JP7446099B2 - Composition for treating infection in root canals and dentinal tubules of teeth - Google Patents
Composition for treating infection in root canals and dentinal tubules of teeth Download PDFInfo
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- JP7446099B2 JP7446099B2 JP2019221658A JP2019221658A JP7446099B2 JP 7446099 B2 JP7446099 B2 JP 7446099B2 JP 2019221658 A JP2019221658 A JP 2019221658A JP 2019221658 A JP2019221658 A JP 2019221658A JP 7446099 B2 JP7446099 B2 JP 7446099B2
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- root canal
- nanobubbles
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Description
本発明は、歯のう蝕治療、抜髄・感染根管治療、歯周疾患治療、修復・補綴治療、インプラント周囲炎治療等に用いる、抗菌剤とプラス帯電性ナノバブル（以下、プラスナノバブルという）とを含有する歯の根管内および根管象牙細管内の感染治療用組成物に関する。 The present invention discloses an antibacterial agent and positively charged nanobubbles (hereinafter referred to as "plus nanobubbles") used for dental caries treatment, pulp extraction/infected root canal treatment, periodontal disease treatment, restoration/prosthetic treatment, peri-implantitis treatment, etc. The present invention relates to a composition for treating infection in the root canal and dentinal tubule of a tooth, which contains the following.
超高齢化社会において歯の健康・機能維持は健康長寿を達成する上で必須である。深い虫歯で神経を除去（抜髄）すると、除去後２０年ぐらいまでの間に再感染して根の下に膿が溜まる根尖性歯周炎（感染根管）となることがあり（頻度１５～２０％、年間１，０００万件）、さらにその約２５％は難治性に陥り、抜歯・破折の一途を辿る。そこで、本発明者は「抜髄しても根尖性歯周炎に至らないようにする歯髄再生治療法」を開発し、すでに臨床研究５症例で安全性を確認し、有効性を示唆した（非特許文献１）。さらにイヌ根尖性歯周炎モデルにおいても、除菌後、抜髄歯と同様の治療法を行うことにより、根尖歯周組織および歯髄の再生に成功している（非特許文献２）。一方、難治性感染根管の病因は通常根管貼薬に用いる水酸化カルシウム製剤に対して耐性のE. faecalis（Enterococcus faecalis）が象牙細管や複雑な細孔をもつ歯根の奥深くに侵入し、バイオフィルムを形成するためと推定されている（非特許文献３）。したがって、難治性感染根管治療においては、根管の洗浄・貼薬、および根尖歯周組織の化学的・物理的刺激の可及的除去法の開発が重要である。 In a super-aging society, maintaining dental health and function is essential to achieving healthy longevity. If the nerve is removed (pulp extraction) due to deep caries, reinfection may occur within about 20 years after removal, resulting in apical periodontitis (infected root canal) in which pus accumulates under the root (frequency: 15 ~20%, 10 million cases per year), and approximately 25% of these become intractable and result in tooth extraction or fracture. Therefore, the present inventor has developed a "pulp regeneration treatment method that prevents apical periodontitis even after pulp extraction," and has already confirmed its safety in five clinical studies and suggested its effectiveness ( Non-patent document 1). Furthermore, in a canine apical periodontitis model, the apical periodontium and dental pulp have been successfully regenerated by performing the same treatment method as for pulp-extracted teeth after eradication (Non-Patent Document 2). On the other hand, the cause of refractory root canal infection is that E. faecalis (Enterococcus faecalis), which is resistant to the calcium hydroxide preparations normally used for root canal patches, invades deep into the dentinal tubules and the tooth root, which has complex pores. It is presumed that this is to form a biofilm (Non-Patent Document 3). Therefore, in root canal treatment for refractory infections, it is important to develop methods for cleaning the root canal, applying medications, and removing chemical and physical stimulation of the apical periodontal tissue as much as possible.
難治性感染根管は咬合に影響を与えるばかりでなく、慢性の感染源として免疫力の衰えた高齢者の全身に多大な影響を及ぼす。骨粗鬆症治療薬服用中の場合顎骨壊死の危険性により抜歯できない場合も多い。また、抜歯してインプラントを適用できる症例は中高齢者では減少する。したがって、難治性感染根管歯の感染を制御し、抜歯や破折を回避し、歯の機能回復を図ることは、超高齢社会で健康維持に重要である。 Refractory infected root canals not only affect occlusion, but also have a significant impact on the entire body of elderly people with weakened immune systems as a source of chronic infection. If a patient is taking osteoporosis medications, it is often not possible to extract the tooth due to the risk of osteonecrosis of the jaw. Furthermore, the number of cases in which a tooth can be extracted and an implant can be applied decreases in middle-aged and elderly people. Therefore, it is important to maintain health in a super-aging society to control infections in refractory infected root canal teeth, avoid tooth extraction and fracture, and restore tooth function.
本発明の発明者は、歯科用ナノバブル発生装置を用いて、ナノサイズの超微細な気泡（マイナス帯電性ナノバブル）の優れた浸透亢進作用を利用して、標的となる患部に薬剤を有利に浸透させ得る薬剤組成物を提案している（特許文献１）。しかし、難治性感染根管歯の感染を制御する薬剤として、マイナス帯電性ナノバブル（以下、マイナスナノバブルという）と併用すると、根管内の除菌ができない抗菌剤があるという問題を見出した。そこで、マイナスナノバブルを抗菌ナノパーティクルと併用することにより、浸透亢進作用やスミヤー層除去効果を発揮でき、１～２週間ごとに根管洗浄および貼薬処置の根管治療を繰り返すことにより根管内の除菌が可能となった。しかしながら、根管完全除菌（根管内細菌が検出限界以下になる）には数回にわたる根管治療が必要という問題があった。 The inventor of the present invention used a dental nanobubble generator to utilize the excellent permeation-enhancing effect of nano-sized ultrafine bubbles (negatively charged nanobubbles) to advantageously penetrate the drug into the target affected area. has proposed a pharmaceutical composition that can induce the effects of cancer (Patent Document 1). However, we have discovered a problem in that some antibacterial agents cannot sterilize the root canal when used in combination with negatively charged nanobubbles (hereinafter referred to as negative nanobubbles) to control infections in refractory infected root canals. Therefore, by using minus nanobubbles in combination with antibacterial nanoparticles, it is possible to increase penetration and remove the smear layer. became possible to sterilize. However, there was a problem in that several root canal treatments were required to completely sterilize the root canal (bring the bacteria in the root canal below the detection limit).
本発明はかかる問題に鑑みてなされたものであって、難治性感染根管歯の感染を制御する薬剤としてより好適な、より短期間で根管完全除菌が可能な、歯の根管への浸透性がより良好であり、スミヤー層除去、細菌除去、バイオフィルム除去のために用いられるプラス帯電性ナノバブル（以下、プラスナノバブルという）含有の歯の根管内および根管象牙細管内の感染治療用組成物を提供することを目的とする。 The present invention was made in view of these problems, and is a drug that is more suitable as a drug for controlling infections in refractory infected root canals, and is capable of completely sterilizing root canals in a shorter period of time. Contains positively charged nanobubbles (hereinafter referred to as "plus nanobubbles"), which have better permeability and are used for smear layer removal, bacteria removal, and biofilm removal. The purpose is to provide therapeutic compositions .
本発明にかかる歯の根管内の洗浄・貼薬用に適した歯の根管内および根管象牙細管内の感染治療用組成物は、以下の構成を備えている。
抗菌剤と、ナノバブルとを含有しており、前記ナノバブルは、その表面がプラスに帯電したプラスナノバブルであることを特徴とする、歯の根管内および根管象牙細管内の感染治療用組成物。
組成物中に含有される表面がプラスに帯電したプラスナノバブルにより水の表面張力が小さくなり、水の浸透性が高くなる。プラスナノバブル水の浸透性が抗菌剤の抗菌作用と相乗的に作用することによって、歯の根管部の深部まで抗菌剤を行き渡らせることができ、歯および口腔内の感染を制御することができる。また、表面がプラスに帯電したプラスナノバブルを用いることにより抗菌効果に優れた歯の根管内および根管象牙細管内の感染治療用組成物となる。
The composition for treating infection in the root canal and dentinal tubule of a tooth, which is suitable for cleaning and applying medicine in the root canal of a tooth according to the present invention, has the following configuration.
A composition for treating infection in a tooth's root canal and root canal dentinal tubule , containing an antibacterial agent and nanobubbles, the nanobubbles being positive nanobubbles whose surfaces are positively charged. .
The positive nanobubbles, whose surfaces are positively charged, contained in the composition reduce the surface tension of water and increase the permeability of water. The permeability of plus nano bubble water works synergistically with the antibacterial action of the antibacterial agent, allowing the antibacterial agent to reach deep into the root canal of the tooth, thereby controlling infections in the tooth and oral cavity. . Furthermore, by using positive nanobubbles whose surfaces are positively charged, the composition can be used to treat infections in the root canals and dentinal tubules of teeth with excellent antibacterial effects.
