注入には経の太い針とシリンジなどを用いることができる。組成物を患部に適用した後、必要に応じて約１０分間放置し、水洗される。 The pharmaceutical composition according to the present embodiment is applied by spreading the composition over the affected area, for example, teeth. In the case of dental caries on the tooth surface, it is preferable to increase the viscosity of the composition and apply it to the affected area. At that time, the pharmaceutical composition may be applied using, for example, a brush with a fine hair bundle. Alternatively, the composition of the present invention can be injected into the root canal. A thick needle and a syringe can be used for injection. After applying the composition to the affected area, if necessary, leave it for about 10 minutes and wash it with water.
　組成物の適用後、医薬組成物は一定期間以上患部に留めておくことが好ましく、その期間は限定されないが、例えば２分以上、好ましくは４分以上、より好ましくは６分以上である。 After application of the composition, the pharmaceutical composition is preferably retained in the affected area for a certain period or longer, and the period is not limited, but is, for example, 2 minutes or longer, preferably 4 minutes or longer, and more preferably 6 minutes or longer.
　本実施形態に係る医薬組成物は、ナノファイバーを含むことでスラリー状となっている。その粘度は消毒の対象や用途に応じて純水や生理食塩水などで適宜調節される。例えば、歯牙根管を消毒する場合、組成物の２０℃～３７℃での粘度は、好ましくは０．５～１００００ｍＰａ・ｓ、より好ましくは１～５０００ｍＰａ・ｓの範囲である。齲蝕の消毒の場合、組成物の２０℃～３７℃における粘度は、好ましくは２５００～１３００００ｍＰａ・ｓ、より好ましくは５０００～６０００ｍＰａ・ｓの範囲である。 The pharmaceutical composition according to this embodiment is in the form of a slurry by containing nanofibers. The viscosity is appropriately adjusted with pure water or physiological saline according to the object of disinfection and the application. For example, when disinfecting a tooth root canal, the viscosity of the composition at 20 ° C. to 37 ° C. is preferably in the range of 0.5 to 10000 mPa · s, more preferably 1 to 5000 mPa · s. In the case of caries disinfection, the viscosity of the composition at 20 ° C. to 37 ° C. is preferably in the range of 2500 to 130000 mPa · s, more preferably 5000 to 6000 mPa · s.
　以下、実施例により本発明をさらに詳しく説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
組成物の調製
　セルロース、キチン、およびキトサンを含む外径１０～２０ｎｍ、長さ数μｍのナノファイバー（スギノマシン社製ＢＩＮＦＩ－ｓ（ビンフィス）：製品名ＢＭ－a10010；長い繊維長のナノファイバーを１０質量％含み、２５℃における最高粘度は１３００００ｍＰａ・ｓ程度）と、生体適合性樹脂としてメタクリレートモノマーとポリメタクリレートとを準備した。それらを、セルロースナノファイバーと生体適合性樹脂との質量比が８５：１５となるように水中に分散させ、よく攪拌した後、混練機に投入した。所定の温度で適切な時間溶融混練することでスラリー状の組成物を調製した（実施例１）。過酢酸の量が２質量％になるよう、過酢酸製剤としてのアセサイド６％消毒液（サラヤ株式会社製）をスラリーに添加した。スラリー状の組成物の粘度は５０００～６０００ｍＰａ・ｓ程度であった。 Preparation of composition Nanofibers having an outer diameter of 10 to 20 nm and a length of several μm containing cellulose, chitin, and chitosan (BINFI-s manufactured by Sugino Machine Limited: product name BM-a10010; nanofibers having a long fiber length It contains 10% by mass and has a maximum viscosity at 25 ° C. of about 130000 mPa · s), and a methacrylate monomer and polymethacrylate were prepared as biocompatible resins. They were dispersed in water so that the mass ratio of the cellulose nanofibers and the biocompatible resin was 85:15, stirred well, and then put into a kneader. A slurry-like composition was prepared by melting and kneading at a predetermined temperature for an appropriate time (Example 1). A 6% aceside disinfectant (manufactured by Saraya Co., Ltd.) as a peracetic acid preparation was added to the slurry so that the amount of peracetic acid was 2% by mass. The viscosity of the slurry-like composition was about 5000 to 6000 mPa · s.