前記プラスナノバブルは、ゼータ電位がプラスで、濃度が１×１０６～１×１０９個／ｍＬ、平均気泡径が１０～３００ｎｍであることが好ましい。 The positive nanobubbles preferably have a positive zeta potential, a concentration of 1×10 6 to 1×10 9 bubbles/mL, and an average bubble diameter of 10 to 300 nm.
前記抗菌剤は、抗菌ナノパーティクル、抗生剤、抗菌薬、抗真菌剤、抗ウィルス剤、根管拡大剤、抗炎症剤、創傷治癒や組織再生を促進する生理活性物質および幹細胞由来セクレトーム・エクソゾーム・ｍｉＲＮＡからなる群のいずれか一つ以上を含むことが好ましい。また、前記抗菌剤が、カチオン性抗菌剤であることがより好ましい。 The antibacterial agents include antibacterial nanoparticles, antibiotics, antibacterial agents, antifungal agents, antiviral agents, root canal expanders, anti-inflammatory agents, physiologically active substances that promote wound healing and tissue regeneration, and stem cell-derived secretomes, exosomes, etc. Preferably, it contains one or more of the group consisting of miRNA. Moreover, it is more preferable that the antibacterial agent is a cationic antibacterial agent.
本発明のプラスナノバブル含有の歯の根管内および根管象牙細管内の感染治療用組成物を含有する、歯の根管内、歯の歯周組織内、歯のう蝕または舌苔の細菌感染治療用組成物。 Bacterial infection in the root canal of the tooth, in the periodontal tissue of the tooth, in caries of the tooth or in the tongue coating, containing the composition for treating infection in the root canal and root canal dentinal tubule containing the plus nanobubbles of the present invention Therapeutic composition.
本発明の歯の根管内および根管象牙細管内の感染治療用組成物は、抗菌剤とプラスナノバブルとを併用することにより、効果的に歯の根管内のスミヤー層の除去、細菌・バイオフィルムの除去ならびに歯髄および根尖歯周組織の抗炎症・治癒促進・再生促進が可能である。したがって、根管の洗浄・貼薬により、難治性感染根管歯を完全除菌し、細菌感染を制御し、治癒・再生が促進できる細菌感染治療用組成物を提供することができる。 The composition for treating infection in the root canal and root canal dentinal tubule of the present invention uses an antibacterial agent and plus nanobubbles in combination to effectively remove the smear layer in the root canal of the tooth, eliminate bacteria and It is capable of removing biofilms and promoting anti-inflammatory, healing, and regeneration of the dental pulp and apical periodontal tissue. Therefore, it is possible to provide a composition for treating bacterial infection that can completely sterilize refractory infected root canal teeth, control bacterial infection, and promote healing and regeneration by cleaning the root canal and pasting the root canal.
本発明の歯の根管内および根管象牙細管内の感染治療用組成物は、抗菌剤とプラスナノバブルとを含有している。好ましくは、組成物の成分である抗菌剤として、抗菌ナノパーティクル、抗生剤、抗菌薬、抗真菌剤、抗ウィルス剤、根管拡大剤、創傷治癒や組織再生を促進する生理活性物質抗炎症剤、創傷治癒や組織再生を促進する生理活性物質および幹細胞由来セクレトーム・エクソゾーム・ｍｉＲＮＡからなる群のいずれか一つ以上を含む。 The composition for treating infection in the root canal and root canal dentinal tubule of the present invention contains an antibacterial agent and plus nanobubbles. Preferably , the antibacterial agent that is a component of the composition includes antibacterial nanoparticles, antibiotics, antibacterial agents, antifungal agents, antiviral agents , root canal expanders, and bioactive substances that promote wound healing and tissue regeneration. It contains at least one of the group consisting of agents, physiologically active substances that promote wound healing and tissue regeneration, and stem cell-derived secretomes, exosomes, and miRNA.
抗菌ナノパーティクルは、シアノアクリレートポリマーすなわちアクリレート系ポリマー粒子であり、細菌壁の糖鎖ペプチド表層と親和性が高い。抗菌ナノパーティクルが細菌に吸着すると、その部分は細菌壁の合成が阻害される。よって、細菌は内圧が保てずに自己融解する特徴を有する。抗菌ナノパーティクルは生分解されるため蓄積されず安全性が高く、耐性ができず自然環境を崩さない。シアノアクリレートナノポリマーの原料として用いられるモノマーの側鎖構造体は直鎖のｎ－ブチル基であり、代謝系にてホルムアルデヒドを生じないため安全である。また、抗菌ナノパーティクルは低濃度で抗菌効果を有する。 Antibacterial nanoparticles are cyanoacrylate polymer particles, that is, acrylate-based polymer particles, and have a high affinity with the surface layer of sugar chain peptides on bacterial walls. When antibacterial nanoparticles adsorb to bacteria, bacterial wall synthesis is inhibited in that area. Therefore, bacteria have the characteristic that they cannot maintain internal pressure and self-lyse. Antibacterial nanoparticles are highly safe because they are biodegradable and do not accumulate, and they do not develop resistance and do not disrupt the natural environment. The side chain structure of the monomer used as a raw material for cyanoacrylate nanopolymer is a linear n-butyl group, which is safe because it does not generate formaldehyde in the metabolic system. Furthermore, antibacterial nanoparticles have antibacterial effects at low concentrations.
抗菌ナノパーティクルの平均粒径は、細菌壁の合成を阻害する観点から、１０～２，０００ｎｍが好ましく、５０～１，０００ｎｍがより好ましく、１００～５００ｎｍがさらに好ましい。本発明において平均粒径とは、モード径（最頻度粒子径）をいう。また、本発明において範囲「Ａ～Ｂ」はＡ以上Ｂ以下を示す The average particle size of the antibacterial nanoparticles is preferably 10 to 2,000 nm, more preferably 50 to 1,000 nm, and even more preferably 100 to 500 nm, from the viewpoint of inhibiting bacterial wall synthesis. In the present invention, the average particle diameter refers to the mode diameter (most frequently occurring particle diameter). Furthermore, in the present invention, the range "A to B" indicates greater than or equal to A and less than or equal to B.
感染治療用組成物に含まれる抗菌ナノパーティクルの濃度（ｗ／ｖ）は、０．０００１～０．３％が好ましく、０．００１～０．０６％がより好ましく、０．００２～０．０１％がさらに好ましい。なお、本発明において抗菌ナノパーティクルの濃度は、重量／容量パーセント（％（ｗ／ｖ））すなわち組成物１００（ｍＬ）に含まれる抗菌ナノパーティクルの重量（ｇ）で示す。 The concentration (w/v) of the antibacterial nanoparticles contained in the infection treatment composition is preferably 0.0001 to 0.3%, more preferably 0.001 to 0.06%, and 0.002 to 0.01%. % is more preferable. In the present invention, the concentration of antibacterial nanoparticles is expressed as weight/volume percent (% (w/v)), that is, the weight (g) of antibacterial nanoparticles contained in 100 (mL) of the composition .
抗菌ナノパーティクルは、例えば、特許第４９６３２２１号に記載の方法により製造することができる。この方法により製造される抗菌ナノパーティクルは多孔性である。このため、抗菌ナノパーティクルの孔の内部に薬剤を抱合させることが可能である。抗菌ナノパーティクルに抱合させる薬剤としては、例えば、アンピシリン、ドキシサイクリン、バンコマイシン、レボフロキサシン等の抗生剤・抗菌剤が挙げられる。また、例えば、抗真菌剤、抗ウィルス剤、消毒剤、根管拡大剤、抗炎症剤、創傷治癒や組織再生を促進する生理活性物質および幹細胞由来セクレトーム・エクソゾーム・ｍｉＲＮＡがあげられる。 Antibacterial nanoparticles can be produced, for example, by the method described in Japanese Patent No. 4963221. Antibacterial nanoparticles produced by this method are porous. Therefore, it is possible to conjugate a drug inside the pores of antibacterial nanoparticles. Examples of the drug to be conjugated to the antibacterial nanoparticles include antibiotics and antibacterial agents such as ampicillin, doxycycline, vancomycin, and levofloxacin. Further examples include antifungal agents, antiviral agents, disinfectants, root canal expanders, anti-inflammatory agents, physiologically active substances that promote wound healing and tissue regeneration, and stem cell-derived secretomes, exosomes, and miRNA.