齲蝕関連細菌の数の測定
　実施例１の組成物を用い、被験者の口腔内における代表的な齲蝕関連細菌であるストレプトコッカス・ミュータンス（Streptococcus mutans）、ストレプトコックス・ソブリヌス（Streptococcus sobrinus）、乳酸桿菌の数を測定した。コントロールには生理食塩水を使用した。 Measurement of the number of caries-related bacteria Using the composition of Example 1, Streptococcus mutans, Streptococcus sobrinus, and Streptococcus sobrinus, which are typical caries-related bacteria in the oral cavity of a subject, The number was measured. Saline was used for control.
　被験者の異なる歯牙にそれぞれ組成物とコントロールを数分間適用し、その後、各適用部位から染色されたプラークを採取した。採取したプラークからＤＮＡを抽出し、ＰＣＲ測定にかけた。その結果、齲蝕関連細菌、特にストレプトコッカス・ミュータンスが減少するという傾向が明らかとなった。 The composition and control were applied to the different teeth of the subjects for several minutes, and then stained plaque was collected from each application site. DNA was extracted from the collected plaque and subjected to PCR measurement. As a result, it became clear that caries-related bacteria, especially Streptococcus mutans, tended to decrease.
滅菌性能実験
　歯牙消毒用組成物の効果を検討するために、長さ5mm、直径5mmの円柱型のシリカモノリスを人工象牙質とみたてて、虫歯菌であるストレプトコッカス・ミュータンス菌と、歯周病菌であるポルフィロモナス・ジンジバリス（Porphyromonas gingivalis）に対する滅菌性能実験を行った。 Sterilization performance experiment In order to examine the effect of the composition for disinfecting teeth, a columnar silica monolith with a length of 5 mm and a diameter of 5 mm is regarded as artificial dentin, and streptococcus mutans, which is a caries bacterium, and periodontal disease. A sterilization performance experiment was conducted on the pathogen Porphyromonas gingivalis.
　歯牙消毒用組成物の抗菌物質として6%過酢酸を、ナノファイバーとしてセルロースナノファイバー（CNF）（外径：３～５ｎｍ；長さ：０．５～１．２μｍ）の粉体を使用した。CNFの乾燥粉体１ｇに対し６％過酢酸を１０ｍｌ（１０ｇ）添加したものを混和することでスラリーを調製した。 6% peracetic acid was used as the antibacterial substance of the tooth disinfecting composition, and cellulose nanofiber (CNF) (outer diameter: 3 to 5 nm; length: 0.5 to 1.2 μm) powder was used as the nanofiber. A slurry was prepared by mixing 1 g of dry powder of CNF with 10 ml (10 g) of 6% peracetic acid added.
　事前にクラスＢの高圧蒸気滅菌器（W＆H社製クラスBオートクレーブ リサ）で滅菌したモノリスが３７℃に冷却された後、複数のモノリスの上部に各菌を綿棒で植菌した。湿度100%、温度37度に設定した培養用の恒温器内でモノリス上の菌を嫌気的に3日間培養した。 After the monolith sterilized in advance with a class B high-pressure steam sterilizer (Class B autoclave Lisa manufactured by W & H) was cooled to 37 ° C., each bacterium was inoculated on the upper part of multiple monoliths with a cotton swab. The bacteria on the monolith were anaerobically cultured for 3 days in a culture incubator set at 100% humidity and 37 ° C.
　外線レーザー（カボ社製ダイアグノデント）をモノリス表面に照射し、上記菌の代謝産物としてのポルフィリンの蛍光発光を確認した。 The surface of the monolith was irradiated with an external laser (DIAGNOdent manufactured by Cabo), and the fluorescence emission of porphyrin as a metabolite of the above bacteria was confirmed.