抗菌ナノパーティクルに抗菌剤を抱合させることで、抗菌ナノパーティクルの吸着性により抗菌剤を細菌壁に付着させ、効果的に抗菌作用を奏する。ただし、上述したとおり、抗菌ナノパーティクルは細菌壁の合成を阻害して細菌を自己融解することにより抗菌作用を奏するから、抗菌剤を抱合させないで用いることもできる。 By conjugating an antibacterial agent to antibacterial nanoparticles, the antibacterial agent adheres to the bacterial wall due to the adsorption properties of the antibacterial nanoparticles, effectively exerting an antibacterial effect. However, as mentioned above, since antibacterial nanoparticles exhibit antibacterial effects by inhibiting bacterial wall synthesis and self-lysing bacteria, they can also be used without being conjugated with an antibacterial agent.
抗菌剤にはナノバブルの性質に影響を及ぼすものも存在する。しかし、抗菌剤を抗菌ナノパーティクルに抱合させた状態で用いることにより、抗菌剤によるナノバブルへの影響を抑制できる。 Some antibacterial agents affect the properties of nanobubbles. However, by using an antibacterial agent conjugated to antibacterial nanoparticles, the influence of the antibacterial agent on nanobubbles can be suppressed.
抗菌ナノパーティクルに薬剤を抱合させる方法としては、薬剤の水溶液中に抗菌ナノパーティクルを浸漬させる方法や、薬剤の共存下において、シアノアクリレート系モノマーをアニオン重合させる方法等が挙げられる。これら例示した二つの方法では、簡便であり抱合率が高くなることから、後者のアニオン重合させる方法がより好ましい。 Examples of methods for conjugating a drug to antibacterial nanoparticles include a method in which the antibacterial nanoparticles are immersed in an aqueous solution of the drug, and a method in which a cyanoacrylate monomer is anionically polymerized in the presence of a drug. Of these two exemplified methods, the latter method of anionic polymerization is more preferred because it is simple and the conjugation rate is high.
抗菌ナノパーティクルに抱合させる薬剤の濃度は、当該薬剤の性質、使用時の容量などに応じて適宜設定することができる。抗菌剤を抱合させる場合、通常、抗菌ナノパーティクル１００重量％中に０．１～０．８重量％程度である。 The concentration of the drug to be conjugated to the antibacterial nanoparticles can be appropriately set depending on the properties of the drug, the volume at the time of use, and the like. When an antibacterial agent is conjugated, the amount is usually about 0.1 to 0.8% by weight based on 100% by weight of antibacterial nanoparticles.
感染治療用組成物の成分である抗菌剤として、上記抗菌ナノパーティクルの他、抗生剤、抗菌薬、抗真菌剤、抗ウィルス剤、消毒剤、根管拡大剤、創傷治癒や組織再生を促進する生理活性物質、抗炎症剤、創傷治癒や組織再生を促進する生理活性物質および幹細胞由来セクレトーム・エクソゾーム・ｍｉＲＮＡが挙げられる。好適にはドキシサイクリン塩酸塩水和物、レボフロキサシン水和物、グルコン酸クロルヘキシジン、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化セチルピリジニウム、グリチルリチン酸モノアンモニウム、アクリノール、次亜塩素酸ナトリウム、ポピドンヨード、フッ化第一錫、ＥＤＴＡ、クエン酸、ＭＴＡＤ、Ｔｅｔｒａｃｌｅａｎ、トリプシン、キモトリプシン、ＣＣＲ３拮抗剤、ＡＬＫ５阻害剤、間葉系幹細胞セクレトーム・エクソゾームである。より好適にはドキシサイクリン塩酸塩水和物、グルコン酸クロルヘキシジン、塩化ベンザルコニウム、塩化セチルピリジニウムである。 In addition to the above-mentioned antibacterial nanoparticles, antibacterial agents that are components of compositions for treating infections include antibiotics, antibacterial agents, antifungal agents, antiviral agents, disinfectants, root canal enlargers, and agents that promote wound healing and tissue regeneration. Examples include physiologically active substances, anti-inflammatory agents, physiologically active substances that promote wound healing and tissue regeneration, and stem cell-derived secretomes, exosomes, and miRNA. Preferred are doxycycline hydrochloride hydrate, levofloxacin hydrate, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, monoammonium glycyrrhizinate, acrinol, sodium hypochlorite, povidone iodine, stannous fluoride. , EDTA, citric acid, MTAD, Tetraclean, trypsin, chymotrypsin, CCR3 antagonist, ALK5 inhibitor, mesenchymal stem cell secretome/exosome. More preferred are doxycycline hydrochloride hydrate, chlorhexidine gluconate, benzalkonium chloride, and cetylpyridinium chloride.
抗菌剤は、そのイオン的な性質により、塩化セチルピリジニウム、塩化クロルヘキシジン、塩化ベンゼトニウム、塩化ベンザルコニウム、塩化デカリウム、グルコン酸クロルヘキシジン等のカチオン性抗菌剤；プロタミン、ドデシルジアミノエチルグリシン等の両性抗菌剤；トリクロサン、３－メチル－４－イソプロピルメチルフェノール、チモール、カルバクロール、ファルネソール、ビサボロール、シネオール等の非イオン性抗菌剤に分類されるが、中でも、口腔内で効果的に抗菌効果を発揮させる観点からカチオン性抗菌剤が好ましい。また、ヒノキチオール；ラウロイルサルコシンナトリウム；ｌ－メントール等の他の一般的な抗菌剤を用いることもできる。 Due to their ionic nature, antibacterial agents include cationic antibacterial agents such as cetylpyridinium chloride, chlorhexidine chloride, benzethonium chloride, benzalkonium chloride, depotium chloride, and chlorhexidine gluconate; amphoteric antibacterial agents such as protamine and dodecyldiaminoethylglycine. ; Classified as nonionic antibacterial agents such as triclosan, 3-methyl-4-isopropylmethylphenol, thymol, carvacrol, farnesol, bisabolol, and cineole, among others, from the viewpoint of effectively exerting antibacterial effects in the oral cavity. A cationic antibacterial agent is preferred. Other common antibacterial agents such as hinokitiol; sodium lauroyl sarcosine; l-menthol can also be used.
本発明の発明者は、既に、歯科用ナノバブル発生装置を用いて、ナノバブルがスミヤー層（根管拡大清掃時に生じる細菌が混じった切削片が象牙質の象牙細管に詰まったもの）を除去できること、人工的にアパタイト表面に作製したE. faecalisのバイオフィルムを除去できることについて特許出願をしている（特願２０１７－１５２５９４）。当該特許出願に係る明細書において、抜去歯のin vitro実験によりナノバブルが象牙細管内１ｍｍ以上深部へ薬剤を浸透させることを明らかにした。なお、以下では、表面の帯電性の正負を問わない場合、単にナノバブルと記載することもある。 The inventor of the present invention has already discovered that nanobubbles can remove the smear layer (the dentinal tubules of dentin are clogged with cuttings mixed with bacteria generated during root canal enlargement cleaning) using a dental nanobubble generator. A patent application has been filed for the ability to remove E. faecalis biofilms artificially created on apatite surfaces (Japanese Patent Application No. 2017-152594). In the specification for the patent application, it was revealed through in vitro experiments on extracted teeth that nanobubbles penetrate the drug deeper than 1 mm into the dentinal tubules. Note that hereinafter, when the chargeability of the surface is positive or negative, it may be simply referred to as nanobubbles.
ナノバブルは、圧壊時に発生するフリーラジカルの作用により菌の増殖を抑制する。さらに溶液中の微粒子（ナノバブル）の周りに形成される電気二重層中の、液体流動が起こり始める「すべり面」の電位であるゼータ電位が、微粒子の流動性、凝集性、保存性などに関係すると考えられる。 Nanobubbles suppress the growth of bacteria through the action of free radicals generated when they are crushed. Furthermore, the zeta potential, which is the potential at the "slip surface" where liquid flow begins in the electric double layer formed around fine particles (nanobubbles) in a solution, is related to the fluidity, cohesiveness, and storage stability of fine particles. It is thought that then.
ナノバブルは、液状もしくはゲル状を呈する形態中に超微細な気泡として含有されており、気体（空気、二酸化炭素、窒素、酸素、オゾン等）がナノサイズの気泡内に導入されている。すなわち、ナノバブルは、高い内圧と帯電荷を有しており、その表面特性やブラウン運動のごとき運動特性等に基づくところの有効な除去促進作用によって、効果的に菌の増殖を抑制できる。ナノバブルに含有される気体は、一種または二種以上を用いることができる。二種以上の気体を用いる場合としては、例えば、気体Ａのみからなるナノバブルと気体Ｂのみからなるナノバブルとの混合物を用いる場合もあれば、気体Ａと気体Ｂとの混合物を含むナノバブルを用いる場合もある。 Nanobubbles are contained as ultrafine bubbles in a liquid or gel-like form, and gas (air, carbon dioxide, nitrogen, oxygen, ozone, etc.) is introduced into the nano-sized bubbles. That is, nanobubbles have a high internal pressure and a high charge, and can effectively suppress the growth of bacteria due to their effective removal promoting action based on their surface characteristics and movement characteristics such as Brownian motion. One kind or two or more kinds of gases can be used as the gases contained in the nanobubbles. When using two or more types of gases, for example, a mixture of nanobubbles consisting only of gas A and nanobubbles consisting only of gas B may be used, or a case where nanobubbles containing a mixture of gas A and gas B are used. There is also.
本発明の感染治療用組成物が液体製剤である場合、これを構成する溶液は水溶液であることが好ましい。本発明において、ナノバブル状態にある気体を含む水溶液をナノバブル水といい、ナノバブル状態にある気体を含むゲルをナノバブルゲルという。 When the composition for treating infection of the present invention is a liquid preparation, the solution constituting it is preferably an aqueous solution. In the present invention, an aqueous solution containing a gas in a nanobubble state is referred to as nanobubble water, and a gel containing a gas in a nanobubble state is referred to as a nanobubble gel.
ナノバブル水において、水溶液のｐＨは特に限定されるものではないが、例えば５．００～７．００の弱酸性から中性とすることが可能である。なお、ナノバブルのゼータ電位の絶対値は、時間を経ても大きくは変化しない。また、ナノバブル水において、硬度は特に限定されるものではないが、例えば硬度２０～３０とすることが可能である。 In nanobubble water, the pH of the aqueous solution is not particularly limited, but can be from weakly acidic to neutral, for example from 5.00 to 7.00. Note that the absolute value of the zeta potential of nanobubbles does not change significantly over time. Furthermore, the hardness of nanobubble water is not particularly limited, but can be set to, for example, 20 to 30.
ナノバブルの気泡径としては、その平均気泡径（モード径、最頻度気泡径）は６０～３００ｎｍが好ましく、８０～２５０ｎｍがより好ましく、更に好適には１００～２００ｎｍがさらに好ましい。ナノバブルの気泡径（直径、サイズ）を上記の範囲に設定することにより、有効な除去促進作用が得られ、抗菌剤との併用によって高い抗菌効果を奏する。ナノバブルの気泡径が小径であるほど、一般的に長期保存の安定性に優れる。 The average bubble diameter (mode diameter, most frequent bubble diameter) of the nanobubbles is preferably 60 to 300 nm, more preferably 80 to 250 nm, and even more preferably 100 to 200 nm. By setting the diameter (diameter, size) of the nanobubbles within the above range, an effective removal promotion effect can be obtained, and when used in combination with an antibacterial agent, a high antibacterial effect can be achieved. Generally, the smaller the diameter of nanobubbles, the better the stability of long-term storage.
ナノバブルは、気泡径がナノサイズであることによりその表面張力により内圧が高くなる。ここで、ナノバブルの内圧は、一般にナノバブルの気泡径に対して、Ｙｏｕｎｇ－Ｌａｐｌａｃｅ（ヤング－ラプラス）の式により求められ、本発明に用いたナノバブルは、約３～３００気圧程度の内圧を有している。 Nanobubbles have a nano-sized bubble diameter, which increases the internal pressure due to their surface tension. Here, the internal pressure of the nanobubbles is generally determined by the Young-Laplace formula for the bubble diameter of the nanobubbles, and the nanobubbles used in the present invention have an internal pressure of about 3 to 300 atmospheres. ing.
このように高い内圧を備えたナノバブルが水溶液中で安定に存在する理由の一つとしては、ナノバブル周辺の電荷をもったイオン成分の存在が挙げられる。すなわち、気泡径が小さくなるにしたがって、余分なイオンが気体と液体との界面に保持され、ゼータ電位が大きくなることがナノバブルの消失抑制に関与していると推定される。イオン成分によって、ナノバブル間やナノバブルと液体との間で静電作用が働き、静電作用がナノバブルの消滅を防いで液中におけるナノバブルを安定化していると考えられる。 One of the reasons why nanobubbles with such high internal pressure exist stably in an aqueous solution is the presence of charged ionic components around the nanobubbles. That is, it is presumed that as the bubble diameter becomes smaller, extra ions are retained at the interface between the gas and the liquid, and the zeta potential becomes larger, which is involved in suppressing the disappearance of nanobubbles. It is thought that the ionic components cause an electrostatic effect between the nanobubbles and between the nanobubbles and the liquid, and the electrostatic effect prevents the nanobubbles from disappearing and stabilizes the nanobubbles in the liquid.
本発明の感染治療用組成物は、表面がプラス（正）に帯電したプラス帯電性のプラスナノバブルを含有している。プラスナノバブル（Plus charged nano-bubble）は、従来の気泡とは異なり、帯電性球状コンデンサと同様の作用を有する。表面が正に帯電したナノバブルを用いることにより、内部がマイナスに帯電した菌に対して電気的なショックを与えることができるから、抗菌効果に優れた感染治療用組成物となる。 The composition for treating infection of the present invention contains positively charged nanobubbles whose surfaces are positively charged. Plus charged nano-bubbles are different from conventional bubbles and have a similar effect to charged spherical capacitors. By using nanobubbles with positively charged surfaces, it is possible to give an electric shock to bacteria whose interior is negatively charged, resulting in a composition for treating infection with excellent antibacterial effects.
菌の内部のゼータ電位は－６０ｍＶ～－３０ｍＶ程度である。このような菌に電気的なショックを与えるために、ナノバブルの水中でのゼータ電位がプラスであるプラスナノバブルが好ましい。そして、そのゼータ電位は、＋５ｍＶ～１５０ｍＶが好ましく、＋２０ｍＶ～１５０ｍＶがより好ましく、＋３０ｍＶ～１５０ｍＶがさらに好ましい。 The zeta potential inside a bacterium is approximately -60 mV to -30 mV. In order to give an electric shock to such bacteria, positive nanobubbles, which have a positive zeta potential in water, are preferable. The zeta potential is preferably +5 mV to 150 mV, more preferably +20 mV to 150 mV, even more preferably +30 mV to 150 mV.
また、ナノバブルの濃度は、一般に規定容積中に含まれるバブル（気泡）の個数として示され、本発明では、１×１０６～１×１０９個／ｍＬが好ましく、１×１０７～１×１０９個／ｍＬがより好ましく、５×１０７～１×１０９個／ｍＬがさらに好ましい。ここで、かかるナノバブルの存在量が少なくなりすぎると、除去促進作用を有利に発揮できなくなるからである。 Further, the concentration of nanobubbles is generally expressed as the number of bubbles contained in a specified volume, and in the present invention, it is preferably 1×10 6 to 1×10 9 bubbles/mL, and 1×10 7 to 1× 10 9 cells/mL is more preferable, and 5×10 7 to 1×10 9 cells/mL is even more preferable. Here, if the amount of nanobubbles present becomes too small, the removal promotion effect cannot be advantageously exerted.
なお、上記の如きナノバブルのサイズやその個数濃度やゼータ電位は、市販のナノ粒子測定装置を用いて測定することができる。例えば、(株)島津製作所のナノ粒子分布測定装置（ＳＡＬＤ－７１００）や、日本カンタム・デザイン(株)のナノ粒子解析装置（ナノサイトＮＳ５００）、マイクロトラック・ベル(株)のＺｅｔａＶｉｅｗ等が挙げられる。また、ゼータ電位の測定装置として、マルバルーン事業部スペクトリス（株)から入手することのできるゼータサイザーナノＺ、大塚電子(株)のゼータ電位測定システム（ＥＬＳＺ－２０００Ｚ）、協和界面化学(株)のゼータ電位測定装置（ＺＣ－３０００）等があげられる。本発明においては、ナノサイトＮＳ５００およびＺｅｔａＶｉｅｗを測定に用いている。このため、測定装置によって測定値が異なる場合、ナノサイトＮＳ５００または同等品、およびのＺｅｔａＶｉｅｗまたは同等品を用いて得られる測定値をナノバブルの特性値とする。 Note that the size, number concentration, and zeta potential of the nanobubbles as described above can be measured using a commercially available nanoparticle measuring device. Examples include the nanoparticle distribution measuring device (SALD-7100) from Shimadzu Corporation, the nanoparticle analysis device (Nanosite NS500) from Nihon Quantum Design Co., Ltd., and the ZetaView from Microtrac Bell Co., Ltd. It will be done. In addition, as zeta potential measuring devices, Zetasizer Nano Z available from Mulballoon Division Spectris Co., Ltd., Zeta Potential Measurement System (ELSZ-2000Z) from Otsuka Electronics Co., Ltd., and Kyowa Interface Science Co., Ltd. Zeta potential measuring device (ZC-3000) etc. In the present invention, Nanosite NS500 and ZetaView are used for measurement. Therefore, if the measured values differ depending on the measuring device, the measured values obtained using NanoSight NS500 or an equivalent product and ZetaView or an equivalent product are taken as the characteristic values of nanobubbles.