　水平に保ったポルフィリン反応の高いモノリスをモスキート鉗子で把持し、その上部に液体状の６％の過酢酸又は調製したスラリーを所定時間（2分、4分、6分、8分、又は10分）作用させた。純水で洗浄した後、さらに恒温器内で三日間培養し、ポルフィリンの反応を示したものを+、ポルフィリン反応を示さないものを-、部分的なポルフィリン反応を示すものを±とした結果を以下に示す。
Figure JPOXMLDOC01-appb-T000001
 A monolith with a high porphyrin reaction kept horizontal is grasped with mosquito forceps, and a liquid 6% peracetic acid or a prepared slurry is placed on the monolith for a predetermined time (2 minutes, 4 minutes, 6 minutes, 8 minutes, or 10 minutes). ) It was allowed to act. After washing with pure water, the cells were further cultured in an incubator for 3 days, and the results obtained as + for those showing a porphyrin reaction,-for those showing no porphyrin reaction, and ± for those showing a partial porphyrin reaction. It is shown below.
Figure JPOXMLDOC01-appb-T000001
　続いて、スラリーで混和した過酢酸を用いてモノリス上面の部分に2分、4分、6分、8分、10分作用させ、純水で洗浄した後、同じく三日間培養した。同様にポルフィリン反応を確認したところ、表面張力によってモノリス上部に過酢酸がとどまっているものは消毒効果が高かった。そのため、スラリー状の過酢酸は歩留まりが良く消毒効果が高いと言える。それぞれの本数において5本ずつ使用し表面張力で長時間表面上にとどまったものは消毒性能が高かった。 Subsequently, the upper surface of the monolith was allowed to act for 2 minutes, 4 minutes, 6 minutes, 8 minutes, and 10 minutes using peracetic acid mixed with the slurry, washed with pure water, and then cultured for 3 days. Similarly, when the porphyrin reaction was confirmed, the disinfectant effect was high when the peracetic acid remained on the upper part of the monolith due to surface tension. Therefore, it can be said that the slurry-like peracetic acid has a good yield and a high disinfecting effect. Those that used 5 of each and stayed on the surface for a long time due to surface tension had high disinfection performance.
　そこで、モノリス表面に消毒用組成物剤が一定時間以上留まることが消毒効果を表す条件ではないかとの仮説を立て、表面張力の影響を受けないように約50度にモノリスを傾けて上記実験を繰り返した。結果を以下に示す。
Figure JPOXMLDOC01-appb-T000002
 Therefore, we hypothesized that the disinfectant composition agent stays on the surface of the monolith for a certain period of time or longer to show the disinfecting effect, and tilt the monolith to about 50 degrees so that it is not affected by surface tension. Repeated. The results are shown below.
Figure JPOXMLDOC01-appb-T000002
　液体は50度も傾けると流れ出すという予測通りの結果となったが、その一方で、スラリー状過酢酸は消毒効果が高いことがわかった。 The result was as expected that the liquid would flow out when tilted by 50 degrees, but on the other hand, it was found that the slurry-like peracetic acid has a high disinfecting effect.
　続いて、内径５ｍｍのシリコンチューブを長さ１．５ｃｍにカットした上でモノリスに取り付け、これを歯牙根幹に見立てた実験を行った。過酢酸と１０質量% CNFを混和したスラリー状の過酢酸溶液を調製し、上記の実験と同じく1グラム（スラリー状）もしくは1ミリリットル（過酢酸水溶液、CNF１０質量％添加過酢酸水溶液）をモノリスの上に作用させた。作用時間は上記実験と同じように2分、4分、6分、8分、10分とし、同時に、振動装置（株式会社コスモデンタル製コスモアイキュア）を用い、モスキート鉗子で把持しモノリスを真下（１８０°に向けて）根管内を洗浄する際の最適振動に相当する31キロヘルツの振動を加えも与えた。1～2分後に過酢酸液体のみのサンプルはチューブ内から飛散した。結果を以下に示す。
Figure JPOXMLDOC01-appb-T000003
 Subsequently, a silicon tube having an inner diameter of 5 mm was cut to a length of 1.5 cm and then attached to a monolith, and an experiment was conducted in which this was regarded as a tooth root trunk. Prepare a slurry-like peracetic acid solution in which peracetic acid and 10% by mass CNF are mixed, and add 1 gram (slurry) or 1 ml (peracetic acid aqueous solution, CNF 10% by mass-added peracetic acid aqueous solution) to the monolith as in the above experiment. Acted on. The action time was 2 minutes, 4 minutes, 6 minutes, 8 minutes, and 10 minutes as in the above experiment. A vibration of 31 kilohertz, which corresponds to the optimum vibration when cleaning the inside of the root canal (toward 180 °), was also applied. After 1 to 2 minutes, the peracetic acid liquid-only sample was scattered from the tube. The results are shown below.