ところで、本発明において、ナノサイズの気泡径を有するナノバブルは、公知の各種のナノバブル発生装置を用いて形成され得るものである。特に、高分子樹脂フィルムに初期破壊現象であるクレーズを生成してなる通気性フィルムを通じて、それによる気体透過量の制御下において、所定の気体を放出せしめることによって、ナノバブルが形成されるようにした装置（例えば、特許第３８０６００８号公報、特許第５３９０２１２号公報に記載）が有利に用いられる。 By the way, in the present invention, nanobubbles having a nano-sized bubble diameter can be formed using various known nanobubble generators. In particular, nanobubbles were formed by releasing a predetermined gas while controlling the amount of gas permeation through a breathable film formed by generating craze, which is an initial destruction phenomenon, in a polymer resin film. Apparatus (as described, for example, in Japanese Patent No. 3806008 and Japanese Patent No. 5390212) are advantageously used.
ナノバブル水もしくはナノバブルゲルの製造方法は、特に限定されるものではないが、例えば下記である。即ち、少なくとも、気体透過部に気体透過量を制限し得る高分子樹脂フィルムにクレーズを生成してなる通気性フィルムを配する筒状の気体透過装置を該筒状の循環路内に設置することにより、該筒状気体透過部の外周径と該筒状循環路の内周径との差異により形成される間隙に、ポンプを用いて液圧を調製して、水もしくはゲル状流動体を導入するとともに、気体透過装置の気体透過部に加圧状態を調整して気体を供給することにより、水もしくはゲル状流動体にナノサイズの微細な気泡が混入される。 Although the method for producing nanobubble water or nanobubble gel is not particularly limited, it is, for example, as follows. That is, at least a cylindrical gas permeation device in which a gas permeation part is provided with an air permeable film formed by forming craze on a polymer resin film capable of restricting the amount of gas permeation is installed in the cylindrical circulation path. By adjusting the hydraulic pressure using a pump, water or a gel-like fluid is introduced into the gap formed by the difference between the outer circumferential diameter of the cylindrical gas permeation part and the inner circumferential diameter of the cylindrical circulation path. At the same time, by adjusting the pressurized state and supplying gas to the gas permeation section of the gas permeation device, nano-sized fine air bubbles are mixed into the water or gel-like fluid.
また、気泡となる気体雰囲気中において、マイクロメーターサイズに微細化された液体を更に破砕することによって、液体に囲まれた帯電したナノバブルを生成させ、これを、重力、遠心力、電磁気力、等を用いて捕集することによって水などの液体に帯電したナノバブル水などのナノバブル分散液を製造できる。 In addition, by further crushing the micrometer-sized liquid in a gas atmosphere to form bubbles, charged nanobubbles surrounded by the liquid are generated, and these are stimulated by gravity, centrifugal force, electromagnetic force, etc. A nanobubble dispersion such as charged nanobubble water can be produced by collecting the nanobubble in a liquid such as water.
気体雰囲気に電場を印加してマイナス側を接地することによってマイナスに帯電したナノバブルを生成させ、破砕する部材を接地することによってプラスに帯電したナノバブルを生成させることができる。 By applying an electric field to a gas atmosphere and grounding the negative side, negatively charged nanobubbles can be generated, and by grounding the member to be crushed, positively charged nanobubbles can be generated.
本発明の感染治療用組成物は、抗菌剤を含有する液体もしくはゲル状の予備組成物と、プラスナノバブルを含有する水の液体あるいはゲルの固体とを混合して調製することができる。なお、感染治療用組成物は、抗菌剤以外の、細胞抽出物、細胞培養上清、微生物発酵産物、植物抽出物、精製タンパク質等の種々の組成物と組み合わせて使用可能である。ただし、これらは、感染治療用組成物の機能、特にナノバブルと抗菌剤との併用による細菌感染制御作用を阻害しない範囲で用いられる。 The composition for treating an infection of the present invention can be prepared by mixing a liquid or gel precomposition containing an antibacterial agent with an aqueous liquid or gel solid containing plus nanobubbles. The composition for treating infection can be used in combination with various compositions other than antibacterial agents, such as cell extracts, cell culture supernatants, microbial fermentation products, plant extracts, and purified proteins. However, these are used to the extent that they do not inhibit the function of the composition for treating infection , particularly the bacterial infection control effect of the combination of nanobubbles and antibacterial agents.
本発明の感染治療用組成物は、口腔内付着物の除去促進剤として用いることができる。口腔内付着物は、例えば、スミヤー層、歯垢（プラーク）、バイオフィルム又は舌苔である。
スミヤー層を除去するための口腔内付着物の除去促進剤では、単にスミヤー層を除去するのみならず象牙質強度を保持する必要がある。なお、スミヤー層は、その一部が象牙細管内まで入り込み、この象牙細管内まで入り込んだスミヤー層はスミヤープラグ又はスミヤー栓と呼ばれることがある。
プラーク、バイオフィルム又は舌苔を除去するための口腔内付着物の除去促進剤では、ナノバブルを含有するゲルであるナノバブルゲルを適用する。ナノバブルゲルの粘度は、特に限定されるものではないが、例えば４５０Ｍｐａ・ｓ以下である。ナノバブルゲルの粘度が高すぎると流動性が低下するため利便性が低下するおそれがあるからである。
The composition for treating infection of the present invention can be used as an agent for promoting the removal of deposits in the oral cavity. Intraoral deposits are, for example, a smear layer, dental plaque, biofilm, or tongue coating.
An agent for promoting the removal of intraoral deposits for removing the smear layer must not only simply remove the smear layer but also maintain dentin strength. Note that a portion of the smear layer penetrates into the dentinal tubules, and the smear layer that penetrates into the dentinal tubules is sometimes called a smear plug or a smear plug.
Nanobubble gel, which is a gel containing nanobubbles, is used as an agent for promoting the removal of intraoral deposits for removing plaque, biofilm, or tongue coating. The viscosity of the nanobubble gel is not particularly limited, but is, for example, 450 Mpa·s or less. This is because if the viscosity of the nanobubble gel is too high, the fluidity will decrease, which may lead to a decrease in convenience.
また、本発明の感染治療用組成物は、中高齢者の狭窄根管を拡大するための根管拡大補助剤として用いることができる。この場合、感染治療用組成物は、根管拡大清掃剤をさらに含むこととなる。根管拡大清掃剤は、特に限定されるものではないが、例えばＥＤＴＡ、クエン酸、ＭＴＡＤ、Ｔｅｔｒａｃｌｅａｎ等が挙げられる。 Furthermore, the composition for treating infection of the present invention can be used as a root canal expansion aid for expanding narrowed root canals in middle-aged and elderly people. In this case, the composition for treating infection will further contain a root canal enlargement cleaning agent. Root canal enlargement cleaning agents include, but are not particularly limited to, EDTA, citric acid, MTAD, Tetraclean, and the like.
本発明の感染治療用組成物は、抗菌剤とプラスナノバブルとの相乗的な作用により、歯の根管内の細菌感染を治療できる。このため、難治性感染根管の洗浄・貼薬、および根尖歯周組織の化学的・物理的刺激の可及的除去に有効な、歯の根管内、歯の歯周組織内、歯のう蝕または舌苔の細菌感染治療用組成物として用いることができる。 The composition for treating infection of the present invention can treat bacterial infection in the root canal of a tooth due to the synergistic action of the antibacterial agent and the plus nanobubbles. Therefore, it is effective for cleaning and applying medicine to refractory infected root canals, and for removing as much as possible the chemical and physical irritation of the apical periodontal tissue. It can be used as a composition for treating dental caries or bacterial infection of tongue coating.
［実施例１］
１歳齢のイヌに全身麻酔を施した後、イヌ上下顎小臼歯部に抜髄処置を行い、根尖部まで＃５０～５５で拡大した。５％次亜塩素酸ナトリウム溶液と３％過酸化水素水で交互洗浄後、さらに生理食塩水で洗浄した。根管口に綿球をおき、根管を開放状態にして１か月そのまま放置した。さらに、生理食塩水で洗浄後、ペーパーポイントで根管内を完全乾燥し、セメントとレジンにて完全に仮封した。４か月後、歯科用ＣＴ（ＣＢＣＴ・コーンビームＣＴ）にて根尖部透過像により、感染根管が作製されたことを確認した（図１）。
[Example 1]
After administering general anesthesia to a 1-year-old dog, pulp extraction was performed on the dog's upper and lower premolars, and the pulp was expanded to the root apex with #50 to 55. After washing alternately with a 5% sodium hypochlorite solution and a 3% hydrogen peroxide solution, it was further washed with physiological saline. A cotton ball was placed at the root canal opening, and the root canal was left open for one month. Furthermore, after washing with physiological saline, the inside of the root canal was completely dried with a paper point and completely temporarily sealed with cement and resin. Four months later, it was confirmed that an infected root canal had been created using a dental CT (CBCT/cone beam CT) transmission image of the root apex (Figure 1).
根管内の細菌数を計測するため、生理食塩水に浸した＃５５の滅菌済みペーパーポイントを根管内に１分入れて釣菌を行い、根管内の細菌簡易培養検査用液体培地プラディア（製品名、昭和薬品化工（株）製）にペーパーポイントを入れた。ついで、段階希釈法にて血液寒天培地バイタルメディア（製品名，極東製薬工業(株)製）に播種し、２日間嫌気培養後コロニーの数をカウントした。 In order to measure the number of bacteria in the root canal, a #55 sterilized paper point soaked in physiological saline was placed in the root canal for 1 minute to collect bacteria, and a liquid medium for simple culture testing of bacteria in the root canal, Pladia, was used. (Product name, manufactured by Showa Yakuhin Kako Co., Ltd.) with paper points. Then, the cells were seeded on a blood agar medium Vital Media (product name, manufactured by Kyokuto Pharmaceutical Industries, Ltd.) using a serial dilution method, and the number of colonies was counted after 2 days of anaerobic culture.
イヌの歯を抜髄後１か月根管開放し４か月封鎖すると、ＣＢＣＴにおいて根尖部に透過像が認められた（図１参照）。ＨＥ染色像においては、歯槽骨の吸収および根尖部歯周組織の破壊がみられ、炎症性細胞の浸潤がみられた。根管内細菌をプラディア培地で観察すると、培地が混濁し陽性を示した。細菌数は無限大であった。よって、抜髄後１か月根管開放し４か月封鎖することにより難治性感染根管モデルが作製できることが示された。 When the root canal of a dog's tooth was opened for 1 month after pulp extraction and sealed for 4 months, a transparent image was observed in the root apex on CBCT (see Figure 1). HE stained images showed resorption of alveolar bone and destruction of the apical periodontal tissue, as well as infiltration of inflammatory cells. When bacteria in the root canal were observed in Pradia medium, the medium became cloudy and showed positive results. The number of bacteria was infinite. Therefore, it was shown that a refractory infected root canal model could be created by opening the root canal for one month after pulp extraction and sealing it for four months.
（イヌ難治性感染根管モデルにおけるナノバブル水と抗菌ナノパーティクルとの併用による根管内の除菌効果）
上記の難治性感染根管に対して、まず、根管内の細菌数を段階希釈法にて２日間嫌気培養後、コロニーの数をカウントした。釣菌後の根管に６％次亜塩素酸ナトリウムと３％過酸化水素水にてそれぞれ計２ｍＬずつ交互に洗浄を行い、さらに生理食塩水５ｍＬにて根管を洗浄した。引き続き、滅菌ペーパーポイントにて根管内を乾燥し、最終濃度で０．００６％ｗ／ｖの抗菌ナノパーティクルを含有するマイナスナノバブル水あるいはプラスナノバブル水２ｍＬを左側上下顎小臼歯の根管内に注入し洗浄を２分行った。右側上下顎小臼歯は最終濃度０．００６％ｗ／ｖの抗菌ナノパーティクルのみ２ｍＬにて洗浄、あるいはプラスナノバブル水のみ２ｍＬにて洗浄した。その後、左側はマイナスナノバブル水あるいはプラスナノバブル水５ｍＬおよび生理食塩水５ｍＬにて洗浄した。右側は生理食塩水のみ５ｍＬにて洗浄した。ペーパーポイントで根管内を完全乾燥し、左側は洗浄と同様の抗菌ナノパーティクル・ナノバブル水、右側は抗菌ナノパーティクルのみあるいはナノバブル水のみをペーパーポイントに浸して根管内に挿入し、貼薬処置を行い、仮封した（図２参照）。
(Bacterial sterilization effect in the root canal by combined use of nanobubble water and antibacterial nanoparticles in a canine refractory infected root canal model)
First, the number of bacteria in the refractory infected root canal was anaerobically cultured for 2 days using a serial dilution method, and then the number of colonies was counted. After fishing, the root canal was alternately washed with 2 mL of 6% sodium hypochlorite and 3% hydrogen peroxide, and further washed with 5 mL of physiological saline. Next, dry the inside of the root canal with a sterile paper point, and add 2 mL of minus nanobubble water or plus nanobubble water containing antibacterial nanoparticles at a final concentration of 0.006% w/v into the root canal of the left upper and lower premolars. The solution was injected and washed for 2 minutes. The right upper and lower premolars were washed with 2 mL of antibacterial nanoparticles only with a final concentration of 0.006% w/v, or with 2 mL of plus nanobubble water only. Thereafter, the left side was washed with 5 mL of minus nano bubble water or plus nano bubble water and 5 mL of physiological saline. The right side was washed with 5 mL of physiological saline only. Completely dry the inside of the root canal with a paper point, and on the left side, use antibacterial nanoparticles and nanobubble water similar to cleaning, and on the right side, soak only antibacterial nanoparticles or only nanobubble water in the paper point, insert it into the root canal, and apply a patch. and temporarily sealed (see Figure 2).
１週間から２週間後に２回目の釣菌を行った後、前回と同様にナノバブル水と抗菌ナノパーティクルあるいは抗菌ナノパーティクルのみあるいはナノバブル水のみを用いて洗浄および貼薬処置を行った。さらにその１週間から２週間後に３回目の釣菌を行い、再度前回と同様の洗浄および貼薬処置を行った。同様の操作を数回行った。釣菌したサンプルは２日間嫌気培養後コロニー数を測定し、統計処理を行った。 After 1 to 2 weeks, a second round of fishing was carried out, followed by washing and medicinal treatment using nanobubble water and antibacterial nanoparticles, only antibacterial nanoparticles, or only nanobubble water in the same manner as before. Furthermore, one to two weeks after that, a third round of fishing was carried out, and the same washing and medicinal treatments as before were carried out again. Similar operations were performed several times. The sample of bacteria was cultured anaerobically for 2 days, and then the number of colonies was measured and subjected to statistical processing.
細菌数はマイナスナノバブル水と抗菌ナノパーティクルの併用（マイナスナノバブル・ナノバーティクル）による洗浄および貼薬により徐々に減少がみられ、５回の洗浄および貼薬により細菌は検出限界以下に減少した。抗菌ナノパーティクルのみ（ナノパーティクル）ではほとんど減少はみられなかった(図３Ａ)。一方、プラスナノバブル水と抗菌ナノパーティクルの併用（プラスナノバブル・ナノパーティクル）による洗浄および貼薬により、細菌数は１回目で急激に減少し、２回目で検出限界以下となった。ただし、プラスナノバブルのみ（プラスナノバブル）では、ほとんど細菌数の変化はみられなかった(図３Ｂ)。よって、抗菌ナノパーティクルのみあるいはプラスナノバブル水のみでは細菌除去効果がないことが示された。この結果から、抗菌ナノパーティクルとナノバブル水との併用による抗菌効果は、ナノバブル水のナノバブル表面が正負のいずれに帯電しているかの影響を受けることが分かる。 The number of bacteria was gradually reduced by washing with a combination of minus nanobubble water and antibacterial nanoparticles (minus nanobubbles and nanoparticles) and applying the medicine, and after washing five times and applying the medicine, the number of bacteria was reduced to below the detection limit. Almost no reduction was observed with antibacterial nanoparticles alone (nanoparticles) (Figure 3A). On the other hand, by washing with a combination of plus nano bubble water and antibacterial nanoparticles (plus nano bubbles/nanoparticles) and patching, the number of bacteria rapidly decreased after the first treatment, and fell below the detection limit after the second treatment. However, with only plus nanobubbles (plus nanobubbles), almost no change in the number of bacteria was observed (Figure 3B). Therefore, it was shown that antibacterial nanoparticles alone or plus nanobubble water alone have no effect in removing bacteria. This result shows that the antibacterial effect of the combined use of antibacterial nanoparticles and nanobubble water is affected by whether the nanobubble surface of the nanobubble water is positively or negatively charged.