Figure JPOXMLDOC01-appb-T000003
　上記結果から、スラリー状過酢酸は振動を加えても必要十分に歯面接触に強く接触していることが示された。 From the above results, it was shown that the slurry-like peracetic acid is in strong enough contact with the tooth surface even when vibration is applied.

Claims (9)

  1. 　ナノファイバーと抗菌物質とを含む、歯牙を消毒するためのスラリー状の医薬組成物。 A slurry-like pharmaceutical composition for disinfecting teeth, which contains nanofibers and an antibacterial substance.
  2. 　ナノファイバーがセルロースナノファイバーである、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the nanofibers are cellulose nanofibers.
  3. 　抗菌物質が過酢酸、酢酸、オクタン酸及び１－ヒドロキシエチリデン－１，１－ジホスホン酸（ＨＥＤＰ）からなる群より選択される１種又は複数種である、請求項１又は２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the antibacterial substance is one or more selected from the group consisting of peracetic acid, acetic acid, octanoic acid and 1-hydroxyethidronic acid-1,1-diphosphonic acid (HEDP). Stuff.
  4. 　抗菌物質が過酢酸である、請求項３に記載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the antibacterial substance is peracetic acid.
  5. 　歯牙が歯牙根管である、請求項１～４のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the tooth is a root canal.
  6. 　２０℃～３７℃での粘度が、１～６０００ｍＰａ・ｓの範囲である、請求項５に記載の記載の組成物。 The composition according to claim 5, wherein the viscosity at 20 ° C. to 37 ° C. is in the range of 1 to 6000 mPa · s.
  7. 　歯牙の消毒が齲蝕又は感染根管の治療又は予防のため、あるいは根管充填のためである、請求項１～６のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, wherein the disinfection of the tooth is for the treatment or prevention of caries or infected root canal, or for root canal filling.
  8. 　齲蝕を消毒するために、２０℃～３７℃での粘度が、５０００～１３００００ｍＰａ・ｓの範囲である、請求項７に記載の医薬組成物。 The pharmaceutical composition according to claim 7, wherein the viscosity at 20 ° C. to 37 ° C. is in the range of 5000 to 130000 mPa · s in order to disinfect caries.
  9. 　ナノファイバーの外径が１ｎｍ～１００ｎｍの範囲であり、長さが０．０１μｍ～５００μｍの範囲である、請求項１～８のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 8, wherein the outer diameter of the nanofiber is in the range of 1 nm to 100 nm and the length is in the range of 0.01 μm to 500 μm.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030156980A1 (en) * 2002-01-16 2003-08-21 Fischer Dan E. Methods for disinfecting and cleaning dental root canals using a viscous sodium hypochlorite composition
JP2016065116A (en) * 2014-09-24 2016-04-28 第一工業製薬株式会社 Aqueous dispersion of cellulose nanofibers, and food products and cosmetics using the same
WO2018064284A1 (en) * 2016-09-30 2018-04-05 Novaflux, Inc. Compositions for cleaning and decontamination

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030156980A1 (en) * 2002-01-16 2003-08-21 Fischer Dan E. Methods for disinfecting and cleaning dental root canals using a viscous sodium hypochlorite composition
JP2016065116A (en) * 2014-09-24 2016-04-28 第一工業製薬株式会社 Aqueous dispersion of cellulose nanofibers, and food products and cosmetics using the same
WO2018064284A1 (en) * 2016-09-30 2018-04-05 Novaflux, Inc. Compositions for cleaning and decontamination

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OGOSHI, TOSHIYUKI: "Environment Using Peracetic Acid Formulations", FOOD CHEMICALS MONTHLY-A TECHNICAL JOURNAL ON FOOD CHEMISTRY AND CHEMICALS, vol. 1 .32, no. no. 2, 2016, pages 67 - 72 *

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