（イヌ難治性感染根管モデルにおけるナノバブル・抗菌ナノパーティクルによる根尖病変の縮小）
難治性根管治療開始時および根管治療開始後２か月から４か月のＣＢＣＴ検査を行った。根尖部の透過像（図４Ａ）をＯｓｉｒｉＸプログラムにより画像解析し、体積を測定した。結果は開始前／開始後の体積比で表した。
その結果、抗菌ナノパーティクルのみを根管治療に用いた場合は２か月経過後１．２であり、４か月経過後１．５となり根尖病変の拡大がみられた（図４Ｂ）。プラスナノバブル水と抗菌ナノパーティクルを併用した場合、術前と比べて、根管治療開始後３か月の時点において、有意に根尖部の骨添加による根尖透過像（根尖病変）の縮小がみられた（**Ｐ＜０．０１）（図４Ｄ）。
(Reduction of apical lesions using nanobubbles and antibacterial nanoparticles in a canine refractory infected root canal model)
CBCT examinations were performed at the start of refractory root canal treatment and from 2 to 4 months after the start of root canal treatment. The transmitted image of the root apex (FIG. 4A) was analyzed using the OsiriX program, and the volume was measured. The results were expressed as the volume ratio before/after the start.
As a result, when only antibacterial nanoparticles were used for root canal treatment, the value was 1.2 after 2 months, and 1.5 after 4 months, indicating expansion of the root apical lesion (Figure 4B) . When Plus Nano Bubble Water and antibacterial nanoparticles were used together , the apical transmission image (periapical lesion) due to bone addition at the apical area was significantly reduced 3 months after starting root canal treatment compared to before surgery. A reduction was observed ( ** P<0.01) (Fig. 4D).
図３Ａ～図３Ｂと図４Ａ～図４Ｄに示した結果から、ナノバブル水と抗菌ナノパーティクルとを併用することにより、難治性感染根管の除菌効果に優れる歯科口腔用組成物が得られることが分かった。また、抗菌ナノパーティクルを併用するナノバブル水として、プラスナノバブル水を用いることにより、マイナスナノバブル水よりも早期に根管内の細菌数を検出限界以下にすることができた。この結果は、表面が正に帯電したプラスナノバブルは、表面が負に帯電したマイナスナノバブルよりも、抗菌ナノパーティクルとの併用による除菌効果が高いことを示唆している。 From the results shown in FIGS. 3A to 3B and 4A to 4D, it is clear that by using nanobubble water and antibacterial nanoparticles in combination, a dental oral cavity composition that has an excellent sterilization effect on refractory infected root canals can be obtained. I understand. Furthermore, by using plus nanobubble water as nanobubble water that is used in combination with antibacterial nanoparticles, it was possible to reduce the number of bacteria in the root canal to below the detection limit earlier than with minus nanobubble water. This result suggests that positive nanobubbles with a positively charged surface have a higher sterilization effect when used in combination with antibacterial nanoparticles than negative nanobubbles with a negatively charged surface.
［実施例２］
（ナノバブル水の個数濃度・粒径分布測定・ゼータ電位測定）
４種類の溶液［５０％プラスナノバブル水、５０％マイナスナノバブル水、最終濃度０．２％グルコン酸クロルヘキシジンと５０％ナノバブル水との混合物、０．２％グルコン酸クロルヘキシジン]をそれぞれ１０ｍＬずつ調製した。調製した溶液について、水中に存在する超微細気泡の個数濃度・粒度分布をナノサイトＮＳ５００およびＺｅｔａＶｉｅｗにより測定した。なお、実施例では、プラスナノバブル水はプラスナノバブル発生装置（ＮＦＰＮＣ００００３α、アクティベーションブラシ型、大平研究所（株）製）で空気と純水を用いて製造したナノバブル水を用いた。マイナスナノバブル水は歯科用ナノバブル発生装置 ＦＯＡＭＥＳＴ ８（登録商標、（株）ナック製）で空気と純水を用いて製造したナノバブル水を用いた。ナノバブル水の％は、ナノバブル発生装置で製造した原液の希釈液における割合を示している。
[Example 2]
(Number concentration/particle size distribution measurement/zeta potential measurement of nanobubble water)
Four types of solutions [50% plus nanobubble water, 50% minus nanobubble water, a mixture of 0.2% chlorhexidine gluconate and 50% nanobubble water at a final concentration, 0.2% chlorhexidine gluconate] were prepared in an amount of 10 mL each. Regarding the prepared solution, the number concentration and particle size distribution of ultrafine bubbles present in water were measured using Nanosite NS500 and ZetaView. In the examples, nanobubble water produced using air and pure water with a plus nanobubble generator (NFPNC00003α, activation brush type, manufactured by Ohira Institute Co., Ltd.) was used. The minus nanobubble water used was nanobubble water produced using a dental nanobubble generator FOAMEST 8 (registered trademark, manufactured by NAC Co., Ltd.) using air and pure water. The % of nanobubble water indicates the proportion of the diluted solution of the stock solution produced by the nanobubble generator.
ナノサイトＮＳ５００およびＺｅｔａＶｉｅｗによる測定は、シリンジでサンプル約５ｍＬを採水し、サンプル注入口にアプライして測定を実施した。結果を表１に示す。なお、表１では、５０％ナノバブル水をＮＢ、最終濃度０．２％グルコン酸クロルヘキシジンと５０％ナノバブル水との混合物をＣＨＸ＋ＮＢ、最終濃度０．２％グルコン酸クロルヘキシジンをＣＨＸと記す。 Measurements using Nanosite NS500 and ZetaView were performed by taking approximately 5 mL of sample water with a syringe and applying it to the sample injection port. The results are shown in Table 1. In Table 1, 50% nanobubble water is indicated as NB, a mixture of chlorhexidine gluconate at a final concentration of 0.2% and 50% nanobubble water is indicated as CHX+NB, and chlorhexidine gluconate at a final concentration of 0.2% is indicated as CHX.
その結果、表１に示すように、最終濃度０．２％グルコン酸クロルヘキシジンと５０％ナノバブル水との混合物では、５０％プラスナノバブル水からのナノバブル減衰が見られなかった。したがって、グルコン酸クロルヘキシジンはナノバブル特性に影響を与えず、ナノバブル水との併用が可能であることが示唆された。なお、ナノバブルを含まないＣＨＸの測定結果は、不純物としてナノサイズの粒子がカウントされたものである。ナノバブル混合あり／なしとの差分を取ることにより、ナノバブル含有／不含を判断することができる。 As a result, as shown in Table 1, in a mixture of chlorhexidine gluconate at a final concentration of 0.2% and 50% nanobubble water, no nanobubble attenuation was observed from 50% plus nanobubble water. Therefore, it was suggested that chlorhexidine gluconate does not affect nanobubble properties and can be used in combination with nanobubble water. Note that the measurement results for CHX that do not contain nanobubbles are those in which nanosized particles are counted as impurities. By taking the difference between whether nanobubbles are mixed or not, it is possible to determine whether nanobubbles are included or not.
［実施例３］
（ナノバブル水による根管象牙質細管浸透作用）
イヌ抜去歯前歯の擬似根管を＃６０まで根管拡大形成し、根尖をユニファスト（多目的常温重合レジン、製品名、(株)ジーシー製）にて閉鎖した。５％次亜塩素酸ナトリウム２ｍＬおよび５ｍＬ生理食塩水で洗浄し、さらにスメアクリーン（３％ＥＤＴＡ水溶液、製品名、日本歯科薬品(株)製）を２分間根管内に適用し、４℃で生理食塩水内にて保存した。根管内をブローチ綿栓にて乾燥した。薬剤として、最終濃度０．００６％（ｗ／ｖ）抗菌ナノパーティクル、０．２％グルコン酸クロルヘキシジン、０．０２％塩化ベンザルコニウム、０．１２％塩化セチルピリジニウム、最終濃度３５μｇ／ｍＬドキシサイクリン塩酸塩水和物を用いて、マイナスもしくはプラスナノバブル水と混合、あるいは薬剤単独（大塚蒸留水希釈）で用いた。さらに薬剤の浸透を検出するために、自家蛍光をもつテトラサイクリンを最終濃度５ｍｇ／ｍＬで混合した。ピペットにて薬液を根管内に輸送して５分間適用し、根管象牙細管内に薬剤を浸透させた。生理食塩水にて洗浄後、ブローチ綿栓にて薬液を除去し、根管内を乾燥させた。歯は歯髄腔が平行になるように金属製の台にユーティリティーワックス（製品名、カボデンタルシステムズジャパン（株）製）、ユニファストＩＩＩ（超速硬性常温重合レジン、製品名、（株）ジーシー製）にて固定した。ユニファストＩＩＩが硬化したらゼーゲミクロトーム（製品名、来夏マイクロシステムズ（株）製）にて厚さ約３００μｍの切片標本を作製し、実体蛍光顕微鏡にて観察した。
[Example 3]
(Root canal dentin tubule penetration effect by nanobubble water)
A pseudo root canal of an extracted anterior tooth of a dog was enlarged to #60, and the root apex was closed with Unifast (multipurpose room temperature polymerization resin, product name, manufactured by GC Corporation). The root canal was washed with 2 mL of 5% sodium hypochlorite and 5 mL of physiological saline, and Smear Clean (3% EDTA aqueous solution, product name, manufactured by Nihon Dental Yakuhin Co., Ltd.) was applied to the root canal for 2 minutes, and the root canal was heated at 4°C. Stored in physiological saline. The inside of the root canal was dried with a broach cotton plug. As drugs, final concentration 0.006% (w/v) antibacterial nanoparticles, 0.2% chlorhexidine gluconate, 0.02% benzalkonium chloride, 0.12% cetylpyridinium chloride, final concentration 35 μg/mL doxycycline hydrochloride. Salt hydrate was used, mixed with minus or plus nanobubble water, or used alone (diluted with Otsuka distilled water). To further detect drug penetration, autofluorescent tetracycline was mixed at a final concentration of 5 mg/mL. The medicinal solution was transported into the root canal using a pipette and applied for 5 minutes to allow the medicinal solution to penetrate into the dentinal tubules of the root canal. After washing with physiological saline, the medicinal solution was removed with a broach cotton plug, and the inside of the root canal was dried. The teeth were placed on a metal stand so that the pulp cavity was parallel to each other using Utility Wax (product name, manufactured by Kabo Dental Systems Japan Co., Ltd.) and Unifast III (super fast-curing room temperature polymerization resin, product name, manufactured by GC Co., Ltd.). It was fixed at. After Unifast III had hardened, sections with a thickness of approximately 300 μm were prepared using a Zege microtome (product name, manufactured by Next Summer Microsystems Co., Ltd.) and observed using a stereofluorescence microscope.
図５Ａ～図５Ｆは、ブタ歯根内の根管壁（ＲＣ）から象牙細管内深部に対して、蛍光薬剤（テトラサイクリン）を浸透させた蛍光実体顕微鏡写真である。また、表２は、象牙細管内深部に対する浸透度を３段階（＋＋、＋、－）で示したものである。図５および表３に示すように、抗菌ナノパーティクルに関しては、マイナスナノバブル水およびプラスナノバブル水とも蒸留水に比べて有意な象牙細管深部への浸透促進がみられた（Ｂ）。また、塩化ベンザルコニウムではナノバブルが正負のいずれに帯電しているかによって差はみられなかったが（Ｄ）、グルコン酸クロルヘキシジン（Ｃ）や塩化セチルピリジニウム（Ｅ）およびドキシサイクリン塩酸塩水和物（Ｆ）ではプラスナノバブル水はマイナスナノバブル水に比べて有意な浸透促進がみられた。これらの結果から、象牙細管内深部に対する抗菌剤の浸透促進効果は、プラスナノバブル水のほうがマイナスナノバブル水よりも優れるといえる。 5A to 5F are fluorescence stereoscopic micrographs of a fluorescent drug (tetracycline) infiltrated from the root canal wall (RC) in the root of a pig tooth to the deep inside of the dentinal tubule. Furthermore, Table 2 shows the degree of penetration deep into the dentinal tubules in three levels (++, +, -). As shown in FIG. 5 and Table 3, with regard to antibacterial nanoparticles, both minus nanobubble water and plus nanobubble water significantly promoted the penetration deep into the dentinal tubules compared to distilled water (B). Furthermore, with benzalkonium chloride, no difference was observed depending on whether the nanobubbles were positively or negatively charged (D), but with chlorhexidine gluconate (C), cetylpyridinium chloride (E), and doxycycline hydrochloride hydrate (F). ), positive nanobubble water significantly promoted penetration compared to negative nanobubble water. From these results, it can be said that positive nanobubble water is better than negative nanobubble water in promoting the penetration of antibacterial agents deep into the dentinal tubules.
［実施例４］
（ブタ根管象牙質スミヤー層除去）
割りやすいように予めＤｉｓｃ（研磨ディスク）で切れ目を入れたブタ歯の擬似根管をＫファイル（製品名、マニー（株）製）にて＃７０まで根管拡大形成し、５％次亜塩素酸ナトリウム２ｍＬ及び３％過酸化水素水２ｍＬにて交互洗浄した。５ｍＬ生理食塩水でさらに洗浄、４℃で生理食塩水内にて保存した。薬剤として、０．２％グルコン酸クロルヘキシジン、０．１２％塩化セチルピリジニウムを用いて、マイナスもしくはプラスナノバブル水、あるいは大塚蒸留水と混合し、９種類のスミヤー層除去剤２ｍＬを５分間適用し、スミヤー層を洗浄した。生理食塩水にて洗浄後、抜歯柑子にて半分に割り、２％グルタールアルデヒドにて１２時間固定し、３０、５０、７０、９０、１００％エタノールにて脱水後、白金１０ｋＶにて蒸着した。蒸着は、マグネトロンスパッタ装置（製品名：ＭＳＰ－２０－ＵＭ、（株）真空デバイス製）を用いて導電膜蒸着（スパッターコーティング）により行った。その後、それぞれの標本を走査電子顕微鏡（製品名：ＶＥ９８００、（株）キーエンス製）にて、根管中央部のところを観察した。
[Example 4]
(Porcine root canal dentin smear layer removal)
A pseudo root canal of a pig tooth was pre-slit with a disc (abrasive disc) to make it easier to split, and the root canal was enlarged to #70 using a K file (product name, manufactured by Manny Co., Ltd.), and then treated with 5% hypochlorite. Washing was carried out alternately with 2 mL of sodium chloride acid and 2 mL of 3% hydrogen peroxide solution. It was further washed with 5 mL of physiological saline and stored in physiological saline at 4°C. Using 0.2% chlorhexidine gluconate and 0.12% cetylpyridinium chloride as drugs, mix them with minus or plus nanobubble water, or Otsuka distilled water, and apply 2 mL of nine types of smear layer removers for 5 minutes. The smear layer was washed. After washing with physiological saline, it was divided in half using a toothpick, fixed in 2% glutaraldehyde for 12 hours, dehydrated with 30, 50, 70, 90, and 100% ethanol, and then platinum was deposited at 10 kV. . The vapor deposition was performed by conductive film vapor deposition (sputter coating) using a magnetron sputtering device (product name: MSP-20-UM, manufactured by Vacuum Device Co., Ltd.). Thereafter, the center of the root canal of each specimen was observed using a scanning electron microscope (product name: VE9800, manufactured by Keyence Corporation).
洗浄後の象牙細管数を計測したところ、スミヤー層は蒸留水ではほとんど除去できなかったが、単独で用いた場合（薬剤なし）、プラスナノバブル水はマイナスナノバブル水よりも有意にスミヤー層除去を促進する効果がみられた（＃＃Ｐ＜０．０１）（図６Ａ、図７）。一方、０．２％グルコン酸クロルヘキシジンおよび０．１２％塩化セチルピリジニウムでは、プラスナノバブル水と併用した場合に、マイナスナノバブル水と併用した場合よりも有意にスミヤー層除去を促進する効果がみられた（＃Ｐ＜０．０５）（図６Ｂ、図６Ｃ、図７）。 When the number of dentinal tubules was measured after cleaning, the smear layer could hardly be removed with distilled water, but when used alone (no drugs), plus nanobubble water promoted smear layer removal significantly more than minus nanobubble water. A positive effect was observed ( ## P<0.01) (Fig. 6A, Fig. 7). On the other hand, when 0.2% chlorhexidine gluconate and 0.12% cetylpyridinium chloride were used in combination with plus nanobubble water, they were more effective in promoting smear layer removal than when used in combination with minus nanobubble water. ( #P <0.05) (Figure 6B, Figure 6C, Figure 7).
本発明は、う蝕治療、抜髄・感染根管治療、歯周病治療、口腔ケアに利用できる。 The present invention can be used for caries treatment, pulp extraction/infected root canal treatment, periodontal disease treatment, and oral care.
Claims (4)
前記ナノバブルは、その表面がプラスに帯電したプラスナノバブルであることを特徴とする、歯の根管内および根管象牙細管内の感染治療用組成物。 Contains antibacterial agents and nanobubbles,
The nanobubbles are positive nanobubbles whose surfaces are positively charged. A composition for treating infection in the root canal and dentinal tubule of a tooth .
前記プラスナノバブルの平均気泡径が１０～３００ｎｍである、
請求項１または２に記載の歯の根管内および根管象牙細管内の感染治療用組成物。 The concentration of the plus nanobubbles is 1×10 6 to 1×10 9 bubbles/mL,
The average bubble diameter of the plus nanobubbles is 10 to 300 nm,
The composition for treating infection in the root canal and dentinal tubule of a tooth according to claim 1 or 2.
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| JP2007518828A (en) | 2004-01-29 | 2007-07-12 | ザ プロクター アンド ギャンブル カンパニー | Oral care compositions containing quaternary ammonium antimicrobial agents with increased levels of bioavailability |
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| JP2011157580A (en) | 2010-01-29 | 2011-08-18 | Univ Of Shiga Prefecture | Electrolytic synthesis method of ozone fine bubble |
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